George was sort of a hard luck guy. Now eighteen years old, he had a history of repeated sinus infections and his pediatrician previously had concerns about potential chronic bronchial infections caused by common bacteria. (The medical records mentioned Haemophilus influenzae and Strep pneumoniae.) His mother told him that when he was very young (about two years old) he had a series of “crouplike” episodes (inflammation of the larynx and trachea with “noisy” breathing) that seemed resistant to antibiotics. These were diagnosed as viral and became less frequent as George got older. Because George had repeated cases of bacterial respiratory infections through puberty, his pediatrician considered the possibility of immunodeficiency and evaluated him further at age thirteen. He had a mildly elevated neutrophil count along with a normal lymphocyte count with a normal ratio of B and T cells. His total immunoglobulin level was slightly low (on the lower borderline of normal). At that time, levels of individual immunoglobulin classes (IgG, IgA, and IgM) were not done. George mentioned that he was extremely sensitive to poison ivy, and, based on that, the pediatrician assumed that delayed hypersensitive reactions (dependent on T cell and macrophage function) were normal. The pediatrician considered the possibility that George had a mild deficiency in B cell function (humoral immunity). She prescribed a course of broad spectrum antibiotics, gave George an intramuscular injection of “gamma globulins” (a crude preparation of Ig prepared from pooled plasma), and asked George to return in two months for further evaluation and possible gamma globulin therapy. George felt much better over the next month with no further sinus or respiratory problems. He did not care for the gamma globulin injection and did not return for further evaluation. George did relatively well over the next four years. He had far fewer sinopulmonary infections but did develop an allergy to a variety of pollens that progressed to mild asthma, which was treated with occasional use of bronchodilators. At age seventeen George began to have mild gastrointestinal problems with bloating, cramping, and diarrhea. His girlfriend Shelly had given up gluten containing products and suggested George try it. George was a skeptic, but to his surprise a gluten free diet helped. It was clear that eating grain products made his gastrointestinal problem worse. George’s pediatrician was doubtful but agreed to order testing when George showed her a food diary that linked his symptoms to gluten consumption. She ordered a TTG-IgA test (which is both highly specific and sensitive for the presence of celiac disease), and it was negative. The pediatrician diagnosed a mild food intolerance (but not celiac disease). George continued his low gluten diet, which made his gastrointestinal condition better (and pleased his girlfriend Shelly). Now George’s luck has become worse. While riding on his motor bike, he hit a wet patch on the road, skidded, and slid into a tree. His blood pressure was low when the emergency responders arrived, and George was rushed to the local hospital. His blood pressure remained low, and he was evaluated for internal bleeding as a result of splenic rupture. His surgeon ordered that blood be available for transfusion should it be needed. There was considerable bleeding during surgery, and transfusion was required postsurgery. Immediately on starting the transfusion, the nurse noted wheezing, hypotension, flushing, and signs of shock. An anaphylactic transfusion reaction was diagnosed, the transfusion was immediately stopped, and intravenous epinephrine and hydrocortisone was administered. George responded satisfactorily and recovered from surgery without further problems.
Discussion
Transfusion reactions can occur from a wide variety of causes (both immune and nonimmune mediated); however, such reactions are uncommon, occurring in about 0.24 percent of all transfusions in the United States. Anaphylactic transfusions are rare, with a reported incidence of 0.005 percent of all units transfused. Death from anaphylaxis related to transfusion is possible but has only been recorded once in the literature (as of 2015). Nevertheless, such reactions are of great concern to transfusion services and are investigated with care. Significant effort is expended to prevent this. So what was George’s problem? Samples of George’s blood plasma were obtained after the reaction and tested for levels of immunoglobulin. He had normal levels of IgG (and associated IgG subclasses), somewhat high IgM, but less than 0.07 g/l IgA (none detectable at the limit of test sensitivity). Normal levels in an adult have a lower limit of about 0.7 g/l IgA. Based on this, George was diagnosed as having selective IgA deficiency (SAD), by far the most common primary immunodeficiency disease. These individuals have no detectable IgA in their blood and secretions. About 1 in 600 Caucasoids have the condition (which some consider an underestimate). The disease is relatively rare in Asian populations. Considering that IgA is the Ig isotype produced in the greatest amount (and second only to IgG in plasma level) and that it is believed to have a critical role in mucosal immunity to bacteria, it is surprising that 90 percent of individuals with SAD are asymptomatic. This figure may underestimate the morbidity associated with SAD because several careful recent studies in Scandinavia indicate a relatively higher mortality in SAD individuals as younger patients (within the first ten to fifteen years of diagnosis). Individuals with SAD have a tenfold or greater prevalence of diseases with an autoimmune component such as celiac disease or type I diabetes and also have a greater prevalence for several others including SLE and rheumatoid arthritis. There is also a less certain indication that allergic disease and possibly certain cancers occur at a somewhat elevated rate. The mechanism for such a propensity for immune disease in SAD remains unknown. Although SAD is often familial, the mechanism of inheritance remains uncertain. It is likely in some cases to be linked to the HLA locus, and a number of other genes have been implicated, but this remains controversial. The B cell defect seems to reside in a stem cell population: (inadvertent) transplantation of hematopoietic stem cells from a SAD donor into a previously normal donor resulted in an IgA defect in the recipient, whereas transplantation of normal stem cells into a SAD recipient cured the disease. George had no IgA (presumably this was a congenital condition), so he has no selftolerance to IgA. SAD patients are considered to be at risk of anaphylaxis following exposure to IgA containing materials. George’s early exposure to pooled Ig (gamma globulin) probably resulted in the formation of IgE antibodies to human IgA present in the blood transfusion. The demonstration of such antibodies in SAD patients following anaphylaxis is often unsuccessful, possibly due to a technical issue as IgE antibodies can be difficult to detect. (In any case, George was not tested posttransfusion.) Although there is controversy over how likely anaphylaxis is in SAD patients following transfusion, transfusion service make a great effort to prevent the exposure of such patients to IgA. For example, red cells to be transfused into SAD patients are repeatedly washed to remove plasma IgA. Some blood transfusion services prepare low IgA IG preparations for use in therapy. George demonstrates the characteristic set of diseases expected in a SAD patient. In particular, celiac disease would not be unlikely. Why was George’s test for the disease negative? The best test for celiac disease depends on finding IgA autoantibodies to a protein termed TTG. Because George has no IgA, his test was negative. Other tests that detect IgG autoantibodies might have been positive (but these tests are considered less reliable than those detecting IgA antibodies). George now wears a med-alert bracelet to warn of his sensitivity to plasma therapy and remains on a gluten free diet.
Etiology and Pathogenesis
Primary immunodeficiency; isolated IgA deficiency, and consequent impaired immunity to sinorespiratory infections. Increased susceptibility to autoimmune disease with celiac disease probable.
Questions
1. Suppose SAD had been diagnosed at age thirteen. What difference (if any) would this have made in George’s medical history?
2. How would George’s medical condition differed if he had X-linked (Bruton) agammaglobulinemia?
3. It is expected that an initial (primary) immunization is necessary prior to the occurrence of anaphylaxis. In many cases of transfusion-related anaphylaxis, no primary exposure to antigen can be demonstrated. What are some potential explanations for this finding?
4. George objected (with good reason) to intramuscular gamma globulin injections, which can be quite painful. What alternative form of medication is currently in common use to treat humoral immunodeficiency?
5. Why might autoimmune diseases such as celiac disease be more common in individuals with SAD?