In this retrospective study evaluating the efficacy of montelukast administration during hospitalization of patients diagnosed with COVID-19, clinical deterioration measured by changes in the COVID-19 Ordinal Scale was significantly lower in patients treated with montelukast compared to non-montelukast between Days 1 and 3. Oxygen escalation occurred in 32% of patients without montelukast versus 10% of patients taking montelukast. This was evident despite the montelukast group being of significantly older age (p = 0.022). Further, patients receiving montelukast had higher rates of baseline asthma and tended to have more cardiac comorbidities, potentially suggesting these patients had increased risk for clinical decompensation during COVID-19 infection. These findings suggest that montelukast may have clinical efficacy in reducing complications of COVID-19. With further evaluation, montelukast may be a potential therapy for COVID-19 infection.
We examined the effects of montelukast on laboratory values associated with COVID-19 illness and found no differences in inflammatory laboratory values including C-reactive protein, D-dimer, ferritin and LDH between montelukast vs non-montelukast patients. It is feasible that there were, in fact, no differences in the trends of laboratory values between patients treated with montelukast vs non-montelukast. However, given the lack of a method to grade these particular laboratory values, the differences in these values could not be accurately compared among patients and changes. We anticipate that the laboratory values of patients could be impacted by montelukast, but we were unable to derive an answer in this dataset. In addition, a limitation to this study was the lack of specific systemic or pulmonary cytokine measurements or serial SARS-CoV-2 viral loads that may better reflect the potential effect of montelukast on virally mediated pathways in SARS-CoV-2 infection. We found no difference in length of hospitalization between the two groups. However, we considered length of stay a subjective indicator of clinical outcome as there is no standardization between physician practices for decisions surrounding discharge time and planning.
Montelukast is a leukotriene receptor antagonist and binds with high affinity and selectivity to the CysLT1 receptor. Eicasanoids including all cysteinyl leukotrienes (LTC4, LTD4, LTE4) are products of arachidonic acid metabolism and are released from cells including mast cells and eosinophils12. These eicosanoids bind to cysteinyl leukotriene (CysLT) receptors which are found in the human airway (including airway smooth muscle cells and airway macrophages) and on other pro-inflammatory cells12. CysLTs have been correlated with the pathophysiology of asthma and allergic rhinitis12. In asthma, leukotriene-mediated effects include airway edema, smooth muscle contraction, and altered cellular activity associated with the inflammatory process. Furthermore, clinical findings indicate that montelukast can be used in the effective management of acute and post viral-induced wheezing13, and it can quickly improve respiratory function in acute asthmatic patients with an increased FEV1 at 60 minutes post-montelukast administration and at all time points up to 120 minutes (n = 583)14. Another study documented data that asthmatic children treated with montelukast had higher lung function, decreased airway inflammation and lower symptom scores compared to the children not receiving montelukast15. While baseline asthma has not been found to be a risk factor for severe outcomes in COVID-19 [16], other comorbidities such as hypertension and diabetes have been correlated with worse prognosis [17]. In our study, 15 patients had a baseline diagnosis of asthma, 11 of whom received Montelukast during hospitalization.
The progression of COVID-19 infection to severe clinical complications owing to ARDS and a hyperinflammatory cytokine syndrome, or cytokine storm18. Secondary hemophagic lymphohistiocytosis (sHLH) is a hyperinflammatory syndrome leading to a fulminant and fatal hypercytokinemia with multiorgan failure in the setting of viral infections, and demonstrates unremitting fever, cytopenias, and hyperferritinemia; pulmonary involvement including ARDS occurs in 50% of patients18. Cytokine profiles resembling sHLH resemble COVID-19 disease severity, with increased IL-2, IL-7, GM-CSF, IFN-Gamma inducible protein 10, monocyte chemoattractant protein 1, macrophage inflammatory protein 1-alpha, and tumor necrosis factor alpha18. Viral hyperinflammation appeared to drive COVID-19 fatalities in Wuhan, China and predictors of mortality from COVID-19 cases in Wuhan included an elevated ferritin (1297.6 ng/mL in non-survivors vs 614 ng/mL in survivors, p < 0.001), and may suggest that fatalities are driven by viral hyperinflammation18. NF-KB (nuclear factor kappa-light-chain-enhancer of activated B cells) can regulate immune responses, and its inhibition by MTK may attenuate the symptoms of COVID-19 by downregulating other inflammatory cytokines such as IL-6 and IL-8, mitigating the severity of infection and decreasing symptoms19.
We noted that treatment with montelukast had interesting results in subpopulations of interest. Sensitivity analysis among those without asthma showed a trend toward fewer events of clinical deterioration in the montelukast group compared to the no montelukast group. While montelukast is commonly used an asthma maintenance therapy, our results suggest a benefit of montelukast independent from that found in its traditional use in asthma. Our sensitivity analyses did not find an independent effect of montelukast when administered along with these agents. Thus, co-administration may have blunted the anti-inflammatory effects of Montelukast in these populations.
Although the standard dosing of montelukast is 10 mg orally per day for allergic rhinitis, asthma, and prevention of exercise-induced asthma, montelukast has a favorable side effect profile with limited toxicities, indicating the potential to employ higher doses with relative safety and the possibility to better downregulate the viral pathophysiology of SARS-CoV-2 infection. Montelukast is safely administered without dose reductions regardless of hepatic or renal insufficiency, and common side effects of montelukast are similar to placebo and with the most common one being headache. Given that montelukast is a well-tolerated and a low-cost agent, information about dose responses/escalation in COVID-19 infection could be an important aspect to evaluate new dosing regimens, and could have impact on the duration and severity of symptoms of COVID-19 as well as which patients are most likely to benefit. These favorable characteristics of Montelukast are especially critical during the COVID-19 pandemic, as preventing clinical deterioration can save the use of depleted resources such as intensive care unit beds and mechanical ventilators.