Struggling with COVID-19 in Adult Inborn Errors of Immunity Patients: A Case Series of Combination Therapy and Multiple Lines of Therapy for Selected Patients

Background: The SARS-CoV-2 infection is now a part of the everyday lives of immunocompromised patients, but the choice of treatment and the time of viral clearance can often be complex, exposing patients to possible complications. The role of the available antiviral and monoclonal therapies is a matter of debate, as are their effectiveness and potential related adverse effects. To date, in the literature, the amount of data on the use of combination therapies and on the multiple lines of anti-SARS-CoV-2 therapy available to the general population and especially to inborn error of immunity (IEI) patients is small. Methods: Here, we report a case series of five adult IEI patients managed as inpatients at three Italian IEI referral centers (Rome, Treviso, and Cagliari) treated with combination therapy or multiple therapeutic lines for SARS-CoV-2 infection, such as monoclonal antibodies (mAbs), antivirals, convalescent plasma (CP), mAbs plus antiviral, and CP combined with antiviral. Results: This study may support the use of combination therapy against SARS-CoV-2 in complicated IEI patients with predominant antibody deficiency and impaired vaccine response

A beacon in the dark: COVID-19 course in CVID patients from two European countries: Different approaches, similar outcomes

Background: CVID patients present an increased risk of prolonged SARS-CoV-2 infection and re-infection and a higher COVID-19-related morbidity and mortality compared to the general population. Since 2021, different therapeutic and prophylactic strategies have been employed in vulnerable groups (vaccination, SARS-CoV-2 monoclonal antibodies and antivirals). The impact of treatments over the last 2 years has not been explored in international studies considering the emergence of viral variants and different management between countries. Methods: A multicenter retrospective/prospective real-life study comparing the prevalence and outcomes of SARS-CoV-2 infection between a CVID cohort from four Italian Centers (IT-C) and one cohort from the Netherlands (NL-C), recruiting 773 patients. Results: 329 of 773 CVID patients were found positive for SARS-CoV-2 infection between March 1st, 2020 and September 1st 2022. The proportion of CVID patients infected was comparable in both national sub-cohorts. During all waves, chronic lung disease, “complicated” phenotype, chronic immunosuppressive treatment and cardiovascular comorbidities impacted on hospitalization, whereas risk factors for mortality were older age, chronic lung disease, and bacterial superinfections. IT-C patients were significantly more often treated, both with antivirals and mAbs, than NL-C patients. Outpatient treatment, available only in Italy, started from the Delta wave. Despite this, no significant difference was found for COVID-19 severity between the two cohorts. However, pooling together specific SARS-CoV-2 outpatient treatments (mAbs and antivirals), we found a significant effect on the risk of hospitalization starting from Delta wave. Vaccination with ≥ 3 doses shortened RT-PCR positivity, with an additional effect only in patients receiving antivirals. Conclusions: The two sub-cohorts had similar COVID-19 outcomes despite different treatment approaches. This points out that specific treatment should now be reserved for selected subgroups of CVID patients, based on pre-existing conditions

Granulomatous Lymphocytic Interstitial Lung Disease (GLILD) in Common Variable Immunodeficiency (CVID): A Multicenter Retrospective Study of Patients From Italian PID Referral Centers

Background: Granulomatous and Lymphocytic Interstitial Lung Diseases (GLILD) is a severe non-infectious complication of Common Variable Immunodeficiency (CVID), often associated with extrapulmonary involvement. Due to a poorly understood pathogenesis, GLILD diagnosis and management criteria still lack consensus. Accordingly, it is a relevant cause of long-term loss of respiratory function and is closely associated with a markedly reduced survival. The aim of this study was to describe clinical, immunological, laboratory and functional features of GLILD, whose combination in a predictive model might allow a timely diagnosis. Methods: In a multicenter retrospective cross-sectional study we enrolled 73 CVID patients with radiologic features of interstitial lung disease (ILD) associated to CVID (CVID-ILD) and 125 CVID patients without ILD (controls). Of the 73 CVID-ILD patients, 47 received a definite GLILD diagnosis while 26 received a clinical-radiologic diagnosis of CVID related ILD defined as uILD. Results: In GLILD group we found a higher prevalence of splenomegaly (84.8 vs. 39.2%), autoimmune cytopenia (59.6 vs. 6.4%) and bronchiectasis (72.3 vs. 28%), and lower IgA and IgG serum levels at CVID diagnosis. GLILD patients presented lower percentage of switched-memory B cells and marginal zone B cells, and a marked increase in the percentage of circulating CD21lo B cells (14.2 vs. 2.9%). GLILD patients also showed lower total lung capacity (TLC 87.5 vs. 5.0%) and gas transfer (DLCO 61.5 vs. 5.0%) percent of predicted. By univariate logistic regression analysis, we found IgG and IgA levels at CVID diagnosis, presence of splenomegaly and autoimmune cytopenia, CD21lo B cells percentage, TLC and DCLO percent of predicted to be associated to GLILD. The joint analysis of four variables (CD21lo B cells percentage, autoimmune cytopenia, splenomegaly and DLCO percent of predicted), together in a multiple logistic regression model, yielded an area under the ROC curve (AUC) of 0.98 (95% CI: 0.95-1.0). The AUC was only slightly modified when pooling together GLILD and uILD patients (0.92, 95% CI: 0.87-0.97). Conclusions: we propose the combination of two clinical parameters (splenomegaly and autoimmune cytopenia), one lung function index (DLCO%) and one immunologic variable (CD21lo%) as a promising tool for early identification of CVID patients with interstitial lung disease, limiting the use of aggressive diagnostic procedures

Use of RAAS Inhibitors and Risk of Clinical Deterioration in COVID-19: Results From an Italian Cohort of 133 Hypertensives.

This is a pre-copyedited, author-produced version of an article accepted for publication in American Journal of Hypertension, following peer review. The version of record: Carla Felice, Chiara Nardin, Gian Luca Di Tanna, Ugo Grossi, Enrico Bernardi, Luca Scaldaferri, Micaela Romagnoli, Luca Tonon, Paola Cavasin, Simone Novello, Riccardo Scarpa, Antonio Farnia, Ernesto De Menis, Roberto Rigoli, Francesco Cinetto, Paolo Pauletto, Carlo Agostini, Marcello Rattazzi, Use of RAAS Inhibitors and Risk of Clinical Deterioration in COVID-19: Results From an Italian Cohort of 133 Hypertensives, American Journal of Hypertension, hpaa096, doi: 10.1093/ajh/hpaa096 is available online at:  https://doi.org/10.1093/ajh/hpaa096BACKGROUND: The effect of chronic use of renin-angiotensin-aldosterone system (RAAS) inhibitors on the severity of COVID-19 infection is still unclear in patients with hypertension. We aimed to investigate the association between chronic use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) and COVID-19-related outcomes in hypertensive patients. METHODS: A single-center study was conducted on 133 consecutive hypertensive subjects presenting to the emergency department with acute respiratory symptoms and/or fever who were diagnosed with COVID-19 infection between 9 and 31 March 2020. RESULTS: All patients were grouped according to their chronic antihypertensive medications (ACEIs, N = 40; ARBs, N = 42; not on RAAS inhibitors, N = 51). There was no statistical difference between ACEIs and ARBs groups in terms of hospital admission rate, oxygen therapy, and need for noninvasive ventilation. Patients chronically treated with RAAS inhibitors showed a significantly lower rate of admission to semi-intensive/intensive care units, when compared with the non-RAAS population (odds ratio (OR) 0.25, confidence interval (CI) 95% 0.09-0.66, P = 0.006). Similarly, the risk of mortality was lower in the former group, although not reaching statistical significance (OR 0.56, CI 95% 0.17-1.83, P = 0.341). CONCLUSIONS: Our data suggest that chronic use of RAAS inhibitors does not negatively affect clinical course of COVID-19 in hypertensive patients. Further studies are needed to confirm this finding and determine whether RAAS inhibitors may have a protective effect on COVID-19-related morbidity and mortality

Comorbidities of sarcoidosis

Sarcoidosis is a heterogeneous disease, which can affect virtually every body organ, even though lungs and intra thoracic lymph nodes are almost universally affected. The presence of noncaseating granulomas is the histopathological hallmark of the disease, and clinical picture depends on the organs affected. Data about interaction between sarcoidosis and comorbidities, such as cardiovascular and pulmonary diseases, autoimmune disorders, malignancy and drug-related adverse events are limited. Several lung conditions can be associated with sarcoidosis, such as pulmonary hypertension and fibrosis, making it difficult sometimes the differentiation between complications and distinctive pathologies. Their coexistence may complicate the diagnosis of sarcoidosis and contribute to the highly variable and unpredictable natural history, particularly if several diseases are recognised. A thorough assessment of specific disorders that can be associated with sarcoidosis should always be carried out, and future studies will need to evaluate sarcoidosis not only as a single disorder, but also in the light of possible concomitant conditions.Key messages Comorbidities in sarcoidosis are common, especially cardiovascular and pulmonary diseases. In the diagnostic workup, a distinction must be made between sarcoidosis-related complaints and complaints caused by other separate disorders. It can be very difficult to distinguish between complications of sarcoidosis and other concomitant conditions. The coexistence of multiple conditions may complicate the diagnosis of sarcoidosis, affect its natural course and response to treatment

TLR7 Gln11Leu single nucleotide polymorphism in patients with sarcoidosis

Sarcoidosis is a multi-factorial systemic disease with increased activity of the cellular immune components which is responsible of the formation of non-caseating granulomas in involved organs. Recent views on the etiology indicate interactions between inherited susceptibility and environmental or lifestyle factors. Concerning genes that may influence susceptibility to sarcoidosis Toll-like receptors (TLRs) may represent plausible candidates. In this present study, we investigated the X-linked TLR7 rs179008/Gln11Leu polymorphism situated on exon 3. SNP genotyping of the TLR7 exon polymorphism was performed by TaqMan allelic discrimination using the StepOnePlus™ Real-Time PCR System (Applied Biosystems). In females, the incidence of the AT genotypes of the polymorphism was significantly lower in sarcoidosis patients compared to control subjects  (P=0.0001). We could observe in control subjects a significant preponderance of the T allele of the TLR7 rs179008/Gln11Leu polymorphism compared to sarcoidosis female patients (P=0.008). In males, no significant differences between patients and controls emerged in allele frequencies of the TLR7 rs179008/Gln11Leu polymorphism. The presence of the TLR7 rs179008/Gln11Leu polymorphism in sarcoidosis may determine an alteration of TLR7 function hampering the signaling pathway involved in the onset of both cellular and humoral autoimmunity. This is consistent with the view that in some circumstances genetic mutations affecting components of the immune system can prevent systemic autoimmunity

\ufeffTLR7 Gln11Leu single nucleotide polymorphism in patients with sarcoidosis.

Sarcoidosis is a multi-factorial systemic disease with increased activity of the cellular immune components which is responsible of the formation of non-caseating granulomas in involved organs. Recent views on the etiology indicate interactions between inherited susceptibility and environmental or lifestyle factors. Concerning genes that may influence susceptibility to sarcoidosis Toll-like receptors (TLRs) may represent plausible candidates. In this present study, we investigated the X-linked TLR7 rs179008/Gln11Leu polymorphism situated on exon 3. SNP genotyping of the TLR7 exon polymorphism was performed by TaqMan allelic discrimination using the StepOnePlus\u2122 Real-Time PCR System (Applied Biosystems). In females, the incidence of the AT genotypes of the polymorphism was significantly lower in sarcoidosis patients compared to control subjects (P=0.0001).We could observe in control subjects a significant preponderance of the T allele of the TLR7 rs179008/Gln11Leu polymorphism compared to sarcoidosis female patients (P=0.008). In males, no significant differences between patients and controls emerged in allele frequencies of the TLR7 rs179008/Gln11Leu polymorphism. The presence of the TLR7 rs179008/Gln11Leu polymorphism in sarcoidosis may determine an alteration of TLR7 function hampering the signaling pathway involved in the onset of both cellular and humoral autoimmunity. This is consistent with the view that in some circumstances genetic mutations affecting components of the immune system can prevent systemic autoimmunity

The Effect of Isotonic Saline Nasal Lavages in Improving Symptoms in SARS-CoV-2 Infection: A Case-Control Study

Background: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) mainly colonizes nasopharynx. In upper airways acute infections, e.g., the common cold, saline nasal irrigations have a significant efficacy in reducing symptoms. The present study aimed to test the efficacy of nasal lavages in upper airways symptoms of Coronavirus Disease 2019 (COVID-19). Methods: A series of consecutive adult subjects who tested positive for SARS-CoV-2 from December 2020 to February 2021 performed daily nasal lavages with saline solution (Lavonase®—Purling, Lugo di Romagna, Italy) for 12 days, starting on the day after the SARS-CoV-2 positive swab. A control group included a historical series of patients who were infected in February-March 2020 and who did not perform lavages. An ad hoc questionnaire regarding symptoms was administered to each subjects at base-line and 10 days after diagnosis (i.e., on the same day of the control swab) in both cases and controls. Results: A total of 140 subjects were enrolled. 68 participants in the treatment group and 72 in the control group were included. 90% of respondents declared the lavages were simple to use and 70% declared they were satisfied. Symptoms of blocked nose, runny nose, or sneezing decreased by an average of 24.7% after the treatment. Blocked nose and sneezing increased in the same period of time in the control group. Ears and eyes symptoms, anosmia/ageusia symptoms, and infection duration (10.53 days in the treatment group and 10.48 days in the control group) didn't vary significantly among the two groups. Conclusion: Nasal lavages resulted to significantly decrease nasal symptoms in newly diagnosed SARS-CoV-2 patients. These devices proved to be well-tolerated and easy to be used. Further studies on a larger number of subjects are needed in order to possibly confirm these preliminary results