New entity of adult ultra-short coeliac disease: the first international cohort and case-control study.

BACKGROUND: Ultra-short coeliac disease (USCD) is defined as villous atrophy only present in the duodenal bulb (D1) with concurrent positive coeliac serology. We present the first, multicentre, international study of patients with USCD. METHODS: Patients with USCD were identified from 10 tertiary hospitals (6 from Europe, 2 from Asia, 1 from North America and 1 from Australasia) and compared with age-matched and sex-matched patients with conventional coeliac disease. FINDINGS: Patients with USCD (n=137, median age 27 years, IQR 21-43 years; 73% female) were younger than those with conventional coeliac disease (27 vs 38 years, respectively, p<0.001). Immunoglobulin A-tissue transglutaminase (IgA-tTG) titres at index gastroscopy were lower in patients with USCD versus conventional coeliac disease (1.8×upper limit of normal (ULN) (IQR 1.1-5.9) vs 12.6×ULN (IQR 3.3-18.3), p<0.001).Patients with USCD had the same number of symptoms overall (median 3 (IQR 2-4) vs 3 (IQR 1-4), p=0.875). Patients with USCD experienced less iron deficiency (41.8% vs 22.4%, p=0.006).Both USCD and conventional coeliac disease had the same intraepithelial lymphocytes immunophenotype staining pattern; positive for CD3 and CD8, but not CD4.At follow-up having commenced a gluten-free diet (GFD) (median of 1181 days IQR: 440-2160 days) both USCD and the age-matched and sex-matched controls experienced a similar reduction in IgA-tTG titres (0.5 ULN (IQR 0.2-1.4) vs 0.7 ULN (IQR 0.2-2.6), p=0.312). 95.7% of patients with USCD reported a clinical improvement in their symptoms. INTERPRETATION: Patients with USCD are younger, have a similar symptomatic burden and benefit from a GFD. This study endorses the recommendation of D1 sampling as part of the endoscopic coeliac disease diagnostic workup.

Persistent villous atrophy predicts development of complications and mortality in adult patients with coeliac disease: a multicentre longitudinal cohort study and development of a score to identify high-risk patients.

OBJECTIVE: Persistent villous atrophy (pVA) in coeliac disease (CD) despite a gluten-free diet (GFD) has unclear meaning. We aimed to (i) study the relationship between pVA and long-term outcomes and (ii) develop a score to identify patients at risk of pVA. DESIGN: This is a multicentre retrospective-prospective study consisting of a study cohort (cohort 1) and an external validation cohort (cohort 2) of patients with biopsy-proven CD diagnosed between 2000 and 2021. Cohort 1 was used to (i) compare long-term outcomes between patients with and without pVA (Marsh ≥3a) at follow-up biopsy and (ii) to develop a score to evaluate the risk of pVA, which was validated in cohort 2. RESULTS: Of 2211 patients, 694 (31%) underwent follow-up duodenal biopsy and were included in the study cohort (491F, 44±16 years). 157/694 (23%) had pVA. Risk of complications (HR 9.53, 95% CI 4.77 to 19.04, p<0.001) and mortality (HR 2.93, 95% CI 1.43 to 6.02, p<0.01) were increased in patients with pVA. A 5-point score was developed and externally validated (receiver operating characteristic area under the curve 0.78, 95% CI 0.68 to 0.89) to stratify patients by risk of pVA: low (0-1 points, 5% pVA), intermediate (2 points, 16% pVA) and high (3-5 points, 73% pVA). Predictors for pVA used in the score were age at diagnosis ≥45 years (OR 2.01, 95% CI 1.21 to 3.34, p<0.01), classical pattern of CD (OR 2.14, 95% CI 1.28 to 3.58, p<0.01), lack of clinical response to GFD (OR 2.40, 95% CI 1.43 to 4.01, p<0.001) and poor GFD adherence (OR 48.9, 95% CI 26.1 to 91.8, p<0.001). CONCLUSIONS: Risk of complications and mortality were increased in patients with pVA. We developed a score to identify patients at risk of pVA and in need of histological reassessment and closer follow-up.

High Prevalence of Functional Gastrointestinal Disorders in Celiac Patients with Persistent Symptoms on a Gluten-Free Diet: A 20-Year Follow-Up Study.

BACKGROUND: Ongoing symptoms in treated celiac disease (CD) are frequent and are commonly thought of as being due to infractions to a gluten-free diet (GFD) or complications. AIMS: To study the etiology and natural history of clinically relevant events (CREs) throughout follow-up and identify predictors thereof to guide follow-up. METHODS: CREs (symptoms/signs requiring diagnostic/therapeutic interventions) occurring in celiac patients between January-2000 and May-2021 were retrospectively collected between June and September 2021 and analysed. RESULTS: One-hundred-and-eighty-nine adult patients (133 F, age at diagnosis 36 ± 13 years, median follow-up 103 months, IQR 54-156) were enrolled. CREs were very common (88/189, 47%), but hardly due to poor GFD adherence (4%) or complications (2%). Interestingly, leading etiologies were functional gastrointestinal disorders (30%), reflux disease (18%) and micronutrient deficiencies (10%). Age at diagnosis ≥ 45 years (HR 1.68, 95%CI 1.05-2.69, p = 0.03) and classical pattern of CD (HR 1.63, 95%CI 1.04-2.54, p = 0.03) were predictors of CREs on a multivariable Cox model. At 5 years, 46% of classical patients ≥ 45 years old at diagnosis were event-free, while this was 62% for non-classical/silent ≥ 45 years, 60% for classical < 45 years, and 80% for non-classical/silent < 45 years. CONCLUSIONS: CREs occurred in almost half of CD patients during follow-up, with functional disorders being very common. New follow-up strategies for adult CD may be developed based on age and clinical pattern at diagnosis.

Non-cognitive skills and social gaps in digital skills: Evidence from ICILS 2018.

Using data from the 2018 round of the International Computer and Literacy Survey (ICILS), this study looks at the effect of non-cognitive skills (e.g., motivation, ambition, and conscientiousness) on digital competences as measured by the Computer and Information Literacy (CIL) test score. Non-cognitive skills may be especially important in low-stakes tests such as ICILS, where students face no consequences - positive or negative - as a result of their performance. The empirical results show that several non-self-reported measures acting as proxies for non-cognitive skills are significant determinants of CIL test scores. Furthermore, the findings point at differences in non-cognitive skills across gender, immigrant background, and socioeconomic status. This suggests that one should be cautious when inferring about inequality in digital competences along these dimensions using low-stakes test scores, and underscores the importance of controlling for non-cognitive skills.

Nomenclature and diagnosis of seronegative coeliac disease and chronic non-coeliac enteropathies in adults: the Paris consensus.

OBJECTIVE: Differential diagnosis of villous atrophy (VA) without coeliac antibodies in adults includes seronegative coeliac disease (CD) and chronic enteropathies unrelated to gluten, ie. non-coeliac enteropathies (NCEs). There is currently no international consensus on the nomenclature and diagnostic criteria for these enteropathies. In this work, a Delphi process was conducted to address this diagnostic and clinical uncertainty. DESIGN: An international task force of 13 gastroenterologists from six countries was recruited at the 16th International Coeliac Disease Symposium, Paris, 2019. Between September 2019 and July 2021, a Delphi process was conducted through mail surveys to reach a consensus on which conditions to consider in the differential diagnosis of VA with negative coeliac serology and the clinical diagnostic approaches required for these conditions. A 70% agreement threshold was adopted. RESULTS: Chronic enteropathies characterised by VA and negative coeliac serology can be attributed to two main clinical scenarios: forms of CD presenting with negative serology, which also include seronegative CD and CD associated with IgA deficiency, and NCEs, with the latter recognising different underlying aetiologies. A consensus was reached on the diagnostic criteria for NCEs assisting clinicians in differentiating NCEs from seronegative CD. Although in adults seronegative CD is the most common aetiology in patients with VA and negative serology, discriminating between seronegative CD and NCEs is key to avoid unnecessary lifelong gluten-free diet, treat disease-specific morbidity and contrast poor long-term outcomes. CONCLUSION: This paper describes the Paris consensus on the definitions and diagnostic criteria for seronegative CD and chronic NCEs in adults.

AGA Clinical Practice Update on the Evaluation and Management of Seronegative Enteropathies: Expert Review.

DESCRIPTION: Our aim was to provide a consensus statement for the best approaches for diagnosis and management of patients with suspected enteropathy, but negative results from serologic tests for celiac disease (seronegative enteropathy). METHODS: We collected findings from published cohort, case-control, and cross-sectional studies of diagnosis and case series and descriptive studies of management of patients believed to have celiac disease or other enteropathies unrelated to gluten, but negative results from serologic tests. BEST PRACTICE ADVICE 1: Review histologic findings with experienced pathologists who specialize in gastroenterology. BEST PRACTICE ADVICE 2: Serologic tests are essential for an accurate diagnosis of celiac disease. For patients with suspected celiac disease but negative results from serologic tests, total IgA level should be measured; patients should also be tested for anti-tissue transglutaminase, IgA against deamidated gliadin peptide, and endomysial antibody (IgA). Patients with total IgA levels below the lower limit of detection and IgG against tissue transglutaminase or deamidated gliadin peptide, or endomysial antibody, should be considered to have celiac disease with selective IgA deficiency rather than seronegative celiac disease. BEST PRACTICE ADVICE 3: Patients' diets should be carefully reviewed and duodenal biopsies should be collected and analyzed at the time of serologic testing to determine exposure to gluten and accuracy of test results. BEST PRACTICE ADVICE 4: Thorough medication histories should be collected from patients, with attention to angiotensin II receptor blockers, such as olmesartan, along with travel histories to identify potential etiologies of villous atrophy. This will guide additional testing. BEST PRACTICE ADVICE 5: Patients should be analyzed for disease-associated variants in human leukocyte antigen genes; results must be carefully interpreted. Negative results can be used to rule out celiac disease in seronegative patients. BEST PRACTICE ADVICE 6: Patients with suspected celiac disease who are seronegative but have villous atrophy and genetic risk factors for celiac disease must undergo endoscopic evaluation after 1-3 years on a gluten-free diet to evaluate improvements in villous atrophy. A diagnosis of seronegative celiac disease can then be confirmed based on clinical and histologic markers of improvement on the gluten-free diet. BEST PRACTICE ADVICE 7: Seronegative patients with an identified cause for enteropathy should be treated accordingly; a follow-up biopsy might or might not be necessary. BEST PRACTICE ADVICE 8: Patients with persistent signs and symptoms who do not respond to a gluten-free diet, and for whom no etiology of enteropathy is ultimately identified, should be treated with budesonide. CONCLUSIONS: These best practice guidelines will aid in diagnosis and management of patients with suspected celiac disease, but negative results from serologic tests.

Determinants and Trends of Adherence to a Gluten-Free Diet in Adult Celiac Patients on a Long-term Follow-up (2000-2020).

BACKGROUND & AIMS: Data on factors governing long-term adherence to a gluten-free diet (GFD) in celiac disease (CD) are scarce. We aimed to determine trends and clinical predictors of long-term GFD adherence in adult CD. METHODS: Initial and long-term (>3 years) GFD adherence, clinical characteristics at baseline and follow-up were collected retrospectively from celiac patients followed-up over 20 years (2000-2020). Predictors of long-term GFD adherence at diagnosis, and follow-up were evaluated by multivariate logistic regression. RESULTS: 248 patients (37 ± 12 years, 186F, median time on a GFD 90 months) were included. Twenty-five (10.1%) had only short-term follow-up (<3 years) while 223 (89.9%) had initial and long-term dietary assessment. 187/223 (83.9%) patients were initially adherent and 36/223 (16.1%) were not. 17/36 (47.2%) patients initially not adherent become adherent, while only 4/187 (2.1%) initially adherent patients became not adherent. In the long-term, 200/223 (89.7%) were adherent and 21/223 (9.4%) patients were not. Adherence improved more frequently than worsened (OR, 39.5; 95% CI, 11.4-178.5; P < .01). Classical symptoms (diarrhea, weight loss) at diagnosis of CD predicted stricter long-term GFD adherence (OR, 3.27; 95% CI, 1.21-8.81; P = .02), while anemia (OR, 0.31; 95% CI, 0.12-0.82; P = .02) and dermatitis herpetiformis (OR, 0.23; 95% CI, 0.06-0.91; P = .04) predicted poorer long-term adherence. At follow-up, initial GFD adherence (OR, 42.70; 95% CI, 10.70-171.00; P = .04) was the major determinant of long-term GFD adherence. CONCLUSIONS: GFD adherence changes over time in <10% of patients, generally improving when it does. Major determinants of long-term GFD adherence are classical symptoms at diagnosis and initial adherence to a GFD. Patients with anemia or dermatitis herpetiformis at diagnosis require stricter dietetic input.

Adherence to international guidelines for the management of Helicobacter pylori infection among gastroenterologists and gastroenterology fellows in Italy: A Survey of the Italian Federation of Digestive Diseases - FISMAD.

BACKGROUND: Information on the management of Helicobacter (H.) pylori infection by gastroenterologists and gastroenterology fellows are scarce. We aimed to assess practice of gastroenterologists and gastroenterology fellows and their adherence to guidelines for diagnosis and treatment of H. pylori infection in Italy. MATERIALS AND METHODS: All gastroenterologists and gastroenterology fellows attending the National Congress of Digestive Diseases - FISMAD were invited to fill-in an on-line questionnaire. The questionnaire included questions on the diagnosis and treatment of H. pylori infection. RESULTS: A total of 279 gastroenterologists and 61 gastroenterology fellows participated to the study. The 13 C-urea breath test was the most preferred method among gastroenterologists and fellows for the diagnosis of H. pylori infection (40.4% and 57.6%, respectively) and the confirmation of eradication (61.3% and 70%, respectively). Sequential therapy was the most preferred first-line treatment of H. pylori for both gastroenterologists and gastroenterology fellows (31.8% and 44%, respectively), followed by bismuth quadruple therapy (31% and 27.6%, respectively) and clarithromycin triple therapy (26.8% and 22.4%, respectively). Only 30% of gastroenterologists and 38.5% of fellows used the clarithromycin triple therapy for the recommended duration of 14 days. Bismuth quadruple therapy was the most preferred second-line therapy for both gastroenterologists and fellows. The majority of gastroenterologists and fellows would prefer an empirical therapy at third line (72.6% and 62.5%, respectively) and a susceptibility-guided therapy at fourth line (46.7% and 71.4%, respectively). CONCLUSIONS: Practices of gastroenterologists and gastroenterology fellows are in line with guidelines' recommendations, apart for the first-line treatment of H. pylori infection. Targeted educational interventions to improve adherence to guidelines are needed.

Long-Term Adherence to a Gluten-Free Diet and Quality of Life of Celiac Patients After Transition to an Adult Referral Center.

BACKGROUND: Modalities for the transition to adult care of celiac patients diagnosed during childhood/adolescence and their impact on long-term adherence to a gluten-free diet (GFD-A), quality of life (QOL) and maintenance of follow-up in adulthood are unknown. AIMS: To evaluate whether timing of transition affects long-term GFD-A, QOL, and continuity of follow-up in adulthood and to identify predictors of long-term GFD-A. METHODS: Clinical and demographic data about pediatric care and adult follow-up at our center were retrospectively collected from clinical notes of celiac patients diagnosed during childhood/adolescence and then referred to our tertiary center. QOL and adult long-term GFD-A were prospectively evaluated with validated questionnaires. These parameters were studied by means of univariate and multivariate statistical analysis. RESULTS: 183 patients (130F, mean age at diagnosis 7.6 ± 5.8 years) were enrolled. Median age at transition to adult care was 20 years (IQR 17-25). There was no relationship between age at transition to adult care, long-term GFD-A, QOL, and continuity of follow-up. GFD-A tended to improve overall from pediatric care to adult referral (OR 2.92, 95% CI 1.13-7.87, p = 0.02) and also throughout adult follow-up (OR 9.0, 95% CI 4.2-19.7, p < 0.01). On multivariable logistic regression analysis, classical symptoms at diagnosis of celiac disease (p = 0.02) and good GFD-A at adult referral (p < 0.01) predicted good long-term GFD-A, while being lost to follow-up predicted poorer long-term GFD-A (p = 0.02). CONCLUSIONS: Clinical characteristics can guide development of personalized strategies for implementing long-term GFD-A and ensure maintenance of regular follow-up in celiac patients diagnosed in childhood/adolescence and transitioning to adult care.

Optimising the follow-up of adult coeliac disease with a clinical-based score to identify patients in need of a histological reassessment: a retrospective single centre study.

Follow-up modalities for adult coeliac patients remain controversial. Non-invasive markers to identify coeliac patients on a gluten-free diet (GFD) with persistence of villous atrophy (VA) are still lacking. We aim to develop a score to stratify coeliac patients on a GFD according to their risk of having persistent VA and to tailor follow-up modalities accordingly. The clinical notes of over 700 coeliac patients attending our unit (September 1999-November 2018) were retrospectively examined. A total of 273 patients on a GFD with a histological follow-up performed 12-24 months after diagnosis were selected. We developed a bivariable model based on diet adherence and clinical response evaluated by previously validated methods. A four-level score (0·5, 1·5, 3, 4) was obtained. Patients on a strict GFD and with good clinical conditions (score 4) have a very low risk of persistence of VA (2 (95 % CI 1, 5) %). Conversely, the risk is very high (46 (95 % CI 25, 68) %) in patients with poor adherence to a GFD and unsatisfactory clinical response (score 0·5). A score of 1·5 (poor GFD adherence and persistent well-being) is linked with a high risk (23 (95 % CI 14, 36) %). Risk is intermediate (6 (95 % CI 3, 10) %) in patients scoring 3 (strict GFD and no/partial clinical improvement). Three patients who developed complications belonged to this scenario. Patients at low risk of persistent VA can be followed-up non-invasively, whereas a biopsy should be repeated in those at high/very high risk. Case-by-case evaluation is needed in patients at intermediate risk. Studies on a larger sample size are required to confirm these data.

Inadvertent and minimal gluten intake has a negligible role in the onset of symptoms in patients with coeliac disease on a gluten-free diet.

Although the quantity of gluten that a well-instructed coeliac patient can involuntarily ingest is <10 mg of gluten/d which cannot induce significant villous damage, coeliac patients often attribute the origin of symptoms to the involuntary ingestion of trace quantities of gluten, either certain or hypothetical. Our aim was to evaluate whether the occurrence of symptoms in coeliac patients who histologically responded to a strict gluten-free diet was related to the involuntary consumption of minimal quantities of gluten. A case-control study to assess the association between gluten exposure and the occurrence of symptoms was designed. Between January 2017 and May 2018, coeliac patients attending our outpatient clinic were interviewed to detect the presence of symptoms. Based on a specifically designed form, patients were also divided into different risk groups of gluten exposure. A total of ninety-five coeliac patients on a strict gluten-free diet and with known histological recovery were enroled. Of them, fifty-two of them reported symptoms and they were enroled as cases; the remaining forty-three patients denied symptoms and were enroled as controls. Although this was not statistically significant, gluten exposure was more frequent in controls (Fisher's exact test, P=0·07). Our results show no relationship between exposure to minimal quantities of gluten and onset of symptoms in coeliac patients. Symptoms are more frequent in patients who have no risk of gluten exposure. It is possible that the presence of these symptoms leads the patients to avoid situations that may place them at risk of gluten exposure.

Two cases of monomorphic epitheliotropic intestinal T-cell lymphoma associated with coeliac disease.

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is an aggressive type of intestinal lymphoma which affects individuals without evidence of enteropathy. In this single-centre case series, we describe the first two cases of MEITL in Caucasian patients suffering from histologically-proven coeliac disease (CD). Original medical records were retrieved and anonymised. All biopsy and surgical MEITL specimens were reviewed by three haematopathologists. Two patients aged 63- and 55-year old at CD diagnosis, subsequently developed a MEITL. MEITL always involved the ileum and was multifocal. Both patients died from complications after surgery, including gastrointestinal bleeding, septic shock and multiorgan failure, with a mean survival since MEITL diagnosis of 15.5 ± 16.3 months. In one case, array-CGH revealed a large deletion on chromosome nine between 9p13.1 and 9p24.1, and a recurrent chromosome gain at 9q33-q34. Our cases indicate that a subset of MEITL may arise in Caucasian patients suffering from CD. The clinical, pathological and molecular features of these cases show a partial overlap with enteropathy-associated T-cell lymphoma.

The high mortality of patients with common variable immunodeficiency and small bowel villous atrophy.

OBJECTIVES: Common variable immunodeficiency (CVID) is a primary humoral immunodeficiency characterised by reduced serum levels of immunoglobulins, recurrent infections, autoimmune phenomena and lymphoproliferative disorders. Gastrointestinal symptoms are very common in these patients and a coeliac-like villous atrophy was described in some of them. Since mortality in CVID is much higher than in the general population, our aim was to evaluate mortality rates and clinical predictors of survival in patients with both CVID and duodenal villous atrophy. PATIENTS AND METHODS: Sex, date of diagnosis of villous atrophy, HLA genomic typing, date of death/last follow-up, type of complication were retrospectively collected from medical files. Univariate analysis for each predictor was conducted and Kaplan-Meier curves were generated to evaluate survival. RESULTS: Twenty-three patients were enrolled (9 females, mean age at diagnosis of villous atrophy 38 ± 13 years) and 8 of them died after a median time of 96 months (25th-75th 60-120 months) corresponding to a mortality rate of 3.9 per 100 person-years (95% CI 1.9-7.7). Mortality was higher in men compared to women (60 vs. 11/1000 person-years), although not statistically significant. Causes of death included onco-haematological disorders and infections. CONCLUSIONS: Although based on a small cohort, our results confirm that patients with CVID and villous atrophy are burdened by a very high mortality mainly due to onco-immunological disorders and infections. Strict follow-up is required in these patients.

Intestinal T-cell lymphoma with enteropathy-associated T-cell lymphoma-like features arising in the setting of adult autoimmune enteropathy.

Enteropathy-associated T-cell lymphoma is regarded as a dismal, late complication of coeliac disease, though a single case of T-cell lymphoma with such features arising in the setting of autoimmune enteropathy of the adult has been reported to date. We aim to describe the case of a 41-year-old woman complaining of severe malabsorption syndrome, who was diagnosed with autoimmune enteropathy based on the presence of flat intestinal mucosa unresponsive to any dietary restriction and positivity for enterocyte autoantibodies. Steroid therapy led to a complete recovery of both mucosal and clinical findings over 12 years, when disease relapse was accompanied by the appearance of monoclonal rearrangement of T-cell receptor-γ and peculiar T-cell phenotypic abnormalities, leading to a rapid transition to an overt T-cell lymphoma with features of the enteropathy-associated subtype. Despite intensive treatment, the patient developed cerebral metastasis and died 9 months later. Our case enhances the concept of enteropathy-associated T-cell lymphoma as a disease that may arise in the setting of enteropathies other than coeliac disease, thus representing a heterogeneous entity. Moreover, our observations support the need of a close follow-up of these patients, coupled with comprehensive characterization of mucosal biopsies.

Seronegative coeliac disease: clearing the diagnostic dilemma.

PURPOSE OF REVIEW: Seronegative coeliac disease is a poorly defined form of coeliac disease that poses an important challenge to clinicians particularly with regards to the differential diagnosis. This is probably because of lack of a consensus on its definition and incorrect use of specific coeliac serology. Seronegative coeliac disease (SCD) is uncommon and epidemiological data are scarce and contrasting. Therefore, the aim of this review is to provide a critical summary of the most recent work on this topic and a definition of SCD. RECENT FINDINGS: SCD is rare among coeliac patients but conversely SCD remains one of the most common causes of seronegative villous atrophy. The diagnostic workup of seronegative villous atrophy (SNVA) must ensure exclusion of other enteropathies before starting patients on a lifelong gluten-free diet. This is crucial in order to ensure that patients are not given the wrong diagnosis, which in turn can have implications for their inappropriate treatment and long-term morbidity. Finally, there is some data to suggest that seronegative enteropathies have a higher mortality than conventional coeliac disease. SUMMARY: Seronegative coeliac disease is a rare condition that accounts for a very small percentage of cases in the large population of coeliac patients. Strict criteria for the diagnosis of this condition need to be fulfilled and prompt identification of these patients is crucial in order to ensure the appropriate intervention on a case-by-case basis.

The Relationship Between Child Mortality Rates and Prevalence of Celiac Disease.

OBJECTIVES: Some evidence suggests that prevalence of celiac disease in the general population is increasing over time. Because the prognosis of celiac disease was a dismal one before discovering the role of gluten, our aim was to investigate a possible relationship between children under-5 mortality rates and prevalence rates of celiac disease. METHODS: Thanks to a literature review, we found 27 studies performed in 17 different countries describing the prevalence of celiac disease in schoolchildren; between 1995 and 2011, 4 studies were performed in Italy. A meta-analysis of prevalence rates was performed. Prevalence was compared between specific country under-5 mortality groups, publication year, and age. RESULTS: In the last decades, under-5 mortality rates have been decreasing all over the world. This reduction is paralleled by an increase of the prevalence of celiac disease. The Spearman correlation coefficient was -63%, 95% confidence interval -82% to -33% (P < 0.001). So, the higher the mortality rate, the lower the prevalence of CD. This finding is confirmed by the meta-analysis of the 4 studies conducted in Italy over time. CONCLUSIONS: The under-5 mortality rate seems to influence the prevalence of celiac disease in the general population. In the near future, the number of patients with celiac disease will increase, thanks to the better environmental conditions that nowadays allow a better survival of children with celiac disease.

Peripheral T-Cell Reactivity to Heat Shock Protein 70 and Its Cofactor GrpE from Tropheryma whipplei Is Reduced in Patients with Classical Whipple's Disease.

Classical Whipple's disease (CWD) is characterized by the lack of specific Th1 response toward Tropheryma whipplei in genetically predisposed individuals. The cofactor GrpE of heat shock protein 70 (Hsp70) from T. whipplei was previously identified as a B-cell antigen. We tested the capacity of Hsp70 and GrpE to elicit specific proinflammatory T-cell responses. Peripheral mononuclear cells from CWD patients and healthy donors were stimulated with T. whipplei lysate or recombinant GrpE or Hsp70 before levels of CD40L, CD69, perforin, granzyme B, CD107a, and gamma interferon (IFN-γ) were determined in T cells by flow cytometry. Upon stimulation with total bacterial lysate or recombinant GrpE or Hsp70 of T. whipplei, the proportions of activated effector CD4+ T cells, determined as CD40L+ IFN-γ+, were significantly lower in patients with CWD than in healthy controls; CD8+ T cells of untreated CWD patients revealed an enhanced activation toward unspecific stimulation and T. whipplei-specific degranulation, although CD69+ IFN-γ+ CD8+ T cells were reduced upon stimulation with T. whipplei lysate and recombinant T. whipplei-derived proteins. Hsp70 and its cofactor GrpE are immunogenic in healthy individuals, eliciting effective responses against T. whipplei to control bacterial spreading. The lack of specific T-cell responses against these T. whipplei-derived proteins may contribute to the pathogenesis of CWD.

What is the best therapy for Whipple's disease? Our point of view.

Although Whipple's disease (WD) has been treated with antibiotics since the early 50s, the best antibiotics and the duration of the therapy have not yet been established. We consider here the pro and cons of the two most commonly used therapies, ceftriaxone followed by trimethoprim-sulfamethoxazole (TMP-SMZ) and hydroxychloroquine in combination with doxycycline. The therapy based on ceftriaxone and TMP-SMZ is efficient in the vast majority of patients for the first few years. However, since reinfections or reactivations can occur, a life-long prophylaxis is necessary and doxycycline is nowadays the best option. We thus propose a therapy based on merging these to therapies together, ceftriaxone, and TMP-SMZ for the first year(s) and then life-long prophylaxis with doxycycline.

Detection of Active Epstein-Barr Virus Infection in Duodenal Mucosa of Patients With Refractory Celiac Disease.

Refractory celiac disease is characterized by mucosal damage in patients with celiac disease despite a gluten-free diet. Little is known about the mechanisms that cause persistent intestinal inflammation in these patients. We performed a case-control study of 17 consecutive patients diagnosed with refractory celiac disease from 2001 through 2014 (median age, 51 y; 10 women) and 24 patients with uncomplicated celiac disease (controls) to determine whether refractory disease is associated with infection by lymphotropic oncogenic viruses. We performed real-time PCR analyses of duodenal biopsy samples from all patients to detect Epstein-Barr virus (EBV), human herpesvirus-8, and human T-cell lymphotropic virus-I, -II, or -III. We used in situ hybridization and immunohistochemical analyses to identify infected cells and viral proteins. We did not detect human herpesvirus-8 or human T-cell lymphotropic viruses in any of the biopsy specimens. However, 12 of 17 (70.5%) biopsy specimens from patients with refractory celiac disease were positive for EBV, compared with 4 of 24 (16.6%) biopsy specimens from controls (P < .001). EBV was detected in inflammatory cells and enterocytes. An analysis of latency- and replication-associated proteins confirmed active infection. Further studies are needed to determine whether EBV infection contributes to the pathogenesis of refractory celiac disease and enteropathy-associated T-cell lymphoma.