Transient Hypogammaglobulinemia of Infancy

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 todays
  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 gt 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 Childrens 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 lt 2 years of age with IgG levels lt 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 Childrens 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

• Childrens 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 (n296) (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 11 ratio of
  THI patients lymphocytes to the parents, 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 11, 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 gt 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 gt 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 (dxed 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. 31447-80, 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.