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

[CIS-PIDD]

I forgot to mention. Fecal A1-antitrypsin was normal at a value of 8.5
mg/dL.

Thanks.

YaeJean


On Thu, Jan 21, 2016 at 9:01 PM, YaeJean Kim <yaejeankim at skku.edu> wrote:

> Dear Mikko and Carsten,
>
> Thank you so much for your questions and suggestions..
> Here are my answers.
>
> - Thanks for the question whether she has really CVID. In fact, we were
> talking about the exome sequencing. But the parents has thought their child
> has CVID for the past several years. So, I am trying to communicate with
> them very cautiously since I just took over the patient this Monday.
>
> - No CMV, HSV, Tb from the gut bx, No CMV or EBV viremia
> - No serious invasive bacterial infection, no molluscum
> - Probable invasive pulmonary aspergillosis (IPA) was diagnosed by
> positive aspergilus antigen and CT findings based on the guidelines when
> she presented with hemoptysis this month. But no fungus was isolated from
> the BAL culture.
>
> - There was a discussion about the possibility of stem cell transplant
> without knowing what it really is but the transplanter is very reluctant to
> do transplant since her general condition is bad with cachexia, liver
> cirrosis, renal tubulopathy, has 3 infections, etc. I am also very
> concerned on her condition and she might not tolerate the transplant
> related toxicities and possible infection aggravation.
> - I have not followed the child before so I have no information on naive T
> cell.
> - We just have an indirect measure of T cell function which seems ok to
> PHA.
>
> - I talked to gastro colleague about nasojeunal tube IgG and I need to
> persuade the parents and the patient. Thank you for the suggestion.
> - Parenteral nutrition has been started but there is no response and also
> has limitation due to liver cirrhosis.
> - No bx done on liver or kidney
>
> I will perform some of the lab tests that have not been done before but
> suggested by you. Thank you.
>
> I will give you updates as her condition changes.
> Thanks a lot for your sincere discussion and suggestion.
>
> Best wishes,
>
> 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
>
> On Thu, Jan 21, 2016 at 6:39 PM, CIS-PIDD <cis-pidd at lists.clinimmsoc.org>
> wrote:
>
>> 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
>>
>>
>>
>> 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> 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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