Severe IgA Deficiency Research Articles

P‐TS‐88 | To Wash or Not to Wash: Managing Transfusion Expectations in a Transplant Patient with Severe IgA Deficiency

P‐TS‐88 | To Wash or Not to Wash: Managing Transfusion Expectations in a Transplant Patient with Severe IgA Deficiency

Guideline on the investigation and management of acute transfusion reactions.

Guideline on the investigation and management of acute transfusion reactions.

PROLONGED BLOOD HYPEREOSINOPHILIA AND EOSINOPHILIC ENTEROCOLITIS FROM PINWORM INFECTION ASSOCIATED WITH IGA AND IGE DEFICIENCY

<h3>Introduction</h3> Pinworm (<i>Enterobius vermicularis</i>) infection is generally considered a benign infection without systemic symptoms. However, severe infections can cause gastrointestinal inflammation, blood eosinophilia and systemic symptoms. What factors contribute to severe disease remains unclear. We present a case of pinworm infection causing prolonged blood hypereosinophilia and eosinophilic enterocolitis in a patient with severe combined IgA and IgE deficiency. <h3>Case Description</h3> A 16-year-old, non-atopic female presented at age 10 with intermittent low-grade fevers, abdominal pain and blood eosinophilia (AEC 3100 cells/mcL). Etiology was undetermined. As her abdominal pain continued, she was diagnosed with IBS; her blood hypereosinophilia persisted and remained unexplained. At age 15, she developed recurrent episodes of abdominal pain, non-bloody watery diarrhea and intermittent emesis. Evaluation revealed severe blood eosinophilia (AEC 6200 cells/mcL), elevated fecal calprotectin (95 mcg/gm) and gastrointestinal (esophagus, stomach, small and large intestine) eosinophilic inflammation. Direct endoscopic visualization, stool and serology testing for parasites were negative. Immunologic evaluation revealed mildly decreased IgG (621 mg/dL), undetectable IgE, low IgA (14.5 mg/dL) and normal IgM. Eosinophilia etiology remained undetermined; she was diagnosed with hypereosinophilic syndrome and treated with mepolizumab (anti–IL-5), which improved her blood eosinophilia but not her symptoms. Repeat EGD/colonoscopy (after 6 months) showed improved gastrointestinal eosinophilia but was notable for direct visualization of pinworms. Mepolizumab was discontinued. Albendazole completely resolved her symptoms; blood eosinophilia and IgG normalized, but IgA and IgE remained undetectable. <h3>Discussion</h3> Pinworms can cause persistent gastrointestinal disease and severe blood hypereosinophilia. We postulate that mucosal immunodeficiency secondary to IgA and IgE deficiency contributed to this presentation.

Celiac Disease.

Celiac Disease.

Atypical presentation of IgA-related immediate reaction with back pain and relative hypotension – anaphylaxis or not?

Anaphylactic transfusion reactions are rare occurring in approximately 1 in 50,000 red cell transfusions.1 One aetiology includes the development of antibodies against transfused IgA in patients with severe IgA deficiency. Diagnosis of IgA-related anaphylaxis involves the measurement of IgA levels and anti-IgA antibodies.2 Recently, the evidence underlying this entity and the causal relationship between laboratory tests and clinical manifestation has been questioned.3 We describe a case of a 50-year-old man with chronic anaemia with an infected enterocutaneous fistula.

Atypical presentation of iga-related immediate reaction with back pain and relative hypotension – Anaphylaxis or not?

Anaphylactic transfusion reactions are rare, occurring in approximately 1 in 50,000 red cell transfusions.1 One aetiology includes the development of antibodies against transfused IgA in patients with severe IgA deficiency. Diagnosis of IgA-related anaphylaxis involves the measurement of IgA levels and anti-IgA antibodies.2 Recently, the evidence underlying this entity and the causal relationship between laboratory tests and clinical manifestation has been questioned.3 We describe a case of a 50-year-old man with chronic anaemia with an infected enterocutaneous fistula. He received six red cell transfusions where he developed severe back pain and relative hypotension within 15–30 minutes of transfusion, settling after transfusion was ceased. He was afebrile with no respiratory, dermatological or gastrointestinal manifestations typical of anaphylaxis. Direct antiglobulin test was negative, and blood cultures were sterile. Tryptase taken 2.6 hours after symptom onset was raised 16 μg/L (0.0–11.4 μg/L). IgA level was <0.10 g/L (0.80–4.40g/L). Anti-IgA titre was 400 U/mL (0–7 U/mL). IgA deficient components were prepared pre-operatively. He subsequently received three washed red cells uneventfully, one during a laparotomy for the enterocutaneous fistula. This case describes an atypical presentation of a rare but important complication of blood transfusion, as well as the diagnostic process and subsequent management.

Variant Ataxia Telangiectasia: Clinical and Molecular Findings and Evaluation of Radiosensitive Phenotypes in a Patient and Relatives

Variant ataxia telangiectasia (A-T) may be an underdiagnosed entity. We correlate data from radiosensitivity and kinase assays with clinical and molecular data from a patient with variant A-T and relatives. The coding region of ATM was sequenced. To evaluate the functional effect of the mutations, we performed kinase assays and developed a novel S-G2 micronucleus test. Our patient presented with mild dystonia, moderately dysarthric speech, increased serum α-fetoprotein but no ataxia nor telangiectasias, no nystagmus or oculomotor dyspraxia. She has a severe IgA deficiency, but does not have recurrent infections. She is compound heterozygote for ATM c.8122G>A (p.Asp2708Asn) and c.8851-1G>T, leading to in frame loss of 63 nucleotides at the cDNA level. A trace amount of ATM protein is translated from both alleles. Residual kinase activity is derived only from the p.Asp2708Asn allele. The conventional G0 micronucleus test, based on irradiation of resting lymphocytes, revealed a radiosensitive phenotype for the patient, but not for the heterozygous relatives. As ATM is involved in homologous recombination and G2/M cell cycle checkpoint, we optimized an S-G2 micronucleus assay, allowing to evaluate micronuclei in lymphocytes irradiated in the S and G2 phases. This test showed increased radiosensitivity for both the patient and the heterozygous carriers. Intriguingly, heterozygous carriers of c.8851-1G>T (mutation associated with absence of kinase activity) showed a stronger radiosensitive phenotype with this assay than heterozygous carriers of p.Asp2708Asn (mutation associated with residual kinase activity). The modified S-G2 micronucleus assay provided phenotypic insight into complement the diagnosis of this atypical A-T patient.

Symptomatic Secondary Selective IgM Immunodeficiency in Adult Man with Undiagnosed Celiac Disease.

Selective IgM immunodeficiency (SIgMID) is a heterogeneous disorder with no known genetic background and may occur as a primary or a secondary condition. Celiac disease has been reported in association with several humeral immunodeficiencies, including isolated severe selective IgA deficiency, panhypogammaglobulinemia, and isolated combined IgA and IgM deficiency. There are only few reported cases of pediatric and adult patients with SIgMID and celiac disease. In this paper, we describe an adult patient with a symptomatic secondary SIgMID associated with undiagnosed celiac disease, with a resolution of clinical symptoms of immunodeficiency and serum IgM normalization following a gluten-free diet.

NK-Cell and B-Cell Deficiency with a Thymic Mass

To the Editor: We report a case of a combined immunodeficiency syndrome, thymic hyperplasia, and impaired lymphatic system function that strongly resembled the phenotype of the Ikaros-null knockout mouse. The patient was well until her early teenage years when she had bacteremia of unknown cause. At menarche, lymphedema developed in her legs. At 16 years of age, she had disseminated varicella–zoster infection, which culminated in a splenectomy for possible splenic rupture. In her 20s and 30s, she had frequent sinopulmonary infections, and severe IgA deficiency and a profound deficiency of natural killer (NK) and B cells were eventually diagnosed. She . . .

Patients with Severe Factor XI Deficiency Who Have An Inhibitor or IgA Deficiency Can Undergo Uneventful Major Surgery by a Single Infusion of Low Dose Recombinant Factor VIIa and Use of Tranexamic Acid.

Inhibitors to factor XI (FXI) can develop following exposure to plasma products in 33% of patients with severe FXI deficiency who are homozygous for the type II nonsense mutation prevalent in Jews (Salomon et al. Blood 2003; 101:4783). Hemostasis in five such patients was previously achieved during surgery by infusion of recombinant factor VIIa (rFVIIa) and tranexamic acid, but two patients experienced arterial thrombosis following surgery (Schulman et al. Hemophilia 2006; 12:223). Conceivably, the rather high dose of rFVIIa used was responsible for the thrombotic events in these patients. In a previous in vitro study, we showed that low concentrations of rFVIIa can correct thrombin generation in plasma of patients with severe FXI deficiency and an inhibitor to FXI (Livnat et al. J Thromb Hemost 2006; 4:192). In the present study we addressed the question whether low doses of rFVIIa and use of tranexamic would be hemostatically effective and less thrombogenic during and after major surgery in patients with severe FXI deficiency in whom plasma derivatives could not be used. Three patients (two with FXI inhibitor and one with severe IgA deficiency) underwent major surgery managed by a single low dose infusion of rFVIIa and administration of tranexamic acid 1 G q.i.d for 7 days (Table). In patient 1 the infusion was given immediately prior to surgery and in patients 2 and 3 at the end of surgery. Hemostasis was achieved in all patients and no thrombosis occurred.No.Sex/ageFXI (U/dL)FXI inhibitor (B.U)OperationSingle dose rVIIa (uG/Kg)Adverse events1M/62< 0.015.0Laparoscopic cholecystectomy30None2M/61< 0.015.0Transuretheral prostatectomy16None3M/630.020*Parathyroidectomy15None* IgA deficiencyThese observations suggest that a single infusion of low dose rFVIIa and use of tranexamic acid can be a safe modality of treatment in patients with severe FXI deficiency who cannot receive blood products. Furthermore, the protocol outlined here may be used to avoid inhibitor formation in patients with extremely severe FXI deficiency who undergo surgery.

Atypical celiac disease with IgA deficiency presenting as Plummer–Vinson syndrome: a case report

A 40-year-old man presented with insidious onset dysphagia for both solids and liquids for 4 years with recurrent oral ulcerations. On examination he was anemic, and barium swallow demonstrated a web in the postcricoid region. As part of the workup for unexplained iron deficiency anemia, a duodenal biopsy was taken that revealed moderate flattening of villi with increased intraepithelial lymphocytes consistent with the diagnosis of celiac disease. However, the serological tests for celiac disease (IgA antiendomysial antibody, IgA antitissue transglutaminase antibody, and IgA antigliadin antibody) were all negative. Serum level of IgA was markedly low. A diagnosis of atypical celiac disease with severe selective IgA deficiency was made. After the institution of a gluten-free diet (GFD), his general condition as well as anemia improved. Histological recovery was documented on repeat duodenal biopsy 6 months after GFD.

Long-term follow-up of health in blood donors with primary selective IgA deficiency.

A 20-year health follow-up study of 159 initially healthy blood donors with a severe deficiency of serum IgA ( < 0.05 x 10(-3) g/L) and of 45 donors with decreased serum IgA (0.05 x 10(-3)-0.8 g/L) was carried out. The findings indicate that persons with a severe deficiency of and decreased serum IgA who are healthy as young adults have an increased susceptibility to pneumonia and recurrent episodes of other respiratory infections and a higher risk of developing autoimmune diseases in middle age. Vitiligo, autoimmune hypothyreosis, milk intolerance, and possible rheumatoid arthritis were associated with severe IgA deficiency, but otherwise different degrees of IgA deficiency seem to be similar with respect to the appearance of diseases. Regardless of the fact that a total of 163 (80%) of the 204 IgA-deficient subjects had-episodes of infections, drug allergy, or autoimmune or atopic disease, the finding of primary, selective IgA deficiency in a healthy adult per se does not seem to predict severe life-threatening illnesses at least during 20 years of life.

SELECTIVE IgA DEFICIENCY AND HYPOGAMMAGLOBULINEMIA IN 4p - (WOLF-HIRSHHORN) SYNDROME. • 51

Immunodeficiency is a predictable (e.g. Chediak-Higashi Syndrome, ataxia-telangiectasia), frequent (e.g. Netherton syndrome, dyskeratosis congenita) or occasional (Chromosome 18p deletion, methylmalonic acidemia) component of 64 recognizable genetic syndromes. (Ming, Stiehm, Graham, Am. J. Human Genetics, 1995). The immunodeficiency can involve the antibody, T cell, natural killer (NK) or phagocytic systems. We have identified severe selective IgA deficiency (IgA < 10 mg/dl) in 3 children, mild selective IgA deficiency (IgA 10-20 mg/dl) in 2 children, and pan-hypogammaglobulinemia in 2 children with the 4p - (Wolf-Hirshhorn) syndrome. These children, ages 1yr. to 5 yr, had frequent respiratory infections and variably deficient antibody responses. One IgA deficient child had an associated IgG2 subclass (2 mg/dl) deficiency. Two have received IVIG with clinical benefit. T cell and B cell studies were normal. Four other children (ages 2½ - 13 yrs) with 4p-syndrome were evaluated and found to be normal.

Long-term follow-up of anti-IgA antibodies in healthy IgA-deficient adults.

A follow-up study of anti-IgA antibodies in 159 healthy blood donors with severe deficiency of serum IgA (< 0.05 mg/L) and in 45 donors with decreased serum IgA levels (0.05-799 mg/L), identified in 1971-1980, was carried out. Initially anti-IgA antibodies were determined by a hemagglutination (HA) method and two reexaminations were done in 1990-1992 by an enzyme immunoassay. The median follow-up period was 19 years, during which anti-IgA level was changed considerably in only four persons, increased in two, and high level antibodies (> 1/1000 by HA) appeared in two. In reexaminations anti-IgA antibodies were found in 30 (19%) subjects with severe IgA deficiency and the antibody levels remained relatively constant in those who had high and medium antibody levels. Anti-IgA antibodies were not found in subjects with decreased, but detectable serum IgA. Thus it seems that only those healthy adults who have severe IgA deficiency develop anti-IgA antibodies and their anti-IgA levels remain fairly constant. Of the 159 subjects with severe IgA deficiency, 66 had a history of IgA exposure, but no correlation to anti-IgA development was noted.

Recurrent extended HLA haplotypes in children with selective IgA deficiency.

HLA supratypes as well as serum IgG, IgA and IgM levels were determined in 44 children and adolescents with severe IgA deficiency (serum IgA less than 5 mg/dl) and in first degree relatives. Frequencies of the HLA alleles B14, DR1, DQW1, C4A2 and C4B2 were significantly higher in the IgA-deficient patients than in the controls. The most recurrent haplotype among patients was B14, DR1 (p less than 10(-4) preferentially associated with A33, A28 or A blank. The supratype B14, Bfs, C4A2, C4B2, DR1, DQW1 was present in a 14-fold higher frequency than in the controls, and strongly suggests the presence of a gene in the HLA region involved in the deficiency of IgA. The fact that this supratype was not always associated with IgA deficiency in the parents and that not all IgA-deficient subjects had this supratype is discussed. Severe IgA deficiency was found in four mothers (two of the four mother-child pairs shared the B14, DR1 haplotype); three other relatives (one father and two brothers) had partial IgA deficiency and did not have the B14, DR1, DQW1 haplotype.

Anti-IgA antibodies in IgA-deficient children.

IgG and IgM isotype antibodies to polyclonal human IgA, myeloma IgA1, and myeloma IgA2 were estimated in 38 IgA-deficient children aged between 0.9 and 15 years. All children had IgM anti-IgA antibodies. IgG antibodies against either polyclonal IgA, IgA1, or IgA2 were present in 63% of the IgA-deficient children. IgG anti-IgA antibodies were detected against all three antigens in 8 of 11 severely IgA-deficient children and in 7 of 27 partially IgA-deficient children, but in only 1 of 23 healthy adult controls. The proportion of children with IgG anti-IgA antibodies was significantly greater in the severely IgA-deficient group in comparison with the partially IgA-deficient group and the adult controls (chi-square test, P less than 0.01 and P less than 0.005, respectively). There was a strong correlation within each IgG subclass between antibody responses toward each of the three IgA antigens. Twenty-four children were followed over a period ranging from 0.9 to 11 years (mean, 2.3 years). Three children who were initially IgG anti-IgA antibody negative became antibody positive and three who were antibody positive became antibody negative. Five children with severe IgA deficiency remained severely IgA deficient and IgG antibodies to IgA persisted in all five at follow-up. The presence of IgG anti-IgA antibodies did not influence the normalization of serum IgA at follow-up in 14 of 19 children who were initially partially IgA deficient.

The Nephrotic Syndrome at Presentation of Insulin‐dependent Diabetes Mellitus; Cause or Coincidence?

Two young women developed the nephrotic syndrome within 2 weeks of presenting with diabetes and starting insulin. One had a renal biopsy which showed changes consistent with 'minimal change nephrotic syndrome' on electron microscopy but no evidence of diabetic glomerulosclerosis. Neither patient received steroids; in one the oedema resolved spontaneously but the other required diuretics. This patient also had severe IgA-deficiency probably associated with epilepsy and/or phenytoin therapy and unrelated to the pathogenesis of the nephrotic syndrome. The nephrotic syndrome may rarely present coincidentally with, or soon after, insulin-dependent diabetes mellitus (IDDM). It must be distinguished from 'insulin oedema' and classical diabetic nephropathy which occurs later in the course of IDDM. All reported cases have either remitted spontaneously or responded to steroids.