Transfusion-associated acquired immune deficiency syndrome in infants

Transfusion-associated acquired immune deficiency syndrome in infants Two preterm infant boys not known to be at risk developed clinical, laboratory, and pathologic features of acquired immune deficiency syndrome (AIDS) after receiving multiple blood transfusions in the neonatal period. Their clinical courses were characterized by failure to thrive, recurrent otitis media, hepatomegaly, and fatal interstitial pneumonia. Laboratory evaluation revealed progressive lymphopenia, reversed T helper/suppressor ratios, increased percentages of B-lymphocytes, decreased lymphoproliferative responses to mitogens, hyperimmunoglobulinemia, and high levels of circulating immune complexes. At postmortem examination thymic involution, lymphocyte depletion in spleen and lymph nodes, and micronodular mineralization in the central nervous system were seen. The findings were not specific for other known congenital immune deficiencies and were most indicative of AIDS. The lack of other risk factors suggests transmission of AIDS via blood transfusions in the neonatal period. (J PEOIATR 105:731, I984)

Joseph A. Church, M.D., and Hart Isaacs, M.D. Los Angeles, California

ACQUIRED IMMUNE DEFICIENCY SYNDROME, which is characterized by profound dysfunction of T-lymphocytemediated immune responses, primarily affects homosexual or bisexual men and their sexual partners, intravenous drug abusers, native Haitians and Haitian immigrants to the United States, and hemophiliacs), 2 In addition, Curran et al. 3 reported 18 adult patients with A I D S who were not members of these high-risk groups but who had received blood component transfusions within 5 years of onset of the illness. A I D S has been seen in infants born to promiscuous or drug-addicted mothers 4~5 and in infants of Haitian parentage. 6 However, there have bee~ only two previous reports of possible transfusion-related A I D S in the pediatric age group. 7,~ We describe two infant boys who died with clinical, laboratory, and pathologic features of A I D S , which developed after they had received multiple blood infusions in the neonatal period.

Adenosine deaminase Acquired immune deficiency syndrome Circulating immune complexes Clq solid-phase assay Cytomegalovirus Epstein-Barr virus Anti-C3 enzyme immunoassay using F(ab')~ fragments B-lymphocytes and activated T-lymphocytes Human T cell leukemia virus T-lymphocytes "Cytotoxic/suppressor" T-lymphocytes "Helper/induc6r~ T-lymphocytes Phytohemagglutinin Purine nucleoside phosphorylase Pokeweed mitogen Raji cell radioimmunoassay Surface immunoglobulin-bearing ceils, B-lymphocytes Trimethoprim-sul fasoxazole

ADA AIDS CIC CIq-SPA CMV EBV F(ab')2 anti-C3 EIA HLA-DR+ cells HTLV Leu I+ cells Leu 2+ cells Leu 3+ cells PHA PNP PWM Raji RIA slg+ cells TMP-SMZ

From the Departments of Pediatrics and Pathology, Children's Hospital of Los Angeles and the University of Southern California School of Medicine. Submitted for publication March 19, 1984; accepted May 4, 1984. Reprint requests: Joseph A. Church, M.D., Allergy-Clinical Immunology Division, Childrens Hospital of Los Angeles, Post Office Box 54700, Terminal Annex, Los Angeles, CA 90054.

CASE REPORTS Patient 1. This 1150 gm boy, and the second of identical twins, was born at 29 weeks gestation to a gravida 1, para 0, 23-year-old white woman. He never required ~assisted ventilation. Blood products, including five aliquots of p~cked red blood cells and two of fresh-frozen plasma, from different donors were administered

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732

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during the first 6 weeks of life. The patient was discharged from the hospital at 2 months of age in apparent good health, weighing 1010 gin. At 9 months of age he developed otitis media, oral candidiasis, and failure to thrive. Recurrent purulent otitis media ensued and became progressively more resistant to medical management. Similarly, the thrush was resistant to treatment with mycostatin, clearing completely only with ketoconazole. Bilateral middle-ear ventilation tubes were placed at 12 and 18 months of age, and bilateral mastoidectomies were performed at 22 months of age. On two occasions treatment with trimethoprim-sulfamethoxazole resulted in generalized urticaria, which subsided after discontinuation of the medication. One week after mastoid surgery, progressive respiratory distress was noted. The patient's mother and father were clinically well, and neither was at high risk for AIDS. This patient's twin required prolonged assisted ventilation, developed severe bronchoputmonary dysplasia, required surgical closure of a patent ductus arteriosus, had a grade IV intraventricular hemorrhage, and eventually died at 10 months of age, never having left the hospital. A postmortem examination was not peformed. Physical examination revealed a small and irritable infant with moderate respiratory distress. He had fever, tachypnea, and tachycardia. Height and weight were each at less than the 5th percentile. Extensive oral thrush was apparent, and functioning middle-ear ventilation tubes were seen. Although inspiratory intracostal and supracostal retractions were noted, the lung fields were clear to auscultation. The patient's liver was palpated 6 cm below the costal margin; the spleen was not palpable. Cardiovascular, neurologic, and dermatologic examinations yielded unremarkable findings. At the time of hospitalization the following routine laboratory values were recorded: Hgb 9.2 gm/dl, WBC 14,300/mm 3 (63% segmented neutrophils, 34% band forms, 1% lymphocytes, 1% monocytes, 1% basophils), lactic dehydrogenase 2350 IU/L, SGOT 319 IU/L, and SGPT 124 IU/L. Chest radiograph revealed bilateral perihilar interstitial infiltrates and a normal cardiac silhouette. Blood gas analysis revealed pH 7.44, Paco: 33 torr, aid Pao2 39 torr in room air. The patient was skin tested for immediate hypersensitivity to trimethoprim-sulfamethoxazole. Despite an equivocal wheal-andflare response to the drug (concentration of skin test solution 16 mg/ml TMP and 80 mg/ml SMZ) a rapid desensitization protocol was initiated. After an initial infusion intravenously of 0.16 mg TMP plus 0.8 mg SMZ, progressively higher doses were infused every 10 minutes until full therapeutic doses were given without adverse effect. An open lung biopsy was diagnostic of Pneumocystis carinii pneumonia. Lung cultures for bacteria, fungi, and viruses were negative. The patient was given TMP-SMZ and ketoconazole, and assisted ventilation, but progressive respiratory acidosis and hypoxemia, ensued, and he died at 2 years of age. Patient 2. This 830 gm boy was born at 28 weeks gestation to a gravida 3, para 2, 31-year-old white mother by normal vaginal delivery. The neonatal course was complicated by respiratory distress syndrome, severe bronchopulmonary dysplasia, hyperbili-

The Journal of Pediatrics November 1984

rubinemia, apnea/bradycardia episodes, and possible sepsis. During 4 months in a neonatal intensive care unit he received 14 aliquots of packed red blood cells, three aliquots of fresh-frozen plasma, and two aliquots of platelets from individual donors. He was discharged in apparent good health, weighing 3990 gm. At 6 months of age the infant was noted to be clinically well and to have a normal hematocrit and platelet count. By 8 months of age he had stopped growing and had developed otitis media, thrush, hepatomegaly, anemia (Hgb 8.0 gm/dl), and thrombocytopenia (platelet count 90,000/ram3). Findings on bone marrow examination and chest radiograph were described as normal, and a needle biopsy of the liver revealed "mild fatty infiltration." Oral administration of TMP-SMZ resulted in acute urticarial reactions on two occasions during the ensuing 3 months. By 11 months of age the recurrent otitis media was resistant to medical treatment and the patient was transferred to Childrens Hospital of Los Angeles for surgical treatment and immunologic evaluation. The patient's mother, father, and two siblings were clinically well. No family member or known contact was a member of a group at high risk for AIDS. Physical examination revealed a small, pale, cyanotic boy in moderate respiratory distress. He had fever, tachypnea, and tachycardia. Height and weight were each at less than the 5th percentile. The patient had bilateral red, bulging tympanic membranes and a purulent nasal discharge.. Oral candidiasis was not found, lnspiratory intraeostal retractions were noted, although the chest was clear on auscultation. The liver was palpable 8 cm below the right costal margin, and a spleen tip was felt. Multiple lymph nodes 0.5 to 1 cm in diameter were present in the inguinal regions; several 0.5 cm lymph nodes were present in the axillae. Petechiae were present on the face and extensor surfaces of the extremities. Cardiovascular and neurologic examinations yielded unremarkable findings. Laboratory values included the following: Hgb 7.8 gm/dl, WBC 9700/mm 3 (55% segmented neutrophils, 11% band forms, 13% lymphocytes, 16% monocytes, 5% basophils), platelet count 77,000/ram 3, LDH 799 1U/L, SGOT 391 IU/L, and SGPT 89 IU/L. Chest radiograph revealed severe bilateral perihilar interstitial infiltrates and normal heart size. Blood gas analysis revealed pH 7.36, Paco2 48 torr, and Pao2 33 torr in room air. The child was skin tested as previously described for immediate hypersensitivity to TMP-SMZ. An equivocal positive reaction was noted, and progressively larger hoses of the drug were infused until therapeutic doses were reached. An open lung biopsy showed extensive intra-alveolar hemorrhage and P. carinii organisms. Lung cultures for bacteria, fungi, and viruses were negative. The patient was given TMP-SMZ, pentamidine, immunoglobulin infusions intravenously, and assisted ventilation. Progressive respiratory acidosis and hypoxemia ensued, and he died at I year of age. The Los Angeles County Department of Health Services has traced the patients', blood donors. At least one donor for each infant was found to be a member of a group at high-risk for AIDS who was clinically well but who had a T helper/suppressor ratio <0.6. There were no common donors in our patients, and other corecipients of blood from the same donors were not traced.

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Table. Immune functions in two children with possible transfusion-associated AIDS

21

lgG (mg/dl) lgA (mg/dl) !gM (mg/dl) IgE (U/ml) Circulating immune comple• Lymph count/mm 3 Leu 1+ cells (%) Leu 2+ cells (%) Leu 3+ cells (%) HLA-DR+ cells (%) slg+ cells (%) PHA response (cpm) PWM response (cpm) ADA activity (units) PNP activity (units)

Patient 1

Patient 2

Age (mo)

Age (too)

22

23

1480 1720 184 70

24

11

727 895 108

3930 767 226 8 +++ 1260 15 6 5 56 56 2885 2349 81 1534

+++

1950

1500 37 6

20 10

1

4

82 86 7038 2271

40 35 3882 1260 125 2129

METHODS

Serum IgG, IgA, and IgM concentrations were determined with rate nephelometry (Beckman Immunochemistry System, Beckman Instruments, Fullerton, Calif.). Serum IgE concentrations were measured with a paper radioimmunosorbent assay (Phadebas Ige PRIST, Pharmacia Diagnostics, Uppsala, Sweden). White blood cell counts and total lymphocyte counts were performed on peripheral blood using standard automated techniques. Mononuclear cells were separated from heparanized blood by density gradient centrifugation over Fieoll-Hypaquei9 Peripheral blood lymphocyte subsets were quantitated using commercially available monoclonal antibodies and an indirect immunofluorescent technique./~ Monoclonal antibodies included Leu 1 for T-lymphocytes, Leu 2 for the suppressor/cytotoxic subset, Leu 3 for the helper/inducer subset, and H L A - D R for B cells and ~ctivated T cells (antibodies obtained from Becton-Dickinson, Sunnyvale, Calif.). Surfac e immunoglobulin-bearing (slg+) lymphocytes were quantitated with a direct itnmunofluorescent technique using fluorescein-conjugated F(ab')2 antihuman immunoglobulin (Kallestad Labbi'atories, Austin, Texas)?' Hepatitis B, cytomegalovirus, and Epstein-Barr virus antibody levels were measured with standard clinical laboratory techniques. Human T cell leukemia virus titers were kindly provided by Biotech Research Laboratories, Rockville, Md. Lymphoproliferative responses to phytohemagglutinin and pokeweed mitogen (Gibco, Grand Island, N.Y.) were assayed with standard microculture techniques using titrated thymidine labeling of newly synthesized D N A ? 2 Circulating immune complexes were

143 35 ll 6 754 469

3800

Normal

400 to 1100 14 to 125 45 to 170 <25 > 1500 71 _+ ll 25_+8 49_+ 11 12 _+ 5 9_+3 >700O >5000 33 to 100 1000 to 2000

measured by Dr. Stanley C. Jordan (University of California, Los Angeles School of Medicine) with three techniques: Raji cell radioimmunoassay, ~3 Clq solid-phase assay, and an F(ab')2 anti-C3 enzyme immunoassay? 4 Red blood adenosine deaminase and purine nucleoside phosphorylase activitieswere measured by Dr. Won G. Ng (Childrens Hosptial of Los Angeles) with a conventional spectrophotometrie assay? 5 Electron microscopic studies of lymph nodes from postmortem specimens were carried out by Dr. Harry Neustein (Childrens Hospital). RESULTS Both children had marked elevations of serum IgA and IgG on at least one occasion (Table). These levels declined in patient 1 as his clinical condition deteriorated. IgM concentrations in both patients and IgE in patient 1 were modestly elevated. Serologic studies for antibodies to hepatitis B, CMV, EBV, and HTLV were negativc. Circulating immune complexes were measured rctrospcctively in frozen sera from both children. Raji-RIA and CIq-SPA studies were negative. However, F(ab')2 anti-C3 EIA revealed extremely elevated levels of circulating immune complexes, >10 mg/ml (normal <34 ug/ml) in both patients. Both children were noted to have progressive lymphopenia, decreased T (Leu 1+) cells, and increased B (HLAD R + and sIg+) cells. Helper T (Leu 3+) ceils were proportignately affected to a greater degree than suppressor T (Leu 2+) cells, and the Leu 3 + / L e u 2+ ratios were <1.0, which is considered abnormdl in our laboratory. A progressive decline in lymphoproliferative responses

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The Journal of Pediatrics November 1984

Fig. 1. Lymph node at autopsy (patient 1). Note severe depletion of lymphoid elements and absence of germinal centers. (Hemtoxylin and eosin; original magnification • )

Fig. 2. ThYmus gland at autopsy (patient 2). Note marked depletion of thymocytes and,decreased numbers and calcification of Hassal corpuscles. (Hematoxylin and eosin; original magnification X150.)

was seen in patient 1. Initially, P H A responses were low normal and P W M responses were significantly depressed. As the patient's clinical condition worsened his lymphocytes became unresponsive to both mit0gens. P H A and P W M responses in patient 2 were decreased on the one occasion on which he was studied. Red blood cell A D A and PNP activities were normal. At postmortem examination the most significant and unusual pathologic findings were recorded in the lymphoid systems, lungs, and central nervous systems.

The lymphoid tissue lesions in these children were very similar and consistent with the autopsy findings reported in adults with AIDS. 16,~7 The spleens exhibited evidence of chronic passive congestion and marked lymphocyte depletion. Similarly, the lymph node architecture was modified as the result of ~evere depletion of T- and B-lymphocytes and loss of germinal centers despi~te suggestive remnants of these structures (Fig. 1). The thymuses were markedly atrophic and depleted of thymocytes; the Hassall corpu scles were decreased in both and calcified in patient 2 (Fig.

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Fig. 3. Area of basal ganglia at autopsy (patient 1). Note micronodular mineralizations in white matter (small arrows) and in blood vessel walls (large arrow). (Hemoxylin and eosin; original magnification •

2). In the experience of our institution, the findings are most consistent with the secondary changes seen in a varietyof fatal perinatal disorders. ~8 Electron microscopic examination of lymph nodes from both patients confirmed marked lymphocyte depletion but did not reveal structures previously reported in adults with AIDS, such as vesicular rosettes ~9or cytoplasmic tubules, z~ Viruslike particles were not seen. In patient 1 sections of lufig demonstrated severe, chronic organizing pneumonia with bronchiolitis and alveolitis obliterans. Within the alveolar spaces a large amount of frothy exudate was noted, and methenamine silver staining revealed numerous P. carinii organisms. In contrast, the lungs of patient 2 showed marked hyperplasia of the alveolar lining cells and a massive mononuclear cell infiltration of the alveoli. Numerous mu!tinucleated g!ant Cells were apparent, some with intracytoplasmic inclusions consistent with paramyxovirus infection. A few P. carinii organisms also were found in methenamine silver-stained sections9 Although the livers were markedly enlarged (twice normal), there was no evidenc e of hepatitis or other infiltrative process; only chronic passive congestion and fatty changes were noted9 A unique pattern of micronodular mineralization was seen in the central nervous systems of these children. This calcinosis was seen in blood vessel walls and perivascular White matter of the basal ganglia in patient 1 (Fig. 3). and throughout the cerebral hemispheres, basal ganglia, pons, and cerebellum in patient 21 This finding is not characteristic of severe prematurity, parathyroid disease, or known infections. Histopathologic evidence of conditions such as

CMV or Toxoplasma infection, which are associated with brain calcification in this age group, was not identified. DISCUSSION The Centers for Disease Control has defined pediatric AIDS as a reliably diagnosed disease at least moderately indicative of underlying cellular immunodeficiency with no known cause of the immune dysfunction. 2~ Specifically excluded are congenital infections, primary immune diseases, and secondary immunodeficiencies associated with immunosuppressive therapy, lymphoreticular malignancy, or starvation. O u r patients had fatal opportunistic infections, progressive lymphopenia, reversed T helper/suppressor ratios, profound T-lymphocyte dysfunction, and markedly elevated levels of serum immunoglobulins. Results of additional laboratory and pathologic studies strongly argue against congenital infection and most of the primary immune deficiencies, such as severe combined immune deficiency or DiGeorge syndrome9 Only the ill-defined syndrome of congenital cellular immune deficiency with immunoglobulins (Nezelof syndrome) zz could not be ruled out with certainty 9 However, the clinical and pathologic evidence suggests that this was not the disorder in our patients. They survived extreme prematurity and multiple blood transfusions without succumbing to infections or graft-versus-host disease and they were clinically well for at least several months after discharge from the neonatal intensive care unit. Progressive lymphopenia in both children and the measured deterioration of T cell function in patient 1 suggested a dynamic process rather than a static, inherent immune

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deficiency. Further, the conditions of many patients with Nezelof syndrome had been reclassified as immunodeficiency with ADA or PNP deficiency.23and these disorders were effectively ruled out in our patients by their normal ADA and PNP activities. Serum immunoglobulinlevels in Nezelof syndrome are usually low or at best normal, seldom reaching the very high levels seen in our patients. The described histopathologic abnormalities of the lymphoid systems were not consistent with those previously seen at our institution in children dying of Nezelof syndrome,2~ but were most indicative of acquired changes similar to those described in a variety of disease states, such as neonatal hepatitis and chronic severe undernutrition? ~ The clinical, laboratory, and pathologic features detailed in this report are similar to those described in adult patients with AIDS L2. ~6.17and are consistent with the recently develoPed provisional case definition of pediatric AIDS. The markedly elevated levels of circulating immune comp!exes in these children were not unexpected; similar findings have been noted in adult AIDS. 2s More puzzling was the strongly positive results with F(ab')2 anti-C3 EIA and negative findings with the Raji-RIA and the Clq-SPA. However, CIC assays correlate poorly with one another because of the different immunochemical or physical properties of CICs detected by various assays. 26 The F(ab')2 anti-C3 EIA proved to be most useful. An additional extraordinary finding in our patients was the extensive central nervous system micronodular mineralization , the cause of which is unknown. It has not been observed in long-term survivors of bronchopulmonary dysplasia or cerebral hypoxia nor in previously described congenital or acquired infections. PerhaPs the lesions reflect changes secondary to a new infectious agent, one that selectively attacks brain cells and T-lymphocytes. Evidence that human T cells and brain cells share certain surface antigen structures has been presented by Whiteside and Rabin,27 who demonstrated that a crude antihuman brain serum raised in rabbits and absorbed with erytrocytes, lyophilyzed liver, and B cells cross reacts with circulating T-lymphocytes and thymocytes. An additional possibility is suggested by the recent report that embryonic thymus develoPment depends on the neural crest. 28 A selective infectious destruction of ceils derived from the neural crest may have resulted in the central nervous system lesions and thymie involution seen in our patients. Similar CNS changes have not been reported in adult AIDS, ~6 perhaps because of brain cell surface antigen differences between infants and adults. Regardless of the specific cause, transfusion-associated pediatric AIDS, as noted in this institution and by others 7 (Medici M, Sconyers S: Personal communication, 1983),

The Journal of Pediatrics November 1984

appears to produce a recognizable clinical pattern. Premature infant boys who require multiple transfusions seem to be at highest risk. Factors that may selectively predispose these infants to AIDS include the immunodeficient state of prematurity,29 the immunologic disadvantages of having a single X chromosome, 3~the immunosuppressive effects of alioantigen exposure, 3~ and the transmission of the AIDS agent in blood from high-risk donors? characteristically, patients are clinically well for 6 to 24 months after discharge from the neonatal intensive care units. Gradually hepatomegaly with or without lymphadenopathy and severe recurrent otitis media develop. Persistent thrush may be attributed mistakenly to the frequent use of antibiotics, and failure to thrive may be ascribed to chronic respiratory infection. Both of our patients had hypersensitivity to TMP-SMZ, a phenomenon noted with regularity in adult A!DS? 2 Eventually the patients die of progressive interstitial pneumonia, usually associated with P. carinii infection. We thank the Los Angeles County Department of Health Services AIDS Program for identifying and evaluating our Patients' blood donors; Dr. Robertson Parkman for reviewing the manuscript; and Mrs. Geri ColdeweY for secretarial assistance.

REFERENCES 1. Gottlieb M, moderator: The acquired immunodeficiencysyndrome. Ann Intern Med 99:208, 1983. 2. Fauci AS, moderator: Acquired immunodefieiencysyndrome: Epidemiologic,clinical, immunologic,and therapeutic considerations. Ann Intern Med 100:92, 1984. 3. Curran JW, Lawrence DN, Jaffe H, et al: Acquired immunodeficiency syndrome (AIDS) associated with transfusions. N Engl J Med 310:69, 1984. 4. Oleskc J, Minnefor A, Cooper R, et al: Immune deficiency syndrome in children. JAMA 249:2345, 1983. 5. Rubinstein A, Sicklick M, Gupta A, et al: Acquired immunodeficiency with reversed T4/T8 ratios in infants born to promiscuous and drug-addicted mothers. JAMA 249:2350, 1983. 6. Scott GB, Buck BE, Leterman JB, Bloom FL, Parks WP: Acquired immunodeficiencysyrcdrome in infants. N Engl J Med 310:76, 1984. 7. Ammann AJ, Cowan MJ, Wara DW, Weintrub P, et al: Acquired immunodeficiencyin an infant: Possible transmission by means of blood products. Lancet 1:956, 1983. 8. Shannon K, Ball ;E, Wasserman RL, et al: Transfusionassociated cytomegalovirus infection and acquired immune deficiency syndrome in an infant. J PEDIATR103:859, 1983. 9. Boyum A: FicolI-Hypaquemethod for separating mononuclear cells and granulocytes from human blood. Scand J Clin Lab Invest 21 (suppl 97): 77, 1966. 10. Schroff RW, Foon KA, Billing RJ, F~hey JL: Immunologic classification of lymphocytic leukemias based on monoclonal antibody-definedcell surface antigens. Blood 59:207, 1982. 11. Winchester RJ, Ross G: Methods for enumerating lymphocyte populationL In Rose NR, Friedman H, editors: Manual

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12.

13.

14.

15.

16.

17.

18.

19.

20. 21.

22.

of clinical immunology. Washington, D.C., 1976, American Society for Microbiology, pp 64-76. Oppenheim J J, Schecter B: Lymphocyte transformation. In Rose NR, Friedman H, editors: Manual of clinical immunology. Washington, D.C., 1976, American Society for Microbiology, pp 81-94. Church JA, Jordan SC, Keens TG, Wang C: Circulating immune complexes in patients with cystic fibrosis. Chest 80:405, 1981. Jordan SC, Lemire J, Border W, et al: False negative anti-DNA antibody activity in infantile systemic lupus erythematosus. J Clin Immunol 4:156, 1984. Hopkinson DA, Cook PJ, Harris H: Further data on the adenosine deaminase (ADA) polymorphism and a report of a new phenotype. Ann Hum Genet 32:361, 1969. Reichert CM, O'Leary TJ, Levens DL, et al: Autopsy pathology in the acquired immune deficiency syndrome. Am J Pathol 112:357, 1983. Elie R, Larouche AC, Arnoux E, et al: Thymic dysptasia in acquired immunodeficiency syndrome. New Engl J Med 308:841, 1983. Landing BH, Yutuc IL, Swanson VL: Infantile lymphoreticular tissue: Effects of perinatal infections and infantile malnutrition. Perspect Pediatr Pathol 5:63, 1979. Ewing EP, Spira T J, Chandler FW, et al: Unusual cytoplasmic body in lymphoid cells of homosexual men with unexplained lymphadenopathy. N Engl J Med 308:819, 1983. Sidhu GS, Stahl RE, El-Sadr W, Zotla-Pazner S: Ultrastructural markers of AIDS. Lancet 1:990, 1983. Centers for Disease Control: Update: Acquired immunodeficiency syndrome (AIDS): United States. MMWR 32:688, 1984. Lawlor G J, Ammann A J, Wright WC, et al: The syndrome of cellular immunodeficiency with immunoglobulins. J PEDIATR 84:183, 1974.

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23. Rubinstein A: Acquired immunodeficiency syndrome in infants. Am J Dis Child 137:825, 1983. 24. Landing BH, Yutuc IL, Swanson VL: Clinicopathologic correlations in immunologic deficiency diseases of children, with emphasis on thymic histologic patterns. In Kobayashi N, editors: Immunodeficiency: Its nature and etiological significance in human diseases. Tokyo, University of Tokyo Press, 1978, pp 3-35. 25. Schroff RW, Gottlieb MS, Prince HE, Chai LL, Fahey JL: Immunological studies of homosexual men with immunodeficiency and Kaposi's sarcoma. Clin Immunol tmmunopathol 27:300, 1983. 26. Barnett EV moderator: Circulating immune complexes: Their immunochemistry, detection and importance. Ann Intern Med 91:430, 1979. 27. Whiteside TL, Rabin BS: Surface immunoglobulin on activated human peripheral blood thymus-derived cells. J Clin Invest 57:762, 1976. 28. Bockman DE, Kirby ML: Dependence of thymus development on derivatives of the neural crest. Science 223:498, 1984. 29. Miller ME: The immunodeficiencies of immaturity. In Stiehm ER, Fulginiti VA, editors: Immunologic disorders in infants and children. Philadelphia, 1980, WB Saunders, pp 219-238. 30. Gatti RA: Biology of the immune response. In Stiehm ER, Fulginiti VA, editors: Immunologic disorders in infants and children. Philadelphia, 1980, WB Saunders, pp 20-35. 31. Talal N, Shearer G: A clinician and a scientist look at acquired immune-deficiency syndrome (AIDS). Immunol Today 4:180, 1983. 32. Jaffe HS, Abrams DI, Ammann A J, et al: Complications of co-trimoxazole in treatment of AIDS-associated Pneumocystis carinii pneumonia in homosexual men. Lancet 2:1109, 1983.