Open access peer-reviewed chapter
Abstract
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) invades the host’s cells via the angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2). ACE2 and TMPRSS2 molecules are highly expressed on the respiratory tract but are also expressed in other organs such as kidneys, heart, and intestine, which could partially explain the multiple organ infection, damage, and failure. During the COVID-19 disease course, patients may develop a dysregulation in the immune response, with an exacerbated production of pro-inflammatory molecules and hypercoagulation, which can collaborate to the increase in tissue damage and death. This chapter will cover general aspects of the innate and adaptive immune response during COVID-19, the impact of comorbidities on the immune response to SARS-CoV-2, and the immune response generated by COVID-19 vaccines.
Keywords
- SARS-CoV-2
- COVID-19
- immunology
- immune response
- inflammation
1. Introduction
SARS-CoV-2 has four main structural proteins: the spike protein (S protein), the nucleocapsid protein (N protein), the matrix protein (M Protein), and envelope protein (E protein) [1, 2]. The SARS-CoV-2 infection starts when the virion enters the host’s cell, through the connection between the viral S protein and the ACE2 receptor and TMPRSS2 on the host’s cells, similarly to severe acute respiratory syndrome coronavirus-1 (SARS-CoV-1) [3].
ACE2 and TMPRSS2 are highly expressed in the lungs, partially explaining the high incidence of respiratory disorders. Nevertheless, ACE2 and TMPRSS2 are expressed in many other different organs in the human body, such as the brain, heart, liver, kidney, colonic epithelial cells, intestine luminal cells, and small intestinal enterocytes [4], with reports of SARS-CoV-2 infection on multiple organs [5]. In addition, SARS-CoV-2 may generate a systemic and exacerbated inflammatory response named “cytokine storm”, which can lead to viral sepsis [6].
Several systemic biomarkers have been associated with the progression of the disease, such as creatinine, urea, C-reactive protein, ferritin, lactate dehydrogenase, and D-dimers in the blood, increase in the neutrophil-to-lymphocyte ratio, and reduction in platelet count in the blood [7, 8, 9, 10, 11, 12, 13, 14, 15]. During COVID-19 the increase in blood levels of chemokines and cytokines increases the pro-inflammatory stimulus and recruitment of immune cells to the infection site. Several risk factors contribute to the disease’s severity, such as comorbidities and co-infections [16, 17, 18] In this chapter, the current knowledge about the innate and adaptative immune response during COVID-19 and the influence of comorbidities will the reviewed.
2. Innate immune response to SARS-CoV-2
Upon infection by SARS-CoV-2 several chemokines (CCL2, CCL3, CCL4, CCL5, CXCL8, CXCL9, and CXL10) and pro-inflammatory cytokines (IFN-γ, TNF, IL-1, IL-6, IL-12) are released, these molecules will induce cell activation, migration, and infiltration of the infected tissue by innate immune cells like monocytes and neutrophils and further activate local cells such as resident macrophages [19]. These cells will further increase the local production of pro-inflammatory mediators, which could result in tissue damage, such as alveolar damage, formation of edema, and reduced lung capacity. In addition, cytokines can generate a systemic effect, resulting in damage to other organs (kidney, liver, spleen, among others) [20]. An increase in circulating pro-inflammatory monocytes and nonclassical monocytes are commonly observed in COVID-19 patients [21, 22].
Concomitantly, the number of neutrophils in the blood increases, and the infiltration of neutrophils to the infected tissue. Upon infiltration, neutrophils release inflammatory mediators, cytokines, and neutrophil extracellular traps (NETs) which can further increase tissue injury and cellular death [23, 24]. The local production of pro-inflammatory factors, viral particles, and cellular death induces the activation of macrophage and dendritic cells (DCs), which will further increase the production of cytokines and chemokines and antigen presentation [20, 25] DCSs are commonly referred to as professional antigen-presenting cells (APCs) and integrate innate and adaptive immune response. In COVID-19 they can uptake SARS-CoV-2 viral particles, be activated, migrate to lymphatic tissue, initiate antigen presentation, and trigger adaptive immune response. Nevertheless, DCs can also be infected by SARS-CoV-2 [26], reducing quantitatively, generating functional impairment, and lower lymphocyte immune response [27].
The complement system has also been implicated in the pathogenesis of COVID-19. The activation of C3 and C5 complement components are correlated with disease severity and lung biopsy from severe COVID-19 patients presented high C3-fragment content [28]. C3-deficient mice are partially protected from respiratory dysfunction after SARS-CoV-1 infection, exhibiting less inflammatory infiltrate in the lungs, reduced production of cytokines and chemokines, but similar viral load in the lung tissue as Wild Type mice [29]. Importantly, treatment with anti-C5a antibodies resulted in clinical improvement in COVID-19 patients [28]. Indicating a possible use of complement-inhibitor to ameliorate lung injury in COVID-19 patients.
The role of eosinophils and basophils in COVID-19 is yet to be fully comprehended. To the moment, a negative correlation is established between circulating eosinophil and basophil count and COVID-19 severity, with patients exhibiting an increase in those cells upon SARS-CoV-2 clearance [30, 31]. Mast cells (MCs) may also play a role in COVID-19, since they can be activated by viral products and release chemokines, cytokines, and inflammatory mediators, increasing vascular permeability and cellular infiltrate [32]. A few reports have indicated that COVID-19 inflammatory syndrome is in many aspects similar to Mast cell activation disease [32, 33].
The frequency of mononuclear and polymorphonuclear myeloid-derived suppressor cells also increases in the blood, but not in the lungs, of COVID-19 patients according to the severity [15, 34]. Importantly, these cells do maintain their immunosuppressive functions in COVID-19 patients [35].
The hyperinflammatory state is also accompanied by a dysregulated anti-inflammatory state, with an increased early IL-10 production, which could curb the anti-viral immune response [36], and impaired T cells (CD4+ and CD8+) and T regulatory cells function [37].
3. Adaptive immunity in COVID-19
Patients with moderate and severe COVID-19 commonly present a reduction in circulating lymphocytes (T cells, B cells, natural killer cells). T CD4+ and T CD8+ cells are reduced in moderate COVID-19 patients and further reduced in more severe patients, with or without a significant change in CD4+/CD8+ ratio [38, 39]. A few reports have identified patients with a specific reduction in CD8+ cells, which is associated with poor prognosis [38]. The reduction of B cells and innate lymphocytes, like NK cells, has also been reported, but to the moment are not currently associated with severity or prognosis [40].
The mechanism for the reduction in lymphocytes is still under investigation, several reports indicate that exhaustion and apoptosis may be the primary causes of lymphopenia [41], and one report indicating direct lymphocyte infections by SARS-CoV-2 [42]. Due to the central role of lymphocytes on anti-SARS-CoV-2 immune response, several interventions to modulate the T cell proliferation or apoptosis are also being investigated [43].
Although the reduced T cell count in the blood of COVID-19 patients may reflect the recruitment to infected tissue or be influenced by the use of steroid treatment to curb the inflammation, some studies have also reported significant T cell reduction in secondary lymphoid organs of patients infected with SARS-CoV-2 [44].
Even with the reduction in lymphocytes, T cell receptor analysis indicated that COVID-19 patients do present an increase in SARS-CoV-2-specific T-cells [45]. Proliferation markers, such as Ki67, and activation markers, such as CD28 and HLA-DR, are increased in both CD4+ and CD8+ cells, including activated, effector, and memory T-cells, in COVID-19 patients in comparison to recovered patients and non-COVID-19 patients [46]. Several reports identified an increased expression of exhaustion and inhibition-associated markers in circulating T cells such as CD39, CTLA4, LAG3, NKG2A, PD-1, and TIM3 [47].
In summary, these results indicate an expansion and overactivation of CD4+ and CD8+ T-cells that could lead to unresponsiveness or cell death. This appears to be true since even with a highly activated profile, CD8+ T cells from COVID-19 patients have a reduced cytokine production after in vivo stimulation [41].
CD4+ T cells may have a dual role in COVID-19, reports have identified that patients with higher activation markers on CD4+ cells have a poor prognosis, and others have identified that patients with higher T helper 1 profile (Th1) present a less severe disease [46, 48]. SARS-CoV-2-specific Th1 cells have been identified, but patients with profiles associated with SARS-CoV-2-specific Th2 and Th17 response have also been identified [49]. Another investigation has also identified an increase in transforming growth factor-β (TGFβ)-producing T cells in COVID-19 patients [50]. CD4+ FOXP3+ T regulatory cells increase during the disease but suffer a reduction in critically ill patients, which could corroborate the hyperactivation of the immune system [47, 50].
3.1 Antibodies and B CELLS
The Production of Antibodies, especially SARS-CoV-2-specific IgM and IgG, have been used as a diagnostic tool for COVID-19, although the presence of virus-specific IgG antibodies does indicate viral clearance [51]. Anti-SARS-CoV-2 antibodies may block and neutralize SARS-CoV-2 and prevent COVID-19 development.
Importantly, reports have identified that asymptomatic, moderate, and severe COVID-19 present different IgM and IgG production courses and may vary in quantity. Severe COVID-19 patients produce anti-SARS-CoV-2 IgG earlier in comparison to moderate patients, and asymptomatic and mild patients produce less neutralizing antibodies in comparison to moderate and severe COVID-19 patients [52].
More importantly, serum antibody titers rapidly decay after COVID-19, with conflicting reports with antibody titers decaying after a few months post-diagnosis [53, 54]. Nevertheless, antigen-specific memory B cells [55], T cells, and other components of the immunological memory remain effective and can be detected in convalescent patients [52, 56]. As memory cells can rapidly respond upon subsequent antigen encounter (infection), some degree of long-term immunity is expected [57].
Since SARS-CoV-2 S protein is necessary for the infection, neutralizing antibodies against this protein could in theory prevent the infection [2]. Both S-protein and N-protein specific IgM and IgG increase after the infection by SARS-CoV-2 [58], with S-protein IgG having a negative correlation with inflammatory markers in COVID-19 patients [58].
COVID-19 patients present a rapid increase in SARS-CoV-2-specific IgM, IgA, and IgG, commonly observed around a week after the infection [51, 59], however, comorbidities may impact not only on the inflammatory response during COVID-19 but also antibody production, reports identified patients with human immunodeficiency virus (HIV) presenting a delayed SARS-CoV-specific IgM and IgG production [60, 61].
4. Comorbidities and severe COVID-19
Several comorbidities have been described as risk factors for the progression of COVID-19 into a severe, critical, and lethal stage. The first reports have identified advanced age, systemic arterial hypertension, and Diabetes Mellitus with a higher hospitalization and severity for COVID-19 patients [62, 63, 64]. Comorbidities may influence COVID-19 severity via an increase in pro-inflammatory response, coagulatory disorders, or different ACE2 expression [65, 66, 67]. Investigations confirmed that old age, systemic arterial hypertension, Diabetes Mellitus [68], obesity [16], alcohol consumption [69], smokers and chronic obstructive pulmonary disease (COPD) [70], heart disease, liver disease and kidney disease [71], cancer [72, 73], immunodeficiencies, transplanted patients [74], and co-infections [17, 74] are in fact risk factor for severe COVID-19 and increase death risk and the presence of two or more comorbidities further increase the death risk [75]. We will review the impact of the most common comorbidities associated with poor COVID-19 prognosis and their influence on the anti-SARS-CoV-2 immune response.
4.1 Old age
The majority of the fatal cases of COVID-19 occurred in elderly individuals [76, 77]. Several facts may explain this phenomenon, such as the accumulations of other comorbidities, immunosenescence, and inflammaging.
Immunosenescence is defined as a decline in the immune system function, characterized by the reduction in qualitative and quantitative responses to infections, neoplasia, and vaccination [78]. With age, the production of naïve lymphocytes (T and B cells) is reduced, and the function of innate immune cells is weakened, therefore negatively impacting the immune response during infections [78]. Concomitantly, the elderly develop a chronic low-grade systemic inflammation, named inflammaging.
The low-grade pro-inflammatory state is characterized by the increase in serum inflammatory mediators, such as C-reactive protein, IL-1, IL-6, and TNF [79, 80], which is associated with an impaired and dysregulated immune response.
In summary, accumulations of other comorbidities such as systemic arterial hypertension and Diabetes Mellitus, immunosenescence, and inflammaging present in elderly patients are likely to contribute to the poorer outcome in COVID-19 [81].
4.2 Systemic arterial hypertension
Systemic Arterial Hypertension is common among hospitalized COVID-19 patients and is associated with higher severity of the disease and mortality [15, 82, 83]. The initial hypothesis for this was that Systemic Arterial Hypertension and the drugs commonly used for its control, like renin–angiotensin–aldosterone system (RAAS) inhibitors that increase expression of ACE2, increasing the susceptibility to SARS-CoV-2 [68]. However, a recent report has not identified an association between the use of RAAS inhibitors and increased severity or death in COVID-19 patients [84].
Other explanations are related to the modulations of ICAM and E-selectin, which are increased in systemic arterial hypertension and can be downregulated by dexamethasone [85, 86]. Dexamethasone treatment during COVID-19 can reduce the death rate in patients receiving both invasive and non-invasive mechanical ventilation [87]. Although no investigation on the modulation of ICAM and E-selecin has been performed, these results further support that the reduction of inflammation during COVID-19 can improve the patients’ outcome [87].
4.3 Metabolic diseases (type 1 and 2 diabetes mellitus and obesity)
Diabetes Mellitus (DM), obesity, and metabolic syndrome increase the levels of circulating pro-inflammatory cytokines in comparison to lean people. This low-grade inflammation is lower than individuals with infections but can influence cellular metabolism and immune response [88, 89]. Obesity affected the frequency and ratio of CD8+ and CD4+ T cells, inducing an increase in inflammatory macrophages [90] and reduces the frequency of T regulatory cells, therefore favoring a more pro-inflammatory profile [91]. In obesity, there is a great increase in memory T cell in the adipose tissue, that upon infection can generate pancreatitis, and increase mortality [92]. Similar to inflammaging, obesity is also characterized by low-grade inflammation, with an increase in the production of chemokines and cytokines by the adipose tissue [92]. Obesity is also associated with several risk factors for COVID-19 such as respiratory dysfunctions, type 2 Diabetes Mellitus (DM2), and hypertension [16].
The type of Diabetes Mellitus is rarely described in COVID-19 investigations [93]. A recent investigation compared the mortality rate among type 1 Diabetes Mellitus (DM1) and DM2 patients during SARS-Co-V-2 infection. The unadjusted mortality rate per 100 000 was 27 for non-DM, 138 in DM type 1 (DM1) and 260 in DM2, the adjusted data verified that the odds ratios of COVID-19-related deaths were 3.51 in DM1 and 2.03 in DM2 [94]. Concluding that both DM types present a greater risk of death by COVID-19 [94].
An important factor is that poor glycemic control can influence the disease course [95], this is supported by several manuscripts that described the deleterious effect of elevated blood glucose levels on the immune response to COVID-19 and DM2 patients with better glycemic control presented a lower death rate in comparison with COVID-19 DM2 patients with hyperglycemia [96, 97, 98]. Diabetic patients also present a low-grade inflammation with an increase in pro-inflammatory cytokines and reactive oxygen species, but an impaired inflammatory response to microbial products [99, 100].
Non-diabetic patients with COVID-19 can also present hyperglycemia [15], and is associated with an increased incidence of severe illness and death risk [101]. Several drugs used for the control of inflammation can modify or induce hyperglycemia during COVID-19 hospitalization [102], which could affect the anti-SARS-CoV-2 immune response. A few manuscripts have hypothesized COVID-19 causes alterations of glucose metabolism, via direct SARS-CoV-2 infection of the pancreatic beta cells [103, 104]. Importantly, metabolic alterations have been described in COVID-19 patients, with and without DM, developing ketosis and ketoacidosis [105]. In a case report, a 29 years old patient, non-DM with a normal glucose level was diagnosed with COVID-19. Two weeks after recovered from COVID-19 was diagnosed with DM1 [106].
Therefore, COVID-19 may also represent a risk factor for the development of DM. A related point to consider is that DM patients may have long-term consequences from COVID19, with an increase in the need for daily insulin [107]. Currently, there is no explanation for this phenomenon, but COVID-19-mediated gastrointestinal dysbiosis could be a factor since the microbiota can influence the development or aggravate metabolic disorders [108]. Also, metformin, a drug commonly used by DM2 patients, may cause alteration on the gut microbiota and impact their anti-SARS-CoV-2 immune response [109, 110].
4.4 Chronic obstructive pulmonary disease (COPD), smoking, and other respiratory disorders
Chronic obstructive pulmonary disease (COPD) affects millions of people worldwide. COPD is characterized by progressive and irreversible airflow limitation due to structural alterations on the small airways. Smoking is the leading cause of COPD, due to the increase in inflammation and pulmonary remodeling [111]. Smoking and COPD are known to increase the risk for respiratory infections [112, 113]. Smokers and COPD patients have been identified among hospitalized COVID-19 patients since early reports [83]. COPD and smoking have been associated with an increased incidence, severity, and poor prognosis in COVID-19 [70, 114, 115, 116].
A common component in tobacco cigarettes and electronic smoking devices is nicotine, which can downregulate Interferon regulatory factor 7 and curb antiviral immune response [117]. COPD patients have a reduction in the expression of type I and type II interferons, and interferon-stimulated genes, therefore having a reduced antiviral response resulting in frequent respiratory exacerbations [118].
Other mechanisms postulated for the increase in susceptibility among those patients are the increase in lung inflammation and oxidative stress [119] and increase in the expression of the ACE2 receptor, SARS-CoV-2 entry receptor, in COPD and Smokers [120].
Interestingly, allergic asthma characterized by a Th2 immune response, with increased production of IL-4, IL-5 and IL-13, is associated with a reduction of the expression of ACE2 receptor [65]. And asthma is associated with a reduction in the severity of COVID-19 [121, 122]. It is important to highlight that non-allergic asthma or neutrophilic asthma increases the production of IL-17 in the lungs, which increases ACE2 expression, therefore possibly increasing the risk for severe COVID-19 [123].
Other respiratory diseases such as bronchiectasis, sarcoidosis, idiopathic pulmonary fibrosis, and lung cancer are also associated with an increase in COVID-19 severity, but further investigations are needed to understand the immune mechanism [124].
Since asthma, smoking and COPD are also commonly associated with other comorbidities, this could further increase the COVID-19 severity and death risk in these populations [125, 126].
4.5 Neoplasia (cancer)
Cancer patients are regarded as more vulnerable to severe COVID-19, due to the direct immunosuppression caused by the tumor or indirectly by the antitumor treatment [127, 128]. Patients with hematological malignancies, such as leukemia and lymphoma, have an exacerbated cellular proliferation with a reduction in the immune response, increasing the susceptibility to infections [129].
Location and cancer stage can also impact COVID-19 development. A recent report among patients with cancer identified that lung cancer, gastrointestinal cancer, and breast cancer are the most common [130]. Patients with stage IV cancer also account for a high number of COVID-19-infected patients [130, 131]. Cancer patients with COVID-19 also have an increase in hospitalization duration and severity [130, 131].
In addition to immune suppression, hospitalized cancer patients or patients undergoing frequent hospital visits may be at great risk for SARS-CoV-2 infection, increasing the necessity for precautionary measures [132, 133].
4.6 Immunodeficiencies
Immunodeficiencies are uncommon and chronic disorders of the immune system, that hinders the ability to develop an appropriate immune response, leading to deficient, exacerbated, or absent response to an infection or disease [134]. The immunodeficiency can be localized in any cell or structure of the immune system, compromising barrier immunity, innate immunity, or adaptive immune.
Immunodeficiency disorders can be divided into primary and secondary immunodeficiencies. Primary immunodeficiencies are a consequence of genetic defects, and secondary immunodeficiencies are caused by external or environmental factors, such as nutritional disorders or HIV [135].
The most common primary immunodeficiency is the common variable immunodeficiency that affects the patients’ ability to mount an appropriate humoral response during infection [136]. These patients are commonly treated with immunoglobulin replacement [137]. A recent case report identified a patient with common variable immunodeficiency and severe COVID-19, that was successfully treated with COVID-19 convalescent plasma [138]. Although it is important to highlight that convalescent plasma treatment has controversial results, even when applied at the beginning of the infection and with high titers of neutralizing antibodies [139, 140, 141].
Reports of patients with primary and secondary immunodeficiencies identified an increase in severity and mortality due to COVID-19 in these patients in comparison with available data on COVID-19 [142, 143]. Also, patients with immunodeficiencies can present other comorbidities, further increasing the death risk by COVID-19 and increased risk for the development of secondary infections during hospitalization [142, 143]. Certain immunodeficiencies compromise specific anti-viral immune responses, for example, TLR7 gene defect, with compromised type I and II interferon production, are linked to severe COVID-19 in young individuals [144].
A common secondary immunodeficiency AIDS, the one caused by HIV, can compromise the anti-viral immune response during COVID-19. Patients with low CD4+ count have a higher severity and mortality risk compared with patients with normal CD4+ count [145]. In patients with HIV viral suppression, other comorbidities may increase patients’ death risk during COVID-19 [30, 145].
4.7 Co-infections
Bacteria and viral co-infections and secondary infection in COVID-19 patients are important factors in the patients’ treatment and outcome [146]. Co-pathogens included bacteria, fungi, parasites and viruses can modulate patients’ immunity and also curb the anti-SARS-CoV-2 immune response [146]. Patients with invasive mechanical ventilation are at greater risk for bacterial co-infections [17, 147], also several patients report diarrhea without gastrointestinal SARS-CoV-2 infection, which could be a secondary gastrointestinal infection or microbiota dysbiosis [108].
Co-infections can increase the susceptibility to severe COVID-19, by an increase in the hyper inflammation or hypercoagulation status [74, 148]. Few reports have investigated the impact of parasites on COVID-19, such as leishmaniasis, toxoplasmosis, malaria, and Chagas disease [148, 149, 150, 151]. Clinical manifestations of those diseases are usually associated with an increased and unregulated type 1 pro-inflammatory response, similar to COVID-19 [151]. In fact, a few case reports identified that chagasic patients with COVID-19 present an exacerbated inflammatory response, with a high lethality [74, 148]. This represents a further difficulty in the treatment of COVID-19, since the combination of drugs for the treatment of COVID-19 and the co-infections, the immune response to the co-infections and possible comorbidities need to be equated.
5. COVID-19 vaccines
COVID-19 vaccines are currently the only prophylactic/curative treatment for COVID-19, since drug repurposing and monoclonal antibodies trials had limited success, and investigations with convalescent plasma have conflicting results [87, 139, 140, 141, 152, 153]. Several vaccines are currently developed and in developing. Due to the high demand for a COVID-19 vaccine, significant advances in vaccine technologies have been made in the last year. Currently, 3 types of vaccines are being administered worldwide: inactivated virus vaccines (IVV) [154], vaccines that use mRNA with lipid nanoparticle (LNP) delivery systems [155], and vaccines containing DNA delivered within non-replicating recombinant adenovirus (AdV) vector systems [156]. AdV and mRNA vaccines aim to induce the production of SARS-CoV-2 S protein and induces the production of neutralizing antibodies [139, 141, 153].
All vaccines can induce the recognition of the viral antigen (immunogen) and also serve as an adjuvant to boost the immune response, the immunogen is recognized by innate immunity receptors such as toll-like receptors 3 and 7, RIG-I, and NOD2 inducing cellular activation and the production of interferons. This process will also induce the migration of DCs to secondary lymphoid organs and prime SARS-CoV-2-specific T cells [139, 141, 153]. Further questions regarding the effectiveness of vaccines are still going to be investigated, especially the long-term immunity and efficacy against new variants.
6. Conclusions
COVID-19 is a hyperinflammatory and hypercoagulation syndrome, with a hallmark increase in inflammatory mediators such as C-reactive protein, creatinine, urea, cytokines, and chemokines in the blood, with an increase in the neutrophil count and reduction in lymphocyte and platelet count. These processes lead to a dysregulated immune response that can be lethal. The overall mortality ratio is still unknown but is higher in patients with comorbidities. Patients with common and rare comorbidities may present differences in the immune response in comparison to healthy individuals.
The COVID-19 pandemic is a hallmark of world history, this systemic disease killed millions, raised ethical dilemmas, and put science and immunology on the daily lives of millions worldwide. Immunological investigations have helped the development of treatments and vaccines for this disease, but many questions are still left to be answered. The current knowledge is limited, but never in the previous history so many researchers around the world were focused on investigations on one disease. Several technologies developed and tested during this pandemic may bring light to other diseases, such as the new technologies in vaccine development and treatments.
Acknowledgments
Ricardo Wesley Alberca has a fellowship from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), Grant Number: 19/02679-7.
References
- 1.
Hu B, Guo H, Zhou P, Shi ZL. Characteristics of SARS-CoV-2 and COVID-19 [Internet]. Vol. 19, Nature Reviews Microbiology. Nature Research; 2021 [cited 2021 Apr 26]. p. 141-54. Available from: www.nature.com/nrmicro - 2.
Batra M, Tian R, Zhang C, Clarence E, Sacher CS, Miranda JN, et al. Role of IgG against N-protein of SARS-CoV2 in COVID19 clinical outcomes. Sci Rep [Internet]. 2021 Dec 1 [cited 2021 Apr 24];11(1):3455. Available from: https://doi.org/10.1038/s41598-021-83108-0 - 3.
Astuti I, Ysrafil. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2): An overview of viral structure and host response. Diabetes Metab Syndr Clin Res Rev [Internet]. 2020 Jul 1 [cited 2021 Apr 19];14(4):407-12. Available from: /pmc/articles/PMC7165108/ - 4.
Dong M, Zhang J, Ma X, Tan J, Chen L, Liu S, et al. ACE2, TMPRSS2 distribution and extrapulmonary organ injury in patients with COVID-19. Biomedicine and Pharmacotherapy. 2020. - 5.
Puelles VG, Lütgehetmann M, Lindenmeyer MT, Sperhake JP, Wong MN, Allweiss L, et al. Multiorgan and Renal Tropism of SARS-CoV-2. The New England journal of medicine. 2020. - 6.
Liu D, Wang Q, Zhang H, Cui L, Shen F, Chen Y, et al. Viral sepsis is a complication in patients with Novel Corona Virus Disease (COVID-19). Med Drug Discov. 2020 Dec 1;8:100057. - 7.
Xie G, Ding F, Han L, Yin D, Lu H, Zhang M. The role of peripheral blood eosinophil counts in COVID-19 patients. Allergy [Internet]. 2020 Jul 13 [cited 2020 Jul 30]; all. 14465. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1111/all.14465 - 8.
Tan L, Wang Q, Zhang D, Ding J, Huang Q, Tang YQ, et al. Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study. Vol. 5, Signal Transduction and Targeted Therapy. 2020. - 9.
Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395(10223):497-506. - 10.
Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, et al. Dysregulation of immune response in patients with COVID-19 in Wuhan, China. Clin Infect Dis. 2020; - 11.
Jamal MH, Doi SA, AlYouha S, Almazeedi S, Al-Haddad M, Al-Muhaini A, et al. A biomarker based severity progression indicator for COVID-19: the Kuwait prognosis indicator score. Biomarkers [Internet]. 2020 Nov 16 [cited 2021 Mar 20];25(8):641-8. Available from: https://www.tandfonline.com/doi/full/10.1080/1354750X.2020.1841296 - 12.
Singh N, Anchan RK, Besser SA, Belkin MN, Cruz MD, Lee L, et al. High sensitivity Troponin-T for prediction of adverse events in patients with COVID-19. Biomarkers [Internet]. 2020 Nov 16 [cited 2021 Mar 20];25(8):626-33. Available from: https://www.tandfonline.com/doi/full/10.1080/1354750X.2020.1829056 - 13.
Salvatici M, Barbieri B, Cioffi SMG, Morenghi E, Leone FP, Maura F, et al. Association between cardiac troponin I and mortality in patients with COVID-19. Biomarkers [Internet]. 2020 Nov 16 [cited 2021 Mar 20];25(8):634-40. Available from: https://www.tandfonline.com/doi/full/10.1080/1354750X.2020.1831609 - 14.
Peiró ÓM, Carrasquer A, Sánchez-Gimenez R, Lal-Trehan N, del-Moral-Ronda V, Bonet G, et al. Biomarkers and short-term prognosis in COVID-19. Biomarkers [Internet]. 2021 Feb 17 [cited 2021 Mar 20];26(2):119-26. Available from: https://www.tandfonline.com/doi/full/10.1080/1354750X.2021.1874052 - 15.
Alberca RW, Andrade MM de S, Castelo Branco ACC, Pietrobon AJ, Pereira NZ, Fernandes IG, et al. Frequencies of CD33+ CD11b+ HLA-DR− CD14− CD66b+ and CD33+ CD11b+ HLA-DR− CD14+ CD66b− cells in peripheral blood as severity immune biomarkers in COVID-19. Front Med. 2020;7:654. - 16.
Alberca RW, Oliveira L de M, Branco ACCC, Pereira NZ, Sato MN. Obesity as a risk factor for COVID-19: an overview. Crit Rev Food Sci Nutr [Internet]. 2020 [cited 2020 Jul 30]; Available from: https://www.tandfonline.com/doi/abs/10.1080/10408398.2020.1775546 - 17.
Lansbury L, Lim B, Baskaran V, Lim WS. Co-infections in people with COVID-19: a systematic review and meta-analysis. J Infect. 2020; - 18.
Alberca GGF, Solis-Castro RL, Solis-Castro ME, Alberca RW. Coronavirus disease–2019 and the intestinal tract: An overview. World J Gastroenterol [Internet]. 2021 Apr 7 [cited 2021 Mar 31];27(13):1255-66. Available from: https://www.wjgnet.com/1007-9327/full/v27/i13/1255.htm - 19.
Khalil BA, Elemam NM, Maghazachi AA. Chemokines and chemokine receptors during COVID-19 infection [Internet]. Vol. 19, Computational and Structural Biotechnology Journal. Elsevier B.V.; 2021 [cited 2021 Apr 22]. p. 976-88. Available from: /pmc/articles/PMC7859556/ - 20.
Temgoua MN, Endomba FT, Nkeck JR, Kenfack GU, Tochie JN, Essouma M. Coronavirus Disease 2019 (COVID-19) as a Multi-Systemic Disease and its Impact in Low- and Middle-Income Countries (LMICs). SN Compr Clin Med [Internet]. 2020 Sep [cited 2021 Apr 22];2(9):1377-87. Available from: /pmc/articles/PMC7371790/ - 21.
Ekşioğlu-Demiralp E, Alan S, Sili U, Bakan D, Ocak İ, Yürekli R, et al. Peripheral innate and adaptive immune cells during COVID-19: Functional neutrophils, pro-inflammatory monocytes and half-dead lymphocytes [Internet]. medRxiv. medRxiv; 2020 [cited 2021 Apr 13]. p. 2020.08.01.20166587. Available from: https://doi.org/10.1101/2020.08.01.20166587 - 22.
Stephenson E, Reynolds G, Botting RA, Calero-Nieto FJ, Morgan MD, Tuong ZK, et al. Single-cell multi-omics analysis of the immune response in COVID-19. Nat Med [Internet]. 2021 Apr 20 [cited 2021 Apr 22];1-13. Available from: http://www.nature.com/articles/s41591-021-01329-2 - 23.
Radermecker C, Detrembleur N, Guiot J, Cavalier E, Henket M, d’Emal C, et al. Neutrophil extracellular traps infiltrate the lung airway, interstitial, and vascular compartments in severe COVID-19. J Exp Med [Internet]. 2020 Dec 7 [cited 2021 Apr 13];217(12). Available from: https://doi.org/10.1084/jem.20201012 - 24.
Veras FP, Pontelli MC, Silva CM, Toller-Kawahisa JE, de Lima M, Nascimento DC, et al. SARS-CoV-2-triggered neutrophil extracellular traps mediate COVID-19 pathology. J Exp Med [Internet]. 2020 Dec 7 [cited 2021 Apr 13];217(12). Available from: /pmc/articles/PMC7488868/ - 25.
Meidaninikjeh S, Sabouni N, Marzouni HZ, Bengar S, Khalili A, Jafari R. Monocytes and macrophages in COVID-19: Friends and foes [Internet]. Vol. 269, Life Sciences. Elsevier Inc.; 2021 [cited 2021 Apr 22]. p. 119010. Available from: /pmc/articles/PMC7834345/ - 26.
Borges RC, Hohmann MS, Borghi SM. Dendritic cells in COVID-19 immunopathogenesis: insights for a possible role in determining disease outcome [Internet]. Vol. 40, International Reviews of Immunology. Taylor and Francis Ltd.; 2021 [cited 2021 Apr 22]. p. 108-25. Available from: https://www.tandfonline.com/action/journalInformation?journalCode=iiri20 - 27.
Zhou R, To KKW, Wong YC, Liu L, Zhou B, Li X, et al. Acute SARS-CoV-2 Infection Impairs Dendritic Cell and T Cell Responses. Immunity. 2020 Oct 13;53(4):864-877.e5. - 28.
Gao T, Hu M, Zhang X, Li H, Zhu L, Liu H, et al. Highly pathogenic coronavirus N protein aggravates lung injury by MASP-2-mediated complement over-activation [Internet]. medRxiv. medRxiv; 2020 [cited 2021 Apr 23]. p. 2020.03.29.20041962. Available from: https://doi.org/10.1101/2020.03.29.20041962 - 29.
Gralinski LE, Sheahan TP, Morrison TE, Menachery VD, Jensen K, Leist SR, et al. Complement activation contributes to severe acute respiratory syndrome coronavirus pathogenesis. MBio [Internet]. 2018 Sep 1 [cited 2021 Apr 23];9(5):1753-71. Available from: http://mbio.asm.org/ - 30.
Alberca R, Aoki V, Sato M. COVID-19 and HIV: Case reports of 2 co-infected patients with different disease courses. World Acad Sci J [Internet]. 2020 Nov 26 [cited 2020 Dec 3];3(1):4. Available from: http://www.spandidos-publications.com/10.3892/wasj.2020.75 - 31.
Xie G, Ding F, Han L, Yin D, Lu H, Zhang M. The role of peripheral blood eosinophil counts in COVID-19 patients. Allergy [Internet]. 2020 Jul 13 [cited 2020 Aug 2];all.14465. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1111/all.14465 - 32.
Afrin LB, Weinstock LB, Molderings GJ. Covid-19 hyperinflammation and post-Covid-19 illness may be rooted in mast cell activation syndrome. Vol. 100, International Journal of Infectious Diseases. Elsevier B.V.; 2020. p. 327-32. - 33.
Brock I, Maitland A. Mast Cells and COVID-19: a case report implicating a role of mast cell activation in the prevention and treatment of Covid-19. 2021 Mar 16 [cited 2021 Apr 23]; Available from: https://doi.org/10.21203/rs.3.rs-330667/v2 - 34.
Falck-Jones S, Vangeti S, Yu M, Falck-Jones R, Cagigi A, Badolati I, et al. Functional monocytic myeloid-derived suppressor cells increase in blood but not airways and predict COVID-19 severity. J Clin Invest [Internet]. 2021 Mar 15 [cited 2021 Apr 26];131(6). Available from: https://doi.org/10.1172/JCI144734DS1 - 35.
Agrati C, Sacchi A, Bordoni V, Cimini E, Notari S, Grassi G, et al. Expansion of myeloid-derived suppressor cells in patients with severe coronavirus disease (COVID-19). Cell Death Differ. 2020; - 36.
Lu L, Zhang H, Dauphars DJ, He YW. A Potential Role of Interleukin 10 in COVID-19 Pathogenesis [Internet]. Vol. 42, Trends in Immunology. Elsevier Ltd; 2021 [cited 2021 Apr 22]. p. 3-5. Available from: https://doi.org/10.1016/j.it.2020.10.012 - 37.
Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, et al. Dysregulation of Immune Response in Patients With Coronavirus 2019 (COVID-19) in Wuhan, China. Clin Infect Dis. 2020;71(15):762-8. - 38.
Urra JM, Cabrera CM, Porras L, Ródenas I. Selective CD8 cell reduction by SARS-CoV-2 is associated with a worse prognosis and systemic inflammation in COVID-19 patients. Clin Immunol [Internet]. 2020 Aug 1 [cited 2021 Apr 22];217:108486. Available from: /pmc/articles/PMC7256549/ - 39.
Zhang H, Wu T. CD4+T, CD8+T counts and severe COVID-19: A meta-analysis [Internet]. Vol. 81, Journal of Infection. W.B. Saunders Ltd; 2020 [cited 2021 Apr 22]. p. e82-4. Available from: /pmc/articles/PMC7305716/ - 40.
Tavakolpour S, Rakhshandehroo T, Wei EX, Rashidian M. Lymphopenia during the COVID-19 infection: What it shows and what can be learned [Internet]. Vol. 225, Immunology Letters. Elsevier B.V.; 2020 [cited 2021 Apr 22]. p. 31-2. Available from: /pmc/articles/PMC7305732/ - 41.
Zheng M, Gao Y, Wang G, Song G, Liu S, Sun D, et al. Functional exhaustion of antiviral lymphocytes in COVID-19 patients [Internet]. Vol. 17, Cellular and Molecular Immunology. Springer Nature; 2020 [cited 2021 Apr 22]. p. 533-5. Available from: https://doi.org/10.1038/s41423-020-0402-2 - 42.
Pontelli MC, Castro IA, Martins RB, Veras FP, Serra L La, Nascimento DC, et al. Infection of human lymphomononuclear cells by SARS-CoV-2 [Internet]. Vol. 7, bioRxiv. bioRxiv; 2020 [cited 2021 Apr 22]. p. 2020.07.28.225912. Available from: https://doi.org/10.1101/2020.07.28.225912 - 43.
Lee J, Park SS, Kim TY, Lee DG, Kim DW. Lymphopenia as a biological predictor of outcomes in COVID-19 patients: A nationwide cohort study. Cancers (Basel) [Internet]. 2021 [cited 2021 Apr 22];13(3):1-15. Available from: https://pubmed.ncbi.nlm.nih.gov/33530509/ - 44.
Kaneko N, Kuo HH, Boucau J, Farmer JR, Allard-Chamard H, Mahajan VS, et al. Loss of Bcl-6-Expressing T Follicular Helper Cells and Germinal Centers in COVID-19. Cell. 2020 Oct 1;183(1):143-157.e13. - 45.
Gutierrez L, Beckford J, Alachkar H. Deciphering the TCR Repertoire to Solve the COVID-19 Mystery [Internet]. Vol. 41, Trends in Pharmacological Sciences. Elsevier Ltd; 2020 [cited 2021 Apr 26]. p. 518-30. Available from: https://doi.org/10.1016/j.tips.2020.06.001 - 46.
Mathew D, Giles JR, Baxter AE, Oldridge DA, Greenplate AR, Wu JE, et al. Deep immune profiling of COVID-19 patients reveals distinct immunotypes with therapeutic implications. Science (80-) [Internet]. 2020 Sep 4 [cited 2021 Apr 26];369(6508). Available from: /pmc/articles/PMC7402624/ - 47.
Chen Z, John Wherry E. T cell responses in patients with COVID-19. Nat Rev Immunol [Internet]. 2020 Sep 1 [cited 2021 Apr 6];20(9):529-36. Available from: www.nature.com/nri - 48.
Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, et al. Clinical and immunologic features in severe and moderate forms of Coronavirus Disease 2019. medRxiv. 2020; - 49.
Weiskopf D, Schmitz KS, Raadsen MP, Grifoni A, Okba NMA, Endeman H, et al. Phenotype and kinetics of SARS-CoV-2-specific T cells in COVID-19 patients with acute respiratory distress syndrome. Sci Immunol [Internet]. 2020 Jun 26 [cited 2021 Apr 26];5(48). Available from: https://immunology.sciencemag.org/content/5/48/eabd2071 - 50.
Wang W, Su B, Pang L, Qiao L, Feng Y, Ouyang Y, et al. High-dimensional immune profiling by mass cytometry revealed immunosuppression and dysfunction of immunity in COVID-19 patients. Cell Mol Immunol [Internet]. 2020 Jun 1 [cited 2021 Apr 26];17(6):650-2. Available from: https://doi.org/10.1038/s41423-020-0447-2 - 51.
Chong Y, Ikematsu H, Tani N, Arimizu Y, Watanabe H, Fukamachi Y, et al. Clinical significance of SARS-CoV-2-specific IgG detection with a rapid antibody kit for COVID-19 patients. Influenza Other Respi Viruses. 2020; - 52.
Alberca GGF, Alberca RW. What is the long-term clinical significance of anti-SARS-CoV-2-specific IgG? Influenza and other Respiratory Viruses. Blackwell Publishing Ltd; 2020. - 53.
Ibarrondo FJ, Fulcher JA, Goodman-Meza D, Elliott J, Hofmann C, Hausner MA, et al. Rapid Decay of Anti-SARS-CoV-2 Antibodies in Persons with Mild Covid-19. The New England journal of medicine. 2020. - 54.
Self WH, Tenforde MW, Stubblefield WB, Feldstein LR, Steingrub JS, Shapiro NI, et al. Decline in SARS-CoV-2 Antibodies After Mild Infection Among Frontline Health Care Personnel in a Multistate Hospital Network—12 States, April–August 2020. MMWR Morb Mortal Wkly Rep [Internet]. 2020 Nov 27 [cited 2021 Apr 24];69(47):1762-6. Available from: http://www.cdc.gov/mmwr/volumes/69/wr/mm6947a2.htm?s_cid=mm6947a2_w - 55.
Hartley GE, Edwards ESJ, Aui PM, Varese N, Stojanovic S, McMahon J, et al. Rapid generation of durable B cell memory to SARS-CoV-2 spike and nucleocapsid proteins in COVID-19 and convalescence. Sci Immunol [Internet]. 2020 Dec 22 [cited 2021 Apr 6];5(54). Available from: http://immunology.sciencemag.org/ - 56.
Dan JM, Mateus J, Kato Y, Hastie KM, Yu ED, Faliti CE, et al. Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection. Science (80-) [Internet]. 2021 Feb 5 [cited 2021 Apr 6];371(6529). Available from: https://doi.org/10.1126/science.abf4063 - 57.
Alberca GGF, Alberca RW. What is the long-term clinical significance of anti-SARS-CoV-2-specific IgG? Influenza and other Respiratory Viruses. 2020. - 58.
Sun B, Feng Y, Mo X, Zheng P, Wang Q, Li P, et al. Kinetics of SARS-CoV-2 specific IgM and IgG responses in COVID-19 patients. Emerg Microbes Infect [Internet]. 2020 Jan 1 [cited 2021 Apr 24];9(1):940-8. Available from: /pmc/articles/PMC7273175/ - 59.
Yu HQ, Sun BQ, Fang ZF, Zhao JC, Liu XY, Li YM, et al. Distinct features of SARS-CoV-2-specific IgA response in COVID-19 patients. European Respiratory Journal. 2020. - 60.
Vizcarra P, Pérez-Elías MJ, Quereda C, Moreno A, Vivancos MJ, Dronda F, et al. Description of COVID-19 in HIV-infected individuals: a single-centre, prospective cohort. Lancet HIV. 2020;7(8):e554-64. - 61.
Wang M, Luo L, Bu H, Xia H. One case of coronavirus disease 2019 (COVID-19) in a patient co-infected by HIV with a low CD4+ T-cell count. Int J Infect Dis. 2020;96:148-50. - 62.
Zhang J jin, Dong X, Cao Y yuan, Yuan Y dong, Yang Y bin, Yan Y qin, et al. Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China. Allergy Eur J Allergy Clin Immunol. 2020;75(7):1730-41. - 63.
Li X, Xu S, Yu M, Wang K, Tao Y, Zhou Y, et al. Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan. J Allergy Clin Immunol. 2020; - 64.
Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054-62. - 65.
Castelo Branco ACC, Sato MN, Alberca RW. The possible dual role of the ACE2 receptor in asthma and SARS-COV2 infection. Front Cell Infect Microbiol. 2020;10:537. - 66.
Merad M, Martin JC. Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages [Internet]. Vol. 20, Nature Reviews Immunology. Nature Research; 2020 [cited 2021 Apr 8]. p. 355-62. Available from: www.nature.com/nri - 67.
Wolff D, Nee S, Hickey NS, Marschollek M. Risk factors for Covid-19 severity and fatality: a structured literature review. Infection. 2020. - 68.
Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? [Internet]. Vol. 8, The Lancet Respiratory Medicine. Lancet Publishing Group; 2020 [cited 2021 Apr 6]. p. e21. Available from: /pmc/articles/PMC7118626/ - 69.
Alberca RW, Rigato PO, Ramos YÁL, Teixeira FME, Castelo Branco ACC, Fernandes IG, et al. Clinical characteristics and survival analysis in frequent alcohol consumers with COVID-19. Front Nutr. 2021;8:260. - 70.
Alberca RW, Lima JC, Oliveira EA de, Gozzi-Silva SC, Ramos YÁL, Andrade MM de S, et al. COVID-19 Disease Course in Former Smokers, Smokers and COPD Patients. Front Physiol. 2021; - 71.
Cheng Y, Luo R, Wang K, Zhang M, Wang Z, Dong L, et al. Kidney disease is associated with in-hospital death of patients with COVID-19. Vol. 97, Kidney International. 2020. p. 829-38. - 72.
Lee LYW, Cazier JB, Starkey T, Briggs SEW, Arnold R, Bisht V, et al. COVID-19 prevalence and mortality in patients with cancer and the effect of primary tumour subtype and patient demographics: a prospective cohort study. Lancet Oncol [Internet]. 2020 Oct 1 [cited 2021 Apr 6];21(10):1309-16. Available from: www.thelancet.com/oncology - 73.
Derosa L, Melenotte C, Griscelli F, Gachot B, Marabelle A, Kroemer G, et al. The immuno-oncological challenge of COVID-19. Nat Cancer [Internet]. 2020 Oct 2 [cited 2021 Apr 6];1(10):946-64. Available from: https://doi.org/10.1038/s43018-020-00122-3 - 74.
Gozzi-Silva SC, Benard G, Alberca RW, Yendo TM, Teixeira FME, Oliveira L de M, et al. SARS-CoV-2 Infection and CMV Dissemination in Transplant Recipients as a Treatment for Chagas Cardiomyopathy: A Case Report. Trop Med Infect Dis [Internet]. 2021 Feb 10 [cited 2021 Feb 19];6(1):22. Available from: https://www.mdpi.com/2414-6366/6/1/22 - 75.
Sousa BLA, Sampaio-Carneiro M, de Carvalho WB, Silva CA, Ferraro AA. Differences among Severe Cases of Sars-CoV-2, Influenza, and Other Respiratory Viral Infections in Pediatric Patients: Symptoms, Outcomes and Preexisting Comorbidities. Clinics (Sao Paulo) [Internet]. 2020 [cited 2021 Apr 6];75:e2273. Available from: http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1807-59322020000100315&lng=en&nrm=iso&tlng=en - 76.
Hoffmann C, Wolf E. Older age groups and country-specific case fatality rates of COVID-19 in Europe, USA and Canada. Infection [Internet]. 2021 Feb 1 [cited 2021 Apr 24];49(1):111-6. Available from: https://doi.org/10.1007/s15010-020-01538-w - 77.
Kang SJ, Jung SI. Age-Related Morbidity and Mortality among Patients with COVID-19. Infect Chemother [Internet]. 2020 Jun 1 [cited 2021 Apr 24];52(2):154-64. Available from: /pmc/articles/PMC7335648/ - 78.
Fulop T, Larbi A, Dupuis G, Page A Le, Frost EH, Cohen AA, et al. Immunosenescence and inflamm-aging as two sides of the same coin: Friends or Foes? [Internet]. Vol. 8, Frontiers in Immunology. Frontiers Media S.A.; 2018 [cited 2021 Apr 24]. p. 1. Available from: /pmc/articles/PMC5767595/ - 79.
Franceschi C, Campisi J. Chronic inflammation (Inflammaging) and its potential contribution to age-associated diseases. Journals of Gerontology–Series A Biological Sciences and Medical Sciences. 2014. - 80.
Franceschi C, Bonafè M, Valensin S, Olivieri F, De Luca M, Ottaviani E, et al. Inflamm-aging. An evolutionary perspective on immunosenescence. In: Annals of the New York Academy of Sciences [Internet]. New York Academy of Sciences; 2000 [cited 2021 Apr 24]. p. 244-54. Available from: https://pubmed.ncbi.nlm.nih.gov/10911963/ - 81.
Pietrobon AJ, Teixeira FME, Sato MN. I mmunosenescence and Inflammaging: Risk Factors of Severe COVID-19 in Older People [Internet]. Vol. 11, Frontiers in Immunology. Frontiers Media S.A.; 2020 [cited 2021 Apr 24]. p. 2728. Available from: www.frontiersin.org - 82.
Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S, et al. Risk Factors Associated with Acute Respiratory Distress Syndrome and Death in Patients with Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA Intern Med. 2020; - 83.
Guan W, Ni Z, Hu Y, Liang W, Ou C, He J, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;382(18):1708-20. - 84.
de Abajo FJ, Rodríguez-Martín S, Lerma V, Mejía-Abril G, Aguilar M, García-Luque A, et al. Use of renin–angiotensin–aldosterone system inhibitors and risk of COVID-19 requiring admission to hospital: a case-population study. Lancet [Internet]. 2020 May 30 [cited 2021 Apr 24];395(10238):1705-14. Available from: www.bifap.org - 85.
De Caterina R, Ghiadoni L, Taddei S, Virdis A, Almerigogna F, Basta G, et al. Soluble E-selectin in essential hypertension: A correlate of vascular structural changes. Am J Hypertens [Internet]. 2001 Mar 1 [cited 2021 Apr 24];14(3):259-66. Available from: https://academic.oup.com/ajh/article-lookup/doi/10.1016/S0895-7061 (00)01276-0 - 86.
Jilma B, Blann AD, Stohlawetz P, Eichler HG, Kautzky-Willer A, Wagner OF. Dexamethasone lowers circulating E-selectin and ICAM-1 in healthy men. J Lab Clin Med [Internet]. 2000 [cited 2021 Apr 24];135(3):270-4. Available from: https://pubmed.ncbi.nlm.nih.gov/10711866/ - 87.
Dexamethasone in Hospitalized Patients with Covid-19—Preliminary Report. N Engl J Med. 2020; - 88.
Moutschen MP, Scheen AJ, Lefebvre PJ. Impaired immune responses in diabetes mellitus: Analysis of the factors and mechanisms involved. Relevance to the increased susceptibility of diabetic patients to specific infections [Internet]. Vol. 18, Diabete et Metabolisme. 1992 [cited 2021 Apr 25]. p. 187-201. Available from: https://europepmc.org/article/med/1397473 - 89.
Daryabor G, Atashzar MR, Kabelitz D, Meri S, Kalantar K. The Effects of Type 2 Diabetes Mellitus on Organ Metabolism and the Immune System [Internet]. Vol. 11, Frontiers in Immunology. Frontiers Media S.A.; 2020 [cited 2021 Apr 25]. p. 1582. Available from: www.frontiersin.org - 90.
Nishimura S, Manabe I, Nagasaki M, Eto K, Yamashita H, Ohsugi M, et al. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med [Internet]. 2009 Aug [cited 2021 Apr 25];15(8):914-20. Available from: https://pubmed.ncbi.nlm.nih.gov/19633658/ - 91.
Wagner NM, Brandhorst G, Czepluch F, Lankeit M, Eberle C, Herzberg S, et al. Circulating regulatory T cells are reduced in obesity and may identify subjects at increased metabolic and cardiovascular risk. Obesity [Internet]. 2013 Mar [cited 2021 Apr 25];21(3):461-8. Available from: https://pubmed.ncbi.nlm.nih.gov/23592653/ - 92.
Misumi I, Starmer J, Uchimura T, Beck MA, Magnuson T, Whitmire Correspondence JK. Obesity Expands a Distinct Population of T Cells in Adipose Tissue and Increases Vulnerability to Infection. CellReports [Internet]. 2019 [cited 2021 Apr 25];27:514-524.e5. Available from: https://doi.org/10.1016/j.celrep.2019.03.030 - 93.
Liang X, Xu J, Xiao W, Shi L, Yang H. The association of diabetes with COVID-19 disease severity: evidence from adjusted effect estimates. Hormones. 2020. - 94.
Barron E, Bakhai C, Kar P, Weaver A, Bradley D, Ismail H, et al. Associations of type 1 and type 2 diabetes with COVID-19-related mortality in England: a whole-population study. Lancet Diabetes Endocrinol. 2020; - 95.
Lei M, Lin K, Pi Y, Huang X, Fan L, Huang J, et al. Clinical Features and Risk Factors of ICU Admission for COVID-19 Patients with Diabetes. J Diabetes Res. 2020;2020. - 96.
Palaiodimos L, Chamorro-Pareja N, Karamanis D, Li W, Zavras PD, Chang KM, et al. Diabetes is associated with increased risk for in-hospital mortality in patients with COVID-19: a systematic review and meta-analysis comprising 18,506 patients. Hormones. 2020; - 97.
Ceriello A. Hyperglycemia and COVID-19: What was known and what is really new? [Internet]. Vol. 167, Diabetes Research and Clinical Practice. Elsevier Ireland Ltd; 2020 [cited 2021 Apr 24]. p. 108383. Available from: /pmc/articles/PMC7445137/ - 98.
Zhu L, She ZG, Cheng X, Qin JJ, Zhang XJ, Cai J, et al. Association of Blood Glucose Control and Outcomes in Patients with COVID-19 and Pre-existing Type 2 Diabetes. Cell Metab. 2020; - 99.
Berbudi A, Rahmadika N, Tjahjadi AI, Ruslami R. Type 2 Diabetes and its Impact on the Immune System. Curr Diabetes Rev [Internet]. 2019 Oct 28 [cited 2021 Apr 24];16(5):442-9. Available from: /pmc/articles/PMC7475801/ - 100.
Mooradian AD, Reed RL, Meredith KE, Scuderi P. Serum levels of tumor necrosis factor and IL-1α and IL-1β in diabetic patients. Diabetes Care [Internet]. 1991 [cited 2021 Apr 24];14(1):63-5. Available from: https://pubmed.ncbi.nlm.nih.gov/1991438/ - 101.
Sachdeva S, Desai R, Gupta U, Prakash A, Jain A, Aggarwal A. Admission Hyperglycemia in Non-diabetics Predicts Mortality and Disease Severity in COVID-19: a Pooled Analysis and Meta-summary of Literature. SN Compr Clin Med. 2020; - 102.
Wang A, Zhao W, Xu Z, Gu J. Timely blood glucose management for the outbreak of 2019 novel coronavirus disease (COVID-19) is urgently needed. Diabetes Res Clin Pract. 2020; - 103.
Hamming I, Timens W, Bulthuis MLC, Lely AT, Navis GJ, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004; - 104.
Pinto BG, Oliveira AE, Singh Y, Jimenez L, Goncalves AN, Ogava RL, et al. ACE2 Expression is Increased in the Lungs of Patients with Comorbidities Associated with Severe COVID-19. medRxiv. 2020; - 105.
Li J, Wang X, Chen J, Zuo X, Zhang H, Deng A. COVID-19 infection may cause ketosis and ketoacidosis. Diabetes, Obes Metab. 2020; - 106.
Marchand L, Pecquet M, Luyton C. Type 1 diabetes onset triggered by COVID-19. Acta Diabetol. 2020; - 107.
Akter F, Mannan A, Mehedi HMH, Rob MA, Ahmed S, Salauddin A, et al. Clinical characteristics and short term outcomes after recovery from COVID-19 in patients with and without diabetes in Bangladesh. Diabetes Metab Syndr Clin Res Rev. 2020; - 108.
Alberca GGF, Solis-Castro RL, Solis-Castro ME, Alberca RW. Coronavirus disease–2019 and the intestinal tract: An overview. World J Gastroenterol [Internet]. 2021 Apr 7 [cited 2021 Apr 24];27(13):1255-66. Available from: https://www.wjgnet.com/1007-9327/full/v27/i13/1255.htm - 109.
Vallianou NG, Stratigou T, Tsagarakis S. Metformin and gut microbiota: their interactions and their impact on diabetes. Hormones. 2019. - 110.
Zuo T, Zhang F, Lui GCY, Yeoh YK, Li AYL, Zhan H, et al. Alterations in Gut Microbiota of Patients With COVID-19 During Time of Hospitalization. Gastroenterology. 2020; - 111.
Marsh S, Aldington S, Shirtchiffe P, Weatherall M, Beasley R. Smoking and COPD: What really are the risks? [1] [Internet]. Vol. 28, European Respiratory Journal. European Respiratory Society; 2006 [cited 2020 Sep 21]. p. 883-4. Available from: www.goldcopd.com . - 112.
Gilca R, de Serres G, Boulianne N, Ouhoummane N, Papenburg J, Douville-Fradet M, et al. Risk factors for hospitalization and severe outcomes of 2009 pandemic H1N1 influenza in Quebec, Canada. Influenza Other Respi Viruses. 2011; - 113.
Aikphaibul P, Theerawit T, Sophonphan J, Wacharachaisurapol N, Jitrungruengnij N, Puthanakit T. Risk factors of severe hospitalized respiratory syncytial virus infection in tertiary care center in Thailand. Influenza Other Respi Viruses. 2020; - 114.
Dai M, Tao L, Chen Z, Tian Z, Guo X, Allen-Gipson DS, et al. Influence of Cigarettes and Alcohol on the Severity and Death of COVID-19: A Multicenter Retrospective Study in Wuhan, China. Front Physiol [Internet]. 2020 Dec 9 [cited 2020 Dec 26];11:588553. Available from: https://www.frontiersin.org/articles/10.3389/fphys.2020.588553/full - 115.
Lian J, Jin X, Hao S, Jia H, Cai H, Zhang X, et al. Epidemiological, clinical, and virological characteristics of 465 hospitalized cases of coronavirus disease 2019 (COVID-19) from Zhejiang province in China. Influenza Other Respi Viruses. 2020; - 116.
Zhao Q, Meng M, Kumar R, Wu Y, Huang J, Lian N, et al. The impact of COPD and smoking history on the severity of Covid-19: A systemic review and meta-analysis. J Med Virol. 2020; - 117.
Han H, Huang W, Du W, Shen Q, Yang Z, Li MD, et al. Involvement of Interferon Regulatory Factor 7 in Nicotine’s Suppression of Antiviral Immune Responses. J Neuroimmune Pharmacol. 2019; - 118.
Singanayagam A, Loo SL, Calderazzo M, Finney LJ, Torralbo MBT, Bakhsoliani E, et al. Antiviral immunity is impaired in COPD patients with frequent exacerbations. Am J Physiol – Lung Cell Mol Physiol. 2019; - 119.
Tian Z, Zhang H, DIxon J, Traphagen N, Wyatt TA, Kharbanda K, et al. Cigarette Smoke Impairs A 2A Adenosine Receptor Mediated Wound Repair through Up-regulation of Duox-1 Expression. Sci Rep. 2017; - 120.
Leung JM, Yang CX, Tam A, Shaipanich T, Hackett TL, Singhera GK, et al. ACE-2 expression in the small airway epithelia of smokers and COPD patients: implications for COVID-19. The European respiratory journal. 2020. - 121.
Alberca RW, Yendo T, Aoki V, Sato MN. Asthmatic patients and COVID-19: Different disease course? Allergy. 2020;1-2. - 122.
Caminati M, Lombardi C, Micheletto C, Roca E, Bigni B, Furci F, et al. Asthmatic patients in COVID-19 outbreak: Few cases despite many cases. J Allergy Clin Immunol. 2020 Jun;0(0). - 123.
Alberca RW. Asthma endotypes and COVID-19. Journal of Asthma. 2020. - 124.
Aveyard P, Gao M, Lindson N, Hartmann-Boyce J, Watkinson P, Young D, et al. Association between pre-existing respiratory disease and its treatment, and severe COVID-19: a population cohort study. Lancet Respir Med [Internet]. 2021 Apr [cited 2021 Apr 26];0(0). Available from: www.thelancet.com/respiratoryPublishedonline - 125.
Cavaillè A, Brinchault-Rabin G, Dixmier A, Goupil F, Gut-Gobert C, Marchand-Adam S, et al. Comorbidities of COPD [cited 2021 Apr 25]. Available from: http://ow.ly/o5Uqu - 126.
Boulet LP. Influence of comorbid conditions on asthma [Internet]. Vol. 33, European Respiratory Journal. European Respiratory Society; 2009 [cited 2021 Apr 26]. p. 897-906. Available from: www.erj.ersjournals.com/misc/ - 127.
Mehta V, Goel S, Kabarriti R, Cole D, Goldfi nger M, Acuna-Villaorduna A, et al. Case Fatality Rate of Cancer Patients with COVID-19 in a New York Hospital System. CANCER Discov | 935 Cancer Discov [Internet]. 2020 [cited 2021 Apr 25];10:935-76. Available from: http://cancerdiscovery.aacrjournals.org/ - 128.
Liu C, Zhao Y, Okwan-Duodu D, Basho R, Cui X. COVID-19 in cancer patients: risk, clinical features, and management [Internet]. Vol. 17, Cancer Biology and Medicine. Cancer Biology and Medicine; 2020 [cited 2021 Apr 12]. p. 519-27. Available from: /pmc/articles/PMC7476081/ - 129.
Curran EK, Godfrey J, Kline J. Mechanisms of Immune Tolerance in Leukemia and Lymphoma [Internet]. Vol. 38, Trends in Immunology. Elsevier Ltd; 2017 [cited 2021 Apr 25]. p. 513-25. Available from: /pmc/articles/PMC6049081/ - 130.
Dai M, Liu D, Liu M, Zhou F, Li G, Chen Z, et al. Patients with cancer appear more vulnerable to SARS-CoV-2: A multicenter study during the COVID-19 outbreak. Cancer Discov [Internet]. 2020 Jun 1 [cited 2021 Apr 25];10(6):783. Available from: https://pubmed.ncbi.nlm.nih.gov/32345594/ - 131.
Zhang L, Zhu F, Xie L, Wang C, Wang J, Chen R, et al. Clinical characteristics of COVID-19-infected cancer patients: a retrospective case study in three hospitals within Wuhan, China. Ann Oncol [Internet]. 2020 Jul 1 [cited 2021 Apr 25];31(7):894-901. Available from: https://pubmed.ncbi.nlm.nih.gov/32224151/ - 132.
Pestana RC, Filho DC, Centrone AF, Waisbeck TMB, Rodrigues HV, Araujo SEA, et al. COVID-19 incidence and outcomes among patients with respiratory symptoms in a cancer center emergency department. Brazilian J Oncol [Internet]. 2020 [cited 2021 Apr 25];16(0):1-5. Available from: http://www.brazilianjournalofoncology.com.br/details/131/en-US/covid-19-incidence-and-outcomes-among-patients-with-respiratory-symptoms-in-a-cancer-center-emergency-department - 133.
Burki TK. Cancer care in the time of COVID-19. Lancet Oncol [Internet]. 2020 May 1 [cited 2021 Apr 25];21(5):628. Available from: https://pubmed.ncbi.nlm.nih.gov/32213339/ - 134.
Ballow M, Notarangelo L, Grimbacher B, Cunningham-Rundles C, Stein M, Helbert M, et al. Immunodeficiencies [Internet]. Vol. 158, Clinical and Experimental Immunology. Blackwell Publishing Ltd; 2009 [cited 2021 Apr 25]. p. 14-22. Available from: /pmc/articles/PMC2801032/ - 135.
Sánchez-Ramón S, Bermúdez A, González-Granado LI, Rodríguez-Gallego C, Sastre A, Soler-Palacín P. Primary and Secondary Immunodeficiency Diseases in Oncohaematology: Warning Signs, Diagnosis, and Management. Front Immunol [Internet]. 2019 Mar 26 [cited 2021 Apr 25];10(MAR):586. Available from: https://www.frontiersin.org/article/10.3389/fimmu.2019.00586/full - 136.
Gereige JD, Maglione PJ. Current Understanding and Recent Developments in Common Variable Immunodeficiency Associated Autoimmunity [Internet]. Vol. 10, Frontiers in Immunology. Frontiers Media S.A.; 2019 [cited 2021 Apr 25]. Available from: https://pubmed.ncbi.nlm.nih.gov/31921101/ - 137.
Abolhassani H, Sagvand BT, Shokuhfar T, Mirminachi B, Rezaei N, Aghamohammadi A. A review on guidelines for management and treatment of common variable immunodeficiency. Vol. 9, Expert Review of Clinical Immunology. 2013. p. 561-75. - 138.
Ribeiro LC, Benites BD, Ulaf RG, Nunes TA, Costa-Lima C, Addas-Carvalho M, et al. Rapid clinical recovery of a SARS-CoV-2 infected common variable immunodeficiency patient following the infusion of COVID-19 convalescent plasma. Allergy, Asthma Clin Immunol [Internet]. 2021 Dec 1 [cited 2021 Apr 25];17(1):14. Available from: https://aacijournal.biomedcentral.com/articles/10.1186/s13223-021-00518-5 - 139.
Libster R, Pérez Marc G, Wappner D, Coviello S, Bianchi A, Braem V, et al. Early High-Titer Plasma Therapy to Prevent Severe Covid-19 in Older Adults. N Engl J Med. 2021; - 140.
Simonovich VA, Burgos Pratx LD, Scibona P, Beruto M V., Vallone MG, Vázquez C, et al. A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia. N Engl J Med. 2020; - 141.
Joyner MJ, Carter RE, Senefeld JW, Klassen SA, Mills JR, Johnson PW, et al. Convalescent Plasma Antibody Levels and the Risk of Death from Covid-19. N Engl J Med. 2021; - 142.
Shields AM, Burns SO, Savic S, Richter AG, Anantharachagan A, Arumugakani G, et al. COVID-19 in patients with primary and secondary immunodeficiency: The United Kingdom experience. J Allergy Clin Immunol. 2021 Mar 1;147(3):870-875.e1. - 143.
Meyts I, Bucciol G, Quinti I, Neven B, Fischer A, Seoane E, et al. Coronavirus disease 2019 in patients with inborn errors of immunity: An international study. J Allergy Clin Immunol [Internet]. 2021 Feb 1 [cited 2021 Apr 25];147(2):520-31. Available from: https://pubmed.ncbi.nlm.nih.gov/32980424/ - 144.
Van Der Made CI, Simons A, Schuurs-Hoeijmakers J, Van Den Heuvel G, Mantere T, Kersten S, et al. Presence of Genetic Variants among Young Men with Severe COVID-19. JAMA – J Am Med Assoc [Internet]. 2020 Aug 18 [cited 2021 Apr 25];324(7):663-73. Available from: https://jamanetwork.com/ - 145.
Dandachi D, Geiger G, Montgomery MW, Karmen-Tuohy S, Golzy M, Antar AAR, et al. Characteristics, Comorbidities, and Outcomes in a Multicenter Registry of Patients With Human Immunodeficiency Virus and Coronavirus Disease 2019. Clin Infect Dis [Internet]. 2020 Sep 9 [cited 2021 Apr 25]; Available from: https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa1339/5903368 - 146.
Lai CC, Wang CY, Hsueh PR. Co-infections among patients with COVID-19: The need for combination therapy with non-anti-SARS-CoV-2 agents? Vol. 53, Journal of Microbiology, Immunology and Infection. Elsevier Ltd; 2020. p. 505-12. - 147.
Richardson S, Hirsch JS, Narasimhan M, Crawford JM, McGinn T, Davidson KW, et al. Presenting Characteristics, Comorbidities, and Outcomes among 5700 Patients Hospitalized with COVID-19 in the New York City Area. JAMA – J Am Med Assoc. 2020; - 148.
Alberca RW et al. Case Report: COVID-19 and Chagas Disease in Two Coinfected Patients. Am J Trop Med Hyg. 2020; - 149.
Jankowiak Ł, Rozsa L, Tryjanowski P, Møller AP. A negative covariation between toxoplasmosis and CoVID-19 with alternative interpretations. Sci Rep [Internet]. 2020 Dec 1 [cited 2021 Apr 25];10(1):12512. Available from: https://doi.org/10.1038/s41598-020-69351-x - 150.
Carvalho SFG, Vieira TM, Moura APV, Andrade MC. Should an intersection between visceral leishmaniasis endemicity and the COVID-19 pandemic be considered? [Internet]. Vol. 144, Medical Hypotheses. Churchill Livingstone; 2020 [cited 2021 Apr 25]. p. 110289. Available from: /pmc/articles/PMC7501079/ - 151.
Hussein MIH, Albashir AAD, Elawad OAMA, Homeida A. Malaria and COVID-19: unmasking their ties [Internet]. Vol. 19, Malaria Journal. BioMed Central Ltd; 2020 [cited 2021 Apr 25]. p. 457. Available from: https://malariajournal.biomedcentral.com/articles/10.1186/s12936-020-03541-w - 152.
Ju B, Zhang Q, Ge J, Wang R, Sun J, Ge X, et al. Human neutralizing antibodies elicited by SARS-CoV-2 infection. Nature. 2020; - 153.
Garibaldi BT, Wang K, Robinson ML, Zeger SL, Bandeen-Roche K, Wang MC, et al. Comparison of Time to Clinical Improvement with vs without Remdesivir Treatment in Hospitalized Patients with COVID-19. JAMA Netw Open [Internet]. 2021 Mar 24 [cited 2021 Apr 26];4(3):e213071–e213071. Available from: https://jamanetwork.com/ - 154.
Zhang Y, Zeng G, Pan H, Li C, Hu Y, Chu K, et al. Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18-59 years: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial. Lancet Infect Dis. 2020; - 155.
Sahin U, Muik A, Derhovanessian E, Vogler I, Kranz LM, Vormehr M, et al. COVID-19 vaccine BNT162b1 elicits human antibody and TH1 T cell responses. Nature. 2020; - 156.
Sadoff J, Gray G, Vandebosch A, Cárdenas V, Shukarev G, Grinsztejn B, et al. Safety and Efficacy of Single-Dose Ad26.COV2.S Vaccine against Covid-19. N Engl J Med [Internet]. 2021 Apr 21 [cited 2021 Apr 26]; NEJMoa2101544. Available from: http://www.nejm.org/doi/10.1056/NEJMoa2101544