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Transient Hypogammaglobulinemia of Infancy <ul><li>Vivek U. Rao, M.D. </li></ul><ul><li>Fellow, Allergy & Immunology </li>...
Transient Hypogammaglobulinemia of Infancy (THI) <ul><li>Medline search: </li></ul><ul><ul><li>Terms used </li></ul></ul><...
THI: Historical Background <ul><li>Transient hypogammaglobulinemia of infancy </li></ul><ul><ul><li>First described in 195...
THI: Incidence <ul><li>True incidence unknown </li></ul><ul><li>Articles over the years have argued about how common THI i...
THI: Incidence <ul><li>Dressler et al. 4 </li></ul><ul><ul><li>Identified THI in only 5 patients after evaluating 8,000 se...
THI: Incidence <ul><li>Royal Children’s Hospital in Victoria, Australia 1   </li></ul><ul><ul><li>Only pediatric immunolog...
THI: Incidence <ul><li>Royal Children’s Hospital in Victoria, Australia 1 </li></ul><ul><ul><li>Study  </li></ul></ul><ul>...
THI: Incidence <ul><li>Children’s Hospital, Sao Paulo, Brazil (Grumach et al.) 5 </li></ul><ul><ul><li>166 cases of primar...
THI: Incidence <ul><li>Japan: Nationwide survey 6 </li></ul><ul><ul><li>Survey 1 </li></ul></ul><ul><ul><ul><li>1700 hospi...
THI: Incidence <ul><li>Japan: Nationwide survey 6 </li></ul><ul><ul><li>Survey 2 </li></ul></ul><ul><ul><ul><li>Physicians...
THI: Pathogenesis <ul><li>Normal values (n=296) (Stiehm) 7 </li></ul>* Mean    1 SD. 200    61 99    27 1158    305 30...
THI: Pathogenesis <ul><li>One view: heterogenous group of errors in immune system 8 </li></ul><ul><li>Alternative view: no...
THI: Pathogenesis <ul><li>Genetic evidence </li></ul><ul><ul><li>Soothill et al. 9 </li></ul></ul><ul><ul><ul><li>11 first...
THI: Pathogenesis <ul><li>Siegel et al.: THI due to deficiency of helper T cells 11 </li></ul><ul><ul><li>In vitro studies...
THI: Pathogenesis <ul><li>Siegel et al. 11 </li></ul><ul><ul><li>Findings </li></ul></ul><ul><ul><ul><li>THI patients had ...
THI: Pathogenesis <ul><li>Siegel et al. 11 </li></ul><ul><ul><li>Findings </li></ul></ul><ul><ul><ul><li>THI patients do n...
THI: Pathogenesis <ul><li>Siegel et al. 11 </li></ul><ul><ul><li>Findings </li></ul></ul><ul><ul><ul><li>THI patients have...
THI: Pathogenesis <ul><li>Siegel et al. 11 </li></ul><ul><ul><li>Findings </li></ul></ul><ul><ul><ul><li>In THI, B cells a...
THI: Pathogenesis <ul><li>Kilic et al. 10 </li></ul><ul><ul><li>Findings </li></ul></ul><ul><ul><ul><li>26 patients with T...
THI: Pathogenesis <ul><li>Other possibilities 12 </li></ul><ul><ul><li>Defective production of cytokines </li></ul></ul><u...
THI: Pathogenesis <ul><li>Kowalczyk et al. (1997) 12 </li></ul><ul><ul><li>30 children with THI (IgG > 2 SD below mean) </...
THI: Pathogenesis <ul><li>Kowalczyk et al. (1997) 12 </li></ul><ul><ul><li>Results </li></ul></ul><ul><ul><ul><li>Normal n...
THI: Pathogenesis <ul><li>Kowalczyk et al. (1997) 12 </li></ul><ul><ul><li>Conclusions </li></ul></ul><ul><ul><ul><li>TNF ...
THI: Pathogenesis <ul><li>Kowalczyk et al. (2002) 13 </li></ul><ul><ul><li>14 with THI (IgG > 2 SD below mean with normal ...
THI: Pathogenesis <ul><li>Kowalczyk et al. (2002) 12 </li></ul><ul><ul><li>Findings </li></ul></ul><ul><ul><ul><li>Increas...
THI: Pathogenesis <ul><li>Kowalczyk et al. (2002) 12 </li></ul><ul><ul><li>Findings </li></ul></ul><ul><ul><ul><li>THI pat...
THI: Associated Infections <ul><li>Can be asymptomatic or have recurrent infections 2 </li></ul><ul><ul><li>URIs </li></ul...
THI: Associated Infections <ul><li>Kilic et al. 10 </li></ul><ul><ul><li>Prospective evaluation of 40 patients in Turkey w...
THI: Associated Infections <ul><li>Kilic et al. 10 </li></ul><ul><ul><li>Clinical features at presentation </li></ul></ul>...
THI: Associated Infections <ul><li>Respiratory infections </li></ul><ul><ul><li>Cano et al. 14 </li></ul></ul><ul><ul><ul>...
THI: Associated Infections <ul><li>Respiratory infections </li></ul><ul><ul><li>Cano et al. 14 </li></ul></ul><ul><ul><ul>...
THI: Associated Infections <ul><li>Clostridium difficile  infection </li></ul><ul><ul><li>Gryboski et al. 15 </li></ul></u...
THI: Associated Infections <ul><li>Clostridium difficile  infection </li></ul><ul><ul><li>Gryboski et al. 15 </li></ul></u...
THI: Associated Infections <ul><li>Clostridium difficile  infection </li></ul><ul><ul><li>Gryboski et al. 15 </li></ul></u...
THI: Associated Infections <ul><li>Bacterial gastroenteritis </li></ul><ul><ul><li>Melamed et al. 16 </li></ul></ul><ul><u...
THI: Associated Infections <ul><li>Bacterial gastroenteritis </li></ul><ul><ul><li>Melamed et al. 16 </li></ul></ul><ul><u...
THI: Associated Infections <ul><li>Pneumocystis carinii  pneumonia 17 </li></ul><ul><ul><li>Case report of 3.5 month old b...
THI: Associated Infections <ul><li>Pneumocystis carinii  pneumonia 17 </li></ul><ul><ul><li>Case report </li></ul></ul>nl ...
THI: Associated Infections <ul><li>Poliomyelitis 18 </li></ul><ul><ul><li>Case report of 6-month old Japanese boy with THI...
THI: Diagnosis <ul><li>No definite criteria for diagnosis 19 </li></ul><ul><ul><li>Occurs in infancy and generally resolve...
THI: Diagnosis <ul><li>Diagnosis can truly be made only retrospectively 20 </li></ul><ul><ul><li>Individuals may have norm...
THI and Risk for Other Diseases <ul><li>Atopy </li></ul><ul><ul><li>Not a prominent feature in most series 1 </li></ul></u...
THI and Risk for Other Diseases <ul><li>Atopy </li></ul><ul><ul><li>Exception: Walker et al. 1 </li></ul></ul><ul><ul><ul>...
THI: Treatment <ul><li>IVIG: To give or not to give? </li></ul><ul><ul><li>Tiller and Buckley 3 </li></ul></ul><ul><ul><ul...
THI: Long-term Outcome <ul><li>Little data available </li></ul><ul><li>Long-term follow-up needed to exclude other etiolog...
THI <ul><li>References: </li></ul><ul><li>Walker AM, Kemp AS, Hill DJ, Shelton MJ. Features of transient hypogammaglobulin...
THI <ul><li>References: </li></ul><ul><li>Soothill JF. Immunoglobulins in first-degree relatives of patients with hypogamm...
THI <ul><li>References: </li></ul><ul><li>Melamed I, Bujanover Y, Igra YS, Schwartz D, Zakuth V, Spirer Z. Campylobacter e...
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Transient Hypogammaglobulinemia of Infancy

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  • IL-10 is an IgG switch factor and may be increased in an attempt to get B cells to differentiate
  • IL-10 is an IgG switch factor and may be increased in an attempt to get B cells to differentiate
  • IL-10 is an IgG switch factor and may be increased in an attempt to get B cells to differentiate
  • IL-10 is an IgG switch factor and may be increased in an attempt to get B cells to differentiate
  • IL-10 is an IgG switch factor and may be increased in an attempt to get B cells to differentiate
  • Transcript of "Transient Hypogammaglobulinemia of Infancy"

    1. 1. Transient Hypogammaglobulinemia of Infancy <ul><li>Vivek U. Rao, M.D. </li></ul><ul><li>Fellow, Allergy & Immunology </li></ul><ul><li>University of Pennsylvania </li></ul><ul><li>Immunodeficiency Conference </li></ul><ul><li>April 11, 2005 </li></ul>
    2. 2. Transient Hypogammaglobulinemia of Infancy (THI) <ul><li>Medline search: </li></ul><ul><ul><li>Terms used </li></ul></ul><ul><ul><ul><li>“ Transient hypogammaglobulinemia” </li></ul></ul></ul><ul><ul><ul><li>“ Transient hypogammaglobulinaemia” </li></ul></ul></ul><ul><ul><ul><li>“ Pediatric” and “hypogammaglobulinemia” </li></ul></ul></ul><ul><ul><ul><li>“ Pediatric” and “hypogammaglobulinaemia” </li></ul></ul></ul><ul><ul><li>68 English articles found </li></ul></ul><ul><ul><li>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 </li></ul></ul>
    3. 3. THI: Historical Background <ul><li>Transient hypogammaglobulinemia of infancy </li></ul><ul><ul><li>First described in 1956 1 </li></ul></ul><ul><ul><li>Characterized by abnormal delay in onset of immunoglobulin synthesis 1 </li></ul></ul><ul><ul><li>Physiologic hypogammaglobulinemia in infants is prolonged </li></ul></ul><ul><ul><ul><li>Usually occurs at 2-4 months, but lasts until 18-36 months in those with THI 2 </li></ul></ul></ul>
    4. 4. THI: Incidence <ul><li>True incidence unknown </li></ul><ul><li>Articles over the years have argued about how common THI is </li></ul><ul><li>Tiller and Buckley (Duke Univ.) 3 </li></ul><ul><ul><li>1978 paper reported only 11 cases of THI out of 10,000 patients who underwent immunoglobulin studies over 12-year period </li></ul></ul><ul><ul><ul><li>Used strict criteria for THI </li></ul></ul></ul><ul><ul><ul><ul><li>At least one Ig class > 2 SDs below normal for age on  2 specimens obtained during infancy </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Subsequent labs must show definite increase in values </li></ul></ul></ul></ul><ul><ul><ul><ul><li>No features to suggest other types of primary immunodeficiency </li></ul></ul></ul></ul>
    5. 5. THI: Incidence <ul><li>Dressler et al. 4 </li></ul><ul><ul><li>Identified THI in only 5 patients after evaluating 8,000 sera in 2 clinics in Germany over 11 years </li></ul></ul>
    6. 6. THI: Incidence <ul><li>Royal Children’s Hospital in Victoria, Australia 1 </li></ul><ul><ul><li>Only pediatric immunology center in the state of Victoria (population 4 million) </li></ul></ul><ul><ul><li>Study reviewed data from immunology lab collected between July 1979 and March 1990 </li></ul></ul><ul><ul><ul><li>Patients < 2 years of age with IgG levels < 5 th percentile considered; those with known immunodeficiencies excluded </li></ul></ul></ul><ul><ul><ul><ul><li>11 boys and 7 girls had “proved THI” (initial IgG low, subsequent level normal) </li></ul></ul></ul></ul><ul><ul><ul><ul><li>28 children had “probable THI” (initial IgG low, but no subsequent data available) </li></ul></ul></ul></ul>
    7. 7. THI: Incidence <ul><li>Royal Children’s Hospital in Victoria, Australia 1 </li></ul><ul><ul><li>Study </li></ul></ul><ul><ul><ul><li>Estimated incidence </li></ul></ul></ul><ul><ul><ul><ul><li>Proved THI: 23 per million births </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Probable THI: 61 per million births </li></ul></ul></ul></ul><ul><ul><ul><li>Estimated incidence of other immunodeficiencies (previously calculated from data from same lab) </li></ul></ul></ul><ul><ul><ul><ul><li>XLA – 7 per million births </li></ul></ul></ul></ul><ul><ul><ul><ul><li>CVID – 12 per million births </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Symptomatic absolute IgA deficiency – 24 per million births </li></ul></ul></ul></ul><ul><ul><ul><ul><li>SCID – 14 per million births </li></ul></ul></ul></ul>
    8. 8. THI: Incidence <ul><li>Children’s Hospital, Sao Paulo, Brazil (Grumach et al.) 5 </li></ul><ul><ul><li>166 cases of primary immunodeficiency over 15 years </li></ul></ul><ul><ul><li>Most common diagnoses </li></ul></ul><ul><ul><ul><li>IgA deficiency – 60 </li></ul></ul></ul><ul><ul><ul><li>THI – 14 (8 male, 6 female) </li></ul></ul></ul><ul><ul><ul><li>Chronic granulomatous disease – 10 </li></ul></ul></ul><ul><ul><ul><li>Complement – 10 </li></ul></ul></ul>
    9. 9. THI: Incidence <ul><li>Japan: Nationwide survey 6 </li></ul><ul><ul><li>Survey 1 </li></ul></ul><ul><ul><ul><li>1700 hospitals and institutes in Japan sent questionnaires asking if they had patients with primary immunodeficiency syndrome 1966-1975 </li></ul></ul></ul><ul><ul><ul><li>641 replied </li></ul></ul></ul><ul><ul><ul><li>628 cases reported </li></ul></ul></ul><ul><ul><ul><ul><li>THI – 116 (18.5%) </li></ul></ul></ul></ul><ul><ul><ul><ul><li>IgA deficiency – 93 (14.8%) </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Selective immunodeficiency other than IgA – 77 (12.3%) </li></ul></ul></ul></ul><ul><ul><ul><ul><li>XLA – 70 (11.1%) </li></ul></ul></ul></ul>
    10. 10. THI: Incidence <ul><li>Japan: Nationwide survey 6 </li></ul><ul><ul><li>Survey 2 </li></ul></ul><ul><ul><ul><li>Physicians who took care of patients reported in first survey, as well as ~ 100 physicians who might be willing to register new cases </li></ul></ul></ul><ul><ul><ul><li>497 patients registered </li></ul></ul></ul><ul><ul><ul><ul><li>CVID – 79 </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Selective IgA deficiency – 74 </li></ul></ul></ul></ul><ul><ul><ul><ul><li>XLA – 58 </li></ul></ul></ul></ul><ul><ul><ul><ul><li>CGD – 54 </li></ul></ul></ul></ul><ul><ul><ul><ul><li>SCID – 46 </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Immunodeficiency with telangiectasia – 35 </li></ul></ul></ul></ul><ul><ul><ul><ul><li>THI – 33 (23 male, 10 female) </li></ul></ul></ul></ul>
    11. 11. THI: Pathogenesis <ul><li>Normal values (n=296) (Stiehm) 7 </li></ul>* Mean  1 SD. 200  61 99  27 1158  305 30 Adult 148  63 59  20 946  124 9 12-16 yr 131  60 79  33 1124  235 9 9-11 yr 124  45 65  25 923  256 18 6-8 yr 93  27 56  18 929  228 28 3-5 yr 71  37 61  19 892  183 33 25-36 mo 50  24 58  23 762  209 59 13-24 mo 37  18 54  23 661  219 56 7-12 mo 28  18 43  17 427  186 33 4-6 mo 21  13 30  11 430  119 29 1-3 mo 2  3 11  5 1031  200 22 Newborn IgA* mg/dl IgM* mg/dl IgG* mg/dl No. of subjects Age
    12. 12. THI: Pathogenesis <ul><li>One view: heterogenous group of errors in immune system 8 </li></ul><ul><li>Alternative view: normal variant of the immune system in which some mature more slowly than others, just like those with delayed growth </li></ul>
    13. 13. THI: Pathogenesis <ul><li>Genetic evidence </li></ul><ul><ul><li>Soothill et al. 9 </li></ul></ul><ul><ul><ul><li>11 first-degree relatives of patients with hypogammaglobulinemia were followed from birth </li></ul></ul></ul><ul><ul><ul><li>4 developed sex-linked hypogammaglobulinemia </li></ul></ul></ul><ul><ul><ul><li>5 had probable THI </li></ul></ul></ul><ul><ul><li>Kilic et al. 10 </li></ul></ul><ul><ul><ul><li>Followed 40 Turkish children with THI </li></ul></ul></ul><ul><ul><ul><li>None had first-degree relatives with known immunologic defects </li></ul></ul></ul><ul><ul><ul><li>None had parents or siblings with abnormal IgG, IgA, or IgM </li></ul></ul></ul>
    14. 14. THI: Pathogenesis <ul><li>Siegel et al.: THI due to deficiency of helper T cells 11 </li></ul><ul><ul><li>In vitro studies using lymphocytes from donors </li></ul></ul><ul><ul><ul><li>17 with THI </li></ul></ul></ul><ul><ul><ul><li>6 who had recovered from THI </li></ul></ul></ul><ul><ul><ul><li>13 age-matched healthy children </li></ul></ul></ul><ul><ul><ul><li>11 parents of children with THI </li></ul></ul></ul>
    15. 15. THI: Pathogenesis <ul><li>Siegel et al. 11 </li></ul><ul><ul><li>Findings </li></ul></ul><ul><ul><ul><li>THI patients had same number of circulating B lymphocytes as healthy controls </li></ul></ul></ul><ul><ul><ul><li>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) </li></ul></ul></ul>
    16. 16. THI: Pathogenesis <ul><li>Siegel et al. 11 </li></ul><ul><ul><li>Findings </li></ul></ul><ul><ul><ul><li>THI patients do not have increased suppressor activity </li></ul></ul></ul><ul><ul><ul><ul><li>Based on creating co-cultures with 1:1 ratio of THI patient’s lymphocytes to the parent’s, then stimulating with pokeweed </li></ul></ul></ul></ul>
    17. 17. THI: Pathogenesis <ul><li>Siegel et al. 11 </li></ul><ul><ul><li>Findings </li></ul></ul><ul><ul><ul><li>THI patients have deficient helper-T-cell function </li></ul></ul></ul><ul><ul><ul><ul><li>T and B cells were separated, recombined 1:1, and cultured for 7 days with pokeweed mitogen </li></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Parental T + parental B  high IgG </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>THI T + THI B  low IgG </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Parental T + THI B  high IgG </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>THI T + parental B  low IgG </li></ul></ul></ul></ul></ul>
    18. 18. THI: Pathogenesis <ul><li>Siegel et al. 11 </li></ul><ul><ul><li>Findings </li></ul></ul><ul><ul><ul><li>In THI, B cells are intrinsically intact </li></ul></ul></ul><ul><ul><ul><ul><li>In vitro infection with EBV (T-cell-independent B-cell activator)  IgG and IgM production similar in THI patients and healthy controls </li></ul></ul></ul></ul><ul><ul><ul><li>Absolute number of CD4+ helper cells decreased in THI patients compared to healthy controls and parents </li></ul></ul></ul><ul><ul><ul><ul><li>Number is normal in those who have recovered from THI </li></ul></ul></ul></ul>
    19. 19. THI: Pathogenesis <ul><li>Kilic et al. 10 </li></ul><ul><ul><li>Findings </li></ul></ul><ul><ul><ul><li>26 patients with THI studied </li></ul></ul></ul><ul><ul><ul><ul><li>Normal CD4 numbers seen in all 26 </li></ul></ul></ul></ul>
    20. 20. THI: Pathogenesis <ul><li>Other possibilities 12 </li></ul><ul><ul><li>Defective production of cytokines </li></ul></ul><ul><ul><li>Abnormal B-cell response to mediators </li></ul></ul><ul><ul><li>Inhibition of B cells by cytokines </li></ul></ul>
    21. 21. THI: Pathogenesis <ul><li>Kowalczyk et al. (1997) 12 </li></ul><ul><ul><li>30 children with THI (IgG > 2 SD below mean) </li></ul></ul><ul><ul><ul><li>10 proved </li></ul></ul></ul><ul><ul><ul><li>20 probable </li></ul></ul></ul><ul><ul><li>15 children with IgA deficiency </li></ul></ul><ul><ul><li>40 controls with recurrent infections but negative immunodeficiency work-up </li></ul></ul><ul><ul><li>In vitro study took PBMCs, stimulated them with phytohemagglutinin, and studied cytokines </li></ul></ul>
    22. 22. THI: Pathogenesis <ul><li>Kowalczyk et al. (1997) 12 </li></ul><ul><ul><li>Results </li></ul></ul><ul><ul><ul><li>Normal numbers of CD3, CD4, CD8, CD19, and CD22 lymphocytes in THI patients </li></ul></ul></ul><ul><ul><ul><li>Increased TNF-alpha and TNF-beta in proved and probable THI </li></ul></ul></ul><ul><ul><ul><li>Increased IL-10 in proved THI </li></ul></ul></ul><ul><ul><ul><li>No change in IL-1, IL4, or IL-6 </li></ul></ul></ul><ul><ul><ul><li>When THI resolved, TNF-alpha and TNF-beta were normal, but IL-10 remained elevated (at 6-12 month follow-up) </li></ul></ul></ul>
    23. 23. THI: Pathogenesis <ul><li>Kowalczyk et al. (1997) 12 </li></ul><ul><ul><li>Conclusions </li></ul></ul><ul><ul><ul><li>TNF may affect B cells by arresting IgG and IgA production </li></ul></ul></ul><ul><ul><ul><li>Balance between TNF and IL-10 may affect development of IgG-producing B cells </li></ul></ul></ul>
    24. 24. THI: Pathogenesis <ul><li>Kowalczyk et al. (2002) 13 </li></ul><ul><ul><li>14 with THI (IgG > 2 SD below mean with normal IgM and IgA) </li></ul></ul><ul><ul><ul><li>All eventually had normalization of IgG </li></ul></ul></ul><ul><ul><li>20 with selective IgA deficiency </li></ul></ul><ul><ul><li>29 controls with recurrent infections but negative work-up for immunodeficiency </li></ul></ul><ul><ul><li>Examined Th1 (TNF-alpha, TNF-beta, IFN-gamma) and Th2 (IL-4, IL-10) cytokines </li></ul></ul>
    25. 25. THI: Pathogenesis <ul><li>Kowalczyk et al. (2002) 12 </li></ul><ul><ul><li>Findings </li></ul></ul><ul><ul><ul><li>Increased frequency of TNF-alpha- and TNF-beta-positive CD3+/CD4+ in THI </li></ul></ul></ul><ul><ul><ul><li>Slightly increased frequency of CD4+/IL-10 (not significant) in THI with no difference in CD4+/IL-4 </li></ul></ul></ul><ul><ul><ul><li>IL-12 but not IL-18 level (both needed for Th1 phenotype) significantly elevated in THI </li></ul></ul></ul><ul><ul><ul><ul><li>IL-12 level decreased significantly when IgG normalized </li></ul></ul></ul></ul>
    26. 26. THI: Pathogenesis <ul><li>Kowalczyk et al. (2002) 12 </li></ul><ul><ul><li>Findings </li></ul></ul><ul><ul><ul><li>THI patients had an increased proportion of IL-12+/CD33+ after stimulation with IFN-gamma/LPS </li></ul></ul></ul><ul><ul><li>Conclusion </li></ul></ul><ul><ul><ul><li>THI associated with an excessive Th1 response in which IL-12 secretion is elevated </li></ul></ul></ul>
    27. 27. THI: Associated Infections <ul><li>Can be asymptomatic or have recurrent infections 2 </li></ul><ul><ul><li>URIs </li></ul></ul><ul><ul><li>Otitis media </li></ul></ul><ul><ul><li>Sinusitis </li></ul></ul><ul><ul><li>Pneumonia (less common) </li></ul></ul>
    28. 28. THI: Associated Infections <ul><li>Kilic et al. 10 </li></ul><ul><ul><li>Prospective evaluation of 40 patients in Turkey with THI </li></ul></ul><ul><ul><li>Criteria for diagnosis </li></ul></ul><ul><ul><ul><li>At least 1 major Ig class  2 SD below mean for age </li></ul></ul></ul><ul><ul><ul><li>Normal specific antibodies to polio antigen and isohemagglutinins </li></ul></ul></ul><ul><ul><ul><li>Intact cellular immunity </li></ul></ul></ul><ul><ul><ul><li>Absence of features of other immunodeficiency syndromes </li></ul></ul></ul>
    29. 29. THI: Associated Infections <ul><li>Kilic et al. 10 </li></ul><ul><ul><li>Clinical features at presentation </li></ul></ul><ul><ul><ul><li>Upper respiratory tract infection 28 (70%) </li></ul></ul></ul><ul><ul><ul><li>Lower respiratory tract infection 11 (27%) </li></ul></ul></ul><ul><ul><ul><li>Otitis media 9 (22%) </li></ul></ul></ul><ul><ul><ul><li>Gastroenteritis 5 (12%) </li></ul></ul></ul><ul><ul><ul><li>Urinary tract infection 3 (7%) </li></ul></ul></ul><ul><ul><ul><li>Lymphadenitis 1 (2%) </li></ul></ul></ul><ul><ul><ul><li>GERD 1 (2%) </li></ul></ul></ul><ul><ul><ul><li>Asthma, allergic bronchitis 11 (27.5%) </li></ul></ul></ul><ul><ul><ul><li>Atopic dermatitis 2 (5%) </li></ul></ul></ul>
    30. 30. THI: Associated Infections <ul><li>Respiratory infections </li></ul><ul><ul><li>Cano et al. 14 </li></ul></ul><ul><ul><ul><li>Followed 13 patients with THI; did further testing on 11 </li></ul></ul></ul><ul><ul><ul><li>Antibodies to respiratory viruses tested </li></ul></ul></ul><ul><ul><ul><ul><li>9 of 11 THI patients tested prior to 17 months lacked specific antibodies despite recurrent respiratory tract infections </li></ul></ul></ul></ul><ul><ul><ul><ul><li>In contrast, 5 of 16 controls lacked specific antibodies </li></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>3 had no prior history of respiratory infections </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>1 had IgG checked and was found to have low level </li></ul></ul></ul></ul></ul>
    31. 31. THI: Associated Infections <ul><li>Respiratory infections </li></ul><ul><ul><li>Cano et al. 14 </li></ul></ul><ul><ul><ul><li>13 patients with THI seen at follow-up between 20 and 44 months of age </li></ul></ul></ul><ul><ul><ul><ul><li>2 never demonstrated positive viral serologies even though IgG normalized </li></ul></ul></ul></ul><ul><ul><ul><ul><li>1 became serology positive at same time IgG normalized </li></ul></ul></ul></ul><ul><ul><ul><ul><li>2 had IgG return to normal before becoming serology positive </li></ul></ul></ul></ul><ul><ul><ul><ul><li>8 demonstrated positive viral serologies prior to normalization of IgG </li></ul></ul></ul></ul>
    32. 32. THI: Associated Infections <ul><li>Clostridium difficile infection </li></ul><ul><ul><li>Gryboski et al. 15 </li></ul></ul><ul><ul><ul><li>Retrospective review of records of infants and children with diarrhea and C. difficile seen over 4-year period </li></ul></ul></ul><ul><ul><ul><ul><li>43 identified with diarrhea and C. difficile </li></ul></ul></ul></ul><ul><ul><ul><ul><li>2 sets of controls used </li></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>20 with abdominal pain and no diarrhea </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>40 with chronic diarrhea and no evidence of C. difficile </li></ul></ul></ul></ul></ul>
    33. 33. THI: Associated Infections <ul><li>Clostridium difficile infection </li></ul><ul><ul><li>Gryboski et al. 15 </li></ul></ul><ul><ul><ul><li>Diarrhea + C. difficile </li></ul></ul></ul><ul><ul><ul><ul><li>15/43 with hypogammaglobulinemia </li></ul></ul></ul></ul><ul><ul><ul><ul><li>12 with low IgA and IgG </li></ul></ul></ul></ul><ul><ul><ul><ul><li>3 with low IgA and normal IgG </li></ul></ul></ul></ul><ul><ul><ul><ul><li>All 15 had normal levels 6-12 months later </li></ul></ul></ul></ul><ul><ul><ul><li>Abdominal pain but no diarrhea </li></ul></ul></ul><ul><ul><ul><ul><li>0/20 with hypogammaglobulinemia </li></ul></ul></ul></ul><ul><ul><ul><li>Diarrhea but no C. difficile </li></ul></ul></ul><ul><ul><ul><ul><li>3/40 with low IgA (all 3 had milk-protein allergy) </li></ul></ul></ul></ul>
    34. 34. THI: Associated Infections <ul><li>Clostridium difficile infection </li></ul><ul><ul><li>Gryboski et al. 15 </li></ul></ul><ul><ul><ul><li>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 </li></ul></ul></ul>
    35. 35. THI: Associated Infections <ul><li>Bacterial gastroenteritis </li></ul><ul><ul><li>Melamed et al. 16 </li></ul></ul><ul><ul><ul><li>Retrospective review of data from a bacteriology lab over 16-month period </li></ul></ul></ul><ul><ul><ul><li>Records of children with stool specimens positive for Campylobacter jejuni analyzed </li></ul></ul></ul><ul><ul><ul><li>51 cases found </li></ul></ul></ul><ul><ul><ul><li>5 were previously diagnosed with an immunodeficiency </li></ul></ul></ul><ul><ul><ul><ul><li>1 combined immunodeficiency </li></ul></ul></ul></ul><ul><ul><ul><ul><li>2 XLA </li></ul></ul></ul></ul><ul><ul><ul><ul><li>1 agammaglobulinemia </li></ul></ul></ul></ul><ul><ul><ul><ul><li>1 THI </li></ul></ul></ul></ul>
    36. 36. THI: Associated Infections <ul><li>Bacterial gastroenteritis </li></ul><ul><ul><li>Melamed et al. 16 </li></ul></ul><ul><ul><ul><li>5 immunodeficiency patients </li></ul></ul></ul><ul><ul><ul><ul><li>More prolonged course of diarrhea (at least 1 week) </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Multiple pathogens isolated from stools </li></ul></ul></ul></ul><ul><ul><ul><li>46 “normal” patients </li></ul></ul></ul><ul><ul><ul><ul><li>Diarrhea lasted 2-7 days </li></ul></ul></ul></ul><ul><ul><ul><ul><li>No other organisms isolated </li></ul></ul></ul></ul><ul><ul><ul><li>THI patient </li></ul></ul></ul><ul><ul><ul><ul><li>Stool also grew Shigella , Salmonella , and E. coli </li></ul></ul></ul></ul>
    37. 37. THI: Associated Infections <ul><li>Pneumocystis carinii pneumonia 17 </li></ul><ul><ul><li>Case report of 3.5 month old boy with PCP pneumonia (dx’ed by BAL) </li></ul></ul><ul><ul><ul><li>Normal specific antibody production following tetanus, diptheria, and Hib immunization </li></ul></ul></ul><ul><ul><ul><li>Normal T cell numbers </li></ul></ul></ul><ul><ul><ul><li>Normal IgM but borderline low IgG and absent IgA </li></ul></ul></ul>
    38. 38. THI: Associated Infections <ul><li>Pneumocystis carinii pneumonia 17 </li></ul><ul><ul><li>Case report </li></ul></ul>nl nl 36 1.77 (2.02-11.76) __ 13 __ 7.51 (2.71-13.78) 17 __ 1.77 (2.02-11.76) 10 <0.07 (nl 0.14-0.69) 2.23 (1.39-8.04) 5 Not detected 3.9 (nl 1.39-8.04) 3.5 IgA (g/l) IgG (g/l) Age (mos)
    39. 39. THI: Associated Infections <ul><li>Poliomyelitis 18 </li></ul><ul><ul><li>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) </li></ul></ul><ul><ul><ul><li>Patient with febrile seizure at 4 months; abnormal eye movements (horizontal nystagmus-like) and no visual recognition at 5 months </li></ul></ul></ul><ul><ul><ul><li>Child never received OPV, but developed poliovirus meningoencephalitis (presumably from contact with someone who was shedding) </li></ul></ul></ul><ul><ul><ul><li>IgG normalized by age 2, with no subsequent episodes of unusual or severe infections </li></ul></ul></ul>
    40. 40. THI: Diagnosis <ul><li>No definite criteria for diagnosis 19 </li></ul><ul><ul><li>Occurs in infancy and generally resolves by 24-36 months </li></ul></ul><ul><ul><li>Usually characterized by serum IgG level  2 SDs below normal </li></ul></ul><ul><ul><li>IgA (and IgM) may also be low </li></ul></ul><ul><ul><li>Antibody responses to protein antigens (diptheria, tetanus) are normal </li></ul></ul>
    41. 41. THI: Diagnosis <ul><li>Diagnosis can truly be made only retrospectively 20 </li></ul><ul><ul><li>Individuals may have normalization of IgG but persistently low IgA levels, thus meeting criteria for selective IgA deficiency </li></ul></ul>
    42. 42. THI and Risk for Other Diseases <ul><li>Atopy </li></ul><ul><ul><li>Not a prominent feature in most series 1 </li></ul></ul><ul><ul><li>Exception: Fineman et al. 21 </li></ul></ul><ul><ul><ul><li>Report of 4 infants seen within a 1-year period </li></ul></ul></ul><ul><ul><ul><li>All 4 had THI, food allergies, and elevated IgE </li></ul></ul></ul>
    43. 43. THI and Risk for Other Diseases <ul><li>Atopy </li></ul><ul><ul><li>Exception: Walker et al. 1 </li></ul></ul><ul><ul><ul><li>Of 15 children with proved THI, 12 had either atopic disease or food allergy/intolerance </li></ul></ul></ul><ul><ul><ul><ul><li>4 with cow milk protein intolerance </li></ul></ul></ul></ul><ul><ul><ul><ul><li>3 with asthma </li></ul></ul></ul></ul><ul><ul><ul><ul><li>2 with asthma and eczema </li></ul></ul></ul></ul><ul><ul><ul><ul><li>1 with asthma and immediate food hypersensitivity reaction </li></ul></ul></ul></ul>
    44. 44. THI: Treatment <ul><li>IVIG: To give or not to give? </li></ul><ul><ul><li>Tiller and Buckley 3 </li></ul></ul><ul><ul><ul><li>Followed 11 children with THI </li></ul></ul></ul><ul><ul><ul><li>None received IVIG, and none had serious infections </li></ul></ul></ul><ul><ul><li>Cano et al. 14 </li></ul></ul><ul><ul><ul><li>Followed 13 patients with THI </li></ul></ul></ul><ul><ul><ul><li>5 received IM IG therapy (usually for a short period of time – 9 months or so) </li></ul></ul></ul><ul><ul><ul><ul><li>Therapy did not seem to delay onset of antibody synthesis </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Conclusion: IM IG should be considered in THI since there is minimal evidence of harm </li></ul></ul></ul></ul>
    45. 45. THI: Long-term Outcome <ul><li>Little data available </li></ul><ul><li>Long-term follow-up needed to exclude other etiologies, such as CVID 2 </li></ul>
    46. 46. THI <ul><li>References: </li></ul><ul><li>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. </li></ul><ul><li>Ballow M. Primary immunodeficiency disorders: antibody deficiency. Journal of Allergy & Clinical Immunology. 109(4):581-91, 2002 Apr. </li></ul><ul><li>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. </li></ul><ul><li>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. </li></ul><ul><li>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. </li></ul><ul><li>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. </li></ul><ul><li>Stiehm ER, Fudenberg HH. Serum levels of immune globulins in health and disease: a survey. Pediatrics. 37(5):715-27, 1966 May. </li></ul><ul><li>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. </li></ul>
    47. 47. THI <ul><li>References: </li></ul><ul><li>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. </li></ul><ul><li>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.   </li></ul><ul><li>Siegel RL. Clinical disorders associated with T cell subset abnormalities. Advances in Pediatrics. 31:447-80, 1984.   </li></ul><ul><li>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.   </li></ul><ul><li>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. </li></ul><ul><li>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. </li></ul><ul><li>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. </li></ul>
    48. 48. THI <ul><li>References: </li></ul><ul><li>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.   </li></ul><ul><li>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. </li></ul><ul><li>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. </li></ul><ul><li>Yates AB, Shaw SG, Moffitt JE. Spontaneous resolution of profound hypogammaglobulinemia. Southern Medical Journal. 94(12):1215-6, 2001 Dec. </li></ul><ul><li>McGeady SJ. Transient hypogammaglobulinemia of infancy: need to reconsider name and definition. Journal of Pediatrics. 110(1):47-50, 1987 Jan. </li></ul><ul><li>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. </li></ul>
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