Chronic intestinal pseudo-obstruction (CIP) is characterized by recurrent intestinal obstruction without any mechanical obstruction (1). The management is mainly supportive and the majority require total parenteral nutrition (TPN) support. Central venous lines (CVL) sepsis and, rarely, hemophagocytic lymphohistiocytosis (HLH) are reported with TPN use. HLH is characterized by fever, splenomegaly, and hemophagocytosis in bone marrow and other tissues (2). HLH in children with CIP and TPN has rarely been reported. We report 2 children with CIP who were receiving home TPN and presented with a febrile illness, which progressed to secondary HLH, also known as macrophage activation syndrome.
A 12-year-old girl with CIP receiving home TPN for 2 years presented with fever and hematemesis. She was receiving 7.2 g/kg carbohydrates, 1.8 g/kg amino acids, and 3.1 g/kg lipids. Antibiotics were started for presumed CVL infection after obtaining blood cultures that grew no pathogens. Fever persisted and she developed pancytopenia and coagulopathy. This was attributed to sepsis. Because her condition worsened in spite of antibiotics, other laboratory tests were ordered, which were significant for elevated serum ferritin and triglycerides and low fibrinogen. HLH was considered, and bone marrow (BM) biopsy showed hemophagocytosis consistent with HLH. Immune evaluation and flow cytometry were normal. Because lipids have been reported to trigger HLH, the lipid infusion was discontinued and she was managed conservatively and her condition improved. She was discharged while receiving TPN without lipid and started on oral essential fatty acid (EFA) supplementation. She has had no further episodes of HLH after 3 years of follow-up.
A 7-year-old boy with CIP receiving home TPN for 3 years presented with fever and axillary lymphadenopathy. He was receiving 9.9 g/kg of carbohydrates, 2 g/kg of amino acids, and 3.2 g/kg of lipids. He was treated with meropenem and gentamicin for pseudomonas CVL sepsis 2 weeks earlier. Blood cultures and viral studies were negative. His fever persisted and he developed multiorgan dysfunction. His serum ferritin and triglycerides were elevated. BM biopsy showed hemophagocytosis consistent with HLH. Immune evaluation was normal. Because of the severity of the condition and the development of multiorgan dysfunction, he was treated with corticosteroids, etoposide, intravenous immunoglobulin, and cyclosporine for 4 weeks with a corticosteroid taper. After a prolonged hospital stay for multiple complications, he was discharged while receiving TPN without lipid and oral EFA. He remained well after 3 years of follow-up.
The typical presentation of HLH includes persistent fever and splenomegaly, often in the setting of an acute infection; however, in some children, the initial presentation is atypical and characteristic findings may be absent. It is therefore important for the clinician to consider the diagnosis of HLH, even if the early presentation is atypical because mortality is high without appropriate treatment. The HLH study group proposed diagnostic guidelines (Table 1) (3). Establishing HLH diagnosis in children with CIP is further complicated by the fact that some of the features associated with HLH are commonly seen with CVL sepsis.
HLH can be seen as part of primary lymphohistiocytosis (genetic mutations) or secondary to infections, malignancy, and autoimmune disease. The distinction between primary and secondary HLH is not always possible because the triggers for both forms can occur with viral infection. The pathophysiology of HLH is unclear, but it appears to involve persistent stimulation of immune response. In primary HLH, genetic defects in the cytotoxic granulocyte pathway result in failure to clear the antigen, leading to persistent stimulation of CD8 cytotoxic lymphocytes, interferon-γ, macrophages, and natural killer cells. This results in excessive amounts of cytokine production, BM infiltration, and organ dysfunction characteristic of HLH. Grossman et al (4) proposed another model wherein expanded immune cytotoxic system failed to contract after effective clearance of antigen as shown in Jak3-deficient mice.
We describe 2 patients with HLH features, as shown in Table 2. Extensive evaluations for immune and infectious etiology were negative. It is unclear whether the occurrence of a rare disorder such as HLH in children with CIP represents a chance occurrence or a potential risk of HLH in this patient population. Possible causes for HLH in our patients include lipid infusion, chronic bacterial overgrowth, unidentified mitochondrial or genetic defect, and an unknown viral pathogen, all of which may alter immune function. Previous reports suggest an association of TPN with lipids and HLH. There are case reports of “fat overload syndrome” and recommended withdrawal with gradual reintroduction of lipids at a lower dosage (5,6). Goulet et al (7) reported clinical, hematologic, and immunologic abnormalities in 7 children following prolonged use of intravenous fat emulsion. The macrophage system was hyperactive in this group of patients and was thought to be related to intravenous fat emulsion in TPN. They recommended reducing the lipid infusion during acute illness. It is interesting to note that many of the features reported in their patients resemble HLH. This raises the question of the role of lipid infusion in children receiving TPN in inducing HLH-like illness. It is possible that the lipids combined with an infectious etiology caused these episodes to be triggered and present so significant clinically because lipids have been shown to activate monocyte and can cause coagulopathy in sick children (8).
We decided to reduce the lipids to <1 g · kg−1 · day−1 and the patients were given EFA. The authors acknowledge that there is no convincing evidence that this strategy was clinically effective in prevention of reoccurrence of HLH in our patients; however, reduction of lipid infusion and monitoring of laboratory tests, including ferritin during systemic infection, should be considered in patients who do not follow the expected clinical course. On the basis of our 2 cases, HLH may occur in patients receiving TPN. Because HLH can mimic line sepsis in children receiving TPN, it should be considered in the differential diagnosis in patients with negative workup and persistent fever. Increased awareness and a high index of suspicion of HLH in patients not responding to CVL infection treatment may help decrease delay in diagnosis because prompt intervention prevents irreversible end-organ damage, mortality, and recurrence of secondary HLH.
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8. Dahlstrom KA, Goulet OJ, Roberts RL, et al. Lipid tolerance in children receiving long-term parenteral nutrition: a biochemical and immunologic study. J Pediatr