September 25, 2022

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COVID-19 pneumonia:  Severe Pneumonia and Immune Disorders

COVID-19 pneumonia:  Severe Pneumonia and Immune Disorders

COVID-19 pneumonia:  Severe Pneumonia and Immune Disorders

Immune state disorder is one of the main reasons for the progression and poor prognosis of severe COVID-19.  Effective immune conditioning is an important strategy to affect the outcome of severe COVID-19 patients.

COVID-19 pneumonia:  Severe Pneumonia and Immune Disorders

Novel coronavirus pneumonia (COVID-19) is an acute respiratory infectious disease caused by new coronavirus (SARS-CoV-2) infection, which has become a prominent problem that seriously threatens human life and health at this stage.

At present, more than 276 million patients worldwide have been diagnosed with OVID-19, and the death toll from severe pneumonia is as high as 5.3 million.

The cumulative number of confirmed COVID-19 cases in some countries is about 100,000, including 4,636 deaths [1-2].

Pneumonia is the main manifestation of SARS-CoV-2 infection.

Clinical patients have fever, cough and dyspnea, which can be accompanied by multiple organ damage, such as heart, liver, kidney, etc., and gradually progress to severe pneumonia, which eventually leads to the death of the patient.

At present, the exact mechanism of severe pneumonia caused by SARS-CoV-2 infection is still unclear, and specific treatment methods are lacking in clinical practice.

The current view is that virus-mediated cell damage, down-regulation of angiotensin-converting enzyme 2 (ACE2) expression caused by dysfunction of the renin-angiotensin-aldosterone system, endothelial cell damage, pulmonary vascular microthrombosis, and immune response Abnormal and hyperinflammatory state are the main pathophysiological features of COVID-19 [3].

Impaired immune response plays an important role in the occurrence and progression of COVID-19, and is considered to be one of the main causes of multiple organ damage and death.

Studies have found that SARS-CoV-2 can invade almost all types of immune cells in the body, and mediate abnormal immune responses in the body by inducing cell response disorder and death, such as inducing monocyte or macrophage hyperactivation and T lymphocytes.

A large amount of apoptosis leads to the imbalance of innate and adaptive immune responses, excessive release of inflammatory factors and hypolymphocymemia [4].

A large number of clinical data show that indicators related to immune disorders, such as neutrophil-to-lymphocyte ratio (NLR) and lymphocyte count decrease, are closely related to the severity and death of COVID-19 patients [5-6].

Therefore, it is of great theoretical significance and clinical application value to fully understand the functional changes and regulatory mechanisms of immune cells during SARSCoV-2 infection for in-depth understanding of the pathophysiological process of COVID-19 and the search for effective treatment methods.

1 Disorders of the innate immune response

1.1 Monocytes/macrophages 

Monocytes/macrophages are the first line of defense of the body’s immune response and the main site of cytokine production.

It has been clear that SARS-CoV-2 can infect peripheral CD14+ monocytes and alveolar macrophages through ACE2-dependent and independent pathways, and the latter rapidly activate and release a large number of chemokines and inflammatory mediators, such as CX-C chemokine.

Ligand (CXCL) 10, CXCL11, CC Chemokine Ligand (CCL) 15, CCL16, CCL19, Granulocyte-Macrophage Stimulating Factor (GM-CSF), Interferon (IFN)-α, Interleukin ( IL)-6, tumor necrosis factor (TNF)-α, further recruit immune cells and effectively remove pathogenic microorganisms [7].

The autopsy results of 2 dead patients with severe COVID-19 showed that the patients had severe lung tissue damage and pathological manifestations of acute respiratory distress syndrome (ARDS), the levels of inflammatory factors in the lung tissue were significantly increased, and a large number of macrophages infiltrated in the alveoli [8].

Cytological analysis found that monocytes and macrophages in peripheral blood and lung tissue were significantly infected with SARS-CoV-2, which was associated with high expression of ACE2 and increased binding of S protein [8].

SARS-CoV-2 positive monocytes showed obvious tissue infiltration and differentiated into inflammatory macrophages, which showed an overactivated state and released a large number of inflammatory mediators, which is one of the main causes of cytokine storm in COVID-19 patients [ 7].

Local high levels of inflammatory factors in the tissue are the direct cause of alveolar epithelial cell damage, and further mediate a large number of microthrombosis by promoting endothelial tissue factor release and abnormal activation of coagulation factors, aggravating tissue damage [9].

Various mechanisms are involved in the process of monocyte tissue infiltration and macrophage hyperactivation induced by SARS-CoV-2 infection, including Toll-like receptor (TLR)-dependent nuclear factor kappa B (NF-κB) and Janus kinase (JAK) – Signal transducer and activator of transcription (STAT) signaling pathway activation, receptor-dependent and -independent pathways Nucleotide oligomerization domain (NOD)-like receptor pyrin domain-related protein (NLRP) 3 inflammatory body activation, etc. [7].

A number of clinical studies have been carried out to downregulate the levels of inflammatory factors in patients with COVID-19, including monoclonal antibodies that antagonize IL-6 and IL-1β, inflammasome activity inhibitors, and TLR4-TIR domain adaptor proteins ( However, there is no clear evidence to slow down the progression of severe COVID-19 and improve prognosis [7].

Using single-cell sequencing technology to analyze immune cells in bronchoalveolar lavage fluid (BALF) of COVID-19 patients, it was found that macrophages in BALF can be subdivided into 4 large subgroups, including FCNhi subgroup, FCNlowSPP1+ subgroup, FCN- SPP1+ subgroup and FABP4+ subgroup.

Compared with mild and normal people, the macrophage subsets of severe COVID-19 patients were significantly dysregulated, showing that the proportion of FCNhi subset, FCNlowSPP1+ subset and FCN-SPP1+ subset was significantly increased, while the proportion of FABP4+ subset was significantly decreased. , even missing [10].

In-depth analysis found that the activities of STAT1, STAT2 and various IFN regulatory factors (IRFs) in the FCNhi subset, FCNlowSPP1+ subset and FCN-SPP1+ subset were enhanced, which was related to inflammatory activity, while the FABP4+ subset was due to the high expression of peroxides.

Enzyme proliferator-activated receptor (PPARG) and basic helix-loop-helix family member e41 (BHLHE41) are involved in lipid metabolism [10].

Fully understand the key links and specific molecular mechanisms of monocyte infiltration and macrophage hyperactivation during SARS-CoV-2 infection, and the use of multi-level and multi-target joint regulation may be the future treatment of severe pneumonia caused by SARS-CoV-2. potential measures.

1.2 Neutrophils The increase in the number of neutrophils and the increase in the proportion of lymphocytes is one of the important immunological features of SARS-CoV-2 infection, which is closely related to the severity of the disease and the prognosis of patients [6].

The increase in circulating and lung tissue neutrophils is the main feature of the innate immune response to COVID-19, which can participate in the innate immune response process of SARS-CoV-2 infection by directly phagocytosing pathogenic microorganisms and forming extracellular traps (NETs)[11] ].

Moderate neutrophil infiltration is an important means to effectively remove pathogenic infection and tissue repair, while excessive neutrophil infiltration and delayed resolution are the main factors causing tissue damage.

It has been reported that compared with patients with mild to moderate COVID-19, the number of neutrophils in the peripheral blood of patients with severe COVID-19 shows a continuously increasing trend, which is significantly associated with worsening of lung imaging changes and poor prognosis [12].

At the same time, the activity of neutrophils was significantly enhanced, and the formation and release of NETs increased. The latter are widely present in bronchoalveoli, pulmonary interstitium and pulmonary blood vessels, which can promote the release of inflammatory factors, endothelial damage and thrombosis, etc., thereby aggravating severe pneumonia. deterioration [11].

Therefore, targeted regulation of the formation and release of NETs may be an effective target for improving lung tissue damage in severe COVID-19 patients.

Studies have confirmed that inhalation or systemic application of deoxyribonuclease (DNase) can dissolve NETs, ​​reduce the level of NETs in lung tissue, improve lung function in patients with cystic fibrosis, and reduce the incidence of secondary infection [13].

Compared with healthy controls and mild patients, the relative abundance of peripheral blood neutrophil subsets in severe COVID-19 patients also changed significantly, and the expression of CD10 was significantly reduced, resulting in CD10LowCD101-CXCR4+/- immature neutrophils.

The proportion of rheumatoid arthritis increased significantly, which may be one of the main reasons for tissue damage [14].

1.3 Dendritic cells Dendritic cells are the most powerful professional antigen-presenting cells in the body, and play an important role in the antiviral immune response, the initiation of adaptive immunity and the maintenance of immune balance.

Dendritic cells include classical dendritic cells (cDCs), plasmacytoid dendritic cells (pDCs) and follicular dendritic cells (FDCs), among which pDCs efficiently recognize viruses and secrete them through the characteristic expression of TLR7 and TLR9 A large number of type I IFNs play an important role in antiviral immunity.

Studies have found that acute SARS-CoV-2 infection leads to a sharp decrease in the number of dendritic cells in circulation, an imbalance in the ratio of cDC to pDC, and an increased cDC/pDC ratio is closely related to poor prognosis [15].

The increased pyroptosis of dendritic cells after SARS-CoV-2 infection is considered to be an important mechanism for the reduction of cell numbers and the uncontrolled release of inflammatory mediators [16].

In addition, dendritic cells in severe COVID-19 patients have obvious maturation and activation barriers, and the expression of surface co-stimulatory molecules CD86 and CD80 is significantly inhibited compared with healthy people, resulting in down-regulation of T lymphocyte immune responses [15].

After SARS-CoV-2 infects monocyte-derived dendritic cells in vitro, the production and release of interferon is significantly inhibited, which is related to the interference of STAT1 phosphorylation in cells by SARS-CoV-2 [17].

At present, there are few reports on the evaluation of the number and function of dendritic cells in severe COVID-19 patients, and the molecular mechanism is still unclear.

Dendritic cells are the key link for bridging innate immunity and adaptive immunity, and their decrease in number and abnormal function will inevitably lead to the obstacle of immune activity of the body.

2 Adaptive immune response disorders

2.1 T lymphocytes 

T lymphocytes mediate the core of adaptive immunity in the body, can effectively recognize antigen signals processed by antigen-presenting cells, rapidly proliferate and differentiate into different effector T cell subsets, and exert immunological effects. It has been clear that both CD4+T and CD8+T lymphocytes are involved in the occurrence and development of COVID-19 [18].

Some data show that under normal circumstances, SARS-CoV-2 reactive T cells are mainly Th1-type lymphocytes, which play antiviral immunity by secreting IFN-γ, TNF-α and IL-2 [19]. However, in severe COVID-19 patients, CD4+ T lymphocytes appear to be polarized towards the Th17 phenotype while the activation of Th1 type cells is inhibited [20].

At the same time, immunosuppressive phenotypic molecules, such as programmed cell death protein (PD) 1 and cytotoxic T lymphocyte antigen (CTLA) 4, have a significant increase in the proportion of positive T lymphocytes, which are significantly positively correlated with poor prognosis [21] .

CD4+T and CD8+T lymphocyte activation disorders are the main characteristic manifestations of adaptive immune response disorders in severe COVID-19 patients.

A large number of clinical observations have confirmed that the decrease in the number of peripheral blood lymphocytes is an important feature of the progression of severe COVID-19, and the numbers of effector, naive and memory CD4+T and CD8+T lymphocytes are significantly reduced [22].

In addition, using single-cell sequencing technology, according to the expression and distribution of T cell phenotype genes, T cells can be subdivided into 12 subgroups, including 6 subtypes of CD4+ T cells (CD3e+CD4+) and 3 subtypes of CD8+ T cells ( CD3e+CD8a+) and three NKT cell subtypes (CD3e+CD4﹣CD8a﹣TYROBP+)[23].

The study found that compared with healthy controls, the proportion of NK and T cells in COVID-19 patients was significantly higher, and compared with mild patients, the proportion of CD8+ T cells in severe patients was lower, which may be due to SARS-CoV-2 virus clearance.

One of the reasons for the decline in ability [10]. However, the exact mechanism of T lymphocyte activation disorder, decrease in number and abnormal differentiation is still inconclusive.

Fully elucidating the key links and regulatory mechanisms of T lymphocyte proliferation, activation and differentiation during SARS-CoV-2 infection will help Develop measures to improve immunosuppression in critically ill COVID-19 patients.

2.2 B lymphocytes 

B cells are the main performers of humoral immunity. They can effectively recognize and bind antigens through the characteristic surface marker B cell receptor (BCR), activate and produce antibodies under the synergistic effect of costimulatory molecules to exert immune opsonizing effects .

The study found that the level of IgM in peripheral blood of patients with newly diagnosed SARS-CoV-2 was significantly increased, while the increase of IgG concentration often indicated that the patients were in the recovery period of SARS-CoV-2 infection, suggesting that the functional status and differentiation direction of B cells were related to SARS-CoV-2 infection.

Patient prognosis is closely related [24]. The proportion of B cells in the peripheral blood of severe COVID-19 patients was significantly lower than that of healthy individuals and mild to moderate patients, but the proportion of plasma cells showed an upward trend, suggesting that SARS-CoV-2 infection caused a decrease in the number and abnormal differentiation of B cells, and was associated with COVID-19 infection. -19 is related to the severity of [25].

In addition, the levels of IgM and IgG in peripheral blood of severe COVID-19 patients increased in a time-dependent manner, but were not significantly correlated with the expansion of plasma cells [25].

The significance and mechanism of B lymphocyte-mediated humoral immunity in antagonizing SARS-CoV-2 infection is still unclear.

Plasma cell expansion and increased antibody production are on the one hand the body’s way of responding to infection, and on the other hand, persistent B cell abnormalities Differentiation and antibody production are potential triggers of immune response disturbances and tissue damage.

Therefore, dynamic monitoring of peripheral blood B cell number and subtype changes, IgM and IgG levels in severe COVID-19 patients may be an important means to effectively understand disease progression and evaluate prognosis.

In addition, a new granulocyte phenotype in B cells was found to be an important immunological feature in severe COVID-19 patients [26].

3 The relationship between immune disorders and multiple organ dysfunction in patients with COVID-19

Multiple organ dysfunction is the main reason for the poor prognosis of severe COVID-19 patients.

Especially under the premise of the lack of specific treatment measures, organ function support is the main means of treating COVID-19 patients.

It has been clear that the deterioration of the local inflammatory microenvironment caused by the imbalance of immune balance and the release of excessive inflammatory factors is an important factor in causing organ function damage caused by SARSCoV-2 infection.

The latter can further damage the vascular endothelium, induce microthrombosis, and lead to tissue damage. ischemia and aggravate organ damage [27].

SARS-CoV-2 has been found in multiple organ cells of COVID-19 patients and can mediate tissue damage by directly inducing tissue cell damage and imbalance of the local immune microenvironment [27].

Studies have found that monocytes infected with SARS-CoV-2 can infiltrate into various tissues and organs through the bloodstream, differentiate into inflammatory macrophages, and become the main initiating factor that induces the massive release of local inflammatory factors [7].

In addition, delayed neutrophil withdrawal has also been shown to be one of the important causes of organ dysfunction in COVID-19 patients.

Lymphocytopenia caused by SARS-CoV-2 infection leads to an imbalance of local innate and adaptive immune responses in tissues, which is a direct factor in local immune microenvironment disturbance and tissue damage.

4 Immune conditioning and clinical application prospects

So far, there is no specific drug for the treatment of COVID-19 in the world, and supportive treatment is still the mainstay in clinical practice, including antiviral, hormone and organ supportive treatment.

Studies have found that a variety of immune conditioning measures have certain effects in slowing the progression of severe COVID-19 and improving prognosis [28].

Anti-inflammatory treatments such as hormones, inflammatory response signaling pathway inhibitors, and targeted cytokines may be potential means to reduce lung injury and improve survival in severe COVID-19 patients [29].

In addition, α-thymosin and mesenchymal stem cells, as well as plasma from convalescent patients, have potential protective effects on severe COVID-19 patients [28].

4.1 Glucocorticoids Glucocorticoids 

have been controversial in the clinical treatment of COVID-19. The 2020 World Health Organization (WHO) guidelines for the diagnosis and treatment of COVID-19 do not recommend glucocorticoids as a routine treatment for COVID-19 [30].

In  Chinese “diagnosis and treatment plan for pneumonia caused by novel coronavirus infection”, it is recommended to use glucocorticoids with caution, but glucocorticoids have been regularly used for basic diseases such as autoimmune disease, nephrotic syndrome, and bronchial asthma before SARS-CoV-2 infection.  Patients use as appropriate [31].

Majmundar et al. [32] analyzed 205 patients with COVID-19 and found that administration of glucocorticoids can reduce the probability of invasive mechanical ventilation, admission to the intensive care unit (ICU), and mortality in severe COVID-19 patients.

Therefore, the application of glucocorticoids in severe COVID-19 patients requires careful evaluation of the infection status and immune status of the patients, and glucocorticoid therapy should be given under the premise of clear indications.

4.2 Anti-inflammatory cytokines 

Cytokine storm is considered to be the main cause of multiple organ damage and high mortality in severe COVID-19 patients. Reducing the body’s inflammatory response and antagonizing the activity of inflammatory factors is of great significance for improving the progression and prognosis of severe COVID-19.

Currently, a variety of antibodies targeting inflammatory factors, such as tocilizumab, which antagonizes IL-6, and anakinra, which antagonizes IL-1, can reduce the use of mechanical ventilation in severe COVID-19 patients and reduce the risk of ICU mortality [33] ].

However, the sample size of current clinical trials is limited, and simply antagonizing the production of inflammatory factors cannot completely block the uncontrolled inflammatory response process in severe COVID-19 patients.

The timing and degree of antagonism are also important factors affecting the therapeutic effect of inflammatory factor antibodies.

4.3 Thymosin α1 

Thymosin α1 can induce the differentiation and maturation of T lymphocytes, enhance cytokine production, and enhance the antibody response of B lymphocytes, which is one of the important measures for immune conditioning of COVID-19 patients.

In a retrospective study of 76 critically ill COVID-19 patients, thymosin alpha 1 administration helped restore lymphopenia and reverse exhausted T lymphocytes, thereby reducing mortality [34]. Further observation confirmed that thymosin α1 can significantly reduce lung tissue damage in severe COVID-19 patients and reduce the 28-day mortality of patients [35].

At present, thymosin α1 has been widely used in the prevention and treatment of COVID-19, but its possible benefit population, application timing, optimal dose and duration are still unclear and need to be further explored.

4.4 Convalescent plasma

Convalescent plasma therapy is based on the presence of a large number of antibodies against SARS-CoV-2 infection in the peripheral blood of convalescent COVID-19 patients, and the process of allowing patients to acquire passive immunity. [36] found that the use of early convalescent plasma for symptomatic SARS-CoV-2 infection in the elderly can significantly slow down the progression of COVID-19 disease.

However, another study suggests that although convalescent plasma therapy can effectively reduce the viral load of patients, it cannot improve the 28-day survival rate of severe COVID-19 patients [37]. In addition, during the COVID-19 pandemic, the source of convalescent plasma is difficult and the technical requirements for production are high, and the application of convalescent plasma in the treatment of severe COVID-19 patients is very limited.

5 Conclusion

Immune state disorder is one of the main reasons for the progression and poor prognosis of severe COVID-19. Effective immune conditioning is an important strategy to affect the outcome of severe COVID-19 patients.

At this stage, the formulation of the immune conditioning program and the selection of measures for severe COVID-19 patients need to consider the following issues:

(1) The assessment of the immune status of the target population is a prerequisite for the need for immune conditioning, and it is necessary to dynamically monitor the number of circulating immune cells in patients

(2) The development of individualized immune conditioning programs is an important development direction to effectively block the progression of severe COVID-19 and improve the prognosis of patients; There is no uniform standard for the specific drugs, timing and dosage of conditioning, and high-quality clinical trials are urgently needed to provide strong evidence, and then put forward clinical application norms.

COVID-19 pneumonia:  Severe Pneumonia and Immune Disorders.

(source:internet, reference only)

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