Recurrent and Opportunistic Infections in Children With Primary Intestinal Lymphangiectasia

Abstract

INTRODUCTION Intestinal lymphangiectasia (IL) is a congenital, acquired or inherited disorder of the lymphatic vessels associated with protein-losing enteropathy. The characteristic morphological lesions of IL are dilated lymphatic channels in the small intestinal mucosa. Because of stasis and, eventually, rupture, lymph leaks into the gastrointestinal tract, which in turn leads to hypoalbuminemia, lymphocytopenia and decreased levels of serum immunoglobulins (1). As a result, this disorder is sometimes associated with humoral and cellular immune deficiencies, while immunoglobulin synthesis rate remains normal (2–4). The major clinical symptoms are edema, diarrhea, and, in some patients, chylous effusions. Only one series of 6 patients have been described so far (5). Although immunoglobulin levels and lymphocyte counts are low, no association with recurrent or opportunistic infections have been described in this secondary immunodeficiency, except for one case report of an adult with a group G streptococcal empyema (6). In this article, we describe a series of 7 patients with IL and the association between the immunologic status and recurrent/opportunistic infections. PATIENTS AND METHODS In this retrospective case analysis, we included children with IL who have been admitted in our clinic between 1984 and 2004. In these cases, the following characteristics were analyzed: history, physical examination, growth and laboratory testing, which includes plasma protein levels, electrolytes, immunologic measurements (lymphocyte phenotyping and immunoglobulin levels) and fecal α-1-antitrypsin. In addition, endoscopy with biopsies, lymphangiography or magnetic resonance imaging was performed to confirm the diagnosis. Patients with secondary IL due to renal or hepatic disorders, inflammatory bowel disease, malignancies, constrictive pericarditis or cardiac surgery (such as the Fontan procedure) were excluded. RESULTS Five girls and 2 boys were included. In all cases, parents were nonconsanguineous. Cardiac ultrasound did not show any obstruction to pulmonary venous flow. In all, renal function was normal throughout the course of the disease. Organomegaly and lymphadenopathy were absent. Treatment of all patients consisted of a low-fat diet, supplemented with medium-chain triglycerides (MCTs), except for patient 6, who received total parenteral nutrition (TPN). MCT diets are commonly used in patients with excessive chylous production. Because MCTs are mainly secreted by enterocytes into the portal venous system, they do not stimulate the intestinal lymphatic flow (7,8). In our patients, the diet was changed according to age. The infants received Monogen, a nutritionally complete whole-whey protein that contains 93% of fats in the form of MCT (9). In older children, the diet was adapted with elimination of long-chain fatty acids and introduction of more medium-chain fatty acids. Three children (patients 1, 2 and 3) with congenital intestinal lymphangiectasia presented with hydrops fetalis, which consisted of generalized edema and severe abdominal distension. Laboratory findings and clinical infections of all patients described below are summarized in Tables 1 and 2. Patient 1 (gestational age, 36 weeks; birth weight, 3.9 kg) had a laparatomy at the age of 11 months, which showed severe dilatation of mesenteric (jejunal) lymph vessels, confirming the diagnosis intestinal lymphangiectasia. Physical examination showed facial anomalies with edema, flat face, flattened nasal bridge and hypertelorism as has been described before in familial nonimmune hydrops fetalis (10,11). Despite the MCT diet, edema and ascites persisted, and several surgical drainages had to be performed. At the age of 5 years, a peritoneal and an intravenous Port-a-Cath were surgically inserted to recirculate the chylous fluid every 3 weeks. Her clinical condition deteriorated, and growth retardation was significant (weight, >P90; length, <P3). At the age of 9 years, she died of respiratory insufficiency due to recurrent Klebsiella pneumoniae infection and severe chylothorax. Patients 2 and 3 were brothers, and the medical history of their mother reports recurrent spontaneous abortions. In patient 2 (gestational age, 29 weeks; birth weight, 2.3 kg), pulmonary hypoplasia, chylothorax and ascites resulted in respiratory insufficiency. The ascites was punctured, and laboratory investigations showed high levels of protein and lipids, suspect for chylous. He died 3 weeks after birth because of an overwhelming sepsis with expanding cardiorespiratory problems. K. pneumoniae was cultured from sputum. Autopsy was performed, and histopathology showed retroperitoneal and mediastinal lymphangiectasia. In patient 3 (gestational age, 32 weeks; birth weight, 3.3 kg), magnetic resonance imaging revealed ascites in the abdomen. However, dilated lymphatic channels could not be detected. No additional investigations were performed. Because his presentation was more or less similar to his brother, it was assumed that intestinal lymphangiectasia would be the cause of his hydrops and ascites. He developed a necrotic enterocolitis of prematurity, which was treated successfully by antibiotics without surgical intervention. He responded well to the MCT-rich diet. No other episodes of protein-losing gastroenteropathy occurred, and he did not experience any remarkable infections. On examination at the age of 1 year, edema had resolved and growth was normal (weight by length, P50).TABLE 1: Laboratory findings of 7 patients with IL at time of diagnosisTABLE 2: Patient's histories of infection and maximum immunoglobulin G and CD4+ levels throughout the whole disease courseThe patients with noncongenital IL all presented with diarrhea and edema, solely or in combination with severe infection. Patient 4 presented at the age of 4 months with frequent, watery, foul-smelling stools and slightly swollen legs. Fever and drowsiness suggested meningitis. This was confirmed by liquor punction, in which Streptococcus pneumoniae was isolated. Despite the successful treatment of the meningitis with penicillin, diarrhea persisted and edema worsened. Fecal α-1-antitrypsin increased up to 53.7 mg/g dry feces, but no abnormalities were seen on upper gastrointestinal endoscopic examination. Nevertheless, she responded well to the MCT-rich diet, as gastrointestinal and immunologic measurements (immunoglobulin levels and lymphocyte subsets) returned to normal. In this period, she had 2 otitis media infections and a urinary tract infection by Escherichia coli. After a year, long-chain triglycerides were successfully added to her diet, and she was dismissed from further follow-up after 1.5 years. On revision 4 years later, she was still in good clinical condition, and laboratory findings were normal. She did not experience any infections. Patient 5 was admitted at the age of 5 months with growth retardation (weight, <P3; length, P10), electrolyte disorders and a very high fecal α-1-antitrypsin. Physical examination revealed a pitting asymmetrical edema of the upper and lower limbs and eyes and abdominal distention with ascites. As in patient 4, the diagnosis could not be confirmed in the intestinal biopsies, although white spots (suggestive of IL) were seen in the proximal duodenum by endoscopy. She responded very well to the MCT diet. Patient 6 presented at the age of 12 years with diarrhea of 4 weeks' duration due to a Cryptosporidium infection. At physical examination, she had periorbital and pretibial edema and hepatomegaly. On upper gastrointestinal endoscopic examination, diffusely scattered white spots were seen in the proximal duodenum. Biopsies showed several dilated lymphatic vessels in the villous apical stroma, consistent with intestinal lymphangiectasia. At present, she is an adult, and her clinical condition is stable, although some laboratory signs are still indicative of IL. Patient 7 presented at the age of 1 year with a history of diarrhea for 3 weeks, tiredness and apathy. Physical examination revealed a pitting asymmetrical edema of the upper and lower limbs and eyes and abdominal distention with ascites. Diagnosis of IL was confirmed by duodenal biopsies as in patient 6. She had recurrent gastroenteritis with Cryptosporidium. Over the last years, the frequency of infections has diminished, but still she has generalized edema for which she is wearing elastic bandages. The last 2 patients appear to be the most severely affected cases alive. They still experience recurrent episodes of crampy abdominal pain and watery foul-smelling diarrhea with a frequency of 6 to 10 stools per day. Regularly, these girls present with tetany in their fingers and feet or wrist (Trousseau sign) due to hypocalciemia. Treatment consists of intravenous administration of albumin and calcium and oral suppletion of minerals and vitamins. Although the MCT diet diminishes the frequency of infections, lymphopenia and hypogammaglobulinemia persist, associated with recurrent opportunistic infections such as Cryptosporidium gastroenteritis. DISCUSSION AND CONCLUSION Although IL is associated with low lymphocyte counts and low immunoglobulin levels, an association with a higher susceptibility to infections has not been described. This, probably because intestinal lymphangiectasia is a rare disease and a rare cause of secondary immunodeficiency. In contrast to the report from Yamamoto (2), we found no selective CD4+ lymphopenia. These authors suggested this might be because of selective gastrointestinal CD4+ T-cell loss. We describe the first known case of congenital lymphedema associated with selective deficit of naive CD4+ T lymphocytes. A high proportion of naive CD4+ T lymphocytes was found in the ascitic fluid, supporting the hypothesis of extravascular sequestration of these cells into lymphedematous tissue. In addition, an infant with congenital lymphoedema and a deficit of naive CD4+ T lymphocyte was reported (12). Here, immunoglobulin levels were normal. The ascites fluid however contained a high proportion of naive CD4+ T lymphocytes, suggesting selective loss of these cells into lymphedematous tissues. No remarkable infections occurred (12). Peripheral expansion must be the mechanism to compensate for the T lymphopenia, most likely driven by infection. Therefore, it is more likely that CD4+ and CD8+ expansion, driven by infections rather than selective T cell loss is the cause of the switch in CD4+/CD8+ ratio in our patients. Measuring T-cell receptor excision cycles in CD4+ and CD8+ subsets could contribute to our understanding of the function of the immune system in the situation of chronic severe loss of antibodies and lymphocytes. In the above-described patients, we found recurrent (and even opportunistic) infections. Clinical presentations and disease courses varied between patients. In cases where intestinal lymphangiectasia could not be confirmed by histological biopsies, other causes of immunodeficiency in combination with edema and ascites were excluded. Most patients responded to an MCT-rich diet; however, although their clinical condition improved, their lymphocyte count and immunoglobulin levels remained low. Mainly, in patients with very low CD4+ counts and immunoglobulin G levels, IL is associated with recurrent and opportunistic infections, leading to a higher morbidity and mortality. Therefore, antimicrobial prophylaxis should be considered in these patients.