Management of Helicobacter pylori infection in Latin America: A Delphi technique-based consensus

AIM: To optimize diagnosis and treatment guidelines for this geographic region, a panel of gastroenterologists, epidemiologists, and basic scientists carried out a structured evaluation of available literature.METHODS: Relevant questions were distributed among the experts, who generated draft statements for consideration by the entire panel. A modified three-round Delphi technique method was used to reach consensus. Critical input was also obtained from representatives of the concerned medical community. The quality of the evidence and level of recommendation supporting each statement was graded according to United States Preventive Services Task Force criteria.RESULTS: A group of ten experts was established. The survey included 15 open-ended questions that were distributed among the experts, who assessed the articles associated with each question. The levels of agreement achieved by the panel were 50% in the first round, 73.3% in the second round and 100% in the third round. Main consensus recommendations included: (1) when available, urea breath and stool antigen test (HpSA) should be used for non-invasive diagnosis; (2) detect and eradicate Helicobacter pylori (H. pylori) in all gastroscopy patients to decrease risk of peptic ulcer disease, prevent o retard progression in patients with preneoplastic lesions, and to prevent recurrence in patients treated for gastric cancer; (3) further investigate implementation issues and health outcomes of H. pylori eradication for primary prevention of gastric cancer in high-risk populations; (4) prescribe standard 14-d triple therapy or sequential therapy for first-line treatment; (5) routinely assess eradication success post-treatment in clinical settings; and (6) select second- and third-line therapies according to antibiotic susceptibility testing.CONCLUSION: These achievable steps toward better region-specific management can be expected to improve clinical health outcomes.     

The role of endoscopy after upper gastrointestinal bleeding in sub-Saharan Africa: A prospective observational cohort study

BackgroundUpper gastrointestinal (UGI) bleed is a common surgical disease in sub-Saharan Africa where there is often a lack of diagnostic and interventional adjuncts such as endoscopy. This study sought to characterize the role of endoscopy in management of acute UGI bleeding.Materials and MethodsThis is a prospective observational analysis of adults presenting with an UGI bleed to a tertiary center in Lilongwe, Malawi, over two years. Patients were classified as having no endoscopy, diagnostic endoscopy, or endoscopy with variceal banding. Bivariate, survival analysis, and logistic regression analyses were used to compare intervention cohorts.Results293 patients were included with 49 patients (16.7%) receiving endoscopy with banding, 65 (22.2%) patients receiving diagnostic endoscopy only, and 179 (61.1%) receiving no endoscopy. Upon survival analysis comparing to the no endoscopy group, cox hazard modelling showed an adjusted hazard ratio over 30 days of 0.12 (95% CI 0.02, 0.88, p=0.038) for the endoscopic banding group and a hazard ratio of 0.39 (95% CI 0.13, 1.16, p=0.090) for the diagnostic endoscopy only group. Physical exam findings consistent with cirrhosis and decreasing age were independent predictors of an endoscopic diagnosis of variceal bleeding.ConclusionEsophagogastric varices are a common cause of UGI bleeding in sub-Saharan Africa and can be predicted with age and physical exam findings. Endoscopy with variceal banding has a survival benefit for patients presenting with acute UGI bleed even with relatively low utilization. Appropriately triaging patients with likely variceal bleeding and improving endoscopy capacity would likely have a significant impact on mortality.     

Protection from hypertension in mice by the Mediterranean diet is mediated by nitro fatty acid inhibition of soluble epoxide hydrolase

Soluble epoxide hydrolase (sEH) is inhibited by electrophilic lipids by their adduction to Cys521 proximal to its catalytic center. This inhibition prevents hydrolysis of the enzymes’ epoxyeicosatrienoic acid (EET) substrates, so they accumulate inducing vasodilation to lower blood pressure (BP). We generated a Cys521Ser sEH redox-dead knockin (KI) mouse model that was resistant to this mode of inhibition. The electrophilic lipid 10-nitro-oleic acid (NO₂-OA) inhibited hydrolase activity and also lowered BP in an angiotensin II-induced hypertension model in wild-type (WT) but not KI mice. Furthermore, EET/dihydroxy-epoxyeicosatrienoic acid isomer ratios were elevated in plasma from WT but not KI mice following NO₂-OA treatment, consistent with the redox-dead mutant being resistant to inhibition by lipid electrophiles. sEH was inhibited in WT mice fed linoleic acid and nitrite, key constituents of the Mediterranean diet that elevates electrophilic nitro fatty acid levels, whereas KIs were unaffected. These observations reveal that lipid electrophiles such as NO₂-OA mediate antihypertensive signaling actions by inhibiting sEH and suggest a mechanism accounting for protection from hypertension afforded by the Mediterranean diet.Soluble epoxide hydrolase (sEH) has a conserved cysteine (Cys521) proximal to its catalytic center. This cysteine can undergo Michael addition with electrophilic lipids, which inhibits hydrolysis of the enzyme’s epoxyeicosatrienoic acid (EET) substrates (1). This in turn elevates EET levels, which mediate blood vessel dilation and lowers blood pressure (BP), especially in the setting of hypertension (2, 3). Diverse sEH inhibitors limit injury in a variety of diseases (4), providing broad cardiovascular protection (5) against hypertension (6, 7), ischemia and reperfusion injury (8, 9), hypertrophy, and heart failure (10), as well as inflammation (11, 12). Consistent with the therapeutic potential of hydrolase inhibitors, sEH null mice are protected from pathological interventions (13). Conversely, genetic alterations that promote enhanced hydrolase activity are a risk factor for human heart failure (14).The endogenous lipid electrophile 10-nitrooctadec-9-enoic acid (nitro-oleic acid, NO₂-OA) inhibits sEH in vitro (1). NO₂-OA and other fatty acid nitroalkenes appear to signal via pleiotropic mechanisms including targeting and activating peroxisome proliferator-activated receptor gamma (PPARγ), the Kelch-like erythroid cell-derived protein with CNC homology (EHC)-associated protein-1 (Keap1), and nuclear factor (erythroid-derived)-like-2 (Nrf2)-regulated antioxidant response genes and inhibiting proinflammatory gene expression regulated by nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) (15, 16). Nitroalkenes are produced by radical addition of nitrogen dioxide (·NO₂) to one or more of the olefinic carbons of an unsaturated fatty acid. Nitrogen dioxide is both a product of oxidative inflammatory reactions involving nitric oxide (NO) and nitrite and the acidification nitrite. When the electron-withdrawing nitro group is bonded to alkenyl groups, this confers an electrophilic reactivity to fatty acids (17, 18). Thus, fatty acid nitroalkenes can modify proteins covalently via reversible Michael addition reactions that overall serves to link cellular metabolic and redox homeostasis with the posttranslational regulation of target protein function.Nitro fatty acids, which have been detected endogenously in plasma and urine of humans, animal models, and plants (19–21), mediate salutary cardiovascular signaling actions (22). For example they relax blood vessels, attenuate platelet activation, and reduce inflammation via cyclic guanosine monophosphate (cGMP)-independent mechanisms (23, 24). Of relevance, the Mediterranean diet is characterized by high consumption of unsaturated fatty acids, especially from olive oil and fish rich in oleic and linoleic acid, together with vegetables rich in nitrite and nitrate (25). The acidic and low-oxygen conditions in the stomach provide an environment for efficient nitration of such unsaturated fatty acids by nitrite (26).NO₂-OA normalizes blood pressure in an angiotensin (Ang) II-induced murine model of hypertension via undefined mechanisms (27). This was notable as pharmacological inhibitors of sEH also lower BP in murine hypertension, including salt- or Ang II-induced models (6, 7). As NO₂-OA inhibits sEH, we hypothesized that this mechanism may account for BP lowering in the setting of hypertension. Furthermore, as the Mediterranean diet both contains nitro fatty acids and can elevate their endogenous generation, this mechanism may contribute to dietary-induced BP decreases that in turn will reduce the risk of adverse cardiovascular event (28).Given the complexity of causally establishing whether nitro fatty acids lower BP by inhibiting sEH, especially in the setting of dietary-induced endogenous fatty acid nitration, we generated a Cys521Ser sEH knockin (KI) mouse. This “redox-inactive” sEH thiol mutant, rendered insensitive to adductive inhibition by lipid electrophiles in vitro, provided a novel model system for testing the impact of lipid nitroalkenes on sEH hydrolysis of vasoactive EET species and downstream physiological responses (1). The data reveal that nitro fatty acids, applied exogenously as a pharmacological agent or generated endogenously as part of the Mediterranean diet, inhibit sEH to elevate plasma EETs, which in turn lower BP.     

Development of a Specimen-Sparing Multichannel Bead Assay to Detect Antiparasite IgG4 for the Diagnosis of Schistosoma and Wuchereria Infections on the Coast of Kenya

To better delineate the impact of parasitic coinfection in coastal Kenya, we developed a novel specimen-sparing bead assay using multiplex flow immunoassay (MFI) technology to simultaneously measure serum or plasma immunoglobulin G4 (IgG4) against Brugia malayi antigen (BMA) and Schistosoma haematobium soluble worm antigen (SWAP). Properties of the bead assay were estimated by latent class analysis using data from S. haematobium egg counts/filarial rapid diagnostic cards (RDTs), parasite-specific enzyme-linked immunosorbent assays (ELISAs), and the multichannel IgG4 assay. For schistosomiasis, the bead assay had an estimated sensitivity of 81% and a specificity of 45%, and it was more sensitive than ELISA or urine egg counts for diagnosing infection. For filariasis, it had a sensitivity of 86% and a specificity of 39%, and it was more sensitive than ELISA or RDT. Measuring antibody by MFI is feasible and may provide more accurate epidemiological information than current parasitological tests, especially in the setting of low-intensity infections.     

Case Report: Trypanosoma cruzi Meningoencephalitis in a Patient with Acquired Immunodeficiency Syndrome

As a result of global migration, a significant number of people with Trypanosoma cruzi infection now live in the United States, Canada, many countries in Europe, and other non-endemic countries. Trypanosoma cruzi meningoencephalitis is a rare cause of ring-enhancing lesions in patients with acquired immunodeficiency syndrome (AIDS) that can closely mimic central nervous system (CNS) toxoplasmosis. We report a case of CNS Chagas reactivation in an AIDS patient successfully treated with benznidazole and antiretroviral therapy in the United States.Trypanosoma cruzi meningoencephalitis is a rare cause of ring-enhancing lesions in patients with acquired immunodeficiency syndrome (AIDS) that can closely mimic central nervous system (CNS) toxoplasmosis. Diagnosis is often delayed and mortality is 79–100% despite treatment^1,2; to our knowledge, only four cases of T. cruzi meningoencephalitis in human immunodeficiency virus (HIV)-infected patients have been reported in the United States.^3–6 None of the four patients have survived. We report a case of CNS Chagas reactivation in an AIDS patient successfully treated with benznidazole and antiretroviral therapy in the United States.A 49-year-old right-handed woman originally from Honduras was admitted to our hospital with a 3-week history of progressive altered mental status, headache, and right-sided weakness. On the day of symptom onset, she presented to an outside hospital and magnetic resonance imaging (MRI) of the brain revealed two ring-enhancing lesions associated with edema. She was also diagnosed with AIDS (CD4 count of 38 cells/μL and an HIV viral load of 375,000 copies/mL). The patient underwent an MRI-guided biopsy of the left parietal lesion and was diagnosed with cerebral Toxoplasmosis. After 14-days, she was discharged to continue treatment of cerebral toxoplasmosis with sulfadiazine and pyrimethamine; however, she was nonadherent with her medications.On admission to our hospital, she was afebrile and physical examination was notable for altered mental status and weakness of the right upper and lower extremities (3/5, Medical Research Council scale) without sensory deficit. The MRI of the brain showed worsening ring-enhancing lesions within the right superior frontal gyrus (1.4 × 1.2 cm) and left parietal lobe (2.4 × 2.2 cm) with moderate vasogenic edema and regional mass effect and adjacent leptomeningeal enhancement. She was started on oral sulfadiazine, pyrimethamine, and glucocorticosteroids. On hospital Day 5, the patient had worsening mental status and a computed tomography of the head showed enlargement of the right frontal lesion with increased edema. A lumbar puncture was performed. Cerebrospinal fluid (CSF) contained three white blood cells/μL and one red blood cell/μL. The CSF protein was 78 mg/dL and glucose was 55 mg/dL. The CSF Gram stain was negative for bacteria but Wright-Giemsa stain revealed numerous flagellated parasites consistent with T. cruzi trypomastigotes (Figure 1). Fungal and acid fast bacilli stain and cultures and CSF cryptococcal antigen were negative. Serologic studies were negative for Toxoplasma IgG and IgM but positive for T. cruzi antibody by the indirect fluorescent antibody test and enzyme immunoassay. The CSF and serum polymerase chain reaction studies were positive for T. cruzi and negative for Toxoplasma. Electrocardiogram and transthoracic echocardiogram were negative for findings to suggest Chagas cardiomyopathy.Open in a separate windowFigure 1.Trypanosoma cruzi trypomastigotes in cerebrospinal fluid (CSF) (Giemsa stain, ×1,000).The brain biopsy histopathology slides were obtained from an outside hospital, which revealed numerous intracellular organisms with rod-shaped kinetoplast, consistent with T. cruzi amastigotes (Figure 2).Open in a separate windowFigure 2.Trypanosoma cruzi amastigotes with rod-shaped kinetoplasts in glial cells (Giemsa stain, ×1,000).Treatment with benznidazole 5 mg/kg/day was started for Chagasic meningoencephalitis and brain abscesses. Her mental status improved gradually, although her right-sided weakness remained unchanged. Antiretroviral therapy was started 17 days after initiation of antitrypanosomal therapy. Repeat MRI of the brain 2 weeks after treatment showed a decrease in the size of the two lesions and surrounding edema. She completed a 60-day induction therapy. At last follow-up 5 months after initial diagnosis, she was clinically stable without evidence of recurrence and her CD4 count was 359 cells/μL with HIV viral load of 162 copies/ml.Chagas disease, or American trypanosomiasis, is estimated to affect ∼8–10 million people in the world, primarily in Latin America and the Caribbean.^7,8 As a result of global migration, a significant number of people with T. cruzi infection now live in the United States, Canada, many countries in Europe, and other non-endemic countries.⁹ In the United States alone, it is estimated that ∼0.3 to 1 million people are infected with T. cruzi.¹⁰Reactivation of chronic T. cruzi infection can occur in immunosuppressed patients such as those with hematologic malignancies, organ transplantation, and AIDS. In Chagas-endemic countries, T. cruzi and HIV coinfection rate ranges from 1.3% to 7.1%.¹¹ Although the chronic phase of Chagas disease in non-immunosuppressed patients most commonly manifests as cardiac disease or gastrointestinal dysfunction, the most common manifestations of T. cruzi reactivation in patients with AIDS are CNS lesions and menigoencephalitis. Most of the reported cases have occurred in HIV-infected patients with a CD4 count < 200 cells/μL.^1,2,12 T. cruzi reactivation in patients with AIDS can closely mimic cerebral toxoplasmosis clinically and radiographically, thus patients are often misdiagnosed resulting in a delay in appropriate treatment.¹²Identification of T. cruzi trypomastigote in CSF is diagnostic of chagasic encephalitis. However, a negative CSF smear does not rule out the disease. In a report of 15 cases from Argentina, CSF direct examination for T. cruzi was positive in 11 of 13 patients.² A brain biopsy may be necessary when the diagnosis remains unclear. The recommended treatment of CNS Chagas reactivation in HIV patients is benznidazole 5 mg/kg daily divided into two doses for 60–90 days and some authors recommend secondary prophylaxis with benznidazole 5 mg/kg three times per week.¹² Nifurtimox is considered an alternative treatment but clinical experience is limited. Immune reconstitution with highly active antiretroviral therapy likely plays an important role in the control of Chagas reactivation but optimal timing for initiation of antiretroviral therapy remains unclear.¹² Chagasic menigoencephalitis should be considered in HIV-infected patients with CNS lesions who are from T. cruzi-endemic areas.     

Case Report: Cutaneous Leishmaniasis in Cuban Immigrants to Texas who Traveled through the Darién Jungle,Panama

Cutaneous leishmaniasis is rarely seen in the United States. Four Cuban immigrants traveled along the same route at different times from Cuba to Ecuador, then northward, including through the Darién Jungle in Panama. These patients had chronic ulcerative non-healing skin lesions and were given a diagnosis of leishmaniasis.Leishmaniasis is a vector-borne disease caused by the protozoan parasite of the genus Leishmania and is spread by the bite of sand flies from the sub-family Phlebotominae.¹ There are various clinical manifestations of leishmaniasis, including cutaneous leishmaniasis (CL), mucocutaneous leishmaniasis, and visceral leishmaniasis. Cutaneous leishmaniasis occurs at the site of the bite, with lesions forming weeks to months later starting with a papule, which then develops into a nodule or plaque-like lesion and progresses to a painless ulceration with an indurated border.We report four cases of CL caused by Leishmania (Viannia) panamensis in Cuban immigrants who traveled through the Darién Gap Jungle between Colombia and Panama on their journey north to the United States. This region has been shown to have high transmission rates of leishmaniasis,² and, in 2012, Panama experienced an outbreak beyond expected endemic rates.³ This case series highlights a previously underappreciated immigration route to the United States for Cubans and the need to include leishmaniasis as a differential diagnosis for non-healing skin ulcers in this patient population.During May 2012–April 2013, four persons who had recently immigrated to the United States from Cuba came to the National School of Tropical Medicine at Baylor College of Medicine''s (BCM) Tropical Medicine Clinic for non-healing skin ulcers. All four persons reported a similar route of travel from Cuba to Texas (Figure 1), although at different times. Each person began their journey by flying to Quito, Ecuador, where they then traveled by bus through Colombia, passing through the cities of Pasto and Cali to Quibdo. In Quibdo, they took a short flight to Bahia Solano, Colombia, where a boat ride then transported them to Punta Ardita near the Panama border. They then traveled by foot through the thick jungle in Darién, Panama, for 5–15 days. During this time, they slept outdoors and reported numerous insect bites. Once through the Darién area, they traveled northward until they entered the United States at the Mexican border.Open in a separate windowFigure 1.Map showing immigration route of a cluster of Cuban patients with cutaneous leishmaniasis caused by Leishmania (V.) panamensis. Note the travel by foot through the thick jungle of the Darién National Park, Panama, where they likely contracted the disease.Once in the United States, the four persons sought medical care at outside clinics for skin lesions that had developed within two months after they passed though the Darién. They were treated for presumed infection with Staphylococcus aureus. The antibiotics had no therapeutic effect, and the lesions continued to grow and develop into non-healing, painless ulcers with accompanying satellite lesions. Once in Houston, Texas, the four persons were directed to the Department of Dermatology at BCM (