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Transient Hypogammaglobulinemia of Infancy

Transient Hypogammaglobulinemia of Infancy. Vivek U. Rao, M.D. Fellow, Allergy & Immunology University of Pennsylvania Immunodeficiency Conference April 11, 2005. Transient Hypogammaglobulinemia of Infancy (THI). Medline search: Terms used “Transient hypogammaglobulinemia”

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Transient Hypogammaglobulinemia of Infancy

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  1. Transient Hypogammaglobulinemia of Infancy Vivek U. Rao, M.D. Fellow, Allergy & Immunology University of Pennsylvania Immunodeficiency Conference April 11, 2005

  2. Transient Hypogammaglobulinemia of Infancy (THI) • Medline search: • Terms used • “Transient hypogammaglobulinemia” • “Transient hypogammaglobulinaemia” • “Pediatric” and “hypogammaglobulinemia” • “Pediatric” and “hypogammaglobulinaemia” • 68 English articles found • 50 were available at the University of Pennsylvania Biomedical Library or via E-journals; the relevant articles will be discussed during the remainder of today’s conference

  3. THI: Historical Background • Transient hypogammaglobulinemia of infancy • First described in 19561 • Characterized by abnormal delay in onset of immunoglobulin synthesis1 • Physiologic hypogammaglobulinemia in infants is prolonged • Usually occurs at 2-4 months, but lasts until 18-36 months in those with THI2

  4. THI: Incidence • True incidence unknown • Articles over the years have argued about how common THI is • Tiller and Buckley (Duke Univ.)3 • 1978 paper reported only 11 cases of THI out of 10,000 patients who underwent immunoglobulin studies over 12-year period • Used strict criteria for THI • At least one Ig class > 2 SDs below normal for age on  2 specimens obtained during infancy • Subsequent labs must show definite increase in values • No features to suggest other types of primary immunodeficiency

  5. THI: Incidence • Dressler et al.4 • Identified THI in only 5 patients after evaluating 8,000 sera in 2 clinics in Germany over 11 years

  6. THI: Incidence • Royal Children’s Hospital in Victoria, Australia1 • Only pediatric immunology center in the state of Victoria (population 4 million) • Study reviewed data from immunology lab collected between July 1979 and March 1990 • Patients < 2 years of age with IgG levels < 5th percentile considered; those with known immunodeficiencies excluded • 11 boys and 7 girls had “proved THI” (initial IgG low, subsequent level normal) • 28 children had “probable THI” (initial IgG low, but no subsequent data available)

  7. THI: Incidence • Royal Children’s Hospital in Victoria, Australia1 • Study • Estimated incidence • Proved THI: 23 per million births • Probable THI: 61 per million births • Estimated incidence of other immunodeficiencies (previously calculated from data from same lab) • XLA – 7 per million births • CVID – 12 per million births • Symptomatic absolute IgA deficiency – 24 per million births • SCID – 14 per million births

  8. THI: Incidence • Children’s Hospital, Sao Paulo, Brazil (Grumach et al.)5 • 166 cases of primary immunodeficiency over 15 years • Most common diagnoses • IgA deficiency – 60 • THI – 14 (8 male, 6 female) • Chronic granulomatous disease – 10 • Complement – 10

  9. THI: Incidence • Japan: Nationwide survey6 • Survey 1 • 1700 hospitals and institutes in Japan sent questionnaires asking if they had patients with primary immunodeficiency syndrome 1966-1975 • 641 replied • 628 cases reported • THI – 116 (18.5%) • IgA deficiency – 93 (14.8%) • Selective immunodeficiency other than IgA – 77 (12.3%) • XLA – 70 (11.1%)

  10. THI: Incidence • Japan: Nationwide survey6 • Survey 2 • Physicians who took care of patients reported in first survey, as well as ~ 100 physicians who might be willing to register new cases • 497 patients registered • CVID – 79 • Selective IgA deficiency – 74 • XLA – 58 • CGD – 54 • SCID – 46 • Immunodeficiency with telangiectasia – 35 • THI – 33 (23 male, 10 female)

  11. THI: Pathogenesis • Normal values (n=296) (Stiehm)7 * Mean  1 SD.

  12. THI: Pathogenesis • One view: heterogenous group of errors in immune system8 • Alternative view: normal variant of the immune system in which some mature more slowly than others, just like those with delayed growth

  13. THI: Pathogenesis • Genetic evidence • Soothill et al.9 • 11 first-degree relatives of patients with hypogammaglobulinemia were followed from birth • 4 developed sex-linked hypogammaglobulinemia • 5 had probable THI • Kilic et al.10 • Followed 40 Turkish children with THI • None had first-degree relatives with known immunologic defects • None had parents or siblings with abnormal IgG, IgA, or IgM

  14. THI: Pathogenesis • Siegel et al.: THI due to deficiency of helper T cells11 • In vitro studies using lymphocytes from donors • 17 with THI • 6 who had recovered from THI • 13 age-matched healthy children • 11 parents of children with THI

  15. THI: Pathogenesis • Siegel et al.11 • Findings • THI patients had same number of circulating B lymphocytes as healthy controls • THI patients had decreased ability to synthesize IgG (and to a lesser extent, IgM) in response to pokeweed mitogen (T-cell-dependent B-cell activator)

  16. THI: Pathogenesis • Siegel et al.11 • Findings • THI patients do not have increased suppressor activity • Based on creating co-cultures with 1:1 ratio of THI patient’s lymphocytes to the parent’s, then stimulating with pokeweed

  17. THI: Pathogenesis • Siegel et al.11 • Findings • THI patients have deficient helper-T-cell function • T and B cells were separated, recombined 1:1, and cultured for 7 days with pokeweed mitogen • Parental T + parental B  high IgG • THI T + THI B  low IgG • Parental T + THI B  high IgG • THI T + parental B  low IgG

  18. THI: Pathogenesis • Siegel et al.11 • Findings • In THI, B cells are intrinsically intact • In vitro infection with EBV (T-cell-independent B-cell activator)  IgG and IgM production similar in THI patients and healthy controls • Absolute number of CD4+ helper cells decreased in THI patients compared to healthy controls and parents • Number is normal in those who have recovered from THI

  19. THI: Pathogenesis • Kilic et al.10 • Findings • 26 patients with THI studied • Normal CD4 numbers seen in all 26

  20. THI: Pathogenesis • Other possibilities12 • Defective production of cytokines • Abnormal B-cell response to mediators • Inhibition of B cells by cytokines

  21. THI: Pathogenesis • Kowalczyk et al. (1997)12 • 30 children with THI (IgG > 2 SD below mean) • 10 proved • 20 probable • 15 children with IgA deficiency • 40 controls with recurrent infections but negative immunodeficiency work-up • In vitro study took PBMCs, stimulated them with phytohemagglutinin, and studied cytokines

  22. THI: Pathogenesis • Kowalczyk et al. (1997)12 • Results • Normal numbers of CD3, CD4, CD8, CD19, and CD22 lymphocytes in THI patients • Increased TNF-alpha and TNF-beta in proved and probable THI • Increased IL-10 in proved THI • No change in IL-1, IL4, or IL-6 • When THI resolved, TNF-alpha and TNF-beta were normal, but IL-10 remained elevated (at 6-12 month follow-up)

  23. THI: Pathogenesis • Kowalczyk et al. (1997)12 • Conclusions • TNF may affect B cells by arresting IgG and IgA production • Balance between TNF and IL-10 may affect development of IgG-producing B cells

  24. THI: Pathogenesis • Kowalczyk et al. (2002)13 • 14 with THI (IgG > 2 SD below mean with normal IgM and IgA) • All eventually had normalization of IgG • 20 with selective IgA deficiency • 29 controls with recurrent infections but negative work-up for immunodeficiency • Examined Th1 (TNF-alpha, TNF-beta, IFN-gamma) and Th2 (IL-4, IL-10) cytokines

  25. THI: Pathogenesis • Kowalczyk et al. (2002)12 • Findings • Increased frequency of TNF-alpha- and TNF-beta-positive CD3+/CD4+ in THI • Slightly increased frequency of CD4+/IL-10 (not significant) in THI with no difference in CD4+/IL-4 • IL-12 but not IL-18 level (both needed for Th1 phenotype) significantly elevated in THI • IL-12 level decreased significantly when IgG normalized

  26. THI: Pathogenesis • Kowalczyk et al. (2002)12 • Findings • THI patients had an increased proportion of IL-12+/CD33+ after stimulation with IFN-gamma/LPS • Conclusion • THI associated with an excessive Th1 response in which IL-12 secretion is elevated

  27. THI: Associated Infections • Can be asymptomatic or have recurrent infections2 • URIs • Otitis media • Sinusitis • Pneumonia (less common)

  28. THI: Associated Infections • Kilic et al.10 • Prospective evaluation of 40 patients in Turkey with THI • Criteria for diagnosis • At least 1 major Ig class  2 SD below mean for age • Normal specific antibodies to polio antigen and isohemagglutinins • Intact cellular immunity • Absence of features of other immunodeficiency syndromes

  29. THI: Associated Infections • Kilic et al.10 • Clinical features at presentation • Upper respiratory tract infection 28 (70%) • Lower respiratory tract infection 11 (27%) • Otitis media 9 (22%) • Gastroenteritis 5 (12%) • Urinary tract infection 3 (7%) • Lymphadenitis 1 (2%) • GERD 1 (2%) • Asthma, allergic bronchitis 11 (27.5%) • Atopic dermatitis 2 (5%)

  30. THI: Associated Infections • Respiratory infections • Cano et al.14 • Followed 13 patients with THI; did further testing on 11 • Antibodies to respiratory viruses tested • 9 of 11 THI patients tested prior to 17 months lacked specific antibodies despite recurrent respiratory tract infections • In contrast, 5 of 16 controls lacked specific antibodies • 3 had no prior history of respiratory infections • 1 had IgG checked and was found to have low level

  31. THI: Associated Infections • Respiratory infections • Cano et al.14 • 13 patients with THI seen at follow-up between 20 and 44 months of age • 2 never demonstrated positive viral serologies even though IgG normalized • 1 became serology positive at same time IgG normalized • 2 had IgG return to normal before becoming serology positive • 8 demonstrated positive viral serologies prior to normalization of IgG

  32. THI: Associated Infections • Clostridium difficile infection • Gryboski et al.15 • Retrospective review of records of infants and children with diarrhea and C. difficile seen over 4-year period • 43 identified with diarrhea and C. difficile • 2 sets of controls used • 20 with abdominal pain and no diarrhea • 40 with chronic diarrhea and no evidence of C. difficile

  33. THI: Associated Infections • Clostridium difficile infection • Gryboski et al.15 • Diarrhea + C. difficile • 15/43 with hypogammaglobulinemia • 12 with low IgA and IgG • 3 with low IgA and normal IgG • All 15 had normal levels 6-12 months later • Abdominal pain but no diarrhea • 0/20 with hypogammaglobulinemia • Diarrhea but no C. difficile • 3/40 with low IgA (all 3 had milk-protein allergy)

  34. THI: Associated Infections • Clostridium difficile infection • Gryboski et al.15 • Conclusion: THI patients are at increased risk of diarrhea from C. difficile, due to increased use of antibiotics or inadequate local antibody response to organism

  35. THI: Associated Infections • Bacterial gastroenteritis • Melamed et al.16 • Retrospective review of data from a bacteriology lab over 16-month period • Records of children with stool specimens positive for Campylobacter jejuni analyzed • 51 cases found • 5 were previously diagnosed with an immunodeficiency • 1 combined immunodeficiency • 2 XLA • 1 agammaglobulinemia • 1 THI

  36. THI: Associated Infections • Bacterial gastroenteritis • Melamed et al.16 • 5 immunodeficiency patients • More prolonged course of diarrhea (at least 1 week) • Multiple pathogens isolated from stools • 46 “normal” patients • Diarrhea lasted 2-7 days • No other organisms isolated • THI patient • Stool also grew Shigella, Salmonella, and E. coli

  37. THI: Associated Infections • Pneumocystis carinii pneumonia17 • Case report of 3.5 month old boy with PCP pneumonia (dx’ed by BAL) • Normal specific antibody production following tetanus, diptheria, and Hib immunization • Normal T cell numbers • Normal IgM but borderline low IgG and absent IgA

  38. THI: Associated Infections • Pneumocystis carinii pneumonia17 • Case report

  39. THI: Associated Infections • Poliomyelitis18 • Case report of 6-month old Japanese boy with THI and neurovirulent variation of Sabin type 2 oral poliovirus (based on PCR of CSF and stool) • Patient with febrile seizure at 4 months; abnormal eye movements (horizontal nystagmus-like) and no visual recognition at 5 months • Child never received OPV, but developed poliovirus meningoencephalitis (presumably from contact with someone who was shedding) • IgG normalized by age 2, with no subsequent episodes of unusual or severe infections

  40. THI: Diagnosis • No definite criteria for diagnosis19 • Occurs in infancy and generally resolves by 24-36 months • Usually characterized by serum IgG level  2 SDs below normal • IgA (and IgM) may also be low • Antibody responses to protein antigens (diptheria, tetanus) are normal

  41. THI: Diagnosis • Diagnosis can truly be made only retrospectively20 • Individuals may have normalization of IgG but persistently low IgA levels, thus meeting criteria for selective IgA deficiency

  42. THI and Risk for Other Diseases • Atopy • Not a prominent feature in most series1 • Exception: Fineman et al.21 • Report of 4 infants seen within a 1-year period • All 4 had THI, food allergies, and elevated IgE

  43. THI and Risk for Other Diseases • Atopy • Exception: Walker et al.1 • Of 15 children with proved THI, 12 had either atopic disease or food allergy/intolerance • 4 with cow milk protein intolerance • 3 with asthma • 2 with asthma and eczema • 1 with asthma and immediate food hypersensitivity reaction

  44. THI: Treatment • IVIG: To give or not to give? • Tiller and Buckley3 • Followed 11 children with THI • None received IVIG, and none had serious infections • Cano et al.14 • Followed 13 patients with THI • 5 received IM IG therapy (usually for a short period of time – 9 months or so) • Therapy did not seem to delay onset of antibody synthesis • Conclusion: IM IG should be considered in THI since there is minimal evidence of harm

  45. THI: Long-term Outcome • Little data available • Long-term follow-up needed to exclude other etiologies, such as CVID2

  46. THI References: • Walker AM, Kemp AS, Hill DJ, Shelton MJ. Features of transient hypogammaglobulinaemia in infants screened for immunological abnormalities. Archives of Disease in Childhood. 70(3):183-6, 1994 Mar. • Ballow M. Primary immunodeficiency disorders: antibody deficiency. Journal of Allergy & Clinical Immunology. 109(4):581-91, 2002 Apr. • Tiller TL Jr, Buckley RH. Transient hypogammaglobulinemia of infancy: review of the literature, clinical and immunologic features of 11 new cases, and long-term follow-up. Journal of Pediatrics. 92(3):347-53, 1978 Mar. • Dressler F, Peter HH, Muller W, Rieger CH. Transient hypogammaglobulinemia of infancy: Five new cases, review of the literature and redefinition. Acta Paediatrica Scandinavica. 78(5):767-74, 1989 Sep. • Grumach AS, Duarte AJ, Bellinati-Pires R, Pastorino AC, Jacob CM, Diogo CL, Condino-Neto A, Kirschfink M, Carneiro-Sampaio MM. Brazilian report on primary immunodeficiencies in children: 166 cases studied over a follow-up time of 15 years. Journal of Clinical Immunology. 17(4):340-5, 1997 Jul. • Hayakawa H, Iwata T, Yata J, Kobayashi N. Primary immunodeficiency syndrome in Japan. I. Overview of a nationwide survey on primary immunodeficiency syndrome. Journal of Clinical Immunology. 1(1):31-9, 1981 Jan. • Stiehm ER, Fudenberg HH. Serum levels of immune globulins in health and disease: a survey. Pediatrics. 37(5):715-27, 1966 May. • Dalal I, Reid B, Nisbet-Brown E, Roifman CM. The outcome of patients with hypogammaglobulinemia in infancy and early childhood. Journal of Pediatrics. 133(1):144-146.

  47. THI References: • Soothill JF. Immunoglobulins in first-degree relatives of patients with hypogammaglobulinaemia. Transient hypogammaglobulinaemia: a possible manifestation of heterozygocity. Lancet. 1(7550):1001-3, 1968 May 11. • Kilic SS, Tezcan I, Sanal O, Metin A, Ersoy F. Transient hypogammaglobulinemia of infancy: clinical and immunologic features of 40 new cases. Pediatrics International. 42(6):647-50, 2000 Dec. • Siegel RL. Clinical disorders associated with T cell subset abnormalities. Advances in Pediatrics. 31:447-80, 1984. • Kowalczyk D, Mytar B, Zembala M. Cytokine production in transient hypogammaglobulinemia and isolated IgA deficiency. Journal of Allergy & Clinical Immunology. 100(4):556-62, 1997 Oct. • Kowalczyk D, Baran J, Webster AD, Zembala M. Intracellular cytokine production by Th1/Th2 lymphocytes and monocytes of children with symptomatic transient hypogammaglobulinaemia of infancy (THI) and selective IgA deficiency (SIgAD). Clinical & Experimental Immunology. 127(3):507-12, 2002 Mar. • Cano F, Mayo DR, Ballow M. Absent specific viral antibodies in patients with transient hypogammaglobulinemia of infancy. Journal of Allergy & Clinical Immunology. 85(2):510-3, 1990 Feb. • Gryboski JD, Pellerano R, Young N, Edberg S. Positive role of Clostridium difficile infection in diarrhea in infants and children. American Journal of Gastroenterology. 86(6):685-9, 1991 Jun.

  48. THI References: • Melamed I, Bujanover Y, Igra YS, Schwartz D, Zakuth V, Spirer Z. Campylobacter enteritis in normal and immunodeficient children. American Journal of Diseases of Children. 137(8):752-3, 1983 Aug. • Smart JM, Kemp AS, Armstrong DS. Pneumocystis carinii pneumonia in an infant with transient hypogammaglobulinaemia of infancy. Archives of Disease in Childhood. 87(5):449-50, 2002 Nov. • Inaba H, Hori H, Ito M, Kuze M, Ishiko H, Asmar BI, Komada Y. Polio vaccine virus-associated meningoencephalitis in an infant with transient hypogammaglobulinemia. Scandinavian Journal of Infectious Diseases. 33(8):630-1, 2001. • Yates AB, Shaw SG, Moffitt JE. Spontaneous resolution of profound hypogammaglobulinemia. Southern Medical Journal. 94(12):1215-6, 2001 Dec. • McGeady SJ. Transient hypogammaglobulinemia of infancy: need to reconsider name and definition. Journal of Pediatrics. 110(1):47-50, 1987 Jan. • Fineman SM, Rosen FS, Geha RS. Transient hypogammaglobulinemia, elevated immunoglobulin E levels, and food allergy. Journal of Allergy & Clinical Immunology. 64(3):216-22, 1979 Sep.

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