126 Archives ofDisease in Childhood 1992; 67: 126-130 Arch Dis Child: first published as 10.1136/adc.67.1.126 on 1 January 1992. Downloaded from associated toxic

C Torres-Martinez, D Mehta, A Butt, M Levin

Abstract toxin-I (TSST-1). TSST-1 and other In the past few years, there appears to have enterotoxins are thought to cause the disorder been a change in the spectrum of disease by activating host inflammatory responses, and caused by group A ,-haemolytic streptococcus in particular by triggering release of cyto- (GABHS), and a toxic shock-like syndrome kines." caused by this organism has recently been In the past four years, there have been a described in adults. We report four children number of reports of a toxic shock-like disorder with an acute illness characterised by rapid occurring in both adults and children, which progression of shock, erythematous , has been associated not with S aureus but multisystem organ involvement, electrolyte with group A j3-haemolytic streptococcus derangements, and who fulfil (GABHS).73 Furthermore, there appears to the previously established diagnostic criteria have been an increase in the prevalence of for toxic shock syndrome. Three of the serious invasive disease due to GABHS in many children had extensive cutaneous and soft parts of the world.126 tissue and the fourth had peritonitis. In order to illustrate the clinical and patho- All four developed bacteraemia. Treatment logical features of the disease, we report four included aggressive cardiovascular resuscita- children with streptococcus associated toxic tion and therapy. Although no shock syndrome and discuss the mechanisms patient died, they suffered multiple and severe involved in its pathogenesis. complications requiring prolonged treatment and hospitalisation. Streptococcal toxic shock syndrome is a separate and clearly defined Patients and methods entity occurring in previously healthy children. Streptococcus associated toxic shock syndrome was diagnosed infourchildren between February 1988 and November 1990. Three were admitted In 1978, Todd and Fishaut described seven to the Hospital for Sick Children, Great children with an acute disease characterised by Ormond Street, London, and one to Guy's http://adc.bmj.com/ , mucous membrane , subcut- Hospital, London (table 1). All four cases aneous oedema, desquamating fulfilled the diagnostic criteria for staphylococcal and rapid progression to and multi- toxic shock syndrome,27 but in each case system organ involvement, and which they GABHS was isolated from the blood (table 2). called staphylococcal toxic shock syndrome.' The disorder subsequently became more widely Table 2 Criteria of staphylococcal toxic shock syndrome in children with associated toxic recognised as an illness affecting young women, (TSS) four streptococcus on September 29, 2021 by guest. Protected copyright. shock syndrome which was associated with vaginal colonisation by and the use of Case No . At least 13% ofcases are not associated 1 2 3 4 with menstruation but with focal staphylococcal Staphylococcal TSS criteria and/or colonisation,3 and a significant Temperature >389°C + + + + proportion of these non-menstrual cases are Rash + + + + Desquamation + + + + children. Hypotension + + + + In the past decade, major advances have Multisystem involvement Gastrointestinal - - + + occurred in the understanding of the patho- Muscular + + - + genesis of staphylococcal toxic shock syndrome. Mucous membrane + + + Renal + Infectious Disease Unit, It is now well established that most cases are Haematological - + + Academic Department caused by a number of related enterotoxins Hepatic + + of Paediatrics, Central nervous system - + - + St Mary's Hospital produced by S aureus, the most common of Medical School, which is the 22 kDa protein called toxic shock +, Present; -, absent. South Wharf Road, London W2 INY C Torres-Martinez Table I Clinical characteristics children with streptococcus associated toxic shock M Levin of four syndrome Department of Case Age Sex Clinical Initial Prodromal GABHS Paediatrics, No presentation symptoms period* isolation Guy's Hospital, London I 10 years F Shock, fasciitis Fever, rash 6 days Blood, skin wound D Mehta 2 22 months F Shock, Fever, focal swelling 12 hours Blood, builae, nose, skin A Butt 3 13 days F Peritonitis, shock Diarrhoea, rash 3 days Blood, nose, peritoneal fluid 4 10 weeks F cellulitis Fever, focal 18 hours Blood Correspondence to: Shock, swelling Professor Levin. *From onset of symptoms to shock. Accepted 14 August 1991 GABHS, Group A ,1 haemolytic streptococci. Streptococcus associated toxic shock 127

Microorganisms were recovered and identified spite of the decompression of her forearm, the according to standard procedures.28 Antibiotic muscles looked progressively less viable over susceptibility was determined by the disc the next few days. A bone scan suggested an Arch Dis Child: first published as 10.1136/adc.67.1.126 on 1 January 1992. Downloaded from diffusion method in the microbiological labora- avascular right ulna. Antibiotic therapy was tories of the respective hospitals. changed to cefotaxime and . Sensation of the right hand disappeared, and three weeks after admission, amputation of the CASE REPORTS right upper limb below the elbow was carried Case I out. Additional amputation of her feet was A previously healthy 10 year old girl experienced avoided, although extensive skin grafting was pain and swelling over both ankles three days necessary. Progressive clinical recovery followed after sustaining a cut below her left knee. She with re-establishment of normal renal, hepatic, subsequendy developed a non-specific macular and pulmonary function. She returned to the erythematous rash and fever and was admitted local hospital five weeks after initial admission. to a local hospital. During the ensuing five days, she became increasingly tachycardic and jaundiced, and blistering areas were noted in Case 2 the right upper limb. A 22 month old girl presented to a local hospital After 24 hours of progressive drowsiness and with a one week history of cough, fever, and hypotension she was transferred to Guy's mild facial swelling. One day before admission, Hospital where, on arrival, she was toxic and she developed multiple red bullae over her lethargic but responsive. Her temperature was trunk and limbs. On admission, she was febrile 39°C, heart rate 150 beats/min, respiratory rate (40 6°C), with a rate of 200 beats/min, and 40/min, and systolic 85 mm Hg. blood pressure of 65/40 mm Hg. She had She had red lips and tongue with conjunctival generalised subcutaneous oedema and delayed hyperaemia and mild icterus. A soft 2/6 systolic peripheral perfusion. A presumptive diagnosis murmur was noted. The was 2 cm below of was made and aggressive fluid the right costal margin. Her ankles and wrists (in excess of 300 ml/kg) was were intensely swollen. A fine papular general- instituted. Initial antimicrobial therapy included ised rash with desquamation, particularly over flucloxacillin, fusidic acid and . the trunk and limbs, was found in conjunction Laboratory investigations recorded haemoglobin with large yellow blisters and necrotic areas over concentration 82 g/l, white cell count 3 5 x 109/1, her right forearm and lateral aspect of her left neutrophils 1 9x 109/1, platelet count 90x 109/1, foot. The pulse in the right radial artery was concentrations of sodium 129 mmol/l, potas- absent, though detectable on Doppler examina- sium 2-7 mmol/l, calcium 1- 86 mmol/l, crea- tion. Initial investigations were as follows: tinine 48 Fmol/l, urea 7-1 mmol/l, albumin 22 haemoglobin concentration 87 g/l, white cell g/l, fibrinogen 4-6 g/l and fibrin degradation count 30x 109/1 with 25 x 109 neutrophils, products >20 [tg/ml, prothrombin time 51 platelet count 251 x 109/l, and erythrocyte sedi- seconds (control 14 second), partial thrombo- http://adc.bmj.com/ mentation rate 45 mm/hour. Biochemical find- plastin time 35 seconds (control 32 seconds), ings showed concentrations of sodium 125 aspartate aminotransferase 152 U/I and creatine mmol/l, urea 22-4 mmol/l, creatinine 175 ,umol/l, phosphokinase 221 U/1. GABHS was grown bilirubin 71 mmol/l and albumin 31 g/l, creatine from blood, fluid from bullae, and her nose. phosphokinase 3108 U/l and aspartate amino- was added to her antimicrobial transferase 181 U/1. Urine contained granular therapy.

casts and blood cells, and was positive for After resuscitation her condition improved on September 29, 2021 by guest. Protected copyright. myoglobin -and protein (3+), urinary sodium but she continued to be febrile and developed was less than 10 mmol/l. Blood cultures and swelling over her left forearm and calf. She was swabs from the cut below the left knee grew referred to the Hospital for Sick Children with a GABHS. possible diagnosis of necrotising fasciitis. On She was resuscitated with large volumes of arrival she was febrile (39°C) with a heart rate of colloid and required inotropic support with 190 beats/min. She had enlarged and tender dobutamine and dopamine. Despite an adequate lymph nodes in the left cervical chain and central venous pressure, she remained poorly generalised subcutaneous oedema. A left sided perfused; a continuous infusion of prostacyclin cervical mass anterior to the carotid vessels was was introduced as a vasodilator. She was elec- demonstrated on cervical ultrasound and tively ventilated and required full sedation and thoracic computed tomography. A technetium paralysis. High dose penicillin and flucloxacillin white cell scan suggested an inflammatory were started. Her oxygen requirement increased lymphadenitis as there was marked focal uptake over the next few hours and radiological changes of the labelled white cells. A nuclear magnetic consistent with adult respiratory distress syn- resonance scan revealed multifocal soft tissue drome appeared. After resuscitation, her renal lesions in the left side of the neck and extending and hepatic function returned slowly to normal. into the superior mediastinum. Surgical ex- Swelling of the soft tissues over her right ploration was carried out, and necrotic tissue wrist and elbow joints became more noticeable. was obtained, but there was no evidence of pus As she was weaned off muscle relaxant drugs, a formation. Histologically, necrotic and infarcted compartment compression syndrome was diag- tissue was seen which contained Gram positive nosed in her right forearm and in both legs. cocci in chains. No growth in culture was Fasciotomy was carried out in all affected limbs observed. Gentamicin was discontinued and and yellow fluid drained from the fasciae. In rifampicin commenced. 128 Torres-Martinez, Mehta, Butt, Levin

Extensive desquamation became apparent by 22 days in hospital having discontinued anti- day 8 after admission. After surgery, the child biotic therapy the day before. She continued started to improve and the fever abated although having intermittent for a further 20 days. Arch Dis Child: first published as 10.1136/adc.67.1.126 on 1 January 1992. Downloaded from she developed severe hypokalaemia (potassium On follow up one and four months later she was concentration 1-4 mmol/l) which responded to found to be asymptomatic and thriving. treatment. She was discharged two weeks later. Extensive virological and bacteriological tests failed to show any other pathogen. There was Case 4 progressive clinical and radiological resolution Pallor and hypothermia developed in a 10 week of the cervical mass over the next six weeks. old girl. Over the next 18 hours a small red Immunological investigations showed normal lesion in the left submandibular region became total immunoglobulins, Nitroblue tetrazolium indurated, swollen, and hot, and extended to reduction and lymphocyte responses and involve both sides of her neck. On admission to subsets, but low IgGj and IgG2 values were the Hospital for Sick Children she was febrile demonstrated on initial investigation. On repeat (39-5°C), her blood pressure was 75/35 mmHg, studies four months later all immune function heart rate 200 beats/min, and respiratory rate tests were normal. 65/min. The oral mucosae were reddened and she was very poorly perfused. She was resusci- tated with plasma and crystalloids, requiring Case 3 350 ml/kg in the first day. In addition, she was A 13 day old girl was referred to the surgical started on flucloxacillin, gentamicin, and unit at the Hospital for Sick Children, London, ampicillin. Two hours after admission she with a three day history of erythematous rash developed metabolic acidosis, bradycardia, and and diarrhoea, for 24 hours, and apnoea, requiring mechanical ventilation. On refusal to feed. On admission, examination her initial investigations she was found to have a showed she had a toxic appearance, central haemoglobin concentration of 80 g/l, sodium cyanosis, and poor peripheral perfusion. Her 123 mmol/l, potassium 2-4 mmol/l, chloride 93 blood pressure was 54/30 mm Hg, heart rate 160 mmol/l, calcium 1-9 mmol/l, high of creatine beats/min, and central temperature 39-2°C with phosphokinase at 826 U/1, and prolonged a gap between central and peripheral tempera- coagulation tests. Two right sided focal seizures ture of 3 6°C. Her abdomen was grossly dis- were observed in the first 6 hours. Cerebrospinal tended and rigid, and the bowel sounds were fluid examination was normal. Blood cultures absent. The rash had become confluent and grew GABHS, and penicillin plus gentamicin spread to her back. Initial investigations were continued. Within the first two days, she recorded haemoglobin concentration 108 g/l, developed progressive anaemia (lowest haemo- white cell count 23-5 x109/l with 93% neutro- globin 70 g/l) requiring packed red blood cells, phils, platelets 92 x 109/1, concentrations of and a generalised erythematous rash which later sodium 125 mmol/l, potassium 3-3 mmol/l, desquamated. Over the next 48 hours, her creatinine 53 tmol/l, urea 9 3 mmol/l, calcium shock resolved but she continued to require http://adc.bmj.com/ 2 1 mmol/l, and albumin 24 g/l, prothrombin ventilation. Mechanical ventilation was stopped time 39 seconds (control 10-14 seconds) and after three days. The cellulitis subsided slowly partial thromboplastin time more than 120 and the patient was discharged on oral anti- seconds. Abdominal radiographs showed con- biotics on day 14. siderable bowel distension and evidence of free fluid.

Over the next 18 hours she became profoundly Discussion on September 29, 2021 by guest. Protected copyright. shocked and required over 300 ml/kg of plasma The four children reported in this series all and crystalloids in the first 18 hours to maintain suffered from a fulminant disorder characterised perfusion, blood pressure, and urine output. A by shock, multisystem involvement, and a laparotomy was performed because a surgical distinctive erythematous rash, which fulfilled cause of the shock and the abdominal findings the diagnostic criteria for toxic shock syndrome, could not be excluded. Purulent peritoneal fluid but was associated not with staphylococcal was found but no other pathology. Microscopic infection but with GABHS sepsis. These cases examination contained 4500 white blood cells/l, are strikingly similar to the reports of strepto- protein 10 g/l, and abundant Gram positive coccal toxic shock syndrome in adults,7-11 and cocci. High dose penicillin was administered. to a similar disorder previously described after Blood and peritoneal cultures grew GABHS varicella infection in three children.'2 13 sensitive to penicillin. The clinical and laboratory features in these After the operation she required mechanical cases are sufficiently distinctive and dramatic ventilation for three days. Two days later she that they could hardly have gone unrecognised began to desquamate and this continued for by clinicians in the past few decades. The more than one week, affecting most of her question therefore arises as to whether the body. Over the next 10 days she continued to growing number of reports of streptococcal have a spiking fever (39-39 5°C), associated toxic shock syndrome represents the emergence with leucocytosis and neutrophilia. Chest radio- of a 'new' streptococcus associated syndrome, graphs showed patchy consolidation in the right or whether it reflects the rediscovery of an lower lobe. Subsequently, her clinical condition entity which may have been more common in improved, and her renal function, electrolyte the preantibiotic era. values, and platelet count slowly returned to Before 1940, streptococcal infections normal. The patient was finally discharged after accounted for a major proportion of infectious Streptococcus associated toxic shock 129

conditions seen in many centres in developed tion and bacteraemia. Desquamation is less countries. Deaths from streptococcal bacter- frequently seen in the streptococcal syndrome. aemia, severe , and were Among 26 adults only eight (31%) had des- Arch Dis Child: first published as 10.1136/adc.67.1.126 on 1 January 1992. Downloaded from common.'0 21 The fatality rate for streptococcal quamation.8 9 In view of the extensive soft bacteraemia was found to be 72% in the total tissue involvement in streptococcal toxic shock, population and 62% in children under 15 years surgical intervention is more commonly required old in 1937.29 Based on the clinical description than in the staphylococcal syndrome. Finally, of the disease in those patients, it is possible that the timing of events may differ from that in the the disorder now termed streptococcal toxic staphylococcal syndrome as the rash in the shock syndrome accounted for some of the streptococcal syndrome may appear late in the severe cases and deaths. With the decline in the disease and coexist with the desquamation. incidence of streptococcal infections in the From the therapeutic point of view, prompt developed world, modern clinicians may have recognition and understanding of the natural simply lost their familiarity with this particular history and progression of the disease should . However, a definite increase in lead to an aggressive intensive care approach. the incidence of serious disease associated with Correction of hypovolaemia by infusion of large GABHS has been noted in the past decade. amounts of colloid, inotropic support, and if Reports describing severe generalised and focal necessary ventilatory assistance must be imple- infections in children with and without underly- mented to correct shock and restore adequate ing disorders have appeared.'1126 In addition, oxygen delivery to the tissues. In addition, there is evidence that non-suppurative compli- prompt antimicrobial therapy should be started, cations of streptococcal infection, such as and penicillin remains the drug of choice for , have re-emerged in scattered GABHS infections. Until the microbial cause areas in the .30 31 Increased has been identified, antistaphylococcal cover prevalence of pathogenic strains of GABHS has should be included. Surgical intervention to been suggested as the explanation for the rising remove focal infection and reduce the amount of number of cases of severe infection.32 toxin released may be necessary. Despite the The pathogenic mechanisms by which the fulminant nature ofthe illness and the prolonged streptococcal toxic shock syndrome is caused and complicated course, complete recovery is are unknown, but it is likely that the production possible with early and aggressive treatment. of one or more toxins induces the clinical manifestations of the disease. GABHS has the Dr Torres-Martinez is supported by a research grant from the Max Friedman Trust. We are grateful to Dr L Stimler for capability to produce at least four serologically us to report his patient. different types of .33 34All of them are allowing pyrogenic, may enhance host susceptibility to lethal endotoxic shock, produce non-specific 1 Todd J, Fishaut M. Toxic shock syndrome associated with phage group 1 staphylococci. Lancet 1978;ii:1116-8. stimulation of T lymphocyte proliferation, 2 Shands KN, Schmid GP, Dann BB, et al. Toxic shock enhance delayed hypersensitivity, and suppress syndrome in menstruating women: its association with

use and Staphylococcus aureus and the clinical http://adc.bmj.com/ immunoglobulin synthesis.34 In addition, they features in 52 cases. N EnglIJ Med 1980;303:1436-42. may act as potent release inducers of tumour 3 Reingold AL, Shands KL, Dann BB, Broome CV. Toxic shock syndrome not associated with menstruation: a review necrosis factor.6 In view of the clinical similar- of 54 cases. Lancet 1982;i:1-4. ities of the staphylococcal toxic shock syndrome 4 Schlievert PM, Shands KL, Dann BB, Schmid GP, Nishimura to it is BD. Identification and characterization of an from the syndrome seen in our patients, of Staphylococcus aureus associated with toxic shock syn- interest that there seems to be considerable drome. J Infect Dis 1981;143:509-16. 5 Todd JK, Franco-Buff A, Lowellin DW, Vasil ML. Pheno- amino acid homology between and A and C typic distinctiveness of Staphylococcus aureus strains

streptococcal toxins and staphylococcal entero- associated with toxic shock syndrome. Infect Immun on September 29, 2021 by guest. Protected copyright. These toxins not have a similar 1984;45:339-44. toxins.35 only 6 Fast DJ, Schlievert PM, Nelson RD. Toxic shock syndrome- structure but also common modes of action on associated staphylococcal and streptococcal pyrogenic toxins are potent inducers of tumour necrosis factor. Infect the immune system. TSST-1 and other staphylo- Immun 1989;S7:291-4. coccal enterotoxins, streptococcal pyrogenic 7 Cone LA, Woodward DR, Schlievert PM, Tomory GS. toxins act as Clinical and bacteriologic observations of a toxic shock-like exotoxins, and some syndrome due to . N Engl J Med , binding to specific variable j3 1987;317:146-9. 8 Bartter T, Dascal A, Carroll K, Curley FJ. 'Toxic strep chain regions of the T cell receptor in association syndrome': a manifestation of group A streptococcus with human class II major histocompatibility infection. Arch Intern Med 1988;148:1421-4. 9 Hribalova C. Streptococcus pyogenes and the toxic shock complex proteins, and stimulating T cell syndrome. Ann Intern Med 1988;108:772. proliferation and cytokine release by the T 10 Stollerman GH. Changing group A streptococcus: the re- appearance of streptococcal 'toxic shock'. Arch Intern Med cells.35 36 Release of these inflammatory 1988;148:1268-70. mediators probably accounts for the clinical 11 Stevens DL, Tanner MH, Winship J, et al. Severe group A streptococcus infections associated with a toxic shock-like manifestations of both the staphylococcal and syndrome and scarlet fever toxin A. N EnglJ Med 1989;321: streptococcal associated diseases. 1-7. 12 Begovac J, Morton E, Lisic M, Beus I, Bozinovic D, Despite the clinical similarities and the Kuzmanovic N. Group A beta-hemolytic streptococcal common mode of action of their related toxins, toxic shock-like syndrome. Pediatr Infect Dis J 1990;9: 369-70. there are a number of clinical differences 13 Bradley JS, Schlievert PM, Sample TG Jr. Streptococcal between the streptococcal and the staphylo- toxic shock-like syndrome as a complication of varicella. Pediatr Infect Dis J 1990;10:77-9. coccal . In staphylococcal toxic shock 14 Dudding B, Humphrey GB, Nesbit ME. 3-hemolytic strepto- the site of is often a coccal septicemia in childhood leukemia. Pediatrics 1969; 43:359-64. trivial focus or asymptomatic colonisation, and 15 Chonmaitre T, Powell KR. Parapneumonic pleural effusion bacteraemia seldom occurs. In contrast, most and empyema in children. Clin Pediatr (Phila) 1983;22: 414-9. cases of streptococcal toxic shock syndrome are 16 Coulter JB, Buchannon CR, Vellodi A. Group A streptococcus associated with severe streptococcal focal infec- infection in the newborn. Lancet 1984;ii:355-6. 130 Torres-Martinez, Mehta, Butt, Levin

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