Food Protein-Induced Enterocolitis Syndrome Food Challenges: Experience from a Large Referral Center.

BACKGROUND: Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy that is diagnosed based on clinical findings, but can be confirmed with oral food challenge (OFC). OFC is more often performed to assess the development of tolerance. Most studies describing OFCs in FPIES are limited in size. OBJECTIVE: We sought to describe our experience with OFCs using our FPIES protocol. Patients were given one-third of serving size with a 4-hour observation period, followed by home titration to full dose. METHODS: We conducted a retrospective chart review of patients who underwent OFC via the FPIES protocol from 2014 to 2017. Data regarding the history of reaction, age at the time of challenge, and reactions during challenge or with home introduction were collected. RESULTS: A total of 169 OFCs were completed under the FPIES protocol, in 119 patients to 19 different foods. Thirty challenges (18%) were positive, with 17 challenges (10%) during initial challenge and 13 (7.7%) during home dosing. Most reactions during initial challenge required intravenous fluids (IVF), but hypotension was uncommon. One hundred thirty-nine (82%) OFCs were negative with home introduction, indicating tolerance to the challenged foods. The mean age of passing a challenge to milk, soy, and grain was earlier than that of other solid foods. CONCLUSIONS: Our data suggest that our FPIES OFC protocol is safe. Early administration of IVF may prevent the development of hypotension. It is difficult to stratify the risk of severe or delayed reaction based on patient characteristics, and more data are needed to identify those appropriate for home introduction.

Differences in egg and milk food challenge outcomes based on tolerance to the baked form.

BACKGROUND: Previous studies suggest inclusion of baked egg and milk in the diet of children with egg or cow's milk (CM) allergy might positively affect native tolerance. However, differences in native food reactivity based on historical baked tolerance are not fully understood. OBJECTIVE: To assess differences in native egg and CM oral food challenge (OFC) outcomes based on presenting history of tolerance and exposure to these foods in the baked form. METHODS: This study is a retrospective review of all egg and CM OFCs at the Children's Hospital of Philadelphia (Philadelphia, Pennsylvania) over 4 years (N = 580). History of baked ingestion was compared with OFC pass rate, eliciting dose, epinephrine use, reaction classification, and recent skin test reaction or specific immunoglobulin E level. RESULTS: There were 115 egg- and 70 CM-positive challenge reactions, with most eliciting anaphylaxis. Children tolerating baked egg passed OFC more frequently (75%) compared with children who avoided baked egg (58%; P = .01) or never ingested egg (45%; P < .0001). For positive reactions, children tolerant of baked egg reacted at higher eliciting doses of native egg (median 3.0 g, range 0.125-15.75 g) compared with those avoiding baked egg (median 0.69 g, range 0.13-10.0 g; P = .03) and those with no egg exposure (median 0.88 g, range 0.13-13.88 g; P = .01). Further, epinephrine use was lower in children tolerating baked egg (10%) compared with children avoiding baked egg (22%; P = .02) and compared with children who never ingested egg (32%; P = .0001). These differences were not observed for CM challenges. CONCLUSION: Children who historically tolerated baked egg were less sensitive to native egg during OFC compared with children whose baked reactivity was largely unknown.

Oral food challenge to wheat: a near-fatal anaphylaxis and review of 93 food challenges in children.

BACKGROUND: Wheat allergy is among the most common food allergy in children, but few publications are available assessing the risk of anaphylaxis due to wheat. METHODS: In this study, we report the case of near-fatal anaphylaxis to wheat in a patient undergoing an oral food challenge (OFC) after the ingestion of a low dose (256 mg) of wheat. Moreover, for the first time, we analyzed the risk of anaphylaxis during an OFC to wheat in 93 children, compared to other more commonly challenged foods such as milk, egg, peanuts, and soy in more than 1000 patients. RESULTS: This study, which includes a large number of OFCs to wheat, shows that wheat is an independent risk factor that is associated with anaphylaxis requiring epinephrine administration (Odds Ratio [OR] = 2.4) and anaphylaxis requiring epinephrine administration to low dose antigen (OR = 8.02). Other risk factors for anaphylaxis, anaphylaxis requiring epinephrine administration, and anaphylaxis to low dose antigen was a history of a prior reaction not involving only the skin (OR = 1.8, 1.9 and 1.8 respectively). None of the clinical variables available prior to performing the OFC could predict which children among those undergoing OFCs to wheat would develop anaphylaxis or anaphylaxis for low dose antigen. CONCLUSION: This study shows that wheat is an independent risk factor that is associated with anaphylaxis requiring epinephrine administration and anaphylaxis requiring epinephrine administration to low dose antigen.

Diagnosis of 22q11.2 deletion syndrome and artemis deficiency in two children with T-B-NK+ immunodeficiency.

Two infants are described who presented with 22q11.2 deletion and a T(-)B(-)NK(+) immune phenotype. For both infants, the initial diagnosis was athymia secondary to complete DiGeorge anomaly. The first infant underwent thymus transplantation but 6 months after transplantation had circulating thymus donor T cells; the patient did not develop recipient naïve T cells. Genetic analyses revealed that both patients had Artemis deficiency, a rare form of severe combined immunodeficiency (SCID). Both infants have subsequently undergone bone marrow transplantation. These cases illustrate the importance and paradox of differentiating SCID from complete DiGeorge anomaly because hematopoietic stem cell transplantation (HSCT) is the preferred treatment for SCID but is ineffective for complete DiGeorge anomaly. However, if the thymus is completely absent, donor stem cells from a HSCT would not be able to be educated.

Clinical conditions associated with PCP in children.

Pneumocystis jirovecii is a leading cause of opportunistic infections among the immune compromised. During the 1980s, attention focused on patients with HIV, however, with the advent of anti-retroviral therapy, we wished to revisit the question of underlying diseases associated with Pneumocystis pneumonia in children. We identified 80 cases from 1986 to 2006 and performed a retrospective chart review to identify clinical characteristics for each of the cases. HIV was the single most common associated underlying condition seen in this cohort, accounting for 39% of the cases overall, however, it was seen in just 15% of the cases since 1998. Transplant recipients and oncology patients together comprised another 39% of the cases, with 9% of cases attributed to primary immune deficiency and another 9% of cases associated with less well-recognized causes of susceptibility. This study documents the ongoing need for vigilance to diagnose Pneumocystis pneumonia in less well-recognized clinical scenarios.

Congenital alterations of NEMO glutamic acid 223 result in hypohidrotic ectodermal dysplasia and immunodeficiency with normal serum IgG levels.

BACKGROUND: Hypomorphic mutations in the nuclear factor-κB (NF-κB) essential modulator (NEMO) gene result in a variable syndrome of somatic and immunologic abnormalities. Clinically relevant genotype-phenotype associations are essential to understanding this complex disease. OBJECTIVE: To study 2 unrelated boys with novel NEMO mutations altering codon 223 for similarity in phenotype in consideration of potential genotype-phenotype associations. METHODS: Clinical and laboratory features, including cell counts, immunoglobulin quantity and quality, natural killer cell cytotoxicity, and Toll-like and tumor necrosis factor receptor signaling, were evaluated. Because both mutations affected NEMO codon 223 and were novel, consideration was given to new potential genotype-phenotype associations. RESULTS: Both patients were diagnosed as having hypohidrotic ectodermal dysplasia and had severe or recurrent infections. One had recurrent sinopulmonary infections and the other necrotizing soft tissue methicillin-resistant Staphylococcus aureus infection and Streptococcus anginosus subdural empyema with bacteremia. NEMO gene sequence demonstrated a 3-nucleotide deletion (c.667_669delGAG) in one patient and a substitution (667G>A) in the other. These findings predict either the deletion of NEMO glutamic acid 223 or it being replaced with lysine, respectively. Both patients had normal serum IgG levels but poor specific antibodies. Natural killer cell cytotoxicity and Toll-like and tumor necrosis factor receptor signaling were also impaired. Serious bacterial infection did not occur in both patients after immunoglobulin replacement therapy. CONCLUSIONS: Two different novel mutations affecting NEMO glutamic acid 223 resulted in clinically relevant similar phenotypes, providing further evidence to support genotype-phenotype correlations in this disease. They suggest NEMO residue 223 is required for ectodermal development and immunity and is apparently dispensable for quantitative IgG production but may be required for specific antibody production.

Invariant natural killer T cells from children with versus without food allergy exhibit differential responsiveness to milk-derived sphingomyelin.

BACKGROUND: A key immunologic feature of food allergy (FA) is the presence of a T(h)2-type cytokine bias. Ligation of the invariant natural killer T cell (iNKT) T-cell receptor (TCR) by sphingolipids presented via the CD1d molecule leads to copious secretion of T(h)2-type cytokines. Major food allergens (eg, milk, egg) are the richest dietary source of sphingolipids (food-derived sphingolipids [food-SLs]). Nonetheless, the role of iNKTs in FA is unknown. OBJECTIVE: To investigate the role of iNKTs in FA and to assess whether food-SL-CD1d complexes can engage the iNKT-TCR and induce iNKT functions. METHODS: PBMCs from 15 children with cow's milk allergy (MA), 12 children tolerant to cow's milk but with allergy to egg, and 13 healthy controls were incubated with α-galactosylceramide (αGal), cow's milk-sphingomyelin, or hen's egg-ceramide. iNKTs were quantified, and their cytokine production and proliferation were assessed. Human CD1d tetramers loaded with milk-sphingomyelin or egg-ceramide were used to determine food-SL binding to the iNKT-TCR. RESULTS: Milk-sphingomyelin, but not egg-ceramide, can engage the iNKT-TCR and induce iNKT proliferation and T(h)2-type cytokine secretion. Children with FA, especially those with MA, had significantly fewer peripheral blood iNKTs and their iNKTs exhibited a greater T(h)2 response to αGal and milk-sphingomyelin than iNKTs of healthy controls. CONCLUSION: iNKTs from children with FA, especially those with MA, are reduced in number and exhibit a T(h)2 bias in response to αGal and milk-sphingomyelin. These data suggest a potential role for iNKTs in FA.

IL-2 induces a WAVE2-dependent pathway for actin reorganization that enables WASp-independent human NK cell function.

Wiskott-Aldrich syndrome (WAS) is a primary immunodeficiency associated with an increased susceptibility to herpesvirus infection and hematologic malignancy as well as a deficiency of NK cell function. It is caused by defective WAS protein (WASp). WASp facilitates filamentous actin (F-actin) branching and is required for F-actin accumulation at the NK cell immunological synapse and NK cell cytotoxicity ex vivo. Importantly, the function of WASp-deficient NK cells can be restored in vitro after exposure to IL-2, but the mechanisms underlying this remain unknown. Using a WASp inhibitor as well as cells from patients with WAS, we have defined a direct effect of IL-2 signaling upon F-actin that is independent of WASp function. We found that IL-2 treatment of a patient with WAS enhanced the cytotoxicity of their NK cells and the F-actin content at the immunological synapses formed by their NK cells. IL-2 stimulation of NK cells in vitro activated the WASp homolog WAVE2, which was required for inducing WASp-independent NK cell function, but not for baseline activity. Thus, WAVE2 and WASp define parallel pathways to F-actin reorganization and function in human NK cells; although WAVE2 was not required for NK cell innate function, it was accessible through adaptive immunity via IL-2. These results demonstrate how overlapping cytoskeletal activities can utilize immunologically distinct pathways to achieve synonymous immune function.