We found that 6% of patients included in our study who completed a five-day course of NM/r developed COVID-19 clinical rebound leading to healthcare provider assessment within 30 days of treatment. Rebound symptoms were predominantly cough and nasal congestion occurring from 1 to 15 days following completion of NM/r. The timing of rebound was similar to prior case reports and cohort studies18,19; however, our cumulative incidence was higher than 0.8% reported in one prior clinical care study10 of outpatients with mild COVID-19. A rigorously conducted prospective study found a considerably higher cumulative incidence of symptom rebound after NM/r of 18.9%, and incidence in those not treated in this study was similar to our study at 7%12. Several studies have observed frequency of symptom rebound similar between those who did and did not receive NM/r2,20. One study of the placebo arm of ACTIV clinical trials found higher COVID-19 symptom rebound at 26%13. These results suggest symptom recrudescence or worsening is common in the natural course of resolving COVID-19 disease regardless of anti-viral treatment. These discrepancies are likely due to study methodology whereby carefully conducted cohort studies performed daily or every other day symptom and nasal swab virology assessments. Thus, they were more likely to pick up mild and/or transient symptom recurrence and overestimate the rate of COVID-9 rebound. Our study relied on both patient and provider reporting to the NM healthcare system and recording in medical records which may not have occurred for many patients with mild rebound illness or who sought care outside of our clinics. In summary, we estimate that COVID-19 symptom rebound frequency after NM/r lies between 6 and 26%, depending on patient characteristics, severity of symptoms, and ease of reporting or symptom assessment.
In terms of risk factors, like other studies, we did not find any significant associations between demographic or clinical characteristics and COVID-19 symptom rebound after NM/r. An interesting observation was an indication that patients with lower immunity to SARS-CoV-2 (less vaccine boosting, lack of prior infection, and co-morbidities) experienced higher frequency of COVID-19 symptom rebound after NM/r. This supports the current hypothesis that NM/r anti-viral activity and reduction of SARS-CoV-2 in tissues is enhanced by strong host immunity. Thus, COVID-19 viral and/or symptom rebound is more likely to occur among those who fail to adequately clear SARS-CoV-2 virus in the upper respiratory tract in a dynamic process. Anti-viral therapies, such as NM/r, inhibit viruses and reduce the potential for severe complications such as pneumonia; however, viral clearance takes time and virus replication after completion of NM/r could increase due to several potential mechanisms. This is supported by in a prior study with frequent early PCR and viral culture sampling that found significantly greater virologic rebound and prolonged shedding of replication-competent SARS-CoV-2 virus after NM/r treatment compared to no COVID-19 therapy21. Contrary to this hypothesis was a carefully conducted immunology study that found individuals treated with NM/r for COVID-19 had similar robust humoral and T-cell immune responses14 regardless of whether they experienced rebound; however, it is unclear whether viral dynamics and clearance were different within upper respiratory tract tissues. In addition, while resistance gene mutations encoding in SARS-CoV-2 protease have been suggested as a cause of viral rebound, this has not yet been observed14,18
Other potential risk factors we identified for clinical rebound after NM/r were female sex, Black race, having co-morbidities, and systemic symptoms. Similar to other studies11, a non-significant, but higher proportion of patients with rebound had systemic symptoms of fever, shortness of breath, myalgia, and headache with their presenting COVID-19 illness, possibly indicating a more severe presentation. These findings are also likely to be the result of higher health awareness and health-seeking behaviors for certain demographic groups. Black race and certain comorbidities have been associated with more severe COVID-19 infection throughout the pandemic22,23. It is unlikely that there is a biological basis to an association with Black race and a higher risk of rebound – rather, it is likely due to the higher prevalence of certain comorbidities among Black individuals24. This is potentially due to multiple factors, including socioeconomic status and access to and treatment within the healthcare system. Interestingly, this lack of access to the healthcare system would be expected to underestimate any potential association between Black race and rebound; this potential association should be investigated further in larger studies. As briefly mentioned above, comorbidities could contribute to rebound for several reasons -- a weaker immune response to SARS-CoV-2 infection and lower viral clearance/control, greater susceptibility to respiratory infection or multi-organ involvement, and greater engagement with the healthcare system.
As reported in many prior studies and case reports, we also found that rebound COVID-19 is generally mild, managed on an outpatient basis, and does not lead to poor health outcomes. Only one case of NM/r rebound in this study led to an ED visit and hospital admission, with the rest managed by ambulatory care or telemedicine. Thus, when weighing benefits and risks of NM/r treatment in light of the potential for rebound COVID-19, recent real-world research continues to show clear benefits of NM/r treatment in high-risk populations regardless of immunity from vaccine or natural infection2.