COVID-19 was first reported in late December, 2019 and has since spread worldwide. It causes mild, moderate, or severe symptoms, such as fever, cough, fatigue, loss of smell and taste, shortness of breath, headache, chest pain, and anxiety

[1, 2]. Long-term COVID-19 is a condition in which recovered patients experience symptoms after recovery [3]. Owing to the limitations of therapeutic options and definite treatment for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, off-label use of many medications has been utilized during the pandemic for infection prophylaxis, treatment, or symptom alleviation, including paracetamol, nonsteroidal anti-inflammatory drugs, azithromycin, calcium, vitamin D, vitamin C, and zinc [4, 5]. In theory, the proposed mechanisms of action for certain medications place them as therapeutic options in targeting the pathophysiological processes of the virus life cycle by interfering with viral entry or attachment to the host cell or by enhancing the immune system response to overcome viral infection. Other agents also have an anti-inflammatory activity that limits the release of inflammatory mediators, causing symptoms and injury to organs in the human body.

The effectiveness of medication in COVID-19 disease post-recovery symptoms, presence, and duration shows an apparent discrepancy in the literature. For example, azithromycin, a macrolide antibiotic with a good safety profile and antiviral, anti-inflammatory, and immunomodulatory activities, has shown some benefits in SARS-CoV-2 infection. However, a randomized clinical trial suggested that oral azithromycin did not affect COVID-19 symptoms [6, 7]. Multiple vitamins, zinc, vitamin C, vitamin D, and calcium, have traditionally been used as immune boosters to reduce symptom severity of the common cold and flu and improve the overall health status. Zinc has in vitro activity against SARS-CoV-2; however, in a randomized clinical trial, zinc gluconate 50 mg daily, alone or in combination with vitamin C, did not reduce symptom duration in outpatients [8, 9]. In addition, a recent study revealed that severe COVID-19 infection was associated with low calcium levels, while vitamin D levels did not correlate with the severity of the infection [10].

Patients with chronic diseases or conditions lasting more than 3 months are more likely to experience severe COVID-19 [11, 12]. Medication for chronic disease management, including angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), statins, metformin, antacids, and histamine H2-receptor antagonists, may have positive or negative outcomes in COVID-19 patients [13]. Theoretically, ACE or ARBs may up-regulate the ACE2 receptor, facilitating viral entry into cells. SARS-CoV-2 virus utilizes the ACE2 receptor for host cell entry; however, blocking angiotensin in the respiratory system could reduce lung injury. Statins have anti-inflammatory activity that might benefit COVID-19 patients. Simultaneously, they might increase the expression of ACE receptors, increasing the risk of viral attachment and entry. Statins have been suggested to be associated with lower mortality risk [14-16]. Histamine H2-receptor antagonists are medications indicated for gastrointestinal oesophageal reflux disease with immunomodulatory effects and anti-inflammatory properties [17], and famotidine has been reported in some studies to improve patient COVID-19 outcomes [18, 19]. Many studies have also reported that metformin, an anti-diabetic drug, reduces the severity and mortality of the infection [20-22]

This study aimed to evaluate the association between different medications used during the COVID-19 pandemic and patients' health status of post-recovery symptoms. Furthermore, it analyzed the findings to offer information on the medication effects on post-COVID-19 patients, symptoms prevention, and certain chronic disease precautions.

During the COVID-19 pandemic, the limited availability of data created a challenging clinical decision for the healthcare society to adopt therapeutic protocols based on scientific evidence to recommend promising medications to treat, prevent, or manage COVID-19 patients. For example, the MATH plus protocol for COVID-19 management developed by Dr. Paul Maric at the Eastern Virginia Medical School includes multiple proposed mechanisms of action and biological effects that are safe, cheap, and readily available. The protocol included vitamin C, vitamin D, zinc, thiamine, melatonin, famotidine, and statins [26]. However, clinical trials and more studies are needed to confirm their benefits in decreasing symptoms and reducing the mortality and morbidity of the disease. According to many studies conducted in different countries related to COVID-19, many patients continue to experience symptoms after infection recovery [25]. In addition, some medications and vitamins affect patients’ health during and post-infection [27, 28].

The majority of the study participants received multiple vitamins as a treatment or prophylaxis for COVID-19 symptoms. However, post-symptom resolutions and durations reported varied among participants based on gender and the type of medication they were taking.

The present research results revealed that females are more likely to experience symptoms after recovery than males [25]. The issue of gender as a potential risk factor for developing post-COVID symptoms has been previously reported in the literature [29, 30]. Nevertheless, other studies reported no difference associated with symptoms of COVID-19 among both genders [24, 31, 32].

The majority of participants who took vitamin C and zinc experienced at least one symptom after recovery, with a significant correlation compared to participants who did not take these vitamins. Meanwhile, studies have shown that vitamin C and zinc intake do not decrease the frequency of symptoms during infection [33, 34]. Multivitamins containing vitamins C and D and zinc have no significant relationship with symptoms after recovery: furthermore, they do not affect symptom severity [35]. Although some studies have recommended vitamin D and claimed that it reduces infection severity [36], our findings showed that it does not affect symptoms after recovery.

Calcium and vitamin D deficiencies affect many body systems and functions. For example, during the COVID-19 pandemic, vitamin D deficiency and low serum calcium levels were associated with poor prognosis and adverse outcomes [36]. In this study, participants who took calcium during the infection did not experience post-infection anxiety and tension. Moreover, calcium has been reported in some studies to improve anxiety and restlessness [37]. In addition, more than half of the participants who took calcium supplements did not continue to experience joint pain. Calcium and vitamin D improve bone, joint, and muscle health and reduce joint pain and inflammation [38]. Furthermore, muscle pain and lack of concentration did not persist in patients who took calcium during COVID-19; calcium deficiency may initiate or exacerbate these symptoms [39]. Furthermore, participants who were on vitamin D for prophylaxis did not endure persistent fatigue, muscle pain, back pain, joint pain, lack of focus, and loss of appetite, which are symptoms of a vitamin D deficiency [40-42], and these participants had high vitamin D storage in their bodies, implying that it could prevent the persistence or exacerbation of these symptoms.

Azithromycin, a commonly prescribed antibiotic for respiratory tract infections, is well tolerated and has a good safety profile. In the present study, most patients who received azithromycin experienced fewer symptoms after recovery, with a significant correlation. However, many studies have suggested that using azithromycin to treat COVID-19 is ineffective [43-45]. An observational study used azithromycin with hydroxychloroquine to prevent bacterial superinfection in COVID-19 patients. Although the study suggested that the combination can reduce viral load and improve the clinical course, the sample size of this study was too small and had no comparator group [46]. Furthermore, in a randomized controlled clinical trial that included hospitalized patients with mild to moderate COVID-19 symptoms, azithromycin alone or in combination with hydroxychloroquine did not improve clinical status in 15 days compared to the standard of care [47].

Most participants in the study who received ACE inhibitors, a medication used for a broad spectrum of cardiovascular disorders, experienced at least one significant symptom after recovery. ACE inhibitors might increase the expression of ACE 2 receptors, which aids viral entry into cells and leads to increased viral load [48]. More than half of the patients on ACE inhibitors did not experience cough or headache after recovery [49], even though the cough is a common side effect. One study suggested that ACE inhibitors were associated with a reduced risk of headache compared to other hypertensive drugs [50]. Furthermore, it is recommended that patients with chronic diseases on ACE inhibitors should not discontinue the medication due to its life-saving effects during COVID-19 infection [51].

Statins are another cardiovascular disease medication recommended by many clinical guidelines for the primary and secondary prevention of atherosclerotic cardiovascular disease. Statins are thought to have immunomodulatory and anti-inflammatory activities. In this study, patients who took statins did not experience continued symptoms after recovery compared to others. In other studies, statins showed an effect on taste loss due to alerting the action of taste buds when sending and receiving nerve signals and the amount of saliva and its content [52]. Furthermore, 69.2% of these participants did not endure a continued loss of appetite, which might have resulted from statins reducing leptin levels, thus decreasing the feeling of fullness [53, 54]. In a meta-analysis, statin therapy was associated with a 35% decrease in the adjusted mortality risk in hospitalized COVID-19 patients [55]. In another meta-analysis of 9,000 COVID-19 patients assessing the risk of severe COVID-19 disease or mortality in statin users versus non-users, the statin group was associated with a reduced risk of severe or fatal SARS-CoV-2 infection (HR 0.7, 95% CI 0.53 to 0.94). Statins can improve post-COVID-19 loss of appetite, and calcium can do so significantly, with an unknown mechanism.

Famotidine is a histamine blocker and is commonly used in gastrointestinal disorders. Subjects who took H2 receptor antagonists experienced post-covid symptoms, although studies have shown that these medications have a promising effect on COVID-19 [56]. Although more than half of the subjects had continued muscle pain and headache, these findings could be attributed to the side effects of the drug [57].

The results of this study may not be extrapolated to the general population due to the small number of participants in subgroups: such as participants with chronic diseases. In addition, critically ill patients who were hospitalized at the time of the study were unable to complete the study. Furthermore, patients who died during the pandemic were not included in the study; therefore, survivor bias might have affected the results. Furthermore, participants who completed the questionnaire may have had a recall bias. In addition, a selection bias might have occurred due to voluntary participation. Finally, the results of chronic disease patients might be confounded due to the disease’s reversed effect on the patients’ health.

The treatment and prophylaxis for COVID-19 disease continue to evolve. In this study, azithromycin has different effects on post-recovery symptoms experienced by patients infected with SARS-CoV-2 and their health status. The results revealed that patients on ACE inhibitors experienced headaches, cough, and general fatigue after recovery. Patients on calcium and vitamin D did not report any recurrence of headaches, continued muscle and joint pain, anxiety and tension, and lack of focus. Patients who took H2 antagonists experienced persistent lack of focus, headaches, fatigue, and muscle pain. Multivitamins did not affect post-recovery symptoms. Expert opinion should be considered in COVID-19 management until randomized controlled trials answer questions and determine medication's role in prevention, treatment strategies, and symptoms of SARS-CoV-2 infection post-recovery.