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Full text of "Invasive strep A : what do we need to know? : hearing before the Human Resources and Intergovernmental Relations Subcommittee of the Committee on Government Operations, House of Representatives, One Hundred Third Congress, second session, July 28, 1994"

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INVASIVE STREP A: WHAT DO WE NEED TO 
KNOW? 

Y 4. G 74/7: ST 8 

Invasive Strep A: Uhat Do He Heed t. . . 

HEARING 

BEFORE THE 

HUMAN RESOURCES AND INTERGOVERNMENTAL 
RELATIONS SUBCOMMITTEE 

OF THE 

COMMITTEE ON 

GOVERNMENT OPERATIONS 

HOUSE OF REPRESENTATIVES 

ONE HUNDRED THIRD CONGRESS 

SECOND SESSION 



JULY 28, 1994 



Printed for the use of the Committee on Government Operations 

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U.S. GOVERNMENT PRINTING OFFICE 
85-648 CC WASHINGTON : 1994 

For sale by the U.S. Government Printing Office 
Superintendent of Documents, Congressional Sales Office, Washington, DC 20402 

ISBN 0-16-046471-4 



>, ' INVASIVE STREP A: WHAT DO WE NEED TO 
KNOW? 

Y 4. G 74/7: ST 8 

Invasive Strep A: Uhat Do He Heed t. . . 

HEARING 

BEFORE THE 

HUMAN RESOURCES AND INTERGOVERNMENTAL 
RELATIONS SUBCOMMITTEE 

OF THE 

COMMITTEE ON 

GOVERNMENT OPERATIONS 

HOUSE OF REPRESENTATIVES 

ONE HUNDRED THIRD CONGRESS 

SECOND SESSION 



JULY 28, 1994 



Printed for the use of the Committee on Government Operations 



% a 





FFR 2 I 895 



U.S. GOVERNMENT PRINTING OFFICE 
85-648 CC WASHINGTON : 1994 

For sale by the U.S. Govemmenl Printing Office 
Superintendent of Documents. Congressional Sales Office. Washington. DC 20402 
ISBN 0-16-046471-4 



COMMITTEE ON GOVERNMENT OPERATIONS 



JOHN CONYERS, Jr. 
CARDISS COLLINS, Illinois 
HENRY A. WAXMAN, California 
MIKE SYNAR, Oklahoma 
STEPHEN L. NEAL, North Carolina 
TOM LANTOS, California 
MAJOR R. OWENS, New York 
EDOLPHUS TOWNS, New York 
JOHN M. SPRATT, JR., South Carolina 
GARY A. CONDIT, California 
COLLIN C. PETERSON, Minnesota 
KAREN L. THURMAN, Florida 
BOBBY L. RUSH, Illinois 
CAROLYN B. MALONEY, New York 
THOMAS M. BARRETT, Wisconsin 
DONALD M. PAYNE, New Jersey 
FLOYD H. FLAKE, New York 
JAMES A. HAYES, Louisiana 
CRAIG A. WASHINGTON, Texas 
BARBARA-ROSE COLLINS, Michigan 
CORRINE BROWN, Florida 
MARJORIE MARGOLIES-MEZVINSKY, 

Pennsylvania 
LYNN C. WOOLSEY, California 
GENE GREEN, Texas 
BART STUPAK, Michigan 



Michigan, Chairman 

WILLIAM F. CLINGER, Jr., Pennsylvania 
AL MCCANDLESS, California 
J. DENNIS HASTERT, Illinois 
JON L. KYL, Arizona 
CHRISTOPHER SHAYS, Connecticut 
STEVEN SCHIFF, New Mexico 
CHRISTOPHER COX, California 
CRAIG THOMAS, Wyoming 
ILEANA ROS-LEHTINEN, Florida 
DICK ZIMMER, New Jersey 
WILLIAM H. ZELIFF, JR., New Hampshire 
JOHN M. MCHUGH, New York 
STEPHEN HORN, California 
DEBORAH PRYCE, Ohio 
JOHN L. MICA, Florida 
ROB PORTMAN, Ohio 
FRANK D. LUCAS, Oklahoma 



BERNARD SANDERS, Vermont 
(Independent) 



Julian Epstein, Staff Director 
Matthew R. FLETCHER, Minority Staff Director 



Human Resources and Intergovernmental Relations Subcommittee 

EDOLPHUS TOWNS, New York, Chairman 
HENRY A. WAXMAN, California STEVEN SCHIFF, New Mexico 

THOMAS M. BARRETT, Wisconsin JOHN L. MICA, Florida 

DONALD M. PAYNE, New Jersey ROB PORTMAN, Ohio 

CRAIG A. WASHINGTON, Texas 

BERNARD SANDERS, Vermont (Ind.) 

Ex Officio 

JOHN CONYERS, JR., Michigan WILLIAM F. CLINGER, JR., Pennsylvania 

Ronald A. Stroman, Staff Director 

J. ALLEN HILL, Professional Staff Member 

MARTINE M. DiCROCE, Clerk 

MARTHA MORGAN, Minority Professional Staff 



(ID 



CONTENTS 



PagB 

Hearing held on July 28, 1994 1 

Statement of: 

Broome, Claire V., M.D., Deputy Director, Centers for Disease Control 

and Prevention 3 

Kaplan, Edward L., M.D., professor of pediatrics, University of Minnesota 
Medical School, and professor, division of epidemiology, University of 
Minnesota School of Public Health, and head, World Health Organiza- 
tion Collaborating Center for Reference and Research on Streptococci ... 44 

Morse, Dale L., M.I)., M.S., director, division of epidemiology and commu- 
nicable diseases, New York State Department of Health 55 

Stevens, Dennis L., M.D., Ph.D, chief, infectious disease section, Veterans 
Affairs Medical Center, Boise, ID 14 

Towns, Hon. Edolphus, a Representative in Congress from the State 
of New York, and chairman, Human Resources and Intergovernmental 

Relations Subcommittee: Opening statement 1 

Letters, statements, etc., submitted for the record by: 

Broome, Claire V., M.D., Deputy Director, Centers for Disease Control 

and Prevention: Prepared statement 6 

Kaplan, Edward L., M.D., professor of pediatrics, University of Minnesota 
Medical School, and professor, division of epidemiology, University of 
Minnesota School of Public Health, and head, World Health Organiza- 
tion Collaborating Center for Reference and Research on Streptococci: 
Prepared statement 47 

Morse, Dale L., M.D., M.S., director, division of epidemiology and commu- 
nicable diseases, New York State Department of Health: Prepared 
statement 57 

Stevens, Dennis L., M.D., Ph.D, chief, infectious disease section, Veterans 
Affairs Medical Center, Boise, ID: 

Article from New England Journal of Medicine, July 6, 1989, relating 

to severe group A streptococcal infections 26 

Prepared statement 16 



(III) 



INVASIVE STREP A: WHAT DO WE NEED TO 

KNOW? 



THURSDAY, JULY 28, 1994 

House of Representatives, 

Human Resources and 
Intergovernmental Relations Subcommittee 
of the Committee on Government Operations, 

Washington, DC. 

The subcommittee met, pursuant to notice, at 10 a.m., in room 
2154, Rayburn House Office Building, Hon. Edolphus Towns (chair- 
man of the subcommittee) presiding. 

Present: Representatives Edolphus Towns, Donald M. Payne, 
Steven Schiff, and Rob Portman. 

Also present: J. Allen Hill, professional staff member; Martine M. 
DiCroce, clerk; and Martha Morgan, minority professional staff, 
Committee on Government Operations. 

OPENING STATEMENT OF CHAIRMAN TOWNS 

Mr. Towns. The Subcommittee on Human Resources and Inter- 
governmental Relations will come to order. 

Today the Subcommittee on Human Resources and Intergovern- 
mental Relations looks at the public health concerns from invasive 
group A streptococcus. Millions of people get some form of strep in- 
fection each year in the United States. Far fewer get invasive infec- 
tions but several thousand die each year. 

Our purposes in the hearing are twofold: first, to take expert tes- 
timony in a public meeting so that the public can be adequately 
and accurately informed about strep A and what they should do to 
protect themselves from its consequences; and second, to consider 
our current state of understanding about strep A, our facilities for 
monitoring and studying it, and determine whether those are ade- 
quate to meet the threat that we are facing. 

Most of us have read or seen reports of the flesh-eating bug. 
Necrotizing fasciitis is a gruesome condition, just as strep toxic 
shock is a scary one. As a grandparent, of course, I know how often 
children have strep throat. If there is a comforting word in all of 
this, it is that children get 80 percent of the mild cases of strep, 
but only 10 percent of the invasive or serious cases. What remains 
unknown is why some people — of any age — will get the mild form 
when exposed to strep, while others get the invasive form. 

Before the 1950's, the many threatening consequences of invasive 
strep made it a source of active concern to public health officials 
everywhere. Since then, our monitoring of strep has dropped dra- 
matically. 

(1) 



Today, it competes with many other infectious diseases for re- 
porting and monitoring resources. Is that a mistake we should cor- 
rect? Are our resources adequately arrayed to detect and respond 
to emerging infectious disease threats? 

At this time, I would like to yield to the ranking minority mem- 
ber of the subcommittee, Congressman Schiff. 

Mr. Schiff. Thank you, Mr. Chairman. 

First I want to thank you very much for holding this hearing. I 
think it is on a very important subject. As you indicated, group A 
streptococcus has been around for a long time, and has been the 
cause for a number of illness, most of which there has ordinarily 
been a speedy recovery from. Most recently I have seen in the 
press, reports of necrotizing fasciitis which I at least had not seen 
before in the media, and it at least suggests to me if not a new dis- 
ease, an outbreak of this disease. 

And what struck me was my recollections of HIV-positive and 
AIDS, when that came into the news in the early 1980's, and I be- 
lieve that those cases were reported in the press very much like 
necrotizing fasciitis is being reported now, as an unusual but ex- 
tremely rare disease. 

We have since learned that AIDS is not obviously a rare disease 
and it is an epidemic in portions of the United States and in por- 
tions of the entire world. And what I believe we should accomplish 
at this hearing is to determine, is there a similar threat from any 
of the diseases that might be caused by group A streptococcus, 
whether it is this particular disease that deals with the loss of skin 
tissue and organ tissue or any other resulting disease. 

And I have to say, Mr. Chairman, nothing would please me bet- 
ter if the experts who are about to testify so state that this is some- 
thing that can be contained and is being contained. But I think the 
threat of this disease is significant enough that we don't want it 
to be another HIV, we don't want to find out 10 years from now 
that it really was something that we didn't do anything about. 

I look forward to the testimony. 

Mr. Towns. Thank you very much, Congressman Schiff. 

At this time, I yield to Congressman Payne for any opening 
statement he might have, or remarks. 

Mr. Payne. Thank you very much, Mr. Chairman. 

Let me commend you this morning for calling this hearing and 
for the leadership that you have taken in many of the issues relat- 
ing to health that we have been dealing with. I also wanted to ex- 
tend my regards to the panel of witnesses who have agreed to pro- 
vide us with their testimony. 

I think the media attention that has been devoted to the out- 
break of the so-called flesh-eating bacteria has probably contrib- 
uted to a general hysteria about the possibilities of a widespread 
epidemic. 

I would hope that during the course of this hearing that we 
would clarify the threat to the public health and correct some of 
the misinformation-feeding frenzy that has been created regarding 
the situation. 

This particular infection of necrotizing fasciitis actually develops 
in about 5 to 10 percent of cases of strep, which is about 1,000 to 



1,500 cases overall. And this invasive infection develops in about 
10 to 20 percent of pediatric cases of strep infection. 

Additionally, there is some evidence that Native Americans may 
be more susceptible to invasive infections, especially in the South- 
west regions, where they are observed to suffer a higher incidence 
of several bacterial diseases. 

One area study found African-Americans are twice as likely as 
whites to contract invasive strep A. The most vulnerable population 
are diabetics, immune-compromised persons, intravenous drug 
users, and alcoholics. These segments of the population often re- 
ceive little or no medical attention until their condition becomes 
critical because their access to medical care is restricted. 

Modern medicine has come a long way in virtually eliminating 
diseases that once proved fatal. We saw this with polio, scarlet 
fever, and rheumatic fever. However, in the last decade, we have 
dropped our guard on diseases like tuberculosis, committing fewer 
and fewer resources each year to protecting the public health. And 
now, as a result, there is a resurgence of a more hostile strain of 
tuberculosis, which is more difficult to treat and deadly. 

The greater issue at hand is that now that the health threat as- 
sociated with strep has been abated, the mechanisms necessary to 
ensure that there is not a resurgence of a strep epidemic are not 
in place. 

To my understanding, it remains to be seen if the CDC is suffi- 
ciently equipped to detect whether or not there is a recurring trend 
in the incidence of invasive strep in our population. Many times we 
move in the wrong direction of cutting in areas where we need to 
have increases, and increases in areas where we don't need them 
in our budgets, as we saw in the 1980's with defense and other 
areas of growth, and we saw a reduction in the services needed, es- 
pecially ior vulnerable populations. 

Mr. Chairman, let me thank you again for calling this hearing 
today. I think there are some very important issues that need to 
be addressed, and I look forward to hearing the testimony of our 
witnesses. 

Mr. Towns. Thank you very much. 

Let me thank you and Congressman Schiff" for your opening 
statements. And I think that you are right, we need to collect infor- 
mation. 

At this time I would like to call on Dr. Claire Broome to come 
to the witness table, Deputy Director of the Centers for Disease 
Control. And Dr. Dennis Stevens, chief of the infectious disease sec- 
tion of the Veterans Affairs Medical Center in Boise, ID. 

May I remind both of you — first of all, let me welcome you to the 
hearing and say that your entire statement will be included in the 
record. If you would just summarize within 5 minutes and allow us 
to raise some questions with you, I think we will be able to accom- 
plish a lot more that way. 

So, Dr. Broome, why don't you begin. 

STATEMENT OF CLAIRE V. BROOME, MJX, DEPUTY DIRECTOR, 
CENTERS FOR DISEASE CONTROL AND PREVENTION 

Dr. Broome. Thank you, Mr. Chairman. I am Dr. Claire Broome, 
Deputy Director of the Centers for Disease Control and Prevention. 



I am pleased to respond to the subcommittee's invitation to provide 
testimony on severe infections caused by group A streptococci. 

Group A streptococci are bacteria which cause a wide variety of 
infections ranging from common, often clinically mild illnesses such 
as strep throat, scarlet fever, and impetigo, to rare and often severe 
infections such as pneumonia, necrotizing fasciitis, and streptococ- 
cal toxic shock syndrome. 

The initial site of infection is usually the nose or throat or the 
skin. Invasive infection develops when the organism gets through 
the usual body defenses leading to infection in the blood, lungs, or 
other normally sterile sites. Bacteria are transmitted person to per- 
son through respiratory secretions. 

Severe and fatal infections caused by group A streptococci have 
been recognized since the 1800's. Necrotizing fasciitis, which was 
first reported in 1918, is characterized by infection and destruction, 
or necrosis, of soft tissue. 

Necrotizing fasciitis usually begins with infection at the site of 
a break in the skin. About 15 percent of necrotizing fasciitis cases 
result in death. 

Streptococcal toxic shock syndrome was first reported in 1987. 
Streptococcal toxic shock syndrome is defined by the isolation of 
group A streptococcus from a normally sterile site and the early de- 
velopment of shock with involvement of multiple organ systems 
such as kidneys, lungs, and liver. The case fatality rate of persons 
with this syndrome exceeds 60 percent. 

To define the incidence of severe infections and identify risk fac- 
tors, CDC has collaborated with State and local health depart- 
ments to conduct surveillance for all group A streptococcal infec- 
tions where the bacteria were isolated from the patients' blood. 
These investigations showed an annual rate of bloodstream infec- 
tion between 3.5 and 6.8 cases per 100,000 persons, approximately 
10,000 to 15,000 cases in the United States each year. 

Among these cases, 10 to 15 percent met the definition for strep- 
tococcal toxic shock syndrome, and 3 to 7 percent had necrotizing 
fasciitis. Rates of disease are higher in Native Americans and Afri- 
can Americans than in whites. The age group at highest risk is the 
elderly. 

What is CDC doing to monitor the occurrence of group A strepto- 
coccal infection? We monitor these infections in several different 
ways. We do special epidemiologic and laboratory surveillance to 
get precise estimates of the rate, and that is the basis for the rates 
I have just quoted to you. 

We also use the network of State and local health departments 
who are contacted by local physicians when clusters of cases occur. 
We also track bacteria sent to the CDC laboratory. CDC is one of 
only two institutions in the United States that can classify group 
A streptococcal isolates by M type, which is a way of subtyping the 
bacterium. 

The recent changes in the occurrence of severe infection and 
streptococcal toxic shock syndrome correspond to a dramatic in- 
crease in the proportion of strains of two particular subtypes, types 
M-l and M-3. Reports from other countries of increases in invasive 
group A streptococcal infections and M-l infections suggest an in- 



creasing proportion of virulent M-l group A streptococci that began 
in the 1980's and continues today. 

CDC has taken several approaches to the prevention and control 
of invasive group A streptococcal infections. These include educat- 
ing physicians and other health care providers through CDC's re- 
ports and other scientific publications, presentations at scientific 
meetings and interviews with the media. We try to inform physi- 
cians so that they consider the diagnosis of severe group A 
streptococci when they see a patient and treat aggressively when 
appropriate. 

Invasive group A streptococcal infection, streptococcal TSS and 
necrotizing fasciitis present examples of emerging public health 
challenges. CDC's strategic plan for addressing these challenges is 
outlined in the document, "Addressing Emerging Public Health 
Threats: A Prevention Strategy for the United States," which I 
would like to submit for the record. 

Mr. Towns. Without objection, so ordered. 

Dr. Broome. Thank you, Mr. Chairman. 

[The information may be found in the subcommittee files.] 

Dr. Broome. Investments in laboratory research and training, 
and prevention and control programs will ensure we are better pre- 
pared to respond to these threats and lessen their impact through 
a prevention-oriented public health policy. 

Thank you for the opportunity to testify before the subcommittee. 
I will be happy to answer your questions. 

[The prepared statement of Dr. Broome follows:] 



4 



DEPARTMENT OE HEALTH & HUMAN SERVICES 



Public Health Service 



Centers for Disease Control 

and Prevention (CDC) 
Atlanta GA 30333 



Statement of 

Claire V. Broome, M.D. 

Deputy Director 

Centers for Disease Control and Prevention 

Public Health Service 

Department of Health and Human Services 

before the 

Subcommittee on Human Resources 
and Intergovernmental Relations 

Committee on Government Operations 

U.S. House of Representatives 



July 28, 1994 



I am Dr. Claire V. Broome, Deputy Director of the Centers 
for Disease Control and Prevention (CDC) . I am pleased to 
respond to the Subcommittee's invitation to provide testimony on 
severe infections caused by group A streptococci bacteria. 

Group A streptococci are bacteria which cause a wide variety 
of infections ranging from common, often clinically mild 
illnesses such as "strep throat," scarlet fever, and impetigo (a 
common skin infection) , to rare and often severe or fatal 
infections such as pneumonia, necrotizing fasciitis, and 
streptococcal toxic shock syndrome (STSS) . Group A streptococcal 
infections also may lead to autoimmune illnesses including 
rheumatic fever, which is a leading cause of chronic valvular 
heart disease, and acute glomerulonephritis, a disease which may 
result in kidney failure. In my testimony, I will respond to the 
issues raised in your letter of invitation concerning the 
clinical, epidemiologic, and laboratory characteristics of severe 
group A streptococcal infections, focusing on the emergence of 
streptococcal toxic shock syndrome and necrotizing fasciitis; 
describe CDC's efforts to monitor these conditions and the trends 
in their occurrence; and comment on the nature of severe group A 
streptococcal disease as a public health threat. 

In addition, I will discuss CDC's recently released 
strategic plan for addressing emerging infectious disease threats 
in the United States. This plan was released in April 1994 and 
addresses the priorities, set forth by the National Academy of 
Science's Institute of Medicine (IOM) , to safeguard the nation 
from the threat of emerging infectious diseases. I would like to 
submit a copy of the CDC plan, "Addressing Emerging Infectious 
Disease Threats: A Prevention Strategy for the United States," 
for your consideration for the record. 

Group A streptococci cause disease only in humans and have 
no reservoir other than man. The initial site of infection is 
generally the upper respiratory tract (nose and throat) or skin. 
Infection may result in clinical illness or the bacteria may be 
carried asymptomatically in the throat or on the skin. Invasive 
infection develops when the organism enters the body through the 
skin or from a, mucosal site, leading to infection in the blood 
(bacteremia), lungs (pneumonia), or other normally sterile sites. 
Community studies have shown that group A streptococci may be 
carried in the throats of up to 30 percent of healthy school 
children. The bacteria are transmitted person-to-person through 
respiratory secretions. Group A streptococci do not survive well 
in the environment so that infection rarely is spread by contact 
with environmental surfaces. 

Severe and fatal infections caused by group A streptococci 
have been recognized since the late- 1800s when it was identified 
as the cause of puerperal sepsis, an infection that resulted in 
the death of thousands of women each year after childbirth. 



8 



Necrotizing fasciitis was first reported in 1918. Following 
a recent cluster of cases with necrotizing fasciitis in 
Gloucestershire, United Kingdom, interest has been heightened in 
this complication of group A streptococcal infection. This 
infection is characterized by infection and destruction 
(necrosis) of soft tissue including fascia or connective tissue, 
muscle, and fat. Necrotizing fasciitis usually begins with 
infection at the site of a break in the skin and may progress 
rapidly. Initial signs are those of a skin infection including 
pain, redness, and swelling, in association with fever. As the 
disease progresses signs of systemic illness, such as shock, may 
occur along with extensive tissue destruction requiring surgical 
removal of diseased tissue or amputation of an extremity. 
Reported case -fatality rates from necrotizing fasciitis have 
ranged from 10 to over 50 percent. In a CDC investigation of 
invasive group A streptococcal infections in San Francisco during 
the period 1991 until May 1994, 14 percent of necrotizing 
fasciitis cases ended in death. 

A previously unrecognized illness, the group A streptococcal 
toxic-shock syndrome (STSS) , was first reported in 1987, although 
cases had most likely occurred before that time. Two years 
later, a report describing 20 patients with STSS from the Rocky 
Mountain states suggested that this syndrome was becoming more 
common. A Working Group of academic and public health experts, 
convened by CDC, published a consensus case definition of the 
syndrome (The Working Group on Severe Streptococcal Infections. 
Defining the Group A Streptococcal Toxic Shock Syndrome. JAMA 
1993 ; 269 ; 390-391) , which is characterized by isolation of group A 
Streptococcus from a normally sterile site and the early 
evolution of clinical signs of low blood pressure (shock) , and 
involvement of multiple organ systems including impairment of the 
kidneys, liver and lungs, disorders of blood clotting, 
generalized skin rash, and soft tissue necrosis. Over half of 
STSS cases begin with an infected skin lesion and one-quarter 
occur in conjunction with pneumonia. The case- fatality rate of 
persons with this syndrome exceeded 60 percent in the San 
Francisco investigation, as well as in a recent investigation in 
Canada. 

To define the incidence of severe infections and identify 
risk factors, CDC has collaborated with State and local health 
departments to conduct surveillance for all group A streptococcal 
disease. All cases where the bacteria were isolated from the 
patient's blood (bacteremic infection) were identified in defined 
populations in parts of California, Arizona, New Mexico, 
Colorado, Ohio, and Maryland. The results of these 
investigations indicated an annual rate of bacteremic infection 
between 3.5 and 6.8 cases per 100,000 population, which would 
translate to an annual occurrence of approximately 10,000 to 
15,000 cases each year in the United States. In all surveillance 
areas, the rate of disease in African- Americans was higher than 



in whites; the highest incidence of disease was identified in 
American Indians, who, in a Pima County, Arizona, study had a 15- 
fold higher risk of disease than other racial or ethnic groups. 
The age group at highest risk was the elderly and, although 
children have high rates of mild group A streptococcal 
infections, they were at low risk for developing bacteremia or 
STSS. Bacteremic disease was most likely to occur during the 
winter and spring months. 

Among the cases of invasive group A streptococcal infection 
detected by surveillance, 10-15 percent met the case definition 
for STSS, and 3-7 percent had necrotizing fasciitis. Risk 
factors for infection included underlying diseases such as 
diabetes mellitus, alcohol and intravenous drug abuse, and HIV 
infection. Breaks in the skin are the most common site from 
which invasive infection develops. These invasive infections may 
range from seemingly insignificant injuries (such as the scratch 
of a thorn while gardening) to major trauma or surgical 
incisions . 

Because there is no ongoing national surveillance for 
invasive group A streptococcal infections, it is difficult to 
determine trends in the occurrence of disease. However, several 
types of evidence suggest an increase in the rate and the 
severity of invasive group A streptococcal infections over the 
past decade. Hospital -based case series in several areas have 
indicated increases in the number of invasive cases in the later 
half of the 1980s. Surveillance for all invasive cases in the 
San Francisco Bay area between 1989-94 showed peaks in disease 
incidence in 1989 and 1994, with the smallest number of cases 
occurring in 1991. In Pima County, although surveillance between 
1987-90 showed no change in the overall rate of disease, there 
was a significant increase in the occurrence of STSS, from 
percent before 1988 to 8 percent in 1989-90. This study 
indicated no change in the occurrence of necrotizing fasciitis. 

Laboratory -based investigations of group A streptococci have 
made important contributions to our understanding of the 
pathogenesis of severe group A streptococcal infections. 
Laboratory -based surveillance data also suggest an increase in 
the rate and severity of disease. Although there are 
approximately 80 different serotypes of group A streptococci, two 
specific serotypes, M-l and M-3, have been associated with the 
recent increase of severe invasive infections. Since 1972, 
approximately 6,000 group A streptococcal isolates have been 
analyzed at CDC. During this period, the serotype distribution 
of invasive isolates has changed dramatically with the proportion 
of M-l strains increasing from 3 percent in 1972 to almost 40 
percent in 1989. Between 1989 and 1993, M-l decreased to 
approximately 15 percent of invasive isolates, but this year has 
again increased to more than 30 percent. Similar, although not 
as dramatic, changes have occurred in the proportion of M-3 



10 



strains which increased from less than 3 percent prior to 19 80 to 
18 percent in 1994. Analysis of the serotype and clinical data 
demonstrates that infection with an M-l or M-3 strain was 
significantly more likely to result in STSS, and in death, than 
infection with other group A streptococcal types. 

CDC investigations to determine possible virulence factors 
for severe group A streptococcal infections demonstrated a 
significant association between STSS and infection with strains 
that produce a specific toxin, pyrogenic exotoxin A. Necrotizing 
fasciitis was associated with the activity of proteases, which 
are enzymes that can break down proteins. Pyrogenic exotoxin A 
production was significantly more likely to be found in M-l and 
M-3 strains than in other group A streptococci. Protease 
activity also was significantly more common among M-l strains. 
Laboratory tests for detection of pyrogenic exotoxin A production 
in isolates collected between the 1950s and the late- 1980s 
demonstrated that few strains produced this toxin during that 
period of time. Recent increases in the proportion of isolates 
making this toxin correspond to changes in the strain 
distribution and the occurrence of STSS. 

There is no evidence that mutations have occurred which 
would increase the virulence of individual group A streptococcal 
strains. Genetic material (DNA) coding for pyrogenic exotoxins 
can be transferred between group A streptococci on plasmids, 
which are small pieces of genetic material that may be inserted 
in some bacterial cells. Whether virus (or phage) mediated 
transfer of plasmids between strains plays any role in the 
changes in disease spectrum remains hypothetical. 

Some group A streptococci have developed resistance to the 
antibiotic erythromycin, a recommended therapy for noninvasive 
infections in penicillin-allergic patients. Clindamycin and 
other effective antibiotics can be used to treat penicillin- 
allergic patients who have invasive infection. No group A 
streptococci strains have yet been documented to be penicillin- 
resistant, and penicillin remains the treatment of choice for 
group A streptococcal infections. 

Although data from other countries are limited, reports from 
Great Britain, Scandinavia, and Australia showed increases in the 
incidence of invasive group A streptococcal infections and in the 
proportion of M-l infections occurring during the late- 1980s. In 
addition, CDC has received isolates from patients with STSS in 
Latin America and Asia all of which have been type M-l. These 
data suggest a pandemic of virulent M-l group A streptococci that 
began in the 1980s and is continuing today. 

Invasive group A streptococcal infections, STSS, and 
necrotizing fasciitis present evolving public health challenges 
and represent a problem of emerging infectious diseases. The 



11 



estimated 10,000 to 15,000 annual cases and 1,500 to 3,000 annual 
deaths from these infections place a substantial burden on the 
health care system. Moreover, the illness can be catastrophic 
and may occur in previously healthy individuals after seemingly 
minor trauma. Additionally, clusters of invasive infection have 
occurred in the military, nursing homes, hospitals, and families. 
Historical data on the occurrence of severe group A streptococcal 
infections in the past 150 years have suggested that, 
superimposed on an overall decline in incidence, occasional 
changes in strain distribution and virulence periodically occur. 
In the second half of the 19th century, significant increases in 
the case- fatality rate for scarlet fever occurred at approximate 
10 -year intervals. During the Second World War, thousands of 
cases of rheumatic fever and other streptococcal infections 
occurred in military trainees; a large proportion of these cases 
were caused by serotypes that are uncommon today. 

Although invasive illness may occur in otherwise healthy 
persons, one's own immune system and other host factors are 
important in determining the likelihood of invasive disease. For 
example, the clinical effect of the same M-l strain infection may 
vary significantly within a family. Investigations of households 
where a case of STSS occurred showed that a strain that causes 
STSS in one family member may result only in a sore throat or 
asymptomatic throat carriage of the bacteria in others. The 
importance of host factors also is suggested by the infrequent 
occurrence of invasive infection and STSS in children, although 
this age group accounts for approximately 80 percent of mild 
group A streptococcal infections. 

The changes in occurrence of severe group A streptococcal 
infections in the past decade emphasize the importance of CDC's 
working with State health departments to monitor the incidence, 
clinical, and laboratory characteristics of invasive infections. 
Currently, there is little routine data collection and reporting 
of invasive group A streptococcal infections. Surveillance of 
infectious diseases in the United States is heavily dependent 
upon voluntary collaborations between CDC and State and local 
health departments, which in turn depend on physician- initiated 
reporting of a limited number of specific, recognized infectious 
diseases. Reporting is generally incomplete. State health 
departments determine which diseases must be reported to them by 
physicians and diagnostic laboratories within their borders and, 
through the Council of State and Territorial Epidemiologists 
(CSTE) , which diseases the States will report to CDC. In many 
States, the demands of current reporting requirements have" 
exceeded the available resources, making additional disease 
reporting difficult. 

Despite these constraints, CDC has responded to the changes 
in severe group A streptococcal infections by collaborating with 
State and local health departments to develop sentinel 
population-based surveillance systems. In addition, changes in 



12 



serotype distribution nationwide have been monitored by- 
laboratory testing of isolates sent to CDC. CDC also has 
provided technical assistance to State health departments in 
investigating outbreaks of severe group A streptococcal 
infections. 

It is important that appropriate surveillance of invasive 
group A streptococcal infections and other emerging pathogens be 
conducted at State and national levels. The capacity to perform 
serotyping for group A streptococcal isolates in the United 
States is only available at CDC and the University of Minnesota. 
This capacity must be maintained, as changes in M-type 
distribution may be used to track changes in clinical disease. 

Enhancing infectious disease surveillance, and strengthening 
the public health infrastructure at the local, State, and Federal 
levels to provide needed laboratory support and training are 
major priorities included in the CDC plan for prevention of 
emerging infectious disease threats. The changes in occurrence 
of severe group A streptococcal infections during the past decade 
demonstrate how infectious diseases may increasingly threaten 
public health and contribute significantly to the escalating 
costs of health care. 

Results from a recent survey by the Council of State and 
Territorial Epidemiologists illustrate the inadequacy of existing 
infectious surveillance by documenting the limited number of 
professional positions dedicated to infectious disease 
surveillance in most states. Funding for communicable disease 
surveillance is largely limited to diseases for which public 
health crises have already developed (TB, HIV/AIDS, sexually 
transmitted diseases, and selected vaccine-preventable diseases). 
No Federal resources are provided to State and local health 
departments to support the national notifiable disease 
surveillance system. The ability of state public health 
laboratories to support the surveillance, diagnosis, and control 
of infectious diseases has diminished. 

Technological advances and changes in the health care system 
will provide opportunities for new approaches to surveillance. 
Managed care systems have resulted in large databases which may 
provide broad-based, high-quality surveillance data. Recent 
efforts to improve electronic data collection from state public 
health laboratories with the introduction of the Public Health 
Laboratory Information System (PHLIS) may facilitate future 
surveillance efforts. 

In addition to comprehensive and innovative surveillance 
systems, effective preparation for emerging infectious diseases 
requires sound foundations in professional expertise, laboratory 
support, and research capability. These foundations support the 
infrastructure needed to address the ongoing, but often changing, 
threats from emerging infections. To meet the broad challenges 



13 



of new and reemerging infectious diseases, CDC must maintain 
modern molecular biologic expertise in infectious disease 
threats, and transfer this technology to State public health 
laboratories. 

Implementation of the CDC plan for prevention of emerging 
infections will require long-term collaborations and partnerships 
with public health agencies, universities, private industry, and 
communities. Improved State and local public health surveillance 
and laboratory capacity are critical components of the plan, 
including training for public health laboratory personnel in 
modern techniques for detection of emerging diseases. Highest 
priority activities would include providing assistance to state 
and local health departments to strengthen epidemiologic and 
laboratory-based surveillance, enhancing diagnostic laboratory 
capacity in health departments and at CDC, and establishing 
sentinel surveillance networks to monitor emerging diseases such 
as invasive group A streptococcal infections, antibiotic- 
resistant diseases, foodborne diseases and community- acquired 
pneumonia. 

CDC has taken several approaches to the prevention and 
control of invasive group A streptococcal infections. These 
approaches have included educating physicians and other health 
care providers through information provided in CDC's Morbidity 
and Mortality Weekly Report and other medical and scientific 
publications, presentations at medical and scientific meetings, 
and interviews with the media. CDC investigation of disease 
clusters have led to recommendations for controlling the spread 
of disease in nursing homes and for preventive therapy or 
chemoprophylaxis in certain settings. Identification of an 
increased risk for severe infection in specific patient groups 
will permit the development of focused interventions to decrease 
risk in those populations. Finally, through collaborations with 
clinicians and laboratory researchers, CDC is working to better 
define optimal treatment for infection and to identify factors 
associated with organism virulence which, in the long term, may 
provide opportunities for prevention through the development of 
effective vaccines. 

Investments in surveillance, laboratory research and 
training, epidemiologic investigations, and integration of 
results into prevention and control programs will ensure that we 
are better prepared to respond to emerging infectious disease 
threats and to lessen their impact. It is crucial that emerging 
infectious diseases be addressed and that the basic principles of 
prevention- oriented public health policy form an integral 
component of our nation's efforts to safeguard health in our 
communities. 

Thank you for the opportunity to testify before the 
subcommittee. I will be happy to answer your questions. 



85-648 0-94-2 



14 

Mr. Towns. Thank you very much, Dr. Broome. 
Dr. Stevens, please proceed. 

STATEMENT OF DENNIS L. STEVENS, M.D., Ph.D, CHIEF, INFEC- 
TIOUS DISEASE SECTION, VETERANS AFFADIS MEDICAL 
CENTER, BOISE, DD 

Dr. Stevens. My name is Dennis L. Stevens. I am chief of infec- 
tious disease at the Veterans Affairs Medical Center, Boise, ID. I 
am here to talk about the clinical aspects of group A streptococcal 
infection as well as to provide a research perspective on the host 
parasite interactions. 

As Dr. Broome has said, we and others have certainly described 
invasive group A streptococcal infections in this country as well as 
other parts of the world. And I am not going to go into all the de- 
tails of the necrotizing fasciitis and toxic strep, but instead would 
like to just make five points that I think I have come to grips with 
in the last 5 or 6 years in working with group A strep. 

First is that I think that the prevalence of this infection has not 
increased dramatically in the last 5 or 6 years, but has remained 
relatively constant, and in fairly low numbers, as Dr. Broome has 
suggested. We continue to see these invasive forms of group A 
streptococcal infection and, as we speak, people in this Nation are 
acquiring this disease and dying. 

The second point is to point out that group A strep is not just 
a cause of toxic strep syndrome and the necrotizing fasciitis but 
causes many other very common maladies of children as well as 
adults. And those have been reiterated by Dr. Broome and cer- 
tainly are incorporated in my testimony. 

The third point is that there are many different kinds of group 
A streptococci, and each type may cause one, two or several dif- 
ferent kinds of group A streptococcal infections, and I would have 
to admit that the scientific community does not understand why 
different strains can cause different kinds of infection, but it is an 
area of hot research investigation at the present time. 

The fourth point is that the virulence of group A strep can vary 
over time, and the literature, the older literature, in particular is 
replete with examples of this. And I would just like to point out 
that perhaps there is no better example than in the case of scarlet 
fever, and I would just like to read you a comment. 

For example, in New York City and Chicago, in 1890, when one 
compares the mortality of scarlet fever from 1890 compared to 
1920, in both cities in 1890 between 25 and 30 percent of all chil- 
dren with scarlet fever died. Twenty-five percent, 25 out of every 
hundred died of scarlet fever. In contrast, by 1920, the mortality 
rate was less than 5 percent, and currently it is less than 0.5 per- 
cent. 

One can conclude from these data that either host factors 
changed or the organism's virulence changed over time. I must re- 
mind the subcommittee that antibiotics were not available until the 
1930's or 1940's; so it had nothing to do with things physicians or 
public health officials did. It had a lot to do with the virulence of 
the organism and its striking changes. 



15 

So that means that we have to keep an eye on the organism and 
we need to monitor the severity of not just the severe forms of 
group A streptococcal infection but all forms, in my opinion. 

The fifth point I would like to make is that humans are really 
the only reservoir of group A strep in nature, and this means that 
many public health measures such as providing potable water, in- 
specting meat, properly cooking pork, practicing safe sex, et cetera, 
things that work very well in other kinds of infectious diseases we 
deal with in the United States today, do not work. And so that 
means that we need to be cognizant of diagnosing and treating 
these kinds of infections very quickly. 

So in summary, I think tnere is a clear and ever-present danger 
of serious group A streptococcal infections in every geographical 
area of the world. If history repeats itself, as it is wont to do, we 
can expect waxing and waning of severe group A streptococcal in- 
fections to occur. 

I think it is difficult for us to predict whether the current severe 
group A streptococcal infections we have seen will decrease, stay 
the same, or increase. But I think we need to be prepared to meet 
that challenge. 

So I think in summary I would say that I think, number one, we 
need to constantly monitor all types of group A streptococcal infec- 
tions and not just zero in on the severe forms. 

We need to improve reporting and active surveillance of these 
diseases. 

We need to determine the precise mechanisms of pathogenesis 
and host response through basic science research. 

We need to monitor antibiotic resistance in this organism, be- 
cause development of penicillin resistance in group A streptococci 
would be a true disaster. 

We need to develop new and novel therapies, including potential 
vaccines as well as better ways to treat shock and tissue destruc- 
tion in these severe infections, because modern treatments still re- 
sult in a very high mortality and morbidity in such cases. 

And I would be glad to answer any questions relative to my testi- 
mony. 

Thank you, sir. 

[The prepared statement of Dr. Stevens follows:] 



16 




Department of Veterans Affairs 

Medical Center 
500 West Fort Street 
Boise ID 83702-4598 

July 28, 1994 



In Reply Betei To 



531/Bldg. 6 



Edolphus "Ed" Towns, Chairman, 
Subcommittee on Human Resources 

and Intergovernmental Relations 
Congress of the United States 
House of Representatives 
2157 Rayburn House Office Building 
Washington D.C. 20515-6143 

Statement of Testimony by Dennis L. Stevens, MD, PhD, Chief Infectious Disease 
Section, Veterans Affairs Medical Center, Boise, Idaho and Professor of Medicine, 
University of Washington School of Medicine, Seattle, WA. 

Congressmen Towns, Members of the Subcommittee on Human Resources and 
Intergovernmental Relations, colleagues and guests: 

It is an honor and a privilege to testify before this group regarding invasive Group A 
streptococcal infections. 

Since the mid-1 980's reports of aggressive Group A streptococcal infections 
associated with shock, multiorgan failure and a high mortality rate began to appear. 
Individuals most commonly affected appeared to be otherwise healthy individuals and 
not those who would be considered immunocompromized. In 50% of cases we could 
not determine the portal of entry. Patients usually developed a prodrome of fever, 
chills, confusion and in 70-80% of cases increasing pain at the site of minor, non- 
penetrating trauma that subsequently became infected. Patients with such infection 
rapidly developed low blood pressure, renal failure, liver failure and shock. (Please 
find an enclosed paper previously published in the New England Journal of Medicine 
which details the salient features of this disease). In spite of antibiotics, intensive 
care unit treatment, intravenous fluids and surgical procedures which frequently 
involved amputation of one or more extremities, 30-70% of patients died. It is the 
later feature of these infections that has caught the fancy of the world press, who 
refer to this organisms as the "Flesh Eating Bacteria". Luckily, the American press 
and television networks have been much more reasonable than the British tabloids in 
their reporting. Over the course of the last 5-10 years, we and others have worked 
diligently to determine what is unique about the strains of streptococci that cause 
such infections, and to investigate the means that this bacteria and its toxins interact 
with the human host to cause such fulminant destruction. 

I would like to make 5 points regarding streptococcal infections which will briefly 



17 



convey my perspectives based upon my work with patients, colleagues and in the 
research laboratory. 

The first point is to put in proper perspective the significance of the recent worldwide 
emergence of severe life threatening streptococcal infections. There is little question 
that in the United States and throughout the world a more severe form of Group A 
streptococcal infections has occurred. It must be emphasized that the numbers of 
these cases has remained low and that the recent flurry in the press has been more 
because of the dramatic nature of these infections than because of a real threat of 
spread of such infection among the populace at large. Studies done by public health 
laboratories in this country and abroad have shown that the risk of an epidemic of 
this type of infection is quite low. However, citizens from many countries have 
developed fulminant streptococcal infections and 30-70% have died in spite of the 
best that modern medicine has to offer. Cases continue to be recognized, though an 
increase in the frequency of these cases has not materialized. 

The second point is to recognize that Group A streptococcus causes many different 
types of infections. Pharyngitis (sore throat) is the most common, and is the leading 
reason why children are taken to pediatricians in the United States. Streptococcal 
pharyngitis causes significant absenteeism in elementary schools and afflicts children 
in day care centers as well. Untreated streptococcal pharyngitis can lead to 
rheumatic fever, scarlet fever and a kidney disease called post-streptococcal 
glomerulonephritis. Rheumatic fever and nephritis occur not during the acute phase 
of infection, but usually 2-3 weeks after the streptococcal infection and are clearly 
due to the host's response to infection rather than the infection per se. A variety of 
skin and soft tissue infections also are caused by Group A streptococcus such as 
erysipelas, impetigo lymphangitis and cellulitis. Ear infections, mastoid infections, 
sinus infections, meningitis, pneumonia, bacteremia, muscle infection (myositis) and 
deep connective tissue infection (necrotizing fasciitis) are other types of infections 
caused by Group A streptococcus. Recently, acquired attention deficits and learning 
disabilities have been reported in some children following Group A streptococcal 
infections as well. 

The third point is that there are many different types of Group A streptococci, and 
each type may cause one, two, or all of the types of infections described above. 

The fourth point is that the virulence of Group A streptococcus can vary over time; 
this is reflected in human terms by changes in the severity of infection. There is no 
better example of this than the statistics on the mortality of scarlet fever in New York 
City and Chicago in 1890 compared to 1920. In both cities in 1890, between 25- 
30% of all children with scarlet fever died. In contrast by 1920 the mortality was 
less than 5%. It must be remembered that antibiotics were not available until the 
1930-1940 era. One can conclude from these data that striking changes in the 
virulence of the organism occurred during this period of time. It is of interest that the 
severity of scarlet fever has remained low during the rest of the 20th century. There 



18 



are many other examples of striking changes in the virulence of Group A 
streptococcal infections throughout history that time does not permit me to describe. 

The fifth point that I would like to make is that humans are the major, if not exclusive, 
reservoir of Group A streptococcus in nature. This means that many public health 
measures such as providing potable water, inspecting meat, properly cooking pork, 
practicing safe sex etc. will do little or nothing to prevent spread of infection among 
the public. This also means that the human host and the pathogen have each 
established a complicated list of factors which interact with each other. It is these 
interactions that determine whether or not an infection will develop. In my opinion, 
understanding of these interactions is of paramount importance if we are to determine 
why certain people develop rheumatic fever for example, and why some do not. Only 
basic science research will establish why in a given family, one child has died of 
streptococcal toxic shock syndrome, another sibling has developed scarlet fever, the 
mother has developed streptococcal pharyngitis, and the father was an asymptomatic 
carrier of this organism. 

In summary, there is a clear and ever-present danger of serious Group A streptococcal 
infection in every geographical area of the world. If history repeats itself, as it is 
want to do, we can expect increased frequency and severity of a wide variety of 
streptococcal infections. 

It is imperative that we: 

constantly monitor and report all types of Group A streptococcal 
infections, 

improve reporting and active surveillance of these diseases, 

determine the precise mechanisms of streptococcal pathogenesis and 
host response through basic science research, 

monitor antibiotic resistance, 

develop new and novel treatments, including potential vaccines, for all 
types of streptococcal infections. 

Those of us who are involved in streptococcal research and patient care must educate 
physicians through the medical and scientific literature, continuing medical education 
courses, conferences and lectureships. 

Finally, in this age of health care reform in which individuals are encouraged to 



19 



participate in health care decisions involving themselves and family members, we 
must provide accurate and understandable information to the general population 
regarding these diseases. 

Thank you for the opportunity to address this committee and for your kind attention. 
Sincerely, 



J> J-fh 



hS -<"WK*. 



DENNIS L. STEVENS, Ph.D., M.D. 
Chief, Infectious Diseases Section 
Veterans Affairs Medical Center 
Boise, ID 

Professor of Medicine 
University of Washington 
Seattle, WA 



20 

Mr. Towns. I thank you very much, Dr. Stevens, and I also 
thank you, too, Dr. Broome. 

At this time I would like to yield 5 minutes to Congressman 
Schifffor any questions that he might have. 

Mr. Schiff. Thank you, Mr. Chairman, for yielding to me. 

I want to thank both Dr. Stevens and Dr. Broome for their testi- 
mony. And I want to say that I suggested this hearing for the fol- 
lowing reason. It is clear, as has been testified to, that streptococ- 
cus infection is not new. It has been among humankind for many, 
many years in one form or another. 

It is also clear that in the news media recently, somewhat em- 
phasized by tabloid journalism, emphasis on the so-called flesh-eat- 
ing disease or the necrotizing fasciitis, as I believe it is formally 
called, that there is a new media attention on streptococcus infec- 
tions. 

And the key question I would like to ask both of you in turn — 
I will start with you, Dr. Broome — is this question. Either through 
an increase in quantity of infections from streptococcus or through 
an increased number of severe forms of infection, do we face a more 
severe threat from streptococcus infections today than we did, say, 
five or 10 years ago? 

Dr. Broome. I do agree with Dr. Stevens that the actual rate of 
bloodstream infections seems to be relatively constant. But I do 
think there has been an increasing proportion caused by strains 
that have been linked to necrotizing fasciitis and the streptococcal 
toxic shock syndrome. So this is one of the reasons we think it is 
so important to monitor the bacteria. 

If you were just counting cases, you might miss this shift. You 
need to look at the clinical syndromes and you need to look at the 
bacteria to identify the fact that there seems to have been a 
change. 

Mr. Schiff. Now, let me state this back to make sure I have it. 
I believe you have testified that the number of cases overall re- 
ported involving group A streptococcus infections has remained rel- 
atively stable, but the number of cases involving the more severe 
diseases that can result from that has increased within that num- 
ber? 

Dr. BROOME. That is correct. I would like to clarify that these 
rates are actually not based on reporting in the usual sense of 
somebody notifying a health department. That is a relatively unre- 
liable way of determining rates of disease, because it can be af- 
fected by things like media attention, for example. 

When we try to get a rate for this disease, we go out and define 
areas and review the microbiology laboratory records to find how 
many isolates of group A streptococci have been made from cul- 
tures of the blood. So for the special studies that we have done, we 
have a fairly good ability to define the rate of disease. 

Mr. Schiff. Dr. Stevens, are you in agreement that the overall 
number is relatively stable but the incidence of a more severe form 
of this streptococcus-caused disease is apparent? 

Dr. Stevens. Well, I think that is a difficult question, and I 
agree that I don't think the reporting has really been adequate. Al- 
though the CDC has done some active surveillance in a five-State 
area and whatnot, still, reporting of this disease is largely, as was 



21 

alluded to, based upon the individual responsiveness of physicians 
and whatnot. It is not mandatory. If a physician is busy, he may 
or may not report to the State health department. 

So I think nationwide the numbers aren't as reliable as they 
could be. They certainly aren't as good as we have with AIDS and 
things of that nature. 

Because I am recognized as someone who is interested in this 
disease and has been for many years, I hear about cases from fran- 
tic physicians calling wanting to know how to manage these cases. 
And so I have a bias, obviously, because I hear about a lot of these 
cases. And I wouldn't want to give you the impression that my ex- 
perience is anywhere reflective of what is actually going on in the 
country. But I get phone calls nearly every day from all over the 
United States about these severe infections. 

I think I would also like to say that although it was stated that 
this can be a disease associated with compromised patients, in fact 
this is a disease that, while it may infect compromised patients, it 
more commonly affects patients who are perfectly well. In fact, it 
is our bias that it takes a good immune system to really develop 
the toxic shock syndrome. And it is really the organism and its 
virulence factors trick the host into overreacting and causing shock 
and multiorgan failure. So it may be less common in compromised 
patients. 

Mr. Schiff. I am getting somewhat of an impression, though, 
that our information and our data on the question I asked about 
what is happening out there as a public health matter is uncertain 
to say the least. Is that right, Dr. Stevens? 

Dr. Stevens. I agree. And I think the CDC has done a great job 
with the resources that it has in doing the study in the five-State 
area. But I think we need to be more cognizant of the total picture 
of group A strep, pharyngitis, scarlet fever, rheumatic fever, and all 
the other complications. 

This is a common disease that causes a tremendous amount of 
economic and physical problems among Americans. And I think we 
need to be more diligent in dealing with it. 

Mr. Schiff. My time is up. I thank both witnesses, and I yield 
back, Mr. Chairman. 

Mr. Towns. Thank you very much, Congressman Schiff. 

At this time I yield to Congressman Payne for any questions that 
he might have. 

Mr. Payne. Thank you very much. 

In your testimonies, you both stated that the number of people 
infected with necrotizing fasciitis is low and remains low. However, 
we have seen with the increase in AIDS, because of people whose 
immune systems are compromised, we have seen a corresponding 
increase in tuberculosis. 

Do you feel, although just listening to your last answer, do you 
feel that there could possibly be an increase in that population that 
have a compromised immune system? 

Dr. Stevens. Well, I will take a shot at that. The group A strep 
is probably one of the most difficult pathogens that we deal with, 
because it can cause such fulminate infections, even in normal peo- 
ple. Certainly elderly individuals, malnutritioned individuals, and 



22 

people who have compromised immune systems who are in the hos- 
pital are also susceptible. 

I don't want to give you the impression that group A strep infec- 
tions never occur in that population. They certainly do. It is just 
that the more fulminate form, the rapid onset of shock and that 
sort of disease, tends to be more common among those of us such 
as in this room that are intact immunologically. But I think it cer- 
tainly is a problem in all individuals irrespective of their immune 
status. 

Dr. Broome. Representative Payne, we do have some data from 
San Francisco, which is one of the areas where we did the special 
studies, and in that population the overall rate of group A strepto- 
coccal bacterinia was 6.5 per 100,000. So it was within the rate 
that we have seen in other areas. 

A number of those patients did have AIDS. So they are one of 
the groups of immunocompromised who are at increased risk for 
invasive group A streptococcal disease. But AIDS is not a major 
contributor to the overall rate. 

Mr. Payne. Let me ask you this. If there should be an outbreak, 
do you think that we are prepared adequately to handle it? 

I don't want to put you on the spot. Mayoe we ought to ask Dr. 
Stevens. But either one of you may want to respond. 

Dr. Broome. Well, as Dr. Stevens has indicated, this is a difficult 
disease to deal with. You cannot — it is not like a food-borne out- 
break where you can remove the contaminated source of food. The 
major approaches are to be sure that physicians are very alert to 
the diagnosis, and treat promptly and aggressively when appro- 
priate. 

If the outbreak occurs in a very defined setting, such as a nurs- 
ing home or a daycare center, it is possible to treat with prophy- 
lactic antibiotics — if you have got a very clearly defined situation. 

The kind of disease that we are talking about is really spread 
throughout the entire population so that those kinds of approaches 
with prophylactic antibiotics would not be feasible. 

I very much support Dr. Stevens' statement that we do need 
more basic science research and efforts for a vaccine development, 
which would be one approach for ultimate prevention of group A 
streptococcal disease. 

Mr. Payne. Just finally, there were examples of this disease in 
England or in other parts of Europe. Has CDC been in any kind 
of formal relations with your European counterparts, and have you 
been able to discover anything? 

Dr. Broome. Yes, we have been in contact with the Public 
Health Laboratory Service in the United Kingdom and we were 
able to ascertain quite promptly that they were investigating a 
small cluster of six cases in Gloucester. But they also knew from 
their laboratory based surveillance that the overall rate of group A 
streptococcal invasive disease was relatively constant, so that they 
could show they were not experiencing a major epidemic. 

And even the cluster of cases in Gloucester were not all of the 
same M subtype, so they did not appear to be related to each other. 
It may have just been one of those very unusual clusters. 

Mr. Payne. Thank you very much. 

Mr. Towns. Thank you very much, Congressman Payne. 



23 

Let me begin by asking: Prior to the media getting involved, this 
thing seemed to have been treated in a very casual kind of way, 
like "don't say anything and don't do anything," basically. Is my 
opinion and my assessment of that accurate? 

Dr. Stevens. I don't think that is true. One of the first articles 
that I think really portrayed this, although there were several case 
reports of toxic strep syndrome prior to 1985 and 1986, was an ar- 
ticle that we were involved in writing in the New England Journal 
of Medicine which actually got a lot of attention from the medical 
community, the scientific community and the press throughout the 
United States and the world. 

About a year later, the late Jim Henson developed a fulminate 
group A streptococcal infection; in his case it was pneumonia. Once 
again there was a tremendous increase in the press coverage, and 
there were articles in newspapers, Newsweek, and CBS nightly 
news and so on. 

So I think back in 1989 and 1990, there was a lot of interest in 
the medical scientific community as well as the American press. I 
don't know why the British press was totally unaware of this, be- 
cause, as you all know, a few months ago when they had the cases 
in England, they acted like this has never been described. And that 
wasn't the case at all. This has been well recognized by the sci- 
entists and medical doctors and CDC, et cetera, here in trie United 
States, 4 or 5 years previously. 

Mr. Towns. Let me ask another question to make certain I have 
a clear understanding here. There are only two labs in the country 
that can do the blood work, is that what you are saying? 

Dr. Broome. Well, group A streptococcus can be isolated by any 
bacteriology laboratory. There is a special subtype 

Mr. Towns. There has been 75 of them, right, at least in terms — 
from my understanding, 75 different bacterias? 

Dr. Broome. The two laboratories I was referring to are able to 
do the specialized subtyping to identify — to track the change in 
strain characteristics over time. So that is what I was referring to 
in my testimony. 

Any bacteriology laboratory in a hospital would be able to isolate 
and identify group A streptococcus without difficulty. 

Mr. Towns. Your lab would be one of the labs you were talking 
about as the two in the country? Yours is one? 

Dr. Broome. Yes. 

Mr. Towns. Let me get some background information. What are 
the warning signs of necrotizing fasciitis and toxic shock? What are 
the warning signs one would look for? 

Dr. Stevens. In the reports you have before you, I could just 
summarize those, since they are written in medical terms. Most pa- 
tients that develop the streptococcal toxic shock syndrome have 
fever and they have chills. Those that develop necrotizing fasciitis 
usually have increasing and excruciating pain, usually in an ex- 
tremity. 

Sometimes there is no other symptom than the pain. There may 
not be any physical evidence of things going on beneath the skin. 
As hours go by, the skin can become red, it can become hot and 
tender, and then bullae or blisters appear over the skin, and at 
that point in time there is usually extensive destruction of tissue, 



24 

not only in the skin but the subcutaneous fat, the fascia and deep 
muscle. 

These people by that time also have shock, organ failure, and 
mortality rates are exceedingly high. So early on, fever and chills 
and unexplained pain are the best signs and symptoms that we 
have to go on. 

Mr. Towns. How quickly should a person seek treatment? 

Dr. Stevens. I am sorry, sir. 

Mr. Towns. How quickly does a person need to get treatment? 

Dr. Stevens. Well, I think by the time they develop pain, prob- 
ably the infection has been incubating for several days. But by the 
time they have pain, things can progress to shock and organ failure 
within 24 hours. So the earlier antibiotic treatment can be begun, 
the better the results. 

So all I can tell you is that patients that have fever, chills, and 
unexplained pain should seek medical care immediately. If caught 
early enough, antibiotics are very effective. 

Mr. Towns. Dr. Stevens, you had an observation that does bear 
on the need for aggressive treatment of mild cases. Do we ever see 
mild strep infections become invasive ones? If so, could you elabo- 
rate on that? 

Dr. Stevens. Well, if you had asked me that question a year ago 
I would have said probably not. But in the last year, I am certainly 
aware of patients that have had run of the mill group A strep phar- 
yngitis who subsequently have developed streptococcal toxic shock 
syndrome. 

And in many of the articles that I have written and other people 
as well, strep pharyngitis or sore throat has been a very unusual 
manifestation of these more fulminate infections. So it can. And so 
for that reason I think that we really have to be very aggressive 
about diagnosing strep throat and treating it appropriately. 

Now, in Scotland, for example, they have pretty much done away 
with doing throat cultures, perhaps because of health care costs, et 
cetera, and I really think that would be a disaster for us to try to 
do in this country. I think we need to know what is going on. We 
need to identify things that are readily treatable. And then we 
need to treat them aggressively. 

I think your point is well taken. Minor problems can develop into 
more severe ones if they aren't dealt with appropriately. 

Mr. Towns. Let me ask a very , very basic question. Do we know 
what role diet plays in strep infections? Does diet play any part in 
this? 

Dr. Broome. As I mentioned, we have been able to show that 
there are increased rates of disease in some populations. We do not 
have good information on more detailed risk factors. And those are 
some of the studies that we would like to do, for example, nutri- 
tional status, or other possible factors which might affect people's 
susceptibility to severe group A streptococcal disease. 

Mr. Towns. My time nas expired. Did any of the other members 
have any other questions? 

Mr. Schiff. Mr. Portman. 

Mr. Towns. I am sorry, we have been joined by Congressman 
Portman. 



25 

Let me thank both of you for your testimony. This is an area that 
I really feel that we need to pursue in a very aggressive fashion, 
as I think Congressman Schiff pointed out, that we might look 
down the road some years from now — I think Congressman Payne 
said as a result of not doing something now in a very aggressive 
kind of way — we find we have really missed the point here. So I 
am hoping we can create the kind of atmosphere and climate to go 
and look and see whether or not diet or some of these other factors 
affect strep infections, and see what we can do to deal with them. 

In order to do that, sometimes you might have to ask for addi- 
tional resources. That is something you might need to begin to 
think about, because I don't think strep infection is going to go 
away. I think we have seen that it is not going to go away. And 
in fact the only way we can hope that we will be able to get it 
under control is by getting the research and getting information to 
be able to treat people and treat them early. I think that is essen- 
tial. 

So I thank both of you for your testimony, Dr. Stevens and Dr. 
Broome. 

Dr. Stevens. Mr. Chairman, could I ask that the articles I sub- 
mitted be included into the record? 

Mr. Towns. Without objection, your entire statement will be in- 
cluded in the record and also the articles you submitted. 

[The information follows:] 



26 



Reprinted From 

The New England 

Journal of Medicine 



Volume 321 JULY 6, 1989 Number I 



SEVERE GROUP A STREPTOCOCCAL INFECTIONS ASSOCIATED WITH A TOXIC 
SHOCK-LIKE SYNDROME AND SCARLET FEVER TOXIN A 

Dennis L. Stevens, M.D., Ph.D., Martha H. Tanner, M.D., Jay Winship, M.D., Raymond Swarts, M.D., 
Kristen M. Ries, M.D., Patrick M. Schlievert, Ph.D., and Edward Kaplan, M.D. 



27 



SEVERE GROUP A STREPTOCOCCAL INFECTIONS ASSOCIATED WITH A TOXIC 
SHOCK-LIKE SYNDROME AND SCARLET FEVER TOXIN A 

Dennis L. Stevens, M.D., Ph.D., Martha H. Tanner, M.D., Jay Winship, M.D., Raymond Swarts, M.D., 
Kristen M. Ries, M.D., Patrick M. Schi.ifvert, Ph.D., and Edward Kaplan, M.D. 



Abstract There is concern that group A streptococci, 
which have caused less serious infections in developed 
countries in recent decades, may be acquiring greater vir- 
ulence. We describe 20 patients from the Rocky Mountain 
region who had group A streptococcal infections from 
1986 to 1988 that were remarkable for the seventy 
of local tissue destruction and life-threatening systemic 
toxicity. 

Among the 20 patients (median age, 36), necrotizing 
fasciitis with or without myositis was the most common 
soft-tissue infection (55 percent). Nineteen patients (95 
percent) had shock. 16 (80 percent) had renal impairment, 
and 1 1 (55 percent) had acute respiratory distress syn- 
drome. The mortality rate was 30 percent. All patients but 



1 had positive tissue cultures for Streptococcus pyogenes; 
1 2 had positive blood cultures. Most of the patients had no 
underlying disease; 2 used intravenous drugs. Strains of 
group A beta-hemolytic streptococci isolated from 10 pa- 
tients were not of a single M or T type ; however, 8 of the 1 
strains produced pyrogenic exotoxin A (scarlet fever toxin 
A, a classic erythrogenic toxin), which has rarely been 
observed in recent years. 

From our study of this cluster of severe streptococ- 
cal infections with a toxic shock-like syndrome, we con- 
clude that in our region, more virulent group A strepto- 
cocci have reappeared that produce the pyrogenic toxin 
A associated with scarlet fever. (N Engl J Med 1989; 
321:1-7.) 



DRAMATIC declines in the prevalence of both 
rheumatic fever and serious infection caused by 
group A streptococci have been observed throughout 
the 20th century in much of the Western world.'" 4 The 
decline has been thought by some 2,3 to be related in 
part to improved socioeconomic conditions, timely 
treatment of streptococcal pharyngitis with antibiot- 
ics, and secondary prophylaxis for rheumatic fever. 2,3 
Stollerman D has argued that this decline is a function 
of the changing potential of the organism to cause 
rheumatic fever and other major diseases. The re- 
cent outbreaks of acute rheumatic fever reported in 
middle-class children in Utah"- 7 as well as in Penn- 
sylvania, 8 California (Navy recruits), 9 Ohio, and 
Missouri (Army recruits), 10 may reflect renewed viru- 
lence of streptococci. Similarly, the recent outbreaks 



From the Infectious Disease Service. Veterans Administration Medical Center. 
Boise. Idaho (D.L.S.); the Department of Medicine. University of Washington. 
Seattle I D LS ); Eastern Idaho Regional Medical Center. Idaho Falls (M H T 1. 
Missoula Community Hospital, Missoula, Mont. |JW.|, Washoe Medical Cen- 
ter Reno. Nev (RSI; University of Utah and Holy Cross Hospital. Salt Lake 
City 1KMR1, and the Department of Microbiology (P.M.S ). the Department 
of Pediatrics (E.K.), and the World Health Organization Collaborating Center for 
Reference and Research on Streptococci (E.K.). University of Minnesota, Min- 
neapolis Address reprint requests to Dr Stevens at 500 W. Fort St , Boise. ID 
83702. 

Supported in part by grants from the Veterans Administration (to Dr Stevens) 
and by a U.S. Public Health Service grant (HL-3661 1 , to Dr. Schlieven) from the 
National Heart. Lung, and Blood Institute and the Minnesota Medical Foun- 
dation 



of streptococcal pharyngitis in the United States, 9 '" 
the newly recognized streptococcal toxic shock-like 
syndrome,' 2 "' 4 and the severe streptococcal infections 
reported recently from Great Britain 15 could all be 
related to changes in the expression of other virulence 
factors of Streptococcus pyogenes. 

During the past two years we have observed an ap- 
parent increase in the virulence of 5. pyogenes, as mani- 
fested by a variety of unusually severe soft-tissue in- 
fections associated with marked systemic toxicity. 
These infections have occurred primarily among nor- 
mal hosts in the Rocky Mountain area of the United 
States. This report describes 20 patients with group A 
streptococcal soft-tissue infection associated with 
high morbidity and mortality. Our study of these 
patients with a streptococcal toxic shock-like syn- 
drome' 2 "' 4 documents the reappearance of scarlatina 
toxin among clinical isolates of streptococci from our 
region. 

Methods 

Case Reporting 

Severe cases of streptococcal soft-tissue infection were first noted 
in January 1984 in Boise. Idaho. The identification and collection of 
subsequent cases in Montana (four cases), Idaho (seven), Utah 
(eight), and Nevada (one) were the result of awareness of the clini- 
cal features of such infections, maintained through communications 
among a group of infectious-disease specialists in the Rocky Moun- 
tain region (the Rocky Mountain Pus Club). Two cases occurred in 



Reprinted from the New England Journal of Medicine 
321:1-7 (July 6), 1989 



28 



THE NEW ENGLAND JOURNAL OF MEDICINE 



July 6, 1989 



1984, one in 1985. five in 1986, five in 1987, and seven in 1988, 
Because such cases of severe streptococcal infection are not reporta- 
ble to state or local health departments, no estimates of the preva- 
lence of this infection are available for the years preceding 1984. 
However, because of the dramatic presentation of this illness, it 
seems unlikely that many earlier cases were overlooked, especially 
in our region of the United States. Our criteria for identifying cases 
were the isolation of £. pyogenes in cultures of blood, body fluid, or 
tissue and evidence of severe soft-tissue, pharyngeal, or blood-borne 
infection. 

Serotyping of Streptococci 

Clinical isolates were obtained from cultures of blood; tissue of 
the fascia, muscle, uterus, vagina, or pharynx; sputum; peritoneal 
fluid; or joint fluid. Organisms suspected to be streptococci were 
identified according to standard bacteriologic criteria. Group A 
streptococci were initially identified by their degree of sensitivity to 
bacitracin and then were grouped in the clinical microbiology labo- 
ratory with the use of Streptex kits (Wellcome Diagnostics, Bur- 
roughs Wellcome, Research Triangle Park, N.C.). Specimens of 
group A streptococci were forwarded to the World Health Organi- 
zation Collaborating Center for Reference and Research on Strepto- 
cocci (University of Minnesota), where serologic grouping and typ- 
ing for M protein, T-agglutination pattern, and opacity factor were 
carried out according to standard techniques. 1 ^ 19 

Pyrogenic Exotoxin 

Isolates of group A streptococci were evaluated for their produc- 
tion of pyrogenic exotoxin, with use of an Ouchterlony immuno- 
diffusion test. 20 Organisms were grown overnight in a dialyzable 
beef-heart medium, 21 without shaking, until the stationary phase at 
37°C was achieved. Subsequently, toxins were concentrated by eth- 
anol precipitation and restoration with distilled water to 1 percent 
of the original culture volume. 21 

Results 

Factors Associated with Group A Streptococcal Soft- 
Tissue Infection 

Sixteen of 20 patients in this series were 50 years 
of age or younger, and 12 were younger than 40 
(Table 1 ) . The mean ages of the 1 1 men and 9 women 
were similar (42 and 39 years). Thirteen of the pa- 
tients were completely well before the onset of their 
illness. 

Two of the seven patients with possible predispos- 
ing factors (Table 2) consumed liberal amounts of 
alcohol (five or six beers per day), although neither 
had clinical signs of alcoholism, and both were gain- 
fully employed. One patient had adult-onset diabetes 
mellitus and required insulin during the infectioi. 
One patient was obese, and another had moderate 
neurologic dysfunction after undergoing craniotomy 
for an acoustic neuroma years before. Two patients 
had used illicit drugs intravenously; one used them 
habitually, and the other had experimented with them 
just before the onset of the streptococcal infection. 

The suspected portal of entry was the skin in nine 
patients and the mucous membrane in four (Table 2). 
Of the latter group, two patients had vaginal infec- 
tions that occurred eight days and five weeks post par- 
turn, respectively; the other two had positive throat 
cultures. Streptococcal infection developed in two pa- 
tients within 48 hours of surgical procedures (suction 
lipectomy in one and hysterectomy in the other), and 
in two others after minor trauma (elbow abrasion dur- 



ing an accident in one, and a small hematoma on the 
hand in the other). The portal of entry was unknown 
in seven patients. 

Symptoms Associated with Streptococcal Infection 

Pain was the most common initial symptom in 17 
patients (85 percent) and was frequently abrupt in 
onset and severe. Four patients required narcotic an- 
algesics to control the pain, and two presented with 
pain and no other physical findings. The pain usually 
involved an extremity but was intraabdominal in two 
patients. Before its onset, four patients had an influen- 
za-like syndrome characterized by fever, chills, myal- 
gia, and diarrhea. Altogether, 5 patients had vomit- 
ing, 6 had diarrhea, 13 had chills, and 5 had myalgia. 

Physical Findings 

Fourteen patients (70 percent) presented with an 
oral temperature above 37°C (Table 3). Two patients 
had hypothermia and shock at the time of admission. 
Eleven patients were confused at admission; one 
patient's mental status deteriorated rapidly to coma, 
and two others were combative. The confusion was 
particularly severe in one patient, who had advanced 
renal failure and shock by the time she was taken 
to the hospital and died within 96 hours. Most pa- 
tients (80 percent) had tachycardia, and over half 
(55 percent) had a systolic blood pressure below 
110 mm Hg. In eight of the nine patients with 
normal blood pressure (systolic pressure, 1 10 mm Hg 
or more), marked hypotension and shock developed 
within four hours of admission. Localized swelling 
and erythema were present in 13 patients (Table 3). 
One additional patient presented with bullous skin 
lesions; two others had soft-tissue swelling alone. No 
patients had a rash typical of scarlatina, although two 
had petechial rash, two had maculopapular rashes, 
and four had desquamation 7 to 14 days after admis- 
sion. Of the four patients who presented without der- 
mal manifestations of infection, one had shock and 
was ultimately found to have endophthalmitis, one 
had fulminant myositis eight hours after presentation, 
one had perihepatitis after a hysterectomy, and one 
presented with spontaneous peritonitis, myocarditis, 
and sepsis. 

Hematologic Tests 

The mean white-cell count was only 1 1,765 cells per 
cubic millimeter. However, the differential cell count 
was striking in that 43 percent of cells were immature 
(band forms, metamyelocytes, or myelocytes). Platelet 
counts were estimated by microscopy as normal in 6 of 
the 20 patients. The mean platelet count exceeded 
216,000 per cubic millimeter in the 13 patients in 
whom quantitative platelet counts were performed; by 
72 hours it had dropped to 129,000. The prothrombin 
time, determined in 10 patients, was prolonged by 
more than three seconds in 6, of whom 4 had bactere- 
mia and 2 did not. Initially, the mean hematocrit val- 
ue was normal (43 percent) for the altitude of the area 



29 



Vol. 321 No. 1 



STREPTOCOCCAL INFECTIONS AND TOXIC SHOCK-LIKE SYNDROME — STEVENS ET AL 



Table 1 Clinical Characteristics and Courses of 20 Patients with Group A Streptococcal Infection. 



Patient No 








(YmOF 








Diagnosis) 


Ace/Sex 


Cunical Presentation 




I (I984) 


66/M 


Myalgia. pharyngitis 


SHCK 

+ 


2(1984) 


41/M 


Joint sepsis, necrotizing 
fasciitis 


+ 


3 (1985) 


29/F 


Cellulitis (right leg. post partum) 


+ 


4(1986) 


67/F 


Cellulitis, osteomyelitis 


+ 


5 (1986) 


63/M 


Shock, pharyngitis, 
endophthalmitis 


+ 


6(1986) 


33/M 


Suppurative thrombophlebitis 


+ 


7(1986) 


30/M 


Cellulitis 


+ 


8(1986) 


42/M 


Necrotizing fasciitis 
(elbow) 


+ 


9(1987) 


33/M 


Necrotizing fasciitis 


+ 


10(1987) 


34/F 


Cellulitis, probable 
myositis 


+ 


11 (1987) 


35/F 


Septic shock, necrotizing 
fasciitis 


+ 


12(1987) 


61/M 


Cellulitis 


+ 


13(1987) 


42/F 


Cellulitis (forearm) 


+ 


14(1988) 


25/F 


Infection at site of suction 
lipectomy 


+ 


15(1988) 


48/F 


Shock, peritonitis (poslhys- 
terectomy) 


+ 


16(1988) 


34/F 


Myometritis (post partum) 


+ 


17 (1988) 


31/M 


Infection (thumb), necro- 
tizing fasciitis 


_ 


18 (1988) 


29/M 


Peritonitis, myocardiopathy 


+ 


19 (1988) 


37/F 


Axillary pain, sore throat 


+ 


20(1988) 


36/M 


Septic shock 


+ 



Clinicai 


I Ml MM 




Outcome 


RENAL 








IMPAIRMENT 


SURGERY 


BACTEREMIA 




+ 


Debridement 


+ 


Died 




Amputation 


" 


Lived 


+ 




+ 


Died 


+ 


Debridement 


+ 


Lived 


+ 




+ 


Lived 


+ 


Debridement 


+ 


Lived 


+ 


Debridement 


- 


Lived 


+ 


Debndement 


+ 


Died 


(dialysis) 








+ 


Debridement 


- 


Lived 


+ 




- 


Died 


(dialysis) 








+ 


Debndement 


- 


Lived 


+ 


Debndement 


+ 


Died 


+ 


Debridement 


- 


Lived 


+ 


Debndement 


- 


Lived 



Laparotomy 

Hysterectomy 
Amputation 



Lived 
Lived 

Lived 
Lived 
Died 



•Acute respiratory distress syndrome 



(700 to 1460 m [2300 to 4800 ft] above sea level); 
however, by 48 to 72 hours it had dropped to 29 
percent. 

Blood Chemistry Values 

Initially, serum creatinine concentrations were ele- 
vated in 17 of 19 patients tested (mean, 222 /xmol per 
liter [2.5 mg per deciliter]), and they increased to a 
mean of 302 /zmol per liter (3.4 mg per deciliter) by 48 
to 72 hours. The concentrations returned to normal 
several weeks to months later in all but two patients; 
both patients had progressive azotemia and required 
dialysis. Serum calcium levels, measured in 15 pa- 
tients, were low on admission (mean, 2.03 mmol per 
liter [8.1 mg per deciliter]) and continued to drop 
over the next three days (mean, 1.65 mmol per liter 
[6.6 mg per deciliter] ) . The mean serum albumin level 
(n = 15) also was low on admission (33 g per liter [3.3 
g per deciliter]) and dropped further by the third hos- 
pital day (23 g per liter [2.3 g per deciliter]). Thus, the 
degree of hypocalcemia was greater than expected 
solely on the basis of the degree of hypoalbuminemia. 
In support of this observation, concentrations of ion- 
ized calcium were also low in the two patients studied 
(0.25 and 0.4 mmol per liter [ 1 .0 and 1 .6 mg per decili- 
ter]). Serum creatine kinase, measured serially, in- 
creased to a mean of 1 13,685 IU in 8 of 10 patients by 



48 to 72 hours. Of these eight patients, one had myo- 
carditis (creatine kinase, 1359 IU; MB fraction, 12 
percent), one had myositis and necrotizing fasciitis, 
and five had necrotizing fasciitis. Three of these five 
also had probable myositis. In two of these last three 



Table 2. Factors Associated with Group A Strepto- 
coccal Soft-Tissue Infection. 





No or Patients 


Factor 


(%) 


No of patients 


20 


Underlying disease 




Diabetes mellitus, adult onset 


1(5) 


Obesity 


K5) 


Alcoholism 


2(10) 


Cerebellar ataxia 


K5) 


Intravenous drug abuse 


2(10) 


No known predisposing factor 


13(65) 


Probable portal of entry 




Skin 




Leg ulcer, osteomyelitis 


1(5) 


Local trauma 


2(10) 


Surgical procedure 


2(10) 


Intravenous drug abuse 


2(10) 


Infected hair follicle 


1(5) 


Chronic leg ulcer 


1(5) 


Mucous membrane 




Vaginal area, post partum 


2(10) 


Pharynx 


2(10) 


Unknown 


7(35) 



85-648 0-94-3 



30 



THE NEW ENGLAND JOURNAL OF MEDICINE 



July 6, 1989 



patients, intractable shock, acute respiratory distress 
syndrome, and renal failure ensued; in neither patient 
was a surgical procedure or an autopsy performed. 

Urinalysis 

The test for hemoglobin (Hemastix) was positive in 
12 of 17 patients. All 12 patients had elevated serum 
creatinine concentrations at the time of admission. 
Five of the 17 patients also had microscopic hematu- 
ria, but invariably with fewer than five red cells per 
high-power field. Thus, the presence of hematuria 
among patients with serious group A streptococcal in- 
fection correlated well with the presence of renal im- 
pairment. 

Bacteriologlc Cultures 

Group A streptococci were grown from blood, body 
fluid, or tissue from all 20 patients. Nineteen had posi- 
tive cultures of tissue obtained by surgical biopsy, fas- 
ciotomy, or percutaneous aspiration. One patient (Pa- 
tient 20), who died in the emergency room, had 
positive blood cultures only. In addition, group A 
streptococci were grown from pharyngeal specimens 
from two patients and from vaginal specimens from 
two others. Overall, 12 patients had positive blood 
cultures (Table 4). 

Clinical Course 

Twelve of the 20 patients (60 percent) had bactere- 
mia, and 6 (30 percent) died. Of these, five died with- 
in 96 hours of admission, and three died within 36 
hours. The morbidity among patients in this series 
was high (Table 4); 13 patients underwent major sur- 
gical procedures, which included fasciotomy (9 pa- 
tients), debridement other than fasciotomy (2), ampu- 
tation (2), exploratory laparotomy (1), intraocular 
aspiration (1), and hysterectomy (1). Desquamation 
of the skin developed in four patients between the 7th 
and 10th days after diagnosis. 



Table 4. Complications of Group A Streptococcal 
Soft-Tissue Infection. 



Table 3. Physical Findings 


at the Time 


of Admission. 








No. of Patients 


Finding 




(*) 


No. of patients 




20 


Temperature (°C) 






€37 




6(30) 


>38 




14 (70) 


Confusion 




11(55) 


Heart rate (beats/min) 






80-99 




4(20) 


100-140 




1 1 (55) 


>140 




5(25) 


Systolic blood pressure (mm 


Hg) 




»110* 




9(45) 


90-109 




4(20) 


70-89 




4(20) 


€69 




3(15) 


Skin 






Swelling only 




2(10) 


Swelling, erythema 




13 (65) 


Bullae 




1(5) 


No swelling 




4(20) 



Complication 


No. of Patients 
(%) 


No. of patients 


20 


Shock 


19 (95) 


Acute respiratory distress syndrome 


11* (55) 


Renal impairment 
Irreversible 
Reversible 


16 (80) 
2 (10) 
14 (70) 


Amputation 


2 (10) 


Desquamation of the skin 


4 (20) 


Fasciotomy 


9t (45) 


Sepsis 


12 (60) 


Death 


6 (30) 



•In eighl of nine patients with high systolic blood pressure (>I10 
mm Hg) on admission, hypotension developed within four hours 



•Diffuse pulmonary edema and hypoita developed in one patient; both 
complications were resolved with diuresis and supplemental oxygen 

^Amputation of a limb was ultimately reuuueu in two patients who 
underwent fasciotomies 



The site of infection was confirmed by surgical in- 
tervention in the majority of cases (Table 1). Necrotiz- 
ing fasciitis was the most common presentation (8 pa- 
tients [40 percent]). Cellulitis alone was found in two 
patients; in one, the serum creatine kinase level was 
normal, and surgical exploration confirmed that mus- 
cle was not infected. Some of the cases of necrotizing 
fasciitis presented clinically as cellulitis (three cases), 
but a poor response to antibiotics or an elevation of 
the creatine kinase level prompted surgical interven- 
tion, on which substantial muscle involvement was 
found. Two patients presented with peritonitis, which 
occurred after a hysterectomy in one patient (Patient 
15) and appeared spontaneously in the other, a moun- 
tain climber (Patient 18), who presented with severe 
pain in the left lower quadrant and one day later 
had myocarditis and group A streptococcal bactere- 
mia. Other patients presented with osteomyelitis, en- 
dophthalmitis, joint sepsis, myometritis, or suppura- 
tive thrombophlebitis. 

Shock was apparent at the time of admission or 
within hours thereafter in 19 patients (Table 4). In 
two patients, the systolic blood pressure became nor- 
mal four to eight hours after they had received inten- 
sive monitoring, dopamine infusion, albumin, and 
electrolyte solutions containing salts. In others, shock 
persisted. Acute respiratory distress syndrome oc- 
curred in 1 1 of the 20 patients and was generally diag- 
nosed after the onset of hypotension. Of the 1 1 pa- 
tients with the syndrome, 10 required intubation, 
supplemental oxygen, and mechanical ventilation. 

Renal impairment was apparent at admission in 17 
patients and persisted or progressed in all 17 for 48 to 
72 hours. Progressive azotemia requiring dialysis de- 
veloped in only two patients. In all the patients who 
survived, serum creatinine values returned to normal 
within four to six weeks (data not shown). 

Characteristics of Clinical Isolates of Group A 
Streptococci 

All strains isolated from the patients were bacitra- 
cin-sensitive, Lancefield group A streptococci (Table 



31 



Vol. 321 No. I 



STREPTOCOCCAL INFECTIONS AND TOXIC SHOCK-LIKE SYNDROME — STEVENS ET AL. 



Table 5. Characteristics ot Clinical Isolates of Group A 
Streptococci. 



Patient No. 


Lancefield 


Type 


Pyrooei 


* 

*ic Exotoxin 


(V* OF 


Group" 










Diagnosis) 
















T 


Mt 


A 


b c 


1 11984) 


A 


3 


3 


+ 


_ 


II (1987) 


A 


1 


1 


+ 


+ - 


12(1987) 


A 


3 


3 


+ 


- - 


13(1987) 


A 


11 


NT 


+ 


+ + 


IS (1988) 


A 


1 


1 


+ 


+ 


16(1988) 


A 


3 


3 


+ 


- - 


18(1988) 


A 


28 


28 


+ 


- - 


18(1988) 


A 


28 


28 


- 


- 


19(l988)t 


A 


1 


1 


- 


+ 


20(1988) 


A 


II 


NT 


+ 


+ - 



'All strains were bacitracin-sensitive and produced streptolysin O 
TMucoid colony NT denotes not typablc 

5). Only one strain of the 10 studied further had mu- 
coid colony morphology; that strain was an M-l. 
M-3— T-3 and M-l-T-1 were the most prevalent strains. 
The prevalence of pyrogenic exotoxin A (scarlet fever 
toxin) was striking among the strains isolated in this 
study (8 of 10 strains). Only one M-l strain and one 
M-28-T-28 strain did not produce this toxin. Two 
different strains of M-28-T-28 were isolated from the 
blood of one patient (Patient 18); one of these strains 
was opacity-factor— positive and pyrogenic exotoxin 
A-negative, and the other strain was opacity-factor- 
negative and pyrogenic exotoxin A-positive. This was 
confirmed by repeated testing. 

Discussion 

This study and others 4 " 15 suggest that the frequency 
of severe group A streptococcal infections may have 
increased. Of the 20 patients we have described, 19 
had shock, 12 had bacteremia, and 6 died of group A 
streptococcal infections. Host factors do not appear to 
explain these outcomes, since 80 percent of our pa- 
tients were less than 50 years of age, most did not have 
underlying disease, none were immunocompromised, 
and most did not have obvious portals of entry. This is 
in striking contrast to other series of patients with 
group A streptococcal sepsis, in which age, diabetes, 
alcoholism, and drug abuse were found to be impor- 
tant risk factors. 22 " 27 

Most patients in our series presented with a soft- 
tissue infection, such as cellulitis or necrotizing fascii- 
tis. In addition, several patients had deeper infection, 
including osteomyelitis, myometritis, peritonitis, sup- 
purative phlebitis, and endophthalmitis. Most pre- 
sented with hypotension, renal dysfunction, hypoalbu- 
minemia, hypocalcemia, and respiratory failure. 
These clinical features and the multisystem failure are 
similar to those described by Todd and Fishaut 28 in 
patients with the staphylococcal toxic shock syndrome 
and by Cone et al., 12 Bartter et al., 13 and Hribalova' 4 
in patients with the streptococcal toxic shock-like syn- 
drome. A major difference between our patients and 
those with staphylococcal toxic shock syndrome 28 is 
that ours had extensive soft-tissue infection and bac- 
teremia. In contrast, that syndrome is usually not 
associated with bacteremia, and the site of infec- 



tion may be difficult to identify. 28 In the present series, 
surgical intervention was of major importance in es- 
tablishing a diagnosis and removing devitalized tissue. 

Some characteristics of group A streptococci that 
recently have been associated with increased virulence 
include mucoid colony morphology (hyaluronic acid 
capsule) and M-l, M-3, and M-l 8 serotypes. 6 - 10152930 
Specifically, mucoid strains of the M-l 8 serotype 
have recently been associated with epidemics of phar- 
yngitis 10 and acute rheumatic fever. 6 In contrast, no 
association has been identified between T or M type 
and either suppurative soft-tissue infection or sepsis 
caused by group A streptococci. 31 The prevalence of 
M and T types among the strains isolated in the pres- 
ent study was also noteworthy, since an epidemic of 
acute rheumatic fever was occurring simultaneously in 
roughly the same area. 6 

Interestingly, 6 of our 10 isolates were M type either 
1 or 3 (Table 5). These findings are in contrast to 
reports from New Zealand, where no specific M or T 
type was associated with severe suppurative infections 
in children. 31 All three of the M-3 strains were isolated 
from patients in Idaho. Only one strain in the current 
series had mucoid colony morphology, and this strain 
was type M-l. This is in marked contrast to an out- 
break of pharyngitis, in which most mucoid strains 
were of M-18 (74 percent) or M-3 (20 percent) type. 10 
The prevalence of pyrogenic exotoxin A among the 
clinical isolates from our patients (8 of the 10 isolates 
examined) was striking. This observation is particu- 
larly important since none of 80 strains of group A 
streptococci isolated from clinical sources in the Unit- 
ed States between 1976 and 1986 produced pyrogenic 
exotoxin A. 2 Similarly, strains of group A streptococci 
isolated during outbreaks of mild scarlet fever in 
England from 1980 to 1985 produced type B and type 
C pyrogenic exotoxin, but none produced type A. 32 
Earlier in this century in the United States, exotoxin A 
was highly prevalent among clinical isolates, particu- 
larly those associated with scarlet fever. 12,33 In addi- 
tion, of four isolated reference strains from patients 
who had severe scarlet fever in England before 1940, 
all produced pyrogenic exotoxin A. 32 In a recent edito- 
rial, Stollerman 5 discussed this issue and concluded 
that changes in the prevalence of type A pyrogenic 
toxin among strains may help to explain the historical 
relation of streptococci to scarlet fever and toxic shock 
syndrome. 

Factors that support a role for streptococcal toxin in 
our patients include the marked destruction of tissue 
and the multiple organ failure. Indeed, the constella- 
tion of renal failure, shock, hypocalcemia, and throm- 
bocytopenia is similar to that seen in staphylococcal 
toxic shock syndrome, which is clearly a toxin-mediat- 
ed illness. That pyrogenic exotoxin A could mediate 
these clinical derangements is strongly suggested by 
its known biologic properties, shared with toxic shock 
syndrome toxin- 1, which include the following 29 ' 32 : 
pyrogenicity, enhancement of susceptibility to endo- 
toxin shock, enhancement of delayed hypersensitivity 
to induced skin rashes, cytotoxicity (including cardiac 



32 



THE NEW ENGLAND JOURNAL OF MEDICINE 



July 6, 1989 



damage), mitogenicity (nonspecific) for T lympho- 
cytes, immunosuppression (of B-lymphocyte func- 
tion), alteration of host antibody response, and mito- 
genic activity in humans and in lymphocytes from 
rabbits. 33 " 36 

In this regard, the observation (Lee PK, Schlievert 
PM: unpublished observations) that pyrogenic exo- 
toxin type A was lethal to rabbits when administered 
by osmotic pumps over seven days, whereas identical 
amounts of type C toxin were not lethal, is important. 
One additional mechanism of shock induced by toxic 
shock syndrome toxin- 1 and probably by pyrogenic 
exotoxin A is direct myocardial depression. 37 The ab- 
sence of a rash in some patients with scarlet fever in 
this study may reflect a lack of previous sensitization 
to pyrogenic exotoxins, which is thought to be neces- 
sary for the production of a rash in scarlet fever. 38 
Numerous patients with the toxic shock syndrome 
have also been reported to be without a demonstra- 
ble rash. 39 

The role of other toxins, such as streptolysin O 
(thiol-activated cytolysin), in the pathogenesis of in- 
fection in our patients is conjectural, yet such toxins 
are lethal, 404 ' produce shock, 4 *' 4 ' and also directly de- 
press myocardial contractility. 42 Perhaps the higher 
prevalence of shock, acute respiratory distress syn- 
drome, renal failure, and death observed in our pa- 
tients could be due in part to the additive effects of 
pyrogenic exotoxin A and streptolysin O (Table 5). 

Other explanations for shock and renal failure must 
also be considered, particularly among patients with 
bacteremia. Bacteremia could have resulted in com- 
plement activation, disseminated intravascular coagu- 
lopathy, and shock mediated by bradykinin or other 
biologically active endogenous mediators. Yet, the 
prevalence of shock, renal failure, and mortality was 
not greater among the patients with bacteremia (92 
percent, 75 percent, and 33 percent, respectively) than 
among those without it (100 percent, 86 percent, and 
25 percent, respectively). In addition, the overall mor- 
tality rate in our series — 30 percent — is similar to 
the rates in other series 21 ' 2 " of patients with streptococ- 
cal bacteremia (12 to 43 percent); in contrast, the 
prevalence of both shock (95 percent) and renal fail- 
ure (80 percent) was markedly higher in our patients. 
Thus, bacteremia by itself is not sufficient to explain 
all the complications observed in the present series. 

Our patients required intensive fluid replacement, 
invasive monitoring, and timely surgical debride- 
ment. 23 ' 43 The antibiotics used were mainly penicillin 
and cephalosporins, and no conclusions about optimal 
antibiotic therapy can be drawn from this small group. 
Yet, it was in cases of such fulminant forms of strepto- 
coccal infection with large numbers of bacteria that 
Eagle noted, experimentally, the failure of treatment 
with penicillin. 44 Other approaches to therapy, such as 
the use of antibiotics that suppress toxin synthesis 45 or 
immunoglobin treatment, will need to be evaluated. 
In summary, the present study describes 20 patients 
from the Rocky Mountain region who had severe 
group A streptococcal infection and a toxic shock-like 



illness. The striking finding in this series was the high 
frequency with which pyrogenic exotoxin A (scarlet 
fever toxin type A) was produced by clinical isolates. 
This finding, together with the complications of acute 
respiratory distress syndrome, renal impairment, and 
shock, supports a role for this toxin, at least in part, as 
a mediator of the streptococcal toxic shock syndrome. 
Because of the serious nature of this infection, further 
studies will need to be carried out to determine the 
prevalence of these strains in our communities and to 
investigate the mechanisms of shock induced by strains 
of 5. pyogenes that produce pyrogenic exotoxin A. 

We are indebted to Dwight Johnson for performing the M, T, and 
opacity-factor typing, to Amy Bryant for the initial bacteriologic 
studies, to Sally Sellers and Robin McGee for assistance in the 
preparation of the manuscript, and to Dr. Fntz Dixon (director, 
Idaho State Department of Health) for supplying us with strains 
from two of the patients. 

References 

1 . Rotta J, Tikhomirov E. Streptococcal diseases worldwide: present status and 
prospects. Bull WHO 1987, 65:769-77. 

2. Land MA, Bisno AJL. Acute rheumatic fever a vanishing disease in subur- 
bia. JAMA 1983; 249:895-8 

3 MassellBF, Chute CO; Walker AM. KurlandGS Penicillin and the marked 
decrease in morbidity and mortality from rheumatic fever in the United 
Stales. N Engl J Med 1988; 318:280-6. 

4 Kaplan EL, Markowitz M. The fall and nse of rheumatic fever in the United 
States: a commentary Int J Cardiol 1988; 21:3-10. 

5 Stollerman GH. Changing group A streptococci: the reappearance of strep- 
tococcal "toxic shock " Arch Intern Med 1988; 148:1268-70 

6 Veasy LG. Wiedmeier SE, Orsmond GS. et al Resurgence of acute rheu- 
matic fever in the intermountain area of the United States. N Engl J Med 
1986; 316:421-7 

7. Acute rheumatic fever — Utah. MMWR 1987; 36:108-15. 

8 Wald ER, Dashefsky B, Feidt C, Chipoms D, Byers C Acute rheumauc 
fever in western Pennsylvania and the tri-state area. Pediatncs 1987; 80:371- 
4. 

9 Acute rheumatic fever at a Navy training center — San Diego, California 
MMWR 1988; 37:101-4. 

10. Acute rheumatic fever among Army trainees — Fort Leonard Wood, Mis- 
souri, 1987-1988. MMWR 1988: 37:519-22. 

11. Hill HR, Zimmerman RA. Reid GVK. Wilson E, Kilton RM Food-bome 
epidemic of streptococcal pharyngitis at the United States Air Force Acade- 
my. N Engl J Med 1969; 280:917-21. 

12. Cone LA, Woodard DR. Schlievert PM. Tomory GS Clinical and bacten- 
ologic observations of a toxic shock-like syndrome due to Streptococcus 
pyogenes- N Engl J Med 1987; 317:146-9. 

13 Bartter T, Dascal A, Carroll K, Curley FJ "Toxic strep syndrome": mani- 
festation of group A streptococcal infection. Arch Intern Med 1988, 
148:1421-4. 

14. Hfibalova V. Streptococcus pyogenes and the toxic shock syndrome. Ann 
Intern Med 1988, 108:772. 

15. Gaworzcwska E, Colman G. Changes in the patterns of infection caused by 
Streptococcus pyogenes. Epidemiol Infect 1988; 100:257-69. 

16. Lancefield RC. A micro precipitin-technic for classifying hemolytic strepto- 
cocci, and improved methods for producing antisera. Proc Soc Exp Biol 
Med 1938; 38:473-8. 

17. Swift HF. Wilson AT, Lancefield KC. Typing group A hemolytic strepto- 
cocci by M precipitin reactions in capdlary pipettes J Exp Med 1943: 
78:127-33. 

18 Griffith F. The serological classification of Streptococcus pyogenes. J Hyg 
1934; 34:542-84. 

19. Johnson DR. Kaplan EL. Microtechnique for serum opacity factor charac- 
terization of group A streptococci adaptable to the use of human sera J Clin 
Microbiol 1988; 26:2025-30 

20 Schlievert PM. Blomsler DA Production of staphylococcal pyrogenic exo- 
toxin type C: influence of physical and chemical factors J Infect Dis 1983; 
147:236-42. 

21. Schlievert PM. Shands KN, Dan BB, Schnud GP. Nishimura RD Identifi- 
cation and characterization of an exotoxin from Staphylococcus aureus asso- 
ciated with toxic-shock syndrome J Infect Dis 1981; 143:509-16. 

22. Bibler MR, Rouan GW. Cryptogenic group A streptococcal bacteremia: 
experience at an urban general hospital and review of the literature. Rev 
Infect Dis 1986. 8 941-51 

23. Adams EM. Gudmundsson S. Yocum DE, Haselby RC, Craig WA, Sund- 
slrom WR. Streptococcal myositis Arch Intern Med 1985; 145:1020-3. 



33 



Vol. 321 No. I 



HERPES SIMPLEX MRUS TYPE 2 IN THE UNITED STATES —JOHNSON ET AL. 



24. Gibbs RS. Bianco JD Streptococcal infection in pregnancy a study of 48 
bacteremias Am J Obstet Gynecol 1981. 140:405-11 

25 Wong VK, Wnght HT Jr Group A beta- hemolytic streptococci as a cause of 
bacteremia in children Am J Dis Child 1988. 142 831-3 

26. Ispahani P. Donald FE, Aveline AJ Streptococcus pyogenes bacterdcmia: 
an old enemy subdued, but not defeated J Infect 1988, 16:37-46. 

27 Quintihani R, EnghGA. Overwhelming sepsis associated with group A beta 
hemolytic streptococci. J Bone Joint Surg [Am) 1971, 53 1391-9 
Todd J. Fishaut M Toxic-shock syndrome associated with phage-group-1 
staphylococci. Lancet 1978:2:1116-8. 

Bclani KK. Visseren F. Garhch D.et al The role of hyaluronic acid capsule 
in phagocytosis of mucoid group A streptococci (GAS) Pediatr Res 1988, 
23 Suppl:364A abstract. 

30 Kaplan EL, Johnson DR. Geary PP Group A streptococcal serotypes 
isolated from patients and sibling contacts during resurgence of rheu- 
matic fever in the United Slates in the mid-1980s. J Infect Dis 1989; 
159:101-2. 

Hamden A, Lennon D Serious suppurative group A streptococcal infections 
in previously well children Pediatr Infect Dis J 1988; 7:714-8 

32 Hallas G. The production of pyrogenic exotoxins by group A streptococci. 
JHyg 1985,95:47-57. 

33 Schlievert PM. Benin KM, Watson DW Production of pyrogenic exotoxin 
by groups of streptococci: association with group A. J Infect Dis 1979; 
140:676-81 

Kim YB. Watson DW Streptococcal exotoxins: biological and pathological 
properties. In: Wannamaker LW, Matsen JM. eds. Streptococci and strepto- 
coccal diseases, recognition, understanding, and management. New' York: 
Academic Press. 1972:33-50. 

Gray ED. Purification and properties of an extracellular blastogen produced 
by group A streptococci. J Exp Med 1979. 149:1438^49. 



28 



29 



'I 



34 



35 



Schlievert PM. Watson DW Biogenic amine involvement in pyrogenicity 
and enhancement oi lethal endotoxin shock by group A streptococcal pyro- 
genic exotoxin. Proc Soc Exp Biol Med 1979. 162269-74 
Olson RD, Stevens DL, Mclish ME Direct effects of purified staphylococ- 
cal toxic shock toxin 1 on myocardial function of isolated rabbit atna. Rev 
Infect Dis 1989; ILSuppl 1S3I3-S3I5 

Schlievert PM. Benin KM. Watson DW Re interpretation of the Dick lest: 
role of group A streptococcal pyrogenic exotoxin Infect Immun 1979, 
26:467-72. 

Reingold AL. Hargrett NT, Dan BB. Shands KN. Strickland BY. Bloome 
CV Nonmenstrual toxic shock syndrome: a review of 1 30 cases Ann Intern 
Med 1982;96:871-4. 

Stevens DL. Troyer BE. Mcmck DT. Mitten JE. Olson RD Lethal effects 
and cardiovascular effects of purified alpha- and theta-toxins from Clostridi- 
um perfrmgens. J Infect Dis 1988; 157 272-9 

Halbert SP. Bircher R. Dahlc E The analysis of streptococcal infections 
V Cardiotoxicity of streptolysin O for rabbits in vivo J Exp Med 1961; 
113:759-84. 

Fisher MH. Kaplan EL. WannamakcrLW Cholesterol inhibition of strepto- 
lysin O toxicity for myocardial cells in tissue culture Proc Soc Exp Biol 
Med 1981; 168:233-7. 

Nather A, Wong FY. Baiasubramaniam P. Pang M Streptococcal necrotiz- 
ing myositis — a rare entity: a report of two cases. Clin Orthop 1987; 
215:206-11. 

Eagle H Experimental approach to the problem of treatment failure with 
penicillin. I. Group A streptococcal infection in mice Am J Med 1952, 
13:389-99. 

Stevens DL, Gibbons AE. Bergstrom R, Winn V. The Eagle effect revisit- 
ed: efficacy of clindamycin, erythromycin, and penicillin in the treatment of 
streptococcal myositis. J Infect Dis 1988; 158:23-8. 



©Copyright, 1989, by the Massachusetts Medical Society 
Printed in the U.S.A. 



34 



STATE-OF-THE-ART CLINICAL ARTICLE 



Invasive Group A Streptococcus Infections 



Dennis L. Stevens 



From the Department of Medicine. University of Washington School of 

Medicine. Seattle. Washington; and the Veterans Affairs Medical Center. 

Infectious Diseases Section. Boise. Idaho 



The late 1980s have witnessed the emergence of severe group A streptococcus (GAS) infection; 
shock, bacteremia, and acute respiratory distress syndrome are common features, and death has 
been associated with this infection in 30% of patients. Such infections have now been described in 
all parts of the United States, Europe, and Australia and have occurred predominantly in other- 
wise healthy adolescents and adults. The characteristic clinical and laboratory features of the 
streptococcal toxic shock syndrome include deep-seated infection associated with shock and 
multiorgan failure. Strains of GAS isolated from patients with invasive disease have been predom- 
inantly M types 1 and 3, which produce pyrogenic exotoxin A or B or both. In this report, the 
clinical and demographic features of streptococcal bacteremia, myositis, and necrotizing fasciitis 
will be presented and compared with those of streptococcal toxic shock syndrome. Current 
concepts of the pathogenesis of invasive streptococcal infection will also be presented in terms of 
the interaction between virulence factors of GAS and host defense mechanisms. Finally, new 
concepts for future treatment of serious streptococcal infections will be proposed. 



Invasive streptococcal infections have been observed for 
several centuries and include the following unique clinical 
illnesses: puerperal sepsis, scarlatina maligna, septic scarlet 
fever, bacteremia, erysipelas, necrotizing fasciitis, gangrene. 
and myositis. Remarkably, all these forms of streptococcal 
infections have, until recently, demonstrated marked attenu- 
ation in terms of incidence and severity. Although modern 
medicine has had major impacts on the prevention of rheu- 
matic fever and puerperal sepsis and penicillin is useful in 
the treatment of group A streptococcus (GAS) infections, the 
mortality rate for certain GAS infections such as scarlet fever 
had declined in North America and Europe well before anti- 
biotics were available. Even though some researchers would 
attribute the decrease in the incidence of senous strepto- 
coccal infections to improved socioeconomic conditions, it 
seems just as likely that in the 1990s we are experiencing 
enhanced expression of the virulence of GAS. This is a dy- 
namic process that waxes and wanes in its ecological niche. 
the skin and mucous membranes of humans. 

Just as a decrease in the incidence of serious infections was 
apparent subsequent to the turn of the century, so are we 



Received 16 August 1991: revised 30 August 1991 

This work was approved by the Human Subjects Office. University of 
Washington School of Medicine. Seattle. Washington, and the Animal Sub- 
jects Committee of the Veterans Affairs Medical Center. Boise. Idaho. 

This work was supported in part by grants from the Department of Vet- 
erans Affairs, The Upjohn Company, and Hoffmann-La Roche Inc. 

Reprints or correspondence: Dr. Dennis L. Stevens. Infectious Diseases 
Section (TI09). Veterans Affairs Medical Center. 500 West Fort Street. 
Boise. Idaho 83702. 

Clinical Infectious Diseases 1992;14:2-13 

This article is in the public domain 



now experiencing more-aggressive GAS infections in a 
unique population of humans who had hitherto been spared 
by such severe infections The course of infection is rapid 
and frequently fatal in spite of the immunocompetent status 
of the host. The fulminant nature of these infections is no 
more impressive than the minor, even trivial, trauma that 
predisposes the young, healthy host to infection. The speed 
with which GAS induces local infection, multiorgan failure, 
and death cannot be matched by any other infectious or- 
ganism. 

A change in (he virulence factors of GAS could explain 
this newfound aggressiveness and could also explain why 
healthy hosts are attacked. Still, if the explanations were this 
simple, why have we not witnessed major epidemics of GAS 
infections due to common-source exposure? Instead we are 
experiencing an increased incidence of sporadic cases in oth- 
erwise healthy, young adults. Similarly, these severe infec- 
tions are not occurring in immunocompromised patients. 
Thus if the presence of a new virulence factor alone were 
sufficient to induce infection, then epidemics would be ex- 
pected. The susceptibility of the human host must vary even 
within regional domains. Since individuals without histories 
of significant bacterial infection are those who are most fre- 
quently infected, the answer must lie within the absence of 
either humoral or cellular immunity to the putative strepto- 
coccal virulence factor. 

Finally, the interaction between GAS and the human host 
is an intimate one. and evidence is mounting that the organ- 
ism has the ability to neutralize and adapt to a variety of host 
defense mechanisms. Alternatively, cell constituents and 
toxins of GAS can induce exaggerated host responses in 
terms of cytokine production or T cell activation. Clinically, 



35 



C1D 1 992; 14 (January) 



Streptococcal Toxic Shock Syndrome 



this unique interaction leads to several presentations of inva- 
sive streptococcal disease such as bacteremia, necrotizing 
fasciitis, myositis, and streptococcal toxic shock syndrome 
(strepTSS) [I]. The features of each of these entities will he 
discussed separately. 

Necrotizing Fasciitis 

Necrotizing fasciitis is a deep-seated infection of the subcu- 
taneous tissue that results in progressive destruction of fascia 
and fat but may spare the skin itself. Historically, Pfanner [2] 
is credited with the first description of what he called necro- 
tizing erysipelas. Several years later Meleney [3] described 
20 cases of hemolytic streptococcal gangrene in China, and 
he argued that this entity was different than erysipelas and 
should have a different name. These cases, as we now know 
them, were probably due to GAS, although at that time Me- 
leney only characterized the organism as hemolytic strepto- 
cocci. In Meleney's series [3], seven of 1 7 patients for whom 
blood cultures were performed had bacteremia due to hemo- 
lytic streptococci, and the only organism isolated from the 
site of infection (or reported) was hemolytic streptococcus. It 
is of interest that all age groups were affected and that the 
mortality rate was 20%. Subsequently, necrotizing fasciitis 
has become the preferred term since bacteria other than 



streptococci, such as Clostridium per/ringens. Clostridium 
septicum. and Staphylococcus aureus, can produce a similar 
pathologic process (see table I). 

Meleney [3] described streptococcal gangrene as charac- 
teristically beginning at the site of trivial or inapparent 
trauma Within 24 hours of the initial lesion — which fre- 
quently appears as only mild erythema — swelling, heat, erv- 
thema. and tenderness develop extensively and rapidly 
spread proximally and distally from the original focus. Dur- 
ing the next 24-48 hours, the erythema darkens, changing 
from red to purple and then to blue, and blisters and bullae 
form that contain clear yellow fluid. On the fourth or fifth 
day, the purple areas become frankly gangrenous. From the 
seventh to the 10th day. the line of demarcation becomes 
sharply defined, and the dead skin begins to separate at the 
margins or breaks in the center, revealing extensive necrosis 
of the subcutaneous tissue Up until this time, the patient 
continues to be febrile and becomes increasingly prostrated 
and more emaciated. In more-severe cases, the process ad- 
vances rapidly until several large areas of skin have become 
gangrenous, and the intoxication renders the patient dull, 
unresponsive, mentally cloudy, or even delirious. Subse- 
quently, the patient may develop metastatic abscesses, bron- 
chopneumonia, or lung abscess [3], 



Table 1. Characteristics of patients with necrotizing fasciitis due to GAS. 









Predisposing factors 


Occurrence 


of 










Events leading to 




Year 


No. of 


Age of patients 




infection 


shock 




Causative bacteria 




[reference) 


cases 


(y) 


Underlying disease 


(% of patients) 


(% of patients) 


{% of patients) 


Mortality rate (%) 


1924(3] 

1970(4] 


20 
NG 


NG but young, 
healthy 

NG' 


None 

Diabetes: peripheral 
Vascular disease 


Minor trauma 

Minor trauma (80); 
surgical 
procedures (20) 


Rare 

II 




Hemolvtic streptococci 

Hemolytic streptococci 
(44.5); Staphylococcus 
aureus(44.5); gram- 


20 

30 overall: 63 in 
diabetics* 


1952(7) 


22 


47 (mean) 1 


None 


Stab wounds; 
gunshot wounds; 
appendectomy; 
contusions, 
abrasions: 


43 




negative organisms 
(1 \.0%) 
Staphylococcus species 
(88); hemolytic 
streptococci and other 
organisms 


9 
20 


1971 |5) 
1982 |6] 


7 
9 


41 (mean)* 
61 (mean) 


Rheumatoid 

arthritis; diabetes 
Diabetes; cachexia. 

peripheral 

vascular disease; 

cirrhosis; 

corticosteroid 


splinters 
Orthopedic 

procedures 
Minor trauma 


57 
77 




GAS 

GAS 


57 
55 


1989(1] 


20 


20-40 


therapy 
None 


Minor trauma 


100 




GAS 


-30 



NOTE NG = not given 

* Mortality among patients >50 years of age was 67% (18 of 44 patients were >50 years of age). 

f All deaths occurred in patients >50 years of age. 

1 All patients <30 y of age had experienced stab wounds, gunshot wounds, or appendectomy. 

1 Mean age of these patients is skewed somewhat by a 2-year-old child who underwent an operation for congenital dislocation of the hip 



36 



CID 1992;14 (January) 



It should be remembered that Meleney's description of 
hemolytic streptococcal gangrene was published in 1924, 
well before the advent of antibiotics [3]. In fact, he was the 
first to advocate aggressive "bear scratch" fasciotomy and 
debridement. Using this approach as well as irrigation with 
Dakin's solution, he observed mortality rates as low as 20%. 
In contrast, data from subsequent reports written during 
1950-1980 suggest that mortality rates >50% are common 
even with antibiotic use and aggressive surgical debridement. 
Table 1 lists the comparative characteristics of patients with 
streptococcal gangrene and necrotizing fasciitis that were 
documented in different reports. 

Necrotizing fasciitis is caused by a variety of etiologic 
agents, including hemolytic streptococcus, S. aureus, and en- 
teric organisms (e.g.. Clostridium species alone or in combi- 
nation). For example, of the 44 patients in the study by Rea 
and Wyrick [4], 19 had cultures positive for S. aureus and 19 
had cultures positive for hemolytic streptococcus; 14 had 
cultures positive for both S. aureus and hemolytic streptococ- 
cus. In that study, 80% of patients had sustained minor 
trauma and 20% developed infection following surgical pro- 
cedures. In addition, most patients had either diabetes or 
peripheral vascular disease. The patients' ages were not men- 
tioned, although 1 8 of the 44 patients were >50 years of age; 
among these patients the mortality rate was 63% in spite of 
antibiotic use and surgery. In an additional study of necrotiz- 
ing fasciitis, S. aureus was isolated from 88% of patients, even 
though the mortality rate among patients was only 8.7%. It is 
of interest that all patients <30 years of age had experienced 
stab wounds, gunshot wounds, or appendectomy. 

Similarly, the study by Quintiliani and Engh [5] of over- 
whelming GAS bacteremia involved seven patients undergo- 
ing orthopedic procedures who developed severe streptococ- 
cal soft-tissue infections; overall. 57% of the patients died. 
The mean age of the patients was 41 years, although this is 
misleading since one of the patients.was only 2 years of age. 
Several patients had either peripheral vascular disease or dia- 
betes. Finally, in the study by Aitken et al. [6], the mean age 
of the patients was 6 1 years, and their infections developed 
following minor trauma. The mortality rate, in spite of antibi- 
otic use and surgery, was 55%. even though most of the pa- 
tients had diabetes, cachexia, peripheral vascular disease, or 
cirrhosis or were receiving corticosteroids. 

If one compares these reports [3-7] with descriptions of 
cases of strepTSS [ 1 ], several differences are apparent. First, 
recent cases have been reported mainly in young, healthy- 
individuals with no underlying disease who sustain some 
minor trauma to an extremity. Previous reports describe 
older patients with multiple medical problems [3-7]. Al- 
though Meleney's patients (who were in China) were young, 
healthy individuals, the mortality rate (20%) [3] among these 
patients was lower (30%-60%) [4-6] than that of recently 
described cases. In addition, the lower mortality reported by 
Meleney occurred at a time when antibiotics were not yet 
available [3]. Perhaps the higher mortality rates documented 



in subsequent reports, in spite of antibiotic use, could be 
related to the patients' underlying diseases, older age, and 
major traumatic experiences, e.g.. orthopedic procedures, 
gunshot wounds, stab wounds, and major intraabdominal 
surgery. Another reason for the increased severity of present 
cases of strepTSS in terms of shock, multiorgan failure, and 
mortality (in spite of the absence of underlying disease, 
younger age, and use of antibiotics) could be the emergence 
of increased virulence of GAS itself [11. 



Streptococcal Myositis 

Streptococcal myositis is an extremely uncommon GAS 
infection. Adams et al. [8] documented only 21 cases that 
had been reported from 1900 to 1985, and Svane [9] found 
only four cases among >20,000 autopsies. In our report of 
20 patients with invasive GAS infection [1], one had myosi- 
tis, three had myositis as well as necrotizing fasciitis, and five 
had necrotizing fasciitis alone. Recently, deep soft-tissue in- 
fections, such as necrotizing fasciitis and myositis, have also 
been described in reports from Norway [10] and Sweden 
[II]. Translocation of GAS from the pharynx to the muscle 
site must occur via hematogenous spread since penetrating 
trauma is usually not sustained. Most reported cases devel- 
oped spontaneously or were secondary to very minor blunt 
trauma or to muscle strain, and most patients had not experi- 
enced symptomatic pharyngitis or tonsillitis [1. 8-13], Se- 
vere pain may be the only presenting symptom, and the early 
physical findings may be only swelling and erythema, even 
though patients may rapidly develop muscle compartmental 
syndromes [1. 8-13]. In most cases a single muscle group 
may be involved; however, because patients are frequently 
bacteremic, multiple sites of myositis or abscess can occur [ 1 , 
8], Distinguishing streptococcal myositis from spontaneous 
gas gangrene due to C. perfringens or C. seplicum [ 1 4] may be 
difficult, although the presence of crepitus or gas in the tissue 
would favor clostridial infection [ 1 2]. Necrotizing fasciitis is 
easily distinguished from myositis anatomically by means of 
surgical exploration or incisional biopsy. Clinical features of 
both conditions overlap, and patients may have symptoms of 
both necrotizing fasciitis and myositis [I, 8]. In published 
reports, the case-fatality rate of necrotizing fasciitis is be- 
tween 20% and 50%. whereas that of GAS myositis is be- 
tween 80% and 1 00% [ 1 , 8- 1 3]. Aggressive surgical debride- 
ment is of extreme importance because of the poor efficacy 
of penicillin described in human cases [ 1 . 8, 9, 1 2, 1 3] as well 
as in experimental streptococcal models of myositis [15, 16] 
(see section on antibiotic efficacy). 



Malignant Scarlet Fever 

Osier [17] described three types of malignant scarlet fever; 
anginose, hemorrhagic, and atactic. The anginose form was 
basically membranous exudation of the throat, with necrosis 



37 



(ID 1992:14 (January) 



SlrcpUKOccal Toxic Shock Syndrome 



of the soft tissues of the pharynx and soft palate. Exudation 
could continue into the trachea, bronchi, eustachian tubes, 
and middle ear. He noted that in some cases necrosis and 
sloughing of tissue about the tonsils were so severe that ne- 
crosis of the carotid artery occurred with fatal hemorrhage. 
Osier did not specify the time course of this form although 
Holt [18] subsequently staled that "the duration of the 
symptoms in fatal cases is from six to fourteen days." In the 
second variety, hemorrhages into the skin, hematuria, and 
epistaxis occurred. "Enfeebled children" were the group 
most commonly associated with this form, and death, when 
it occurred, was usually within the first 2-3 days of illness 
[17, 18]. The third form described by Osier was atactic scar- 
let fever, in which children presented with the characteristics 
of acute intoxication The disease began with great sever- 
ity, causing high fever, extreme restlessness, headache, and 
delirium Patients' temperatures were frequently between 
I07°F and 108°F. and Osier stated that ". . . rare cases 
have been observed in which the thermometer has registered 
even higher." Convulsions, coma, severe dyspnea, and rapid 
feeble pulses were the most common presenting signs. Death 
occurred within 24-48 hours [17] 

Weaver [ 1 9] combined all these definitions into the follow- 
ing groups: mild, moderate, toxic, and septic. Thus, benign 
scarlet fever could be either mild or moderate, and the fatal 
or malignant form of scarlet fever could be either septic or 
toxic. The toxic cases invariably began with a severe sore 



throat, marked fever ( 107°F-I08°F). delirium, skin rash, 
and painful cervical lymph nodes [ 1 7]. In severe toxic cases 
(similar to the malignant scarlet fever described by Osier (17] 
and Rotch [20]). fulminating fevers to 107°F-108°F. pulse 
rates of 130-160. severe headache, delirium, convulsions, 
little if any skin rash, and death within 24 hours were the 
usual findings. These cases occurred before the advent of 
antibiotics, antipyretics, and anticonvulsants The septic 
cases were similar to those described by Wood |2 1] as scarla- 
tina anginosa and by Osier [ 1 7] as the anginose form of scar- 
let fever In septic cases, local invasion of the soft tissues of 
the neck was the prominent feature along with subsequent 
upper-airway obstruction, otitis media with perforation, pro- 
fuse mucopurulent drainage from the nose, bronchopneumo- 
nia, and death The clinical characteristics of the various 
types of scarlet fever are listed in table 2. Note that necrotiz- 
ing fasciitis and myositis were not described in association 
with scarlet fever, the only exception being locally invasive 
infection of the soft tissues of the neck as a complication of 
pharyngitis. 

Bacteremia 

Bacteremia associated with GAS pharyngitis is uncom- 
mon, and even during scarlet fever it occurs in only 0.3% of 
febrile patients (22). In the past, streptococcal bacteremia 
occurred most commonly in very young individuals and in 



Table 2. Comparison of the clinical characteristics of severe GAS infections. 



Type of GAS 

infection 


Other names 


Clinical presentation 


Complications 


Years of age 
(% of patients) 


Predisposing factors 


Scarlet fever 


Benign scarlet fever; 


Fever; pharyngitis; scarlatina 


Late rheumatic fever or 


<I0(90) 


None . 




moderate scarlet 


rash: desquamation 


glomerulonephritis; 








fever, scarlet fever 




death rare 








simplex 










Septic scarlet 


Scarlatina anginosa; 


Scarlet fever with local 


Otitis sinusitis; 


<!0(90) 


Preantibiotic era 


fever 


malignant sore 
throat; garrotillo: 
morbus 
strangulalons; 
ulcerative angina 


suppuration and invasion 
of deeper structures 


meningitis; airway 
obstruction, 
bacteremia; 
cavernous vein 
thrombosis 






Toxic scarlet 


Malignant scarlet 


Scarlet fever with 


Convulsions; coma; 


<I0(<?0) 


Preanlibiolic era. lack of 


fever 


fever; atactic 


hyperpyrexia and either 


sudden death 




anticonvulsants. 




scarlet fever 


neurological 
complications or 
cardiovascular collapse: 
rash evanescent or absent 






antipyretics, and iv fluids 


Bacteremia 




Fever; bacteremia, shock 


D1C; shock; death 


«*1 and >75 


Diabetes, burns; newborns; 


Myositis: 


Necrotizing 


Fever; bullous skin lesions; 


Renal failure; shock: 




institutionalized elderly 
-Diabetes, severe trauma 


necrotizing 

fasciitis 


erysipelas; 
streptococcal 


renal failure 


death 




surgery 


StrepTSS 


gangrene 


Fever, shock; rash or bullous 


ARDS. renal failure; 


Any age, but the 


Minor trauma, surgery; 






skin lesion; early renal 


loss of limb: death 


majonty are 


viral illness; nonsteroidal 






failure, thrombocytopenia 




20-60 ( ■ ■ • ) 


therapv (?) 



NOTE. Ellipses = data not available; DIC = disseminated intravascular coagulation; ARDS = acute repiratory distress syndrome. 



38 



Stevens 



CID 1992:14 (January) 



the elderly [23-32]. Among children, predisposing factors 
other than scarlet fever include burns, varicella, malignant 
neoplasm, immunosuppression, and age of <2 years [23- 
32], In patients with scarlet fever, the pharynx is the most 
common source of GAS, and frequently such patients have 
complications that include extension of infection into the 
sinuses, peritonsillar tissue, or mastoids (septic scarlet fever 
or the anginose form of scarlet fever) [ 1 9, 20]. The integu- 
ment is the most common source of GAS in patients with 
burns and varicella; in the latter patients, bacteremia occurs 
later as the vesicles are crusting and drying up [22]. The least 
common source of bacteremia in children is the lower respira- 
tory tract, and bacteremia from this source may be associated 
with prior viral infections. For example, secondary bacterial 
pneumonia has occurred in ~}.0% of patients with varicella 
and invariably occurs in children <7 years of age [22]; in 
adults GAS pneumonia complicating varicella is rarely 
found, although primary varicella pneumonia occurs com- 
monly. Among the children with varicella studied by Bul- 
lowa and Wischik [22], GAS bacteremia occurred in ~0.5% 
of patients. 

In elderly patients the source of GAS infection is invari- 
ably the skin and is associated with cellulitis or erysipelas 
[23-32]. GAS sepsis in the elderly has also been associated 



with diabetes, peripheral vascular disease, malignancy, and 
use of corticosteroids [23-32]. Epidemics of GAS bacteremia 
associated with soft-tissue infection among the elderly have 
been reported in the past and more recently by the Centers 
for Disease Control (Atlanta) [33]. In most reports (see table 
3), the mean age of patients with bacteremia was between 
50-60 years. Not surprisingly, mortality rates of 35%-80% 
have been described among this patient population [23-32]. 
In the past, the occurrence of GAS bacteremia was rare in 
individuals 14-40 years of age [23-32]. In the distant past, 
puerperal sepsis accounted for most of the cases of bacter- 
emia in this age group [23]. Today such cases still occur but 
are rare, largely because of the epidemiological and "infec- 
tion control" policies put forth by Semmelweiss in Europe 
and Holmes in the United States. Intravenous drug abuse has 
emerged as a leading cause of GAS bacteremia in this age 
group in the modern era (table 3) [29, 32]. In contrast, in our 
study of invasive GAS infection in the Rocky Mountain area, 
only \Q% of patients had a history of intravenous drug abuse, 
and the greatest prevalence of GAS bacteremia occurred in 
previously healthy adolescents and young adults. This find- 
ing has also been substantiated by pediatricians [33] and by 
public health officials in England [34], Norway [10], the 
United States [35], and Sweden [11], Martin and Hoiby [10] 



Table 3. The clinical and epidemiological features of GAS bacteremia during 1937-1989 











Presence of underlying 


No. of 






Year 


No. of 


Years of age 


Site or type of infection 


disease or condition 


patients with 


Mortality 


Causative 


[reference] 


patients 


{% of patients) 


[% of patients) 


(% of patients) 


shock 


rate (%) 


organism 


1937 [23] 


69 


0-20 


Throat, ear. mastoid 







55 


GAS 




41 


20-40 


Puerperal sepsis 







56 


GAS 




61 


>40 


Cellulitis, erysipelas 







80* 




1969 |24| 


19 


>50 


Soft tissue (>50) 


74 




57 


GAS 


1971 [6] 


7 


41 (mean)' 


Soft tissue (100) 


100 








1988 [25] 


40 


53 (mean) 


Soft tissue (58). respiratory 
tract (20) 


52' 


39(RFm 1 1 
of 40) 


35 


GAS 


1970(26] 


49 


54 (mean) 


Soft tissue (33); respiratory 
tract (33): unknown (33) 


100' 


18 


45" 


GAS 


1973 [27| 


44 


>60 


Soft tissue (60) 


55 


NS 


7 


GAS 


1981 |28] 


58 


59 (mean) 


Soft tissue (72) 


50 


NS 


22 


GAS 


1985 [29] 


40 


32 6 (mean) 


Soft tissue (68); 
endocarditis (27) 


100' 


20 


5 


GAS 


1988 [30] 


67 


>50(53) 

20-40(31) 

<20(I6) 


Soft tissue (~60) 
No site identified (37) 


-30 




48 


GAS" 


1989 |31] 


20 


<ll(35) 
>55(55) 
19-22(10) 


Pneumonia (30) 


64 




35 


GAS 


1991 [32] 


58 


<20(9) 

20-40(34)* 

>40(57) 


Soft tissue (72) 


28 


NS 




GAS 



NOTE Ellipses = data not given; RF = renal failure; NS = no shock. 

" All patients underwent orthopedic procedures. 

1 Forty percent of patients had nonfatal systemic disease, and 1 5% had fatal underlying disease. 

1 All patients had major underlying diseases. 

I All patients were intravenous drug abusers. 

II Forty-five of 67 cases were due to M type 1 . 3. 4. or 12 These strains accounted for 22 to 28 deaths. 

* Mean age of intravenous drug abusers was 33 years. Among all other patients, the mean age was 55 years 



39 



C1D 1992:14 (January) 



Streptococcal Toxic Shock Syndrome 



have comprehensively demonstrated that the prevalence of 
GAS bacteremia in Norway has increased in all age groups, 
but the greatest increase (600%-800%) has been in adoles- 
cents and young adults (10]. Thus, the demographics of pa- 
tients with invasive streptococcal infections have changed 
dramatically in the past 4-6 years [1, 10, 11, 33-35]. 

Streptococcal Toxic Shock Syndrome 

Recently, cases of severe invasive GAS infections have 
been reported with increasing frequency, predominantly in 
North America and Europe [1, 10, II, 33-40]. Such cases 
are particularly dramatic since in previous years the fre- 
quency, severity, and complications T>f GAS infections had 
decreased. In the late 1980s, reports of invasive GAS infec- 
tions associated with bacteremia, deep soft-tissue infection, 
shock, and multiorgan failure (see case definition in table I ) 
began to appear Since 1985 >30 reports or abstracts have 
documented the appearance of aggressive streptococcal in- 
fections associated with bacteremia and shock in all age 
groups [1, 10, 11, 33-40]. Patients between the ages of 20 
and 50 years are most commonly afflicted, and such patients 
frequently do not have predisposing underlying diseases 
[23-32]. This is in sharp contrast to the previous reports of 
GAS bacteremia, in which patients were either <10 years 
of age or >60 years of age and in which most patients also 
had underlying diseases such as cancer, renal failure, leuke- 
mia, or severe burns or were receiving therapy with corticoste- 
roids or other immunosuppressive drugs [23-32]. Although 
younger, healthier individuals are most commonly infected, 
bacteremia, severe soft-tissue infection, shock, acute respira- 
tory distress syndrome (ARDS). and renal failure are com- 
mon complications of severe invasive GAS infection, and 
reports indicate that overall 30% of patients with this infec- 
tion have died in spite of aggressive modern treatments. 

Acquisition of GAS 

The portal of entry of streptococci is the skin or mucous 
membranes, although a definite portal of entry cannot be 
ascertained in 45% of cases [3]. Rarely, patients with, symp- 
tomatic pharyngitis develop strepTSS as a complication. Sim- 
ilarly, most women who develop strepTSS have no history of 
vaginal infection. Thus, currently the mucous membranes 
serve more as a source of bacteria than as a site of symptom- 
atic local infection. Suction lipectomy, hysterectomy, vagi- 
nal delivery, bunionectomy, and bone pinning have also pro- 
vided a portal of entry in many cases (author's unpublished 
observations). Rarely, the organism has been acquired 
through person-to-person contact. For example, a paramedic 
developed strepTSS after resuscitating a young child dying of 
strepTSS [41]. In one instance, two patients who had under- 
gone suction lipectomy performed by the same surgeon on 
the same day developed strepTSS within 24-48 hours of the 
procedure, and one patient died (author's unpublished ob- 



servations). For the most part, these infections have occurred 
sporadically and have not been associated with clusters of 
cases or minor epidemics Most commonly, the streptococcal 
infection begins at a site of minor local trauma that fre- 
quently does not result in a break in the skin [ 1 ]. For exam- 
ple, numerous cases have developed within 24-72 hours of 
minor nonpenetrating trauma that results in hematoma or a 
deep bruise (e.g.. to the calf), and some cases have even 
developed following muscle strain [1]. Viral infections such 
as varicella and influenza have provided a portal of entry in 
other cases [I]. Primary varicella in children and young 
adults is also associated with strepTSS, and the portal of 
entry of streptococci is usually the varicella vesicle, although 
in children with GAS pneumonia it is likely the oropharynx. 
In our study [ 1 ), a virus-like prodrome suggestive of influ- 
enza preceded the onset of strepTSS by several days in 
adults Although influenza has only rarely been docu- 
mented, many patients had received therapy with amanta- 
dine hydrochloride during this early phase of the illness. It is 
of interest that such patients rarely develop GAS pneumo- 
nia, and most of these patients present with deep-seated soft- 
tissue infection instead. In some cases the use of nonsteroidal 
antiinflammatory agents may have either masked the present- 
ing symptoms or predisposed the patient to more-severe 
streptococcal infections and shock. Among the patients who 
received such treatment, the initial clinical diagnosis was 
frequently deep-vein thrombophlebitis. In such cases the 
diagnosis of deep soft-tissue infection was frequently delayed 
because of the lengthy process of performing Doppler exami- 
nations and obtaining venograms. Thus, antimicrobial ther- 
apy was delayed and frequently not initiated until renal fail- 
ure. ARDS, or shock became manifest. 



Symptoms of StrepTSS 

Pain, the most common initial symptom of strepTSS, oc- 
curred in 85% of cases in our study [1] and was abrupt in 
onset and very severe. In some cases pain was not associated 
with tenderness or physical findings. Frequently, the pa- 
tient's pain was so severe that parenteral narcotic analgesics 
were prescribed. The pain most commonly involved an ex- 
tremity but also mimicked symptoms and pain associated 
with peritonitis, pelvic inflammatory disease, acute myocar- 
dial infarction, or pericarditis [1]. Before the onset of pain, 
20% of patients had an influenza-like syndrome character- 
ized by fever, chills, myalgia, and diarrhea. 



Physical Findings of StrepTSS 

In our study [I], fever was the most common presenting 
sign, although on admission to the hospital 10% of patients 
presented with profound hypothermia and shock Confusion 
was noted in 55% of patients, and in some patients it pro- 
gressed to coma or combativeness. On admission 80% of pa- 



40 



Stevens 



CID 1 992:14 (January) 



tients had tachycardia and 55% had systolic blood pressure of 
<1 10 mm Hg (table 4). Although 45% of patients had nor- 
mal blood pressure (systolic pressure, > 1 10 mm Hg) on ad- 
mission, all of these patients developed hypotension within 
the subsequent 4 hours. Eighty percent of patients developed 
evidence of soft-tissue infection, and localized swelling and 
erythema were the most common findings at the time of ad- 
mission. An ominous sign was the progression of soft-tissue 
swelling to formation of vesicles and then bullae, which took 
on a violaceous or bluish coloration. Soft-tissue infection 
evolved to necrotizing fasciitis or myositis in 70% of cases 
and in these cases surgical debridement, fasciotomy, or am- 
putation was required. For the 20%. of patients for whom 
there was no evidence of soft-tissue infection, a variety of 
clinical presentations Were observed; these included en- 
dophthalmitis, myositis, perihepatitis, peritonitis, myocardi- 
tis, and overwhelming sepsis. 

Laboratory Test Results for Patients with Strep I s.S 

Evidence of renal involvement was apparent at the time of 
admission by the pressence of hemoglobinuria and serum 
creatinine levels that were >2. 5-fold the normal value (table 
4). By 48 hours (see table 4), the measured creatinine levels 
had increased steadily to 3.5-fold the normal value. For 
every patient who presented with an elevated serum creati- 
nine level, the results of testing the urine for hemoglobin 
(Hemastix) were also positive. The serum albumin level was 
3.3 g/dL (mean value) on admission and dropped to 2.3 
g/dL by 48 hours. Hypoalbuminemia was associated with 
hypocalcemia on admission and throughout the hospital 
course. The cause of hypocalcemia was unknown but was in 
part related to concomitant hypoalbuminemia; however, 
since the ionized calcium level was also low [ I ], other mecha- 
nisms must have been operative. The serum creatine kinase 
level was useful in detecting the presence of deeper soft-tis- 
sue infections, and when the level was elevated or rising, 
there was a good correlation with necrotizing fasciitis or 
myositis [1]. 

The initial laboratory studies demonstrated mild leukocy- 
tosis (mean leukocyte count, 12,000 cells/mm 3 ) and a pro- 
found left shift (see table 4). The mean percentage of imma- 
ture neutrophils (including band forms, metamyelocytes, 
and myelocytes) was 43%. The mean platelet count was nor- 
mal on admission but dropped to 1 29,000 cells/mm 3 within 
48 hours [ 1 ]. Initially, the mean hematocrit values were nor- 
mal for the altitude at which they were measured but 
dropped dramatically by 48 hours (i.e., from 43% to 29%). 

Bacteriologic Cultures 

Cultures of blood were positive for GAS in 60% of cases, 
and those of specimens from the site of infection were posi- 
tive for GAS in 95% of cases [1], The types of infection in- 
cluded peritonitis, necrotizing fasciitis, myositis, cellulitis, 
empyema, endophthalmitis, suppurative thrombophlebitis. 



Table 4. Clinical summary of StrepTSS. 



Category, characteristic 




Value 


Physical findings {% of patients w- 


ith finding) 




Fever >38°C 




70 


Confusion 




55 


Heart rate >100 




80 


Hypotension 




100 


Cutaneous signs 






Swelling 




10 


Swelling and erythema 




65 


Bullae 




5 


Desquamation (late) 




20 


Results of laboratory tests' 






White blood cells (per mm 3 ) 




11.765/- ■ • 


Immature granulocvtes (%) 




43/--. 


Platelets (per mm J ) 




216.000/129,000 


Creatinine (mg/dL) 




2.5/3.4 


Calcium (mg/dL) 




8.1/6.6 


Albumin (g/dL) 




3.3/2.3 


Creatine phosphokinase (IU) 




3.000/100.000 


Complication (% of patients with 


complication) 




Shock 




95 


Acute respiratory distress syndrome 


55 


Renal impairment 




80 


Irreversible 




10 


Reversible 




70 


Sepsis 




60 


Death 




30 



NOTE. Early symptoms of StrepTSS are vague and involve a virus-like 
prodrome; pain and redness of an extremity, which are usually severe; and 
confusion. 

• Mean values on admission/at 48 hours. 



meningitis, and infections of a bone or joint or the myome- 
trium 



Clinical Course 

Shock was apparent at the time of admission or within 4-8 
hours in virtually all patients. In 10% of patients, the systolic 
blood pressure returned to normal 4-8 hours after adminis- 
tration of antibiotics, albumin, and electrolyte solutions con- 
taining salts or dopamine (see table 4). In other patients 
shock persisted. Similarly, renal dysfunction progressed or 
persisted in all patients for 48-72 hours in spite of treatment, 
and several palients required dialysis for 10-20 days [1]. In 
all patients who survived, serum creatinine levels returned to 
normal within 4 to 6 weeks. Renal dysfunction preceded 
shock in many patients and was apparent early in the course 
of shock in all other patients. ARDS occurred in 55% of pa- 
tients and generally developed after the onset of hypotension 
[1], The severity of ARDS was such that supplemental oxy- 
gen, intubation, and mechanical ventilation were necessary 
for 90% of patients who developed this syndrome [1]. Sixty 
percent of patients were bacteremic. and overall 30% of pa- 
tients died [ 1 ]. Morbidity was also high; 1 3 patients under- 
went major surgical procedures, which included fasciotomy. 



41 



CTD 1 992; 1 4 (January! 



Streptococcal Toxic Shock Syndrome 



surgical debridement, exploratory laparotomy, intraocular as- 
piration, amputation, and hysterectomy [ I ]. 

Characteristics of Clinical Isolates of GAS 

Our study [ 1 ] demonstrated that M types 1 and 3 of GAS 
were the most common isolates from patients with shock and 
multiorgan failure Studies in conjunction with the World 
Health Organization Streptococcal Reference Laboratory 
[42], the Centers for Disease Control [35]. the CanaUian 
Centers for Disease Control [43], and the British Reference 
Laboratories in Colindale [34] and reports from Sweden 
[11], Norway [10], and the German Democratic RepubVic 
[44] also have documented that M types 1 and 3 as well as 
types 12 and 28 are most frequently isolated from such pa- 
tients. Our study [ 1 ]. a more recent report [42] of a larger 
series of patients with invasive streptococcal infections, and 
studies involving different kinds of streptococcal infection 
have demonstrated that pyrogenic exotoxin A and/or exo- 
toxin B is found in the majority of patients with severe infec- 
tion. Outbreaks of GAS infection in Norway [10]. Sweden 
[II]. and Great Britain [34] have been primarily due to M 
type I strains of GAS that produce pyrogenic exotoxin B. 

Current Hypotheses Regarding Mechanisms of Shock 
and Tissue Destruction Caused by Virulent GAS 

Some infections associated with strains of GAS that pro- 
duce streptococcal pyrogenic exotoxin A (SPEA) are charac- 
teristically associated with shock. ARDS. renal failure, and 
tissue destruction [ 1 ]. Pyrogenic exotoxins induce fever in 
humans and animals and also participate in shock by lower- 
ing the threshold for exogenous endotoxin [45-47]. SPEA 
and streptococcal pyrogenic exotoxin B (SPEB) induce hu- 
man mononuclear cells to synthesize not only tumor necro- 
sis factor-a (TNF-a) [48. 49] but also interleukin-10 [49] 
and interleukin-6 [49], thereby suggesting that TNF-a could 
mediate fever, shock, and tissue injury observed in patients 
withstrepTSS[l]. 

M protein contributes to invasiveness through its ability to 
impede phagocytosis of streptococci by human polymor- 
phonuclear leukocytes [50]. Conversely, type-specific anti- 
body to M protein enhances phagocytosis [50]. Following 
infection with a particular M type of GAS. specific antibody 
confers resistance to challenge with viable GAS of that M 
type [50]. 

Could strepTSS be related to the ability of SPEA or M 
protein type I or 3 to act as "super antigens" [51]? There are 
data to suggest that SPEA and a number of staphylococcal 
toxins (toxic shock syndrome toxin 1 and staphylococcal en- 
terotoxins A, B, and C) can stimulate T cell responses 
through their ability to bind to both the class II major histo- 
compatibility complex of antigen-presenting cells and the V„ 
region oftheTcell receptor [51]. Thus, direct stimulation of 
helper T cells can occur in the absence of classic antigen 



processing. The net effect would be to induce T cell stimula- 
tion with production of cytokines that are capable of mediat- 
ing shock and tissue injury Recently. Kotb et al. [52] have 
shown that a digest of M protein type 6 can also stimulate T 
cell responses by this mechanism. 

Finally. Cleary et al. [53] have provided evidence that sev- 
eral virulence factors of GAS (M protein. C, peptidase, etc.) 
may be located within a specific locus on the genome and 
that their expression is under the control of an upstream 
DNA sequence or regulon. Factors that affect the regulon 
could markedly increase or decrease the expression of viru- 
lence factors of GAS. 

The interaction between these microbial virulence factors 
and an immune or nonimmune host determines the epidemi- 
ological factors, clinical syndrome, and outcome of infec- 
tion. Figure 1 illustrates the potential outcomes following 
the contact of immune and nonimmune individuals with 
SPEA-producing strains of M type 1 GAS. This model ex- 
plains ( 1 ) why epidemics have not materialized and (2) why 
different clinical manifestations can occur in the same com- 
munity. We conclude that M types I and 3 likely facilitate 
invasiveness of the organisms on the basis of the antiphago- 
cytic properties of M proteins of streptococcal groups classi- 
fied by Lancefield. Although the antiphagocytic properties of 
these specific M types (type 1 and type 3) have not been 
investigated, such studies would be of major importance. 
The initial encounter between a virulent M type 1 or 3 strain 
and the host will not result in infection if the host has circu- 
lating or mucosal antibody to the specific M type. A less 
invasive strain (such as M type 4) that produces pyrogenic 
exotoxin A, B. or C could cause local pharyngitis and subse- 
quent scarlet fever if the host did not have antibody to either 
M protein type 4 or pyrogenic toxin. 



M-1* SPEA* 


Strain 




<-^> 






Host 






+ anti-M-1 ^^^" \- 


anti-M- 


i 


Abortive *r* .Infection 


(local) 


infection anti-SPEA(-) s' 


I 

Jacterei 




Scarlet Fever * 1 


nia 


(Benign) 


/\ 




anti-SPEA + 


/ N 


anti-SPEA (-1 


Shock (rare) 


r 


Toxic Shock Syndrome 


DIC 




Shock (common) 


Death 




Multiorgan failure 


• Newborns 




Necrotizing fasciitis 


• Elderly 




Death 


• Debilitated 




• Children 


• Compromised 


• Adults 



Figure 1. Pathogenesis of scarlet fever, bacteremia, and toxic 
shock syndrome. M-1* SPEA* = a GAS strain that contains M 
protein type 1 and pyrogenic exotoxin A (SPEA); 4-anti-M-l = the 
presence of antibody to M protein type I ; -anti-M- 1 = the absence 
of antibody to M protein type 1; anti-SPEA + = antibody to SPEA; 
and DIC = disseminated intravascular coagulation. 



42 



10 



CID 1 992; 1 4 (January) 



We hypothesize that once invasion of mucosal or epithe- 
lial barriers by GAS of M type 1 or 3 has occurred in a host 
without specific antibody to M protein, tissue invasion and 
possibly bacteremia will occur. If the invading strains also 
produce pyrogenic exotoxins (A or B but probably not C), 
then their expression results in shock, multiorgan failure, 
and tissue destruction. The latter scenario would be expected 
in patients who lack specific antibody to the pyrogenic exo- 
toxin produced by the invading strain. That this hypothesis is 
correct is supported by the recent finding of Holm and 
Bergholm [11]; these researchers found that among patients 
in Sweden who had invasive streptococcal infection caused 
by M type 1 strains producing SPEB, only those who lacked 
antibody to pyrogenic exotoxin B developed shock. Con- 
versely, we hypothesize that in patients who have preexisting 
antibody to one or all pyrogenic exotoxins, GAS strains 
might cause bacteremia alone without soft-tissue infection, 
shock, or multiorgan failure. In this case, the outcome would 
be dependent upon underlying disease, the patient's age, and 
iatrogenic immunosuppression. 



localized infection; stage II, circulating toxins; stage III, cir- 
culating cytokines; and stage IV, shock and multiorgan fail- 
ure. The therapeutic strategy will be ( 1 ) to destroy the organ- 
ism at stage I with antimicrobial agents, preferably ones that 
suppress toxin production; (2) to neutralize the circulating 
toxin at stage II with monoclonal antibodies to specific tox- 
ins or possibly gamma globulin; and (3) to neutralize the 
circulating cytokines at stage III. Thus, new antibiotics must 
be studied in severe types of human infection, neutralizing 
monoclonal antitoxin antibodies must be developed, and 
clinical investigations involving antibodies to as well as re- 
ceptor antagonists for TNF-cr and interleukin-1 should be 
initiated. 

Editor's note. The author is interested in receiving strains 
of GAS isolated from patients with invasive streptococcal 
disease and also in obtaining tissue specimens or serum sam- 
ples for measurement of cytokine levels. Please call (208) 
389-7964 for information and send specimens to the follow- 
ing address: Infectious Diseases (T-109), Veterans Affairs 
Medical Center, 500 West Fort Street, Boise, Idaho 83702. 



Current and Future Directions in Therapy for Severe 
GAS Infections 

Penicillin, erythromycin, and clindamycin are the drugs of 
choice for the treatment of GAS infections. Yet for patients 
with severe infections (such as necrotizing fasciitis or myosi- 
tis) in whom large numbers of streptococci are found, peni- 
cillin's remarkable efficacy is diminished. Eagle's study [15] 
and our study [16] suggest that the failure of penicillin in this 
setting is due to the slower growth rate of streptococci at 
large inoculum sizes. Clinically such numbers of streptococci 
are probably only encountered in overwhelming sepsis, nec- 
rotizing fasciitis, or myositis. Other antibiotics that are more 
effective than penicillin in experimental models of myositis 
include, in decreasing order of efficacy, clindamycin, erythro- 
mycin, and ceftriaxone [16, 54]. The reasons that these 
agents are more effective have not been established but may 
be due in part to the suppression of M protein synthesis or 
toxin production by protein synthesis inhibitors such as clin- 
damycin and erythromycin [55], In the United States erythro- 
mycin resistance is low (<4.0%), although in Japan it 
reached 72% in 1975. The reason for ceftriaxone's modestly 
greater efficacy in this setting is not known but could be due 
to the greater affinity of ceftriaxone for streptococcal penicil- 
lin-binding proteins. 

In situations where infection is well established, prompt 
surgical drainage, debridement, fasciotomy, or amputation 
may be necessary. If sufficient quantities of toxin have been 
produced and absorbed to induce shock-producing quanti- 
ties of cytokines, the mortality is high even in the younger, 
healthier group of patients who seem to be most susceptible. 
Thus, early recognition of infection and prompt antibiotic 
therapy are mandatory. Future strategies will be directed to 
the diagnosis of the specific stage of strepTSS, i.e., stage 1. 



Acknowledgments 

The author thanks Kelly Thompson for his word processing 
skill and Amy Bryant and Sean Hackett for their dedicated re- 
search efforts. 

References 

I. Stevens DL. Tanner MH. Winship J. el al. Severe group A streptococ- 
cal infections associated with a toxic shock-like syndrome and scar- 
lel fever toxin A N Engl J Med 1989;321:1-6. 

2 Pfanner W Zur Kenntnis und Behandlung des nekrotisierenden Erysi- 
pels. Deutsche Ztschr Chir 1918; 144: 108. 

3. Meleney FL. Hemolytic streptococcus gangrene. Arch Surg 1924; 
9:317-64 

4 Rea. WJ. Wynck WJ Jr. Necrotizing fasciitis. Ann Surg 1970:1 72:957- 
64. 

5. Quintihani R. Engh GA Overwhelming sepsis associated with group A 

beta hemolytic streptococci J Bone Joint Surg [Am] 1971:53:1391- 
9 

6. Aitken DR. Macketl MCT. Smith LL The changing pattern of hemo- 

lytic streptococcal gangrene Arch Surg 1982;! 17:561-7. 
7 Wilson B. Necrotizing fasciitis Am Surg 1952:18:416-31 

8. Adams EM. Gudmundsson S. Yocum DE. Haselby RC. Craig WA. 

Sundstrom WR Streptococcal myositis. Arch Intern Med 1985; 
145:1020-3. 

9. Svane S. Peracute spontaneous streptococcal myositis: a report on 2 

fatal cases with review of literature. ActaChirScand 1971,137:155- 

63. 
10. Martin PR. Hoiby EA. Streptococcal serogroup A epidemic in Norway 

1987-1988 . Scand J Infect Dis 1990;22:421-9 
II Holm SE. Bergholm AM Pathogenic aspects of an outbreak of serious 

streptococcal infections in Sweden 1988-89 [abstract no LI ]. In: XI 

Lanceheld International Symposium on Streptococcal Diseases 

(Siena. Italy) 1990 

12. Yoder EL. Mendez J. KJiatib R. Spontaneous gangrenous myositis in- 

duced by Streptococcus pyogenes: case report and review of the litera- 
ture. Rev Infect Dis 1987;9:382-5. 

13. Nather A. Wong FYH. Balasubramaniam P. Pang M Streptococcal 

necrotizing myositis: a rare entity A report of two cases. Clin Orthop 
1987:215:206-11. 



43 



CID 1992:14 (January) 



Streptococcal Toxic Shock Syndrome 



M Stevens DL. Musher DM. Watson DA. el al Spontaneous, nontrau- 
matic gangrene due to Clostridium septicum. Rev Infect Dis 
1990;12:286-96. 

15 Eagle H. Experimental approach to the problem of treatment failure 
with penicillin I Group A streptococcal infection in mice Am J 
Med 1952;13:389-99. 

16. Stevens DL, Gibbons AE. Bergstrom R. Winn V The Eagle effect 
revisited: efficacy of clindamycin, erythromycin, and penicillin in the 
treatment of streptococcal myositis. J Infect Dis 1988;158:23-8. 

17 Osier W The principles and practice of medicine 2nd ed New York: 

Appleton. 1895:71-80. 

1 8 Holt LE. The diseases of infancy and childhood New York: Appleton. 

1898888-910. 

1 9. Weaver GH. Scarlet fever. In: Abt IA. ed. Pediatrics Philadelphia: WB 

Saunders. 1925:298-362 

20. Rotch TM. Pediatrics: the hygienic and medical treatment of children 

Philadelphia: JB Lippincott. 1896 532-72. 
2 1 Wood GB A treatise on the practice of medicine. 5th ed. Vol I , Phila- 
delphia: JB Lippincott. 1858:427-41. 

22. Bullowa JGM. Wischik S Complications of varicella 1 Their occur- 

rence among 2.534 patients. Am J Dis Child 1935.19 923-6. 

23. KeeferCS. Ingelfinger FJ. Spmk WW Significance of hemolytic strep- 

tococcic bacteremia: a study of two hundred and forty-six patients 
Arch Intern Med 1937;60:1084-97. 

24 Duma RJ. Weinberg AN. Medrek TF. Kunz U. A bactenologic and 
clinical study of streptococcal bacteremia In Streptococcal Infec- 
tions. 48th ed. Williams & Wilkms. 1969 87- 1 27. 

25. Ispahani P. Donald FE. Avelme AJD Streptococcus pyogenes bacter- 
emia: an old enemy subdued, but not defeated J Infect 1988; 16:37- 
46. 

26 Henkel JS. Armstrong D, Blevins A. Moody MD. Group A tf-hemolylic 

streptococcus bacteremia in a cancer hospital JAMA 1970; 
211:983-6. 

27 Hable KA. Horslmeier C. Wold AD. Washington JA II. Group A 0-he- 

molylic sireptococcemia: bactenologic and clinical study of 44 cases 
Mayo Clin Proc 1973;48:336-9 

28 Trence DL. Khan MY. Gerding DN Bela-hemolytic streptococcal bac- 

teremia in adults association with cold weather in Minnesota Minn 
Med 1981:64.675-9. 

29 Barg NL. Kish MA. Kauffman CA. Supena RB. Group A streptococcal 

bacteremia in intravenous drug abusers Am J Med 1985;78:569-74. 

30 Francis J. Warren RE. Streptococcus pyogenes bacteraemia in Cam- 

bridge— a review of 67 episodes. Q J Med 1988;68:603-13 

31 Bamham M Invasive streptococcal infections in the era before the ac- 

quired immune deficiency syndrome: a 10 years' compilation of pa- 
tients with streptococcal bacteraemia in North Yorkshire. J Infect 
1989:18:231-48. 

32. Braunstein H Characteristics of group A streptococcal bacteremia in 

patients at the San Bernardino County Medical Center Rev Infect 
Dis 1991;13:8-11 

33. Wheeler MC. Roe MH. Kaplan EL, Schlievert PM. Todd JK. Outbreak 

of group A streptococcus septicemia in children: clinical, epidemio- 
logic, and microbiological correlates. JAMA 1991;266:533-7. 

34. Gaworzewska E. Colman G. Changes in the pattern of infection caused 

by Streptococcus pyogenes. Epidemiol Infect 1988;100:257-69. 

35. Schwartz B. Facklam RR. Bneman RF Changing epidemiology of 

group A streptococcal infection in the USA. Lancet 1990:336:1 167- 
71. 

36. Bartter T. Dascal A. Carroll K. Curley FJ. "Toxic strep syndrome": a 

manifestation of group A streptococcal infection. Arch Intern Med 
1988;148:1421-4. 
37 Hnbalova V Streptococcus pyogenes and the toxic shock syndrome [let- 
ter], Ann Intern Med 1988; 108:772. 



38. Greenberg RN. Willoughby BG, Kennedy DJ, Otto TJ. McMillian R. 

Bloomster TG. Hypocalcemia and "toxic" syndrome associated with 
streptococcal fasciitis. South Med J 1983;76:916-8. 

39. Jackson MA. Olson LC. Buny VF Pediatric group A streptococcal 

(GAS) disease with multi-organ dysfunction [abstract no 652]. In: 
Program and abstracts of the 30th Intersoencc Conference on Anti- 
microbial Agents and Chemotherapy (Atlanta). Washington. DC: 
American Society for Microbiology. 1990:195. 

40. Thomas JC, Carr SJ. Fujioka K. Waterman SH Community-acquired 

group A streptococcal deaths in Los Angeles County. J Infect Dis 
1989;160:1086-7 
4 1 Valenzuela TD. Hooton TM, Kaplan EL. Schlievert P. Transmission of 
'toxic strep' syndrome from an infected child to a firefighter dunng 
CPR. Ann Emerg Med 1991;20:123-5. 

42. Hauser AR. Stevens DL. Kaplan EL. Schlievert PM Molecular epide- 

miology of pyrogenic exotoxins from Streptococcus pyogenes iso- 
lates associated with toxic shock-like syndrome. J Clin Microbiol 
1991;29:1562-7. 

43. Farley JD. Woo V, Shaw C. Smith JA. Invasive streptococcal disease in 

British Columbia Can Dis Wkly Rep 1990;16:257-9. 

44. Kohler W Streptococcal toxic shock syndrome Zcntralblatt fiir Bak- 

teriologie 1990;272:257-64. 

45. Watson DW Host-parasite factors in group A streptococcal infections: 

pyrogenic and other effects of immunologic distinct exotoxins re- 
lated to scarlet fever toxins. J Exp Med I960;! 1 1:255-83. 

46. Kim YB. Watson DW A purified group A streptococcal pyrogenic 

exotoxin. Physicochemical and biological properties including the 
enhancement of susceptibility to endotoxin lethal shock. J Exp Med 
1970:131:611-28. 

47. Knoll H. Holm SE, Gerlach D, Ozegowski JH, Kohler W. Tissue cages 

for study of experimental streptococcal infection in rabbits III. Influ- 
ence of immunization with erythrogenic tor.in type A (ET A) and its 
toxoid on subsequent infection with an ET A producing strain. Zen- 
tralblatt fur Baktenologie. Mikrobiologie. und Hygiene [A] 
1988:269:366-76 

48. Fast DJ. Schlievert PM. Nelson RD. Toxic shock syndrome-associated 

staphylococcal and streptococcal pyrogenic toxins are potent in- 
ducers of tumor necrosis factor production. Infect Immun 
1989;57:291-4 
49 Hackett S. Schlievert P. Stevens D. Cytokine production by human 
mononuclear cells in response to streptococcal exotoxins [abstract 
no I89AL Clin Res 1991 ;39. 

50. Lancefield RC. Current knowledge of type-specific M antigens of group 

A streptococci. J Immunol 1962;89:307-13. 

5 1 . Mollick J A. Rich RR. Characterization of a superantigen from a patho- 

genic strain of Streptococcus pyogenes [abstract no 213A], Clin Res 
1991:39. 

52. KotbM. Tomai M. MajumdarG, Walker J. Beachey EH Cellular and 

biochemical responses of human T lymphocytes stimulated with 
streptococcal M protein [abstract no L77]. In: XI. Lancefield Interna- 
tional Symposium on Streptococcal Diseases (Siena. Italy) 1990. 

53. Cleary R. Chen C. Lapenta D. Bormann N. Heath D. Haanes E. A 

virulence regulon in Streptococcus pyogenes, (abstract no 19]. In: III 
International Conference on Streptococcal Genetics (Minneapolis) 
Washington. DC: American Society for Microbiology, 1990 

54. Stevens DL. Gibbons AE. Comparative efficacies of newer antibiotics 

in the treatment of experimental streptococcal myositis [abstract no 
A45J. In; Proceedings of the annual meeting of the American Society 
for Microbiology. Washington. DC: American Society for Microbiol- 
ogy. 1989. 

55. Gemmell CG. Peterson PK. Schmeling D. et al. Potentiation of opson- 

ization and phagocytosis of Streptococcus pyogenes following growth 
in the presence of clindamycin J Clin Invest 1981:67: 1249-56. 



44 

Mr. Towns. I call the second panel, Dr. Dale Morse, New York 
State epidemiologist, and Dr. Edward Kaplan, head of the World 
Health Organization laboratory in the University of Minnesota. 

I remind you that your entire witness statement will be included 
in the record. We would like for you to summarize within 5 min- 
utes so the Members will have an opportunity to raise questions 
with you. 

Dr. Kaplan, I guess for continuity, why don't we begin with you. 

STATEMENT OF EDWARD L. KAPLAN, M.D., PROFESSOR OF PE- 
DIATRICS, UNIVERSITY OF MINNESOTA MEDICAL SCHOOL, 
AND PROFESSOR, DP7ISION OF EPD3EMIOLOGY, UNTVERSITY 
OF MINNESOTA SCHOOL OF PUBLIC HEALTH, AND HEAD, 
WORLD HEALTH ORGANIZATION COLLABORATING CENTER 
FOR REFERENCE AND RESEARCH ON STREPTOCOCCI 

Dr. Kaplan. Thank you, Mr. Chairman. I am very grateful for 
the invitation and the opportunity to meet with you this morning. 

I am Edward Kaplan. I am a pediatrician and currently professor 
of pediatrics at the University of Minnesota Medical School and 
also professor in the School of Public Health's Division of Epidemi- 
ology. 

Furthermore, I come to you as head of the World Health Organi- 
zation, Streptococcal Reference Laboratory at the University of 
Minnesota, which is probably, without asking what the other lab- 
oratory was that Dr. Broome referred to, the other one that can 
type these organisms in the United States at the present time. 

I have worked in the area of streptococcal infections in epidemiol- 
ogy and so on for almost 30 years, and bring to you not only the 
laboratory perspective, but in addition, that of a clinician who has 
taken care of patients. 

And since streptococcal infections have been referred to by some- 
one as an occupational disease of school children, as a pediatrician 
I feel particularly appropriate to be here, and for that reason I am 
very grateful. 

A lot has been said about this problem this morning, and things 
which I had intended to say— but rather than repeat those for you, 
I would like to touch on some of the things I think, Mr. Chairman, 
are important. 

I think group A streptococcal infections continue to constitute an- 
other of the very common infectious diseases which continue to 
have the potential for causing severe trouble, both from a medical 
as well as a public health point of view. These are important and 
have continued to be important, and I think we have to understand 
the background of these infections in order to understand what has 
happened recently. 

I think one of the most important issues is that most streptococ- 
cal infections are not severe infections. In fact, it has been esti- 
mated, recent figures that I have seen, that there are about 4 mil- 
lion cases of streptococcal sore throat in the United States yearly. 
Those are soft data, admittedly, but it gives you some idea of the 
magnitude of what we are dealing with. 

It is not these uncomplicated infections that have had us con- 
cerned over the years. It is their consequences, particularly dis- 
eases like rheumatic fever and glomerulonephritis, which used to 



45 

be called Bright's Disease. It is the complications of these diseases 
that cause a great deal of concern. For example, in the U.S. Navy 
alone during the Second World War, there were some 20,000 cases 
of acute rheumatic fever, it has been estimated. 

This concern was brought very well, I think, to the medical popu- 
lation, to medical practitioners and to the public, and for these dis- 
eases, these complications tended to disappear since the Second 
World War. We have had very few cases up to about 10 years ago. 
We have no complete understanding of why this occurred but there 
are some suggestions. 

For example, in upstate New York, in Rochester, in Monroe 
County, a throat culture program there over the last 20 years 
showed no decrease in the number of uncomplicated streptococcal 
infections, but when they looked at the incidence of rheumatic fever 
and glomerulonephritis, this fell off remarkably between the mid- 
1960's and mid-1980's, and maybe we became a little complacent 
and forgot this infection has great potential for causing problems. 

It still came back to us. For example, there have been almost 275 
cases of acute rheumatic fever noted in Salt Lake City, UT, be- 
tween 1985 and 1992, a city where they were seeing three to six 
cases per year in the previous years. 

Recently, within the last month or two, I am aware of at least 
two other small outbreaks of acute rheumatic fever. So it is the 
issue of the streptococcal infection itself, not simply the issue, as 
I see it, of toxic shock or necrotizing fasciitis that should concern 
us. 

As has been pointed out, the incidence, accurate incidence fig- 
ures — and I would certainly agree with my two colleagues who just 
testified before you, accurate incidence figures are very difficult to 
come by — but I think we have to say that this severe infection rep- 
resents a relatively rare complication. I think a lot of this is the 
result of maybe an exaggerated response in some cases by some ir- 
responsible members of the press. This certainly was the case, be- 
cause we have seen this infection, as Dr. Stevens pointed out, for 
the last 10 years in this country. 

Why did this happen? Well, we don't really know the reasons. 
And I think if there is one message I would like to leave with you, 
we don't fully understand why this has happened. We don't under- 
stand its epidemiology, nor do we understand the basic science that 
is involved. 

We do know that infectious diseases are cyclic in their nature. 
And we see this with influenza and a number of other diseases. 
But the molecular basis we don't understand. 

Therefore, Mr. Chairman, I would say one of the things we do 
need is more epidemiologic research and more basic research. 

I would point out, with all respect to our colleagues at the CDC 
who provide an extraordinarily important service to this country, 
that the committee should be at least made aware of the fact that 
most streptococcal research, the majority of it, takes place in uni- 
versities and other institutes throughout the country. So it is not 
only needed, added needed resources at the CDC, which I think are 
important, but I think the whole problem of research on streptococ- 
cal infection needs to be addressed with more resources. I think 
they are inadequate at the present time. 



46 



I think that we would like to— well, I will just stop right now by 
saying thank you once again for the opportunity to appear before 
you. I would be delighted to answer any questions that you have 

[The prepared statement of Dr. Kaplan follows:] 



47 



TESTIMONY PREPARED FOR 
The Human Resources and Intergovernmental Operations 

Subcommittee 

of the 

Committee on Government Operations 

United States House of Representatives 

July 28, 1994 



Edward L. Kaplan, M.I). 

Department of Pediatrics 

University of Minnesota Medical School 

420 Delaware St. SE 

Minneapolis, MN 55455 



Congressman Towns, Committee Members, Ladies and Gentlemen: I 
would first like to thank you for the invitation and the opportunity to appear before 
this Subcommittee to discuss the important medical and public health issues 
pertaining to and resulting from the group A streptococcal infections and their 
complications which have been so highly publicized during the past several 
weeks. 

I am Edward L. Kaplan. Currently I am a Professor in the Department of 
Pediatrics at the University of Minnesota Medical School in Minneapolis, and also 
hold an appointment of Professor in the Division of Epidemiology at the University 
of Minnesota School of Public Health in Minneapolis. Additionally, of relevance to 
my appearance here today, I serve as Head of the World Health Organization 
Collaborating Center for Reference and Research on Streptococci located in the 
Department of Pediatrics at the University of Minnesota Medical School, a 
position I have held for the past nine years. Relevant to my qualifications to 
appear, to give testimony, and to answer questions before this Subcommittee on 
this subject is the fact that I have worked in the field of streptococcal infections 
and research for the past twenty nine years. I have been interested in and have 
published scientific papers relating to the diagnosis, treatment and prevention of 
these infections and their complications, the epidemiology of the infections, the 
pathogenesis of the infections and their complications (such as rheumatic 
fever/rheumatic heart disease and severe infections such as the streptococcal 
toxic shock-like syndrome, and the public health implications of group A 
streptococcal infections). Finally, I have and continue to give clinical medical 



48 



care to these patients and their contacts. I should also add that my clinical, 
epidemiological and laboratory experience includes significant experience in 
dealing with these infections and their complications in countries around the 
world where I have served in the role of consultant to Ministries of Health and to 
the World Health Organization to address these problems and to assist in the 
implementation of effective public health control programs. Details of these 
qualifications and interests are available in the accompanying biographical 
material and curriculum vitae. 

Mr. Chairman, the Subcommittee's interest in assessing the impact of the 
problem of "Invasive Strep A: What do we need to know?" and group A 
streptococcal infections in general is very timely. This is not only because of the 
recent publicity given to these severe infections in this country and abroad, but 
especially because in my opinion and in the opinion of other clinicians, public 
health authorities and laboratory scientists, group A streptococcal infections 
constitute another of the common infections which continue to have the potential 
for causing significant morbidity and mortality even at the close of the twentieth 
century. 

In order to specifically address the questions originally posed in your letter 
of invitation, I believe it necessary and important to provide background 
information about these infections. Allow me to first outline this information for 
your information before more completely addressing your questions. The 
background material will provide some of the answers you have asked for 

There are a number of different kinds of streptococcal bacteria. 
(Streptococci are not viruses.) Today I will limit my comments to those 
streptococci which are called beta hemolytic streptococci because of the reaction 
that they cause on specific blood agar cultures plates in the laboratory. Although 
we can differentiate these beta hemolytic streptococci into several groups 
(designated by the letters A, B, C, G, etc.) by specific serological laboratory 
reactions, today I will concentrate only on the group A organisms. These are the 
ones which are most frequently the cause of beta hemolytic streptococcal 
infections in humans. Among the group A streptococci, there are at least 80 
different kinds known as serotypes (these are designated by numbers such as 1, 2, 
3, 4, etc.). However, there are, as we and others have shown, numerous other as 
yet either uncharacterized or incompletely characterized group A serotypes. 

The most common type of human clinical infections caused by group A 
streptococci are those of the upper respiratory tract and of the skin. Most 
frequently the former infections are referred to as streptococcal pharyngitis or 
pharyngo tonsillitis, or "strep throat", and the latter are referred to as "impetigo". 
These are very frequent infections, especially among children. In fact, these have 
been referred to as an "occupational disease of school children" because they are 
so common. It is difficult to provide you with precise incidence data because of 
reasons that I will come to in a moment, However, one group of estimates that I 
have seen which was prepared for the pharmaceutical industry suggested that 
there were at least four million cases of group A streptococcal pharyngitis during 
the year 1992 in the United States alone. All of us can recall having had "strep 



49 



throat" on numerous occasions as a school child, and we recall our own 
children's similar experience. Available data suggest that the use of antibiotics 
has not reduced the incidence of these infections since antibiotics were added to 
our therapeutic armamentarium. However, not only do these infections 
frequently involve school children, but also they have a propensity to involve other 
"crowded" or high risk situations such as medical facilities and even in military 
posts where outbreaks of group A streptococcal infections and their sequelae 
occur from time to time. 

Most group A streptococcal infections are not severe. True, they do 
commonly cause the sudden onset of severe sore throat with high fever and often 
times abdominal pain and headache. The are a cause of absenteeism from school 
and from the work place, but they are most frequently limited to the upper 
respiratory tract. Fortunately, the organism usually can be eradicated from the 
upper respiratory tract or from the skin by the appropriate use of antibiotics. 
Antibiotic resistance has not been a problem with the group A streptococcus, in 
contrast to many other bacteria that have been described. 

However, it is not the uncomplicated group A streptococcal infections of the 
upper respiratory tract or of the skin which have caused major concerns to 
physicians and to public health authorities over the years. For approximately fifty 
years we have known that these infections, if left untreated or undiagnosed, may 
result in what are referred to as non-suppurative complications, and these are 
more serious and dangerous problems. Rheumatic fever and the accompanying 
damage to heart valves can occur after these infections, as can a kidney disease 
called glomerulonephritis (or what many of us heard our parents call terms like 
"Bright's Disease") . Studies at the end of the decade of the 1940s and during the 
early 1950s showed clearly that prompt diagnosis and antibiotic therapy of 
streptococcal sore throat essentially can prevent rheumatic fever. The prestigious 
Lasker Award in Medicine was awarded for this outstanding clinical and 
epidemiological research. These studies made a very significant impact on 
management of an important and yet common bacterial infection. 

Due to comprehensive educational campaigns directed both at the medical 
profession and at the lay public by organizations such as the American Heart 
Association, a greater understanding and a more encompassing approach to 
these infections resulted. It was an important step that is quite relevant to what 
we are discussing here today. 

During the decades of the 1960s and 1970s and during the early part of the 
decade of the 1980s it is quite interesting that the incidence rates of complications 
of group A streptococcal infections were significantly reduced here in the United 
States, as well as in the industrialized countries of the world. Incidence rates of 
rheumatic fever dropped, for example, almost twenty fold. Careful studies in a 
number of places around the country documented this. One comprehensive study 
was carried out in Baltimore. Many cities such as Boston, New York, Baltimore, 
and Chicago which had entire hospitals devoted to the care of patients with 
rheumatic fever closed these hospitals during the 1970s. State health 
departments which had maintained rheumatic fever registries for decades 



50 



discontinued them. This happened, for example, in my own state of Minnesota in 
1982. This decrease has not been experienced in many of the developing countries 
of the world, countries which as you are aware, make up approximately two 
thirds of the world population. There these complications have remained very 
important with incidence rates as high as or even higher than they had been in 
the United States several decades ago. Some attributed this reduction in the 
complications of streptococcal infections in the United States to the availability of 
antibiotics and to increases in standards of living here as well as to the availability 
of medical care. But these explanations, while undoubtedly having some impact, 
do not satisfactorily explain this apparent decrease in these complications. 
Because we do not yet fully understand precisely how these group A streptococcal 
infections cause rheumatic fever and severe systemic infections despite more 
than four decades of clinical, epidemiological, basic and applied research, we 
have no way of complete understanding why the decrease occurred. 

There are some important clues. For example, in Monroe County in 
upstate New York, a comprehensive throat culture program for school children 
during twenty years between the mid 1960s to the mid 1980s suggested that while 
the number of cases of uncomplicated streptococcal sore throat did not 
significantly decrease during the twenty year period of time, the number of cases 
of rheumatic fever and glomerulonephritis fell almost to a non detectable level. 
This finding suggested that it was not simply that the incidence of the 
complications decreased, it was almost as if the group A streptococcal bacteria 
which caused these infections did not have the capability to lead to complications. 

This example is important for two reasons. One is that this type of 
information probably lead to unwarranted complacency in the medical and public 
health communities. The disease had disappeared and was no longer a problem 
to be reckoned with in the United States (even though this clearly was not the case 
in other parts of the world). Microbiologists did not know what the "virulence 
factor" was that seemed no longer to be present, and clinicians and public health 
authorities were not very concerned because they did not see the disease. Many 
primary care physicians who were recent graduates of medical schools had never 
actually seen a patient with rheumatic fever, for example. A second important 
reason is that the epidemiological evidence suggested that the number of 
uncomplicated infections had not appreciably changed and, yet, the number of 
complications resulting from group A infections had decreased. 

With that information in mind, let me attempt to relate this to the current 
situation in which we find ourselves and the reason for this hearing. In the mid 
1980s this situation with group A infections began to change. There is what I 
believe to be convincing epidemiological evidence that, in the mid 1980s, severe 
group A streptococcal infections and complications of these infections were 
increasing. For example, several reported outbreaks of rheumatic fever were 
described from several parts of the country. The largest was that reported from 
Utah where it has been determined that more than 274 cases occurred between 
1985 and 1992. This compares with an average of about 3-6 cases per year during 
the late 1970s and early 1980s. There was published epidemiological evidence 
suggesting that there were increases noted in more than twenty states. Of 



51 



relevance has been the fact that these outbreaks did not occur in socially and 
economically disadvantaged populations, but among middle class suburban 
populations with ready access to medical care. This was not just in children, but 
there were at least two outbreaks of rheumatic fever described among military 
recruits. 

Similarly, during the mid to late 1980s, other types of severe infections with 
group A streptococcal disease were reported. Among the first significant series 
was a report published in the New England Journal of Medicine in July 1989. 
Twenty cases of streptococcal toxic shock-like syndrome were described. The 
mortality in that report and in other published series from United States and 
abroad has been as high as 30%. So it is important to recognize that these severe 
infections dia not begin to occur in 1994 as reported recently by the tabloid press in 
England. They have been occurring since the mid to late 1980s. The initial 
reports in the United States also sparked interest and, to some degree, 
exaggeration by the press. After the initial reports, public interest declined until 
1990 when Mr. Jim Henson died of complications of a group A streptococcal 
infection and then there was another period of heightened press interest, some of 
it quite exaggerated. We believe that the severe infections continued to occur in 
this country, as is documented by numerous published reports in medical 
journals. The same was true elsewhere in the world, particularly in Europe. 

These infections have the potential for being very rapidly progressive. 
While precise mechanisms of entry of the bacteria into the body are not entirely 
clear, the group a streptococcus may enter the blood stream either through a 
break in the skin or from via the upper respiratory tract. While there are no 
bacteria that I am aware of that accurately can be described as "flesh eating," 
these group A streptococci associated with the severe systemic infections may 
cause necrosis of tissue and failure of organ systems such as the kidneys, the 
liver and the lungs. The virulence may well be related to the production of certain 
bacterial toxins by the bacteria which then cause pathological changes in the vital 
organ systems of the body and may then lead to the considerable tissue damage. 

In June of this year there were reports of "flesh eating" bacteria in the 
British tabloids and the American public was once again made aware of this 
problem. Now, it is important to recognize that all states do not require reporting 
of group A streptococcal infections. In fact, there is a suggestion that less than 
half of the 50 states require any kind of reporting of group A streptococcal 
infections; some of the state requirements are only used in very specialized 
situations such as food borne outbreaks or hospital nursery outbreaks. This 
makes accurate determination of incidence of this problem extremely difficult, if 
not impossible. 

A significant proportion of what has been publicized since June of this year 
has been considered by those with expertise in the field to represent exaggerated 
reporting by some of the electronic and print media. This is not to say that these 
severe infections are not more common now than they were in the early 1980s and 
before. But, despite the fact that there are, as far as I am aware, no published 
reliable figures documenting the precise incidence in the United States, most 



52 



scientists, epidemiologists and clinicians believe that this form of systemic 
infection is a relatively rare manifestation of group A streptococci. I concur. At 
the present time there is no need for public panic; there is a definite need for more 
complete understanding of the epidemiology and pathogenesis of the disease. 

I believe that these severe group A streptococcal infections are more 
common than they once were; but these severe infections are not new. Careful 
examination of the medical literature clearly reveals that this type of infection has 
been observed and reported in the past, but not the recent past. Additionally, there 
is evidence to suggest that this became more common in the late 1980s. From our 
own experience, we think it likely reached a peak in the years 1990-1992 and has 
been decreasing, although certainly remaining more common than before the 
1980s. Unfortunately, neither surveillance nor anecdotal reports will allow us to 
do more than to extrapolate estimates to determine any idea of the number of 
cases now or in the future. I do believe that the numbers of cases that have been 
estimated in many recent press reports have been exaggerated and are not 
founded upon clear supporting data. 

The same is likely to be true for rheumatic fever, another very important 
complication of group A streptococcal infections. I think one can arrive at the 
informed conclusion that rheumatic fever is more common in the United States 
now than it was ten years ago, even though we probably have seen the peak of the 
"resurgence" three years ago. This opinion is based on an estimate, but I can 
provide document able examples from reports made to our laboratory from several 
different geographic areas in the United States during the past year. 

There are no infallible means of clinically recognizing severe group A 
streptococcal systemic infection. The process may start as a rather vague flu-like 
syndrome with muscle aches and pains and a low grade temperature before it 
begins to rapidly progress. It may begin as an infected small cut or abrasion. It 
may present in other even less specific ways. It can be quite difficult for 
physicians to clinically diagnose in its early stages. Therefore, it usually is even 
more of a problem for untrained non-medical individuals. Fortunately this severe 
form of group A streptococcal infection likely is quite rare ! The best advice to be 
offered at this time to the lay public regarding protection is that one should use 
common sense, and if there is an infection or if there are constitutional symptoms 
that normally would be of concern, the affected individual should seek medical 
care from his or her medical care giver. Reports in the press have suggested 
some guidelines for assisting the public in this difficult task. I would caution that 
none of these guidelines are so specific as to be absolutely diagnostic. Therefore, 
common sense remains the best approach to be used by the lay public. 

Finally, in completing the background information and before addressing 
the issues related to what measures might be taken to address these infections, let 
me attempt to briefly address the enigma of why has this occurred. I believe that 
there is evidence to suggest that we have seen the introduction of more virulent 
strains of group A streptococci into some of the general population. We do not 
know yet exactly why these organisms are more virulent, in the same manner 
that we do not know exactly why we have seen a "resurgence" of acute rheumatic 



53 



fever during the past seven years. There are some important clues that have 
come from recent epidemiological and laboratory research in this country and 
from abroad. But this introduction and/or spread of strains with increased 
virulence should not be surprising. Examination of the history of infectious 
diseases and also of group A streptococcal infections in particular reveals a cyclic 
nature in the occurrence of infectious diseases. Historians recall the epidemics of 
plague and of small pox occurring in European cities during the middle ages. 
Recorded data reveal the cyclic nature of outbreaks of severe scarlet fever in 
Brighton, England at the end of the 19th century. (Scarlet fever is somewhat 
related to the type of severe streptococcal infections being considered in these 
hearings.) Public health authorities know the cyclic nature of influenza; there 
was a massive world wide pandemic in 1918 that is reported to have caused more 
than twenty million deaths. There have been epidemics in the late 1950s, in the 
late 1960s and from time to time since then. The cyclic nature of most infectious 
diseases is not only recognized for humans, but also for the animal kingdom. 
Outbreaks of rabies in bats and other animals on the East Coast have occurred 
recently, and we are aware of periodic outbreaks of tularemia (rabbit fever) and 
plague in prairie dogs in the west. 

Therefore, the fact that we are seeing the introduction of some relatively few 
virulent strains of group A streptococci at the present time should not be 
unexpected. What we still do not fully understand is why this is happening. 
What are the changes among the group A streptococcal organisms that lead to its 
enhanced virulence? What causes the changes and what predisposes to the 
changes? What can physicians and the public health community do to more 
accurately predict these changes and their consequences? From a practical point 
of view, what can be done to more effectively treat the unfortunate few who 
contract this relatively rare infection, an infection with a recorded mortality rate 
of as high as 30% even with the best of medical care? 

The Centers for Disease Control has been asked to assist in the 
understanding of this disease process and, as stated, the CDC has attempted to 
increase surveillance of these infections. However, recall that group A 
streptococcal infections are very common infections and one needs to understand 
more about the uncomplicated infections before fully understanding the 
epidemiology and pathogenesis of the complicated ones. It can be difficult to 
accurately assess the change in incidence of such a disease. This is for the 
reasons noted previously. To accurately predict the infections may be impossible, 
but it would require much more comprehensive surveillance if this were deemed 
advisable. On the other hand, I think that physicians are becoming more aware 
of these serious group A streptococcal infections. There has been a considerable 
amount of descriptive clinical material written in the recent medical literature 
about the disease. 

Of interest to this Subcommittee should be the fact that many physicians 
are almost being inundated by the public inquiring because of what, at least in my 
opinion, are unnecessarily alarming reports. For example, as a result of this I 
find that pediatricians are being asked if mosquito bites cause the disease. 



54 



If I may, I would like to suggest that this infection, part of a spectrum of 
group A streptococcal infections of various kinds and of varied severity, still 
remains an enigma to clinicians and to biomedical scientists. There are many 
important basic questions that remain unanswered. I would respectfully submit 
that this group A streptococcal infection or syndrome is a classic example of yet 
another very common infection that has the potential for causing significant 
morbidity, mortality and expense but receives less than optimal appreciation of its 
potential for causing disease until either a famous person contracts it or the press 
publicizes it (perhaps sometimes to an extreme, as has been the case in a number 
of the reports published or broadcast during the past month or six weeks). From 
my comments it is possible to appreciate without difficulty the number of 
important gaps in our basic knowledge about the group A streptococcus and its 
infections and complications. When there were more than 20,000 cases of acute 
rheumatic fever reported in the U.S. Navy alone during the Second World War, it 
is not difficult to appreciate a response to needed research. These infections both 
here and also elsewhere in the world have shown us that they still constitute a 
significant threat. We need to learn more about how to control such threats. 
While it clearly is not the point of this hearing to examine the need for research 
funds for the medical and public health communities, one cannot discuss the 
pertinent aspects of these group A streptococcal infections without uncovering the 
existing gaps in our knowledge and concluding that these will need to be closed 
before this type of infection and its consequences can be prevented. 

I want to emphasize that this need for more information and better control 
methods is not only one needed for the Centers for Disease Control and for the 
Public Health Service, but I think it appropriate to state that a very significant 
proportion - perhaps even the majority - of group A streptococcal-related research 
(including basic research into the mechanisms of disease, epidemiological 
research of group A streptococcal infections, and applied clinical research into 
diagnosis and treatment of these infections) takes place in laboratories and clinics 
at Universities and Institutes around this country and, indeed, around the world. 
Needs for these productive research laboratories and other facilities are not fully 
being met at the present time. Thus, while there is definitely a need for more 
attention to this matter at the Centers for Disease Control and within the Public 
Health Service, to adequately address the issue will require attention and 
resources made available to other facilities where expertise and experience are 
located. 

Once again, Mr. Chairman and Members of the Subcommittee, I would 
like to thank you for the opportunity to appear before you today and to address this 
important issue. I will be glad to attempt to answer your questions or to respond 
to your observations. 



7/28/94 



55 

Mr. Towns. Thank you very much, Dr. Kaplan. 
Dr. Morse, you may proceed. 

STATEMENT OF DALE L. MORSE, MJX, M.S., DIRECTOR, DIVI- 
SION OF EPIDEMIOLOGY AND COMMUNICABLE DISEASES, 
NEW YORK STATE DEPARTMENT OF HEALTH 

Dr. Morse. Thank you, Mr. Chairman. 

My name is Dale Morse and I am director of the division of epi- 
demiology and the State epidemiologist for the New York State De- 
partment of Health. On behalf of the department, I would like to 
thank you for the opportunity to testify today and share our 
thoughts and concerns. 

Today I will be discussing invasive group A strep in New York 
State. But first I would like to address it in a broader context be- 
cause it represents merely one symptom of the larger problem of 
emerging infections. 

This emphasis is crucial because invasive GAS is but one of mul- 
tiple important emerging infectious diseases which are being recog- 
nized as new, reemergent, drug resistant, nosocomially transmitted 
and/or epidemic in nature. This is essential because while today's 
scare terminology of flesh-eating bacteria has aroused the public, 
the press, and the scientific community's interest, the term could 
easily be applied to other tissue-invading organisms, such as 
Methicillin-Resistant Staph Aureus, or expanded to other orga- 
nisms with such tabloid selling phrases as "mind eating" [meningo- 
coccus, rabies, et cetera] "lung eating" [hantavirus, et cetera] "blood 
eating^ [HIV, malaria, ehrlichia], "gut eating" [for example, 
vancomycin resistant enterococcus E. coli 0157:H7, 
Cryptosporidium], et cetera. 

The major point for consideration is that they all require similar 
public health approaches and should be addressed on a comprehen- 
sive, rather than an individual basis. 

As we have heard from the previous speakers, invasive group A 
strep is a severe manifestation of an infection with an organism 
which is found very commonly in normal, well individuals; occurs 
frequently as strep throat and impetigo, and is seen less frequently 
in association with scarlet fever, glomerulonephritis, toxic shock- 
like syndrome, and rheumatic fever. 

Invasive GAS is rare, with an estimated 10,000-15,000 cases an- 
nually in the United States, which would extrapolate to approxi- 
mately 700 to 1,000 cases a year in New York. To be honest, we 
don't know the exact number because it is not notifiable nationally, 
nor is it legally required to be reported in New York. 

Historically, in New York, group A strep infections occurring on 
dairy farms were made reportable in the early 1900's because of 
raw milk associated outbreaks, but this became a nonissue with 
pasteurization and therefore was officially removed in 1986. 

While not reportable, during the last decade we have responded 
to numerous press and public inquiries, especially after Jim 
Henson's untimely death due to such an infection in 1990 in New 
York City. We have distributed informational materials to hospitals 
and local health units on how to deal with the problem and infor- 
mation fact sheets, which is an attachment. 



56 

We have also investigated several group-based strep infections in 
schools, camps, and nursing home outbreaks. Another example is 
attached as a reference. And periodically we have reviewed hospital 
discharges of related conditions such as rheumatic fever to look for 
any potential increases, and also reviewed laboratory reports to 
look for any unusual clustering. 

As an example, from September 1992 through January 1994, we 
worked with the State laboratory to solicit reports from 395 li- 
censed bacteriology labs on an all-sterile site, that is blood and 
CSF, isolates of invasive group A strep of residents of New York 
State outside of New York City. While incomplete, that review of 
reported cases showed no differences by age or sex. 

Cases occurred throughout the year with a peak in the winter, 
which you would expect from a seasonal perspective. Isolates were 
scattered among 14 counties and represented 20 different M and T 
types, and there was no evidence of time-space clusters. While 
somewhat reassuring, this type of passive surveillance is far from 
ideal, as it captured information on only about 10 to 15 percent of 
the estimated number of invasive group A illnesses. 

New York has approximately 50 communicable diseases which 
are legally reportable by physicians, laboratories and health care 
institutions. Diseases are added to the list based on frequency, se- 
verity, transmissibility and preventability, such as vaccine or con- 
tact investigation for treatment. 

In addition, outbreaks are legally reported and investigated. De- 
spite its severity, invasive group A strep has not been made report- 
able because it doesn't meet the other criteria. 

Furthermore, active surveillance for invasive group A strep alone 
would be time consuming and costly. Instead, it would be more cost 
effective to include invasive group A strep surveillance as part of 
a larger effort to conduct surveillance and control of a host of 
emerging pathogens. 

Unfortunately, there are few if any resources to deal with a num- 
ber of the currently notifiable conditions, let alone the 
nonreportable emerging ones such as invasive group A strep. 

As an example, there are no Federal funds to support State and 
local reporting to the nationally notifiable disease system. And 95 
percent of CDC Federal infectious disease funds are limited to sur- 
veillance in four categories, TB, HIV/AIDS, STDs and immunizable 
diseases. In New York, a similarly small percentage of funds is de- 
voted to such agents, and New York's efforts exceed those of most 
other States in tnis regard. 

In summary, inadequate resources are being devoted to invasive 
group A strep for research, for potential vaccine development, and 
other items which have been mentioned. But it only represents one 
leak in the dike. Rather than giving token funds to support fingers 
to plug this one hole alone, it would be more effective for Congress 
to nelp plug and control all emerging infection leaks by rebuilding 
the dike's infrastructure which has been neglected and eroded over 
the past two decades. Providing $150 million to fund CDC's emerg- 
ing infection initiatives and increasing public health care support 
dollars to States would be an important step in the right direction. 

Thank you. I would be happy to answer any questions. 

[The prepared statement of Dr. Morse follows:] 



57 

NEW YORK STATE DEPARTMENT OF HEALTH 

DIVISION OF EPIDEMIOLOGY 



Testimony Before The 



Subcommittee on Human Resources and Intergovernmental Relations 



Congressional Committee on Government Operations 



ON 



INVASIVE GROUP A STREP" 



Presented By 

Dale L. Morse. MD. MS 

July 28. 1994 



58 



CONGRESSIONAL TESTIMONY 



Good morning, my name is Dr. Dale Morse and I am Director. Division of 
Epidemiology, and the State Epidemiologist for the New York State 
Department of Health. On behalf of the Department. I would like to 
thank you for the opportunity to testify today and share our thoughts 
and concerns. 



Today I will be discussing invasive Group A strep (GAS) in New York 
State, but first I would like to address it in a broader context because 
it represents merely one symptom of the larger problem of emerging 
infections. This emphasis is crucial because invasive GAS is but one of 
multiple important emerging infectious diseases which are being 
recognized as new. re-emergent, drug-resistant, nosocomially transmitted 
and/or epidemic in nature. This more global perspective is essential. I 
repeat essential . because while today's scare terminology of "flesh 
eating bacteria" has aroused the public, press and scientific 
community's interest, the term could easily be applied to other tissue 
invading organisms (e.g.. Methicillin Resistant Staph Aureus), or 
expanded to other organisms with such tabloid selling phrases as "mind 
eating" (e.g.. meningococcus, rabies, herpes simplex) . "lung eating" 
(e.g.. hanta virus, drug-resistant pneumococcus . multiple drug-resistant 
TB). "blood eating" (e.g.. HIV. malaria, ehrlichia), "gut eating" (e.g.. 
vancomycin-resistant enterococcus. E. col i 0157 : H7 . Cryptosporidium), 
etc. The major point for consideration is that they all require similar 
public health approaches and should be addressed on a comprehensive 
rather than an individual basis. 



As we have heard from the previous speakers, invasive Group A strep is a 
severe manifestation of an infection with an organism which is found 
very commonly in normal well individuals; occurs frequently as strep 
throat; and is seen less frequently in association with scarlet fever, 
glomerulonephritis, toxic shock-like syndrome, and rheumatic fever. 
Invasive GAS is rare, with an estimated 10.000-15.000 cases annually in 
the United States, which would extrapolate to approximately 700-1.000 
cases a year in New York. To be honest, we don't know the exact number 
because it is not notifiable nationally, nor is it legally required to 
be reported in New York. 

Historically. GAS infections occurring on dairy farms were made 
reportable in New York in the early 1900 's because of raw milk 
associated outbreaks, but this became a non- issue with the advent of 
pasteurization and was therefore officially removed as a reportable 
condition in 1986. While not reportable, during the last decade we have 
responded to numerous press and public inquiries (especially after Jim 
Henson's untimely death due to such an infection in 1990. in New York 
City); distributed informational materials to hospitals and local health 
units (Attachment 1); investigated several GAS school, camp and nursing 
home outbreaks (Attachment 2): and. periodically reviewed hospital 



59 



discharges of related conditions such as rheumatic fever and laboratory 
reports to look for an increased incidence or unusual clustering. As an 
example, from September 1992-January 1994 we worked with the State 
laboratory to solicit reports from 395 licensed bacteriology labs on all 
sterile site (blood. CSF) isolates of invasive GAS among residents of 
New York State outside of New York City. While incomplete, a review of 
the 86 reported cases showed no differences by age or sex (Attachment 
3). Cases occurred throughout the year and more frequently during 
winter (as expected). Isolates were scattered over 14 counties, 
represented 20 different M and T types, and there was no evidence of 
clusters or outbreaks. While somewhat reassuring, this type of 
"passive" surveillance is far from ideal, as it captured information on 
only about 10-15 percent of the estimated number of invasive GAS 
illnesses. 



New York has approximately 50 communicable diseases which are legally 
reportable by physicians, laboratories and health care institutions. 
Diseases are added to the list based on frequency. severity, 
transmissibility and preventability. In addition, outbreaks are legally 
reportable and investigated. Despite its severity, invasive GAS has not 
been made reportable because it doesn't meet the other criteria. 
Furthermore, "active surveillance" for "invasive GAS" alone would be 
time-consuming and costly. Instead, it would be more cost effective to 
include invasive GAS surveillance as part of a larger effort to conduct 
surveillance and control of a host of emerging pathogens. Unfortunately, 
there are few. if any, resources to deal with a number of the currently 
notifiable conditions, let alone the non-reportable emerging ones, such 
as invasive GAS. As an example, there are no federal funds to support 
State and local reporting to the nationally notifiable disease system, 
and 95 percent of CDC federal infectious disease funds are limited to 
surveillance in four categories (TB. HIV/AIDS. STD's and immunizable 
diseases). In New York, a similarly small percentage of funds is 
devoted to such agents, and New York's efforts exceed those of most 
other states in this regard. 



Additional Comments : Establishment of "active" surveillance for 
invasive GAS would be difficult and expensive because, while invasive 
GAS is rare. GAS infections are extremely common. Requiring reports of 
all GAS would be impossible because of the sheer volume. Limiting 
reporting to only blood and CSF isolate infections would miss some 
cases, but be more manageable. However, it would still require regular 
contact with the 395 labs which might identify such isolates in New York 
State. Furthermore, since laboratory reports provide only limited 
information, meaningful surveillance would require intensive follow-up 
of individual cases to obtain demographic, clinical and epidemiologic 
data. This would require field staff to collect information from 
laboratories, physicians, hospitals, patients and their families. 



60 



Since the same laboratories usually process specimens on other emerging 
infections, it would be more efficacious to establish a more 
comprehensive system which would electronically transmit selected 
disease reports to state health departments and on to CDC for national 
surveillance, and to local health units for expedited follow-up. The 
need for establishing such an "emerging infection warning surveillance 
system" appears obvious, but would require more than "token" resources. 



In summary, inadequate resources are being devoted to invasive GAS. but 
it only represents one leak in the dike. Rather than giving token funds 
to support fingers to plug this one hole, it would be more effective for 
Congress to help plug and control all the emerging infection leaks by 
rebuilding the dike's infrastructure, which has been neglected and 
eroded over the past two decades. Providing $150 million to fund CDC's 
emerging infection initiatives and increasing public health core support 
dollars to states would be important steps in the right direction. 



Thank you. I would be happy to answer any questions. 



Attachment 1 -- GAS Informational Material for Hospital and Local Health Units 
Attachment 2 -- Sample New York State Department of Health GAS Manuscript 
Attachment 3 -- Invasive GAS Lab Survey 



61 



Attachment I 



From: MAILER --ALBNYDH2 Date and time 06/24/94 12:40:03 

Fr1, 24 Jun 94 12:40:03 EDT 
Received: by dohlf.hcom.gov (4. l/SMI-4 . O-DNI ) 

Id AA27485; Fr1 , 24 Jun 94 12:28:23 EDT 
Date: Frl , 24 Jun 94 12:28:23 EDT 
From: cpc01Pa1bnydh2 

Message-Id: <9406241628. AA27485Pdohlf . hcom.gov> 
To: cpc01@albnydh2 

Subject: Perspective on Group A Streptococcal Infections 

Attention To: Hospital Chief Executive Officer 



E-Mail Message for Hospitals and Local Health Departments: 

"Please, distribute to appropriate medical, 
Infection control and laboratory staff" 

Bureau of Communicable Disease Control 
New York State Department of Health 

June 27, 1994 

PERSPECTIVE ON GROUP A STREPTOCOCCAL INFECTIONS 

A. Morbidity/Mortality Trends 

B. Clinical Spectrum 

C. Public Health Aspects 

D. Questions and Answers 1n GAS 

E. References 

Several recent news media reports describing cases of necrotizing 
fasciitis due to Group A Streptococcal (GAS) Infections have lacked a 
scientific perspective on the disease and have failed to describe the 
overall context In which these cases have occurred. This Informational 
report 1s Intended to provide comments on trends of GAS, describe the 
spectrum of disease and highlight some of the public health Issues. 

A. Morbidity /Mortality Trends 



The absence of national or statewide surveillance data on GAS 
makes 1t difficult to Identify changes In the epidemiology of GAS disease. 
However, a number of published laboratory based studies conducted 1n 
certain geographic areas have Identified Increases 1n Invasive GAS 
Infections In Arizona between 1985 and 1990 (1), Colorado between 
1980 and 1990 (2) and Ontario between 1987 and 1991 (3). 

Although complete surveillance data for Invasive GAS 1n New York 
State 1s not available, a limited survey (unpublished data) of GAS Isolated 
from sterile sites 1n upstate hospital labs between 9/92-1/94 Identified 
86 cases. No distinct time/space clusters were found, all age groups were 
affected, male to female ratio was 1:1 and 20 different M/T types (strains) 
were Identified. More cases occurred between September 1993 and 



62 



January 1994 than for the same period September 1992-January 1993. Case 
outcome or frequency of necrotizing fasciitis was not available. The short 
duration of the study did not allow for trend analysis. Data must be 
collected 1n a consistent manner for multiple years 1n order to detect any 
significant changes 1n the Incidence. 

B. Clinical Spectrum 



In 1993 the CDC Working Group on Strep Infections proposed the 
following classification of GAS (4). 

Class Clinical Expressions 



Streptococcal Toxic Shock 



II Other Invasive Infections defined by 

Isolation from a sterile site Including 
bacteremia or meningitis (with no 
Identified focus); and cellulitis, 
wound Infections, necrotizing fasciitis 
puerpural sepsis, septic arthritis 
(with an Identified focus) 

HI Scarlet Fever 

IV Non-1nvas1ve Infections such as strep 

throat or Impetigo 

V Nonsuppurative sequelae such as acute 

rheumatic fever or glomerulonephritis. 

The clinical ^i««*tTrT expression 1s mediated by a combination of 
host Immune factors and virulence factors of the organism. The 
classification scheme reflects the broad clinical spectrum associated with 
GAS. The most common expression 1s streptococcal pharyngitis. 
Streptococcal toxic shock, septicemia and other Invasive forms occur 
Infrequently. Based on CDC estimates of 10,000-15,000 cases of Invasive 
GAS per year 1n the United States, New York State would be expected to have 
700 to 1050 per year. 

C. Public Health Aspects 



In the absence of an effective vaccine, the public health focus 
1s to encourage prompt diagnosis and treatment of streptococcal infection 
and educate the public regarding the epidemiology of GAS. The widespread 
publicity regarding necrotizing faclltls, although sensationalized by some 
of the media, may encourage patients to seek medical attention early 1n the 
course of their Infection and minimize the risk of serious sequelae. 

Although sporadic GAS 1s not presently a reportable disease, 
outbreaks occurring 1n schools, colleges, camps, health care facilities and 
state Institutions must be reported to the local/state health department. 
Toxic Shock Syndrome (TSS), a Class I disease has been a reportable disease 
since 1986. However we are also Interested In collecting surveillance data 
on other Invasive forms (Class II). 



63 



In order to obtain additional data on sporadic cases, the BCDC 
requests that: 

1. hospitals report cases of Invasive GAS on a 
voluntary basis (defined as a patient with GAS 
Isolated from a sterile site) to the local 
health department using the standard DOH 389 
Confidential Case Report Form. A supplemental 
data form available from the NYSDOH has 
recently been developed to collect additional 
epidemiologic Information. 

2. laboratories continue to submit GAS cultures 
obtained from sterile sites and from patients 
with necrotizing faclltls to the NYSDOH 
Laboratory for M/T Typing. 

A question and answer sheet Intended for a general audience Is 
attached. Questions regarding laboratory aspects can be directed to 
Clinical Microbiology Unlt-NYSDOH-WCL&R at (518) 474-4177. To report 
cases, contact your local health department. For questions regarding the 
general epidemiology of GAS, call your local health department or the 
NYSDOH or NYCHD. 

Greg Balzano Buffalo/Rochester (716) 847-4519 

Peter Drabkln Albany (518) 473-4439 

Rich Gallo/Helalne Le1b New Rochelle/Long Island (914) 632-4133 

Marty Toly Syracuse (315) 426-7620 

John Marr MD (NYSDOH) NYC (212) 613-2440 

or 

Marcy Layton MO (NYCHD) NYC (212) 788-4193 

Additional Information available from the Bureau of Communicable 
Disease Control, New York State Department of Health at (518) 473-4439 
Includes: 

1. An example of a "Dear Doctor" letter on GAS developed by 
the Westchester County Health Department for those local 
health departments or hospital administrators who wish to 
communicate further with the medical community on this area. 

2. Supplemental Case Report Form for GAS. 

D. Question and Answer Sheet Adapted from U.S. Centers for Disease Control 



on Group A Streptococcal Necrotizing Fasciitis 

May 26, 1994 
Q. What 1s 1t? 

A. Necrotizing fasciitis Is a condition where muscle and fat tissue 
are broken down as a consequence of Infection. Necrotizing 
faclltls Is one manifestation of severe group A streptococcal 
infections. Other severe signs of illness that often occur 
with fasciitis are shock and organ failure (for example, 
kidney failure). Death may occur In 20-30X of patients with 



64 



necrotizing fasciitis. Other patients will require surgery, 
possibly Including amputation. 

Q. How common 1s It? 

A. Studies conducted 1n the late 1980' s Indicated that severe group A 
streptococcal Infections were becoming more common. Based on 
surveillance data from 1990, we estimate that 10-15,000 severe 
Infections occur 1n the U.S. each year, resulting In 2-3,000 
deaths. Intensive surveillance 1n the U.S. for severe group A 
streptococcal infections has not been conducted since 1991. 

Of all persons with severe group A streptococcal Infections, 
necrotizing fasciitis occurs 1n 5-10%. Persons of all ages may 
be Infected although most disease occurs 1n adults. Often 
Infection begins at the site of a break 1n the skin (a surgical 
or nonsurgical wound). 

Q. Why does 1t occur? 

A. Both the organism and host susceptibility likely play a role 1n 
necrotizing fasciitis. While most group A streptococcal cause 
only mild infections (such as "strep throat") some types may 
cause more severe disease. One factor that may be linked to 
necrotizing fasciitis Is the production by some group A 
streptococci of proteases, enzymes that break down proteins. Host 
susceptibility also Is important. Investigation of family clusters 
shows that the same type of bacteria can cause severe Infection in 
one family member and mild or asymptomatic disease 1n others. 

Q. How does necrotizing fasciitis kill? 

A. Persons with necrotizing fasciitis are likely to develop spread 

and growth of the organism 1n many areas, including the bloodstream. 
When this growth continues unchecked 1t can lead to overwhelming 
bacterial infection and death. 

Q. What can I do about It? 

A. Necrotizing fasciitis often occurs 1n persons with wound due to 
surgery or Injury which then become Infected. Persons with such 
wounds should take appropriate measures to keep the wounds clean 
and should seek medical attention 1f signs of Infection occur. 
The Infection can be treated with readily available antibiotics. 

Q. Can I safely travel to England where cases have been reported In the 
press? 

A. Yes. Traveling to any area 1n England will not Increase 
your risk of getting this disease. There are no travel 
restrictions for travel to any area 1n the U.K. Cases occur sporadically 
throughout the U.S., Canada and elsewhere. 



Q. Is there a vaccine for this disease? 
A. No. 



65 



E. REFERENCES 



1. Hoge C, Schwartz B, Changing Epidemiology of 
Invasive GAS. JAMA 1993; 269:384-389. 

2. Wheeler M, Roe M, Outbreak of GAS Septicemia 
In Children JAMA 1991: 266:533-537. 

3. Oemers et al, Severe Group A Strep 1n Ontario 
1987-1991, Clinical Infectious Diseases 1993; 
16:792-800. 

4. CDC Working Group on Severe Strep Infections 
JAMA 1993; 269:390-391. 



66 



i)\i koi i\n Hum' 



r.rim Mini <h.\ 



Attacnment i 



Dili mhi r 1992 



Readers' Forum 



Two Outbreaks of Primarily Noninvasive Group A 
Streptococcal Disease in the Same Nursing Home, 

New York, 1991 

Louise-Ann McNutt. PhD; Aida E. Casiano-Colon. PhD: F Bruce Coles. DO: Dale L Morse. MD. MS. Manlyn Menegus. PhD: 
Annemane Groth-Juncker. MD; Janet Lansky. MS: Karen Bell. MD; Benjamin Schwartz. MD 



Group A Streptococcus has been identified as the 
cause of several outbreaks of infection in residents of 
nursing homes. 1 " 1 These reports described outbreaks 
that included persons with severe invasive disease as 
well as more limited infection. The purpose of this 
report is to describe an investigation of two consecu- 
tive outbreaks of group A Streptococcus that occurred 
in a single nursing home, where all affected residents 
had disease of mild to moderate disease severity. This 
report focuses on the identification of risk factors for 
infection and describes the approach used to control 
the spread of infection in the nursing home. 

BACKGROUND 

In January 1991. medical staff at nursing home A 
recognized an increase in the occurrence of group A 
Streptococcus infections in residents of a 46-bed locked 
mental health unit which primarily housed persons 
with dementia. This unit is located in the main 
building of a 471-bed, three-building facility. In May 
1991. a second outbreak of group A Streptococcus 



affected residents of a skilled nursing care area on the 
floor directly above the mental health unit. Epidemiol- 
ogic investigations were conducted to identify the 
extent of the outbreaks, modes of transmission, and 
potential risk factors for infection. 

METHODS 

Case Definition and Case Finding 

A confirmed case resident was defined as any 
nursing home A resident with a positive group A 
Streptococcus culture between December 25. 1990. 
and July 4, 1991. A possible case resident was defined 
as any mental health unit resident with signs and 
symptoms consistent with group A Streptococcus infec- 
tion, but for whom a culture was not obtained between 
December 25. 1990, and February 25. 1991. 

We identified cases among mental health unit 
residents by reviewing medical records, reviewing the 
microbiology log, and culturing potentially infected 
sites from persons with group A Streptococcus- 
compatible illness. In addition, surveillance throat. 



From the Bureau of Communicable Disease Control. New York State Department of Health. Albany. New York (Drs. McNutt. Morse, 
and Coles); the Division of Field Epidemiology. Epidemiology Program Office, the Centers for Disease Control. Atlanta. Georgia (Dr. 
McNutt); the Clinical Microbiology Laboratory, University of Rochester Medical Center, Rochester. New York (Drs. Casiano-Colon and 
Menegus). St. Johns Home. Rochester, New York (Dr. Groth-Juncker and Ms Lansky). Department of Medicine. University of Rochester 
Medical Center. Rochester. New York (Dr. Groth-Juncker); Monroe County Health Department, Rochester, New York (Dr. Bell); 
Epidemiology Section. Respiratory Diseases Branch. Division of Bacterial Diseases. National Center for Infectious Diseases, the Centers 
for Disease Control, Atlanta. Georgia (Dr. Schwartz) 

The authors thank Drs. John Elliott and Richard Facklamfor laboratory support and Dr Laura Fehrsfor review of the manuscript 

Results from these investigations were presented in part at the American Public Health Association Meetings. Atlanta. Georgia. 
November 1991. 

Address repnnt requests to Dale L Morse. MD. New York State Department of Health. Bureau of Communicable Disease Control. 
Corning Tower Building. Room 651. Empire State Plaza. Albany, NY 12237. 

McNutt LA. Casiano-Colon AE. Coles FB. et al. Tieo outbreaks of primarily noninvasive group A streptococcal disease m the same 
nursing home. New York. 1991 Infect Control Hosp Epidemiol. 1992; 13:74*751. 



67 



Vol. 13 No. 12 



READERS FoRIM 



749 




TABLE 1 

Sites of Group A Streptococcal Infections.- Nursing 
Home A, New York, 1991 



Outbreak*! 



Outbreak #2 



FIGURE. Group A streptococcal 'nfection in residents ana staff m 
nursing nome A By date of symptom onset. New Vbrk. 1990-1991. 
OutOreak »1 . left) and outoreak #2 ingnt). 



vaginal, and nasal cultures were collected from con- 
senting residents. For visitors and staff members, only 
surveillance throat cultures were obtained. Case find- 
ing in other areas of the building were similar, but 
surveillance throat or nasal cultures were obtained 
only for close contacts of infected residents. 

ATTACK RATES AND RISK FACTOR 
INVESTIGATION 

The existence of an outbreak(s) was determined 
by comparing group A Streptococcus attack rates in the 
affected areas to rates from other areas of the nursing 
home and from the previous year. To determine 
whether spatial clustering of case residents occurred, 
room locations were plotted. 

We conducted a cohort study of risk factors of all 
residents of the mental health unit during the out- 
break period. Potential risk factors, studied through a 
retrospective chart review, included demographics, 
behavioral factors, predisposing medical conditions, 
and the degree of nursing care, characterized by the 
amount of assistance needed with activities of daily 
living (e.g., feeding, toileting, bathing, and dressing). 
Categorical variables were analyzed by calculating 
relative risks (RR) and 95% confidence intervals (Cy. 
Significance of association was determined using 
Fisher's exact test or chi square test as appropriate. A 
p value of .05 or less was considered statistically 
significant. 

Laboratory Methods 

Group A Streptococcus isolates were identified at 
a local hospital laboratory using standard methods 
(i.e.. bacitracin susceptibility and streptex grouping). 
Available group A Streptococcus isolates were for- 
warded to the Centers for Disease Control for M- 
typing and T-typing. 3 

RESULTS 

Outbreak #1 

Of the 46 mental health unit residents. 13 (28%) 
met the confirmed and 11 (24%) met the possible case 







Cutture- 




CuKure- 


sit. 




Conflimsd 


PoMlMa 


Cofmnnad 


Wound/cellulius 


5 


5 


■» 


Eye 




3 


5 


1 


Ear 




2 





1 


Nose 




2 


1 


1 


Spurum 




2 








Lymph node 




1 


1 





Throat* 




1 








* Five residents had rwo 


sites at injection 






* \sympiomaljc 


identified by surveillance o 


Irunng 





definition, respectively, [nfection in the 24 case resi- 
dents occurred between January 5, 1991. and Febru- 
ary 2. 1991 (Figure). All available group A Streptococcus 
isolates were M-nontypeable. T-Imp 19. No group A 
Streptococcus infections had been documented in the 
mental health unit for at least 2 years prior to this 
outbreak. No group A Streptococcus organisms were 
isolated from residents living anywhere else in the 
nursing home during January and February 1991 
(Fisher's exact test, /x.OOl). 

Sites of infection in the cases were diverse. Ten 
residents had cutaneous infections (i.e.. wounds, celluli- 
tis) most often at sites without an apparent pre- 
existing lesion; 8 residents had purulent conjunctivitis 
(Table 1). Two residents were hospitalized, and there 
were no deaths. All surveillance throat cultures from 
mental health staff (n = 37) and visitors (n = 15) and all 
vaginal cultures from residents (n = 38) were nega- 
tive. 

The risk of group A Streptococcus infection was 
significanth/ increased in residents needing total assis- 
tance with daily living (RR = 3.85, CL^ 1.06-14.29) 
and in residents with one or more chronic underlying 
conditions (e.g.. diabetes, cancer) (RR = 2.44. CI 95 = 
1.01-5.88) (Table 2). Analyses limited to confirmed 
case residents versus noncase residents (excluding 
possible case residents) yielded similar results. No 
clustering of cases by room location within the mental 
health unit was observed. 

During the week prior to the outbreak, one nurse 
worked with symptomatic pharyngitis and reported 
having a positive throat culture for group A Streptococ- 
cus at her private physician's office. Although we could 
not epidemiologicalry confirm this nurse as the source 
of resident infections, several factors suggest that she 
may have introduced the group A Streptococcus into the 
facility and played a role in its transmission. These 



68 



750 


IsEEcTION C 


ONTR.OL VND HosHTAL E 


riDEMIOLOG 4 




December 1992 


TABLE 2 












Stldyof Potential Rjsk F 


ACTOR ExTOSLRES. 


Mental Health Unit. 


Nt rsing Home A 


New York 


JaMVAJOT 1, 


1991 — Febri \ry 3, 1991; Confirmed and 


Possible Case Residents Versis Noncase Residents 






Qroup A 


Non-Qroup A 










Streptococcus* 


Straptococcus 


Rolatlv* 


ConfManca 




Potential Risk Factor* 


(n = 24) 


(n = 22) 


Man 


Limits 


P 


Gender itemalei 


19 


19 


1.25 


0.67-2.33 


702 


Race (Caucasian) 


.'3 


20 


160 


0.32-8.14 


0467 


Median age (years) 


79 


81 


NA+ 






Assistance with daily living 












Needs total assistance 


>•) 


12 


3.85 


106-14.29 


004 


No/ moderate assistance 


■> 


10 








Mobility 


„ 










Chairbound or >50%bed 


10 


4 


1.64 


0.98-2.70 


0.084 


No/ little assistance 


14 


18 








Predisposing diseases 
One or more 


20 


11 


2.44 


1.01-5.88 


0.016 


None 


4 


11 








Medications* 
1 or more 


18 


11 


1.75 


0.87-3.57 


0.079 


None 


6 


11 








Skin lesions 
Yes 


U 


9 


1 10 


0.63-1.91 


0736 


No 


13 


13 








Visitors 
Yes 


7 


5 


1.17 


0.65-2.09 


0.619 


No 


17 


17 








Absences from unit 
Yes 


6 


10 


0.63 


0.31-1.25 


146 


No 


18 


12 








Mental status 
Confused/disoriented 


17 


14 


1.18 


0.63-2.22 


0.603 


Lethargy, apathy 


7 


8 








Incontinence 
a 50% of the time 


17 


11 


1.56 


0.81-3.03 


0.148 


<50% of the time 


7 


11 








Nutrition 
Eats <75% of diet 


16 


16 


0.88 


0.50-1.54 


0.655 


Eats 3 75% of diet 


8 


6 








Oral fluids 
<75* recommended 


8 


7 


1.03 


0.58-1.85 


0.913 


3 75* recommended 


16 


15 








Wandering behavior 
Yes 


10 


8 


1.25 


032-4.86 


0.713 


No 


14 


14 








■ Group A streptococcal disease (culture-confirmed In- 131 and possible In -111). 

* Not applicable 

t Chemotherapy steroids, malgesics narcopcs. hypnotics, psychoactive drugs 









include a persistent sore throat while on therapy with 
subsequent group A Streptococcus-positive culture, more 
contact with case residents than noncase residents 
during the early outbreak period, and nursing assign- 
ments including only the affected unit, in contrast with 



most nursing staff who worked throughout the facility. 
In addition, the absence of symptoms and negative 
cultures from other staff members and visitors and the 
minimal movement of residents in and out of the 
nursing home suggest that this nurse was the most 



69 



Vol. 13 No. 12 



Readers' Forum 



751 



likely source of the group A Streptococcus strain causing 
the mental health unit outbreak. Her isolates were 
unavailable for M-typing and T-typing. 

OutbreaJc #2 

An additional 6 group A Streptococcus culture- 
confirmed case residents were identified in nursing 
home A between May 23, 1991, and July 4, 1991 
(Figure). Prior to this cluster, one nurse had a positive 
group A Streptococcus culture (isolate not available). 
This outbreak included 5 (11%) of 46 residents on one 
floor and 1 (2%) of 46 residents two floors above 
(Figure). All resident isolates were M-nontypeable, 
T-3/13. Again, the most common site of infection was 
cutaneous (Table 1). The five residents on one floor all 
were clustered in one of three nursing areas (chi 
square = 11.59. p = .003). 

Infection Control 

The nursing home implemented aggressive infec- 
tion control measures. These included cohorting resi- 
dents and staff, requiring masks and gloves with 
changes between resident contacts, and reinforcing 
handwashing behaviors. In the mental health unit, 
additional control measures included bathing resi- 
dents" with a germicidal soap and disinfection of all 
contact surfaces. No chemoprophylaxis to prevent 
secondary spread was given. 

CONCLUSIONS 

These outbreaks highlight the potential role of ill 
employees in transmitting group A Streptococcus infec- 
tion and the apparent effectiveness of infection control 
measures focused on barrier precautions in halting 
the spread of disease. 

The employee health policy at nursing home A is 
typical of many others 6 in that if an employee is noted 
to be ill, they are required to take sick leave or, if that 
benefit is exhausted, leave without compensation. As 
a result, ill employees come to work and avoid 
precautions that could draw attention to themselves. 
The New York State Department of Health recom- 
mendations to nursing home A stated that sympto- 
matic or culture-positive staff who could be a source 



for disease transmission must use barrier precautions 
or be removed from resident contact until a negative 
culture was obtained. In general, it is optimal for 
symptomatic personnel to be excluded from caring for 
high-risk residents, such as the elderly. Where this is 
not feasible, careful handwashing is essential, and the 
use of masks may be beneficial. 7 

Use of chemoprophylaxis appears to have been of 
benefit in aborting group A Streptococcus nursing 
home outbreaks that involved severe morbidity and 
mortality. 23 In contrast, in these two outbreaks of mild 
to moderate infection severity, no prophylaxis was 
necessary. Both outbreaks resolved quickly after 
improving infection control measures focusing on 
barrier precautions. 

M-typing and T-typing were used to confirm links 
between cases within each outbreak and document 
that the two outbreaks were distinct During the 
second outbreak, typing was used to guide infection 
control efforts. Without typing, aggressive and costly 
infection control measures, including chemoprophy- 
laxis and cohorting of residents and staff, would have 
been implemented throughout the facility based on 
the assumption that the second cluster of cases 
represented an extension of the original outbreak and 
a failure of barrier control measures. 

REFERENCES 

1. Rubin FL, Norden CW. Heisler B. Korica Y An outbreak of 
Streptococcus pyogenes infections in a nursing home. Ann Intern 
Med. 1984:101:494-496. 

2. Centers for Disease Control. Nursing home outbreaks of inva- 
sive group A streptococcal infections— Illinois, Kansas. North 
Carolina, and Texas. MMWR. 1990:39:577-579. 

3. Auerbach SB, Schwartz B. Williams D . et al. Outbreak of group A 
streptococcal infections in a nursing home: lessons on preven- 
tion and control. Arch Intern Med. 1992:152:1017-1022. 

4. Harkness GA, Bendey DW, Mottley M. Lee J. Streptococcus 
pyogenes outbreak in a long-term care facility. Am J Infect 
Control. 1992:20:142-148. 

5. Moody MD. Padula J. Lizana D. Hall CT Epidemiologic charac- 
terization of group A streptococci by TaggtutinaQon and M 
precipitation tests in the public health laboratory. Health Lab Sri. 
1965:2:149-161. 

6. Garibaldi RA. Brodine S. Matsumjya A. Infections among patients 
in nursing homes: policies, prevalence, problems. N Engi J Med. 
1981305:731-735. 

7. Centers for Disease Control Guidelines for infection control in 
hospital personnel. /nfcrt Control 1983:4 (suppl) 325-349. 



70 



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71 

Mr. Towns. Let me thank both of you for your testimony. 

Let me begin, Dr. Stevens, you remarked that many common 
public health approaches to infectious diseases do not work for 
strep A. Would you comment on that? I would like to hear you, Dr. 
Kaplan, on that. 

Dr. Kaplan. I am sorry, sir. I thought you said Dr. Stevens. I 
misunderstood that. 

Mr. TOWNS. Dr. Stevens said that. It was Dr. Stevens' remark, 
if I remember correctly, that many common public health ap- 
proaches to infectious diseases do not work for strep A. That was 
his comment. So I would like to get your opinion. 

Dr. Kaplan. Group A streptococci, as I pointed out, are very 
prevalent in the community. It is very widespread. If you go into 
any schoolroom in any community of the States or districts that 
you represent, in the middle of the winter, anywhere between 5 
and 20 percent of the children in that schoolroom may have group 
A streptococci in their upper respiratory tract, in their throat. That 
doesn't mean they are ill at this point. 

And perhaps he can correct me, if I were to try and interpret 
that, it is so widespread in the community that one cannot hope 
to wipe it out, so to speak, because there are many normal carriers 
of this organism. And therefore the common types of approaches to 
disease, epidemics and so on, really don't work when you have such 
a widespread organism. 

If I can for just a second, I think if we don't understand the un- 
complicated forms of an infection, if you will, it is very difficult for 
us then to understand the complicated form, the necrotizing 
fasciitis, the rheumatic fever. That is why it is so important that 
we do address the issue of this common infection. 

Mr. Towns. Dr. Morse, would you have some comments on that? 

Dr. Morse. In terms of public health approaches, we unfortu- 
nately don't have a vaccine, for example, that we would use to try 
to control this infection. We don't do contact investigations to treat 
contacts, necessarily. But I believe I would point out that there are 
some public health approaches that could be applied to this condi- 
tion that haven't been. 

For example, traditionally in public health, you do surveillance, 
and not just passive surveillance but you try to establish active 
surveillance through laboratory based reports, through hospital 
and physician reporting of the severe infections. So more could be 
done in that regard in terms of looking at the problem, defining it. 

Additional epidemiology studies could be done to identify individ- 
uals getting this infection combined with laboratory testing to de- 
termine if there are clusters or outbreaks where public health ac- 
tion would be taken, for example, an outbreak in a nursing home 
with an invasive group A strep. 

We do cohorting and other infection control procedures to try to 
control it. Education is also a public health approach. It is impor- 
tant to educate both public and health care providers in order to 
recognize manifestations quickly. 

Finally, based on knowledge gained from this surveillance, we 
consider targeted interventions with evaluation. And there are 
other diseases with past experience that we have developed ways 
of controlling through public health approaches. 



72 

Mr. Towns. Dr. Morse, your testimony suggests that strep A 
should not have a higher demand on our monitoring and reporting 
resources. Is that correct? 

Dr. Morse. I am sorry, repeat the question, please. 

Mr. Towns. Your testimony suggests that strep A should not 
have a higher demand on our monitoring and reporting resources. 
Is that correct? Is that your position? 

Dr. Morse. Not exactly. I guess what I was trying to refer to is 
that I felt it should be put in context with setting up a system to 
conduct surveillance for all emerging infections. To set up a system 
for group A strep by itself could be fairly time consuming and re- 
quire a lot of resources. 

For example, there is some logistic difficulties in following up re- 
porting. Group A strep itself is very common, and a number of hos- 
pital laboratories throughout the country could type for that. So if 
just group A strep infections were made reportable it would be a 
logistic nightmare in terms of the volume. There would just be too 
many cases to follow up on. 

If we tried to focus on cases that were more severe or invasive 
and focused on central nervous system infections and blood cul- 
tures, that would be easier. And limited to fewer labs, but it 
wouldn't pick up all the cases that didn't have that kind of culture. 

Logistically in New York State we would have to depend on 395 
labs to report those types of infections. But that wouldn't provide 
us with enough information. We would need field staff working 
with local health departments to collect additional information 
from physicians on those cases. 

So it would be a very time-consuming and costly effort to mount 
a surveillance activity by group A strep alone. But a lot of the same 
mechanisms could be used for other infections. 

Mr. Towns. Dr. Kaplan, do you have any comments on that? 

Dr. Kaplan. Well, there is no question with the volume that I 
mentioned to you, that Dr. Morse is quite correct, to make it re- 
portable in every instance would be an administrative and financial 
nightmare. I would certainly agree with that. 

On the other hand, and perhaps my figures are not precisely up 
to date, but the last time I saw the figures that were reported, less 
than half of the States in the United States had a requirement for 
reporting streptococcal infections of any type, be they severe or 
common. And many of those that did require reporting had only 
very specific kinds of reporting required, for example, food-borne 
outbreaks or outbreaks in hospital nurseries. I think we probably 
could do a little better with that. 

In other words, I think probably a realistic approach is some- 
where in between the two. I think we could do better than we are 
now. Many States don't require reporting and therefore we don't 
have any idea of the problem until after the cat is out of the bag, 
as it were. 

Mr. Towns. My time has expired. 

Congressman Schiff. 

Mr. Schiff. Thank you, Mr. Chairman. 

Dr. Kaplan, Dr. Morse, I would like to ask you the same ques- 
tions that I believe you heard me ask your colleagues. I want to 
preface it by saying that, again, on the one hand we know that 



73 

streptococcus infections have been around for a long, long time. 
And again, we also know, as Dr. Kaplan has observed, there has 
been very recently a great deal of reporting about streptococcus in- 
fection, particularly the so-called flesh-eating disease or necrotizing 
fasciitis, and oftentimes in a sensationalized kind of way. 

So what I want to do is put this in perspective. What I want to 
know is, from your observations as medical doctors and profes- 
sionals, either tnrough an increased number of reported or known 
streptococcus A infections or through an increased number of se- 
vere forms of diseases that can be caused by group A streptococcus, 
even if the overall number is the same, or for any other factor, do 
we face a different situation today in terms of the threat to public 
health by streptococcus A infections than we did, say, 5 or 10 years 
ago? 

Dr. Kaplan, may I call on you first, please. 

Dr. Kaplan. Yes, thank you, sir. My own personal opinion of 
this, and I think there are data to support this, is that there is no 
question in my mind that we are seeing more of these severe infec- 
tions now than we did 10 years ago. I referred briefly in my re- 
marks to the cyclic nature of infectious diseases. 

The precise magnitude of that I think remains yet to be clearly 
defined at this point. Now, once that happens, and Dr. Stevens re- 
ferred to this in his testimony also, we have had three ups and 
downs, if you will. 

Initially when this was reported in the mid-1980's when Mr. 
Henson died and then more recently, as we see these increases in 
the amount of information that is given to the public through the 
press, then there are going to be more cases reported. And I think 
Dr. Broome reported the fact that this causes an artifact, too. 

So the answer to your question specifically is, yes, I think there 
are more. My other answer is, we are not in the middle of an out- 
break. It still remains, fortunately, rare. These complications re- 
main rare. The more publicity we get, the more reporting we get, 
which gives us an uneven assessment of this. 

Mr. ScfflFF. Is there any particular reason you would offer as to 
why the increased number of severe infections, complications is oc- 
curring now? 

Dr. Kaplan. I think, in my own opinion, it has to be related at 
least in large part to the appearance of organisms which are more 
virulent than they were 10 years ago. If you go back, for example, 
and look at streptococcal disease over a period of time, for example, 
if you look at Great Britain in the United Kingdom at the end of 
the last century, you see the same kind of cyclic phenomenon with 
scarlet fever, which is another manifestation of streptococcal infec- 
tions. 

I think it is clear from literature thus far that we are seeing or- 
ganisms more likely to be virulent at this point, the emergence. If 
you ask me why that is the case, I can't answer it, and I am not 
sure anybody else can fully answer it at this point. 

Mr. Schiff. But let me go back to the beginning of the hearing. 
I said I recommended this hearing to the chairman because the re- 
porting, most recent reporting of these kinds of infections reminded 
me, at least personally, of the development of AIDS. It was re- 
ported as a very rare type of disease of an unusual nature but basi- 



74 

cally not as a public health threat. And of course we all know now, 
more than 10 years later, it is not the case. 

So when you say you believe there is a more virulent strain of 
group A streptococcus, I am wondering if you mean something new 
that we can't control with penicillin, or is otherwise some kind of 
special threat. 

Dr. Kaplan. Your point is well taken. First of all, it should be 
stated categorically that resistance of group A streptococci to peni- 
cillin has not increased. That is in contrast to many other microbes 
that we have to deal with clinically. So I think that is not the situ- 
ation. 

What you are really asking me to do is to foretell what is going 
to happen 2 months or 2 years down the line. If I had to guess- 
timate, I would say this comparison with AIDS probably will not 
come to pass with the group A streptococcus. But I would empha- 
size that is a guess. 

The basis for that is anecdotal. We don't have complete data that 
would allow us to make those projections, at least I am unaware 
of published complete data. 

Mr. Schiff. Dr. Morse, you have obviously heard the questions. 
I would like your view. Essentially the question is, do we face a 
greater threat to public health in some way from group A strepto- 
coccal infections than we did five or 10 years ago? 

Dr. Morse. Briefly, from what the other speakers have presented 
and some reports in the literature, it appears there are some in- 
creases in certain types of invasive group A strep and certain 
strains which have more severe sequelae, as other people have 
mentioned. 

In terms of New York State, we have not seen a marked in- 
crease, but I would point out that ours is a pretty passive reporting 
system. When we have looked at hospital discharge data for severe 
sequelae, for example, rheumatic fever, we haven't seen an increase 
in those type of cases. 

And through our reporting network, like the laboratory reports 
that came in passively, we didn't see evidence of clusters or out- 
breaks occurring. However, that is an incomplete picture. We 
haven't heard reports of increased outbreaks from hospitals. 

I think the press focusing attention on this kind of rare disease 
but one that has high mortality and affects normal individuals, 
though, points out the need to have a better active surveillance sys- 
tem to look at emerging pathogens such as this one. And people are 
no longer willing to accept the high mortality. For example, men- 
ingitis was a disease that now there is a vaccine for, and certainly 
invasive group A strep infections infect as many New Yorkers a 
year. So there does have to be more active surveillance to look at 
this and other infections. 

Mr. Schlff. Mr. Chairman, before I yield back, I would like to 
make the observation that what I am hearing from all four wit- 
nesses is, when you set aside the sensationalized press about some 
of the more severe diseases that can be caused by streptococcus A, 
there appears to be a general agreement that there is an increase 
in the number of the severe forms of diseases that can be caused 
by streptococcus A, and it could well be this is a natural cyclical 



75 

result. It could be the result that the press reporting has brought 
out reports of the cases to the agencies that keep track of it. 

On the other hand, the witnesses are also stating they are not 
quite certain. Certainly they are stating they are not certain where 
this is going to go. So I would suggest that when this hearing is 
concluded, we consider a report to the full committee that asks the 
Centers for Disease Control at the very least to monitor group A 
streptococcus infections more closely around the country and to ad- 
vise the Congress of what they find. 

I want to thank the witnesses, and I yield back. 

Mr. Towns. Without objection, so ordered. Thank you very much. 

At this time I yield to Congressman Payne. 

Mr. Payne. Thank you very much. 

I think that is an excellent recommendation, and I would like to 
associate myself with that. 

I wonder, Dr. Morse, how are some diseases designated as being 
actively monitored? You mentioned a comprehensive approach is 
needed to curb a prevalent tide of infectious diseases. 

For example, right now in New Jersey, we are experiencing an- 
other outbreak of E. coli infection. We had 35 cases reported re- 
cently throughout the State. And the very disturbing part of it is 
that it is very evenly divided throughout the State. It seems like 
it may not be just a single-source problem. 

If the correct approach is not used, then we are not adequately 
prepared to deal with a potential epidemic. We saw, as I mentioned 
before, resurgence of tuberculosis. 

Can you comment on an appropriate approach to dealing with 
strep A? 

And second, as you have indicated, there is no reporting require- 
ment for strep A. Either one of you may want to deal with this. 
How are you able to keep track of the disease? Is it just the fact 
that New York may have more initiative or Minnesota? And of 
course New Jersey. But if other States do not, how are we going 
to be able to monitor the disease's progression? 

And also, of course, it was not a problem that occurred in New 
York. But the recent Legionnaire's disease that recurred on a 
cruise trip to New Yorkers is once again an example. 

How are we going to follow up on this? 

Dr. Morse. I guess I would recommend approaching this simi- 
larly for group A strep with other of these rare emerging infections, 
and that is probably by improving the infrastructure to set up sur- 
veillance systems, to look at these infections, and to focus, for ex- 
ample, on laboratory-based reporting as a beginning point from lab- 
oratories that can report to State health departments with follow- 
up by local health unions to collect additional epidemiologic infor- 
mation. 

One way of doing that is with laboratory based reporting to 
States, those reports could go on to CDC and also to local health 
departments. So part of this is using modern technology to improve 
the infrastructure that has eroded over the last several years in a 
number of States. 

The potential of making it legally reportable obviously needs to 
be considered, and we are considering that. As I mentioned, there 
are logistic problems because group A strep infection by itself is so 



76 

common that it would not be logistically possible, so you would 
have to focus on maybe the most severe invasive forms, perhaps 
around bloodstream infections or central nervous system infections. 

Again, though, to be effective, to make it reportable, there would 
have to be additional resources to really make it worthwhile. If we 
just get the laboratory reports with no additional information, that 
is not very meaningful. 

So I guess the ways in terms of approaching it would be improv- 
ing the infrastructure to have surveillance for this type of condi- 
tion, focusing surveillance on certain States is certainly possible, as 
Dr. Broome mentioned, the five-State system, but that would have 
missed, for example, huntavirus or other conditions if you pick the 
wrong States. 

So I think there is a need to improve surveillance for emerging 
infections on a larger basis. I think the State systems have the ca- 
pability, but in recent years they have lost some of the capacity in 
terms of resources, and that has to be addressed now as we go into 
the era of health care reform as well because local health units 
may be losing additional resources as they are no longer providing 
primary care and some of the people that were involved with that 
were also doing public health followup as well. 

Dr. Kaplan. Congressman Payne, I would really address this in 
two ways. One relates to priorities, of course, and the other relates, 
as Dr. Morse just said, to resources. I think resources are impor- 
tant in two aspects. Keeping track of these, in my own State, in 
Minnesota, we had a very large rheumatic fever registry which we 
kept track of for many years. This was discontinuedin 1982 simply 
because of lack of resources. And this is documentable in other 
States also. 

So I think if there are resources that are available, a lot better 
job can be done. Just exactly how one wants to do it, of course, can 
e determined. 

The second approach that I would take to answer your question 
would be, there are an awful lot of questions that are unknown 
that the four of us who have talked to you today have been unable 
to answer about this organism. We need more basic research. We 
need more epidemiologic research. We need more applied research 
in how do you diagnose and treat this. That, once again, comes 
back to funding. And that funding is on a little different level than 
at the State health department level. 

It is in the form of research, not only in CDC, as I pointed out 
in my testimony, but I think elsewhere, where there is an incred- 
ible amount of expertise in this country. Streptococcal infections 
are a major problem around the world and this country has been 
a leader in that field for many years. We have an awful lot of ex- 
pertise here. And it is funding that is going to help us successfully 
address this. 

Mr. PAYNE. Thank you very much. I see my time has expired. 

I think the points you bring out here are very important, prior- 
ities and resources, and the resources are allocated by the prior- 
ities. So I am not sure which comes first. It should be — and one dis- 
turbing thing in the past, I think there is a new spirit in CDC and 
NIH, but in the past, a decade ago, the priorities were not based 
necessarily on the severity of the problem. The priorities were 



{J 



77 

based on maybe politics. When the first AIDS's case was diagnosed 
in 1978, it wasn't until 1982 that the administration at that time 
decided to have a $200,000 allocation to study this thing called 
AIDS, because it afflicted people who were ne'er-do-wells, they 
were people who were doing the wrong thing, they were out of the 
mainstream, on the margin of society they were poor people, they 
were drug abusers, they were homosexual people. And so the prior- 
ities were not high. The priorities were very low. As a matter of 
fact, it remained Tow through the 1980's because these were people 
who were not important. 

And so I know that this affects people, Native Americans, African 
Americans, alcoholics to some degree, people who have deficient im- 
mune systems, people who are intravenous drug users. And I am 
hoping, with the new CDC and NIH leadership, that we do not fall 
into the category again of this being a low priority, and therefore 
lower resources being applied to it. 

And I also agree that in addition to the research being done on 
the CDC level, I understand about $11 billion is spent annually on 
research to the Federal Government, through universities. But 
about $12 billion is spent by private industry, pharmaceutical com- 
panies and the rest, where the applied research is done. So there 
would have to be the combination or coordination of the two. 

But I am concerned that we don't — you know, when the Legion- 
naire's disease came out, there was a tremendous amount of re- 
sources put into that. If you remember, it was 15, 20 years ago. 
Why? They were veterans, they were practically all white men, 
they were good Americans who served their country, they were 
former, you know, high-level personnel, and as I mentioned, former 
veterans. And so there was a concern that the resources went into 
it, and they detected in a relatively short time a very difficult dis- 
ease to detect. 

As I indicated, the resources, when it came to AIDS, were not 
there because it was a totally different population. 

And lastly, women have been left out. When they did the testing 
of aspirin on the effect of strokes, 22,000 men were used, and not 
a single woman. But stroke and heart disease afflict women at 
higher rates than men. So women were also put in this other cat- 
egory. 

Thank you. 

Mr. Towns. The gentleman's time has expired. 

I now yield to Congressman Portman. 

Mr. Portman. Thank you, Mr. Chairman, and thank you for hav- 
ing the hearing. You and the ranking member have done a service 
I think to bring these witnesses before us and clarify many of the 
issues we have seen reported in the media. It certainly puts this 
flesh-eating bacteria in perspective. 

I have had a number of questions that have already been ad- 
dressed by the panelists. I do think I ought to give Dr. Kaplan a 
chance to respond to Mr. Payne's comments, because he seems 
eager to do that. 

Dr. Kaplan. Thank you. 

I just wanted to agree with the Congressman, to point out that 
historically streptococcal infections have been associated with so- 



78 

cially and economically disadvantaged populations. And it is impor- 
tant to know that. 

However, it is equally important, it seems to me, to note that in 
the recent outbreaks, especially those related to rheumatic fever, if 
one looks at the data, for example, from Salt Lake City, this has 
occurred in middle class populations, with ready access to medical 
care. So it is not quite so simple, at least in my opinion. 

We think that the former is related to crowding, because infec- 
tious diseases obviously spread with crowding. But it really affects 
a very broad base of the population. And I think you are quite right 
that we have to look at all aspects. 

Thank you for that opportunity. 

Mr. Portman. You are welcome. 

I agree with Mr. Schiff, it would be good to have some follow up 
and to have a report go to the full committee on the issue of group 
A streptococcus generally and certainly the flesh-eating bacteria 
that has been in the press so much. 

I guess my questions that remain, Dr. Morse and Dr. Kaplan, 
really go to the issue of how to increase the monitoring. You talked 
a lot about surveillance, Dr. Morse, the need for more infrastruc- 
ture and funding for that. 

One of the specific questions I have had is how to have more 
international reporting and information gathered. It seems to me 
that this particular issue is one we have seen raised in Europe, 
Australia, really around the world. 

Is there a need for some sort of international clearinghouse? Can 
CDC play that role? Or do you all see the need for some other 
international body to play that role? I would like to hear from both 
of you on that. 

Dr. Kaplan. If you like, as mentioned, I do head a World Health 
Organization streptococcal reference laboratory. There is a network 
of these, and there is great interest around the world. Streptococcal 
infections are an incredibly large problem around the world. They 
are the major cause of cardiovascular disease, rheumatic fever, in 
developing countries, which make up two-thirds of the world's pop- 
ulation. 

The World Health Organization has taken note of this new resur- 
gence, and in fact there will be meetings held, and there are ongo- 
ing meetings to discuss the approach. 

Once again we come back to priorities and resources. When you 
see what is happening in Rwanda, for example, where do we put 
this in terms of priority? 

So there is an international, ongoing effort to address these is- 
sues in the developing countries which have no resources, and 
where this is a very major problem, as well as what we have seen 
in Western Europe in the last few years, in Australia and New Zea- 
land, and in Southeast Asia. 

So the answer to your question is, basically there is. It always 
can be enhanced. Once again we come back to the same issues of 
priorities and resources. 

Mr. Portman. And it is your view that the World Health Organi- 
zation would be the appropriate body? 

Dr. Kaplan. It would certainly be one of those, and it is. As a 
matter of fact, I can tell you that I just talked about this with them 



79 

within the last week, and there is great interest and there is effort 
that will be extended there, at least two WHO meetings that I 
know about that will take place within the next 6 months to take 
care of this. 

Dr. Morse. I would agree with Dr. Kaplan's comments. There is 
a need for international monitoring. WHO, CDC, are good places to 
start, plus the reference laboratories like Dr. Kaplan works with in 
terms of WHO. 

The European Community has a network they are developing 
with the Public Health Laboratory Service in England. I guess one 
concern would be the developing countries. Most current surveil- 
lance is in the developed countries, and I don't think we should for- 
get the developing ones. Working with WHO and CDC and other 
agencies that already have contacts would probably be useful. 

I just want to address one other comment in terms of the mon- 
itoring. I know a lot of this depends on priorities and where re- 
sources will go to set this up. But I guess I would point out one 
thing that hasn't, I don't think, been discussed too much, are 
costs — whether the costs that are involved currently in terms of 
hospitalization and chronic sequelae — we shouldn't forget that 
those costs hopefully would be reduced by putting some priority 
and funding into preventive-type action. I didn't want to lose sight 
of that. 

Mr. Portman. Thank you. 

Thank you, Mr. Chairman. 

Mr. Towns. Thank you very much, Congressman Portman. 

Let me just conclude by saying that I agree with you. I think 
that a piecemeal approach is not a solution to the problem. I don't 
think that we really can tackle the problem until we have enough 
information; and in order to get the information, we have to mon- 
itor. There is no other way. 

I think you are right. We will find if we monitor and move ag- 
gressively, in the long run we might be able to save money, but one 
thing is certain: We definitely would be able to save lives, and I 
think that is very, very important. 

As we talk about health care reform and talk about the Health 
Security Act, I think that infectious disease is something that 
should be talked about as well; the fact is that electronic reporting 
of some sort should be a part of this discussion. If we are really 
going to reform health care, in the sense that I look at reform — 
the more I hear about it around here I am not hearing reform, I 
am hearing retreat. So I am having a problem with that. 

But I think if we are going to look at the monitoring that we 
have, the kind of electronic reporting system which could be put in 
place, that would not require a lot of energy or time on anybody's 
part because there will be uniformity of recordkeeping and things 
of that nature, that would be able to give us the information that 
we need to give you so that you would be able to really monitor 
this. Because I am hearing something here that I must admit that 
I am excited about the fact that you are saying that this situation 
is overblown and grossly exaggerated and it is not as bad as the 
media would say, but at the same time you are saying to us: We 
are really not sure what is going on because we don't have all the 
information, and we don't have the necessary resources to go and 



80 

to do the kind of things that need to be done, so therefore we are 
giving you our best at this time. We need to look further. I think 
that is an honest assessment. I think that conclusion is very impor- 
tant. 

I must say that I am happy to know that, while strep infections 
are common among children, the gruesome invasive infections are 
not common, especially among children. That is encouraging. But 
at the same time when you don't have all the information, you 
wonder about those kinds of statements as well. When we say tnat 
we do not have the monitoring, that some States don't do anything, 
and that we hear about it basically through the media. 

Let me iust say I was back in my district some time ago, and 
they had done an interesting analysis wherein over the past week 
they found out that five people had cars that were stolen from one 
block. So they decided to do some research. They went and inter- 
viewed everybody that lived on the block, only to find out that 90 
percent of the people that lived on that block had had their cars 
stolen over the last 10 years. 

They thought it was something that happened over a week. But 
came to realize this had been going on for quite some time, but no- 
body had talked about it. 

I am concerned that what we are dealing with here might be big- 
ger than what we realize it is, but we have not been talking about 
it. I think the analogy used by Congressman Payne about AIDS 
definitely could be used here. I think we need to guard against it, 
we need to be careful, and I think that in order to do that we have 
to have as much material as possible. 

So along with the report, Congressman Schiff, I would like to 
take that a step further. I think that we should meet with CDC; 
I think we should meet to try to see what can be done to get the 
resources to the proper places. I think that we are talking here 
about commitment. To me, this is very, very important. 

So I would say to you that I will ask for such a meeting to see 
if we can talk about getting this coordination going, because here, 
again, this might be bigger than we realize it is. 

I would like to thank the witnesses for coming and for testifying. 

This hearing is now concluded. 

[Whereupon, at 11:40 a.m., the subcommittee adjourned, to re- 
convene subject to the call of the Chair.] 

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