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Re: PLE after Fontan Operation and Immunological Dysfunction.

Dear Editor

The response by Prof Tarnok [1] is both interesting and thought provoking. The suggestion of mature immune system in this group will need further clarification. Thymectomy is often performed as part of their initial surgery; hence the nature of T cell response in this group may be different from other patients with PLE. This is further complicated by the presence of heterotaxy and asplenia. I have encountered severe disseminated chicken pox in a patient with PLE and the ensuing systemic response can be life threatening. Immunoglobulin replacement, prophylactic antibiotics against opportunistic infections and specific protection against varicicella is routine practice in most centres. With a mortality nearing 50% in five years, the incidence of secondary malignancies in this group may be not apparent, as the incidence is known to increase with age and survival.

There is insufficient data to support infection as the trigger for the onset of PLE. It is likely that there is a degree of elementory loss of protein and lymphocytes before developing clinically manifest PLE. Increased compensatory mechanisms may initially maintain normal levels resulting in a delicately balanced state. Acute infections could trip this towards clinically manifest PLE. We agree with Tarnok that infection in PLE might be a symptom of an impaired immune system during the early stages of clinically manifest PLE rather than a causal factor.

The most important underlying haemodynamic problem is elevated systemic venous pressure inherent to the Fontan circulation. But is this the reason for PLE? There are many arguments against this: 1. Except for a case report (1), PLE is not a recognised complication of elevated venous pressure in patients with portal hypertension. 2. There is no difference in the right heart pressures between patients who develop PLE and those who do not (3). 3. PLE does not improve in all patients after decompressing the venous pathways (enlarging fenestration or relief of obstruction). As suggested by Powell and group (3), prolonged cardiopulmonary bypass time or factors related to prolonged bypass, appears to predispose to PLE. It is now well established that there is alteration in the intestinal mucosal function following cardiopulmonary bypass, and the effect of repeated bypass procedure on persistent hypoxemia will need further evaluation. In the setting of inherent systemic venous hypertension, other co-existing predisposing factors like Ischemic insult to the gut, elevated mesenteric vascular resistance (3), and localised lymphangiectasia (4) needs to be closely evaluated, for successful management of these patients. PLE after Fontan palliation remains a devastating complication. This group of patients are small in number at a given centre, and understanding the pathogenesis and developing management strategies will require multicentre collaborative work.

References

1. Tarnok A. Does PLE after Fontan palliation refer to immunodeficiciency? [electronic response to Chakrabarti et al; Acquired combined immunodeficiency associated with protein losing enteropathy complicating Fontan operation] heartjnl.com 2004 http://heart.bmjjournals.com/cgi/eletters/89/10/1130#207

2. Stanley AJ, Gilmour HM, Ghosh S et al. Transjugular intrahepatic portosystemic shunt as treatment of protein loosing enteropathy caused by portal hypertension. Gastroenterology 1996; 111:1679-82.

3. Powell AJ, Gauvreau K, Jenkins KJ, Blume ED, Mayer JE, Lock JE. Perioperative risk factors for development of protein losing enteropathy following a Fontan procedure. Am J cardiol 2001;88:1206-1209.

4. Rychik J, Gui-Yang S Relation of mesenteric vascular resistance after Fontan operation and protein losing enteropathy. Am J cardiol 2002;90:672- 674.

5. Connor FL, Angelides S, Gibson M, Larden BW, Roman MR, Jones O, Currie BG, Day AS and Bohane TD. Successful Resection of Localised Intestinal Lymphangiectasia post Fontan: Role of 99mTechnetium-Dextran Scintigraphy. Pediatrics;2003;112:242-247.

Send letter to journal:
Re: Does PLE after Fontan palliation refer to immunodeficiency?

Dear Editor

We have read with great interest the manuscript by Chakrabarti et al.[1] on immunodeficiency in patients suffering from protein losing enteropathy (PLE) after Fontan palliation. The authors reported of lymphopenia and T-lymphocyte loss in two children with PLE. The infrequency of this syndrome and the even rarer immunological investigation of affected patients makes these observations very precious. According to a literature search only four additional references focused on the immunocytes in PLE patients with Fontan palliation. Koch et al. [2] and Garty [3] reported of one child, Cheung et al. of six [4] and our group of eight.[5] This sums up to 18 children with PLE and Fontan circulation in whom T-lymphocyte loss is reported. Furthermore, it was shown that this loss is selective for helper T-lymphocytes (Th) and hardly affects cytotoxic T-lymphocytes (Tc).[2-5] Decrease in B lymphocyte and natural killer cell counts was not observed [2,4] except in one case.[3]

Immunodeficiency

But is this selective loss really an immunodeficiency? With the present knowledge this is still questionable. Immunodeficiency is defined as the defective function of one or more components of the immune system. However, dysfunction of components of the immunesystem has not been shown yet. There is one additional argument that makes the interpretation of the cell loss as immunodeficiency questionable. In patients with immunodeficiency an increased frequency of immunological problems such as recurrent and opportunistic infections, certain types of malignancies among others should be expected. However, in the reported 18 children with PLE and T-cell loss only two (11%) suffered from recurrent infections worth mentioning,[3,6] agreeing with the infection rate of 16% reported by Mertens et al. [7] in their multicentric study. It can not be excluded that this immunodeficiency was the consequence of immunosuppressive therapy. Obviously, this low frequency of reported opportunistic infections does not exclude immunodeficiency and we propose to screen more carefully infection frequency in Fontan patients with and without PLE. There is some additional argument why PLE patients, in spite of massive Th -cell loss, still maintain a relatively intact immunity. Most PLE patients have relatively mature immunesystem. PLE developed in the patients of the above mentioned studies at a median age of 10.3yrs (range: 5.5 – 17yrs).[1-4, 6] This agrees well with the study of Mertens et al. (median: 11.7 yrs).[7] At this age the memory B-cells responding to “known” infections are present and cells responding to viral infections and malignant cells, Tc cells and NK/NKT – cells, remain in the circulation. In a detailed study by Fuss et al. [5] on PLE patients with lymphangiectasia (without congenital heart disease and Fontan palliation) it was shown that by the Th cell loss mostly naive Th cells but not memory cells are affected. This is in agreement with studies of our group on Fontan patients with PLE.[5] Therefore, in spite of the dramatic Th cell loss the level of memory Th cells is maintained and a fairly normal immune defence is possible.

Trigger of PLE

As stated by Chakrabarti et al. [1] it is still an open question why PLE occurs with a very heterogeneous time delay after Fontan palliation. Rychik and Spray (9) observed frequently infections at PLE onset and postulated that they may be one trigger for PLE. We have shown that seven of eight patients had at PLE onset acute infections of mostly gastric origin.[6] Infections of different origin are not unusual in children. Therefore, infection can be one stimulus but it must be postulated that other additional factors are necessary to lead to PLE. Obviously, increased systemic venous pressure is one risk factor [7] and clinical difficulties may arise when thereby the lymphatic system begins to fail.[10] Fontan circulation also leads to the impairment of gut, lung and liver perfusion and affects these organs.[10,11,12] Gut perfusion alterations, as an example, may impair the intestinal immune defence.[13] PLE is most certainly the common endpoint of a multifaceted disease. We have postulated that also a specific genetic background or a predisposition for autoimmune disease [14] could be yet unrecognised important factors. Genetic analysis needs in future to be launched to answer this question in detail.

Prediction of PLE

In their paper Chakrabarti et al. [1] make an important point in stating that regular immunological screening of Fontan patients is of importance in order to define risk groups for PLE. We strongly support this approach. We have recently published in a retrospective study on 15 children evidence that immunological screening may be of use for discriminating Fontan patients without PLE risk from those who show transient signs of protein loss or develop manifest PLE.[15] Based on the mathematical approach of data mining we could select a panel of laboratory parameters that seem to be useful for risk assessment and may be tested by other laboratories. Our results show that NK and Tc cell count as well as serum L-selectin, IgE, and Ca₂+ may play role in PLE manifestation after Fontan palliation. Alterations of the cell count of CD8positive T-cell receptor gamma,delta positive lymphocytes in the peripheral blood of risk patients may in addition also indicate an impaired gut mucosal immune function as these cells represent a major population of the gut’s defence line.[13] By further testing and optimising the immunological panel, individual risk assessment may become possible in future. This should lead to the improved prophylactic and therapeutic management of risk patients [1,9] and hopefully to the avoidance of PLE.

References

1. Chakrabarti S, Keeton BR, Salmon AP, et al. Acquired combined immunodeficiency associated with protein losing enteropathy complicating Fontan operation. Heart 2003;89:1130-1.

2. Koch A, Hofbeck M, Feistel H, et al. Circumscribed intestinal protein loss with deficiency in CD4+ lymphocytes after the Fontan procedure. Eur J Pediatr 1999;158:847-50.

3. Garty BZ. Deficiency of CD4+ lymphocytes due to intestinal loss after Fontan procedure. Eur J Pediatr 2001;160:58-9.

4. Cheung YF, Tsang HY, Kwok JS. Immunologic profile of patients with protein-losing enteropathy complicating congenital heart disease. Pediatr Cardiol 2002;23:587-93.

5. Lenz D, Sauer U, Hambsch J, et al. Immune alterations following protein losing-enterophathy (PLE) after Glenn/Fontan surgery are similar to those after systemic lupus erythematosus (SLE) and celiac disease (CD): Indications for an autoimmune disease. Immunbiology 2000;203:217.

6. Lenz D, Hambsch J, Schneider P, et al. Protein-losing enteropathy in patients with Fontan circulation: is it triggered by infection? Crit Care 2003;7:185-90.

7. Mertens L, Hagler DJ, Sauer U, et al. Protein-losing enteropathy after the Fontan operation: an international multicenter study. PLE study group. J Thorac Cardiovasc Surg 1998;115:1063-73.

8. Fuss IJ, Strober W, Cuccherini BA, et al. Intestinal lymphangiectasia, a disease characterized by selective loss of naive CD 45 RA+ lymphocytes into the gastrointestinal tract. Eur J Immunol 1998;28:4275-85.

9. Rychik J, Spray TL. Strategies to treat protein-losing enteropathy. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 2002;5:3- 11.

10. Bull K. The Fontan procedure: lessons from the past. Heart 1998;79:213-4.

11. Yamagishi M, Kurosawa H, Hashimoto K, et al. The role of plasma endothelin in the Fontan circulation. J Cardiovasc Surg (Torino) 2002;43:793-7.

12. Narkewicz MR, Sondheimer HM, Ziegler JW, et al. Hepatic dysfunction following the Fontan procedure. J Pediatr Gastroenterol Nutr 2003;36:352-7.

13. Wang J, Whetsell M, Klein JR. Local hormon networks and intestinal T cell homeostasis. Science 1997; 275:1937-9.

14. Lenz D, Hambsch J, Sauer U, et al. Detection of allo- and autoreactive antibodies in patients with protein losing enteropathy (PLE) who underwent Fontan surgery. Cardiol Young 2003;13:251.