[CIS PIDD] [cis-pidd] Chronic norovirus enteritis, update and Q

Mon Jan 5 01:09:43 EST 2015

HI Mikko, 

just since you asked for more genes, LRBA is a candidate at the edge between ALPS-U and CVID. 
The article you might have been thinking of is by Rensing-Ehl et al Clin Immunol 2010

greetings

klaus
Prof. Dr. med. Klaus Warnatz

UNIVERSITÄTSKLINIKUM FREIBURG
University Medical Center Freiburg
Center for Chronic Immunodeficiency
Division of Rheumatology and Clinical Immunology

Tel: +49-761-270-77640 / FAX -71000 / Pager: 12-7100

Breisacher Str. 117, 79106 Freiburg, Germany
klaus.warnatz at uniklinik-freiburg.de
http://www.uniklinik-freiburg.de/cci

Am 05.01.2015 um 06:43 schrieb Seppänen Mikko:

> Dear Armando
>  
> Many thanks for your input!
>  
> Like You point out, she does have some overlap findings though she is actually not the most likely CVID+ALPS -overlap in our cohort (none of these thus far have had anything explanatory in their whole exome sequencing either, we are analyzing them side by side also). DNTs have been measured, they are in the normal upper limit, like often in CVIDs. I think I read a rather a recent excellent article on this subject, 2.5% is not the best threshold in this situation (would love to advertise it, but the authors’ names escape my mind at the moment). B12 is not high.
>  
> And she had wt exomes in all known ALPS- and ALPS-like genes, thus diagnostically I am reluctant to proceed further until we have a plausible (most likely novel) candidate. I am grateful for the input of all, also when suggesting genes, but we do analyze all known (and about >600 projected) AR and AD PIDD genes routinely when performing WES. WES is not 100% exact, some exomes of some genes are missing (and one needs to learn which ones are, depends on the method one chooses), for some genes the read depth tends to be a little too low (depending on the method one uses), there are some genes too homologous (like some FcRs, IGH@, C4A&C4B, some CGD genes) and some too complex (like DOCK8)  to really analyze by WES-
> ..thus if You come up with a gene that You know has these issues I am most grateful if You point this out! We use the newest Agilent.
>  
> The case report I definitely have not read, sounds very interesting indeed (and reiterates what Kate and Klaus suggest). May need to discuss this with Jos as well?
>  
> Happy New Year!
>  
> Mikko Seppänen, MD, Finland
>  
> Lähettäjä: Armando Partida Gaytán [mailto:e.diuxe at gmail.com] 
> Lähetetty: 4. tammikuuta 2015 4:03
> Vastaanottaja: CIS-PIDD
> Aihe: Re: [cis-pidd] Chronic norovirus enteritis, update and Q
>  
> Dear Mikko:
>  
> Indeed very interesting case, I hope soon you can help your patient to improve.
>  
> Some things you mentioned [i.e. ITP + AINP (Evans) + splenomegaly + a non specific inflammatory bowel disease + lung inflammation with mild follicular bronchiolitis] fit well into ALPS or ALPS-like syndrome. So i wanted to ask if DNT (CD3+TCRab+CD4-CD8-) had been determined, as well as vitamin B12, sFASL, IL-10 levels, IL-18 levels, lymphocyte apoptosis tests, etc. I know ALPS or ALPS-like syndrome is a diagnosis not easy to fit in, but considering the difficult scenario, just wanted to mention it. 
>  
> And as previos mails have mentioned, I think rapamycin should be tried. A previous report, mentions on a simiar case:
>  
> Pleconaril-resistant chronic parechovirus-associated enteropathy in agammaglobulinaemia. by
> van de Ven AA1, Douma JW, Rademaker C, van Loon AM, Wensing AM, Boelens JJ, Sanders EA, van Montfrans JM.
> Antivir Ther. 2011;16(4):611-4. doi: 10.3851/IMP1792.
>  
> reported quote: "pleconaril did not have any effect on viral replication. Symptoms improved on immunosuppressive therapy, suggesting infection-related immune dysregulation in an immunocompromised host."
>  
> Salutes.
>  
> On Sat, Jan 3, 2015 at 12:19 PM, Seppänen Mikko <Mikko.Seppanen at hus.fi> wrote:
> Thanks for all of Your kind replies!
> 
> Philipp: no I have not, a good suggestion. I have tried to find info on newer agents and their activity against norovirus, seems like not much has been published..
> 
> Klaus: certainly we did check for monoallelic CTLA4 mutations.
> 
> My thanks to Drs Bleesing and Sokolic also for invaluable information on colostrum and p.o. IgG dosing! If needed I will try all of these if possible, in the patient's case this seems vital... including Entocort or even rapamycin...
> 
> Mikko Seppänen, Finland
> 
> 
> ________________________________________
> Lähettäjä: philipp.henneke at uniklinik-freiburg.de [philipp.henneke at uniklinik-freiburg.de]
> Lähetetty: 31. joulukuuta 2014 19:57
> Vastaanottaja: CIS-PIDD
> Kopio: CIS-PIDD
> Aihe: Re: [cis-pidd] Chronic norovirus enteritis, update and Q
> 
> Have you already tried nitazoxanide, which has good activity against norovirus? It may be worth a try.
> Regards
> Philipp
> 
> Philipp Henneke, MD
> Professor
> Head Ped. Infectious Dis & Rheumatology
> UNIVERSITY MEDICAL CENTER FREIBURG
> Center for Chronic Immundefiency (CCI)
> Center for Pediatrics & Adolesc. Medicine
> phone assist/ office + 49(0)761270 77640
> mobil +49 (0)162 285 2481
> fax +49 (0) 761 270 77600
> Breisacherstr. 117-2.OG, 79106 Freiburg
> Germany
> philipp.henneke at uniklinik-freiburg.de
> http://www.cci.uniklinik-freiburg.de
> 
> 
> 
> -----Bodo Grimbacher <bodo.grimbacher at uniklinik-freiburg.de> schrieb: -----
> An: "CIS-PIDD" <cis-pidd at lists.clinimmsoc.org>
> Von: Bodo Grimbacher <bodo.grimbacher at uniklinik-freiburg.de>
> Datum: 31.12.2014 17:34
> Betreff: Re: [cis-pidd] Chronic norovirus enteritis, update and Q
> 
> When I was an MD student in Freiburg (so many years ago:),
> our Hospital's “Milk-unit” also offered human colostrum.
> I wonder whether this is still available?
> Best wishes for the New Year 2015!
> Yours, Bodo
> ****************************************
> Univ.-Prof. Dr. med. B. Grimbacher
> 
> Scientific-Director
> CCI-Center for Chronic Immunodeficiency
> UNIVERSITÄTSKLINIKUM FREIBURG
> Tel.: 0761 270-77731  Fax: -77744
> Engesserstraße 4, 79108 Freiburg
> bodo.grimbacher at uniklinik-freiburg.de
> www.uniklinik-freiburg.de/cci
> 
> Von: "Bleesing, Jacob" < Jack.Bleesing at cchmc.org<mailto:Jack.Bleesing at cchmc.org>>
> Antworten an: CIS-PIDD <cis-pidd at lists.clinimmsoc.org<mailto:cis-pidd at lists.clinimmsoc.org> >
> Datum: Wednesday 31 December 2014 13:42
> An: CIS-PIDD < cis-pidd at lists.clinimmsoc.org<mailto:cis-pidd at lists.clinimmsoc.org>>
> Betreff: RE: [cis-pidd] Chronic norovirus enteritis, update and Q
> 
> Just an FYI to consider setting up in Europe (if not already underway).
> 
> https://clinicaltrials.gov/ct2/show/NCT02025478
> 
> We are expanding this trial to use breastmilk for norovirus – both in the context of BMT and PID (based on promising results in the MILK study).
> 
> Regards,
> 
> Jack
> 
> From: Klaus Warnatz [mailto:klaus.warnatz at uniklinik-freiburg.de ]
> Sent: Wednesday, December 31, 2014 6:40 AM
> To: CIS-PIDD
> Subject: Re: [cis-pidd] Chronic norovirus enteritis, update and Q
> 
> Hi Mikko,
> 
> this is a problem that many of us face. After failing all your attempts:
> I do think that it is worth keeping her on gluten-free diet with the DQ8+, add immunosuppression. It was not clear to me whether she was on steroids or not.
> Immunosuppressive therapy doesn't clear the norovirus infection but improves the diarrhea in several patients.
> We usually start with budesonide 9mg/day (1x3mg capsule opened and supplied with smashed apple) if not sufficient we continue with systemic steroids and if that fails rapamycine.
> Did you check her for CTLA4 deficiency (decreasing B cells, GI etc) but could be others.
> Do you think she had NRH? portal hypertension?
> 
> greetings and a happy new year to all
> 
> klaus
> 
> Prof. Dr. med. Klaus Warnatz
> 
> UNIVERSITÄTSKLINIKUM FREIBURG
> University Medical Center Freiburg
> Center for Chronic Immunodeficiency
> Division of Rheumatology and Clinical Immunology
> 
> Tel: +49-761-270-77640 / FAX -71000 / Pager: 12-7100
> 
> Breisacher Str. 117, 79106 Freiburg, Germany
> klaus.warnatz at uniklinik-freiburg.de<mailto:klaus.warnatz at uniklinik-freiburg.de>
> http://www.uniklinik-freiburg.de/cci
> 
> Am 31.12.2014 um 07:33 schrieb Mikko Sepp �nen:
> 
> 
> Dear all,
> 
> we have now attempted to our most affected patient all other in Listserve-suggested means of therapy (IFN, IFN+ escalated riba, the latter has caused further diarrhea and vomiting) except daily p.o. IgG , to no avail. IFN+ escalated riba for 2.5 weeks did not clear norovirus. Due to the side effects and further weight loss caused by it, the patient cannot continue this approach.
> 
> Q: Robert Sokolic suggested 5ml/day of Gamunex, mixed with orange juice. Was a 5% or 10% prep used at the time?
> I seem to recall that someone had recently used this approach successfully as well. Their dose?
> 
> Patient case in more detail:
> 
> The patient is 31-y young recently married female, 174 cm tall, weighs only 40 kg now (!!!), has CVID of unknown genetic origin (WES: no known genes).
> 
> CVID noted after ITP --> ITP+AINP (Evans)and  S.aureus sepsis 2004, recurrent LRTIs since 1998. Bronchiectasis already when diagnosed, HRCT mild follicular bronchiolitis.
> 
> EGD- and IC-scopy performed a year ago, after following celiac diet no active cellular inflammation which You could treat with immunomodulators, however severe malabsorption of protein, calories, lipid soluble vitamins continues....
> 
> Ciprofloxacin a.s.f. attempted ex juvantibus to no avail, bacterial overgrowth seems unlikely. Further causes for diarrhea tested and not found (We are actually preparing a manuscript on GI manifestations in CVIDs in our cohort, this lady has been tested for all known and unknown alternative causes...).
> 
> We are left with - in biopsies after celiac diet very moderate - enteropathy resembling coeliac disease with only subtotal villus atrophy (HLA-DQ8+), mild chronic PBC-like cholangiopathy: sinus dilation with mild sinusoidal fibrosis in biopsy, in ERC mild cholangipathy (Adursal), chronic norovirus, severe diarrhea and severe malabsorption. She also has gastroparesis of completely unknown origin (no SFN, no diabetes...).
> 
> She further has asthma, lymphatic hyperplasia (spleen 13 cm). She receives s.c. Gammanorm 16.5% 120ml /week (SIC!), P-IgG before norovirus therapy attempts 12.9-13.1, now 10.9 g/l...(more diarrhea)
> 
> She has no switched-memory B cells, during follow up loses all B cells from blood (no thymoma), CD4 and CD8 counts normal, NKs 0.04 (low). Her Treg counts are normal, though function seemed somewhat but mildly impaired. Rapamycin not attempted.
> 
> Any further suggestions?
> 
> I appreciate Your time spent, thanks in advance,
> 
> Mikko Seppänen, MD, PhD
> Helsinki, Finland
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