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1.
Cell ; 2021.
Article in English | ScienceDirect | ID: covidwho-1536467

ABSTRACT

Summary COVID-19-induced ‘acute respiratory distress syndrome’ (ARDS) is associated with prolonged respiratory failure and high mortality, but the mechanistic basis of lung injury remains incompletely understood. Here, we analyzed pulmonary immune responses and lung pathology in two cohorts of patients with COVID-19 ARDS using functional single cell genomics, immunohistology and electron microscopy. We describe an accumulation of CD163-expressing monocyte-derived macrophages that acquired a profibrotic transcriptional phenotype during COVID-19 ARDS. Gene set enrichment and computational data integration revealed a significant similarity between COVID-19-associated macrophages and profibrotic macrophage populations identified in idiopathic pulmonary fibrosis. COVID-19 ARDS was associated with clinical, radiographic, histopathological, and ultrastructural hallmarks of pulmonary fibrosis. Exposure of human monocytes to SARS-CoV-2, but not Influenza A virus or viral RNA analogs, was sufficient to induce a similar profibrotic phenotype in vitro. In conclusion, we demonstrate that SARS-CoV-2 triggers profibrotic macrophage responses and pronounced fibroproliferative ARDS.

2.
Nature ; 2021 Oct 25.
Article in English | MEDLINE | ID: covidwho-1483137

ABSTRACT

SARS-CoV-2 is a single-stranded RNA virus that causes coronavirus disease 2019 (COVID-19). Given its acute and often self-limiting course, components of the innate immune system are likely central in controlling virus replication thereby determining clinical outcome. Natural killer (NK) cells are innate lymphocytes with notable activity against a broad range of viruses, including RNA viruses1,2. NK cell function may be altered during COVID-19 despite increased representation of NK cells with an activated and 'adaptive' phenotype3,4. Here we show that viral load decline in COVID-19 correlates with NK cell status and that NK cells can control SARS-CoV-2 replication by recognizing infected target cells. In severe COVID-19, NK cells show remarkable defects in virus control, cytokine production and cell-mediated cytotoxicity despite high expression of cytotoxic effector molecules. Single-cell RNA-sequencing (scRNA-seq) of NK cells along the time course of the entire COVID-19 disease spectrum reveals a unique gene expression signature. Transcriptional networks of interferon-driven NK cell activation are superimposed by a dominant TGFß response signature with reduced expression of genes related to cell-cell adhesion, granule exocytosis and cell-mediated cytotoxicity. In severe COVID-19, serum levels of TGFß peak during the first 2 weeks of infection, and serum obtained from these patients profoundly inhibits NK cell function in a TGFß-dependent manner. Our data reveal that untimely production of TGFß is a hallmark of severe COVID-19 and may inhibit NK cell function and early virus control.

3.
BMC Infect Dis ; 21(1): 901, 2021 Sep 03.
Article in English | MEDLINE | ID: covidwho-1455938

ABSTRACT

BACKGROUND: The detection of severe acute respiratory syndrome coronavirus (SARS-CoV-2) is challenging, particularly in post-mortem human tissues. However, there is increasing evidence for viral SARS-CoV-2 manifestation in non-respiratory tissues. In this context, it is a current matter of debate, whether SARS-CoV-2 shows hepatotropism. CASE PRESENTATION: Here, we report a case of an 88-year-old women with massive SARS-CoV-2 viremia, severe jaundice and clinical signs of an acute hepatitis, who died within a few days from an acute liver failure without showing any clinical signs of pneumonia. Autopsy revealed a severe chronic and acute liver damage with bile duct infestation by SARS-CoV-2 that was accompanied by higher expressions of angiotensin-converting enzyme-2 (ACE2), Cathepsin L and transmembrane serine protease 2 (TMPRSS2). CONCLUSION: Our findings indicate an enhanced biliary susceptibility to viral infection with SARS-CoV-2, that might have resulted from pre-existing severe liver damage. Furthermore, our findings emphasize the differential diagnosis of coronavirus disease 2019 (COVID-19)-associated liver failure in the clinical setting of an inexplicable jaundice.


Subject(s)
COVID-19 , Liver Failure, Acute , Aged, 80 and over , Female , Humans , Liver Cirrhosis/complications , Liver Failure, Acute/etiology , Peptidyl-Dipeptidase A , SARS-CoV-2
4.
Mucosal Immunol ; 14(6): 1381-1392, 2021 11.
Article in English | MEDLINE | ID: covidwho-1366810

ABSTRACT

The SARS-CoV-2 pandemic has so far claimed over three and a half million lives worldwide. Though the SARS-CoV-2 mediated disease COVID-19 has first been characterized by an infection of the upper airways and the lung, recent evidence suggests a complex disease including gastrointestinal symptoms. Even if a direct viral tropism of intestinal cells has recently been demonstrated, it remains unclear, whether gastrointestinal symptoms are caused by direct infection of the gastrointestinal tract by SARS-CoV-2 or whether they are a consequence of a systemic immune activation and subsequent modulation of the mucosal immune system. To better understand the cause of intestinal symptoms we analyzed biopsies of the small intestine from SARS-CoV-2 infected individuals. Applying qRT-PCR and immunohistochemistry, we detected SARS-CoV-2 RNA and nucleocapsid protein in duodenal mucosa. In addition, applying imaging mass cytometry and immunohistochemistry, we identified histomorphological changes of the epithelium, which were characterized by an accumulation of activated intraepithelial CD8+ T cells as well as epithelial apoptosis and subsequent regenerative proliferation in the small intestine of COVID-19 patients. In summary, our findings indicate that intraepithelial CD8+ T cells are activated upon infection of intestinal epithelial cells with SARS-CoV-2, providing one possible explanation for gastrointestinal symptoms associated with COVID-19.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Duodenum/immunology , Immunity, Mucosal , Intestinal Diseases/immunology , Intestinal Mucosa/immunology , Intraepithelial Lymphocytes/immunology , Lymphocyte Activation , SARS-CoV-2/immunology , Adult , Aged , Animals , Apoptosis , CD8-Positive T-Lymphocytes/virology , COVID-19/pathology , COVID-19/virology , Case-Control Studies , Cell Proliferation , Chlorocebus aethiops , Duodenum/pathology , Duodenum/virology , Female , Host-Pathogen Interactions , Humans , Intestinal Diseases/pathology , Intestinal Diseases/virology , Intestinal Mucosa/pathology , Intestinal Mucosa/virology , Intraepithelial Lymphocytes/virology , Male , Re-Epithelialization , SARS-CoV-2/pathogenicity , Vero Cells , Viral Load
5.
Blood ; 136(Supplement 1):46-46, 2020.
Article in English | PMC | ID: covidwho-1338956

ABSTRACT

Introduction: By now, the pandemic spread of COVID-19 (coronavirus disease 2019) has claimed more than 600,000 lives. The adaptive immune response seems to play a major role in the progression of the disease, since entry of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is determined by a spike protein recognized by T helper cells. This has been linked to the clinical finding of severe lymphocytopenia in these patients. However, detailed cellular immune responses in the bone marrow (BM) and in the spleen (SPL) of COVID-19 patients have not been addressed yet. Here, we provide novel immunologic insight with potential for therapeutic management and risk stratification in COVID-19.Material and Methods: We performed complete autopsies on 11 confirmed COVID-19 and 4 non-COVID-19 deceased, who were matched for risk profile and age. SARS-CoV-2 load was measured by rt-PCR (quantitative real-time polymerase chain reaction) targeting the SARS-CoV-2 E-gene in purified RNA extracts from 50mg of pulmonary tissue (MagNAPure 96 system, Viral NA Large Volume Kit, Roche). For histopathology, representative tissue samples of decalcified BM and SPL were fixed in 4 % buffered formalin, dehydrated and paraffin embedded. Sections were stained with HE, PAS, Giemsa-, Gomori- and Prussian blue stain. Furthermore, BM and SPL were stained with immunohistochemical reagents, namely MPO (Myeloperoxidase), CD235, CD34, CD117, CD68, CD61, CD20, CD3, CD4, CD8, CD138, HLA-DR (Human Leucocyte antigen - DR isotype), PD-1, PD-L1 (Programmed cell death protein and ligand 1), Ki67 and Caspase3 (Ventana Ultra and LEICA Bond III). Additionally, we performed in-situ hybridization of EBV (Epstein-Barr-Virus;LEICA Bond MAX), followed by PCR of the EBV nuclear antigen 1 (Thermo Fisher and Roche). Histopathology was evaluated by at least two hematopathologists. Clinical data were obtained from patients' files. Statistical analysis was done using GraphPad Prism8 Software. Inc, 2018.Results: Of all COVID-19 deceased, 73% (n = 8/11) showed BM hypercellularity, increased granulocyte / erythrocyte ratios, and left shift of erythro- and granulopoiesis with anemia and an increase of immature granulocytes in the peripheral blood. Thromboembolic events were present in 82% (n = 9/11) of COVID-19 patients and related to an increase and left shift of megakaryopoiesis in the BM. In the BM of patients with severe bacterial superinfection of COVID-19 pneumonia, we observed an early increase of PD-L1 expression on myeloid cells, lymphocytic apoptosis, and time-dependent macrophage anergy with a continuous loss of antigen-presenting capacity. Furthermore, we found CD20+ B-cell depletion in either BM or SPL in 64% (n = 7/11) of COVID-19 patients with B-cell counts of less than 1% in the BM and 1-5% in the SPL, followed by complete plasma cell depletion. This was reflected by severe lymphocytopenia in the peripheral blood. In contrast, BM T-cell counts were nearly as high in COVID-19 decedents (median 10%) as in cases not related to COVID-19 (median 12.5%). Interestingly, there was a tendency towards higher pulmonary SARS-CoV-2 RNA load in COVID-19 patients with B-cell depletion, as we observed maximum viral copy numbers of up to 1,150,000 / 10,000 cells in patients with B-cell depletion as compared to 6,500 / 10,000 cells in patients with B-cell preservation. EBV was absent in all cases. Clinical characteristics and time-intervals between initial symptoms and death of COVID-19 patients were heterogenous, therefore preventing the detection of a clinical risk profile in patients with B-cell depletion.Conclusion: Our results show that severe lymphocyte depletion in COVID-19 deceased is caused by a substantial loss of B-cells which is in turn associated with viral SARS-CoV-2 burden and presumably results from excessive activation of the adaptive immune system. It is yet to be determined how B-cell specific pathways are affected by SARS-CoV-2 and whether this might serve as a therapeutic target of interest. Moreover, we provide morphologic evidence, that COVID-19 pneu onia with bacterial superinfection is aggravated by sepsis acquired immunodeficiency. Since the latter is associated with an epigenetically determined switch to endotoxin tolerance, our findings may additionally aid in risk stratification of COVID-19 patients who undergo severe bacterial superinfection during the disease.

6.
Nat Commun ; 12(1): 3818, 2021 06 21.
Article in English | MEDLINE | ID: covidwho-1279876

ABSTRACT

Viruses manipulate cellular metabolism and macromolecule recycling processes like autophagy. Dysregulated metabolism might lead to excessive inflammatory and autoimmune responses as observed in severe and long COVID-19 patients. Here we show that SARS-CoV-2 modulates cellular metabolism and reduces autophagy. Accordingly, compound-driven induction of autophagy limits SARS-CoV-2 propagation. In detail, SARS-CoV-2-infected cells show accumulation of key metabolites, activation of autophagy inhibitors (AKT1, SKP2) and reduction of proteins responsible for autophagy initiation (AMPK, TSC2, ULK1), membrane nucleation, and phagophore formation (BECN1, VPS34, ATG14), as well as autophagosome-lysosome fusion (BECN1, ATG14 oligomers). Consequently, phagophore-incorporated autophagy markers LC3B-II and P62 accumulate, which we confirm in a hamster model and lung samples of COVID-19 patients. Single-nucleus and single-cell sequencing of patient-derived lung and mucosal samples show differential transcriptional regulation of autophagy and immune genes depending on cell type, disease duration, and SARS-CoV-2 replication levels. Targeting of autophagic pathways by exogenous administration of the polyamines spermidine and spermine, the selective AKT1 inhibitor MK-2206, and the BECN1-stabilizing anthelmintic drug niclosamide inhibit SARS-CoV-2 propagation in vitro with IC50 values of 136.7, 7.67, 0.11, and 0.13 µM, respectively. Autophagy-inducing compounds reduce SARS-CoV-2 propagation in primary human lung cells and intestinal organoids emphasizing their potential as treatment options against COVID-19.


Subject(s)
COVID-19/metabolism , COVID-19/virology , SARS-CoV-2/metabolism , Animals , Antinematodal Agents/pharmacology , Autophagosomes/metabolism , Autophagy , Autophagy-Related Proteins/metabolism , COVID-19/drug therapy , COVID-19/pathology , Cells, Cultured , Chlorocebus aethiops , Cricetinae , Disease Models, Animal , Humans , Lung/metabolism , Lung/pathology , Lung/virology , Metabolome , Niclosamide/pharmacology , Organoids , SARS-CoV-2/isolation & purification , Spermidine/pharmacology , Spermine/pharmacology
7.
JAMA Neurol ; 78(8): 948-960, 2021 08 01.
Article in English | MEDLINE | ID: covidwho-1265359

ABSTRACT

Importance: Myalgia, increased levels of creatine kinase, and persistent muscle weakness have been reported in patients with COVID-19. Objective: To study skeletal muscle and myocardial inflammation in patients with COVID-19 who had died. Design, Setting, and Participants: This case-control autopsy series was conducted in a university hospital as a multidisciplinary postmortem investigation. Patients with COVID-19 or other critical illnesses who had died between March 2020 and February 2021 and on whom an autopsy was performed were included. Individuals for whom informed consent to autopsy was available and the postmortem interval was less than 6 days were randomly selected. Individuals who were infected with SARS-CoV-2 per polymerase chain reaction test results and had clinical features suggestive of COVID-19 were compared with individuals with negative SARS-CoV-2 polymerase chain reaction test results and an absence of clinical features suggestive of COVID-19. Main Outcomes and Measures: Inflammation of skeletal muscle tissue was assessed by quantification of immune cell infiltrates, expression of major histocompatibility complex (MHC) class I and class II antigens on the sarcolemma, and a blinded evaluation on a visual analog scale ranging from absence of pathology to the most pronounced pathology. Inflammation of cardiac muscles was assessed by quantification of immune cell infiltrates. Results: Forty-three patients with COVID-19 (median [interquartile range] age, 72 [16] years; 31 men [72%]) and 11 patients with diseases other than COVID-19 (median [interquartile range] age, 71 [5] years; 7 men [64%]) were included. Skeletal muscle samples from the patients who died with COVID-19 showed a higher overall pathology score (mean [SD], 3.4 [1.8] vs 1.5 [1.0]; 95% CI, 0-3; P < .001) and a higher inflammation score (mean [SD], 3.5 [2.1] vs 1.0 [0.6]; 95% CI, 0-4; P < .001). Relevant expression of MHC class I antigens on the sarcolemma was present in 23 of 42 specimens from patients with COVID-19 (55%) and upregulation of MHC class II antigens in 7 of 42 specimens from patients with COVID-19 (17%), but neither were found in any of the controls. Increased numbers of natural killer cells (median [interquartile range], 8 [8] vs 3 [4] cells per 10 high-power fields; 95% CI, 1-10 cells per 10 high-power fields; P < .001) were found. Skeletal muscles showed more inflammatory features than cardiac muscles, and inflammation was most pronounced in patients with COVID-19 with chronic courses. In some muscle specimens, SARS-CoV-2 RNA was detected by reverse transcription-polymerase chain reaction, but no evidence for a direct viral infection of myofibers was found by immunohistochemistry and electron microscopy. Conclusions and Relevance: In this case-control study of patients who had died with and without COVID-19, most individuals with severe COVID-19 showed signs of myositis ranging from mild to severe. Inflammation of skeletal muscles was associated with the duration of illness and was more pronounced than cardiac inflammation. Detection of viral load was low or negative in most skeletal and cardiac muscles and probably attributable to circulating viral RNA rather than genuine infection of myocytes. This suggests that SARS-CoV-2 may be associated with a postinfectious, immune-mediated myopathy.


Subject(s)
COVID-19/pathology , Muscle, Skeletal/pathology , Myocarditis/pathology , Myocardium/pathology , Myositis/pathology , Aged , Aged, 80 and over , Autopsy , CD8-Positive T-Lymphocytes/pathology , COVID-19/metabolism , COVID-19 Nucleic Acid Testing , COVID-19 Serological Testing , Case-Control Studies , Female , Histocompatibility Antigens Class I/metabolism , Histocompatibility Antigens Class II/metabolism , Humans , Killer Cells, Natural/pathology , Leukocytes/pathology , Macrophages/pathology , Male , Middle Aged , Muscle, Skeletal/metabolism , Myocarditis/metabolism , Myocardium/metabolism , Myositis/metabolism , RNA, Viral/metabolism , SARS-CoV-2 , Sarcolemma/metabolism , Time Factors
8.
Int J Infect Dis ; 108: 274-281, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1253010

ABSTRACT

OBJECTIVES: Studies on coronavirus disease 2019 (COVID-19) usually focus on middle-aged and older adults. However, younger patients may present with severe COVID-19 with potentially fatal outcomes. For optimized, more specialized therapeutic regimens in this particular patient group, a better understanding of the underlying pathomechanisms is of utmost importance. METHODS: Our study investigated relevant, pre-existing medical conditions, clinical histories, and autopsy findings, together with SARS-CoV-2-RNA, determined by qPCR, and laboratory data in six COVID-19 decedents aged 50 years or younger, who were autopsied at the Charité University Hospital. RESULTS: From a total of 76 COVID-19 patients who underwent an autopsy at our institution, six (7.9%) were 50 years old or younger. Most of these younger COVID-19 decedents presented with pre-existing medical conditions prior to SARS-CoV-2 infection. These included overweight and obesity, arterial hypertension, asthma, and obstructive sleep apnea, as well as graft-versus-host disease following cancer and bone marrow transplantation. Furthermore, clinical histories and autopsy results revealed a disproportionally high prevalence of thromboembolism and ischemic organ damage in this patient cohort. Histopathology and laboratory results indicated coagulopathies, signs of immune dysregulation, and liver damage. CONCLUSIONS: In conclusion, pre-existing health conditions may increase the risk of severe and fatal COVID-19 in younger patients, who may be especially prone to developing thromboembolic complications, immune dysregulation, and liver damage.


Subject(s)
COVID-19 , Hypertension , Aged , Autopsy , Humans , Middle Aged , Overweight , SARS-CoV-2
9.
Nat Commun ; 12(1): 1961, 2021 03 30.
Article in English | MEDLINE | ID: covidwho-1169399

ABSTRACT

The pathogenesis of severe COVID-19 reflects an inefficient immune reaction to SARS-CoV-2. Here we analyze, at the single cell level, plasmablasts egressed into the blood to study the dynamics of adaptive immune response in COVID-19 patients requiring intensive care. Before seroconversion in response to SARS-CoV-2 spike protein, peripheral plasmablasts display a type 1 interferon-induced gene expression signature; however, following seroconversion, plasmablasts lose this signature, express instead gene signatures induced by IL-21 and TGF-ß, and produce mostly IgG1 and IgA1. In the sustained immune reaction from COVID-19 patients, plasmablasts shift to the expression of IgA2, thereby reflecting an instruction by TGF-ß. Despite their continued presence in the blood, plasmablasts are not found in the lungs of deceased COVID-19 patients, nor does patient IgA2 binds to the dominant antigens of SARS-CoV-2. Our results thus suggest that, in severe COVID-19, SARS-CoV-2 triggers a chronic immune reaction that is instructed by TGF-ß, and is distracted from itself.


Subject(s)
Antibodies, Viral/immunology , COVID-19/immunology , SARS-CoV-2/immunology , Transforming Growth Factor beta/immunology , Adult , Aged , Aged, 80 and over , COVID-19/virology , Female , Humans , Immunoglobulin A/immunology , Immunoglobulin G/immunology , Interleukins/immunology , Male , Middle Aged , Plasma Cells/immunology , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology
10.
Sci Rep ; 11(1): 4263, 2021 02 19.
Article in English | MEDLINE | ID: covidwho-1091460

ABSTRACT

Infection by the new corona virus strain SARS-CoV-2 and its related syndrome COVID-19 has been associated with more than two million deaths worldwide. Patients of higher age and with preexisting chronic health conditions are at an increased risk of fatal disease outcome. However, detailed information on causes of death and the contribution of pre-existing health conditions to death yet is missing, which can be reliably established by autopsy only. We performed full body autopsies on 26 patients that had died after SARS-CoV-2 infection and COVID-19 at the Charité University Hospital Berlin, Germany, or at associated teaching hospitals. We systematically evaluated causes of death and pre-existing health conditions. Additionally, clinical records and death certificates were evaluated. We report findings on causes of death and comorbidities of 26 decedents that had clinically presented with severe COVID-19. We found that septic shock and multi organ failure was the most common immediate cause of death, often due to suppurative pulmonary infection. Respiratory failure due to diffuse alveolar damage presented as immediate cause of death in fewer cases. Several comorbidities, such as hypertension, ischemic heart disease, and obesity were present in the vast majority of patients. Our findings reveal that causes of death were directly related to COVID-19 in the majority of decedents, while they appear not to be an immediate result of preexisting health conditions and comorbidities. We therefore suggest that the majority of patients had died of COVID-19 with only contributory implications of preexisting health conditions to the mechanism of death.


Subject(s)
COVID-19/mortality , Cause of Death , Hospital Mortality , Adult , Aged , Aged, 80 and over , Autopsy , Berlin/epidemiology , COVID-19/complications , COVID-19/therapy , COVID-19/virology , Comorbidity , Female , Hospitals, Teaching/statistics & numerical data , Humans , Hypertension/epidemiology , Male , Middle Aged , Multiple Organ Failure/mortality , Multiple Organ Failure/virology , Myocardial Ischemia/epidemiology , Obesity/epidemiology , Prospective Studies , SARS-CoV-2/isolation & purification , Shock, Septic/mortality , Shock, Septic/virology
12.
Nat Neurosci ; 24(2): 168-175, 2021 02.
Article in English | MEDLINE | ID: covidwho-1060446

ABSTRACT

The newly identified severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, a pandemic respiratory disease. Moreover, thromboembolic events throughout the body, including in the CNS, have been described. Given the neurological symptoms observed in a large majority of individuals with COVID-19, SARS-CoV-2 penetrance of the CNS is likely. By various means, we demonstrate the presence of SARS-CoV-2 RNA and protein in anatomically distinct regions of the nasopharynx and brain. Furthermore, we describe the morphological changes associated with infection such as thromboembolic ischemic infarction of the CNS and present evidence of SARS-CoV-2 neurotropism. SARS-CoV-2 can enter the nervous system by crossing the neural-mucosal interface in olfactory mucosa, exploiting the close vicinity of olfactory mucosal, endothelial and nervous tissue, including delicate olfactory and sensory nerve endings. Subsequently, SARS-CoV-2 appears to follow neuroanatomical structures, penetrating defined neuroanatomical areas including the primary respiratory and cardiovascular control center in the medulla oblongata.


Subject(s)
Brain/virology , COVID-19/virology , Olfactory Mucosa/virology , SARS-CoV-2/pathogenicity , Central Nervous System , Humans , RNA, Viral/genetics , Smell/physiology , Virus Internalization
13.
Int J Infect Dis ; 103: 628-635, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-1002639

ABSTRACT

OBJECTIVES: In coronavirus disease 2019 (COVID-19), the adaptive immune response is of considerable importance, and detailed cellular immune reactions in the hematological system of patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are yet to be clarified. METHODS: This study reports the morphological characterization of both bone marrow and spleen in 11 COVID-19 decedents with respect to findings in the peripheral blood and pulmonary SARS-CoV-2 burden. RESULTS: In the bone marrow, activation and left shift were found in at least 55% of patients, which was mirrored by peripheral anaemia, granulocytic immaturity and multiple thromboembolic events. Signs of sepsis-acquired immunodeficiency were found in the setting of an abscess-forming superinfection of viral COVID-19 pneumonia. Furthermore, a severe B cell loss was observed in the bone marrow and/or spleen in 64% of COVID-19 patients. This was reflected by lymphocytopenia in the peripheral blood. As compared to B cell preservation, B cell loss was associated with a higher pulmonary SARS-CoV-2 burden and only a marginal decrease of of T cell counts. CONCLUSIONS: The results of this study suggest the presence of sepsis-related immunodeficiency in severe COVID-19 pneumonia with superinfection. Furthermore, our findings indicate that lymphocytopenia in COVID-19 is accompanied by B cell depletion in hematopoietic tissue, which might impede the durability of the humoral immune response to SARS-CoV-2.


Subject(s)
B-Lymphocytes/immunology , Bone Marrow/immunology , COVID-19/immunology , Lymphopenia/etiology , SARS-CoV-2 , Sepsis/immunology , Spleen/immunology , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged
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