Transmission, and the Immune System Nourishment
8.6 Cytokine Storm: A Defensive Strategy Protecting
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
8.6.1.2 Tracing Kinetics of Changes in Cytokine Levels in COVID-19 Cytokines Add Their Character
to the Progression of COVID-19
A negative association between cytokine levels and T-cell counts (total and CD4+ and CD8+
subsets), as well as the reduction in cytokine lev- els during treatment, poses the accumulation of cytokines as a critical inhibitor of T-cell survival and proliferation (Diao et al. 2020).
The Changes of IL-6 and IL-10 Are Most Remarkable During COVID-19
The study (Liu et al. 2020) monitored serum lev- els of cytokines, e.g., IL-2, IL-4, IL-6, IL-10, IFNγ, and TNFα, during the clinical course of disease in patients with severe and mild COVID- 19. For the mild group, a straight line described no fluctuations in concentrations of all cytokines. The severe group showed a very dif- ferent profile of cytokines. For the cytokines IL-2, IL-4, IFNγ, and TNFα, there was one peak concentration on the fourth to the sixth day. The most potent fluctuations occurred in the concen- trations of IL-6 and IL-10.
Another kinetic study of cytokines (IL-2, IL-4, IL-6, IL-10, IL-17, IFNγ, TNFα, and IL-12P70) highlighted IL-6 as the only cytokine that increased in more than 50% of patients with COVID-19 (N = 49), with the median detection time of 7 days (range: 2–26 days) (Li et al. 2020a). Analysis of individual patient data indicated that for the most COVID-19-associated cytokines, e.g., IL-6, IL-10, and IFNγ, the peak concentration occurs at 8 days, which begins to decrease within the subsequent 2–3 days (Li et al. 2020a). Higher levels of IL-6 occurred in patients with severe than those with mild disease. Higher levels of IL-10 happened in patients with an underlying condition.
8.6.1.3 IL-6: The Well-Documented Cytokine in COVID-19 IL-6 Levels in Relation to the Severity of COVID-19
Overall, more than 50% of patients display increased levels of IL-6. Of note, patients with higher COVID-19 severity, as defined by chest
computed tomography (CT) scan scores, exhibit significantly higher concentrations of IL-6 com- pared to cases with lower disease severity (Wang et al. 2020b).
IL-6 Levels in Relation to the Criticality of COVID-19
Among the investigated cytokines, IL-6 seems to be of high value because its increase was observed in all critically ill patients admitted to ICU (Wang et al. 2020c), while the increase of other cyto- kines, e.g., IL-10, IL-4, and IFNγ, existed in less than half of those patients. Monitoring patient status along with measurement of IL-6 levels showed that the increase of IL-6 could predict that respiratory condition may worsen shortly and pulmonary inflammation may progress as represented in chest CT (Wang et al. 2020c).
IL-6 Levels in Relation to the Viral Load of COVID-19
The study of patients with throat-swab specimen that tests positive showed that the SARS-CoV-2 nucleic acid could be detected in critically ill patients, but not in patients having a mild or severe form of the disease (Chen et al. 2020b).
Critically ill patients with COVID-19 show ten- fold higher levels of IL-6 compared to patients with mild and severe COVID-19, and SARS- CoV- 2 RNAaemia relates directly with IL-6 lev- els (Chen et al. 2020b). In this manner, IL-6 levels of 100 pg/ml or more are considered as a biomarker of mortality and RNAaemia in patients with COVID-19 (Chen et al. 2020b).
IL-6 Levels in Relation to the Prognosis of COVID-19
There is a direct linear correlation between serum IL-6 and CT imaging scores and the reduction of IL-6 levels during treatment (Wang et al. 2020b).
8.6.2 Inflammatory Markers
Inflammatory markers, mainly C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), lactate dehydrogenase (LDH), procalcitonin (PCT), serum amyloid A (SAA), and ferritin, rise in patients with COVID-19.
8.6.2.1 Inflammatory Markers in Relation to the Severity of COVID-19
Patients with a severe form of the disease and patients admitted to ICU show higher baseline levels of inflammatory markers, particularly CRP, compared to patients with mild COVID-19 and patients not admitted to ICU (Liu et al. 2020;
Zhou et al. 2020). Compared to patients with lower chest CT scan scores, patients with higher chest CT scan scores have higher levels of CRP, ESR, and serum amyloid A (Wang et al. 2020b).
However, CRP seems to be the most important one because of its meaningful correlation with CT scan score in terms of the higher the CRP lev- els are, the higher the CT scan score, and there- fore the more the COVID-19 is severe.
8.6.2.2 Inflammatory Markers
in Relation to the Complications of COVID-19
Cardiac complications, including tachycardia, electrocardiography abnormities, diastolic dys- function, elevated myocardial enzymes, and acute myocardial injury, are prevalent in patients with COVID-19. High CRP levels can predict those who will develop cardiac complications (Xu et al. 2020a).
8.6.2.3 Inflammatory Markers in Relation to the Prognosis of COVID-19
Treatment reduces CRP and ESR levels, and therefore, CRP and ESR offer an excellent prog- nostic biomarker. In particular, elevated CRP lev- els are predictive of liver injury, as indicated in high ALT levels (Li et al. 2020b).
8.6.3 Differentially Expressed Genes in Bronchoalveolar Lavage Fluid and Peripheral Blood from Patients
with COVID-19
The near-total absence of viral reads and ACE2 expression in PBMC provides evidence that SARS-CoV-2 does not directly infect PBMC,
despite the presence of a high number of viral reads in BALF samples (Xiong et al. 2020).
Quantitative transcriptome analysis selected about 1000 and 500 differentially expressed genes (DEGs) in BALF and PBMC among patients with COVID-19 compared to controls.
The upregulated genes in BALF include those involved in viral invasion strategies such as cotranslational protein targeting to membrane, protein targeting to the endoplasmic reticulum, and viral transcription. While the downregulated genes can act mainly on immune cell activation, the upregulated genes in PBMC play a role in activating the immune responses, especially complement activation, humoral immune response mediated by circulating immunoglobu- lin, and B cell-mediated immunity, and in induc- ing inflammatory processes and regulation of acute inflammatory response. Also, genes differ- entially downregulated in PBMC from patients with COVID-19 are recognized for their partici- pation in processes related to the maturation of immune cells, such as chemotaxis and migration.
Pathways enriched by upregulated genes in BALF include ribosome, protein processing in the endoplasmic reticulum, phagosome, pentose phosphate pathway, carbon metabolism, and lysosome (Xiong et al. 2020). Upregulated genes in PBMC contribute to cell cycle and P53 signaling pathways. In contrast, downregulated genes take part in viral protein interaction with cytokine and cytokine receptor, NF-kappa B (NF-kB) signaling pathway, Toll-like receptor (TLR) signaling pathway, and IL-17 signaling pathway. P53 signaling plays a role in cell cycle control and apoptosis, and its upregulation and mediated apoptosis may explain reduced counts of PBMC, e.g., lymphocytes in patients with COVID-19.
As for their gene expression, patients with COVID-19 show increased expression of cyto- kines IL-10, CCL2/MCP-1, CXCL10/IP-10, CCL3/MIP-1A, and CCL4/MIP1B in BALF (Xiong et al. 2020). The change in the expression of IL-10, IL-36RN, IL-36G, TNFSF15, CCL5, TNFSF10, CXCL1, and IL-33 depends on dis- ease severity.
8.7 The Scenario of How