Anti-inflammatory Tetracycline activity may modulate COVID-19 severity

By Dr. Liji Thomas, MDJul 30 2020

The current COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), seems to attack the human airway epithelium primarily. In severely affected patients, the illness progresses to hypoxemic respiratory failure and acute respiratory distress syndrome (ARDS). The latter is treatable mainly by supportive management.

However, the need for effective treatment remains an urgent one, especially since the evidence is piling up that hyper-inflammatory and immunopathogenic effects are significant contributors to the progression of the illness and the severe pneumonic phenotype. The focus of many researchers is on finding drugs that can mitigate this by their anti-inflammatory and immunomodulatory effects while not producing significant toxicity.

Prophylaxis with tetracyclines in ARDS: Potential therapy for COVID-19-induced ARDS?. Image Credit: Kateryna Kon / Shutterstock

*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

The Study: Tetracyclines Benefit ARDS Patients

The current study published on the preprint server medRxiv* in July 2020 supports the use of tetracyclines as potential immunomodulatory drugs in COVID-19. These drugs are known to have an anti-inflammatory action as well as having broad-spectrum antibacterial activity. This includes their ability to suppress the proliferation of T cells and decrease the production of inflammatory signaling molecules. They have been used to treat HIV and malaria.

The researchers in this study aimed to explore the efficacy of these drugs in patients with ARDS, in a small retrospective study of patients in multiple institutions over the previous two decades. The drugs in use were minocycline, doxycycline, and tetracycline, used in 49, 50, and 24 patients, respectively. The outcomes explored were whether tetracyclines could decrease the need for mechanical ventilation and the duration of stay in the intensive care unit (ICU) among patients with ARDS relative to other ARDS patients who had not received these drugs within the previous year.

The study revealed that patients who had received minocycline or doxycycline a year before developing ARDS were 75% less likely to require mechanical ventilation during their hospitalization period. With all three drugs in the study, treatment with these drugs was associated with a marked reduction in the duration of ICU stay. The timing of administration (prior to vs. during the ARDS diagnosis) did not appear to have any association with the outcomes evaluated, except for doxycycline. The findings remained valid after adjusting for other illnesses, age, sex, smoking, and immunosuppression.

Tetracyclines Are Powerful Immunomodulators

This is not unique to this viral infection, either. The researchers point out, “The temporal relationship with tetracycline antibiotics’ conditioning of the immune system has been previously demonstrated in numerous clinical settings, including multiple sclerosis, rheumatoid arthritis, major depressive disorder, and inflammatory bowel disease.”

Moreover, much is known about how these drugs bring about their anti-inflammatory effects from prior research. For instance, these molecules reduce the expression of CD40 ligands on T cells, cause inflammatory mast cells to enter apoptosis, and reduce metalloprotease activity via the chelation of their cofactor, zinc. Coronaviruses are known to require metalloprotease activity in order to reproduce, and thus the latter action would suppress the infectious potential of SARS-CoV-2.

Secondly, coronaviruses typically boost the proliferation of mast cells in the respiratory epithelium and so promote local lung inflammatory responses. This would be effectively inhibited by tetracyclines.

Implications and Future Directions

The relative cheapness, ready availability, and high tolerability of tetracyclines should encourage their testing in randomized trials to explore their potential as preventives for patients who are at high risk for COVID-19 and especially for ARDS.

The researchers commented, “Our results proffer the potential for tetracyclines to provide prophylactic benefit in reducing ventilatory support and duration of ICU stay for ARDS patients.”

The small number of patients and the retrospective observational design notwithstanding, the size of the reduction and its consistency across all three drugs warrants further investigation, they feel, into the possibility of using them as preventive therapy for patients who develop ARDS during infection with SARS-CoV-2.

*Important notice: medRxiv 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.