[CIS PIDD] [cis-pidd] Persistent panlymphopenic 17 years old boy, HIV negative and non-steroid treatment. Remarkably benign infectios history without receiving prophylaxis

Sat Apr 14 23:18:46 EDT 2018

Hi, Dr. Tricas:

I'll let others comment on what primary immunodeficiency would present as adolescent-onset CD4 and B cell preferential lymphopenia.  My ideas would've been ADA and PNP -- but you've checked that already.

But to clarify -- you mentioned that TCRab+ is 26%, TCRgd+ is 4%.  Is the total T cell (CD3+) denominator for this 30%, or 100% (since you did say T-CD132+ = 100%, and by your other numbers, T cells are ~50% of lymphocytes)?   If there is a fraction of T cells that carry neither TCRab or gd, then the differential direction will go a wicked different direction.  (TAP or other adapter protein hypomorph??)

As far as secondary immunodeficiency, it is strange for lymphopenia due to infection to putz around for 2 years without budging -- you either get better, or you get worse.  The EBV and HHV6 viremias may explain this ... but I think it's more likely that it's the other way around (the lymphopenia is allowing viral reactivation) -- if indeed the lymphopenia remains persistent.  If the lymphopenia is resolving, then I'll go the other direction.

What other findings are there in symptomatology or laboratories?  Any rashes?  Ataxia?  Fevers?  Diarrhea?  Weight loss?  Arthritis?  Elevated liver function tests?  Anemia?  Hypoalbuminemia?

If the patient has absolutely nothing at present, I am confused as to what this may be.

If he does have symptoms, I would hunt for a cause.  Indolent infections would include tuberculous and atypical mycobacteria, viral infections like HHV8 and HTLV (depending where he lives and ethnic background), zoonoses including malaria, brucellosis, salmonellosis, leptospirosis and toxoplasmosis, and certain endemic fungi (again, depending where he lives).

(I'm an infectious diseases pediatrician -- "negative infectious workup" means absolutely nothing to me unless I know what had been checked and what infections the patient may have been possibly exposed to.)

There are also other "oddball" exposures that can look like this -- chronic cannabinoid / alcohol use, syphilis, anorexia, zinc deficiency, thoracic duct anomaly ...

In terms of oncology, I suspect lymphoma would be the higher on the differential given the negative bone marrow aspirate, as well as his age.

I hope this helps.

   - K

Karl O. A. Yu, M.D., Ph.D., F.A.A.P.
Scientist II and Assistant Director, Center for Infectious Diseases and Immunology
RGH Research Institute | Rochester General Hospital | Rochester Regional Health
1425 Portland Ave., Rochester, NY   14621
Tel  585-922-3709  |  Fax  585-922-2415

________________________________
From: cis-pidd at lyris.dundee.net [cis-pidd at lyris.dundee.net] on behalf of CIS-PIDD [cis-pidd at lists.clinimmsoc.org]
Sent: Friday, April 13, 2018 10:30 AM
To: CIS-PIDD
Subject: [cis-pidd] Persistent panlymphopenic 17 years old boy, HIV negative and non-steroid treatment. Remarkably benign infectios history without receiving prophylaxis

Dear colleagues.
My name is Lourdes Tricas, MD and I'm working for Hospital Universitario Central de Asturias (Oviedo, Spain).
I would greatly appreciate your comments on this case of severe lymphopenia (HIV negative and non-steroid treatment) in a boy since age of 14 years old whose cause we can't find.

Questions:
1st.- If it´s a secondary immunodeficiency, what other causes should we look for?
2nd.- Can it be a primary immunodeficiency despite the fact that at age of 11 years old a whole blood count showed normal number of lymphocytes and the genetic study  is normal?

Clinical summary:
Birth date: November 2000.
No family consanguinity, two sisters, the oldest has brain paralysis possibly due to CMV infection during pregnancy.
HIV negative.
Non-steroid treatment.

History of infections without receiving any prophylaxis:
At age of 5 years: Varizella with normal evolution and recovery.
At age of 16 years: Herpes Zoster in hemitorax and recovery with antiviral treatment.
At age of 16 years: Fungus skin infection with good evolution with treatment.
No history of Bacteria infections.

Laboratory findings:
In 2011 (boy was 11 years old) normal whole blood count: Leucocytes=6100 cells /μL, Neutrophils = 2900 cells/μL, Lymphocytes = 1700 cells/μL, Monocytes=400 cells/μL, Eosinophils=1100 cells/μL and Basophils =0 cells/μL.

From December 2014 to the present time whole blood counts showed severe lymphopenia: Leucocytes = 3278±716 cells/μL, Neutrophils = 2566±693 cells/μL, Lymphocytes = 194±53 cells/μL, Monocytes = 396±148 cells/μL, Eosinophils = 75±30 cells/μL and Basophils = 13±5 cells/μL.

Absolute counts of T and B lymphocyte subsets are very low and absolute count of NK cells is normal but in low limit.
From 2017 to 2018: T cells = 86±11 cells/μL (normal range= 800-3500 cells/μL), TCD4 = 35±3 cells/μL (normal range= 400-2100 cells/μL), TCD8 = 51±8 cells/μL (normal range= 200-1200 cells/μL), B cells = 6±1 cells/μL
(normal range = 200-600 cells /μL), NK cells = 72±15 cells /μL (normal range = 72±15 cells/μL (normal range = 70-1200 cells/μL) and ratio TCD4/TCD8= 0.67±0.1 ( normal range = 0.9-3.4).

CD4+ Recent Thymic Emigrants (RTEs) CD4+CD45RA+CD31+ cells in peripheral blood are normal = 13%. (reference range for age 18-25 years = 6-51%).
In peripheral blood: T-CD132+ = 100%,  T-HLA-DR+ = 28%, TCRαβ+ = 26%, TCRγδ+ = 4%.

Normal proliferation of Peripheral Blood Mononuclear Cells after 5 and 7 days in vitro stimulated with PHA and monoclonal antibodies anti-CD3 and anti-CD28 respectively.

Normal study of bone marrow.

ADA y PNP activity is Normal.

Serology:
Normal sera Immunoglobulins: IgG = 6.3 g/L (normal range = 6.6-16.2 g/L), IgA = 0.6 g/L (normal range = 0.6-3.5 g/L), IgM = 0.4 g/L (normal range = 0.4-2.4g/L) and IgE = 35.3 KU/L (normal range = 0-85 KU/L).
No presence of autoantibodies anti-lymphocytes checked by flow cytometry.
Normal production of antibodies: measles IgG, parotiditis IgG, varizella zoster IgG, EBV-VCA IgG, EBV-EBNA IgG and CMV IgG.
No antibodies againts HTLV1+2 IgG and Herpes Simplex 1+2 IgG.

Viral study:
Normal viral study in peripheral blood: Not detectable: DNA-CMV, DNA-EBV, DNA-Herpes type 6, DNA-Herpes type 7, DNA-Adenovius, RNA-HIV, RNA-HTLV.
Normal viral study in pharingeal swab: Not detectable: RNA-Influenza A , RNA-Influenza B, RNA-VRS, RNA-Metapneumovirus, RNA-Parainfluenza, RNA-Coronavirus, RNA-Rhinovirus, RNA-Enterovirus, DNA-Adenovirus, DNA-Herpes type 7, DNA-CMV but recently DNA-EBV = 5686 copies/1000 cells and DNA-Herpes type 6 = 74349 copies/1000 cells.

Genetc Study:
A molecular cause for this persistent lymphopenia has not been determined. All coding bases of RAG1, RAG2, DCLRE1C, IL2Rϒ and 99.58% of JAK3 have been sequenced and not clearly pathogenic variant was identified. The following heterozygous sequence variants of uncertain clinical significace were identified and not confirmed: IL7R c.1357T>C p.(Ser453Pro), RFX5 c.1409G>A p. (Arg470Gln). All coding bases of IL7R and RFX5 have been sequenced and no second variant was identified.

Thank you very much in advance for your comments and help.
Best regards
Lourdes Tricas, MD, PhD
Immunology Department, Hospital Universitario Central de Asturias, Oviedo, Spain.

Rochester Regional Health Email Disclaimer
This email and any files transmitted with it are confidential and intended solely for the use of the individual or entity to whom they are addressed. If you have received this email in error please delete it from your system. This footnote also confirms that this email message has been swept for the presence of computer viruses.
[http://www.myrochealth.com/wp-content/uploads/rrh-logo.jpg]

---
You are currently subscribed to cis-pidd as: pagid at list.clinimmsoc.org.
To unsubscribe click here: http://cts.dundee.net/u?id=96396833.5a9591ccd1e327fe6bc4d1543298c482&n=T&l=cis-pidd&o=4860585
or send a blank email to leave-4860585-96396833.5a9591ccd1e327fe6bc4d1543298c482 at lyris.dundee.net
-------------- next part --------------
An HTML attachment was scrubbed...
URL: <https://pairlist7.pair.net/pipermail/pagid/attachments/20180415/7f47fdf7/attachment-0001.html>