High Plasma Levels of Activated Factor VII-Antithrombin Complex Point to Increased Tissue Factor Expression in Patients with SARS-CoV-2 Pneumonia: A Potential Link with COVID-19 Prothrombotic Diathesis.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causal agent of coronavirus disease 2019 (COVID-19), in which coagulation abnormalities and endothelial dysfunction play a key pathogenic role. Tissue factor (TF) expression is triggered by endothelial dysfunction. Activated factor VII-antithrombin (FVIIa-AT) complex reflects indirectly FVIIa-TF interaction and has been proposed as a potential biomarker of prothrombotic diathesis. FVIIa-AT plasma concentration was measured in 40 patients (30 males and 10 females; 64.8 ± 12.3 years) admitted with SARS-CoV-2 pneumonia during the first pandemic wave in Italy. Two sex- and age-matched cohorts without COVID-19, with or without signs of systemic inflammation, were used to compare FVIIa-AT data. The FVIIa-AT plasma levels in COVID-19 patients were higher than those in non-COVID-19 subjects, either with or without inflammation, while no difference was observed among non-COVID-19 subjects. The association between COVID-19 and FVIIa-AT levels remained significant after adjustment for sex, age, C-reactive protein, renal function, fibrinogen, prothrombin time and activated partial thromboplastin time. Our results indicate that SARS-CoV-2 infection, at least during the first pandemic wave, was characterized by high FVIIa-AT levels, which may suggest an enhanced FVIIa-TF interaction in COVID-19, potentially consistent with SARS-CoV-2-induced endotheliopathy.

Red Blood Cell Morphologic Abnormalities in Patients Hospitalized for COVID-19.

Peripheral blood smear is a simple laboratory tool, which remains of invaluable help for diagnosing primary and secondary abnormalities of blood cells despite advances in automated and molecular techniques. Red blood cells (RBCs) abnormalities are known to occur in many viral infections, typically in the form of mild normo-microcytic anemia. While several hematological alterations at automated complete blood count (including neutrophilia, lymphopenia, and increased red cell distribution width-RDW) have been consistently associated with severity of COVID-19, there is scarce information on RBCs morphological abnormalities, mainly as case-reports or small series of patients, which are hardly comparable due to heterogeneity in sampling times and definition of illness severity. We report here a systematic evaluation of RBCs morphology at peripheral blood smear in COVID-19 patients within the first 72 h from hospital admission. One hundred and fifteen patients were included, with detailed collection of other clinical variables and follow-up. A certain degree of abnormalities in RBCs morphology was observed in 75 (65%) patients. Heterogenous alterations were noted, with spiculated cells being the more frequent morphology. The group with >10% RBCs abnormalities had more consistent lymphopenia and thrombocytopenia compared to those without abnormalities or <10% RBCs abnormalities (p < 0.018, and p < 0.021, respectively), thus underpinning a possible association with an overall more sustained immune-inflammatory "stress" hematopoiesis. Follow-up analysis showed a different mortality rate across groups, with the highest rate in those with more frequent RBCs morphological alterations compared to those with <10% or no abnormalities (41.9%, vs. 20.5%, vs. 12.5%, respectively, p = 0.012). Despite the inherent limitations of such simple association, our results point out towards further studies on erythropoiesis alterations in the pathophysiology of COVID-19.

The role of hypoxia and inflammation in the regulation of iron metabolism and erythropoiesis in COVID-19: The IRONCOVID study.

Coronavirus Disease (COVID-19) can be considered as a human pathological model of inflammation combined with hypoxia. In this setting, both erythropoiesis and iron metabolism appear to be profoundly affected by inflammatory and hypoxic stimuli, which act in the opposite direction on hepcidin regulation. The impact of low blood oxygen levels on erythropoiesis and iron metabolism in the context of human hypoxic disease (e.g., pneumonia) has not been fully elucidated. This multicentric observational study was aimed at investigating the prevalence of anemia, the alterations of iron homeostasis, and the relationship between inflammation, hypoxia, and erythropoietic parameters in a cohort of 481 COVID-19 patients admitted both to medical wards and intensive care units (ICU). Data were collected on admission and after 7 days of hospitalization. On admission, nearly half of the patients were anemic, displaying mild-to-moderate anemia. We found that hepcidin levels were increased during the whole period of observation. The patients with a higher burden of disease (i.e., those who needed intensive care treatment or had a more severe degree of hypoxia) showed lower hepcidin levels, despite having a more marked inflammatory pattern. Erythropoietin (EPO) levels were also lower in the ICU group on admission. After 7 days, EPO levels rose in the ICU group while they remained stable in the non-ICU group, reflecting that the initial hypoxic stimulus was stronger in the first group. These findings strengthen the hypothesis that, at least in the early phases, hypoxia-driven stimuli prevail over inflammation in the regulation of hepcidin and, finally, of erythropoiesis.

Red Blood Cell Morphologic Abnormalities in Patients Hospitalized for COVID-19

Peripheral blood smear is a simple laboratory tool, which remains of invaluable help for diagnosing primary and secondary abnormalities of blood cells despite advances in automated and molecular techniques. Red blood cells (RBCs) abnormalities are known to occur in many viral infections, typically in the form of mild normo-microcytic anemia. While several hematological alterations at automated complete blood count (including neutrophilia, lymphopenia, and increased red cell distribution width—RDW) have been consistently associated with severity of COVID-19, there is scarce information on RBCs morphological abnormalities, mainly as case-reports or small series of patients, which are hardly comparable due to heterogeneity in sampling times and definition of illness severity. We report here a systematic evaluation of RBCs morphology at peripheral blood smear in COVID-19 patients within the first 72 h from hospital admission. One hundred and fifteen patients were included, with detailed collection of other clinical variables and follow-up. A certain degree of abnormalities in RBCs morphology was observed in 75 (65%) patients. Heterogenous alterations were noted, with spiculated cells being the more frequent morphology. The group with >10% RBCs abnormalities had more consistent lymphopenia and thrombocytopenia compared to those without abnormalities or <10% RBCs abnormalities (p < 0.018, and p < 0.021, respectively), thus underpinning a possible association with an overall more sustained immune-inflammatory “stress” hematopoiesis. Follow-up analysis showed a different mortality rate across groups, with the highest rate in those with more frequent RBCs morphological alterations compared to those with <10% or no abnormalities (41.9%, vs. 20.5%, vs. 12.5%, respectively, p = 0.012). Despite the inherent limitations of such simple association, our results point out towards further studies on erythropoiesis alterations in the pathophysiology of COVID-19.

Iron metabolism in infections: Focus on COVID-19.

Iron is a micronutrient essential for a wide range of metabolic processes in virtually all living organisms. During infections, a battle for iron takes place between the human host and the invading pathogens. The liver peptide hepcidin, which is phylogenetically and structurally linked to defensins (antimicrobial peptides of the innate immunity), plays a pivotal role by subtracting iron to pathogens through its sequestration into host cells, mainly macrophages. While this phenomenon is well studied in certain bacterial infections, much less is known regarding viral infections. Iron metabolism also has implications on the functionality of cells of the immune system. Once primed by the contact with antigen presenting cells, lymphocytes need iron to sustain the metabolic burst required for mounting an effective cellular and humoral response. The COVID-19 pandemic has boosted an amount of clinical and translational research over the possible influences of nutrients on SARS-CoV-2 infection, in terms of either susceptibility or clinical course. Here we review the intersections between iron metabolism and COVID-19, belonging to the wider domain of the so-called "nutritional immunity". A better understanding of such connections has potential broad implications, either from a mechanistic standpoint, or for the development of more effective strategies for managing COVID-19 and possible future pandemics.

Is Ferroptosis a Key Component of the Process Leading to Multiorgan Damage in COVID-19?

Even though COVID-19 is mostly well-known for affecting respiratory pathology, it can also result in several extrapulmonary manifestations, leading to multiorgan damage. A recent reported case of SARS-CoV-2 myocarditis with cardiogenic shock showed a signature of myocardial and kidney ferroptosis, a novel, iron-dependent programmed cell death. The term ferroptosis was coined in the last decade to describe the form of cell death induced by the small molecule erastin. As a specific inducer of ferroptosis, erastin inhibits cystine-glutamate antiporter system Xc-, blocking transportation into the cytoplasm of cystine, a precursor of glutathione (GSH) in exchange with glutamate and the consequent malfunction of GPX4. Ferroptosis is also promoted by intracellular iron overload and by the iron-dependent accumulation of polyunsaturated fatty acids (PUFA)-derived lipid peroxides. Since depletion of GSH, inactivation of GPX4, altered iron metabolism, and upregulation of PUFA peroxidation by reactive oxygen species are peculiar signs of COVID-19, there is the possibility that SARS-CoV-2 may trigger ferroptosis in the cells of multiple organs, thus contributing to multiorgan damage. Here, we review the molecular mechanisms of ferroptosis and its possible relationship with SARS-CoV-2 infection and multiorgan damage. Finally, we analyze the potential interventions that may combat ferroptosis and, therefore, reduce multiorgan damage.

Fatal cytokine release syndrome by an aberrant FLIP/STAT3 axis.

Inflammatory responses rapidly detect pathogen invasion and mount a regulated reaction. However, dysregulated anti-pathogen immune responses can provoke life-threatening inflammatory pathologies collectively known as cytokine release syndrome (CRS), exemplified by key clinical phenotypes unearthed during the SARS-CoV-2 pandemic. The underlying pathophysiology of CRS remains elusive. We found that FLIP, a protein that controls caspase-8 death pathways, was highly expressed in myeloid cells of COVID-19 lungs. FLIP controlled CRS by fueling a STAT3-dependent inflammatory program. Indeed, constitutive expression of a viral FLIP homolog in myeloid cells triggered a STAT3-linked, progressive, and fatal inflammatory syndrome in mice, characterized by elevated cytokine output, lymphopenia, lung injury, and multiple organ dysfunctions that mimicked human CRS. As STAT3-targeting approaches relieved inflammation, immune disorders, and organ failures in these mice, targeted intervention towards this pathway could suppress the lethal CRS inflammatory state.

Assessment of COVID-19 progression on day 5 from symptoms onset.

BACKGROUND: A major limitation of current predictive prognostic models in patients with COVID-19 is the heterogeneity of population in terms of disease stage and duration. This study aims at identifying a panel of clinical and laboratory parameters that at day-5 of symptoms onset could predict disease progression in hospitalized patients with COVID-19. METHODS: Prospective cohort study on hospitalized adult patients with COVID-19. Patient-level epidemiological, clinical, and laboratory data were collected at fixed time-points: day 5, 10, and 15 from symptoms onset. COVID-19 progression was defined as in-hospital death and/or transfer to ICU and/or respiratory failure (PaO2/FiO2 ratio < 200) within day-11 of symptoms onset. Multivariate regression was performed to identify predictors of COVID-19 progression. A model assessed at day-5 of symptoms onset including male sex, age > 65 years, dyspnoea, cardiovascular disease, and at least three abnormal laboratory parameters among CRP (> 80 U/L), ALT (> 40 U/L), NLR (> 4.5), LDH (> 250 U/L), and CK (> 80 U/L) was proposed. Discrimination power was assessed by computing area under the receiver operating characteristic (AUC) values. RESULTS: A total of 235 patients with COVID-19 were prospectively included in a 3-month period. The majority of patients were male (148, 63%) and the mean age was 71 (SD 15.9). One hundred and ninety patients (81%) suffered from at least one underlying illness, most frequently cardiovascular disease (47%), neurological/psychiatric disorders (35%), and diabetes (21%). Among them 88 (37%) experienced COVID-19 progression. The proposed model showed an AUC of 0.73 (95% CI 0.66-0.81) for predicting disease progression by day-11. CONCLUSION: An easy-to-use panel of laboratory/clinical parameters computed at day-5 of symptoms onset predicts, with fair discrimination ability, COVID-19 progression. Assessment of these features at day-5 of symptoms onset could facilitate clinicians' decision making. The model can also play a role as a tool to increase homogeneity of population in clinical trials on COVID-19 treatment in hospitalized patients.

Vaccine efficacy and iron deficiency: an intertwined pair?

Vaccines are the most effective measure to prevent deaths and illness from infectious diseases. Nevertheless, the efficacy of several paediatric vaccines is lower in low-income and middle-income countries (LMICs), where mortality from vaccine-preventable infections remains high. Vaccine efficacy can also be decreased in adults in the context of some common comorbidities. Identifying and correcting the specific causes of impaired vaccine efficacy is of substantial value to global health. Iron deficiency is the most common micronutrient deficiency worldwide, affecting more than 2 billion people, and its prevalence in LMICs could increase as food security is threatened by the COVID-19 pandemic. In this Viewpoint, we highlight evidence showing that iron deficiency limits adaptive immunity and responses to vaccines, representing an under-appreciated additional disadvantage to iron deficient populations. We propose a framework for urgent detailed studies of iron-vaccine interactions to investigate and clarify the issue. This framework includes retrospective analysis of newly available datasets derived from trials of COVID-19 and other vaccines, and prospective testing of whether nutritional iron interventions, commonly used worldwide to combat anaemia, improve vaccine performance.

Neurological symptoms and axonal damage in COVID-19 survivors: are there sequelae?

The persistence of neurological symptoms after SARS-CoV-2 infection, as well as the presence of late axonal damage, is still unknown. We performed extensive systemic and neurological follow-up evaluations in 107 out of 193 consecutive patients admitted to the COVID-19 medical unit, University Hospital of Verona, Italy between March and June 2020. We analysed serum neurofilament light chain (NfL) levels in all cases including a subgroup (n = 29) of patients with available onset samples. Comparisons between clinical and biomarker data were then performed. Neurological symptoms were still present in a significant number (n = 49) of patients over the follow-up. The most common reported symptoms were hyposmia (n = 11), fatigue (n = 28), myalgia (n = 14), and impaired memory (n = 11) and were more common in cases with severe acute COVID-19. Follow-up serum NfL values (15.2 pg/mL, range 2.4-62.4) were within normal range in all except 5 patients and did not differentiate patients with vs without persistent neurological symptoms. In patients with available onset and follow-up samples, a significant (p < 0.001) decrease of NfL levels was observed and was more evident in patients with a severe acute disease. Despite the common persistence of neurological symptoms, COVID-19 survivors do not show active axonal damage, which seems a peculiar feature of acute SARS-CoV-2 infection.

Chronic fatigue syndrome: an emerging sequela in COVID-19 survivors?

SARS-CoV-2 survivors may report persistent symptoms that resemble myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). We explored (a) ME/CFS-like symptom prevalence and (b) whether axonal, inflammatory, and/or lung changes may contribute to ME/CFS-like symptoms in SARS-CoV-2 survivors through clinical, neuropsychiatric, neuropsychological, lung function assessment, and serum neurofilament light chain, an axonal damage biomarker. ME/CFS-like features were found in 27% of our sample. ME/CFS-like group showed worse sleep quality, fatigue, pain, depressive symptoms, subjective cognitive complaints, Borg baseline dyspnea of the 6-min walking test vs. those without ME/CFS-like symptoms. These preliminary findings raise concern on a possible future ME/CFS-like pandemic in SARS-CoV-2 survivors.

Long-Term Patient-Centred Follow-up in a Prospective Cohort of Patients with COVID-19.

INTRODUCTION: To better define COVID-19 long-term impact we prospectively analysed patient-centred outcomes, including general health and symptom duration. METHODS: Barthel index (BI), St. George's Respiratory Questionnaire adapted to patients with COVID-19 (aSGRQ) and WHO Clinical Progression Scale (CPS) were measured at enrolment and at 6 weeks from the onset of symptoms. Persistence of most frequently reported symptoms was assessed at 6 weeks and, among symptomatic patients, at 12 weeks from the onset of symptoms. Predictors of impaired general health over time were identified using an ordinal multilevel multivariate model. RESULTS: A total of 448 patients (55% men, median age 56 years) were enrolled. WHO-CPS showed mild, moderate and severe disease in 48%, 42% and 10% of patients at admission and mild disease in all patients at follow-up, respectively. BI and aSGRQ were normal in 96% and 93% patients before COVID-19 but only in 47% and 16% at COVID-19 diagnosis and in 87% and 65% at 6-week follow-up. Male gender was identified by all three assessments as a predictor of impaired general health (BI, OR 2.14, p < 0.0001; aSGRQ, OR 0.53, p = 0.003; WHO-CPS, OR 1.56, p = 0.01). Other predictors included age, ICU admission and comorbidities (e.g. cardiovascular disease and cancer) for BI, hospital admission for aSGRQ, age and presence of comorbidities for WHO-CPS. At 6- and 12-week follow-up, 39% and 20% of patients, respectively, were still reporting symptoms. Fatigue and breathlessness were the most frequently reported symptoms. CONCLUSIONS: Long-term follow-up facilitates the monitoring of health impairment and symptom persistence and can contribute to plan tailored interventions.

Clinical factors associated with death in 3044 COVID-19 patients managed in internal medicine wards in Italy: results from the SIMI-COVID-19 study of the Italian Society of Internal Medicine (SIMI).

During the COVID-19 2020 outbreak, a large body of data has been provided on general management and outcomes of hospitalized COVID-19 patients. Yet, relatively little is known on characteristics and outcome of patients managed in Internal Medicine Units (IMU). To address this gap, the Italian Society of Internal Medicine has conducted a nationwide cohort multicentre study on death outcome in adult COVID-19 patients admitted and managed in IMU. This study assessed 3044 COVID-19 patients at 41 referral hospitals across Italy from February 3rd to May 8th 2020. Demographics, comorbidities, organ dysfunction, treatment, and outcomes including death were assessed. During the study period, 697 patients (22.9%) were transferred to intensive care units, and 351 died in IMU (death rate 14.9%). At admission, factors independently associated with in-hospital mortality were age (OR 2.46, p = 0.000), productive cough (OR 2.04, p = 0.000), pre-existing chronic heart failure (OR 1.58, p = 0.017) and chronic obstructive pulmonary disease (OR 1.17, p = 0.048), the number of comorbidities (OR 1.34, p = 0.000) and polypharmacy (OR 1.20, p = 0.000). Of note, up to 40% of elderly patients did not report fever at admission. Decreasing PaO2/FiO2 ratio at admission was strongly inversely associated with survival. The use of conventional oxygen supplementation increased with the number of pre-existing comorbidities, but it did not associate with better survival in patients with PaO2/FiO2 ratio < 100. The latter, significantly benefited by the early use of non-invasive mechanical ventilation. Our study identified PaO2/FiO2 ratio at admission and comorbidity as the main alert signs to inform clinical decisions and resource allocation in non-critically ill COVID-19 patients admitted to IMU.

Importance of Cardiopulmonary Exercise Testing amongst Subjects Recovering from COVID-19.

The cardiopulmonary exercise test (CPET) provides an objective assessment of ventilatory limitation, related to the exercise minute ventilation (VE) coupled to carbon dioxide output (VCO2) (VE/VCO2); high values of VE/VCO2 slope define an exercise ventilatory inefficiency (EVin). In subjects recovered from hospitalised COVID-19, we explored the methodology of CPET in order to evaluate the presence of cardiopulmonary alterations. Our prospective study (RESPICOVID) has been proposed to evaluate pulmonary damage's clinical impact in post-COVID subjects. In a subgroup of subjects (RESPICOVID2) without baseline confounders, we performed the CPET. According to the VE/VCO2 slope, subjects were divided into having EVin and exercise ventilatory efficiency (EVef). Data concerning general variables, hospitalisation, lung function, and gas-analysis were also collected. The RESPICOVID2 enrolled 28 subjects, of whom 8 (29%) had EVin. As compared to subjects with EVef, subjects with EVin showed a reduction in heart rate (HR) recovery. VE/VCO2 slope was inversely correlated with HR recovery; this correlation was confirmed in a subgroup of older, non-smoking male subjects, regardless of the presence of arterial hypertension. More than one-fourth of subjects recovered from hospitalised COVID-19 have EVin. The relationship between EVin and HR recovery may represent a novel hallmark of post-COVID cardiopulmonary alterations.

Residual Lung Function Impairment Is Associated with Hyperventilation in Patients Recovered from Hospitalised COVID-19: A Cross-Sectional Study.

Patients who have recovered from COVID-19 show persistent symptoms and lung function alterations with a restrictive ventilatory pattern. Few data are available evaluating an extended period of COVID-19 clinical progression. The RESPICOVID study has been designed to evaluate patients' pulmonary damage previously hospitalised for interstitial pneumonia due to COVID-19. We focused on the arterial blood gas (ABG) analysis variables due to the initial observation that some patients had hypocapnia (arterial partial carbon dioxide pressure-PaCO2 ≤ 35 mmHg). Therefore, we aimed to characterise patients with hypocapnia compared to patients with normocapnia (PaCO2 > 35 mmHg). Data concerning demographic and anthropometric variables, clinical symptoms, hospitalisation, lung function and gas-analysis were collected. Our study comprised 81 patients, of whom 19 (24%) had hypocapnia as compared to the remaining (n = 62, 76%), and defined by lower levels of PaCO2, serum bicarbonate (HCO3-), carbon monoxide diffusion capacity (DLCO), and carbon monoxide transfer coefficient (KCO) with an increased level of pH and arterial partial oxygen pressure (PaO2). KCO was directly correlated with PaCO2 and inversely with pH. In our preliminary report, hypocapnia is associated with a residual lung function impairment in diffusing capacity. We focus on ABG analysis's informativeness in the follow-up of post-COVID patients.

Clinical risk scores for the early prediction of severe outcomes in patients hospitalized for COVID-19.

Coronavirus disease of 2019 (COVID-19) is associated with severe acute respiratory failure. Early identification of high-risk COVID-19 patients is crucial. We aimed to derive and validate a simple score for the prediction of severe outcomes. A retrospective cohort study of patients hospitalized for COVID-19 was carried out by the Italian Society of Internal Medicine. Epidemiological, clinical, laboratory, and treatment variables were collected at hospital admission at five hospitals. Three algorithm selection models were used to construct a predictive risk score: backward Selection, Least Absolute Shrinkage and Selection Operator (LASSO), and Random Forest. Severe outcome was defined as the composite of need for non-invasive ventilation, need for orotracheal intubation, or death. A total of 610 patients were included in the analysis, 313 had a severe outcome. The subset for the derivation analysis included 335 patients, the subset for the validation analysis 275 patients. The LASSO selection identified 6 variables (age, history of coronary heart disease, CRP, AST, D-dimer, and neutrophil/lymphocyte ratio) and resulted in the best performing score with an area under the curve of 0.79 in the derivation cohort and 0.80 in the validation cohort. Using a cut-off of 7 out of 13 points, sensitivity was 0.93, specificity 0.34, positive predictive value 0.59, and negative predictive value 0.82. The proposed score can identify patients at low risk for severe outcome who can be safely managed in a low-intensity setting after hospital admission for COVID-19.

Spotlight on Cardiovascular Scoring Systems in Covid-19: Severity Correlations in Real-world Setting.

OBJECTIVES AND METHODS: the current understanding of the interplay between cardiovascular (CV) risk and Covid-19 is grossly inadequate. CV risk-prediction models are used to identify and treat high risk populations and to communicate risk effectively. These tools are unexplored in Covid-19. The main objective is to evaluate the association between CV scoring systems and chest X ray (CXR) examination (in terms of severity of lung involvement) in 50 Italian Covid-19 patients. Results only the Framingham Risk Score (FRS) was applicable to all patients. The Atherosclerotic Cardiovascular Disease Score (ASCVD) was applicable to half. 62% of patients were classified as high risk according to FRS and 41% according to ASCVD. Patients who died had all a higher FRS compared to survivors. They were all hypertensive. FRS≥30 patients had a 9.7 higher probability of dying compared to patients with a lower FRS. We found a strong correlation between CXR severity and FRS and ASCVD (P < 0.001). High CV risk patients had consolidations more frequently. CXR severity was significantly associated with hypertension and diabetes. 71% of hypertensive patients' CXR and 88% of diabetic patients' CXR had consolidations. Patients with diabetes or hypertension had 8 times greater risk of having consolidations. CONCLUSIONS: High CV risk correlates with more severe CXR pattern and death. Diabetes and hypertension are associated with more severe CXR. FRS offers more predictive utility and fits best to our cohort. These findings may have implications for clinical practice and for the identification of high-risk groups to be targeted for the vaccine precedence.

Asthma in a large COVID-19 cohort: Prevalence, features, and determinants of COVID-19 disease severity.

BACKGROUND: Asthma prevalence among COVID-19 patients seems to be surprisingly low. However the clinical profile of COVID-19 asthmatic patients and potential determinants of higher susceptibility/worse outcome have been scarcely investigated. We aimed to describe the prevalence and features of asthmatic patients hospitalized for COVID-19 and to explore the association between their clinical asthma profile and COVID-19 severity. METHODS: Medical records of patients admitted to COVID-Units of six Italian cities major hospitals were reviewed. Demographic and clinical data were analyzed and compared according to the COVID-19 outcome (death/need for ventilation vs discharge at home without requiring invasive procedures). RESULTS: Within the COVID-Units population (n = 2000) asthma prevalence was 2.1%. Among the asthmatics the mean age was 61.1 years and 60% were females. Around half of patients were atopic, blood eosinophilia was normal in most of patients. An asthma exacerbation in the 6 months before the Covid-Unit admittance was reported by 18% of patients. 24% suffered from GINA step 4-5 asthma, and 5% were under biologic treatment. 31% of patients were not on regular treatment and a negligible use of oral steroid was recorded. Within the worse outcome group, a prevalence of males was detected (64 vs 29%, p = 0.026); they suffered from more severe asthma (43 vs 14%, p = 0.040) and were more frequently current or former smokers (62 vs 25%, p = 0.038). CONCLUSIONS: Our report, the first including a large COVID-19 hospitalized Italian population, confirms the low prevalence of asthma. On the other side patients with GINA 4/5 asthma, and those not adequately treated, should be considered at higher risk.

Cytomegalovirus-Induced Gastrointestinal Bleeding and Pancreatitis Complicating Severe Covid-19 Pneumonia: A Paradigmatic Case.

COVID-19 is a new pandemic disease whose pathophysiology and clinical description are still not completely defined. Besides respiratory symptoms and fever, gastrointestinal (GI) symptoms (including especially anorexia, diarrhea, and abdominal pain) represent the most frequent clinical manifestations. Emerging data point out that severe SARS-CoV-2 infection causes an immune dysregulation, which in turn may favor other infections. Here we describe a patient with severe COVID-19 pneumonia who developed in the resolving phase abdominal pain associated with cytomegalovirus (CMV)-induced duodenitis with bleeding and pancreatitis. A high level of suspicion toward multiple infections, including CMV, should be maintained in COVID-19 patients with heterogeneous clinical manifestations.