Epidemiology and Risk Factors of Healthcare-Associated Infections in Critically Ill Patients in a Tertiary Care Teaching Hospital in Nepal: A Prospective Cohort Study.

BACKGROUND: Healthcare-associated infection (HAI) is an important public health problem, particularly in intensive care units (ICUs). We aimed to examine the epidemiology and risk factors of HAIs in our ICUs and study their microbiological profile. METHODS: We evaluated 100 consecutive patients in 3 medical and surgical ICUs of a tertiary care teaching hospital daily starting in January 2016 using the Centers for Disease Control and Prevention definitions and methods. We determined the incidence and sites of HAIs, identified the causative microorganism, and studied their antibiotic sensitivity profiles. We investigated risk factors for the development of an HAI using a multiple logistic regression model. RESULTS: Of 300 patients, 129 patients (43%) developed HAIs (55.96 HAI events per 1000 ICU-days). Pneumonia was the most common type of HAI (57, 41%). Escherichia coli was the most frequently isolated microorganism (20, 29%) and 74% of the pathogens isolated were multi-drug resistant. The presence of an invasive device (Odds Ratio, 4.29; 95% Confidence Interval, 2.52-7.51) and use of sedation (Odds Ratio, 2.24; 95% Confidence Interval, 1.31-3.87) were the statistically significant risk factors for HAIs. CONCLUSIONS: We found a high incidence of HAIs in our ICUs and a high burden of multidrug-resistant microorganisms highlighting the importance of infection control and antibiotic stewardship.

Serum Helicobacter pylori antibody reactivity in seven Asian countries using an automated latex aggregation turbidity assay.

BACKGROUND AND AIM: To determine the application range of diagnostic kits utilizing anti-Helicobacter pylori antibody, we tested a newly developed latex aggregation turbidity assay (latex) and a conventional enzyme-linked immunosorbent assay (E-plate), both containing Japanese H. pylori protein lysates as antigens, using sera from seven Asian countries. METHODS: Serum samples (1797) were obtained, and standard H. pylori infection status and atrophy status were determined by culture and histology (immunohistochemistry) using gastric biopsy samples from the same individuals. The two tests (enzyme-linked immunosorbent assay and latex) were applied, and receiver operating characteristics analysis was performed. RESULTS: Area under the curve (AUC) from the receiver operating characteristic of E-plate and latex curves were almost the same and the highest in Vietnam. The latex AUC was slightly lower than the E-plate AUC in other countries, and the difference became statistically significant in Myanmar and then Bangladesh as the lowest. To consider past infection cases, atrophy was additionally evaluated. Most of the AUCs decreased using this atrophy-evaluated status; however, the difference between the two kits was not significant in each country, but the latex AUC was better using all samples. Practical cut-off values were 3.0 U/mL in the E-test and 3.5 U/mL in the latex test, to avoid missing gastric cancer patients to the greatest extent possible. CONCLUSIONS: The kits were applicable in all countries, but new kits using regional H. pylori strains are recommended for Myanmar and Bangladesh. Use of a cut-off value lower than the best cut-off value is essential for screening gastric cancer patients.

Utility of Precision Medicine in the Management of Diabetes: Expert Opinion from an International Panel.

AIM: The primary objective of this review is to develop a practice-based expert group opinion on the role of precision medicine with a specific focus on sulfonylureas (SUs) in diabetes management. BACKGROUND: The clinical etiology, presentation and complications of diabetes vary from one patient to another, making the management of the disease challenging. The pre-eminent feature of diabetes mellitus (DM) are chronically elevated blood glucose concentrations; however, in clinical practice, the exclusion of autoimmunity, pregnancy, pancreatic disease or injury and rare genetic forms of diabetes is crucial. Within this framework, precision medicine provides unique insights into the risk factors and natural history of DM. Precision medicine goes beyond genomics and encompasses patient-centered care, molecular technologies and data sharing. Precision medicine has evolved in the field of diabetology. It has helped improve the efficacy of SUs, a class of drugs, which have been effectively used in the management of diabetes mellitus for decades, and it has enabled the expansion of SUs use in diabetes patients with genetic mutations. REVIEW RESULTS: After due discussions, the expert group analyzed studies that focused on the use of SUs in diabetes patients with genomic variations and rare mutations. The expert group opined that SUs are important glucose-lowering drugs and that precision medicine helps in improving the efficacy of SUs by matching them to those patients who will benefit most. CONCLUSION: Precision medicine opens new vistas for the effective use of SUs in unexpected patient populations, such as those with genetic mutations.

Effective therapeutic regimens in two South Asian countries with high resistance to major Helicobacter pylori antibiotics.

Background: Nepal and Bangladesh have a high prevalence of Helicobacter pylori with high resistance rates to clarithromycin, metronidazole, and levofloxacin. Here, we evaluated the susceptibility and genetic mutations of 5 alternative antibiotics against isolates from both countries to obtain an effective treatment regimen for H. pylori eradication. Methods: We used the agar dilution method to determine the minimal inhibitory concentration of 5 alternative antibiotics against 42 strains from Nepal and 56 from Bangladesh and performed whole genome mutation analysis. Results: No resistance to furazolidone or rifabutin and a high susceptibility of sitafloxacin (95.2% in Nepal and 98.2% in Bangladesh) were observed. In contrast, resistance to rifaximin (52.4% in Nepal and 64.3% in Bangladesh) was high. Moreover, resistance to garenoxacin was higher in Bangladesh (51.6%) than in Nepal (28.6%, P = 0.041), most likely due to its correlation with levofloxacin resistance (P = 0.03). Garenoxacin and rifaximin were significantly correlated in Bangladesh (P = 0.014) and occurred together with all sitafloxacin-resistant strains. Mutations of gyrA could play a significant role in garenoxacin resistance, and double mutations of A87 and D91 were associated with sitafloxacin resistance. Analysis of the rpoB gene demonstrated well-known mutations, such as V657I, and several novel mutations, including I2619V, V2592 L, T2537A, and F2538 L. Conclusions: Rifabutin can be cautiously implemented as therapy for H. pylori infection due to its interaction with the tuberculosis endemic in Bangladesh. The high susceptibility of furazolidone and sitafloxacin suggests their possible future application in Nepal and Bangladesh.

Helicobacter pylori bab characterization in clinical isolates from Bhutan, Myanmar, Nepal and Bangladesh.

BACKGROUND: Helicobacter pylori BabA is an important outer membrane protein that involves in the attachment to the gastric mucosa and enhances the virulence property of the bacterium. This study was aimed to characterize the bab genotypes, to evaluate its association with cagA, vacA and clinical diseases as well as degree of gastric inflammation. METHODS: H. pylori isolates from four countries were subjected for the characterization of bab. The locus specific forward and bab specific reverse primers were used to get the specific products by PCR, which could distinguish the three locus (A, B and C). The histological activities were evaluated according to the Updated Sydney system. RESULT: In patients from high risk countries (Bhutan and Myanmar) relatively higher frequencies of strains with babA-positivity (91.8% and 90.7%, respectively), babA at locus A (98% and 91.2%, respectively) and with single babA (96.8% and 91.2%, respectively) were found. Strains with two loci occupied were the most prevalent in Bhutan (84.6%), Myanmar (74.7%), Nepal (58.3%) and Bangladesh (56.9%). The genotype babA at locus A/babB at locus B/bab-negative at locus C (babA/babB/-) was the most common genotype isolated from Bhutan (82.7%), Myanmar (58.7%), Nepal (32%) and Bangladesh (31.4%) among all genotypes assessed. This genotype was also associated with the peptic ulcer disease (P = 0.013) when compared to gastritis. babA-positive characteristics and the genotype babA/babB/- exhibited the enhanced histological activities. CONCLUSIONS: The higher prevalence of virulence associated babA-positive characteristics and enhanced histological activities in Bhutan than in Myanmar, Nepal and Bangladesh might partly explain why the peoples in Bhutan are at higher risk for developing severe gastric complications.

Nepalese Helicobacter pylori Genotypes Reflects a Geographical Diversity than a True Virulence Factor

Background: The data about the association between Helicobacter pylori putative virulence factors; iceA and jhp0562/ß-(1,3)galT with clinical outcomes are still controversial. We identified and analyzed two putative H. pylori virulence factors in Nepalese strains. Methods: The iceA and jhp0562/ß-(1,3)galT allelic types were determined by polymerase chain reaction amplification. Histological analysis were classified according to the updated Sydney system and the Operative Link on Gastritis Assessment (OLGA) system. Results: Among 49 strains, iceA1 negative/iceA2 positive (iceA2-positive) was predominant type (57.1%, 28/49) and 20 (40.8%) were iceA1 positive/iceA2 negative. The remaining one (2.0%) was positive for both iceA1 and iceA2 (iceA1/iceA2-mixed). Patients infected with iceA1-positive strains tended to be higher OLGA score than iceA2-positive strains [1.45 [1] vs. 0.07 [0.5], P = 0.09, respectively). The jhp0562 negative/ß-(1,3)galT positive was predominant type (25/51, 49.0%), followed by double positive for jhp0562/ß-(1,3)galT (15/51, 29.4%) and jhp0562 positive/ß-(1,3)galT negative (11/51, 21.6%). Activity in the corpus was significantly higher in jhp0562 negative/ß-(1,3)galT positive than double positive of jhp0562/ß-(1,3)galT positive [mean (median); 1.24 (1) vs. 0.73 (1), P = 0.03]. There was association between iceA and subtype of vacA signal region (e.g., s1a, s1b or s1c) and combination subtypes of signal and middle regions (e.g., s1a-m1c) (P = 0.02, r = 0.29; and P = 0.002, r = 0.42, respectively). In addition, jhp0562/ß-(1,3)galT genotypes associated with cagA pre-EPIYA type (e.g., 6 bp-, 18 bp-, or no deletion-type) (P = 0.047, r = 0.15). Conclusion: The inconsistency results of the association between iceA, jhp0562/ß-(1,3)galT and histological scores suggesting that these genes may associate with genetic heterogeneity rather than as a true virulence factor.

Serum Free T3 to Free T4 Ratio as a Useful Indicator for Differentiating Destruction Induced Thyrotoxicosis from Graves' Disease.

INTRODUCTION: Thyrotoxicosis is a common disease encountered in Endocrine Outpatient Department (OPD). Two common causes of thyrotoxicosis are Destruction Induced Thyrotoxicosis (DIT) and Graves' Disease (GD). Differentiating DIT and GD based on clinical findings, is often not possible due to nonspecific symptoms. Thyroid scan is considered most reliable method for differentiating DIT and GD. AIM: To differentiate DIT and GD using the ratio of free triiodothyronine (fT3) and free thyroxine (fT4) thus avoiding thyroid technetium scan which is expensive and not accessible in developing countries like Nepal. MATERIALS AND METHODS: Patients attending Endocrine OPD with diagnosis of thyrotoxicosis at their first visit in which Thyroid technetium scan could be done were taken as sample. The study was conducted from mid-June 2016 to February 2017 and total 55 samples were taken. Only selected cases were taken where diagnostic dilemma was present. Report of Thyroid Function Test (TFT) of patient at their first visit and findings of thyroid scan were recorded. Ratio of freeT3 and freeT4 was obtained in each case. ROC curve was plotted and the cut off value for differentiation of DIT and GD was obtained. All data were analysed using SPSS software version 20.0. RESULTS: Mean ratio of fT3 to fT4 in GD and DIT was 0.395 and 0.287 respectively which was significant. On ROC analysis, cut off ratio for differentiating GD and DIT was 0.30 with sensitivity of 87% and specificity of 62.5%. CONCLUSION: It is recommended that thyroid scan can be avoided if ratio of fT3 and fT4 is less than 0.3 and a diagnosis of DIT can be made.

Emerging Helicobacter pylori levofloxacin resistance and novel genetic mutation in Nepal.

BACKGROUND: The prevalence of Helicobacter pylori antibiotic susceptibility in the Nepalese strains is untracked. We determined the antibiotic susceptibility for H. pylori and analyzed the presence of genetic mutations associated with antibiotic resistance in Nepalese strains. RESULTS: This study included 146 consecutive patients who underwent gastroduodenal endoscopy in Kathmandu, Nepal. Among 42 isolated H. pylori, there was no resistance to amoxicillin and tetracycline. In contrast, similar with typical South Asian patterns; metronidazole resistance rate in Nepalese strains were extremely high (88.1 %, 37/42). Clarithromycin resistance rate in Nepalese strains were modestly high (21.4 %, 9/42). Most of metronidazole resistant strains had highly distributed rdxA and frxA mutations, but were relative coincidence without a synergistic effect to increase the minimum inhibitory concentration (MIC). Among strains with the high MIC, 63.6 % (7/11) were associated with frameshift mutation at position 18 of frxA with or without rdxA involvement. However, based on next generation sequencing data we found that one strain with the highest MIC value had a novel mutation in the form of amino acid substituted at Ala-212, Gln-382, Ile-485 of dppA and Leu-145, Thr-168, Glu-117, Val-121, Arg-221 in dapF aside from missense mutations in full-length rdxA. Mutations at Asn-87 and/or Asp-91 of the gyrA were predominantly in levofloxacin-resistant strains. The gyrB mutation had steady relationship with the gyrA 87-91 mutations. Although three (44.4 %) and two (22.2 %) of clarithromycin resistant strains had point mutation on A2143G and A2146G, we confirmed the involvement of rpl22 and infB in high MIC strains without an 23SrRNA mutation. CONCLUSIONS: The rates of resistance to clarithromycin, metronidazole and levofloxacin were high in Nepalese strains, indicating that these antibiotics-based triple therapies are not useful as first-line treatment in Nepal. Bismuth or non-bismuth-based quadruple regimens, furazolidone-based triple therapy or rifabutin-based triple therapy may become alternative strategy in Nepal.

Inequality and inequity in healthcare utilization in urban Nepal: a cross-sectional observational study.

Inequality in access to quality healthcare is a major health policy challenge in many low- and middle-income countries. This study aimed to identify the major sources of inequity in healthcare utilization using a population-based household survey from urban Nepal. A cross-sectional survey was conducted covering 9177 individuals residing in 1997 households in five municipalities of Kathmandu valley between 2011 and 2012. The concentration index was calculated and a decomposition method was used to measure inequality in healthcare utilization, along with a horizontal inequity index (HI) to estimate socioeconomic inequalities in healthcare utilization. Results showed a significant pro-rich distribution of general healthcare utilization in all service providers (Concentration Index: 0.062, P < 0.001; HI: 0.029, P < 0.05) and private service providers (Concentration Index: 0.070, P < 0.001; HI: 0.030, P < 0.05). The pro-rich distribution of probability in general healthcare utilization was attributable to inequalities in the level of household economic status (percentage contribution: 67.8%) and in the self-reported prevalence of non-communicable diseases such as hypertension (36.7%) and diabetes (14.4%). Despite the provision of free services by public healthcare providers, our analysis found no evidence of the poor making more use of public health services (Concentration Index: 0.041, P = 0.094). Interventions to reduce the household economic burden of major illnesses, coupled with improvement in the management of public health facilities, warrant further attention by policy-makers.

Helicobacter pylori Infection and Gastric Mucosal Atrophy in Two Ethnic Groups in Nepal.

Serum anti-Helicobacter pylori antibodies and pepsinogens (PGs) have been used as gastric cancer screening and gastric mucosal status markers. Nepal is a low risk country for gastric cancer. However, the mountainous populace in the northern region culturally linked to Tibet as well as Bhutan, a neighboring country, have a high risk of GC. We collected gastric biopsy specimens and sera from 146 dyspeptic patients living in Kathmandu, Nepal. We also examined the sera of 80 volunteers living in the mountainous regions of the Himalayas. The optimal cut-off was calculated for serum biomarkers against the histology. Kathmandu patients (43.8%) were serologically positive for H. pylori infection, which was significantly lower than that for the mountainous (61.3%, P = 0.01). The same results also found in the prevalence of PG-positivity, PG I levels and PG I/II ratios (P = 0.001, P <0.0001 and P = 0.03, respectively). Moreover, the PG I/II ratios were significantly, and inversely correlated with the OLGA score (r = -0.33, P <0.009). The low incidence of gastric cancer in Nepal can be attributed to low gastric mucosal atrophy. However, the mountainous subjects have high-risk gastric mucosal status, which could be considered a high-risk population in Nepal.

Molecular Epidemiology of Helicobacter pylori Infection in Nepal: Specific Ancestor Root.

Prevalence of Helicobacter pylori infection in Nepal, a low-risk country for gastric cancer, is debatable. To our knowledge, no studies have examined H. pylori virulence factors in Nepal. We determined the prevalence of H. pylori infection by using three different tests, and the genotypes of virulence factors were determined by PCR followed by sequencing. Multilocus sequence typing was used to analyze the population structure of the Nepalese strains. The prevalence of H. pylori infection in dyspeptic patients was 38.4% (56/146), and was significantly related with source of drinking water. In total, 51 strains were isolated and all were cagA-positive. Western-type-cagA (94.1%), cagA pre-EPIYA type with no deletion (92.2%), vacA s1a (74.5%), and m1c (54.9%) were the predominant genotypes. Antral mucosal atrophy levels were significantly higher in patients infected with vacA s1 than in those infected with s2 genotypes (P = 0.03). Several Nepalese strains were H. pylori recombinants with genetic features of South Asian and East Asian genotypes. These included all East-Asian-type-cagA strains, with significantly lesser activity and inflammation in the corpus than the strains of the specific South Asian genotype (P = 0.03 and P = 0.005, respectively). Although the population structure confirmed that most Nepalese strains belonged to the hpAsia2 population, some strains shared hpEurope- and Nepalese-specific components. Nepalese patients infected with strains belonging to hpEurope showed higher inflammation in the antrum than strains from the Nepalese specific population (P = 0.05). These results support that ancestor roots of Kathmandu`s people not only connected with India alone.

Use of nucleoside analogs in patients with chronic hepatitis B in Nepal: A prospective cohort study in a single hospital.

AIM: There still remain many concerns about the present status of antiviral therapy for chronic hepatitis B in developing countries in Asia, where the monitoring systems of virological markers have not been well established, despite the high prevalence of hepatitis B virus (HBV) infection. To investigate it in Nepal, this prospective cohort study was conducted at the Teaching Hospital of Tribhuvan University in Kathmandu. METHODS: From 2007 to 2012, 65 patients were consecutively enrolled, 44 of whom received nucleoside analogs (NA), such as lamivudine (LMV), adefovir or tenofovir (TDF), on the decision of the local hepatologist. Virological determinations were performed in Japan, by using the serially collected serum samples at the Teaching Hospital. Statistical analysis was performed, using Mann-Whitney U-test or Fisher's exact test. RESULTS: The younger, especially female patients of reproductive age were more frequently prescribed with these NA, and an increased preference for the use of TDF was observed over time. However, there was insufficient follow up of the NA-treated patients in this cohort, and not a few patients developed emergence of NA-resistant HBV: known resistance to LMV in 3 patients and incidental resistance to non-administrated NA in four patients. CONCLUSION: The results of the present study indicate that education for physicians as well as for infected patients regarding the proper use of NA, together with establishment of appropriate monitoring systems for virological markers, is warranted to prevent an increase in NA-resistant HBV infections in Nepal.

Catastrophic household expenditure on health in Nepal: a cross-sectional survey.

OBJECTIVE: To determine the incidence of - and illnesses commonly associated with - catastrophic household expenditure on health in Nepal. METHODS: We did a cross-sectional population-based survey in five municipalities of Kathmandu Valley between November 2011 and January 2012. For each household surveyed, out-of-pocket spending on health in the previous 30 days that exceeded 10% of the household's total expenditure over the same period was considered to be catastrophic. We estimated the incidence and intensity of catastrophic health expenditure. We identified the illnesses most commonly associated with such expenditure using a Poisson regression model and assessed the distribution of expenditure by economic quintile of households using the concentration index. FINDINGS: Overall, 284 of the 1997 households studied in Kathmandu, i.e. 13.8% after adjustment by sampling weight, reported catastrophic health expenditure in the 30 days before the survey. After adjusting for confounders, this expenditure was found to be associated with injuries, particularly those resulting from road traffic accidents. Catastrophic expenditure by households in the poorest quintile were associated with at least one episode of diabetes, asthma or heart disease. CONCLUSION: In an urban area of Nepal, catastrophic household expenditure on health was mostly associated with injuries and noncommunicable diseases such as diabetes and asthma. Throughout Nepal, interventions for the control and management of noncommunicable diseases and the prevention of road traffic accidents should be promoted. A phased introduction of health insurance should also reduce the incidence of catastrophic household expenditure.

International collaborative survey on epidemiology of hepatitis E virus in 11 countries.

We conducted seroepidemiological studies on antibody prevalence to hepatitis E virus (HEV) in 5,233 sera from 11 countries to ascertain the present state of HEV infection on a global basis. The prevalence of anti-HEV IgG increased with age in these tested countries, but the rate of antibody positivity was over 20% in the 16-30 year-old group in most of the participating countries, except for Japan, the USA, and Spain. Of patients with acute hepatitis of unknown etiology from Nepal, 56% (14/25) were positive for the IgM class of anti-HEV antibody. In addition, HEV RNAs in the serum from 3 Nepali patients who had the IgM antibody were detected by nested PCR and all of the HEV genes isolated belonged to genotype 1. Our results indicate that HEV is spreading worldwide, not only in developing countries, but also in more industrialized countries than previously thought.

High prevalence of hepatitis B virus pre-s mutant in countries where it is endemic and its relationship with genotype and chronicity.

It has been reported that hepatitis B virus (HBV) mutants carrying mutations in the pre-S region can be found in infected patients. In this study, we investigated the prevalence of the HBV variant with the pre-S mutant in different geographic regions, including countries with low and high levels of endemic HBV infection, and analyzed the correlation with clinical findings. We examined 387 HBV DNA-positive serum samples from individuals among 12 countries, consisting of Vietnam, Myanmar, Thailand, China, Korea, Nepal, Japan, Russia, Spain, United States, Bolivia, and Ghana. HBV pre-S mutants were detected in 71 (18.3%) of 387 serum samples tested. This mutant was the most prevalent in Vietnam (36%), followed by Nepal (27.3%), Myanmar (23.3%), China (22.4%), Korea (14.3%), Thailand (10.5%), Japan (7.7%), and Ghana (4.3%). In contrast, no case with this mutation was found in Russia, Spain, United States, and Bolivia. Among the HBV deletion mutations, 15.5% (11 of 71) occurred in the pre-S1 and 46.5% (33 of 71) in the pre-S2 regions. Eight (11.3%) cases had a mutation in both the pre-S1 and pre-S2 regions. In addition, a point mutation at the pre-S2 starting codon was observed in 19 (26.7%) cases. The detection rate of the HBV mutant in patients with hepatocellular carcinoma was significantly higher than in other patients (P < 0.05). Furthermore, these mutants were found more frequently in genotype B (25%) and genotype C (24.5%) than in the other genotypes (P < 0.05). Our results indicated that there was a high prevalence of HBV pre-S mutation in regions of endemic HBV infection in Asia. Furthermore, the pre-S mutation appeared to be correlated with hepatocellular carcinoma and HBV genotypes.

Kikuchi-Fujimoto disease in Nepal: a study of 6 cases.

CONTEXT: Kikuchi-Fujimoto disease is a benign disorder, predominantly affecting young women with a predilection for cervical lymphadenopathy. Although the disease has been recognized worldwide, to our knowledge no cases have been reported previously from Nepal. OBJECTIVES: To determine the prevalence of Kikuchi-Fujimoto disease in Nepal and to analyze clinicopathologic features. METHODS: We reviewed 6 cases of Kikuchi-Fujimoto disease recorded at 3 different hospitals in Nepal during a period from June 1998 to June 2002. Clinical data and histopathology are presented. RESULTS: This study included 5 females and 1 boy, aged 13 to 32 years. These patients presented with prolonged fever and lymphadenopathy. The 5 female patients had cervical lymphadenopathy, and the boy had axillary lymphadenopathy. Complete blood counts revealed raised erythrocyte sedimentation rates in all patients and anemia in 2 patients. The size of excised lymph nodes (in greatest dimension) ranged from 1.5 to 5 cm. Typical histologic features were seen, namely, architectural effacement due to presence of pale nodular lymphohistiocytic foci with karyorrhectic debris, coagulation necrosis, eosinophilic debris, and absence of granulocytic infiltration. In a follow-up of the cases, disease recurrence was not found. CONCLUSION: Our study emphasizes that Kikuchi-Fujimoto disease should be considered as one of the differential diagnoses in patients with prolonged fever and cervical lymphadenopathy and that it should be differentiated from tuberculous lymphadenitis in regions where tuberculosis is prevalent.