Nonmenstrual Toxic Shock Syndrome in a Young Child With Human Immunodeficiency Virus Infection

Although infections with Staphylococcus aureus are not uncommon in HIV-infected children,1-3 toxic shock syndrome (TSS) has not been reported previously in a young child with HIV disease. Case reports of nonmenstrual TSS in adults with HIV disease,4-7 as well as one report in an HIV-infected adolescent with hemophilia,8 describe an insidious, prolonged and often recurrent pattern of disease. We describe a prolonged and recurrent case of TSS in a 6-year-old HIV-infected girl. Case report. A 6-year-old HIV-infected girl was seen after fever, dyspnea and diarrhea for 1 day. Her birth history was unremarkable. At 9 months of age she was hospitalized for fever and had generalized lymphadenopathy. Serologic testing for HIV-1 was positive. Her compliance with follow-up was erratic, but serum HIV antibody reactivity was documented beyond 18 months of age. One day before admission she developed fever, dyspnea and diarrhea consisting of five watery stools without blood or mucus. She had no vomiting. Her caretakers denied use of any medications. In the emergency room she was tachypneic with an otherwise nonspecific examination. She was sent for chest radiography; upon return, she was noted to be dyspneic, tachycardic and hypotensive with cool extremities. She was treated for presumed septic shock, was resuscitated with intravenous fluids and dopamine and was given cefotaxime. On admission to the intensive care unit her temperature was 101.9°F, heart rate 153/min, respiratory rate 54/min and blood pressure 57/34 mm Hg. She was lethargic and disoriented. She had developed diffuse erythroderma, most prominently on the face. The extremities were cool and pale; carpal-pedal spasms were observed. Conjunctivae, nasal and oral mucus membranes were erythematous. Oral thrush and caries were present. Tympanic membranes were erythematous with good mobility. The chest was clear to auscultation with no murmur. The peripheral pulse were weak. No hepatosplenomegaly was detected. Axillary and inguinal lymphadenopathy was present. Movement of her extremities elicited pain consistent with myalgia. Neurologic examination was normal with the exception of mental status depression. Treatment with the initial regimen begun in the emergency room was continued. Initial laboratory studies demonstrated an elevated white blood cell count of 6500/mm3 (61% segmented neutrophils, 2% band forms, 36% lymphocytes, 1% monocytes), hematocrit 29% and platelet count of 208 000/mm3. Arterial blood gas analysis showed pH 7.48, pCO2 18 mm Hg, pO2 94 mm Hg and bicarbonate 14 meq/l. Serum sodium was 132 meq/l, potassium 4.4 meq/l, chloride 99 meq/l, blood urea nitrogen 57 meq/dl and creatinine 4.8 mg/dl. Serum calcium was 5.8 mg/dl, albumin 3.1 g/l, aspartate aminotransferase 1134 units/l, alanine aminotransferase 375 units/l, lactate dehydrogenase 2099 units/l and creatine phosphokinase 399 units/l. Cerebrospinal fluid was normal. Chest radiograph showed cardiomegaly. An echocardiogram revealed normal anatomy and ejection fraction 35%. Repeat laboratory studies several hours later were remarkable for an arterial blood pH of 7.53 and further elevation of creatine phosphokinase to 1062 units/l. In addition to fever, diarrhea, myalgias, tetany, conjunctival injection, erythroderma and shock, clinical condition also included renal failure, hepatitis, hypocalcemia and a mixed metabolic acidosis and respiratory alkalosis, evolving over 48 h. Toxic shock syndrome was considered a single, unifying diagnosis. However, no obvious source of S. aureus infection was detected on examination. Oxacillin treatment was added to the antibiotic regimen to provide improved coverage for S. aureus. Prophylaxis against Pneumocystis carinii pneumonia (PCP) with trimethoprim-sulfamethoxazole (TMP-SMX) was initiated and a single dose of intravenous immunoglobulin was administered. Multiple blood cultures showed no growth. Cultures of pharynx, nares, external ear canals and vagina were reported as “normal flora.” One stool culture was positive for Pseudomonas species and one urine specimen grew Candida albicans; however, subsequent cultures of urine and stool were negative. Analysis of lymphocyte subsets revealed total CD4 14/mm3 (1%), total CD8 528/mm3 (37%), ratio 0.03. Computerized tomography of the head revealed cerebral atrophy and maxillary sinusitis. By Hospital Day 4 the child was much improved with normalization of hepatic and renal functions. On the sixth hospital day she was transferred out of intensive care, but later that evening she developed fever, tachypnea and hypotension (blood pressure 61/42). A 3-mm purpuric lesion resembling a septic embolus was noted on her left ankle. She was again treated with intravenous fluids and dopamine. Antibiotics were changed to ticarcillin-clavulanate potassium (Timentin®) and vancomycin and she was given 1 unit of packed red blood cells for treatment of anemia (hematocrit 24%). She improved overnight with aggressive management and stabilized for the remainder of her hospital stay with the exception of intermittent fevers and transient hypotension for several hours on Hospital Day 14. Desquamation of the palms and soles developed during the second week of hospitalization. The child received ticarcillan-clavulanate potassium and vancomycin for 14 days and was discharged on Hospital Day 22. Before discharge the white blood cell count dropped to 1300/mm3 and TMP-SMX was discontinued. She was given one dose of intravenous pentamidine for PCP prophylaxis. Other discharge serum findings included creatinine 0.5 mg/dl, calcium 10 mg/dl, asparatate aminotransferase 237 units/l, alanine aminotransferase 193 units/l, creatine phosphokinase 30 units/l and hematocrit 34%. She was discharged home on didanosine therapy. Three weeks after discharge she was readmitted with fever, vomiting and diarrhea lasting for 3 days. She was receiving didanosine and had begun taking TMP-SMX 2 days earlier for the first time since it was discontinued in the hospital. The family denied use of any other medications. Physical examination at that time revealed temperature 102°F, heart rate 159/min, respiratory rate 64/min, blood pressure 75/41 mm Hg. Conjunctival erythema, facial erythroderma, dusky extremities and myalgias were notable. Pertinent laboratory findings included white blood cell count 16 500/mm3 (69% segmented neutrophils, 17% band forms, 9% lymphocytes, 4% monocytes), hematocrit 30% and platelet count 177 000/mm3. Creatinine was 3.7 mg/dl, calcium 6.6 mg/dl, albumin 4.2 g/dl, asparatate aminotransferase 2790 units/l, alanine aminotransferase 638 units/l and creatine phosophokinase 1763 units/l. Arterial blood gas revealed pH 7.50, pCO2 17 mm Hg, pO2 133 mm Hg, and bicarbonate 13 meq//l. Recurrent TSS was considered the principal diagnosis, but allergy to TMP-SMX was considered. She was treated with ticarcillin-clavulanate. TMP-SMX was discontinued. She improved within several days and had no further relapses during the hospital course. No desquamation was noted. Repeat computerized tomography scan of the head confirmed the presence of persistent maxillary sinusitis. She received a total of 10 days of therapy with intravenous antibiotics and was discharged on the 13th hospital day; she was instructed to take rifampin for 10 days and cephradine for 3 months. Maxillary sinus drainage was performed as an outpatient and cultures grew S. aureus. No similar episodes occurred during 10 months of follow-up. She was maintained on a regimen of monthly intravenous immunoglobulin, monthly intravenous pentamidine and didanosine as well as additional supportive therapies. Discussion. Despite frequent infections with S. aureus there have been no reports of toxic shock syndrome or staphylococcal toxin-related disorders in HIV-infected children, according to our review of the medical literature. Cases in HIV-infected adolescents and adults are rare, but when TSS has been described it had a prolonged and recurrent course.4-8 Our patient met the case definition for TSS: fever; diffuse macular erythroderma; desquamation; hypotension; and multisystem involvement of three or more organs.9 On admission the child was febrile and hypotensive with a diffuse erythematous rash and a history of gastrointestinal dysfunction. She developed renal failure, hepatic dysfunction, alteration in consciousness, mucous membrane involvement, severe myalgias and subsequent desquamation of the palms and soles. S. aureus was subsequently isolated from her maxillary sinuses. Studies were not obtained for toxic shock syndrome toxin 1 or for enterotoxins A, B and C. Sinusitus is diagnosed frequently in children with HIV disease; it was found to be the fourth most common bacterial infection in a cohort of 376 HIV-infected children enrolled in a clinical trial of IVIG prophylaxis.10 The disease course in those children was most often subacute, with nonspecific chronic symptoms. Similarly our patient did not have evidence of acute sinusitus. Rather the diagnosis was made by computerized tomography scan and was later confirmed with sinus aspiration. Ferguson and Todd11 reported three cases of TSS in nonimmunocompromised children attributed to S. aureus sinusitis. They proposed that local growth conditions of sinusitus may favor the toxic shock syndrome toxin 1-producing staphylococci. The course of disease in this child was complicated by two episodes of recurrent TSS, the first occurring during treatment. The second episode occurred more than 6 weeks after initial presentation. Recurrent disease is seen in both menstrual and nonmenstrual TSS.12 The adolescent with HIV and TSS described by Kline and Dunkle8 had persistent and recurrent symptoms during a 3-month period. Cone et al.6 described five HIV-infected adults with recalcitrant, erythematous, desquamating disorders associated with toxin-producing staphylococci. Thought to be variants of TSS these disorders were characterized by prolonged duration (mean, 50 days) and recurrent symptoms. Recurrence has been associated with delayed production of antibody to TSST-1 as well as inadequate antimicrobial therapy. In our patient with HIV disease we suspect that recurrent disease occurred because of inadequate treatment of S. aureus sinusitis. Sinus drainage was not performed until resolution of the second episode of TSS. Early drainage is the hallmark of treatment of toxic shock syndrome associated with a focal infection. Had the sinus been drained at the time of admission, relapse may not have occurred. We presume that the prolonged course of antibiotic treatment with sinus drainage ultimately resulted in eradication of the organism. In light of her degree of immune compromise it appears likely that her immune response and antibody production were limited as well. Allergic drug reactions occur commonly in HIV-infected individuals and TMP-SMX allergy was considered in this case. At the time of admission, however, the family denied use of any medications including sulfonamides. TMP-SMX therapy was begun on hospitalization for PCP prophylaxis preceding the second episode of hypotension, was discontinued secondary to neutropenia and was then started again 2 days before to the third episode of presumed TSS. In light of the temporal association between TMP-SMX administration and the recurrent episodes of disease, the child was not subsequently challenged with the medication and monthly infusions with intravenous pentamidine were initiated for PCP prophylaxis. S. aureus infections are seen frequently in adults and children with HIV infection. The integral role of the T-helper cells and endogenous mediators in the events of TSS may explain why this syndrome has not been seen more often in HIV-infected individuals. The wide range of complex and progressive immune deficits of HIV may limit individual susceptibility to S. aureus toxins and limit host ability to mount the immune response associated with the pathophysiologic events observed in TSS. Atul Shah, M.D.; William Moss, M.D., M.P.H.; Susan Champion, M.D., M.P.H.; Elaine J. Abrams, M.D.