Non-severe Disease Research Articles

The Prognostic Value of Olfactory Dysfunction in Patients with COVID-19: The COVIDORA Study.

Among all studies describing COVID-19 clinical features during the first wave of the pandemic, only a few retrospective studies have assessed the correlation between olfac-tory dysfunction (OD) and the evolution of disease severity. The main aim was to assess whether OD is a predictive factor of COVID-19 severity based on the patient's medical management (outpa-tient care, standard hospital admission, and ICU admission). A national, prospective, mul-ticenter cohort study was conducted in 20 public hospitals and a public center for COVID-19 screen-ing. During the first wave of the pandemic, from 6 April to 11 May 2020, all patients tested positive for COVID-19 confirmed by RT-PCR underwent two follow-up ENT consultations within 10 days of symptom onset. The main outcome measures were the evolution of medical management (out-patient care, standard hospital admission, and ICU admission) at diagnosis and along the clinical course of COVID-19 disease. Among 481 patients included, the prevalence of OD was 60.7%, and it affected mostly female patients (74.3%) under 65 years old (92.5%), with fewer comor-bidities than patients with normal olfactory function. Here, 99.3% (290/292) of patients with OD presented with non-severe COVID-19 disease. Patients reporting OD were significantly less hospi-talized than the ones managed as outpatients, in either a standard medical unit or an ICU. Conclu-sions: As regards the clinical course of COVID-19 disease, OD could predict a decreased risk of hospitalization during the first wave of the pandemic.

A Descriptive, Retrospective Analysis of COVID-19 Passive Antibody Therapy and Its Effects on Morbidity and Mortality in Patients Receiving B-Cell-Depleting Therapies.

Patients receiving B-cell-depleting therapies (BCDT) are at an increased risk for severe COVID-19. Passive antibody therapy (PAT), including COVID-19 convalescent plasma (CCP) and monoclonal antibodies (mAb), may be an effective treatment in this population. Real-world data on PAT effectiveness are limited. To evaluate response to PAT measured through 90-day all-cause morbidity and mortality, we performed a retrospective review of patients who contracted COVID-19 within a year from the last BCDT. From 64 included patients, the majority were Caucasians (95%), female (56%), vaccinated (67%), treated outpatients (64%), with multiple comorbidities. Examined BCDT were rituximab (55%), obinutuzumab (33%), ocrelizumab (11%) and ofatumumab (1%), used for underlying hematological malignancy (HEM) (40%), multiple sclerosis (34%), and rheumatoid arthritis (16%). Of seven deceased patients, three died from COVID-19. All three were elderly males with multiple comorbidities, treated inpatient for severe COVID-19. Four of 41 patients treated as outpatients were hospitalized for non-COVID-19-related reasons. All deceased and hospitalized patients had an underlying HEM. All but one were on rituximab. PAT may be an effective treatment for patients receiving BCDT, especially if given early for non-severe disease. Patients with underlying HEM may be at increased risk for severe disease compared with others receiving the same BCDT.

Sex hormones and the total testosterone:estradiol ratio as predictors of severe acute respiratory syndrome coronavirus 2 infection in hospitalized men.

The predictive ability of the early determination of sex steroids and the total testosterone:estradiol ratio for the risk of severe coronavirus disease 2019 or the potential existence of a biological gradient in this relationship has not been evaluated. To assess the relationship of sex steroid levels and the total testosterone:estradiol ratio with the risk of severe acute respiratory syndrome coronavirus 2 infection in men, defined as the need for intensive care unit admission or death, and the predictive ability of each biomarker. This was a prospective observational study. We included all consecutive adult men with severe acute respiratory syndrome coronavirus 2 infections in a single center admitted to a general hospital ward or to the intensive care unit. Sex steroids were evaluated at the centralized laboratory of our hospital. We recruited 98 patients, 54 (55.1%) of whom developed severe coronavirus disease in 2019. Compared to patients with nonsevere coronavirus disease 2019, patients with severe coronavirus disease 2019 had significantly lower serum levels of total testosterone (111±89vs. 191±143ng/dL; p<0.001), dehydroepiandrosterone (1.69±1.26vs. 2.96±2.64ng/mL; p<0.001), and dehydroepiandrosterone sulfate (91.72±76.20vs. 134.28±98.261μg/dL; p=0.009), significantly higher levels of estradiol (64.61±59.35vs. 33.78±13.78 pg/mL; p=0.001), and significantly lower total testosterone:estradiol ratio (0.28±0.31vs. 0.70±0.75; p<0.001). The lower the serum level of androgen and the lower the total testosterone:estradiol ratio values, the higher the likelihood of developing severe coronavirus disease 2019, with the linear trend in the adjusted analyses being statistically significant for all parameters except for androstenedione (p=0.064). In the receiver operating characteristic analysis, better predictive performance was shown by the total testosterone:estradiol ratio, with an area under the curve of 0.77 (95% confidence interval 0.68-0.87; p<0.001). Our results suggest that men with severe acute respiratory syndrome coronavirus 2 infection, decreased androgen levels and increased estradiol levels have a higher likelihood of developing an unfavorable outcome. The total testosterone:estradiol ratio showed the best predictive ability.

Pharmaceutical cost dynamics for the treatment of rifampicin-resistant tuberculosis in children and adolescents in South Africa, India, and the Philippines.

Rifampicin-resistant (RR) tuberculosis (TB) in children is a major global health concern but is often neglected in economics research. Accurate cost estimations across the spectrum of paediatric RR-TB treatment regimens are critical inputs for prioritisation and budgeting decisions, and an existing knowledge gap at local and international levels. This normative cost analysis was nested in a Phase I/II pharmacokinetics, safety, tolerability, and acceptability trial of TB medications in children in South Africa, the Philippines and India. It assessed the pharmaceutical costs of 36 childhood RR-TB regimens using combinations from 16 different medicines in 34 oral formulations (adult and child-friendly) in 11 weight bands in children <15 years of age. The analysis used local and Global Drug Facility pricing, and local and international guideline recommendations, including adaptions of BPaL and BPaLM regimens in adults. Costs varied significantly between regimen length, age/weight banding, severity of disease, presence of fluroquinolone resistance, and different country guideline recommendations. WHO recommended regimen costs ranged 12-fold: from US$232 per course (short regimen in non-severe disease) to US$2,761 (long regimen in severe, fluroquinolone-resistant disease). Regimen treating fluoroquinolone-resistant infection cost US$1,090 more than comparable WHO-recommended regimen. Providing child-friendly medicine formulations in <5-year-olds across all WHO-recommended regimens is expected to cost an additional $380 (range $212-$563) per child but is expected to have wider benefits including palatability, acceptability, adherence, tolerability, and dose accuracy. There were substantial differences in regimen affordability between countries when adjusted for purchasing power and domestic spending on health. Appropriate, effective, and affordable treatment options are an important component of the fight against childhood RR-TB. A comprehensive understanding of the cost and affordability dynamics of treatment options will enable national TB programs and global collaborations to make the best use of limited healthcare resources for the care of children with RR-TB.

Analysis of lymphocyte subsets in COVID-19 patients: a retrospective observational study

In this retrospective study, we analyzed the possible predictive changes in lymphocyte subsets of Coronavirus Disease 19 (COVID-19) hospitalized patients. We enrolled 107 COVID-19 patients older than 18 years of age, admitted to Alessandria Hospital with a confirmed diagnosis of SARS-CoV-2 infection by Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR), who performed the analysis of lymphocyte subsets, between 2020 March 01 and 2021 May 31. Patients have been split up into two groups, based on clinical manifestations: group 1 non-severe disease (n=44) and group 2 severe disease (n=63), according to the World Health Organization (WHO) interim guidance. For the comparison between the two groups of patients, statistical significance was tested with the Mann-Whitney and the Chi-Square test. In the group of patients with severe disease, the blood cell analysis showed a significant reduction in the counts of total lymphocytes, absolute CD3 lymphocytes, and CD8 lymphocytes, as well as a significant reduction in monocyte percent and a very significant increase in neutrophil counts. From the results obtained, it can be stated that lymphocytopenia is associated with the progression of the disease and increased mortality.

Exploring the relationship between SARS-CoV-2 variants, illness severity at presentation, in-hospital mortality and COVID-19 vaccination in a low middle-income country: A retrospective cross-sectional study.

COVID-19 morbidity and mortality varied globally through the pandemic. We studied the relationship of SARS-CoV-2 variants of concern (VOC) with COVID-19 severity and mortality among hospitalized patients in Pakistan. A retrospective review of clinical, laboratory, and vaccination data of 197 COVID-19 adult patients at the Aga Khan University Hospital, Karachi between April 2021, and February 2022 was performed. SARS-CoV-2 VOC identified in respiratory samples were analyzed. Univariate and multivariate analysis was conducted to identify factors associated with COVID-19 outcomes. The median age of cases was 55 years and 51.8% were males. Twenty-four percent of females were pregnant. Of COVID-19 cases, 48.2% had nonsevere disease, while 52.8% had severe/critical disease. Hypertension (48%) and diabetes mellitus (41%) were common comorbids. SARS-CoV-2 VOC identified comprised; Omicron (55.3%), Beta (14.7%), Alpha (13.7%), Delta (12.7%), and Gamma (3.6%) variants. Most (59.7%) study subjects were unvaccinated. Of vaccines, 88% had received inactivated virus COVID-19 vaccines. Increased risk of severe disease was associated with age ≥50 years (odds ratio [OR]: 5.73; 95% confidence interval [CI]: [2.45-13.7]), as well as with diabetes mellitus (OR: 4.24; 95% CI: [1.82-9.85]). Full vaccination (OR: 0.25; 95% CI: [0.11-0.58]) or infection with Omicron (OR: 0.42; 95% CI: [0.23-0.74]) was associated with reduced disease severity. The risk of mortality increased with age ≥50 years (OR: 5.07; 95% CI: [1.92-13.42]) and a history of myocardial infarction (OR: 5.11; 95% CI: [1.45-17.93]) whilst, infection with Omicron was found to reduce the risk (OR: 0.22; 95% CI: [0.10-0.53]). Our study describes the relationship between the severity of COVID-19, in-hospital mortality in relation to SARS-CoV-2 variants, and the impact of COVID-19 vaccination in Pakistan. Outcomes were more favorable in younger individuals, after vaccinations and with Omicron variant infections. Most cases received inactivated virus vaccines therefore these data highlight the protection provided against severe COVID-19.

Skeletal complications in patients with hemophilia: a single-center experience

BackgroundArthropathy is a common complication in patients with hemophilia. We examined the prevalence of this skeletal complication in patients with hemophilia who were registered at a Comprehensive Hemophilia Center in Shiraz, Southern Iran.Materials and MethodsIn this cross-sectional study, an orthopedic specialist visited 448 patients and conducted screenings for skeletal complications. The assessment included evaluating the type of hemophilia, disease severity, treatment modality, the presence of inhibitors, and the identification of skeletal complications.ResultsNinety patients with hemophilia A, with a mean age (SD) of 31.6 (14.4) years, and 10 patients with hemophilia B, with a mean age of 30.5 (20.6) years, were assessed. The most frequently affected joints were the knee and ankle joints. In the univariate analysis, patients with severe disease were more likely to exhibit synovitis, a target joint, and bone disease compared to patients with non-severe disease. Additionally, a history of treated or active hepatitis and an annual bleeding rate showed significant associations with the target joint. In the multivariable logistic regression analysis, disease severity (OR 14.43, 95% CI 1.6–129.6) and a higher age at diagnosis (OR 1.06, 95% CI 1.00–1.13) increased the likelihood of developing osteoporosis. A history of hepatitis (OR 3.67, 95% CI 1.28–10.48) was identified as an independent risk factor for the target joint.ConclusionSkeletal complications are a common occurrence in hemophilia. Regular consultations with orthopedic specialists, focusing on bleeding control and hepatitis prevention, are essential for reducing the impact of this debilitating complication.

Specific immunoglobulin E profiles in sensitized Swedish and Spanish children with severe asthma

Aim: Asthma affects millions of people worldwide and generates a considerable economic impact. This study aims to compare the specific immunoglobulin E (sIgE) profile in sensitized children with severe asthma from two countries with great geographic and climatic differences. Methods: A cross-sectional study was performed using serum samples analysed with a multiplex tool in 47 children from Sweden and 29 children from Spain. Results: Patients from Spain were significantly more often sensitized to house dust mites, cockroaches, dogs, Alternaria, Cladosporium, pollen from olive trees, cypress, Platanus, and Parietaria, and to Anisakis and shrimp. Swedish patients were significantly more often sensitized to cats, pollen from birch, hazel, and Alnus, and to apple, soy, and peanut (all P &lt; 0.05). With regard to sensitization to allergen molecules, lipid transfer proteins (LTPs), cross-reactive carbohydrate determinant (CCD)-bearing proteins and tropomyosins were more frequent in Spain, while sensitization to pathogenesis-related class 10 proteins (PR-10) molecules and to peanut storage proteins were more common in Sweden. Conclusions: The immunoglobulin E (IgE) profile in sensitized children with severe asthma differed greatly between Sweden and Spain. The profile results were more similar to that reported in the literature for other sensitized children from the same geographic areas with non-severe disease than to that of severe asthmatics from different areas.

Analysis of clinical characteristics and risk factors between elderly patients with severe and nonsevere Omicron variant infection

BACKGROUND Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to millions of confirmed cases and deaths worldwide. Elderly patients are at high risk of developing and dying from COVID-19 due to advanced age, decreased immune function, intense inflammatory response, and comorbidities. Shanghai has experienced a wave of infection with Omicron, a new variant of SARS-CoV-2, since March 2022. There is a pressing need to identify clinical features and risk factors for disease progression among elderly patients with Omicron infection to provide solid evidence for clinical policy-makers, public health officials, researchers, and the general public. AIM To investigate clinical characteristic differences and risk factors between elderly patients with severe and nonsevere Omicron SARS-CoV-2 variant infection. METHODS A total of 328 elderly patients with COVID-19 admitted to the Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from April 2022 to June 2022 were enrolled and divided into a severe group (82 patients) and a nonsevere group (246 patients) according to the diagnosis and treatment protocol of COVID-19 (version 7). The clinical data and laboratory results of both groups were collected and compared. A chi-square test, t test, Mann-Whitney U test, hierarchical log-rank test, univariate and multivariate logistic regression, and hierarchical analyses were used to determine significant differences. RESULTS The severe group was older (84 vs 74 years, P &lt; 0.001), included more males (57.3% vs 43.9%, P = 0.037), had a lower vaccination rate (P &lt; 0.001), and had a higher proportion of comorbidities, including chronic respiratory disease (P = 0.001), cerebral infarction (P &lt; 0.001), chronic kidney disease (P = 0.002), and neurodegenerative disease (P &lt; 0.001), than the nonsevere group. In addition, severe disease patients had a higher inflammatory index (P &lt; 0.001), greater need for symptomatic treatment (P &lt; 0.001), longer hospital stay (P = 0.011), extended viral shedding time (P = 0.014), and higher mortality than nonsevere disease patients (P &lt; 0.001). No difference was observed in the application of Paxlovid in the severe and nonsevere groups (P = 0.817). Oxygen saturation, cerebral infarction, and D-dimer were predictive factors for developing severe disease in patients with COVID-19, with D-dimer having an excellent role (area under the curve: 90.1%, 95%CI: 86.1-94.0%). In addition, D-dimer was a risk factor for developing severe COVID-19 according to multivariate stratified analysis. CONCLUSION The clinical course of severe COVID-19 is complex, with a higher need for symptomatic treatment. D-dimer is a suitable biomarker for identifying patients at risk for developing severe COVID-19.

Characteristics of COVID-19 Infections and Severe Outcomes in a Multinational Study in Latin America During the Circulation Period of the Delta Variant in the Pediatric Population

Abstract Background SARS-CoV-2 infection had specific characteristics in the pediatric population described in previous studies. These clinical features included specific COVID-19 presentation, antibiotic usage, and predictors of disease severity. In addition to patient related factors, external influences could affect COVID-19 outcomes. The features of children with COVID-19 of five Latin American countries were described. Study participants were members of the Prevencionistas e Infectólogos para Cáncer Pediátrico en América Latina (PRINCIPAL) Network of the Global Infectious Diseases Program at St Jude Children's Research Hospital. This study aims to analyze the differences between patients with non-severe and severe disease when the circulation of the Delta variant was predominant, and few children had received SARS-CoV-2 vaccines. Methods This is a retrospective, observational, multinational study that included children with a confirmed diagnosis of COVID-19 between January 2021 and January 2022. Epidemiological, clinical, and treatment characteristics are described and compared between patients with severe and non-severe disease. Frequencies and percentages are presented as well as median and interquartile ranges (IQR). Comparisons were made using the chi-squared test for proportions and the Wilcoxon test for nonparametric quantitative variables. Results 745 patients were included. Patients had a median age of 51 (13-139) months, 194 (26%) had comorbidities, and 701 (94%) presented with symptomatic disease. Fever was present in 524 (74.8%) patients, respiratory symptoms in 550 (78.5%), followed by gastrointestinal manifestations in 218 (31.1%). X-ray findings were abnormal in 175/362 patients, with interstitial infiltrates being the most common finding, 123 (70.7%). Almost a third of patients (29%) received an antibiotic; ceftriaxone was most frequently prescribed in 123/216 cases. Of 745 patients, 526 (70.8%) were hospitalized, of which 165 (31.4%) required PICU admission. Patients presenting with severe disease and requiring PICU admission we more likely to have a comorbidity, 128 (22%) vs. 66 (40%), p&amp;lt;0.001. Mucocutaneous findings or adenitis were more frequently described in severe cases, 19 (11.5) vs. 18 (5.0%), p=0.007. Regarding laboratory results, low lymphocytes 2445 vs. 1676 (p&amp;lt;0.001) and low platelets 294,000 vs. 250,000 (p=0.0002) were most common in patients with severe disease. The proportion of patients with lymphocytopenia was also higher in those with severe disease, 39% vs. 52% p= 0.010. Not surprisingly, antibiotic usage (broad and narrow spectrum) was higher in patients admitted to the PICU (32 vs. 16.5%) p=0.001, despite no significant difference in the frequency of bacterial coinfection (5.56% vs. 9.7% p=0.081) when compared to patients with non-severe disease. Specific treatment strategies were more frequent in PICU patients (39.1% vs. 72.1%) p&amp;lt;0.001, and steroids were the most frequently used drug, 35.2% vs. 70.7% (p&amp;lt;0.001). Table 1. Conclusions Regardless of the variant, COVID-19 is an important cause of hospitalization in children. Fever, respiratory and gastrointestinal symptoms are the most frequent manifestations in children. Despite the low frequency of bacterial coinfection, a high proportion of antibiotic usage is described. Compared to recent publications, mucocutaneous involvement, lower lymphocyte and platelet counts, and higher inflammatory markers were more frequently found in admissions to the PICU. Currently, with higher vaccine coverage and more comprehensive knowledge of the disease, optimization of pediatric COVID-19 management is expected, especially concerning antibiotic use. It is essential to continue multicenter surveillance of the behavior of COVID-19 in the pediatric population.

Autoreactive T cells targeting type II pneumocyte antigens in COVID-19 convalescent patients

BackgroundThe role of autoreactive T cells on the course of Coronavirus disease-19 (COVID-19) remains elusive. Type II pneumocytes represent the main target cells of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Autoimmune responses against antigens highly expressed in type II pneumocytes may influence the severity of COVID-19 disease. ObjectiveThe aim of this study was to investigate autoreactive T cell responses against self-antigens highly expressed in type II pneumocytes in the blood of COVID-19 patients with severe and non-severe disease. MethodsWe collected blood samples of COVID-19 patients with varying degrees of disease severity and of pre-pandemic controls. T cell stimulation assays with peptide pools of type II pneumocyte antigens were performed in two independent cohorts to analyze the autoimmune T cell responses in patients with non-severe and severe COVID-19 disease. Target cell lysis assays were performed with lung cancer cell lines to determine the extent of cell killing by type II PAA-specific T cells.Results: We identified autoreactive T cell responses against four recently described self-antigens highly expressed in type II pneumocytes, known as surfactant protein A, surfactant protein B, surfactant protein C and napsin A, in the blood of COVID-19 patients. These antigens were termed type II pneumocyte-associated antigens (type II PAAs). We found that patients with non-severe COVID-19 disease showed a significantly higher frequency of type II PAA-specific autoreactive T cells in the blood when compared to severely ill patients. The presence of high frequencies of type II PAA-specific T cells in the blood of non-severe COVID-19 patients was independent of their age. We also found that napsin A-specific T cells from convalescent COVID-19 patients could kill lung cancer cells, demonstrating the functional and cytotoxic role of these T cells. ConclusionsOur data suggest that autoreactive type II PAA-specific T cells have a protective role in SARS-CoV-2 infections and the presence of high frequencies of these autoreactive T cells indicates effective viral control in COVID-19 patients. Type II-PAA-specific T cells may therefore promote the killing of infected type II pneumocytes and viral clearance.

Flow Cytometric Analysis of Lymphocyte Subsets of Covid-19 Patients from A Single Centre in Turkey

Background:&#x0D; Lymphocyte counts have been shown to negatively correlate with the severity and different outcomes in Covid-19. The aim of this single centre study is to analyse the distribution of lymphocyte subsets in response to SARS-CoV-2 infection and its relation to the severity, course and prognosis of the disease.&#x0D; Methods:&#x0D; Blood samples were obtained from 67 consecutive patients between April 2020 and July 2020. Data on other laboratory parameters, and clinical course were collected retrospectively from patient files and patints were defined to have as severe or non-severe (mild/moderate) disease. Leukocyte subsets to be studied were identified by using flow cytometric analysis. Patients were allocated into 3 groups based on the day of blood sample collection for the flow cytometric analysis: Days 0-7, Days 8-14 and Days &gt;14 as Group I, Group II and Group III, respectively. In 10 available of 67 patients an additional flow cytometric analysis was done 7-10 days after the initial sampling.&#x0D; Results:&#x0D; Lower total lymphocyte, CD3 positive, CD4 positive and B-cell counts were identified in severe infection compared to non-severe infection group which were also correlated with high serum CRP, D-dimer and ferritin levels. NK and monocyte counts were not different between the two groups. Activation markers CD38 and HLA-DR on CD4 and CD8 positive lymphocytes also were not different in either group. &#x0D; Conclusion:&#x0D; CD3 and CD4 lymphopenia were lower in accordance with previous studies and were associated with severe disease. The expectancy of high activation markers was not met. Future studies with detailed subgroup analyses at different time-points, and immune profiling after vaccination as well as during new infection in vaccinated patients will shed more light on our general knowledge of the immune response to COVID-19 and viruses in general.

Procalcitonin is elevated in severe malaria and is a promising biomarker of severe malaria and multi-organ dysfunction: A cross-sectional study and meta-analysis

BackgroundElevated procalcitonin (PCT) has been reported in bacterial infection and is positively associated with the severity of the disease. Patients with severe Plasmodium falciparum malaria also display higher procalcitonin levels compared to those with non-severe disease, indicating a possible role for bacterial infection in severe disease, however this observation remained variable in different study population. Furthermore, the significance of PCT in different clinical categories of severe malaria has not been evaluated so far. MethodsA total of 74 P. falciparum-infected subjects were enrolled in the study comprising of 55 cases complicated malaria [cerebral malaria- 14; non-cerebral severe malaria- 21; multi-organ dysfunction- 20] and 19 uncomplicated cases. Serum levels of PCT were quantified by fluorescence immunoassay. For meta-analysis, the literature search was performed in different databases, and all relevant articles were screened, and eligible reports were identified based on predefined inclusion and exclusion criteria. The meta-analysis was performed by comprehensive meta-analysis software V3 and MedCalc 20.218. ResultsPatients with severe P. falciparum malaria had significantly higher PCT levels compared to uncomplicated cases (p = 0.01). Analysis of PCT in different categories of patients with severe malaria revealed significantly elevated PCT in multi-organ dysfunctions compared to those with uncomplicated malaria (p = 0.004) and cerebral malaria (p = 0.05). Interestingly the receiver operating characteristics curve analysis showed procalcitonin as a promising biomarker for differentiating severe malaria (AUC: 0.697, p = 0.01) and multi-organ dysfunction (AUC: 0.704, p = 0.007) from uncomplicated malaria and other clinical categories of falciparum malaria, respectively. Furthermore, meta-analysis also revealed an elevated procalcitonin in severe malaria and it could be an important biomarker in the management of severe disease. ConclusionsPCT is elevated in P. falciparum-infected patients and could be a good biomarker for diagnosis of severe malaria and multi-organ dysfunction. It can help in the management of severe disease with additional treatment options.

Increased blood pressure after nonsevere COVID-19.

Various sequelae have been described after nonsevere coronavirus disease 2019 (COVID-19), but knowledge on postacute effects on blood pressure is limited. This is a cross-sectional analysis of blood pressure profiles in individuals after nonsevere COVID-19 compared with matched population-based individuals without prior COVID-19. Data were derived from the ongoing and prospective Hamburg City Health Study, a population-based study in Hamburg, Germany, and its associated COVID-19 program, which included individuals at least 4 months after COVID-19. Matching was performed by age, sex, education, and preexisting hypertension in a 1 : 4 ratio. Four hundred and thirty-two individuals after COVID-19 (mean age 56.1 years) were matched to 1728 controls without prior COVID-19 (56.2 years). About 92.8% of COVID-19 courses were mild or moderate, only 7.2% were hospitalized, and no individual had been treated on an intensive care unit. Even after adjustment for relevant competing risk factors, DBP [+4.7 mmHg, 95% confidence interval (95% CI) 3.97-5.7, P < 0.001] was significantly higher in individuals after COVID-19. For SBP, a trend towards increased values was observed (+1.4 mmHg, 95% CI -0.4 to 3.2, P = 0.120). Hypertensive blood pressures at least 130/80 mmHg (according to the ACC/AHA guideline) and at least 140/90 mmHg (ESC/ESH guideline) occurred significantly more often in individuals after COVID-19 than matched controls (odds ratio 2.0, 95% CI 1.5-2.7, P < 0.001 and odds ratio 1.6, 95% CI 1.3-2.0, P < 0.001, respectively), mainly driven by changes in DBP. Blood pressure is higher in individuals after nonsevere COVID-19 compared with uninfected individuals suggesting a significant hypertensive sequela.

Clinical Characteristics of Hospitalized Patients With COVID-19: A Retrospective Cohort Study in Pakistan.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a global pandemic of severe upper respiratory tract infections known as COVID-19. This single-center study aimed to investigate the demographics, comorbidities, symptoms, and disease severity of COVID-19 patients in Pakistan. A retrospective descriptive study was conducted at the Pakistan Kidney and Liver Institute and Research Center from April 2020 to August 2020. A total of 430 PCR-positive COVID-19 patients were categorized into symptomatic and asymptomatic groups. The symptomatic group was further classified into severe and non-severe subgroups. Patients' demographics, comorbid conditions, presenting symptoms, laboratory parameters, and clinical outcomes were assessed in these two subgroups. Statistical tests were applied to determine significant differences. A total of 430 patients with COVID-19 presented in our center, of whom 334 (78%) were symptomatic and included in the study. Severe disease was observed in 83 (24.8%) symptomatic patients, with a male predominance (75.9%) and higher mean age (61.7 ± 13.2). Travel to high-risk destinations (p < 0.002) and close contact with COVID-19 patients (p < 0.001) were significant risk factors. Major comorbid conditions included diabetes mellitus (30.5%) and hypertension (39.8%). Frequent symptoms included fever (71.8%), cough (68.8%), dyspnea (53.8%), and myalgias (35.9%). Higher C-reactive protein (median = 12.76 vs. 1.45, p = 0.001), ferritin (median = 996.70 vs. 628, p = 0.004), and D-dimers (median = 1121 vs. 439.50, p = 0.009) were noted in severe vs non-severe disease. Lymphopenia was more prevalent in severe vs. non-severe disease (83.1% vs. 14.3% p-value = 0.033). More deaths (28.9%) and ICU admissions (53%) with a prolonged hospital stay (median = 25 days, IQR = 16.0-31.0) were noted in the severe group. This retrospective study provides insights into the clinical characteristics and outcomes of COVID-19 patients. Age, male gender, comorbidities, and specific symptoms were associated with disease severity. Inflammatory markers, including D-dimers, ferritin, and CRP, were elevated in severe cases. These findings contribute to a better understanding of COVID-19 and may aid in clinical management and decision-making for patients affected by the disease.

SLC6A1 variant pathogenicity, molecular function and phenotype: a genetic and clinical analysis.

Genetic variants in the SLC6A1 gene can cause a broad phenotypic disease spectrum by altering the protein function. Thus, systematically curated clinically relevant genotype-phenotype associations are needed to understand the disease mechanism and improve therapeutic decision-making. We aggregated genetic and clinical data from 172 individuals with likely pathogenic/pathogenic (lp/p) SLC6A1 variants and functional data for 184 variants (14.1% lp/p). Clinical and functional data were available for a subset of 126 individuals. We explored the potential associations of variant positions on the GAT1 3D structure with variant pathogenicity, altered molecular function and phenotype severity using bioinformatic approaches. The GAT1 transmembrane domains 1, 6 and extracellular loop 4 (EL4) were enriched for patient over population variants. Across functionally tested missense variants (n = 156), the spatial proximity from the ligand was associated with loss-of-function in the GAT1 transporter activity. For variants with complete loss of in vitro GABA uptake, we found a 4.6-fold enrichment in patients having severe disease versus non-severe disease (P = 2.9 × 10-3, 95% confidence interval: 1.5-15.3). In summary, we delineated associations between the 3D structure and variant pathogenicity, variant function and phenotype in SLC6A1-related disorders. This knowledge supports biology-informed variant interpretation and research on GAT1 function. All our data can be interactively explored in the SLC6A1 portal (https://slc6a1-portal.broadinstitute.org/).

COVIDpro: Database for Mining Protein Dysregulation in Patients with COVID-19.

The ongoing pandemic of the coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 still has limited treatment options. Our understanding of the molecular dysregulations that occur in response to infection remains incomplete. We developed a web application COVIDpro (https://www.guomics.com/covidPro/) that includes proteomics data obtained from 41 original studies conducted in 32 hospitals worldwide, involving 3077 patients and covering 19 types of clinical specimens, predominantly plasma and serum. The data set encompasses 53 protein expression matrices, comprising a total of 5434 samples and 14,403 unique proteins. We identified a panel of proteins that exhibit significant dysregulation, enabling the classification of COVID-19 patients into severe and non-severe disease categories. The proteomic signatures achieved promising results in distinguishing severe cases, with a mean area under the curve of 0.87 and accuracy of 0.80 across five independent test sets. COVIDpro serves as a valuable resource for testing hypotheses and exploring potential targets for novel treatments in COVID-19 patients.

Duration of prodromal phase and severity of hemolytic uremic syndrome.

Some data have recognized an association between shorter prodromal phase and severe episode of Shiga toxin-producing Escherichia coli-related hemolytic uremic syndrome (STEC-HUS). Our aims were to confirm such association and analyze characteristics of STEC-HUS patients according to duration of the prodromal phase. Patients treated from 2000 to 2022 were compared according to the presence of severe (> 10days of dialysis and/or extra-renal complications) or non-severe disease. Association between prodromal phase duration and disease severity was assessed by ROC curve and by classifying the cohort in 3 groups according to time to diagnosis. Non-severe (n = 145) and severe (n = 71) cases were compared. The latter had shorter prodromal phase, higher leukocyte count, hemoglobin, lactic dehydrogenase, liver enzymes, C-reactive protein, urea and creatinine, and lower albumin and sodium; only prodromal phase duration (p = 0.02) and leukocyte count (p = 0.02) remained significant in multivariate analysis. By ROC curve analysis, time to diagnosis resulted in a poor predictor of outcomes (AUC = 0.27). Since prodromal phase duration was 5days (IQR 3-7), we divided the cohort into Groups A (1-2days), B (3-7days), and C (≥ 8days). Rates of severe disease were 75.8%, 29.6%, and 11.4%, respectively. Taking Group B as reference, Group A patients had higher risk of complications (p = 0.00001; OR 7.4, 95% CI: 2.98-18.7) while Group C ones had significantly less risk (p = 0.02; OR 0.3, 95% CI: 0.1-0.91). This study found that duration of prodromal phase is an independent predictor of complicated STEC-HUS and confirms that shorter prodromal phase is associated with worse prognosis. A higher resolution version of the Graphical abstract is available as Supplementary information.

Management and outcome of COVID-19 in CTLA-4 insufficiency

AbstractDespite the high incidence of COVID-19 worldwide, clinical experience with severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) in inborn errors of immunity remains limited. Recent studies have shown that patients with defects in type 1 interferon (IFN)-related pathways or those with autoantibodies against type 1 IFNs develop severe COVID-19. We reported the clinical course of 22 patients with CTLA-4 insufficiency and COVID-19 and retrospectively examined autoantibodies against type 1 IFNs at baseline. Data were obtained from the patient interviews and chart reviews. Screening for anti-IFN autoantibodies was performed using a multiplex particle-based assay. Student t test, Mann Whitney, analysis of variance, or χ2 tests were used where appropriate. Twenty-two patients aged from 8 months to 54 years, with genetically confirmed CLTA-4 insufficiency, developed COVID-19 from 2020 to 2022. The most common symptoms were fever, cough, and nasal congestion, and the median duration of illness was 7.5 days. Twenty patients (91%) developed mild COVID-19 and were treated as outpatients. Two patients were hospitalized because of COVID-19 pneumonia but did not require mechanical ventilation. Ten (45%) patients were vaccinated at the time of their first COVID-19 infection. Eleven patients received outpatient treatment with monoclonal antibodies against the SARS-CoV-2 spike protein. During the study period, 17 patients were vaccinated against SARS-CoV-2, with no severe vaccine-related adverse effects. Although median anti-S titers following vaccination or infection were lower in patients receiving immunoglobulin replacement therapy (IGRT) (349 IU/dL) than in those not receiving IGRT (2594 IU/dL; P = .15); 3 of 9 patients on IGRT developed titers >2000 IU/dL. All patients tested negative for autoantibodies against IFN-α, IFN-β, and IFN-ω at baseline. Most patients with CTLA-4 insufficiency and COVID-19 had nonsevere disease, lacked autoantibodies against type 1 IFNs, and tolerated messenger RNA vaccines with few adverse effects. Whether our findings can be extrapolated to patients receiving CTLA-4-targeting checkpoint inhibitors requires further studies.

Prevalence and Clinical Characteristics of Children With Nonsevere Tuberculosis in Spain.

To assess the prevalence and characteristics of nonsevere TB among children in Spain. It has been recently demonstrated that these children can be treated with a 4-month regimen instead of the classical 6-month treatment regimen, with the same effectivity and outcomes, decreasing toxicity and improving adherence. We conducted a retrospective cohort study in a cohort of children ≤16 years of age with TB. Nonsevere TB cases included smear-negative children with respiratory TB confined to 1 lobe, with no significant airway obstruction, no complex pleural effusion, no cavities and no signs of miliary disease, or with peripheral lymph-node disease. The remaining children were considered to have severe TB. We estimated the prevalence of nonsevere TB and compared the clinical characteristics and outcomes between children with nonsevere and severe TB. A total of 780 patients were included [46.9% males, median age 5.5 years (IQR: 2.6-11.1)], 477 (61.1%) of whom had nonsevere TB. Nonsevere TB was less frequent in children <1 year (33% vs 67%; P < 0.001), and >14 years of age (35% vs 65%; P = 0.002), mostly diagnosed in contact tracing studies (60.4% vs 29.2%; P < 0.001) and more frequently asymptomatic (38.3% vs 17.7%; P < 0.001). TB confirmation in nonsevere disease was less frequent by culture (27.0% vs 57.1%; P < 0.001) and by molecular tests (18.2% vs 48.8%; P < 0.001). Sequelae were less frequent in children with nonsevere disease (1.7 vs 5.4%; P < 0.001). No child with nonsevere disease died. Two-thirds of children had nonsevere TB, mostly with benign clinical presentation and negative microbiologic results. In low-burden countries, most children with TB might benefit from short-course regimens.