Debate on drugs that may aggravate COVID-19.

To the Editor:

The Journal of Allergy and Clinical Immunology: In Practice published a contingency planning article by Shaker et al to guide the allergists/immunologists through the coronavirus disease 2019 (COVID-19) pandemic. They provided suggestions for a logical approach to quickly adjust our services to mitigate risk to both medical staff and patients during the pandemic, while social distancing is being encouraged. In this context, there is an ongoing worldwide debate regarding the use of angiotensin-converting enzyme (ACE) inhibitors and ibuprofen in patients with COVID-19. The concern is that these drugs could worsen the prognosis of patients with the infection.

The 2 coronaviruses of the “severe acute respiratory syndrome,” China, 2002/2003, and of the “Middle East respiratory syndrome,” Middle Eastern countries, 2012, use angiotensin-converting enzyme 2 (ACE2) and dipeptidyl peptidase 4, respectively, as their receptors to infect human cells. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the coronavirus involved in COVID-19, also depends on ACE2 for cell entry.

Drugs that inhibit ACE paradoxically upregulate ACE2 expression on the cell surface and could theoretically facilitate coronavirus infection and progression. There is no definitive evidence that this effect is clinically relevant, but some retrospective observational studies suggest an association between the use of these drugs and a worse outcome of COVID-19. A cause-effect association cannot be confirmed, and ACE inhibitors could be confounding factors that indicate comorbidities, such as cardiopathy, hypertension, and diabetes, besides advancing age, which are well-recognized risk factors for worse outcome of COVID-19. Myocardial injury, indicated by increased serum levels of troponin T, and cardiovascular disease had a significant association with fatal outcomes of COVID-19. Moreover, withdrawal of ACE inhibitors could aggravate an underlying disease and make patients more unstable to overcome a coronavirus infection.

Coincidentally or not, the receptors of coronavirus, ACE2 and dipeptidyl peptidase 4, are enzymes that break down bradykinin in addition to their main functions. After SARS-CoV-2 binding to ACE2, the viral complex undergo endocytosis and surface ACE2 is downregulated (Figure 1 ). ACE also degrades bradykinin and drugs that inhibit this enzyme lead to an increase in tissue bradykinin and may even trigger cough and angioedema in hypersensitive individuals. We speculate whether the excess of bradykinin in patients taking ACE inhibitors could complicate coronavirus infection, because of its effects of vasodilation, increase in vascular permeability, and cough reflex exacerbation. However, no study has been done investigating this hypothesis and current data do not justify the discontinuation of ACE inhibitors in patients at risk or with COVID-19.

Figure 1

Interaction between the renin-angiotensin-aldosterone system and the bradykinin system. During SARS-CoV-2 infection, there is downregulation of ACE2 at type II pneumocytes surface, decreasing bradykinin degradation. ACE also degrades bradykinin, and drugs that inhibit this enzyme increase bradykinin levels. Red dashed line (ACE, ACE2, and DPP4 degrade bradykinin); blue dashed line (ACE2 degrades angiotensin I to angiotensin 1-9 and angiotensin II to angiotensin 1-7); blue solid line (conversion of angiotensin I to angiotensin II). DPP4, Dipeptidyl peptidase 4.

Some experts' opinions and unpublished French cases suggested an association between the use of ibuprofen and a worse outcome of COVID-19, but there are no studies supporting this hypothesis. A recent publication stated that ibuprofen also increases ACE2 expression, but the authors did not provide the reference that supports this statement. Ibuprofen use could be a marker of disease severity and not necessarily the cause of a worse prognosis. Patients more toxemic and symptomatic, having fever, asthenia, and myalgia, are more prone to use nonsteroidal anti-inflammatory drugs (NSAIDs). If ibuprofen is indeed associated with worse COVID-19 outcomes, whether or not a possible association would relate to the specific agent ibuprofen or the larger group of NSAIDs would require further investigation. The European Medicines Agency concluded that there is currently no scientific evidence establishing a link between ibuprofen or NSAIDs and worsening of COVID-19.

Knowledge of SARS-CoV-2 infection increases daily and further studies are needed to better understand the influence, if any, of ACE inhibitors and NSAIDs in COVID-19 severity. At present, there is no evidence to generate even a weak recommendation to discontinue these medications during the pandemic. Patients' care must be personalized, and ACE inhibitors and/or NSAIDs may be used if indicated, after weighing the benefits and risks.