Neutrophilia and hyperamylasemia in patients with immediate food allergy.

BACKGROUND: Presently, little is known about the laboratory data several hours after oral food challenge (OFC) in patients with immunoglobulin (Ig)E-mediated immediate food allergy (FA). METHODS: One hundred and twelve subjects who underwent OFC at the present institute between 1 June 2016 and 31 March 2018, were enrolled in this study. Changes in laboratory data several hours after OFC were examined. RESULTS: OFC was positive in 76 patients and negative in 36. Increase in absolute neutrophil count (ANC) was significantly higher in OFC-positive than in OFC-negative subjects (median, 2,306/µL vs 637/µL; P < 0.00001). On multivariate regression analysis, a significant correlation was seen between neutrophilia and the development of gastrointestinal symptoms (t = 3.63; P < 0.001). Serum interleukin-6 increased in 43.8% of the patients with marked neutrophilia and had a significant positive correlation with ANC (r = 0.64; P < 0.001). Serum amylase increased in 33.3% of the OFC-positive patients and was >100 U/L (median, 642 U/L) in five patients in whom serum lipase also increased markedly (1,197 U/L). There was a significant negative correlation between increase in serum amylase and decrease in absolute eosinophil count (r = -0.36, P < 0.01). CONCLUSIONS: Marked neutrophilia was seen after OFC in patients with immediate FA presenting gastrointestinal symptoms, which may provide an insight into the relationship between symptoms and laboratory data. A considerable increase in serum amylase after OFC was also seen in patients with immediate FA, suggesting that the pancreas is a target organ for immediate FA.

Increased serum cortisol on oral food challenge in infants with food protein-induced enterocolitis syndrome.

BACKGROUND: An increase in absolute neutrophil count (ANC) is seen after oral food challenge test (OFC) in patients with food protein-induced enterocolitis syndrome (FPIES). Although it has been suggested that interleukin (IL)-8 is involved in this phenomenon, a possible role for cortisol has not yet been studied. METHODS: Six positive OFC in five patients with FPIES due to cows' milk (CM) proteins, and two negative OFC in two patients with suspected FPIES were analyzed. Absolute neutrophil count, serum IL-8, and serum cortisol were measured before OFC, 6 and 24 h after the ingestion of CM formula. RESULTS: For the positive OFC, ANC measured 6 h after the ingestion of CM formula was significantly higher than that measured before the OFC (median, 8,761 versus 2,297/µL; P < 0.05). Significant increases in serum cortisol and IL-8 were observed 6 h after OFC (cortisol, median 1,119 pg/mL before versus 2,141 pg/mL after, P < 0.05; IL-8, median 15.5 pg/mL before versus 165.3 pg/mL after, P < 0.05). The change ratio (i.e. ratio of that after OFC to that before OFC) of ANC was significantly correlated not only with that of serum IL-8 (r = 0.90, P < 0.01) but also with that of serum cortisol (r = 0.76, P < 0.05). Moreover, the serum cortisol change ratio was significantly higher in subjects with vomiting than in those without (median, 2.5 versus 1.0, P < 0.05). CONCLUSIONS: Serum cortisol, in combination with IL-8, affects the increase in ANC after OFC.

Prognosis of infantile food protein-induced enterocolitis syndrome in Japan.

BACKGROUND: Although serum C-reactive protein (CRP) and the percentage of eosinophils in peripheral blood (Eo) are increased at onset in infants with food protein-induced enterocolitis syndrome (FPIES), the relationship of these laboratory findings to prognosis is presently unknown. METHODS: Correlation of serum CRP and Eo at onset with prognosis was analyzed in 32 patients with FPIES caused by cow's milk (CM). RESULTS: The rate of tolerance acquisition was 18.8%, 56.3%, 87.5%, and 96.9% at the ages of 6, 12, 24, and 36 months, respectively. Serum CRP increased in 50% of subjects at onset (median, 0.21 mg/dL; range, <0.20-18.2 mg/dL) and Eo was elevated in 71.9% of subjects at onset (median, 7.1%; range, 1.0-50.5%). Age at tolerance acquisition was significantly positively correlated with serum CRP at onset (r = 0.45, P < 0.01), and significantly negatively correlated with Eo at onset (r = -0.36, P < 0.05). Although CM-specific immunoglobulin E antibody (sIgE) was positive in nine of 32 FPIES patients at onset (median, 0.93; range, 0.38-18.9 kU/L), it decreased thereafter. CM-sIgE at onset did not correlate significantly with prognosis (r = 0.22, P > 0.05). CONCLUSIONS: Serum CRP is not only an indicator of the activity of intestinal inflammation, it is also a useful parameter of poor prognosis in FPIES. In contrast, eosinophilia at onset could be used as a marker of good prognosis, suggesting that it has some beneficial effects in the pathophysiology of FPIES.

Cytokine profile after oral food challenge in infants with food protein-induced enterocolitis syndrome.

BACKGROUND: Although food protein-induced enterocolitis syndrome (FPIES) is supposed to be caused by inflammation, the role of cytokines has not yet been clarified. METHODS: To elucidate the role of cytokines in the development of symptoms and abnormal laboratory findings at an oral food challenge (OFC), changes in serum cytokine levels were analyzed for 6 OFCs in 4 patients with FPIES. The result of OFC was judged positive if any gastrointestinal (GI) symptoms (vomiting, diarrhea, or bloody stool) were induced. RESULTS: Among 11 cytokines profiled, serum levels of interleukin (IL)-2, IL-5, and IL-8 were clearly increased in all 4 positive OFCs in which elevations of the serum level of C-reactive protein (CRP) and peripheral blood neutrophilia were also seen. The level of serum IL-10 also rose in 2 positive OFCs. Remarkable increases in the serum level of interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), IL-6, and IL-12 were observed in a positive OFC where the serum level of CRP rose markedly (6.75 mg/dL). The serum levels of IL-5 were also elevated in 2 negative OFCs. No apparent specific correlations were found between cytokines and GI symptoms. CONCLUSIONS: These results suggest that IL-2 and IL-8 are involved in the antigen-specific immune responses in most patients with FPIES. Further studies are needed to elucidate the significance of these cytokine in the pathogenesis of FPIES.

Eosinophilia in infants with food protein-induced enterocolitis syndrome in Japan.

BACKGROUND: Many Japanese infants with food protein-induced enterocolitis syndrome (FPIES) show eosinophilia, which has been thought to be a characteristic of food protein-induced proctocolitis (FPIP). METHODS: To elucidate the characteristics of eosinophilia in Japanese FPIES patients, 113 infants with non-IgE-mediated gastrointestinal food allergy due to cow's milk were enrolled and classified into FPIES (n = 94) and FPIP (n = 19). RESULTS: The percentage of peripheral blood eosinophils (Eo) was increased in most FPIES patients (median, 7.5%), which was comparable with that in FPIP patients (9.0%). Among FPIES patients, Eo was the highest in patients who had vomiting, bloody stool, and diarrhea simultaneously (12.9%) and lowest in patients with diarrhea alone (3.2%). Eo showed a significant positive correlation with the incidence of vomiting (Cramer's V = 0.31, p < 0.005) and bloody stool (Cramer's V = 0.34, p < 0.0005). A significant difference was found in Eo between early- (≤10 days, n = 56) and late-onset (>10 days, n = 38) FPIES (median, 9.8% vs. 5.4%; p < 0.005). IL-5 production by peripheral blood T cells stimulated with cow's milk protein in early-onset FPIES was significantly higher than that in late-onset FPIES (67.7 pg/mL vs. 12.5 pg/mL, p < 0.01), and showed a significant positive correlation with Eo (rs = 0.60, p < 0.01). CONCLUSIONS: This study demonstrated two types of eosinophilia in Japanese FPIES infants: conspicuous and mild eosinophilia in early- and late-onset FPIES patients, respectively. Conspicuous eosinophilia in early-onset FPIES is suggested to be caused by abnormally high IL-5 production.

Targeted use of prednisolone with the second IVIG dose for refractory Kawasaki disease.

BACKGROUND: Prednisolone (PSL) has been suggested to be useful for the treatment of Kawasaki disease (KD) resistant to i.v. immunoglobulin (IVIG), but much remains to be elucidated regarding its use. METHODS: A total of 1087 subjects were involved in a two-study multicenter prospective investigation of the effects of acute phase therapy on IVIG-resistant KD. Subjects resistant to the first dose of IVIG were classified into high (≥10 mg/dL) and low (<10 mg/dL) serum C-reactive protein (CRP) groups after the first dose of IVIG. RESULTS: In the first study, the efficacy of the second dose of IVIG in the high CRP group was significantly lower than in the low CRP group (47.8% vs 76.8%, P < 0.005). In the second study, PSL was co-administered with the second dose of IVIG to the high CRP patients (intensified regimen). The efficacy of the intensified regimen was similar to that of the second dose of IVIG in the low CRP group (79.4% vs 83.3%). Although the difference in the incidence of persistent coronary artery lesions (CAL) between the high and low CRP groups was significant in the first study (19.6% vs 3.0%, P < 0.005), it was not significant in the second study (8.8% vs 2.4%). CONCLUSIONS: The targeted use of PSL with the second dose of IVIG in KD patients resistant to the first dose of IVIG and who are predicted to be resistant to the second dose of IVIG, appears to be effective.

Phosphatase and tensin homolog (PTEN) mutation can cause activated phosphatidylinositol 3-kinase δ syndrome-like immunodeficiency.

BACKGROUND: Activated phosphatidylinositol 3-kinase δ syndrome (APDS) is a recently discovered primary immunodeficiency disease (PID). Excess phosphatidylinositol 3-kinase (PI3K) activity linked to mutations in 2 PI3K genes, PIK3CD and PIK3R1, causes APDS through hyperphosphorylation of AKT, mammalian target of rapamycin (mTOR), and S6. OBJECTIVE: This study aimed to identify novel genes responsible for APDS. METHODS: Whole-exome sequencing was performed in Japanese patients with PIDs. Immunophenotype was assessed through flow cytometry. Hyperphosphorylation of AKT, mTOR, and S6 in lymphocytes was examined through immunoblotting, flow cytometry, and multiplex assays. RESULTS: We identified heterozygous mutations of phosphatase and tensin homolog (PTEN) in patients with PIDs. Immunoblotting and quantitative PCR analyses indicated that PTEN expression was decreased in these patients. Patients with PTEN mutations and those with PIK3CD mutations, including a novel E525A mutation, were further analyzed. The clinical symptoms and immunologic defects of patients with PTEN mutations, including lymphocytic AKT, mTOR, and S6 hyperphosphorylation, resemble those of patients with APDS. Because PTEN is known to suppress the PI3K pathway, it is likely that defective PTEN results in activation of the PI3K pathway. CONCLUSION: PTEN loss-of-function mutations can cause APDS-like immunodeficiency because of aberrant PI3K pathway activation in lymphocytes.

Serum C-reactive protein in food protein-induced enterocolitis syndrome versus food protein-induced proctocolitis in Japan.

BACKGROUND: Some infants with food protein-induced enterocolitis syndrome (FPIES) have increased serum C-reactive protein (CRP) and fever in Japan. The aim of this study was therefore to clarify and compare the incidence of this in patients with FPIES versus patients with food protein-induced proctocolitis (FPIP). METHODS: One hundred and sixteen infants with non-IgE-mediated gastrointestinal food allergies were enrolled in this study and classified into three phenotypes: FPIES presenting with vomiting and/or diarrhea (n = 47); FPIP with bloody stool alone (n =19); and the mixed phenotype (MP), bloody stool with vomiting and/or diarrhea (n = 50). RESULTS: Serum CRP was increased in 55.3% of the FPIES group, similar to that in the MP group (54.0%), and significantly higher than in the FPIP group (15.8%; P < 0.01). Fever was observed in 29.8% of the FPIES group, significantly higher than in the MP group (8.0%; P < 0.01) and in the FPIP group (0%; P < 0.05). Patients with fever had significantly higher serum CRP than patients without fever (median, 12.8 vs <0.2 mg/dL, P < 0.00001). CONCLUSIONS: Serum CRP was significantly higher in the FPIES group than in the FPIP group. This suggests that serum CRP is a useful marker for differentiating the pathogenesis of FPIES from FPIP. From the perspective of serum CRP, the pathology of the intestinal inflammation in MP subjects is suggested to be similar to that of FPIES.

Chronic active EBV infection with features of granulomatosis with polyangiitis.

Herein, we report the case of a 13-year-old boy with multiple recurrent ulcers on his legs. He developed severe sinusitis at 10 years of age and had significant weight loss (6 kg) in the 2 months prior to admission. Histology of tissue biopsied from the ulcer indicated small vessel vasculitis and granulomatous inflammation. Given that these findings met the diagnostic criteria for granulomatosis with polyangiitis (GPA), he was treated with immunosuppressive agents. Further pathology, however, indicated Epstein-Barr virus (EBV)-encoded RNA (EBER) in most lymphocytes in the same sample. The EBER-positive lymphocytes were mainly CD4-positive T cells. The EBV-DNA load in the peripheral blood was also abnormally increased (1.0 × 10(4) copies/µg DNA). Thus, the diagnosis was established as chronic active EBV infection (CAEBV). This case illustrates the necessity of careful differential diagnosis of CAEBV owing to its clinical resemblance and pathological overlap with GPA.

Increased C-reactive protein and fever in Japanese infants with food protein-induced enterocolitis syndrome.

BACKGROUND: Increased C-reactive protein (CRP) and fever are observed in some infants with food protein-induced enterocolitis syndrome (FPIES) in Japan, but the reproducibility of these findings has not yet been confirmed on oral food challenge (OFC). METHODS: Fourteen infants with FPIES induced by cow's milk (CM) formula were enrolled. OFC using CM formula was performed on each infant once or repeatedly (total 18 tests), with a stepwise incremental protocol in an infection-controlled setting. CRP was measured 24 h after the last ingestion of the CM formula. RESULTS: Increased CRP was observed in 11 of the 18 OFC conducted (median, 2.60 mg/dL; range, 0.22-4.84 mg/dL). Fever was induced in six occasions during OFC. Serum CRP in the patients with fever increased to median 3.76 mg/dL (range, <0.7-4.84 mg/dL), which was significantly higher than that of the patients without fever (median <0.1 mg/dL; range, <0.1-2.6 mg/dL; P < 0.001). CRP during OFC significantly correlated with that at disease onset (rs = 0.62, P < 0.02). Three of the four patients with fever at disease onset also had fever during OFC. CONCLUSIONS: Increased CRP and fever are reproducible during OFC in some infants with FPIES, suggesting that these are not accidental phenomena, but instead are associated with FPIES itself in Japanese patients.

Close Positive Correlation between the Lymphocyte Response to Hen Egg White and House Dust Mites in Infants with Atopic Dermatitis.

BACKGROUND: It was recently hypothesized that food allergens sensitize infants with atopic dermatitis (AD) via the skin. If this is the case, an intimate positive correlation should be observed between immune responses to both food and indoor allergens. METHODS: One hundred and seven infants with AD and 32 controls were enrolled. The proliferation of lymphocytes stimulated with hen egg white (EW) or house dust mite (HDM) allergens was measured by means of an allergen-specific lymphocyte stimulation test (ALST). Cytokine production was measured in 13 patients and 4 controls. RESULTS: ALST responses for EW (EW-ALST) were significantly higher in AD infants than in control subjects (stimulation index: 7.98 vs. 2.54, p < 0.0001). HDM-ALST responses were also significantly higher in AD infants than in controls (stimulation index: 5.09 vs. 1.44, p < 0.0001). A significant positive correlation was seen between HDM-ALST and EW-ALST responses in AD infants aged 5-6 months (rs = 0.77, p < 0.000001). Serum levels of EW-specific IgE (EW-IgE) were significantly correlated with both EW-ALST (rs = 0.43, p < 0.05) and HDM-ALST levels (rs = 0.47, p < 0.05) in AD patients aged 3-4 months. Serum EW-IgE levels in AD infants were significantly correlated with the ratio of IL-4/IFN-γ production from lymphocytes stimulated with EW (rs = 0.62, p < 0.01) and with HDM (rs = 0.67, p < 0.005). CONCLUSIONS: This study describes the close positive correlation between EW- and HDM-specific immune responses in infants with AD. These results may support the hypothesis that both food and indoor allergens concurrently sensitize infants via the skin.

Usefulness of lymphocyte stimulation test for the diagnosis of intestinal cow's milk allergy in infants.

BACKGROUND: Bottle-fed infants sometimes develop intestinal cow's milk allergy (ICMA). Because cow's milk-specific IgE antibody (CM-IgE) levels are normal, the lymphocyte stimulation test (LST) has been proposed as an alternative diagnostic test for ICMA. The present study evaluated the diagnostic value of LST in a large number of patients with ICMA in Japan. METHODS: Ninety-six infants who developed intestinal symptoms after ingestion of cow's milk formula and showed remission of symptoms after elimination of this food were enrolled as patients with probable ICMA. Seventy-two subjects with normal CM-IgE levels and a positive result in an oral food challenge test (OFCT) for cow's milk formula were diagnosed with ICMA. Another 10 infants with normal CM-IgE levels and a negative OFCT result were diagnosed with nonspecific intestinal symptoms (NIS). The status of cell-mediated immunity against cow's milk proteins was estimated by LST for κ-casein. RESULTS: In the 72 patients with ICMA (38 boys and 34 girls), the median age at onset was 9 days. Sixty-two of 72 (86.1%) patients with ICMA tested positive in the LST for κ-casein. In contrast, only 2 of the 10 NIS infants tested positive. The incidence of a positive LST result was significantly higher in the ICMA group than in the NIS group (p < 0.0001). The area under the receiver-operating characteristic curve for this test was as high as 0.856. CONCLUSIONS: This study strongly suggests that the LST for κ-casein is a useful diagnostic test for ICMA.

Skin infiltration of CD56(bright) CD16(-) natural killer cells in a case of X-SCID with Omenn syndrome-like manifestations.

We observed a patient with X-linked severe combined immunodeficiency (X-SCID) with Omenn syndrome-like manifestations. X-linked inheritance, absence of CD132 expression and impaired response to interleukin-2 (IL-2) indicated that the case is typical of X-SCID due to gamma(c) defect. However, this case was unusual in that circulating natural killer (NK) cells were increased and nearly half of these NK cells exhibited the CD56(bright) CD16(-) phenotype. A missense mutation was found within exon 5 of the IL2RG gene. The identical mutation was detected within NK, CD4(+) T and B cells. Engraftment of maternally derived NK cells or gene reversion was ruled out. The erythroderma-like skin lesion was characterized by infiltration of the dermis by CD56(bright) NK cells admixed with CD1a(+) dendritic cells (DC). Expression of mRNA for inflammatory cytokines was significantly enhanced within the skin. This may be the first human case to demonstrate that close cell-to-cell contact between DC and NK cells provides an effective alternative pathway for NK cell differentiation/activation in vivo.

Infantile hepatic dysfunction improved by elimination of cows' milk formulas.

We present three infants who showed hypertransaminasemia without extrahepatic symptoms, which improved by eliminating cows' milk formulas. The levels of milk protein-specific lymphocyte proliferation were elevated in all three patients. These cases indicate the importance of food allergy in the diagnosis of infantile hepatic dysfunction.

Ovalbumin-induced IL-4, IL-5 and IFN-gamma production in infants with atopic dermatitis.

BACKGROUND: Although hen's eggs are considered a cause of infantile atopic dermatitis (AD), little is known about cytokine production upon egg stimulation in infants with AD. OBJECTIVE: This study aimed to characterize the production of IL-4, IL-5 and IFN-gamma upon stimulation with ovalbumin (OVA), a representative allergenic protein of egg, in infants with AD. METHODS: Peripheral blood mononuclear cells (PBMCs) from 68 children with AD, including 46 infants (<1 year), were stimulated with OVA and the production of IL-4, IL-5 and IFN-gamma was measured with ELISA kits. RESULTS: Upon stimulation with OVA, the production of IL-4 and IL-5, but not IFN-gamma, by PBMCs was significantly higher in infants with AD than in non-atopic controls. OVA-induced IL-5 production peaked in younger infants (2-5 months) and then decreased with age increase. In contrast, OVA-induced IL-4 production peaked at the age of 1-2. This coincided with the serum level of egg white-specific IgE (EW-IgE). There was a significant positive correlation between IL-5 production and the severity of symptoms in infants with AD, while IL-4 production significantly correlated with the serum level of EW-IgE. CONCLUSION: These results demonstrate that OVA-induced IL-5 production fluctuates with age in a different manner than IL-4 or EW-IgE. Our results suggest that egg contributes to the development of AD in younger infants by inducing the production of IL-5, but not IL-4.

Japanese cedar-pollen-specific IL-5 production in infants with atopic dermatitis.

BACKGROUND: Although food allergens and house dust mites are thought to contribute to the development of atopic dermatitis (AD) in infants, the influence of pollens has not yet been well defined. OBJECTIVE: This study attempted to clarify the effect of Japanese cedar pollens (JCPs), which are scattered in Japan between February and April, on AD in infants. METHODS: In the first study, seasonal changes in the number of patients who first visited our institute due to AD were analyzed by reviewing medical records of 184 infants with AD. In the second study, peripheral blood mononuclear cells from 81 children (50 infants <1 year and 31 older children) with AD were stimulated with a standardized JCP allergen. The production of IL-5 was measured and its correlation with the severity of AD in infants was analyzed. RESULTS: The number of infants who first visited the institute due to AD peaked in spring. JCP-specific IL-5 production began to increase immediately after the first contact with JCPs in infants with AD. The production of IL-5 in infants with AD exposed to JCPs was significantly higher than in control subjects (p < 0.002) or in AD infants never exposed to JCPs (p < 0.02). There was a significant positive correlation between IL-5 production and the severity of AD in infants (p < 0.0001). CONCLUSION: These results suggest that JCPs play an important role in the aggravation of infantile AD in spring by inducing IL-5 production.

Theophylline suppresses IL-5 and IL-13 production, and lymphocyte proliferation upon stimulation with house dust mite in asthmatic children.

BACKGROUND: Although theophylline has long been used as a medication for bronchial asthma (BA), much remains to be elucidated about its action on Th2 cells, which play a critical role in the development of BA. OBJECTIVE: This study aimed to clarify the effect of theophylline on Th2 cells in an allergen-specific manner in children with BA. METHODS: Peripheral blood mononuclear cells (PBMCs) from 32 children with BA were stimulated with house dust mite (HDM) or a purified HDM allergen Der f 1 in the presence or absence of theophylline at a therapeutic concentration (5-20 microg/ml). The proliferation of lymphocytes and the secretion of IL-5 and IL-13 were measured to estimate the influence of theophylline. RESULTS: Theophylline at a concentration of 20 microg/ml significantly suppressed lymphocyte proliferation induced by 6-day culture with HDM or Der f 1. It also significantly reduced the production of IL-5 and IL-13 upon stimulation with HDM or Der f 1. Suppression of cytokine production and lymphocyte proliferation increased with concentrations of theopylline between 5 and 20 microg/ml. CONCLUSION: Theophylline suppresses the proliferation of lymphocytes and the production of proinflammatory Th2 cytokines, IL-5 and IL-13 induced by stimulation of PBMCs with HDM in children with BA.

Development of the capacity of peripheral blood mononuclear cells to produce IL-4, IL-5 and IFN-gamma upon stimulation with house dust mite in children with atopic dermatitis.

BACKGROUND: Imbalances of IL-4 and IFN-gamma production are widely known to increase IgE synthesis in allergic individuals, and IL-5 is known to play a critical role in the pathogenesis of various allergic diseases. However, little is known about how Th cells specific to house dust mite (HDM) develop the capacity to produce these cytokines in children with atopic dermatitis (AD). OBJECTIVE: This study aims to clarify when HDM-specific Th cells develop the capacity to produce IL-4, IL-5 and IFN-gamma in children with AD. METHODS: The production of IL-4, IL-5 and IFN-gamma by peripheral blood mononuclear cells (PBMCs) upon stimulation with HDM was measured in 91 children with AD and 37 control subjects. The changes in the cytokine production with age were analyzed transectionally and longitudinally. RESULTS: IL-4 production by HDM-stimulated PBMCs in children with AD was already increased before age 1. Thereafter, it continuously rose until reaching a near-maximum level at age 2. Growth-related changes in the production of IL-5 resembled those in the production of IL-4 and peaked at age 1. The production of these cytokines was very low in control subjects up to age 2 and then gradually increased, albeit never above the levels measured in AD children. The production of IFN-gamma in children with AD reached a near-maximum level during the first year of life and diminished after age 3. Although IFN-gamma production in controls was lower than that in AD children during infancy, it continuously rose even after age 3 and surpassed the levels measured in AD children. The level of serum HDM-specific IgE antibody began to increase after age 1 following the rise of IL-4 production. Essentially the same relationship among IL-4, IFN-gamma and IgE synthesis was seen in a longitudinal study of 6 AD infants, in whom HDM-specific IgE was initially negative but later turned positive. CONCLUSIONS: These findings suggest that the capacity of HDM-specific Th cells to produce IL-4, IL-5 and IFN-gamma develops and effectively matures during the first 3 years of life in children with AD.