**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 virusspecific 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 [62–64]. Comorbidities may influence COVID-19 severity via an increase in pro-inflammatory response, coagulatory disorders, or different ACE2 expression [65–67]. 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.

#### *Immune Response to COVID-19 DOI: http://dx.doi.org/10.5772/intechopen.98964*

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 [96–98]. 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, 114–116].

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].
