Pathogenic airway neutrophilia drives ARDS in Black patients with severe COVID-19 in case study

By Susha Cheriyedath, M.Sc.Jun 9 2021

A hallmark of the coronavirus disease 2019 (COVID-19) pathogenesis is the huge range of clinical presentations and outcomes, ranging from asymptomatic and mild to acute respiratory distress syndrome (ARDS) and often fatal multiorgan failure. There have been disturbing disparities in COVID-19-associated mortality in Black/African-American (AA) patients in some areas of the US, with nearly 70% of deaths in Black/AA patients. However, there are not many targeted studies focusing on the features of disease severity in this demographic.

Study: Pathogenic neutrophilia drives acute respiratory distress syndrome in severe COVID-19 patients. Image Credit: Kateryna Kon / Shutterstock

*Important notice: bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Neutrophilia in severe COVID-19

The diversity in COVID-19 disease poses a major challenge to identifying the factors affecting progression to severe disease. Many studies have reported systemic hyperinflammatory responses in association with disease severity. A cytokine storm has been observed in patients with severe disease and is said to cause rapid COVID-19 progression and immune dysregulation.

The pathophysiology of severe COVID-19 disease parallels that of sepsis with clinical presentation showing granulocytosis, aberrant myeloid activation, elevated proinflammatory cytokine production, altered dendritic cell (DCs) population dynamics, and lymphopenia.

With reports of neutrophilia in the peripheral blood, the neutrophil to lymphocyte ratio became an independent risk factor for progression to severe disease. A previous study on ARDS following sepsis showed sustained neutrophilia in association with worse prognosis and death compared to patients with resolved neutrophilia and an increase in tissue-resident alveolar macrophages. Hence neutrophilia is another shared feature between sepsis and COVID-19.

Although many studies have explored neutrophil responses in COVID-19 patients, there are no in-depth studies focusing on neutrophil activity in the lungs. The extent of contribution of neutrophils to cytokine storm, tissue damage, and ARDS in patients with severe COVID-19 is not fully understood.

Analyzing immune profiles from airways and blood samples of Black/AA patients

Researchers from the US used a systems immunology approach where they combined high-dimensional flow cytometry and multi-omics single-cell sequencing analyses of immune profiles taken from the airways and matching blood samples of Black/AA patients. The team has released their study as a preprint on the bioRxiv* server.

The results showed low viral burden and pronounced pulmonary neutrophilia as characteristics of severe COVID-19 disease, with neutrophil phenotypes displaying advanced cytokine storm and ARDS features. Cell-cell communication and trajectory analysis showed a subset of circulating S100A12+ /CXCR4+ mature neutrophils infiltrating the lung via the IL-8/CXCR2 axis.

“We also observed that inflammatory CXCR4+ T cells are increased in the lungs of severe COVID-19 patients suggesting that lung-homing inflammatory T cells may also contribute to immunopathology.”

Recruited neutrophils become transcriptionally active and pathogenic with exacerbated production of IL-8, IL-1β, IL-6, and CCL3/4 49 and elevated levels of myeloperoxidase and neutrophil elastase. Inflammatory monocytes recruited through neutrophil-derived CCL3/4 also produce increased neutrophil chemotactic factor IL-8, enhancing sustained neutrophilia in the airways. The IL-8/CXCR2 axis thus becomes a potential therapeutic target to decrease pathogenic neutrophilia and control ARDS in patients with severe COVID-19.

“Notably, the CXCL8 (IL-8)/CXCR2 emerges as a key potential target for next-generation immunomodulatory therapy to reduce pathogenic neutrophilia and constrain severe disease in patients.”

Findings highlight the role of neutrophilia in immunopathophysiology of severe COVID-19

The study presents compelling evidence showing neutrophils are responsible for the dysregulated hyperinflammatory response that cause ARDS in severe COVID-19 patients. Neutrophil frequency and inflammatory profiles show that neutrophils, apart from being the most abundant leukocyte population in the airways, also produce the effector molecules such as IL-8, IL-1β, and IL-6 linked to disease severity. They also produce potent proteases like NE and MPO that are inherently inflammatory and cause lung pathology.

Moreover, this work offers evidence of a neutrophil feedforward loop in which IL-8, produced by airway neutrophils and some myeloid and stromal cells, is the primary recruitment chemokine for circulating neutrophils and thus enhances neutrophilia in the inflamed airways.

Overall, these findings show the association of neutrophilia and immunopathophysiology in severe COVID-19 and how transcriptionally active and highly inflammatory neutrophils in the lungs drive ARDS despite a significantly low viral burden. Treatment options that target neutrophil recruitment and retention at the inflammation site could help control ARDS in patients with severe illnesses, especially those who are most vulnerable to COVID-19 mortality.

*Important notice: bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.