Preventing a Covid-19 Pandemic

Dear Editor,

SARS-CoV-2 binds to the respiratory cells via the angiotensin-converting enzyme 2 (ACE2)
receptor. In a recent report, it has been noted that ACE2 can be increased by ACE inhibitors
and ARBs and, importantly, by ibuprofen [1]. Consequently, it has been hypothesized that
treatment with ACE2-stimulating drugs including ibuprofen may increase the risk of
developing severe and fatal COVID-19.

Notably, the World Health Organization (WHO) has very recently officially recommended
avoiding ibuprofen for COVID-19 symptoms [2]. However, the European Medicine Agency
(EMA) notes that there is currently no scientific evidence establishing a link between
ibuprofen and worsening of COVID 19 and in line with EU national treatment guidelines,
patients and healthcare professionals can continue using NSAIDs (like ibuprofen) as per
the approved product information [3]. On the other hand, prior to the COVID-19 epidemic,
in May 2019, EMA’s safety committee has started a review of ibuprofen and ketoprofen
following a survey by the French National Agency for Medicines and Health Products Safety
suggesting that infection due to chickenpox and some bacterial infections could be made
worse by these medicines [3,4].

Ibuprofen may be hazardous through augmentation of some effects of bradykinin in
COVID-19 and some other infections.

Of note, ibuprofen has been noted to augment some effects of bradykinin in vivo [7]. We
suggest that this effect may be a further and additional mechanism of ibuprofen’s
potentially adverse effect in COVID-19 infection and is to be investigated.

In animal studies, in the setting of endotoxin inhalation, loss of ACE2 function in lung led to
activation of the des-Arg9 bradykinin /bradykinin receptor B1 axis and subsequent release
of proinflammatory chemokines from airway epithelia, increased neutrophil infiltration,
and exaggerated lung inflammation and injury. It seems that a reduction in pulmonary
ACE2 activity contributes to the pathogenesis of lung inflammation, in part because of
exaggerated bradykinin signaling [5]. Bradykinin is a potent pro-inflammatory and
vasodilator peptide and a component of the contact system has important
pathophysiological role in septic shock in general [6].


  1. Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at
    increased risk for COVID-19 infection?
  5. Chhinder P. Sodhi et al. Attenuation of pulmonary ACE2 activity impairs inactivation of
    des-Arg9 bradykinin/BKB1R axis and facilitates LPS-induced neutrophil infiltration. Am J
    Physiol Lung Cell Mol Physiol. 2018 Jan 1; 314(1): L17–L31..
  6. Nicola H. The role of contact system in septic shock: the next target? An overview of the
    current evidence. J Intensive Care. 2017;5:31.
  7. Baraniuk JN, Silver PB, Kaliner MA, Barnes PJ. Ibuprofen augments bradykinin-induced
    glycoconjugate secretion by human nasal mucosa in vivo. J Allergy Clin Immunol. 1992

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