Respiratory droplets are the primary means of human transmission of SARS-CoV-2, with an incubation period of one to two weeks ^[1][27]. The virulence mechanism of SARS-CoV-2 is widely believed to be mediated by binding to the ACE2 receptor, with subsequent ACE2 overexpression ^[2][28]. The increased ACE2 expression can lead to structural damage in the alveolar wall and hyperinflammatory status. It was noted that pulmonary edema and exudates are prominent in patients with COVID-19 ^[3][29]. Inflammatory factors were significantly elevated in a subpopulation of COVID-19 patients ^[4][30]; hyperinflammatory conditions of extreme sepsis have been well-mentioned ^[5][31]. Though, it is unclear to what level COVID-19-related inflammation is comparable or distinct from that usually seen in sepsis. Multiple case reports have indicated that patients with severe COVID-19 disorder display complications from hypercoagulability ^[6][32], as for microscopic thrombi and pulmonary emboli ^[7][8][33,34].

The main target of the SARS-CoV-2-induced cytokine storm is the lungs ^[9][35]. Tissue destruction due to the spread of SARS-CoV-2-infected cells can promote a dysfunctional immune response mediated mainly by macrophages that dysregulates the cytokine secretory pattern ^[10][36]. The virus’s invasion and replication are associated with a prompt release of proinflammatory cytokines and death of the cells, contributing to the release of the molecular patterns related to the damage and further amplifying the inflammatory response ^[11][12][37,38]. The exaggerated release of these cytokines is one of the ARDS mechanisms and multiple organ failure (MOF) in COVID-19 ^[13][39].

Tight intercellular communication usually occurs between lung epithelial cells expressing ACE2 and macrophages ^[14][40]. Macrophages have T-lymphocyte viral antigens, leading to T-cell subsets engagement and activation ^[15][41]. In response to the viral infection, an adaptive immune response with subsequent Th1 feature should release antiviral cytokines such as type I interferons (IFNs). Nevertheless, serious infections with coronavirus SARS may be associated with low IFN production levels, which have been previously documented ^[16][42].

The latest studies have shown elevated levels of inflammatory cytokines in patients with COVID-19, such as interleukins and tumor necrosis factor (TNF)-α ^[17][11] (Table 1). Moreover, fibroblast growth factor, granulocyte colony-stimulating factor (G-CSF), macrophage inflammatory protein 1, and granulocyte-macrophage colony-stimulating factor (GM-CSF) were reported to be elevated ^[18][43]. Interestingly, a significant correlation between the critical illness/intensive care unit (ICU) admission of COVID-19 patients and serum levels of IL-6 and TNF-α has been documented ^[19][44]. By interacting with its receptor, TNF-α may induce T-cell apoptosis, and IL-6 may suppress the activation of normal T cells that participate in the occurrence of lymphocytopenia. This feature is sometimes found in COVID-19 patients ^[20][45]. A recent study demonstrated a negative association between the total count of T cells, CD4+, and CD8+, and the TNF-α and IL-6 levels in ICU patients due to the COVID-19 ^[21][46].

In inflammatory sites, hypoxia is a common feature of multiple effects on the disease due to activating certain factors such as hypoxia-inducible factor-1α (HIF-1α) ^[31][47]. In COVID-19, HIF-1α overexpression can result in a cytokine storm by activating and stabilizing immune cells, with a subsequent release of inflammatory cytokines via vascular leakage and disruption of the alveolar–interstitial complex barrier ^[32][33][48,49].

Interestingly, there is increased evidence of the genetic role reporting the effect of common variants on the risk and COVID-19 severity (Table 1). Some of these variants affect the genes involved in innate immunity and inflammation through several pathways. This gene polymorphism has a different geographic distribution that could influence the impact of the infection, hence the different results that are reported by studies conducted in different countries ^[29][34][50,51].

The common variants of the two proteins most involved in the infection by SARS-CoV-2, namely ACE2 and Tmprss2, have different effects upon the infectiously and severity of COVID-19. Moreover, the factors that modulates these genes such as OM-85, a standardized lysate of bacteria, can be potential treatments ^[30][35][36][52,53,54] (Table 1).

The current literature lacks solid evidence considering the molecular mechanisms underlying the interactions between COVID-19 and coinfections. To date, the proposed mechanisms for microbial infections in patients with SARS-CoV-2 likely underpin superinfections rather than explaining the increased risk of coinfections.

One of the most widely accepted mechanisms for bacterial superinfection in SARS-CoV-2 relies on experimental investigations assessing the interactions between influenza virus and coinfections with other pathogens. The initial reports demonstrated significant synergistic interactions between influenza virus and Streptococcus pneumoniae, which results in a higher risk of bacterial pneumonia and considerable mortality and morbidity ^[37][87]. These interactions come predominantly from influenza virus-induced disruption of the respiratory epithelium and the overexpression of neuraminidase activity ^[38][88], leading to higher bacterial adherence coupled with the impaired clearance of Streptococcus pneumoniae due to the excessive expression of T-cell-mediated interferon-gamma ^[39][89]. These interactions favor bacterial adhesion and invasion into the respiratory epithelium and secondary bacterial pneumonia. Previous experimental evidence noted that nonlethal pneumococcal exposure can potentiate influenza infection and lead to death in mice ^[40][90]. Human studies have supported such evidence and reported a significant increase in the risk of death amongst patients with influenza infection and concurrent Streptococcus pneumoniae ^[37][87].

However, in the setting of SARS-CoV-2 infection, the mechanisms underlying virus-induced epithelial damage do not fully explain the increased risk of coinfection in patients with SARS-CoV-2. Previous authors hypothesized that SARS-CoV-2 plays a role in disturbing immunity and interferon counteraction towards bacterial colonization and proliferation; such a disruption is believed to stem from the hyperinflammatory status induced by SARS-CoV-2 infection and the overexpression of the NSP1 and ORF6 proteins. Besides, SARS-CoV-2-inducted airway dysfunction may further potentiate bacterial coinfection through the disruption of innate immunity ^[41][91]. The role of SARS-CoV-2 may also extend to genetic signaling within monocytes, which is attributed to similar actions of previous human coronaviruses. It was found that SARS-CoV dysregulates the expression of immune function-related genes in monocytes, particularly genes that stimulate interferon α/β and cathepsin/proteasome activities. Besides, it differentially regulates the genes responsible for Toll-like receptor (TLR) and other inflammatory mediator signaling, which establishes a suitable proinflammatory environment for bacterial coinfection ^[42][92]. Additional proposed mechanisms for bacterial coinfection in patients with SARS-CoV-2 include the distribution of the gut–lung axis by the virus and NL63-mediated enhanced adherence to virus-infected cell lines ^[43][44][93,94].

While the abovementioned mechanisms were postulated based on evidence regarding the interactions between bacterial coinfection and influenza or SARS-CoV viruses, SARS-CoV-2 appears to have distinct molecular mechanisms through its associated immunosuppression. As previously mentioned, the virulence mechanism of SARS-CoV-2 is mediated by binding to the ACE2 receptor expressed on the platelets, leading to a prothrombotic cascade of platelet activation, cellular aggregation, overexpression of the P-selectin and integrin, activation of GP11b/111a, and platelet spreading ^[42][92]. Other potential mechanisms are for platelet activation in patients with SARS-CoV-2 induction of platelet LR7 during the viremic phase ^[45][95]. Regardless of the underlying mechanism, platelet activation is likely to induce an immunosuppression status during the late stage of COVID-19 through overexpression of P-selectin glycoprotein ligand-1 (PSGL-1); microvascular occlusion through cellular aggregates; and excessive release of proinflammatory chemokines, cytokines, and IL-6 ^[46][20]. Besides, platelet-mediated activation of neutrophil extracellular traps (NETs) can exacerbate the risk of bacterial superinfection through their cytotoxic effects on the respiratory epithelium ^[47][96].

Lastly, the extensive use of antibiotics during the early waves of the pandemic might have particularly contributed to the development of the increased risk of bacterial superinfection in patients with SARS-CoV-2 and the development of resistant strains.

The assessment of the risk of coinfection and superinfection in SARS-CoV-2 patients should entail their impact on the outcomes of hospitalized patients, which would reflect the urge for investigating the presence of coinfection, monitoring superinfection, and even initiating empirical antimicrobial therapy. Bacterial coinfection and superinfection may negatively affect the outcomes of COVID-19 patients due to the expected lethal synergism previously observed with influenza virus ^[37][87]. Besides, bacterial superinfection may exaggerate the hyperinflammatory status, leading to a cytokine storm ^[41][91]. Two previous reports found that patients with bacterial coinfections were associated with in-hospital mortality. Likewise, amongst 289 hospitalized patients with COVID-19, the rate of bacterial coinfection was 8.7%, and they were found to have a higher risk of mortality, need for mechanical ventilation, or ICU admission. In Musuuza et al.’s meta-analysis, the risk of death was significantly higher amongst hospitalized COVID-19 patients than with patients without coinfection or superinfection (odds ratio (OR) = 3.31, p < 0.001). Notably, patients with superinfection had a higher incidence of mechanical ventilation than patients with coinfections, while patients with coinfections had longer hospital stays ^[48][26]. In a more recent review by Adalbert et al., the risk of mortality, need for mechanical ventilation, or ICU admission was notably high among COVID-19 patients with co-current Staphylococcus aureus.

In terms of viral coinfection, Guan et al. extracted the data from 12 studies that assessed the impact of influenza coinfection in patients with SARS-CoV-2. The pooled estimates found that the viral coinfection did not significantly increase the risk of in-hospital mortality, while it significantly reduced the risk of critical illness ^[49][25]. Likewise, Cheng et al. found no association between viral coinfection and in-hospital mortality ^[50][97]. In a recently reported real-world study from the U.S., patients with influenza coinfection were found to have a marginally higher risk of hospital admissions ^[51][98]. The trend towards a lower risk of severe COVID-19 in patients with influenza coinfection can be attributed to several factors. Firstly, influenza virus was found to stimulate the development of non-neutralizing antibodies that can bind to other pathogens, including SARS-CoV-2. This explanation is supported by evidence from previous reports that demonstrated a lower risk of severe COVID-19 in patients with a history of influenza vaccination; influenza vaccination may trigger a nonspecific immune response that can act to cover SARS-CoV-2. Another explanation is the observed reduction in the hyperinflammatory status amongst SARS-CoV-2 patients with influenza coinfection, contributing to a lower risk of severe outcomes ^[48][26].

Nonetheless, the favorable outcomes of COVID-19 in patients with influenza coinfection do not seem to extend to other viral infections. A recent review by Tsheten et al. concluded that patients with dengue coinfection had a high risk of mortality and critical illness. However, the included studies from this resviearchw were mostly case series, and further high-quality evidence is still needed to characterize the association between viral coinfection and SARS-CoV-2 outcomes ^[52][99].

While it is widely postulated that parasitic coinfection may reduce the severity of SARS-CoV-2 infection and has an inverse correlation with COVID-19-related adverse outcomes, only a few studies have investigated the impact of parasitic coinfection on the outcomes of COVID-19 patients. In a recent cohort study on 751 patients with SARS-CoV-2 from Ethiopia, patients with parasitic coinfection had a significantly lower risk of mortality than patients without the coinfection. Besides, COVID-19 patients with Malaria coinfection demonstrated good prognosis when compared with patients without malaria coinfection ^[53][100]. The authors postulated that this negative correlation is attributed to the lower risk of noncommunicable diseases in patients with parasitic coinfection and the effect of parasitic infection in levitating hyperinflammation ^[54][83].