[CIS PIDD] [cis-pidd] Opinion on a challenging case of suspected primary immunodeficiency

[CIS-PIDD]

Dear All

I need opinions on this difficult case of suspected primary immunodeficiency
Here is a summary of the case:

A 2-year-old, boy first born to non-consanguineous marriage (with three
first trimester abortions and pregnancy induced hypertension in the mother)
by emergency caesarean with birth weight of 3.5 kg with smooth perinatal
transition.

Till 9 months of age he was doing well. At 9 months of age, he had
exanthematous febrile illness (clinical diagnosis *Hand Foot Mouth disease*
).

At age of 12 months, watery diarrhea followed by bloody diarrhea, treated
for suspected food protein induced enterocolitis syndrome (? eosinophilic
colitis) [Given milk protein free diet and oral prednisolone for total of 3
months and oral mesalamine for 5 months till the age of 18 months]. On this
treatment, his symptoms improved.

At 19 months of age, similar GI symptoms. Investigation, showed elevated
serum IgE, positive fecal calprotectin, persistent leukocytosis with
thrombocytosis. He was given IVIG (intravenous immunoglobulin) in April
2017 in view of suspected immunodeficiency. Colonoscopy and biopsy showed
lymphoid aggregates in colon with formation of lymphoid follicles in lamina
propria, lymphoid cells infiltrating into the crypt (autoimmune colitis),
moderately dense lymphomononuclear cell infiltrate admixed with
eosinophils. No features suggestive of inflammatory bowel disease. A panel
of exome sequencing for 200 genes (including STAT3, STAT1, STAT2, STAT4,
STAT5b, DOCK8, complement components, PIK3R1, IL21, IL21R, common SCID
genes, genes for MSMD, gene for ALPS, IRAK4 etc.) showed no mutation.

July 2017 (age 21 months), diarrhea and respiratory symptoms with
consolidation on chest X ray with *blood c/*s showing growth of *pseudomonas
species*. CT chest showed multiple small pulmonary nodules with *cavitatory
pneumonia*. Pleural biopsies revealed subacute inflammation (no evidence of
TB and nocardia). Azithromycin, Meropenem and oral amoxicillin-clavulinic
acid for 25 days. Autoimmune workup ANCA, ANA, ds DNA, Anti MPO IgG, Anti
PR3 IgG- were negative.

*September 2017 (age 24 months),* *he presented to our institute* with
persistent fever spikes and respiratory symptoms without any bowel
symptoms. Hemogram showed anemia, high leucocyte count and mild
thrombocytosis (Hb – 81 gm/L, significant leukocytosis with neutrophilic
predominance (Total leucocyte count 33.1 x109/L, DLC-P61, L26M11E02) and
thrombocytosis Platelet count- 560 x109/L), high erythrocyte sedimentation
rate (83mm/hr). Lung MRI showed multiple cavitatory nodules in bilateral
lungs (increased in size and number when compared from CT chest at 21
months of age). Fine needle aspiration from these nodules showed gram
positive cocci but no organism on culture. Stool for calprotectin is normal
and autoimmune markers are all normal again.

D*ate *

*Investigation *

*Report *

*Normal range *

29/09/2017

IgG

8.04 (gram/L)

3.7 to 15.8 gram /L

IgA

*1.44 (gram/L)*

*3.0 to 1.30 gram /L*

IgM

1.28(gram/L)

5.0 to 2.2 gram /L

29/09/2017

NBT

Normal



29/09/2017

DHR

Normal



03/10/2017

Ig G 1

5.35gram/L

3.33  to 7.29 gram/L

Ig G2

1.93gram/L

0.40 to 1.88 gram/L

Ig G4

0.01 gram/L

0.05 to 0.31 gm/L

29/09/2017

CD 3+ cells

63%

43 to 76%

CD 19+ cells

13.30%

14 to 44%

CD 56+ cells

18.00%

04 to 23%

CD 3+56+cells

01.15%

-

03/10/2017

CD3+CD4+

61.52%

33 to 58%

CD3+CD8+

31.91%

11 to 25 %

CD4/CD8 ratio

01.92

1.3 -6.3



His immunoglobulin profile as well as NBT/DHR, lymphocyte subset, naïve
CD3+ T cells, CD40 ligand, CD18, CD4/CD8 ratio, pSTAT3 levels, HIV serology
all are showing normal results. On further workup he was found to have
*Elevated
Ig E – 677kU/L with reduced CD 4+ IFN gamma cells (1.9% as compared to
14.6% in control) and Th17 cells numbers (0.3% as compared to 1.3% in
control) [He was given steroids in past but now off steroids for 6 months].
*Tubercular workup with with gastric lavage, tuberculin skin test,
Bronchoscopy lavage, pus from FNAC are all negative.

After multiple sterile blood cultures, culture on 13/10/17 showed*
methicillin resistant Staphylococcus aureus- MRSA* which is being treated
with Teicoplanin because patient is allergic to vancomycin. Bronchoalveolar
lavage (BAL) culture grew MDR Klebsiella Pneumoniae sensitive to colistin,
which has been initiated. BAL for fungal smear is negative but BAL for
galactomann was 3.4 ( positive) and patient is being treated with
amphotericin-B for that. BAL for CMV DNA is PCR positive. However CMV viral
load from blood is negtaive. He has been given 2 gm /kg of IVIG. Despite
all these measures for more last 3 weeks, he is running high grade fever
along with persisting cough and chest infiltrates and elevated inflammatory
markers.

My queries are-

1.     What could be the possible immunodeficiency here (Could this still
be STAT3 deficiency or DOCK-8 deficiency)?

2.     What additional testing can be done?

3.     Significance of low Th17 cells and CD4+IFNgamma cells when a patient
has received steroids in the past?


Thanks




-- 

*Regards*

*Dr ANKUR JINDAL*

*Senior Resident (DM)*

*Pediatric immunology and rheumatology unit,*

*Advance Pediatrics Centre,*

*Post Graduate Institute of Medical Education and research,*

*Chandigarh*

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