Final Diagnosis -- Severe allergic reaction to plasma proteins

FINAL DIAGNOSIS

Severe allergic reaction to plasma proteins (most likely IgA)

DISCUSSION

Introduction

The immunoglobulin IgA is the most abundant immunoglobulin in the human body. It is found in tissues and in secretions especially from the GI tract and the respiratory tract in the form of saliva, tears, breast milk, but has very low levels in serum. This reflects its role in mucosal immunity and the development of tolerance. Approximately 5 to 15 g of IgA (66mg/kg/day) ¹ is produced daily in an adult and this is more than any other immunoglobulin. IgA exists as two isoforms, IgA1 and IgA2. In the circulation, IgA exists as a monomer. In secretions it is present in dimeric form, and the complex also includes a J chain and a secretory piece (Figure 1). All of these components are necessary in order for secretory IgA to preserve its function¹. IgA2 after forming a dimer has a shorter hinge than IgA1, and is therefore thought to confer more resistance to bacterial proteolytic enzymes¹. There is preliminary evidence indicating that normal levels of IgA vary based on certain demographic characteristics such as age, ethnicity, gender, and body habitus¹.

Clinical Significance of IgA deficiency

Primary antibody deficiency (PAD) is defined as a reduction or absence of one or more immunoglobulin without a contributory disorder or cause. IgA deficiency (IgAD) is the most common PAD. The definition of IgAD is a measurement of <7 to <5 mg/dL (the range is selected depending upon the lowest local laboratory detectable testing limit) in patients over the age of 4 years². Age 4 is used to avoid premature diagnosis of transient deficiency that may be present in younger children with delayed IgA development². Although the prevalence of IgAD varies significantly in different areas and among races, it has been estimated to 1:328 in the United States³. IgA deficiency has expanded since its first description in 1964 in two healthy subjects, it has become known that IgA deficiency can be both clinically manifested and associated with a myriad of other diseases. It has also been found that among patients initially diagnosed with autoimmune diseases the prevalence of IgA deficiency is increased. However, the reciprocal is also true: patients initially diagnosed with IgA deficiency have been found to have a higher prevalence of autoimmune diseases. Most individuals identified as IgAD are asymptomatic and identified incidentally during laboratory evaluation for celiac disease, allergy, or autoimmune disease by medical specialists working in rheumatology, hematology, internal medicine, and allergy testing⁴. Although incidental diagnosis of IgAD may not be of clinical significance to the specialists seeking disease diagnosis, it can be associated with future implications for blood transfusion administration and with the increased risks of development of recurrent sinopulmonary infections, gastrointestinal infections and disorders, and autoimmune diseases⁴.

IgAD transfusion reaction

Allergic blood transfusion reactions are one of the most common adverse transfusion events, but there are no reliable estimate regarding the incidence of IgA allergic reaction. The first reported case of anaphylactic transfusion reaction associated with IgAD was published more than 40 years ago⁵. The pathophysiology of IgA-mediated anaphylaxis in humans has not been clearly elaborated. Given that mast cells, IgE, FceR, and histamine are generally considered major players in anaphylaxis reactions, IgG-mediated systemic anaphylaxis was recently demonstrated in the murine system involving FccRs, basophils and platelet activating factor (PAF) as major players (Figure 2). In this reaction, PAF rather than histamine was the major chemical mediator that induced systemic anaphylaxis⁶. This study showed that both IgG and IgE mechanisms are involved in IgA-mediated anaphylaxis. Although it remains uncertain whether this pathway is present in humans, there is supportive evidence for this mechanism.

Signs and symptoms of IgA anaphylactic reactions include hives, rash, pruritis, angioedema, dyspnea, stridor, wheezing, hypotension, syncope, arrhythmia, shock, cramps, diarrhea, and vomiting⁷. These signs and symptoms are common to any anaphylactic reaction and do not differentiate the etiology of the reaction.

Although pre-transfusion medications such as acetaminophen and diphenhydramine are not always effective⁶, most transfusion reactions are easily treated. When urticaria occurs, diphenhydramine may be administered. Severe urticarial reactions may require treatment with methylpredonisolone or predonine. Once a severe reaction develops or anaphylaxis occurs, prompt action should be taken to maintain oxygenation levels and stabilize hypotension. Epinephrine may be administered intramuscularly or subcutaneously. In case the patient is unconscious or in shock, epinephrine may be given intravenously. If bronchospasm is present, respiratory symptoms may not respond to epinephrine, and adding a beta II agonist or aminophylline may be required. The three approaches that have been employed to transfuse IgA-deficient patients with anti-IgA are: (1) autologous blood transfusion, (2) transfusion with fully washed red blood cell (RBC) or platelet (PLT) components, or (3) transfusion components from IgA-poor blood donors³.

Miscellaneous facts

Gonorrhea patients can have low IgA levels/function due to the ability of the bacteria to cleave IgA into its Fab and Fc fragments. Other bacterial such as pneumococcus may also have this ability.

CASE CONCLUSION The patient's symptoms resolved after treatment with solumedrol and Benadryl. The patient received 2 units of washed red blood cells several hours later without any adverse reactions reported. Laboratory investigation for hemolysis was negative. Since the patient had a transfusion history of receiving 4 units of unwashed red blood cells without allergic reaction in 10/2000, an IgA level was measured and determined to be less than 7 mg/dL (normal range: 82 - 453 mg/dL). It was recommended that the patient receive washed cellular blood components and be premedicated with antihistamines and steroids for future transfusions. The patient subsequently underwent EGD and was found to have a large ulcerated jejunal mass proven to be a large B-cell lymphoma.

REFERRENCE

1. Singh K1, Chang C, Gershwin ME. IgA deficiency and autoimmunity. Autoimmun Rev. 2014 Feb;13(2):163-77.
2. Mertin S, Thomson I. What you need to know about IgA deficiency: A case study. J Am Assoc Nurse Pract. 2014 May;26(5):268-72.
3. Feng ML, Zhao YL. Prevalence of immunoglobulin A deficiency in Chinese blood donors and evaluation of anaphylactic transfusion reaction risk. Transfus Med. 2011 Oct;21(5):338-43.
4. Yei, L. Selective IgA deficiency. J Clin Immunol. 2010 Jan;30(1):10-6.
5. Vyas GN, Perkins HA. Anaphylactoid transfusion reactions associated with anti-IgA. Lancet. 1968 Aug 10;2(7563):312-5.
6. Hirayama F. Current understanding of allergic transfusion reactions: incidence, pathogenesis, laboratory tests, prevention and treatment. Br J Haematol. 2013 Feb;160(4):434-44.
7. Sandler SG1, Mallory D. IgA anaphylactic transfusion reactions. Transfus Med Rev. 1995 Jan;9(1):1-8.

Contributed by Stell Patadji, MD and Lirong Qu, MD, PhD