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.

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.

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.

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.

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.

[Evaluation of the allergenicity of ß-casein in Japanese children with cow milk allergy by using the basophil activation test].

BACKGROUND: Among the casein components, αs-casein (αs-CAS) is considered the major allergen in Japan, and there are very few reports on the allergenicity of ß-casein (ß-CAS). In this study, we compared the allergenicity of ß-CAS with that of αs-CAS in Japanese children with cow milk allergy (CMA). METHOD: The allergenicity of αs-CAS and ß-CAS in 29 CMA patients and 11 control subjects was assessed using the basophil activation test (BAT). The accuracy of the BAT to distinguish the patients with CMA from the control subjects was estimated using a receiver operating characteristic (ROC) analysis and was expressed as the area under the curve (AUC). RESULTS: BAT results for CM were positive in 93.1% of the CMA patients. The results of the ß-CAS-BAT and αs-CAS-BAT were found to be positive in 86.2% and 69.0% of the CMA patients, respectively, however, the difference was not significant. The AUC for the ß-CAS-BAT was 0.893, which was not significantly different from that for the αs-CAS-BAT (0.859). CONCLUSIONS: These results suggest that the allergenicities of ß-CAS and αs-CAS are similar in Japanese patients with CMA.

Successful treatment of erythema nodosum with salazosulfapyridine in a 9-year-old patient with chronic non-bacterial osteomyelitis.

We report a 9-year-old Japanese girl with chronic non-bacterial osteomyelitis (CNO) accompanied by recurrent erythema nodosum (EN) which was successfully treated with salazosulfapyridine (SASP). She was referred to our hospital because of recurrent erythema on her lower extremities and persistent knee and ankle arthralgia, which had been present for approximately 1 year. Although naproxen, a nonsteroidal anti-inflammatory drug, was initiated, her symptoms frequently recurred. Magnetic resonance imaging demonstrated multiple distinct high-intensity signals in the talus bones suggestive of multiple bone oedemas. Additionally, a histological examination of erythematous lesions was consistent with the histopathological findings of EN. She was diagnosed as having CNO complicated by EN, and received 250 mg/day of SASP as a second-line treatment, which showed partial response of both skin and bone lesions. Following increase in the dose of SASP to 500 mg/day resulted in complete remission of her skin and bone lesions. In conclusion, our findings suggest that SASP is effective not only for CNO bone lesions but also for EN. SASP could serve as a second-line therapeutic option at least for some cases of CNO complicated by EN refractory to nonsteroidal anti-inflammatory drugs.

Hypothermia, bradycardia, and hypotension during glucocorticoid or cyclosporine A therapy in a boy with Kikuchi-Fujimoto disease.

Kikuchi-Fujimoto disease (KFD) is an inflammatory disease of unknown aetiology characterised by fever and cervical lymphadenopathy. Although KFD is a self-limiting disease, patients with severe or long-lasting course require glucocorticoid therapy. We presently report a 17-year-old boy with KFD who had seven relapses since the onset at 4 years old. He suffered from hypothermia, bradycardia, and hypotension during the treatment with prednisolone or methylprednisolone. All of his vital signs recovered after cessation of the drug in addition to fluid replacement and warming. Thus, glucocorticoid was effective but could not be continued because of the adverse event. Although hypothermia developed during the treatment with 5 mg/kg/day of cyclosporine A (CsA) at his second relapse, he was successfully treated with lower-dose CsA (3 mg/kg/day). Thereafter, he had five relapses of KFD until the age of 12 years and was treated by 1.3-2.5 mg/kg/day of CsA. Hypothermia accompanied by bradycardia and hypotension developed soon after concomitant administration of ibuprofen at his fifth and sixth relapses even during low-dose CsA therapy. Conclusively, glucocorticoid, standard dose of CsA, or concomitant use of non-steroidal anti-inflammatory drugs may cause hypothermia, bradycardia, and hypotension and needs special attention. Low-dose CsA could be a choice for such cases with KFD.

Fully gapped pairing state in spin-triplet superconductor UTe2.

The recently discovered superconductor UTe2 is a promising candidate for spin-triplet superconductors, but the symmetry of the superconducting order parameter remains highly controversial. Here, we determine the superconducting gap structure by the thermal conductivity of ultraclean UTe2 single crystals. We find that the a-axis thermal conductivity divided by temperature κ/T in zero-temperature limit is vanishingly small for both magnetic field H‖a and H‖c axes up to H/Hc2 ∼ 0.2, demonstrating the absence of nodes around the a axis contrary to the previous belief. The present results, combined with the reduction of nuclear magnetic resonance Knight shift, indicate that the superconducting order parameter belongs to the isotropic Au representation with a fully gapped pairing state, analogous to the B phase of superfluid 3He. These findings reveal that UTe2 is likely to be a long-sought three-dimensional strong topological superconductor, hosting helical Majorana surface states on any crystal plane.