Background and Objectives: Group A Streptococcus (GAS) is a leading cause of acute pharyngitis with seasonal outbreaks. The coronavirus disease 2019 (COVID-19) pandemic significantly altered respiratory infection trends; however, its impact on GAS pharyngitis (GAS-P) incidence remains unclear. Additionally, data on co-infections with GAS and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are limited. In this study, temporal trends in GAS-P incidence and characteristics of GAS-SARS-CoV-2 co-infections in Japan were examined. Materials and Methods: In this observational study, data from patients who visited the Tokyo Shinagawa Hospital between January 2019 and December 2024 were retrospectively analyzed. Data on GAS and SARS-CoV-2 test results and patient demographics were extracted from medical records. The study period was categorized based on COVID-19-related public health measures as follows: pre-COVID-19 social period (January 2019-April 2020), restricted social period (May 2020-April 2023), and post-restriction period (May 2023-December 2024). GAS incidence stratified by sex, age, and period was calculated. Clinical characteristics of patients co-infected with GAS and SARS-CoV-2 were analyzed. Results: Among 4837 GAS tests, 463 (9.6%) were positive. GAS positivity rates varied significantly: 11.4% (pre-COVID-19), 7.1% (restricted social period), and 12.6% (post-restriction period; p < 0.001). The proportion of pediatric cases decreased significantly during the restricted social period (24.8-5.3%) before rising sharply in the post-restriction period (47.1%, p < 0.001). Among 151 patients tested for GAS and SARS-CoV-2, 14 (9.3%) had co-infections, which were identified exclusively after July 2022. Most patients exhibited mild symptoms, primarily fever and sore throat, with decreased lymphocyte counts despite normal white blood cell counts. Conclusions: In our cohort, the incidence of GAS pharyngitis temporarily declined during COVID-19-related public health measures and subsequently increased, particularly among children, after restrictions were lifted. Limited testing may contribute to the underdiagnosis of GAS-SARS-CoV-2 co-infections. Further large-scale studies are warranted to assess microbial interactions, disease severity, and long-term outcomes.

Neurodegenerative diseases are chronic progressive disorders that impair memory, cognition, and motor functions, leading to conditions such as dementia, muscle weakness, and speech difficulties. Aging disrupts the stringent balance between pro- and anti-inflammatory cytokines, increasing neuroinflammation, which contributes to neurodegenerative diseases. The aging brain is particularly vulnerable to infections due to a weakened and compromised immune response and impaired integrity of the blood-brain barrier, allowing pathogens like viruses to trigger neurodegeneration. Coronaviruses have been linked to both acute and long-term neurological complications, including cognitive impairments, psychiatric disorders, and neuroinflammation. The virus can induce a cytokine storm, damaging the central nervous system (CNS) and worsening existing neurological conditions. Though its exact mechanism of neuroinvasion remains elusive, evidence suggests it disrupts the blood-brain barrier and triggers immune dysregulation, leading to persistent neurological sequelae in elderly individuals. This review aims to understand the interaction between the peripheral immune system and CNS glial cells in aged individuals, which is imperative in addressing coronavirus-induced neuroinflammation and concomitant neurodegeneration.

Differences in immune profiles of children and adults with COVID-19 have been previously described. However, no systematic studies have been reported from infants hospitalized with severe disease. We applied a multidimensional approach to decipher the immune responses of SARS-CoV-2 infected infants (n = 26; 10 subacute, 11 moderate and 5 severe disease; median age = 1.6 months) and matched controls (n = 14; median age = 2 months). Single cell (scRNA-seq) profiling of PBMCs revealed substantial alterations in cell composition in SARS-CoV-2 infected infants; with most cell-types switching to an interferon-stimulated gene (ISGhi) state including: (i) CD14+ monocytes co-expressing ISGs and inflammasome-related molecules, (ii) ISGhi naive CD4+ T cells, (iii) ISGhi proliferating cytotoxic CD8+ T cells, and (iv) ISGhi naive and transitional B cells. We observe increased serum concentrations of both interferons and inflammatory cytokines in infected infants. Antibody responses to SARS-CoV-2 are also consistently detected in the absence of anti-IFN autoantibodies. Compared with infected adults, infants display a similar ISG signature in monocytes but a markedly enhanced ISG signature in T and B cells. These findings provide insights into the distinct immune responses to SARS-CoV-2 in the first year of life and underscore the importance of further defining the unique features of early life immunity.

Disease presentation and progression can vary greatly in heterogeneous diseases, such as COVID-19, with variability in patient outcomes, even within the hospital setting. This variability underscores the need for tailored treatment approaches based on distinct clinical subgroups.

This study aimed to identify COVID-19 patient subgroups with unique clinical characteristics using real-world data (RWD) from electronic health records (EHRs) to inform individualized treatment plans.

A Factor Analysis of Mixed Data (FAMD)-based agglomerative hierarchical clustering approach was employed to analyze the real-world data, enabling the identification of distinct patient subgroups. Statistical tests evaluated cluster differences, and machine learning models classified the identified subgroups.

Three clusters of COVID-19 in patients with unique clinical characteristics were identified. The analysis revealed significant differences in hospital stay durations and survival rates among the clusters, with more severe clinical features correlating with worse prognoses and machine learning classifiers achieving high accuracy in subgroup identification.

By leveraging RWD and advanced clustering techniques, the study provides insights into the heterogeneity of COVID-19 presentations. The findings support the development of classification models that can inform more individualized and effective treatment plans, improving patient outcomes in the future.

To investigate the predictive effect and determine the cut-off values of complete blood count parameters in severe COVID-19 hospitalized patients in the United Arab Emirates.

A retrospective observational analytical study analyzed data from 738 medical records of COVID-19 hospitalized patients across several healthcare centers in the United Arab Emirates between 29 January 2020 and 14 October 2021. Complete blood count ratios and indices on admission were evaluated for COVID-19 severity using receiver operating characteristic curves, sensitivity, and specificity.

Main complete blood count-based ratios and indices significantly predicting severe COVID-19 were elevated ratios index (optimal cut-off point ≥3; AOR = 2.8, 95% CI: 1.77-4.42), systemic immune-inflammation index (≥1259.95; AOR = 2.4, 95% CI: 1.53-3.87), systemic inflammation response index (≥3.96; AOR = 2.9, 95% CI: 1.79-4.72), aggregate index of systemic inflammation (≥949.02; AOR = 2.3, 95% CI: 1.43-3.77), platelet-to-lymphocyte ratio (≥188.91; AOR = 2.2, 95% CI: 1.39-3.53), derived neutrophil-to-lymphocyte ratio (≥2.91; AOR = 3.0, 95% CI: 1.84-4.87), and neutrophil-to-lymphocyte ratio (≥6.01; AOR = 3.2, 95% CI: 1.98-5.12).

Identifying hematological markers' predictive effects and their cut-off values can aid healthcare providers in risk classification and the development of tailored treatment plans. It can also provide cheap, quick, and easy guidance for surveillance systems to lessen the impact of any future outbreaks.

Background: Elderly patients infected with SARS-CoV-2 are at higher risk of developing cytokine storm and severe outcomes; however, specific immunological and proteomic biomarkers for early prediction remain unclear in this vulnerable group. Methods: We enrolled 182 elderly COVID-19 patients from the Chinese PLA General Hospital between November 2022 and April 2023, categorizing them based on progression to respiratory failure requiring mechanical ventilation (defined as severe progression). Olink proteomic analysis was performed on admission serum from 40 propensity score-matched samples, with differentially expressed proteins (DEPs) validated by cytometric bead array (CBA) in 178 patients. To predict severe progression, a model was developed using a 70% training set and validated on a 30% validation set. LASSO regression screened features followed by logistic regression and receiver operating characteristic (ROC) analysis to optimize the model by incrementally incorporating features ranked by random forest importance. Results: Elderly patients progressing to severe COVID-19 exhibited early immune dysregulation, including neutrophilia, lymphopenia, monocytopenia, elevated procalcitonin (PCT), C-reactive protein (CRP), interleukin-6 (IL-6), neutrophil-to-lymphocyte ratio (NLR), and systemic immune-inflammation index (SII), as well as coagulation dysfunction and multi-organ injury. Proteomics identified a set of biomarkers, including tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), and revealed disruptions in signaling pathways, including the mTOR and VEGF signaling pathways. The optimal predictive model, which incorporated PCT, IL-6, monocyte percentage, lymphocyte count, and TRAIL, achieved an area under curve (AUC) of 0.870 (0.729-1.000) during validation. TRAIL levels negatively correlated with fibrinogen (p < 0.05). Conclusions: Elderly COVID-19 patients with severe progression demonstrate early immune dysregulation, hyperinflammation, coagulation dysfunction, and multi-organ injury. The model we proposed effectively predicts disease progression in elderly COVID-19 patients, providing potential biomarkers for early clinical risk stratification in this vulnerable population.

Background: The COVID-19 pandemic revealed an unexpected pattern known as the "smoker's paradox", with lower rates of severe disease among smokers compared to non-smokers, highlighting the need for the specific investigation of disease progression in non-smoking populations. Objective: To identify early mortality predictors in non-smoking patients with severe COVID-19 through the evaluation of clinical, laboratory, and oxygenation parameters. Methods: This retrospective observational cohort study included 59 non-smokers hospitalized with COVID-19 between November and December 2020. Clinical parameters, laboratory findings, and respiratory support requirements were analyzed on Days 1 and 7 of hospitalization. ROC curves were constructed to assess the predictive value of the parameters. Results: The overall mortality rate was 54.2%. The seventh-day SOFA score showed the strongest predictive value (AUC = 0.902, p = 0.004), followed by pCO2 (AUC = 0.853, p = 0.012). Significant differences between survivors and non-survivors were observed in acid-base parameters, oxygenation indices, and hematological markers. Mortality rates varied significantly with ventilation type: 84.6% for IMV and 50% for NIMV, with no deaths in HFNC patients. Conclusions: Multiple parameters measured on Day 7 of hospitalization demonstrate significant predictive value for mortality in non-smoking COVID-19 patients, with the SOFA score being the strongest predictor. The type of respiratory support significantly influences outcomes, suggesting the importance of careful ventilation strategy selection.

Xuebijing injection has been recommended as a therapeutic approach for individuals with severe and critical COVID-19. This study aims to explore the correlation of neutrophil to lymphocyte platelet ratio (NLPR) with the severity and prognosis of COVID-19, and the effect of XBJ on the prognosis of patients with COVID-19 in different inflammatory states.

This was a retrospective study conducted at Wuhan Union Hospital in China. COVID-19 patients admitted between November 1, 2022 and February 1, 2023 were included. In predicting prognosis for individuals with COVID-19, new inflammatory indicators were used, and their prognostic value was assessed by using Cox regression models and receiver operating characteristic curves. Furthermore, a calculation was made to determine the cutoff value for NLPR. Relative risk and Cox regression models were used to examine the effects of Xuebijing injection on prognosis in patient cohorts that had been stratified by the NLPR cutoff.

This research included 455 participants with COVID-19, with a mean age of 72 years. Several inflammatory indicators were found to be strongly correlated with prognosis, and NLPR shows the greatest predictive power. Patients with NLPR > 3.29 exhibited a mortality rate of 17.3%, which was 6.2 times higher than in patients with NLPR ≤ 3.29. Importantly, providing Xuebijing injection to patients with NLPR > 3.29 was associated with a lower risk of 60-day all-cause mortality. However, there was no discernible improvement in survival among patients with NLPR ≤ 3.29 who received Xuebijing injection.

NLPR is the most reliable inflammatory marker for predicting prognosis among individuals with COVID-19, and can accurately identify individuals who may benefit from Xuebijing injection. Please cite this article as: Liao M, Zhang LT, Bai LJ, Wang RY, Liu Y, Han J, Liu LH, Qi BL. Xuebijing injection reduces COVID-19 patients mortality as influenced by the neutrophil to lymphocyte platelet ratio. J Integr Med. 2025; 23(3): 282-288.

Contributions of leukocytes to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) defense have been reported extensively. However, it remains unclear whether there are different leukocyte responses to ancestral SARS-CoV-2 and its variants.

We analyzed peripheral blood leukocyte and subtype concentrations from 575 COVID-19 patients and 950 non-COVID-19 subjects registered at the University of Connecticut John Dempsey Hospital between 2020 and 2022, which covers the ancestral strain, Delta, and Omicron variants.

We found that neutrophils, immature granulocytes, and monocytes were elevated, and lymphocytes were reduced after infection. These hyperactive neutrophils/immature granulocytes and suppressed lymphocytes/monocytes were associated with poorer prognosis in ancestral strain infection. Different from the ancestral strain, hyperactive immature granulocytes were not shown in the decedents of Delta infection, and immature granulocyte concentration was not observed to be associated with mortality. In Omicron infection, suppressed lymphocytes and monocytes were not shown in the decedents, and lymphocyte/monocyte concentrations were not associated with mortality.

Our findings provided insights into different leukocyte immune responses to ancestral SARS-CoV-2, Delta, and Omicron variants.

Background: Tuberculosis and COVID-19 co-infection poses significant clinical challenges, with pulmonary TB (PTB) and extrapulmonary TB (extraPTB) potentially influencing disease progression and outcomes differently. This study aims to compare the clinical manifestations, inflammatory markers, and outcomes between PTB and extraPTB patients with SARS-CoV-2 co-infection. Methods: A retrospective, cross-sectional study was conducted on 55 hospitalized adults with TB-COVID-19 co-infection from March 2020 to March 2022. Patients were divided into PTB (n = 32) and extraPTB (n = 23) groups. Demographic, clinical, laboratory, and imaging data were collected and analyzed using statistical models, including ANCOVA, LASSO regression, and Random Forest classification, to identify key predictors of hospitalization duration and mortality. Results: PTB patients had significantly lower BMI, worse oxygenation status, and greater lung involvement on CT compared to extraPTB patients. CRP was elevated in PTB, while IL-6 levels were higher in extraPTB. Hospitalization duration was primarily influenced by inflammatory and coagulation markers (IL-6, D-dimer, neutrophil count, systemic inflammatory index), while higher BMI was associated with shorter stays. Mortality risk was strongly correlated with oxygenation impairment (worst SpO2, SpO2 at diagnosis), inflammatory burden (CRP, LDH), and CT severity score, rather than TB localization. Conclusions: TB localization did not independently affect hospitalization duration or mortality risk. Instead, severe lung involvement, systemic inflammation, and hypoxemia were the strongest predictors of poor outcomes. These findings emphasize the importance of early risk stratification based on respiratory and inflammatory markers to optimize patient management. Further research is needed to clarify the long-term impact of TB-COVID-19 co-infection, particularly in extraPTB cases.

Several studies explored factors related to adverse clinical outcomes among COVID-19 patients but lacked analysis of the impact of the temporal data shifts on the strength of association between different predictors and adverse outcomes. This study aims to evaluate factors related to patients and hospitals in the prediction of in-hospital mortality, need for invasive mechanical ventilation (IMV), and intensive care unit (ICU) transfer throughout the pandemic waves.

This multicenter retrospective cohort included COVID-19 patients from 39 hospitals, from March/2020 to August/2022. The pandemic was divided into waves: 10/03/2020-14/11/2020 (first), 15/11/2020-25/12/2021 (second), 26/12/2021-03/08/2022 (third). Patient-related factors included clinical, demographic, and laboratory data, while hospital-related factors covered funding sources, accreditation, academic status, and socioeconomic characteristics. Shapley additive explanation (SHAP) values derived from the predictions of a light gradient-boosting machine (LightGBM) model were used to assess potential risk factors for death, IMV and ICU.

Overall, 16,958 adult patients were included (median age 59 years, 54.7% men). LightGBM achieved competitive effectiveness metrics across all periods. Temporal drifts were observed due to a decrease in various metrics, such as the recall for the positive class [ICU: 0.4211 (wave 1) to 0.1951 (wave 3); IMV: 0.2089 (wave 1) to 0.0438 (wave 3); death: 0.2711 (wave 1) to 0.1175 (wave 3)]. Peripheral arterial oxygen saturation to the fraction of inspired oxygen ratio (SatO2/FiO2) at admission had great predictive capacity for all outcomes, with an optimal cut-off value for death prediction of 227.78. Lymphopenia had its association strength increased over time for all outcomes, optimal threshold for death prediction of 643 × 109/L. Thrombocytopenia was the most important feature in wave 2 (ICU); overall, values below 143,000 × 109/L were more related to death.

Data drifts were observed in all scenarios, affecting potential predictive capabilities of explainable machine learning methods. Upon admission, SatO2/FiO2 values, platelet and lymphocyte count were significant predictors of adverse outcomes in COVID-19 patients. Overall, inflammatory response markers were more important than clinical characteristics. Limitations included sample representativeness and confounding factors. Integrating the drift's knowledge into models to improve effectiveness is a challenge, requiring continuous updates and monitoring of performance in real-world applications.

Not applicable.

Myocarditis is a common inflammatory heart disease in children and young adults, with fulminant myocarditis (FM) being the most severe form due to its rapid onset and high mortality rate. However, the precise pathological immune subsets and molecular change in myocarditis, particularly FM, remain unknown.

We performed single-cell RNA sequencing of pediatric peripheral blood mononuclear cells during the acute and recovery phases of FM. A viral myocarditis (MC) mouse model was established using CVB3. Deletion and adoptive transfer of CD8+T cells, as well as blockade of CXCR4, were conducted in vivo. CD8+T cells were sorted and cultivated in vitro, then stimulated with CXCL12 and CXCR4 antagonists to investigate the mechanism of CD8+T cell overactivation.

CD8+T cells show significant activation, amplification, enhanced cytotoxicity, and increased chemotactic ability in FM. Deletion of CD8+T cells alleviates myocardial injury and improves cardiac function in MC mice, while adoptive transfer of CD8+T cells from MC mice aggravates myocardial inflammation and injury. The transcriptomic analysis reveals elevated CXCR4 expression in CD8+T cells in acute FM. In vitro experiments demonstrate that the CXCL12/CXCR4 axis drives the overactivation and cytotoxicity of CD8+T cells. In vivo treatment with a CXCR4 antagonist effectively reduces CD8+T cell accumulation in the heart, alleviates myocardial inflammation, and improves cardiac function in MC mice.

These findings provide deeper insights into the immune landscape of pediatric FM, uncovering a novel role of the CXCL12/CXCR4 axis in driving CD8+T cell responses in myocarditis. Furthermore, they highlight the CXCL12/CXCR4 axis as a promising therapeutic target for myocarditis treatment.

The objective of this study was to better understand immune failure mechanisms during severe acute respiratory syndrome coronavirus 2, SARS-CoV-2 infection, which are critical for developing targeted vaccines and effective treatments. We collected 34 cases representing different disease severities and performed high-quality single-cell TCR/BCR sequencing to analyze the peripheral immune cell profiles. Additionally, we assessed antibody-neutralizing activity through in vitro experiments. Our integrated multiomics analysis uncovers a profound immune paradox in severe COVID-19: hyperinflammation coexists with immunosuppression, driven by distinct yet interconnected dysregulatory mechanisms. Severe patients develop robust humoral immunity, evidenced by clonally expanded plasma cells producing neutralizing antibodies (e.g., IGHG1-dominated responses) and antigen-specific T cell activation. However, these protective responses are counteracted by myeloid-driven immunosuppression, particularly CD14+ HMGB2+ monocytes exhibiting metabolic reprogramming and HLA-DR downregulation, coupled with progressive T cell exhaustion characterized by IFN-γ/TNF-α hyperactivation and impaired antigen presentation. Importantly, prolonged viral persistence in severe cases arises from a failure to coordinate humoral and cellular immunity-antibody-mediated neutralization cannot compensate for defective cytotoxic T cell function and monocyte-mediated immune suppression. These findings highlight the necessity for therapeutic strategies that simultaneously enhance antibody effector functions (e.g., Fc optimization), restore exhausted T cells, and reverse myeloid suppression. They also highlight the importance of vaccines designed to elicit balanced B cell memory and durable T cell responses, which are critical to preventing severe disease progression. By addressing the dual challenges of hyperinflammation and immunosuppression, such approaches could restore immune coordination and improve outcomes in severe COVID-19.

Background: While the rapid deployment of SARS-CoV-2 vaccines had a significant impact on the ongoing COVID-19 pandemic, rapid viral immune evasion and waning neutralizing antibody titers have degraded vaccine efficacy. Nevertheless, vaccine manufacturers and public health authorities have a number of options at their disposal to maximize the benefits of vaccination. In particular, the effect of booster schedules on vaccine performance bears further study. Methods: To better understand the effect of booster schedules on vaccine performance, we used an agent-based modeling framework and a population pharmacokinetic model to simulate the impact of boosting frequency on the durability of vaccine protection against infection and severe acute disease. Results: Our work suggests that repeated dosing at frequent intervals (three or more times a year) may offset the degradation of vaccine efficacy, preserving the utility of vaccines in managing the ongoing pandemic. Conclusions: Given the practical significance of potential improvements in vaccine utility, clinical research to better understand the effects of repeated vaccination would be highly impactful. These findings are particularly relevant as public health authorities worldwide have reduced the frequency of boosters to once a year or less.

In kidney transplant recipients (KTRs), immune monitoring of peripheral lymphocyte subsets (PLS) reflects the real immune status and aids in the diagnosis of the occurrence and development of infectious diseases, including COVID-19. Exploring the PLS of COVID-19 pneumonia in KTRs is important.

In this study, a total of 103 KTRs were divided into mild pneumonia (MP) and severe pneumonia (SP) groups, as well as a stable group. The clinical information and PLS data were assessed via t or Mann-Whitney test and receiver operating curve analysis. Logistic regression was employed to identify the risk factors, and Spearman's correlation analysis was used to identify correlations.

Lymphopenia is a common manifestation of COVID-19 in KTRs, and it is positively related to the severity of COVID-19 pneumonia. The CD3 + T-cell count had the highest AUC between the MP and the SP. Multiple PLS measures were found to be independent risk factors for COVID-19 pneumonia progression in KTRs.

This study revealed a robust correlation between PLS and severe COVID-19 pneumonia progression in KTRs. PLS monitoring could facilitate real-time diagnosis and therapy for infection, as well as timely and precisive adjustment of immunosuppression instructions, for KTRs with COVID-19.

The implementation of COVID-19 policy and the rapid development of SARS-CoV-2 vaccines in the early pandemic significantly contained numerous outbreaks and reduced the severity and mortality of COVID-19. However, the population immunity induced by existing vaccines was insufficient to prevent SARS-CoV-2 outbreaks. The host immunity induced by the wide spread of Omicron variants and its influence on emerging SARS-CoV-2 variants are attracting broad attention. In this study, a clinical data analysis of the patients indicated that pre-vaccination reduced inflammatory responses and mitigated the severity of COVID-19 cases caused by natural infection with Omicron BA.5.2. The analysis of adaptive immune responses indicated that natural infection with BA.5.2 induced robust and broad immune responses, including both humoral and T cell-mediated immune responses (IFN-γ) against highly conserved viral antigens, and provided cross-reactive neutralization against various viral variants. Collectively, we report that the natural infection with Omicron BA.5.2 induced broad cross-reactive immunity against SARS-CoV-2 variants, which suggests that the development of a live attenuated SARS-CoV-2 vaccine with desired safety, high efficacy, broad spectrum, and long-term immune persistence is feasible. Therefore, we suggest that herd immunity, achieved through vaccination with attenuated vaccines, combined with booster doses of existing vaccines and antiviral therapy for people with high viral loads, may contribute to the eradication of this virus.

Zinc plays an important role in the functioning of the immune system. Zinc deficiency leads to increased susceptibility to inflammatory and infectious diseases. There are few studies investigating the role of zinc in the development and progression of COVID-19 in children, and their findings remain inconsistent. This study aimed to determine the zinc levels in children with COVID-19 and assess their association with symptoms, inflammation markers, and disease progression.

A prospective cohort study included hospitalized patients under 18 years who had a confirmed diagnosis of SARS-CoV-2 infection. Serum zinc concentrations were measured using a colorimetric method. Based on zinc levels, the children were divided into two groups: the first group had concentrations below 10.7 μmol/L, indicating zinc deficiency, while the second group had levels above 10.7 μmol/L, which was considered within the optimal range.

In total, 140 hospitalized patients with COVID-19 were examined. Zinc deficiency was identified in 40 children (28.6%), while optimal levels were found in 100 children (71.4%). Zinc status did not depend on the age of the children. Among the symptoms of acute SARS-CoV-2 infection, children with zinc deficiency showed a trend toward more frequent fever occurrences (p = 0.0654). No significant impact of zinc status was observed on the severity of COVID-19 or the duration of hospitalization. Children with zinc deficiency had higher median values of the neutrophil-to-lymphocyte ratio (NLR) (1.84 vs. 1.09, p = 0.0010), C-reactive protein (CRP) levels (9.65 vs. 3.96 mg/L, p = 0.0053), and fibrinogen levels (2.88 vs. 2.07 g/L, p = 0.0057) compared to those with adequate zinc levels. Additionally, the percentage of patients with a NLR greater than 4, elevated CRP, and fibrinogen levels was higher in the zinc-deficient group (p = 0.0017, p = 0.0107, p = 0.0338, respectively).

Zinc deficiency was observed in 28.6% of children with COVID-19 and was not dependent on age. Children with hypozincemia had higher levels of inflammation markers, including the neutrophil-to-lymphocyte ratio and CRP.

We aimed to evaluate the effects of both the expression and serum levels of Epidermal growth factor (EGF) and Transforming growth factor-β1 (TGF-β1) genes in patients with different degrees of cellular damage as mild, moderate, severe, and critical illness that can lead to fibrosis caused by SARS-CoV-2. Totally 45 individuals (male: 21(46.67%); female: 24(53.33%)) with COVID-19 infection were included in this study. Four groups were constituted as mild (n = 16)], moderate (n = 10), severe (n = 10), and critical (n = 9) according to the severity of the disease. Blood samples were drawn from the patients, and all of the hemograms, EGF and TGFβ1 gene expression, and serum levels were evaluated. The mean age of individuals was 57.311 ± 18.383 (min: 28, max: 94). Significant differences were found among the groups for PLT (χ2 = 9.955; p = 0.019), CRP (χ2 = 7.693; p = 0.053), Ferritin (χ2 = 22.196; p < 0.001), D-dimer (χ2 = 21.982; p = 0.000), LDH (χ2 = 21.807; p < 0.001) and all these parameters (exclude PLT in severe groups) was increased depending on the severity of the disease. Additionally, significant differences were detected for EGF (χ2 = 29.528; p < 0.001), TGFB1 (χ2 = 28.981; p < 0.001) expression (that increased depending on the disease severity), and EGF (χ2 = 7.84; p = 0.049), TGFB1 (χ2 = 17.451; p = 0.001) serum concentration levels (that decreased depending on the disease severity). This study found statistically significant differences for both EGF 2-ΔΔCt. TGFβ1 2-ΔΔCt and EGF, TGFβ1 serum concentration values among all patient groups. As disease severity increased, EGF 2-ΔΔCt. TGFβ1 2-ΔΔCt levels increased, while EGF and TGFβ1 serum concentration levels decreased. Perhaps this study will be useful in managing COVID-19 infection severity and pulmonary fibrosis cases secondary to COVID-19.

Background: As COVID-19 has become an epidemic, we conducted an open-label study aimed to identify immunogenicity and reactogenicity of boosters of the BNT162b2 vaccine in a real-world cohort of long-survivor metastatic lung cancer patients (LS-mLC pts). Methods and Analysis: According to the timing of the booster dose (BD) and SARS-CoV-2 infection (Cov-I) during anticancer treatment (ACT), between October 2021 and February 2022, we prospectively enrolled 166 cancer patients into five parallel cohorts. The primary endpoints were seroprevalence of IgG Anti-spike-RBD (anti-S IgG) at two pre-defined timepoints (T1: +30-90 days after BD; T2: +6 months +/- 4 weeks after BD). As an exploratory endpoint, we compared the median pre-vaccination value of four cytokines (IL-6, IL-2R, TNF-α, IL-10) with post-BD values in immunotherapy-treated pts (IO-pts). Results: The anti-S IgG seropositivity rate was 100% at T1 and 98.8% at T2. After 6 months, hybrid immunisation was associated with a higher median anti-S IgG titre compared to vaccine-alone-induced seroconversion (p < 0.0001). In uninfected pts, the median anti-S IgG titre was significantly lower in IO-pts compared to non-IO-pts (p = 0.02); no difference was found when comparing myelosuppressive or not ACT. Among the 68 IO-pts, 5 pts (7.3%) showed a significant increase (≥1.5 fold) of at least two cytokines in post-BD samples, without reporting ir-AEs. Conclusions: Boosters of the COVID-19 mRNA vaccine were effective and safe. In IO-pts without recent Cov-I, additional BDs should be considered to prolong serological immunity.

High mutation rates in SARS-CoV-2, particularly among immunocompromised patients living with HIV, continue to complicate the current COVID-19 pandemic. The threshold for severe COVID-19 and a greater risk of mortality have increased in many immunocompromised individuals due to a weakened immune system. Low CD4+ T-cell counts in people living with both HIV and COVID-19 lead to prolonged disease duration and, therefore, an increased likelihood of viral infection with SARS-CoV-2 mutations in such individuals. These mutations could decrease the efficiency of ongoing vaccines and cause new outbreaks. Recently, the rise of new mutations in this patient population has created increasing concern; however, few data are currently available on the direct association of HIV infection with SARS-CoV-2 mutations. This review highlights the implications of SARS-CoV-2 and HIV co-infection, highlighting the need for extra caution and monitoring of the immune-compromised population during a pandemic. Access to HIV care and COVID-19 treatments, careful surveillance, and adapted health strategies are key to reducing risks and protecting these populations. Further research is required to elucidate the dynamics of mutations and develop intervention methods to manage COVID-19 among immunocompromised patients.

COVID-19 exhibits complex pathophysiological manifestations, characterized by significant clinical and biological heterogeneity. Identifying phenotypes may enhance our understanding of the disease's diverse trajectories, benefiting clinical practice and trials.

This study included adult patients with COVID-19 from Xinhua Hospital, affiliated with Shanghai Jiao Tong University School of Medicine, between December 15, 2022, and February 15, 2023. The k-prototypes clustering method was employed using 50 clinical variables to identify phenotypes. Machine learning algorithms were then applied to select key classifier variables for phenotype recognition.

A total of 1376 patients met the inclusion criteria. K-prototypes clustering revealed two distinct subphenotypes: Hypo-inflammatory subphenotype (824 [59.9%]) and Hyper-inflammatory subphenotype (552 [40.1%]). Patients in Hypo-inflammatory subphenotype were younger, predominantly female, with low mortality and shorter hospital stays. In contrast, Hyper-inflammatory subphenotype patients were older, predominantly male, exhibiting a hyperinflammatory state with higher mortality and rates of organ dysfunction. The AdaBoost model performed best for subphenotype prediction (Accuracy: 0.975, Precision: 0.968, Recall: 0.976, F1: 0.972, AUROC: 0.975). "CRP", "IL-2R", "D-dimer", "ST2", "BUN", "NT-proBNP", "neutrophil percentage", and "lymphocyte count" were identified as the top-ranked variables in the AdaBoost model.

This analysis identified two phenotypes based on COVID-19 symptoms and comorbidities. These phenotypes can be accurately recognized using machine learning models, with the AdaBoost model being optimal for predicting in-hospital mortality. The variables "CRP", "IL-2R", "D-dimer", "ST2", "BUN", "NT-proBNP", "neutrophil percentage", and "lymphocyte count" play a significant role in the prediction of subphenotypes. Use the identified subphenotypes for risk stratification in clinical practice. Hyper-inflammatory subphenotypes can be closely monitored, and preventive measures such as early admission to the intensive care unit or prophylactic anticoagulation can be taken.

The severity of COVID 19 symptoms has a direct correlation with lymphopenia, affecting natural killer (NK) cells. SARS-CoV-2 specific "memory" NK cells obtained from convalescent donors can be used as cell immunotherapy. In 2022 a phase I, dose-escalation, single center clinical trial was conducted to evaluate the safety and feasibility of the infusion of CD3-/CD56+ NK cells against moderate/severe cases of COVID-19 (NCT04578210). Six participants with pneumonia and/or lymphopenia were infused. Four patients received a single-dose infusion of NK cells of 1×106/kg, and the following two patients a dose of 2×106/kg of NK cells. All participants' clinical status and inflammation markers were monitored. No serious adverse events were reported after infusion. Exploratory outcomes included the donor chimerism, NK-cell immunophenotype evolution, and immune lymphocyte reconstitution. This study provides preliminary evidence supporting the idea that treatment of COVID-19 patients with moderate/severe symptoms using NK from COVID-19 convalescent donors is feasible and safe.

Although the SARS-CoV-2 infection has established risk groups, identifying biomarkers for disease outcomes is still crucial to stratify patient risk and enhance clinical management. Optimal efficacy of COVID-19 antiviral medications relies on early administration within the initial 5 d of symptoms, assisting high-risk patients in avoiding hospitalization and improving survival chances. The complete blood count (CBC) can be an efficient and affordable option to find biomarkers that predict the COVID-19 prognosis due to infection-induced alterations in various blood parameters. This study aimed to associate hematological parameters with different COVID-19 clinical forms and utilizes them as disease outcome predictors. We performed a CBC in blood samples from 297 individuals with COVID-19 from Belo Horizonte, Brazil. Statistical analysis, as well as ROC Curves and machine learning Decision Tree algorithms were used to identify correlations, and their accuracy, between blood parameters and disease severity. In the initial 4 d of infection, traditional hematological COVID-19 alterations, such as lymphopenia, were not yet apparent. However, the monocyte percentage and granulocyte-to-lymphocyte ratio (GLR) proved to be reliable predictors for hospitalization, even in cases where patients exhibited mild symptoms that later progressed to hospitalization. Thus, our findings demonstrate that COVID-19 patients with monocyte percentages lower than 7.7% and a GLR higher than 8.75 are assigned to the hospitalized group with a precision of 86%. This suggests that these variables can serve as important biomarkers in predicting disease outcomes and could be used to differentiate patients at hospital admission for managing therapeutic interventions, including early antiviral administration. Moreover, they are simple parameters that can be useful in minimally equipped health care units.

The emergence of the COVID-19 pandemic made it critical to understand the immune and inflammatory responses to the SARS-CoV-2 virus. It became increasingly recognized that the immune response was a key mediator of illness severity and that its mechanisms needed to be better understood. Early infection of both tissue and immune cells, such as macrophages, leading to pyroptosis-mediated inflammasome production in an organ system critical for systemic oxygenation likely plays a central role in the morbidity wrought by SARS-CoV-2. Delayed transcription of Type I and Type III interferons by SARS-CoV-2 may lead to early disinhibition of viral replication. Cytokines such as interleukin-1 (IL-1), IL-6, IL-12, and tumor necrosis factor α (TNFα), some of which may be produced through mechanisms involving nuclear factor kappa B (NF-κB), likely contribute to the hyperinflammatory state in patients with severe COVID-19. Lymphopenia, more apparent among natural killer (NK) cells, CD8+ T-cells, and B-cells, can contribute to disease severity and may reflect direct cytopathic effects of SARS-CoV-2 or end-organ sequestration. Direct infection and immune activation of endothelial cells by SARS-CoV-2 may be a critical mechanism through which end-organ systems are impacted. In this context, endovascular neutrophil extracellular trap (NET) formation and microthrombi development can be seen in the lungs and other critical organs throughout the body, such as the heart, gut, and brain. The kidney may be among the most impacted extrapulmonary organ by SARS-CoV-2 infection owing to a high concentration of ACE2 and exposure to systemic SARS-CoV-2. In the kidney, acute tubular injury, early myofibroblast activation, and collapsing glomerulopathy in select populations likely account for COVID-19-related AKI and CKD development. The development of COVID-19-associated nephropathy (COVAN), in particular, may be mediated through IL-6 and signal transducer and activator of transcription 3 (STAT3) signaling, suggesting a direct connection between the COVID-19-related immune response and the development of chronic disease. Chronic manifestations of COVID-19 also include systemic conditions like Multisystem Inflammatory Syndrome in Children (MIS-C) and Adults (MIS-A) and post-acute sequelae of COVID-19 (PASC), which may reflect a spectrum of clinical presentations of persistent immune dysregulation. The lessons learned and those undergoing continued study likely have broad implications for understanding viral infections' immunologic and inflammatory consequences beyond coronaviruses.

This study aimed to compare platelet count, platelet indices, lymphocyte, and systemic inflammation indices between surviving and non-surviving COVID-19 patients, measured at admission and on the eighth day of hospitalization.

A retrospective cohort study was conducted on COVID-19 patients hospitalized at Hasan Sadikin General Hospital, Bandung, from March to December 2020. Patient characteristics and laboratory data were sourced from medical records and the Clinical Pathology Laboratory. Bivariate analysis was performed to determine the comparison of platelet indexes between Surviving and Non-Surviving COVID-19 patients depending on data distribution. Significantly correlated variables in Bivariate analysis were included in the ROC analysis, with the AUC used to identify optimal threshold values for laboratory parameters.

Data from 132 patients were analyzed, with 106 (80.3%) surviving and 32 (19.7%) not surviving. Non-surviving patients had lower platelet count, PLTCT, and lymphocyte levels but higher MPV and PDW compared to survivors. Receiver operating characteristic (ROC) analysis revealed that on day 1, lymphocytes had a higher area under the curve (AUC) than MPV. On day 8, lymphocytes had the highest AUC, followed by platelet count, MPV, PLTCT, and PDW.

Platelet indices, lymphocyte counts, and systemic inflammation index have the potential to distinguish the severity of COVID-19.

Lymphopenia and failure of lymphocytes to mount an early IFN-γ response correlate with increased mortality in COVID-19. Given the essential role of CD4 helper and CD8 cytotoxic cells in eliminating viral pathogens, this profound loss in lymphocytes may impair patients' ability to eliminate the virus. IL-7 is a pleiotropic cytokine that is obligatory for lymphocyte survival and optimal function.

We conducted a prospective, double-blind, randomized, placebo-controlled trial of CYT107, recombinant human IL-7, in 109 critically ill, patients with lymphopenia who have COVID-19. The primary endpoint was to assess CYT107's effect on lymphocyte recovery with secondary clinical endpoints including safety, ICU and hospital length-of-stay, incidence of secondary infections, and mortality.

CYT107 was well tolerated without precipitating a cytokine storm or worsening pulmonary function. Absolute lymphocyte counts increased in both groups without a significant difference between CYT107 and placebo. Patients with COVID-19 receiving CYT107 but not concomitant antiviral medications, known inducers of lymphopenia, had a final lymphocyte count that was 43% greater than placebo (P = 0.067). There were significantly fewer treatment-emergent adverse events in CYT107 versus placebo-treated patients (P < 0.001), consistent with a beneficial drug effect. Importantly, CYT107-treated patients had 44% fewer hospital-acquired infections versus placebo-treated patients (P = 0.014).

Given that hospital-acquired infections are responsible for a large percentage of COVID-19 deaths, this effect of CYT107 to decrease nosocomial infections could substantially reduce late morbidity and mortality in this highly lethal disease. The strong safety profile of CYT107 and its excellent tolerability provide support for trials of CYT107 in other potential pandemic respiratory viral infections.

NCT04379076, NCT04426201, NCT04442178, NCT04407689, NCT04927169.

Funding for the trial was provided by RevImmune and the Cancer Research Institute.

Background and Objectives: Immune checkpoint inhibitors such as PD-1 and TIM-3 play an important role in regulating the host immune response and are proposed as potential prognostic markers and therapeutic targets in severe cases of COVID-19. We evaluated the expression of PD-1 and TIM-3 on T cells, as well as the concentration of sPD-1 in plasma, to clarify the role of these molecules in patients infected with SARS-CoV-2. Materials and Methods: In this retrospective observational study, we analysed the expression of PD-1 and TIM-3 on CD4+ and CD8+ T cells upon admission and after 7 days of hospitalisation in 770 adult patients. We also evaluated sPD-1 levels in the plasma of 145 patients at different stages of COVID-19 and of 11 control subjects. Molecules were determined using conventional flow cytometry and ELISA and the data were statistically processed. Results: We observed a significantly higher expression of PD-1 on CD4+ cells in deceased patients than in those with mild-to-moderate disease. All patients with COVID-19 exhibited a significantly higher expression of TIM-3 on both CD4+ and CD8+ T cells compared to controls. After 1 week of hospitalisation, there was no significant change in PD-1 or TIM-3 expression on CD4+ or CD8+ T cells across the studied groups. sPD-1 concentrations were not significantly different between survivors and non-survivors. Plasma sPD-1 levels did not correlate with PD-1 expression on T cells, but a significant correlation was observed between CD4+ PD-1 and CD8+ PD-1. Using machine-learning algorithms, we supported our observations and confirmed immunological variables capable of predicting survival, with AUC = 0.786. Conclusions: Analysis of the immune response may be useful for monitoring and predicting the course of COVID-19 upon admission. However, it is essential to evaluate complex immune parameters in conjunction with other key clinical and laboratory indicators.

Low blood absolute lymphocyte count (ALC) may predict severe COVID-19 outcomes. Knowledge gaps remain regarding the relationship of ALC trajectory with clinical outcomes and factors associated with lymphopenia.

Our post hoc analysis of the Therapeutics for Inpatients with COVID-19 platform trial utilized proportional hazards models to assess relationships between Day (D) 0 lymphopenia (ALC < 0.9 cells/uL), D0 severe lymphopenia (ALC < 0.5 cells/uL) or lymphopenia trajectory between D0 and D5 with mortality and secondary infections, and with sustained recovery using Fine-Gray models. Logistic regression was used to assess relationships between clinical variables and D0 lymphopenia or lymphopenia trajectory.

D0 lymphopenia (1426/2579) and severe lymphopenia (636/2579) were associated with increased mortality (aHR 1.48; 1.08, 2.05, p = 0.016 and aHR 1.60; 1.20, 2.14, p = 0.001) and decreased recovery (aRRR 0.90; 0.82, 0.99, p = 0.033 and aRRR 0.78; 0.70, 0.87, p < 0.001 respectively). Trial participants with persistent D5 lymphopenia had increased mortality, and increased secondary infections, and participants with persistent or new lymphopenia had impaired recovery, as compared to participants with no lymphopenia. Persistent and new lymphopenia were associated with older age, male sex; prior immunosuppression, heart failure, aspirin use, and normal body mass index; biomarkers of organ damage (renal and lung), and ineffective immune response (elevated IL-6 and viral nucleocapsid antigen levels). Similar results were observed with severe lymphopenia.

Lymphopenia was predictive of severe COVID-19 outcomes, particularly when persistent or new during hospitalization. A better understanding of the underlying risk factors for lymphopenia will help illuminate disease pathogenesis and guide management strategies.

The apoptotic molecule Fas and its ligand FasL are involved in the process of T-lymphocyte death, which may lead to lymphopenia, a characteristic of severe coronavirus disease 2019 (COVID-19). In this study, we investigated the influence of polymorphisms in the FAS and FASL genes, FAS and FASL gene expression, and plasma cytokine levels on COVID-19 severity and long COVID occurrence. A total of 116 individuals with severe COVID-19 and 254 with the non-severe form of the disease were evaluated. In the post-COVID-19 period, samples from 196 individuals with long COVID and 67 from people who did not have long COVID were included. Genotyping and quantification of gene expression were performed via real-time PCR, and cytokine measurement was performed via flow cytometry. The AA genotype for FAS rs1800682 (A/G) and the TT genotype for FASL rs763110 (C/T) were associated with increased FAS and FASL gene expression, respectively (p < 0.005). Higher plasma IFN-γ levels were associated with higher FAS and FASL gene expression (p < 0.05). Among individuals with non-severe COVID-19, carriers of the AA genotype for FAS rs1800682 (A/G) had higher levels of FAS expression, more symptoms, and higher IFN-γ levels (p < 0.05). No association of the evaluated markers with long COVID were observed. The AA genotype of FAS rs1800682 (A/G) and the TT genotype of FASL rs763110 (C/T) influence the levels of FAS and FASL gene expression. Higher gene expression of FAS and FASL may lead to greater inflammation in COVID-19 patients, with higher levels of IFN-γ and T lymphocyte death.