Health Care Utilisation in a Cohort of Patients with Primary and Secondary Antibody Deficiency in the United Kingdom

Introduction: This study investigates the frequency of hospital attendances, emergency care attendances and geographical influences on service interaction in cohorts of patients with primary and secondary antibody deficiency, to inform future service planning and delivery.Methods: The COVID-19 in Antibody Deficiency (COV-AD) study was a United Kingdom study that enrolled 525 participants between April 2021 and September 2022. Data on health care utilisation was extracted from a screening cohort of participants at one participating site (Birmingham, UK). Hospital attendance (i.e. all outpatient and inpatient care episodes, including hospital-based IVIG treatment) and emergency care attendance patterns were analysed. Geographical differences in travel times to hospitals and associated costs were considered for all participants at all recruiting sites.Results: Individuals with antibody deficiency had a median of 7 hospital attendances per year. A diagnosis of secondary antibody deficiency, and antibody deficiency severe enough to require treatment with immunoglobulin replacement were associated with an increased frequency of hospital attendance. 12.7% of the cohort attended the Emergency Department at least once in the preceding twelve months. Individuals with secondary antibody deficiency were at greater risk of requiring emergency care over the preceding one-year and five-year periods. Individuals receiving subcutaneous immunoglobulin lived further from their local immunology centre and were more likely to engage with the COV-AD research study remotely, via dried blood spots sampling.Conclusion: This study highlights the utilisation of emergency and secondary care usage amongst patient with immunodeficiency and may inform service adaptation and development to better accommodate patient needs and circumstances

Current Practices and Considerations in Lung Biopsy for Suspected Granulomatous-Lymphocytic Interstitial Lung Disease: A Clinician Survey

Introduction: This study explores clinicians’ diagnostic practices and perceptions in the context of granulomatous-lymphocytic interstitial lung disease (GLILD), a pulmonary manifestation of common variable immunodeficiency disorder. The aim was to gain valuable insights into key aspects, such as the utilization of radiological features for diagnostic purposes, indications for lung biopsy, preferred biopsy techniques, and the relative importance of different histopathological findings in confirming GLILD. Method: A survey targeting expert clinicians was conducted, focusing on their experiences, practices, and attitudes towards lung biopsy in suspected GLILD cases. Results: The survey revealed that the majority of respondents accepted high-resolution computed tomography as a sufficient alternative to biopsy for making a probable GLILD diagnosis in most patients. There was a consensus among most respondents that the presence of extrapulmonary granulomatous disease is adequate for making a diagnosis of GLILD where the chest imaging and clinical picture are consistent. When a biopsy was recommended, there was notable variation in the preferred initial biopsy technique, with 35% favouring transbronchial biopsy. Conclusion: Our findings underscore the complexity of diagnosing GLILD, indicating varied clinician opinions on the necessity and efficacy of lung biopsies. They highlight the need for further research and the development of consistent diagnostic criteria and management protocols, ultimately aiming to enhance the accuracy and safety of GLILD diagnosis and treatment strategies

Quality of Life and Social and Psychological Outcomes in Adulthood Following Allogeneic HSCT in Childhood for Inborn Errors of Immunity

BACKGROUND: Hematopoietic stem cell transplant (HSCT) is well established as a corrective treatment for many inborn errors of immunity (IEIs) presenting in childhood. Due to improved techniques, more transplants are undertaken and patients are living longer. However, long-term complications can significantly affect future health and quality of life. Previous research has focused on short-term medical outcomes and little is known about health or psychosocial outcomes in adulthood. OBJECTIVE: This project aimed to ascertain the long-term social and psychological outcomes for adults who underwent HSCT for IEI during childhood. METHODS: Adult patients, who had all undergone HSCT for IEI during childhood at two specialist immunology services at least 5 years previously, were invited to participate in the study. Questionnaires and practical tasks assessed their current functioning and circumstances. Information was also gathered from medical notes. Data was compared with population norms and a control group of participant-nominated siblings or friends. RESULTS: Eighty-three patients and 46 matched controls participated in the study. Patients reported significantly better physical health-related quality of life than the general population norm, but significantly worse than matched controls. Patient's self-reported physical health status and the perceived impact of their physical health on everyday life were worse than matched controls and patients reported higher levels of anxiety and lower mood than the general population. For those where their IEI diagnosis was not associated with a learning disability, cognitive function was generally within the normal range. CONCLUSIONS: Patients who have had a HSCT in childhood report mixed psychosocial outcomes in adulthood. More research is needed to establish screening protocols and targeted interventions to maximize holistic outcomes. CLINICAL IMPLICATIONS: Screening for holistic needs and common mental health difficulties should be part of routine follow-up. Information should be provided to patients and families in order to support decision-making regarding progression to transplant and the early identification of any difficulties

Common variable immunodeficiency disorder-related liver disease is common and results in portal hypertension and an increased risk of death

Background: Common variable immunodeficiency disorder (CVID) manifests with recurrent infections and inflammatory complications, including liver disease. We report the clinical features, natural history, and outcomes of patients with CVID-related liver disease (CVID-rLD) from a tertiary immunology and hepatology center. // Methods: Two hundred eighteen patients were identified; CVID-rLD was defined by persistently abnormal liver function tests or evidence of chronic liver disease (CLD) or portal hypertension (PHTN) by radiological or endoscopic investigation, after exclusion of other causes. Patients with CVID-rLD were investigated and managed following a joint pathway between immunology and hepatology services. Data, including clinical parameters, investigations, and outcomes, were retrospectively collected. // Results: A total of 91/218 (42%) patients had evidence of CVID-rLD, and 40/91 (44%) had PHTN. Patients with CVID-rLD were more likely to have other noninfectious complications of CVID (85/91, 93.4% vs. 75/127, 59.1%, p<0.001) including interstitial lung disease, gut disease, and autoimmune cytopenias. Nodular regenerative hyperplasia (NRH) was identified in 63.8% of liver biopsies, and fibrosis in 95.3%. Liver stiffness measurements (LSMs) were frequently elevated (median 9.95 kPa), and elevated LSM was associated with PHTN. All-cause mortality was higher in those with CVID-rLD (24/91, 26.4% vs. 14/127, 11%, p=0.003), which was the only organ complication associated with mortality (HR 2.24, 1.06–4.74, p=0.04). Factors predicting mortality in CVID-rLD included PHTN, increasing fibrosis, and LSM. // Conclusions: Liver disease is a common complication of CVID as part of complex, multi-organ involvement and is associated with high rates of PHTN and an increased hazard of mortality

Persistent SARS-CoV-2 PCR Positivity Despite Anti-viral Treatment in Immunodeficient Patients

PURPOSE: COVID-19 infection in immunodeficient individuals can result in chronically poor health, persistent or relapsing SARS-CoV-2 PCR positivity, and long-term infectious potential. While clinical trials have demonstrated promising outcomes using anti-SARS-CoV-2 medicines in immunocompetent hosts, their ability to achieve sustained viral clearance in immunodeficient patients remains unknown. We therefore aimed to study long-term virological outcomes in patients treated at our centre. METHODS: We followed up immunocompromised inpatients treated with casirivimab-imdevimab (Ronapreve) between September and December 2021, and immunocompromised patients who received sotrovimab, molnupiravir, nirmatrelvir/ritonavir (Paxlovid), or no treatment from December 2021 to March 2022. Nasopharyngeal swab and sputum samples were obtained either in hospital or in the community until sustained viral clearance, defined as 3 consecutive negative PCR samples, was achieved. Positive samples were sequenced and analysed for mutations of interest. RESULTS: We observed sustained viral clearance in 71 of 103 patients, none of whom died. Of the 32/103 patients where sustained clearance was not confirmed, 6 died (between 2 and 34 days from treatment). Notably, we observed 25 cases of sputum positivity despite negative nasopharyngeal swab samples, as well as recurrence of SARS-CoV-2 positivity following a negative sample in 12 cases. Patients were then divided into those who cleared within 28 days and those with PCR positivity beyond 28 days. We noted lower B cell counts in the group with persistent PCR positivity (mean (SD) 0.06 (0.10) ×109/L vs 0.22 (0.28) ×109/L, p = 0.015) as well as lower IgA (median (IQR) 0.00 (0.00-0.15) g/L vs 0.40 (0.00-0.95) g/L, p = 0.001) and IgM (median (IQR) 0.05 (0.00-0.28) g/L vs 0.35 (0.10-1.10) g/L, p = 0.005). No differences were seen in CD4+ or CD8+ T cell counts. Antiviral treatment did not impact risk of persistent PCR positivity. CONCLUSION: Persistent SARS-CoV-2 PCR positivity is common among immunodeficient individuals, especially those with antibody deficiencies, regardless of anti-viral treatment. Peripheral B cell count and serum IgA and IgM levels are predictors of viral persistence

Autosomal Dominant STAT6 Gain of Function Causes Severe Atopy Associated with Lymphoma

The transcription factor STAT6 (Signal Transducer and Activator of Transcription 6) is a key regulator of Th2 (T-helper 2) mediated allergic inflammation via the IL-4 (interleukin-4) JAK (Janus kinase)/STAT signalling pathway. We identified a novel heterozygous germline mutation STAT6 c.1255G > C, p.D419H leading to overactivity of IL-4 JAK/STAT signalling pathway, in a kindred affected by early-onset atopic dermatitis, food allergy, eosinophilic asthma, anaphylaxis and follicular lymphoma. STAT6 D419H expression and functional activity were compared with wild type STAT6 in transduced HEK293T cells and to healthy control primary skin fibroblasts and peripheral blood mononuclear cells (PBMC). We observed consistently higher STAT6 levels at baseline and higher STAT6 and phosphorylated STAT6 following IL-4 stimulation in D419H cell lines and primary cells compared to wild type controls. The pSTAT6/STAT6 ratios were unchanged between D419H and control cells suggesting that elevated pSTAT6 levels resulted from higher total basal STAT6 expression. The selective JAK1/JAK2 inhibitor ruxolitinib reduced pSTAT6 levels in D419H HEK293T cells and patient PBMC. Nuclear staining demonstrated increased STAT6 in patient fibroblasts at baseline and both STAT6 and pSTAT6 after IL-4 stimulation. We also observed higher transcriptional upregulation of downstream genes (XBP1 and EPAS1) in patient PBMC. Our study confirms STAT6 gain of function (GOF) as a novel monogenetic cause of early onset atopic disease. The clinical association of lymphoma in our kindred, along with previous data linking somatic STAT6 D419H mutations to follicular lymphoma suggest that patients with STAT6 GOF disease may be at higher risk of lymphomagenesis.245 words

Biallelic deleterious germline SH2B3 variants cause a novel syndrome of myeloproliferation and multi-organ autoimmunity

SH2B3 is a negative regulator of multiple cytokine receptor signalling pathways in haematopoietic tissue. To date, a single kindred has been described with germline biallelic loss-of-function SH2B3 variants characterized by early onset developmental delay, hepatosplenomegaly and autoimmune thyroiditis/hepatitis. Herein, we described two further unrelated kindreds with germline biallelic loss-of-function SH2B3 variants that show striking phenotypic similarity to each other as well as to the previous kindred of myeloproliferation and multi-organ autoimmunity. One proband also suffered severe thrombotic complications. CRISPR-Cas9 gene editing of zebrafish sh2b3 created assorted deleterious variants in F0 crispants, which manifest significantly increased number of macrophages and thrombocytes, partially replicating the human phenotype. Treatment of the sh2b3 crispant fish with ruxolitinib intercepted this myeloproliferative phenotype. Skin-derived fibroblasts from one patient demonstrated increased phosphorylation of JAK2 and STAT5 after stimulation with IL-3, GH, GM-CSF and EPO compared to healthy controls. In conclusion, these additional probands and functional data in combination with the previous kindred provide sufficient evidence for biallelic homozygous deleterious variants in SH2B3 to be considered a valid gene-disease association for a clinical syndrome of bone marrow myeloproliferation and multi-organ autoimmune manifestations

Is It Safe to Switch From Intravenous Immunoglobulin to Subcutaneous Immunoglobulin in Patients With Common Variable Immunodeficiency and Autoimmune Thrombocytopenia?

BackgroundA significant amount of common variable immunodeficiency (CVID) patients manifest with autoimmunity. Particularly, autoimmune thrombocytopenia (AITP) is commonly seen. Intravenous immunoglobulins (IVIG) are an established treatment option for both, CVID and AITP. Nonetheless, due to fewer systemic side effects, immunoglobulins are increasingly applied subcutaneously (SCIG).ObjectiveTo compare the efficacy and safety of IVIG and SCIG treatment in patients with both CVID and clinical relevant thrombocytopenia in the prevention of AITP bouts.MethodsPatients with both CVID and AITP were enrolled at the Centre for Chronic Immunodeficiency in Freiburg, Germany and at the Royal Free Hospital, London, UK. Clinical and laboratory features of patients were collected and analyzed.ResultsThis retrospective study recruited 61 adult patients between 19 and 71 years of age who had a diagnosis of CVID and at least one bout of thrombocytopenia defined as a platelet count of &lt;50,000/μl if bleeding episodes occurred, or a platelet count of &lt;20,000/μl without bleeding. Thirty patients received immunoglobulin through IVIG, and 31 patients were on SCIG replacement. One patient of the IVIG-group was excluded, because of a diffuse large B-cell lymphoma. We did not find a higher occurrence of thrombocytopenic events in CVID patients who received SCIG, compared to CVID patients who had IVIG, but we identified a low IgG through level as a risk factor for AITP bouts.ConclusionSCIG is at least as safe as IVIG for patients with CVID and concomitant AITP. However, an IgG through level under 7 g/l is a key factor for the development of AITP

The PID Odyssey 2030:outlooks, unmet needs, hurdles, and opportunities — proceedings from the IPOPI global multi-stakeholders’ summit (June 2022)

IPOPI held its first Global Multi-Stakeholders’ Summit on 23-24 June 2022 in Cascais, Portugal. This IPOPI initiative was designed to set the stage for a stimulating forward-thinking meeting and brainstorming discussion among stakeholders on the future priorities of the PID community. All participants were actively engaged in the entire Summit, bringing provocative questions to ensure a high level of discussion and engagement, and partnered in identifying the outlooks, unmet needs, hurdles and opportunities of PIDs for 2030. The topics that were covered include diagnosis (e.g., newborn screening [NBS], genomic sequencing— including ethical aspects on the application of genomics on NBS, the role of more accurate and timely diagnostics in impacting personalized management), treatment (e.g., the therapeutic evolution of immunoglobulins in a global environment, new therapies such as targeted therapies, new approaches in curative therapies), the interactions of Primary ID with Secondary ID, Autoinflammatory Diseases and other diseases as the field experiences an incessant evolution, and also the avenues for research in the field of humanities and human sciences such as Patient-Reported Outcome Measures (PROMs), Patient-Reported Experience Measures (PREMs), and Health-Related Quality Of Life (HRQoL). During this meeting, all participants contributed to the drafting of recommendations based on our common understanding of the future opportunities, challenges, and scenarios. As a collection of materials, perspectives and summaries, they are succinct and impactful and may help determine some of the next key steps for the PID community.</p