Brain Lesion in a Patient With Influenza

A 63-year-old female with past medical history significant of diabetes, active tobacco abuse, and chronic obstructive pulmonary disease presented to an outside hospital with a 3-day history of productive cough, shortness of breath, and fatigue. On presentation, she was afebrile and hemodynamically stable with oxygen saturation of 96% in ambient air. Her examination was notable for expiratory wheezes but was otherwise unremarkable. Laboratory workup revealed a white blood cell count of 3200 cells per mm3. Chest x-ray revealed no cardiopulmonary disease. Nasopharyngeal rapid influenza antigen testing, however, was positive for influenza B. The patient was treated with 1 dose of 125 mg intravenous methylprednisolone, as well as nebulized albuterol and ipratropium. Upon discharge from the emergency department, she was prescribed oral oseltamivir 75 mg twice daily for 5 days and oral prednisone 50 mg daily for 5 days. She presented again to the emergency department 4 days later with worsening cough and shortness of breath. Physical exam was significant for oxygen saturation of 93% on room air, respiratory distress, continued wheezing, and coarse breath sounds. Repeat chest x-ray revealed nodular areas of opacity throughout the lungs bilaterally, raising suspicion for multifocal pneumonia. Bacterial superinfection was suspected, and the patient was admitted to the hospital. Empiric ceftriaxone and doxycycline were addition to oseltamivir. Sputum cultures grew methicillin-sensitive Staphylococcus aureus and Streptococcus pneumoniae. Antibacterial agents were changed to cefazolin and vancomycin. Blood cultures remained negative. On hospital day 10, the patient was noted to be lethargic and confused. A computed tomography scan of the head without contrast revealed large right occipital intraparenchymal hemorrhage measuring 3.4 cm by 2.9 cm, and she was transported to our institution for neurosurgical intervention. Magnetic resonance imaging of the brain confirmed right occipital parenchymal hemorrhage. Additionally, small hemorrhages within frontal lobes bilaterally, right cerebellum, and brachium pontis with surrounding edema, concerning for brain abscesses, were noted (Figure 1). Emergent burr hole craniotomy was performed. The lesion in the occipital lobe was resected and debulked. Gross purulence was noted. Peridoic acid-Schiff staining on the intraoperative sample is shown (Figure 2). Magnetic resonance imaging revealing multiple lesions suggestive of bleed/abscess. Periodic acid–Schiff stain revealing septate narrow angle branching hyphae. What is your diagnosis? Diagnosis: Neuroinvasive aspergillosis in a patient with influenza Bronchoscopy and brain biopsy were performed on the day of transfer at our institution. Periodic acid–Schiff and Grocott methenamine silver stain (Figure 3) on the brain lesion revealed narrow angle branching septate, suggestive of Aspergillus infection. Voriconazole was initiated. Both bronchoalveolar lavage and brain tissue cultures grew Aspergillus fumigatus. Testing for human immunodeficiency virus and chronic granulomatous disease with neutrophil oxidative burst were negative. Serum galactomannan was 0.09 index (interpreted as negative). Despite antifungal therapy, the patient developed worsening neurologic status. A magnetic resonance imaging (MRI) scan was repeated, which revealed increasing size of the abscesses as well as worsening surrounding edema. The family elected for hospice care, and the patient passed away several days later. Grocott methenamine silver stain revealing septate narrow angle branching hyphae. Bacterial superinfection with Streptococcus and Staphylococcus is a recognized complication of influenza [1]. Less commonly considered, but clearly proven, is the propensity of Aspergillus to cause invasive pulmonary disease during primary illness from influenza [2, 3]. The first case of invasive pulmonary aspergillosis (IPA) in a patient with influenza was made post-mortem [4]. Over the past few years, however, more such cases have been reported in the literature. In a case series and literature review of cases published in 2016, a total of 57 cases of invasive aspergillosis associated with severe influenza illness were reported [5]. A larger, retrospective multicenter study published by Schauwvleighe et al in 2018 reported IPA in close to 20% (83/432) of patients who were admitted to the intensive care unit (ICU) for severe influenza infection [6]. The authors identified influenza as an independent risk factor for IPA. Additionally, higher APACHE score, male sex, and use of corticosteroids 4 weeks prior to ICU admission were also associated with invasive aspergillosis [6]. Three-month mortality was significantly high at 51% in this group of patients [6]. Although the exact mechanism by which Aspergillus infects patients with influenza is not known, several hypotheses have been proposed. The pathogenesis is probably multifactorial. Disruption of ciliary clearance by the influenza virus along with impaired mucosal immunity in the respiratory tract likely creates a conducive environment for invasion of Aspergillus, a ubiquitous microbe in the environment [7]. Viral-induced lymphopenia and changes in T helper 1 and 2 cells also have been implicated in the pathogenesis [8, 9]. Of note, typical risk factors for IPA such prolonged neutropenia, organ transplantation and hematological malignancies need not be present to heighten suspicion for this superinfection. Patients without these typical immunosuppressive states have clearly been found to have IPA post-influenza [2, 5]. Patients with chronic obstructive pulmonary disease (COPD) may already be colonized with Aspergillus, and viral mediated changes in the respiratory tract likely promote invasive fungal infection in that environment. However, because superinfection is known to occur in patients without chronic respiratory disease, aspergillosis may occur de novo. In their study, Schauwvleighe et al had particularly excluded patients known to be colonized with Aspergillus or with prior history of IPA [6]. Both viral types A and B have been implicated in Aspergillus superinfection [6, 10]. Although IPA is a known entity post-influenza illness, neuroinvasive aspergillosis has been reported very rarely. Two cases of “proven” neuro-aspergillosis have been described in the last 15 years [11, 12]. Lee et al reported a 65-year-old patient with history of COPD who was admitted with influenza [11]. She had received antibiotics for bacterial superinfection, as well as corticosteroids. Computed tomography of the head, done for worsening mental status, revealed multiple parenchymal lesions. Respiratory and brain lesions grew Aspergillus. Unfortunately, the patient succumbed to the illness. Another recent case reported by Kim et al was of a young type 1 diabetic male who also had bacterial superinfection with influenza [12]. He did not receive steroids, however. MRI of the head revealed multiple rim enhancing lesions. Pulmonary and brain biopsy specimens yielded A. fumigatus. Although the patient had residual neurological deficits, he survived the illness. In addition to these 2 proven cases of neuroinvasive aspergillosis, we found 3 other cases, which raised suspicion for this entity, but definitive diagnosis was not performed in any one of them [13–15].Central nervous system (CNS) imaging had revealed findings suggestive of brain abscess, bleeding, and cerebral infarction. Because Aspergillus is angio-invasive, we suspect CNS involvement by Aspergillus may have been the cause for vascular manifestations in these cases, similar to ours. Our case should serve as a reminder to clinicians to be aware of the potential for invasive aspergillosis as a complication of influenza infection, even in seemingly low-risk patient populations or patients diagnosed with a concurrent bacterial pneumonia. The recovery of Aspergillus from respiratory culture (especially from a severely ill patient or a patient with worsening clinical status despite appropriate antiviral/antibacterial therapy) should prompt consideration of further workup and initiation of empiric antifungal therapy. Neurologic involvement should warrant urgent imaging. Finally, corticosteroids should be withheld in influenza infection, unless indicated for another reason, because their use has been associated with unfavorable outcomes in patients with IPA [6]. Acknowledgments. The authors thank Dr Kymberly Gyure for help with the pathology slides. Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.