Adult Primary Immunodeficiency Research Articles

Evaluation of the Effectiveness of the 6 Warning Signs of the European Society for Immunodeficiencies for Primary Immunodeficiencies in Older Adults

Introduction: Diagnostic delay in cases of primary immunodeficiency (PID) is a significant problem for clinicians, and most do not have sufficient awareness of this uncommon disorder. The European Society for Immunodeficiencies (ESID) has developed 6 warning signs to increase awareness of adult PIDs. The aim of this study was to determine the prevalence of PID in older adults regardless of the reason for presentation and to evaluate the effectiveness of the 6 warning signs of ESID in the diagnosis of PIDs. Methods: The study included 1,331 patients aged ≥65 years who presented at our clinic for any reason and were questioned about the ESID 6 warning signs for PIDs. After the exclusion of reasons for secondary immunodeficiency (SID), all the patients underwent immunological evaluation for the diagnosis of potential underlying PIDs. Results: After excluding 6 patients diagnosed with SID, PID was diagnosed in 16 (1.2%) of 1,325 older adults using ESID warning signs. The most common reasons for presentation were infection (69%) in the PID group and urticaria and/or angioedema (41.5%) in the non-PID group. The most common PID subgroup was common variable immunodeficiency (50%). In 12 of the patients diagnosed with PID, there was at least 1 positive ESID warning sign. In 4 patients, PID was determined despite negative ESID warning signs. The patients diagnosed with PID showed a significant, minimal level of agreement with questions 1 and 4 of the ESID warning signs (p < 0.001, ĸ = 0.204, p = 0.005, ĸ = 0.208, respectively). Conclusion: The ESID warning signs do not encompass all the symptoms and findings of PIDs. There is a need for more infection-centered questions to determine PIDs in older adults. Therefore, the ESID warning signs should be further developed.

FRI568 Hashimoto’s Thyroiditis With Negative Antibodies In Association With Common Variable Immunodeficiency

Abstract Disclosure: I.C. Ebrahim: None. K.F. Brown: None. N.O. Vietor: None. T.D. Hoang: None. M.K. Shakir: None. Introduction: Common variable immunodeficiency (CVID) is associated with several autoimmune manifestations including Hashimoto’s thyroiditis (HT). We report a 47-year-old male with CVID and HT with negative thyroid antibodies (Abs). Case Report: A 47-year-old male, while undergoing coronary calcium scan in 2021, was found to have scattered lung nodules. Follow-up Ct scans showed interval increase in size of lung nodules and a PET scan confirmed bilateral lung nodules which demonstrated hypermetabolic activity and scattered hypermetabolic lymph nodes, suggesting infectious or inflammatory processes. PET scan also revealed thyromegaly with diffusely increased uptake, suggesting thyroiditis. Serum immunoglobulins were measured: IgA &amp;lt; 5 mg/dL (normal 70-400), IgG 334 mg/dL (normal 700-1600), and IgM &amp;lt; 25 mg/dL (normal 40-230). Serum immunoglobulins levels from depository serum samples collected in 2005 also showed similarly low values. CBC was normal, excluding any bone marrow disorders. There was no family history of immunodeficiency or thyroid disorders. On review of systems patients did not have any symptoms of hypothyroidism. Exam: thyroid 50-gms diffusely enlarged with no palpable nodules; heart and lung exam was normal. Laboratory tests including comprehensive metabolic panel, serum complement CH 50, leukemia/lymphoma panel, T/B - lymphocyte/Natkiller, CRP were all normal. Thyroid functions: TSH 5.6 mc1U/mL (0.27-4.2), Free T4 1.20 ng/dL (0.93-1.71), TPO Ab &amp;lt; 9 IU/mL (0-34), TG Ab &amp;lt; 1.0 1U/mL (0.0-0.9), thyrotropin receptor Ab &amp;lt; 0.3 IU/L (&amp;lt;1.0), thyroid stimulating immunoglobulin &amp;lt; 0.10 1U/L (0.06-0.55). Serum thyroid Ab levels from depository samples collected in 2005 also showed normal values. FNA of thyroid showed atypical lymphoid infiltrates and an excision biopsy of the thyroid isthmus confirmed lymphocytic thyroiditis. A PET avid right inguinal lymph node biopsy showed a reactive lymph node. Additional lab evaluation also showed low post vaccination pneumococcal titers. With pan-hypoglobulinemia and low vaccine response, a diagnosis of CVID was made. Patient preferred watchful waiting than iv immunoglobulin therapy. Additionally, the patient has HT with negative thyroid Abs and although patient had mild subclinical hypothyroidism patient elected no treatment. Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency in adults. Autoimmune manifestations occur in 22% of CVID patients and these include autoimmune cytopenia, pernicious anemia, rheumatoid arthritis, vitiligo, and/or HT. Interestingly, our patient did not manifest any thyroid Abs thus it may be postulated that thyroid follicles destruction in HT is mediated predominantly by thyroid-specific B and T cells rather than by thyroid antibodies. Presentation: Friday, June 16, 2023

Clinical and immunological characterisation of patients with common variable immunodeficiency related immune thrombocytopenia

Primary Immune thrombocytopenia (ITP) is an autoimmune disease. Secondary ITP occurs in patients with underlying diseases such as common variable immunodeficiency (CVID). CVID is one of the most common symptomatic primary immunodeficiencies in adults, characterised by infectious and non-infectious symptoms. Amongst CVID patients, ITP is the most frequent autoimmune manifestation. In this single-centre study, we performed a clinical and immunological characterisation of 20 patients with CVID-related ITP and 20 ITP patients without CVID to compare severity and remission rates. We found that patients with CVID-related ITP had a higher WHO Bleeding Scale at initial diagnosis yet showed higher remission rates and required less treatment. Patients with ITP needed up to seven therapy options and were often treated with second-line drug therapy, whilst only one CVID-related ITP patient required second-line drug therapy. Therefore, we show that the course of thrombocytopenia in patients with CVID-related ITP is milder. Furthermore, we show that soluble interleukin-2 receptor (sIL-2R, CD25) was higher in CVID-related ITP compared to ITP patients and could accurately classify patient cohorts with an Area Under the Receiver Operating Characteristic of 0.92. Whilst none of the ITP patients had a history of immunodeficiency, we found immunological abnormalities in 12 out of 18 patients. Therefore, we recommend screening ITP patients for CVID and other immunodeficiencies to detect immune abnormalities early, as we found patients with reduced immunoglobulin levels as well as severe lymphocytopenia in our ITP cohort.

Disturbed lipid profile in common variable immunodeficiency - a pathogenic loop of inflammation and metabolic disturbances.

The relationship between metabolic and inflammatory pathways play a pathogenic role in various cardiometabolic disorders and is potentially also involved in the pathogenesis of other disorders such as cancer, autoimmunity and infectious diseases. Common variable immunodeficiency (CVID) is the most common primary immunodeficiency in adults, characterized by increased frequency of airway infections with capsulated bacteria. In addition, a large proportion of CVID patients have autoimmune and inflammatory complications associated with systemic inflammation. We summarize the evidence that support a role of a bidirectional pathogenic interaction between inflammation and metabolic disturbances in CVID. This include low levels and function of high-density lipoprotein (HDL), high levels of triglycerides (TG) and its major lipoprotein very low-density lipoprotein (VLDL), and an unfavorable fatty acid (FA) profile. The dysregulation of TG, VLDL and FA were linked to disturbed gut microbiota profile, and TG and VLDL levels were strongly associated with lipopolysaccharides (LPS), a marker of gut leakage in blood. Of note, the disturbed lipid profile in CVID did not include total cholesterol levels or high low-density lipoprotein levels. Furthermore, increased VLDL and TG levels in blood were not associated with diet, high body mass index and liver steatosis, suggesting a different phenotype than in patients with traditional cardiovascular risk such as metabolic syndrome. We hypothesize that these metabolic disturbances are linked to inflammation in a bidirectional manner with disturbed gut microbiota as a potential contributing factor.

T cell immunity following COVID-19 vaccination in adult patients with primary antibody deficiency - a 22-month follow-up.

Primary antibody deficiencies, such as common variable immunodeficiency (CVID), are heterogenous disease entities consisting of primary hypogammaglobulinemia and impaired antibody responses to vaccination and natural infection. CVID is the most common primary immunodeficiency in adults, presenting with recurrent bacterial infections, enteropathy, autoimmune disorders, interstitial lung diseases and increased risk of malignancies. Patients with CVID are recommended to be vaccinated against SARS-CoV-2, but there are relatively few studies investigating humoral and cellular responses to immunization. We studied the dynamics of humoral and cell-mediated immunity responses up to 22 months in 28 patients with primary immunodeficiency and three patients with secondary immunodeficiency receiving ChAdOx1, BNT162b2 and mRNA-1273 COVID-19 vaccines. Despite inadequate humoral response to immunization, we demonstrate a robust T cell activation likely protecting from severe COVID-19.

Prevalence of Gastrointestinal (GI), Hepatic, and Infectious Manifestations in Patients with Common Variable Immunodeficiency (CVID)

RationaleCommon variable immunodeficiency (CVID) is the most common, symptomatic, primary immunodeficiency in adults. Gastrointestinal (GI) and hepatic manifestations in CVID remain poorly delineated. We assessed the prevalence of GI, hepatic, and infectious manifestations among patients with CVID and correlated the findings with immunophenotype. MethodsWe conducted a retrospective cohort study of CVID patients at our large, academic center. We evaluated baseline patient characteristics, GI, hepatic, and infectious manifestations of 319 CVID patients. Laboratory studies and immunologic profiles of the patients were evaluated. Results: 291/319 CVID patients (91%) had documented GI or hepatic manifestations. The most common GI symptoms were diarrhea (n = 153), vomiting/dysphagia (n = 146), abdominal pain (n = 117), and weight loss/malabsorption/protein wasting (n = 43). Autoimmune/inflammatory GI disease was reported in 72/319 (23%) of patients. 135/238 (57%) of patients had abnormal liver biochemistries at some point [ALT: 63/135 (47%), AST: 78/135 (58%), Alkaline phosphatase: 76/135 (56%)]. Chronic inflammatory hepatitis was identified in 43/319 (13%); including autoimmune hepatitis (n = 32), transaminitis hepatitis (n = 6), infectious hepatitis (n = 6). Other hepatic conditions were portal hypertension (n = 30), liver cirrhosis (n = 18), and nonalcoholic fatty liver disease (n = 15). 23/319 (7%) had undergone transient elastography, 42/319 (13%) had undergone liver biopsy, of which 22/42 (52%) had a diagnosis of nodular regenerative hyperplasia. The most common GI infections were H. pylori (n = 22), C. difficile (n = 18), Giardia (n = 8). Low absolute CD3+ cells were associated with autoimmune hepatitis [OR 2.91; 95%CI (1.07–7.87); P = 0.03], portal hypertension [OR 5.14; 95%CI (1.86–14.17); P = 0.002], autoimmune/inflammatory GI disease [OR 2.69; 95%CI (1.13–6.41); P = 0.02], and IBD [OR 5.09; 95%CI (1.07–24.20); P = 0.04]. Low absolute CD4+ cells were associated with portal hypertension [OR 5.11; 95%CI (1.87–13.93); P = 0.001], autoimmune/inflammatory GI disease [OR 3.47; 95%CI (1.49–8.12); P = 0.004], and autoimmune gastroenteropathy [OR 3.78; 95%CI (1.44–9.92); P = 0.007]. Low absolute CD19+ cells were associated with autoimmune gastroenteropathy [OR 3.66; 95%CI (1.16–11.6); P = 0.02]. Low switched memory B-cells (IgM-IgD-CD27+CD19+) were associated with autoimmune gastroenteropathy [OR 5.07; 95%CI (1.35–19.04); P = 0.01], and portal hypertension [OR 5.89; 95%CI (1.13–28.16); P = 0.02]. Conclusions: CVID patients had a high prevalence of GI, hepatic, and infectious manifestations, which was associated with more severe immunophenotypes.

Retrospective Study on Vaccine Responses and Natural Course of COVID-19 Infections in Primary Immunodeficiency

We conducted a retrospective study in the adult primary immunodeficiency clinic at UAB examining COVID-19 infection and COVID-19 antibody response from vaccination, natural infection, and immunoglobulin replacement from February 2021 to November 2022. Our goal was to determine if nucleocapsid and spike antibodies could be found in our PID patients and if these antibodies could be derived from natural infection, vaccination, or antibody replacement exclusively or combinatory. We hypothesized that increasing antibodies would be detected in our population as the COVID period extended.Two hundred and forty-five subjects were tracked over 336 clinic visits during this period. Our PID population included subjects with CVID, XLA, thymoma, hypogammaglobulinemia, IgA deficiency, IgG subclass deficiency, specific antibody deficiency, Down syndrome, IgM deficiency, and patients with recurrent sinopulmonary infections. We had 196 females and 45 males in our study.In our patient population, 47% of our patient had known COVID-19 infection. Of those 47%, 21% of those infected patients had COVID-19 at least twice. Of those infected, three did not have COVID-19 spike antibodies and chose not to get vaccinated either. Two of those patients were not on IVIG and one was on Pangyza. Of those infected, 70% (n = 80) were on IgG infusions compared to those uninfected, 77% (n = 96) were on IgG infusions. Of interest, we had three XLA patients and all three had COVID-19 infection in the summer 2021. Two of them tested positive for nucleocapsid and spike antibodies in high titers and they were receiving Gammagard or Gamunex infusions, suggesting that these immunoglobulin preparations contain COVID-19 antibodies.We are still in the process of analyzing our data to see if diagnosis, IgG preparations, date of testing, B cell numbers, and drugs play a role in producing nucleocapsid antibodies and high spike antibody titers.

A UNIQUE CLINICAL PRESENTATION OF COMMON VARIABLE IMMUNODEFICIENCY: MALAKOPLAKIA OF RECTUM.

<h3>Introduction</h3> Common variable immunodeficiency (CVID) is the most common primary immunodeficiency in adults and present with a broad range of clinical manifestations including granulomatous diseases. Malakoplakia is a rare chronic granulomatous disease (CGD) that can affect multiple organs and shown as a manifestation in immunocompromised individuals. In this case report, we present rectal malakoplakia as a clinical manifestation of a CVID in patient for the first time. <h3>Case Description</h3> This is a 62-year-old man with no significant past medical history except hypertension. He did not report recurrent infections, autoimmune disorders or malignancy. Recently, the patient underwent first screening colonoscopy, had a resection of one tubular polyp of rectum and the biopsy of polyp contained malakoplakia. Underlying etiology for rectal malakoplakia was investigated and all results were unremarkable except serum protein electrophoresis showing hypogammaglobulinemia without monoclonal gammopathy. Serum immunoglobulin levels were low (IgG: 538, IgA: 65 and IgM: 14, mg/dL). Flow cytometry analyses of lymphocytes showed markedly decreased absolute cell counts of CD4⁺ (221/ul) and CD19⁺ (28/ul) cells with low memory and switched-memory B-cells. <h3>Discussion</h3> This is a unique case of a completely asymptomatic patient who was incidentally found to have rectal malakoplakia. Work up for malakoplakia led to the diagnosis of CVID. CVID present with a broad range of clinical manifestations including granulomatous disease, however, rectal malakoplakia - a rare chronic granulomatous disease, was never reported as a manifestation of CVID. Although this patient is currently asymptomatic, it will be crucial to closely monitor his immune profile and clinical manifestations.

Which glomerular filtration rate estimation formula should be used for nephrological evaluation in patients with common variable immune deficiency

Background: Common variable immunodeficiency (CVID) is the most common primary immunodeficiency in adults. In addition to renal complications of the disease, there may be an increased likelihood of renal dysfunction due to sucrose in immunoglobulin replacement therapies or other drugs used in treatment. In CVID patients, it is important to monitor patients for renal complications at routine intervals. We compared creatinine-based calculation methods for estimated glomerular filtration rate (eGFR) such as Modification of Diet in Renal Disease (MDRD), Cockcroft-Gault (CG), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) with 24-hour urine creatinine clearance measurement. We aimed to investigate which calculation method was more reliable and consistent in this patient population. Methods: The records of 14 patients who had clinical follow-up at our hospital were retrospectively reviewed. Patients’ eGFR values were measured by three different methods (CKD-EPI, MDRD , and CG formulas). The 24-hour urinary creatinine clearance of all patients and e-GFR calculated by the formula were compared. Results: The eGFR calculated using the MDRD formula was 122.99±41.22 mL/min/1.73 m2, whereas the eGFR measured using the 24-hour urinary creatinine clearance was 99.64(83.35-156.58) mL/min/1.73 m2. Moreover, eGFR calculated by CKD-EPI formula was 113.83±26.46 mL/min/1.73 m2, while eGFR calculated by CG formula was 133.52±45.35 mL/min/1.73 m2. 24-hour urinary creatinine clearance was positively correlated with MDRD, CKD-EPI and CG formulas (r=0.726, p=0.003, r=0.634, p=0.015, r=0.806, p=0.001, respectively). Conclusions: We found that all creatinine-based formulas used in clinical practice for eGFR measurement correlate with 24-hour urine creatinine clearance in patients with CVID. In addition, we have shown that eGFR calculated with the formula CKD-EPI is more closely related to 24-hour urinary creatinine clearance. Therefore, we believe that the eGFR measurement calculated with CKD-EPI is more useful for nephrological follow-up of patients with CVID. It should be noted that our study has some limitations due to the small number of patients.

Общая вариабельная иммунная недостаточность: сложности своевременной диагностики (клинический случай)

Common variable immunodeficiency (CVID) belongs to the group of primary immunodeficiencies with a predominant deficiency in antibody synthesis and the most common diagnosis among clinically significant cases of primary immunodeficiency in adults. The main laboratory criterion for this disease is considered to be hypogammaglobulinemia (a decrease in the level of IgG less than 4.5 g/l with a decrease in the level of IgA, with/without a decrease in the level of IgM). Clinical manifestations of CVID are diverse: infectious syndrome (chronic infections of the lower respiratory tract, sinusitis, otitis, infectious diarrhea, septic arthritis), autoimmune syndrome (cytopenias, systemic rheumatic diseases), non-infectious pathology of the gastrointestinal tract (celiac-like or IBD-like syndromes , nodular hyperplasia of the mucosa), interstitial lung diseases, pathological non-malignant lymphoproliferation (lymphadenopathy, hepatosplenomegaly), oncological diseases, the formation of non-caseating granulomas in the internal organs). Due to the lack of a typical clinical picture, the diagnosis of CVID in adults is often made many years late, especially if the clinical picture is dominated by non-infectious manifestations. The article presents a clinical case when the patient had recurrent lymphadenopathy as the main symptom for several years. After examination by various specialists, she was referred to an immunologist because hypoproteinemia and a sharp decrease in the gamma fraction of globulins have been revealed. An immunological study revealed agammaglobulinemia and a pronounced imbalance of T-lymphocyte subpopulations (a significant decrease in the number of CD4+ cells and an increase in CD8+ cells). The clinical significance of T-lymphocyte disorders in CVID, the need for treatment with adequate doses of intravenous immunoglobulins are discussed.

Common Variable Immunodeficiency Disorders, T-Cell Responses to SARS-CoV-2 Vaccines, and the Risk of Chronic COVID-19

COVID-19 has had a calamitous effect on the global community. Despite intense study, the immunologic response to the infection is only partially understood. In addition to older age and ethnicity, patients with comorbidities including obesity, diabetes, hypertension, coronary artery disease, malignancy, renal, and pulmonary disease may experience severe outcomes. Some patients with primary immunodeficiency (PID) and secondary immunodeficiency also appear to be at increased risk from COVID-19. In addition to vulnerability to SARS-CoV-2, patients with PIDs often have chronic pulmonary disease and may not respond to vaccines, which exacerbates their long-term risk. Patients with common variable immunodeficiency disorders, the most frequent symptomatic PID in adults and children, have a spectrum of B- and T-cell defects. It may be possible to stratify their risk for severe COVID-19 based on age, ethnicity, the severity of the T-cell defect, and the presence of other comorbidities. Patients with common variable immunodeficiency disorders and other immunodeficiencies are at risk for Chronic COVID-19, a dangerous stalemate between a suboptimal immune response and SARS-CoV-2. Intra-host viral evolution could result in the rapid emergence of vaccine-resistant mutants and variants of high consequence; it is a public health emergency. Vaccination and prevention of Chronic COVID-19 in immunodeficient patients is therefore of the utmost priority. Having a reliable diagnostic assay for T-cell immunity to SARS-CoV-2 is critical for evaluating responses to vaccines in these patients. New treatments for SARS-CoV-2 such as NZACE2-Pātari are likely to be particularly beneficial for immunodeficient patients, especially those who fail to mount a robust T-cell response to COVID-19 vaccines.

Common variable immunodeficiency disorder: a clinical case

Primary immunodeficiency is a rare congenital pathology associated with failure of immune system, manifested by disturbances of its functions. These defects lead to increased susceptibility of patients to various infectious agents, as well as the development of autoimmune, malignant and other diseases. Primary immunodeficiency is classified as a rare disease, which was previously associated with a poor prognosis with a high risk of mortality in childhood. To date, the emergence of highly effective treatment methods has changed the course and prognosis of these diseases. Clinicians of various specialties increasingly meet with this pathology in everyday practice, including adult age cohorts. In this regard, early diagnosis of primary immunodeficiency in adults becomes relevant, being associated with choosing optimal therapy, prevention of severe internal organ damage, determination of management strategy for the patient, as well as the need to identify inherited disorders and provide information to the patient’s family. Delayed verification of the diagnosis may cause disability of the patient and development of irreversible, often fatal complications. This article presents our own clinical case with a newly diagnosed clinical condition: Common variable immunodeficiency disorder (CVID), the most common form of primary immunodeficiency in adults. The symptoms of common variable immunodeficiency disorder appear in these patients in adulthood, but a high-quality collected history of the disease will allow you to trace symptoms in the patients even since early childhood. There is a common gap for several years between the onset of the disease and clinical diagnosis, since erroneous diagnosis is often made due to non-specific clinical symptoms that resemble other, more frequent diseases. The prognosis of patients with CVID depends on several factors: frequency of infections, structural disorders in the lungs, the occurrence of autoimmune diseases and the success of infection prevention. Thus, a variety of clinical forms of primary immunodeficiency, lack of awareness of doctors about this pathology, complexity of immunological examination in the general medical network lead to the fact that CVID is not diagnosed for long terms, and patients do not receive the necessary pathogenetic therapy. There is a need for drawing attention of doctors of various disciplines to the fact that the recurrent inflammatory processes of various localization, which are difficult to respond to adequate traditional therapy, may be caused by changes in the immune system, including congenital, genetically determined immunodeficiency.

Rapid clinical recovery of a SARS-CoV-2 infected common variable immunodeficiency patient following the infusion of COVID-19 convalescent plasma

BackgroundCommon variable immunodeficiency is the most prevalent symptomatic primary immunodeficiency in adults. Affected patients fail to mount an appropriate humoral response against community acquired infectious diseases and recent reports have provided data supporting the increased susceptibility of these patients to severe SARS-CoV-2 infections. In this context, the infusion of COVID-19 convalescent plasma could represent an effective therapeutic strategy.Case presentation25-year old woman diagnosed with common variable immunodeficiency in 2013, developed severe COVID-19 that rapidly progressed to pneumonia presenting with multiple bilateral lung opacities that were both central and peripheral and presented as ground-glass and consolidation types involving all lobes, bilaterally. As blood oxygen saturation decayed and lung abnormalities were not responsive to large spectrum antibiotics and corticosteroids, patient was placed on mechanical ventilation and compassionate-use of approved COVID-19 convalescent donor plasma was introduced. The patient presented a rapid response to the approach and mechanical ventilation could be interrupted 24 h after first dose of COVID-19 convalescent donor plasma. As a whole, the patient received four doses of 200 mL convalescent plasma during a period of 6 days. There was rapid improvement of clinical status, with interruption of supplemental oxygen therapy after 6 days and reduction of lung abnormalities as evidence by sequential computed tomography scans.ConclusionsThis is a single patient report that adds to other few reports on common variable immunodeficiency and agammaglobulinemia, suggesting that COVID-19 convalescent donor plasma could be a valuable therapeutic approach to treat patients affected by dysgammaglobulinemias and presenting severe COVID-19.

Hospitalizations and Critical Illness in Adult Primary Immunodeficiency Patients

Adult patients with primary immunodeficiency (PID) face high morbidity and mortality, but sparse literature is available describing this population. We hypothesized that compared to patients without PID, this population would experience a greater burden of comorbidities and be more likely to require intravenous antibiotics, hospital admission, and intensive care.

A multicenter survey on the aspects of everyday life in adult patients with primary antibody deficiencies treated with immunoglobulin G replacement during the COVID-19 pandemic.

IntroductionThe COVID-19 pandemic has changed many aspects of everyday life. Patients with primary immunodeficiency (PID) are in a particularly difficult situation. The purpose of the present study was to contribute to the very limited research on the everyday aspects of functioning in PID patients during the COVID-19 pandemic.MethodsThe survey included 85 adult PID patients treated with immunoglobulin replacement therapy in four reference centers for immunology. Everyday functioning of the patients as well as their opinion concerning new solutions in medical care were analyzed.ResultsDuring the pandemic, the percentage of patients experiencing fear/anxiety has increased from 47% to 70%. The wide dissemination of information about the SARS-CoV-2 in the media has increased anxiety in 40% of the patients. Patients diagnosed with PID were most afraid of the exposure to contact with strangers, especially in public places. As many as 67 respondents (79%) considered the introduction of restrictions concerning social functioning as good. Only every fifth person learned about the pandemic from reliable sources. Eighty three percent of the patients receiving immunoglobulin substitution experienced less fear of SARS-CoV-2 infection. The patients positively evaluated the solutions related to the direct delivery of drugs to the place of residence in order to continue home IgRT therapy. Fifty three respondents (62.5%) believed that the possibility of a remote consultation was a very good solution.ConclusionIt is necessary to increase educational activities concerning the pandemic provided by health care professionals, as patients obtain information mainly from the media and the Internet, which adversely affects the feeling of anxiety. The pandemic, in addition to the very negative impact on patients and the deterioration of their daily functioning, has made patients appreciate their life more, devote more time to family and friends, and do things they like.

Primary Humoral Immune Deficiencies: Overlooked Mimickers of Chronic Immune-Mediated Gastrointestinal Diseases in Adults.

In recent years, the incidence of immune-mediated gastrointestinal disorders, including celiac disease (CeD) and inflammatory bowel disease (IBD), is increasingly growing worldwide. This generates a need to elucidate the conditions that may compromise the diagnosis and treatment of such gastrointestinal disorders. It is well established that primary immunodeficiencies (PIDs) exhibit gastrointestinal manifestations and mimic other diseases, including CeD and IBD. PIDs are often considered pediatric ailments, whereas between 25 and 45% of PIDs are diagnosed in adults. The most common PIDs in adults are the selective immunoglobulin A deficiency (SIgAD) and the common variable immunodeficiency (CVID). A trend to autoimmunity occurs, while gastrointestinal disorders are common in both diseases. Besides, the occurrence of CeD and IBD in SIgAD/CVID patients is significantly higher than in the general population. However, some differences concerning diagnostics and management between enteropathy/colitis in PIDs, as compared to idiopathic forms of CeD/IBD, have been described. There is an ongoing discussion whether CeD and IBD in CVID patients should be considered a true CeD and IBD or just CeD-like and IBD-like diseases. This review addresses the current state of the art of the most common primary immunodeficiencies in adults and co-occurring CeD and IBD.

Functions of Tfh Cells in Common Variable Immunodeficiency.

Common variable immunodeficiency is the most common clinical primary immunodeficiency in adults. Its hallmarks are hypogammaglobulinemia and compromised B-cell differentiation into memory or antibody-secreting cells leading to recurrent infections. This disease is heterogeneous, with some patients harboring multiple complications such as lymphoproliferative disorders, autoimmune manifestations, or granulomatous inflammation. The mechanisms leading to these complications remain elusive despite numerous associations found in the literature. For instance, although described as a B cell intrinsic disease, numerous abnormalities have been reported in other immune cell compartments. Here, we tuned our attention to follicular helper T cells, a CD4+ T cell population specialized in B cell help, considering the recent publications showing an involvement of these cells in CVID pathogenesis.

Differing Performance of the Warning Signs for Immunodeficiency in the Diagnosis of Pediatric Versus Adult Patients in a Two-Center Tertiary Referral Population.

Primary immunodeficiency (PID) represents disorders with a spectrum of clinical presentations. The medical community seeks clinical features to prompt evaluation for immunodeficiency given improved prognosis with early identification. We hoped to identify clinical characteristics that would improve the diagnostic accuracy of the widely disseminated Jeffrey Modell Foundation warning signs for immunodeficiency. We performed a retrospective chart review in a two-center North American cohort of patients with PID. Charts of 137 pediatric and 400 adult patients with PID were evaluated for the presence of these warning signs and compared to controls with normal preliminary biochemical immune evaluation. Fewer than 45% of adults with PID presented with ≥ 2 warning signs, while diagnostic utility was improved in the pediatric population where the warning signs were found to be 64% sensitive. The warning signs found in a significantly increased proportion compared to controls differed for pediatric PID patients (recurrent pneumonia (OR 2.9, p< 0.001), failure to thrive (OR 2.1, p< 0.001), need for IV antibiotics (OR 2.1, p< 0.001), serious bacterial infection (OR 4.8, p< 0.001), recurrent otitis media (OR 1.5, p= 0.027)), versus adult PID patients (recurrent otitis media (OR 2.9, p< 0.001), recurrent sinusitis (OR 2.1, p< 0.001), diarrhea with weight loss (OR 2.2, p< 0.001), recurrent viral infection (OR 3.3 p< 0.001)). In evaluation for additional criteria to promote identification of immunodeficiency, linear regression models showed slightly improved diagnostic accuracy of the warning signs with the addition of autoimmunity in our pediatric PID cohort (8.7% v 2.8%, p< 0.001, ROC 0.58). Adult PID patients demonstrated atopy more frequently than controls (48.0% vs 40.3%, p= 0.011), while atopy was found to have a negative association with the presence of PID in the pediatric age group (OR 0.3, p< 0.01). No improvement in diagnostic accuracy of the warning signs was found with the addition of allergic disease, autoimmunity, or malignant and benign proliferative disease in the adult cohort. We demonstrate poor diagnostic performance of warning signs for immunodeficiency in patients with PID in a retrospective chart review. Divergent warning signs of statistically significant diagnostic utility were found in pediatric versus adult patients. We suggest education of physicians on differing presentations of possible immunodeficiency between age groups, and expansion of the warning signs to include non-infectious comorbidities such as autoimmunity in pediatric patients.

Delayed Diagnosis and Complications of Predominantly Antibody Deficiencies in a Cohort of Australian Adults.

Predominantly antibody deficiencies (PADs) are the most common type of primary immunodeficiency in adults. PADs frequently pass undetected leading to delayed diagnosis, delayed treatment, and the potential for end-organ damage including bronchiectasis. In addition, PADs are frequently accompanied by comorbid autoimmune disease, and an increased risk of malignancy. To characterize the diagnostic and clinical features of adult PAD patients in Victoria, Australia. We identified adult patients receiving, or having previously received immunoglobulin replacement therapy for a PAD at four hospitals in metropolitan Melbourne, and retrospectively characterized their clinical and diagnostic features. 179 patients from The Royal Melbourne, Alfred and Austin Hospitals, and Monash Medical Centre were included in the study with a median age of 49.7 years (range: 16-87 years), of whom 98 (54.7%) were female. The majority of patients (116; 64.8%) met diagnostic criteria for common variable immunodeficiency (CVID), and 21 (11.7%) were diagnosed with X-linked agammaglobulinemia (XLA). Unclassified hypogammaglobulinemia (HGG) was described in 22 patients (12.3%), IgG subclass deficiency (IGSCD) in 12 (6.7%), and specific antibody deficiency (SpAD) in 4 individuals (2.2%). The remaining four patients had a diagnosis of Good syndrome (thymoma with immunodeficiency). There was no significant difference between the age at diagnosis of the disorders, with the exception of XLA, with a median age at diagnosis of less than 1 year. The median age of reported symptom onset was 20 years for those with a diagnosis of CVID, with a median age at diagnosis of 35 years. CVID patients experienced significantly more non-infectious complications, such as autoimmune cytopenias and lymphoproliferative disease, than the other antibody deficiency disorders. The presence of non-infectious complications was associated with significantly reduced survival in the cohort. Our data are largely consistent with the experience of other centers internationally, with clear areas for improvement, including reducing diagnostic delay for patients with PADs. It is likely that these challenges will be in part overcome by continued advances in implementation of genomic sequencing for diagnosis of PADs, and with that opportunities for targeted treatment of non-infectious complications.

Prevalence and clinical challenges among adults with primary immunodeficiency and recombination-activating gene deficiency

Prevalence and clinical challenges among adults with primary immunodeficiency and recombination-activating gene deficiency