Case 2: Rash, fever and headache….first, do no harm

A 16-year-old healthy boy presented with a two-day history of pruritic painful rash involving his left abdomen and back in a T9 to T10 distribution. In addition, he had a fever, blurry vision, painful eye movements and a headache. The patient had a history of varicella-zoster virus infection without complications when he was eight years of age, and his past medical history was unremarkable. There were no sick contacts, and his vaccinations were current. He had not received the varicella vaccine.

On examination, his temperature was 37.4°C, his heart rate was 72 beats/min, his respiratory rate was 16 breaths/min and his blood pressure was 137/66 mmHg. He was alert with normal neurological findings, except for pain elicited on bilateral upward and extreme lateral gaze. There were clusters of six to eight slightly scabbed, erythematous papules in a left T9 to T10 distribution, with a single vesicular lesion noted over the left upper scapula. The rest of the examination was unremarkable.

Laboratory evaluation revealed a peripheral white blood cell count of 7×10⁹/L (neutrophil count of 4.11×10⁹/L and lymphocyte count of 2×10⁹/L), hemoglobin level of 139 g/L, platelet count of 188×10⁹/L and normal chemistry profile with a creatinine level of 62 μmol/L. The cerebral spinal fluid revealed a white blood cell count of 165×10⁶/L with 97% lymphocytes, red bood cell count of 105×10⁶/L, glucose level of 2.4 mmol/L and protein level of 0.83 g/L. The cerebral spinal fluid polymerase chain reaction was positive for varicella-zoster virus.

Intravenous acyclovir (30 mg/kg/day divided every 8 h) and cefotaxime (2 g taken intravenously every 6 h) were initiated. Intravenous fluid was started at 15 mL/h to maintain vein patency. Despite nursing description of minimal oral intake secondary to nausea, quantitative fluid balance was not documented. On day 2, the patient developed a truncal, erythematous, morbilliform rash. Cefotaxime was discontinued; however, the rash persisted for five more days. On hospital day 4, the patient developed hypertension ranging between 155/80 mmHg and 168/97 mmHg, and his creatinine level had increased to 203 μmol/L.

Case 2 Diagnosis: Herpes Zoster with Aseptic Meningitis and Acyclovir-Induced Renal Toxicity

The renal insufficiency and resultant hypertension was believed to be secondary to acyclovir-induced renal toxicity, and the acyclovir was immediately discontinued. The hypertension and enlarged echogenic kidneys seen on ultrasound had both resolved by one month after discharge.

Herpes zoster (HZ) is uncommon in healthy children. The incidence of HZ ranges between 0.74 per 1000/year in children zero to nine years of age, and 10.1 per 1000/year in adults 80 to 89 years of age. Resulting from the reactivation of dormant varicella-zoster virus (VZV) in the dorsal sensory root ganglia, HZ more commonly affects the elderly and the immunocompromised. Risk factors for HZ in immunocompetent children include intrauterine and infantile (younger than one year of age) VZV, due to decreased specific cellular immunity and subsequent prolonged viremia.

In children, HZ is generally characterized by minimal pain and pruritis. Lesions appear as clusters of vesicles involving sensory dermatomes that crust over the following week. In contrast to adult HZ, postherpetic neuralgia is rare in children. The distribution of HZ is variable and depends on the health status and age of the child; dissemination is more common in immunocompromised individuals. Our patient, although healthy, presented with a rash involving his left, lower thoracic and cervical dermatomes. He also had evidence of central nervous system involvement.

Although rare, aseptic meningitis has been documented in healthy children with HZ infection. Approximately 30% to 50% of HZ patients have pleocytosis in the cerebral spinal fluid. In general, these reports involve children whose primary VZV occurred before one year of age. Our patient, however, developed aseptic meningitis with his HZ, despite having contracted chickenpox at eight years of age. This is an unusual presentation because our patient’s history was not suggestive of an immunodeficiency.

The diagnosis of HZ is based on clinical findings, direct fluorescent antigen, Tzanck smear, serology or viral culture. In addition, molecular testing (real-time polymerase chain reaction) can differentiate wildtype from vaccine strains of varicella virus. Once diagnosed, the indications for acyclovir therapy include immunocompromised children, trigeminal involvement of HZ, Ramsay Hunt syndrome and meningoencephalitis. Healthy children with an uncomplicated course of HZ do not usually require antiviral therapy.

Documented adverse effects associated with acyclovir include mild nausea, vomiting, diarrhea and abdominal pain. Rare side effects include neurological, hematological, hepatic and renal toxicity. Several cases of acute renal failure have been reported, usually in the context of fluid restriction to prevent cerebral edema in patients with encephalitis. The combination of ceftriaxone and high-dose acyclovir may further increase the risk of nephrotoxicity. Our patient, without purposeful fluid restriction, developed acute renal failure after four days of intravenous (IV) acyclovir therapy. Cefotaxime was discontinued within 24 h of hospitalization, once cerebral spinal fluid viral polymerase chain reaction results were obtained. Decreased oral fluid intake, combined with inadequate IV hydration, may have contributed to the development of renal insufficiency in our patient. Important factors that have been identified in avoiding nephrotoxicity when using IV acyclovir include, making sure that it is dosed by ideal body mass (and not just body weight), that the patient is optimally hydrated (usually recommend 1.5 times maintenance, unless fluid restricted), and close monitoring of urine output (minimal 1 mL/kg/h), accurate ins and outs, daily weight and serum creatinine. The use of concurrent nephrotoxic agents should be avoided, and the dose of acyclovir must be adjusted for any renal impairment.

Prevention of VZV infection includes the live attenuated VZV vaccine. Licensed for use in Canada in 1998, the varicella vaccine is currently available in all provinces and territories (except Yukon) through routine immunization programs. Children 12 months to 12 years of age currently require one dose in Canada, whereas children older than 12 years of age require two doses, separated by one month. In addition to dramatically reducing the morbidity and mortality of VZV infection in children, vaccination also reduces the risk of HZ compared with wildtype varicella infection (14 cases/100,000 person-years versus 68/100,000 person-years).

Clinical Pearls

• Although uncommon, immunocompetent children can develop HZ with dissemination and central nervous system involvement.

• IV acyclovir treatment in healthy children with HZ should be carefully monitored to avoid acute renal failure.

• Important factors that have been identified in avoiding nephrotoxicity when using IV acyclovir include making sure that it is dosed by ideal body mass (and not just body weight), that the patient is optimally hydrated (usually recommend 1.5 times maintenance, unless fluid restricted), and close monitoring of urine output (minimal 1 mL/kg/h), accurate ins and outs, daily weight and serum creatinine.