[CIS-PAGID] Hypogam following Fontan

[Fleisher, Thomas (NIH/CC/DLM) [E]]

She is acting like a patient with intestinal lymphangiectasia either primary or secondary. Pericardial constriction can present this way so ruling out this should be a primary concern since that is treatable (abstract below). This could also be the result of a leak from the thoracic duct but I assume "previously healthy" means that there has been no thoracotomy or other intervention that could have led to damaging the thoracic duct. If it is not secondary to pericardial constriction, then you have to consider either a process we described more than 30 years ago that appears to represent an IL secondary to some undefined inflammatory process (PDF attached), the possibility of a lymphoid malignancy causing a secondary IL (abstract below) or primary IL (abstract below).

J Pediatr. 1975 Apr;86(4):548-54.
Constrictive pericarditis, intestinal lymphangiectasia, and reversible immunologic deficiency.
Nelson DL, Blaese RM, Strober W, Bruce R, Waldmann TA.
Abstract
A patient with constrictive pericarditis, secondary intestinal lymphangiectasia, and protein-losing enteropathy was demonstrated to have the characteristic immunologic deficiency associated with intestinal lymphangiectasia: hypogammaglobulinemia, lymphocytopenia, cutaneous anergy, impaired allograft rejection. and diminished in vitro lymphocyte proliferative responses. Following surgical correction of the cardiac abnormality, the intestinal lymphangiectasia and protein-losing gastroenteropathy resolved and was accompanied by a slow but progressive return of normal immune function. This documented reversal of the immunologic deficiency in intestinal lymphangiectasia supports the concept that the immune defect in this syndrome is due to the excessive loss of lymphocytes and immunoglobulins into the gastrointestinal tract.

N Engl J Med. 1979 Mar 15;300(11):605-6.
Corticosteroid-responsive intestinal lymphangiectasia secondary to an inflammatory process.
Fleisher TA, Strober W, Muchmore AV, Broder S, Krawitt EL, Waldmann TA. (PDF attached)

Gastroenterology. 1981 Jan;80(1):166-8.
Resolution of longstanding protein-losing enteropathy in a patient with intestinal lymphangiectasia after treatment for malignant lymphoma.
Broder S, Callihan TR, Jaffe ES, DeVita VT, Strober W, Bartter FC, Waldmann TA.
Abstract
In 1956 we evaluated a patient who had a debilitating disease of a 2 yr duration, characterized by recurrent vomiting, diarrhea, cachexia, massive edema, hypoproteinemia, and dilated intestinal lymphatics. During our initial evaluation of this patient, we observed that 42% of her circulating protein pool was lost into her gastrointestinal tract daily, whereas normal gastrointesinal loss of protein does not exceed 1.6%. Her disease appeared to represent a classic example of intestinal lymphangiectasia. She was treated symptomatically for 13 yr with essentially no change. In 1969 the patient developed a stage IV diffuse, undifferentiated (non-Burkitt's) malignant lymphoma. Using immunoperoxidase staining, the neoplastic cells were found to contain cytoplasmic IgMKappa, suggesting that the lymphoma had a monoclonal B-cell origin. She was successfully treated with cyclophosphamide, vincristine, and prednisone. Shortly after the initiation of this systemic combination chemotherapy, her serum protein concentration returned to normal, her edema resolved, and she was cured of gastrointestinal symptoms. Moreover, repeat studies revealed that her protein loss had fallen to only 2%. The simultaneous cure of both the intestinal lymphangiectasia and lymphoma with combination chemotherapy suggests new relationships between these conditions as well as new possibilities for the treatment of acquired forms of intestinal lymphangiectasis associated with overwhelming gastrointestinal protein loss.

J Clin Invest. 1967 Oct;46(10):1643-56.
Intestinal lymphangiectasia: a protein-losing enteropathy with hypogammaglobulinemia, lymphocytopenia and impaired homograft rejection.
Strober W, Wochner RD, Carbone PP, Waldmann TA.
Abstract
Intestinal lymphangiectasia is a disease characterized by dilated intestinal lymphatics, protein-losing enteropathy, hypoalbuminemia, and edema. The immunologic status of 18 patients with intestinal lymphangiectasia was studied. Concentrations of IgG, IgA, and IgM were measured by immune precipitation and metabolism of these three immunoglobulins was studied using purified radioiodinated proteins. The serum concentration and total body pool of each immunoglobin were greatly reduced. The fraction of the intravascular protein pool catabolized per day was increased to 34% for IgG, 59% for IgA, and 66% for IgM; these are in contrast with control values of 7%, 28%, and 17%, respectively. Synthetic rates of the immunoglobulins were normal or slightly increased. Primary circulating antibody response was tested in five patients with Vi and tularemia antigens. Titers elicited in patients with the Vi antigen were significantly lower than those seen in a control group, whereas no difference was seen between patient and control responses to the tularemia antigen. Lymphocytopenia was noted in patients with intestinal lymphangiectasia. The mean circulating lymphocyte count was 710 +/- 340/mm(3) in contrast to 2500 +/- 600/mm(3) in controls. Cellular hypersensitivity was studied with skin tests and skin grafts. 91% of normal individuals reacted to at least one of the four skin test antigens: purified protein derivative, mumps, Trichophyton, and Candida albicans; in contrast, only 17% of patients with intestinal lymphangiectasia had a positive reaction. Each of three patients tested with dinitrochlorobenzene had a negative reaction. Finally, all four patients who received skin homografts have retained these grafts for at least 12 months. The immunological disorders in patients with intestinal lymphangiectasia appear to result from loss of immunoglobulins and lymphocytes into the gastrointestinal tract secondary to disorders of lymphatic channels. Lymphocyte depletion then leads to skin anergy and impaired homograft rejection.



Thomas A. Fleisher, M.D.
Chief, Department of Laboratory Medicine
NIH Clinical Center
301 496-5668 (T)
301 402-1612 (F)

-----Original Message-----
From: Dowling, Paul MD [mailto:pdowling at cmh.edu] 
Sent: Friday, December 16, 2011 2:52 PM
To: pagid at list.clinimmsoc.org
Subject: Re: [CIS-PAGID] Hypogam following Fontan

Dear Colleagues:

I have an interesting case related to the previous one described above concerning protein/antibody loss.
Previously healthy 10 year old female presenting with acute R side abdominal swelling. Imaging identified a large right sided plerual effusion that was immediately drained (almost 1000mL) with chest tube placed soon after. No source for the effusion could be identified as child has been healthy. Cytology on the pleural fluid was largely lymphocytic (97%), gram stain negative without any organism or suspicion for infectious orgin. All cutures including blood and pleural fluid have been negative to date.

Child continues to drain massive amounts of chylous material from the chest tube, exceeding 6,000mL in just under 72 hours. With this, we have seen her lymphocytes fall over time to an ALC of 900 this morning. Total serum protein 4.7 g/dL and albumin 2.4.  Pleural effusion protein was 575mg/dL. Light's criteria would indicate this as more of an exudative effusion by calculation. Flow cytometry revealed pan lymphopenia with a CD4/CD8 ratio of nearly 1, with preservation of B and NK cell lines. We are concerned because her IgG is falling as well. Currently, 430 yesterday and today now 400.  We are assuming this is from the lymphatic fluid loss from the effusion but cannot be 100% sure. We are also checking stool alpha1 antitrypsin as well as urine protein, both pending.

We have also pending: pneumoccocal and tetanus titers, along wtih mitogen/antigen stim assay.

The possibility of replacing IgG exists if her level continues to fall. However, we are unsure if this would be appropriate given her high volume protein loss. We are considering pharmocokinetics after administering IVIG in attempt to monitor how fast her level will fall should she need it. It is not possible to check an IgG level in her pleural fluid.

Presently, she is not septic, febrile or infectious. She recently underwent bone biopsy of the 8th and 10th ribs after osteopenic and possibly lytic appearing lesions were noted in these ribs on CT. She has a congential absence of the 9th rib. The possibility for malignancy exists as the source of her effusion and we are awaiting pathology.
One other interesting possibility that our other teams have included on the differential is Gorham's Disease, which may explain the changes seen in her ribs and possible a lymphatic proliferation, however this is rare and a diagnosis of exclusion.

We are awaiting the results of an anergy panel  to ensure adequate lymphocyte function in the face of her lymphopenia while waiting for mitogen/antigen studies. Any further assistance you can provide to us on replacement of her IgG in this type of scenario would be helpful. Thank you.


Sean Stanga, M.D.
Fellow, Allergy/Immunology
Children's Mercy Hospital
2401 Gillham Rd
Kansas City, MO 64108
(816)-234-3097

Paul Dowling, MD
Children's Mercy Hospital
________________________________
From: pagid-bounces at list.clinimmsoc.org [pagid-bounces at list.clinimmsoc.org] On Behalf Of Ballas, Zuhair [zuhair-ballas at uiowa.edu]
Sent: Thursday, December 01, 2011 1:49 PM
To: pagid at list.clinimmsoc.org
Subject: Re: [CIS-PAGID] Hypogam following Fontan

Joe
There are also some reports suggesting octreotide might attenuate the loss
Zuhair


From: pagid-bounces at list.clinimmsoc.org [mailto:pagid-bounces at list.clinimmsoc.org] On Behalf Of Church, Joseph
Sent: Thursday, December 01, 2011 10:37 AM
To: pagid at list.clinimmsoc.org
Subject: Re: [CIS-PAGID] Hypogam following Fontan

Burcin:  Thank you for your response.  I certainly will keep that approach in mind.  JC

From: pagid-bounces at list.clinimmsoc.org<mailto:pagid-bounces at list.clinimmsoc.org> [mailto:pagid-bounces at list.clinimmsoc.org]<mailto:[mailto:pagid-bounces at list.clinimmsoc.org]> On Behalf Of Burcin Uygungil
Sent: Thursday, December 01, 2011 8:32 AM
To: pagid at list.clinimmsoc.org<mailto:pagid at list.clinimmsoc.org>
Subject: Re: [CIS-PAGID] Hypogam following Fontan

Hi Joe,

I am a mere fellow but I just wrote a review on primary intestinal lymphangiectasia and I think that the same issues apply to this is case of secondary protein losing enteropathy.  In addition to IgG replacement (subq might be better) - you could also try a dietary approach with a high MCT (medium chain triglyceride) diet.  This usually involves a formula so you might need to speak with a dietician to make it more palatable for a 7 year old.  I have seen that it really works in a handful of patients.

Burcin Uygungil
Johns Hopkins Hospital
On Thu, Dec 1, 2011 at 10:17 AM, Church, Joseph <JChurch at chla.usc.edu<mailto:JChurch at chla.usc.edu>> wrote:
Colleagues:

I am seeing a 7yo girl with hypoplastic left heart syndrome s/p Fontan procedure.

As many of these patients she has developed progressively decreasing IgG.  Her tetanus, Hib and pneumococcal antibodies remain protective, and she has had no serious infections.  She also has T-lymphopenia.

Of particular interest is that her low IgG (currently 155 mg/dL) seems out of proportion to her hypoalbuminemia (2.9-3.2 mg/dL).

Has anyone seen this combination of findings?

I am leaning toward beginning Ig replacement because of the progressive decrease in IgG levels.

Thanks for your help.

Joe Church
Children's Hospital Los Angeles





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--
Burcin

"If you want to progress in your life and grow, act not to react"
                                                                       -Yogi Bhajan


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