Innate immune deficiencies are associated with severity and poor prognosis in patients with COVID-19

COVID-19 can cause acute respiratory distress syndrome, leading to death in many individuals. Evidence of a deleterious role of the innate immune system is accumulating, but the precise mechanisms involved remain unclear. In this study, we investigated the links between circulating innate phagocytes and severity in COVID-19 patients. We performed in-depth phenotyping of neutrophil and monocyte subpopulations and measured soluble activation markers in plasma. Additionally, anti-microbial functions (phagocytosis, oxidative burst, and NETosis) were evaluated on fresh cells from patients. Neutrophils and monocytes had a strikingly disturbed phenotype, and elevated concentrations of activation markers (calprotectin, myeloperoxidase, and neutrophil extracellular traps) were measured in plasma. Critical patients had increased CD13low immature neutrophils, LOX-1 + and CCR5 + immunosuppressive neutrophils, and HLA-DRlow downregulated monocytes. Markers of immature and immunosuppressive neutrophils were strongly associated with severity. Moreover, neutrophils and monocytes of critical patients had impaired antimicrobial functions, which correlated with organ dysfunction, severe infections, and mortality. Together, our results strongly argue in favor of a pivotal role of innate immunity in COVID-19 severe infections and pleads for targeted therapeutic options.

Plitidepsin as a successful rescue treatment for prolonged viral SARS-CoV-2 replication in a patient with previous anti-CD20 monoclonal antibody-mediated B cell depletion and chronic lymphocytic leukemia

Background There is an urgent need for highly efficacious antiviral therapies in immunosuppressed hosts who develop coronavirus disease (COVID-19), with special concern for those affected by hematological malignancies. Case presentation Here, we report the case of a 75-year-old male with chronic lymphocytic leukemia who was deficient in CD19+CD20+ B-lymphocyte populations due to previous treatment with anti-CD20 monoclonal antibodies. The patient presented with severe COVID-19 pneumonia due to prolonged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and was treated with two courses of the antiviral plitidepsin on a compassionate use basis. The patient subsequently achieved an undetectable viral load, and his pneumonia resolved. Conclusions Treatment with plitidepsin was well-tolerated without any further hematological or cardiovascular toxicities. This case further supports plitidepsin as a potential antiviral drug in SARS-CoV-2 patients affected by immune deficiencies and hematological malignancies.

Pre-Existing Hypertension Is Related with Disproportions in T-Lymphocytes in Older Age

Age-related immune deficiencies increase the risk of comorbidities and mortality. This study evaluated immunosenescence patterns by flow cytometry of naïve and memory T cell subpopulations and the immune risk profile (IRP), expressed as the CD4/CD8 ratio and IgG CMV related to comorbidities. The disproportions in naïve and memory T cells, as well as in the CD4/CD8 ratio, were analysed in 99 elderly individuals (71.9 ± 5.8 years) diagnosed with hypertension (n = 51) or without hypertension (n = 48), using an eight-parameter flow cytometer. The percentage of CD4+ T lymphocytes was significantly higher in hypertensive than other individuals independently from CMV infections, with approximately 34% having CD4/CD8 > 2.5, and only 4% of the elderly with hypertension having CD4/CD8 < 1. The elderly with a normal BMI demonstrated the CD4/CD8 ratio ≥ 1 or ≤ 2.5, while overweight and obese participants showed a tendency to an inverted CD4/CD8 ratio. CD4/CD8 ratio increased gradually with age and reached the highest values in participants aged >75 years. The decline in CD4+ naïve T lymphocytes was more prominent in IgG CMV+ men when compared to IgG CMV+ women. The changes in naïve and memory T lymphocyte population, CD4/CD8, and CMV seropositivity included in IRP are important markers of health status in the elderly that are dependent on hypertension.

A Review of Primary Immunodeficiency Diseases with Skin Manifestations

Introduction: Primary immunodeficiencies (PID) are rare heterogeneous disorders with defects in which one or more components of the immune system are malfunctioning. Clinical presentations of the patients according to type of immunodeficiency are variable. The majority of these patients are susceptible to infections depending on the type of disorder. In these patients, one of the most important and common symptoms is a skin manifestation that in many cases helps to diagnose the disease. Skin symptoms can include infectious-inflammatory-autoimmune-allergic manifestations and malignancies. In some cases, skin involvement can be the initial manifestation of immunodeficiency diseases, so understanding the relationship between the type of primary immunodeficiency and the type of skin involvement is very important in diagnosing the disease. The majorities of skin diseases are not pathogenomonic in primary immunodeficiencies and may be seen in other diseases with normal levels of immunity. However, there are numerous skin findings that are so characteristic of immunodeficiency diseases that it is necessary to evaluate the immune system. Conclusion: Skin is an organ that may be involved in many diseases, including primary immunodeficiency. Sometimes skin is the first organ involved in immune deficiencies. Therefore, recognizing skin manifestations in these patients is one of the most important factors in early diagnosis of these people.

Multisystem Inflammatory-like Syndrome in a Child Following COVID-19 mRNA Vaccination

A 12-year-old male was presented to the hospital with acute encephalopathy, headache, vomiting, diarrhea, and elevated troponin after recent COVID-19 vaccination. Two days prior to admission and before symptom onset, he received the second dose of the Pfizer-BioNTech COVID-19 vaccine. Symptoms developed within 24 h with worsening neurologic symptoms, necessitating admission to the pediatric intensive care unit. Brain magnetic resonance imaging within 16 h of admission revealed a cytotoxic splenial lesion of the corpus callosum (CLOCC). Nineteen days prior to admission, he developed erythema migrans, and completed an amoxicillin treatment course for clinical Lyme disease. However, Lyme antibody titers were negative on admission and nine days later, making active Lyme disease an unlikely explanation for his presentation to hospital. An extensive workup for other etiologies on cerebrospinal fluid and blood samples was negative, including infectious and autoimmune causes and known immune deficiencies. Three weeks after hospital discharge, all of his symptoms had dissipated, and he had a normal neurologic exam. Our report highlights a potential role of mRNA vaccine-induced immunity leading to MIS-C-like symptoms with cardiac involvement and a CLOCC in a recently vaccinated child and the complexity of establishing a causal association with vaccination. The child recovered without receipt of immune modulatory treatment.

Rapid longitudinal SARS-CoV-2 intra-host emergence of novel haplotypes regardless of immune deficiencies

On February 2020, the municipality of Vo’, a small town near Padua (Italy), was quarantined due to the first coronavirus disease 19 (COVID-19)-related death detected in Italy. The entire population was swab tested in two sequential surveys. Here we report the analysis of the viral genomes, which revealed that the unique ancestor haplotype introduced in Vo’ belongs to lineage B and, more specifically, to the subtype found at the end of January 2020 in two Chinese tourists visiting Rome and other Italian cities, carrying mutations G11083T and G26144T. The sequences, obtained for 87 samples, allowed us to investigate viral evolution while being transmitted within and across households and the effectiveness of the non-pharmaceutical interventions implemented in Vo’. We report, for the first time, evidence that novel viral haplotypes can naturally arise intra-host within an interval as short as two weeks, in approximately 30% of the infected individuals, regardless of symptoms severity or immune system deficiencies. Moreover, both phylogenetic and minimum spanning network analyses converge on the hypothesis that the viral sequences evolved from a unique common ancestor haplotype, carried by an index case. The lockdown extinguished both viral spread and the emergence of new variants, confirming the efficiency of this containment strategy. The information gathered from household was used to reconstructs possible transmission events.

Characteristics and clinical outcomes of patients hospitalized with laboratory-confirmed COVID-19—Puerto Rico, March–August 2020

Hispanics are the majority ethnic population in Puerto Rico where we reviewed charts of 109 hospitalized COVID-19 patients to better understand demographic and clinical characteristics of COVID-19 and determine risk factors for poor outcomes. Eligible medical records of hospitalized patients with confirmed COVID-19 illnesses were reviewed at four participating hospitals in population centers across Puerto Rico and data were abstracted that described the clinical course, interventions, and outcomes. We found hospitalized patients had a median of 3 underlying conditions with obesity and diabetes as the most frequently reported conditions. Intensive care unit (ICU) admission occurred among 28% of patients and 18% of patients died during the hospitalization. Patients 65 or older or with immune deficiencies had a higher risk for death. Common symptoms included cough, dyspnea, and fatigue; less than half of patients in the study reported fever which was less frequent than reported elsewhere in the literature. It is important for interventions within Hispanic communities to protect high-risk groups.

PREPARATIVE ISOLATION OF SPECIFIC ANTIGENS OF FULL CELL LYSATE M. BOVIS

Bovine tuberculosis is a serious problem for agriculture all over the world and causes huge economic losses. At the same time, infections caused by Mycobacterium bovis not only affect animal husbandry and the food industry, but also pose a threat to public health, as M. bovis is often isolated as a pathogen of tuberculosis, especially in patients with various immune deficiencies. The situation is aggravated by the lack of simple and accessible methods for diagnosing tuberculosis in cattle, which significantly impedes the monitoring of infection and the application of appropriate preventive measures. Serological tests, due to their relatively cheap cost, rapidity, rather high sensitivity and specificity, are able to compete with the allergic test during mass examinations of cows. In the present study, we present the results on the study of the antigenic structure of mycobacteria and the isolation of the most specific antigenic components from the lysate of the M. Bovis cell wall destroyed on the Fast Prep 24 device. The developed method allows obtaining a serologically active antigenic fraction with a high degree of purity with a molecular weight of 28 kDa.

Atopic manifestations are underestimated clinical features in various primary immunodeficiency disease phenotypes

Background: Atopic manifestations are describedas clinical feature of variousprimary immunodeficiency disease (PID) phenotypes and in particular frequently reported in the combined immune deficiencies. The prevalence of atopic manifestations in other PIDs remains largely unknown. Objective: To evaluate the prevalence of atopic manifestations in other PIDs and to identify in which PIDsatopic manifestations are most common in order to improve patient care. Methods: A partner-controlled questionnaire-based study was performed in pediatric and adult PID patients. Subsequently, data of diagnostic tests for atopic manifestations (i.e. diagnostic criteria for AD, spirometry, specific IgE against food and inhalant allergens) were collected in adult patients to confirm patient-reported atopic manifestations. Results: Forty-seven children and 206 adults with PIDs, and 56 partner-controls completed the questionnaire. Thirty-five (74.5%) pediatric and 164 (79.6%) adult patients reported to have ever experienced one or more atopic manifestations compared with 28 (50.0%) partner-controls. In adult patients vs. partner-controls, prevalence of atopic dermatitis was 49.5% vs. 27.3% (p=0.003), food allergy10.7% vs. 1.9% (p=0.031), asthma 55.7% vs. 14.8% (p<0.001) and allergic rhinitis 49.8% vs. 21.8% (p<0.001).The frequency of current atopic manifestationsreported by patients washigher than the prevalence based on diagnostic tests (atopic dermatitis 11.2%, food allergy 1.9%, asthma 16.4% and allergic rhinitis 11.5%). Conclusions: Atopic manifestations are prevalent clinicalfeatures in a large spectrum of PIDs and in our cohort frequently present in patients with combined immune deficiencies and predominant antibody deficiencies. Evaluation of atopic manifestations should be considered in patients with PIDs.