Intravenous vitamin C as adjunctive therapy for enterovirus/rhinovirus induced acute respiratory distress syndrome

Fowler III, Alpha A; Kim, Christin; Lepler, Lawrence; Malhotra, Rajiv; Debesa, Orlando; Natarajan, Ramesh; Fisher, Bernard J; Syed, Aamer; DeWilde, Christine; Priday, Anna; Kasirajan, Vigneshwar

Key words: Intravenous vitamin C; Acute respiratory distress syndrome; Enterovirus/rhinovirus; Acute lung injury; Extracorporeal membrane oxygenation INTRODUCTION Viral diseases can produce the acute respiratory distress syndrome (ARDS) [1] . Pandemic viruses are the most common viruses that produce lung injury. Influenza viruses and coronaviruses (e.g., H5N1, H1N1 2009, severe acute respiratory syndrome coronavirus, and middle east respiratory syndrome coronavirus) are potentially lethal pathogens known to produce lung injury and death from ARDS [2] [3] [4] [5] . At the tissue level, lung injury results from increased permeability of the alveolarcapillary membrane that leads to hypoxia, pulmonary edema, and intense cellular infiltration, particularly neutrophilic infiltration. The exact pathogenesis of virusinduced ARDS is slowly becoming understood. Unlike the "cytokine storm" occurring in bacterial sepsis that leads to up-regulation of pro-inflammatory cytokines [e.g., interleukin-1β (IL-1β), IL-8, IL-6] and generation of reactive nitrogen and oxygen species in the vascular space, viruses such as the influenza virus target alveolar epithelium, disabling sodium pump activity, damaging tight junctions, and inducing cell death in infected cells. Cytokines produced by virally infected alveolar epithelial cells activate adjacent lung capillary endothelial cells which then leads to neutrophil infiltration. Subsequent production of reactive oxygen and nitrogen species by infiltrating neutrophils further damages lung barrier function [1] . Apart from pandemic viruses other viruses, are increasingly reported to produce severe ARDS. While most of the approximately 100 strains of enterovirus primarily infect the gastrointestinal tract, enterovirus-D68 (EV-D68) has tropism for the respiratory tract. EV-D68 produces acute respiratory disease ranging from mild upper respiratory tract symptoms to severe pneumonia and lung injury as in the case we describe here. In an outpatient setting, EV-D68 disease has manifested most commonly among persons younger than 20 years and adults aged 50-59 years [6] . In August 2014, EV-D68 emerged as a cause of severe respiratory infections with hospitals in Illinois and Missouri reporting an increased incidence of rhinovirus and enterovirus infection [7] . In this report, 30 of 36 isolates from the nasopharyngeal secretions of patients with severe respiratory illness were identified as EV-D68. Following these reports, an unusually high number of patients with severe respiratory illness were admitted to these facilities, presumably with EV-D68 infection. Enterovirus-D68 leading to ARDS has been reported in China, Japan, and in the United States [8] [9] [10] [11] . The report by Farrell et al [11] , describes a previously healthy 26-year-old woman who developed severe ARDS following an enterovirus-D68 infection. Despite all critical care support measures, the patient required protracted mechanical ventilation for 32-d, necessitating tracheostomy and endoscopic gastrostomy tube placement. She was discharged alive 55 d following admission. Enterovirus and rhinovirus were recovered from the respiratory secretions of the patient we report here. Extracorporeal membrane oxygenation was rapidly required in our patient's care following failure of conventional mechanical ventilation. The patient reported by Farrell et al [11] is the full extent of support required for patients with ARDS who ultimately develop a fibroproliferat