Primary intestinal lymphangiectasia diagnosed by video capsule endoscopy in a patient with immunodeficiency presenting with Morganella morganii bacteraemia.

A 24-year-old woman with a medical history of chronic lower extremity oedema, abdominal pain, diarrhoea and recurrent pulmonary infections presented with sepsis from right lower extremity cellulitis. Blood cultures grew Morganella morganii Laboratory evaluation revealed lymphopaenia, hypogammaglobulinaemia, a low CD4+ T-cell count and nutritional deficiencies resulting from protein-losing enteropathy (PLE). CT showed small bowel wall thickening in the jejunum and ileum. Primary intestinal lymphangiectasia (PIL) was the likely diagnosis that explained her PLE and immunodeficiencies. Video capsule endoscopy is an important diagnostic tool for distal small bowel pathology and confirmed patchy areas of lymphangiectasia of the jejunum and ileum. Secondary causes of lymphangiectasia were ruled out. Clinically significant immunodeficiency from PIL has not been frequently documented, and this case adds to the literature of rare infections associated with PIL. Treatment with intravenous antibiotics resolved her septicaemia, while dietary modifications improved her oedema, abdominal pain and diarrhoea.

[Type 1 diabetes and autoimmune polyendocrine syndromes]. / Diabetes melito tipo 1 no contexto das poliendocrinopatias auto-imunes.

Type 1 diabetes (T1D) is associated with autoimmune thyroid disease (AIT), celiac disease (CD), Addison's disease (AD), and other autoimmune diseases. These diseases can occur simultaneously in defined syndromes with distinct pathophysiology and characteristics: autoimmune polyendocrine syndromes (APSs) and the immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX). APSs were initially defined as a multiple endocrine gland insufficiency associated to an autoimmune disease in a patient. APS-1 is characterized by the evidence of chronic candidiasis, chronic hypoparathyroidism, AD and T1D could be present as part of this syndrome. The combination of autoimmune adrenal insufficiency with AIT and/or type 1 autoimmune diabetes mellitus defines APS-2. AIT associated to other autoimmune diseases (excluding AD and/or hypoparathyroidism) are the main characteristics of APS-3. Different clinical combinations of autoimmune diseases which were not included in the previous groups are the characteristics of APS-4. IPEX is a recessive disorder characterized by the neonatal onset of T1D, infections, enteropathy, thrombocytopenia and anemia, as well as endocrinopathy, eczema and cachexia. These disorders are not common, but their consequences can be life threatening when the diagnosis is overlooked, and the treatment is the same prescribed for isolated disease presentation.

Immune reconstitution and recovery of FOXP3 (forkhead box P3)-expressing T cells after transplantation for IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome.

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome is a rare X-linked disorder that usually presents in early childhood with immune enteropathy, diabetes mellitus, and other autoimmune complications. The disease is caused by mutations in the forkhead box P3 gene, a transcription factor that is essential for the development and function of regulatory T cells. This population of cells plays an essential role in controlling immune responses and preventing autoimmunity. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome is often initially treated with immunosuppressive drugs, but only allogeneic hematopoietic stem cell transplantation has offered the possibility of cure. We recently performed an unrelated donor transplant in a child with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome by using a reduced-intensity conditioning regimen. This transplant provided a rare opportunity to gain valuable insight into the regeneration of the immune system after transplantation. Clinical recovery was associated with the emergence of regulatory T cell populations, the majority of which expressed memory phenotype markers and raised important questions about the origin and longevity of the FOXP3(+) regulatory T cell pool.

Diabetes melito tipo 1 no contexto das poliendocrinopatias auto-imunes: [revisão] / Type 1 diabetes and autoimmune polyendocrine syndromes: [review]

Três entidades clínicas distintas, causadas por desarranjos genéticos, estão associadas a múltiplas desordens auto-imunes: síndrome linfoproliferativa auto-imune, poliendocrinopatias auto-imunes (APSs) e desregulação imune, poliendocrinopatia, enteropatia ligada ao X (IPEX). O diabetes melito auto-imune ou tipo 1 (DM1) pode estar presente nas APSs e na IPEX. A APS-1 caracteriza-se pela associação de candidíase crônica, hipoparatireoidismo e insuficiência adrenal auto-imune ou idiopática (doença de Addison), no entanto, o diabetes melito tipo 1 pode estar presente em até 12 por cento dos casos. A APS-2 inclui a doença de Addison (sempre presente), a doença tireoidiana auto-imune e o diabetes melito tipo 1, enquanto na APS-3 a doença tireoidiana se associa a outra doença imunológica, excluindo a insuficiência adrenal e o hipoparatireoidismo, e a APS-4 é composta por combinações diferentes das descritas anteriormente. Já a IPEX caracteriza-se por alteração rara da regulação auto-imune que resulta doenças auto-imunes de início precoce, envolvendo pâncreas, tireóide, intestino com diarréia secretora grave, eczema e anemia. O diagnóstico e o tratamento das doenças componentes das poliendocrinopatias e da IPEX são semelhantes ao da patologia na forma isolada.

Type 1 diabetes (T1D) is associated with autoimmune thyroid disease (AIT), celiac disease (CD), Addison's disease (AD), and other autoimmune diseases. These diseases can occur simultaneously in defined syndromes with distinct pathophysiology and characteristics: autoimmune polyendocrine syndromes (APSs) and the immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX). APSs were initially defined as a multiple endocrine gland insufficiency associated to an autoimmune disease in a patient. APS-1 is characterized by the evidence of chronic candidiasis, chronic hypoparathyroidism, AD and T1D could be present as part of this syndrome. The combination of autoimmune adrenal insufficiency with AIT and/or type 1 autoimmune diabetes mellitus defines APS-2. AIT associated to other autoimmune diseases (excluding AD and/or hypoparathyroidism) are the main characteristics of APS-3. Different clinical combinations of autoimmune diseases which were not included in the previous groups are the characteristics of APS-4. IPEX is a recessive disorder characterized by the neonatal onset of T1D, infections, enteropathy, thrombocytopenia and anemia, as well as endocrinopathy, eczema and cachexia. These disorders are not common, but their consequences can be life threatening when the diagnosis is overlooked, and the treatment is the same prescribed for isolated disease presentation.

Eosinophilic gastroenteritis with cytomegalovirus infection in an immunocompetent child.

A 3-year-old boy developed transient protein-losing gastroenteropathy associated with cytomegalovirus (CMV) infection. Both IgG and IgM antibodies to CMV were positive in a serologic blood test. Upper gastrointestinal endoscopy showed multiple erosions throughout the body of the stomach, without enlarged gastric folds. Histological examination of the biopsy specimens indicated eosinophilic gastroenteritis and CMV infection. The patient had complete resolution without specific therapy for CMV in four weeks. An allergic reaction as well as CMV infection played important roles in the pathogenesis of this case.

Cows milk protein enteropathy and granulomatous duodenitis in a newborn.

Cow's milk protein enteropathy is a symptom complex that composed of severe diarrhoea and malnutrition. This disorder is caused by non-immunoglobulin E-mediated food allergy. Its clinical features and natural course have been explained in many reports, of different types of cow's milk and soy reactions. In the present article, we describe a newborn patient who presented with chronic diarrhoea and failure to thrive diagnosed as cow's milk protein enteropathy. The duodenal biopsy revealed granulomatous duodenitis which has not been described before. Her clinical and pathological findings responded well to cow's milk elimination. We suggest that food allergies should be considered in differential diagnosis of patients with chronic diarrhoea and failure to thrive.

Mechanistic associations of a mild phenotype of immunodysregulation, polyendocrinopathy, enteropathy, x-linked syndrome.

BACKGROUND & AIMS: The syndrome of immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) is a rare disorder resulting in the expression of multiple autoimmune and allergic features. Early onset enteropathy and type 1 diabetes (T1D) are the most common clinical features. The IPEX syndrome is caused by mutations of the FOXP3 gene, which is essential for the development of regulatory T cells (Treg). We describe 2 unrelated patients with IPEX syndrome with a mild clinical phenotype and with novel FOXP3 mutations and the phenotypic and functional characterization of their Treg cells. METHODS: The FOXP3 gene was analyzed by sequencing amplimers from genomic DNA. Treg cells were characterized by evaluating the number of CD4+CD25+ T cells and their functional ability to suppress the proliferation of autologous CD4+CD25- effector T cells stimulated with anti-CD3 and anti-CD28 antibodies. RESULTS: A 7-year-old boy and a 24-year-old man presented with autoimmune enteropathy characterized by early onset persistent diarrhea not associated with T1D or other endocrinopathies. These 2 patients carry novel FOXP3 mutations that do not abrogate the function of the forkhead domain. They have normal numbers of CD4+CD25+ T lymphocytes, however, these show severely defective suppressive function in vitro. CONCLUSIONS: Our 2 patients show that IPEX patients may present with early onset enteropathy and long-term survival without T1D or other endocrinopathies. This milder phenotype may be associated with FOXP3 mutations that do not abrogate the function of the forkhead domain.

Successful long-term treatment with cyclosporin A in protein losing gastroenteropathy.

Protein-losing gastroenteropathy (PLG) can occur as a manifestation of various diseases including autoimmune disorders, and optimal therapy of these underlying diseases may be the only effective remedy for PLG. In the present report, we describe a case of a 54-year-old woman with PLG associated with an autoimmune disease, presumably CREST syndrome. She failed to respond to steroid treatment. Subsequently, cyclosporine was initiated, which resulted in a rapid recovery. The patient was successfully treated with low-dose cyclosporine for five years. There has not been, to our knowledge, any report of PLG successfully treated with cyclosporine. Cyclosporine therapy may be effective not only in inducing but also in maintaining complete remission in patients with autoimmune-associated PLG, especially refractory or intolerable to steroids and/or immunosuppressive therapies.

Protein-losing enteropathy in patients with Fontan circulation: is it triggered by infection?

INTRODUCTION: Protein-losing enteropathy (PLE) is a recognised complication of the Fontan circulation. Its pathogenesis is not fully understood, however, and it is unclear why its onset occurs months or even years after Fontan surgery. PATIENTS: We report a 4.5-year-old girl with Fontan circulation who developed PLE almost 1 year after surgery. At the time of onset the patient had rotavirus enteritis and streptococcal tonsillitis. We have reviewed the records of seven other patients with longstanding PLE. In six of these patients we identified infections at the onset of symptoms. None of our patients had evidence of opportunistic infection. DISCUSSION AND CONCLUSION: The immune system of patients with PLE is compromised, but reports on recurrent opportunistic infections are rare. The present observations suggest that infection and inflammation may be associated with the onset of PLE. The mechanism of how infection may trigger PLE warrants further investigation.

Protein-losing enteropathy after fontan surgery: is assessment of risk patients with immunological data possible?

BACKGROUND: Protein-losing enteropathy (PLE) is a late complication of the Fontan type surgery for univentricular heart characterized by massive enteric protein loss. The pathogenesis of PLE is not fully understood, and it is unclear why the onset of PLE varies widely and occurs months or even years after surgery. Besides characteristic laboratory findings, a typical cellular feature concerns the almost selective loss of CD4(+) lymphocytes at an only slightly changed CD8(+) lymphocyte count. The present pilot study aimed to test whether immunological or laboratory parameters differ in patients at risk for PLE. METHODS: From children (n = 15) with Fontan type circulation, extensive cellular, humoral, and clinical laboratory data were analyzed. Patients without enteric protein loss (group I, n = 8), with transient phases of enteric protein loss in the absence of gastric infections (group II, n = 6), and one PLE patient (group III) were distinguished. The 90 data columns obtained in phases with normal serum protein levels were compared. RESULTS: Clear differences were apparent between patients prior to PLE onset (group III), patients that in at least one occasion exhibited PLE signs (group II), and patients without detectable PLE signs (group I). The most discriminatory parameters between the three patient groups were NK and CD8(+)TCRalphabeta(+), CD8(+)TCRgammadelta(+) cell counts, including sL-selectin, IgE, and Ca(2+) (average recognition index = 91.5%, negative/positive prediction/sensitivity/specificity > 83%). CONCLUSIONS: The results of this study seem to provide access to the early detection of PLE patients.

Clinical and molecular features of the immunodysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome.

Immunodysregulation, polyendocrinopathy, enteropathy, X linked (IPEX, OMIM 304790) is a rare, recessive disorder resulting in aggressive autoimmunity and early death. Mutations in FOXP3 have been identified in 13 of 14 patients tested. Research in the mouse model, scurfy, suggests that autoimmunity may stem from a lack of working regulatory T cells. We review published reports regarding the genetics, clinical features, immunology, pathology, and treatment of IPEX. We also report three new patients who were treated with long term immunosuppression, followed by bone marrow transplantation in two. IPEX can be differentiated from other genetic immune disorders by its genetics, clinical presentation, characteristic pattern of pathology, and, except for high IgE, absence of substantial laboratory evidence of immunodeficiency. While chronic treatment with immunosuppressive drugs may provide temporary benefit for some patients, it does not cause complete remission. Remission has been observed with bone marrow transplantation despite incomplete engraftment, but the long term outcome is uncertain.

Immunologic profile of patients with protein-losing enteropathy complicating congenital heart disease.

The immunologic profile of patients with congenital heart disease complicated by protein-losing enteropathy (PLE) is undefined. The aim of this study was to assess the lymphocyte subpopulation and immunglobulin (Ig) pattern in patients with PLE complicating congenital heart disease. The immunologic profile of six patients with congenital heart disease complicated by PLE was compared to that of controls without PLE matched for age and cardiac interventions. Enteric protein loss was documented by Tc99m-labeled albumin scintigraphy. The lymphocyte subpopulations were enumerated using flow cytometry, whereas serum IgG, IgA, and IgM concentrations were measured by the turbidimetric technique. The cardiac diagnoses included complex cyanotic heart disease post-Fontan procedure (n = 3), and one each of tetralogy of Fallot, restrictive cardiomyopathy, and valvar pulmonary stenosis. In patients with PLE, the T lymphocyte (CD3+) count was significantly lower (300 +/- 186 vs 2070 +/- 1171/microl, p = 0.017); both the helper/inducer lymphocytes (CD4+) (127 +/- 158 vs 927+/- 377/microl, p = 0.006) and suppressor/cytotoxic lymphocytes (CD8+) (129 +/- 49 vs 850 +/- 695/microl, p = 0.057) reduced with reversal of CD4(+)/CD8(+) ratio (0.81 +/- 0.68 1.64 +/- 0.89, p = 0.027). Furthermore, IgG level was significantly reduced (5.12 +/- 2.84 vs 12.5 +/- 1.58 g/L, p = 0.005) and IgA level tended to be lower (1.36 +/- 1.37 vs 2.50 +/- 0.80 g/L, p = 0.095). In contrast, the B lymphocyte (CD19+) count (340 +/- 151 vs 618 +/- 427/microl, p = 0.25), natural killer cell count (CD16(+) 56(+) CD3(-)) (252 +/- 212 vs 276 +/- 251/microl, p = 0.85), and IgM level (0.98 +/- 0.59 vs 1.12 +/- 0.25 g/L, p = 0.67) were similar for both groups. None of the patients developed opportunistic or severe viral infections. Abnormal immunologic profile of both the cellular and humoral arms of the immune system occurs in patients with congenital heart disease complicated by PLE. Nonetheless, these abnormalities perhaps appear quantitative rather than qualitative in nature, although further functional studies of antibody production and lymphocyte proliferation assays are required to support this proposition.

Use of whole-gut lavage to measure intestinal immunity in healthy Sierra Leonean children.

In view of the potential roles of intestinal immunodeficiency and hypersensitivity in the infection/diarrhea/malnutrition cycle, we need a safe and ethical method to study intestinal immunity of children in the developing world. Work in adults has shown that the fluid obtained by whole-gut lavage (WGLF), essentially a gut perfusate, can be used to assess intestinal immunity, inflammation, and gut losses of protein and blood. Gut lavage was successfully performed in 24 of 25 "normal" children aged 6-9 years, from Freetown, Sierra Leone, with parental informed consent. WGLF was treated with protease inhibitors, stored at -20 degrees C, and transferred to Edinburgh for laboratory studies. These showed that no child had occult blood loss but four had evidence of protein-losing enteropathy. Compared with values for Scottish adults, WGLF from the Sierra Leonean children had significantly higher concentrations of IgA and IgM and of IgA and IgM antibodies to dietary antigens and to Salmonella typhi lipopolysaccharide. In three children, very low levels of IgA and IgA antibody were present: Two of these were the only cases with detectable sIL2R in lavage fluid, indirect evidence of intestinal T cell activation; tumor necrosis factor was not detectable. Substantial information on childrens' intestinal immunity can be obtained by the method described.

Mixed connective tissue disease associated with protein losing enteropathy: successful treatment with intravenous cyclophosphamide therapy.

A patient with mixed connective tissue disease who developed protein losing enteropathy (PLE) is described. The PLE and other symptoms improved dramatically after monthly intravenous administration of 700 mg/day cyclophosphamide three times combined with oral prednisolone, while they were ineffective to the treatment with intravenous methyl-prednisolone 500 mg per day for 3 days. The serum level of CA125 antigen paralleled the severity of symptoms, signs and laboratory data associated with PLE. Thus, pleural effusion, ascites, edema and hypoalbuminemia improved along with the decrease in the level of CA125, suggesting that CA125 might be a marker of the activity of PLE.

Cellular immunodeficiency in protein-losing enteropathy. Predominant reduction of CD3+ and CD4+ lymphocytes.

Cellular immunological abnormalities were studied in a patient with protein-losing enteropathy associated with constrictive pericarditis. Analysis of lymphocyte subpopulations in peripheral blood showed lymphopenia with a decrease of CD3+ and CD4+ T cells, whereas CD8+ lymphocytes, B cells and NK cells were within the normal range. Fecal loss of lymphocytes as a cause of lymphopenia was evidenced by a marked excretion of 111-indium-labeled peripheral blood mononuclear cells via stool. Proliferative responses against several mitogens were severely reduced as was in vitro IgG production. Delayed-type hypersensitivity reaction against a variety of antigens was absent. Vaccination with tick-borne encephalitis virus, used for primary immunization, and with the recall antigen tetanus toxoid resulted in a blunted antibody response. After pericardectomy, the severity of enteric protein loss declined, serum immunoglobulin levels returned to the normal range, and total lymphocytes and CD3+ and CD4+ counts increased but remained low even 12 months after surgery. Fecal loss of lymphocytes was found to be reduced after pericardectomy, but was higher than that seen in a disease control patient with active inflammatory bowel disease. In vitro immunoglobulin production returned to normal, DTH could be demonstrated against purified protein derivative and proteus antigen, but mitogen-driven blastogenic response of lymphocytes remained low. Revaccination with tick-borne encephalitis and tetanus toxoid antigens seven months after surgery resulted in a dramatic increase of serum levels of antibodies against both antigens, comparable to that seen in healthy control individuals.(ABSTRACT TRUNCATED AT 250 WORDS)

Protein-losing enteropathy in systemic lupus erythematosus.

Two patients with systemic lupus erythematosus (SLE) presented with anasarca, pleural effusions and severe hypoalbuminema. Both were demonstrated to have protein-losing enteropathy, a rare complication of SLE. Other causes of gastrointestinal protein loss were excluded. There were marked similarities in both cases including circulating ANF with speckled staining, anti-(U1)RNP antibodies and low serum complement levels. Complete remission was achieved in both with prednisolone. Anti-(U1)RNP may be a marker for a subset of SLE in which protein-losing enteropathy is a major manifestation.

The Cronkhite-Canada syndrome with focus on immunity and infection. Report of a case.

A 64-year-old man developed diffuse gastrointestinal polyposis, protein-losing enteropathy, skin pigmentation, hair loss, and unique nail changes. He also exhibited pulmonary tuberculosis and impaired immunity with skin anergy, poor lymphocyte mitogens stimulation test, and low serum immunoglobulin. We discuss the relationship of infection, nutrition, immunity, and the Cronkhite-Canada syndrome.

[Severe malabsorption syndrome and exudative enteropathy in hypogammaglobulinemia: complete involution with intravenous immunoglobulin substitution]. / Schweres Malabsorptionssyndrom und exsudative Enteropathie bei Hypogammaglobulinämie: Völlige Rückbildung unter intravenöser Immunglobulin-Substitution.

A 35 year old woman with primary hypogammaglobulinaemia developed intestinal villous atrophy, a severe malabsorption syndrome, osteomalacia and protein-losing enteropathy. The syndrome did not respond to treatment with antibiotics, vitamins, or gluten free diet. Regular intravenous administration of a native immunoglobulin preparation induced continuous elevation of IgG serum levels above 240 mg/dl. This led to rapid, complete and persistent normalisation of all clinical symptoms and pathologic findings. Additional therapy was not required. Side effects of the treatment that has now been maintained for 48 months were not observed.