[CIS PIDD] [cis-pidd] Profound panhypogammaglobulinemia - To treat or not to treat and how?

[Seppänen Mikko]

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]
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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