Investigating the Relationship Between COVID-19 and Celiac Disease. A Dual Research Approach.

Background: Most evidence on the coronavirus disease 2019 (COVID-19) pandemic, has been obtained from web- or telephone-based surveys. In particular, few laboratory data, often incomplete, have been reported on the frequency of COVID-19-related serology at celiac disease (CD) diagnosis or on the effects of COVID-19 on the development of CD-specific autoimmunity. Objectives: The objective of this retrospective cross-sectional case/control study was to: (1) evaluate the frequency of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in 78 children and adolescents at CD diagnosis (CD, 44 females, median age 7.4 years); (2) evaluate the frequency of IgA-anti-transglutaminase antibodies (IgA-tTGAbs) in 97 nonceliac patients (50 females, median age 9.0 years) who contracted SARS-CoV-2 infection during the pandemic (February-April 2021). As a control (CTRL) group, we analyzed 141 healthy subjects (79 females, median age 9.8 years) enrolled during the pandemic. Methods: SARS-CoV-2 IgM- and IgG-antibodies were detected by chemiluminescent microparticle immunoassays. IgA-tTGAbs were detected by a fluid-phase radioimmunoassay. Results: Six out of 78 (7.7%) CD patients tested positive for SARS-CoV-2Abs, with a frequency not significantly different from CTRL subjects (9.2%). None of the 97 nonceliac COVID-19 patients tested positive for IgA-tTG antibodies. Conclusion: These 2 distinct research approaches showed (1) similar frequencies of SARS-CoV-2 immunoreactivities in CD patients and CTRL subjects and, (2) no ability of SARS-CoV-2 to induce a CD-specific immune response, at least in the 3-4 months following SARS-CoV-2 infection.

A new double immunohistochemistry method to detect mucosal anti-transglutaminase IgA deposits in coeliac children.

BACKGROUND: Intestinal transglutaminase (TG2) IgA deposits represent early marker of coeliac disease (CeD) and can predict the evolution towards intestinal atrophy. AIMS: To validate a double immunohistochemistry method for the determination of intestinal TG2 IgA deposits on formalin-fixed paraffin-embedded biopsies. METHODS: Immunohistochemistry was tested on: 1) children with overt CeD [persistently positive serum IgA anti-tissue transglutaminase type 2 (TGA-IgA) with moderate or low titer, and histological findings of CeD]; 2) potential CeD (persistently positive serum TGA-IgA and normal intestinal mucosa) and 3) controls (negative serum TGA-IgA and normal intestinal mucosa). RESULTS: Samples from 61 children were analyzed (32 overt CeD, 14 potential CeD, and 15 controls). Deposits appeared as focal, multifocal, or confluent extracellular foci of red and brown staining colocalization in the sub-epithelium and around mucosal vessels. Deposits were present in all 32 children with overt CeD and in 9/14 potential CeD. Deposits were never observed in the 15 controls. Patients with higher serum level of TGA-IgA and with mucosal atrophy showed mostly a multifocal/diffuse pattern of deposits distribution. The bulb appeared most severely involved. In potential CeD deposits showed mainly a focal distribution. CONCLUSION: Our results indicate double immunohistochemistry as promising diagnostic tool to improve diagnosis of CeD.

COVID-19 and celiac disease: A pathogenetic hypothesis for a celiac outbreak.

BACKGROUND: A growing body of evidence supports the intestinal trophism of SARS-CoV-2, with ciliated cells and intestinal enterocytes being target cells because of the high expression of ACE2 and TMPRSS2. Indeed, COVID-19 promotes a "cytokine storm" in the intestinal mucosa: the resulting epithelial damage leads to increased barrier permeability, allowing the passage of gliadin in the intestinal lamina. METHODS: Based on current literature, we hypothesize the role of COVID-19 as a potential trigger factor for celiac disease in predisposed patients. CONCLUSIONS: Genetically predisposed patients could be more likely to develop celiac disease following SARS-CoV-2 infection, making COVID-19 a candidate culprit for a potential outbreak of celiac disease in the forthcoming future.

Association between Elevated TGA-IgA Titers and Older Age at Diagnosis with Absence of HBV Seroconversion in Celiac Children.

Patients with celiac disease can have a low rate of protective hepatitis B (HBV) antibody titers after vaccination. We aimed to evaluate the HBV seroconversion in celiac disease (CD) children at the time of diagnosis as well as to identify the presence of possible predictive factors. Celiac disease children were prospectively enrolled and tested for antibodies against the S protein of HBV (HBsAg) at time of diagnosis between January 2009 and February 2020. Based on the serologic response to the vaccine, "responders" and "non-responders" were identified. Statistical analysis has been performed through R statistical software (3.5.1 version, R core Team) Of 96 CD children evaluated, 41.7% (n = 40) showed non-protective or absent antibody titers against HBV. Elevated IgA-antibodies against transglutaminase 2 (TGA-IgA) values and older age at diagnosis were associated with an absent seroconversion to HBV vaccine, while presenting symptoms were not significant. An elevated prevalence of absent seroconversion to HBV vaccine exists in this cohort of CD patients at the time of disease diagnosis. Elevated TGA-IgA titers and older age at diagnosis seem to negatively predict seroconversion. Further studies are needed to identify the real profile of "non-responders", aiming to organize surveillance and eventual revaccination strategy.

Increased GLP-1 response to oral glucose in pre-pubertal obese children.

BACKGROUND: Gastrointestinal hormones, such as glucagon-like peptide (GLP-1), have been hypothesized to play a role in the pathogenesis of obesity-related complications. However, few data are available in youth. The objective of this study was to investigate the GLP-1 response to oral glucose load in obese pre-pubertal children and its relationship with insulin secretion. METHODS: Ten pre-pubertal obese children [five boys; 10.5±1.6 years; body mass index-standard deviation score (BMI-SDS): 2.2±0.5] and 10 controls (eight boys; 9.9±1.2 years; BMI-SDS: -0.7±0.5) underwent a modified oral glucose tolerance test (OGTT) to evaluate post-load glucose, insulin and GLP-1 responses. Insulin sensitivity [homeostasis model assessment of insulin resistance (HOMA-IR), whole body insulin sensitivity index (WBISI)] and secretion [HOMA-beta, insulinogenic index (IGI)] indexes, area under the curve (AUC) for glucose, insulin and GLP-1 were calculated. RESULTS: In obese children GLP-1 AUC values were higher and correlated with BMI-SDS (r=0.45; p=0.04), HOMA-IR (r=0.53; p=0.01) and fasting glucose (r=0.68; p=0.001). CONCLUSIONS: Obese children showed an increased GLP-1 response to oral glucose. These changes might likely represent a compensatory mechanism to avoid post-prandial hyperglycemia and allow a normal glucose tolerance.

Apparent life-threatening events could be a wake-up call for sleep disordered breathing.

INTRODUCTION: Polysomnographic recordings of children with an apparent life-threatening event (ALTE) have often displayed signs of partial or complete obstruction during sleep. Various studies have focused on facial dysmorphia in infants with ALTE and tried to establish a correlation between ALTE and obstructive sleep apnoea. Our study evaluates the phenotypic characteristics and the presence of sleep disorders in pre-school children who had at least one ALTE in the first year of life. MATERIALS AND METHODS: We analyzed a group of pre-school children (mean age 5.21 ± 0.90 years) who were referred for an ALTE between 2008 and 2010. Children with no history of ALTEs were recruited as a control group. A detailed personal and family history was obtained for all the participants. Moreover, all the children underwent a general clinical examination and an ear, nose, and throat and orthodontic assessment. A clinical score was calculated according to the previously validated Sleep Clinical Record (SCR). RESULTS: In the ALTE group (n = 107), snoring (25.2% vs. 6.1%), apnoeas (19.6% vs. 4.3%), restless sleep (31.7% vs. 6.1%), and habitual mouth breathing (35.5% vs. 12.2%, P < 0.05) were significantly more common (P < 0.05) than in the control group (n = 115). The ALTE group also displayed a higher frequency of Angle class II (27.1% vs. 15.7%, P < 0.05), narrow palate (72.9% vs. 51.3%, P < 0.05), and Friedman palate position (grades III-IV) (31.7% vs. 16.6%, P < 0.05) than the control group. Moreover, 38/107 (35.5%) children in the ALTE group had a positive SCR score compared with 14/115 controls (12.2%) (P < 0.05). CONCLUSIONS: Pre-school age children with previous ALTE had a higher frequency of sleep disordered breathing and malocclusion phenotypes. The occurrence of ALTEs may be predictive of the development of sleep disordered breathing and highlight the importance of a long-term follow-up. Pediatr Pulmonol. 2016;51:1403-1408. © 2016 Wiley Periodicals, Inc.

Celiac disease in a large cohort of children and adolescents with recurrent headache: A retrospective study.

BACKGROUND: The clinical picture of celiac disease is changing with the emergence of subclinical forms and growing evidence reporting associated neurological disorders. AIMS: To establish the prevalence of celiac disease in children suffering from recurrent headache. METHODS: In our retrospective study we collected charts from 1131 children attending our tertiary care Centre for Paediatric Headache over the period 2001-2012. They were screened for celiac disease and positive patients were referred to our Operative Unit for Coeliac disease and confirmed positive children underwent upper endoscopy with multiple duodenal biopsies. Celiac children started a gluten-free diet. RESULTS: 883 children (481 females; median age, 9.8 years, range 3-19) performed celiac disease screening, and among them, 11 children (7 females; median age, 8.2 years, range: 4.8-13.9) were diagnosed with celiac disease. Seven children (5 females, median age, 11.9 years, range: 10.3-13.9) had been diagnosed as celiac prior to the neurological evaluation. The prevalence of celiac disease in our sample is 2.04% vs. 1.2% of the general population (p=0.034). CONCLUSIONS: Our study demonstrates, on a large series, that celiac disease prevalence is doubled in patients with chronic headache. Screening for celiac disease could be advised as part of the diagnostic work-up in these paediatric patients, particularly among pharmacological non-responders.

Autonomic imbalance during apneic episodes in pediatric obstructive sleep apnea.

OBJECTIVES: To investigate the activity of the autonomic nervous system (ANS) during sleep in children with obstructive sleep apnea (OSA), in order to detect a possible cardiac ANS imbalance analyzing heart rate variability (HRV). METHODS: 43 subjects between 4 and 12 years of age (7.26 ± 2.8 years), undergoing a diagnostic assessment for OSA were evaluated. A time domain index (R-apnea index) was developed to evaluate HRV strictly related to obstructive events during sleep. Poincaré plot of RR intervals during the whole night was calculated. RESULTS: R-apnea index was negatively correlated with apnea hypopnea index (AHI) (r=-0.360, p=0.028). AHI and the duration of the disease were the only variables that were significantly correlated with R-apnea index. Three groups were subsequently created according to polysomnographic findings considering AHI. R-apnea index resulted significantly lower in patient with severe OSA compared to primary snoring/mild OSA subjects (p<0.05). Looking at Poincaré plot, SD1 showed a diminishing trend with severity of OSA, however not reaching statistical significance. CONCLUSIONS: Our findings suggest an autonomic impairment in OSA children evidenced by the altered HRV both in the very short term (R-apnea index) and in short term (SD1). SIGNIFICANCE: R-apnea index is an easy and cheap method to undelay early ANS imbalance.

Use of the sleep clinical record in the follow-up of children with obstructive sleep apnea (OSA) after treatment.

PURPOSE: The aim of our study was to evaluate the utility of the sleep clinical record (SCR) in the follow-up of children with obstructive sleep apnea (OSA) after treatment. METHODS: SCR was completed and overnight polysomnography (PSG) was performed in all enrolled children (T0), with SCR considered positive for scores ≥6.5, as previously validated. Patients underwent adenotonsillectomy (T&A), rapid maxillary expansion (RME), and medical therapy according to severity of OSA and clinical features. Six months after completing therapy, the second overnight PSG and SCR (T1) were performed. RESULTS: For all subjects, both Apnea-Hypopnea Index (AHI) and total SCR score decreased significantly (<0.005) from T0 to T1. For SCR items, clinical examination (item 1) and reported sleep respiratory symptoms (item 2) ameliorated significantly (<0.005). However, hyperactivity or inattention (item 3) decreased significantly (<0.005) after treatment only in T&A group, while no differences in AHI and SCR scores occurred in the medically treated group. At T1, SCR was positive in 95.6 % of children with AHI ≥1, with a concordance of 100 % in the T&A and RME groups, resulting in a positive predictive value of 100 %. A poor concordance (38.3 % in T&A group and 53.4 % in RME group) was found when SCR < 6.5. Children with SCR ≥ 6.5 at T1 showed higher AHI compared to patients with SCR < 6.5 (5.7 ± 5.9 ev/h vs 1.78 ± 1.76 ev/h; p < 0.005). CONCLUSIONS: SCR emerges as a potentially useful instrument for follow-up of children with OSA after treatment.

Diagnosis of Pediatric Obstructive Sleep Apnea Syndrome in Settings With Limited Resources.

IMPORTANCE: Although polysomnographic (PSG) testing is the gold standard for the diagnosis of obstructive sleep apnea syndrome (OSAS) in children, the number of pediatric sleep laboratories is limited. Developing new screening methods for identifying OSAS may reduce the need for PSG testing. OBJECTIVE: To evaluate the combined use of the sleep clinical record (SCR) and nocturnal oximetry testing for predicting PSG results in children with clinically suspected OSAS. DESIGN, SETTING, AND PARTICIPANTS: Prospective study over 10 months. A cohort of 268 consecutive children (mean [SD], age 6 [3] years) referred for clinically suspected OSAS was studied at a pediatric sleep center at a university hospital. Children with disorders other than adenotonsillar hypertrophy or obesity were excluded. MAIN OUTCOMES AND MEASURES: Mild OSAS (obstructive apnea-hypopnea index [AHI], 1-5 episodes/h) and moderate-to-severe OSAS (AHI, >5 episodes/h) were the main outcome measures. Sleep clinical record scores greater than or equal to6.5 were considered positive, as were McGill oximetry scores (MOS) greater than 1, and these positive scores were the main explanatory variables in our study. Each participant was evaluated by the SCR, followed by pulse oximetry test the first night and PSG test in the sleep laboratory the second night. RESULTS: Of the total participants, 236 (88.1%) were diagnosed with OSAS, 236 (88.1%) had a positive SCR score, and 50 (18.7%) had a positive MOS. Participants with positive SCR scores had significantly increased risk of an AHI greater than or equal to 1 (adjusted odds ratio [AOR], 9.3; 95% CI, 3.7-23.2; P < .001). Children with an MOS greater than 1 were significantly more likely to have an AHI greater than 5 episodes/h than children with an MOS equal to 1 (AOR, 26.5; 95% CI, 7.8-89.2; P < .001). A positive SCR score had satisfactory sensitivity (91.9%) and positive predictive value (91.9%) but limited specificity (40.6%) and negative predictive value (40.6%) for OSAS. An MOS greater than 1 had excellent specificity (97.4%) and positive predictive value (94%) but low sensitivity (39.2%) and fair negative predictive value (60.8%) for moderate-to-severe OSAS among children with a positive SCR score. The combination of SCR scores and MOS correctly predicted primary snoring, mild OSAS, or moderate-to-severe OSAS in 154 of 268 (57.4%) participants. CONCLUSIONS AND RELEVANCE: The combined use of the SCR score and nocturnal oximetry results has moderate success in predicting sleep-disordered breathing severity when PSG testing is not an option.

Cognitive function in preschool children with sleep-disordered breathing.

PURPOSE: The purposes of this study were to assess cognitive functions in preschool children with sleep-disordered breathing (SDB) and to compare them with matched control children. METHODS: A clinical sample of 2.5- to 6-year-old children with SDB was recruited. All children underwent sleep clinical record (SCR), which is a polysomnography (PSG)-validated questionnaire for diagnosing SDB, a polysomnography and a neurocognitive assessment. Normal controls were recruited from a kindergarten. They underwent the SCR and the cognitive assessment. RESULTS: We studied 41 children with primary snoring (PS)-mild obstructive sleep apnea syndrome (OSAS; M/F = 15/26, mean age 4.43 ± 0.94), 36 children with moderate-severe OSAS (M/F = 22/14, mean age 4.33 ± 1.02), and 83 controls (M/F = 33/50, mean age 4.5 ± 0.64). In the two groups, no differences were found in duration and age of onset of SDB, while a significant difference emerged in SCR score (p < 0.005). No differences emerged in the three groups in Verbal IQ, Performance IQ, and Global IQ scores, nor in any cognitive subtests. CONCLUSIONS: We demonstrated that SDB of all severities is not associated with cognitive impairment compared to the control group in preschool age.

Rapid maxillary expansion outcomes in treatment of obstructive sleep apnea in children.

OBJECTIVES: The objectives of this study were to confirm the efficacy of rapid maxillary expansion in children with moderate adenotonsillar hypertrophy in a larger sample and to evaluate retrospectively its long-term benefits in a group of children who underwent orthodontic treatment 10 years ago. METHODS: After general clinical examination and overnight polysomnography, all eligible children underwent cephalometric evaluation and started 12 months of therapy with rapid maxillary expansion. A new polysomnography was performed at the end of treatment (T1). Fourteen children underwent clinical evaluation and Brouilette questionnaire, 10 years after the end of treatment (T2). RESULTS: Forty patients were eligible for recruitment. At T1, 34/40 (85%) patients showed a decrease of apnea-hypopnea index (AHI) greater than 20% (ΔAHI 67.45% ± 25.73%) and were defined responders. Only 6/40 (15%) showed a decrease <20% of AHI at T1 and were defined as non-responders (ΔAHI -53.47% ± 61.57%). Moreover, 57.5% of patients presented residual OSA (AHI > 1 ev/h) after treatment. Disease duration was significantly lower (2.5 ± 1.4 years vs 4.8 ± 1.9 years, p <0.005) and age at disease onset was higher in responder patients compared to non-responders (3.8 ± 1.5 years vs 2.3 ± 1.9 years, p <0.05). Cephalometric variables showed an increase of cranial base angle in non-responder patients (p <0.05). Fourteen children (mean age 17.0 ± 1.9 years) who ended orthodontic treatment 10 years previously showed improvement of Brouilette score. CONCLUSION: Starting an orthodontic treatment as early as symptoms appear is important in order to increase the efficacy of treatment. An integrated therapy is needed.

Impact of obesity on cognitive outcome in children with sleep-disordered breathing.

OBJECTIVES: The objective of this study was to evaluate the impact of obesity on cognitive impairment, in children with obstructive sleep apnoea (OSA), children with OSA and obesity, and in normal controls. METHODS: Thirty-six children with OSA (group 1), 38 children with OSA and obesity (group 2) and 58 normal controls (group 3) were studied. The Total intelligence quotient (T-IQ), Verbal IQ (V-IQ) and the Performance IQ (P-IQ) scores were obtained using the Wechsler Intelligence Scale for Children - Third Edition Revised. All participants' parents filled out the questionnaire containing the attention deficit and hyperactive disorder rating scale to investigate symptoms of hyperactivity and attention deficit. Obese and non-obese children with sleep-disordered breathing (SDB) underwent polysomnography. RESULTS: T-QI and P-QI scores were significantly lower in group 2 with higher performance impairment at the subtest compared to other groups. In obese children, V-IQ was significantly correlated with age of onset (r = 0.335, p = 0.05) and duration of SDB (r = -0.362, p = 0.02), while P-IQ and T-IQ were correlated with body mass index (BMI) percentile (r = -0.341, p = 0.03) and respiratory disturbance index (RDI) (r = -0.321, p = 0.05), respectively. RDI and BMI negatively influenced T-IQ in obese children with OSA. No correlation was found between sleep parameters and IQ scores or subtest scores in all groups. CONCLUSIONS: Obese children with OSA showed higher cognitive impairment. Obesity has an additive and synergic action with that exerted by OSA, speeding up the onset of complications.

Oropharyngeal exercises to reduce symptoms of OSA after AT.

PURPOSE: This study evaluated the efficacy of oropharyngeal exercises in children with symptoms of obstructive sleep apnea syndrome (OSA) after adenotonsillectomy. METHODS: Polysomnographic recordings were performed before adenotonsillectomy and 6 months after surgery. Patients with residual OSA (apnea-Hypopnea Index, AHI > 1 and persistence of respiratory symptoms) after adenotonsillectomy were randomized either to a group treated with oropharyngeal exercises (group 1) or to a control group (group 2). A morphofunctional evaluation with Glatzel and Rosenthal tests was performed before and after 2 months of exercises. All the subjects were re-evaluated after exercise through polysomnography and clinical evaluation. The improvement in OSA was defined by ΔAHI: (AHI at T1 - AHI at T2)/AHI at T1 × 100. RESULTS: Group 1 was composed of 14 subjects (mean age, 6.01 ± 1.55) while group 2 was composed of 13 subjects (mean age, 5.76 ± 0.82). The AHI was 16.79 ± 9.34 before adenotonsillectomy and 4.72 ± 3.04 after surgery (p < 0.001). The ΔAHI was significantly higher in group 1 (58.01 %; range from 40.51 to 75.51 %) than in group 2 (6.96 %; range from -23.04 to 36.96 %). Morphofunctional evaluation demonstrated a reduction in oral breathing (p = 0.002), positive Glatzel test (p < 0.05), positive Rosenthal test (p < 0.05), and increased labial seal (p < 0.001), and lip tone (p < 0.05). CONCLUSIONS: Oropharyngeal exercises may be considered as complementary therapy to adenotonsillectomy to effectively treat pediatric OSA.

SURGICAL AND NON-SURGICAL THERAPY OF OBSTRUCTIVE SLEEP APNEA SYNDROME IN CHILDREN.

Interventions of paediatric obstructive sleep apnea syndrome are complex, varied and multidisciplinary. The goal of the treatment is to restore optimal breathing during the night and to relieve associated symptoms. Evidence suggests that the surgical intervention with removal of the tonsils and adenoids will lead to significant improvements in the most incomplicated cases, as recently reported from a meta-analysis. However, post-operative persistence of this syndrome in paediatric population is more frequent than expected, which supports the idea of the complexity of this syndrome. Adenotomy alone may not be sufficient in children with OSAS, because it does not address oropharyngeal obstruction secondary to tonsillar hyperplasia. Continuous positive airway pressure can effectively treat this syndrome in selected groups of children, improving both nocturnal and daytime symptoms, but poor adherence is a limiting factor. For this reason, CPAP is not recommended as first-line therapy for OSAS when adenotonsillectomy is an option. It is now being investigated the incorporation of nonsurgical approaches for milder forms and for residual OSAS after surgical intervention. Althought adeno-tonsillar hypertrophy is the most common for OSAS in children; obesity is emerging as an equally important etiological factor. Therefore an intensive weight reduction program and adequate sleep hygiene are also important lifestyle changes that may be very effective in mitigating the symptoms of this syndrome. Pharmacological therapy (leukotriene antagonists, topical nasal steroids) is usually use for mild forms of OSAS and in children with associated allergic diseases. Special orthodontic treatment and oropharyngeal exercises are a relatively new and promising alternative therapeutic modality used in selected groups of children with OSAS.

The celiac iceberg: characterization of the disease in primary schoolchildren.

OBJECTIVE: Celiac disease (CD) has a prevalence of 0.55% to 1% in Italy. Identifying CD in schoolchildren to characterize CD iceberg and evaluate the effect of diagnosis in screening-detected children. METHODS: A total of 7377 5- to 8-year-old children were invited to participate. A total of 5733 salivary samples were collected and tested for anti-transglutaminase antibodies (tTGAb), using a fluid-phase radioimmunoassay. Salivary tTGAb-positive children were analyzed for serum antibodies (anti-endomysium antibodies, radioimmunoassay, and enzyme-linked immunosorbent assay tTGAb). Positive children underwent endoscopy and then started gluten-free diet (GFD) and periodical follow-up. RESULTS: Forty-six subjects were found salivary tTGAb-positive and 16 border-line. Forty-five of 46 and 5 of 15 of them were also serum antibody-positive. Forty-two children showed duodenal villous atrophy and 1 had only type 1 lesions. Three children started GFD without performing endoscopy. CD prevalence (including 23 previously diagnosed children with CD) was 1.2%. Considering all 65 celiacs in our sample, a silent CD was found in 64%, typical in 28%, atypical in 7%, and potential in 1%. All patients showed strict adherence to GFD, weight and stature increase, and well-being improvement. Eighty-five percent and all but 2 screening-detected children with CD had Italian parents. CONCLUSIONS: Our sample size, representative of primary schoolchildren of our region, demonstrated that CD prevalence is growing in Italy, with a modified clinical spectrum and iceberg deepness.