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1.
MEDICC Rev ; 24(2): 26-34, 2022 May 16.
Article in English | MEDLINE | ID: covidwho-1865784

ABSTRACT

INTRODUCTION: Immunity in cancer patients is modified both by the cancer itself and by oncospecific treatments. Whether a patient's adaptive immunity is impaired depends on their levels of naive lymphocytes and other cell populations. During the COVID-19 pandemic, cancer patients are at greater risk of progressing to severe forms of the disease and have higher mortality rates than individuals without cancer, particularly while they are receiving cancer-specific therapies. An individual's protection against infection, their response to vaccines, and even the tests that determine the humoral immune response to SARS-CoV-2, depend on lymphocyte populations, meriting their study. OBJECTIVE: Estimate blood concentrations of lymphocytes involved in the immune response to new pathogens in cancer patients. METHODS: We carried out an analytical study of 218 cancer patients; 124 women and 94 men, 26-93 years of age, who were treated at the National Oncology and Radiobiology Institute in Havana, Cuba, March-June, 2020. Patients were divided into five groups: (1) those with controlled disease who were not undergoing cancer-specific treatment; (2) those undergoing debulking surgery; (3) patients undergoing chemotherapy; (4) patients undergoing radiation therapy and (5) patients currently battling infection. We evaluated the following peripheral blood lymphocyte subpopulations via flow cytometry: B lymphocytes (total, naive, transitional, memory, plasmablasts and plasma cells); T lymphocytes (total, helper, cytotoxic and their respective naive, activated, central memory and effector memory subsets); and total, secretory and cytotoxic natural killer cells and T natural killer cells. We also estimated neutrophil/lymphocyte ratios. Lymphocyte concentrations were associated with controlled disease and standard cancer therapy. For variables that did not fall within a normal distribution, ranges were set by medians and 2.5-97.5 percentiles. The two-tailed Mann-Whitney U test was used to measure the effect of sex and to compare lymphocyte populations. We calculated odds ratios to estimate lymphopenia risk. RESULTS: All cancer patients had lower values of naive helper and cytotoxic T lymphocyte populations, naive B lymphocytes, and natural killer cells than normal reference medians. Naive helper T cells were the most affected subpopulation. Memory B cells, plasmablasts, plasma cells, activated T helper cells, and cytotoxic central memory T cells were increased. Patients undergoing treatment had lower levels of naive lymphocytes than untreated patients, particularly during radiation therapy. The risk of B lymphopenia was higher in patients in treatment. The odds ratio for B lymphopenia was 8.0 in patients who underwent surgery, 12.9 in those undergoing chemotherapy, and 13.9 in patients in radiotherapy. CONCLUSIONS: Cancer and conventional cancer therapies significantly affect peripheral blood B lymphocyte levels, particularly transitional T helper lymphocytes, reducing the immune system's ability to trigger primary immune responses against new antigens.


Subject(s)
COVID-19 , Lymphopenia , Neoplasms , Cuba , Female , Humans , Lymphocyte Subsets , Male , Neoplasms/therapy , Pandemics , SARS-CoV-2
2.
J Trop Pediatr ; 68(3)2022 04 05.
Article in English | MEDLINE | ID: covidwho-1860907

ABSTRACT

BACKGROUND: Studies on age-related differences in clinical and laboratory features of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are limited. We aimed to evaluate the demographic, clinical, laboratory findings of SARS-CoV-2 infection in children younger than 6 months old and compare them with older children. METHODS: A single-center retrospective study, including 209 confirmed SARS-CoV-2 infection cases, was conducted between 11 March 2020 and 1 September 2021. The case group consisted of 47 patients younger than 6 months old, whereas the control group consisted of 162 patients older than 6 months old. RESULTS: The mean age of the case group was 2.77 ± 1.52 months, and the control group was 101.89 ± 65.77 months. Cough was statistically higher in the control group, and poor feeding was higher in the case group (p = 0.043, 0.010). The underlying disease rate was statistically higher in the control group; however, the hospitalization rate was higher in the case group (p = 0.036, 0.001). The case group had significantly lower median values of the absolute neutrophil count, hemoglobin and higher median values of white blood cell, absolute lymphocyte count and platelet than the control group (p < 0.05). C-reactive protein, fibrinogen values were significantly lower, and procalcitonin, D-dimer, troponin T, N-terminal pro-B-type natriuretic peptide significantly higher in the case group (p < 0.05). Lymphopenia was more common in the control group, whereas neutropenia was more common in the case group (p = 0.001, 0.011). CONCLUSIONS: We showed that most children younger than 6 months old had mild and asymptomatic SARS-CoV-2 infection; however, the hospitalization rate was higher, and neutropenia was more common in older children. Lay summaryStudies on age-related differences in clinical and laboratory features on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in pediatric patients are limited. We aimed to evaluate the demographic, clinical and laboratory findings of SARS-CoV-2 infection in children younger than 6 months old and compare them with older children. A single-center retrospective study was conducted, including 209 SARS-CoV-2 infection cases. The case group consisted of 47 patients younger than 6 months old, and the control group consisted of 162 patients older than 6 months old. Most children younger than 6 months old had mild and asymptomatic SARS-CoV-2 infection; however, the hospitalization rate was higher than older children. Neutropenia was more common in patients younger than 6 months than older children with SARS-CoV-2 infection, even if underlying diseases were excluded.


Subject(s)
COVID-19 , Lymphopenia , Neutropenia , Adolescent , COVID-19/diagnosis , Child , Humans , Infant , Neutropenia/epidemiology , Retrospective Studies , SARS-CoV-2
3.
Mikrobiyol Bul ; 56(2): 357-364, 2022 Apr.
Article in Turkish | MEDLINE | ID: covidwho-1818596

ABSTRACT

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection emerged in China at the end of 2019 and caused coronavirus disease 2019 (COVID-19). The lymphopenia seen in COVID-19 increases the incidence of susceptibility to other microorganisms and may cause co-infections. As the signs and symptoms of the diseases overlap with other infectious diseases and due to the intensity in health services, the diagnosis of co-infections becomes difficult and the treatment may be delayed. Therefore, infections accompanying COVID-19 cause an increase in morbidity and mortality.The isolation and quarantine measures taken during the COVID-19 process have reduced the number of infections transmitted from person to person. However, there was no significant decrease in diseases transmitted by food, such as salmonellosis. During the pandemic, salmonellosis continued to be a problem, especially in endemic areas such as Pakistan, and an increase in Salmonella infections associated with backyard poultry has been reported in countries such as the United States. A co-infection of COVID-19 and enteric fever associated with travel to Pakistan was reported for the first time in the literature in February 2021. In this case report, the first co-infection of COVID-19 and Salmonella in our country was presented. A 56-yearold male patient with no known systemic disease was admitted to the hospital with fever, shortness of breath, weakness and myalgia lasting for three days. SARS-CoV-2 polymerase chain reaction test was positive. The patient has been hospitalized and favipiravir, moxifloxacin, and methylprednisolone were started. Blood cultures were taken from the patient whose clinical picture worsened and fever continued despite of the medical treatment. Salmonella enterica spp. enterica was isolated and ceftriaxone treatment was started. The patient's anamnesis was deepened, but no diarrhea, abdominal pain, suspicious food consumption, travel history were determined. From the second day of the ceftriaxone treatment, the patient's fever decreased and no growth was detected in the control blood cultures. Ceftriaxone treatment was completed in 14 days and the patient was discharged on the 28th day. Approximately 87-95% of Salmonella strains isolated in our country are S.enterica spp. enterica, and S.enterica spp. enterica was also isolated in our case. Salmonella infections most commonly present as gastroenteritis, but the risk of bacteremia increases in case of immunosuppression. Although there was no additional disease in our case, it was considered that the infection in the form of bacteremia occurred due to an immunosuppression caused by COVID-19. In this context; drawing blood cultures of patients hospitalized with the diagnosis of COVID-19 is very important in terms of detecting co-infections and superinfections, and administering appropriate antibiotic therapy at appropriate treatment times. Presentation of first case of Salmonella bacteremia and simultaneous COVID-19 infection in our country was the strong side of our report. In addition, our case is also important as being the first SARS-CoV-2 and Salmonella co-infection unrelated to Pakistan in the literature. The limitation of our case was that S.enterica spp. enterica detected in the blood culture could not be subtyped and the stool culture could not be examined. However, this does not constitute a diagnostic requirement. In addition, the patient's pre-COVID-19 Salmonella carrier status was also unknown. As a result, patients become vulnerable to other infections due to the lymphopenia seen in COVID-19. Therefore, Salmonella bacteremia can be seen with SARS-CoV-2 infection without a comorbid condition. Drawing blood cultures in hospitalized patients with the diagnosis of COVID-19 is very important in terms of detecting concomitant infections in a short time. In patients whose clinical condition does not improve and fever continues despite of treatment, blood cultures should be taken, especially in the case of an advanced immunosuppresive treatment plan, and it should always be kept in mind that secondary infections and co-infections may occur.


Subject(s)
Bacteremia , COVID-19 , Coinfection , Lymphopenia , Salmonella Infections , Salmonella enterica , Bacteremia/drug therapy , Ceftriaxone/therapeutic use , Coinfection/drug therapy , Coinfection/epidemiology , Humans , Lymphopenia/drug therapy , Male , Middle Aged , Pakistan/epidemiology , SARS-CoV-2 , Salmonella Infections/diagnosis , Salmonella Infections/drug therapy , Salmonella Infections/epidemiology
4.
Eur Rev Med Pharmacol Sci ; 26(7): 2579-2585, 2022 04.
Article in English | MEDLINE | ID: covidwho-1811979

ABSTRACT

OBJECTIVE: The aim of the study was to detect the effect of COVID-19 on lymphocyte and platelet parameters among Sudanese patients admitted to Intensive Care unit (ICU) and emergency (ER). PATIENTS AND METHODS: This cross-sectional study was carried out on a total of 787 Sudanese individuals (487 confirmed COVID-19 cases and 300 apparently healthy individuals as controls, in duration between April 2020 to December 2020). Platelets (PLTs) and platelet indices, mean platelet volume (MPV), platelet distribution width (PDW), plateletcrit (PCT) and platelet larger cell ratio (PLCR) were investigated as part of the complete blood count (CBC) for the case and control group. Also, the neutrophil lymphocyte ratio (NLR) and platelet lymphocyte ratio (PLR) were calculated, and the results were statistically analyzed by SPSS version 21. RESULTS: The severity of the disease was also affected by the patient's age: 262 COVID-19 cases admitted to ICU were over 50 years old, compared to only four patients in the mild group. Regarding hematological parameters, the absolute lymphocyte count, PLTs, MPV, PDW, and P-LCR were significantly different between cases and control groups (p-values = 0.000, 0.002, 0.000, 0.000, and 0.000, respectively). PLR and NLR levels were found to be significantly higher as disease severity increased; p-values = 0.000 and 0.000, respectively. The study also demonstrated that lymphopenia was associated with severe COVID-19 infection (in 93% of ICU patients, 59.9% of ER, and 9% of the mild group), while thrombocytopenia was detected only among 30.8% of ICU patients. CONCLUSIONS: Lymphopenia and thrombocytopenia are associated with severe COVID-19 infection. NLR and PLR were markedly increased with COVID-19.


Subject(s)
COVID-19 , Lymphopenia , Thrombocytopenia , Blood Platelets , Cross-Sectional Studies , Humans , Intensive Care Units , Lymphocytes , Mean Platelet Volume , Middle Aged , Neutrophils , Platelet Count , Retrospective Studies , Thrombocytopenia/epidemiology
6.
J Assoc Physicians India ; 70(4): 11-12, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1801582

ABSTRACT

The triaging of COVID 19 patients is of paramount importance to plan further management. There are several clinical and laboratory parameters that help in categorizing the disease severity, triaging, and prognostication. Little is known about the prognostic significance of eosinopenia in predicting the severity of COVID 19 from large hospital data especially from low- and middle-income countries. The objective of this study is to evaluate the level of eosinopenia as an early prognostic marker for assessing the outcomes in COVID 19 patients and to assess the superiority of eosinopenia as a prognostic marker for assessing the outcomes in COVID 19 patients compared to lymphopenia and neutrophil: lymphocyte ratio (NLR). MATERIAL: The study was carried out in a tertiary care hospital. A retrospective longitudinal approach was adopted wherein the hospital records of COVID 19 patients were analysed. Two separate groups of patients were included for analysis to describe the association between initial eosinophil counts of the patients and the clinical outcomes. In the first group, the disease severity in terms of clinical and radiological parameters was compared in patients of COVID 19 presenting with and without the presence of initial eosinopenia. Commonly used markers for triage namely lymphopenia and NLR were compared with the presence of initial eosinopenia among the patients who progressed to moderate and severe disease. In the second group, an analysis of eosinopenia was made among the patients who succumbed to the illness. OBSERVATION: It was seen that 29.6% of patients with eosinopenia had moderate and severe disease compared to those without eosinopenia where only 10.8 % had moderate disease, none had severe disease. It was seen that 19.7% of patients with eosinopenia but no lymphopenia had more severe disease compared to patients with lymphopenia but no eosinopenia where 10.8% of the patients had moderate disease, none had severe disease. In patients younger than 60 years who died of COVID 19, it was found that initial eosinopenia was found in 86 % whereas a high neutrophil: lymphocyte ratio >17 was seen in only 25.6% of patients who died. Thus, implying that is eosinopenia is an important marker of disease severity in COVID 19. CONCLUSION: Eosinopenia is an important parameter in the evaluation of COVID 19 and the presence of it should alert the clinicians regarding the further progression of the disease. It is not only an important marker but also an early marker for severe disease.


Subject(s)
Agranulocytosis , COVID-19 , Leukopenia , Lymphopenia , Biomarkers , Eosinophils , Humans , Prognosis , Retrospective Studies
7.
J Virol ; 96(9): e0003822, 2022 05 11.
Article in English | MEDLINE | ID: covidwho-1788914

ABSTRACT

Due to the limitation of human studies with respect to individual difference or the accessibility of fresh tissue samples, how severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection results in pathological complications in lung, the main site of infection, is still incompletely understood. Therefore, physiologically relevant animal models under realistic SARS-CoV-2 infection conditions would be helpful to our understanding of dysregulated inflammation response in lung in the context of targeted therapeutics. Here, we characterized the single-cell landscape in lung and spleen upon SARS-CoV-2 infection in an acute severe disease mouse model that replicates human symptoms, including severe lung pathology and lymphopenia. We showed a reduction of lymphocyte populations and an increase of neutrophils in lung and then demonstrated the key role of neutrophil-mediated lung immunopathology in both mice and humans. Under severe conditions, neutrophils recruited by a chemokine-driven positive feedback produced elevated "fatal signature" proinflammatory genes and pathways related to neutrophil activation or releasing of granular content. In addition, we identified a new Cd177high cluster that is undergoing respiratory burst and Stfahigh cluster cells that may dampen antigen presentation upon infection. We also revealed the devastating effect of overactivated neutrophil by showing the highly enriched neutrophil extracellular traps in lung and a dampened B-cell function in either lung or spleen that may be attributed to arginine consumption by neutrophil. The current study helped our understanding of SARS-CoV-2-induced pneumonia and warranted the concept of neutrophil-targeting therapeutics in COVID-19 treatment. IMPORTANCE We demonstrated the single-cell landscape in lung and spleen upon SARS-CoV-2 infection in an acute severe disease mouse model that replicated human symptoms, including severe lung pathology and lymphopenia. Our comprehensive study revealed the key role of neutrophil-mediated lung immunopathology in SARS-CoV-2-induced severe pneumonia, which not only helped our understanding of COVID-19 but also warranted the concept of neutrophil targeting therapeutics in COVID-19 treatment.


Subject(s)
COVID-19 , Lung , Neutrophils , Animals , COVID-19/immunology , Disease Models, Animal , Humans , Lung/pathology , Lung/virology , Lymphopenia/virology , Mice , Neutrophils/immunology , SARS-CoV-2 , Spleen/pathology , Spleen/virology
8.
Intern Emerg Med ; 17(4): 1115-1127, 2022 Jun.
Article in English | MEDLINE | ID: covidwho-1787874

ABSTRACT

Uncontrolled inflammation following COVID-19 infection is an important characteristic of the most seriously ill patients. The present study aims to describe the clusters of inflammation in COVID-19 and to analyze their prognostic role. This is a retrospective observational study including 15,691 patients with a high degree of inflammation. They were included in the Spanish SEMI-COVID-19 registry from March 1, 2020 to May 1, 2021. The primary outcome was in-hospital mortality. Hierarchical cluster analysis identified 7 clusters. C1 is characterized by lymphopenia, C2 by elevated ferritin, and C3 by elevated LDH. C4 is characterized by lymphopenia plus elevated CRP and LDH and frequently also ferritin. C5 is defined by elevated CRP, and C6 by elevated ferritin and D-dimer, and frequently also elevated CRP and LDH. Finally, C7 is characterized by an elevated D-dimer. The clusters with the highest in-hospital mortality were C4, C6, and C7 (17.4% vs. 18% vs. 15.6% vs. 36.8% vs. 17.5% vs. 39.3% vs. 26.4%). Inflammation clusters were found as independent factors for in-hospital mortality. In detail and, having cluster C1 as reference, the model revealed a worse prognosis for all other clusters: C2 (OR = 1.30, p = 0.001), C3 (OR = 1.14, p = 0.178), C4 (OR = 2.28, p < 0.001), C5 (OR = 1.07, p = 0.479), C6 (OR = 2.29, p < 0.001), and C7 (OR = 1.28, p = 0.001). We identified 7 groups based on the presence of lymphopenia, elevated CRP, LDH, ferritin, and D-dimer at the time of hospital admission for COVID-19. Clusters C4 (lymphopenia + LDH + CRP), C6 (ferritin + D-dimer), and C7 (D-dimer) had the worst prognosis in terms of in-hospital mortality.


Subject(s)
COVID-19 , Lymphopenia , Biomarkers , COVID-19/complications , Ferritins , Humans , Inflammation , Prognosis , Registries , Retrospective Studies , SARS-CoV-2
9.
EBioMedicine ; 78: 103978, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1768041

ABSTRACT

BACKGROUND: Severe COVID-19 T-cell lymphopenia is more common among older adults and entails poor prognosis. Offsetting the decline in T-cell count during COVID-19 demands fast and massive T-cell clonal expansion, which is telomere length (TL)-dependent. METHODS: We developed a model of TL-dependent T-cell clonal expansion capacity with age and virtually examined the relation of T-cell clonal expansion with COVID-19 mortality in the general population. FINDINGS: The model shows that an individual with average hematopoietic cell TL (HCTL) at age twenty years maintains maximal T-cell clonal expansion capacity until the 6th decade of life when this capacity rapidly declines by more than 90% over the next ten years. The collapse in the T-cell clonal expansion capacity coincides with the steep increase in COVID-19 mortality with age. INTERPRETATION: Short HCTL might increase vulnerability of many older adults, and some younger individuals with inherently short HCTL, to COVID-19 T-cell lymphopenia and severe disease. FUNDING: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.


Subject(s)
COVID-19 , Lymphopenia , Adult , Aged , Aging , Humans , T-Lymphocytes , Telomere/genetics , Young Adult
10.
BMC Infect Dis ; 22(1): 295, 2022 Mar 26.
Article in English | MEDLINE | ID: covidwho-1765437

ABSTRACT

BACKGROUND: In the Emergency Department (ED), early and accurate recognition of infection is crucial to prompt antibiotic therapy but the initial presentation of patients is variable and poorly characterized. Lymphopenia is commonly associated with bacteraemia and poor outcome in intensive care unit patients. The objective of this retrospective study was to assess the prevalence of community-acquired infection in a cohort of unselected patients admitted to the ED with undifferentiated symptoms and severe lymphopenia. METHODS: This is a retrospective single-center study conducted over a 1 year-period before the COVID-19 pandemic. Consecutive adult patients admitted to the ED with severe lymphopenia (lymphocyte count < 0.5 G/L) were studied. Patients with hematological or oncological diseases, HIV infection, hepato-cellular deficiency, immunosuppression, or patients over 85 years old were excluded. Diagnoses of infection were validated by an independent adjudication committee. The association between various parameters and infection was assessed using a multivariate logistic regression analysis. RESULTS: Of 953 patients admitted to the ED with severe lymphopenia, 245 were studied (148 men; mean age: 63 ± 19 years). Infection was confirmed in 159 patients (65%) (bacterial: 60%, viral: 30%, other: 10%). Only 61 patients (25%) were referred to the ED for a suspected infection. In the univariate analysis, SIRS criteria (OR: 5.39; 95%CI: 3.04-9.70; p < 0.001) and temperature ≥ 38.3 °C (OR: 10.95; 95%CI: 5.39-22.26; p < 0.001) were strongly associate with infection. In the multivariate analysis, only SIRS criteria (OR: 2.4; 95%CI: 1.48-3.9; p < 0.01) and fever (OR: 3.35; 95%CI: 1.26-8.93; p = 0.016) were independently associated with infection. CONCLUSIONS: The prevalence of underlying infection is high in patients admitted to the ED with lymphopenia, irrespective of the reason for admission. Whether lymphopenia could constitute a valuable marker of underlying infection in this clinical setting remains to be confirmed prospectively in larger cohorts. TRIAL REGISTRATION: No registration required as this is a retrospective study.


Subject(s)
COVID-19 , HIV Infections , Lymphopenia , Adult , Aged , Aged, 80 and over , COVID-19/epidemiology , Emergency Service, Hospital , HIV Infections/complications , HIV Infections/epidemiology , Humans , Lymphopenia/diagnosis , Male , Middle Aged , Pandemics , Prevalence , Retrospective Studies
11.
Am J Respir Crit Care Med ; 205(12): 1403-1418, 2022 Jun 15.
Article in English | MEDLINE | ID: covidwho-1765220

ABSTRACT

Rationale: Lymphopenia is common in severe coronavirus disease (COVID-19), yet the immune mechanisms are poorly understood. As inflammatory cytokines are increased in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, we hypothesized a role in contributing to reduced T-cell numbers. Objectives: We sought to characterize the functional SARS-CoV-2 T-cell responses in patients with severe versus recovered, mild COVID-19 to determine whether differences were detectable. Methods: Using flow cytometry and single-cell RNA sequence analyses, we assessed SARS-CoV-2-specific responses in our cohort. Measurements and Main Results: In 148 patients with severe COVID-19, we found lymphopenia was associated with worse survival. CD4+ lymphopenia predominated, with lower CD4+/CD8+ ratios in severe COVID-19 compared with patients with mild disease (P < 0.0001). In severe disease, immunodominant CD4+ T-cell responses to Spike-1 (S1) produced increased in vitro TNF-α (tumor necrosis factor-α) but demonstrated impaired S1-specific proliferation and increased susceptibility to activation-induced cell death after antigen exposure. CD4+TNF-α+ T-cell responses inversely correlated with absolute CD4+ counts from patients with severe COVID-19 (n = 76; R = -0.797; P < 0.0001). In vitro TNF-α blockade, including infliximab or anti-TNF receptor 1 antibodies, strikingly rescued S1-specific CD4+ T-cell proliferation and abrogated S1-specific activation-induced cell death in peripheral blood mononuclear cells from patients with severe COVID-19 (P < 0.001). Single-cell RNA sequencing demonstrated marked downregulation of type-1 cytokines and NFκB signaling in S1-stimulated CD4+ cells with infliximab treatment. We also evaluated BAL and lung explant CD4+ T cells recovered from patients with severe COVID-19 and observed that lung T cells produced higher TNF-α compared with peripheral blood mononuclear cells. Conclusions: Together, our findings show CD4+ dysfunction in severe COVID-19 is TNF-α/TNF receptor 1-dependent through immune mechanisms that may contribute to lymphopenia. TNF-α blockade may be beneficial in severe COVID-19.


Subject(s)
COVID-19 , Lymphopenia , CD4-Positive T-Lymphocytes , CD8-Positive T-Lymphocytes , Cytokines , Humans , Infliximab , Leukocytes, Mononuclear , Receptors, Tumor Necrosis Factor , SARS-CoV-2 , Tumor Necrosis Factor Inhibitors , Tumor Necrosis Factor-alpha
12.
Mult Scler Relat Disord ; 61: 103785, 2022 May.
Article in English | MEDLINE | ID: covidwho-1763908

ABSTRACT

BACKGROUND & OBJECTIVES: Certain disease modifying therapies may negatively impact the humoral response to SARS-CoV-2 vaccines. Many MS related clinical, demographic, and immunological characteristics can also affect vaccine response but those have not been fully explored. This study aimed to investigate potential correlations between clinical, demographic, and immunological variables in MS patients to post-vaccination spike protein antibody positivity rates and levels. METHODS: Patients with MS and related neuroimmunological disorders who requested verification of the immune response to the SARS-COV-2 vaccine were tested for the spike protein antibody from January to October 2021. We performed an exploratory analysis to compare patients with positive versus negative spike protein antibody. RESULTS: Fifty patients (mean age 53 ±12, 78% females) were included. There were 29 patients with positive post-vaccination spike protein antibody (58%) and 21 with negative antibody (42%). Patients with negative antibody were more likely to have been on B-cell therapy (86% vs 31%, P=.001) while positive patients were more likely to have been on a fumarate (31% vs 4.8%, P=.03). Thirty percent of positive patients on fumarate therapy had mild lymphopenia. No differences existed between groups in gender, age, race, disease phenotype, vaccine brand, and lymphocyte counts. Among patients on B-cell therapy, 33% had a positive spike protein antibody. There was an association between detectable CD19 cells at time of vaccination and positive humoral response to vaccination (P=0.049). There was no relationship between subgroups in terms of vaccine timing relative to B-cell therapy dose. Hypogammaglobulinemia was not associated with seroconversion rates, however it was associated with decreased quantitative spike protein antibody levels (p=0.045). DISCUSSION: B-cell therapy is associated with a negative humoral response to SARS-COV-2 vaccines. Patients on B-cell depleting therapy with detectable CD19 counts at the time of vaccination were associated with a positive humoral response. There was no relationship between hypogammaglobinemia and seroconversion rate, however it was associated with decreased spike protein antibody levels. The fumarates are associated with positive humoral response even in the presence of mild lymphopenia.


Subject(s)
COVID-19 , Lymphopenia , Multiple Sclerosis , Antibodies, Viral , COVID-19/prevention & control , COVID-19 Vaccines , Female , Fumarates , Humans , Lymphocyte Count , Male , Multiple Sclerosis/drug therapy , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/therapeutic use , Vaccination
13.
Int J Mol Sci ; 23(4)2022 Feb 17.
Article in English | MEDLINE | ID: covidwho-1760640

ABSTRACT

Tuberculosis is still an important medical and social problem. In recent years, great strides have been made in the fight against M. tuberculosis, especially in the Russian Federation. However, the emergence of a new coronavirus infection (COVID-19) has led to the long-term isolation of the population on the one hand and to the relevance of using personal protective equipment on the other. Our knowledge regarding SARS-CoV-2-induced inflammation and tissue destruction is rapidly expanding, while our understanding of the pathology of human pulmonary tuberculosis gained through more the 100 years of research is still limited. This paper reviews the main molecular and cellular differences and similarities caused by M. tuberculosis and SARS-CoV-2 infections, as well as their critical immunological and pathomorphological features. Immune suppression caused by the SARS-CoV-2 virus may result in certain difficulties in the diagnosis and treatment of tuberculosis. Furthermore, long-term lymphopenia, hyperinflammation, lung tissue injury and imbalance in CD4+ T cell subsets associated with COVID-19 could propagate M. tuberculosis infection and disease progression.


Subject(s)
COVID-19/etiology , Tuberculosis/diagnosis , Tuberculosis/etiology , COVID-19/immunology , Coinfection , Host-Pathogen Interactions , Humans , Inflammation/microbiology , Inflammation/pathology , Inflammation/virology , Lymphopenia/microbiology , Lymphopenia/virology , Mycobacterium tuberculosis/pathogenicity , SARS-CoV-2/pathogenicity
14.
Elife ; 112022 Mar 11.
Article in English | MEDLINE | ID: covidwho-1742931

ABSTRACT

Background: Risk of severe COVID-19 increases with age, is greater in males, and is associated with lymphopenia, but not with higher burden of SARS-CoV-2. It is unknown whether effects of age and sex on abundance of specific lymphoid subsets explain these correlations. Methods: Multiple regression was used to determine the relationship between abundance of specific blood lymphoid cell types, age, sex, requirement for hospitalization, duration of hospitalization, and elevation of blood markers of systemic inflammation, in adults hospitalized for severe COVID-19 (n = 40), treated for COVID-19 as outpatients (n = 51), and in uninfected controls (n = 86), as well as in children with COVID-19 (n = 19), recovering from COVID-19 (n = 14), MIS-C (n = 11), recovering from MIS-C (n = 7), and pediatric controls (n = 17). Results: This observational study found that the abundance of innate lymphoid cells (ILCs) decreases more than 7-fold over the human lifespan - T cell subsets decrease less than 2-fold - and is lower in males than in females. After accounting for effects of age and sex, ILCs, but not T cells, were lower in adults hospitalized with COVID-19, independent of lymphopenia. Among SARS-CoV-2-infected adults, the abundance of ILCs, but not of T cells, correlated inversely with odds and duration of hospitalization, and with severity of inflammation. ILCs were also uniquely decreased in pediatric COVID-19 and the numbers of these cells did not recover during follow-up. In contrast, children with MIS-C had depletion of both ILCs and T cells, and both cell types increased during follow-up. In both pediatric COVID-19 and MIS-C, ILC abundance correlated inversely with inflammation. Blood ILC mRNA and phenotype tracked closely with ILCs from lung. Importantly, blood ILCs produced amphiregulin, a protein implicated in disease tolerance and tissue homeostasis. Among controls, the percentage of ILCs that produced amphiregulin was higher in females than in males, and people hospitalized with COVID-19 had a lower percentage of ILCs that produced amphiregulin than did controls. Conclusions: These results suggest that, by promoting disease tolerance, homeostatic ILCs decrease morbidity and mortality associated with SARS-CoV-2 infection, and that lower ILC abundance contributes to increased COVID-19 severity with age and in males. Funding: This work was supported in part by the Massachusetts Consortium for Pathogen Readiness and NIH grants R37AI147868, R01AI148784, F30HD100110, 5K08HL143183.


Subject(s)
COVID-19 , Lymphopenia , Amphiregulin , COVID-19/complications , Child , Female , Humans , Immunity, Innate , Inflammation , Male , SARS-CoV-2 , Systemic Inflammatory Response Syndrome , T-Lymphocyte Subsets
15.
Biomolecules ; 12(3)2022 03 13.
Article in English | MEDLINE | ID: covidwho-1742313

ABSTRACT

Severe COVID-19 disease leads to hypoxemia, inflammation and lymphopenia. Viral infection induces cellular stress and causes the activation of the innate immune response. The ubiquitin-proteasome system (UPS) is highly implicated in viral immune response regulation. The main function of the proteasome is protein degradation in its active form, which recognises and binds to ubiquitylated proteins. Some proteasome subunits have been reported to be upregulated under hypoxic and hyperinflammatory conditions. Here, we conducted a prospective cohort study of COVID-19 patients (n = 44) and age-and sex-matched controls (n = 20). In this study, we suggested that hypoxia could induce the overexpression of certain genes encoding for subunits from the α and ß core of the 20S proteasome and from regulatory particles (19S and 11S) in COVID-19 patients. Furthermore, the gene expression of proteasome subunits was associated with lymphocyte count reduction and positively correlated with inflammatory molecular and clinical markers. Given the importance of the proteasome in maintaining cellular homeostasis, including the regulation of the apoptotic and pyroptotic pathways, these results provide a potential link between COVID-19 complications and proteasome gene expression.


Subject(s)
COVID-19 , Lymphopenia , COVID-19/genetics , Humans , Hypoxia , Inflammation/genetics , Lymphopenia/genetics , Prospective Studies , Proteasome Endopeptidase Complex/genetics , Proteasome Endopeptidase Complex/metabolism
16.
Signal Transduct Target Ther ; 7(1): 57, 2022 02 23.
Article in English | MEDLINE | ID: covidwho-1702971

ABSTRACT

The coronavirus disease 2019 (COVID-19) is a highly transmissible disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that poses a major threat to global public health. Although COVID-19 primarily affects the respiratory system, causing severe pneumonia and acute respiratory distress syndrome in severe cases, it can also result in multiple extrapulmonary complications. The pathogenesis of extrapulmonary damage in patients with COVID-19 is probably multifactorial, involving both the direct effects of SARS-CoV-2 and the indirect mechanisms associated with the host inflammatory response. Recognition of features and pathogenesis of extrapulmonary complications has clinical implications for identifying disease progression and designing therapeutic strategies. This review provides an overview of the extrapulmonary complications of COVID-19 from immunological and pathophysiologic perspectives and focuses on the pathogenesis and potential therapeutic targets for the management of COVID-19.


Subject(s)
Acute Kidney Injury/complications , COVID-19/complications , Cytokine Release Syndrome/complications , Disseminated Intravascular Coagulation/complications , Lymphopenia/complications , Myocarditis/complications , Pulmonary Embolism/complications , Acute Kidney Injury/drug therapy , Acute Kidney Injury/immunology , Acute Kidney Injury/virology , Anticoagulants/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19/immunology , COVID-19/virology , Clinical Trials as Topic , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/virology , Disseminated Intravascular Coagulation/drug therapy , Disseminated Intravascular Coagulation/immunology , Disseminated Intravascular Coagulation/virology , Endothelial Cells/drug effects , Endothelial Cells/immunology , Endothelial Cells/virology , Humans , Immunity, Innate/drug effects , Immunologic Factors/therapeutic use , Lymphopenia/drug therapy , Lymphopenia/immunology , Lymphopenia/virology , Myocarditis/drug therapy , Myocarditis/immunology , Myocarditis/virology , Pulmonary Embolism/drug therapy , Pulmonary Embolism/immunology , Pulmonary Embolism/virology , Renin-Angiotensin System/drug effects , Renin-Angiotensin System/immunology , SARS-CoV-2/drug effects , SARS-CoV-2/growth & development , SARS-CoV-2/pathogenicity
17.
Environ Sci Pollut Res Int ; 29(29): 44404-44412, 2022 Jun.
Article in English | MEDLINE | ID: covidwho-1669936

ABSTRACT

Previous ecological studies suggest the existence of possible interplays between the exposure to air pollutants and SARS-CoV-2 infection. Confirmations at individual level, however, are lacking. To explore the relationships between previous exposure to particulate matter < 10 µm (PM10) and nitrogen dioxide (NO2), the clinical outcome following hospital admittance, and lymphocyte subsets in COVID-19 patients with pneumonia. In 147 geocoded patients, we assessed the individual exposure to PM10 and NO2 in the 2 weeks before hospital admittance. We divided subjects according to the clinical outcome (i.e., discharge at home vs in-hospital death), and explored the lymphocyte-related immune function as an index possibly affecting individual vulnerability to the infection. As compared with discharged subjects, patients who underwent in-hospital death presented neutrophilia, lymphopenia, lower number of T CD45, CD3, CD4, CD16/56 + CD3 + , and B CD19 + cells, and higher previous exposure to NO2, but not PM10. Age and previous NO2 exposure were independent predictors for mortality. NO2 concentrations were also negatively related with the number of CD45, CD3, and CD4 cells. Previous NO2 exposure is a co-factor independently affecting the mortality risk in infected individuals, through negative immune effects. Lymphopenia and altered lymphocyte subsets might precede viral infection due to nonmodifiable (i.e., age) and external (i.e., air pollution) factors. Thus, decreasing the burden of air pollutants should be a valuable primary prevention measure to reduce individual susceptibility to SARS-CoV-2 infection and mortality.


Subject(s)
Air Pollutants , Air Pollution , COVID-19 , Lymphopenia , Air Pollutants/analysis , Air Pollution/analysis , Environmental Exposure/analysis , Hospital Mortality , Humans , Immunity , Lymphopenia/chemically induced , Nitrogen Dioxide/analysis , Particulate Matter/analysis , SARS-CoV-2
18.
Front Immunol ; 12: 799896, 2021.
Article in English | MEDLINE | ID: covidwho-1662583

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection results in rapid T lymphocytopenia and functional impairment of T cells. The underlying mechanism, however, remains incompletely understood. In this study, we focused on characterizing the phenotype and kinetics of T-cell subsets with mitochondrial dysfunction (MD) by multicolor flow cytometry and investigating the association between MD and T-cell functionality. While 73.9% of study subjects displayed clinical lymphocytopenia upon hospital admission, a significant reduction of CD4 or CD8 T-cell frequency was found in all asymptomatic, symptomatic, and convalescent cases. CD4 and CD8 T cells with increased MD were found in both asymptomatic and symptomatic patients within the first week of symptom onset. Lower proportion of memory CD8 T cell with MD was found in severe patients than in mild ones at the stage of disease progression. Critically, the frequency of T cells with MD in symptomatic patients was preferentially associated with CD4 T-cell loss and CD8 T-cell hyperactivation, respectively. Patients bearing effector memory CD4 and CD8 T cells with the phenotype of high MD exhibited poorer T-cell responses upon either phorbol 12-myristate-13-acetate (PMA)/ionomycin or SARS-CoV-2 peptide stimulation than those with low MD. Our findings demonstrated an MD-associated mechanism underlying SARS-CoV-2-induced T lymphocytopenia and functional impairment during the acute phase of infection.


Subject(s)
COVID-19/complications , Lymphopenia/complications , Lymphopenia/etiology , Mitochondrial Diseases/etiology , Adult , Aged , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/drug therapy , COVID-19/immunology , Female , Humans , Immunologic Memory/immunology , Ionomycin/therapeutic use , Lymphopenia/immunology , Male , Middle Aged , Mitochondria/immunology , Mitochondrial Diseases/immunology , Phosphorylcholine/analogs & derivatives , Phosphorylcholine/therapeutic use , Polymethacrylic Acids/therapeutic use
19.
Front Endocrinol (Lausanne) ; 12: 774346, 2021.
Article in English | MEDLINE | ID: covidwho-1662575

ABSTRACT

Background: Both lymphopenia and thyroid dysfunction are commonly observed among COVID-19 patients. Whether thyroid function independently correlates with lymphocyte counts (LYM) remains to be elucidated. Methods: We included consecutive adults without known thyroid disorder admitted to Queen Mary Hospital for COVID-19 from July 2020 to April 2021 who had thyroid-stimulating hormone (TSH), free thyroxine (fT4), free triiodothyronine (fT3) and LYM measured on admission. Results: A total of 541 patients were included. Median LYM was 1.22 x 109/L, with 36.0% of the cohort lymphopenic. 83 patients (15.4%) had abnormal thyroid function tests (TFTs), mostly non-thyroidal illness syndrome (NTIS). Patients with lymphopenia had lower TSH, fT4 and fT3 levels than those without. Multivariable stepwise linear regression analysis revealed that both TSH (standardized beta 0.160, p<0.001) and fT3 (standardized beta 0.094, p=0.023), but not fT4, remained independently correlated with LYM, in addition to age, SARS-CoV-2 viral load, C-reactive protein levels, coagulation profile, sodium levels and more severe clinical presentations. Among the 40 patients who had reassessment of TFTs and LYM after discharge, at a median of 9 days from admission, there were significant increases in TSH (p=0.031), fT3 (p<0.001) and LYM (p<0.001). Furthermore, patients who had both lymphopenia and NTIS were more likely to deteriorate compared to those who only had either one alone, and those without lymphopenia or NTIS (p for trend <0.001). Conclusion: TSH and fT3 levels showed independent positive correlations with LYM among COVID-19 patients, supporting the interaction between the hypothalamic-pituitary-thyroid axis and immune system in COVID-19.


Subject(s)
COVID-19/complications , Lymphocytes/pathology , Lymphopenia/epidemiology , SARS-CoV-2/isolation & purification , Thyroid Diseases/epidemiology , Thyrotropin/blood , Triiodothyronine/blood , Adult , Aged , COVID-19/virology , China/epidemiology , Female , Hospitalization , Humans , Lymphocyte Count , Lymphopenia/blood , Lymphopenia/immunology , Lymphopenia/virology , Male , Middle Aged , Thyroid Diseases/blood , Thyroid Diseases/immunology , Thyroid Diseases/virology , Thyroid Function Tests , Thyroid Hormones/blood
20.
J Leukoc Biol ; 111(6): 1287-1295, 2022 Jun.
Article in English | MEDLINE | ID: covidwho-1650087

ABSTRACT

Immune cell dysregulation and lymphopenia characterize COVID-19 pathology in moderate to severe disease. While underlying inflammatory factors have been extensively studied, homeostatic and mucosal migratory signatures remain largely unexplored as causative factors. In this study, we evaluated the association of circulating IL-6, soluble mucosal addressin cell adhesion molecule (sMAdCAM), and IL-15 with cellular dysfunction characterizing mild and hypoxemic stages of COVID-19. A cohort of SARS-CoV-2 infected individuals (n = 130) at various stages of disease progression together with healthy controls (n = 16) were recruited from COVID Care Centres (CCCs) across Mumbai, India. Multiparametric flow cytometry was used to perform in-depth immune subset characterization and to measure plasma IL-6 levels. sMAdCAM, IL-15 levels were quantified using ELISA. Distinct depletion profiles, with relative sparing of CD8 effector memory and CD4+ regulatory T cells, were observed in hypoxemic disease within the lymphocyte compartment. An apparent increase in the frequency of intermediate monocytes characterized both mild as well as hypoxemic disease. IL-6 levels inversely correlated with those of sMAdCAM and both markers showed converse associations with observed lympho-depletion suggesting opposing roles in pathogenesis. Interestingly, IL-15, a key cytokine involved in lymphocyte activation and homeostasis, was detected in symptomatic individuals but not in healthy controls or asymptomatic cases. Further, plasma IL-15 levels negatively correlated with T, B, and NK count suggesting a compensatory production of this cytokine in response to the profound lymphopenia. Finally, higher levels of plasma IL-15 and IL-6, but not sMAdCAM, were associated with a longer duration of hospitalization.


Subject(s)
COVID-19 , Interleukin-15/blood , Lymphopenia , CD8-Positive T-Lymphocytes , Cell Adhesion Molecules , Cytokines , Humans , Interleukin-6 , Lymphopenia/etiology , SARS-CoV-2
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