Introduction

Influenza is one of the most frequent causes of pediatric respiratory disease resulting every year in roughly 870.000 hospitalizations in children younger than 5 years of age [1]. The infection is usually self-limiting, although some complications can develop, especially in pediatric and elderly populations, and immunocompromised patients. The incidence of influenzaassociated pediatric deaths reported in the US each year is 0.15 per 100.000 children and it is highest among children aged <6 months (0.66 per 100.000) [2]. Notably, according to the available literature, influenza-associated neurologic complications are not rare in children hospitalized with influenza, occurring in up to 18% of this population. [3 - 11]. Children account for most neurologic complications, which are associated with higher morbidity and mortality [12, 13]. A previously underlying condition is associated with an increased risk of neurological complications and a worse prognosis [4, 14, 15]. Reported neurological manifestations of influenza include febrile seizures, non-febrile seizures, Encephalopathy/Encephalitis (IAE), Guillain-Barré Syndrome, stroke, and myelitis. Antiviral agents such as neuraminidase inhibitors, and immunomodulatory treatments (corticosteroids, intravenous immunoglobulin), are currently administered but the evidence of their efficacy is limited. Nowadays, there are no available biomarkers to predict outcomes [16, 17]. We report a unique case of a fatal influenza-associated neurological complication in a neuro-oncologic child admitted to a tertiary pediatric Hematology Oncology Center. We also did a review of the literature concerning this topic.

Case report

A 1-7-year-old boy presented with torticollis with left neck deviation and ataxia. The craniocervical RMI showed a cervicalmedullary lesion involving the medulla oblongata, the cervical cord down to C3, and the left cerebellar vermis. Due to the infiltrative features of the tumor, lacking a clear cleavage plan, a subtotal tumor removal was performed with the use of intraoperative neurophysiological monitoring. Post-operatively the patient presented a left arm hyposthenia and some dysphagia, which both gradually improved with physiotherapy. No tracheostomy was required. The histological diagnosis was consistent with a lowgrade neuroglial neoplasm with desmoplasia, BRAF gene mutated. Based on the small residual tumor and the benign features of the tumor, no adjuvant therapy was considered at this stage and the child was followed up with a control MRI initially every 3 months. After 11 months from intervention, the MRI showed evidence of progression. Therefore, chemotherapy according to the SIOP LGG 2004 protocol was started in June [18]; standard induction consisted of ten weekly doses of Vincristine (VCR) 1.5 mg/m2 and four single doses of carboplatin (CBDCA) 550 mg/m2 at 3-week intervals followed by three cycles of simultaneous VC at 4-week intervals. Importantly, the patient did not receive the annual influenza vaccination for the following fall-winter season. After 10 days from the eighth line of vincristine/carboplatin, in the month of January, the patient presented to the emergency department of a peripheral hospital with a three-day history of cough and fever. On examination he was in good clinical condition, the only significant finding was the presence of crackles at the base of the right lung. The lab tests showed hemoglobin 111 g/L, platelets 188 x109/L, leucocytes 1,08 x 109/L, polymorphonucleated 0,79 x 109/L, Reactive C Protein (CPR) 27 mg/L [NV <5 mg/L], Lactic Dehydrogenase (LDH) 579 U/L [NV 120-300 U/L], while the remaining blood tests were unremarkable. A para-hilar right consolidation was seen at a chest X-ray consistent with the diagnosis of pneumonia. The patient was started on antibiotic therapy with intravenous Ceftriaxone 75 mg/Kg/day and Clarithromycin 15 mg/ Kg/die. A few hours later, he developed a febrile seizure (a tonic crisis) that required three subsequent doses of benzodiazepines. Yet, post-critic hypotonia and drowsiness persisted. The cranial CT scan was negative for acute events such as bleeding, edema, or cerebral hypertension. Because of the neurological status and the underlying condition, he was transferred to our referral center. At the arrival, he was drowsy, unarousable with fixed pupil reactions bilaterally. He was in oxygen therapy in a nasal cannula with good oxygen saturation. Eupneic, a normal vesicular murmur with some bilateral crackles was appreciated. Cardiac and abdominal examinations were not significant. Given the worsening neurological conditions, the cranial CT scan was repeated but still unremarkable, while the EEG was not diagnostic. The chemicalphysical analysis of Cerebral-Spinal Fluid (CSF) obtained by lumbar puncture was negative as well as cultures and the extended bacterial-viral search by polymerase chain reaction for E. coli, H. influenzae, L. monocytogenes, N. meningitidis, S. agalactiae, S. pneumoniae, Cytomegalovirus, Enterovirus, Herpes simplex 1, Herpes simplex 2, Human herpesvirus 6, Parechovirus, Varicella zoster virus, Cryptococcus neoformans/gattii. Serum B-D glucan and galactomannan were persistently negative. A chest X-ray was performed and no consolidations nor effusion or pneumothorax were found. The patient was started on broad-spectrum antibiotic therapy with meropenem, teicoplanin, ciprofloxacin, and on antimycotic therapy with fluconazole 8mg/Kg/die and acyclovir 750 mg/m2/day in three doses as antiviral and then G-CSF was added as neutrophil count dropped below 0.5 x 109/L. During hospitalization, at day +2, he had two other episodes of afebrile seizures, and an anti-edema therapy with dexamethasone was added. He underwent a naso-faringeal swab for pneumotropic agents and blood cultures. Because of the worsening of the clinical condition with a Glasgow Coma Scale of 8, at day +2 from hospitalization, he was admitted to PICU where analgesicsedation with fentanyl and midazolam and an antiepileptic therapy with levetiracetam were started. On the same day, a cranial MRI excluded a progression of the underlying glioma (Figure 1). At days +3 and +4 the patient received a course of Intravenous Immunoglobulins as anti-inflammatory therapy (1 g/kg/day). At the nasopharyngeal swab film array, we finally found positivity for A-influenza and A-H1-influenza. In retrospect, flu-like symptoms were reported by the patient’s mother and sibling. A diagnosis of Influenza Associated Encephalopathy (IAE) was made. He started Oseltamivir therapy at 5 mg/Kg/day on day six from the hospitalization and after 9 days from the onset of fever. On day +7 a Chest X-ray showed a new left lung consolidation. The neurological status remained stable and non-reversible, he developed an increscent respiratory distress with the development of oxygen dependency, and he needed non-invasive mechanical ventilation. In three days, there was a progressive worsening that finally led to the exitus. The parents agreed with the decision to not proceed with an invasive procedure (tracheal intubation) because of the irreversibility of the neurological status and the poor prognosis. The parents refused necropsy. The events described above are listed in Table 1.

Figure 1: On the left (A-C): last follow-up MRI before the acute event (10 days before). On the right (B-D): MRI during the acute event. A-B Axial FLAIR weighted sequences. C-D Sagittal T2 weighted sequences with contrast medium. The residual cervical-medullary lesion involving the dorsal region of medulla oblongata, the cervical cord down to C3, and inferior cerebellar peduncles (> left) is remained the same comparing the last follow-up MRI and the MRI performed during the acute event. The contrast enhancement is remained the same. No evidence of new elements is shown, excluding a disease progression to explain the patient’s neurological status.

Table 1: Timeline of principal events reported in the case.

Discussion

This is a case of probable Influenza-Related Encephalopathy (IAE) in an oncological patient immunocompromised by chemotherapy. There are still limited population-based studies on the clinical characteristics and burden of seasonal Influenzaassociated neurological complications in the pediatric age group. The salient features of various studies conducted in the last ten years involving children with neurological manifestations of influenza are shown in Table 2.

The pathogenesis of neurologic events has not been clearly established, with both direct invasion of neural cells and inflammatory response seeming to play a role in the process [14]. The oncologic pediatric population has not been considered in any study regarding neurologic complications of influenza, but some studies demonstrated a major incidence and worse prognosis in children with generic pre-existing chronic conditions or neurological illnesses. A patient with medulloblastoma was included in a Chinese study [19]. In two Italian studies, a rate of 33% of underlying neurological conditions was found in patients hospitalized with neurological complications of influenza [13, 20]. The clinical spectrum of influenza-associated complications in children comprises different clinical entities with different prognoses. The neurological manifestation of influenza associated with the worst outcome is IAE. The mortality rate of IAE was 10.9% in a recent large retrospective study in Hong Kong [10]. Children requiring Pediatric Intensive Care Unit (PICU) admission for influenza-associated encephalopathy/encephalitis have high mortality and morbidity rates [17]; in fact, the studies conducted in the PICU setting reported also higher mortality rates: 37,5% in the study published by Lin CH et al. [19]. The hospitalized patients with influenza and neurological complications compared to other influenza in-patients without neurological manifestations had longer in-patient lengths of stays, higher rates of antiviral therapy use and mechanical ventilator use, and higher PICU admissions and influenza-related deaths [4, 15, 19]. Children <6 years old showed the highest estimated incidence of IANCs and death; in the recent retrospective study in Hong Kong, 85.5% of the IANC cases were patients aged <6 years old. This may support the fact that younger patients are more susceptible to the complications of influenza infections [10, 16]. In this case, the PCR for the influenza virus was not performed on CSF, but according to literature findings, Influenza-virus is rarely isolated from the CSF. The lack of detectable virus in CSF may be due to low viral load or the clearance of the virus from the CSF prior to sampling or may suggest that neurological manifestations are due to post-infectious inflammation rather than a direct effect of the virus. CSF cytology, protein, and glucose levels are normal in most cases, but mild pleocytosis or elevated protein levels are occasionally observed. In the case reported here, we didn’t have any CT scan or MRIpositive findings. In the literature imaging positive findings are reported in a variable percentage of cases; 8% in the Chinese series [19]. Influenza should be considered in the differential diagnosis of children presenting with encephalitis and/or acute onset of neurological symptoms during the influenza season by searching respiratory viruses at least in the nasopharyngeal aspirate. Treatment is primarily supportive, and some patients may need to be referred to an intensive care unit. Antiviral therapy with a neuraminidase inhibitor is recommended especially in patients who present within 48 hours from the onset of symptoms to reduce viral replication. However, no conclusive evidence exists that oseltamivir alters the course of IAE [15, 21]. Our patient received

antiviral medication and IVIG, without any evident benefit. The efficacy of corticosteroids, IVIG, plasmapheresis, and hypothermia require further studies to be assessed. A prompt diagnosis and supportive therapy are an important burden; however, prevention is the crucial point. This case also highlights the potential role of annual influenza vaccination to prevent its complications, especially in particular populations like oncologic pediatric patients. Although influenza vaccines are strongly recommended in this group of patients, the rates of vaccination continue to be suboptimal and both parents and pediatricians fail to recognize these comorbidities as high-risk influenza conditions [13]. These findings emphasize the strategic importance of influenza immunization and highlight the need for a more active approach to vaccination in chronic patients and their family members to reduce the infectious risk.

Table 2: The salient features of various studies conducted in the last ten years involving children with neurological manifestations of influenza. IANCs: Influenza Associated Neurological Complications. IAE: Influenza-Associated Encephalitis. ANE: Acute Necrotizing Encephalopathy. PICU: Pediatric Intensive Care Unit. N/A: Not Available