To the editor

The recently published review by Kosmaczewska and Frydecka1 prompted us to investigate how the dysregulation of the immune system during coronavirus disease 2019 (COVID-19) might affect patients with concomitant chronic pulmonary diseases. Herein, we present our novel hypothesis relevant to the pathogenesis of cytokine storm in COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily targets the lungs and results in pneumonia and acute respiratory distress syndrome. Therefore, patients with pre-existing pulmonary diseases are more likely to develop severe symptoms of infection. Surprisingly, recent epidemiological data have shown that comorbid chronic respiratory conditions do not represent major risk factors in patients with COVID-19. Cystic fibrosis (CF) is an interesting example. There is emerging evidence indicating that the severity of SARS-CoV-2 infection in CF is milder than predicted, even though CF is frequently associated with diabetes, a strong predictor of severe course of SARS-CoV-2 infection.2 Furthermore, patients with CF are at increased risk of severe infection with other viruses affecting the respiratory system. Influenza viruses, the H1N1 virus in particular, have been shown to cause disease progression in lung CF. Therefore, many countries categorized people with CF as highly vulnerable to COVID-19 and advised them to stay at home in order to minimize the risk of contracting the virus.3

The fatal outcome of COVID-19 is associated with cytokine storm and acute respiratory distress syndrome. Interleukin 6 (IL-6) is considered the key cytokine in the pathogenesis of cytokine storm. Remarkably, in most studies, IL-6 levels are reported to be increased in severe COVID-19, and elevated IL-6 levels have been associated with higher mortality.4

We hypothesize that constitutively low levels of IL-6 present in the inflamed airway tract of patients with CF may contribute to inhibiting the cytokine storm associated with severe SARS-CoV-2 infection and, hence, limit the severity of the infection in this population. We examined a group of 39 patients with advanced lung CF and confirmed chronic Pseudomonas aeruginosa infection. The patients’ sputa contained an unusual combination of high proinflammatory IL-8 levels (median, 1178 pg/ml) accompanied by the extremely low levels of proinflammatory cytokine IL-6 (median, 243 pg/ml) and the anti-inflammatory cytokine IL-10 (median, 196 pg/ml). Low sputum IL-6 levels were also associated with high tumor necrosis factor α levels in an independent study of patients with CF. Importantly, IL-6 suppression was limited to the sputum, while systemic IL-6 production was normal.5 This phenomenon is not observed in other chronic inflammatory pulmonary diseases.

The mechanism of suppressed IL-6 production in the airways of patients with CF remains unclear. However, these observations have relevant implications for the treatment of SARS-CoV-2. The association between the localized suppression of IL-6 in the airways of patients with CF and decreased SARS-CoV-2 infection morbidity provides strong support for targeting IL-6 production or IL-6 receptor blockade in patients with COVID-19. Furthermore, the localized cytokine imbalance in patients with CF highlights the role of monitoring local (sputum) cytokine levels during any therapeutic intervention.