Dynamic changes in the immune response correlate with disease severity and outcomes during infection with SARS-CoV-2

Abstract Background:The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly spread throughout China and all over the world. Little is known about the dynamic changes in the patient immune responses to SARS-CoV-2, and how different responses are correlated with disease severity and outcomes.Method:74 patients with confirmed COVID-19 were enrolled in this prospective research. The demographic information, medical history, symptoms, signs and laboratory results were analyzed and compared between severe and non-severe patients. The leukocytes, lymphocyte subsets and inflammatory cytokines were longitudinally collected.Results:Of the 74 patients included, 17 suffered from severe disease. The severe patients tended be older (65.29 ± 12.33 years vs. 45.37 ± 18.66 years), and had a greater degree of underlying disease (41.18% vs. 24.56%) , lower baseline lymphocytes counts (0.69 ± 0.36 × 10⁹ vs. 1.46 ± 0.75 × 10⁹) , higher neutrophil-lymphocyte-ratios (NLRs; 3.76 (3.15–5.51) vs. 2.07 (1.48–2.93)) and lower baseline eosinophil counts (0.01 ± 0.01 × 10⁹ vs. 0.05 ± 0.07 × 10⁹), than that in non-severe patients. The baseline helper T (Th) cells (335.47 vs. 666.46/mL), suppressor T(Ts) cells (158 vs. 334/mL), B cells (95 vs. 210/mL), and natural killer (NK) cells (52 vs. 122/mL) were significantly decreased in severe cases compared to that in non-severe cases. In addition, the baseline neutrophils and B cells were positively correlated with the severity of COVID-19 and the baseline lymphocytes and Th cells were negatively correlated with the severity of COVID-19. The dynamic change of T cells, Th cells and IFN-γ in the severe cases were parallel to the amelioration of the disease.Conclusions:Collectively, our study provides novel information on the kinetics of the immune responses in a cohort of COVID-19 patients with different disease severities. Furthermore, our study indicates that both innate and adaptive immune responses correlate with better clinical outcomes.

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Airway antibodies wane rapidly after COVID-19 but B cell memory is generated across disease severity

10.1101/2020.11.25.20238592 ◽

2020 ◽

Author(s):

Alberto Cagigi ◽

Meng Yu ◽

Sara Falck-Jones ◽

Sindhu Vangeti ◽

Björn Österberg ◽

...

Keyword(s):

B Cells ◽

Immune Responses ◽

B Cell ◽

Disease Severity ◽

Severe Disease ◽

Memory B Cells ◽

Antibody Responses ◽

Full Spectrum ◽

Viral Spread ◽

Specific Memory

AbstractUnderstanding immune responses following SARS-CoV-2 infection in relation to COVID-19 severity is critical for predicting the effects of long-term immunological memory on viral spread. Here we longitudinally assessed systemic and airway immune responses against SARS-CoV-2 in a well-characterized cohort of 147 infected individuals representing the full spectrum of COVID-19 severity; from asymptomatic infection to fatal disease. High systemic and airway antibody responses were elicited in patients with moderate to severe disease, and while systemic IgG levels were maintained after acute disease, airway IgG and IgA declined significantly. In contrast, individuals with mild symptoms showed significantly lower antibody responses but their levels of antigen-specific memory B cells were comparable with those observed in patients with moderate to severe disease. This suggests that antibodies in the airways may not be maintained at levels that prevent local virus entry upon re-exposure and therefore protection via activation of the memory B cell pool is critical.SummaryCOVID-19 severity determines the level of systemic and airway IgG and IgA but while IgG are maintained in plasma during convalescence, antibodies wane rapidly in the airways.However, comparable levels of antigen-specific memory B cells are generated across disease severity.

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ANTIBODY RESPONSE TO COVID-19 INFECTION- CLINICAL VARIABLES AT PLAY

10.1101/2020.11.20.20234500 ◽

2020 ◽

Author(s):

Anuj Parkash ◽

Parul Singla ◽

Meenu Bhatia

Keyword(s):

Immune Response ◽

Immune Responses ◽

Disease Severity ◽

Statistical Significance ◽

Severe Disease ◽

Initial Symptom ◽

Igg Antibody ◽

Duration Of Symptoms ◽

Clinical Variables ◽

Significant Difference

ABSTRACTBackgroundThe current COVID19 pandemic began in December 2019 and rapidly expanded to become a global pandemic. The COVID 19 presents multitude of clinical disorders, ranges from asymptomatic infection to severe disease, which can accompanied by multisystem failure leading to death. The immune response to SARS CoV 2 is understood to involve all the components of the system that together causes viral elimination and recovery from the infection. However, such immune responses implicated in the disease has varied presentation ranging from mild to a severe form, which appears to hinge on the loss of the immune regulation between protective and altered responses. In this study, we want to unravel this association of immune responses to various clinical variables, which might have a major role to play, while generating the immune response. The objective was to test this hypothesis in our settings and comparing the results of serologic tests from a group of COVID 19 patients and will analyzed the disease severity in comparison.MethodsTesting for SARS COV2 IgG Antibody was done with chemiluminescent assay on the Ortho Clinical Diagnostic’s (OCD) Vitros 5600 platform.ResultsA total of 106 COVID 19 patients were included in this study, of whom 61 were male and 45 were female. Their mean age was 43.7 years (range 17–83) and the median interval between initial symptom onset and sample collection was 12.33 days. Eighty patients (82%) had mild or moderate symptoms and twenty-six patients (18%) had severe symptoms. The antibody titers were positive in 99 patients (93%) and were found negative in 7 patients (7%). When comparing patients with mild/moderate symptoms and patients with severe/critical diseases, no statistically significant difference was observed between their gender ratios (P = 0.373) and age composition (P = 0.224).ConclusionsThe data presented in this research study did not find any statistical significance between SARS CoV 2 IgG antibody levels with COVID 19 disease severity, duration of symptoms, age, gender, and length of convalescence.

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Dynamic change in lymphocyte count in the early stage is a potential predictor of the severity of COVID-19

10.21203/rs.3.rs-18253/v1 ◽

2020 ◽

Author(s):

Xi Zhang ◽

Yonghao Du ◽

Lei Shi ◽

Tianyan Chen ◽

Yingren Zhao ◽

...

Keyword(s):

Lymphocyte Count ◽

Early Stage ◽

Dynamic Change ◽

Severe Disease ◽

Chest Ct ◽

Dynamic Changes ◽

Potential Predictor ◽

Illness Onset ◽

Over Time ◽

Severe Patient

Abstract Background Lymphopenia is associated with COVID-19 severity. Herein we describe the dynamic changes in lymphocyte count during hospitalization and explore a possible association with the severity of COVID-19.Methods In this retrospective study, 13 non-severe COVID-19 patients diagnosed at admission were enrolled. One patient progressed to severe disease. Dynamic changes in lymphocyte count and CT score of all patients were analyzed.Results Lymphocyte count changed significantly in the non-severe patients over time (admission vs day 5, P=0.685; day 5 vs day 15, P<0.001). Lymphocyte count of the severe patient fluctuated, and even decreased within the first 12 days post-admission, before increasing gradually. Chest CT scores of nine (75%) non-severe patients on the 5th day of hospitalization were higher than at admission, but decreased gradually thereafter (admission vs day 5, P<0.001, day 5 vs day 15, P=0.004). In the severe patient, CT score continued to increase for 2 weeks after admission, before decreasing gradually.Conclusions Non-severe COVID-19 patients had significantly increased lymphocyte count and decreased CT score 1 week after illness onset. Dynamic change in lymphocyte count in the early stages of COVID-19 may be helpful to identify the patients who are more likely to develop severe or critical illness.

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Dynamic change and clinical relevance of post-infectious SARS-CoV-2 antibody responses

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab122 ◽

2021 ◽

Author(s):

P W G Mallon ◽

W Tinago ◽

A Garcia Leon ◽

K McCann ◽

G Kenny ◽

...

Keyword(s):

Disease Severity ◽

Symptom Onset ◽

Post Infection ◽

Dynamic Change ◽

Severe Disease ◽

Additive Models ◽

Antibody Responses ◽

Rapid Decline ◽

Relative Differences ◽

Post Infectious

Abstract Background Although reports suggest that most individuals with COVID-19 develop detectable antibodies post infection, the kinetics, durability, and relative differences between IgM and IgG responses beyond the first few weeks after symptom onset remain poorly understood. Methods Within a large, well-phenotyped, diverse, prospective cohort of subjects with and without SARS-CoV-2 PCR-confirmed infection and historical controls derived from cohorts with high prevalence of viral coinfections and samples taken during prior flu seasons, we measured SARS-CoV-2 serological responses (both IgG and IgM) using commercially available assays. We calculated sensitivity and specificity, relationship with disease severity and mapped the kinetics of antibody responses over time using generalised additive models. Results We analysed 1,001 samples from 752 subjects, 327 with confirmed SARS-CoV-2 (29.7% with severe disease) spanning a period of 90 days from symptom onset. Sensitivity was lower (44.1-47.1%) early (<10 days) after symptom onset but increased to >80% after 10 days. IgM positivity increased earlier than IgG-targeted assays but positivity peaked between day 32 and 38 post onset of symptoms and declined thereafter, a dynamic that was confirmed when antibody levels were analysed, with more rapid decline observed with IgM. Early (<10 days) IgM but not IgG levels were significantly higher in those who subsequently developed severe disease (signal / cut-off 4.20 (0.75-17.93) versus 1.07 (0.21-5.46), P=0.048). Conclusions This study suggests that post-infectious antibody responses in those with confirmed COVID-19 begin to decline relatively early post infection and suggests a potential role for higher IgM levels early in infection predicting subsequent disease severity

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Dynamic change and clinical relevance of post-infectious SARS-CoV-2 antibody responses

10.1101/2021.01.24.20248381 ◽

2021 ◽

Author(s):

PWG Mallon ◽

W Tinago ◽

A Garcia Leon ◽

K McCann ◽

G Kenny ◽

...

Keyword(s):

Disease Severity ◽

Symptom Onset ◽

Post Infection ◽

Dynamic Change ◽

Severe Disease ◽

Additive Models ◽

Antibody Responses ◽

Rapid Decline ◽

Relative Differences ◽

Post Infectious

AbstractBackgroundAlthough reports suggest that most individuals with COVID-19 develop detectable antibodies post infection, the kinetics, durability, and relative differences between IgM and IgG responses beyond the first few weeks after symptom onset remain poorly understood.MethodsWithin a large, well-phenotyped, diverse, prospective cohort of subjects with and without SARS-CoV-2 PCR-confirmed infection and historical controls derived from cohorts with high prevalence of viral coinfections and samples taken during prior flu seasons, we measured SARS-CoV-2 serological responses (both IgG and IgM) using commercially available assays. We calculated sensitivity and specificity, relationship with disease severity and mapped the kinetics of antibody responses over time using generalised additive models.ResultsWe analysed 1,001 samples from 752 subjects, 327 with confirmed SARS-CoV-2 (29.7% with severe disease) spanning a period of 90 days from symptom onset. Sensitivity was lower (44.1-47.1%) early (<10 days) after symptom onset but increased to >80% after 10 days. IgM positivity increased earlier than IgG-targeted assays but positivity peaked between day 32 and 38 post onset of symptoms and declined thereafter, a dynamic that was confirmed when antibody levels were analysed, with more rapid decline observed with IgM. Early (<10 days) IgM but not IgG levels were significantly higher in those who subsequently developed severe disease (signal / cut-off 4.20 (0.75-17.93) versus 1.07 (0.21-5.46), P=0.048).ConclusionsThis study suggests that post-infectious antibody responses in those with confirmed COVID-19 begin to decline relatively early post infection and suggests a potential role for higher IgM levels early in infection predicting subsequent disease severity.

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Stochastic Model of the Adaptive Immune Response Predicts Disease Severity and Captures Enhanced Cross-Reactivity in Natural Dengue Infections

Frontiers in Immunology ◽

10.3389/fimmu.2021.696755 ◽

2021 ◽

Vol 12 ◽

Author(s):

Hung D. Nguyen ◽

Sidhartha Chaudhury ◽

Adam T. Waickman ◽

Heather Friberg ◽

Jeffrey R. Currier ◽

...

Keyword(s):

Immune Response ◽

Immune Responses ◽

Stochastic Model ◽

Disease Severity ◽

Secondary Infection ◽

Severe Disease ◽

Adaptive Immune Response ◽

Cross Reactivity ◽

Adaptive Immune ◽

Severe Manifestation

The dengue virus circulates as four distinct serotypes, where a single serotype infection is typically asymptomatic and leads to acquired immunity against that serotype. However, the developed immunity to one serotype is thought to underlie the severe manifestation of the disease observed in subsequent infections from a different serotype. We developed a stochastic model of the adaptive immune response to dengue infections. We first delineated the mechanisms initiating and sustaining adaptive immune responses during primary infections. We then contrasted these immune responses during secondary infections of either a homotypic or heterotypic serotype to understand the role of pre-existing and reactivated immune pathways on disease severity. Comparison of non-symptomatic and severe cases from heterotypic infections demonstrated that overproduction of specific antibodies during primary infection induces an enhanced population of cross-reactive antibodies during secondary infection, ultimately leading to severe disease manifestations. In addition, the level of disease severity was found to correlate with immune response kinetics, which was dependent on beginning lymphocyte levels. Our results detail the contribution of specific lymphocytes and antibodies to immunity and memory recall that lead to either protective or pathological outcomes, allowing for the understanding and determination of mechanisms of protective immunity.

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Comprehensive Profiling of Inflammatory Factors Revealed That Growth Differentiation Factor-15 Is an Indicator of Disease Severity in COVID-19 Patients

Frontiers in Immunology ◽

10.3389/fimmu.2021.662465 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xiangyun Teng ◽

Jiaqi Zhang ◽

Yaling Shi ◽

Yuntao Liu ◽

Yanqing Yang ◽

...

Keyword(s):

Disease Severity ◽

Dynamic Change ◽

Inflammatory Factors ◽

Control Groups ◽

Dynamic Changes ◽

Neutrophil Lymphocyte Ratio ◽

Severe Group ◽

Healthy Control ◽

Functional Relevance ◽

Potential Biomarkers

To systematically explore potential biomarkers which can predict disease severity in COVID-19 patients and prevent the occurrence or development of severe COVID-19, the levels of 440 factors were analyzed in patients categorized according to COVID-19 disease severity; including asymptomatic, mild, moderate, severe, convalescent and healthy control groups. Factor candidates were validated by ELISA and functional relevance was uncovered by bioinformatics analysis. To identify potential biomarkers of occurrence or development of COVID-19, patient sera from three different severity groups (moderate, severe, and critical) at three time points (admission, remission, and discharge) and the expression levels of candidate biomarkers were measured. Eleven differential factors associated with disease severity were pinpointed from 440 factors across 111 patients of differing disease severity. The dynamic changes of GDF15 reflect the progression of the disease, while the other differential factors include TRAIL R1, IGFBP-1, IGFBP-4, VCAM-1, sFRP-3, FABP2, Transferrin, GDF15, IL-1F7, IL-5Rα, and CD200. Elevation of white blood cell count, neutrophil count, neutrophil-lymphocyte ratio (NLR), Alanine aminotransferase and Aspartate aminotransferase, low lymphocyte and eosinophil counts in the severe group were associated with the severity of COVID-19. GDF15 levels were observed to be associated with the severity of COVID-19 and the dynamic change of GDF15 levels was closely associated with the COVID-19 disease progression. Therefore, GDF15 might serve as an indicator of disease severity in COVID-19 patients.

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Disrupted Resolution Mechanisms Favor Altered Phagocyte Responses in Covid-19

Circulation Research ◽

10.1161/circresaha.121.319142 ◽

2021 ◽

Author(s):

Duco Koenis ◽

Issa Beegun ◽

Charlotte Jouvene ◽

Gabriel Amador Aguirre ◽

Patricia R Souza ◽

...

Keyword(s):

Immune Responses ◽

Disease Severity ◽

Clinical Symptoms ◽

Tissue Injury ◽

Severe Disease ◽

Lipid Mediator ◽

Activation Markers ◽

And Function ◽

The Relationship ◽

Activation Status

Rationale: Resolution mechanisms are central in both the maintenance of homeostasis and the return to catabasis following tissue injury and/or infections. Amongst the pro-resolving mediators, the essential fatty acid-derived specialized pro-resolving lipid mediators (SPM) govern immune responses to limit disease severity. Notably, little is known about the relationship between the expression and activity of SPM pathways, circulating phagocyte function and disease severity in patients infected with novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leading to coronavirus disease 2019 (COVID-19). Objective: Herein, we investigated the link between circulating SPM concentrations and phagocyte activation status and function in COVID-19 patients (n=39) compared to healthy (n=12) and post-COVID-19 (n=8) volunteers. Methods and Results: Lipid mediator profiling demonstrated that plasma SPM concentrations were upregulated in patients with mild COVID-19 and are downregulated in those with severe disease. SPM concentrations were correlated with both circulating phagocyte activation status and function. Perturbations in plasma SPM concentrations and phagocyte activation were retained after the resolution of COVID-19 clinical symptoms. Treatment of patients with dexamethasone upregulated both the expression of SPM biosynthetic enzymes in circulating phagocytes and plasma concentration of these mediators. Furthermore, incubation of phagocytes from COVID-19 patients with SPM rectified their phenotype and function. This included a downregulation in the expression of activation markers, a decrease in the Tissue Factor and inflammatory cytokine expression, and an upregulation of bacterial phagocytosis. Conclusions: The present findings suggest that downregulation of systemic SPM concentrations is linked with both increased disease severity and dysregulated phagocyte function. They also identify the upregulation of these mediators by dexamethasone as a potential mechanism in host protective activities elicited by this drug in COVID-19 patients. Taken together, our findings elucidate a role for altered resolution mechanisms in the disruption of phagocyte responses and the propagation of systemic inflammation in COVID-19.

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Underlying Disease Severity as a Major Risk Factor for Nosocomial Clostridium difficile Diarrhea

Infection Control and Hospital Epidemiology ◽

10.1086/501989 ◽

2002 ◽

Vol 23 (11) ◽

pp. 653-659 ◽

Cited By ~ 176

Author(s):

Lorraine Kyne ◽

Stavros Sougioultzis ◽

Lynne V. McFarland ◽

Ciarán P. Kelly

Keyword(s):

Cohort Study ◽

Clostridium Difficile ◽

Disease Severity ◽

Prospective Cohort Study ◽

Prospective Cohort ◽

Severe Disease ◽

Underlying Disease ◽

Hospitalized Patients ◽

Antibiotic Prescribing ◽

Predictive Values

Objective:To determine the diagnostic accuracy of an index of underlying disease severity (Horn's index) in identifying patients with a high probability of having nosocomial Clostridium difficile diarrhea as a complication of antimicrobial therapy.Design:A prospective cohort study of 252 adult patients admitted to the hospital and receiving antibiotics. Risk factors for C. difficile diarrhea were first determined retrospectively in a different cohort of 300 hospitalized patients (primary cobort) and then prospectively in this cohort of 252 hospitalized patients receiving antibiotics (secondary cohort). At the time of hospital admission, disease was rated by clinicians as mild (1), moderate (2), severe (3), or extremely severe (4) using a modified Horn's index. Multivariable logistic regression analysis was used to determine the odds ratio (OR) for C. difficile diarrhea associated with increasing levels of disease severity.Setting:An urban teaching hospital affiliated with a medical school in Boston, Massachusetts.Results:The incidence of nosocomial C. difficile diarrhea was 8.7% in the primary cohort and 11% in the secondary cohort. In the prospective cohort study (secondary cohort), the OR for C. difficile diarrhea associated with extremely severe disease was 17.6 (95% confidence interval, 5.8 to 53.5). The sensitivity, specificity, and positive and negative predictive values of a Horn's index score of 3 or more (severe to extremely severe disease) as a predictor of nosocomial C. difficile diarrhea were 79%, 73%, 27%, and 96%, respectively.Conclusions:These findings provide a means of early stratification of hospitalized patients receiving antibiotics according to their risk for nosocomial C. difficile diarrhea. Patients with severe to extremely severe disease at the time of admission may benefit from careful monitoring of antibiotic prescribing and early attention to infection control issues. In the future, these “high-risk” patients may benefit from prophylaxis studies of novel agents being developed to prevent C. difficile diarrhea.

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Tissue Proteases and Immune Responses: Influencing Factors of COVID-19 Severity and Mortality

Pathogens ◽

10.3390/pathogens9100817 ◽

2020 ◽

Vol 9 (10) ◽

pp. 817

Author(s):

Natália Mulinari Turin de Oliveira ◽

Isabella Fernandes da Silva Figueiredo ◽

Liziane Cristine Malaquias da Silva ◽

Karien Sauruk da Silva ◽

Laryssa Regis Bueno ◽

...

Keyword(s):

Immune Responses ◽

Disease Severity ◽

Severe Disease ◽

Age Groups ◽

The Elderly ◽

Current Data ◽

Individual Characteristics ◽

Expression Levels ◽

The Individual ◽

Global Population

The coronavirus disease 19 (COVID-19) is caused by the highly transmissible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has affected the global population despite socioeconomic status and amazed surveillance agencies for its incidence, mortality, and recovery rates. COVID-19 affects all age groups; however, it is suggested to progress into severe disease and cause mortality in over 10% of the confirmed cases, depending on the individual characteristics of the affected population. One of the biggest unanswered questions it is why only some individuals develop into the severe stages of the disease. Current data indicate that most of the critically ill are the elderly or those with comorbidities such as hypertension, diabetes, and asthma. However, it has been noted that, in some populations, severe disease is mostly observed in much younger individuals (<60-years old) with no reported underlying medical conditions. Certainly, many factors may contribute to disease severity including intrinsic host factors such as genetic variants, the expression levels of tissue proteins, among others. Considering all these aspects, this review aims to discuss how the expression levels of tissue proteases and the different profiles of immune responses influence the susceptibility to COVID-19 as well as disease severity and outcome.

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