History

Previous studies based on analysis of blood donor banks have suggested that up to 90% of patients with selective immunoglobulin A deficiency (SIgAD) are asymptomatic. However, recent follow-up studies demonstrate that 80% of individuals with IgAD developed symptoms later in their life.^[70]Symptomatic patients have a history significant for recurrent otitis media, sinusitis, bronchitis, pneumonia, GI tract infections, severe allergic reaction following infusions with immunoglobulins or blood transfusions, or, in children, failure to thrive.

Recurrent sinopulmonary infection is the most common illness associated with IgAD. Most upper and lower respiratory tract infections are caused by bacterial or viral pathogens characteristic of community-acquired pneumonia. Patients with concomitant IgG type 2 subclass deficiency may have a higher risk for recurrent infections from S pneumoniae, H influenzae, M catarrhalis, or Staphylococcus aureus.
Various GI tract infections with viruses, bacteria, and G lamblia parasites manifest as chronic diarrhea with or without malabsorption. Biopsy specimens may show nodular lymphoid hyperplasia with flattened villi.
Food allergy and other atopic disorders, such as allergic conjunctivitis, rhinitis, urticaria, atopic dermatitis, and asthma, are common in patients with IgAD.
Of patients with IgAD, 10-44% have anti-IgA antibodies, and these patients may have severe adverse reactions to IgA-containing materials such as blood, plasma, or immunoglobulin.^[71]

Physical

Patients present with various signs of recurrent respiratory tract infections; including swelling, pain, or tenderness upon palpation over the maxillary and frontal sinuses; chronic otorrhea and/or scarred or perforated tympanic membranes and decreased auditory acuity or even deafness; chronic nasal discharge; fever; nonproductive or productive cough; and dyspnea. GI findings may include abdominal distention, focal tenderness to direct palpation (without rebound), cramps after eating, diffuse pain, and increased peristalsis.^{[72, 73]}

Causes

The underlying causes of most cases of this heterogeneous disease remain unknown. Familial inheritance has been recognized in 25% of affected individuals, suggesting a strong genetic influence.

Case reports of some affected families indicate that inheritance may be autosomal dominant or recessive. In other families in which multiple members are affected, the pattern of inheritance does not conform to strict Mendelian rules.
- In some families, the immunodeficiency can appear to skip generations; in others, one family member in a given generation may have IgAD, while another in the same generation may have common variable immunodeficiency (CVID), suggesting variable expressivity and penetrance of disease susceptibility gene(s).
- Recent studies have shown that susceptibility to either CVID or IgAD may be linked to specific alleles of the major histocompatibility complex, suggesting that these alleles, or alleles of closely linked genes with which they are in linkage disequilibrium, are somehow involved in the pathogenesis of CVID and IgAD.
IgA deficiency is a particularly notable aspect of ataxia-telangiectasia and related disorders in which mutations in DNA processing/repair mechanisms interfere with rearrangements of immunoglobulin and T-cell receptor genes. Other signs of ataxia-telangiectasia should be carefully sought in children presenting with IgAD, particularly if they also have developmental delays. These manifestations may occur before the telangiectases are obvious.
In his 1991 report of 2 mothers with IgAD, de Laat suggests that transplacental passage of anti-IgA antibodies can also cause IgAD in an infant by inducing excessive IgA-specific T-cell suppressor activity.^[74]
Certain drugs may also cause IgAD, but this form usually resolves once the medication is stopped. The following drugs have been implicated:
- D-penicillamine
- Sulfasalazine
- Aurothioglucose
- Fenclofenac
- Gold
- Captopril
- Zonisamide
- Phenytoin
- Valproic acid
- Thyroxine
- Chloroquine
- Carbamazepine
- Hydantoin
- Levamisole
- Ibuprofen
- Salicylic acid
- Cyclosporin A
Infections may cause transient IgAD. The following have been recognized as causes:
- Rubella
- Cytomegaloviruses
- Toxoplasma gondii
- Congenital rubella and Epstein-Barr virus infection - May result in persistent IgAD
IgAD can follow bone marrow transplantation from an IgA-deficient donor into a histocompatible sibling not previously deficient in IgA.
Occupational exposure to benzene: Workers maintaining cargo tanks that contain crude oil residues were exposed to benzene, as documented by blood and urine samples and exposure measurements. Tank workers showed a decline in IgA from baseline to pre-next shift, with suppression correlating with benzene concentrations in blood and urine and time spent in the tank. Declines in IgM and CD4 T cells were also noted.^[75]

Differential Diagnoses

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Media Gallery

Chest radiograph of a 50-year-old man with immunoglobulin A deficiency and severe bilateral pneumonia. He also had congenital heart disease. Serum immunoglobulin G and immunoglobulin M levels were normal.
Lateral chest radiograph of a 50-year-old man with immunoglobulin A deficiency and severe bilateral pneumonia.
Portable chest radiograph of a 50-year-old man with acute respiratory distress syndrome as a complication of severe bilateral pneumonia. The patient died from respiratory failure 2 days after this x-ray film was taken.

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Author

Marina Y Dolina, MD Consulting Physician, Wellspan Lung, Sleep and Critical Care Consultants and Pulmonary Services, York Hospital, Wellspan Health System

Marina Y Dolina, MD is a member of the following medical societies: American College of Chest Physicians, American Medical Association, American Thoracic Society, Pennsylvania Medical Society

Disclosure: Nothing to disclose.

Coauthor(s)

Rebecca Bascom, MD, MPH Professor of Medicine, Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, Pennsylvania State College of Medicine, Milton S Hershey Medical Center; Graduate Faculty Member, Pennsylvania State University College of Medicine and The Huck Institutes of the Life Sciences

Rebecca Bascom, MD, MPH is a member of the following medical societies: American Thoracic Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Michael R Simon, MD, MA Clinical Professor Emeritus, Departments of Internal Medicine and Pediatrics, Wayne State University School of Medicine; Professor, Department of Internal Medicine, Oakland University William Beaumont University School of Medicine; Adjunct Staff, Division of Allergy and Immunology, Department of Internal Medicine, William Beaumont Hospital

Michael R Simon, MD, MA is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Allergy, Asthma and Immunology, American College of Physicians, American Federation for Medical Research, Michigan Allergy and Asthma Society, Michigan State Medical Society, Royal College of Physicians and Surgeons of Canada, Society for Experimental Biology and Medicine

Disclosure: Have a 5% or greater equity interest in: Secretory IgA, Inc. ; siRNAx, Inc.<br/>Received income in an amount equal to or greater than $250 from: siRNAx, Inc.

Chief Editor

Michael A Kaliner, MD Clinical Professor of Medicine, George Washington University School of Medicine; Medical Director, Institute for Asthma and Allergy

Michael A Kaliner, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Association of Immunologists, American College of Allergy, Asthma and Immunology, American Society for Clinical Investigation, American Thoracic Society, Association of American Physicians

Disclosure: Nothing to disclose.

Additional Contributors

Melvin Berger, MD, PhD Adjunct Professor of Pediatrics and Pathology, Case Western Reserve University; Senior Medical Director, Clinical Research and Development, CSL Behring, LLC

Melvin Berger, MD, PhD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association of Immunologists, American Pediatric Society, American Society for Clinical Investigation, Clinical Immunology Society

Disclosure: Received salary from CSL Behring for employment; Received ownership interest from CSL Behring for employment; Received consulting fee from America''s Health insurance plans for subject matter expert for clinical immunization safety assessment network acvtivity of cdc.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author, Bettina C Hilman, MD, to the development and writing of this article.

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