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INFLUENZA B INFECTION ASSOCIATED WITH ENCEPHALITIS: TREATMENT WITH OSELTAMIVIR

2002; Lippincott Williams & Wilkins; Volume: 21; Issue: 2 Linguagem: Inglês

10.1097/00006454-200202000-00021

1532-0987

John P. Straumanis, Milagritos D. Tapia, James C. King,

Bacterial Infections and Vaccines

Encephalitis associated with acute influenza infection is unusual in nonepidemic years. A case of a 10-year-old child with influenza B encephalitis and profound weakness who was treated with oseltamivir is presented. This case illustrates several of the unusual findings associated with influenza infections and the result of treatment of influenza B encephalitis with oseltamivir. Encephalitis associated with acute influenza infection, although relatively uncommon, has been sporadically reported during the past century and has usually been encountered in major epidemics. 1 The pathophysiologic mechanism of encephalitis remains unclear and attempts to culture influenza virus from either the cerebrospinal fluid (CSF) or brain tissue have had only limited success. More recently influenza RNA has been detected in the CSF of patients with acute encephalitis by reverse transcriptase polymerase chain reaction (RT-PCR) techniques. 2, 3 Chemotherapeutic agents such as rimantadine and amantadine have been available to treat influenza A infections, and recently oseltamivir has been licensed for the treatment of influenza A and B infections. Although amantadine is known to penetrate into the cerebrospinal fluid, there was very limited information on its use in patients with influenza A encephalitis. 4 There are no reports of patients treated with oseltamivir for influenza A- or B-related encephalitis. This report describes a child with influenza B encephalitis to increase awareness of this entity and to relate our experience in using oseltamivir as a treatment for this illness. Case report. Presentation. In January, 2001, RL, a 10-year-old previously healthy boy, developed an influenza-like illness 3 days before admission characterized by a mild cough, fever to 39.4°C, lethargy, dizziness and headache. On the day of admission RL was taken to a local emergency department secondary to increased lethargy and the development of respiratory difficulties. His initial vital signs were a heart rate of 115/min, respiratory rate of 37/min, blood pressure of 110/67 mm Hg, temperature of 37.3°C, a room air oxygen saturation of 87% by pulse oximetry and an estimated weight of 35 kg. His Glasgow coma score was 13 (3 eye opening, 5 verbal, 5 motor). Blood and urine bacterial cultures were obtained, and the child was given ceftriaxone intravenously. Because of upper airway obstruction from secretions, placement of a nasopharyngeal airway trumpet was attempted without success and resulted in profound epistaxis. He was then transferred to the pediatric intensive care unit at the University of Maryland Hospital for Children. On arrival to the pediatric intensive care unit, RL was obtunded and in obvious respiratory distress because of the inability to clear secretions and blood from his airway. Although he had a Glasgow coma score of 10 (3 eye opening, 2 verbal, 5 motor), he was able to maintain his oxygen saturations as measured by pulse oximetry without evidence of hypoxia. Physical examination was remarkable for the absence of meningismus and papilledema. His deep tendon reflexes were +1 to 2/4 and 0 to 1/4 in the in the upper and lower extremities, respectively, and his Babinski reflexes were up going bilaterally. His motor strength was assessed as +5/5 globally. Intubation was performed with rapid sequence induction, at which time his tracheal secretions were bloody initially but rapidly cleared. Initial laboratory testing. The patient’s white blood cell (WBC) count was 7300 cells/μl, with a differential of 70% neutrophils, 17% band forms, 11% lymphocytes and 2% monocytes. His hemoglobin was 12 g/dl, and platelet count was 27 000/μl. Coagulation studies, liver function tests and evaluation of renal function were normal. Cranial computerized tomography was normal. Two units of platelets were administered, and then a lumbar puncture was performed. Examination of the CSF revealed a WBC of 15 cells/μl, a red blood cell count of 0 cells/μl, glucose of 79 mg/dl and a protein of 17 mg/dl. Direct immunofluorescent testing of the nasopharyngeal aspirate for respiratory viruses was positive for influenza B and was later confirmed by cell culture. Respiratory virus cultures of the CSF were negative. Hospital course. The patient received oseltamivir, 75 mg twice daily, via nasogastric tube for 5.5 days. In addition vancomycin and ceftriaxone were continued for 72 h until bacterial cultures of the blood, CSF and urine were negative. RL had a prolonged hospitalization because of his abnormal neuromuscular status. He remained comatose for 3 days and then developed waxing and waning levels of consciousness for an additional 5 days. On Hospital Day 6 (Day 5.5 of oseltamivir), he developed a new onset of fever. Repeat CSF analysis at that time revealed 18 WBC/μl with 17% neutrophils and 85% lymphocytes and 1240 red blood cells/μl on a traumatic lumbar puncture. The CSF protein was 28 mg/dl, and the glucose was 82 mg/dl. Magnetic resonance imaging with gadolinium found no evidence of intracranial abnormality but did reveal pansinusitis for which he was given amoxicillin/clavulanic acid. The platelet count stabilized after 48 h of hospitalization and normalized by the end of the first week. CSF viral cultures were negative. By Hospital Day 8 RL was afebrile, alert, awake and able to communicate via an electronic speller. However, his cough and gag reflexes were absent, and his strength was appreciably diminished and globally assessed to be +2/5. Deep tendon reflexes were absent as well. He remained intubated until Hospital Day 21. The serum creatine phosphokinase on hospital Day 12 was normal (53 units/l). An electromyogram (EMG) and nerve conduction study, performed on Hospital Day 14, demonstrated multifocal sensory motor neuropathy without evidence of demyelination. RL gradually developed increasing strength and deep tendon reflexes and regained his gag and cough reflexes. Repeat nasopharyngeal samples for influenza B antigen and respiratory viral cultures were negative on Hospital Day 20. He was successfully extubated on Hospital Day 21 and was discharged to an inpatient rehabilitation facility on Hospital Day 24. At the time of discharge his strength was assessed as +4.5 to 5/5, and deep tendon reflexes were +1 to 2/4. His cognitive function appeared normal, and he was able to ambulate with the assistance of a walker. On follow-up in the neurology clinic 1 month after discharge, he was neurologically and cognitively normal. Special studies. The two samples of CSF, one pretreatment and one 3 h after the last dose of oseltamivir, were tested for the presence of RNA coding for influenza B hemagglutinin, neuraminidase and nucleoprotein using RT-PCR. Only the pretreatment CSF sample was positive for the influenza B neuraminidase RNA. RT-PCR was not performed on plasma or whole blood. CSF and plasma obtained 3 h after the last dose of oseltamivir were assayed for the parent drug and its active metabolite, oseltamivir carboxylate, using gas chromatography. Oseltamivir and oseltamivir carboxylate were undetectable in the CSF. The plasma concentration of oseltamivir was 6.9 ng/ml, and that of oseltamivir carboxylate was 401 ng/ml. Discussion. Encephalitis in association with acute influenza infection is an uncommon event. However, in Japan there has been a recent increase in frequency of influenza-associated encephalitis and encephalopathy. 3, 5, 6 North American reports indicate that 4 to 7% of the cases of encephalitis are associated with influenza. 7, 8 More recently PCR technology has been used to detect influenza viral RNA in CSF. 2, 3 As this technique becomes more widely available, additional cases of influenza-associated encephalitis may be identified and the incidence could be better understood. Although oseltamivir has been shown to decrease the length of influenza illness, decrease viral shedding during influenza infection and be effective prophylaxis against influenza infection, 9 its use in the treatment of influenza B encephalitis has not been previously reported. As noted in our patient there was no evidence that oseltamivir crossed the blood-brain barrier, but there was clearance of viral RNA from the CSF. Influenza RNA has been detected in the CSF up to 9 weeks after acute infection. 10 The viral clearance in our patient might have been the result of the child’s own immune response. The role of oseltamivir in this process is unclear. As the pathogenesis of influenza-associated encephalitis is further elucidated, the role of antiviral agents might become better defined. The RT-PCR testing was positive for only the influenza B neuraminidase RNA and negative for influenza B hemagglutinin and nucleoprotein. There are no accurate standards for sensitivity available to evaluate the assay. PCR technology can theoretically detect a single copy of the RNA genome. In practice the RNA signal can be degraded or lost through the steps of isolation, reverse transcription and PCR. The diagnosis of disease cannot be made with the isolation of a single gene, especially when other genes are not identified. This could be the result of contamination, low copy number or degradation of the RNA. However, in addition to the RT-PCR results this child also had clinical findings of encephalitis, a CSF pleocytosis and nasopharyngeal evidence of influenza B infection to make the diagnosis of influenza B encephalitis. The weakness seen in our patient was profound. Potential causes of weakness in the present case could have included myopathy, Guillain-Barré syndrome or a postinfectious or autoimmune mediated etiology. The low serum creatine phosphokinase values and EMG findings make influenza-related myopathy unlikely. The normal CSF protein concentration and EMG findings are not consistent with Guillain-Barré syndrome. The EMG results in the present case suggest a possible multifocal sensory motor neuropathy. The mechanism of this neuropathy is not known. Because of his altered mental status, the timing of the onset of the weakness was unclear. If the weakness did not begin until his mental status was improving, the etiology may have been postinfectious with an onset ∼10 days after the initial symptoms of influenza. Cases of polyneuropathy after influenza infection have been reported to be caused by a postinfectious, immune mediated mechanism. 11–13 This latter entity most resembles the clinical and EMG findings of the present case. Finally the thrombocytopenia with hemorrhage seen in our case was an unusual finding. Four similar cases with either purpura or petechiae but without active bleeding in association with influenza infection have been previously reported. 14, 15 The platelet count nadir ranged from 73 000 to 108 000/μl in these cases. The cause of the severe thrombocytopenia resulting in hemorrhage in our patient was unclear, but it resolved spontaneously. Acknowledgements. We thank Dr. Jonathan McCullers at St. Judes Research Hospital for performing the influenza RT-PCR on the CSF. We thank Dr. Hugh Wiltshire from Roche Discovery Welwyn and Carolyn Serpe from BAS Analytical Systems for arranging and running the quantitative serum and CSF gas chromatography assays for oseltamivir and oseltamivir carboxylate.