Estimated global and regional causes of deaths from diarrhoea in children younger than 5 years during 2000-21: a systematic review and Bayesian multinomial analysis.

BACKGROUND: Information on the causes of deaths from diarrhoea in children younger than 5 years is needed to design improved preventive and therapeutic approaches. We aimed to conduct a systematic analysis of studies to report estimates of the causes of deaths from diarrhoea in children younger than 5 years at global and regional levels during 2000-21. METHODS: For this systematic review and Bayesian multinomial analysis, we included 12 pathogens with the highest attributable incidence in the Global Enteric Multicenter Study. We searched PubMed, Scopus, Embase, Web of Science, Global Health Index Medicus, Global Health OVID, IndMed, Health Information Platform for the Americas (PLISA), Africa-Wide Information, and Cochrane Collaboration for articles published between Jan 1, 2000, and Dec 31, 2020, using the search terms "child", "hospital", "diarrhea", "diarrhoea", "dysentery", "rotavirus", "Escherichia coli", "salmonella", "shigella", "campylobacter", "Vibrio cholerae", "cryptosporidium", "norovirus", "astrovirus", "sapovirus", and "adenovirus". To be included, studies had to have a patient population of children younger than 5 years who were hospitalised for diarrhoea (at least 90% of study participants), at least a 12-month duration, reported prevalence in diarrhoeal stools of at least two of the 12 pathogens, all patients with diarrhoea being included at the study site or a systematic sample, at least 100 patients with diarrhoea, laboratory tests done on rectal swabs or stool samples, and standard laboratory methods (ie, quantitative PCR [qPCR] or non-qPCR). Studies published in any language were included. Studies were excluded if they were limited to nosocomial, chronic, antibiotic-associated, or outbreak diarrhoea or to a specific population (eg, only children with HIV or AIDS). Each article was independently reviewed by two researchers; a third arbitrated in case of disagreement. If both reviewers identified an exclusion criterion, the study was excluded. Data sought were summary estimates. Data on causes from published studies were adjusted when necessary to account for the poor sensitivity of non-qPCR methods and for attributable fraction based on quantification of pathogens in children who are ill or non-ill. The causes of deaths from diarrhoea were modelled on the causes of hospitalisations for diarrhoea. We separately modelled studies reporting causes of diarrhoea in children who were hospitalised in low-income and middle-income countries (LMICs) and in high-income countries (HICs). FINDINGS: Of 74 282 papers identified in the initial database search, we included 138 studies (91 included data from LMICs and 47 included data from HICs) from 73 countries. We modelled estimates for 194 WHO member states (hereafter referred to as countries), including 42 HICs and 152 LMICs. We could attribute a cause to 1 003 448 (83·8%) of the estimated 1 197 044 global deaths from diarrhoea in children younger than 5 years in 2000 and 360 730 (81·3%) of the estimated 443 833 global deaths from diarrhoea in children younger than 5 years in 2021. The cause with the largest estimated global attribution was rotavirus; in LMICs, the proportion of deaths from diarrhoea due to rotavirus in children younger than 5 years appeared lower in 2021 (108 322 [24·4%] of 443 342, 95% uncertainty interval 21·6-29·5) than in 2000 (316 382 [26·5%] of 1 196 134, 25·7-28·5), but the 95% CIs overlapped. In 2000, the second largest estimated attribution was norovirus GII (95 817 [8·0%] of 1 196 134 in LMICs and 225 [24·7%] of 910 in HICs); in 2021, Shigella sp had the second largest estimated attribution in LMICs (36 082 [8·1%] of 443 342), but norovirus remained with the second largest estimated attribution in HICs (84 [17·1%] of 490). INTERPRETATION: Our results indicate progress in the reduction of deaths from diarrhoea caused by 12 pathogens in children younger than 5 years in the past two decades. There is a need to increase efforts for prevention, including with rotavirus vaccine, and treatment to eliminate further deaths. FUNDING: Bill & Melinda Gates Foundation via Johns Hopkins University and the University of Virginia.

Low Rate of Infectious Enterocolitis in Allogeneic Stem Cell Transplant Recipients with Acute Diarrhea: A Prospective Study by the GETH-TC.

Acute diarrhea is a common and debilitating complication in recipients of allogeneic hematopoietic stem cell transplantation (HCT). In this prospective, observational, and multicenter study we examined all episodes occurring in the first 6 months of 142 consecutive adult patients who underwent a reduced-intensity conditioning HCT in 10 Spanish tertiary university hospitals. Fifty-four patients (38%) developed a total of 75 acute diarrhea episodes. The median time from HCT to the first episode was 38 days (4-157). The main cause of enterocolitis was lower GI-aGVHD (38%), followed by infections (21%) and drug-related toxicity (8%). Causative infectious causes were identified in only 16/75 episodes (21%). C. difficile-related infection was the most common infectious agent with an incidence and recurrence of 13% and 2%, respectively. With a median follow-up for survivors of 32 months, the non-relapse mortality (NRM) and the overall survival (OS) at 1 year, were 20% (95% C.I.: 14-28%) and 69% (95% C.I.: 61-77%), respectively. Development of enterocolitis was not associated with higher NRM (p = 0.37) or worse OS (p = 0.9). This real-life study confirms that the diagnosis and management of acute diarrhea in the early stages after HCT is challenging. Nosocomial infections seem to be relatively uncommon, probably due to more rational use of antibiotics.

Outcomes of Immune Checkpoint Inhibitor-related Diarrhea or Colitis in Cancer Patients With Superimposed Gastrointestinal Infections.

BACKGROUND AND OBJECTIVE: Immune-mediated diarrhea and colitis (IMDC) is a common adverse event in cancer patients receiving immune checkpoint inhibitors (ICIs). Gastrointestinal (GI) infections can co-occur with IMDC, and its impact on the course and outcome of IMDC remains unclear. PATIENTS AND METHODS: We retrospectively reviewed cancer patients who received ICIs and developed IMDC between January 2015 and September 2019. GI multiplex panel is used to assess GI infection. The study group included patients with positive infection except those who are only positive for Clostridioides difficile or cytomegalovirus. The control group is IMDC patients with negative infection using frequency matching. Patients' disease course and outcome were compared between groups. RESULTS: A total of 72 patients with IMDC were included: 22 in the study group and 50 as control. Escherichia coli of different pathotypes was observed in 17 patients. Five patients had viral infections, for example, adenovirus, norovirus, and sapovirus. Patients with GI infections more frequently had grade 3 or 4 colitis (43% vs. 18%, P=0.041). Overall, GI infections were not associated with different risks of IMDC recurrence or overall survival. Antibiotics treatment did not affect the requirement for infliximab or vedolizumab but relate to a higher risk of IMDC recurrence (50.0% vs. 0.0%, P=0.015). CONCLUSIONS: In our study, concomitant GI infections are associated with more severe symptoms in IMDC patients. Antimicrobial treatment did not circumvent the need for immunosuppressive therapy for IMDC or improve the clinical outcome. Concomitant GI infection was not associated with a higher risk of IMDC recurrence or poor overall survival.

Association between pertuzumab-associated diarrhoea and rash and survival outcomes in patients with HER2-positive metastatic breast cancer: Exploratory analysis from the CLEOPATRA trial.

BACKGROUND: Skin rash and diarrhoea are known side-effects of pertuzumab. Studies with other anti-HER2 agents suggested that adverse events correlate with patient outcomes. In this exploratory cohort of patients with metastatic HER2-positive breast cancer included in the CLEOPATRA trial we evaluated the value of rash and diarrhoea as prognostic markers and as predictors of pertuzumab benefit. METHODS: This is a retrospective analysis of the multicenter, prospective, randomised CLEOPATRA trial. We defined two analytic cohorts: cohort 1 (C1) included patients from treatment initiation, and cohort 2 (C2) included patients after discontinuation of docetaxel. A landmark analysis was introduced to deal with immortal-time bias. Study endpoints were progression-free survival (PFS) and overall survival (OS). Univariable and multivariable Cox proportional hazards models were used. RESULTS: Of the 808 patients and after application of the landmark analysis, C1 and C2 included 777 and 518 patients, respectively. In C1, rash occurred in 271 patients (34.9%) and diarrhoea in 470 (60.5%). Rash was prognostic for PFS and OS (C1: adjusted hazard ratio [aHR] = 0.66 [95% CI = 0.48-0.91], p = 0.010]; C2: aHR 0.52 [95% CI = 0.30-0.89], p = 0.018) in both cohorts, while diarrhoea was only prognostic for PFS in cohort 2 (aHR = 0.65 [95% CI = 0.46-0.91], p = 0.011). Rash and diarrhoea were not predictive of pertuzumab benefit (in terms of PFS/OS) in the two cohorts. CONCLUSIONS: In patients treated with pertuzumab, trastuzumab, and docetaxel, rash is prognostic whenever it occurs during treatment, while diarrhoea only has prognostic value when occurring after docetaxel discontinuation. However, neither rash nor diarrhoea predict pertuzumab benefit.

An inducible intestinal epithelial cell-specific NHE3 knockout mouse model mimicking congenital sodium diarrhea.

The sodium-hydrogen exchanger isoform 3 (NHE3, SLC9A3) is abundantly expressed in the gastrointestinal tract and is proposed to play essential roles in Na+ and fluid absorption as well as acid-base homeostasis. Mutations in the SLC9A3 gene can cause congenital sodium diarrhea (CSD). However, understanding the precise role of intestinal NHE3 has been severely hampered due to the lack of a suitable animal model. To navigate this problem and better understand the role of intestinal NHE3, we generated a tamoxifen-inducible intestinal epithelial cell-specific NHE3 knockout mouse model (NHE3IEC-KO). Before tamoxifen administration, the phenotype and blood parameters of NHE3IEC-KO were unremarkable compared with control mice. After tamoxifen administration, NHE3IEC-KO mice have undetectable levels of NHE3 in the intestine. NHE3IEC-KO mice develop watery, alkaline diarrhea in combination with a swollen small intestine, cecum and colon. The persistent diarrhea results in higher fluid intake. After 3 weeks, NHE3IEC-KO mice show a ∼25% mortality rate. The contribution of intestinal NHE3 to acid-base and Na+ homeostasis under normal conditions becomes evident in NHE3IEC-KO mice that have metabolic acidosis, lower blood bicarbonate levels, hyponatremia and hyperkalemia associated with drastically elevated plasma aldosterone levels. These results demonstrate that intestinal NHE3 has a significant contribution to acid-base, Na+ and volume homeostasis, and lack of intestinal NHE3 has consequences on intestinal structural integrity. This mouse model mimics and explains the phenotype of individuals with CSD carrying SLC9A3 mutations.

Impacto poblacional a 10 años de la vacunación contra rotavirus en México / Population impact of rotavirus vaccination in Mexico after 10 years

Resumen: Objetivo: Evaluar el impacto de la vacunación contra rotavirus (RV) a 10 años de su universalización sobre la morbimortalidad por enfermedad diarreica aguda (EDA) en niños mexicanos menores de cinco años. Material y métodos: Se compararon las medianas anuales de casos nuevos, defunciones y hospitalizaciones por EDA del periodo pre y posuniversalización; se calcularon reducciones absolutas y relativas, considerando significativos valores de p<0.05. Resultados: La mortalidad, hospitalizaciones y casos nuevos por EDA en menores de cinco años disminuyeron 52.6, 46 y 15.5% respectivamente, en el periodo posuniversalización. Durante la temporada de RV las reducciones en la mortalidad, hospitalizaciones y casos nuevos fueron de 66.9, 64.7 y 28.7%, respectivamente. Conclusiones: A partir de la universalización de la vacuna de RV en México, se aprecian reducciones importantes y sostenidas en la mortalidad, hospitalizaciones e incidencia por EDA, con menor impacto en esta última. El mayor impacto se observa durante la temporada de RV.

Abstract: Objective: To evaluate the impact of rotavirus (RV) vaccination after 10 years of it´s universalization on morbidity and mortality from Acute Diarrheal Disease (ADD) in mexican children under five years of age. Materials and methods: Annual median numbers for ADD new cases, hospitalizations and deaths were compared between pre and post universalization periods; absolute and relative reductions were calculated, considering p<0.05 values as significant. Results: Mortality, hospitalizations and new cases from ADD in children under five decreased 52.6, 46, and 15.5% respectively, in the posuniversalization period. During rotavirus seasons, reduction in mortality, hospitalizations and new cases was 66.9, 64.7, and 28.7% respectively. Conclusions: As of the universal introduction of RV vaccination in Mexico, significant and sustained reductions are appreciated for mortality and hospitalizations from ADD, less so for incidence. A most prominent effect is observed during the winter season.

Overview of acute diarrheal disease at the dawn of the 21st century: The case of Mexico / Panorama de la enfermedad diarreica aguda en los albores del siglo XXI: el caso de México

Abstract: Objective: To provide an overview of morbidity and mortality due to acute diarrheal disease in Mexico in order to understand its magnitude, distribution, and evolution from 2000 to 2016. Materials and methods: We carried out a longitudinal ecological study with secondary sources of information. We used data from epidemiological surveillance, health services, and vital statistics. We calculated and mapped measures of utilization of health services rates and mortality due to diarrheal diseases. Results: Diarrhea morbidity decreased by 42.1% across the period. However, emergency department attendances increased by 50.7% in the Ministry of Health. The hospitalization rate and mortality among the general population decreased by 37.6 and 39.7%, respectively, and the infant mortality rate decreased by 72.3% among children under five years of age. Chiapas and Oaxaca had the highest mortality among the states of Mexico. Conclusions: Cases of diarrhea, including rotavirus, have decreased in Mexico. However, in 2016, 3.4 per 100 000 people died due to diarrhea, which could have been avoided with health promotion.

Resumen: Objetivo: Ofrecer un panorama de la morbimortalidad por enfermedad diarreica aguda (EDA) entre 2000 y 2016 en México, para entender su magnitud, distribución y evolución. Material y métodos: Estudio ecológico longitudinal, con fuentes de información secundarias. Se analizaron datos de vigilancia epidemiológica, prestación de servicios y estadísticas vitales. Se calcularon tasas de utilización de servicios y mortalidad. Resultados: La morbilidad por EDA disminuyó 42.1% en el periodo, sin embargo, la atención por urgencias aumentó 50.7% en SS. La tasa de hospitalización descendió 37.6% y la mortalidad 39.7% en población general y 72.3% en menores de cinco años. Chiapas y Oaxaca fueron los estados con mayor tasa de mortalidad. Conclusiones: Los casos de diarrea, incluyendo los de rotavirus, han disminuido en el país. Sin embargo, en 2016 se encontró una tasa de 3.4 por 100 000 personas que mueren por EDA, lo cual podría evitarse con promoción de la salud.

As Clinical Markers, Hand-Foot-Skin Reaction and Diarrhea Can Predict Better Outcomes for Hepatocellular Carcinoma Patients Receiving Transarterial Chemoembolization plus Sorafenib.

Background: Combination therapy of transarterial chemoembolization plus sorafenib (TACE-S) has been proven to be safe and effective for hepatocellular carcinoma (HCC); however, this combination therapy is associated with a high incidence of adverse events (AEs). Our study focused on the relationships between AEs and treatment outcomes and aimed to discover AE-based clinical markers that can predict the survival benefits of combination treatment. Methods: From January 2010 to June 2014, a total of 235 HCC patients treated with TACE-S were retrospectively enrolled. Major sorafenib-related AEs were prospectively recorded, and their correlations with overall survival (OS) were analysed using time-dependent covariate Cox regression analyses. Results: The majority of the patients (200, 85.1%) were male, and the median age was 51 years old. After two years of follow-up, the median OS of the study population reached 12.4 months. In all, 218 patients (92.8%) presented at least one AE, and 174 (74.0%) suffered AEs ≥2 grade. Based on time-dependent multivariate analyses, the development of hand-foot skin reaction (HFSR) ≥2 grade (HR = 0.43, 95% CI: 0.32-0.58, P < 0.001) and diarrhoea ≥1 grade (HR = 0.72, 95% CI: 0.53-0.97, P=0.029) were identified as independent predictors of prolonged OS. Moreover, patients who developed both HFSR ≥2 grade and diarrhoea ≥1 grade achieved better outcomes than those patients who developed either or neither of these AEs (HR = 1.51, 95% CI: 1.11-2.06, P=0.009). Conclusions: The development of HFSR ≥2 grade or diarrhoea ≥1 grade during TACE-S treatment indicated prolonged OS, and these AEs should be considered important clinical markers for predicting patient prognoses.

Effect of Early Adverse Events on Survival Outcomes of Patients with Metastatic Colorectal Cancer Treated with Ramucirumab.

BACKGROUND: Studies of patients treated with bevacizumab and other vascular epithelial growth factor (VEGF) inhibitors have reported that hypertension adverse events (AEs) are associated with improved overall survival (OS) or progression-free survival (PFS). OBJECTIVE: Our objective was to evaluate the association between early AEs and survival outcomes for patients treated with ramucirumab, an antibody targeting the VEGF receptor-2 (VEGFR-2), plus FOLFIRI for metastatic colorectal cancer (mCRC). METHODS: Data from 529 patients treated with ramucirumab plus FOLFIRI for mCRC in the RAISE clinical trial (NCT01183780) were evaluated to see whether early (first 6 weeks of therapy) AEs predicted subsequent OS and PFS. A Cox proportional hazard approach was used to evaluate associations between early AEs and survival outcomes. A secondary analysis between FOLFIRI and placebo was conducted as a sensitivity analysis. RESULTS: Of 529 patients treated with ramucirumab plus FOLFIRI, 479 were alive and progression free at 6 weeks after commencing therapy. No significant association was identified between hypertension occurring within the first 42 days of ramucirumab plus FOLFIRI therapy and OS (grade 1-2, hazard ratio [HR] 0.90 [95% confidence interval (CI) 0.66-1.24]; grade 3+, HR 1.02 [95% CI 0.67-1.55]; P = 0.803) or PFS (grade 1-2, HR 0.98 [95% CI 0.74-1.28]; grade 3+, HR 0.93 [95% CI 0.64-1.37]; P = 0.93). However, there was a significant association between diarrhea occurring within the first 42 days of ramucirumab plus FOLFIRI therapy and worse OS (grade 1-2, HR 0.96 [95% CI 0.76-1.20]; grade 3+, HR 2.72 [95% CI 1.67-4.44]; P = 0.001) and PFS (grade 1-2, HR 1.01 [95% CI 0.83-1.23]; grade 3+, HR 2.22 [95% CI 1.43-3.45]; P = 0.005). No other AEs were significantly associated with OS or PFS. CONCLUSIONS: Ramucirumab-induced hypertension was not associated with improved OS and PFS in patients with mCRC treated with ramucirumab and FOLFIRI, but severe diarrhea was associated with poorer OS and PFS. CLINICAL TRIAL REGISTRATION: No. NCT01183780.

Outbreak of cryptosporidiosis due to Cryptosporidium parvum subtype IIdA19G1 in neonatal calves on a dairy farm in China.

Neonatal diarrhea is one of the most important syndromes in dairy cattle. Among enteropathogens, Cryptosporidium spp. are primary causes of diarrhea, but outbreaks due to cryptosporidiosis are rarely reported in cattle. From January to April in 2016, severe diarrhea was observed in over 400 neonatal dairy calves on a large dairy farm in Jiangsu Province of East China. Approximately 360 calves died due to watery diarrhea despite antibiotic therapy. In this study, 18 fecal specimens were collected from seriously ill calves on this farm during the diarrhea outbreak, and analysed for common enteropathogens by enzymatic immunoassay (EIA). In a post-outbreak investigation, 418 and 1372 specimens collected from animals of various age groups were further analysed for rotavirus and Cryptosporidium spp. by EIA and PCR, respectively, to assess their roles in the occurrence of diarrhea on the farm. Cryptosporidium spp. were genotyped using established techniques. Initial EIA tests showed that 15/18 seriously ill calves during the outbreak were positive for Cryptosporidium parvum, while 8/18 were positive for rotavirus. The overall infection rate of Cryptosporidium in pre-weaned calves on the farm was 22.7%, with odds of the Cryptosporidium infection during the outbreak 4.4-23.5 times higher than after the outbreak. Four Cryptosporidium spp. were identified after the outbreak including C. parvum (n = 79), Cryptosporidium ryanae (n = 48), Cryptosporidium bovis (n = 31), and Cryptosporidium andersoni (n = 3), with co-infections of multiple species being detected in 34 animals. Infection with C. parvum (73/79) was found in the majority of calves aged ≤3 weeks, consistent with the age of ill calves during the outbreak. All C. parvum isolates were identified as subtype IIdA19G1. In the post-outbreak investigation, C. parvum infection was associated with the occurrence of watery diarrhea in pre-weaned calves, C. ryanae infection was associated with moderate diarrhea in both pre- and post-weaned calves, while no association was identified between rotavirus infection and the occurrence of diarrhea. Results of logistic regression analysis further suggested that C. bovis infection might also be a risk factor for moderate diarrhea in calves. Thus, we believe this is the first report of a major outbreak of severe diarrhea caused by C. parvum IIdA19G1 in dairy calves. More attention should be directed toward preventing the dissemination of this virulent subtype in China.

A decade of antiretroviral therapy in Uganda: what are the emerging causes of death?

BACKGROUND: The roll out of antiretroviral therapy (ART) in Sub-Saharan Africa led to a decrease in mortality. Few studies have documented the causes of deaths among patients on long term antiretroviral therapy in Sub-Saharan Africa. Our objective was to describe the causes of death among patients on long term ART in Sub-Saharan Africa. METHODS: We used data from a prospective cohort of ART naïve patients receiving care and treatment at the Infectious Diseases Institute in Kampala, Uganda. Patients were followed up for 10 years. All deaths were recorded and possible causes established using verbal autopsy. Deaths were grouped as HIV-related (ART toxicities, any opportunistic infections (OIs) and HIV-related malignancies) and non-HIV related deaths while some remained unknown. We used Kaplan Meier survival methods to estimate cumulative incidence and rates of mortality for all causes of death. RESULTS: Of the 559, (386, 69%) were female, median age 36 years (IQR: 21-44), 89% had WHO clinical stages 3 and 4, and median CD4 count at ART initiation was 98 cells/µL (IQR: 21-163). A total of 127 (22.7%) deaths occurred in 10 years. The HIV related causes of death (n = 70) included the following; Tuberculosis 17 (24.3%), Cryptococcal meningitis 10 (15.7%), Kaposi's Sarcoma 7(10%), HIV related toxicity 6 (8.6%), HIV related anemia 5(7.1%), Pneumocystis carinii Pneumonia (PCP) 5 (7.1%), HIV related chronic diarrhea 4 (5.7%), Non-Hodgkin Lymphoma 3 (4.3%), Herpes Zoster 2 (2.8%), other 10 (14.3%). The non-HIV related causes of death (n = 20) included non-communicable diseases (diabetes, hypertension, stroke) 6 (30%), malaria 3 (15%), pregnancy-related death 2 (10%), cervical cancer 2 (10%), trauma 1(5%) and others 6 (30%). CONCLUSION: Despite the higher rates of deaths from OIs in the early years of ART initiation, we observed an emergence of non-HIV related causes of morbidity and mortality. It is recommended that HIV programs in resource-limited settings start planning for screening and treatment of non-communicable diseases.

Comparison of Common Monogenic Defects in a Large Predominantly Antibody Deficiency Cohort.

BACKGROUND: Predominantly antibody deficiencies (PADs) are the most common primary immunodeficiencies, characterized by hypogammaglobulinemia and inability to generate effective antibody responses. OBJECTIVE: We intended to report most common monogenic PADs and to investigate how patients with PAD who were primarily diagnosed as suffering from agammaglobulinemia, hyper-IgM (HIgM) syndrome, and common variable immunodeficiency (CVID) have different clinical and immunological findings. METHODS: Stepwise next-generation sequencing and Sanger sequencing were performed for confirmation of the mutations in the patients clinically diagnosed as suffering from agammaglobulinemia, HIgM syndrome, and CVID. RESULTS: Among 550 registered patients, the predominant genetic defects associated with agammaglobulinemia (48 Bruton's tyrosine kinase [BTK] and 6 µ heavy chain deficiencies), HIgM syndrome (21 CD40 ligand and 7 activation-induced cytidine deaminase deficiencies), and CVID (17 lipopolysaccharides-responsive beige-like anchor deficiency and 12 atypical Immunodeficiency, Centromeric instability, and Facial dysmorphism syndromes) were identified. Clinical disease severity was significantly higher in patients with µ heavy chain and CD40 ligand mutations compared with patients with BTK (P = .003) and activation-induced cytidine deaminase (P = .009) mutations. Paralysis following live polio vaccination was considerably higher in patients with µ heavy chain deficiency compared with BTK deficiency (P < .001). We found a genotype-phenotype correlation among patients with BTK mutations regarding clinical manifestation of meningitis and chronic diarrhea. Surprisingly, we noticed that first presentations in most patients with Immunodeficiency, Centromeric instability, and Facial dysmorphism were respiratory complications (P = .008), whereas first presentations in patients with lipopolysaccharides-responsive beige-like anchor deficiency were nonrespiratory complications (P = .008). CONCLUSIONS: This study highlights similarities and differences in the clinical and genetic spectrum of the most common PAD-associated gene defects. This comprehensive comparison will facilitate clinical decision making, and improve prognosis and targeted treatment.

Evaluation of risk factors for a fulminant Clostridium difficile infection after cardiac surgery: a single-center, retrospective cohort study.

BACKGROUND: Clostridium difficile (CD) is the most common pathogen causing nosocomial diarrhea. The clinical presentation ranges from mild diarrhea to severe complications, including pseudomembranous colitis, toxic megacolon, sepsis, and multi-organ failure. When the disease takes a fulminant course, death ensues rapidly in severe and complex cases. Preventive screening or current prophylactic therapies are not useful. Therefore, this study was conducted to detect risk factors for a fulminant CD infection (CDI) in patients undergoing cardiac surgery. METHODS: Between April 1999 and April 2011, a total of 41,466 patients underwent cardiac surgery at our institution. A review of our hospital database revealed 1256 patients (3.0%) with post-operative diarrheal disease who tested positive for CD; these patients comprised the cohort of this observational study. A fulminant CDI occurred in 153 of these patients (12.2%), which was diagnosed on the basis of gastrointestinal complications, e.g. pseudomembranous colitis, and/or the need for post-cardiac surgery laparotomy. Demographic, peri-operative, and survival data were analyzed, and predictors of a fulminant CDI were assessed by binary logistic regression analysis. RESULTS: The 30-day mortality was 6.1% (n = 77) for the entire cohort, with significantly higher mortality among patients with a fulminant CDI (21.6% vs. 4.0%, p <  0.001). Overall mortality (27.7%, n = 348) was also higher for patients with a fulminant course of the disease (63.4% vs. 22.8%, p <  0.001), and a laparotomy was required in 36.6% (n = 56) of the fulminant cases. Independent predictors of a fulminant CDI were: diabetes mellitus type 2 (OR 1.74, CI 1.15-2.63, p = 0.008), pre-operative ventilation (OR 3.52, CI 1.32-9.35, p = 0.012), utilization of more than 8 units of red blood cell concentrates (OR 1.95, CI 1.01-3.76, p = 0.046) or of more than 5 fresh-frozen plasma units (OR 3.38, CI 2.06-5.54, p <  0.001), and a cross-clamp time > 130 min (OR 1.93, CI 1.12-3.33, p = 0.017). CONCLUSIONS: We identified several independent risk factors for the development of a fulminant CDI after cardiac surgery. Close monitoring of high-risk patients is important in order to establish an early onset of therapy and thus to prevent a CDI from developing a fulminant course after cardiac surgery.

Paired Phase II Studies of Erlotinib/Bevacizumab for Advanced Bronchioloalveolar Carcinoma or Never Smokers With Advanced Non-Small-cell Lung Cancer: SWOG S0635 and S0636 Trials.

BACKGROUND: Before mutation testing of the epidermal growth factor receptor (EGFR) gene was recognized as highly associated with the activity of EGFR tyrosine kinase inhibitors (TKIs), clinically defined patient populations with bronchioloalveolar carcinoma (BAC) and never smokers were identified as likely to benefit from EGFR TKIs. From preclinical and clinical data suggesting potentially improved efficacy with a combination of an EGFR TKI and the antiangiogenic agent bevacizumab, the Southwestern Oncology Group (SWOG) initiated paired phase II trials to evaluate the combination of erlotinib/bevacizumab in patients with advanced BAC (SWOG S0635) or never smokers with advanced lung adenocarcinoma (SWOG S0636). MATERIALS AND METHODS: Eligible patients with BAC or adenocarcinoma with BAC features (SWOG S0635) or never smokers with advanced lung adenocarcinoma (SWOG S0636) received erlotinib 150 mg/day with bevacizumab 15 mg/kg until progression or prohibitive toxicity. Never smokers with BAC were preferentially enrolled to SWOG S0636. The primary endpoint for both trials was overall survival. RESULTS: A total of 84 patients were enrolled in the SWOG S0635 trial and 85 in the SWOG S0636 trial. The objective response rate was 22% (3% complete response) in the SWOG S0635 trial and 50% (38% confirmed; 3% complete response) in the SWOG S0636 trial. The median progression-free survival was 5 and 7.4 months in the S0635 and S0636 trials, respectively. The median overall survival was 21 and 29.8 months, respectively. Toxicity consisted mainly of rash and diarrhea in both trials. CONCLUSION: Although the field has moved toward molecular, rather than clinical, selection of patients as optimal candidates for EGFR TKI therapy, these results support the hypothesis that a subset of patients in whom erlotinib is particularly active could receive an incremental benefit from the addition of bevacizumab.

Long-term follow-up of IPEX syndrome patients after different therapeutic strategies: An international multicenter retrospective study.

BACKGROUND: Immunodysregulation polyendocrinopathy enteropathy x-linked (IPEX) syndrome is a monogenic autoimmune disease caused by FOXP3 mutations. Because it is a rare disease, the natural history and response to treatments, including allogeneic hematopoietic stem cell transplantation (HSCT) and immunosuppression (IS), have not been thoroughly examined. OBJECTIVE: This analysis sought to evaluate disease onset, progression, and long-term outcome of the 2 main treatments in long-term IPEX survivors. METHODS: Clinical histories of 96 patients with a genetically proven IPEX syndrome were collected from 38 institutions worldwide and retrospectively analyzed. To investigate possible factors suitable to predict the outcome, an organ involvement (OI) scoring system was developed. RESULTS: We confirm neonatal onset with enteropathy, type 1 diabetes, and eczema. In addition, we found less common manifestations in delayed onset patients or during disease evolution. There is no correlation between the site of mutation and the disease course or outcome, and the same genotype can present with variable phenotypes. HSCT patients (n = 58) had a median follow-up of 2.7 years (range, 1 week-15 years). Patients receiving chronic IS (n = 34) had a median follow-up of 4 years (range, 2 months-25 years). The overall survival after HSCT was 73.2% (95% CI, 59.4-83.0) and after IS was 65.1% (95% CI, 62.8-95.8). The pretreatment OI score was the only significant predictor of overall survival after transplant (P = .035) but not under IS. CONCLUSIONS: Patients receiving chronic IS were hampered by disease recurrence or complications, impacting long-term disease-free survival. When performed in patients with a low OI score, HSCT resulted in disease resolution with better quality of life, independent of age, donor source, or conditioning regimen.

Clinical signs, profound acidemia, hypoglycemia, and hypernatremia are predictive of mortality in 1,400 critically ill neonatal calves with diarrhea.

Profound acidemia impairs cellular and organ function and consequently should be associated with an increased risk of mortality in critically ill humans and animals. Neonatal diarrhea in calves can result in potentially serious metabolic derangements including profound acidemia due to strong ion (metabolic) acidosis, hyper-D-lactatemia, hyper-L-lactatemia, azotemia, hypoglycemia, hyperkalemia and hyponatremia. The aim of this retrospective study was to assess the prognostic relevance of clinical and laboratory findings in 1,400 critically ill neonatal calves with diarrhea admitted to a veterinary teaching hospital. The mortality rate was 22%. Classification tree analysis indicated that mortality was associated with clinical signs of neurologic disease, abdominal emergencies, cachexia, orthopedic problems such as septic arthritis, and profound acidemia (jugular venous blood pH < 6.85). When exclusively considering laboratory parameters, classification tree analysis identified plasma glucose concentrations < 3.2 mmol/L, plasma sodium concentrations ≥ 151 mmol/L, serum GGT activity < 31 U/L and a thrombocyte count < 535 G/L as predictors of mortality. However, multivariable logistic regression models based on these laboratory parameters did not have a sufficiently high enough sensitivity (59%) and specificity (79%) to reliably predict treatment outcome. The sensitivity and specificity of jugular venous blood pH < 6.85 were 11% and 97%, respectively, for predicting non-survival in this study population. We conclude that laboratory values (except jugular venous blood pH < 6.85) are of limited value for predicting outcome in critically ill neonatal calves with diarrhea. In contrast, the presence of specific clinical abnormalities provides valuable prognostic information.

Gastrointestinal Histoplasmosis: A Case Series.

Histoplasmosis is an invasive mycosis caused by inhalation of the spores of dimorphic fungi Histoplasma capsulatum. The disease manifests in the lung as acute or chronic pulmonary histoplasmosis and in severe cases gets disseminated in multiple organs like skin, adrenal gland, central nervous system, lymph node, liver, spleen, bone marrow, and gastrointestinal tract. It occurs most commonly in immunodeficient patients like HIV-positive patients and transplant recipients, while immunocompetent hosts are affected rarely. In cases of gastrointestinal histoplasmosis, the samples are collected for culture and biopsy should be sent for histopathological examination for definitive diagnosis. We conducted a retrospective study of colonic biopsies performed in the department of gastroenterology in a tertiary care hospital of north India from January 2014 to December 2015. Five cases of colonic histoplasmosis were diagnosed on histopathology out of which 4 patients were from north India while 1 patient was from Myanmar. The patients presented with various complaints, including loose stools, diarrhea, altered bowel habits, and gastrointestinal bleeding. The prognosis is very good after early and aggressive treatment while the disease is fatal if it remains untreated. In our study, 2 patients died within few days of diagnosis due to delay in the diagnosis, dissemination, and associated complications. Other patients were started on amphotericin B deoxycholate and are under follow-up. An early diagnosis of gastrointestinal histoplasmosis is important as appropriate treatment leads to long-term survival while untreated cases are almost fatal.

Morbidity and mortality in severely burned children with Clostridium difficile-associated diarrhea.

BACKGROUND: Clostridium difficile is a key culprit underlying nosocomial infectious diarrhea. We investigated the effect of C difficile-associated diarrhea (CDAD) on morbidity and mortality in severely burned children and CDAD risk factors. METHODS: After review of 2,840 records, 288 pediatric burn patients were identified as having stool output of >10 mL•kg(-1)•min(-1) for ≥2 successive days and had stool samples immunoassayed for toxins A and B. A case control analysis was performed by matching cases to controls via logistic regression and propensity scores so that age, admission time, and time of occurrence could be controlled; the endpoints were mortality and hospitalization time. RESULTS: Eighteen patients tested positive for C difficile toxins (median age, 4 years; mean total body surface area burned, 59%). In the CDAD group, unadjusted in-hospital mortality was 28% (odds ratio, 5.4; 95% CI, 1.7-16.7; P = .01). Hospitalization averaged 48 days in the CDAD group and 38 days in the non-CDAD group (P = .24). Duration of stay per percent total body surface area burned was greater in the CDAD group (0.82 ± 0.4 vs 0.60 ± 0.4; P = .03), as were prolonged bouts of diarrhea complicated by acidosis (13 ± 16 vs 4 ± 5 days; P < .005). Of the 18 possible risk factors evaluated, inhalation injury diagnosed at admission occurred more often in CDAD patients than matched controls (59% vs 31%; P = .04). CONCLUSION: CDAD during hospitalization is associated with greater mortality after burns. Inhalation injury increases the likelihood of C difficile infection. Whether C difficile infection is an indication of greater illness among certain burned patients is unknown.

Refractory diarrhea: A paraneoplastic syndrome of neuroblastoma.

Neuroblastoma (NB) is the most common extracranial solid tumor in children. Diarrheal NB is quite rare and is not easy to diagnose in the early stage. Six cases of diarrheal NB in our hospital treated from 1996 to 2006 were retrospectively analyzed, including characteristics such as electrolyte imbalance, pathologic features, vasoactive intestinal peptide (VIP) immunohistochemical staining results, treatment, and prognosis. All patients were boys with 3-8 loose or watery stools each day and routine fecal tests were normal. Abdominal tumors were identified by B-ultrasound. Drugs were ineffective. Three patients underwent surgery, and the remaining three patients received surgery and chemotherapy. Diarrhea stopped after treatment in five patients. Two patients died due to intractable hypokalemia. The tumor was located in the adrenal gland in four patients, in the upper retroperitoneum in one patient, and in the presacral area in one patient. Pathologic findings were NB and ganglioneuroblastoma. Five patients were at clinical stage I-II, and one was at stage III. Four patients survived (followed-up for 6 mo to 4 years). Immunohistochemical staining for VIP was positive. Refractory diarrhea is a paraneoplastic syndrome of NB and is rare. Patients aged 1-3 years who present with chronic intractable diarrhea should be followed closely. Intractable diarrhea, hypokalemia, and dysplasia are the initial clinical manifestations. Increased VIP is characteristic of this disease. Potassium supplementation plays a vital role in the treatment procedure, especially preoperatively. The prognosis of diarrheal NB is good following appropriate treatment.

The effectiveness of a rotavirus vaccine in preventing hospitalizations and deaths presumably due to acute infectious diarrhea in Brazilian children: a quasi-experimental study

INTRODUCTION: Rotavirus is the main etiologic agent of acute infectious diarrhea in children worldwide. Considering that a rotavirus vaccine (G1P8, strain RIX4414) was added to the Brazilian vaccination schedule in 2006, we aimed to study its effectiveness and safety regarding intestinal intussusception. METHODS: A quasi-experimental trial was performed in which the primary outcome was the number of hospitalizations that were presumably due to acute infectious diarrhea per 100,000 children at risk (0-4 years old). The secondary outcomes included mortality due to acute infectious diarrhea and the intestinal intussusception rates in children in the same age range. We analyzed three scenarios: Health Division XIII of the State of São Paulo (DRS XIII) from 2002 to 2008, the State of São Paulo, and Brazil from 2002 to 2012. RESULTS: The averages of the hospitalization rates for 100,000 children in the pre- and post-vaccination periods were 1,413 and 959, respectively, for DRS XIII (RR=0.67), 312 and 249, respectively, for the State of São Paulo (RR=0.79), and 718 and 576, respectively, for Brazil (RR=0.8). The mortality rate per 100,000 children in the pre- and post-vaccination periods was 2.0 and 1.3, respectively, for DRS XIII (RR=0.66), 5.5 and 2.5, respectively, for the State of São Paulo (RR=0.47), and 15.0 and 8.0, respectively, for Brazil (RR=0.53). The average annual rates of intussusception for 100,000 children in DRS XIII were 28.0 and 22.0 (RR=0.77) in the pre- and post-vaccination periods, respectively. CONCLUSIONS: A monovalent rotavirus vaccine was demonstrated to be effective in preventing the hospitalizations and deaths of children that were presumably due to acute infectious diarrhea, without increasing the risk of intestinal intussusception. .