[CIS PIDD] [cis-pidd] Disseminated VZV , Lymphopaenia

[Seppänen Mikko]

Dear Ravishankar,

Some random thoughts in a rush.

Therapy-wise, first check that high-dose aciclovir i.v. dosage used (up to 12 mg/kg q8h)? If used already, try continuous infusion 2mg/kg/h (see NEJM 336:732, 1997 for hemorrhagic disseminated VZV)??If so, remember to hydrate.
Very rarely resistance problem, thus would not choose another drug lightly, being quite toxic. Unless You are able to get FV-100, valomaciclovir or some other promising, less toxic new drug?
(Has NIH experience using cytokine therapies in similar cases?)

This patient is even at risk of delayed stroke from VZV cerebral angiitis?

I do not believe that aciclovir or VZV itself cause these blood counts. PCP prophylaxis vs. sulpha+trim vs severe lymphopenia not attractive? Alternative modes of prophylaxis rather.

VZIG: You may try to use IMHO, expensive, very experimental, but could be important/life-saving (or then not) in this case?
Peripheral NK/LGL malignancy, any skin lesions to check?? Other cytopenias to note?
LOCID?
STAT1 GOF, very late-onset?
Or some form of very late-onset hypomorphic SCID, since pan-lymphopenia, not really ICL thus?


(Is she EBV-PCR negative?, below summary at this point a little unclear?)


Hope this helps a little,

Mikko Seppänen, MD
Helsinki
________________________________
Lähettäjä: Ravishankar.Sargur at sth.nhs.uk [mailto:Ravishankar.Sargur at sth.nhs.uk]
Lähetetty: 31. lokakuuta 2013 16:21
Vastaanottaja: CIS-PIDD
Aihe: [cis-pidd] Disseminated VZV , Lymphopaenia

Dear All,

Appreciate your thoughts and advice.

I am seeing a 60 year old previous well ( till Feb 2013) Afro-Caribbean lady.

PMH is significant for Right breast cancer 2011 - Grade 3 ductal carcinoma treated with wide local excision, radiotherapy and letrozole hormonal therapy

She presented with a rash in T1 / T2 dermatomes in Aug 2013 to start with, which became disseminated.

1                    Disseminated VZV infection - vesicular rash, pneumonitis, and probable VZV encephalitis - VZV +ve in blister fluid, Blood and CSF
2                    Staph Aureus sepsis secondary to herpetic skin lesion infection
3                    Reduction in mental acuity since August 2013
4                    Significant pan-lymphocytopaenia  - with Absolute lymphocyte count hovering between 160 to 450

Two days back the CD4 count plummeted to '7'  and we were asked to review her.

Of note she has had chicken pox in childhood and handled it normally.

No previous history of susceptibility to infections.

Oct 2013 -- IgG- 5.08 g/L( 6 -16 g/l); IgA - 0.44 g/L ( 0.8 -4 g/L) ; IgM  < 0.18 ( 0.5 - 2 g/L) - These are interesting as they were normal in August 2013 - IgG : 7 g/l; IgA - 0.45 g/L & IgM - 0.41 g/L.

Bone marrow - Normal  except for reactive changes, no evidence of Myeloproliferative / Lymphoproliferative disease.
Normal neutrophils, platelets, RBC counts.

She initially presented in August 2013 -- and been treated with IV Acyclovir - but relapsed twice.

Differential

  1.  HIV, HTLV1, 2, EBV , CMV ( serology, PCR) checked several times - ALL  negative
  2.  Secondary Immunedeficiency - No evidence of Lymphoproliferative disease - we have arranged a PET scan ( Normal CT scan)
  3.  Nothing to suggest Sarcoidosis
  4.  not on any medications which could cause lymphopaenia
  5.  Could this be Idiopathic T cell Lymphocytopaenia ( ICL)
  6.  No feature of  autoimmunity
  7.  Could ongoing lymphocytopaenia - secondary to Aciclovir toxicity - Our virologists think it is highly unlikely
  8.  Is there Aciclovir resistence - again unlikely - we are doing the tests and looking at Aciclovir levels

Plan

  1.  Continue IV acyclovir
  2.  Prophylaxis for PCP / fungi etc - given the very low CD4 counts
  3.  treat secondary infections aggressively
  4.  haemaologists & oncologists are looking for a underlying lymphoprolifative disease / malignancy

Questions


  1.  Can VZV cause significant lymphopaenia of this magnitude ?
  2.  Is there a role for VZIG / IVIG
  3.  If one hypothesis this could be ICL ( while looking for a cause for significant lymphopaenia) -- Has anyone used T - cell adjuvants / Cytokines : IL-7 / IL2 / IFN- gamma in this scenario ?

IL-7 has been used in a couple of ICLs with good results. There is a IL-7 study which just completed recruitment but still active -  See - http://clinicaltrials.gov/ct2/show/study/NCT00839436?term=interleukin+7&rank=8&show_desc=Y#desc

Others have also tried IL-2 - http://www.ncbi.nlm.nih.gov/pubmed/10337025  ; This one is very similar to our case - http://www.ncbi.nlm.nih.gov/pubmed/10993296   -- Rx with IL-2 .


Any other thoughts ?

Thank you

Ravi

Dr Ravishankar Sargur
MD, FRCPath, FRCP
Consultant Clinical Immunologist & Clinical Lead
Immunology, NGH
Sheffield Teaching Hospitals Foundation NHS Trust.
Northern General Hospital
Herries Road
Sheffield - S5 7AU
UK

Honorary Senior Lecturer
Dept of Infection and Immunity
University of Sheffield

Training Programme Director
Immunology
East Midlands Deanery and Yorkshire & Humber Deanery

Email : ravishankar.sargur at sth.nhs.uk<mailto:ravishankar.sargur at sth.nhs.uk>
Phone - 0044 114 27 15704
________________________________
From: Riedl, Marc [mailto:mriedl at ucsd.edu]
Sent: 30 October 2013 14:50
To: CIS-PIDD
Subject: Re: [cis-pidd] Profound panhypogammaglobulinemia - To treat or not to treat and how?

Soheil,

As mentioned by others, I do everything I can to get the Medical Director on the phone.  This "peer-to-peer" conversation is typically within your right to arrange (though they will try to delay and dodge it), but in my experience this is almost always successful in securing the proper treatment.  As you suggested, these Medical Directors typically have zero experience or expertise in PID and when pushed directly on the phone will admit this and capitulate.  I also use stronger language:  this is standard-of-care for the condition and the patient is at risk for fatal sepsis (I use the word death) for which the insurance company will be liable given that you are providing the appropriate medical recommendations.

Best,

Marc

Marc Riedl, MD, MS
Associate Professor of Medicine
Division of Rheumatology, Allergy & Immunology
University of California, San Diego
9500 Gilman Dr, Mail Code 0732
La Jolla, CA  92093
Tel 858.822.6766  Fax 858.642.3791

From: Soheil Chegini <schegini at yahoo.com<mailto:schegini at yahoo.com>>
Reply-To: CIS-PIDD <cis-pidd at lists.clinimmsoc.org<mailto:cis-pidd at lists.clinimmsoc.org>>
Date: Wednesday, October 30, 2013 7:20 AM
To: CIS-PIDD <cis-pidd at lists.clinimmsoc.org<mailto:cis-pidd at lists.clinimmsoc.org>>
Subject: Re: [cis-pidd] Profound panhypogammaglobulinemia - To treat or not to treat and how?

Thank you all for your comments and suggestions. I am still struggling to provide my patient with what I believe to be appropriate care and want to ask you again for your input.

Unfortunately, Independence Blue Cross sees no urgency to act on this case and my appeal has fallen on deaf ears. I have no way of knowing whether the insurance physician, Dr. Karen White, who deemed this patient is not eligible for IgG supplementation is even qualified to make that determination. The clinical appeals coordinator is a nurse without any immunology background and I have already done what I could to convince her of the necessity. I would like to ask whether I can refer this patient to any entity such as IDF or Jeffrey Modell Foundation that could offer him legal counseling and advice or represent him by flexing its legal muscle to help him get IgG approved. Thank you again for your help and advice.

Here is an update on the results of his follow-up lab results:
IgG 136
IgA <4
IgM 2
ABO group: A; reverse type failed to show anti-B
Isohemagglutinins (A1, A2 and B) <1:2
Lymphocyte mitogen and Ag stimulation was normal to PHA, ConA and PWM as well as candida and tetanus.

Here is the note I sent to IBC:

Kelli Kobb, RN
Clinical Appeals Coordinator
Independence Blue Cross
P.O Box 41820
Philadelphia, PA 19101-1820
Fax: 888-671-5274


Dear Ms. Kobb,

I am writing to appeal your denial of appropriate care to one of my patients, Mr.  , who has profound panhypogammaglobulinemia and requires prophylactic immunoglobulin replacement.

I am very concerned about his risk of a catastrophic infection and for that reason applied for authorization to start appropriate treatment with subcutaneous prophylactic immunoglobulin replacement. Unfortunately, this was denied IBC because he has not had a significant infectious history. I have appealed IBC's initial denial, but I have not received a final decision about my appeal yet. I wonder whether you would have this patient obtain a second opinion by a specialist treating immunodeficiency conditions or provide any ideas about how to proceed in the care if this patient to avert a potentially disastrous outcome that would undoubtedly result in a costly litigation.


Thank you very much in advance for helping my patient and allowing him to receive state of the art care for this kind of humoral immunodeficiency.


Sincerely,


Soheil Chegini, M.D.

On Monday, October 14, 2013 2:11 AM, Carla Gianelli <gianellicarla at gmail.com<mailto:gianellicarla at gmail.com>> wrote:
Dear Soheil,
 I agree with Mikko that this case looks like IDVC.
Did you rule out Celiac Disease? The serologic test could be negative with IgA isotope so take in count to do it with IgG (anti-tissue transglutaminase antibodies (tTGA) or anti-endomysium antibodies (EMA). Or if it it still suspect biopsy of the small intestine could be performed to confirm the diagnosis.
Kind regards,
Carla Gianelli
Clinical Immunology
Hospital Ramón y Cajal.
Madrid. Spain.

2013/10/14 Seppänen Mikko <Mikko.Seppanen at hus.fi<mailto:Mikko.Seppanen at hus.fi>>
Dear Soheil,

I of course agree with all previous comments, and to me Your case looks in all ways like a very typical CVID (or Good's, like said), even by looking at tetanus and diphteria (latter is low) responses.

I would as well order (if not yet done, in my opinion should be part of initial workup even before vaccine responses checked): electrophoresis of urine and serum, B12-TC2, (S-MetMal), fS-A-vit, TSH, T4.

There is some data on infection risk with this low Igs, check Quinti I et al (the Italian cohort) as well as Oxford cohort (Chapel H and Misbah S among authors), both of which found that IgG around 400-500 is the threshold after which the risk of infection skyrockets...I have, after 17 years of practice, yet to see the patient who - with that low levels - woud not develop a life-threatening infection or die w/o treatment, given a reasonable follow up period. Not all agree with therapy so one "gets" to follow up what happens... I guess most of us share this opinion?

And about valproic acid: it could be one of the factors leading to this, but since the patient has already a full-blown CVID phenotype, I am not aware of any reports describing a recovered Ig-production after it has been stopped? is anyone else? IgAD+IgG2D can recover though, see for example Hammastrom L et al for review.
Personally, I think (IMHO) that if person develops CVID-like after valproic acid/gold/SSP or other old antirheumatic or anticonvulsant, they probably have genetic predisposing factors (would not include them to primary CVID studies though)?

Yours

Mikko Seppänen
MD PhD Assoc prof
Immunodeficiency Unit, Helsinki Finland


________________________________
Lähettäjä: Soheil Chegini [mailto:schegini at yahoo.com<mailto:schegini at yahoo.com>]
Lähetetty: 11. lokakuuta 2013 23:49
Vastaanottaja: CIS-PIDD
Aihe: [cis-pidd] Profound panhypogammaglobulinemia - To treat or not to treat and how?
Dear Colleagues,

I am writing to ask for your advice in the management of a 52 y.o. man, whom I was consulted to evaluate for panhypogammaglobulinemia.  I was concerned about his risk of a catastrophis infection and applied for authorization to start his treatment with SCIg, which was denied by his insurance IBC because he has not had a significant infectious history. This decision has been appealed, but I would appreciate your advice until a final decision is made.

His most recent IgG was 136, IgA <4, IgM 2 on Sept 13, 2013. After vaccination, he boosted his tetanus and diphtheria titers from 0.30 to 1.54, and from 0.02 to 0.22, respectively, but failed to respond to Pneumovax with all 14 tested serotypes <0.3 pre- and post vaccination. He has no detectable hemagglutinins. FACS analysis of his lymphocytes showed CD3 of 785 (75%) and CD4 428 (40%) that are just below the expected levels, but otherwise unremarkable. The lab (Quest) could not properly set up mitogen and antigen proliferation studies and ABO blood typing and yet I will have to send him back to the lab to have that done.

He presented in April 2013 with anemia and prolonged diarrhea that had persisted since March 2012 to his gastroenterologist, who then referred him to me. Over that period he had lost a significant amount of his body weight, from 266 lbs. down to 189 lbs. Subsequently, he had an extensive workup that identified giardiasis, which was appropriately treated with metronidazole and resolved completely after completion of the course with corresponding weight gain of about 10 lbs. In this process he was discovered to be IgA-deficient on May 10, 2013 among several other pertinent abnormal findings. Further investigation revealed very low gamma globulins, and immunoglobulin levels across the board. Mesenteric and sub mandibular lymphadenopathy was noted on his abdominal and neck CT scans, but hematology/oncology evaluation and bone marrow and inguinal lymph node biopsy ruled out hematologic malignancies. In addition, biopsies from his small bowel polyps did not show pathologic changes consistent with lymphoma. He had significant respiratory infection in March 2013 that he describes as a flu with fevers and chills, cough and shortness of breath, for which he was seen by his primary physician. At that time, he did not have any radiographic imaging of his chest and was empirically treated with an antibiotic for 10 days. He was sick for six days, but gradually recovered without any complications. He was diagnosed with bipolar disorder in 2005 and was placed on Depakote that has been effective in stabilizing his mood. Otherwise his PMH is unremarkable.

Here is a synopsis of his lab data before I first saw him on Jul 31, 2013; hemoglobin: 13.7 g/dL; hematocrit: 40.6; RBC count: 4.42; normal RBC Indices, WBC 9.7 and platelet count 203. Differential was remarkable for neutrophilia, absolute neutrophil count (ANC) of 8200 and with 84% neutrophils and lymphocytopenia with 9% lymphocytes and absolute lymphocyte count (ALC) of 873; otherwise normal. CMP) revealed low total protein at 5.2 with normal albumin at 3.7 (globulin level 1.5 g/dL); IgG was 110, IgM was 7 and IgA < 7 mg/mL and IgE< 1U/mL; SPEP revealed low beta and gamma globulins.

Chest CT scan on May 18, 2013 was within normal limits, but CT of his neck demonstrated a prominent left submandibular lymph node that measured less than 1 cm in each dimension. Abdominal CT scan at that time and again on July 13, 2013 revealed mesenteric lymphadenopathy without any significant change, and multiple areas of small bowel intussusception without evidence of obstruction.

I felt that the diagnosis of CVID) cannot be established despite profound panhypogammaglobulinemia until other defined causes of hypogammaglobulinemia have been excluded. He has had persistent unexplained enteropathy after eradication of giardia, but no history of recurrent infections or non-infectious complications such as auto-immune cytopenia, polyclonal lymphocytic proliferation. I suspected that his treatment with an anticonvulsant, valproic acid (Depakote) since 2005 for bipolar disorder could induce secondary hypogammaglobulinemia. I instructed the patient to see his psychiatrist, who in the interim has stopped Depakote 3 weeks ago. Even if that is the culprit, I would need to be very optimistic to expect a rapid resolution of secondary hypogammaglobulinemia. I have not repeated his lab workup yet, but am expecting another set of immunoglobulins in about 2 weeks.

Thank you very much for your help and guidance.

Soheil Chegini, M.D.
Exton Allergy & Asthma Associates
656 West Lincoln Hwy.
Exton, PA 19341
Phone: (610) 269-3066
Fax: (610) 269-8615
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