Role of [68Ga]DOTANOC PET/computed tomography and [131I]MIBG scintigraphy in the management of patients with pheochromocytoma and paraganglioma: a prospective study.

PURPOSE: The primary aim of study was to compare role of iodine-131 (I-131)-labeled metaiodobenzylguanidine ([I]MIBG) and gallium-68 (Ga-68)-labeled DOTA-l-Nal3-octreotide ([Ga]DOTANOC) PET/computed tomography (CT) in patients with pheochromocytoma (PCC) and paraganglioma (PGL), subsequent follow-up to see management. The secondary aim was to see association of germline mutation in histopathologically proven patients. PROCEDURES: We performed [Ga]DOTANOC PET/CT and [I]MIBG in 106 patients (61 men; age: 38.5 ± 16.2 years) of known or suspected PCC/PGL. Following scans, 16 histopathologically proven patients were screened for germline mutations. RESULTS: [I]MIBG detected 41 lesions in 34 patients and [Ga]DOTANOC PET/CT detected more than 79 lesions in 55 patients. The mean duration of follow-up was 20.6 ± 16.5 months. Management following scans: surgery in 35 patients (positive histopathology in 34 patients, negative in 1 patient); lutecium-177 (Lu-177)-labeled DOTA-0-Tyr-3 octreotate ([Lu]DOTATATE) therapy in 2 patients; chemotherapy in 1 patient; conservative therapy in 34 patients; no therapy in 17 patients; 2 patients have died and 3 were lost to follow-up. Among 12 previously operated, 2 patients showed metastatic disease and 1 showed residual disease. Out of 16 patients who underwent genotypic analysis (15 operated), 8 were positive for germline mutations. Mutations were seen in SDHB, RET, VHL, MDH2 and SDHA genes, including two germline mutations in two patients. Deletion was observed in one patient in SDHB gene and substitution in all other mutations. Four novel mutations in MDH2 (c.1005G>C, c.916G>A, c.580G>A) and SDHB (c.378_380delAAT) were observed (SRA accession: PRJNA551457). CONCLUSIONS: [Ga]DOTANOC PET/CT should be considered as a first-line investigation in PCC/PGL especially at high risk of metastasis and screening of persons with familial syndrome.

Need to re-look cut-off of Aspergillus-specific IgE levels in children with ABPA.

The cut-offs for total and specific IgE used for diagnosing ABPA in children have been adopted from adult literature and have not been validated in the paediatric population. To establish the ideal cut-offs of total IgE and Aspergillus-specific IgE for the diagnosis of ABPA in children. This study was a prospective observational case-control study, conducted in a tertiary care hospital in North India, enrolling 140 children with partly controlled and uncontrolled asthma. Seventy children had ABPA based on the Rosenberg-Patterson Criteria (Cases) whereas 70 children were without ABPA (Controls). All children were subjected to clinical examination and investigations such as absolute eosinophil count, total IgE, Aspergillus-specific IgE, Aspergillus skin prick test and radiological tests. ROC curve analysis was done to determine the ideal cut-offs of total and specific IgE to diagnose ABPA. The ROC curve analysis determined 1204IU/L as the cut-off value of total IgE with a sensitivity of 79.7% (95%CI 68.31% to 88.44%) and specificity of 53.1% (95%CI 40.23 to 65.7). The ROC analysis of specific IgE levels of children with ABPA determined the cut-off value of 0.49 KAU/L with a sensitivity of 94.03% (95%CI 85.41 to 98.35) and specificity of 88.89% (95%CI 75.94% to 96.29%). We propose that the cut-offs of total and specific IgE need to be relooked in the paediatric population. Cut-offs of total IgE as 1204 IU/L and for Aspergillus-specific IgE as 0.49KAU/L seem appropriate. Large multicentric studies should be conducted to determine the ideal values for diagnosing paediatric ABPA.

Asthma and Fungus: Role in Allergic Bronchopulmonary Aspergillosis (ABPA) and Other Conditions.

Asthma is an allergic, respiratory disorder characterized by hyper responsiveness of the airway to external stimuli. Considerable research is currently being directed towards understanding the role of environmental and genetic factors contributing to the development of asthma and its severity. Recent years have seen a substantial rise in evidence linking fungi to asthma. Few major clinical conditions associated with fungal sensitization and hypersensitive immune response are Allergic bronchopulmonary aspergillosis (ABPA), Allergic fungal rhinosinusitis (AFRS) and Severe asthma with fungal sensitization (SAFS). The most common fungi implicated in these conditions belong to genus Aspergillus, although an association with several other fungi has been described. In this review authors discuss the varying clinical characteristics of fungus induced respiratory complications in individuals with asthma. They also highlight the epidemiology of these conditions including their prevalence in children and their fungal etiological profile. Laboratory diagnostic methods and clinical case definitions have also been discussed. Future studies evaluating the role of fungal exposure and susceptibility to asthma are required. Till date there are no guidelines for the diagnosis and treatment of ABPA in pediatric population, thus it is also imperative to establish validated clinical definitions of fungal allergic manifestations in pediatric patients with asthma to fully understand this complex interaction.

Correlation of cutaneous sensitivity and cytokine response in children with asthma.

BACKGROUND: Food allergy occurs in a significant portion of pediatric asthma. Various cells and their mediators/cytokines play a pivotal role in orchestrating the airway inflammatory response in asthma. OBJECTIVE: To study the cutaneous hypersensitivity, Th1, Th2, and Th17 response of pediatric population with asthma and genetic predisposition to atopy, by determining total immunoglobulin E (IgE) level in response to various food allergens. MATERIALS AND METHODS: Fifty asthmatic children with a history of worsening symptoms by various food allergens (study group) and twenty healthy children (control group) were included. Food allergy was assessed through skin prick test (SPT) of various food allergens. Total serum IgE level was measured by sandwich ELISA, and T-cell (Th1, Th2, and Th17)-dependent cytokines were measured by flow cytometry. RESULTS: All 50 asthmatic children in the study group showed SPT positivity against various food allergens (rice = 17; banana, fish and groundnut = 10; wheat = 9; milk and orange = 7; egg = 6; and mango = 4). The average total IgE level in the study group was 316.8 ± 189.8 IU/mL. A significant positive correlation of total IgE with interleukin 17 (IL-17) (r = 0.796; P < 0.0001), IL-13 (r = 0.383; P = 0.01), and IL-4 (r = 0.263; P = 0.043) level was noted. A significant negative correlation of total IgE was noted with interferon gamma (r = -0.5823; P < 0.0001) and IL-10 (r = -0.4474; P < 0.001) level and the duration of breastfeeding (r = -0.31, P = 0.03). CONCLUSIONS: The present study found a positive correlation between total serum IgE level and Th2, Th17 cytokines in a pediatric population with asthma. A significant negative correlation was found between the duration of breastfeeding and the cytokines.

Correlation of TSLP, IL-33, and CD4 + CD25 + FOXP3 + T regulatory (Treg) in pediatric asthma.

OBJECTIVE: Newly discovered cytokines TSLP and IL33 are being studied as important indicators of Th2 inflammation and their effect on Treg cells is likely to modulate immune response. We attempted to study TSLP and IL-33 and then correlated with Tregs in order to find possible biomarker in these patients. METHODS: Sixty-five children (37 with asthma only and 28 with asthma and rhinitis) aged 6.4 ± 3.2 years (patient group) and 15 healthy children aged 8.0 ± 2.6 years (control group) were recruited in this study. In vitro analysis of TSLP and IL-33 was done in serum samples of 65 newly diagnosed children for allergic asthma and 15 healthy children using the sandwich ELISA method. The expression of Treg cells (CD4 + CD25 + FOXP3+) was analyzed by flow cytometry. RESULTS: The mean TSLP in the patient group (592 ± 68 pg/ml) was significantly higher than controls (215 ± 45 pg/ml) (p < 0.05). Alternatively, the expression of FOXP3 + T reg cells was significantly lower in the patient group (52 ± 36) compared with the controls (95.9 ± 3.6) (p = 0.003). IL-33 was also significantly higher (4044 ± 413 pg/ml) in the patient group compared with the controls (3282 ± 331.5 pg/ml) (p = 0.0001). The expression of Treg cells was negatively correlated with the TSLP (r = -0.23, p = 0.07). Asthma control test (ACT) was also negatively correlated with TSLP in the patient group (r = -0.14, p > 0.05). CONCLUSION: Children with asthma show elevated serum levels of TSLP, which correlated negatively with asthma control test and Treg cells. TSLP may be used as a biomarker for inflammation in pediatric asthma patients.

The diagnostic criteria for allergic bronchopulmonary aspergillosis in children with poorly controlled asthma need to be re-evaluated.

AIM: The aim of this study was to examine the association between allergic bronchopulmonary aspergillosis (ABPA) and poorly controlled asthma in children and appraise the diagnostic criteria. METHODS: The study included 100 children with poorly controlled asthma. We diagnosed ABPA using the Aspergillus skin test, pulmonary function test, total and specific immunoglobulin E (IgE) to Aspergillus fumigatus, chest radiograph and high-resolution computed tomography. Patients were diagnosed and classified according to the Rosenberg-Patterson criteria for ABPA. The cut-off value for total serum IgE was calculated by receiver operating characteristics curve analysis. RESULTS: Of 100 children with poorly controlled asthma, 26 patients were ABPA positive. There was a significant difference in the forced expiratory volume in 1-sec/forced vital capacity ratio between ABPA positive (0.78 ± 0.14) and negative (0.87 ± 0.15) children (p = 0.008). ABPA positive children were categorised as seropositive, central bronchiectasis and other radiological findings. The receiver operating characteristics curve was constructed, and a value of 1200 IU/mL of total IgE was observed, with 88.5% sensitivity and 70.5% specificity. CONCLUSION: This study showed an association between ABPA and poorly controlled asthma in children and suggests a higher cut-off value of total IgE for the diagnosis of ABPA.