[CIS PIDD] [MARKETING]Re: [MARKETING][cis-pidd] CVID and profuse diarrhea

Thu Jan 21 04:39:09 EST 2016

Great Carsten!

All in all, I agree with everything Carsten added, additional genes include PIK3R1, maybe even others (depending on biopsy findings, possible autoimmune diagnoses, whether CMV/EBV viremia is found, if granulomas, if infiltrates are of mixed cellularity/nodular in affected organs).

Due to the aspergillus (any warts? molluscum? any dental or muscle abscesses previously?Pseudomonas?), LRBA might be the best candidate, but would not bet it is specifically that since we know too little of the other options still...
Treg numbers low? CTLA4/FoxP3/CD25/Helios expression low in these?

I did raise the option of SCTx since personally I feel just like Carsten, I think donors should already be searched for, since in case the worst infections can be gotten under control and if lung functions decent, this (or CTLA4-Ig fusion protein in case of LRBA, CTLA4) might be viable options.
Just forgot to add this sentence, my apologies!

Ribavirin alone has resulted in disappointments in almost all PIDD patients I have heard of, thus I would add-  to begin with - a second potential antiviral agent in fear of secondary resistance development (and prepare for the fact that all in all it seems very tough to eradicate without improved host immunity).

Thanks Carsten for these additions -  and for the superb lectures you gave last week here in Finland!

Mikko

oyl Mikko Seppänen
Harvinaissairauksien yksikkö (HAKE), HUS

Mikko Seppänen, MD, PhD, Associate professor
Specialist in Internal Medicine and Infectious Diseases
Head, Rare Disease Center, Helsinki University Hospital (HUH)
Children's Hospital, P.O.Box 280
FI-00029 HUS
FINLAND
&
Senior Consultant (PIDD)
Adult Immunodeficiency Unit
Inflammation Center, HUH

phone +358 9 47180201
GSM +358 50 4279606
fax +358 9 47174703

Lähettäjä: CIS-PIDD [mailto:cis-pidd at lists.clinimmsoc.org]
Lähetetty: 21. tammikuuta 2016 10:32
Vastaanottaja: CIS-PIDD
Aihe: [MARKETING]Re: [MARKETING][cis-pidd] CVID and profuse diarrhea

I agree with Mikko: there are (too) many problems in a child with "CVID" and I would evaluate for the possibility of an underlying CID (have you followed naive T-cells over time? Is there an expansion of g/d T cells or do you see increased senescence (e.g. by CD57 expression)?  How is the T-cell function? B-cell subsets (CD21?)
Depending on the results you may consider a leaky SCID or one of the more recently described defects (e.g. PI3Kd, CTLA4, LRBA, STAT3, ...): with some of these maybe having some additional (somewhat specific) treatment options (sirolimus, PI3Kd inhinitors in the future, abatacept, a-IL6, ...). Mikko also pointed towards SCT: certainly risky with the described infection pattern, but probably also important to evaluate (in case the patient stabilizes in the near future). With the back-up of antimicrobial treatment/prophylaxis a clinically well observed treatmend with steroids (e.g. 1mg/kg of prednisone for 2 weeks and then taper) might be helpful with the observed immune dysregulation (before playing with other immunosuppressive drugs). Regarding the norovirus infection the oral ribavirin you started sounds like a good idea and I would wait for the effect over the next weeks (and rather try additional systemic steroids for the moment). Good luck, BW Carsten

--

PD Dr. Carsten Speckmann

Pediatrician

Group Leader: Benign lymphoproliferative disorders

Pediatric Hematology and Oncology

and Center for Chronic Immunodeficiency

University of Freiburg

Germany

phone: +49 (0)761 270 43010

fax: +49 (0)761 270 45990

www.uniklinik-freiburg.de/cci/studien/alps.html<http://www.uniklinik-freiburg.de/cci/studien/alps.html>

Am 21.01.2016 06:42, schrieb CIS-PIDD:
Hi Yae-Jean,

Your listing of all her troubles left me with a lot of questions and just as worried as you?

In my opinion she needs urgent re-evaluation of her diagnosis, her disease is unlikely CVID, rather some CID despite normal looking CD4 and CD8 subsets. Quite a number of candidates spring to mind, so many indeed that urgent exomes would be truly nice. Immunomodulatory agents could then be considered in unblinded fashion.

To pinpoint fewer candidates the exact biopsy findings might help?

SCTx would be risky with 3 active infections. Have you already attempted salmonella eradication w antibiotics? Which ones?

Noro th attempt with p.o./ nasojejunal IgG + Alinia + IFN? All at the same time?

At the moment her lungs seem to be in bad shape, what is her diffusion capacity? Aspergillus: means of dg- restricted to lungs in imaging and blood tests or systemic? Biopsy?

Fecal antitrypsin? protein losing enteropathy seems likely with that history and hypoalbuminemia, extent of intestinal lymphangiectasia seems limited if no CD4&8 lymphopenia? Has PN been started to improve nutritional status?

The cause of tubulopathy, biopsy findings? Lymphadenopathy, the same? Liver biopsy?

Yours,

Mikko

Oyl Mikko Seppänen
Harvinaissairauksien yksikkö (HAKE)

Head, Rare Disease Center,
Helsinki University Hospital (HUH)
FINLAND

phone +358 947180201
GSM +358 50 4279606
fax +358 9 47174703

CIS-PIDD <cis-pidd at lists.clinimmsoc.org<mailto:cis-pidd at lists.clinimmsoc.org>> kirjoitti 21.1.2016 kello 5.52:
Dear all,

I have a difficult case of CVID patient whom I recently started to see and would like to ask your opinions

- 18 year old female diagnose as CVID at the age of 3 years in 2002
- currently, bronchiectasia with probable invasive aspergilosis, liver cirrhosis, renal tubulopathy, and significant diarrhea with PCR only positive salmonella and norovirus

<2002>
- was diagnosed as CVID with a hx of frequent pneumonia
- managed to grow along growth curve until age 10-11
- failure to grow since age 12
- performed ok school life on IVIG without hospitalization until 2010-11

<20010-11>
- hospitalization for work-up on poor weight gain and GI pathology
- 2010: pathology reported, esophageal varix grade I,  duodenal bx showed atrophy of villi, apoptotic bodies with increased intraepithelial lymphocytes, abdomen CT showed multiple LN enlargement and enterocolitis, hepatosplenomegaly
- 2011: bx of terminal ileum showed also above findings and intestinal lymphangiectaisa

<2015>
- In August, she developed really really serious profuse diarrhea.
- significant weight loss and now the body weight is  25-30 kg, seriously cachexia condition since then
- extensive parasite, bacterial, viral, fungal infection as for enteric pathogen revealed positive PCR for salmonella spp. and norovirus in the stool and no other cultured organisms
- colon bx showed lots of damaged mucosa and massive neutrophil infiltration, crypt abscesses, increased lymphocyte infiltration than before.
- I reviewed the slides with the pathologist and he says her pathology looks somewhat different from inflammatory bowel diseases (UC or Crohn's disease)

<2016>
- Early this month, she presented to ER with hemopysis -> w/u showed possible invasive  pulmonary aspergillois, for this she is on ambisome
- She still has serious diarrhea 15 times per day.  Her output is almost over 3000 cc and she is 26 kg today.
- Salmonella and norovirus PCR is still positive as of Jan 2016 >) oral rifaximin and ribavirin were started 5 days ago.
- It seems like whatever she eats or we infuse, she cannot hold nutrients, electrolytes in her body.

<labs>
- Initial labs in July 2002 was
lympho subset: CD3 2870, CD4 1790, CD8 1080, B cells 160 (5%), NK cell 5
Ig G 33, IgA 6, IgM 4 mg/dL
- As I reviewed her past labs, her IgG level has been in 200-400 mg/dL on IVIG tx and IgA and IgM levels has been also less than 5 mg/dL..

- Labs in December 2015 was
CD3 2072 cells /uL, CD4 833, CD8 1175, B cells 0, NK 43 cells/uL
hypoalbuminemia, electrolyte imbalance, etc..

At this point, I would like to ask your opinion on management option. Is there anything that I can do further for her?
- I plan to f/u PCR for salmonella and norovirus after two wks of tx and also perform terminal ileum and colon bx to see the pathology change. But I am not sure whether pathogens would be easily cleared and the pathology would be improved..
- I am thinking she might need some immunomoluatory agents or steroid..but I am concerned with her lung (aspergillosis) and gut pathogens (salmonella and noro) at this point..Maybe can I try at least oral budesonide?

I would appreciate your thoughts and suggestion.

Regards,

YaeJean

Yae-Jean Kim, MD, PhD

Associate Professor
Division of Infectious Diseases and Immunodeficiency
Department of Pediatrics,
Samsung Medical Center,
Sungkyunkwan University School of Medicine,
81 Irwon-ro, Gangnam-gu, Seoul, South Korea

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