A infant withrecurrent bacterial infection and

persistent oral candidiasis

2011-01-26

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Age/Gender: 5-month-old boy

Body Height: 64cm (3rd-10th percentile)

Body Weight: 5 kg(< 3rd percentile)

Admission Date: May 28, 2004

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Birth history: G3P3, full term, BBW 3130 g, no perinatalinsult

At 3m/oAdmission because of UTI with E.coli infection

At 4m/o Admission due to oral candidiasis and poor appetite

At 5 m/orefer to our hospital with E.coli urosepsis,

bronchopneumonia, and persistent oral candidiasis

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Acute ill looking, poor muscle tone

Conscious: clear

Oral thrush over buccal mucosa

Paucity of lymph nodes and tonsils

Tachypnea with O2 cannula supportnasal flaring, subcostal retractions, bilateral crackles

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Hemogram

WBC(/uL) 9900

Hb(mg/dL) 12.6

MCV 74.1

Plt 222K

Seg(%) 92

Lym(%) 3

Mon(%) 5

ALC 297/uL

Biochemistry

BUN (mg/dL) 9

Cr (mg/dL); 0.3

ALT (U/L) 65

CRP (mg/L) 41.1

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What are the impression& further management ?

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% 參考值

T-CD3 0.2 51-84

B-CD19 98.2 6-41

T-Help CD4

0.5 35-64

T-SuppCD8

<1 12-28

NK cell 1.2 3-18

mg/dL 參考值

IgG 278 292-814

IgA < 5.53 8.1-84

IgM 25.4 33-108

Panhypogammaglobulinemia,Low percentages of T and NK cellsElevated percentage of B cells

cells/uL 參考值

T cell 6 2500-5600

B cell 291 300-3000

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Primary immunodeficiencybased on recurrent infection, persistent candidiasis, failure to thrive, lymphopenia

Excluding secondary immunodeficiencies:Premature and newbornHereditary and metabolic diseasesImmunosuppressive agentsInfectious diseasesInfiltrative and hematologic diseasesSurgery and traumaMiscellaneous

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PCR identified the presence of P. carinii in BAL fluid→Pneumocystis carinii (jirovecii) pneumonia

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BCG scar?

Suppurative granulomatous inflammation with mycobacterial infection→Disseminated bacillus Calmette-Guerin disease

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X

Fischer A, Le Deist F, Hacein-Bey-Abina S, et al.

Immunol Rev. 2005;203:98-109.

Cavazzana-Calvo M, Lagresle C, Hacein-Bey-Abina S, et al.

Annu Rev Med. 2005;56:585-602.

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Role of γc receptor complexes for multiple cytokines

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Molecular study: Obviously decreased IL-2R common γ chain expression on rest CD4+ cells

Isotype control IL-2R γchainControl

Patient 18

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The HLA types of the patient were

A1101, 2601; B3802, B4002; DRB1 0403, 1602

The HLA types of the donor were

A2619, 2601; B15, B4002; DRB1 0403, 1602

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PCPHepatitis due

to Barktar(primaquine)

Disseminated BCG disease (4 month)

Stop IVIG supply

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93/5/28 8/11 8/14 8/17 8/26 9/4 10/11 99/8/13

WBC 9900 3000 3120 1330 5200 6700 6900 7400

Hb 12.6 10.2 9.5 9.4 7.9 8.8 9.4 12.2

MCV 74.1 86.9 86.0 88.8 84.3 95.1 85.8 81.5

PLT 222K 179K 221K 360K 458K 314K 453K 226K

Seg 92 80 94.5 84 77.3 57 72 71

Lym/Aty 3 16 1 1 9.3 15 8 23

Mono 5 4 2.5 10 13.0 12 16 6

ALC 297 120 312 133 484 1005 552 1702

STR 6%8/12 UCBT

STR 20%

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Before After (2 Month ) After (6 Month)

T-CD3 0.2 68.8 68.5

B-CD19 98.2 1.0 22.2

T-Help CD4 0.5 52.7 44.6

T-SuppCD8

<142.3 28.5

NK cell 1.2 25 8.6

T cell 6 cells/uL 379 cells/uL 1846 cells/uL

B cell 291 cells/uL 5 cells/uL 602 cells/uL

CD 45 RO 0.5 62 9.4

CD 45 RA 97.9 38 30.8

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Before After2 Month

IgG 278 522

IgA < 5.53 < 6.13

IgM 25.4 94.1

After11 Month

After13 Month

837 966

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BCG

0

10000

20000

30000

40000

50000

60000

2.50% 5.00% 2.50% 5.00% 2.50% 5.00% 2.50% 5.00%

Pre- Post-2M Post-6M Post-10M

Time (Month)

Del

ta c

pm

Patient Control 3 years later..

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A 5-month-old boy

Failure to thrive, dyspnea, intermittent cyanosis for 1 month Pneumocystis carinii pneumonia and thymic hypoplasia

T-B+NK- type SCID identified with IL-2RG Arg226Cys mutation

Unrelated cord blood transplantation on 2007/8/8.Engraftment with mixed chimerism post-transplant three weeks. Good clinical condition without any medications

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曾小弟參加2009年臍帶移植~希望再生六週年慶

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A 4-month-old girl

Candidiasis over back, neck and genital area for 1 month. Interstitial pneumonia (pneumocystis carinii) T-B-NK+ SCID with RAG2 mutationHesitate to perform stem cell transplantation

Unrelated peripheral blood progenitor cells transplantation on 2009/12/25 while exacerbating respiratory distress

Deceased of sudden pneumomediastinum and subcutaneous emphysema despite of successful engraftment post-transplant 4 months

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Whitish patch or spot

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Discussion---on emphasis of early diagnosis

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How to recognize PIDs earlier, especially SCID

• High suspicion by clinical features (warning signs)

• Prenatal diagnosis if families with identified genetic defects

• Newborn screening to quantify T-cell receptor excision circle

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Website http://www.cgmh.org.tw/chldhos/intr/c4a80/06index003.htm

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• Intravenous immunoglobulins (IVIG):

hypogammaglobulinemia and recurrent infections

• Stem cell transplantation (bone marrow or cord blood) :

severe combined immunodeficiencies, severe T cell defects,

severe PMN defects

• Interferon-gamma (IFN-γ):

refractory recurrent mycobacteria or salmonella infections

• Granulocyte-colony stimulating factor (G-CSF):

intermittently neutropenia

• Prophylactic treatment:

T-cell and phagocytic defects to prevent opportunity infections

Basic principle of management:

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J Pediatr 1997;130:378-387

Rebecca H. Buckley, MD

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Other well-defined immunodeficiency syndromes 70 (35.5%) Predominate antibodies deficiencies 51 (25.9%)T- and B-cell immunodeficiencies 33 (16.8%)Congenital defects of phagocyte number, function or both 23 (11.7%) Complement deficiencies 15 (7.6%) Disease of immune dysregulation 4 (2.0%) Autoinflammatory disorders 1 (0.5%)Defects in innate immunity: None

Lee WI, Jaing TH, Hsieh MY, et al. J Clin Immunol. 2005; 25:162-73; 2006; 26:274-83 and update

Distribution of Taiwanese PIDs patients

(197 patients during 1985-2010)

Overview

7 mortality in 14 SCID

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How to recognize PIDs earlier, especially SCID

• High suspicion by clinical features (warning signs)

• Prenatal diagnosis if families with identified genetic defects

• Newborn screening to quantify T-cell receptor excision circle

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P D F c r e a t e d w i t h p d f F a c t o r y t r i a l v e r s i o n www.pdffactory.com

How to recognize PIDs earlier, especially SCID

• High suspicion by clinical features (warning signs)

• Prenatal diagnosis if families with identified genetic defects

• Newborn screening to quantify T-cell receptor excision circle

P D F c r e a t e d w i t h p d f F a c t o r y t r i a l v e r s i o n www.pdffactory.com

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Methods of monitoring T cell reconstitution. Deletion of the TCRD locus from within the TCRA locus is a common requirement for productive rearrangement of the a-chain (A). The resultant signal joint (sj) T-cell rearrangement excision circlet (TREC) can be quantified by realtime polymerase chain reaction (PCR) allowing assessment of thymic output. Because episomal DNA does not replicate but remains stable over time, the TRECs are diluted out by cell divisions as the T cells age (B)

British Journal of Haematology, 2004,124, 407–420

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NB screening for SCID ?

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For early recognize de novo SCID patients…

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Foundation from:

Chang-Gung Medical Research Progress Grant (CMRPG)

National Science Council Grant (NSC)

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Thanks for your attention !

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