In a recent study published in Scientific Reports, researchers investigated whether anti‑interleukin 6 (IL‑6) monoclonal antibodies were related to heterogenous treatment effects between female and male coronavirus disease 2019 (COVID-19) patients.

Study: Biological sex is related to heterogeneous responses to IL-6 receptor inhibitor treatment in COVID-19—A retrospective cohort study. Image Credit: DC Studio/Shutterstock.com

Background

The clinical course of COVID-19 is variable, starting from mild symptoms to severe lung discomfort, acute respiratory distress syndrome (ARDS), or death. Greater COVID-19 severity and mortality have been reported amongst men than women. Thus, differences in immunological responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might underpin sex-based differences in COVID-19 outcomes.

The current study’s authors have previously reported higher inflammatory cytokine levels in men than women despite similar viral loads, age, the extent of hypoxemia at clinical presentation, and organ support requirements, indicating exaggerated immune responses in men. Additionally they demonstrated that interleukin-6 levels strongly correlate with COVID-19 severity and associated mortality.

In regards to the study

Constructing on their previous work, in the current retrospective cohort study, researchers determined the connection between biological gender and interleukin-6 inhibition therapy on COVID-19 severity outcomes, resembling disease progression to pulmonary failure and death.

The study included 1,274 individuals aged 18 years and older (median age of 64 years), amongst whom 58% were men, 44% were white, and 15% received anti-interleukin-6 antibodies. Commonly obtained clinical information was extracted from electronic medical records of hospitalized adults with polymerase chain response (PCR)-confirmed SARS-CoV-2 infection between March 1, 2020, and June 30, 2022.

As well as, individuals infected with SARS-CoV-2 through the initial COVID-19 wave until December 11, 2020 [i.e., until the SARS-CoV-2 Alpha variant of concern (VOC)-dominant period, based on the COVID-19 Genomics, United Kingdom (COG-UK) information] were included within the evaluation in the event that they required oxygen (O2) supplementation during their hospital stay.

Cox proportional hazards regression modeling was performed to calculate the hazard ratios (HRs), adjusting for age, steroid usage, ethnicity, C‑reactive protein (CRP) levels (as a surrogate for COVID-19 severity), and the causative SARS-CoV-2 variant.

Anti-interleukin-6 receptor monoclonal antibody therapy was administered to hospitalized COVID-19 patients with CRP levels above 75.0 mg/L and ICU-admitted COVID-19 patients requiring respiratory assistance (high-flow O2 treatment, mechanical ventilation, or non-invasive-type positive pressure ventilation) inside a day of hospitalization.

The team avoided using anti-interleukin-6 receptor monoclonal antibodies for SARS-CoV-2-infected individuals with suspected or known bacterial infections, aspartate transaminase (AST) or alanine transaminase (ALT) levels greater than five-fold higher than the traditional limit, neutrophil counts below 2 × 109, or platelet counts below 50 × 109. The connection between interleukin-6 inhibition therapy and CRP trajectory was assessed. Individuals who were deceased inside 2 days of hospitalization (n=16) were excluded from the evaluation.

Results and discussion

Of the 1,274 participants, 189 individuals received anti-interleukin-6 receptor monoclonal antibody treatment, including 73 (14%) female and 116 (16%) male COVID-19 patients. The Alpha VOC (41%) accounted for many cases, followed by the Wuhan-Hu-1 strain (32%), and the Delta VOC (21%). Baseline CRP and lymphocyte counts were 87 mg/L and 1 × 106/mL, respectively.

Among the many participants, 23% received Remdesivir, two patients received a Janus kinase (JAK) inhibitor, and 188 anti-IL-6 receptor monoclonal antibody recipients also received steroids.

At hospitalization, 69% of people required oxygen supplementation alone, and only 6% required mechanical ventilation. The general hospital mortality rate was 23%. A statistically significant association was observed between gender and anti‑interleukin-6 receptor antibody usage on progression to pulmonary failure or death. Amongst individuals who didn’t receive anti‑interleukin 6 receptor antibody treatment, mortality risk was marginally higher amongst males (HR, 1.6), whereas amongst anti‑IL‑6 receptor antibody recipients, the danger was lower amongst males (HR, 0.9).

Likewise, amongst individuals who didn’t receive IL-6 inhibition treatment, male COVID-19 patients were at an increased risk of pulmonary failure or mortality than female patients (HR, 1.1). Contrastingly, amongst IL-6 inhibitor recipients, male patients showed a lower risk of pulmonary respiratory failure and death than their female counterparts (HR, 0.7).

IL-6 inhibition therapy was linked to a bigger reduction in serological CRP levels with time in comparison with no IL-6 inhibition therapy. The team observed heterogeneous effects with anti‑interleukin 6 antibody treatment between females and males, with interleukin-6 inhibition therapy conferring a greater advantage in stopping disease progression to pulmonary failure or death amongst men.

Multiple genes related to immune functions are situated on the X chromosome; due to this fact, X-linked mosaicism confers a highly polymorphic genetic expression, which enables females to reply with a more expanded immunological repertoire than men.

Along with higher pro-inflammatory cytokines, males have greater expression of viral entry aspects, resembling angiotensin-converting enzyme 2 (ACE2), in addition to accessory proteases, cathepsin L (CTSL), and transmembrane protease serine 2 (TMPRSS2) in alveolar type 2 and airway secretory cells. Moreover, males have demonstrated poor T lymphocyte responses, that are linked to worse clinical outcomes.

Overall, the study findings showed that interleukin-6 inhibition therapy leads to heterogeneous immunological responses between female and male COVID-19 patients. There was a statistically significant interaction between IL-6 inhibition therapy use and disease progression to pulmonary failure or death, with males having a greater advantage related to therapy use.

The findings indicated that the inclusion of gender as a research parameter could promote the identification of COVID-19 pathophysiological mechanisms and aid in developing targeted treatments.