Review Article

COVID-19 Cytokine Storm, Co-Infections, and Secondary Infections: Recent Information and Clinical Implications

Ahmad Shahzaib1*, Tabish Raza2 and Aisha Areej2

1Department of Physiology, University of Veterinary and Animal Sciences, Lahore, 54000, Pakistan; 2Department of Physiology, Faculty of Life Sciences, Government College University, Faisalabad, Pakistan.

Received | January 22, 2023; Accepted | March 24, 2023; Published | May 19, 2023

*Correspondence | Ahmad Shahzaib, Department of Physiology, University of Veterinary and Animal Sciences, Lahore, 54000, Pakistan; Email: [email protected]

Citation | Shahzaib. A., Raza, T., and Areej, A., 2023. COVID-19 cytokine storm, co-infections, and secondary infections: Recent information and clinical implications. Hosts and Viruses, 10: 1-13.

DOI | https://dx.doi.org/10.17582/journal.hv/2023/10.1.13

Keywords: Coronavirus, Cytokine storm, Co-infection, Secondary infection, Mucormycosis

Copyright: 2023 by the authors. Licensee ResearchersLinks Ltd, England, UK.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

Introduction

Human coronaviruses account for 10–30% of all common cold infections annually (Paules et al., 2020). Coronaviruses, which live in the upper respiratory tract, cause mild to moderate flu-like illnesses. However, more deadly and violent coronaviruses have ascended with the potential to invade the lungs and cause severe pneumonia. In Asia in 2003, severe acute respiratory syndrome coronavirus (SARS-CoV) affected over 8,000 people and induced mortality in 10% of the infected population. In 2012, the Middle East respiratory syndrome coronavirus (MERS-CoV) spread throughout the Middle East, infecting 2,468 people with a mortality rate of more than 30% (Ramaswamy et al., 2021). The emerging SARS-CoV-2 pandemic, on the other hand, has worldwide implications, affecting all countries and territories and creating a situation unlike any other in recent history.

Severe COVID-19 cases are characterized by acute respiratory distress syndrome (ARDS) and a powerful cytokines storm (CS). The virus attaches to target cells using spike protein, which is primed by transmembrane protease, serine 2 (TMPRSS2) (Torres Acosta and Singer, 2020). The co-expression of ACE2 and TMPRSS2 is necessary for virus infection to begin in respiratory track cells. After infecting the nasal mucosa and eliciting a weak innate immune response, the virus spreads to the lower respiratory tract.

Viral infections damage the pulmonary tract by impairing acquired and innate immune responses and provide an atmosphere conducive to commensal pathogens adherence, growth, and invasion. Commensal pathogens colonize mucosal cavities asymptomatically and survive indefinitely until the conditions are right for their propagation and infection. The chances of bacterial coinfection or secondary infection among patients infected with respiratory viruses vary between 11 and 35% (Klein et al., 2016). Influenza is the best illustration of viral-bacterial coinfections. MacIntyre et al. (2018) suggest that bacterial superinfections can worsen influenza infections, raising inflammatory markers and increasing the risk of death. During the 1918 influenza pandemic, bacterial co-infections accounted for most fatal cases (Morens et al., 2008). Similarly, bacterial pneumonia exacerbated the 2009 H1N1 pandemic, affecting 4-33% of hospitalized patients (Crotty et al., 2015). Respiratory fungal infections, on the other hand, are less common despite the fact that they are challenging to treat and may result in life-threatening infections. Opportunistic pathogens such as Aspergillus, Candida, Cryptococcus, and Pneumocystis can cause clinical severe illnesses in patients with compromised immune systems (Li et al., 2019).

Coinfections are not uncommon in COVID-19. In a meta-analysis of COVID-19 trials, Langford et al. (2020) discovered bacterial co-infection in 3.5% of the patients and secondary bacterial infection in 14.3%. Similarly, Lai et al. (2020) reviewed available literature on COVID-19 and secondary infections. The authors observed that COVID-19-associated co- and secondary infection prevalence ranged from 0.6% to 45.0% (Lai et al., 2020). Secondary infections are particularly more common in hospitalized patients. Chong et al. (2021) reported that the prevalence of fungal infections (6.3%) is lower than bacterial infections (16%) in hospitalized COVID-19 patients. However, the second wave of COVID-19 delta variant in the Indian subcontinent has seen the high prevalence of secondary infection with mucormycosis. The fungal infection of the sinuses in patients recently treated for covid-19 is challenging to treat and mostly fatal (Dyer, 2021).

The immunodynamics of COVID-19 superinfections are poorly understood, resulting in a significant research gap. Furthermore, there is a scarcity of information on fungal superinfections, especially mucormycosis. This paper aims to review immune-inflammatory processes in COVID-19 patients who are co-infected with bacterial and fungal pathogens. The paper will also compare the disease complications caused by the bacterial and fungal pathogens identified.

COVID-19 infection

SARS-CoV-2 is an enveloped RNA beta-coronavirus that originated in Wuhan, China, in December 2019 and initiated the global COVID-19 pandemic. The exponential dissemination of SARS-CoV-2 has negatively affected the healthcare sector and undermined the global financial system. The virus is highly contagious with an R0 of 3, meaning that each case infects three other people on average. This starts a chain reaction with an infection doubling period of one week or less, resulting in communities of 60–80% infection rates if left unchecked. According to the World Health Organization, 14% of infected cases are severe that require hospitalization, 5% require intensive care admission and ventilation, and about 4% of the infected die (Organization, 2020). COVID-19 overtook tuberculosis as the leading cause of global mortality due to a single infectious pathogen in 2020 (Chakaya et al., 2021).

Acute respiratory distress syndrome

SARS-CoV-2 not only triggers antiviral immune responses but can also induce unconstrained systemic hyperinflammation in critically ill patients, as evidenced by increased pro-inflammatory cytokine release. COVID-19 phasic progress begins with typified respiratory symptoms and fever that may evolve into critical complications such as hyperinflammation, ARDS, coagulopathy, and multi-organ failure. ARDS and cytokine storm (CS) are the hallmarks of critical COVID-19. According to preliminary estimates, CS promotes uncontrolled inflammation, which leads to ARDS and accounts for most COVID-19 fatalities (Jiang et al., 2020). Yang et al. (2020) reported that up to 67% of critically ill COVID-19 patients suffered ARDS and organ failure. A more recent retrospective case study suggests that the incidence of ARDS in hospitalized patients was 32.5% and up to 89.9% in critical cases (Argenziano et al., 2020).

Hypercytokinemia and excessive inflammatory response leads to ARDS, inducing broad endothelial-barrier breakdown and acute lung injury. SARS-CoV-2 infects the pulmonary mucosa and activates local and peripheral immunocytes. In a perfect physiological scenario, the immune response would be proportionate to defend against infection and maintain host survival. Activation of immunocytes and production of cytokines is a natural phenomenon that occurs as part of the host’s innate and adaptive immune systems physiological response to infections. Inflammatory cytokines cause fever, cell death, and vascular damage that may lead to widespread collateral tissue damage and remote organ injury. Thus, beyond infection control, elevated levels of inflammatory cytokines promote immune-mediated tissue damage and worsen the disease state on the magnitude and kinetics of CS. After an acute infection, a CS develops locally and spreads through blood circulation (Fara et al., 2020), inducing systemic inflammation and fever. Unorganized or partly neutralizing antibodies and responses from CD4+ and CD8+ T cells have been linked to COVID-19 ARDS.

Mangalmurti and Hunter (2020) elaborate dynamics of CS, suggesting super-replicative microorganisms and co-infected bacterially derived superantigens as potential stimulants for sustained elevated cytokines production. Increased levels of IFN-γ correlate with high viral load. IFN-γ and TNF-α, in combination with IL-6, are considered strong predictors of severe COVID-19 illness and ICU admission (Zheng et al., 2020). The origin of IFN-γ has been a point of contention, but it is generally agreed that IFN-γ is produced by CD4 TH cells, which facilitates CD8 T cell differentiation and triggers their cytotoxic abilities. TNF-α induces hyaluronan-synthase-2 in fibroblasts, EpCAM+, and CD31+ lung alveolar tissue of COVID-19 patients and leads to ARDS (Shi et al., 2020). In the case of CS, this may be considered a secondary side-effect of the pro-inflammatory cascade, which manifests crosstalk with the affected tissue to self-sustain amplify, resulting in CS enhancement at systemic level. Therefore, plasma concentrations of IL-1, IL-7, IL-8, IL-9, IFN-γ, and TNF-α are reported high in COVID-19 patients suffering from multiple bilateral lobular pneumonia (Huang et al., 2020a). These cytokines are released from damaged alveolar tissue and are early immune drivers in ARDS patients of COVID-19.

SARS-CoV-2 immune response and cytokine storm

SARS-CoV-2 enters through the nasal cavity and aspirates into the lungs, where it begins rapid replication and is met with a robust innate immune response including immunocytes infiltration and cytokines production (Cyprian et al., 2021b). The overproduction of cytokines is caused by the activation of the innate immune system via pattern recognition receptors (PRRs) and toll-like receptors (TLR-4), which recognize pathogen-associated molecular patterns (PAMPs) on infected epithelial and immune cells (Fung and Liu, 2019). Molecular interactions between PAMP and PRR induce phagocytosis and activate the intracellular signaling cascade, which enhances the production of cytokines and inhibits the propagation of the virus (Fung and Liu, 2019). Cytokines promote innate immune cell recruitment, including natural killer (NK) cells, dendritic cells (DC), polymorphonuclear cells, and monocytes, which further secrete chemokines (IP, MCP-1, and MIG) and activate more leukocytes in a positive feedback loop (Gustafsson et al., 2008). Immunocytes are drawn to the site of infection, where they perform several antimicrobial functions and produce IL-1, IL-6, IL-12, and TNF in response to PAMPs and damage-associated molecular patterns (DAMPs). Although both innate and adaptive immune responses contribute to CS. An innate immune response dominated by neutrophils and monocytes to a bystander bacterial coinfection is sufficient to induce a CS that eschews the classic immune response kinetics (Shambat et al., 2020). Activation of PAMPs and DAMPs promotes phagocytosis and the production of pro-inflammatory cytokines, which impede viral multiplication and activate lymphocytes. Other innate immune cells, such as NK cells, DC, and polymorphonuclear leukocytes, are recruited by inflammatory cytokines to release a variety of chemokines, including MIG, MCP-1, and IP-10 (Coveney et al., 2020). The innate immune responses that contribute to CS are previously reviewed and briefly explained (Coveney et al., 2020; Rodrigues et al., 2020). Commencing with early COVID-19 interaction with ACE2, the machinery for pro-inflammatory cytokines production starts, including RNA synthesis, nuclear translocation, and transcription for pro-inflammatory cytokines (Coveney et al., 2020; Rodrigues et al., 2020).

Although the innate immune system is enough to develop an effective CS, the activation of T cells to produce large amounts of effector cytokines (IL-2, IL-6, IL-10, IFN, and TNF) is also essential in the development of CS. T cells specific for SARS-CoV-2 appear relatively early in COVID-19 patients and continue to grow over time (Weiskopf et al., 2020). SARS-CoV-2 spike protein elicit the strongest T cell responses, producing T effector and T helper 1 (TH1), TH2, and TH17 cytokines (Weiskopf et al., 2020). Huang et al. (2020) reported lymphopenia and CS in critically ill COVID-19 ARDS patients, although T-cell counts gradually recovered in survivors. In response to viral infection, the temporary rise in CD4+, CD8+, CD38+, and HLA-DR+ T cells is reported in non-severe, recovered COVID-19 patients after resolution of clinical symptoms (Thevarajan et al., 2020; Xu et al., 2020). Stimulating PBMCs from COVID-19 ARDS patients with SARS-CoV-2 MP and S antigens results in the production of IFN-γ, TNF-α, IL-2, IL-5, IL-13, IL-10, IL-9, IL-17A, IL-17F and IL-22 (Weiskopf et al., 2020). Weiskopf et al. (2020) observed that SARS-CoV-2 S antigen stimulation elicited considerable cytokines production specifically from Th1 (IFN-γ, TNF-α and IL-2), Th2 (IL-5, IL-13, IL-9 and IL-10), and Th17 (IL-17A, IL-17F and IL-22). Luo et al. (2021) observed an increase in IL-6, IL-2, IL-10, and IL-17 cytokines and exhausted effector T cells in the lungs and peripheral blood.

After complete remission of symptoms, activated T and B cells and their products (antibodies and cytokines) remain in the blood for at least seven days, implying that substantial antiviral adaptive immune responses are essential (Thevarajan et al., 2020). T and B cells play a role in the antiviral adaptive immune response that is essential for at least partial protection against COVID-19 and contribute to the innate immune responses that occur during CS.

IL-6 and TNF-α activate B cell-mediated immune response, including antibody production. Antibodies are directed toward viral surface proteins, primarily the S glycoprotein and nucleocapsid protein, neutralizing infection of cells and tissues expressing angiotensin-converting enzyme 2 (ACE2) (Tai et al., 2020). The primary function of neutralizing antibodies is to bind to antigenic proteins and interact with Fc γ-receptors to modulate subsequent immune responses. Recent reports of primary humoral immunodeficiencies in COVID-19 suggest that antibodies do not play a significant role in the SARS-CoV-2 immune response (Quinti et al., 2020; Soresina et al., 2020). However, one observation that perplexes scientists is the correlation between ARDS symptoms and IgA, IgM, and IgG concentrations, which appear to be higher in patients with poor clinical outcomes (Okba et al., 2020). Changes in circulating B cell subpopulations, including an increase in plasma blasts and a relative decrease in memory B cells, were also observed to correlate with the severity of inflammation in COVID-19 patients (De Biasi et al., 2020). Woodruff et al. (2020) observed that extrafollicular B cell responses in COVID-19 were associated with IL-6, CXCL10, and CRP concentrations and morbidity. The precise role of IL-6 in the development of ARDS in COVID-19 is unspecified. Perhaps, it is suggested that IL-6 is involved in the activation, differentiation, and survival of both B and T cells and the production of cytokines and immunoglobulins from these cells. Furthermore, elevated IL-6 secretions trigger autoimmunity, chronic inflammation, and autoantibody hypergammaglobulinemia (Vatansever and Becer, 2020).

However, in early clinical trials, overexpression of IL-6 did not give a useful clinical indication for anti-IL-6 COVID-19 therapy. The COVID-19 clinical trial (COVACTA) of Tocilizumab, an anti-IL-6 receptor antagonist medication that excluded patients with other bacterial or fungal infections, found that it had no meaningful effect on clinical status or mortality (Rosas et al., 2021). Although, in follow-up trials of hospitalized patients (Recovery) and ICU patients (REMAP-CAP), Tocilizumab improved survival and other health outcomes (Anonymous, 2021a; b). Another potential candidate for COVID-19 treatment is an anti-human IL-1R7 antibody that inhibits IL-18-mediated inflammatory signaling (suppressing IFNγ and IL-6 production and NFκB activation) (Li et al., 2021). IL-18 is a key cytokine in macrophage activation syndrome. Elevated blood concentrations of IL-18 correlate with other inflammatory markers and represent the severity of COVID-19. For these reasons, it’s worth noting that many of the COVID-19-specific biomarkers have already been linked to other infections, including bacteria, yeast, other viruses, or even allergies (Seo and Webster, 2002; Rose-John et al., 2017). To filter out specific cytokine release patterns, it is crucial to consider bacterial sepsis, viral coinfections, and allergies.

SARS-CoV-2 co-infections and secondary infections

Bacterial, fungal, and viral co-infections and secondary infections have been observed in COVID-19. Several systematic reviews and meta-analyses have been conducted to determine the prevalence rate of these infections. The outcomes of these reviews are summarized below to show the percentages of co-infections, secondary infections, antibiotic usage, and commonly discovered pathogens. The most reported bacterial and fungal pathogens in COVID-19 patients are Staphylococcus aureus, Pseudomonas, Acinetobacter, Klebsiella, Aspergillus, and Candida spp. (Musuuza et al., 2021; Westblade et al., 2021). Two reviews were also conducted to observe HIV and HBV co-infections and disease severity in COVID-19 patients (Ssentongo et al., 2021; Zhu and Peltekian, 2021). Despite the low occurrence of bacterial co-infections, patients were nonetheless given empirical antibiotic therapy in most of the studies. For example, Musuuza et al. (2021) reviewed 118 COVID-19 studies reporting 19% (14-25%) co-infection and 24% (19-30%) secondary infection. Antibiotic use was recorded in 70% (83/118) of these studies, with 98% (81/83) reporting antibiotic administration. In a review of 49 observational and case series studies, Chong et al. (2021) report 60-100% antibiotic use despite low secondary bacterial and fungal infection rates of 16% and 6.3%, respectively.

 

Table 1: Summary of published meta-analysis and systemic reviews describing co-infections and secondary infections.

Reference	Co-infection	Secondary infection	Study design	Common pathogens	Antibiotic usage*
Rawson et al. (2020)	5.6%	13.7%	Cohort: 1/9 Case series: 8/9	Acinetobacter baumannii, Klebsiella pneumoniae, Aspergillus, and Candida spp.	72%
Langford et al. (2020)	3.5% (0.4-6.7%)	14.3% (9.6-18.9%)	Cohort: 24/24	Mycoplasma spp., Haemophilus influenzae, and P. aeruginosa	71.8%
Lansbury et al. (2020)	7% (3-12%)		Trial: 1/30 Cohort: 7/30 Case series: 22/30	Mycoplasma pneumonia, P. aeruginosa, and H. influenzae	>90%
Chong et al. (2021)		Bacteria: 16% (4.8–42.8%) Fungi: 6.3% (0.9–33.3%)	Observational: 28/49, Case series: 21/49	P. aeruginosa, Staphylococcus aureus, K. pneumoniae, Aspergillus spp.,	60-100%
Westblade et al. (2021)	2.88%	0.07%	Cohort: 8/10 Case series: 2/10	S. aureus, Streptococcus pneumoniae Enterococcis spp., and P. aeruginosa	35-100%
Ssentongo et al. (2021)	1.22% (0.26-4.17%)		Case series: 22/22	Human immunodeficiency virus	NR
Zhu et al. (2021)	7.3%		Cohort: 6/6	Hepatitis B virus	NR
Musuuza et al. (2021)	19% (14-25%)	24% (19-30%)	Trial: 1/118 Case control: 2/118 Cohort: 71/118 Case series: 44/118	S. aureus (7.7/2.7)$, Acinetobacter spp. (4.1/22.3), Influenza A (22.3/0), Candida spp. (1/18.8), and Aspergillus (6.7/13.5)	98%

 

*NA antibiotic usage not reported in the study. $Percentage of co-infection/secondary infections combined.

 

Bacterial infections

Bacterial co-infections aggravate viral respiratory infections and are common causes of immune dysfunction and mortality. Respiratory viral infections damage the pulmonary mucosa, allowing commensal pathogens to invade and multiply, resulting in secondary infection. The treatment concept of COVID-19 CS has been met with skepticism because the premise of suppressing the immune system in an infectious disease goes against basic medicine practicing principles. Particularly when the source of the CS is a coinfection or secondary bacterial infection, which can result in a poor prognosis. While hypercytokinemia may be needed for antiviral clearance in COVID-19 patients, literature shows that IL-6 levels are also significantly elevated in ARDS and bacterial sepsis alone (Leisman et al., 2020). Leisman et al. (2020) reported that, on average IL-6 concentrations were approximately 100 times higher in patients with cytokine release syndrome, 27 times higher in patients with sepsis, and 12 times higher in patients with ARDS unrelated to COVID-19. This suggests that dysregulated cytokine response can aid in the subsequent development of bacterial infections that further overamplify hypercytokinemia.

Because there is a paucity of literature on COVID-19 patients in terms of well-defined pathophysiology of bacterial infections, this section will review information from previous viral-bacterial co-infections. Following a viral infection, physical and immunological factors might weaken the respiratory tract resistance to bacterial pathogens. Poor mucociliary clearance during a viral infection allows bacteria to attach to mucins more efficiently and enhances bacterial colonization (Hendaus and Jomha, 2020). In order to aid bacterial adhesion, viral infections can increase the production of binding proteins while decreasing the production of antimicrobial peptides in alveolar cells. (Avadhanula et al., 2006). Bacterial adhesion, growth, and microbial dysbiosis, are facilitated by viral-induced dysregulation of proinflammatory cytokines (Cyprian et al., 2021b). Robinson et al. (2015) observed that antimicrobial peptides, including CAMP, lipocalin2, REG3B, S100A8, and S100A9, were downregulated during influenza infection, promoting bacterial pneumonia. Similarly, infections with the respiratory syncytial virus (RSV) and adenovirus (ADV) stimulate the release of the surface glycoprotein adhesion molecule-1 (ICAM-1), which promotes H. influenzae infection. RSV infections also increase S. pneumoniae adherence to nasopharyngeal and pneumocyte type II cells, resulting in bacterial overgrowth and secondary infection (Nguyen et al., 2015).

COVID-19 patients hospitalized for an extended period are more likely to develop secondary bacterial infections, with the most common pathogens being S. aureus, Pseudomonas aeruginosa, and Klebsiella pneumonia (Westblade et al., 2021). Falcone et al. (2020) reported 109 episodes of superinfections in 69 (21.9%) patients over 19 days (range 11–29.75) of hospitalization. Enterobacterales (44.9%), polymicrobial (18.3%), Gram-negative bacilli (15.6%), Gram-positive bacteria (15.6%), and fungi (5.5%) were the most common pathogen for superinfection. Garcia-Vidal et al. (2021) found that compared with the nosocomial superinfections, community-acquired co-infections in COVID-19 patients were uncommon and were primarily caused by S. pneumoniae and S. aureus. Hospital-acquired bacterial superinfections, mostly caused by P. aeruginosa and Escherichia coli, were more common and lethal with worse outcomes (Garcia-Vidal et al., 2021).

Antibiotic therapy is often used in COVID-19 patients, regardless of bacterial secondary or co-infections. The World Health Organization (WHO) does not advise using antibiotics in suspected, mild, or moderate COVID-19 infections, particularly broad-spectrum antibiotics on the watch and reserve list. Chedid et al. (2021) reviewed COVID-19 clinical studies revealing that the average rate of antibiotic treatment in disease management is 74.0%, while only 17.6% of patients have secondary infections. Similarly, Garcia-Vidal et al. (2021) found that only 7.2% of COVID-19 patients had co-infection, while 87.1% had at least one antibiotic treatment. The disparities between co-infected COVID-19 patients and the antibiotics treatment suggest that antibiotic prescriptions are being misused among COVID-19 patients. Another epidemic hazard hiding behind the COVID-19 pandemic is antimicrobial resistance, which has the potential to become a double-edged sword due to antibiotic overuse. Antibiotic overuse in COVID-19 patients could lead to widespread antimicrobial resistance, making resistant infections more likely to arise and spread. Table 1 reviews antibiotic usage in COVID-19 papers, as reviewed in clinical trials, case series, and cohort studies.

Fungal infections

Although we know that fungal superinfections increase disease severity and are associated with high mortality, whether COVID-19 increases the likelihood of secondary fungal infections is still up for debate. Aspergillus and Candida species are the most frequent invasive fungal pathogens linked to COVID-19 infection (Chiurlo et al., 2021). The other less frequently reported fungal superinfections in COVID-19 patients are Cryptococcus spp., Histoplasma spp., Mucormycetes, and Pneumocystis jirovecii (Song et al., 2020). Aspergillus infection has been linked to a high morbidity and mortality rate in COVID-19 patients, often complicating critically ill patients. Pulmonary Aspergillosis is a difficult infection to diagnose and treat, and it can have catastrophic consequences in patients undergoing tissue transplantation, neutropenia, immunodeficiencies, and immunosuppressive therapy (Baddley, 2011). Chiurlo et al. (2021) reviewed the incidence of invasive Aspergillosis (1.7% to 34.4%) in COVID-19 patients and found that the co-infected patients had a significant mortality rate. According to some studies, there is an overall mortality rate of 48-55% due to Aspergillosis in COVID-19 patients (Chong and Neu, 2021; Mitaka et al., 2021). Zhu et al. (2020) described a large case series of 243 COVID-19 patients, 23.3% of whom were co-infected with Aspergillosis, depicting mild to acute symptoms. Pathogenesis of Aspergillosis and COVID-19 coinfection may involve IL-10 and IL-6 cytokines (Lai and Yu, 2021). Clemons et al. (2000) observed that IL-10 has deleterious effects during systemic Aspergillosis, resulting in increased Th2, decreased Th1 responses, and down-regulation of macrophage activity of which increase susceptibility to a fungal pathogen.

Candida albicans, a common human intestinal flora, a proclivity for infecting severely ill patients with compromised immune systems, resulting in high mortality. Compared to the controls, SARS-CoV-2-infected patients may be more susceptible to invasive candidiasis (Mastrangelo et al., 2020). Several studies revealed that 0.03 to 10% of hospitalized COVID-19 patients had Candida coinfection (Table 1) (Chiurlo et al., 2021). Falcone et al. (2021) observed that candidiasis develops late during the disease course (one-week post-hospitalization) and is associated with a prolonged hospital stay and a significantly high mortality rate (>50%). Lamers et al. (2020) observed that SARS-CoV-2 damages enterocytes and disrupts the integrity of the intestinal barrier, allowing commensal microorganisms to invade and coinfect. Therefore, COVID-19 patients are reported to have a higher prevalence of systemic translocation of gut pathogens, and the fungal microbiome is skewed toward an increased presence of Candida spp. (Zuo et al., 2020; Cyprian et al., 2021a).

Mucormycosis is an uncommon fungal infection caused by a genus of myocytes called Rhizopus. The most recent COVID-19 outbreak in India was accompanied by a second catastrophe in the shape of chronic mucormycosis, which was extremely difficult to treat and had a high mortality rate (Sahoo et al., 2021). Mucormycosis, also known as black fungus, infected more than 30,000 patients in India recovering from severe COVID-19 infection (Vinay et al., 2021). Fekkar et al. (2021) observed that 4.8% of COVID-19 patients admitted to ICUs were diagnosed with invasive pulmonary mucormycosis. Furthermore, according to a nationwide study in France, seventeen COVID-19 patients were co-infected with mucormycosis and suffered from diabetes, hematological malignancies, and organ transplantation (Danion et al., 2021). Mucormycosis has long been linked to poorly managed diabetes and other immunosuppressive disorders or immunosuppressive therapy.

The possible causes of the co-occurrence of SARS-CoV-2 and fungal infections are currently being investigated. Perhaps, many risk factors for fungal infections, such as diabetes, immunosuppression, and old age, are substantially represented in the SARS-CoV-2 infected population (Richardson et al., 2020). Furthermore, excessive use of immunosuppressants, such as IL-6 receptor antagonists, steroids, or antibiotics, might also promote the growth of opportunist pathogens and exacerbate disease outcomes.

Conclusions and Recommendations

In COVID-19 patients, secondary infections and coinfections are prevalent. COVID-19 disrupts the protective lining of the respiratory and digestive tracts and dysregulates the host immunological response, making patients vulnerable to secondary infections. The consequences of coinfections are exacerbated because of underlying disorders, healthcare-related risk factors, and COVID-19-related therapeutics. Excessive antibiotics, steroids, and immunosuppressive drug administration have become a pandemic within a pandemic. Unsupervised medication lurked potentially hazardous infections with opportunistic pathogens. Although more information on the prevalence, etiology, and pathogenesis of bacterial and fungal coinfections in COVID-19 is becoming available, clinical trials and prospective studies are still needed to improve the treatment regime of complex infections.

Author’s Contribution

All authors contributed equally.

Conflict of interest

The authors have declared no conflict of interest.

References

Anonymous, 2021a. Interleukin-6 receptor antagonists in critically Ill patients with Covid-19. N. Engl. J. Med., 384: 1491-1502. https://doi.org/10.1056/NEJMoa2100433

Anonymous, 2021b. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): A randomised, controlled, open-label, platform trial. Lancet, 397: 1637-1645.

Argenziano, M.G., Bruce, S.L., Slater, C.L., Tiao, J.R., Baldwin, M.R., Barr, R.G., Chang, B.P., Chau, K.H., Choi, J.J., Gavin, N., Goyal, P., Mills, A.M., Patel, A.A., Romney, M.S., Safford, M.M., Schluger, N.W., Sengupta, S., Sobieszczyk, M.E., Zucker, J.E., Asadourian, P.A., Bell, F.M., Boyd, R., Cohen, M.F., Colquhoun, M.I., Colville, L.A., De Jonge, J.H., Dershowitz, L.B., Dey, S.A., Eiseman, K.A., Girvin, Z.P., Goni, D.T., Harb, A.A., Herzik, N., Householder, S., Karaaslan, L.E., Lee, H., Lieberman, E., Ling, A., Lu, R., Shou, A.Y., Sisti, A.C., Snow, Z.E., Sperring, C.P., Xiong, Y., Zhou, H.W., Natarajan, K., Hripcsak, G., and Chen, R., 2020. Characterization and clinical course of 1000 patients with coronavirus disease 2019 in New York: Retrospective case series. Br. Med. J., 369: m1996. https://doi.org/10.1136/bmj.m1996

Avadhanula, V., Rodriguez, C.A., Devincenzo, J.P., Wang, Y., Webby, R.J., Ulett, G.C., and Adderson, E.E., 2006. Respiratory viruses augment the adhesion of bacterial pathogens to respiratory epithelium in a viral species and cell type-dependent manner. J. Virol., 80: 1629-1636. https://doi.org/10.1128/JVI.80.4.1629-1636.2006

Baddley, J.W., 2011. Clinical risk factors for invasive aspergillosis. Med. Mycol., 49: S7-S12. https://doi.org/10.3109/13693786.2010.505204

Chakaya, J., Khan, M., Ntoumi, F., Aklillu, E., Razia, F., Mwaba, P., Kapata, N., Mfinanga, S., Hasnain, S.E., Katoto, P.D.M.C., Bulabula, A.N.H., Sam-Agudu, N.A., Nachega, J.B., Tiberi, S., Mchugh, T.D., Abubakar, I., and Zumla, A., 2021. Global tuberculosis report 2020 reflections on the global TB burden, treatment and prevention efforts. Int. J. Infect. Dis., 113(Suppl. 1) S7-S12. https://doi.org/10.1016/j.ijid.2021.02.107

Chedid, M., Waked, R., Haddad, E., Chetata, N., Saliba, G., and Choucair, J., 2021. Antibiotics in treatment of COVID-19 complications: A review of frequency, indications, and efficacy. J. Infect. Publ. Health, 14: 570-576. https://doi.org/10.1016/j.jiph.2021.02.001

Chiurlo, M., Mastrangelo, A., Ripa, M., and Scarpellini, P., 2021. Invasive fungal infections in patients with COVID-19: A review on pathogenesis, epidemiology, clinical features, treatment, and outcomes. New Microbiol., 44: 71-83.

Chong, W.H., and Neu, K.P., 2021. Incidence, diagnosis and outcomes of COVID-19-associated pulmonary aspergillosis (CAPA): A systematic review. J. Hosp. Infect., 113: 115-129. https://doi.org/10.1016/j.jhin.2021.04.012

Chong, W.H., Saha, B.K., Ananthakrishnan, R., and Chopra, A., 2021. State of the art review of secondary pulmonary infections in patients with COVID-19 pneumonia. Infection, https://doi.org/10.1007/s15010-021-01602-z

Clemons, K.V., Grunig, G., Sobel, R.A., Mirels, L.F., Rennick, D.M., and Stevens, D.A., 2000. Role of IL-10 in invasive aspergillosis: Increased resistance of IL-10 gene knockout mice to lethal systemic aspergillosis. Clin. Exp. Immunol., 122: 186-191. https://doi.org/10.1046/j.1365-2249.2000.01382.x

Coveney, C., Tellier, M., Lu, F., Maleki-Toyserkani, S., Jones, R., Bart, V.M.T., Pring, E., Alrubayyi, A., Richter, F.C., Scourfield, D.O., Rehwinkel, J., Rodrigues, P.R.S., Davies, L.C., Gea-Mallorquí, E., and Consortium, T.O.C.C.L., 2020. Innate immunology in COVID-19, a living review. Part I: Viral entry, sensing and evasion. Oxf. Open Immunol., 1. https://doi.org/10.1093/oxfimm/iqaa004

Crotty, M.P., Meyers, S., Hampton, N., Bledsoe, S., Ritchie, D.J., Buller, R.S., Storch, G.A., Micek, S.T., and Kollef, M.H., 2015. Epidemiology, co-infections, and outcomes of viral pneumonia in adults: An observational cohort study. Medicine, 94: e2332. https://doi.org/10.1097/MD.0000000000002332

Cyprian, F., Sohail, M.U., Abdelhafez, I., Salman, S., Attique, Z., Kamareddine, L., and Al-Asmakh, M., 2021. SARS-CoV-2 and immune-microbiome interactions: Lessons from respiratory viral infections. Int. J. Infect. Dis., 105: 540-550. https://doi.org/10.1016/j.ijid.2021.02.071

Danion, F., Letscher-Bru, V., Guitard, J., Sitbon, K., Dellière, S., Angoulvant, A., Desoubeaux, G., Botterel, F., Bellanger, A.P., Gargala, G., Uhel, F., Bougnoux, M.-E., Gerber, V., Michel, J., Cornu, M., Bretagne, S., Lanternier, F., and Group, T.C.M.S., 2021. High mortality of COVID-19 associated mucormycosis in France: a nationwide retrospective study. medRxiv, 2021.2007.2005.21260041. https://doi.org/10.1101/2021.07.05.21260041

De Biasi, S., Lo Tartaro, D., Meschiari, M., Gibellini, L., Bellinazzi, C., Borella, R., Fidanza, L., Mattioli, M., Paolini, A., Gozzi, L., Jaacoub, D., Faltoni, M., Volpi, S., Milić, J., Sita, M., Sarti, M., Pucillo, C., Girardis, M., Guaraldi, G., Mussini, C., and Cossarizza, A., 2020. Expansion of plasmablasts and loss of memory B cells in peripheral blood from COVID-19 patients with pneumonia. Eur. J. Immunol., 50: 1283-1294. https://doi.org/10.1002/eji.202048838

Dyer, O., 2021. Covid-19: India sees record deaths as black fungus spreads fear. Br. Med. J., 373: n1238. https://doi.org/10.1136/bmj.n1238

Falcone, M., Tiseo, G., Giordano, C., Leonildi, A., Menichini, M., Vecchione, A., Pistello, M., Guarracino, F., Ghiadoni, L., Forfori, F., Barnini, S., and Menichetti, F., 2021. Predictors of hospital-acquired bacterial and fungal superinfections in COVID-19: A prospective observational study. J. Antimicrob. Chemother., 76: 1078-1084. https://doi.org/10.1093/jac/dkaa530

Falcone, M., Tiseo, G., Giordano, C., Leonildi, A., Menichini, M., Vecchione, A., Pistello, M., Guarracino, F., Ghiadoni, L., Forfori, F., Barnini, S., Menichetti, F., and Group, T.P.C.S., 2020. Predictors of hospital-acquired bacterial and fungal superinfections in COVID-19: A prospective observational study. J. Antimicrob. Chemother., 76: 1078-1084. https://doi.org/10.1093/jac/dkaa530

Fara, A., Mitrev, Z., Rosalia, R.A., and Assas, B.M., 2020. Cytokine storm and COVID-19: A chronicle of pro-inflammatory cytokines. Open Biol., 10: 200160. https://doi.org/10.1098/rsob.200160

Fekkar, A., Lampros, A., Mayaux, J., Poignon, C., Demeret, S., Constantin, J.M., Marcelin, A.G., Monsel, A., Luyt, C.E., and Blaize, M., 2021. Occurrence of invasive pulmonary fungal infections in patients with severe COVID-19 admitted to the ICU. Am. J. Respir. Crit. Care Med., 203: 307-317. https://doi.org/10.1164/rccm.202009-3400OC

Fung, T.S., and Liu, D.X., 2019a. Human coronavirus: Host-pathogen interaction. Ann. Rev. Microbiol., 73: 529-557. https://doi.org/10.1146/annurev-micro-020518-115759

Garcia-Vidal, C., Sanjuan, G., Moreno-García, E., Puerta-Alcalde, P., Garcia-Pouton, N., Chumbita, M., Fernandez-Pittol, M., Pitart, C., Inciarte, A., Bodro, M., Morata, L., Ambrosioni, J., Grafia, I., Meira, F., Macaya, I., Cardozo, C., Casals, C., Tellez, A., Castro, P., Marco, F., García, F., Mensa, J., Martínez, J.A., Soriano, A., Rico, V., Hernández-Meneses, M., Agüero, D., Torres, B., González, A., De La Mora, L., Rojas, J., Linares, L., Fidalgo, B., Rodriguez, N., Nicolas, D., Albiach, L., Muñoz, J., Almuedo, A., Camprubí, D., Angeles Marcos, M., Camprubí, D., Cilloniz, C., Fernández, S., Nicolas, J.M., and Torres, A., 2021. Incidence of co-infections and superinfections in hospitalized patients with COVID-19: A retrospective cohort study. Clin. Microbiol. Infect., 27: 83-88. https://doi.org/10.1016/j.cmi.2020.07.041

Gustafsson, K., Ingelsten, M., Bergqvist, L., Nyström, J., Andersson, B., and Karlsson-Parra, A., 2008. Recruitment and activation of natural killer cells in vitro by a human dendritic cell vaccine. Cancer Res. 68: 5965-5971. https://doi.org/10.1158/0008-5472.CAN-07-6494

Hendaus, M.A., and Jomha, F.A., 2020. Covid-19 induced superimposed bacterial infection. J. Biomol. Struct. Dyn., 39(11): 4185-4191. https://doi.org/10.1080/07391102.2020.1772110

Huang, C., Wang, Y., Li, X., Ren, L., Zhao, J., Hu, Y., Zhang, L., Fan, G., Xu, J., Gu, X., Cheng, Z., Yu, T., Xia, J., Wei, Y., Wu, W., Xie, X., Yin, W., Li, H., Liu, M., Xiao, Y., Gao, H., Guo, L., Xie, J., Wang, G., Jiang, R., Gao, Z., Jin, Q., Wang, J., and Cao, B., 2020. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet, (London, England). 395: 497-506. https://doi.org/10.1016/S0140-6736(20)30183-5

Jiang, F., Deng, L., Zhang, L., Cai, Y., Cheung, C.W., and Xia, Z., 2020. Review of the clinical characteristics of coronavirus disease 2019 (COVID-19). J. Gen. Intern. Med., 35: 1545-1549. https://doi.org/10.1007/s11606-020-05762-w

Klein, E.Y., Monteforte, B., Gupta, A., Jiang, W., May, L., Hsieh, Y.H., and Dugas, A., 2016. The frequency of influenza and bacterial coinfection: A systematic review and meta-analysis. Influenza Other Respir. Viruses 10: 394-403. https://doi.org/10.1111/irv.12398

Lai, C.C., and Yu, W.L., 2021. COVID-19 associated with pulmonary aspergillosis: A literature review. J. Microbiol. Immunol. Infect. (Wei mian yu gan ran za zhi) 54: 46-53. https://doi.org/10.1016/j.jmii.2020.09.004

Lai, C.C., Wang, C.Y., and Hsueh, P.R.. 2020. Co-infections among patients with COVID-19: The need for combination therapy with non-anti-SARS-CoV-2 agents? J. Microbiol. Immunol. Infect., 53: 505-512. https://doi.org/10.1016/j.jmii.2020.05.013

Lamers, M.M., Beumer, J., Van Der Vaart, J., Knoops, K., Puschhof, J., Breugem, T.I., Ravelli, R.B.G., Paul Van Schayck, J., Mykytyn, A.Z., Duimel, H.Q., Van Donselaar, E., Riesebosch, S., Kuijpers, H.J.H., Schipper, D., Van De Wetering, W.J., De Graaf, M., Koopmans, M., Cuppen, E., Peters, P.J., Haagmans, B.L., and Clevers, H., 2020. SARS-CoV-2 productively infects human gut enterocytes. Science, 369: 50-54. https://doi.org/10.1126/science.abc1669

Langford, B.J., So, M., Raybardhan, S., Leung, V., Westwood, D., Macfadden, D.R., Soucy, J.R., and Daneman, N., 2020. Bacterial co-infection and secondary infection in patients with COVID-19: A living rapid review and meta-analysis. Clin. Microbiol. Infect., 26: 1622-1629. https://doi.org/10.1016/j.cmi.2020.07.016

Lansbury, L., Lim, B., Baskaran, V., and Lim, W.S., 2020. Co-infections in people with COVID-19: A systematic review and meta-analysis. J. Infect., 81: 266-275. https://doi.org/10.1016/j.jinf.2020.05.046

Leisman, D.E., Ronner, L., Pinotti, R., Taylor, M.D., Sinha, P., Calfee, C.S., Hirayama, A.V., Mastroiani, F., Turtle, C.J., Harhay, M.O., Legrand, M., and Deutschman, C.S., 2020. Cytokine elevation in severe and critical COVID-19: A rapid systematic review, meta-analysis, and comparison with other inflammatory syndromes. Lancet Respir. Med., 8: 1233-1244. https://doi.org/10.1016/S2213-2600(20)30404-5

Li, S., Jiang, L., Beckmann, K., Højen, J.F., Pessara, U., Powers, N.E., De Graaf, D.M., Azam, T., Lindenberger, J., Eisenmesser, E.Z., Fischer, S., and Dinarello, C.A., 2021. A novel anti-human IL-1R7 antibody reduces IL-18-mediated inflammatory signaling. J. Biol. Chem., 296: 100630. https://doi.org/10.1016/j.jbc.2021.100630

Li, Z., Lu, G., and Meng, G., 2019. Pathogenic fungal infection in the lung. Front. Immunol., 10: 1524-1524. https://doi.org/10.3389/fimmu.2019.01524

Luo, X.H., Zhu, Y., Mao, J., and Du, R.C., 2021. T cell immunobiology and cytokine storm of COVID-19. Scand. J. Immunol., 93: e12989. https://doi.org/10.1111/sji.12989

Macintyre, C.R., Chughtai, A.A., Barnes, M., Ridda, I., Seale, H., Toms, R., and Heywood, A., 2018. The role of pneumonia and secondary bacterial infection in fatal and serious outcomes of pandemic influenza a(H1N1)pdm09. BMC Infect. Dis., 18: 637. https://doi.org/10.1186/s12879-018-3548-0

Mangalmurti, N., and Hunter, C.A., 2020. Cytokine storms: Understanding COVID-19. Immunity, 53: 19-25. https://doi.org/10.1016/j.immuni.2020.06.017

Mastrangelo, A., Germinario, B.N., Ferrante, M., Frangi, C., Li Voti, R., Muccini, C., and Ripa, M., 2020. Candidemia in COVID-19 patients: Incidence and characteristics in a prospective cohort compared to historical non-COVID-19 controls. Clin. Infect. Dis., https://doi.org/10.1093/cid/ciaa1594

Mitaka, H., Kuno, T., Takagi, H., and Patrawalla, P., 2021. Incidence and mortality of COVID-19-associated pulmonary aspergillosis: A systematic review and meta-analysis. Mycoses, 64: 993-1001. https://doi.org/10.1111/myc.13292

Morens, D.M., Taubenberger, J.K., and Fauci, A.S., 2008. Predominant role of bacterial pneumonia as a cause of death in pandemic influenza: implications for pandemic influenza preparedness. J. Infect. Dis., 198: 962-970. https://doi.org/10.1086/591708

Musuuza, J.S., Watson, L., Parmasad, V., Putman-Buehler, N., Christensen, L., and Safdar, N., 2021. Prevalence and outcomes of co-infection and superinfection with SARS-CoV-2 and other pathogens: A systematic review and meta-analysis. PLoS One, 16: e0251170. https://doi.org/10.1371/journal.pone.0251170

Nguyen, D.T., Louwen, R., Elberse, K., Van Amerongen, G., Yüksel, S., Luijendijk, A., Osterhaus, A.D.M.E., Duprex, W.P., and De Swart, R.L., 2015. Streptococcus pneumoniae enhances human respiratory syncytial virus infection in vitro and in vivo. PLoS One, 10: e0127098-e0127098. https://doi.org/10.1371/journal.pone.0127098

Okba, N.M.A., Müller, M.A., Li, W., Wang, C., Geurtsvankessel, C.H., Corman, V.M., Lamers, M.M., Sikkema, R.S., De Bruin, E., Chandler, F.D., Yazdanpanah, Y., Le Hingrat, Q., Descamps, D., Houhou-Fidouh, N., Reusken, C., Bosch, B.J., Drosten, C., Koopmans, M.P.G., and Haagmans, B.L., 2020. Severe acute respiratory syndrome coronavirus 2-specific antibody responses in coronavirus disease patients. Emerg. Infect. Dis., 26: 1478-1488. https://doi.org/10.3201/eid2607.200841

Organization, W.H., 2020. Coronavirus disease 2019 (COVID-19): Situation report, pp. 86.

Paules, C.I., Marston, H.D., and Fauci, A.S., 2020. Coronavirus infections more than just the common cold. J. Am. Med. Assoc., 323: 707-708. https://doi.org/10.1001/jama.2020.0757

Quinti, I., Lougaris, V., Milito, C., Cinetto, F., Pecoraro, A., Mezzaroma, I., Mastroianni, C.M., Turriziani, O., Bondioni, M.P., Filippini, M., Soresina, A., Spadaro, G., Agostini, C., Carsetti, R., and Plebani, A., 2020. A possible role for B cells in COVID-19? Lesson from patients with agammaglobulinemia. J. Allergy Clin. Immunol., 146: 211-213.e214. https://doi.org/10.1016/j.jaci.2020.04.013

Ramaswamy, A., Brodsky, N.N., Sumida, T.S., Comi, M., Asashima, H., Hoehn, K.B., Li, N., Liu, Y., Shah, A., Ravindra, N.G., Bishai, J., Khan, A., Lau, W., Sellers, B., Bansal, N., Guerrerio, P., Unterman, A., Habet, V., Rice, A.J., Catanzaro, J., Chandnani, H., Lopez, M., Kaminski, N., Dela Cruz, C.S., Tsang, J.S., Wang, Z., Yan, X., Kleinstein, S.H., Van Dijk, D., Pierce, R.W., Hafler, D.A., and Lucas, C.L., 2021. Post-infectious inflammatory disease in MIS-C features elevated cytotoxicity signatures and autoreactivity that correlates with severity. medRxiv, 2020.2012.2001.20241364. https://doi.org/10.1101/2020.12.01.20241364

Rawson, T.M., Moore, L.S.P., Zhu, N., Ranganathan, N., Skolimowska, K., Gilchrist, M., Satta, G., Cooke, G., and Holmes, A., 2020. Bacterial and fungal coinfection in individuals with coronavirus: A rapid review to support COVID-19 antimicrobial prescribing. Clin. Infect. Dis., 71: 2459-2468. https://doi.org/10.1093/cid/ciaa530

Richardson, S., Hirsch, J.S., Narasimhan, M., Crawford, J.M., Mcginn, T., Davidson, K.W., Barnaby, D.P., Becker, L.B., Chelico, J.D., Cohen, S.L., Cookingham, J., Coppa, K., Diefenbach, M.A., Dominello, A.J., Duer-Hefele, J., Falzon, L., Gitlin, J., Hajizadeh, N., Harvin, T.G., Hirschwerk, D.A., Kim, E.J., Kozel, Z.M., Marrast, L.M., Mogavero, J.N., Osorio, G.A., Qiu, M., and Zanos, T.P., 2020. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York city area. J. Am. Med. Assoc., 323: 2052-2059. https://doi.org/10.1001/jama.2020.6775

Robinson, K.M., Kolls, J.K., and Alcorn, J.F., 2015. The immunology of influenza virus-associated bacterial pneumonia. Curr. Opin. Immunol., 34: 59-67. https://doi.org/10.1016/j.coi.2015.02.002

Rodrigues, P.R.S., Alrubayyi, A., Pring, E., Bart, V.M.T., Jones, R., Coveney, C., Lu, F., Tellier, M., Maleki-Toyserkani, S., Richter, F.C., Scourfield, D.O., Gea-Mallorquí, E., Davies, L.C., and Consortium, T.O.C.C.L., 2020. Innate immunology in COVID-19 a living review. Part II: dysregulated inflammation drives immunopathology. Oxf. Open Immunol. 1. https://doi.org/10.1093/oxfimm/iqaa005

Rosas, I.O., Bräu, N., Waters, M., Go, R.C., Hunter, B.D., Bhagani, S., Skiest, D., Aziz, M.S., Cooper, N., Douglas, I.S., Savic, S., Youngstein, T., Del Sorbo, L., Cubillo Gracian, A., De La Zerda, D.J., Ustianowski, A., Bao, M., Dimonaco, S., Graham, E., Matharu, B., Spotswood, H., Tsai, L., and Malhotra, A., 2021. Tocilizumab in hospitalized patients with severe Covid-19 pneumonia. New Eng. J. Med., 384: 1503-1516. https://doi.org/10.1056/NEJMoa2028700

Rose-John, S., Winthrop, K., and Calabrese, L., 2017. The role of IL-6 in host defence against infections: Immunobiology and clinical implications. Nat. Rev. Rheumatol., 13: 399-409. https://doi.org/10.1038/nrrheum.2017.83

Sahoo, J.P., Panda, B., Mishra, A.P., and Samal, K.C., 2021. The unseen fungal infections. An extra thrust aggravating COVID second wave in India. Biotech. Res. Today, 3: 354-356.

Seo, S.H., and Webster, R.G., 2002. Tumor necrosis factor alpha exerts powerful anti-influenza virus effects in lung epithelial cells. J. Virol., 76: 1071-1076. https://doi.org/10.1128/JVI.76.3.1071-1076.2002

Shambat, S.M., Gómez-Mejia, A., Schweizer, T.A., Huemer, M., Chang, C.-C., Acevedo, C., Pijuan, J.B., Vulin, C., Miroshnikova, N., Hofmänner, D.A., Wendel Garcia, P.D., Hilty, M.P., Karl, P.B., Schüpbach, R.A., Brugger, S.D., and Zinkernagel, A.S., 2020. Neutrophil and monocyte dysfunctional effector response towards bacterial challenge in critically-ill COVID-19 patients. bioRxiv, 2020.2012.2001.406306. https://doi.org/10.1101/2020.12.01.406306

Shi, Y., Wang, Y., Shao, C., Huang, J., Gan, J., Huang, X., Bucci, E., Piacentini, M., Ippolito, G., and Melino, G., 2020. COVID-19 infection: The perspectives on immune responses. Cell Death Differ., 27: 1451-1454. https://doi.org/10.1038/s41418-020-0530-3

Song, G., Liang, G., and Liu, W., 2020. Fungal co-infections associated with global COVID-19 pandemic: A clinical and diagnostic perspective from China. Mycopathologia, 185: 599-606. https://doi.org/10.1007/s11046-020-00462-9

Soresina, A., Moratto, D., Chiarini, M., Paolillo, C., Baresi, G., Focà, E., Bezzi, M., Baronio, B., Giacomelli, M., and Badolato, R., 2020. Two X-linked agammaglobulinemia patients develop pneumonia as COVID-19 manifestation but recover. Pediatr. Allergy Immunol., 31: 565-569. https://doi.org/10.1111/pai.13263

Ssentongo, P., Heilbrunn, E.S., Ssentongo, A.E., Advani, S., Chinchilli, V.M., Nunez, J.J., and Du, P., 2021. Epidemiology and outcomes of COVID-19 in HIV-infected individuals: A systematic review and meta-analysis. Sci. Rep., 11: 6283. https://doi.org/10.1038/s41598-021-85359-3

Tai, W., He, L., Zhang, X., Pu, J., Voronin, D., Jiang, S., Zhou, Y., and Du, L., 2020. Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: Implication for development of RBD protein as a viral attachment inhibitor and vaccine. Cell Mol. Immunol., 17: 613-620. https://doi.org/10.1038/s41423-020-0400-4

Thevarajan, I., Nguyen, T.H.O., Koutsakos, M., Druce, J., Caly, L., Van De Sandt, C.E., Jia, X., Nicholson, S., Catton, M., Cowie, B., Tong, S.Y.C., Lewin, S.R., and Kedzierska, K., 2020. Breadth of concomitant immune responses prior to patient recovery: A case report of non-severe COVID-19. Nat. Med., 26: 453-455. https://doi.org/10.1038/s41591-020-0819-2

Torres-Acosta, M.A., and Singer, B.D., 2020. Pathogenesis of COVID-19-induced ARDS: Implications for an aging population. Eur. Respir. J., 56: 2002049. https://doi.org/10.1183/13993003.02049-2020

Vatansever, H.S., and Becer, E., 2020. Relationship between IL-6 and COVID-19 to be considered during treatment. Future Virol., 15: 817-822. https://doi.org/10.2217/fvl-2020-0168

Vinay, K., Rudramurthy, S.M., and Dogra, S., 2021. Emergence of mucormycosis during covid-19 pandemic and dermatological manifestations. Indian Dermatol. Online J., 12: 493. https://doi.org/10.4103/idoj.idoj_406_21

Weiskopf, D., Schmitz, K.S., Raadsen, M.P., Grifoni, A., Okba, N.M.A., Endeman, H., Van Den Akker, J.P.C., Molenkamp, R., Koopmans, M.P.G., Van Gorp, E.C.M., Haagmans, B.L., De Swart, R.L., Sette, A., and De Vries, R.D., 2020. Phenotype and kinetics of SARS-CoV-2-specific T cells in COVID-19 patients with acute respiratory distress syndrome. Sci. Immunol., 5: eabd2071. https://doi.org/10.1126/sciimmunol.abd2071

Westblade, L.F., Simon, M.S., and Satlin, M.J., 2021. Bacterial coinfections in coronavirus disease 2019. Trends Microbiol., https://doi.org/10.1016/j.tim.2021.03.018

Woodruff, M.C., Ramonell, R.P., Nguyen, D.C., Cashman, K.S., Saini, A.S., Haddad, N.S., Ley, A.M., Kyu, S., Howell, J.C., Ozturk, T., Lee, S., Suryadevara, N., Case, J.B., Bugrovsky, R., Chen, W., Estrada, J., Morrison-Porter, A., Derrico, A., Anam, F.A., Sharma, M., Wu, H.M., Le, S.N., Jenks, S.A., Tipton, C.M., Staitieh, B., Daiss, J.L., Ghosn, E., Diamond, M.S., Carnahan, R.H., Crowe, J.E., Hu, W.T., Lee, F.E.-H., and Sanz, I., 2020. Extrafollicular B cell responses correlate with neutralizing antibodies and morbidity in COVID-19. Nat. Immunol., 21: 1506-1516. https://doi.org/10.1038/s41590-020-00814-z

Xu, Z., Shi, L., Wang, Y., Zhang, J., Huang, L., Zhang, C., Liu, S., Zhao, P., Liu, H., Zhu, L., Tai, Y., Bai, C., Gao, T., Song, J., Xia, P., Dong, J., Zhao, J., and Wang, F.S., 2020. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir. Med., 8: 420-422. https://doi.org/10.1016/S2213-2600(20)30076-X

Yang, X., Yu, Y., Xu, J., Shu, H., Xia, J.A., Liu, H., Wu, Y., Zhang, L., Yu, Z., Fang, M., Yu, T., Wang, Y., Pan, S., Zou, X., Yuan, S., and Shang, Y., 2020. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: A single-centered, retrospective, observational study. Lancet Respir. Med., 8: 475-481. https://doi.org/10.1016/S2213-2600(20)30079-5

Zheng, M., Gao, Y., Wang, G., Song, G., Liu, S., Sun, D., Xu, Y., and Tian, Z., 2020. Functional exhaustion of antiviral lymphocytes in COVID-19 patients. Cell Mol. Immunol., 17: 533-535. https://doi.org/10.1038/s41423-020-0402-2

Zhu, J.H., and Peltekian, K.M., 2021. HBV coinfection and in-hospital outcomes for COVID-19: A systematic review and meta-analysis. Can. Liver J., 4: 16-22. https://doi.org/10.3138/canlivj-2020-0029

Zhu, N., Zhang, D., Wang, W., Li, X., Yang, B., Song, J., Zhao, X., Huang, B., Shi, W., Lu, R., Niu, P., Zhan, F., Ma, X., Wang, D., Xu, W., Wu, G., Gao, G.F., and Tan, W., 2020. A novel coronavirus from patients with pneumonia in China, 2019. N. Engl. J. Med., 382: 727-733. https://doi.org/10.1056/NEJMoa2001017

Zuo, T., Zhan, H., Zhang, F., Liu, Q., Tso, E.Y.K., Lui, G.C.Y., Chen, N., Li, A., Lu, W., Chan, F.K.L., Chan, P.K.S., and Ng, S.C., 2020. Alterations in fecal fungal microbiome of patients with COVID-19 during time of hospitalization until discharge. Gastroenterology, 159: 1302-1310.e1305. https://doi.org/10.1053/j.gastro.2020.06.048