Transmission, and the Immune System Nourishment
8.5 Immune Profile of Peripheral Blood in Patients
in type I SARS-CoV-2 strains. Higher transla- tional efficiencies might increase the production rate of type II SARS-CoV-2 particles, and conse- quently, we might expect that type II SARS- CoV- 2 strains tend to become in a corresponding degree more contagious than type I SARS-CoV-2 strains.
8.3 Neither the Window of Viral
milieu, marked by the production of various inflammatory mediators, tissue injury-related enzymes, and biomarkers of hypercoagulation (Wang et al. 2020b). Figure 8.5 gives an over- view of the body burden of and biomarker changes well-associated with COVID-19. Below, we will provide a rapid review of COVID-19- related changes in the immune system.
8.5.1 White Blood Cell
The majority of cases with COVID-19 show nor- mal white blood cell counts (WBC) (Guan et al.
2020; Wang et al. 2020a). Among patients with abnormal WBC counts, low counts are about six
times more prevalent than high counts (Guan et al. 2020). More than 60% of patients with severe COVID-19 have low WBC counts, while less than 30% of patients with mild and moderate disease show low WBC counts (Guan et al.
2020). The median count of WBC is higher in patients who require admission to the intensive care unit (ICU) than patients who do not need the ICU (Huang et al. 2020; Wang et al. 2020a).
However, another study found no such difference between ICU and not-ICU patients (Zhou et al.
2020).
8.5.1.1 Lymphocytes
Lymphopenia is a common laboratory finding (Fathi and Rezaei 2020) present early on since
Fig. 8.5 The body burden of COVID-19
the symptoms appear, even in patients with mild COVID-19 (Guan et al. 2020) and even in those who have normal WBC count (Cai et al. 2020).
On admission, patients whose conditions progressed to the critically ill, patients who required admission to ICU, and patients who died from disease had a median lymphocyte count lower than that of patients whose condition was mild or severe, patients who do not require the ICU, and patients who survived (Huang et al.
2020; Wang et al. 2020a; Yang et al. 2020a; Chen et al. 2020b; Zhou et al. 2020). Up to about 96%
of the population with severe and critical COVID- 19 has lymphopenia (Guan et al. 2020). A lym- phocyte count of less than 1100 per mm3 can predict elevation in alanine aminotransferase (ALT) and, therefore, COVID-19-related hepatic injury (Li et al. 2020b).
T Cells
T-Cell Pattern in Relation to the Deterioration of COVID-19
As the disease continues to deteriorate, the lym- phocyte count steadily decreases (Fig. 8.6). The study (Jiang et al. 2020) placed patients with
COVID-19 into three categories – remission (N = 74), deterioration (N = 26), and death (N = 12) – and provided a peripheral T-cell pro- file of patients in three general stages: early, advanced, and late stage. Throughout the stages, total lymphocyte count (TLC) in remitting patients was steadily higher than that in patients of deterioration and death groups. TLC in patients of the death group was lower than patients of the other two groups and steadily decreased during the disease progression. The initial normal TLC decreased in the advanced stage in patients in the deterioration group. For all three subsets of T cells, e.g., CD3+ T cells, CD4+ T cells, and CD8+ T cells, in the advanced stage of COVID- 19, patients who obtained the remission had greater counts compared with patients who deteriorated, and these patients, in turn, had greater counts than those who died (Fig. 8.7). The three groups of patients did not differ in B-cell counts. During a follow-up of 1 month, counts of CD4+ T and CD8+ T cells averaged above nor- mal in most of the remission patients. On the con- trary, the CD4+ T- and CD8+ T-cell values were below normal in most of the patients in the dete- rioration and death groups.
Fig. 8.6 Peripheral blood lymphocyte count during the progression of COVID-19
T-Cell Pattern in Relation to the Severity of COVID-19
A study of 40 patients with COVID-19 moni- tored the kinetics of lymphocyte counts within 16 days after the onset of disease and compared that between severe and mild disease (Liu et al.
2020). On the first 6 days after the onset of dis- ease, patients with severe COVID-19 had lower counts of total lymphocyte, CD3+ T cells, CD4+
T cells, and CD8+ T cells, pointing to the lowest levels on the fourth to the sixth day. Since the seventh day, the counts in the severe group began to increase so that on the sixteenth day, there was no difference between severe and mild COVID- 19 patients in counts of total lymphocytes.
T-Cell Pattern in Relation to the Criticality of COVID-19
A retrospective study of 522 patients with con- firmed COVID-19 reveals that more than 70% of patients had reduced counts of total T cells, CD4+ T cells, and CD8+ T cells (Diao et al.
2020). Patients admitted to the ICU had lower counts of these cells than patients not admitted to ICU. Among non-ICU patients, those who were in a severe or critical state of disease produced lower counts of total T cells, CD4+ T cells, and CD8+ T cells compared to their counterparts.
Interestingly, an analysis of total T-cell counts and T-cell subsets in different age groups reflected that the count of these cells changes in an age- dependent manner such that the highest counts of total T cells, CD4+ T cells, and CD8+ T cell are
seen in patients with less than 20 years of age while the lowest counts of these cells occur in patients of 60 years and above.
T Cells Become Reduced, Exhausted, and Overwhelmed in COVID-19
The change in T cells is profound. Not only the counts of total T cells and T-cell subsets decrease, but the function of these cells becomes less effec- tive as the expression of immune inhibitory receptors increases over time during the disease.
Individuals with COVID-19 have a higher pro- portion of T cells expressing programmed cell death protein 1 (PD-1), an immune checkpoint that contributes to CD8+ T-cell exhaustion dur- ing chronic infections and cancers through affect- ing T-cell receptor signaling, that controls without COVID-19. Among COVID-19 patients, those who require ICU would, in turn, have a higher proportion of PD-1+ CD8+ T cells compared to non-ICU patients. A follow-up of a few cases provided evidence that the counts of CD8+ T cells start increasing, while PD-1 moves in the direction of decreasing expression throughout the prodromal phase of the disease (Diao et al. 2020).
A study of 33 patients with severe COVID-19 showed that compared to patients who do not require ICU, the counts of total T cells, CD4+ T cells, and CD8+ T cells were lower in patients admitted to ICU, who, in turn, had lower counts than healthy controls (Zhou et al. 2020). Despite lower counts, T cells become activated in patients with severe COVID-19, as indicated by an
Fig. 8.7 Peripheral blood T-cell count in the advanced stage of COVID-19
increased expression of CD69, CD38, and CD44 on both CD4+ T and CD8+ T cells, OX40 (CD134) on CD4+ T cells, and 41BB (CD137) on CD8+ T cells. In parallel, they will become exhausted as represented in the increased expres- sion of Tim3 and PD-1 on both CD4+ T and CD8+ T cells. Intracellular staining highlighted the higher percentage of CD4+ T cells expressing IL-6 and GM-CSF, but not TNFα, in patients with severe COVID-19 than healthy controls and patients admitted to ICU than patients not requir- ing ICU. Also, CD8+ T cells expressing GM-CSF, but not IL-6 and TNFα, were increased in ICU than non-ICU patients. CD4+ T cells that express both IFNγ and GM-CSF existed merely in patients with severe COVID-19 who are admitted to ICU.
Besides lower counts of lymphocyte subsets (CD3+ T cells, CD4+ T cells, and CD8+ T cells), there is an increased CD4/CD8 ratio in the major- ity of critically ill patients with COVID-19 admit- ted to ICU (Wang et al. 2020c). Generally, an increased CD4/CD8 ratio relates to autoimmune diseases, while a decreased ratio commonly occurs in viral infections. These lines of evidence support the idea that COVID-19 tends to develop an autoimmune-like condition rather than merely resemble a viral infection.
B Cells and Natural Killer (NK) Cells
At all the time points within the clinical course of the disease, patients with severe COVID-19 did not differ in the number of B cells and natural killer (NK) cells from patients with mild COVID- 19 (Liu et al. 2020) (Fig. 8.8). Among patients with severe COVID-19, ICU and non- ICU patients did not differ in counts of B and NK cells (Zhou et al. 2020). However, when the con- dition progressed to critically ill, the number of NK cells decreased below normal levels (Wang et al. 2020c).
8.5.1.2 Monocytes
Patients with severe COVID-19, either requiring or not requiring ICU, had lower counts of mono- cytes than healthy controls (Zhou et al. 2020).
However, the proportion of monocytes express- ing both CD14 and CD16 was higher in patients
with severe COVID-19, especially those who require the ICU (Zhou et al. 2020). Generally, these monocytes, known as intermediate cyto- kines, exhibit a pro-inflammatory behavior (Zhou et al. 2020). In particular, peripheral blood mono- cytes from ICU patients with COVID-19 express high levels of IL-6 and GM-CSF (Zhou et al.
2020).
8.5.1.3 Neutrophils
Studies indicate that on admission, the median count of neutrophils is higher in i, patients who were in a severe condition compared to patients who were in a mild condition; ii, patients whose condition was or progressed to critically ill com- pared to patients whose condition was mild or severe or not progressed to critically; and iii, patients admitted to the ICU compared to patients not admitted to the ICU (Huang et al. 2020; Wang et al. 2020a; Chen et al. 2020b; Liu et al. 2020).
Kinetics of neutrophil counts during the clinical course of 16 days following SARS-CoV-2 infec- tion corroborates sustained higher counts in patients with severe disease compared to patients with mild disease (Liu et al. 2020). The study (Liu et al. 2020) identified neutrophil to CD8+
T-cell ratio, neutrophil to lymphocyte ratio, WBC counts, and neutrophil counts as the best predic- tors of COVID-19 severity.
8.5.2 Immunoglobulins
At the baseline, patients with severe and mild forms of COVID-19 showed no difference in lev- els of immunoglobulins IgA, IgG, and IgM (Liu et al. 2020). The detection of both IgM and IgG tends to increase by time (Zhang et al. 2020d).
For IgM, the detection rates were estimated using ELISA to be about 50% and 80% on day 0 and 5.
The corresponding rates for IgG were 80% and 100%. More precisely, a kinetic study of 49 patients with COVID-19 estimated that IgM and IgG simultaneously happen, and their detection rates rise at the median of 10 days after the onset of infection (Li et al. 2020a). In particular, S-IgM and N-IgM exist in about 39% and 51% of patients at the median of 10 (range: 3–20 days)
and 9 (range: 2–16 days) days after the onset of infection (Li et al. 2020a). S-IgG and S-IgM appeared in about 63% and 41% of patients at a median of 9 days (range: 2–22 days) (Li et al.
2020a). Only about 10% of patients must pro- duce high levels of antibodies, and in these patients, S-IgG is the only antibody that remained high over 30 days after infection (Li et al. 2020a).
8.5.3 Complement Factors
Baseline levels of complements C3 and C4 were not different between patients with severe and mild forms of COVID-19 (Liu et al. 2020).
8.6 Cytokine Storm: A Defensive