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Papers by Carolina Grande

Journal of Translational Medicine, 2021

An amendment to this paper has been published and can be accessed via the original article.

Journal of Translational Medicine, 2020

The outbreak of the novel coronavirus disease 2019 (COVID-19) and consequent social distancing pr... more The outbreak of the novel coronavirus disease 2019 (COVID-19) and consequent social distancing practices have disrupted essential clinical research functions worldwide. Ironically, this coincides with an immediate need for research to comprehend the biology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the pathology of COVID-19. As the global crisis has already led to over 15,000 deaths out of 175,000 confirmed cases in New York City and Nassau County, NY alone, it is increasingly urgent to collect patient biospecimens linked to active clinical follow up. However, building a COVID-19 biorepository amidst the active pandemic is a complex and delicate task. To help facilitate rapid, robust, and regulated research on this novel virus, we report on the successful model implemented by New York University Langone Health (NYULH) within days of outbreak in the most challenging hot spot of infection globally. Using an amended institutional biobanking protocol, these eff...

Effective public response to a pandemic relies upon accurate measurement of the extent and dynami... more Effective public response to a pandemic relies upon accurate measurement of the extent and dynamics of an outbreak. Viral genome sequencing has emerged as a powerful approach to link seemingly unrelated cases, and large-scale sequencing surveillance can inform on critical epidemiological parameters. Here, we report the analysis of 864 SARS-CoV-2 sequences from cases in the New York City metropolitan area during the COVID-19 outbreak in Spring 2020. The majority of cases had no recent travel history or known exposure, and genetically linked cases were spread throughout the region. Comparison to global viral sequences showed that early transmission was most linked to cases from Europe. Our data are consistent with numerous seeds from multiple sources and a prolonged period of unrecognized community spreading. This work highlights the complementary role of genomic surveillance in addition to traditional epidemiological indicators.

American Journal of Gastroenterology, 2011

Journal of clinical pathology, Jan 27, 2018

Refractory coeliac disease type II (RCDII), a rare complication of coeliac disease (CD) associate... more Refractory coeliac disease type II (RCDII), a rare complication of coeliac disease (CD) associated with high morbidity, requires identification of a clonal population of phenotypically aberrant intraepithelial lymphocytes (IELs) for diagnosis. However, data regarding the frequency and significance of clonal T cell receptor (TCR) gene rearrangements (TCR-GRs) in small bowel (SB) biopsies of patients without RCDII are limited. We analysed results of TCR-GR analyses performed on SB biopsies at our institution over a 3-year period, which were obtained from eight active CD, 172 CD on gluten-free diet (GFD), 33 RCDI, and three RCDII patients and 14 patients without CD. TCR-GR patterns were divided into clonal, polyclonal and prominent clonal peaks (PCPs) and these patterns were correlated with clinical and pathological features. Clonal TCR-GR products were detected in biopsies from 67% of patients with RCDII, 17% of patients with RCDI and 6% of patients with GFD. PCPs were observed in all...

Gastroenterology, 2012

BACKGROUND. Celiac disease (CD) is an autoimmune enteropathy that affects 1% of the general popul... more BACKGROUND. Celiac disease (CD) is an autoimmune enteropathy that affects 1% of the general population. The association between CD and other autoimmune disorders is well established and increased prevalence of CD has been found in patients with type 1 diabetes (7%) and autoimmune thyroiditis (2%). Some reports on co-morbidity of CD and alopecia areata (AA), an autoimmune skin disorder that causes hair loss, have shown a variable hair re-growth upon institution of a gluten-free diet. No studies have addressed the association between CD and the different clinical subtypes of AA, which vary in duration and degree of hair loss. The aim of this study was to investigate the prevalence of CD across the phenotypic spectrum of AA using serological screening methods that have high sensitivity and specificity for CD diagnosis. METHODS. Sera obtained through the National Alopecia Areata Registry of the United States from 16 patients with transient AA (AAT), 24 with patchy persistent AA (AAP), 27 with total scalp hair loss (AT) and 32 with complete body hair loss (AU), were screened for CD using a commercial ELISA kit against combined antitissue transglutaminase and anti-deamidated gliadin peptide IgA and IgG antibodies (anti-tTG/DGP) from INOVA Diagnostics Inc. Titers >20 IU were considered positive and titers >30 IU were considered strongly positive and suggestive of CD. RESULTS. Of 99 samples (females=64, males=35), a total of 9 (9%) patients (all female) were positive for anti-tTG/ DGP antibodies (range 20.4-61.7 IU) and 4% (2 AT, 1 AU and 1 AAP) were strongly positive. By type of presentation, anti-tTG/DGP titers were elevated in 15% AT, 9% AU and 8% AAP patients but in none of AAT patients. CONCLUSIONS. These results demonstrate that AA patients have a higher prevalence of CD-associated antibodies (9%) than the general population (~3%). CD seropositivity is present in the more severe forms of AA, where hair loss is experienced for more than one year and/or results in total loss of hair from the scalp and/or body. Patients with the least severe form of the disease, transient hair loss lasting less than one year, do not appear to have an elevated risk for CD. Screening for CD is recommended in AA for early detection and institution of a gluten-free diet.

Gastroenterology, 2012

and four kits (2.5%, 95% CI 0.8%-6.4% of total) were returned and confirmed to be positive by stu... more and four kits (2.5%, 95% CI 0.8%-6.4% of total) were returned and confirmed to be positive by study investigators. Five participants (3.1%) were unable to interpret the test, and of these five tests, 4 kits were returned of which 2 were un-interpretable by investigators and 2 were negative. In the 34 kits not returned, one was read as positive (2.9%), one was uninterpretable (2.9%) and the rest were negative. Demographics and comorbidities were similar in participants who tested positive and negative with the exception that positive results were more common in male participants. See Table 1 for clinical characteristics of the study population. Investigator and participant readings were concordant in 95.6% of cases. Conclusions: 96.6% of the participants were able to perform self-administered, pointof-care celiac testing and report a positive or negative result. Further, the reported test result was highly concordant with physician assessment. While this study did not allow for definitive assessment for celiac disease, the percent positive results (2.5%) is within the expected range for this population and prior studies support high sensitivity and specificity of this assay. It is notable also that the majority of positive tests were in men, a population in whom celiac diagnostic rates are particularly low. Overall, self-administered, point-of-care celiac testing appears to be viable and may be an effective strategy for evaluation of at-risk individuals who may not otherwise be tested for CD. Table1. Demographics of screened subjects *One kit was not returned and one kit was read as negative by investigators. **One of the kits reported to be negative by subjects was interpreted to be positive by the investigators. ***Some co-morbidity entries were unfilled by subjects.

Journal of clinical pathology, 2015

A severe syndrome characterised by life-threatening diarrhoea and severe sprue-like histology has... more A severe syndrome characterised by life-threatening diarrhoea and severe sprue-like histology has been described in patients taking the angiotensin receptor blocker (ARB) olmesartan. It is unknown whether there are any histopathological changes in patients without severe diarrhoea exposed to this medication. It is also unknown whether other ARBs cause sprue-like histology. Retrospective cohort study of patients with abdominal pain undergoing upper gastrointestinal endoscopy with duodenal biopsy who were taking ARBs. Patients taking olmesartan (n=20) and a non-olmesartan ARB (n=20) were compared with age and sex-matched controls. Histological features (classic sprue-like and other inflammatory changes) were analysed. No single histopathological finding was significantly more common in olmesartan-using patients than controls. However, 10 of 20 olmesartan patients had one or more sprue-like histological features compared with 4 of 20 age-matched and sex-matched controls not taking ARBs...

Mayo Clinic Proceedings, 2014

Objective-To investigate a recent association between use of the angiotensin receptor-blocker (AR... more Objective-To investigate a recent association between use of the angiotensin receptor-blocker (ARB) olmesartan and a severe enteropathy resembling celiac disease. Patients and Methods-We searched our endoscopy database for all outpatient esophagogastroduodenoscopy (EGD) or colonoscopy examinations in patients at least 50 years of age during the dates January 1, 2007 to March 31, 2013. Cases were those whose examination indication was diarrhea, and controls were those whose examination indication was esophageal reflux (EGD) or colorectal cancer screening (colonoscopy). We compared cases to controls with regard to the proportion of those listing olmesartan among their medications. Secondary exposures were the proportion of those taking non-olmesartan ARBs or other anti-hypertensive medications. We also examined biopsy results to determine if there were histologic changes associated with olmesartan use. Results-We identified 2088 patients undergoing EGD and 12428 patients undergoing colonoscopy meeting inclusion criteria. On multivariate analysis, there was no statisticallysignificant association between olmesartan and diarrhea among those undergoing EGD (OR 1.99 95% CI 0.79-5.00) or colonoscopy (OR 0.63 95% CI 0.23-1.74). Review of pathology reports of the EGD and colonoscopy groups showed no association between olmesartan use and the histologic diagnosis of celiac disease (p=0.61) or microscopic colitis (p=1.0), respectively.

PLoS ONE, 2014

IgA nephropathy is the most common form of primary glomerulonephritis worldwide. Mucosal infectio... more IgA nephropathy is the most common form of primary glomerulonephritis worldwide. Mucosal infections and food antigens, including wheat gluten, have been proposed as potential contributing environmental factors. Increased immune reactivity to gluten and/or association with celiac disease, an autoimmune disorder triggered by ingestion of gluten, have been reported in IgA nephropathy. However, studies are inconsistent about this association. We aimed to evaluate the proposed link between IgA nephropathy and celiac disease or immune reactivity to gluten by conducting a comprehensive analysis of associated serologic markers in cohorts of well-characterized patients and controls. Study participants included patients with biopsy-proven IgA nephropathy (n = 99), unaffected controls of similar age, gender, and race (n = 96), and patients with biopsy-proven celiac disease (n = 30). All serum specimens were tested for IgG and IgA antibodies to native gliadin and deamidated gliadin, as well as IgA antibody to transglutaminase 2 (TG2). Anti-TG2 antibody-positive nephropathy patients and unaffected controls were subsequently tested for IgA anti-endomysial antibody and genotyped for celiac disease-associated HLA-DQ2 and-DQ8 alleles. In comparison to unaffected controls, there was not a statistically significant increase in IgA or IgG antibody reactivity to gliadin in individuals with IgA nephropathy. In addition, the levels of celiac disease-specific serologic markers, i.e., antibodies to deamidated gliadin and TG2, did not differ between IgA nephropathy patients and unaffected controls. Results of the additional anti-endomysial antibody testing and HLA genotyping were corroborative. The data from this case-control study do not reveal any evidence to suggest a significant role for celiac disease or immune reactivity to gluten in IgA nephropathy.

Modern Pathology, 2009

Collagenous sprue is associated with high morbidity; however, the etiology of this disorder is un... more Collagenous sprue is associated with high morbidity; however, the etiology of this disorder is unclear. Data regarding the pathological and clinical manifestations of patients with collagenous sprue are also limited. We, thus, undertook this study to gain insight into the etiology, disease manifestations and outcomes of collagenous sprue. We searched our departmental database (1999-2008) to identify cases of collagenous sprue and to obtain clinical and laboratory data. Small bowel histology, including thickness of subepithelial collagen, intra-epithelial lymphocyte phenotype and results of T-cell clonality assays were evaluated. Nineteen patients (15 women, 4 men, age 22-80 years, mean 57 years) were identified. Seventeen (89%) had celiac disease and two had unclassified sprue; 9 of 17 (53%) celiac disease patients had refractory disease; 5 of 15 (33%) lacked diarrhea (atypical presentation), including 2 of 6 (33%) with active (untreated) celiac disease and 3 of 9 (33%) with refractory celiac disease. Autoimmune disorders were seen in 12 of 19 (63%) patients and microscopic colitis (n ¼ 7), lymphocytic gastritis (n ¼ 2) or collagenous gastritis (n ¼ 2) were seen in nine patients. Subepithelial collagen thickness was mildly (n ¼ 6), moderately (n ¼ 10), or markedly (n ¼ 3) increased and villous atrophy was total (n ¼ 13) or subtotal (n ¼ 6). Phenotypically aberrant intraepithelial lymphocytes were not detected in any case. Polymerase chain reaction analysis showed a dominant T-cell clone in the only patient with refractory celiac disease type II. Histological improvement occurred in 7 of 11 (64%) patients. Overall, 8 of 19 (42%) responded to gluten-free diet, including 2 of 9 (22%) with refractory celiac disease and 10 responded to immunomodulatory therapy, including 6 of 9 (67%) with refractory celiac disease. Only one patient died from complications of refractory celiac disease. No patient developed lymphoma. The vast majority of our patients with collagenous sprue had celiac disease. Although, many patients required immunomodulatory therapy for symptom control, a subset responded to gluten-free diet alone. In our experience, collagenous sprue patients had relatively good clinical outcomes.

Journal of Clinical Pathology, 2011

Background and Aims Coeliac disease (CD) diagnosis requires the detection of characteristic histo... more Background and Aims Coeliac disease (CD) diagnosis requires the detection of characteristic histological alterations of small bowel mucosa, which are prone to interobserver variability. This study evaluated the agreement in biopsy interpretation between different pathology practice types. Methods Biopsies from community hospitals (n¼46), university hospitals (n¼18) and commercial laboratories (n¼38) were blindly assessed by a pathologist at our institution for differences in histopathology reporting and agreement in diagnosis of CD and degree of villous atrophy (VA) by k analysis. Results Agreement for primary diagnosis was very good between this institution and university hospitals (k¼0.888), but moderate compared with community hospitals (k¼0.465) or commercial laboratories (k¼0.419). Diagnosis differed in 26 (25%) cases, leading to a 20% increase in CD diagnosis after review. Among those diagnosed with CD by both institutions (n¼49), agreement in degree of VA was fair (k¼0.292), with moderate agreement between the authors and commercial laboratories (k¼0.500) and fair with university hospitals (k¼0.290) or community hospitals (k¼0.211). The degree of VA was upgraded in 27% and downgraded in 2%. Within different Marsh score categories, agreement was poor (k<0.0316) for scores 1 and 2, both missed at other centres, and fair or moderate for scores 3a and 3b. Information regarding degree of VA and intraepithelial lymphocytosis was lacking in 26% and 86% of reports and non-quantifiable descriptors, eg, 'blunting' or 'marked atrophy' were prevalent. Conclusions CD-related histological changes are underdiagnosed in community-based hospitals and commercial pathology laboratories. Because incorrect biopsy interpretation can cause underdiagnosis of CD, greater CD awareness and uniformity in small bowel biopsy reporting is required among pathologists.

Journal of Clinical Gastroenterology, 2013

Background: Classification of refractory celiac disease (RCD) is based on the presence or absence... more Background: Classification of refractory celiac disease (RCD) is based on the presence or absence of monoclonal expansions of intraepithelial lymphocytes (IELs) with an aberrant immunophenotype. Goals: To investigate the contribution of IEL parameters toward mortality and morbidity in RCD.

Gastroenterology, 2009

Only two of the 48 patients could be classified as having an abnormal number of mast cells (more ... more Only two of the 48 patients could be classified as having an abnormal number of mast cells (more than 20 MC/HPF). Conclusion: Gastrointestinal mucosal mast cells are not increased in patients with active celiac disease. Though increased numbers of mast cell are routinely observed in the sub mucosa of celiac patients, it is important to make the distinction between the exact location of mast cells and their corresponding function or actions.

Gastroenterology, 2010

G A A b st ra ct s inclusion in formalin (Group 1) and the rest were directly included in formali... more G A A b st ra ct s inclusion in formalin (Group 1) and the rest were directly included in formalin (Group 2). All biopsies were reviewed blind by two pathologists and consensus was reached about their mucosal orientation and epithelium integrity. Results. Biopsies from20 patients were included (mean age 31.05, δ2 14.81, 13 women/7 men, 5 pediatric cases). AcTG were positive in 7 patients. HLA DQ2 was present in 15 patients, HLA DQ8 in 3 patients, 2 patients presented both HLA types. One hundred and twelve biopsies were obtained (mean 5.6 per patient, δ2 0.76). Two patients presented intraepithelial lymphocytosis compatible with Marsh 1, 7 patients presented a Marsh III lesion, 1 patient a non-specific chronic duodenitis and the rest were normal. Group 1 comprised by 59 biopsies (mean 2.95 per patient, δ2 0.88) and there were 53 biopsies in group 2 (mean 2.65 per patient, δ2 0.59). The pathologist considered the mucosa to be well-oriented in 84 % (50/59) of biopsies of group 1 vs. 47 % (25/53) in group 2 (p<0.001). Twelve biopsies of group 1 and 13 biopsies of group 2 were denudated (p N.S.). Only three patients had one or no biopsy belonging to Group 1 well oriented vs. 13 patients when biopsies of group 2 were considered (p=0.003). Conclusions. A significant proportion of endoscopic duodenal biopsies are not well-oriented. Manual orientation of duodenal endoscopic biopsies at the moment of their obtention is useful to improve their quality without its manipulation affecting the integrity of the epithelium.

Gastroenterology, 2010

G A A b st ra ct s inclusion in formalin (Group 1) and the rest were directly included in formali... more G A A b st ra ct s inclusion in formalin (Group 1) and the rest were directly included in formalin (Group 2). All biopsies were reviewed blind by two pathologists and consensus was reached about their mucosal orientation and epithelium integrity. Results. Biopsies from20 patients were included (mean age 31.05, δ2 14.81, 13 women/7 men, 5 pediatric cases). AcTG were positive in 7 patients. HLA DQ2 was present in 15 patients, HLA DQ8 in 3 patients, 2 patients presented both HLA types. One hundred and twelve biopsies were obtained (mean 5.6 per patient, δ2 0.76). Two patients presented intraepithelial lymphocytosis compatible with Marsh 1, 7 patients presented a Marsh III lesion, 1 patient a non-specific chronic duodenitis and the rest were normal. Group 1 comprised by 59 biopsies (mean 2.95 per patient, δ2 0.88) and there were 53 biopsies in group 2 (mean 2.65 per patient, δ2 0.59). The pathologist considered the mucosa to be well-oriented in 84 % (50/59) of biopsies of group 1 vs. 47 % (25/53) in group 2 (p<0.001). Twelve biopsies of group 1 and 13 biopsies of group 2 were denudated (p N.S.). Only three patients had one or no biopsy belonging to Group 1 well oriented vs. 13 patients when biopsies of group 2 were considered (p=0.003). Conclusions. A significant proportion of endoscopic duodenal biopsies are not well-oriented. Manual orientation of duodenal endoscopic biopsies at the moment of their obtention is useful to improve their quality without its manipulation affecting the integrity of the epithelium.

Journal of Translational Medicine, 2021

An amendment to this paper has been published and can be accessed via the original article.

Journal of Translational Medicine, 2020

The outbreak of the novel coronavirus disease 2019 (COVID-19) and consequent social distancing pr... more The outbreak of the novel coronavirus disease 2019 (COVID-19) and consequent social distancing practices have disrupted essential clinical research functions worldwide. Ironically, this coincides with an immediate need for research to comprehend the biology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the pathology of COVID-19. As the global crisis has already led to over 15,000 deaths out of 175,000 confirmed cases in New York City and Nassau County, NY alone, it is increasingly urgent to collect patient biospecimens linked to active clinical follow up. However, building a COVID-19 biorepository amidst the active pandemic is a complex and delicate task. To help facilitate rapid, robust, and regulated research on this novel virus, we report on the successful model implemented by New York University Langone Health (NYULH) within days of outbreak in the most challenging hot spot of infection globally. Using an amended institutional biobanking protocol, these eff...

Effective public response to a pandemic relies upon accurate measurement of the extent and dynami... more Effective public response to a pandemic relies upon accurate measurement of the extent and dynamics of an outbreak. Viral genome sequencing has emerged as a powerful approach to link seemingly unrelated cases, and large-scale sequencing surveillance can inform on critical epidemiological parameters. Here, we report the analysis of 864 SARS-CoV-2 sequences from cases in the New York City metropolitan area during the COVID-19 outbreak in Spring 2020. The majority of cases had no recent travel history or known exposure, and genetically linked cases were spread throughout the region. Comparison to global viral sequences showed that early transmission was most linked to cases from Europe. Our data are consistent with numerous seeds from multiple sources and a prolonged period of unrecognized community spreading. This work highlights the complementary role of genomic surveillance in addition to traditional epidemiological indicators.

American Journal of Gastroenterology, 2011

Journal of clinical pathology, Jan 27, 2018

Refractory coeliac disease type II (RCDII), a rare complication of coeliac disease (CD) associate... more Refractory coeliac disease type II (RCDII), a rare complication of coeliac disease (CD) associated with high morbidity, requires identification of a clonal population of phenotypically aberrant intraepithelial lymphocytes (IELs) for diagnosis. However, data regarding the frequency and significance of clonal T cell receptor (TCR) gene rearrangements (TCR-GRs) in small bowel (SB) biopsies of patients without RCDII are limited. We analysed results of TCR-GR analyses performed on SB biopsies at our institution over a 3-year period, which were obtained from eight active CD, 172 CD on gluten-free diet (GFD), 33 RCDI, and three RCDII patients and 14 patients without CD. TCR-GR patterns were divided into clonal, polyclonal and prominent clonal peaks (PCPs) and these patterns were correlated with clinical and pathological features. Clonal TCR-GR products were detected in biopsies from 67% of patients with RCDII, 17% of patients with RCDI and 6% of patients with GFD. PCPs were observed in all...

Gastroenterology, 2012

BACKGROUND. Celiac disease (CD) is an autoimmune enteropathy that affects 1% of the general popul... more BACKGROUND. Celiac disease (CD) is an autoimmune enteropathy that affects 1% of the general population. The association between CD and other autoimmune disorders is well established and increased prevalence of CD has been found in patients with type 1 diabetes (7%) and autoimmune thyroiditis (2%). Some reports on co-morbidity of CD and alopecia areata (AA), an autoimmune skin disorder that causes hair loss, have shown a variable hair re-growth upon institution of a gluten-free diet. No studies have addressed the association between CD and the different clinical subtypes of AA, which vary in duration and degree of hair loss. The aim of this study was to investigate the prevalence of CD across the phenotypic spectrum of AA using serological screening methods that have high sensitivity and specificity for CD diagnosis. METHODS. Sera obtained through the National Alopecia Areata Registry of the United States from 16 patients with transient AA (AAT), 24 with patchy persistent AA (AAP), 27 with total scalp hair loss (AT) and 32 with complete body hair loss (AU), were screened for CD using a commercial ELISA kit against combined antitissue transglutaminase and anti-deamidated gliadin peptide IgA and IgG antibodies (anti-tTG/DGP) from INOVA Diagnostics Inc. Titers >20 IU were considered positive and titers >30 IU were considered strongly positive and suggestive of CD. RESULTS. Of 99 samples (females=64, males=35), a total of 9 (9%) patients (all female) were positive for anti-tTG/ DGP antibodies (range 20.4-61.7 IU) and 4% (2 AT, 1 AU and 1 AAP) were strongly positive. By type of presentation, anti-tTG/DGP titers were elevated in 15% AT, 9% AU and 8% AAP patients but in none of AAT patients. CONCLUSIONS. These results demonstrate that AA patients have a higher prevalence of CD-associated antibodies (9%) than the general population (~3%). CD seropositivity is present in the more severe forms of AA, where hair loss is experienced for more than one year and/or results in total loss of hair from the scalp and/or body. Patients with the least severe form of the disease, transient hair loss lasting less than one year, do not appear to have an elevated risk for CD. Screening for CD is recommended in AA for early detection and institution of a gluten-free diet.

Gastroenterology, 2012

and four kits (2.5%, 95% CI 0.8%-6.4% of total) were returned and confirmed to be positive by stu... more and four kits (2.5%, 95% CI 0.8%-6.4% of total) were returned and confirmed to be positive by study investigators. Five participants (3.1%) were unable to interpret the test, and of these five tests, 4 kits were returned of which 2 were un-interpretable by investigators and 2 were negative. In the 34 kits not returned, one was read as positive (2.9%), one was uninterpretable (2.9%) and the rest were negative. Demographics and comorbidities were similar in participants who tested positive and negative with the exception that positive results were more common in male participants. See Table 1 for clinical characteristics of the study population. Investigator and participant readings were concordant in 95.6% of cases. Conclusions: 96.6% of the participants were able to perform self-administered, pointof-care celiac testing and report a positive or negative result. Further, the reported test result was highly concordant with physician assessment. While this study did not allow for definitive assessment for celiac disease, the percent positive results (2.5%) is within the expected range for this population and prior studies support high sensitivity and specificity of this assay. It is notable also that the majority of positive tests were in men, a population in whom celiac diagnostic rates are particularly low. Overall, self-administered, point-of-care celiac testing appears to be viable and may be an effective strategy for evaluation of at-risk individuals who may not otherwise be tested for CD. Table1. Demographics of screened subjects *One kit was not returned and one kit was read as negative by investigators. **One of the kits reported to be negative by subjects was interpreted to be positive by the investigators. ***Some co-morbidity entries were unfilled by subjects.

Journal of clinical pathology, 2015

A severe syndrome characterised by life-threatening diarrhoea and severe sprue-like histology has... more A severe syndrome characterised by life-threatening diarrhoea and severe sprue-like histology has been described in patients taking the angiotensin receptor blocker (ARB) olmesartan. It is unknown whether there are any histopathological changes in patients without severe diarrhoea exposed to this medication. It is also unknown whether other ARBs cause sprue-like histology. Retrospective cohort study of patients with abdominal pain undergoing upper gastrointestinal endoscopy with duodenal biopsy who were taking ARBs. Patients taking olmesartan (n=20) and a non-olmesartan ARB (n=20) were compared with age and sex-matched controls. Histological features (classic sprue-like and other inflammatory changes) were analysed. No single histopathological finding was significantly more common in olmesartan-using patients than controls. However, 10 of 20 olmesartan patients had one or more sprue-like histological features compared with 4 of 20 age-matched and sex-matched controls not taking ARBs...

Mayo Clinic Proceedings, 2014

Objective-To investigate a recent association between use of the angiotensin receptor-blocker (AR... more Objective-To investigate a recent association between use of the angiotensin receptor-blocker (ARB) olmesartan and a severe enteropathy resembling celiac disease. Patients and Methods-We searched our endoscopy database for all outpatient esophagogastroduodenoscopy (EGD) or colonoscopy examinations in patients at least 50 years of age during the dates January 1, 2007 to March 31, 2013. Cases were those whose examination indication was diarrhea, and controls were those whose examination indication was esophageal reflux (EGD) or colorectal cancer screening (colonoscopy). We compared cases to controls with regard to the proportion of those listing olmesartan among their medications. Secondary exposures were the proportion of those taking non-olmesartan ARBs or other anti-hypertensive medications. We also examined biopsy results to determine if there were histologic changes associated with olmesartan use. Results-We identified 2088 patients undergoing EGD and 12428 patients undergoing colonoscopy meeting inclusion criteria. On multivariate analysis, there was no statisticallysignificant association between olmesartan and diarrhea among those undergoing EGD (OR 1.99 95% CI 0.79-5.00) or colonoscopy (OR 0.63 95% CI 0.23-1.74). Review of pathology reports of the EGD and colonoscopy groups showed no association between olmesartan use and the histologic diagnosis of celiac disease (p=0.61) or microscopic colitis (p=1.0), respectively.

PLoS ONE, 2014

IgA nephropathy is the most common form of primary glomerulonephritis worldwide. Mucosal infectio... more IgA nephropathy is the most common form of primary glomerulonephritis worldwide. Mucosal infections and food antigens, including wheat gluten, have been proposed as potential contributing environmental factors. Increased immune reactivity to gluten and/or association with celiac disease, an autoimmune disorder triggered by ingestion of gluten, have been reported in IgA nephropathy. However, studies are inconsistent about this association. We aimed to evaluate the proposed link between IgA nephropathy and celiac disease or immune reactivity to gluten by conducting a comprehensive analysis of associated serologic markers in cohorts of well-characterized patients and controls. Study participants included patients with biopsy-proven IgA nephropathy (n = 99), unaffected controls of similar age, gender, and race (n = 96), and patients with biopsy-proven celiac disease (n = 30). All serum specimens were tested for IgG and IgA antibodies to native gliadin and deamidated gliadin, as well as IgA antibody to transglutaminase 2 (TG2). Anti-TG2 antibody-positive nephropathy patients and unaffected controls were subsequently tested for IgA anti-endomysial antibody and genotyped for celiac disease-associated HLA-DQ2 and-DQ8 alleles. In comparison to unaffected controls, there was not a statistically significant increase in IgA or IgG antibody reactivity to gliadin in individuals with IgA nephropathy. In addition, the levels of celiac disease-specific serologic markers, i.e., antibodies to deamidated gliadin and TG2, did not differ between IgA nephropathy patients and unaffected controls. Results of the additional anti-endomysial antibody testing and HLA genotyping were corroborative. The data from this case-control study do not reveal any evidence to suggest a significant role for celiac disease or immune reactivity to gluten in IgA nephropathy.

Modern Pathology, 2009

Collagenous sprue is associated with high morbidity; however, the etiology of this disorder is un... more Collagenous sprue is associated with high morbidity; however, the etiology of this disorder is unclear. Data regarding the pathological and clinical manifestations of patients with collagenous sprue are also limited. We, thus, undertook this study to gain insight into the etiology, disease manifestations and outcomes of collagenous sprue. We searched our departmental database (1999-2008) to identify cases of collagenous sprue and to obtain clinical and laboratory data. Small bowel histology, including thickness of subepithelial collagen, intra-epithelial lymphocyte phenotype and results of T-cell clonality assays were evaluated. Nineteen patients (15 women, 4 men, age 22-80 years, mean 57 years) were identified. Seventeen (89%) had celiac disease and two had unclassified sprue; 9 of 17 (53%) celiac disease patients had refractory disease; 5 of 15 (33%) lacked diarrhea (atypical presentation), including 2 of 6 (33%) with active (untreated) celiac disease and 3 of 9 (33%) with refractory celiac disease. Autoimmune disorders were seen in 12 of 19 (63%) patients and microscopic colitis (n ¼ 7), lymphocytic gastritis (n ¼ 2) or collagenous gastritis (n ¼ 2) were seen in nine patients. Subepithelial collagen thickness was mildly (n ¼ 6), moderately (n ¼ 10), or markedly (n ¼ 3) increased and villous atrophy was total (n ¼ 13) or subtotal (n ¼ 6). Phenotypically aberrant intraepithelial lymphocytes were not detected in any case. Polymerase chain reaction analysis showed a dominant T-cell clone in the only patient with refractory celiac disease type II. Histological improvement occurred in 7 of 11 (64%) patients. Overall, 8 of 19 (42%) responded to gluten-free diet, including 2 of 9 (22%) with refractory celiac disease and 10 responded to immunomodulatory therapy, including 6 of 9 (67%) with refractory celiac disease. Only one patient died from complications of refractory celiac disease. No patient developed lymphoma. The vast majority of our patients with collagenous sprue had celiac disease. Although, many patients required immunomodulatory therapy for symptom control, a subset responded to gluten-free diet alone. In our experience, collagenous sprue patients had relatively good clinical outcomes.

Journal of Clinical Pathology, 2011

Background and Aims Coeliac disease (CD) diagnosis requires the detection of characteristic histo... more Background and Aims Coeliac disease (CD) diagnosis requires the detection of characteristic histological alterations of small bowel mucosa, which are prone to interobserver variability. This study evaluated the agreement in biopsy interpretation between different pathology practice types. Methods Biopsies from community hospitals (n¼46), university hospitals (n¼18) and commercial laboratories (n¼38) were blindly assessed by a pathologist at our institution for differences in histopathology reporting and agreement in diagnosis of CD and degree of villous atrophy (VA) by k analysis. Results Agreement for primary diagnosis was very good between this institution and university hospitals (k¼0.888), but moderate compared with community hospitals (k¼0.465) or commercial laboratories (k¼0.419). Diagnosis differed in 26 (25%) cases, leading to a 20% increase in CD diagnosis after review. Among those diagnosed with CD by both institutions (n¼49), agreement in degree of VA was fair (k¼0.292), with moderate agreement between the authors and commercial laboratories (k¼0.500) and fair with university hospitals (k¼0.290) or community hospitals (k¼0.211). The degree of VA was upgraded in 27% and downgraded in 2%. Within different Marsh score categories, agreement was poor (k<0.0316) for scores 1 and 2, both missed at other centres, and fair or moderate for scores 3a and 3b. Information regarding degree of VA and intraepithelial lymphocytosis was lacking in 26% and 86% of reports and non-quantifiable descriptors, eg, 'blunting' or 'marked atrophy' were prevalent. Conclusions CD-related histological changes are underdiagnosed in community-based hospitals and commercial pathology laboratories. Because incorrect biopsy interpretation can cause underdiagnosis of CD, greater CD awareness and uniformity in small bowel biopsy reporting is required among pathologists.

Journal of Clinical Gastroenterology, 2013

Background: Classification of refractory celiac disease (RCD) is based on the presence or absence... more Background: Classification of refractory celiac disease (RCD) is based on the presence or absence of monoclonal expansions of intraepithelial lymphocytes (IELs) with an aberrant immunophenotype. Goals: To investigate the contribution of IEL parameters toward mortality and morbidity in RCD.

Gastroenterology, 2009

Only two of the 48 patients could be classified as having an abnormal number of mast cells (more ... more Only two of the 48 patients could be classified as having an abnormal number of mast cells (more than 20 MC/HPF). Conclusion: Gastrointestinal mucosal mast cells are not increased in patients with active celiac disease. Though increased numbers of mast cell are routinely observed in the sub mucosa of celiac patients, it is important to make the distinction between the exact location of mast cells and their corresponding function or actions.

Gastroenterology, 2010

G A A b st ra ct s inclusion in formalin (Group 1) and the rest were directly included in formali... more G A A b st ra ct s inclusion in formalin (Group 1) and the rest were directly included in formalin (Group 2). All biopsies were reviewed blind by two pathologists and consensus was reached about their mucosal orientation and epithelium integrity. Results. Biopsies from20 patients were included (mean age 31.05, δ2 14.81, 13 women/7 men, 5 pediatric cases). AcTG were positive in 7 patients. HLA DQ2 was present in 15 patients, HLA DQ8 in 3 patients, 2 patients presented both HLA types. One hundred and twelve biopsies were obtained (mean 5.6 per patient, δ2 0.76). Two patients presented intraepithelial lymphocytosis compatible with Marsh 1, 7 patients presented a Marsh III lesion, 1 patient a non-specific chronic duodenitis and the rest were normal. Group 1 comprised by 59 biopsies (mean 2.95 per patient, δ2 0.88) and there were 53 biopsies in group 2 (mean 2.65 per patient, δ2 0.59). The pathologist considered the mucosa to be well-oriented in 84 % (50/59) of biopsies of group 1 vs. 47 % (25/53) in group 2 (p<0.001). Twelve biopsies of group 1 and 13 biopsies of group 2 were denudated (p N.S.). Only three patients had one or no biopsy belonging to Group 1 well oriented vs. 13 patients when biopsies of group 2 were considered (p=0.003). Conclusions. A significant proportion of endoscopic duodenal biopsies are not well-oriented. Manual orientation of duodenal endoscopic biopsies at the moment of their obtention is useful to improve their quality without its manipulation affecting the integrity of the epithelium.

Gastroenterology, 2010

G A A b st ra ct s inclusion in formalin (Group 1) and the rest were directly included in formali... more G A A b st ra ct s inclusion in formalin (Group 1) and the rest were directly included in formalin (Group 2). All biopsies were reviewed blind by two pathologists and consensus was reached about their mucosal orientation and epithelium integrity. Results. Biopsies from20 patients were included (mean age 31.05, δ2 14.81, 13 women/7 men, 5 pediatric cases). AcTG were positive in 7 patients. HLA DQ2 was present in 15 patients, HLA DQ8 in 3 patients, 2 patients presented both HLA types. One hundred and twelve biopsies were obtained (mean 5.6 per patient, δ2 0.76). Two patients presented intraepithelial lymphocytosis compatible with Marsh 1, 7 patients presented a Marsh III lesion, 1 patient a non-specific chronic duodenitis and the rest were normal. Group 1 comprised by 59 biopsies (mean 2.95 per patient, δ2 0.88) and there were 53 biopsies in group 2 (mean 2.65 per patient, δ2 0.59). The pathologist considered the mucosa to be well-oriented in 84 % (50/59) of biopsies of group 1 vs. 47 % (25/53) in group 2 (p<0.001). Twelve biopsies of group 1 and 13 biopsies of group 2 were denudated (p N.S.). Only three patients had one or no biopsy belonging to Group 1 well oriented vs. 13 patients when biopsies of group 2 were considered (p=0.003). Conclusions. A significant proportion of endoscopic duodenal biopsies are not well-oriented. Manual orientation of duodenal endoscopic biopsies at the moment of their obtention is useful to improve their quality without its manipulation affecting the integrity of the epithelium.