[CIS PIDD] [cis-pidd] Is it PID or Secondary Immunodeficiency?

Tue Aug 29 21:37:15 EDT 2017

Thanks Karl !
Yes , I agree that Ig replacement  has not brought  any goodness ( at least not so far)
A few clarifications and typo mistakes :
Patient had good antibody titers( Hiflu, Diphtheria( without vaccination ) and pneumococcal( post vaccination) however, lost protection of pneumococcal titers within 12 months . This is what prompted previous physician to diagnose her  with CVID . My arguments against this  diagnosis are :1) I am not sure about your experience but we see loss of protection in pneumococcal titers at least 20% cases without any clinical issues 2) These pneumococcal titers were obtained when kid was <4 year of age ( about 3 ½) and my experience is  that pneumococcal titers fluctuate at this young age 3) No history of recurrent infections or auto immune issues
Finally, during my encounter with this kid , she was  not exactly sick looking but what I noticed that kid was just vomiting even during my exam . No muscle wasting
Basically kid is having vomiting , diarrhea , some tongue lesions(not documented but by history,)  definite deceleration in growth ( weight and height)
Also clarification on the dose it is 800 mg /kg/month divided into weekly doses of  (200 mg/kg/week)

Agree with clean slate exam ( mother is very resistant to stop Ig replacement , she is not satisfied with her progress but does not want to stop Ig infusions)
Agree with diet/nutrition deficiencies
No anemia
Chronic infection work up is not done and we will do it as you have suggested . Also we are doing work up for GI/Renal loss
Many thanks
Look forward any further input

Ejaz

Ejaz Yousef MD
Nemours Children Specialty Care
Jacksonville, FL

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Subject: RE: [cis-pidd] Is it PID or Secondary Immunodeficiency

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Hi, Dr. Yousef:

I may be in the minority here - but I have doubts that the child needs the IgG replacement.  If 800 mg/kg/week (really?) doesn't do anything, I doubt going up on the dose would do much.

I would suggest a clean slate re-examination.  Consider diet/nutritional deficiencies - Fe, folate, B6 and B12 deficiency can give the tongue changes ... and the B deficiencies would go together with chronic diarrhea issues (any anemia?).   Vit D deficiency would go with headaches - if you believe some of the literature.  With the Asperger syndrome, there may be some behavioral issues that make proper diet a longstanding challenge.

You mentioned on exam, she looked "sick."  Was there any muscle wasting?  The mitochondrial cytopathies (e.g., MELAS) are very rare, but this could tie together multiple systems' involvement.  The hypogamma (with intact anti-vaccine titers) would just then be secondary to the renal/GI hit.

With the hypogamma and diarrhea, though, I would suggest a workup ... make sure chronic infection (e.g., enterovirus, Giardia, etc.) is not a cause of all this.

       - Karl

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., Room R-403, Rochester, NY   14621
Tel  585-922-3709  |  Fax  585-922-2415

From: cis-pidd at lyris.dundee.net<mailto:cis-pidd at lyris.dundee.net> [mailto:cis-pidd at lyris.dundee.net] On Behalf Of CIS-PIDD
Sent: Monday, August 28, 2017 9:53 PM
To: CIS-PIDD
Subject: [cis-pidd] Is it PID or Secondary Immunodeficiency

Dear experts:
I would like to seek your expert opinion on a 8 years old white female with Asperger's syndrome  who was referred to my practice for continuation of Ig replacement therapy
She was diagnosed with CVID little less than 4 years of age due to following history:
Patient presented to the previous allergist with h/o intermittent diaper rash and diarrhea  since 9 months of age .Until that  that time  she had 3 ear infections. Had an hospital admission  for dehydration secondary to coxsackie virus and oral blisters. No history of pneumonia or recurrent skin infections. Has not had any serious infections requiring hospitalizations.
She  had bloodwork done to evaluate the rash and was found to have low immunoglobulins(IgG 323, IgA 7, IgM 26).  Normal  absolute lymphocyte counts and excellent  response to protein antigens (Diptheria, H.flu).

Allergist  reordered  CBC, Immunoglobulins and  pneumococcal titers and complement screen that showed CBC, complement panel WNL, IgG 348, IgA 12, IgM 36; Pneumococcoal titers were low and was advised to receive booster from PCP and repeat titers  turned protective 11 out of 14 serotypes.

She was diagnosed with Transient hypogammaglobinemia(resolved)

12 months later  she  continued to have  abnormal, foul smelling stools. No recurrent skin or respiratory infections. She was hospitalized for vomiting, diarrhea and dehydration and some labs were obtained showed low IgG A M, low subclasses, and elevated protein on urinalysis. (IgG 312, IgA 17, IgM 25; IgG1 213, IgG2 67, IgG3 11, IgG4 1.7; Urinalysis (elevated protein),no cause identified for her symptoms.
Once again no  recurrent Sino pulmonary infections or skin infections. Diagnosed with secondary hypogammaglobinemia( GI/Urinary loos)

For some reason her allergist ordered a  repeat Immunoglobulins levels and Pneumococcal titers were obtained results showed   IgG 367, IgA 16, IgM 41; IgG1 239, IgG2 71, IgG3 11, IgG4 1.5, low pneumococcal titers (4/23  serotypes protective); normal lymphocyte subset

Summary of labs at that  time(<4 years of age)  was as follows :
8/30/12   IgG 367, IgA 16, IgM 41; IgG1 239, IgG2 71, IgG3 11, IgG4 1.5, low pneumococcal titers (4 serotypes out of 23  protective); normal lymphocyte subset
7/17/12   IgG 312, IgA 17, IgM 25; IgG1 213, IgG2 67, IgG3 11, IgG4 1.7
1/04/11   IgG 420, IgA 15, IgM 53; protective pneumococcal titers (11 serotypes out of 14 )
9/21/10   IgG 348, IgA 12, IgM 36; CBC, complement panel normal, low pneumococcal titers
5/27/10   IgG 333, IgA 9 , IgM 27
1/05/10   Lymphocyte subset panel, Diptheria/H. flu titers normal
10/27/09 IgG 323, IgA 7, IgM 26
She was diagnosed with Common variable immunodeficiency (CVID and started on SqQ Ig replacement therapy

She continued to have intermittent loose stools non specific abdominal pain .  Seen by GI and EGD done showed "Deuodonitis" and was started on PPI

For next couple of years  she has had only one episode of ear infection but continued to have diarrhea and developed some  new complaints

1)intermittent episodes of non-bloody, non-bilious vomiting without specific triggers. Has had increased frequency of stool, but no persistent diarrhea. Has had some straining and constipation.
2) Mood changes and behavior issues
3) Deceleration of growth

IgG level: 948

Ig infusion  dose increased from 2 g to 2.5 gm weekly to see if there is an improvement in GI symptoms however,no improvement in GI symptoms

Next year IgG level was  782 mg/Dl  had one episode  of respiratory illness ( treated with short course of Zithromax)

Reevaluated after 6 months: Continued to have intermittent GI symptoms and also started having  chronic headaches and joint pain (wrists, back, knees). Noticed no association of symptoms with timing of Ig  infusions..

Normal LFTs and BMP

In next 6 months and patient had another adenoidectomy and also had 4 ear infections since after surgery.
In addition noticed  weight loss ,onset of intermittent sore throat, tongue swelling and hypo pigmented lesions ( treated with magic mouthwash and nystatin with little improvement.

Continues on 2.5 gm (400 mg/kg) of SCIG infusions weekly. However, IgG levels dropped to 737 mg/Dl.. CBC and lymphocyte enumeration panel normal
Her allergist increased Immunoglobulins to  to 3 g once again without any improvement in her GI symptoms, mood , headaches and intermittent fevers( not documented) despite increasing Ig dose

Later there was recurrence of  swollen tongue with hypo pigmented lesions, and fissures over the next  4 months. Has been treated repeatedly with nystatin and magic mouthwash with little improvement. Treated with Tylenol and Motrin. Autoimmune labs were ordered by GI and were normal.

IgG Level dropped to 739

Summary  : 8 years old with history of GI symptoms ( intermittent vomiting, diarrhea and abdominal pain) with thinning hair, looking "sickly", having excessive thirst and hunger with insatiability and  by history intermittent tongue lesions( once monthly and stay for 5-6 days)  ( normal exam) finally poor growth ( Height dropped form  60th percentile at the  age of 6 to 25 percentile now ) and weight loss
No history of recurrent infections (total courses of antibiotics in her life were about 12 and at least 4 of these were after starting Immunoglobulin replacement ). No anemia or thrombocytopenia,.lymphopenia or leukopenia .
Low Immunoglobulins before starting replacement therapy
Robust Diphtheria and H infl titers
Normal post vaccine pneumococcal titers in the past however, dropped in one year ( titers obtained  when she was less than 4 years of age) and was started on replacement therapy

Seen by Rheumatology and  they did not feel any auto immune pathology however, so far ESR and CRP normal  other labs pending
Seen by Endo : Not clear about the etiology of poor growth ruled out adrenal insufficiency .
 While her  medical history is somewhat complex, her exam findings today are relatively benign.  I do not find any active signs of inflammatory arthritis, systemic lupus or other auto immune disease such as Behcet's.

Her Ig replacement dose has been increased to 5 g (800 mg/kg) . Even with this dose she still  has had the same issues

I have obtained her IgG level and it was  757( done last week) on 5 g weekly dose (800mg /kg)

Last pre albumin level done a year ago was low(13)

My question(s) :
Is it PID or secondary Immunodeficiency ( GI , urinary loss) .She has history of low immunoglobulins which seem to worsen with GI illness.  The cause of her hypogammaglobinemia is unclear at this time. Certainly her levels seem to drop when she is having GI illness.

If it is PID then what should be our course of action on someone who is already receiving   high dose Ig replacement therapy for the last 5 years without any improvement in her symptoms ( actually deterioration of GI symptoms and growth curve)

Any suggestion would be appreciated

Thanks

Ejaz Yousef MD
Nemours Children Specialty Care
Jacksonville, FL

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