Burns (1990) 16, (3), 221-224
221
Printed in Great Britain
Toxic shock syndrome
in scalded children*
R. P. Cole and P. G. Shakespeare Wessex Centre for Plastic and Maxillofacial Salisbury, Wiltshire, UK
Surgery and Laing Laboratory
Five patients showing clinical signr resembling the ‘toxic shock syndrome presented over a crnonth period at the Wesspx Regional Bums Centre. Toxin-producing isolates of Staphylococcus aureus were made from wound swabs in four of the five patients. Four diferent phase types producing four different toxins were observed. Seven other patients yielded staphylococci from wound swabs but did not develop the toxic shock syndrome. In three of these latter patients the staphylococcus isolated wlls totin produn’ng. Since the syndrowz carries a s&r&ant mortality risk it is desirable that it is recognized and treated without delay. To this end a simplified set of criteria for the identification of probable toxic shock syndrome uses is proposed. The observations suggest that toxic shock syndrome is more ~0mrnonthan previously supposed. The syndrome may show a broad spectrum in its clinical presentation, and involve a wide range of staphylococcal phage types with possible involvement of several different enterotoxins.
Introduction The toxic shock syndrome (TSS) was first described by Todd et al. (1978) in seven children aged 8-17 years who were not burned patients. One child died. Since the original description, most reports of TSS have described its occurrence in menstruating women in association with the use of tampons. However, several cases of TSS have been reported in burned patients. Seven cases were reported by Frame et al. (1985), of whom four died. Three further cases were reported by Farmer et al. (1985), Holt et al. (1987) and Egan and Clark (1988). Brain et al. (1988) described two further cases. Overall it is estimated that TSS carries a mortality risk of approximately 11 per cent (de Saxe et al., 1985). The diagnosis of TSS is made retrospectively, mainly on clinical grounds. Depending upon the features present, a diagnosis of ‘definite’ TSS or ‘probable’ TSS is made. ‘Definite’ TSS is the presence of all six diagnostic criteria listed in Table I. ‘Probable’ TSS is either the presence of any five of the six criteria listed in Tuabk I or the presence of all criteria listed in Tuble II. In de Saxe’s review (de Saxe et al., 1985) only half of the non-menstrual cases of TSS satisfied all six of the criteria required to diagnose ‘definite’ TSS. The *Since this paper was prepared the simplified criteria have been used prospectively to identify three further cases of ‘probable’ TSS in scalded children. All three cases showed wound colonization with Staphylococcus aurew, two of which were phage typable. All three isolates were toxin producing, the non-typable isolate producing SEB, the typable isolates (29152 and 29/52/79) both producing TSST-I.
Butterworth-Heinema 0305-4179/90/03022144 dc 1990
Ltd
for Burn Injury Investigation,
Odstock
Hospital,
commonest diagnostic criteria absent from non-menstrual TSS cases were hypotension and desquamation. It has been suggested that to diagnose TSS post mortem requires a modified set of criteria (de Saxe et al., 1985) because desquamation occurs during the convalescent phase. This Table I. Toxic shock syndrome case definition* 1. Fever (temperature 3 39.2X [102-F]) 2. Rash (diffuse macular erythroderma) 3. Desquamation, l-2 weeks after onset of illness, particularly of palms and soles 4. Hypotension (systolic blood pressure < 90 mmHg for adults or < 5th percentile by age for children < 16 years of age; or orthostatic syncope) 5. Involvement of three or more of the followina oraan svstems: A. Gastrointestinal (vomiting or diarrhoea at-onset of illness) B. Muscular (severe myalgia or creatine phosphokinase level ~2 x ULN) C. Mucous membrane (vaginal, oropharyngeal or conjunctival hyperaemia) D. Renal (BUN or Cr>2 x ULN or >,5 white blood cells per high power field - in the absence of a urinary tract infection) E. Hepatic (total bilirubin, SGOT (AST), or SGPT (APT) 22 x ULN) F. Haematological (platelets d 100 x 1 O-s.l- ‘) G. Central nervous system (disorientation or alterations in consciousness without focal neurological signs when fever and hypotension are absent) . 6. Negative results on the followmg tests, If obtamed: A. Blood, throat or cerebrospinal fluid cultures B. Serological tests for Rocky Mountain spotted fever, leptospirosis or measles ‘The criteria are taken from Centre for Disease Control (1980). ULN, upper limit of normal range; BUN, blood urea nitrogen; Cr. serum creatinine.
Table II. Diagnostic categories of toxic shock syndrome (TSS) Probable TSS ( 2 3 criteria and desquamation or > 5 criteria without desquamation) Temperature > 38.9-C Rash Hypotension, orthostatic dizziness or syncope Myalgia Vomiting, diarrhoea or both Mucous membrane inflammation (conjunctivitis, pharyngitis. vaginitis) Clinical or laboratory abnormalities of 32 organ systems Reasonable evidence for absence of other aetiologies *The criteria are taken from Tofte and Williams (1981).
Bums (1990) Vol. 16/No. 3
222
anomaly means that TSS, is, by definition, a non-fatal condition because to fulfil all the six criteria for definite diagnosis the patient must have reached the convalescent stage. Another anomaly is that early intervention may alter the course of the disease and therefore preclude its diagnosis. Difficulty also occurs when applying some of the criteria, for example myalgia or headache, to small children. The symptoms of TSS are caused by the direct effects of the toxin on the tissues, mediator-dependent effects and sequelae to -organ damage secondary to hypotension (Mittag, 1988). Staphylococci may produce eight different including enterotoxins, toxic-shock-syndrome-toxin-~ (TSST-I). In menstrual cases of TSS, over 90 per cent of strains produce TSST-I, whereas in non-menstrual cases only 60-65 per cent of strains produce TSST-1 (de Saxe et al., 1985; Garbe et al., 1985). There has been no detailed report of phage types and toxins produced in staphylococci isolated from burned patients. The present study reports five cases of probable TSS in burned patients, with descriptions of the organisms involved. The dficulties encountered with the diagnosis (and possible underdiagnosis) are discussed.
Patients and case reports Over the 4-month study period, 36 children under the age of 4 years were admitted to the Wessex Regional Burns Centre with burns ranging from 0.25 to 41 per cent total body surface area (TBSA). Most of the injuries were caused by scalds (33), the remainder being contact burns. The mean age of the children was 15 months (range &47 months). The mean burn area was 12 per cent of total body surface. Children were resuscitated using one plasma volume (45 ml/kg body weight) of human albumin solution (Human Plasma Protein Fraction, HPPF, 45 g/l albumin) per 15 per cent of body surface area burned; half given over the first 8 h after injury and half given over the next 16h (Cason, 1981). Oral maintainence fluids of LOO-120mVkg body weight were given orally. Additional fluid was given to replace losses due to pyrexia, vomiting, diarrhoea and ‘shock depending on clinical assessment of electrolyte balance and circulatory state. Burns were dressed with nitrofurazoneimpregnated gauze unless the hands were involved, when silver sulphadiazine (Flamazine) and plastic bag dressings were used. As a routine procedure prophylactic systemic antibiotics are not given and no patient in this study had received them. All bums were swabbed on admission and nose and throat swabs were also taken. Burns were swabbed at dressing changes. Any staphylococci isolated from bum wounds were sent for phage typing and toxin production studies. Five children developed probable TSS during the study period. The mean bum area of this group was 20 per cent BSA and the mean age 18 months (range 14-23 months). Staphylococci were isolated from 11 of the 36 burned children. Four different phage types were isolated from five probably TSS cases, all of which were toxin-producing strains. Seven children showed staphylococcal isolates but did not develop probable TSS. Three of these isolates were toxin-producing strains of which two were TSST-1 producers. Clinical details of the five cases of probable TSS are as follows: CaSel A 19-month-old girl was admitted with a 15 per cent TBSA scald
assessed as mainly superficial. She was resuscitated with HPPF as
described above. The day following her injury she became irritable, passed several loose stools and her core temperature rose to 40°C. She showed a lymphopenia with lymphocyte count of 1.9 x 10’. The following day she was tachycardic and cold peripherally. She was treated with penicillin (125mg) and erythromycin (125mg) given orally qds for 7 days and received normal human immunoglobulin (3 g) intravenously. Over the following 48 h her condition improved. She underwent surgery to repair some small unhealed areas approximately 2 weeks later. Cultures taken from her bums on day 4 after injury grew a Staph. aurew, phage type 94196, which produced staphyloccocal enterotoxin (SE) B. case2
A 19-month-old
boy was admitted with a scald of 41 per cent TBSA. He was resuscitated with HPPF as previously indicated (see above Case I). The next day he became restless and irritable with a core temperature of 39°C. The following day he was shocked, tachypnoeic and had a core temperature of 40°C. He showed a lymphopenia with lymphocyte count of 2.5 x 109/1, and passed several loose stools. He was treated with gentamicin (20 mg, tds) and fludoxacillin (125 mg, qds) given intravenously for 5 days, and received a blood transfusion. He made a gradual recovery and his bums healed spontaneously. A staphylococcus phage type 29/52/79&O producing both TSST-I and SEC was isolated from wound swabs collected on day 2 after injury. case 3 A 21-month-old girl was admitted with an 8 per cent TBSA mixed depth scald. For the first 48 h her progress was uneventful, but she then developed a core temperature of 39.8’C, diarrhoea and a generalized rash. She showed a lymphopenia with lymphocyte count of 1.7 x 10’. The next day she was irritable, shocked and pyrexial. She was treated with penicillin (150 mg) and flucloxacillin (125mg) given intravenously qds for 3 days, with the same dosage continued orally for 1 week. Her condition stabilized and improved over the following 4 days. Small areas of unhealed burn were grafted at 3 weeks after injury. The staphylococcus isolated from her wounds on day 4 after injury was phase type 47/53/54/ 84 which produced SEC and SED. case4 A 23-month-old boy was admitted with a scald, mostly superficial, of 25 per cent TBSA. He was resuscitated uneventfully with HPPF. The following day he was pyrexial with core temperature of 39.5”C. Over the next 2 days his pyrexia persisted, he vomited repeatedly and became irritable. His serum urea level was normal but serum creatinine rose to 114 pmol/l. He showed a lymphopenia with lymphocyte count of 0.4 x 109/1. He became shocked, developed oedematous oral and nasal mucosae and an erythematous rash. He was treated with penicillin (150mg) and flucloxacillin (125 mg) given intravenously qds over 6 days. Over the next 4 days his condition improved and on day 7 he was given a blood transfusion. The staphylococcus isolated from the scald on day 3 after injury was phage type 29/42/53/85, producing SEB. case5 A 14-month-old girl was admitted with a 25 per cent TBSA mixed depth scald. She was resuscitated uneventfully with HPPF. The following day she vomited repeatedly and passed several loose stools. The next day she became irritable, developed a pyrexia with core temperature of 39”C, shock and a metabolic acidosis. Her serum creatinine level was KWpmol/l and she showed a thrombocytopenia with platelet count of 32 x lop/1and a lymphopenia with a lymphocyte count of 1.6x lO’/i. She was given an infusion of sodium bicarbonate (5 mM) and treated with flucloxacillin (120 mg) given intravenously qds over 7 days. Two
223
Cole and Shakespeare:Toxic shock syndrome in scalded children
days later she developed an erythematous rash. Her general improved. The involvement of Staph. sp.
Table III. Staphylococcal
phage types and toxin production
condition subsequently
in this case is uncertain since a swab was not taken from
the wound
immediately before the start of antibiotic treatment. Summary details of the microbiological findings in these cases are shown in
Table III.
Discussion A simplified set of criteria to diagnose TSS is desirable when managing burned children in order to enable the initiation of treatment as early as possible. Burned children are probably immunocompromised by their injury and are therefore likely to be more susceptible to the effects of circulating toxins produced by bacterial colonization of their burns (Frame et al., 1987). Early intervention should reduce sequelae such as metabolic acidosis, clotting abnormalities, convulsions and death. The simplified set of criteria shown in Tubk IV were used to initiate treatment in the cases reported in this study. Five of the six criteria are found in the case definitions of ‘definite’ and ‘probable’ TSS. The sixth criterion, lymphopenia, was included because burned children with TSS show a significantly greater fall in lymphocyte count than control patients (Brain et al., 1988). Retrospective analysis of the five cases fulfilling these criteria led to the diagnosis of ‘probable’ TSS being made in all five cases. There is considerable controversy surrounding the management of TSS. In theory it should be possible to prevent TSS by eradicating all staphylococci on admission to the Bums Unit. Topical agents such as pseudomonic acid (mupirocin) are highly effective against Gram-positive cocci. However, there have been reports of mupirocin-resistant strains (Baird and Coia, 1987; Rahman et al., 1987) and of reactions to the polyethylene glycol base (Daly, 1987). Flucloxacillin has been given prophylactically to all burned children (Frame et al., 1985) but widespread use of this antibiotic may encourage the development of resistant strains of bacteria (Finch, 1988). It has been suggested that closed dressings predispose patients to TSS because they act as a mechanical barrier which provides a culture medium for staphylococcal colonization in a similar way to tampons in menstruating women (Egan and Clark, 1988). None of the reported cases occurred when the bums were treated by exposure. Less controversial measures include aggressive monitoring, intravenous fluids and parenteral antistaphylococcal therapy. Transfusion of fresh blood or blood products may confer passive immunity by the provision of immunoglobulins in the IgG-1, IgG-2 and IgG-3 subclasses (Frame et al., 1985, 1987). It has been shown that TSS patients lack pre-immunity to TSST-1 in all four IgG subclasses (Christenson et al., 1986). Immunoglobulin transfusion was used in treating Case 1 in the present study. Staphylococci can produce eight enterotoxins, A, B, C,, C,, C,, D, E, F. Enterotoxin F is also known as toxic-shocksyndrome-toxin-l (TSST-1). These toxins are relatively low molecular weight glycoproteins. There need not be active infection of the burn wound for TSS to occur and where details are given in previous case reports (Frame et al., 1985; Holt et al., 1987) the burn wounds of the patients appeared clean. TSS is not restricted to patients with large TBSA bums. The mean TBSA in the series reported by Frame et al. (1985) was 19 per cent (range 4-10 per cent). The case reported by Egan and Clark (1988) involved a patient with 5 per cent TBSA bum. Details of staphylococcal phage types and toxins in TSS
Case 1 2 3 4 5
Table Iv.
Phage types
Toxin
94196 29f52/79fao 47/53i54/84 29i42t53ia5 No staphylococcus isolated
SEB TSST-1, SEC SEC, SED SEB --
Toxic shock syndrome - simplified criteria
for children
Pyrexia B 39°C Rash Shock Diarrhoea and/or vomiting Irritability Lymphopenia
cases in burned patients have been poorly documented. In the five cases where phage typing was performed (Frame et al., 1985; Holt et al., 1987; Egan and Clark, 1988) all were phage type 29 or 29/53. Toxin studies were reported in only two cases. One produced TSST-1 (Holt et al., 1987), the other SEB (Farmer et al., 1985). In the present series of patients reported, four different phage types and four different toxins, SEB, SEC, SED and TSST-1, were implicated. The response to circulating staphylococcal toxins is variable and not always related to pre-existing antibody status. Following an outbreak of a TSST-1 producing strain of Staph. Rt(reCISon a Burns Unit, two patients who had low antibody levels to TSST-I when colonized did not develop TSS (Amow et al., 1984). In particular one of the patients showed a clear serological response to the toxin but was asymptomatic. This implies that toxin production failed to reach clinically significant levels and supports the hypothesis that TSS is not an all or nothing response to staphylococcal toxin. It has been suggested that a broad clinical spectrum of TSS exists because certain patients are more genetically susceptible to the toxin or because different circulating levels of toxin produce different effects (Tofte and Williams, 1981). Approximately one-quarter to one-third of human staphylococcal isolates produce TSST-1 (Notermans et al., 1983), although it should be emphasized that these observations were made in vitro. Antibodies to TSST-1 have been demonstrated in over 90 per cent of normal healthy adult subjects (Notermans et al., 1983). This suggests that most people have encountered TSST-1 producing strains and developed antibodies without suffering TSS. Only 30 per cent of children between 1 and 2 years of age have titres > 1: 100 against TSST-1 (Vergeront et al., 1983). Maternal antibody to TSST-1 has been detected in babies up to 9 months of age (Vergeront et al., 1983). This might explain the age distribution in reported cases. In the 10 cases where details are available, only one occurred in a child under 12 months of age (Frame et al., 1985). It should be emphasized that no staphylococcal microbiological or serological criteria are involved in the diagnosis of TSS. The condition may therefore be diagnosed without the identification of toxin-producing staphylococci, without the demonstration of a rise in antibody titres against the toxin responsible, and in particular without the confirmation of a circulating toxin. Three cases of a ‘toxic strep. syndrome’
224
have been reported (Bartter et al., 1988), all of which fulfilled the criteria for identification as TSS. It was proposed that because Type A streptococcal exotoxin and staphylococcal enterotoxin B show an amino acid homology, TSS may be caused by organisms other than staphylococci. The five cases of TSS in the present series occurred over a period of 4 months. In Frame’s series of cases (Frame et al., 1985) the seven cases described occurred within a T-month period. These figures suggest that TSS is underdiagnosed or occurs in outbreaks. However the cases reported in the present study were caused by different phase type staphylococci, an observation which to some extent rules out an outbreak of the condition. Of the 99 or so cases reported in Britain up to 1984, over one-fifth were reported from just four hospitals (de Saxe et al., 1985). If the evidence for the involvement of a wide range of toxins and a broad clinical spectrum of the condition’s presentation are correct, then it is evident that TSS in burned children may be far more common than the sporadic case reports would suggest.
Acknowledgements We are grateful for the assistance of the nursing staff at the Wessex Regional Burns Centre (WRBC) who performed routine collection of microbiological samples from the patients. We acknowledge the helpful contribution of Mr L. F. A. Rossi, Director of the WRBC, to this project and are grateful for his encouragement and advice. We are grateful to Dr Sharon Patrick and the staff of the Public Health Laboratory Service (PHLS) Laboratory at Odstock Hospital, together with the PHLS Central Laboratory at Colindale, who identified the bacterial strains and characterized the toxins.
References AmowP. M., Chou T., Weil D.
et al. (1984) Spread of a toxic-shock syndrome associated strain of Staphylococcus aureus and measurement of antibodies to staphylococcal enterotoxin F. J. Infect. Dis., 149, 103. Baird D. and Coia J. (1987) Mupirocin-resistant Staphylococcus aureus. Lancet ii, 387. Bartter T., Dascal A., Carroll K. et al. (1988) Toxic Strep. syndrome’. Arch. In&m. Med. 148, 1421. Brait i A. N., Frame J. D. and Eve M. D. (1988) Early lymphopenia in burned children with and without the toxic shock syndrome. Burns 14,120. Cason J. S. (1981) Treahnent af Burns. London: Chapman and Hall, London, p. 24.
Bums (1990) Vol. 16/No.
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Centre for Disease Control (CDC) (1980) Follow-up on Toxic Shock Syndrome. MMWR 29,442. Christenson B., Johansson P. J. and Oxelius V. A. (1986) Imbalanced serum IgG subclass pattern in toxic shock syndrome patients: deficiency of specific IgCl and lgC4 subclass antibodies to toxic shock syndrome toxin-l. Clin. Erp. lmmunol. 66, 443. Daly B. M. (1987) Bactroban allergy due to polyethylene glycol. contact De??n. 17‘48. de Saxe M. J., Hawtin P. and Wieneke A. A. (1985) Toxic shock syndrome in Britain - epidemiology and microbiology. Postgrad. Med. 1.61,s. Egan W. C. and Clark W. R. (1988) The toxic shock syndrome in a bum victim. Burns 14,135. Farmer B. A., Bradley J. S. and Smiley P. W. (1985) Toxic shock syndrome in a scald bum victim. 1. Trauma 25,1004. Finch R. (1988) Skin and soft tissue infections. Lancpti, 164. Frame J. D., Eve M. D., Hackett M. E. J. et al. (1985) The toxic shock syndrome in burned children. Bums 11,234. Frame J. D., Bird D., Eve M. D. et al. (1987) IgG subclass levels in thermally injured children. Scarui. 1. Plad. Reconstr. Surg. 21,323. Garbe P. L., Arko R J., Reingold A. L. et al. (1985) Staphylocom aureus isolates from patients with non-menstrual toxic shock syndrome. ]AMA 250,2538. Holt P. A., Armstrong A. M., Norfolk G. A. et al. (1987) Toxic-shock syndrome due to staphylococcal infection of a bum. Br. ]. Clin. Pratt. 41,582. Mittag H-C. (1988) Toxic Shock syndrome and th other SfaphylccoccaI Toticoses. New York: Schattauer, p. I 70. Notermans S., van Leeuwen W. J., Dufrenne J. et al. (1983) Serum antibodies to enterotoxins produced by Staphylococcus aureus with special reference to enterotoxin F and the toxic shock syndrome.]. Clin. Microbial. 18, 1055. Rahman M., Noble W. C. and Cookson B. (1987) Mupirocinresistant Staphylococcus aureus. Lancet ii, 387. Todd J., Fishaut M., Kapral F. et al. (1978) Toxic shock syndrome associated with phage group-1 staphylococci. Lmcet ii, 1116. Tofte R. W. and Williams D. N. (1981) Toxic shock syndrome: evidence of a broad clinical spectrum. J.. 246,2163. Vergeront J. M., Stolz S. J., Crass B. A. et al. (1983) Prevalence of serum antibody to staphylococcal enterotoxin F among Wisconsin residents: implications for the toxic shock syndrome. ]. Infed. Dis. 148,692.
Paper
accepted
30 November
1989.
Correspondence should be addressed to: Mr R. P. Cole, Wessex Centre for Plastic and Maxillofacial Surgery, Odstock Hospital, Salisbury, Wiltshire, SP2 8BJ, UK.
221
Printed in Great Britain
Toxic shock syndrome
in scalded children*
R. P. Cole and P. G. Shakespeare Wessex Centre for Plastic and Maxillofacial Salisbury, Wiltshire, UK
Surgery and Laing Laboratory
Five patients showing clinical signr resembling the ‘toxic shock syndrome presented over a crnonth period at the Wesspx Regional Bums Centre. Toxin-producing isolates of Staphylococcus aureus were made from wound swabs in four of the five patients. Four diferent phase types producing four different toxins were observed. Seven other patients yielded staphylococci from wound swabs but did not develop the toxic shock syndrome. In three of these latter patients the staphylococcus isolated wlls totin produn’ng. Since the syndrowz carries a s&r&ant mortality risk it is desirable that it is recognized and treated without delay. To this end a simplified set of criteria for the identification of probable toxic shock syndrome uses is proposed. The observations suggest that toxic shock syndrome is more ~0mrnonthan previously supposed. The syndrome may show a broad spectrum in its clinical presentation, and involve a wide range of staphylococcal phage types with possible involvement of several different enterotoxins.
Introduction The toxic shock syndrome (TSS) was first described by Todd et al. (1978) in seven children aged 8-17 years who were not burned patients. One child died. Since the original description, most reports of TSS have described its occurrence in menstruating women in association with the use of tampons. However, several cases of TSS have been reported in burned patients. Seven cases were reported by Frame et al. (1985), of whom four died. Three further cases were reported by Farmer et al. (1985), Holt et al. (1987) and Egan and Clark (1988). Brain et al. (1988) described two further cases. Overall it is estimated that TSS carries a mortality risk of approximately 11 per cent (de Saxe et al., 1985). The diagnosis of TSS is made retrospectively, mainly on clinical grounds. Depending upon the features present, a diagnosis of ‘definite’ TSS or ‘probable’ TSS is made. ‘Definite’ TSS is the presence of all six diagnostic criteria listed in Table I. ‘Probable’ TSS is either the presence of any five of the six criteria listed in Tuabk I or the presence of all criteria listed in Tuble II. In de Saxe’s review (de Saxe et al., 1985) only half of the non-menstrual cases of TSS satisfied all six of the criteria required to diagnose ‘definite’ TSS. The *Since this paper was prepared the simplified criteria have been used prospectively to identify three further cases of ‘probable’ TSS in scalded children. All three cases showed wound colonization with Staphylococcus aurew, two of which were phage typable. All three isolates were toxin producing, the non-typable isolate producing SEB, the typable isolates (29152 and 29/52/79) both producing TSST-I.
Butterworth-Heinema 0305-4179/90/03022144 dc 1990
Ltd
for Burn Injury Investigation,
Odstock
Hospital,
commonest diagnostic criteria absent from non-menstrual TSS cases were hypotension and desquamation. It has been suggested that to diagnose TSS post mortem requires a modified set of criteria (de Saxe et al., 1985) because desquamation occurs during the convalescent phase. This Table I. Toxic shock syndrome case definition* 1. Fever (temperature 3 39.2X [102-F]) 2. Rash (diffuse macular erythroderma) 3. Desquamation, l-2 weeks after onset of illness, particularly of palms and soles 4. Hypotension (systolic blood pressure < 90 mmHg for adults or < 5th percentile by age for children < 16 years of age; or orthostatic syncope) 5. Involvement of three or more of the followina oraan svstems: A. Gastrointestinal (vomiting or diarrhoea at-onset of illness) B. Muscular (severe myalgia or creatine phosphokinase level ~2 x ULN) C. Mucous membrane (vaginal, oropharyngeal or conjunctival hyperaemia) D. Renal (BUN or Cr>2 x ULN or >,5 white blood cells per high power field - in the absence of a urinary tract infection) E. Hepatic (total bilirubin, SGOT (AST), or SGPT (APT) 22 x ULN) F. Haematological (platelets d 100 x 1 O-s.l- ‘) G. Central nervous system (disorientation or alterations in consciousness without focal neurological signs when fever and hypotension are absent) . 6. Negative results on the followmg tests, If obtamed: A. Blood, throat or cerebrospinal fluid cultures B. Serological tests for Rocky Mountain spotted fever, leptospirosis or measles ‘The criteria are taken from Centre for Disease Control (1980). ULN, upper limit of normal range; BUN, blood urea nitrogen; Cr. serum creatinine.
Table II. Diagnostic categories of toxic shock syndrome (TSS) Probable TSS ( 2 3 criteria and desquamation or > 5 criteria without desquamation) Temperature > 38.9-C Rash Hypotension, orthostatic dizziness or syncope Myalgia Vomiting, diarrhoea or both Mucous membrane inflammation (conjunctivitis, pharyngitis. vaginitis) Clinical or laboratory abnormalities of 32 organ systems Reasonable evidence for absence of other aetiologies *The criteria are taken from Tofte and Williams (1981).
Bums (1990) Vol. 16/No. 3
222
anomaly means that TSS, is, by definition, a non-fatal condition because to fulfil all the six criteria for definite diagnosis the patient must have reached the convalescent stage. Another anomaly is that early intervention may alter the course of the disease and therefore preclude its diagnosis. Difficulty also occurs when applying some of the criteria, for example myalgia or headache, to small children. The symptoms of TSS are caused by the direct effects of the toxin on the tissues, mediator-dependent effects and sequelae to -organ damage secondary to hypotension (Mittag, 1988). Staphylococci may produce eight different including enterotoxins, toxic-shock-syndrome-toxin-~ (TSST-I). In menstrual cases of TSS, over 90 per cent of strains produce TSST-I, whereas in non-menstrual cases only 60-65 per cent of strains produce TSST-1 (de Saxe et al., 1985; Garbe et al., 1985). There has been no detailed report of phage types and toxins produced in staphylococci isolated from burned patients. The present study reports five cases of probable TSS in burned patients, with descriptions of the organisms involved. The dficulties encountered with the diagnosis (and possible underdiagnosis) are discussed.
Patients and case reports Over the 4-month study period, 36 children under the age of 4 years were admitted to the Wessex Regional Burns Centre with burns ranging from 0.25 to 41 per cent total body surface area (TBSA). Most of the injuries were caused by scalds (33), the remainder being contact burns. The mean age of the children was 15 months (range &47 months). The mean burn area was 12 per cent of total body surface. Children were resuscitated using one plasma volume (45 ml/kg body weight) of human albumin solution (Human Plasma Protein Fraction, HPPF, 45 g/l albumin) per 15 per cent of body surface area burned; half given over the first 8 h after injury and half given over the next 16h (Cason, 1981). Oral maintainence fluids of LOO-120mVkg body weight were given orally. Additional fluid was given to replace losses due to pyrexia, vomiting, diarrhoea and ‘shock depending on clinical assessment of electrolyte balance and circulatory state. Burns were dressed with nitrofurazoneimpregnated gauze unless the hands were involved, when silver sulphadiazine (Flamazine) and plastic bag dressings were used. As a routine procedure prophylactic systemic antibiotics are not given and no patient in this study had received them. All bums were swabbed on admission and nose and throat swabs were also taken. Burns were swabbed at dressing changes. Any staphylococci isolated from bum wounds were sent for phage typing and toxin production studies. Five children developed probable TSS during the study period. The mean bum area of this group was 20 per cent BSA and the mean age 18 months (range 14-23 months). Staphylococci were isolated from 11 of the 36 burned children. Four different phage types were isolated from five probably TSS cases, all of which were toxin-producing strains. Seven children showed staphylococcal isolates but did not develop probable TSS. Three of these isolates were toxin-producing strains of which two were TSST-1 producers. Clinical details of the five cases of probable TSS are as follows: CaSel A 19-month-old girl was admitted with a 15 per cent TBSA scald
assessed as mainly superficial. She was resuscitated with HPPF as
described above. The day following her injury she became irritable, passed several loose stools and her core temperature rose to 40°C. She showed a lymphopenia with lymphocyte count of 1.9 x 10’. The following day she was tachycardic and cold peripherally. She was treated with penicillin (125mg) and erythromycin (125mg) given orally qds for 7 days and received normal human immunoglobulin (3 g) intravenously. Over the following 48 h her condition improved. She underwent surgery to repair some small unhealed areas approximately 2 weeks later. Cultures taken from her bums on day 4 after injury grew a Staph. aurew, phage type 94196, which produced staphyloccocal enterotoxin (SE) B. case2
A 19-month-old
boy was admitted with a scald of 41 per cent TBSA. He was resuscitated with HPPF as previously indicated (see above Case I). The next day he became restless and irritable with a core temperature of 39°C. The following day he was shocked, tachypnoeic and had a core temperature of 40°C. He showed a lymphopenia with lymphocyte count of 2.5 x 109/1, and passed several loose stools. He was treated with gentamicin (20 mg, tds) and fludoxacillin (125 mg, qds) given intravenously for 5 days, and received a blood transfusion. He made a gradual recovery and his bums healed spontaneously. A staphylococcus phage type 29/52/79&O producing both TSST-I and SEC was isolated from wound swabs collected on day 2 after injury. case 3 A 21-month-old girl was admitted with an 8 per cent TBSA mixed depth scald. For the first 48 h her progress was uneventful, but she then developed a core temperature of 39.8’C, diarrhoea and a generalized rash. She showed a lymphopenia with lymphocyte count of 1.7 x 10’. The next day she was irritable, shocked and pyrexial. She was treated with penicillin (150 mg) and flucloxacillin (125mg) given intravenously qds for 3 days, with the same dosage continued orally for 1 week. Her condition stabilized and improved over the following 4 days. Small areas of unhealed burn were grafted at 3 weeks after injury. The staphylococcus isolated from her wounds on day 4 after injury was phase type 47/53/54/ 84 which produced SEC and SED. case4 A 23-month-old boy was admitted with a scald, mostly superficial, of 25 per cent TBSA. He was resuscitated uneventfully with HPPF. The following day he was pyrexial with core temperature of 39.5”C. Over the next 2 days his pyrexia persisted, he vomited repeatedly and became irritable. His serum urea level was normal but serum creatinine rose to 114 pmol/l. He showed a lymphopenia with lymphocyte count of 0.4 x 109/1. He became shocked, developed oedematous oral and nasal mucosae and an erythematous rash. He was treated with penicillin (150mg) and flucloxacillin (125 mg) given intravenously qds over 6 days. Over the next 4 days his condition improved and on day 7 he was given a blood transfusion. The staphylococcus isolated from the scald on day 3 after injury was phage type 29/42/53/85, producing SEB. case5 A 14-month-old girl was admitted with a 25 per cent TBSA mixed depth scald. She was resuscitated uneventfully with HPPF. The following day she vomited repeatedly and passed several loose stools. The next day she became irritable, developed a pyrexia with core temperature of 39”C, shock and a metabolic acidosis. Her serum creatinine level was KWpmol/l and she showed a thrombocytopenia with platelet count of 32 x lop/1and a lymphopenia with a lymphocyte count of 1.6x lO’/i. She was given an infusion of sodium bicarbonate (5 mM) and treated with flucloxacillin (120 mg) given intravenously qds over 7 days. Two
223
Cole and Shakespeare:Toxic shock syndrome in scalded children
days later she developed an erythematous rash. Her general improved. The involvement of Staph. sp.
Table III. Staphylococcal
phage types and toxin production
condition subsequently
in this case is uncertain since a swab was not taken from
the wound
immediately before the start of antibiotic treatment. Summary details of the microbiological findings in these cases are shown in
Table III.
Discussion A simplified set of criteria to diagnose TSS is desirable when managing burned children in order to enable the initiation of treatment as early as possible. Burned children are probably immunocompromised by their injury and are therefore likely to be more susceptible to the effects of circulating toxins produced by bacterial colonization of their burns (Frame et al., 1987). Early intervention should reduce sequelae such as metabolic acidosis, clotting abnormalities, convulsions and death. The simplified set of criteria shown in Tubk IV were used to initiate treatment in the cases reported in this study. Five of the six criteria are found in the case definitions of ‘definite’ and ‘probable’ TSS. The sixth criterion, lymphopenia, was included because burned children with TSS show a significantly greater fall in lymphocyte count than control patients (Brain et al., 1988). Retrospective analysis of the five cases fulfilling these criteria led to the diagnosis of ‘probable’ TSS being made in all five cases. There is considerable controversy surrounding the management of TSS. In theory it should be possible to prevent TSS by eradicating all staphylococci on admission to the Bums Unit. Topical agents such as pseudomonic acid (mupirocin) are highly effective against Gram-positive cocci. However, there have been reports of mupirocin-resistant strains (Baird and Coia, 1987; Rahman et al., 1987) and of reactions to the polyethylene glycol base (Daly, 1987). Flucloxacillin has been given prophylactically to all burned children (Frame et al., 1985) but widespread use of this antibiotic may encourage the development of resistant strains of bacteria (Finch, 1988). It has been suggested that closed dressings predispose patients to TSS because they act as a mechanical barrier which provides a culture medium for staphylococcal colonization in a similar way to tampons in menstruating women (Egan and Clark, 1988). None of the reported cases occurred when the bums were treated by exposure. Less controversial measures include aggressive monitoring, intravenous fluids and parenteral antistaphylococcal therapy. Transfusion of fresh blood or blood products may confer passive immunity by the provision of immunoglobulins in the IgG-1, IgG-2 and IgG-3 subclasses (Frame et al., 1985, 1987). It has been shown that TSS patients lack pre-immunity to TSST-1 in all four IgG subclasses (Christenson et al., 1986). Immunoglobulin transfusion was used in treating Case 1 in the present study. Staphylococci can produce eight enterotoxins, A, B, C,, C,, C,, D, E, F. Enterotoxin F is also known as toxic-shocksyndrome-toxin-l (TSST-1). These toxins are relatively low molecular weight glycoproteins. There need not be active infection of the burn wound for TSS to occur and where details are given in previous case reports (Frame et al., 1985; Holt et al., 1987) the burn wounds of the patients appeared clean. TSS is not restricted to patients with large TBSA bums. The mean TBSA in the series reported by Frame et al. (1985) was 19 per cent (range 4-10 per cent). The case reported by Egan and Clark (1988) involved a patient with 5 per cent TBSA bum. Details of staphylococcal phage types and toxins in TSS
Case 1 2 3 4 5
Table Iv.
Phage types
Toxin
94196 29f52/79fao 47/53i54/84 29i42t53ia5 No staphylococcus isolated
SEB TSST-1, SEC SEC, SED SEB --
Toxic shock syndrome - simplified criteria
for children
Pyrexia B 39°C Rash Shock Diarrhoea and/or vomiting Irritability Lymphopenia
cases in burned patients have been poorly documented. In the five cases where phage typing was performed (Frame et al., 1985; Holt et al., 1987; Egan and Clark, 1988) all were phage type 29 or 29/53. Toxin studies were reported in only two cases. One produced TSST-1 (Holt et al., 1987), the other SEB (Farmer et al., 1985). In the present series of patients reported, four different phage types and four different toxins, SEB, SEC, SED and TSST-1, were implicated. The response to circulating staphylococcal toxins is variable and not always related to pre-existing antibody status. Following an outbreak of a TSST-1 producing strain of Staph. Rt(reCISon a Burns Unit, two patients who had low antibody levels to TSST-I when colonized did not develop TSS (Amow et al., 1984). In particular one of the patients showed a clear serological response to the toxin but was asymptomatic. This implies that toxin production failed to reach clinically significant levels and supports the hypothesis that TSS is not an all or nothing response to staphylococcal toxin. It has been suggested that a broad clinical spectrum of TSS exists because certain patients are more genetically susceptible to the toxin or because different circulating levels of toxin produce different effects (Tofte and Williams, 1981). Approximately one-quarter to one-third of human staphylococcal isolates produce TSST-1 (Notermans et al., 1983), although it should be emphasized that these observations were made in vitro. Antibodies to TSST-1 have been demonstrated in over 90 per cent of normal healthy adult subjects (Notermans et al., 1983). This suggests that most people have encountered TSST-1 producing strains and developed antibodies without suffering TSS. Only 30 per cent of children between 1 and 2 years of age have titres > 1: 100 against TSST-1 (Vergeront et al., 1983). Maternal antibody to TSST-1 has been detected in babies up to 9 months of age (Vergeront et al., 1983). This might explain the age distribution in reported cases. In the 10 cases where details are available, only one occurred in a child under 12 months of age (Frame et al., 1985). It should be emphasized that no staphylococcal microbiological or serological criteria are involved in the diagnosis of TSS. The condition may therefore be diagnosed without the identification of toxin-producing staphylococci, without the demonstration of a rise in antibody titres against the toxin responsible, and in particular without the confirmation of a circulating toxin. Three cases of a ‘toxic strep. syndrome’
224
have been reported (Bartter et al., 1988), all of which fulfilled the criteria for identification as TSS. It was proposed that because Type A streptococcal exotoxin and staphylococcal enterotoxin B show an amino acid homology, TSS may be caused by organisms other than staphylococci. The five cases of TSS in the present series occurred over a period of 4 months. In Frame’s series of cases (Frame et al., 1985) the seven cases described occurred within a T-month period. These figures suggest that TSS is underdiagnosed or occurs in outbreaks. However the cases reported in the present study were caused by different phase type staphylococci, an observation which to some extent rules out an outbreak of the condition. Of the 99 or so cases reported in Britain up to 1984, over one-fifth were reported from just four hospitals (de Saxe et al., 1985). If the evidence for the involvement of a wide range of toxins and a broad clinical spectrum of the condition’s presentation are correct, then it is evident that TSS in burned children may be far more common than the sporadic case reports would suggest.
Acknowledgements We are grateful for the assistance of the nursing staff at the Wessex Regional Burns Centre (WRBC) who performed routine collection of microbiological samples from the patients. We acknowledge the helpful contribution of Mr L. F. A. Rossi, Director of the WRBC, to this project and are grateful for his encouragement and advice. We are grateful to Dr Sharon Patrick and the staff of the Public Health Laboratory Service (PHLS) Laboratory at Odstock Hospital, together with the PHLS Central Laboratory at Colindale, who identified the bacterial strains and characterized the toxins.
References AmowP. M., Chou T., Weil D.
et al. (1984) Spread of a toxic-shock syndrome associated strain of Staphylococcus aureus and measurement of antibodies to staphylococcal enterotoxin F. J. Infect. Dis., 149, 103. Baird D. and Coia J. (1987) Mupirocin-resistant Staphylococcus aureus. Lancet ii, 387. Bartter T., Dascal A., Carroll K. et al. (1988) Toxic Strep. syndrome’. Arch. In&m. Med. 148, 1421. Brait i A. N., Frame J. D. and Eve M. D. (1988) Early lymphopenia in burned children with and without the toxic shock syndrome. Burns 14,120. Cason J. S. (1981) Treahnent af Burns. London: Chapman and Hall, London, p. 24.
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Centre for Disease Control (CDC) (1980) Follow-up on Toxic Shock Syndrome. MMWR 29,442. Christenson B., Johansson P. J. and Oxelius V. A. (1986) Imbalanced serum IgG subclass pattern in toxic shock syndrome patients: deficiency of specific IgCl and lgC4 subclass antibodies to toxic shock syndrome toxin-l. Clin. Erp. lmmunol. 66, 443. Daly B. M. (1987) Bactroban allergy due to polyethylene glycol. contact De??n. 17‘48. de Saxe M. J., Hawtin P. and Wieneke A. A. (1985) Toxic shock syndrome in Britain - epidemiology and microbiology. Postgrad. Med. 1.61,s. Egan W. C. and Clark W. R. (1988) The toxic shock syndrome in a bum victim. Burns 14,135. Farmer B. A., Bradley J. S. and Smiley P. W. (1985) Toxic shock syndrome in a scald bum victim. 1. Trauma 25,1004. Finch R. (1988) Skin and soft tissue infections. Lancpti, 164. Frame J. D., Eve M. D., Hackett M. E. J. et al. (1985) The toxic shock syndrome in burned children. Bums 11,234. Frame J. D., Bird D., Eve M. D. et al. (1987) IgG subclass levels in thermally injured children. Scarui. 1. Plad. Reconstr. Surg. 21,323. Garbe P. L., Arko R J., Reingold A. L. et al. (1985) Staphylocom aureus isolates from patients with non-menstrual toxic shock syndrome. ]AMA 250,2538. Holt P. A., Armstrong A. M., Norfolk G. A. et al. (1987) Toxic-shock syndrome due to staphylococcal infection of a bum. Br. ]. Clin. Pratt. 41,582. Mittag H-C. (1988) Toxic Shock syndrome and th other SfaphylccoccaI Toticoses. New York: Schattauer, p. I 70. Notermans S., van Leeuwen W. J., Dufrenne J. et al. (1983) Serum antibodies to enterotoxins produced by Staphylococcus aureus with special reference to enterotoxin F and the toxic shock syndrome.]. Clin. Microbial. 18, 1055. Rahman M., Noble W. C. and Cookson B. (1987) Mupirocinresistant Staphylococcus aureus. Lancet ii, 387. Todd J., Fishaut M., Kapral F. et al. (1978) Toxic shock syndrome associated with phage group-1 staphylococci. Lmcet ii, 1116. Tofte R. W. and Williams D. N. (1981) Toxic shock syndrome: evidence of a broad clinical spectrum. J.. 246,2163. Vergeront J. M., Stolz S. J., Crass B. A. et al. (1983) Prevalence of serum antibody to staphylococcal enterotoxin F among Wisconsin residents: implications for the toxic shock syndrome. ]. Infed. Dis. 148,692.
Paper
accepted
30 November
1989.
Correspondence should be addressed to: Mr R. P. Cole, Wessex Centre for Plastic and Maxillofacial Surgery, Odstock Hospital, Salisbury, Wiltshire, SP2 8BJ, UK.
