Manifestations Of Immunodeficiency Research Articles

A novel frameshift variant in the ADA2 gene of a patient with a neurological phenotype: a case report

BackgroundAdenosine deaminase 2 (ADA2) deficiency is an inherited autoinflammatory syndrome caused by a defect in the ADA2 gene. Most common manifestations include peripheral vasculopathy, early-onset stroke, immunodeficiency, and haematological manifestations. Patients with pathogenic variants that are more detrimental to ADA2’s enzymatic function (e.g. frameshift) have been reported to be prone to developing hematological phenotype. We report here the case of a 13-year-old Caucasian girl with a novel frameshift variant in the ADA2 gene and a clinical phenotype of early-onset stroke.Case presentationThe patient was admitted to hospital with complaints of weakness in her right arm, unilateral facial weakness and speech problems. Her initial laboratory workup was normal; however, magnetic resonance imaging of her brain confirmed acute/subacute ischaemic changes in the posterior limb of the left-sided internal capsule and in the apical part of the thalamus. She also had manifestations of immunodeficiency – recurrent skin infections and otitis, chronic Molluscum contagiosum infection in anamnesis and B cell deficiency with a low level of serum IgA. The patient’s DNA was analysed and two pathogenic variants were identified in the ADA2 gene, confirming a diagnosis of adenosine deaminase 2 (ADA2) deficiency. While one of the variants (c.506G > A (p.Arg169Gln)) has been reported previously, the other one is a novel frameshift variant, namely, c.464del (p.Pro155Hisfs*29). The patient received stroke rehabilitation, which significantly improved her functional state. Tumour necrosis factor inhibitor and methotrexate treatment was commenced, and the patient has remained stable with no further ischaemic events.ConclusionsAlthough rare, ADA2 deficiency should be considered in patients with early-onset stroke, especially with concomitant manifestations of inflammatory features or immunodeficiency. This case report extends the genotypic spectrum of ADA2 deficiency.

HHV-7 encephalitis as the first manifestation of immunodeficiency

HHV-7 encephalitis as the first manifestation of immunodeficiency

The Role of ZEB2 in Human CD8 T Lymphocytes: Clinical and Cellular Immune Profiling in Mowat–Wilson Syndrome

The Zeb2 gene encodes a transcription factor (ZEB2) that acts as an important immune mediator in mice, where it is expressed in early-activated effector CD8 T cells, and limits effector differentiation. Zeb2 homozygous knockout mice have deficits in CD8 T cells and NK cells. Mowat–Wilson syndrome (MWS) is a rare genetic disease resulting from heterozygous mutations in ZEB2 causing disease by haploinsufficiency. Whether ZEB2 exhibits similar expression patterns in human CD8 T cells is unknown, and MWS patients have not been comprehensively studied to identify changes in CD8 lymphocytes and NK cells, or manifestations of immunodeficiency. By using transcriptomic assessment, we demonstrated that ZEB2 is expressed in early-activated effector CD8 T cells of healthy human volunteers following vaccinia inoculation and found evidence of a role for TGFß-1/SMAD signaling in these cells. A broad immunological assessment of six genetically diagnosed MWS patients identified two patients with a history of recurrent sinopulmonary infections, one of whom had recurrent oral candidiasis, one with lymphopenia, two with thrombocytopenia and three with detectable anti-nuclear antibodies. Immunoglobulin levels, including functional antibody responses to protein and polysaccharide vaccination, were normal. The MWS patients had a significantly lower CD8 T cell subset as % of lymphocytes, compared to healthy controls (median 16.4% vs. 25%, p = 0.0048), and resulting increased CD4:CD8 ratio (2.6 vs. 1.8; p = 0.038). CD8 T cells responded normally to mitogen stimulation in vitro and memory CD8 T cells exhibited normal proportions of subsets with important tissue-specific homing markers and cytotoxic effector molecules. There was a trend towards a decrease in the CD8 T effector memory subset (3.3% vs. 5.9%; p = 0.19). NK cell subsets were normal. This is the first evidence that ZEB2 is expressed in early-activated human effector CD8 T cells, and that haploinsufficiency of ZEB2 in MWS patients had a slight effect on immune function, skewing T cells away from CD8 differentiation. To date there is insufficient evidence to support an immunodeficiency occurring in MWS patients.

Interstitial Lung Disease in Children With Selected Primary Immunodeficiency Disorders-A Multicenter Observational Study.

Primary immunodeficiencies (PIDs) are rare disorders of the immune system encompassing inborn errors of immunity. Primary antibody deficiencies constitute the largest group of PID with common variable immunodeficiency (CVID) being the most common symptomatic form. Combined immunodeficiencies (CID) accompanied by antibody deficiency can mimic CVID and these patients need the verification of the final diagnosis. Respiratory involvement, especially interstitial lung disease (ILD), poses a relevant cause of morbidity and mortality among patients with PID and in some cases is the first manifestation of immunodeficiency. In this study we present a retrospective analysis of a group of children with primary immunodeficiency and ILD - the clinical, radiological, histological characteristics, treatment strategies and outcomes. Eleven children with PID-related ILD were described. The majority of them presented CVID, in three patients CID was recognized. All patients underwent detailed pulmonary diagnostics. In eight of them histological analysis of lung biopsy was performed. We noted that in two out of 11 patients acute onset of ILD with respiratory failure was the first manifestation of the disease and preceded PID diagnosis. The most common histopathological diagnosis was GLILD. Among the analyzed patients three did not require any immunosuppressive therapy. All eight treated children received corticosteroids as initial treatment, but in some of them second-line therapy was introduced. The relevant side effects in some patients were observed. The study demonstrated that the response to corticosteroids is usually prompt. However, the resolution of pulmonary changes may be incomplete and second-line treatment may be necessary.

АНАЛИЗ ПРИЧИН СМЕРТИ, СТРУКТУРЫ ВТОРИЧНОЙ И СОПУТСТВУЮЩЕЙ ПАТОЛОГИИ ВИЧ-ИНФИЦИРОВАННЫХ ПАЦИЕНТОВ ГОМЕЛЬСКОЙ ОБЛАСТИ

Background. The analysis of the spectrum of causes of death associated with HIV infection presents some difficulties, since a significant number of deaths of HIV-infected patients are not directly related to the manifestation of immunodeficiency. The goal is to determine the spectrum of secondary diseases, the immediate and main causes of death, as well as target organs for opportunistic infections and diseases of HIV-infected patients in Gomel region. Material and methods. The case histories, data of of infectious diseases and the protocols of pathological autopsies of HIV-infected patients in the Svetlogorsk district of Gomel region for 2012-2018 were studied. Results. Among HIV-infected deceased patients, men predominate (more than 60%), aged 35 to 44 years (about 50%). The number of deceased patients with the experience of infection from 1 to 12 years is decreasing and increasing from 13 to 21 years (28.4%). Life expectancy after HIV infection is 10.5 ± 4.9 years. Among HIV-infected deceased patients who had indicators of immune status, the content of CD4 + lymphocytes were less than 200 cells in 63.8% of patients, in 23.3% the number of CD4 + cells at the time of death was less than 50. Viral load in 22.4% of deaths at the time of death exceeded 500,000 copies/μl, the majority (89.2%) of the dead had the 4th clinical stage of HIV infection. Conclusions. In 74.6% of patients, HIV infection was the main disease and the main cause of death. Among the spectrum of secondary diseases that caused death pneumocystis pneumonia, progressive multifocal leukoencephalopathy, cryptococcal infection, toxoplasmosis of the brain, tuberculosis, lymphomas, CMV-infection, generalized candidiasis, atypical mycobacteriosis, pulmonary aspergillosis and others were identified. In 25.4% of cases, HIV infection was regarded as concomitant rather than the main pathology, among which liver cirrhosis and other pathologies predominated: acute cerebrovascular accident, coronary heart disease, chronic rheumatic heart disease, dilated cardiomyopathy, chronic alcoholic disease and others. The increase in the number of autopsies and constant monitoring of the causes of death of HIV-infected deaths and associated opportunistic infections and diseases will improve the quality and speed up the time-to-life diagnosis of various pathologies in HIV-infected patients.

HETEROZYGOUS MUTATIONS OF THE MAJOR HISTOCOMPATIBILITY CLASS-II ASSOCIATED MOLECULES

Introduction Major histocompatibility class II (MHC-II) molecules are transmembrane proteins that have a fundamental role in the development and control of the immune system. The expression of MHC-II molecules is tightly regulated. Four disease-causing genes have been identified that control the transcription of MHC-II genes including MHC-II transactivator (CIITA) and Regulatory Factor X Associated Ankyrin Containing Protein (RFXANK). Homozygous mutations affecting the transcription of these genes leads to a primary immunodeficiency known as MHC-II deficiency. Here we report two cases with severe clinical manifestations of immunodeficiency in patients with heterozygous mutations of the CIITA and RFXANK proteins. Case Description Case 1: A 34-year-old female presented for recurrent respiratory tract infections since childhood. She had previously been treated with prophylactic antibiotics and intravenous immunoglobulin (IVIG) therapy without improvement. She continued to require hospitalization every two months for resistant infections. Immunodeficiency workup demonstrated a decrease of B cells and immunoglobulins. Genetic testing showed a heterozygous variant in CIITA. Case 2: An 18-year-old female presented for autoimmune cytopenias, large lymphadenopathy, and recurrent infections since childhood including recurrent otitis media, sinusitis, and bronchitis. Immunodeficiency workup demonstrated a decrease in immunoglobulin levels, B cells, and T cells. Genetic testing showed a heterozygous variant in RFXANK. Discussion Homozygous mutations of transcription factors of MHC-II molecules leads to a primary immunodeficiency known as MHC-II deficiency. Although difficult to classify, heterozygous mutations of the MHC-II deficiency related genes may still present with clinically significant immunodeficiency.

Herpès chronique périnéal résistant à l’aciclovir révélateur d’une leucémie lymphoïde chronique

Chronic HSV infection is a cause of chronic perineal ulcerations. We report a case of a chronic and refractory HSV infection revealing chronic lymphoid leukaemia. An 85-year-old woman with an 8-month history of chronic perineal ulcerations was referred to our dermatology department. She had no previous medical history of herpes infection. Skin biopsies ruled out carcinoma but were consistent with HSV infection. A local swab was positive for HSV2. Treatment with valaciclovir and intravenous acyclovir (ACV) at the recommended doses was ineffective. Laboratory tests revealed type-B chronic lymphoid leukaemia. Molecular biology studies confirmed the presence of ACV-resistant HSV via decreased thymidine kinase activity (stop codon: M183stop). Foscarnet was administered for a period of 3weeks with almost complete healing of the ulcerations. Treatment was stopped prematurely due to acute renal insufficiency and the remaining lesions were treated using imiquimod cream. Valaciclovir was prescribed to prevent further episodes. The condition recurred a mere 11months later. The prevalence of ACV-resistant HSV is 0.32% in immunocompetent patients and 3.5% in immunocompromised patients. Insufficient dosing regimens or prolonged treatment with TK inhibitors result in the local selection of pre-existing mutant HSV viruses. Foscarnet, a DNA polymerase inhibitor, is the treatment of choice in HSV-resistant infections. ACV-resistant HSV is less virulent and replicates less, with reactivations being mainly due to wild-type HSV latent in the neural ganglia. Valaciclovir can be used as a preventive treatment. To our knowledge, this is the first case of ACV-resistant HSV infection revealing chronic lymphoid leukaemia. Chronic perineal ulcerations can be the first manifestation of immunodeficiency seen for example with haematological diseases. In the event of clinical resistance of an HSV infection to recommended thymidine kinase inhibitor regimens, the use of foscarnet should be considered.

Rare Presentation of Large Cell Lymphoma

Lymphoma is a common cancer of childhood. Its pathologic subtype of anaplastic large cell Non-Hodgkins Lymphoma (NHL) is rare and spread to the central nervous system (CNS) is even rarer. We present here such a case who presented to us with an acute history of fever and diplopia and co-existent polyarthritis since 8 years diagnosed as NHL with CNS involvement. CNS involvement is a rare presenting manifestation of NHL and is an important cause of morbidity and mortality in these patients. Chronic arthritis could be a risk factor or manifestation of immunodeficiency or immune dysregulation when associated with lymphoma. It is important to suspect NHL in children presenting with these symptoms for prompt evaluation and better clinical outcome.

Ecthyma Gangrenosum in a Previously Healthy Infant

Ecthyma Gangrenosum in a Previously Healthy Infant

Immunological and Hematological Findings Associated with Thymic Epithelial Neoplasms

AbstractAbstract 1742 Introduction:Although it is well known that thymic epithelial neoplasms are associated with autoimmune and manifestations of immunodeficiency, the extent to which abnormatilies in clinical hematological or immunological function occur in this population has not been completely documented. This retrospective study aimed to characterize the clinical hematological and immunological features of patients with thymic epithelial neoplasms. Methods:From a cohort of 512 patients with thymic epithelial neoplasms, 79 patients (33 males, 46 females) with diagnosed autoimmune/immunodeficiency conditions or signs and/or symptoms suggesting an autoimmune or immunodeficiency state were evaluated by standard immunogical and hematological testing. “Autoimmune conditions” included myasthenia gravis, pure red cell aplasia (PRCA), thyroiditis/hypothyroidism, glomerulonephritis, Sjõgren's syndrome, systemic lupus erythematosus, transverse myelitis, Issac's syndrome, Raynaud's disease, granuloma annulare, vitiligo, alopecia, dermatomyositis, Morvan's syndrome and chronic urticaria. Conditions designated as “immunodeficiencies” included Good's syndrome, onychomycosis, recurrent oral candidiasis, herpes zoster and opportunistic infections designated as AIDS-defining illnesses. Results were collected and tabulated from data in the electronic medical record CareWeb™, the web browser version of the Regenstrief Medical Records System of the Indiana University and Melvin and Bren Simon Cancer Center. Results:Pure red cell aplasia (PRCA) was present in 6 (7.6%) and Good's syndrome in 7 (8.9%) patients. Cytopenias were diagnosed in 40 (50.6%); anemia in 25 (31.6%); leucopenia in 12 (15.2%) and thrombocytopenia in 7 (8.9%) patients. IgG, IgA and IgM levels were low in 12 (15.2%), 9 (11.4%) and 15 (18.9%) patients respectively. Quantification of peripheral blood lymphocyte immunophenotypes revealed increases in CD2+ (n=44; 57.1%), CD3+ (n=33; 41.8%) and CD8+ (32; 40.5%) cell percentages and decreases in CD4+ (25; 31.6%) and CD19+ (36; 46.2%) cell percentages. Inverted CD4/CD8 ratios were present in 18 (23.7%) patients. The presence of “immunodeficiency condition(s)” was associated with a high CD8+ percentage (p=0.040), low CD19+ percentage (p=0.025) and an inverted CD4/CD8 ratio (p=0.034). The presence of an “autoimmune condition(s)” was associated with a high/normal CD4+ percentage (p=0.038). A high CD2+ percentage was associated with lower mean IgG and IgA levels (p=0.030 and p=0.017, respectively). Patients with high CD3+ and CD8+ percentages had lower mean IgA levels (p=0.046 and p=0.013, respectively). A low CD19+ percentage was strongly associated with lower mean IgG and IgA levels (p=0.004 and p=0.001, respectively). No associations were observed between lymphocyte subpopulation percentages and mean serum IgM levels. Conclusion:Although we observed a number of patients with PRCA and Good's syndrome, this selected cohort of patients with thymic epithelial neoplasms had a broad spectrum of cytopenias and concomitant autoimmune/immunodeficiency conditions. We observed high T cell percentages and low B cell percentages compared to adult normal values. High T cell profiles were commonly attributed to increased CD8+ percentages. Patients with autoimmune conditions are more likely to have normal or high CD4+ percentages; patients with clinical immunodeficiencies are more likely to have high CD8+, low CD19+ percentages and inverted CD8/CD4 ratios. These observations suggest a role for the assessment of immunoglobulin levels and lymphocyte immunophenotypes in patients with thymic epithelial neoplasms and associated immune mediated conditions. Disclosures:No relevant conflicts of interest to declare.

Doença de Graves e deficiência de IgA como manifestações da síndrome de deleção 22q11.2

The 22q11.2 deletion syndrome (22q11.2DS) is related to a high phenotypic variability including the velocardiofacial/DiGeorge spectrum. Autoimmune, endocrine and immunodeficiency manifestations have been reportedly associated with the syndrome. The objective of this study was to report a case of 22q11.2DS associated with IgA deficiency and Graves disease and review literature in order to verify the frequency of syndrome alterations. Autoimmune disorders have been increasingly related to 22q11.2DS, and new phenotypes are being incorporated in the clinical spectrum of this syndrome. In our study we found that Graves disease in association with 22q11.2DS was reported in only sixteen patients, and fifteen cases were described in the last 13 years. Based on the incidence and on the amplitude of this recognized spectrum, we reinforce the findings of literature that Graves disease should be included on the 22q11.2DS manifestations, which would lead us to seek it with 22q11.2 deletion patients.

MHC class 2 deficiency and X‐linked agammaglobulinaemia in a consanguineous extended family

Manifestations of immunodeficiency within the same family are presumed to be the same disease. We report a consanguineous extended family where four patients have immunodeficiency, three have X-linked agammaglobulinaemia and one has major histocompatibility complex class 2 deficiency. Within one family, two rare genetic diseases with similar clinical manifestations can occur.

Genetic Susceptibility to Fungal Infections

Mucocutaneous and invasive Candida infections are common manifestations of immunodeficiency. In most cases, the cause of an impaired immune response (e.g., chemotherapy, HIV infection, diabetes) is evident. Two research groups recently conducted genetic and immunologic analyses of families containing many individuals who suffer chronically or repeatedly from superficial or invasive yeast infections but have no obvious immunocompromising condition. Studying a family of Dutch ancestry whose members had …

A case of HIV co‐infected with hepatitis B virus precore/core deletion mutant treated by entecavir

We report a case of a HIV and hepatitis B virus (HBV)-co-infected patient to whom entecavir (ETV) was administered initially before the notification regarding the potential mutagenesis effect on HIV against the nucleoside analog. Since initial evaluations indicated the advanced stage of chronic hepatitis B and preserved numbers of peripheral CD4+ lymphocytes without the manifestation of immunodeficiency, priority was given to the management of HBV. We started HBV therapy with ETV at a dose of 0.5 mg daily without using any HIV drugs. The viral loads of both HBV and HIV-1 decreased gradually during the 5 months following the initial administration of ETV. HBV was well controlled by the gradual replacement of ETV with highly-active antiretroviral therapy against HIV with a regimen including atazanavir, emtricitabine, and tenofovir. HBV was genotyped as A2 with the quasispecies pool consisting of the -1G precore/core deletion mutant strain.

Monocyte disorder causing cellular immunodeficiency: a family study

We report a familial type of monocyte dysfunction not recognized previously. This disorder was observed in a young adult man with a long clinical history of recurrent, self-limited episodes of cryptogenic fever accompanied by digestive and respiratory symptoms and repeated oral and skin infections. Lectin-induced lymphocyte transformation was reduced and skin tests revealed anergy to tuberculin and candidin. Monocytes from this patient exhibited markedly diminished expression of cytoskeletal vimentin intermediate filaments, HLA-DR antigens and immunological receptors for IgG Fc and C3b. These abnormal monocytes demonstrated impaired phagocytosis and reduced accessory cell function on PHA-mediated lymphocyte activation. Release of soluble lymphocyte-activating factors by these cells was found to be defective. Lymphocytes from the patient responded appropriately to lectin in the presence of normal monocytes. Two family members of the proband presented similar monocyte defects although they only manifested minor clinical symptoms. This syndrome underlines the interest of testing monocyte markers and function in subjects with clinical manifestations of immunodeficiency.

Perforating Neutrophilic and Granulomatous Dermatitis of the Newborn—A Clue to Immunodeficiency

We report two newborns with a widespread cutaneous eruption consisting of discrete papules which evolved into vesicles, pustules, crusts, and ulcers. These healed over a 2-week period with scarring. Histopathology showed three main features--histiocytic granulomas, neutrophilic infiltration, and transepidermal elimination of degenerated collagen and debris through hair follicles. Both patients had congenital immunodeficiency. This skin condition of the newborn, with distinct clinical and histopathologic features, is a manifestation of immunodeficiency that has not been previously described.

Presentación atípica de inmunodeficiencia variable común sin clínica infecciosa

BackgroundCommon variable immunodeficiency (CVID) is a primary immunodeficiency disease, the hallmark of which is hypogammaglobulinemia and poor specific antibody responses. Patients usually have recurrent bacterial infections, but there are a number of other comorbid disorders, including autoimmune disease and neoplasms. Most patients are diagnosed as adults, and delay in identifying the antibody defect is common. In the present report, we illustrate atypical initial presentation without infections in CVID Clinical observationIn 5 out of 30 patients with CVID (16.6 %) diagnosed in our hospital in the Autonomous Community of Madrid, the first manifestation of immunodeficiency was not an infection. Three patients presented with immune cytopenias (thrombocytopenic purpura [n = 2] and hemolytic anemia [n = 1]); one patient had pernicious anemia and one patient had insulin-dependent diabetes as the first clinical feature of CVID. Four patients had IgG levels below 400 mg/dl ConclusionsAtypical presentations of CVID must be recognized to prevent delayed diagnosis. Presentation of CVID as an autoimmune disease in the absence of recurrent infections prompts us to suggest baseline testing of immunoglobulin levels in patients presenting with autoimmune disorders

Tuberculosis and AIDS: Is the white plague up and coming?

We have studied the effect of the HIV epidemic on the incidence of tuberculosis in an inner city area of London which has a high incidence of acquired immunodeficiency syndrome (AIDS). During the period 1985-1991, there was a steady increase in the number of new AIDS cases, whilst the numbers of notifications and laboratory isolates of Mycobacterium tuberculosis remained largely unchanged. Before 1990 there were few cases of tuberculosis in HIV-infected individuals but in the past 2 years there has been a marked increase. In 44% of patients, the site of infection was pulmonary, in 39% extrapulmonary and in 17% pulmonary and extrapulmonary. There were no previous manifestations of immunodeficiency in 58% of patients. This is the first study to show an association between tuberculosis and HIV in the U.K. and supports the suggestion that there is an increased incidence of tuberculosis in patients with HIV infection who are not intravenous drug users.

Varicella Pneumonia as the Presenting Manifestation of Immunodeficiency

Varicella Pneumonia as the Presenting Manifestation of Immunodeficiency

No Evidence for a Role of Alcohol or Other Psychoactive Drugs in Accelerating Immunodeficiency in HIV-1—Positive Individuals

In a multicenter cohort study of homosexual men, the proportion of seropositives at enrollment who developed the acquired immunodeficiency syndrome (AIDS) during the following 18 months ranged from 5.5% to 8.2% in 1597 alcohol drinkers vs 9.2% in 109 nondrinkers with no clear trend according to use, and from 6.3% to 9.6% for 1662 users vs 7.2% for 83 nonusers of psychoactive drugs prior to enrollment. Among seropositive men with low initial T helper lymphocyte counts, those who continued to use drugs showed no significantly higher 18-month risk of AIDS than nonusers (13% vs 10%); the corresponding risks were 13% and 15%, respectively, for continued heavier vs continued lighter consumption of alcohol. No other manifestations of immunodeficiency were positively associated with substance use prior to enrollment. Prior use was not associated with low mean T helper cell counts at enrollment, and continued drug or alcohol use after enrollment was not associated with greater subsequent decline in counts. As used in a large cohort of homosexual men, psychoactive substances did not enhance the progression of human immunodeficiency virus infection.