Is Interleukin-6 blockade a viable strategy to prevent progression of acute respiratory distress syndrome in non-COVID viral pneumonia?

To the editor

We recently cared for a 48-year-old female who presented with fever, malaise, and shortness of breath for one week. Chest X-ray showed bilateral diffuse consolidations. A nasal swab respiratory panel by polymerase chain reaction (PCR) was positive for Human Parainfluenza Virus (HPIV) serotype 2. Three separate COVID-19 PCR tests were negative, and so was a COVID-19 antibody test. She was initially treated with intravenous methylprednisone and empiric antibiotics. During the hospital stay, the patient became progressively hypoxic and was placed on a high-flow nasal cannula with peak oxygen requirements of 70% FiO2. An initial computed tomography (CT) of the chest with contrast demonstrated bilateral diffuse pulmonary infiltrates. Her worsening oxygen requirements were secondary to ventilation-perfusion mismatch from viral pneumonia and subsequent ARDS. The patient's interleukin (IL)−6 level was notably elevated at 198 pg/mL. After a prolonged and complicated hospital stay of 53 days, the patient was eventually discharged to a rehabilitation facility on supplemental oxygen. In this letter, we hope to explore the potential role of tocilizumab in non-COVID viral pneumonia, such as those caused by influenza and parainfluenza.

Tocilizumab is an IL-6 inhibitor that was first approved by the Food and Drug Administration (FDA) in 2008 for the management of rheumatoid arthritis. This medication has since been widely used to manage multiple disease processes that rely on IL-6-mediated inflammation, such as juvenile idiopathic arthritis (JIA), systemic sclerosis-associated interstitial lung disease, giant cell arteritis, and cytokine release syndrome (CRS). COVID-19, like other forms of viral pneumonia, invokes IL-6-mediated inflammation, subsequent cytokine release syndrome, and progressive and persistent lung damage despite decreasing viral loads [1]. In patients with COVID-19 pneumonia, IL-6 levels greater than 55 pg/mL were associated with severe disease, and levels greater than 80 pg/mL were associated with increased mortality [2]. Hence, IL-6 blockade quickly became a popular therapeutic option as it demonstrated efficacy in reducing the composite outcome of intubation or 30-day mortality when used along with dexamethasone in patients with moderate-severe COVID-19 pneumonia. However, evidence is unclear on improvements in other clinical endpoints such as hypoxia or length of stay [2,3]. Even though COVID-19-related hospitalizations have reached an all-time low in many parts of the United States, we believe it is essential to take home the lessons from the current pandemic and how they translate to the management of other previously common disease processes such as influenza and parainfluenza viral pneumonia. Influenza-related annual hospitalizations in the United States before the pandemic were 380,000. We would like to examine if IL-6 blockade could be a viable strategy to prevent disease progression in other viral pneumonia, such as those caused by influenza and parainfluenza.

Viral infections such as those caused by influenza and parainfluenza are generally limited to upper respiratory symptoms such as rhinorrhoea, sore throat, and cough in most patients. However, these viral infections in some patients lead to an overwhelming hyperimmune response, cytokine release syndrome, widespread lung damage, and progression to ARDS [4]. The influenza virus, after it infects the alveoli of the host, targets the epithelial cells and damages its amiloride-sensitive sodium channels (ENaCs). This leads to loosening of the alveolar tight junctions causing leakage of intercellular fluid into the alveoli. Infected epithelial cells induce the production of cytokines such as CCL2, CCL5, and CXCL10, interferon α, TNF α, IL-6, and interferon γ, attracting neutrophils and macrophages, thereby promoting cell death [4]. Hence, in patients with influenza-induced ARDS, widespread lung damage is evident in parts of the lung with seemingly low viral loads, indicating the overall hyperactive immune response is the primary reason for the lung damage [5]. Correspondingly, therapies directed against the viruses are inadequate to curb the immune response, which seems to self-propagate even when the viral load drops. These mechanisms are part of the protective strategies of the host in its defense against viral invasion, allowing infected cells to be killed and removed [6]. It is unclear what host factors play a role in determining whether the host develops ARDS or has a mild self-limiting immune response.

In-vitro and in-vivo studies have demonstrated the upregulation of IL-6 levels during viral infections [6]. Early during a viral infection, IL-6 has a primary protective effect and is a critical mediator in mobilizing the immune response towards virus-infected cells. Influenza-induced upregulation of molecules known as ‘suppression of cytokine-3 (SOCS3)’ has been linked with elevated IL-6 levels in patients [7]. Experiences from in-vitro studies also suggest that overexpression of IL-6 levels may also lead to viral persistence by impairing the action of Th1 cells and CD 8 cells [6]. IL-6 levels have also been deemed as potential biomarkers for determining the severity of certain respiratory viral infections [8,9]. Even though the mechanisms of intrapulmonary spread of different viral infections vary, IL-6 remains one of the key players in their progression to ARDS [6]. Hence, there is a theoretical basis for assuming that IL-6 blockade may be a viable strategy to reduce downstream inflammation and ARDS induced by viral infections.

Aside from the predominantly positive experience of using IL-6 blockade with tocilizumab in patients with COVID-19 pneumonia, there are no published clinical studies on its use in patients with other respiratory virus infections such as influenza or parainfluenza. A retrospective review by Kawada et al. in 2013 showed that influenza infections were less severe in patients undergoing treatment with an IL-6 inhibitor for juvenile idiopathic arthritis [10]. We could not help but wonder if IL-6 blockers such as tocilizumab, if given at the appropriate time, would have prevented progression to ARDS in our patient, especially considering her very high IL-6 levels early on during the hospitalization. Large-scale studies may be required to determine the safety and efficacy of tocilizumab in preventing the development of ARDS in other forms of viral pneumonia, such as those caused by influenza and parainfluenza viruses. Due to the known protective effect of IL-6 early on in a viral infection, the timing of administration of IL-6 blockade would also be a matter of great clinical interest.

Declaration of Competing Interest

The authors declare that we have no conflict of interest.

Data availability

• No data was used for the research described in the article.