Manish Butte

Autoimmun Rev. 2021 Jun 9:102872. doi: 10.1016/j.autrev.2021.102872. Online ahead of print.

ABSTRACT

OBJECTIVE: To describe the prevalence, clinical presentation and current treatment regimens of inflammatory bowel disease (IBD) in patients with primary immunodeficiency disorders (PIDs).

METHODS: A systematic review was conducted. The following databases were searched: MEDLINE, Embase, Web of Science, the Cochrane Library and Google Scholar.

RESULTS: A total of 838 articles were identified, of which 36 were included in this review. The prevalence of IBD in PIDs ranges between 3.4% and 61.2%, depending on the underlying PID. Diarrhea and abdominal pain were reported in 64.3% and 52.4% of the patients, respectively. Colon ulceration was the most frequent finding on endoscopic evaluation, while cryptitis, granulomas, ulcerations and neutrophilic/lymphocytic infiltrates were the most frequently reported histopathological abnormalities. Described treatment regimens included oral corticosteroids and other oral immunosuppressive agents, including mesalazine, azathioprine and cyclosporin, leading to clinical improvement in the majority of patients. In case of treatment failure, biological therapies including TNF- α blocking agents, are considered.

CONCLUSIONS: The overall prevalence of IBD in patients with PID is high, but varies between different PIDs. Physicians should be aware of these complications and focus on characteristic symptoms to reduce diagnostic delay and delay in initiation of treatment. Treatment of IBD in PIDs depends on severity of symptoms and may differ between various PIDs based on distinct underlying pathogenesis. An individualized diagnostic and therapeutic approach is therefore warranted.

PMID:34118459 | DOI:10.1016/j.autrev.2021.102872

Joint Bone Spine. 2021 Jun 8:105236. doi: 10.1016/j.jbspin.2021.105236. Online ahead of print.

ABSTRACT

OBJECTIVE: To analyze whether immune-mediated diseases (IMDs) occurs in sarcoidosis more commonly than expected in the general population, and how concomitant IMDs influence the clinical presentation of the disease.

METHODS: We searched for coexisting IMDs in patients included in the SARCOGEAS-cohort, a multicenter nationwide database of consecutive patients diagnosed according to the ATS/ESC/WASOG criteria. Comparisons were made considering the presence or absence of IMD clustering, and odds ratios (OR) and their 95% confidence intervals (CI) were calculated as the ratio of observed cases of every IMD in the sarcoidosis cohort to the observed cases in the general population.

RESULTS: Among 1737 patients with sarcoidosis, 283 (16%) patients presented at least one associated IMD. These patients were more commonly female (OR 1.98, 95%CI 1.49-2.62) and were diagnosed with sarcoidosis at an older age (49.6 vs 47.5 years, p<0.05). The frequency of IMDs in patients with sarcoidosis was nearly 2-fold higher than the frequency observed in the general population (OR 1.64, 95%CI 1.44-1.86). Significant associations were identified in 17 individual IMDs. In comparison with the general population, the IMDs with the strongest strength of association with sarcoidosis (OR > 5) were common variable immunodeficiency (CVID) (OR 431.8), familial Mediterranean fever (OR 33.9), primary biliary cholangitis (OR 16.57), haemolytic anemia (OR 12.17), autoimmune hepatitis (OR 9.01), antiphospholipid syndrome (OR 8.70), immune thrombocytopenia (OR 8.43), Sjogren syndrome (OR 6.98), systemic sclerosis (OR 5.71), ankylosing spondylitis (OR 5.49), IgA deficiency (OR 5.07) and psoriatic arthritis (OR 5.06). Sex-adjusted ORs were considerably higher than crude ORs for eosinophilic digestive disease in women, and for immune thrombocytopenia, systemic sclerosis and autoimmune hepatitis in men.

CONCLUSION: We found coexisting IMDs in 1 out of 6 patients with sarcoidosis. The strongest associations were found for immunodeficiencies and some systemic, rheumatic, hepatic and hematological autoimmune diseases.

PMID:34116201 | DOI:10.1016/j.jbspin.2021.105236

Cell. 2021 Jun 5:S0092-8674(21)00626-7. doi: 10.1016/j.cell.2021.05.009. Online ahead of print.

ABSTRACT

Cytomegaloviruses (CMVs) have co-evolved with their mammalian hosts for millions of years, leading to remarkable host specificity and high infection prevalence. Macrophages, which already populate barrier tissues in the embryo, are the predominant immune cells at potential CMV entry sites. Here we show that, upon CMV infection, macrophages undergo a morphological, immunophenotypic, and metabolic transformation process with features of stemness, altered migration, enhanced invasiveness, and provision of the cell cycle machinery for viral proliferation. This complex process depends on Wnt signaling and the transcription factor ZEB1. In pulmonary infection, mouse CMV primarily targets and reprograms alveolar macrophages, which alters lung physiology and facilitates primary CMV and secondary bacterial infection by attenuating the inflammatory response. Thus, CMV profoundly perturbs macrophage identity beyond established limits of plasticity and rewires specific differentiation processes, allowing viral spread and impairing innate tissue immunity.

PMID:34115982 | DOI:10.1016/j.cell.2021.05.009

Mol Genet Genomic Med. 2021 Jun 10:e1732. doi: 10.1002/mgg3.1732. Online ahead of print.

ABSTRACT

BACKGROUND: X-linked hyper-IgM syndrome (XHIGM) is a rare primary immunodeficiency caused by CD40 ligand defects.

METHODS: We identified three patients with XHIGM in Ho Chi Minh City, Vietnam. Whole-exome sequencing, immunological analyses and western blot were performed to investigate phenotypic and genotypic features.

RESULTS: Despite showing symptoms typical of XHIGM, including recurrent sinopulmonary infections, oral ulcers and otitis media, the diagnosis was significantly delayed. One patient developed anti-phospholipid syndrome, which has been documented for the first time in XHIGM syndrome. Two patients had elevated IgM levels and all of them had low IgG levels. Exome sequencing revealed mutations in the CD40LG gene: one novel splicing mutation c.156+2T>A and two previously characterised mutations (non-frameshift deletion c.436_438delTAC, stop-gain c.654C>A). Due to these mutations, the CD40 ligand was not expressed in any of the three patients, as demonstrated by western blot analysis.

CONCLUSION: This is the first report of XHIGM syndrome in Vietnam indicates that an effective diagnostic strategy, such as sequencing analysis, contributes to reliable diagnosis and subsequent therapy.

PMID:34114358 | DOI:10.1002/mgg3.1732

J Clin Immunol. 2021 Jun 10. doi: 10.1007/s10875-021-01077-5. Online ahead of print.

ABSTRACT

INTRODUCTION: Patients with inborn errors of immunity (IEI) have a compromised or inappropriate immune response. Although they might be considered a high-risk group for severe SARS-CoV-2 infection, the reported impact of COVID-19 in these patients has been reassuring, while the differential susceptibility of distinct types of IEI remains unclear.

OBJECTIVE: We aimed to describe the findings and outcomes of our known patients with IEI who were diagnosed with COVID-19.

METHODS: In a retrospective study from March 2020 to February 2021, four centers in Mexico collected clinical, laboratory, and genetic data from pediatric and adult patients with known diagnoses of IEI who presented with COVID-19, based on compatible symptoms and positive SARS-CoV-2 testing or known household exposure.

RESULTS: We report 31 patients with known IEI from Mexico who presented with SARS-CoV-2 infection. Seventy-four percent were male, 52% were pediatric, and 81% survived. Their ages ranged from 5 months to 56 years, with a median of 17 years. Sixty-five percent had predominant antibody deficiencies, 48% were hospitalized, and 26% required ICU. Pediatric patients had a higher hospital admission rate than adults. Inpatient mortality was 40%, and ICU mortality rate was 63%. Forty-eight percent developed pneumonia, while 36% had evidence of hyperinflammation (4 adults and 7 children). Predominant laboratory features were lymphopenia and thrombocytopenia, seen in 70 and 44% of patients, respectively. The serum D-dimer median value was 2.6 (0.5-20.6) μg/mL, and the median highest ferritin value was 1015 (32-10,303) ng/mL. Intravenous immunoglobulin was used in 80% of patients. Other treatments included macrolides (39%) and corticosteroids (29%). Six patients died from secondary infection or uncontrolled systemic inflammation.

DISCUSSION: Although impaired immunity due to IEI may be a predisposing factor for severe COVID-19, most of our patients with IEI who acquired the SARS-CoV-2 infection developed a well-tolerated infection and survived, as have more than 80% of worldwide reported patients to date. An impaired immune or inflammatory response may be a predisposing factor for some and a protective factor for others. A systematic review of the literature could help identify those patients at risk of severe disease and complications. Healthcare-associated infections should be aggressively prevented.

PMID:34114122 | DOI:10.1007/s10875-021-01077-5

Int Med Case Rep J. 2021 Jun 3;14:377-380. doi: 10.2147/IMCRJ.S303038. eCollection 2021.

ABSTRACT

BACKGROUND: Immunoglobulin A deficiency (IgAD) is the most common form of primary immunodeficiency in western countries. It can be associated with the development of autoimmune diseases both in adults and in children even though the exact pathophysiology is not fully defined.

CASE PRESENTATION: We report here a case of a young patient who developed nephrotic syndrome secondary to membranoproliferative glomerulonephritis associated with the incidental finding of IgAD. We began corticosteroid therapy and angiotensin-converting enzyme inhibitor, and we observed partial remission of the nephrotic syndrome after about nine months; nonetheless, in the following follow-up visits, a progressive decline of renal function was found.

CONCLUSION: Our case extends the spectrum of hitherto described glomerulonephritides associated with IgAD which were described until now.

PMID:34113180 | PMC:PMC8185457 | DOI:10.2147/IMCRJ.S303038

J Allergy Clin Immunol. 2021 Jun 7:S0091-6749(21)00891-5. doi: 10.1016/j.jaci.2021.04.039. Online ahead of print.

ABSTRACT

BACKGROUND: Heterozygous germline mutations in cytotoxic T-lymphocyte-associated antigen-4 (CTLA4) impair the immunomodulatory function of regulatory T cells. Affected individuals are prone to life-threatening autoimmune and lymphoproliferative complications. A number of therapeutic options are currently used with variable effectiveness.

BJECTIVE: To characterize the responsiveness of patients with CTLA-4 insufficiency to specific therapies and provide recommendations for the diagnostic work-up and therapy at an organ-specific level.

METHODS: Clinical features, laboratory findings, and response to treatment were reviewed retrospectively in an international cohort of 173 CTLA4 mutation carriers. Patients were followed between 2014 and 2020 for a total of 2,624 months from diagnosis. Clinical manifestations were grouped based on organ-specific involvement. Medication use and response were recorded and evaluated.

RESULTS: Among the 173 CTLA4 mutation carriers, 123 (71%) had been treated for immune complications. Abatacept, rituximab, sirolimus, and corticosteroids ameliorated disease severity especially in case of cytopenias and lymphocytic organ-infiltration of the gut, lungs and central nervous system. Immunoglobulin replacement was effective in infection prevention. Only four (25%) of 16 patients with cytopenia who were splenectomized had a sustained clinical response. Cure was achieved with stem cell transplantation in 13 (72%) of 18 patients. As a result of the above, organ-specific treatment pathways were developed.

CONCLUSION: Systemic immunosuppressants and abatacept may provide partial control but require ongoing administration. Allogeneic hematopoietic stem cell transplantation offers a possible cure for patients with CTLA-4 insufficiency.

CLINICAL IMPACT: The benefits and risks of symptomatic and curative therapies need to be considered when deciding on the best treatment for patients with CTLA-4 insufficiency.

PMID:34111452 | DOI:10.1016/j.jaci.2021.04.039

J Clin Immunol. 2021 Jun 8. doi: 10.1007/s10875-021-01068-6. Online ahead of print.

NO ABSTRACT

PMID:34101091 | DOI:10.1007/s10875-021-01068-6

Immunol Invest. 2021 Jun 7:1-12. doi: 10.1080/08820139.2021.1933516. Online ahead of print.

ABSTRACT

Objective: Wiskott Aldrich Syndrome is an X-linked primary immunodeficiency disorder characterized by microthrombocytopenia, severe immunodeficiency, and eczema. To define clinical-laboratory features, genetic defects (known/novel) of 23 patients of Wiskott Aldrich Syndrome/X-linked Thrombocytopenia (WAS/XLT) cohort, establish relationships between molecular defects and clinical features if present, evaluate patients who underwent hematopoietic stem cell transplantation (HSCT) and did not.Methods: Qualitative analysis from patients’ hospital files and Sanger sequencing for molecular diagnosis was performed. Twenty-two WAS patients and one XLT patient were included in the study.Results: The median age of diagnosis was 15 months (2.5-172 months). The most common symptom was otitis media and all patients had microthrombocytopenia. Autoimmune findings were detected in 34.7% (8 patients) of the patients; three patients (13%) had positive anti-nuclear antibody (ANA), three patients (13%) hemolytic anemia, one patient autoimmune neutropenia, two patients vasculitis, and one patient demyelinating polyneuropathy. Nine of the 23 (39,1%) patients had HSCT with nearly 90% success. We identified 13 different mutations in our cohort; seven were novel.Conclusions: HSCT is the only curative treatment for WAS. The study confirms that early diagnosis is very important for the success of therapy, so we must increase awareness in society and physicians to keep an eye out for clues. Our study cohort and follow-up period are not sufficient to establish phenotype-genotype correlation, so a larger cohort from various centers with longer follow-up will be more decisive.

PMID:34098853 | DOI:10.1080/08820139.2021.1933516

Pediatr Allergy Immunol. 2021 Jun 7. doi: 10.1111/pai.13571. Online ahead of print.

ABSTRACT

BACKGROUND: Inborn errors of immunity (IEIs) are a group of conditions affecting immune system development and function. Due to their clinical heterogeneity and lack of provider awareness, patients suffer from long diagnostic delays that increase morbidity and mortality. Next generation sequencing facilitates earlier diagnosis and treatment of IEIs, but too often patients are unable to see the benefit of this technology due to gaps in providers’ knowledge regarding which patients to test and barriers to accessing sequencing.

METHODS: Here we provide detailed clinical phenotyping and describe the impact of genetic sequencing on a cohort of 43 patients with monogenic IEIs seen in a tertiary care center from 2014-2019. Data was abstracted from a chart review and a panel of clinical immunologists were consulted on the impact of genetic sequencing on their patients.

RESULTS: We found that our patients had significant diagnostic delays, averaging 3.3 years; had diverse manifestations of immune system dysfunction; and demonstrated highly complex medical needs, with on average 7.9 subspecialties involved in their care and 4.9 hospitalizations prior to definitive treatment. Our results also demonstrate the benefits of genetic testing, as it provided the majority of our patients with a diagnosis, and positively impacted their treatment, follow-up and prognosis.

CONCLUSION: This paper expands the paucity of literature on genetically confirmed IEIs in North America, and supports the expansion of access to genetic testing for patients with clinical features suggesting IEI, such as those presented in our cohort.

PMID:34097760 | DOI:10.1111/pai.13571