Fatal Case of Influenza B Virus Pneumonia in a Preterm Neonate

Influenza B infection typically has low mortality. A 1020-g neonate had a septic clinical picture and pneumonia. Influenza B virus was isolated from nasopharyngeal and tracheal aspirates. The infant died. Influenza B virus infection is a common disease in children and adults with a high morbidity and low mortality. Morbidity and mortality in pediatric patients are largely confined to patients with cardiopulmonary disease or compromised immunity. 1 In preterm neonates, who are considered immunocompromised, clearance of influenza B virus may be delayed because of immature T cell function. 2 Moreover preterm neonates may lack maternal antibodies against influenza B virus, which puts them at risk of acquiring an influenza B virus infection. 3 We report a preterm neonate with a fatal influenza B virus pneumonia. Case report. A 1020-g boy was delivered at a gestational age of 292/7 weeks by cesarean section because of intrauterine growth retardation. The Apgar score was 2/9/10 at 1, 5 and 10 min, respectively. Chest radiograph showed a mild respiratory distress syndrome. Continuous positive airway pressure was applied because of respiratory distress. From Days 2 to 6 he needed mechanical ventilation. No surfactant was administered. Supplemental oxygen was given during periods of intubation only. On Day 3 broad spectrum antibiotic treatment with penicillin and amikacin was started because bacterial sepsis was suspected. Leukocyte count was decreased and serum C-reactive protein was increased (2.9 × 10 9 /l and 20 mg/l, respectively). Blood cultures, drawn from the arterial and venous umbilical catheter, and culture of cerebrospinal fluid (CSF) and urine remained negative. On Day 8 he appeared septic and required mechanical ventilation for 3 days. Penicillin and amikacin were replaced by meropenem. The venous umbilical catheter was removed because a catheter-related infection was suspected. (The arterial umbilical catheter had already been removed on Day 4.) Blood cultures, drawn from a peripheral vein and the venous umbilical catheter, showed S taphylococcus epidermidis and confirmed the diagnosis of catheter-associated sepsis. For this reason meropenem was stopped, and the patient was treated with vancomycin for 1 week. On Day 14 the mother experienced symptoms of an influenza-like illness. The father experienced influenza-like symptoms 5 days later. On Day 17 the patient’s condition deteriorated. He developed severe respiratory distress and was mechanically ventilated. Leukocyte count and serum C-reactive protein were increased (32.1 × 10 9 /l and 97 mg/l, respectively). A chest radiograph showed consolidation of the right lung with air bronchogram, silhouette sign of the right diaphragm and right cardiac contour. Peribronchial thickening was seen in the left lung. Because bacterial pneumonia was suspected, meropenem was started. Bacterial cultures of blood, CSF, urine and tracheal aspirate were negative. Meropenem was stopped on Day 21. Viral cultures of the patient from nasopharynx and tracheal aspirate, obtained on Day 19, grew influenza B virus. Serology and PCR on influenza B virus were not performed. Viral cultures of feces remained negative. On Day 23 broad spectrum antibiotic treatment with penicillin and amikacin was started because a bacterial superinfection was suspected. The patient had convulsions, which were treated with phenobarbital. Serum electrolytes were normal. Serum glucose was decreased (1.9 mmol/l). Because meningitis could not be excluded, antibiotic treatment was changed to penicillin and cefotaxime. Antibiotics were stopped 3 days later because blood and CSF cultures remained negative. Viral cultures of CSF, obtained on Day 23, were negative. On Day 24 treatment with dexamethasone was started to prevent further pulmonary damage. Nevertheless the patient developed interstitial pulmonary emphysema and a left-sided pneumothorax, which was managed by intercostal tube drainage. On Day 28 ultrasound of the brain revealed severe periventricular leukomalacia. Based on the severe and progressive ventilatory problems and poor neurologic prognosis, further treatment was withdrawn, and the child died on Day 33. No parental consent was obtained for autopsy. Discussion. To our knowledge this is the first case report of a preterm neonate with a fatal influenza B virus pneumonia. Three outbreaks in neonatal units have been described previously in the literature, all related to influenza A virus infection. 4–6 The prevalence of influenza B virus pneumonia in neonates is unknown. Liou et al. 7 described a 3-month-old female infant, born at 34 weeks gestational age, who died of respiratory failure caused by influenza B virus infection. Troendle et al. 1 reported a term female infant with Turner’s syndrome and a hypoplastic left heart who died of respiratory decompensation caused by influenza B virus infection and a superimposed bacterial bronchopneumonia. Influenza B virus is transmitted to neonates by inhalation of airborne particles coming from neonatal intensive care unit (NICU) personnel or visitors of NICU patients, both experiencing respiratory symptoms. Peak virus replication occurs 1 to 3 days after inoculation of the virus, and virus shedding can persist for >13 days in young children. 2 Influenza B virus activity in the Netherlands was increased during admittance of our patient. 8 Because the mother of our patient experienced symptoms of an influenza-like illness, it seems likely that she has been the source of the influenza B virus. However, for emotional reasons viral cultures were not taken from the mother. Prevention of transmission of influenza B virus from NICU personnel or visitors of NICU patients to (preterm) neonates is essential as long as there are no specific antiviral agents approved for use in neonates. Local epidemiologic surveillance should be taken into consideration when considering influenza as a cause of illness in the NICU. Therefore NICU personnel and visitors of patients should not be permitted on the NICU when experiencing a respiratory illness. Currently risk for transmission can further be reduced by immunization with trivalent inactivated influenza vaccine of NICU personnel and parents. Experimentally administered intranasally, cold-adapted, live, attenuated vaccine can be given; however, this vaccine is not licensed or commercially available in the US and Europe. Immunization of NICU personnel and parents is not a standard procedure in the Netherlands. Prevention by immunization of the (preterm) neonate before 6 months of age with currently available vaccines may not be efficient because of poor antibody response. 9 The use of maternal immunization during pregnancy, resulting in higher infant levels of vaccine-specific IgG, might protect the neonate against influenza B virus infection. 10 However, preterm infants might not receive sufficient maternal protective antibodies. Immunization of women during the 2nd or 3rd trimester of gestation, if these periods or the delivery are expected to occur during the epidemic season, is currently recommended during routine obstetrical care in the US, but not in Europe. 11 Clinical manifestations of influenza B virus pneumonia in neonates are atypical. They mimic symptoms of bacterial sepsis, as was demonstrated in our patient, and may delay the diagnosis of a viral infection. 2 Viral causes should be considered in neonates with an atypical course of respiratory distress syndrome, especially when other people in the patient’s surroundings experience symptoms of an influenza-like illness. Although chest radiography could be of value in differentiating between bacterial and viral pneumonia, in our patient it was not completely consistent with the characteristic radiographic appearance, including peribronchial infiltrates, hyperexpansion and segmental or lobar atelectasis. 12 To our knowledge respiratory distress syndrome in the first days after birth and the occurrence of influenza B infection 17 days later are not related. Interstitial pulmonary emphysema and pneumothorax are more likely the result of barotrauma caused by intensive mechanical ventilation. The seizures did not seem related to influenza B virus infection, in that viral cultures of CSF were negative. More likely the underlying cause was periventricular leukomalacia or hypoglycemia. The peripheral white blood cell count can be variable during an influenza virus infection. Lymphopenia and neutrophilia with left shift are frequently described in infants. 2 Viral culture remains the standard for diagnosis of influenza B virus infection, but results are not available for several days. Theoretically PCR could provide rapid diagnosis of influenza B virus infection, but unfortunately this test, because of costs and workload, is rarely available on a frequent basis. Direct detection of viral antigens by immunofluorescence in nasal fluid could detect the infection immediately but probably has limited sensitivity. 13 For neonates, treatment for influenza B virus pneumonia is not available. Amantadine and rimantadine are active only against influenza A virus. If administered by inhalation or intranasally, zanamavir, a neuraminidase inhibitor, is effective against influenzas A and B. 14 If administered orally, however, zanamavir is not effective because of poor bioavailability. This may limit its usefulness for neonates. The neuraminidase inhibitor oseltamivir is administered via the oral route. However, its safety and efficacy have only been established in adults. 15 In the future it might be useful in the treatment of (preterm) neonates.