Selective IgA deficiency temporally associated with Epstein-Barr virus infection

Selective IgA deficiency temporally associated with Epstein-Barr virus infection

268 4. 5. 6. 7. 8. Clinical and laboratory observations dilatation in children with febrile urinary tract infection or bacteriuria. A JR 1987;14...

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dilatation in children with febrile urinary tract infection or bacteriuria. A JR 1987;148:483-6. Svanborg Ed6n C, de Man P. Bacterial virulence in urinary tract infection. Infect Dis Clin North Am 1987;1:731-50. Mfirild S, Wettergren B, Hellstr6m M, et al. Bacterial virulence and inflammatory response in infants with febrile urinary tract infection or screening bacteriuria. J PEDIATR 1988;112:348-54. de Man p, Jodal U, Lincoln K, Svanborg Ed6n C. Bacterial attachment and inflammation in the urinary tract. J Infect Dis 1988;158:29-35. Mfirild S, Hellstr6m M, Jodal U, Svanborg Ed6n C. Fever, bacteriuria and concomitant disease in children with urinary tract infection. Pediatr Infect Dis J 1989;8:36-41. He!lstr6m M, Hjfilmfis K, Jacobsson B, Jodal U, Od6n A. Normal ureteral diameter in infancy and childhood. Acta Radiol Diagn 1985;26:433-9.

The Journal of Pediatrics August 1989

9. Bradley JW. Distribution-free statistical tests. Englewood Cliffs, N.J.: Prentice-Hall, 1968:68-86. 10. Jodal U. The natural history of bacteriuria in childhood. Infect Dis Clin North Am 1987;1:713-29. 11. Roberts JA, Suarez G, Kaack B, K~illenius B, Svensson S. Experimental pyelonephritis in the monkey. VII. Ascending pyelonephritis in the absence of vesicoureteral reflux. J Urol 1985;133:1068-75. 12. Linder H, Engberg I, Mattsby Baltzer I, Jann K, Svanborg Eden C. Induction of inflammation bY Escherichia coli on the mucosal level: requirement for adherence and endotoxin. Infect Immun 1988;56:1309-13. 13. Roberts JA, Domingue GJ. Experimental pyelonephritis in the monkey. II. The prognostic value of radionuclide evaluation of the urinary tract. Invest Urol 1975;12:374-80.

Selective IgA deficiency temporally associated with Epstein-Barr virus infection Frank T, Saulsbury, MD From the Department of Pediatrics, University of Virginia Medical Center, Charlottesville

Selective IgA deficiency is the most c o m m o n immunodeficiency syndrome, with a prevalence of approximately 1 in 500 individuals.l,2The variability in the clinical and laboratory features suggests that IgA deficiency has multiple causes? ,2 Autosomal d o m i n a n t and recessive inheritance patterns have been described in a few families, but most cases are sporadic. 2 Acquired deficiency of IgA has been linked to a n u m b e r of drugs, including phenytoin, dpenicillamine, gold, and sulfasalazine? -4 A n infectious cause has been suggested by reports of IgA deficiency in some children with congenital rubella infection? Despite the expanding list of genetic and environmental factors associated with IgA deficiency, the basic defects responsible for this c o m m o n immunodeficiency are largely unknown. Indeed it is unclear whether l g A deficiency is predominantly a congenital or an acquired disorder. This report describes a child who had IgA deficiency after Epstein-Barr virus infection.

Submitted for publication Dec. 14, 1986; accepted Feb. 7, 1989. Reprint requests: Frank T. Saulsbury, MD, Department of Pediatrics, Box 386, University of Virginia Medical Center, Charlottesville, VA 22908.

CASE REPORT The patient was born at 39 weeks uncomplicated gestation and weighed 3360 gm at birth. He had several episodes of otitis media and gastroenteritis during the first 6 months of life, and his weight gain was suboptimal. Serum immunoglobulin concentrations at 6 months of age were all within the normal range for age (Table). The patient was hospitalized at 7 months of age for evaluation of poor weight gain. Physical examination disclosed a thin infant with a weight of 5.5 kg (<5th percentile) and a length of 67.5 cm (25th percentile). The remainder of the physical examination was unremarkable. Further immunologic studies revealed normal EBV

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serum immunoglobulin concentrations (Table). The patient's blood group was O, and serum isoagglutinin titers were 1 : 16 and 1:32 to A and B blood group antigens, respectively. The serum tetanus antitoxin titer was 1:40, and the serum diphtheria antitoxin titer was 1:320; repeat testing 2 weeks after booster immunizations revealed a fourfold rise in serum antibody to both antigens. Laboratory evaluation failed to disclose a cause for the poor weight gain. The patient had a good appetite and gained 1 kg during his 1-month hospitalization. His failure to thrive was attributed to psychosocial problems. The child had normal growth and excellent health until 3V2

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Clinical and laboratory observations

269

T a b l e . Immunologic studies Age

Immunoglobulin concentrations* IgG IgA IgM Lymphocyte populations'{" CD3 (T cells) CD4 (helper T cells) CD8 (suppressor T cells) CD19 (B cells) Surface IgG (B cel.ls) Surface IgA (B cells) Surface IgM (B cells) Surface IgD (B cells) EBV antibody titers IgM-viral capsid antigen IgG-viral capsid antigen Epstein-Barr nuclear antigen

6 mo

7 mo

31/2 yr

4 yr

5 yr

7 yr

8 yr

510 39 110

498 49 126

ND ND ND

1300 <1.1 157

1410 <1.1 160

1230 17 143

1120 18 130

67 33 17 19 2 5 15 22 <1:10 1:160 <1:5

<1:10 1:640 >1:5

70 42 24 21 4 8 14 12 <1:10 1:640 >1:10

ND, Not done. *Expressed as milligrams per deciliter. tExpressed as percentage of total peripheral blood lymphocytes. years of age, when fever and abdominal pain developed. Physical examination showed enlarged cervical lymph nodes and hepatosplenomegaly. Laboratory studies revealed a hematocrit value of 37%, a white blood cell count of 11,400 cells/tzl with 8% bands, 12% segmented neutrophils, 66% lymphocytes, and 12% atypical lymphocytes, and a platelet count of 407,000/ul. A urine culture for cytomegalovirus was negative. A rapid slide test for heterophil antibody had negative results, but EBV antibody titers obtained 2 weeks later confirmed a recent EBV infection (Table). The patient recovered uneventfully. He was reevaluated, 9 months later, at 4 years of age. Repeat EBV serologic tests were indicative of a past infection with the appearance of antibody to EBV nuclear antigen. Serum immunoglobulin concentrations at 4 years of age revealed a selective deficiency of IgA with normal values for IgG and IgM. Peripheral blood lymphocyte populations were enumerated by means of flow cytometry with monoclonal antibodies to a variety of cell surface determinants. These studies revealed normal numbers and percentages of peripheral blood T cells, helper T cells, suppressor T cells, and B cells. Moreover, the patient had normal numbers of peripheral blood B cells expressing surface IgA (Table). Repeat testing at 5 years of age demonstrated persistent selective IgA deficiency. At 7 years of age the patient had a serum IgA concentration of 17 mg/dl, which was still well below the lower limit of normal for age (normal range 33 to 202 mg/dl). To exclude the possibility that this result was due to antirumiaant antibody, ~ we quantitated IgA in the same serum sample with rabbit antiserum, and the concentration was 23 mg/dl. IgM, IgG, and IgG subclass concentrations were normal. Serum antibody to Haemophilus influenzae capsular polysaccharide was 1650 ng/ml (normal >100 ng/ml) after immunization 2 years previously. Likewise, the patient again had a normal antibody titer to tetanus

toxoid (0.17 IU/ml). Lymphocyte populations were again normal. At 8 years of age the serum lgA concentration was still low at 18 mg/dl; IgG and IgM concentrations were normal. The child had remained in excellent health and has no signs or symptoms attributable to IgA deficiency. DISCUSSION The patient acquired IgA deficiency after he h a d normal serum immunoglobulin concentrations at 6 a n d 7 m o n t h s of age. A t 3V2 years of age he had typical infectious mononucleosis, and antibody testing confirmed a recent EBV infection. U n f o r t u n a t e l y , serum immunoglobulin concentrations were not measured during the acute phase of his illness. I g A deficiency was diagnosed a t 4 years of age, 9 months after the E B V infection. W i t h the exception of the EBV infection, h e was in excellent h e a l t h between 7 months and 4 years, a n d he was not given any drugs implicated in I g A deficiency? -4 IgA was a g a i n detected in his serum at 7 years of age, b u t the concentration was well below the n o r m a l limit for age. Thus, a l t h o u g h definitive proof is lacking, the evidence suggests t h a t the patient's IgA deficiency was related to his EBV infection. N o r m a l IgA production is highly dependent on intact, well-regulated T cell function. 6 Infection with E B V evokes characteristic cellular responses consisting of the appearanee of activated suppressor T cells and cytotoxic cells directed against EBV-infected B lymphocytes. 7' 8 T h e cellular i m m u n e responses to EBV infection are immunosuppressive, and transient abnormalities in a n u m b e r of T cell-mediated functions have been described in individuals

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Clinical and laboratory observations

with EBV infection.9 Recently Junker et al. 1~ reported transient immune dysfunction, including defective antibody production, in patients with infectious mononucleosis. Thus it is not difficult to envision transient IgA deficiency after EBV infection, given the highly T cell-dependent nature of IgA production and the immunosuppressive cellular immune response to EBV infection. In addition to being the most common immunodeficiency syndrome, IgA deficiency has perhaps the widest range of clinical manifestations of any immunodeficiency disease. Some individuals with IgA deficiency have no symptoms; others have a variety of illness, including recurrent sinopulmonary infections, atopic diseases, gastrointestinal tract malabsorption, autoimmune diseases, and malignancy. 1'2 The patient in this report has had no symptoms attributable to his IgA deficiency. The patient's IgA deficiency may be transient; he had diminished but measurable IgA in his serum at 7 and 8 years of age. Reports document recovery of selective IgA deficiency in children. TM n The patient differs from other patients with transient IgA deficiency because he has not yet achieved a normal IgA level. A longer period of observation will be necessary to characterize his immunodeficiency as transient or permanent. The mechanisms governing recovery remain as enigmatic as the cause of the immunodeficiency. Although IgA deficiency is the most prevalent immunodeficiency disease, understanding of the etiology and pathogenesis remains rudimentary. With the exception of a few patients with drug-induced IgA deficiency, the age of onset is unknown. Most prevalence studies have employed healthy adult blood donors. There are few comparable data concerning the prevalence of IgA deficiency in infants and children; such information might provide insight into the causes.

The Journal of Pediatrics August 1989

This report describes a child with acquired IgA deficiency temporally related to an EBV infection. Thus EBV infection should be considered in the differential diagnosis of acquired IgA deficiency. REFERENCES

1. Ammann AJ, Hong R. Selective IgA deficiency:presentation of 30 cases and a review of the literature. Medicine 1971; 50:223-35. 2. BurksAW, Steele RW. SelectiveIgA deficiency.Ann Allergy 1986;57:3-8. 3. Stanworth DR, Johns P, Williamson N, et al. Drug induced lgA deficiency in rheumatoid arthritis. Lancet 1977;1: 1001-2. 4. Leickly FE, Buckley RH. Development of IgA and IgG2 subclass deficiency after sulfasalazine therapy. J PEDIATR 1986;108:481-2. 5. Soothill JF, Hayes K, Dudgeon JA. The immunoglobulinsin congenital rubella. Lancet 1966;2:1385-8. 6. Elson CO. T cells specific for IgA switching and for IgA B cell differentiation. Immunol Today 1983;4:189-90. 7. Tosato G, Magrath I, Koski I, et al. Activation of suppressor T cells during Epstein-Barr virus-induced infectious mononucleosis. N Engl Med 1979;301:1133-7. 8. De Waele M, Thielemans C, Van Camp BKG. Characterization of immunoregulatory T cells in EBV-induced infectious mononucleosis by monoelonal antibodies. N Engl J Med 1981;304:460-2. 9. Reinherz El, O'Brien C, Rosethal P, Schlossman SF. The cellular basis for viral-induced immunodeficiency:analysis by monoclonal antibodies. J Immunol 1980;125:1269-74. 10. Junker AK, Ochs HD, Clark EA, et al. Transient immune deficiency in patients with acute Epstein-barr virus infection. Clin Immunol Immunopathol 1986;40:436-46. 11. Ostergaard PA. Clinical and immunological features of transient IgA deficiency in children. Clin Exp lmmunol 1980;40:561-5. 12. Blum PM, Hong R, Stiehm ER. Spontaneous recovery of selective IgA deficiency.Clin Pediatr 1982;21:77-80.

Periodic Cushing syndrome in a short boy: Usefulness of the ovine corticotropin releasing hormone test Maria Teresa G o m e z Muguruza, MD, a n d G e o r g e P. Chrousos, MD From the Developmental Endocrinology Branch of the National Institute of Child Health and Human Development, National Institutes of Health, Bethesde, Maryland

Submitted for publication Oct. 24, 1988; accepted Feb. 7, 1989. Reprint requests: Maria Teresa Gomez, MD, Developmental Endocrine Branch, National Institutes of Health, Bldg. 10, Rm. 10N262, Bethesda, MD 20892.

Periodic hormonogenesis occurs in all three forms of Cushing syndrome: pituitary Cushing disease, tumors producing ectopic adrenocorticotropic hormone, and cortisol-secreting adrenal adenomas and carcinomas?-4 The