PEDIATRICS Vol. 107 No. 5 May 2001, pp. 1181-1183

EXPERIENCE AND REASON:
A Family Cluster of Streptococcal Toxic Shock Syndrome in Children: Clinical Implication and Epidemiological Investigation

	ABSTRACT

Top Abstract Introduction Methods Results Discussion References

Background.  Most invasive group A streptococcal (GAS) disease occurs sporadically. Reports of family clusters of these infections are scanty, and most invasive disease occurs in adults. We describe a family cluster of streptococcal toxic shock syndrome (STSS) involving 3 children and present the results of an epidemiologic investigation.

Patients and Methods.  During a 16-day period, 3 children in a family developed STSS with an interval of 7 and 9 days, respectively, between the onset of disease. Cases 2 and 3 had GAS isolated from blood culture. Case 2 was fatal. Pharyngeal culture survey of the family members and schoolchildren was conducted. Antibiogram, serotyping, detection of exotoxin genes, and random amplified polymorphic DNA patterns of the disease strains and survey strains were examined.

Results.  One of 15 family members sampledthe sister of the index caseand 7 (5.6%) of 125 schoolchildren sampled had GAS isolated from pharyngeal cultures. Of the 10 strains examined, 2 isolates from the patients, 1 from the sister of index case, and 2 from the classmates of case 2 (the fatal case) had an identical pattern of both genotype and phenotype.

Conclusion.  We describe a family cluster of STSS involving 3 children caused by a single clone and provide additional data regarding invasive GAS infection subsequent to household contact. Additional studies should be conducted in conjunction with surveillance to define better the magnitude of risk in household contacts and to identify settings in which subsequent infections may occur.  Key words:  group A Streptococcus, streptococcal toxic shock syndrome, family cluster, children.

Until the late 1980s, the incidence of severe group A streptococcal (GAS) infections had declined markedly.^1,2 Since 1987, a resurgence of invasive GAS infections has been reported in the form of the recently described streptococcal toxic shock syndrome (STSS).^3-8 For the most part the infections have occurred sporadically and have rarely been associated with clusters of cases.^9-14 Reports of family clusters of invasive GAS infection are scant, and, where reported, most invasive diseases have occurred in adults.^10,13-16

In this report, we describe a family cluster of STSS involving 3 children and the results of an epidemiologic investigation.

	PATIENTS

During a 16-day period, 3 children in an extended family developed STSS. Cases 2 and 3 are siblings and are also cousins of the index case. The interval between the onset of diseases was 7 and 9 days, respectively. All 3 patients were previously healthy males. There was no recent history of varicella and upper respiratory infection in them. Except for the lack of bacterial evidence in case 1, all 3 cases met the consensus definition of STSS proposed in 1993⁸that is, hypotension in combination with at least 2 of the following: renal impairment, coagulation or liver abnormalities, adult respiratory distress syndrome, rash, and necrotizing fasciitis.

Case 1

A 4-year-old boy was admitted to Chang Gung Children's Hospital on February 25, 1999, with a 1-day history of fever, abdominal pain, vomiting, diarrhea, and general malaise. On admission, the patient appeared lethargic with sunken eyes and dry lips. His temperature was 38.8°C; blood pressure, 75/32 mm Hg; pulse rate, 128 beats per minute; and respiratory rate, 32 breaths per minute. A diffuse erythematous rash on the trunk and neck was noted. Initial laboratory studies showed a leukocyte count of 16 100/mm³ (21% band forms, 75% segmented neutrophils, 4% lymphocytes), a platelet count of 156 000/mm³, and a C-reactive protein (CRP) value of 357 mg/L (normal, 0-10). Sixteen hours later, his blood pressure dropped to 63/25 mm Hg, the thrombocyte count decreased to 68 000/mm³, and blood urea nitrogen (BUN) increased to 38 mg/dL (normal, <20). Intravenous saline and dopamine were administered. Therapy with penicillin G and ceftizoxime was initiated. The patient's condition stabilized 2 days later. Skin exfoliation over the trunk and extremities was noted on February 27 and persisted until March 20. Therapy with penicillin was continued for 14 days total, and recovery was uneventful. No GAS was isolated from either blood or throat cultures.

Case 2

An 8-year-old boy developed fever, chills, vomiting, diarrhea, and general malaise 7 days after his cousin (case 1) became ill. Two days later, he was brought to a local hospital because of coldness and cyanosis of the limbs and dyspnea. At the emergency department, he appeared cyanotic and tachypneic. His temperature was 35.9°C; blood pressure, 64/38 mm Hg; pulse rate, 157 beats per minute; respiratory rate, 40 breaths per minute. Moist rales were found over the right lung field, and tenderness over the epigastric area was detected. Initial artery blood gas showed severe metabolic acidosis (pH 7.003, HCO₃ 7.9 mmol/L) and hypoxemia (PaO₂ 28.4 mmol/L). Laboratory studies resulted in the following: leukocyte count, 4600/mm³ (87% segmented neutrophils, 8% lymphocytes, 5% monocytes); platelet count, 49 000/mm³; CRP value, 315 mg/L; BUN, 57 mg/dL; serum creatinine, 3.8 mg/dL; aspartate transaminase, 166 mg/dL; alanine transaminase, 100 mg/dL; and creatine phosphokinase, 3501 U/L (normal, <170) with 5.5% MB fraction. Chest roentgenography showed segmental pneumonia over the right lower lung field.

Because of cyanosis and severe respiratory distress, the patient was intubated. Intravenous saline was infused and dopamine was administered. Therapy with ampicillin was started. The patient's condition deteriorated despite this management for 2 hours. An attempt was made to transfer the patient to a medical center; unfortunately, he progressed to a state of shock and unresponsiveness on the way and died. The blood culture taken at the local hospital subsequently yielded Streptococcus pyogenes.

Case 3

A 6-year-old boy, a younger brother of case 2, was admitted to Chang Gung Children's Hospital on March 13, 1999 (17 days after the index case became ill) because of fever, vomiting, diarrhea, and abdominal pain for 1 day. On admission, his temperature was 38.9°C; blood pressure, 77/44 mm Hg; pulse rate, 140 beats per minute; and respiratory rate, 26 breaths per minute. A diffuse erythematous rash on the trunk was noted. Initial laboratory studies showed a leukocyte count of 7000/mm³ (41% band forms, 55% segmented neutrophils, 4% lymphocytes), platelet count of 271 000/mm³, and CRP value of 22 mg/L. The patient was transferred to the pediatric intensive care unit immediately because of impending shock. Intravenous saline was infused, and inotropic agents, including dopamine, dobutamine, and epinephrine, were administered. Therapy with ceftriaxone, amikacin, and vancomycin was initiated, and 1 dose of intravenous immunoglobulin (2 g/kg) was infused. Two days later, the platelet count decreased to 43 000/mm³, petechia were noted, and thus a platelet transfusion was administered. The patient's condition was stabilized on the fourth hospital day, and the inotropic agents were discontinued gradually. A blood culture taken on admission yielded S pyogenes. Antibiotics were shifted to penicillin alone, and this was continued for 14 days total, with the addition of rifampin for the last 4 days. Recovery was uneventful.

	METHODS

Top Abstract Introduction Methods Results Discussion References

When we became aware that these cases represented a family cluster of STSS, we immediately notified the health bureau of the local government and conducted a pharyngeal culture survey of the family members and certain exposed schoolmates.

Survey of Family Members and Schoolchildren

The 3 cases lived in a large, 3-generation family, consisting of 7 small households. These families lived next to one another in a large 3-floor condominium building with 7 units. Except during festivals, the family meals were prepared and eaten separately. The children usually played together and sometimes shared food and water with each other. There were 34 persons in this extended family, but 13 members had been residing out of town. Excluding the 3 cases of STSS, pharyngeal culture for GAS was obtained from 15 of the 18 members at home, including 7 adults and 8 children.

Another family, relatives of the cases, lived in the neighborhood (several hundred meters away) and consisted of 3 adults and 5 children. Three childrenaged 5, 8 and 10 years, respectivelyhad high fever, sore throat, and mild cough on March 17 (the survey day). Pharyngeal culture was obtained from all of the 8 relatives.

At that time, case 3 and the elder sister of the index case (aged 5 years) attended a kindergarten class in a separate building, several hundred meters away from the elementary school. The children stayed in the kindergarten during the daytime of each weekday. Case 2 (class A, second grade) and his elder sister (class B, third grade) and elder brother (class C, fifth grade) attended the elementary school. Except for the whole day on Tuesday, the pupils in class A spent the morning time in the school every day; whereas the pupils in classes B and C stayed in the school during the daytime of each weekday except Wednesday. On March 17, 1999, pharyngeal cultures were systematically obtained from the children attending the kindergarten (13 children), class A (38 children), class B (38 children), and class C (36 children). The subject numbers and results of the pharyngeal culture survey are shown in Table 1. All pharyngeal specimens were collected using the Venturi Transystem (Copan, Italia Brescia, Italy), then transported to and processed in our microbiologic laboratory within 4 hours.

Laboratory Evaluation Methods for GAS Isolates

Isolates were confirmed as S pyogenes with the use of standard techniques. Antimicrobial susceptibility of the isolates was determined by the E-test (PDM Epsilometer, AB Biodisk, Solna, Sweden). The T-protein patterns of the isolates were determined by the slide agglutination method, as previously described.¹⁷ M serotyping is not feasible in Taiwan. The presence of speA, speB, and speC genes as well as serotypes M1, M6, and M12 was assessed with the polymerase chain reaction (PCR).¹⁷ Random amplified polymorphic DNA (RAPD) patterns by means of arbitrarily primed polymerase chain reaction (APPCR) of the isolates were performed with 2 arbitrary oligonucleotide primers OPA01: 5'-CAGGCCCTTC-3' and OPC-05: 5'-GATGACCGCC-3'. The reaction mixture for PCR and PCR conditions were followed as described previously.¹⁸

	RESULTS

Top Abstract Introduction Methods Results Discussion References

Of the 15 family members screened, only 1 child, who was the elder sister of the index case, had GAS isolated from pharyngeal culture. None of the 8 neighborhood family members was a carrier of GAS. One of 13 children in the kindergarten sampled had a throat culture positive for S pyogenes. Of the elementary schoolchildren sampled, positive results were noted in 2 children (8%) from class A, 4 children (11%) from class C, and none from class B, respectively. Overall, 6% of the children tested were positive for S pyogenes. The results of the pharyngeal culture survey are shown in Table 1. Including 2 isolates from the blood cultures of cases 2 and 3, a total of 10 isolates were obtained for analysis.

Of the 10 isolates examined, 2 isolates from the patients' blood cultures (strains 1 and 2), 1 isolate from the sister of the index case (strain 5), and 2 isolates (strains 3 and 4) from class A had an identical antimicrobial susceptibility profile, T-type (serotype T4), and RAPD pattern (type A). Four isolates (strains 6-9) from class C and 1 isolate (strain 10) from the kindergarten had an identical antimicrobial susceptibility profile and T-type (serotype T12), but for RAPD pattern, strains 9 and 10 were similar (type B), strains 7 and 8 were similar (type C), and strain 6 was unique (type D). The detailed antimicrobial susceptibility profiles, serotypes, and RAPD patterns (Fig 1) of these 10 isolates are shown in Table 2. These 10 isolates were not type M-1, M-6, or M-12. SpeB gene could be detected in all 10 isolates while speA and speC genes could not.

View larger version (119K): [in this window] [in a new window]   Fig. 1.   Gel electrophoresis of APPCR products obtained with primers OPC5 (upper panel) and OPA1 (lower panel). Lane M represents molecular weight marker (1 kb ladder); lanes 1 and 2, isolates from Cases 2 and 3; lanes 3 and 4, isolates from class A; lane 5, isolates from the sister of the index case; lanes 6 to 9, isolates from class C; lane 10, isolate from the kindergarten; and lanes 11 to 15, unrelated reference isolates.

	DISCUSSION

Top Abstract Introduction Methods Results Discussion References

This outbreak of STSS, caused by a single clone of S pyogenes, involved 3 children in a family. Person-to-person transmission of S pyogenes among these cases was documented by both genotyping and phenotyping methods of the related isolates. Although the index case lacked bacterial evidence of GAS infection, the diagnosis of STSS was presumed by the epidemiologic evidence of subsequent cases and the recovery of the same clone of S pyogenes from the pharyngeal culture of his sister, accompanied by a similar clinical manifestation. Previous reports^10,13-16 regarding family clusters of GAS infection indicate that children experience the vast majority of mild GAS infections, and play a major role in the spread of infection within families; most invasive GAS infections occur in adults, with the rate increasing with age. However, the risk of secondary cases of invasive infections in children cannot be ignored,¹⁰ a fact highlighted by the 2 subsequent cases of STSS in children, 1 fatal, reported in this article. To our knowledge, this is the first report of familial transmission of STSS in children in Taiwan.

Pharyngeal GAS infections can be acquired from either symptomatically or asymptomatically infected persons. GAS transmission occurs easily among close contacts in family, child care, school, and military training settings. After the introduction of the organism, the GAS carrier rate is typically higher, ranging from 20% to 80%,^19-21 among family members, schoolchildren, and military personnel. Cockerill et al²¹ demonstrated that the frequency of the outbreak clone among pharyngeal carriers was significantly higher in schoolchildren in the outbreak area. In the present study, the positive rate of pharyngeal culture for GAS did not increase and was still <10% among the schoolchildren as well as family members. In the investigation of an outbreak of scarlet fever at a child care center reported from Taiwan,¹⁸ the incidence of throat carriage of GAS among 131 children and 24 staff members without scarlet fever at the center was also <10%. It is possible that GAS colonization can occur in sites other than the throat and that GAS may be transmitted through routes other than exposure to large respiratory droplets.

The strains of GAS prevailing in Taiwan appeared to differ in different times and regions. During 1992 and 1993, the isolates of serotype T12 accounted for 42.3% of 78 clinical isolates and 87.5% of the 24 isolates recovered from throat swab samples from southern Taiwan.²² Serotype T4 was the predominant type of 83 clinical isolates from northern Taiwan during 1996 to 1998.²³ However, minimal inhibitory concentrations (MICs) of erythromycin were high among these isolates, and more than half of all isolates from both periods were resistant to erythromycin (MIC >0.5 µg/mL). In the present study, erythromycin MICs were high in the outbreak strains (serotype T4).

It has been documented that the presence of speA and its encoding toxin SPEA is strongly correlated with invasive GAS disease and STSS. In a previous study from Taiwan,¹⁷ speA was present in only 13% of 8 STSS-associated strains, while speB was present in all of 72 invasive disease, including STSS, isolates. A similar picture (negative speA but positive speB) was also noted in all 25 strains isolated from an investigation of an outbreak of scarlet fever at a child care center in Taiwan.¹⁸ The same is true in both the outbreak and colonizing strains in this study.

The issue of whether antimicrobial prophylaxis is warranted in prevention of invasive GAS disease among household contact was recently discussed by a working group on prevention of invasive GAS infection, and a consensus statement was published.¹⁶ No definite recommendation could be made at that time because of insufficient data. The present report, although still inconclusive, provides additional data of subsequent invasive GAS infection after household contact to support the strategy of antimicrobial prophylaxis. However, additional studies should be conducted in conjunction with surveillance to define better the magnitude of risk in household contacts and to identify settings in which subsequent infections occur.

Yhu-Chering Huang, MD, PhD^*
Po-Ren Hsueh, MD
Tzou-Yien Lin, MD^*
Dah-Chin Yan, MD^§
Shao-Hsuan Hsia, MD
^* Division of Pediatric Infectious Diseases
 Department of Laboratory Medicine, National Taiwan University Hospital
^§ Pediatric Allergy/Immunology
 Pediatric Critical Care Medicine
Chang Gung Children's Hospital
Chang Gung University
Kweishan, Taoyuan, Taiwan

	FOOTNOTES

Received for publication Apr 27, 2000; accepted Aug 30, 2000.

Reprint requests to (Y-C.H.) Chang Gung Children's Hospital, 5, Fu-Shin Street, Kweishan, Taoyuan, Taiwan. E-mail: kere{at}adm.cgmh.com.tw

	ABBREVIATIONS

GAS, group A streptococcus/streptococcal; STSS, streptococcal toxic shock syndrome; CRP, C-reactive protein; BUN, blood urea nitrogen; PCR, polymerase chain reaction; RAPD, random amplified polymorphic DNA; APPCR, arbitrarily primed polymerase chain reaction; MIC, minimal inhibitory concentration.

	REFERENCES

Top Abstract Introduction Methods Results Discussion References

1. Massel BF, Chute CG, Walker AM, Kurland GS Penicillin and the marked decrease in morbidity and mortality from rheumatic fever in the United States. N Engl J Med 1988; 318:280-286 [Abstract]
2. Stevens DL Invasive group A streptococcal infections: the past, present and future. Pediatric Infect Dis J 1994; 13:561-566 [Medline]
3. Cone LA, Woodard DR, Schilevert PM, Tomory GS Clinical and bacteriologic observations of a toxic shock-like syndrome due to Streptococcus pyogenes. N Engl J Med 1987; 317:146-149 [Medline]
4. Hribalova V Streptococcus pyogenes and the toxic shock syndrome. Ann Intern Med 1988; 108:772
5. Stevens DL, Tanner MH, Einship J, Severe group A streptococcal infections associated with a toxic shock-like syndrome and scarlet fever toxin A. N Engl J Med 1989; 321:1-8 [Abstract]
6. Begovac J, Marton E, Lisic M, Beus I, Bozinovic D, Kuzmanovic N Group A beta-hemolytic streptococcal toxic shock-like syndrome. Pediatr Infect Dis J 1990; 9:369-370 [CrossRef][Medline]
7. Hoge CW, Schwartz B, Talkington DF, Breiman RF, MacNeill EM, Englender SJ The changing epidemiology of invasive group A streptococcal infections and the emergence of streptococcal toxic shock-like syndrome: a retrospective population-based study. JAMA 1993; 269:384-389 [Abstract/Free Full Text]
8. Working Group on Severe Streptococcal Infections Defining the group A streptococcal toxic shock syndrome: rationale and consensus definition. JAMA 1993; 269:390-391 [Abstract/Free Full Text]
9. Centers for Disease Control Nursing home outbreaks of invasive group A streptococcal infectionsIllinois, Kansas, North Carolina, and Texas. MMWR Morb Mortal Wkly Rep 1990; 39:577-579 [Medline]
10. Schwartz B, Elliott JA, Butler JC, Clusters of invasive group A streptococcal infections in family, hospital, and nursing home settings. Clin Infect Dis 1992; 15:277-284 [Medline]
11. Centers for Disease Control and Prevention Outbreak of invasive group A Streptococcus associated with varicella in a childcare centerBoston, Mass . MMWR Morb Mortal Wkly Rep 1997; 46:944-949 [Medline]
12. Cannaday P, McNitt T, Horn K, Goodpasture H, Gentry LO A family outbreak of serious streptococcal infection. JAMA 1976; 236:585-587 [Abstract/Free Full Text]
13. DiPresio JR, File TM, Stevens DL, Gardner WG, Petropoulos G, Dinsa K Spread of serious disease-producing M3 clones of group A Streptococcus among family members and health care workers. Clin Infect Dis 1996; 22:490-495 [Medline]
14. Gamba M-A, Martinelli M, Schaad HJ, Familial transmission of a serious disease-producing group A Streptococcus clone: case report and review. Clin Infect Dis 1997; 24:1118-1121 [Medline]
15. Davies HD, McGeer A, Schwartz B, Invasive group A streptococcal infections in Ontario, Canada. N Engl J Med 1996; 335:547-554 [Abstract/Free Full Text]
16. Working Group on Prevention of Invasive Group A Streptococcal Infections Prevention of invasive group A streptococcal disease among household contacts of case-patients: Is prophylaxis warranted? JAMA 1998; 279:1206-1210 [Abstract/Free Full Text]
17. Hsueh PR, Wu JJ, Tsai PJ, Liu JW, Chuang YC, Luh KT Invasive group A streptococcal disease in Taiwan is not associated with the presence of streptococcal pyrogenic exotoxin genes. Clin Infect Dis 1998; 26:584-589 [Medline]
18. Hsueh PR, Teng LJ, Lee PI, Outbreak of scarlet fever at a hospital day care center: analysis of strain relatedness with phenotypic and genotypic characteristics. J Hosp Infect 1997; 36:191-200 [CrossRef][Medline]
19. Dingle JH, Badger GF, Jordan WS. Streptococcal infections. In: Dingle JH, Badger FG, Jordan WS, eds. Illness in the Home. Cleveland, OH: Case Western Reserve University; 1964:97-117
20. Holmstrom L, Nyman B, Rosengren M, Wallander S, Ripa T Outbreaks of infections with erythromycin-resistant group A streptococci in child day care centers. Scand J Infect Dis 1990; 22:179-185 [Medline]
21. Cockerill FR III, MacDonald KL, Thompson RL, An outbreak of invasive group A streptococcal disease associated with high carriage rates of the invasive clone among school-aged children. JAMA 1997; 277:38-43 [Abstract/Free Full Text]
22. Hsueh PR, Chen HM, Huang AH, Wu JJ Decreased activity of erythromycin against Streptococcus pyogenes in Taiwan. Antimicrob Agents Chemother 1995; 39:2239-2242 [Abstract]
23. Tseng HY, Hsueh PR, Lee PI, Huang LM, Lee CY, Luh KT. Extremely high proportion of M-phenotype in clinical isolates of erythromycin-resistant Streptococcus pyogenes in Taiwan. The 158th Scientific Meeting of the Chinese Taipei Pediatric Association; April 1999