COVID-19 management in patients with comorbid conditions

Abstract

The novel coronavirus disease 2019 (COVID-19) causes serious respiratory illness and related disorders. Vulnerable populations, including those with chronic obstructive pulmonary disease, heart disease, diabetes, chronic kidney disease, obesity, and the elderly, face an increased risk of severe complications. As the pandemic evolves, various diagnostic techniques are available to detect severe acute respiratory distress syndrome (SARS-CoV-2), including clinical presentation, rapid antigen/antibody testing, molecular testing, supplemental laboratory analysis, and imaging. Based on peer-reviewed data, treatment options include convalescent plasma transfusion, corticosteroids, antivirals, and immunomodulatory medications. Convalescent plasma therapy, historically used in outbreaks like Middle East respiratory syndrome, Ebola, and SARS, is suggested by the World Health Organization for critically ill COVID-19 patients when vaccines or antiviral drugs are unavailable. Neutralizing antibodies in convalescent plasma help control viral load and improve patient outcomes, especially when administered early, though effectiveness varies. The United States Food and Drug Administration has authorized its emergency use for severe COVID-19 cases, but potential risks such as transfusion reactions and transfusion-related acute lung injury require further investigation to establish definitive efficacy. Antiviral agents like Remdesivir, an adenosine nucleotide analog, inhibit viral RNA polymerase and have shown efficacy in reducing COVID-19 severity, leading to its emergency use authorization for hospitalized patients. Other antivirals like ritonavir, lopinavir, and umifenovir disrupt viral replication and entry, but their effectiveness against SARS-CoV-2 remains under investigation. Dexamethasone, a corticosteroid, has been used in critically ill COVID-19 patients to reduce inflammation and prevent respiratory failure, as shown in the RECOVERY trial. Other immunosuppressants like ruxolitinib, baricitinib, and colchicine help modulate the immune response, reducing cytokine storms and inflammation-related complications. However, corticosteroids carry risks such as hyperglycemia, immunosuppression, and delayed viral clearance, requiring careful administration. Systematic reviews of clinical studies revealed that hydroxychloroquine with or without azithromycin did not decrease viral load nor reduce the severity of symptoms, but increased mortality among acutely hospitalized patients. There was no improvement in patients’ clinical conditions after 15 days compared to standard treatment. The United States Food and Drug Administration has revoked the authorization for the use of hydroxychloroquine in COVID-19 patients due to the null benefit-risk balance. Monoclonal antibodies like itolizumab, gimsilumab, sarilumab, and tocilizumab are being studied for their ability to reduce the severe inflammatory response in COVID-19 patients, particularly cytokine release syndrome and acute respiratory distress syndrome. These antibodies target specific immune pathways to decrease pro-inflammatory cytokines, with some showing promising results in clinical trials, though their use remains under investigation. The Clustered Regularly Interspaced Short Palindromic Repeats/Cas13 family of enzymes, sequenced from many COVID-19-positive patients, can potentially inhibit SARS-CoV-2 replication, cleave the RNA genome, and aid in the amplification of the genome assay. Cas13 can also target emerging pathogens via an adeno-associated virus vector when delivered to the infected lungs. In addition to pharmacological agents, vaccines effectively prevent symptomatic infection, reduce hospitalizations, minimize mortality rates, and ultimately reduce the severity of the disease. This paper aims to explore the management of patients with underlying conditions who present with COVID-19 to lessen the burden on healthcare systems.

Key Words: COVID-19; Comorbidity; Diabetes; Heart disease; Chemotherapy; Vaccine; Therapeutic management

Core Tip: Effective management of coronavirus disease 2019 in patients with comorbid conditions is vital to reduce severe complications, limit hospitalizations and ease the pressure on healthcare systems. This requires employing thorough diagnostic methods, tailoring pharmacological treatments to individual patient profiles, and encouraging widespread vaccination to boost immunity efforts. An integrated approach ensures better patient outcomes and supports public health resilience during ongoing and future infectious disease challenges.

INTRODUCTION

Coronavirus disease 2019 (COVID-19) causes respiratory illness and complications, with vulnerable groups and the elderly facing higher risks. Several research studies have been conducted globally to examine this continuously evolving disease. Specifically, given the alarming rates of morbidity and mortality associated with COVID-19, many studies have been conducted, and some are still ongoing, to determine factors associated with the exacerbation of the illness. Data collected by the Centers for Disease Control and Prevention (CDC), analyzed underlying conditions and contributory factors to COVID-19-related deaths for each age group in the United States from February 1 to December 19, 2020[1]. An estimated 6% of the overall 285078 deaths were due to the virus itself, whereas an additional 2.9% of deaths were seen in those with a history of health conditions[1]. Emerging evidence suggested that individuals with underlying comorbidities such as chronic obstructive pulmonary disease (COPD), heart disease, diabetes, chronic kidney disease (CKD), tuberculosis (TB), and obesity have an increased risk of susceptibility[2-4], as well as life-threatening complications[4]. The presence of these comorbidities can lead to a higher prevalence of severe COVID-19 cases, increased mortality rates, and prolonged recovery times. Studies showed that individuals with COPD are at a higher risk of severe COVID-19 outcomes, including hospitalization and mortality. COPD can exacerbate respiratory symptoms and lead to complications like acute respiratory distress syndrome (ARDS) and the need for mechanical ventilation[5]. COVID-19 can cause inflammation of the heart muscle and blood vessels, leading to complications such as heart attacks, arrhythmias, and heart failure. People with pre-existing heart conditions are at a higher risk of severe illness and death from COVID-19[6]. Diabetes increases the risk of severe COVID-19 complications, including higher rates of hospitalization and mortality. High blood sugar levels can increase inflammation, worsening COVID-19 outcomes[7,8]. Individuals with CKD, especially those on dialysis or with a kidney transplant, are at a higher risk of severe COVID-19 illness. COVID-19 can cause acute kidney injury, further complicating the condition of those with CKD[9,10]. COVID-19 patients with TB have a higher risk of mortality and poorer treatment outcomes if TB treatment is interrupted[11]. Obesity is linked to impaired immune function and decreased lung capacity, increasing the risk of severe COVID-19 illness. Obese individuals are more likely to require hospitalization, intensive care, and invasive ventilation[12]. Consequently, the management of COVID-19 patients with these specific conditions requires a concerted effort and effective monitoring. Moreover, the treatment of these comorbidities may lead to drug interactions, which may be life-threatening for the patient[13]. Consequently, addressing the special management of a COVID-19 patient becomes extremely relevant to avoid complications[14].

Since the outbreak in 2019, various approaches have been used to manage COVID-19 and its complications. Many therapeutics with known safety profiles have been repurposed for the management of COVID-19[15]. On May 1, 2020, the United States Food and Drug Administration (FDA) issued an emergency use authorization (EUA) for remdesivir, an antiviral drug, to be used for the treatment of hospitalized COVID-19 patients[16]. The major risk of this approach has been severe drug-drug interaction resulting from the combination of antiviral drugs and polypharmacy for the treatment of existing chronic conditions[16,17] For example, combining hydroxychloroquine (HCQ) and azathioprine has led to an increased risk of QT interval prolongation, which in turn could trigger tachycardia in the patients[17]. Also, in COVID-19 patients with comorbidities, there is an additional potential risk of interaction between antiviral drugs and the multiple medications prescribed for the treatment of their preexisting conditions. This is of greater significance in people who self-medicate, particularly among the low- and middle-income countries with restricted access to quality healthcare services[18]. To date, except for HCQ, the therapeutic agents used in the management of COVID-19 comorbid patients have received limited significant research attention. This paper aims to present and review the management of these vulnerable patient populations who have a higher likelihood of being infected and developing severe complications of COVID-19 than other populations. Highlighting the treatment initiatives in infected, at-risk individuals would be of great value in limiting the number of fatal cases, reducing the burden on healthcare systems, and complementing the government’s guidance and public health strategy on mitigating the patients’ risks for the management of COVID-19.

LITERATURE SEARCH

An electronic literature search was conducted across several databases, including PubMed, Google Scholar, EBSCOhost, Mendeley, and MEDLINE Plus. The following search terms and keywords were used in various combinations across these databases: “coronavirus”, “COVID-19”, “SARS-CoV-2”, “comorbidity”, “treatment”, and “management”. Boolean operators (e.g., AND, OR) were utilized to refine the search results. The search was limited to peer-reviewed articles published from January 1, 2020, to December 31, 2024. Filters were applied to exclude non-English language articles, non-peer-reviewed sources, and studies that do not relate to human populations. Additionally, only studies available in full-text format were considered. Studies were included if they focused on COVID-19 and its comorbidities, treatment options, or management strategies. The selected articles had to provide original data or detailed reviews, and studies with clear methodologies were prioritized. Studies were excluded if they did not directly address COVID-19 or related topics, were outside the specified publication date range, or were not peer-reviewed. Articles that were not focused on the clinical or epidemiological aspects of COVID-19, such as those purely focused on virology or basic science, were also excluded.

MANAGEMENT OF COMORBIDITIES IN PATIENTS WITH COVID-19

Clinical characteristics

Individuals who are infected with severe acute respiratory distress syndrome corona virus-2 (SARS-CoV-2) may develop a wide spectrum of mild to severe symptoms including fever, fatigue, chills, nasal congestion, cough, shortness of breath, myalgia, dyspnea, loss of taste and smell, sore throat, runny nose, vomiting, and diarrhea, respiratory rate ≥ 30 beats/minute, partial pressure of oxygen/fraction of inspired oxygen < 300, arterial oxygen saturation ≤ 93% and lung infiltrate > 50%, shock, ARDS, and multiple organ failure[19,20]. Symptoms can appear 2-14 days after being infected with the virus; however, up to 81% of patients are asymptomatic[20]. According to Guan et al[21], the normal clinical presentation of the illness seen among the 1099 cases who were COVID-19 positive, included fever (88.7%), cough (67.8%), weariness (38.1%), sputum creation (33.7%), shortness of breath (18.7%), sore throat (13.9%), and migraine (13.6%). In addition, several COVID-19 patients demonstrated gastrointestinal symptoms, i.e., diarrhea (3.8%) and vomiting (5.0%). Although studies have shown that pyrexia is the prevailing presentation in COVID-19-positive patients, the severity of pyrexia varies from moderate to low[21]. Therefore, unjustifiable accentuation of pyrexia should not be the only indication for assessment of infection in clinical settings and screening. Furthermore, due to the high rate of screening and advancement in testing for COVID-19, the prognosis is favorable[21,22]. However, an increase in morbidity and mortality is seen in patients who are of advanced age or those with chronic conditions such as cardiovascular disease (CVD) and diabetes[22]. In addition, sepsis and ARDS are common causes of death among those who are sick with COVID-19[22]. The illustration in Figure 1 further identifies the clinical symptoms related to COVID-19, highlighting that fever, cough, and myalgia are the most reported symptoms[23].

Figure 1 The main clinical symptoms of coronavirus disease 2019 positive patients from December 2019 to February 2020. Data collected from Li et al[23].

Comorbidities

COVID-19, an evolving illness, has generated a lot of conflicting information in the medical community. Due to the novelty of this disease, information is evolving, but research suggests that patients with comorbidities are at greater risk of having severe disease[24]. It has been noted that comorbidities increase the deleterious effect of COVID-19[24,25]. Given current data, elderly patients, especially those in long-term care facilities, and individuals of all ages combating chronic disease with one or more comorbidities are more susceptible to life-threatening complications when they contract COVID-19[24]. Literature is evolving with the fact that COVID-19 is more prevalent in patients with comorbidities, including CVD, chronic respiratory diseases, diabetes, obesity, CKD, and elderly patients[24]. The complications in patients with comorbidities could be explained by the potential increase in angiotensin-converting enzyme 2 (ACE-2) gene expression, especially in the epithelial cells of the lungs, intestines, kidneys, and blood vessels[25]. Thus, ACE-2 gene expression is significantly increased in patients with hypertension and type 1 or type 2 diabetes[25]. It follows that ACE inhibitors and angiotensin receptor blockers that are used in the management of CVD will increase the expression of ACE-2 genes, especially in the heart and kidney, which in turn will facilitate the entry of the virus into the host cell and enhance the propensity of infection[25]. In the same vein, increased expression of ACE-2 genes has been reported in elderly patients, predisposing them to infection[25]; however, more research evidence is required.

Individuals with ailments such as diabetes, hypertension, lung disease, liver issues, CVD, malignant growth, and patients on chemotherapy, smokers, obese patients, and those taking steroids continuously are at a higher risk of severe SARS-CoV-2 infection[2,24]. Hospitalized patients with moderate to severe asthma may experience additional complications, further damaging their respiratory tracts, prompting asthmatic assaults, pneumonia, and respiratory demise[25]. Mortality in COVID-19 is not a well-understood topic yet, though data continues to evolve. As depicted in Figure 2, obesity had the highest fatality rate, while the prevalence predominated amongst patients with malignancy and diabetes[2]. Also, COPD and TB increase the severity and risk of complications from COVID-19 due to pre-existing lung damage and impaired immune responses. Patients with COPD are more susceptible to severe COVID-19 because of chronic inflammation and reduced lung function, leading to higher hospitalization and mortality rates. Similarly, TB can exacerbate COVID-19 outcomes by weakening the immune system and causing structural lung damage, which increases vulnerability to severe respiratory failure[26,27]. These factors thus highlight the need for targeted healthcare strategies to manage these high-risk groups.

Figure 2 Comorbidities associated with coronavirus disease 2019 positive patients. Data collected from Ejaz et al[2].

Factors associated with hospitalization and duration

A retrospective analysis conducted by Wu et al[28] explored factors that influenced the duration of hospitalization in Wuti Fangcang Hospital among 136 COVID-19-positive patients. These factors consist of fever at admission, bilateral pneumonia, and diabetes[17,24]. Overall, the mean time for hospitalization was 10.3 days[28]. As depicted in Table 1 and Figure 3, the longest period of hospitalization was associated with patients having a fever (3.5 days longer), followed by bilateral pneumonia on computed tomography (CT), which was 3.4 days longer[28]. A similar pattern was seen in patients with diabetes compared to those without the disease. Although asymptomatic patients had a shorter length of stay than symptomatic patients, the difference was not statistically significant (P = 0.12)[28]. Key mechanisms and associated factors that influence the likelihood of hospitalization and the duration of stay for COVID-19 patients are: (1) Underlying health conditions or comorbidities like obesity, diabetes, CVDs, and CKDs; (2) Age, where older patients especially those over 65 years are at high risk of disease severity due to a decline in immune function and comorbidity; (3) Sex, where higher rates of severe outcomes were found in male patients probably due to differences in immune response and higher prevalence of risk factors like CVD in men; (4) Immunosuppression, where COVID-19 severity is higher in the individuals with weakened immune systems; and (5) Socioeconomics and demographic characteristics, where race, ethnicity and socioeconomic status played a significant role[24,29].

Figure 3 Factors associated with hospital duration. Data collected from Wu et al[28].

Table 1 Factors associated with hospitalization.

Factors	Length of hospital stay
Fever before hospitalization	3.5 days longer (95%CI: 1.39-5.63, P = 0.002)
Bilateral pneumonia on computed tomography scan	3.4 days longer (95%CI: 0.49-6.25, P = 0.023)
Diabetes	3.2 days longer (95%CI: 0.2-6.56, P = 0.065)

Factors influencing length of hospital stay among non-severe coronavirus disease 2019 patients, Fangcang Hospital, China (11 February-1 March, 2020). Data collected from Wu et al[26]. CI: Confidence interval.

Diagnosis of COVID-19

Numerous diagnostic techniques are available to detect SARS-CoV-2, each having advantages and disadvantages. Initial clinical presentations of flu-like symptoms (i.e., rhinorrhea, headache, fever, cough, sore throat, shortness of breath, diarrhea, malaise, and vomiting) warrant additional testing for disease confirmation and diagnosis[30]. The gold standard for diagnosing COVID-19 is molecular testing. It consists of real-time reverse transcription-polymerase chain reaction (RT-PCR) which is used for the detection of the nucleic acid of SARS-CoV-2, colloidal gold-based immunochromatographic strip that targets viral immunoglobulin M (IgM) and G (IgG) antibodies, enzyme-linked immunosorbent assay for detecting IgM and IgG antibodies by an anti-SARS-CoV-2 enzyme, and nucleic acid amplification test for genomic viral RNA[30-33]. In addition to molecular testing, clinicians may supplement laboratory testing with elevated lactate dehydrogenase, C-reactive protein, and erythrocyte sedimentation rates; decreased albumin; and lymphopenia and imaging studies such as chest CT, chest radiography, and lung ultrasonography to solidify the diagnosis and avoid missing an active infection[30,31].

Typically, early diagnosis and treatment of COVID-19 from the clinical symptoms of the disease are exceedingly difficult or impossible. For instance, the highly sensitive chest CT scan is used as a confirmatory diagnosis technique for COVID-19 patients; however, its specificity is quite low. Usually, the diffusion of the ground-glass opacity from the peripheral and lower region of the lungs to the center and throughout the lungs in the CT scan corresponds to a steady progression of the disease[30-32]. Thus, higher computable scores of the chest CT scan correspond to a more advanced form of COVID-19[28]. However, the low specificity can be enhanced by the real-time quantitative PCR technique[30-32]. In essence, a combination of clinical symptoms, CT scan, and real-time quantitative PCR results is used to confirm the diagnosis of COVID-19; however, COVID-19 complications are difficult to predict or treat before they occur[30-33].

Role of the immune system

The two branches of the immune system, innate and adaptive immunity, work together to protect against various microbes. Innate immunity consists of the skin and mucous membranes acting as physical barriers, natural killer cells, and phagocytes. Adaptive immunity consists of T cells, B cells, antibodies, and cytokines[34]. While innate immunity acts quickly in its ability to identify and neutralize pathogens within hours, adaptive immunity takes a longer time before its activity commences, is more specific in its response, and can protect for months to years[34]. The immune response against SARS-CoV-2 involves T-helper (TH) cell pathways that coordinate both immunity. TH1 cells primarily drive antiviral responses by activating cytotoxic T cells and macrophages through cytokines like interferon-gamma (IFN-γ), which enhances viral clearance. Meanwhile, TH2 and TH17 responses contribute to inflammation and antibody production, but excessive activation can lead to immune dysregulation and severe COVID-19 pathology[35]. SARS-CoV-2 infection occurs when the virus enters the host cell through the enzyme ACE-2[36]. ACE-2 is found on the cell membrane of various tissues, including the lungs, heart, kidneys, brain, intestine, and endothelial cells. ACE-2 also helps to mediate angiotensin, which controls vasoconstriction, blood pressure, inflammatory cytokines regulated by tumor necrosis factor-alpha (TNF-α), and interleukin 6 (IL-6)[37]. Infected cells can also release cytokines, which further activate the adaptive immune response by recruiting more immune cells. However, there are two types of immune responses mounted against SARS-CoV-2: A normal immune response involving neutralization of the virus and an overactive immune response that leads to further complications, such as cytokine release syndrome (CRS)[34]. This faulty response occurs as immune cells continue to accumulate and signal the overproduction of pro-inflammatory cells to circulate and damage surrounding tissues and organs. Severe COVID-19 patients exhibit deficient levels of IFNs; this downregulation of host cell IFN can cause a devastating imbalance in the immune response and prolong the pro-inflammatory state[34].

Antibody-dependent enhancement is also observed in severely ill COVID-19 patients; this harmful process is due to activated B cells producing non-neutralizing antibodies against the virus[34]. While multiple treatment modalities are being investigated to either strengthen the normal immune response, decrease the harmful effects of an overactive immune response, or target the virus studies indicate that there are often poorer outcomes associated with older patients and patients with comorbidities such as COPD, diabetes, hypertension, CVD, and malignancy. Smokers also have poor outcomes[38].

The immunopathology of COVID-19 infection involves cellular and molecular changes in the host’s immune system from which the immune biomarkers relating to COVID-19 complications could be identified in the late phase of the disease as potential drug targets for the prediction, monitoring, and treatment of COVID-19 complications[13]. However, they cannot be used as prognostic biomarkers for COVID-19 complications in the early phase, and accurate prediction, monitoring, and treatments for COVID-19 complications cannot be made without evaluating the cellular or tissue viral replication. Also, since COVID-19 is an inflammatory disease, there is an early rise in the inflammatory mediators in the early phase of COVID-19, followed by a decline because of anti-inflammatory responses, especially in milder disease[13]. However, in severe diseases with hyper-inflammation and a lack of anti-inflammatory responses, the result is hyper-coagulation and cytokine storm or high levels of recruited white blood cells, which worsens the disease[13]. The mortality in severe cases has been attributed to hypoxemia and cardiovascular complications resulting from abnormal blood clotting. Several potential pharmacotherapies are still under investigation for the treatment of COVID-19.

THERAPEUTICS

Convalescent plasma

In the past, the World Health Organization (WHO) recommended the use of convalescent plasma as an empirical treatment during the Middle East respiratory syndrome (MERS) 2015 outbreak, the Ebola outbreak in 2014, and the 2003 SARS-CoV outbreak[39]. WHO suggests using convalescent plasma for treating critically ill COVID-19 patients, especially when the administration of vaccines and antiviral drugs is not feasible[38]. Convalescent plasma consists of serum obtained from the patient and enhanced with passive neutralizing antibodies from recovered COVID-19 patients[34]. The neutralizing antibodies delivered with convalescent plasma will help to control the viral load, while non-neutralizing antibodies may help with prophylaxis and recovery[38].

Data from the use of convalescent plasma against other viral infections indicate viral neutralization by way of antibody-induced cellular cytotoxicity, activation of complement, and phagocytosis[38]. While the dosage of convalescent plasma varies, some clinical trials have used one unit (200 mL) for prophylaxis and one to two units for treatment. The duration of effectiveness is estimated to range from weeks to a few months[38]. In a retrospective, non-randomized study[40], forty SARS patients who were refractory to ribavirin and 1.5 g of methylprednisolone received either 200-400 mL of convalescent plasma or additional doses of methylprednisolone[38]. The patients who received convalescent plasma had a higher hospital discharge rate of up to 22 days and a lower mortality rate compared to those who received steroids only. The study also showed that convalescent plasma was more effective when given early, as patients who received it after day 16 were seen to have a worse outcome[38]. In China, one uncontrolled study had five severe COVID-19 cases that were refractory to steroid and antiviral treatment but showed signs of improvement after receiving a 400 mL transfusion of convalescent plasma, while another study also conducted in China had ten patients reporting significant progress after three days of convalescent plasma transfusion[39].

The emergent use of convalescent plasma has proven to be useful in past epidemics where there was inadequate time to produce immunoglobulin preparations[38]. To decrease mortality, countries such as Turkey and the United States started collecting plasma using apheresis devices from confirmed COVID-19 patients who had recovered and storing it in blood banks. On March 24, 2020, the FDA published a recommendation stating strict guidelines for plasma donors and currently does not approve the use of convalescent plasma as prophylaxis. The FDA allowed the use of convalescent plasma for laboratory-confirmed COVID-19 patients who meet the criteria of a life-threatening disease, such as those in respiratory failure, septic shock, or multiorgan failure. In addition, patients with severe disease such as dyspnea, tachypnea > 30/minute, a blood oxygen saturation of < 93%, lung infiltrates > 50% within 24 to 48 hours, and a partial pressure of oxygen/fraction of inspired oxygen < 300 are potential candidates. The adverse effects of convalescent plasma therapy are like those of other plasma therapies. There is a risk of infection from viral transmission or bacterial contamination; immunologic reactions like serum sickness; transfusion reactions such as tremors, fever, allergic reactions - urticaria; and transfusion-related acute lung injury (TRALI). Although there have not been any severe adverse effects reported in past studies of convalescent plasma transfusions, the most concerning would be TRALI, as critically ill COVID-19 patients have a higher chance of having ARDS or disseminated intravascular coagulation, both of which are risk factors for TRALI[38].

The administration of convalescent plasma for the management of hospitalized COVID-19 patients was issued an EUA in August 2020[41] and has been revised. Currently, it only approves the use of convalescent plasma to treat people with compromised immune systems who have COVID-19, and the plasma must have high levels (titer) of antibodies[42]. Infectious Diseases Society of America (IDSA) guidelines only recommend the use within 8 days of infection and high titer among ambulatory patients with mild-to-moderate COVID-19 at high risk for progression to severe disease who have no other treatment options[42]. Data suggest that the neutralizing antibodies isolated from this therapy block the binding between the receptor-binding domain of the S protein and the ACE-2 receptor, further indicating that this therapeutic approach may manage the disease course[43]. Despite that, preliminary investigations with convalescent plasma have been deemed beneficial, additional scientific evaluation is necessary for definitive efficacy[41,44].

Remdesivir and other antivirals

Disrupting the replication of SARS-CoV-2 is being investigated with antiviral drugs, such as remdesivir, lopinavir, ribavirin, ritonavir, favipiravir, and umifenovir (arbidol)[33,45]. Unlike remdesivir, ribavirin, and favipiravir, both monophosphoramidate prodrugs to the guanine analog did not produce any supportive evidence for their benefit in COVID-19 patients[44]. Remdesivir (Veklury) is an adenosine nucleotide analog developed in 2016 after the Ebola outbreak in Africa[40,43,44]. It works as an RNA-dependent RNA polymerase inhibitor, thereby reducing viral multiplication[43,44]. Once the virus docks and fuses into the host cell, the viral contents, such as the nucleocapsid and viral RNA, are released into the host cell cytoplasm, where the translation of viral proteins is initiated[34,36] as well as viral replication, assembly, and maturation[6]. Moreover, remdesivir is a phosphoramidite prodrug that, once metabolized into the active form, inhibits viral replication by interfering with the viral RNA polymerase[40,45]. It inhibits viral RNA synthesis through chain termination due to the triphosphate form resembling adenosine triphosphate and then gets incorporated into the viral RNA by the viral RNA polymerase due to its being mistaken for a nucleotide[40].

As of August 2020, an EUA was given to remdesivir for its use in the management of all COVID-19 hospitalized adult and pediatric patients[46,47]. In MERS-CoV-infected rhesus monkeys, remdesivir completely prevented viral replication when used 24 hours before infection, and it showed significant clinical benefits, including reduction of lung lesions and viral replication, when used 12 hours after inducing viral infection[48]. Also, the in vitro studies by the Wuhan Virus Research Institute indicated that remdesivir is the most effective and fastest-acting antiviral drug for COVID-19, with an inhibitory concentration (IC₅₀) of 0.069 μM against SARS-CoV-2 and IC₅₀ of 0.074 μM against MERS-CoV[48]. Several other randomized double-blind placebo-controlled human clinical studies have shown that remdesivir demonstrated faster time to clinical improvement than placebo and the Kaplan-Meier estimate of mortality within 14 days were 7.1% with remdesivir and 11.9% with placebo, and remdesivir significantly increased recovery rate, decreased mortality, and decreased risk of potentially serious adverse events[48].

SARS-CoV-2 shares many similarities with SARS-CoV-1, as both are enveloped RNA viruses with similar viral surface proteins[49]. SARS-CoV-2 also shares approximately 82% of its RNA genome with SARS-CoV-1[40], although their RNA polymerases are approximately 96% similar, indicating that SARS-CoV-1 RNA polymerase inhibitors may also be effective on SARS-CoV-2 RNA polymerase[40]. Therefore, remdesivir is currently considered for the treatment of COVID-19 based on previous in vivo studies regarding its use against the Ebola virus and other coronaviruses[40]. The presence of the viral exoribonuclease (ExoN) has proven to be problematic when developing an effective nucleoside, as the ExoN serves as a proofreading enzyme and corrects errors as the RNA develops[50]. Remdesivir is an effective antiviral agent as it can partially evade proofreading by the ExoN due to its ability to insert itself into the replicating RNA more easily than nucleotides. In addition, it acts as a delayed chain terminator, which binds to a free 3′-OH group and terminates RNA synthesis downstream[50]. Remdesivir has been shown to have a comparatively safe profile, as demonstrated in previous studies with the treatment of MERS and the Ebola virus outbreak[40]. In a compassionate use study, where fifty-three COVID-19 patients were injected with 200 mg intravenous (IV) remdesivir on the first day and 100 mg/IV/daily for the remaining nine days, the most common adverse effects noted were increased hepatic enzymes (23%), diarrhea (9%), rash (8%), renal impairment (8%), and hypotension (8%). Serious adverse effects were experienced by twelve patients who were intubated at baseline (23%), the most prevalent being multiple organ dysfunction syndromes, septic shock, and acute kidney injury[40].

Ritonavir and lopinavir, a class of protease inhibitors, are synthetically derived drugs that use CoV proteinase 3CLpro or 3C-like protease to cleave the proteins into smaller fragments[43,44]. Once cleaved into smaller fragments, the growth of SARS-CoV-2 is inhibited, thus disrupting the infectivity and replication of the virus[26,44]. Moreover, camostat mesylate, a serine protease inhibitor with anti-inflammatory, antifibrotic, and potential antiviral properties, inhibits the cellular entry of SARS-CoV-2 in host lung cells via the blockade of transmembrane protease, serine 2[43,51]. In addition, umifenovir (arbidol) has been shown to decrease the incidence of infection by inhibiting the viral fusion of SARS-CoV-2[43,52]. This drug impairs viral entry by slowing clathrin-coated vesicle intracellular trafficking, promoting clearance of the viral load and decreasing mortality[43]. The IDSA guideline suggested initiating remdesivir within seven days of symptom onset and the use of nirmatrelvir/ritonavir (Paxlovid), three-day treatment with remdesivir, mol-nupiravir, and neutralizing monoclonal antibodies as options for the treatment and management of ambulatory patients[42].

IMMUNOMODULATORS

Immunomodulators are substances that help regulate or modify the immune system’s response. These can either enhance the immune response (immunostimulants) or suppress it (immunosuppressants), depending on the need. Both approaches are critical, but their use depends on the stage and severity of COVID-19. Immunosuppressants, e.g., corticosteroids and Janus kinase (JAK) inhibitors, may be necessary to control excessive immune reactions, whereas immunostimulants enhance the body’s ability to fight the virus (e.g., IFNs, monoclonal antibodies, vaccines).

Corticosteroids

Dexamethasone is a corticosteroid used for its anti-inflammatory effect in the management of COVID-19 patients; however, the timing and dosage of administration are very important in the disease prognosis[34,53]. Timely or early administration of corticosteroids inhibits the initiation of the body’s immune defense mechanism, a state of immunosuppression[34], its antifibrotic and vasoconstrictive abilities[53], which increase the viral load and consequently lead to adverse effects. Therefore, corticosteroids are only used in critically ill patients. WHO has recommended against the routine use of corticosteroids in the management of COVID-19 patients because of the potential for delayed viral clearance, which potentially constitutes serious side effects, but they should be used only in severe ARDS[34,53]. Dexamethasone may be administered with the hope of minimizing inflammation and inflammatory-mediated lung injury in COVID-19 patients and decreasing the chances of advancing to respiratory failure and death[34]. The disease has been documented to cause a rapid deterioration in the patient’s condition and cause acute hypoxemic respiratory failure requiring intubation and supplemental oxygen[53]. In the Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial, an open-label study conducted in the United Kingdom, it was found that 6 mg of oral or IV dexamethasone, given once per day for ten days reduced mortality by one-third in ventilated patients, and one-fifth in other patients receiving oxygen therapy[34,54]. The RECOVERY trial also revealed that the treatment approach was significant for patients with hypoxemia who were under respiratory support[53]. While dexamethasone can be given to children and the elderly, the RECOVERY trial used 40 mg of oral prednisolone or 80 mg of IV hydrocortisone twice a day instead of dexamethasone for those who were pregnant or breastfeeding[34].

Despite its proven efficacy with past inflammatory disease processes such as ARDS, pneumonia, and septic shock[53], there are still some inquiries regarding the effectiveness of corticosteroids in COVID-19[34]. Large amounts of corticosteroids have been known to cause hyperglycemia in people with diabetes and provoke a state of “steroid-induced diabetes” in those at risk of diabetes, and for diabetic patients in the hospital, it can cause a severe and potentially fatal hyperglycemic hyperosmolar state. While there are guidelines to limit such injuries for patients with severe COVID-19 infection receiving dexamethasone, these guidelines may not be appropriate[54].

Patients with severe COVID-19 may also experience a “cytokine storm” when SARS-CoV-2 induces CRS as early as the second week of infection. CRS is triggered by an initial release of pro-inflammatory cytokines from activated T cells and B cells, which go on to activate immune cells and endothelial cells to produce pro-inflammatory molecules[55]. The activation of macrophages, dendritic cells, immune cells and endothelial cells, pro-inflammatory cytokines such as IL-6, IL-1, TNF-α, IFN-α, IFN-β, and IFN-γ, continues this pro-inflammatory circuit of lymphocyte activation, followed by a massive release of cytokines (cytokine storm). This inflammatory state also affects the blood vessel lining, making it more permeable. As a result, more pro-inflammatory cytokines leak through, which worsens the inflammation[55]. An example of the havoc that is caused by this process can be seen at the blood-brain barrier, as pro-inflammatory cytokines alter its permeability, which can lead to edema, red blood cell extravasation, and activation of microglial cells, leading to reactive gliosis and other neurological disturbances[55]. CRS in COVID-19-infected patients is also associated with insulin resistance and decreased insulin production, and with the administration of corticosteroids, which also inhibits glucose metabolism, patients are at risk of worsening hyperglycemia, ketoacidosis, and hyperglycemic hyperosmolar state[54].

In summary, dexamethasone is a synthetic glucocorticoid with potent anti-inflammatory, antisecretory, and immunosuppressive effects, thus a crucial therapeutic agent in the management of severe SARS-CoV-2 infections (severe COVID-19), which is characterized by excessive inflammation and exaggerated immune response or “cytokine storm”[56]. Its mechanism of action involves binding to the glucocorticoid receptors, followed by a cascade of anti-inflammatory and immunosuppressive responses. Thus, it reinforces the immune responses in COVID-19 by promoting the expression of anti-inflammatory cytokines (IL-4, IL-10, and helper T and B-cells), and reducing inflammation by inhibiting inflammatory transcription factors[57]. Dexamethasone has also been reported to regulate the ion channels by activating sodium ion absorption through the epithelial sodium channel Na⁺ channels and inhibiting chloride ion secretion through the cystic fibrosis transmembrane conductance regulator Cl^- channels to reduce the airway fluid secretion, thus preventing pulmonary edema.

Other corticosteroids and calcineurin inhibitors

In general, corticosteroids offer immunosuppression and anti-inflammatory effects, which have been shown to reduce elevated inflammatory responses[44]. Budesonide, a corticosteroid, has been shown to shorten the recovery time when inhaled early in the disease process[58]. On the other hand, tacrolimus (calcineurin inhibitor) and prednisolone (corticosteroid) showed clinical efficacy when used in severe COVID-19 Lung injury by inhibiting pro-inflammatory cytokines[59]. Similarly, cyclosporine (calcineurin inhibitor), an immunosuppressant and steroid-sparing agent, suppressed lethal inflammation and inhibited cyclophilin enzymes in severe COVID-19 patients[60]. Cyclophilin is the enzyme CoV uses to support itself[60].

JAK inhibitors

Ruxolitinib, an INF-Janus-associated kinase (JAK1/2) inhibitor, can be administered to normalize INF gene transcripts induced by SARS-CoV-2 in lung epithelial cells, as JAK inhibitors play a role in inflammation[61]. Ruxolitinib in conjunction with remdesivir, an inhibitor of C3a protein produced by infected cells, may reduce thrombotic adverse effects and decrease the risks associated with viral replication[61]. Moreover, baricitinib, another JAK inhibitor, provides anti-inflammatory and antiviral properties that inhibit viral entry into the target host cells[43]. Whereas other potent anti-inflammatory agents such as colchicine act as immunosuppressants and inhibitors of IL-1 and IL-6 by preventing viral replication through inhibiting microtubule formation[45,62,63]. Colchicine inhibits the expression of E-selectin and disrupts inflammasome activation, therefore reducing neutrophil production of free radicals[64], and potentially offers therapy in select patients contraindicated for other drugs[63,65]. Colchicine is safe, widely available, cost-effective, and orally administered[65]. However, IDSA guidelines recommend against its use in hospitalized patients with COVID-19 and suggest against its use in ambulatory patients[42]. IDSA guidelines recommend the use of baricitinib with remdesivir instead of remdesivir alone among hospitalized patients with severe COVID-19 who are contraindicated for corticosteroids. The guideline suggests tofacitinib rather than no tofacitinib among hospitalized adults with severe COVID-19 who are not on non-invasive or invasive mechanical ventilation[42].

Agents with immunomodulatory effects

Ivermectin: Ivermectin, an antiparasitic drug, has shown promising results in reducing SARS-CoV-2 in vitro[35,37,59-63]. Although not approved by the FDA for the treatment of COVID-19, ongoing investigational studies are being conducted on the possible therapeutic benefits[43,44,66-70]. One such instance pertains to a phase 3 study in Thailand among patients afflicted with the dengue virus. Ivermectin was found to be safe among this population at the administered dosage despite its potential adverse effects[69]. However, it did not produce any result of clinical significance[62]. Even though the dengue virus is a completely different virus from SARS-CoV-2, the information obtained from this study can be applied to the management of COVID-19 patients[69]. IDSA guidelines recommend against the use of ivermectin for both ambulatory persons and hospitalized patients because the undesirable effects outweigh the desirable effects[42].

Chloroquine and HCQ: Immunomodulatory agents, chloroquine (CQ) and HCQ, are known for their preventative and therapeutic actions towards uncomplicated malaria as well as other conditions such as acute or chronic rheumatoid arthritis and lupus erythematosus[60]. HCQ was widely used as an off-label prescription for the treatment of different dermatological conditions and antiphospholipid syndrome in healthcare settings all over the world[17]. However, because of the urgent need for effective treatment for the COVID-19 infection, many countries and health communities began to use the off-label HCQ with little to no clinical evidence of its efficacy or benefit-risk balance of the therapy. In one study of 100 COVID-19 positive patients, these antimalarial drugs showed a reduction in pneumonia-like distress by inhibiting the entry of the viral particles by blocking IL-6, when compared to the control group[44]. Although there are a few in vitro data and review studies on the role of CQ in the management of SARS-CoV-2 infection, there are no published clinical trials with CQ and HCQ; thus, the Infectious Diseases Society of America recommends their use only in clinical trials[42]. One of the in vitro studies indicates the effectiveness of HCQ in limiting the replication of SARS-CoV-2 by inhibiting viral proteins’ glycosylation, virus assembly, nucleic acid synthesis, and virus release. When taken with azithromycin (AZT), a collegial effect occurs; however, potentially severe adverse effects may arise. A combination of CQ, HCQ, and AZT has been found to prolong the QT interval. This is the basis for its restricted use in clinical studies to verify its clinical efficacy and safety profile in patients. Some systematic reviews of clinical studies revealed that HCQ with or without AZT did not decrease viral load nor reduce the severity of symptoms, but increased mortality among acutely hospitalized patients[42]. It was reported that there was no improvement in the patients’ clinical conditions after 15 days compared to standard treatment. Currently, the FDA has revoked the authorization for the use of HCQ in patients with COVID-19 because of the null benefit-risk balance[17]. Also, the IDSA guidelines recommend against the use of HCQ/CQ alone for prophylaxis and treatment due to moderate certainty of evidence, and a combination of both HCQ/CQ plus AZT due to low certainty of evidence[42].

Monoclonal antibodies: There is ample evidence that monoclonal antibodies are suitable for the treatment of COVID-19. Some of the most devastating effects of a COVID-19 infection stem from its associated complications, such as CRS and macrophage activation syndrome[34]. CRS often arises secondary to COVID-19 pneumonia; these patients display large amounts of pro-inflammatory cytokines, chemokines, and growth factors, which can quickly deteriorate into ARDS[34]. In a recent study, Caballero et al[71] reported a high abundance of CD3⁺ T cells and CD4⁺ T cells found in the lungs of deceased COVID-19 patients. Both mature T cells and immature B cells carry glycoprotein CD6 on the surface. CD6 is responsible for signaling between antigen-presenting cells and activated T cells, which initiates the release of more pro-inflammatory cytokines.

Itolizumab is an IgG1 monoclonal antibody that targets CD6 and inhibits the cascading immune response. It has been shown to decrease serum levels of IL-6, TNF-α, and IFN-γ[71]. A study in Cuba, involving seventy confirmed COVID-19 patients, all with illnesses ranging from moderate to severe, who were treated with itolizumab from April 4, 2020, to May 13, 2020, and were observed to assess the ability of itolizumab to help stop lung function from declining[71]. The data from the study indicated that itolizumab managed to successfully diminish cytokine release, and that the viral load was negative in patients who had recovered, indicating that itolizumab may not interfere with the adaptive immune response[66]. The study also showed that only 14.3% of the patients experienced adverse effects, the most common being fever, chills, nausea, vomiting, headache, skin rash, and tremors[71]. It was concluded that the best time to use itolizumab is before patients become critically ill or at the onset of respiratory distress.

Gimsilumab, a human monoclonal antibody, targets the granulocyte-macrophage colony-stimulating factor as elevated granulocyte-macrophage colony-stimulating factor levels further increase pro-inflammatory cytokines. Gimsilumab is expected to prevent and treat ARDS and lung injury in COVID-19 patients; therefore, it is currently in phase 2 clinical trials[34]. Furthermore, sarilumab and tocilizumab are FDA-approved IL-6 receptor blockers used to decrease the immune response in inflammatory conditions such as rheumatoid arthritis. They are both currently under investigation for their ability to treat COVID-19 patients[34]. Leronlimab is another monoclonal antibody that is being studied as an agent against COVID-19 and is currently indicated for the treatment of breast cancer and human immunodeficiency virus (HIV). Leronlimab blocks C-C chemokine receptor type 5 that HIV uses to enter cells. Currently, there are no recommendations for the use of immunomodulatory therapy for COVID-19 pneumonia; however, careful use of immunomodulators may prove to be beneficial to COVID-19 patients experiencing complications from CRS, such as ARDS and multiorgan failure[34].

Clustered Regularly Interspaced Short Palindromic Repeats/Cas13 and stem cell research

The Clustered Regularly Interspaced Short Palindromic Repeats/Cas13 are a family of enzymes that have been sequenced from many COVID-19-positive patients. This family can potentially inhibit SARS-CoV-2 replication, cleave the RNA genome, and aid in the amplification of the genome assay, making them valuable tools for detecting and combating the virus[44,72]. Cas13 can also target emerging pathogens via adeno-associated virus vector, which, when delivered to the infected lungs, may help prevent or reduce infection[44]. This targeted delivery could enable Cas13 to act directly on viral RNA in the lungs, potentially reducing the severity of infection and supporting recovery. The ability to use Clustered Regularly Interspaced Short Palindromic Repeats/Cas13 for both detection and treatment makes it a versatile tool in the fight against COVID-19 and potentially future viral pandemics.

Meanwhile, stem cells, particularly mesenchymal stromal cells (MSCs), are being explored for their therapeutic potential in treating COVID-19. Stem cells express IFN-gamma, which allows them to be resistant to viral infections[59]. A critical pathological factor in COVID-19 patients deals with the release of proinflammatory cytokines, which contribute to tissue damage and worsen the condition. MSCs may play a key role in addressing this problem due to their ability to modulate immune responses and promote tissue repair. These cells have shown the ability to inhibit the overproduction of inflammatory cytokines while supporting tissue repair. Additionally, MSCs can help reduce the viral load of SARS-CoV-2, offering promising benefits for patients suffering from the virus by reducing both inflammation and infection levels[49].

Supplemental agents

Uncompelling evidence in the treatment of COVID-19 symptom duration has not been noted in patients consuming high-dose zinc gluconate and/or ascorbic acid (vitamin C) when compared to standard therapeutic regimens[73]. Despite their widespread use, studies have not consistently shown a significant impact of these vitamins on symptom resolution. Zinc is known for its role in immune function, but its ability to directly affect the course of COVID-19 remains uncertain. Vitamin C, with its antioxidant properties, has been explored for its potential to reduce inflammation and boost immune response, but further evidence is needed to confirm its effectiveness in COVID-19 management[73]. On the contrary, epigallocatechin-3-gallate, a substance found in green tea, did improve acute lung injury in both pre- and post-COVID-19 disease[74]. Catechin is thought to regulate inflammatory cytokines, thus inhibiting SARS-CoV proteins[74]. Moreover, epigallocatechin-3-gallate works by regulating inflammatory cytokines and inhibiting the activity of SARS-CoV-2 proteins, thus showing potential as a supportive treatment option for lung health during viral infection.

Furthermore, vitamin D plays a significant role in adaptive immunity (strengthening the immune system)[45,75] by affecting cell maturation, proliferation, and differentiation, in addition to having a direct effect on ACE-2 receptors[76,77]. Vitamin D can help to reduce the severity of COVID-19 illness in areas where hypervitaminosis D is rife[75]. This connection highlights the importance of maintaining adequate vitamin D levels, as deficiencies may increase susceptibility to viral infections like COVID-19. Given its broad influence on immune responses, vitamin D supplementation could potentially play a key role in reducing the severity of COVID-19, particularly in high-risk populations.

Similarly, folic acid (vitamin B9) is essential for rapid cell proliferation and the synthesis of pyrimidines, purines, and methionine for DNA, RNA, and protein synthesis[45]. This makes folic acid vital for immune function and tissue repair, particularly in response to viral infections. In combination with other therapeutic agents like AZT, CHQ, and vitamin C, folic acid is currently being tested in clinical trials for the management of high-risk COVID-19 patients. These trials aim to evaluate the potential synergistic effects of B9 with other treatments to optimize patient outcomes, particularly in preventing severe disease progression and improving recovery[45]. Overall, while the evidence supporting high-dose zinc and vitamin C in COVID-19 treatment remains inconclusive, other vitamins, such as D and B9, show more promising roles in immune modulation and in supporting the body’s defense against SARS-CoV-2. Further research is needed to clarify the exact mechanisms by which these vitamins can contribute to improved treatment strategies and outcomes for COVID-19 patients, especially in high-risk groups.

VACCINES

The COVID-19 pandemic continued its destructive trajectory, with the WHO reporting over 3 million deaths worldwide as of April 2021[78]. Therefore, the need to distribute a reliable and efficient vaccine to the public was necessary. Developing a vaccine on a global scale in a short window of time can prove challenging. To increase the chances of success, the WHO suggested accelerating testing of possible COVID-19 vaccine candidates; as of June 2020, there were 120 contenders[79], and by early September 2020, a draft list of COVID-19 vaccine applicants was released, of which 34 were at various stages in clinical trials[80]. The Fusogenix DNA vaccine is a DNA plasmid vaccine that has a proteo-lipid vehicle that uses plasmid DNA, encoding for the virus’s various immunogenic antigens, neutral lipids, and fusion-associated small trans-membrane proteins to deliver nucleic acids to its target cells. The antigens elicit an immune response by stimulating both B and T cells. Preclinical in vivo studies indicated that the Fusogenix DNA vaccine has high immunogenicity, efficacy, and safety[34].

On May 12, 2020, the FDA accelerated the development of the mRNA-1273 vaccine, a lipid nanoparticle primed with an mRNA that encodes for the S protein of SARS-CoV-2[34]. The mRNA vaccine does not contain a live virus and, therefore, does not pose a risk of infection in a vaccinated person, nor does it interact with a person’s DNA, as it never enters the nucleus of the cell[81]. Data from its phase 1 clinical trial have indicated well-tolerated neutralizing antibody levels comparable to convalescent plasma at the 25 μg, 100 μg, and 250 μg dose levels. The safety data collected from the phase 1 trial also warranted abandoning the 250 μg dose level in phase 2, with phase 3 trials further assessing efficacy and safety at a dose of 100 μg[34]. MRNA vaccines use a piece of mRNA to instruct cells to produce a protein, typically a part of the virus, such as the spike protein of SARS-CoV-2, that triggers an immune response and have shown high efficacy rates in preventing COVID-19. There is no risk of causing disease since they do not use a live virus; however, they can cause short-term side effects like fever and fatigue[82].

Three mRNA vaccines that initially received EUA by the FDA and were recommended by the CDC are the Pfizer-BioNTech COVID-19 vaccine, the Moderna vaccine, and the Johnson & Johnson/Janssen vaccine for active immunization against COVID-19 in the United States and other countries[83]. The Pfizer and Moderna vaccines are 2-dose series separated by 21 and 28 days, respectively, while the Johnson & Johnson vaccine is a single shot[83]. The Johnson & Johnson (Janssen) COVID-19 vaccine expired as of May 6, 2023, and is no longer available in the United States, while Pfizer’s vaccine has been updated multiple times to address the emergence of new virus variants. Initially, bivalent vaccines in 2022 targeted both the original virus and Omicron variants BA.4 and BA.5. In 2023, a monovalent shot focused on the XBB lineage of Omicron. By 2024, a new vaccine had been developed to protect against the KP.2 variant. Previous versions are no longer in use. Also, Moderna’s vaccine has undergone multiple updates to address the emergence of new variants of the virus. Initially, bivalent vaccines in 2022 targeted both the original virus and Omicron variants BA.4 and BA.5. In 2023, a monovalent shot focused on the XBB lineage of Omicron. By 2024, a new vaccine was developed to protect against the KP.2 variant. Previous versions are no longer in use[84]. Recently, EUA was granted for an updated version of the Novavax COVID-19 vaccine that more closely targets currently circulating variants[83]. The Novavax COVID-19 vaccine, adjuvanted (2024-2025 formula) includes a monovalent (single) component that corresponds to the Omicron variant JN.1 strain of SARS-CoV-2 and has the potential to protect against current variants, including JN.1, KP.2, and KP.3, based on non-clinical data[85]. The vaccine, also known as Nuvaxovid or Covovax, is a non-mRNA protein-subunit vaccine with an efficacy of over 90% in preventing COVID-19 infection as well as hospitalization, severe illness, and death. Previous versions are no longer recommended. Vaccination is still ongoing in the United States; about 70% have been fully vaccinated, and 81% have received at least one dose[86].

Other vaccine candidates being developed include the Ad5-nCOV vaccine, which is based on the adenovirus, and the Sputnik V vaccine, which is based on dual adenovirus vectors saddled with a gene fragment coding for the S protein of the SARS-CoV-2[34,82]. The Ad5-nCOV vaccine was developed by China, and the results from phase 1 and phase 2 studies proved the vaccine to have a strong immune response and were approved by the Chinese military[34]. The Sputnik V vaccine was approved for early use by the Russian Ministry of Health, and its phase 1 and phase 2 clinical trials also indicated strong antibody and cellular immune responses[34,82]. Both vaccines are designed using viral vectors. Viral vector vaccines use a different virus (not the one causing the disease) to deliver genetic material into cells. This genetic material instructs cells to produce a protein that triggers both T-cells and B-cells’ immune response without developing the disease, and they do not require ultra-cold storage, unlike the mRNA vaccines[82]. As viruses mutate[87], the effectiveness of vaccines can decrease as new variants emerge, especially if these variants have mutations that allow them to partially escape the immune system; vaccines may need adjustments to remain effective, which, in the case of COVID-19, involves updating the vaccine’s genetic code to match new variants.

CDC data for 2023-2024 reported that the updated COVID-19 vaccines were 54% effective in preventing COVID-19 from mid-September 2023 to January 2024 and provided significant protection against the XBB lineage and the JN.1 variant, which became dominant recently[88]. Also, a systematic review and meta-analysis by Zeng et al[89] reported the vaccine efficacy against the following variants: Alpha: 88.0% [95% confidence interval (CI): 83.0-91.5]; Beta: 73.0% (95%CI: 64.3-79.5); Gamma: 63.0% (95%CI: 47.9-73.7); Delta: 77.8% (95%CI: 72.7-82.0) and Omicron: 55.9% (95%CI: 40.9-67.0). Boosters were more effective, with 95.5% against Delta and 80.8% against Omicron[89]. The findings underscore the importance of updated vaccines and booster doses in maintaining protection against evolving variants.

COVID-19 vaccines have a positive long-term impact on the immune system, even in populations with pre-existing immune impairments. Vaccination helps reduce the severity of illness and provides a critical layer of protection, especially for vulnerable groups like cancer patients and the elderly. COVID-19 vaccines are generally safe and effective for cancer patients, reducing the risk of severe illness, hospitalization, and death, although the immune response may be less robust in patients undergoing treatments like chemotherapy or those who have recently had stem cell transplants; hence, It is advised that cancer patients, especially those undergoing active treatment, get vaccinated and receive booster shots as recommended[90-92]. Although older adults often have a weaker immune system, which can affect the vaccine’s efficacy, COVID-19 vaccines still provide significant protection against severe outcomes in this age group; thus, vaccination remains crucial for this group due to their higher risk of severe illness from COVID-19[93-95].

Optimizing treatment protocols: Future research directions

Due to the high transmissibility of SARS-CoV-2, the propensity of developing resistance to antiviral agents is quite high thus, the elderly and patients with chronic comorbidity are at the greatest risk of severe cases of COVID-19. However, younger patients can also develop long-term complications. Although remdesivir has been authorized by the FDA for emergency use, its clinical effectiveness is uncertain, and its side effects, like liver toxicity and allergic reactions, have limited its use[96]. On the other hand, literature is replete with robust data demonstrating the effectiveness of dexamethasone in reducing mortality in hospitalized patients with severe COVID-19[97]. Conversely, its immunosuppressive effects can cause serious side effects like osteoporosis, glaucoma, diabetes, and secondary infections[97,98]. Other side effects include neuropsychiatric complications, cardiovascular events, lung infections, and/or liver damage, among other ailments[97,99]. Therefore, combinations of therapeutic agents that can balance antiviral efficacy and immune modulation with minimal side effects would be critical to the successful treatment of severe COVID-19 cases in comorbid conditions.

For example, a combination of therapeutic agents that target different stages of viral replication, like nirmatrelvir and ritonavir (PAXLOVID^TM). Ritonavir is an HIV-1 protease inhibitor but is not active against SARS-CoV-2. However, it inhibits the cytochrome P450 3A-mediated metabolism of nirmatrelvir, leading to increased plasma concentration of nirmatrelvir, which is the active peptidomimetic inhibitor of SARS-CoV-2 protease (Mpro)[99]. Also, combining antiviral agents with monoclonal antibodies can lower the risk of COVID-19 pathogenesis in comorbid patients by providing passive immunity, especially in comorbid patients with chronic (immunosuppressed) conditions, and reducing the propensity for breakthrough infections. For example, Calderón-Parra et al[100] studied the clinical efficacy and safety profile of antiviral-monoclonal antibodies combinations in high-risk immunocompromised patients. They concluded that a combination of sotrovimab and an antiviral agent was associated with reduced risk of COVID-19 progression and decreased mortality rate compared with monotherapy, particularly in patients with severe humoral immunosuppression. They also affirmed that the adverse effects of combination therapy were mild and comparable to monotherapy.

The exaggerated and uncontrolled release of pro-inflammatory cytokines (cytokine storm) through the JAK-signal transducer and activation of transcription pathway in severe COVID-19 patients can exacerbate the disease progression. Therefore, blocking the JAK-signal transducer and activation of transcription signaling can reduce the release of cytokines like IL-2, IL-6, and TNF-α and consequently reduce disease progression. JAK inhibitors (baricitinib/tofacitinib) have been reported to inhibit members of numb-associated kinase family, like AP2-associated kinase 1 and cyclin G-associated kinase, which regulate the ACE-2 transmembrane protein, the receptor to which SARS-CoV-2 binds to infect humans. Thus, JAK inhibitors can effectively control the cytokine storm. The clinical effectiveness of several JAK inhibitors has been studied, including baricitinib, ruxolitinib, and tofacitinib. Although they all bind directly to active kinases, they have varying affinities and relatively short half-lives of 12.5 hours, 4 hours, and 3 hours for baricitinib, ruxolitinib, and tofacitinib, respectively. However, baricitinib has been shown to strongly inhibit JAK1 and JAK2 enzymes with low IC₅₀ of 4.0-5.9 nM and 6.6-8.8 nM, respectively, suppressing both innate and adaptive immunity. Thus, baricitinib has been strongly recommended, particularly in combination with corticosteroids, in patients with severe COVID-19 cases. Combinations of immunomodulators like JAK Inhibitors and corticosteroids (dexamethasone) have also been reported to control hyperinflammation and cytokine storm. Similarly, IL-6 inhibitors like infliximab/adalimumab can be combined with remdesivir to regulate inflammation while maintaining antiviral action[101].

Recently, Saranya et al[102] developed a systematic framework for predicting and validating drug combinations for COVID-19 comorbidities, specifically type 2 diabetes and hypertension. They concluded that drug repurposing is an effective alternative to modifying the treatment of COVID-19 and its comorbidities. For example, the authors prioritized tocilizumab and gliclazide as effective drug combinations for the treatment of COVID-19 in patients with type 2 diabetes comorbidity, while a combination of tocilizumab and lidocaine (or bacitracin) is effective in COVID-19 patients with food-borne bacterial infection comorbidity[102].

As the development of antiviral drugs continues to evolve in response to COVID-19, vaccine strategies are also being refined to address emerging variants, such as Omicron subvariants JN.1, LP.8.1, KP.3.1.1, and XEC[78,87,103-105], and long-term protection enhancement. These variants often feature mutations that can help the virus evade immunity, either from prior infection or vaccination. To better target evolving strains, mRNA formulations and viral vector platforms have been adjusted, booster doses introduced, and ongoing research is essential to optimize strategies for adapting vaccines and ensuring long-term immunity[106]. Researchers are also exploring next-generation vaccines that provide broader protection against multiple variants and even different coronaviruses[107]. COVID-19 vaccines, particularly mRNA vaccines, have been shown to leave a lasting impact on the immune system. Recent research indicates that they induce long-lasting changes in the innate immune cells through epigenetic modifications with the “training” of the immune system to enhance the body’s ability to defend against future infections, potentially broadening protection beyond just COVID-19[108].

Social distancing and other non-pharmaceutical interventions have been essential in controlling the spread of COVID-19, but their long-term socio-economic impacts warrant further investigation. Regarding the economic impact, social distancing measures can lead to significant job losses, particularly in sectors like retail, hospitality, and travel, ultimately resulting in increased poverty and financial insecurity; moreover, many small businesses struggle to survive prolonged periods of reduced customer traffic, leading to permanent closures and the economic fallout disproportionately affects low-income and vulnerable populations, exacerbating existing inequalities[109-114]. As for the social impact, extended social isolation can lead to increased rates of anxiety, depression, and other mental health issues; as well, school closures and remote learning can negatively impact educational outcomes, particularly for students from disadvantaged backgrounds; equally, increased time at home can lead to higher rates of domestic violence. Efficient implementation of social distancing during future pandemics involves early intervention, support systems, public communication, and an integrated approach. Implementing social distancing early in the outbreak can delay the epidemic curve, giving healthcare systems time to prepare with a focus on high-risk areas and populations to minimize economic disruption while effectively controlling the spread. Furthermore, providing financial assistance to affected individuals and businesses to mitigate economic impacts and enhancing access to mental health support to address the psychological effects of isolation. In addition, communicating the importance and rationale behind social distancing measures clearly to ensure public compliance and maintaining transparency about the duration and expected outcomes of measures to build trust and cooperation. Lastly, using social distancing in conjunction with other interventions like testing, contact tracing, and vaccination to maximize effectiveness, and adapting measures based on real-time data and emerging evidence to respond effectively to changing circumstances[109-114]. Future research should further explore the broader effects of these measures on mental health, economic stability, and social dynamics. Additionally, it is crucial to identify strategies for efficiently implementing these interventions during future pandemics, balancing public health needs with minimizing disruptions to daily life and economic activity. Understanding these impacts will help optimize the use of non-pharmaceutical interventions in future global health crises[115].

LIMITATIONS

This study has certain limitations that could influence the review outcomes. As a narrative review rather than a systematic review with meta-analysis, there is a potential selection bias in the articles chosen, which may impact the results. Additionally, ongoing research on the therapeutic management of COVID-19 means our study might not include the latest findings that could alter future guidelines. Therefore, we recommend conducting a more comprehensive study using a systematic review with meta-analysis to address these limitations.

CONCLUSION

SARS-CoV-2, the virus responsible for COVID-19, has spread globally and affected every aspect of human life. Due to its rapid transmission, the medical community has been urgently working to understand the virus, treat those infected, and develop an effective vaccine. As efforts to develop an effective vaccine continue, it is equally crucial to identify and protect vulnerable populations who face a heightened risk of severe illness and complications. Vulnerable populations, including those with comorbidities such as COPD, heart disease, diabetes, CKD, and obesity, are at higher risk of infection and severe complications. Treatment options include convalescent plasma transfusion, corticosteroids, antivirals, and immunomodulatory medications. However, access to these treatments is not universal, and side effects can lead to patient non-compliance. Despite efforts to contain and treat the virus, vaccination continues to prevent new cases and combat virus variants, while global efforts aim to eradicate the disease. Precautions such as wearing masks, diligent handwashing, and practicing social distancing remain essential to prevent the spread of the virus. Comorbidities not only increase the risk of contracting the infection but also exacerbate the severity of the illness and complicate treatment, requiring careful management to avoid interactions and adverse reactions. While antiviral and immunomodulatory medications show promise, corticosteroids, for example, have been found to reduce mortality but may cause serious adverse effects in specific populations. Given these complexities, ongoing research is essential to optimize treatment approaches and mitigate risks. Moreover, future research should focus on refining treatment protocols for vulnerable groups, exploring combination therapies, and investigating long-term vaccine effectiveness, particularly in patients with comorbid conditions. Additionally, studies on non-pharmaceutical interventions and the broader impact of social distancing measures are crucial in preparing for future pandemics.