NK cells

NK cells are the effector lymphocytes that regulate various microbial infections by preventing their progression and resulting in tissue damage. Several recent studies have also shown that NK cells interact with other immune cells, highlighting that NK cells may reduce or intensify immunological reactions [31]. Macrophages and DCs become activated during viral infection and release IL-12, IFN-γ, and IL-18, which then activate NK cells. NK cells can induce cell apoptosis, degranulation, and antibody-dependent cell-facilitated cytotoxicity (ADCC) [31]. In a recent study, it was concluded that a decrease in NK cell number and activity in patients with severe symptoms decreases the clearance of infected and activated cells [32]. This leads to an unregulated rise in tissue-damaging inflammatory markers [32]. These inflammatory responses are responsible for a significant risk of mortalities linked to ARDS [33]. In a study, it was observed that NK cells may help immune-immune cell interactions to prevent excessive inflammation and tissue damage [34]. But they are not observed to involve in the increased inflammatory responses seen in ARDS [34]. Therefore, in COVID-19, NK cells play a crucial role in the transition from a beneficial to a detrimental immune response.

Macrophages

There is growing evidence that suggests macrophages, both recruited blood macrophages, and resident AMs are important players in the etiology of ARDS. Macrophages are found to play a subtle role in the development of inflammatory responses. There are two types of AMs involved in ARDS, i.e., M1 and M2. M1 produces IL-1β, IL-6, monocyte chemoattractant protein 1 (MCP-1), and TNF-α which participate in tissue injury by neutrophilic inflammation and induce pro-inflammatory conditions. M2, on the contrary, produces anti-inflammatory cytokines such as arginine 1 (Arg-1), IL-10, and tumor growth factor β (TGF-β) by inducing tissue repair and remodeling [35, 36]. After clearance of infection from the body, the rehabilitation phase occurs where M1 macrophages change into M2 macrophages which plays a pivotal role in repairing the damaged lung tissue [37]. The late stage of ALI/ARDS, pulmonary fibrosis, is brought on by excessive collagen deposition and fibroblast proliferation. The ratio of M1 to M2 macrophages at this stage determines the progress and severity of pulmonary fibrosis. Therefore, it is possible to anticipate that controlling macrophage polarisation will accelerate the development of fibrosis in ALI/ARDS [38].

It is feasible for SARS-CoV-2 to infect macrophages and monocytes through angiotensin-converting enzyme 2 (ACE2)-independent and ACE2-dependent routes. If this occurs, the infected cells will lose their ability to fight off viruses and elicit adaptive immune responses [38]. Macrophages also play a crucial role in evoking the adaptive immune response to tackle the infection. However, their dysregulated activities can cause organ harm in patients, primarily by escalating acute inflammation, encouraging cytokine storms, and lengthening fibrotic consequences. As a result, they significantly aggravate the condition and cause ARDS, which frequently results in the death of people with COVID-19 [39–41]. Infiltration of interstitial mononuclear inflammation into the lung tissues was also validated by clinical-pathological examination of COVID-19 patients’ biopsy samples [42, 43]. Nevertheless, the molecular mechanisms behind the aberrant inflammatory responses in histology and serology brought on by SARS-CoV-2 infection are yet unknown.

DCs

DCs are well-known professional antigen-presenting cells (APCs) they can either serve as a primary player in the innate immune response defense against pathogen infection or they can also behave as masterminds in ensuing adaptive immune response. These are found to be connecting links between innate and adaptive immune systems. It is found that SARS-CoV-2 pneumocytes release viruses, PAMPs, and DAMPs. DCs get stimulated by PAMPs and DAMPs and this leads to naive DCs maturation [44, 45]. In a recent study, it is already been noted that there is a real increase in mature DCs in BALF of patients, this indicates that DCs are involved in lung immune response during SARS-CoV-2 infection [46].

ILCs

ILCs are the newly discovered innate immune subsets. According to the proposed nomenclature, these cells are of 3 types, ILC1, ILC2, and ILC3, these are known to be mirror images of Th cells Th1, Th2, and Th17 respectively [47]. They are the ones who upon initial encounter with an incoming pathogen regulate the immune response and hence have a crucial role in immune surveillance. These lack specific antigenic receptors and therefore are found to be activated under the influence of cytokines or there might be some unknown receptors triggering their activation. Alarmins such as IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) are released by damaged epithelium, these alarmins work on ILC2 to promote the proliferation and function of effector cells. ILC2 response is inhibited by IFN-β from restored epithelium and IFN-α from macrophages. Additionally, ILC2 converts to T-bet expressing ILC1 under the presence of cytokines IL-12, IL-18, and IL-1β [48]. ILC2 recruits’ eosinophils to the inflammation site resulting in tissue recovery. It has been showed that that C-C chemokine receptor (CCR) 10⁺ ILC2 expanded under recovery condition, although the mechanism driving lung repair are not entirely understood, concluding that ILCs have become important participants following acute injuries [49–51]. ILC2 has been described as a double-edged sword in the context of respiratory infections, aiding lung pathogenicity and homeostasis in both chronic and acute contexts. Similarly, IL-22 is observed to be increased post-infection indicating a positive role of ILC3 in tissue repair [49–51]. A thorough understanding of ILCs in respiratory tract infection is still required to understand their intricate cellular and molecular interactions under host-pathogen encounters.

Other innate immune cells

Along with the above-mentioned innate immune subsets, granulocytes are also found to be involved in COVID-19-induced ARDS. According to a few studies, neutrophils number is increased in COVID-19 infection, this can be the signature of increased immune defense but the incidence of alveolus damage is also increased due to respiratory burst, degranulation, and NET formation [52–54]. These immune responses via neutrophils lead to inflammation in the lungs and cause damage to the endothelium that ultimately leads to impaired oxygenation [52–54]. Not only neutrophils but eosinophils and basophils are also found associated with lung damage during the COVID-19 infection. These granulocytes are a major marker of inflammatory home. In the case of eosinophils, their involvement in lung injury is still not clear, their count is found to be decreased during the initial phase of ARDS but increases in the late phase. They may emerge as effector cells that cause tissue damage or may be simply involved in an immune response to lung injury and repair [9, 55, 56].

B lymphocytes

The body’s B cells primarily carry out humoral immunity. Upon antigen activation, they can develop into plasma cells, making certain antibodies and playing a little part in immune defense. The generation of antibodies that block the invasion of SARS-CoV-2 into cells is carried out by B cells, however, it is yet unclear how long recovering COVID-19 patients would retain their immunological memory [59, 60]. B cells can be directly activated by antigens via B cell receptor (BCR) or Th2 cells. Plasma B cells secrete IgM, IgA, and IgG which mediates the neutralization of antigens by recognizing the spike protein. Also, in recovered patients these increase with time as observed in the data obtained. B cells can connect to viral proteins through their antigen receptors in response to most viral infections, helping to control viral infections by secreting effector molecules (IL-2, IL-4, IL-6, IFN-γ, and TNF-α) [61]. Enhanced IgG and IgA-secreting B cells and abnormalities in the circulating B cell subsets, and decreased Bregs immuno-suppressiveness might lead to respiratory tract inflammation and several lung pathologies [62]. The relative significance of the major players engaged in the pathophysiology of ARDS is still difficult to determine. More research is required to link and clarify the diverse cloud of B cell responses in COVID-19-induced ARDS.

T lymphocytes

The CD4⁺ and CD8⁺ subsets of T cells are essential for both autoimmune and inflammatory responses. There have been some theories about how SARS-CoV-2 causes lung damage. SARS-CoV-2 might primarily affect T cells, which would worsen the patient’s condition. It has been shown that SARS-CoV-2 induces immunological activation of T cells to produce antiviral responses. CD8⁺ T lymphocytes were a frequent marker that was observed as an independent predictor of COVID-19 severity and therapy response [63]. According to several studies, it was concluded that the CD8⁺ T cell response and CD4⁺ T cell response are different in the case of mild and severe disease respectively [64].

The majority of recovered patients’ CD4⁺ and CD8⁺ T cells produce a substantial number of antiviral immune responses against spike proteins, which clearly shows the importance of T lymphocytes in viral clearance and recovery [65]. In COVID-19 patients, Grifoni et al. [66] assessed CD4⁺ and CD8⁺ T cells’ responses to SARS-CoV-2. All cases showed SARS-CoV-2-specific CD4⁺ T cell and antibody responses, and the majority also showed SARS-CoV-2-specific CD8⁺ T cell responses. A significant finding was the presence of pre-existing SARS-CoV-2-cross-reactive T-cell responses in healthy donors, suggesting the possibility of pre-existing immunity in the general population [66, 67]. Hence, they were able to positively correlate the T-cell responses with the antigen titers. A pathogenic synergy of T cell-associated bystander effects leads to aberrant or overactive immune responses in SARS-CoV-2 infected patients which further leads to significant tissue damage [68, 69]. With regard to understanding the potential involvement of the immune system in the disease, these data together give light on the potential differences in T-cell responses as a function of disease severity.

Remdesivir

Remdesivir is the first Food and Drug Administration (FDA)-approved drug for COVID-19 hospitalized patients. It is an adenosine analog that acts as an inhibitor of viral RNA polymerase and thereby, disrupts viral replication. Both in vivo and in vitro, remdesivir has been reported to suppress MERS-CoV and SARS-CoV [70, 71]. In a recent study, remdesivir was demonstrated to be highly efficient against SARS-CoV-2 infection in vitro [72]. However, in a randomized clinical trial (RCT), Wang et al. [73] showed that remdesivir did not exhibit any significant clinical benefits in hospitalized people. Contrastingly, the final results of another RCT concluded that remdesivir is superior to placebo and speeds up recovery in patients with lower respiratory tract infections who were hospitalized with COVID-19 [74].

Favipiravir

Favipiravir is a viral RNA polymerase inhibitor, which has exhibited a crucial impact against influenza A and B [75]. Recent studies show that favipiravir significantly improved viral clearance and pulmonary CT scan outcomes in COVID-19 patients [76]. Takahashi et al. [77] suggested that favipiravir may help improve respiratory function even in serious or critical circumstances by preventing the progression of pneumonia and the generation of cytokines.

Chloroquine and hydroxychloroquine

Chloroquine (Clq) and its hydroxylated version, hydroxy Clq (HClq) are two antimalarial medications that interfere with ACE2 binding, which prevents viral entrance. They also alter the pH of endosomes and lysosomes, which can prevent viral fusion with host cells [78]. Additionally, these drugs prevent the release of cytokines that promote inflammation. Clq has been particularly demonstrated to reduce lung damage induced by influenza A H5N1 virus in preclinical animal models [79] and SARS-CoV-2 infection in vitro [72]. The addition of Clq/HClq to routine therapy for patients hospitalized with severe COVID-19, on the other hand, dramatically exacerbated their clinical state in an RCT. According to the findings of this study, people who have a more serious case of COVID-19 pneumonia shouldn’t use Clq/HClq [80]. Another controlled trial reported that Clq/HClq does not add anything to the therapy of COVID-19 patients [81]. Since the HClq trial failed to show any benefit, the National Institute of Health and WHO dropped the trial for hospitalized COVID-19 patients [81].

Corticosteroids

In cases of SARS-CoV-2-induced cases of cytokine storm, corticosteroids with anti-inflammatory, antifibrotic, and vasoconstrictive actions have been explored for the potential improvement of lung damage caused by inflammation in patients with ARDS [82]. The duration of corticosteroid therapy is a very important parameter and should be considered. The efficacy of corticosteroid therapy in critically ill COVID-19 patients was assessed in several clinical studies. A clinical trial that assessed the effectiveness of intravenous dexamethasone administration in COVID-19 patients found that it increased days alive and free of mechanical ventilation over 28 days by a statistically significant amount compared to standard treatment alone [83]. Villar et al. [84] found in a multicentre, randomized controlled study that early dexamethasone medication might reduce overall deaths and ventilator time in patients with established moderate-to-severe ARDS. According to some preliminary trial results, methylprednisolone and dexamethasone can be used for the severe form of COVID-19 [85]. In a different study, it was discovered that methylprednisolone performed better than dexamethasone in treating COVID-19 hypoxic patients [86]. Currently, several phase 2/3 clinical trials are looking into the efficacy and safety of methylprednisolone in patients with COVID-19 ARDS. These studies should hopefully shed further light on the role of steroids in these patients.

Convalescent plasma

Nearly all COVID-19 patients who have recovered have convalescent plasma from their blood, which contains neutralizing antibodies against viral proteins [87]. In light of this, investigating the safety and effectiveness of convalescent plasma treatment in COVID-19 patients may be advantageous [88]. Hoffmann et al. [89] showed that SARS-CoV serum from convalescent patients conferred defense against SARS-CoV-2 infection, and this approach may be successful if employed preventatively. In a study by Shen et al. [90], convalescent plasma was used to treat 5 critically ill patients with laboratory-confirmed COVID-19 and ARDS. This resulted in a rapid reduction in viral load and improved patient outcomes. Furthermore, according to Allahyari et al. [91], early convalescent plasma delivery can aid in easing the symptoms of severely ill COVID-19 patients who are experiencing mild to moderate ARDS and are in danger of deteriorating into a critical condition.

Mesenchymal stromal cell therapies

Mesenchymal stromal cells (MSCs) have demonstrated immunoregulatory abilities that can reduce inflammatory responses. According to a study by Chan et al. [92], MSC treatment has favorable impacts on acute lung damage caused by H5N1 and may be helpful for patients who have severe pulmonary infections brought on by influenza viruses like H5N1 and H7N9. The results of a trial conducted by Lanzoni et al. [93] on the safety and effectiveness of allogeneic umbilical cord-derived MSC (UC-MSC) infusions in patients with ARDS associated with COVID-19 proved the safety of UC-MSC infusions for COVID-19 patients with ARDS and that when compared to controls, UC-MSC therapy decreased mortality and recovery time. Another double-blind, placebo-RCT found that administering UC-MSC accelerated the recovery of lung lesions and enhanced the function of the integrated reserve [94]. In preclinical ARDS model investigations, MSCs were proven to be efficient and safe, and the outcomes of the COVID-19 clinical trials revealed their potential effectiveness. However, more extensive studies are required to confirm MSC’s efficacy, particularly in ARDS patients who have been diagnosed with COVID-19.

IL-6 inhibitors

It has been discovered in the pathogenesis of COVID-19 pneumonia, that there is a cytokine release syndrome with significant proinflammatory cytokine secretion, including IL-6, IL-1, and TNF-α [95]. It has been demonstrated that the immunomodulatory medication thalidomide, which acts to increase apoptosis, has positive benefits in experimental bacterial- and viral-induced ARDS. It is a potent inhibitor of IL-6 and enhances T-cell responses [96]. A study of 21 patients with SARS-CoV-2-induced ARDS showed that tocilizumab (TCZ), an IL-6 receptor antagonist improved lung opacity and lung oxygenation and decreased the number of white blood cells [97]. A single center-based study with 100 patients in Italy observed improvements in their clinical outcomes in more than three-quarters of patients after evaluating the efficacy of intravenous administration of TCZ in the treatment of severe COVID-19 pneumonia and ARDS patients [98, 99]. Pinzon et al. [100] evaluated the data about the efficacy of IL-6 inhibitors in the treatment of COVID-19 by conducting a systematic review and meta-analysis. IL-6 medications have demonstrated efficacy in decreasing mortality in COVID-19 patients, especially in those with severe illness.

IVIG and monoclonal antibodies

The exact mechanisms of action of IVIG in immune-mediated diseases are still not fully understood, but IVIG may interact with immune cell receptors, pathogenic proteins, or other proteins that are linked to inflammation, thus acting on the host’s hyperimmune reactions [101]. A double-blind RCT demonstrated that the administration of IVIG to patients with severe COVID-19 infection who did not respond to initial therapy massively improved their clinical outcome [102]. In another study, early IVIG treatment reduced mortality and shorter ventilator time in patients with COVID-19-related ARDS [103]. Monoclonal antibodies targeting the spike protein are also preferred for immunotherapy to prevent the attachment and entry of SARS-CoV-2. The combination of numerous monoclonal antibodies that each recognise a different epitope on the viral surface, called a monoclonal antibody mixture, may help neutralise the virus. Several studies have shown that treatment with monoclonal antibodies can reduce the viral load [104].

Vaccines

Multiple vaccines have recently been developed and nearly every country is currently immunizing its population to tackle the COVID-19 pandemic. Even though several COVID-19 vaccines have been developed, more potent vaccines are still required to meet the demand on a global scale. Intranasal COVID-19 vaccines are also now being produced, and they have demonstrated a promising capacity to elicit a considerable amount of antibody-mediated immune response, robust cell-mediated immunity, and the additional capacity to elicit protective mucosal immunity. COVID-19 vaccines can be classified into vaccines based on attenuated SARS-CoV-2 virus, viral vector vaccines, nucleic acid-based vaccines, and vaccines based on subunit particles. At the forefront of vaccine development right now there are many COVID-19 vaccine candidates based on the original Wuhan-Hu-1 strain. Vaccines including NVX-CoV2373 (∼96%), BNT162b2 (∼95%), mRNA-1273 (∼94%), Sputnik V (∼92%), AZD1222 (∼81%), BBIBP-CorV (∼79%), Covaxin (∼78%), Ad26.CoV.S (∼66%), and CoronaVac (∼51%) have shown efficacy over 50% against symptomatic COVID-19 patients. Promising COVID-19 vaccines with various modes of action have shown good safety and clinical efficacy profiles in clinical trials (Table 1).

Heparin

Growing evidence links the pathophysiology of severe COVID-19 respiratory failure to abnormal coagulation, most especially, pulmonary microvascular thrombosis [105]. Other studies are being conducted to see if nebulized heparin can lower mortality in severe COVID-19 patients.

Probiotics

Probiotic strains have gained more and more recognition as a potent ally in the fight against and prevention of respiratory tract infections in recent times. It has been demonstrated that treatment with probiotic bacteria affects the production of inflammatory cytokines in the lungs, which has been associated with COVID-19 lethality [106]. According to a controlled trial, probiotics may lower the incidence of ventilator-associated pneumonia (VAP) and reduce the duration of antibiotic use for VAP [107]. Numerous preclinical research on probiotics has thus far concentrated on influenza and pneumonia, showing advantages from oral or nasal administration of probiotics, which increased survival, decreased weight loss, decreased viral loads in the lung, and minimized bronchial epithelial damage [108–110]. The best evidence supporting the effectiveness of probiotics was discovered for five disorders, including acute respiratory tract infections, according to a meta-analysis of 52 published studies that looked into the ability of probiotics to prevent or treat a variety of pathological conditions [111]. Another recent study showed that a daily oral diet with Lacticaseibacillus rhamnosus for a short time modulates the inflammatory response in a murine model of acute lung inflammation [112]. Raheem et al. [113] have reported the preventative effect of Lactobacillus casei on ALI induced by lipopolysaccharide. The beneficial role of probiotics has been linked to many processes, including their capacity to support intestinal integrity and maintain intestinal permeability, competition with pathogens for nutrients and attachment sites, regulation of immune cell activity against invading pathogens, and the prevention of excessive immune responses and inflammation. There are a quite number of clinical trials which have been conducted or are currently being conducted to decipher the therapeutic role of probiotic supplementation in COVID-19. Probiotics are also being exploited to ameliorate the inflammatory axis in COVID-19-induced ARDS. Although the outcomes of these investigations are encouraging, more thorough research must be done to reach firm conclusions.

Diet

Depending on the vaccination rate over a certain period, social acceptability or resistance, and insufficient social distance, the virus can persist in a population for too long before it mutates, even in the presence of effective vaccines. Whilst the administration of the SARS-CoV-2 vaccine generally cannot completely prevent infection, it does offer immunization to lessen severe illness and ARDS [114, 115]. Therefore, it is pertinent and important to find cures that, alone or as adjuvant therapies, alleviate this severe lung disease.

Omega-3 polyunsaturated fatty acids (PUFAs), in particular, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have recently been discovered to support the immune system to fight inflammation, promote the generation of pre-resolving mediators, and regulate platelet aggregation and thrombosis [116]. It has been discovered that fatty acids (FAs) cause B cells to respond and develop into plasma B-cells that produce IgA or IgG. To combat pathogens, PUFAs also encourage the production of effector T-cells like Th1 and Th17 during infection. Because of this, n-3 PUFAs have attracted a lot of attention as possible treatments for both the prevention and treatment of inflammatory diseases [24]. Currently, some researchers suggest using n-3 PUFAs as immunomodulatory and antiviral medications to treat COVID-19, its consequences, and its progression, including ARDS [117, 118].