Beyond the effects of HIV infection and integrase inhibitors-based therapies on oral bacteriome.

Oral microbiome is the second largest microbial community in humans after gut. Human immunodeficiency virus (HIV) infection triggers an impairment of the immune system which could favour the growth and the colonization of pathogens in the oral cavity, and this dysbiosis has been associated with oral manifestations that worsen the quality of life of these patients. Antiretroviral therapy (ART) could also drive changes in specific oral bacterial taxa associated with such periodontal diseases. Integrase strand transfer inhibitors (INSTIs), therapy of choice in the treatment of naive HIV-patients, are able to reverse the impact of HIV infection on systemic inflammation, gut permeability, and gut bacterial diversity/richness. The objective of this study was to analyse the effects of HIV infection per se and INSTIs on salivary bacteriome composition, taking into consideration other factors such as smoking, that could also have a significant impact on oral microbiome. To accomplish this objective, 26 non-HIV-infected volunteers and 30 HIV-infected patients (15 naive and 15 under INSTIs-regimen) were recruited. Salivary samples were collected to measure lysozyme levels. Oral bacteriome composition was analysed using 16S rRNA gene sequencing. Naive HIV-infected patients showed statistically higher levels of lysozyme compared to controls (p < 0.001) and INSTIs-treated patients (p < 0.05). Our study was unable to detect differences in α nor ß-diversity among the three groups analysed, although significant differences in the abundance of some bacterial taxonomical orders were detected (higher abundance in the phylum Pseudomonadota, in the order Acholeplasmatales, and in the genera Ezakiella and Acholeplasma in the naive group compared to controls; and higher abundance in the phylum Mycoplasmatota, in the order Acholeplasmatales, and in the genera Acholeplasma and uncultured Eubacteriaceae bacterium in the INTIs-treated HIV-infected patients compared to controls). These differences seem to be partially independent of smoking habit. HIV infection and INSTIs effects on oral microbiota seem not to be very potent, probably due to the modulation of other factors such as smoking and the greatest outward exposure of the oral cavity.

Candidatus Neoehrlichia mikurensis Infection in Patient with Antecedent Hematologic Neoplasm, Spain1.

We report a confirmed case of Candidatus Neoehrlichia mikurensis infection in a woman in Spain who had a previous hematologic malignancy. Candidatus N. mikurensis infections should be especially suspected in immunocompromised patients who exhibit persistent fever and venous thrombosis, particularly if they live in environments where ticks are prevalent.

Bartonella Endocarditis in Spain: Case Reports of 21 Cases.

Blood culture negative endocarditis (BCNE) is frequent in infective endocarditis (IE). One of the causes of BCNE is fastidious microorganisms, such as Bartonella spp. The aim of this study was to describe the epidemiologic, clinical characteristics, management and outcomes of patients with Bartonella IE from the "Spanish Collaboration on Endocarditis-Grupo de Apoyo al Manejo de la Endocarditis infecciosa en España (GAMES)"cohort. Here we presented 21 cases of Bartonella IE. This represents 0.3% of a total of 5590 cases and 2% of the BCNE from the GAMES cohort. 62% were due to Bartonella henselae and 38% to Bartonella quintana. Cardiac failure was the main presenting form (61.5% in B. hensalae, 87.5% in B. quintana IE) and the aortic valve was affected in 85% of the cases (76% in B. henselae, 100% in B. quintana IE). Typical signs such as fever were recorded in less than 40% of patients. Echocardiography showed vegetations in 92% and 100% of the patients with B. henselae and B. quintana, respectively. Culture was positive only in one patient and the remaining were diagnosed by serology and PCR. PCR was the most useful tool allowing for diagnosis in 16 patients (100% of the studied valves). Serology, at titers recommended by guidelines, only coincided with PCR in 52.4%. Antimicrobial therapy, in different combinations, was used in all cases. Surgery was performed in 76% of the patients. No in-hospital mortality was observed. One-year mortality was 9.4%. This article remarks the importance for investigating the presence of Bartonella infection as causative agent in all BCNE since the diagnosis needs specific microbiological tools and patients could benefit of a specific treatment.

Gender differences for frailty in HIV-infected patients on stable antiretroviral therapy and with an undetectable viral load.

BACKGROUND: Patients with HIV infection suffer from accelerated aging. In this context, frailty could be a relevant problem that aggravates the quality of life (QoL) and morbi-mortality of these patients. Our objective was to determine the prevalence of frailty and pre-frailty in HIV-infected patients in our cohort as well as their risk factors and QoL. METHODS: This was a prospective cross-sectional study of HIV-infected people aged ≥18 years on a stable antiretroviral regimen (ART) ≥1 year. Frailty was defined by ≥3 of 5 Fried's criteria: weight loss, low physical activity, exhaustion, weak grip strength and slow walking time. Variables related to sociodemographics, HIV infection, comorbidities, polypharmacy, and QoL were evaluated. Independent predictors of frailty were evaluated using collinearity in a multivariate logistic regression analyses (backward stepwise elimination). RESULTS: The 248 people studied has a mean age of 49 years, 63.7% were male, and 81% were Caucasian. The prevalence of pre-frailty and fragility was 39.1% and 4.4%, respectively. The main route of HIV acquisition was heterosexual (47.2%). At the inclusion time 26.6% of the patients had AIDS events, 60.9% were anti-HCV negative, and 91.5% had HIV RNA <50 copies/mL (84.3% for ≥1 year); 10.9% had >2 comorbidities, and 13.3% were receiving >5 non-HIV drugs. Frailty patients had a higher age (p 0.006), more sensitive deficits (visual or auditory) (p 0.002), a greater number of falls during the previous year (p 0.0001), a higher Charlson comorbidity index (p 0.001), and a higher VACS index (p 0.001). All comorbidities, excluding bone and liver, were significantly more frequent in fragile patients. The presence of >2 comorbidities and treatment with >5 drugs not related to HIV they were also more frequent in frail patienst (p 0.0001 and p 0.004, respectively). Independent predictors of pre-frailty/frailty in the multivariable analysis differ in men (VACS index, C-reactive protein [CRP], and falls) and women (CRP, AIDS, and menopause). Patients with pre-frailty/frailty had some indicator of a lower QoL. CONCLUSION: Factors associated with pre-frailty/frailty in HIV-infected patients differ by gender, which should be considered when establishing measures for prevention. The role of menopause in the risk of pre-frailty/frailty warrants further investigations.

Outpatient Parenteral Antibiotic Treatment for Infective Endocarditis: A Prospective Cohort Study From the GAMES Cohort.

BACKGROUND: Outpatient parenteral antibiotic treatment (OPAT) has proven efficacious for treating infective endocarditis (IE). However, the 2001 Infectious Diseases Society of America (IDSA) criteria for OPAT in IE are very restrictive. We aimed to compare the outcomes of OPAT with those of hospital-based antibiotic treatment (HBAT). METHODS: Retrospective analysis of data from a multicenter, prospective cohort study of 2000 consecutive IE patients in 25 Spanish hospitals (2008-2012) was performed. RESULTS: A total of 429 patients (21.5%) received OPAT, and only 21.7% fulfilled IDSA criteria. Males accounted for 70.5%, median age was 68 years (interquartile range [IQR], 56-76), and 57% had native-valve IE. The most frequent causal microorganisms were viridans group streptococci (18.6%), Staphylococcus aureus (15.6%), and coagulase-negative staphylococci (14.5%). Median length of antibiotic treatment was 42 days (IQR, 32-54), and 44% of patients underwent cardiac surgery. One-year mortality was 8% (42% for HBAT; P < .001), 1.4% of patients relapsed, and 10.9% were readmitted during the first 3 months after discharge (no significant differences compared with HBAT). Charlson score (odds ratio [OR], 1.21; 95% confidence interval [CI], 1.04-1.42; P = .01) and cardiac surgery (OR, 0.24; 95% CI, .09-.63; P = .04) were associated with 1-year mortality, whereas aortic valve involvement (OR, 0.47; 95% CI, .22-.98; P = .007) was the only predictor of 1-year readmission. Failing to fulfill IDSA criteria was not a risk factor for mortality or readmission. CONCLUSIONS: OPAT provided excellent results despite the use of broader criteria than those recommended by IDSA. OPAT criteria should therefore be expanded.

Lack of Adrenomedullin Results in Microbiota Changes and Aggravates Azoxymethane and Dextran Sulfate Sodium-Induced Colitis in Mice.

The link between intestinal inflammation, microbiota, and colorectal cancer is intriguing and the potential underlying mechanisms remain unknown. Here we evaluate the influence of adrenomedullin (AM) in microbiota composition and its impact on colitis with an inducible knockout (KO) mouse model for AM. Microbiota composition was analyzed in KO and wild type (WT) mice by massive sequencing. Colitis was induced in mice by administration of azoxymethane (AOM) followed by dextran sulfate sodium (DSS) in the drinking water. Colitis was evaluated using a clinical symptoms index, histopathological analyses, and qRT-PCR. Abrogation of the adm gene in the whole body was confirmed by PCR and qRT-PCR. KO mice exhibit significant changes in colonic microbiota: higher proportion of δ-Proteobacteria class; of Coriobacteriales order; and of other families and genera was observed in KO feces. Meanwhile these mice had a lower proportion of beneficial bacteria, such as Lactobacillus gasseri and Bifidobacterium choerinum. TLR4 gene expression was higher (p < 0.05) in KO animals. AM deficient mice treated with DSS exhibited a significantly worse colitis with profound weight loss, severe diarrhea, rectal bleeding, colonic inflammation, edema, infiltration, crypt destruction, and higher levels of pro-inflammatory cytokines. No changes were observed in the expression levels of adhesion molecules. In conclusion, we have shown that lack of AM leads to changes in gut microbiota population and in a worsening of colitis conditions, suggesting that endogenous AM is a protective mediator in this pathology.

Coxiella burnetii in bulk tank milk and antibodies in farm workers at Montería, Colombia / Coxiella burnetii en leche de tanque y anticuerpos en trabajadores rurales en Montería, Colombia / Coxiella burnetii em leite de tanque bovina e anticorpos em trabalhadores rurais de Montería, Colômbia

Background: Q fever is a zoonotic disease caused by Coxiella burnetii. In Colombia it is not a notifiable disease in humans and is most likely under diagnosed. There are no studies about its prevalence in important reservoir species, such as cattle. Objective: the aim of this study was to investigate the frequency of C. burnetii infection in cattle farms and determine the frequency of antibodies in farm workers at risk in rural areas of Montería, Córdoba (Colombia). Methods: eleven cattle farms were randomly chosen to investigate the infection by C. burnetii. Bulk tank milk samples of each farm were analyzed by conventional PCR for DNA detection of transposase gene IS1111 of C. burnetii. Serum samples from 61 apparently healthy people living in eight farms were analyzed by indirect inmunofluorescence against phase II IgG antibodies to C. burnetii. Results: we report the presence of C. burnetii DNA in 45% of bulk tank milk samples from cattle farms and a 61% frequency of antibodies (IgG phase II ≥1/64) in farm workers at risk. Conclusion: our results demonstrate the circulation of this bacterium in the studied farms in Montería, Colombia, showing that at-risk farm workers have a high antibody frequency.

Antecedentes: la fiebre Q es una zoonosis causada por Coxiella burnetii. En Colombia no es una enfermedad notificable en humanos y probablemente es subdiagnosticada. De otro lado, no se han realizado estudios acerca de su prevalencia en importantes reservorios como los bovinos. Objetivos: el objetivo de este estudio fue determinar la frecuencia de infección por C. burnetii en fincas de ganado bovino y determinar la frecuencia de la presencia de anticuerpos en trabajadores de fincas en riesgo en áreas rurales del municipio de Montería, Córdoba (Colombia). Métodos: once fincas de ganado bovino fueron aleatoriamente seleccionadas para investigar la frecuencia de infección por C. burnetii. Muestras de leche de tanque de cada finca fueron analizadas mediante PCR convencional para detección del gen transposasa IS1111 de C. burnetii. Asimismo, se colectaron muestras de suero sanguíneo de 61 personas aparentemente saludables que vivían en ocho de las fincas estudiadas, las cuales fueron analizadas mediante el ensayo de inmunofluorescencia indirecta para detección de anticuerpos IgG contra fase II de C. burnetii. Resultados: en este estudio se reporta la presencia de ADN de C. burnetii en 45% de las muestras de leche de tanque de las fincas ganaderas estudiadas y una frecuencia de anticuerpos contra C. burnetii (IgG Fase II ≥1/64) del 61% en trabajadores de fincas en riesgo. Conclusiones: los resultados de este estudio demuestran la circulación de C. burnetii en las fincas estudiadas de un área de Montería, Colombia. También, los trabajadores de fincas en situación de riesgo presentan una alta frecuencia de anticuerpos contra este patógeno.

Antecedentes: a febre Q é uma zoonose causada por Coxiella burnetii. Na Colômbia não é uma doença de notificação obrigatória em seres humanos e é provavelmente subdiagnosticada. Além disto, não há estudos sobre sua prevalência nas principais espécies de reservatórios, como os bovinos. Objetivos: determinar a frequência de infecção por C. burnetii em fazendas de gado de leite e determinar a frequência de anticorpos em trabalhadores rurais em risco do município de Montería, Córdoba (Colômbia). Métodos: 11 fazendas de gado leiteiro foram selecionadas aleatoriamente para investigar a frequência de infecção por C. burnetii. Amostras de leite do tanque de cada fazenda foram analisadas por PCR convencional para a detecção do gene IS1111 transposase de C. burnetii. Além disso, amostras de soro de 61 pessoas aparentemente saudáveis que vivem em oito das propriedades estudadas foram analisadas por imunofluorescência indireta para a detecção de anticorpos IgG contra C. burnetii fase II. Resultados: neste estudo, o DNA de C. burnetii foi encontrado em 45% das amostras de leite do tanque, e uma frequência de anticorpos contra C. burnetii (fase II IgG ≥ 1/64) de 61% em trabalhadores rurais em risco. Conclusões: os resultados deste estudo demonstram a circulação de C. burnetii em algumas fazendas de gado em uma área de Montería, Colômbia. Além disso, os trabalhadores rurais em situação de risco têm uma alta frequência de anticorpos contra este patógeno.

Spinal cord toxoplasmosis in human immunodeficiency virus infection/acquired immunodeficiency syndrome.

Neurological complications in patients with human immunodeficiency virus infection/acquired immunodeficiency syndrome (HIV/AIDS) are still common, even in the era of highly active antiretroviral therapy. Opportunistic infections, immune reconstitution, the virus itself, antiretroviral drugs and neurocognitive disorders have to be considered when establishing the differential diagnosis. Toxoplasmic encephalitis remains the major cause of space-occupying lesions in the brain of patients with HIV/AIDS; however, spinal cord involvement has been reported infrequently. Here, we review spinal cord toxoplasmosis in HIV infection and illustrate the condition with a recent case from our hospital. We suggest that most patients with HIV/AIDS and myelitis with enhanced spine lesions, multiple brain lesions and positive serology for Toxoplasma gondii should receive immediate empirical treatment for toxoplasmosis, and a biopsy should be performed in those cases without clinical improvement or with deterioration.

Aproximación clínica y principales rickettsiosis transmitidas por garrapatas presentes en Latinoamérica / Clinical approach and main tick-borne rickettsiosis present in Latin America

Tick-borne rickettsial diseases are potentially life threatening infections that in Latin America have an emerging and reemerging character. Until few years ago, Rickettsia rickettsia was the only tick-borne rickettsia present in America; but nowadays several other species such as R. parkeri and R. massiliae are causing disease in humans in the region. In addition, new species are being described; although their pathogenicity has not been confirmed they should be considered as potential pathogens. Since the microbiological diagnosis of rickettsioses can take days or weeks, a high clinical suspicion and early start of appropriate treatment are crucial. In this review the distribution and main clinical manifestations of tick-borne rickettsial diseases in Latin America are detailed. Since R. felis has been found in ticks and the role of this vector has not been clarified, we have included a section about this pathogen.

Las rickettsiosis transmitidas por garrapatas son infecciones potencialmente letales, que en Latinoamérica tienen carácter emergente y re-emergente. Hasta hace escasos años, la única rickettsiosis transmitida por garrapatas era causada por Rickettsia rickettsii, pero en la actualidad existen otras especies como R. parkeri y R. massiliae que están provocando enfermedad en humanos en la región. Por otro lado, se están describiendo candidatos a nuevas especies de Rickettsia, que aunque no han probado su patogenicidad deben considerarse como potencialmente patógenos. Dado que el diagnóstico microbiológico puede tardar días o semanas, resulta fundamental una alta sospecha clínica y la instauración precoz de un tratamiento adecuado. En esta revisión se detalla la distribución y principales manifestaciones clínicas de las rickettsiosis transmitidas por garrapatas en Latinoamérica. Se ha incluido una sección sobre la infección por R. felis, por haberse encontrado esta especie en garrapatas, y no haberse aclarado el papel de este vector en su ciclo epidemiológico.

Guías Latinoamericanas de la RIICER para el diagnóstico de las rickettsiosis transmitidas por garrapatas / Latinamerican guidelines of RIICER for diagnosis of tick-borne rickettsioses

Tick-borne rickettsioses are worldwide infectious diseases that are considered emerging and re-emerging. Until recently the only tick-borne rickettsiosis present in Latin America was Rickettsia rickettsii infection, but to date, with the incorporation of new tools as PCR and sequencing and the quick cellular close tube cultures (Shell-vial), new species has been involved as human pathogens. In these guidelines, we offer an update of the microbiological assays for diagnosing rickettsioses. Besides we have included a section in which the most important hard ticks involved in human rickettsioses in Latinoamerica are detailed.

Las rickettsiosis transmitidas por garrapatas son afecciones de distribución mundial, que por diferentes motivos se pueden considerar emergentes y reemergentes. Hasta hace escasos años la única rickettsiosis transmitida por garrapatas en Latinoamérica era la infección por Rickettsia rickettsii, pero en la actualidad y fundamentalmente, gracias a la incorporación de nuevas herramientas para el diagnóstico microbiológico como la reacción en cadena de la polimerasa y secuenciación o el cultivo celular rápido en tubo cerrado, se han descrito e involucrado otras especies de Rickettsia en la producción de patología humana. En estas guías se detallan y describen las diferentes técnicas utilizadas para el diagnóstico microbiológico de las rickettsiosis. Además, se incluye una sección en la que se detallan las especies más importantes de garrapatas duras relacionadas con las rickettsiosis en Latinoamérica, con claves para su clasificación taxonómica.

Maraviroc, a CCR5 antagonist, prevents development of hepatocellular carcinoma in a mouse model.

Chronic liver disease may result in a sequential progression through fibrosis, cirrhosis and lead, eventually, to hepatocellular carcinoma (HCC). Hepatic stellate cells (HSC) seem to be responsible for the fibrogenic response through the activation of an autocrine loop involving the chemokine receptor, CCR5. However, the role of CCR5 in HCC remains poorly understood. Since this receptor is also one of the main ports of entry for the human immunodeficiency virus (HIV), several CCR5 inhibitors are being used in the clinic to reduce viral load. We used one of these inhibitors, maraviroc (MVC), in a mouse model of diet-induced HCC to investigate whether this intervention would reduce disease progression. Animals treated with MVC on top of a normal control diet did not present any evidence of toxicity or any morphological change when compared with non-treated mice. Animals treated with MVC presented higher survival, less liver fibrosis, lower levels of liver injury markers and chemokines, less apoptosis, lower proliferation index, and lower tumor burden than their counterparts receiving only the hepatotoxic diet. In addition, MVC inhibits HSC activation markers such as phosphorylation of p38 and ERK, and increases hepatocyte survival. This study suggests that MVC, a well tolerated and clinically characterized drug, may be used as a preventative treatment for HCC. Clinical studies are needed to demonstrate the efficacy of this drug, or other CCR5 inhibitors, in patients with high risk of developing HCC.

Rickettsia parkeri: a Rickettsial pathogen transmitted by ticks in endemic areas for spotted fever rickettsiosis in southern Uruguay / Rickettsia parkeri: patógeno rickettsial transmitido por garrapatas en áreas endémicas de rickettsiosis por fiebre manchada en el sur de Uruguay

At first Rickettsia conorii was implicated as the causative agent of spotted fever in Uruguay diagnosed by serological assays. Later Rickettsia parkeri was detected in human-biting Amblyomma triste ticks using molecular tests. The natural vector of R. conorii, Rhipicephalus sanguineus, has not been studied for the presence of rickettsial organisms in Uruguay. To address this question, 180 R. sanguineus from dogs and 245 A. triste from vegetation (flagging) collected in three endemic localities were screened for spotted fever group (SFG) rickettsiosis in southern Uruguay. Tick extracted DNA pools were subjected to PCR using primers which amplify a fragment of the rickettsial gltA gene. Positive tick DNA pools with these primers were subjected to a second PCR round with primers targeting a fragment of the ompA gene, which is only present in SFG rickettsiae. No rickettsial DNA was detected in R. sanguineus. However, DNA pools of A. triste were found to be positive for a rickettsial organism in two of the three localities, with prevalences of 11.8% to 37.5% positive pools. DNA sequences generated from these PCR-positive ticks corresponded to R. parkeri. These findings, joint with the aggressiveness shown by A. triste towards humans, support previous data on the involvement of A. triste as vector of human infections caused by R. parkeri in Uruguay.

Inicialmente, Rickettsia conorii fue señalada como el agente causal de la fiebre manchada en Uruguay, diagnosticada mediante pruebas serológicas. Posteriormente, Rickettsia parkeri fue detectada mediante técnicas moleculares en garrapatas Amblyomma triste colectadas sobre humanos. El vector natural de R. conorii, Rhipicephalus sanguineus, no ha sido estudiado en cuanto a rickettsias en Uruguay. Para abordar este tema, 180 R. sanguineus fueron colectados sobre perros y 245 A. triste sobre vegetación en tres localidades consideradas endémicas para fiebres manchadas en el sur de Uruguay. El ADN de las garrapatas fue extraído en pools y sometido a una primera PCR utilizando cebadores que amplifican un fragmento del gen gltA, presente en prácticamente todas las especies de Rickettsia. Las muestras positivas fueron sometidas a una segunda PCR con cebadores que amplifican un fragmento del gen ompA, presente sólo en rickettsias del grupo de las fiebres manchadas (GFM). No se detectó ADN rickettsial en R. sanguineus. Sin embargo, muestras de A. triste fueron positivas a rickettsiales en dos de las tres localidades estudiadas, con prevalencias de pools positivos del 11.8 y 37.5% respectivamente. La secuenciación del ADN evidenció la presencia de R. parkeri. Basados en estos resultados junto a los anteriores y la agresividad de A. triste hacia los humanos, se concluye que esta garrapata es vector de rickettsiosis humana por R. parkeri en Uruguay.

A patient from Argentina infected with Rickettsia massiliae.

The first confirmed case of Rickettsia massiliae infection in the New World (Buenos Aires, Argentina) is described. To date, only two cases of human infection had been reported in Europe. The patient, a woman, had a fever, a palpable purpuric rash on the upper and lower extremities, and a skin lesion (eschar) on the right leg compatible with tache noire. When interviewed, she reported having had contact with dog ticks. After treatment with doxycycline for 12 days, her symptoms resolved. Rickettsia massiliae infection was diagnosed by molecular-based detection of the microorganism in a biopsy specimen of the eschar.