Discussion
infection, COVID-19 disease, shortness of breath
VIRUS, SARS-COV-2 INFECTION, ADVERSE EVENTS, DISEASE, RESPIRATORY INFECTIONS IN CHILDREN, ORF, INFECTION
SARS-CoV-2 infection progression starts with viral entrance mediated by the spike glycoprotein’s interaction with the host ACE2 receptor molecule. Following translocation from nucleus to the endoplasmic reticulum (ER), the sigma-1 receptor (among other factors) plays a role in viral replication. It has been suggested that azelastine can inhibit the entry of the SARS-CoV-2 into the nasal mucosa by binding to the ACE2 receptor and also act via binding to the main protease of SARS-CoV-2 and to the host cell’s sigma-1 receptor, therewith facilitating both viral entry and replication-inhibiting effectsThe current proof-of-concept study served to investigate if nasally applied azelastine may have the potential to reduce the viral load (via blocking viral entry and viral replication) in patients tested positively for SARS-CoV-2.Since the start of the COVID-19 pandemic, its treatment via the nasal route has been studied for a range of drugsThe availability of a self-administrable nasal spray reducing subsequent viral transmission would have great impacts for the community as correlations between SARS-CoV-2 viral load and infectiousness have been shownOur study population was characterized by an initial mean viral load of logUpon treatment, a gradual decline of viral load from baseline (day 1) to day 11 of treatment was observed in all three study groups. This is similar to the natural SARS-CoV-2 clearance time of approximately 2 weeks. However, examples of prolonged nasal positivity have also been reported, and many factors are known to have an influence on the individual viral load and clearanceImportantly, the AUC analysis depicting the viral load decrease based on the detection of the ORF 1a/b gene over the 11-day treatment period showed a significantly greater reduction of virus load in the 0.1% azelastine group compared to placebo. Bearing in mind that viral load might be a surrogate measure of infectiousness, those results are encouraging as they indicate that azelastine may be a promising candidate for preventing the spread of this disease.Interestingly, significantly greater decrease in viral load was shown on day 4 of treatment in patients with high viral burden (Ct < 25) treated with 0.1% azelastine compared to placebo, indicating that azelastine treatment may be advantageous for this patient population, particularly at an early timepoint of infection. Recent publications indicating that in vitro infectivity correlates with high virus concentrations (Ct ≤ 25) in nasal swabsOf note, we cannot rule out the possibility that the placebo (nasal spray buffer) contributed to viral clearance. In a study examining the effect of azelastine nasal spray on upper respiratory infections in children, it was found that the placebo group, receiving hypertonic saline solution (twice daily) also produced a favourable response compared to those receiving no treatmentThe current study demonstrated a gradual decrease of patients’ symptoms and improvements of quality of life. Although no significant differences between groups regarding the total symptom score was shown, it may be speculated that the 0.1% azelastine spray may have positive influences on single symptoms such as “shortness of breath”, which was improved significantly greater in this treatment group compared to placebo at early time points of infection. It would be desirable to study azelastine treatment in a greater COVID-19 population to get further insights on azelastine’s effects on individual symptoms and to determine its potential on long-term symptoms. Quality of life was assessed with the SF-36 questionnaire as no COVID-19 specific patient-reported outcome measures were available at the time of study. We are aware that this limited the capture of COVID-19 specific issues as questions were not specifically aimed for COVID-19 patients. It would be desirable to use a validated, COVID-19 specific questionnaire in future studies, and first attempts for its development are promisingPatients of the current trial were eligible upon positive PCR test results, and if enrolled no later than 48 h after swab sampling. Thus, it should be kept in mind that treatment started at a time point where the peak of viral load had probably passed. Although it may be expected that the azelastine might be most efficacious during very early time points after infection, its application in the current study setting could only be started during the symptomatic phase of the disease. Importantly, this scenario corresponds to current COVID-19 treatment regimens (e.g., with monoclonal antibodies or antiviral substances), which are usually started at ≤ 5–7 days upon start of symptoms but are still efficacious. Thus, antibody therapy (bamlanivimab and etesevimab) in positively tested, non-hospitalized patients demonstrated that treatment resulted in decreased SARS-CoV-2 viral load by logImportantly, newly emerging virus variants have the potential to evade the immune response, thereby affecting the efficacy of specific therapies and underlining the importance of new treatment strategies. This is exemplified by the emergence of the highly immune evasive omicron variant that is resistant to many monoclonal antibodies authorized for clinical useGenerally, treatment with azelastine appeared safe in SARS-CoV-2 positive patients: no serious adverse events were reported in the current study, and the number of adverse events was comparable between groups. Of note, the known bitter taste of azelastine was only negatively reported by a single patient, and compliance between treatment groups was comparable (mean ± SD: 97 0.12 ± 9.7% compliance), thus indicating that the taste did not negatively influence treatment adherence.Our study showed both strengths and limitations. Thus, eligibility criteria were designed carefully to investigate a clearly defined, homogeneous study population of low-risk patients with a narrow age range. In addition, intervals between swab sampling were short and the overall number of performed PCR tests was high to allow a very close determination of the viral clearance. However, the overall small number of participants limits conclusions, and results should be interpreted with care. Of note, the mean viral load value showed small variability, thereby supporting the power of the current study.Overall, the current results are encouraging; however, further studies should be carried out to strengthen the findings, and treatment should be extended to other age and risk groups and cover individuals with different levels of symptom severity.Of note, pharmacometric analyses of our data indicate that more frequent applications of the nasal spray may be more appropriate for efficient treatmentBearing in mind the low number of participants in the current proof-of-concept study, the results still build a promising foundation for a currently running phase III study, during which effects of azelastine nasal spray on symptom severity and progression to severe COVID-19 disease are investigated in a greater patient population.