Long-COVID is Associated with Impaired Red Blood Cell Function.

COVID-19 disease, caused by the severe acute respiratory syndrome virus 2 (SARS-CoV-2), induces a broad spectrum of clinical symptoms ranging from asymptomatic cases to fatal outcomes. About 10-35% of all COVID-19 patients, even those with mild COVID-19 symptoms, continue to show symptoms, i. e., fatigue, shortness of breath, cough, and cognitive dysfunction, after initial recovery. Previously, we and others identified red blood cell precursors as a direct target of SARS-CoV-2 and suggested that SARS-CoV-2 induces dysregulation in hemoglobin- and iron-metabolism contributing to the severe systemic course of COVID-19. Here, we put particular emphasis on differences in parameters of clinical blood gas analysis and hematological parameters of more than 20 healthy and Long-COVID patients, respectively. Long-COVID patients showed impaired oxygen binding to hemoglobin with concomitant increase in carbon monoxide binding. Hand in hand with decreased plasma iron concentration and transferrin saturation, mean corpuscular hemoglobin was elevated in Long-COVID patients compared to healthy donors suggesting a potential compensatory mechanism. Although blood pH was within the physiological range in both groups, base excess- and bicarbonate values were significantly lower in Long-COVID patients. Furthermore, Long-COVID patients displayed reduced lymphocyte levels. The clinical relevance of these findings, e. g., as a cause of chronic immunodeficiency, remains to be investigated in future studies. In conclusion, our data suggest impaired erythrocyte functionality in Long-COVID patients, leading to diminished oxygen supply. This in turn could be an explanation for the CFS, dyspnea and anemia. Further investigations are necessary to identify the underlying pathomechanisms.

Validation of risk scores for prediction of severe pneumonia in kidney transplant recipients hospitalized with community-acquired pneumonia.

PURPOSE: Risk scores for community-acquired pneumonia (CAP) are widely used for standardized assessment in immunocompetent patients and to identify patients at risk for severe pneumonia and death. In immunocompromised patients, the prognostic value of pneumonia-specific risk scores seems to be reduced, but evidence is limited. The value of different pneumonia risk scores in kidney transplant recipients (KTR) is not known. METHODS: Therefore, we retrospectively analyzed 310 first CAP episodes after kidney transplantation in 310 KTR. We assessed clinical outcomes and validated eight different risk scores (CRB-65, CURB-65, DS-CRB-65, qSOFA, SOFA, PSI, IDSA/ATS minor criteria, NEWS-2) for the prognosis of severe pneumonia and in-hospital mortality. Risk scores were assessed up to 48 h after admission, but always before an endpoint occurred. Multiple imputation was performed to handle missing values. RESULTS: In total, 16 out of 310 patients (5.2%) died, and 48 (15.5%) developed severe pneumonia. Based on ROC analysis, sequential organ failure assessment (SOFA) and national early warning score 2 (NEWS-2) performed best, predicting severe pneumonia with AUC of 0.823 (0.747-0.880) and 0.784 (0.691-0.855), respectively. CONCLUSION: SOFA and NEWS-2 are best suited to identify KTR at risk for the development of severe CAP. In contrast to immunocompetent patients, CRB-65 should not be used to guide outpatient treatment in KTR, since there is a 7% risk for the development of severe pneumonia even in patients with a score of zero.

Validation of the qSOFA and CRB-65 in SARS-CoV-2-infected community-acquired pneumonia.

Rationale: Prognostic accuracy of the quick sequential organ failure assessment (qSOFA) and CRB-65 (confusion, respiratory rate, blood pressure and age (≥65 years)) risk scores have not been widely evaluated in patients with SARS-CoV-2-positive compared to SARS-CoV-2-negative community-acquired pneumonia (CAP). The aim of the present study was to validate the qSOFA(-65) and CRB-65 scores in a large cohort of SARS-CoV-2-positive and SARS-CoV-2-negative CAP patients. Methods: We included all cases with CAP hospitalised in 2020 from the German nationwide mandatory quality assurance programme and compared cases with SARS-CoV-2 infection to cases without. We excluded cases with unclear SARS-CoV-2 infection state, transferred to another hospital or on mechanical ventilation during admission. Predefined outcomes were hospital mortality and need for mechanical ventilation. Results: Among 68 594 SARS-CoV-2-positive patients, hospital mortality (22.7%) and mechanical ventilation (14.9%) were significantly higher when compared to 167 880 SARS-CoV-2-negative patients (15.7% and 9.2%, respectively). All CRB-65 and qSOFA criteria were associated with both outcomes, and age dominated mortality prediction in SARS-CoV-2 (risk ratio >9). Scores including the age criterion had higher area under the curve (AUCs) for mortality in SARS-CoV-2-positive patients (e.g. CRB-65 AUC 0.76) compared to SARS-CoV-2 negative patients (AUC 0.68), and negative predictive value was highest for qSOFA-65=0 (98.2%). Sensitivity for mechanical ventilation prediction was poor with all scores (AUCs 0.59-0.62), and negative predictive values were insufficient (qSOFA-65=0 missed 1490 out of 10 198 patients (∼15%) with mechanical ventilation). Results were similar when excluding frail and palliative patients. Conclusions: Hospital mortality and mechanical ventilation rates were higher in SARS-CoV-2-positive than SARS-CoV-2-negative CAP. For SARS-CoV-2-positive CAP, the CRB-65 and qSOFA-65 scores showed adequate prediction of mortality but not of mechanical ventilation.

Bacterial Patterns and Empiric Antibiotic Use in COPD Patients With Community-Acquired Pneumonia.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is strongly associated with the development of community-acquired pneumonia (CAP). Limited data are available on risk factors for difficult to manage bacteria such as Pseudomonas aeruginosa in COPD patients with CAP. Our objective was to assess the microbiological patterns associated with risk factors that determine empiric antibiotic therapy in hospitalized COPD patients with CAP. METHODS: We performed a secondary data analysis of an international, multicenter, observational, point-prevalence study involving hospitalized COPD patients with CAP from March to June 2015. After identifying the risk factors associated with different microorganisms, we developed a scoring system to guide decision-making about empiric anti-pseudomonal antibiotic therapy in this population. RESULTS: We enrolled 689 hospitalized COPD patients with CAP with documented microbiological testing. The most frequent microorganisms isolated were Streptococcus pneumoniae (8%) and Gram-negative bacteria (8%), P. aeruginosa (7%) and Haemophilus influenzae (3%). We developed a scoring system incorporating the variables independently associated with P. aeruginosa that include a previous P. aeruginosa isolation or infection (OR 14.2 [95%CI 5.7-35.2]), hospitalization in the past 12 months (OR 3.7 [1.5-9.2]), and bronchiectasis (OR 3.2 [1.4-7.2]). Empiric anti-pseudomonal antibiotics were overutilized in COPD patients with CAP. The new scoring system has the potential to reduce empiric anti-pseudomonal antibiotic use from 54.1% to 6.2%. CONCLUSIONS: COPD patients with CAP present different microbiological profiles associated with unique risk factors. Anti-pseudomonal treatment is a critical decision when selecting empiric antibiotic therapy. We developed a COPD scoring system to guide decision-making about empiric anti-pseudomonal antibiotic therapy.

Unmet needs in pneumonia research: a comprehensive approach by the CAPNETZ study group.

INTRODUCTION: Despite improvements in medical science and public health, mortality of community-acquired pneumonia (CAP) has barely changed throughout the last 15 years. The current SARS-CoV-2 pandemic has once again highlighted the central importance of acute respiratory infections to human health. The "network of excellence on Community Acquired Pneumonia" (CAPNETZ) hosts the most comprehensive CAP database worldwide including more than 12,000 patients. CAPNETZ connects physicians, microbiologists, virologists, epidemiologists, and computer scientists throughout Europe. Our aim was to summarize the current situation in CAP research and identify the most pressing unmet needs in CAP research. METHODS: To identify areas of future CAP research, CAPNETZ followed a multiple-step procedure. First, research members of CAPNETZ were individually asked to identify unmet needs. Second, the top 100 experts in the field of CAP research were asked for their insights about the unmet needs in CAP (Delphi approach). Third, internal and external experts discussed unmet needs in CAP at a scientific retreat. RESULTS: Eleven topics for future CAP research were identified: detection of causative pathogens, next generation sequencing for antimicrobial treatment guidance, imaging diagnostics, biomarkers, risk stratification, antiviral and antibiotic treatment, adjunctive therapy, vaccines and prevention, systemic and local immune response, comorbidities, and long-term cardio-vascular complications. CONCLUSION: Pneumonia is a complex disease where the interplay between pathogens, immune system and comorbidities not only impose an immediate risk of mortality but also affect the patients' risk of developing comorbidities as well as mortality for up to a decade after pneumonia has resolved. Our review of unmet needs in CAP research has shown that there are still major shortcomings in our knowledge of CAP.

Risk Assessment for Patients with Chronic Respiratory Conditions in the Context of the SARS-CoV-2 Pandemic Statement of the German Respiratory Society with the Support of the German Association of Chest Physicians.

Assessing the risk for specific patient groups to suffer from severe courses of COVID-19 is of major importance in the current SARS-CoV-2 pandemic. This review focusses on the risk for specific patient groups with chronic respiratory conditions, such as patients with asthma, chronic obstructive pulmonary disease, cystic fibrosis (CF), sarcoidosis, interstitial lung diseases, lung cancer, sleep apnea, tuberculosis, neuromuscular diseases, a history of pulmonary embolism, and patients with lung transplants. Evidence and recommendations are detailed in exemplary cases. While some patient groups with chronic respiratory conditions have an increased risk for severe courses of COVID-19, an increasing number of studies confirm that asthma is not a risk factor for severe COVID-19. However, other risk factors such as higher age, obesity, male gender, diabetes, cardiovascular diseases, chronic kidney or liver disease, cerebrovascular and neurological disease, and various immunodeficiencies or treatments with immunosuppressants need to be taken into account when assessing the risk for severe COVID-19 in patients with chronic respiratory diseases.

Early post-discharge mortality in CAP: frequency, risk factors and a prediction tool.

There are few data on mortality after discharge with community-acquired pneumonia (CAP). Therefore, we evaluated risk factors for 30-day post-discharge mortality after CAP. We included all patients of the prospective multi-national CAPNETZ study between 2002 and 2018 with (1) hospitalized CAP, (2) survival until discharge, and (3) complete follow-up data. The study endpoint was death within 30 days after discharge. We evaluated risk factors including demographics, comorbidities, admission CAP severity, and laboratory values and treatment-related factors in uni- and multivariable analyses. A total of 126 (1.6%) of 7882 included patients died until day 30 after discharge, corresponding to 26% of all 476 deaths. After multivariable analysis, we identified 10 independent risk factors: higher age, lower BMI, presence of diabetes mellitus, chronic renal or chronic neurological disease (other than cerebrovascular diseases), low body temperature or higher thrombocytes on admission, extended length of hospitalization, oxygen therapy during hospitalization, and post-obstructive pneumonia. By addition these factors, we calculated a risk score with an AUC of 0.831 (95%CI 0.822-0.839, p < 0.001) for prediction of post-discharge mortality. Early post-discharge deaths account for » of all CAP-associated deaths and are associated with patient- and CAP-severity-related risk factors. Additional studies are necessary to replicate our findings in independent cohorts. Study registration: NCT02139163.

One Gene, Many Facets: Multiple Immune Pathway Dysregulation in SOCS1 Haploinsufficiency.

Background: Inborn errors of immunity (IEI) present with a large phenotypic spectrum of disease, which can pose diagnostic and therapeutic challenges. Suppressor of cytokine signaling 1 (SOCS1) is a key negative regulator of cytokine signaling, and has recently been associated with a novel IEI. Of patients described to date, it is apparent that SOCS1 haploinsufficiency has a pleiotropic effect in humans. Objective: We sought to investigate whether dysregulation of immune pathways, in addition to STAT1, play a role in the broad clinical manifestations of SOCS1 haploinsufficiency. Methods: We assessed impacts of reduced SOCS1 expression across multiple immune cell pathways utilizing patient cells and CRISPR/Cas9 edited primary human T cells. Results: SOCS1 haploinsufficiency phenotypes straddled across the International Union of Immunological Societies classifications of IEI. We found that reduced SOCS1 expression led to dysregulation of multiple intracellular pathways in immune cells. STAT1 phosphorylation is enhanced, comparably with STAT1 gain-of-function mutations, and STAT3 phosphorylation is similarly reduced with concurrent reduction of Th17 cells. Furthermore, reduced SOCS1 E3 ligase function was associated with increased FAK1 in immune cells, and increased AKT and p70 ribosomal protein S6 kinase phosphorylation. We also found Toll-like receptor responses are increased in SOCS1 haploinsufficiency patients. Conclusions: SOCS1 haploinsufficiency is a pleiotropic monogenic IEI. Dysregulation of multiple immune cell pathways may explain the variable clinical phenotype associated with this new condition. Knowledge of these additional dysregulated immune pathways is important when considering the optimum management for SOCS1 haploinsufficient patients.

Individual HLA-A, -B, -C, and -DRB1 Genotypes Are No Major Factors Which Determine COVID-19 Severity.

HLA molecules are key restrictive elements to present intracellular antigens at the crossroads of an effective T-cell response against SARS-CoV-2. To determine the impact of the HLA genotype on the severity of SARS-CoV-2 courses, we investigated data from 6,919 infected individuals. HLA-A, -B, and -DRB1 allotypes grouped into HLA supertypes by functional or predicted structural similarities of the peptide-binding grooves did not predict COVID-19 severity. Further, we did not observe a heterozygote advantage or a benefit from HLA diplotypes with more divergent physicochemical peptide-binding properties. Finally, numbers of in silico predicted viral T-cell epitopes did not correlate with the severity of SARS-CoV-2 infections. These findings suggest that the HLA genotype is no major factor determining COVID-19 severity. Moreover, our data suggest that the spike glycoprotein alone may allow for abundant T-cell epitopes to mount robust T-cell responses not limited by the HLA genotype.

[Prevention by vaccination of adult patients with pulmonary diseases]. / Prävention durch Impfung pneumologisch vorerkrankter Erwachsener: Pneumokokkenpneumonie, Influenza, Pertussis, Herpes Zoster und "coronavirus disease 2019".

The key priority in patients with chronic lung diseases is currently immunization against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); all vaccines approved for this showed high effectiveness against severe infections. For patients with chronic pulmonary diseases the recommendations by the Standing Committee on Vaccination include not only the standard vaccinations in adulthood but also the so-called indication vaccinations. These include vaccinations against pneumococci and influenza. Advances include the recent development of new pneumococcal conjugate vaccines containing additional serotypes and the recommendation of a more effective high-dose vaccine against influenza for persons over 60 years old. With the next scheduled booster vaccination against tetanus and diphtheria a combination vaccine with pertussis antigen should be used. For patients with chronic lung disease the herpes zoster vaccine is recommended over the age of 50 years.

Validation of the qSOFA score compared to the CRB-65 score for risk prediction in community-acquired pneumonia.

OBJECTIVE: The qSOFA (quick sepsis-related organ failure assessment) score shows similarities to the CRB-65 pneumonia score, but its prognostic accuracy in patients with community-acquired pneumonia (CAP) has not been extensively evaluated. Our aim was to validate the qSOFA (-65) score in a large cohort of CAP patients. METHODS: We conducted a retrospective population-based cohort study including all CAP cases hospitalized between 1st January 2014 and 31st December 2018 from the German nationwide mandatory quality assurance programme. We excluded cases transferred from another hospital, with mechanical ventilation present on admission, and without documented respiratory rate. Predefined outcomes were hospital mortality and need for mechanical ventilation. RESULTS: Among the 1,262,250 included cases, hospital mortality was 12.4% and the mechanical ventilation rate was 7.1%. All CRB and qSOFA criteria were associated with both outcomes, but the qSOFA had inferior sensitivity compared to the CRB-65 for mortality prediction. Including the age criterion ≥65 years, qSOFA-65 and CRB-65 performed similarly (AUC 0.69, 95%CI 0.69-0.69 versus 0.68, 95%CI 0.68-0.68). A qSOFA-65 of 0 was associated with fewer missed deaths (3328, 2.0%) compared to a CRB-65 of 0 (5480, 2.4%). The sensitivity of the suggested qSOFA cut-off of ≥2 for sepsis was low (mortality 25.8%, 95%CI 25.6-26.0%; mechanical ventilation 24.1%, 95%CI 23.8-24.4%). Results were similar when frail and palliative patients were excluded. CONCLUSIONS: The qSOFA parameters show prognostic accuracy similar to the CRB parameters in CAP, but the sepsis cut-off of ≥2 lacked sensitivity. For sensitive mortality prediction, the age criterion ≥65 years should be added to the qSOFA.

Limited prognostic accuracy of the CRB-65 and qSOFA in patients presenting with pneumonia and immunosuppression.

BACKGROUND: Scores for risk prediction used in immunocompetent patients with sepsis or pneumonia are poorly evaluated in immunocompromised patients. Therefore, we evaluated the prognostic value of the qSOFA- and CRB-65-criteria in immunocompromised patients presenting with pneumonia. METHODS: Retrospective cohort study including consecutive patients hospitalized with pneumonia and immunosuppression without treatment restrictions. The qSOFA and CRB-65 criteria were documented in the emergency department. Outcome was defined as need of mechanical ventilation (MV) or vasopressor support (VS) and/or hospital-mortality. RESULTS: 41 of 198 (21%) patients reached the outcome and 10% died. Both, the CRB-65 and qSOFA- were independently associated with the outcome (all p<0.01), but age was not predictive. ROC curve analysis showed moderate predictive potential for both scores (CRB-65: AUC 0.63 and qSOFA: 0.69). With scores of 0, the negative predictive values were below 90% (CRB-65: 9/60 and qSOFA: 12/105 missed patients). With scores > 1, the positive predictive values were 36% (CRB-65) and 58% (qSOFA), respectively. CONCLUSIONS: Both, the qSOFA and the CRB-65 only showed moderate prognostic value, and negative predictive values were inadequate to exclude organ failure or death in patients with immunosuppression. In this population, age was not a predictive parameter. Patients with > 1 positive vital sign criterion measured by both scores should be assessed for organ failure.