Trends in overall opportunistic illnesses, Pneumocystis carinii pneumonia, cerebral toxoplasmosis andMycobacterium avium complex incidence rates over the 30 years of the HIV epidemic: a systematic review

BACKGROUND: The natural history of HIV infection has changed dramatically after the introduction of highly active antiretroviral therapy. Currently, opportunistic illnesses still represent a major cause of death and hospitalization in this population. In this study, we review the trends in opportunistic illnesses incidence rates and compare the results observed in high-income settings with that for low/middle-income settings, with special attention given to studies from Brazil. METHODS: We systematically searched Pubmed, Web of Science, Lilacs and Google scholar for publications on HIV associated opportunistic illness. Studies reporting rates based on person-time for all opportunistic illnesses and/or the three opportunistic infections of interest, namely,Pneumocystis carinii pneumonia, cerebral toxoplasmosis, and Mycobacterium avium complex were included. RESULTS: Significant reductions in the incidence rates were demonstrated for opportunistic illnesses overall and also for the specific opportunistic infections included in the present study, both in high and low/middle-income settings. Out of the 37 studies included in the present review, almost 70% were from high-income settings. All the studies conducted in low/middle-income settings were single center studies and four were from Brazil. We found no study from Brazil reporting annual incidence rates of opportunistic illnesses. CONCLUSIONS: Opportunistic illnesses remain an important public health problem. To better guide health policies in low/middle-income settings, multicenter cohort studies should be encouraged. Studies from Brazil are urgently needed to assess the current burden of opportunistic illnesses in our population and to support the planning of HIV/AIDS health care services organization. .

Enfermedad pulmonar por especies del complejo Mycobacterium avium intracellulare y correspondencia terapéutica / Mycobacterium avium intracellulare complex pulmonary disease species and therapeutic match

Introducción: la preocupación mundial ante las enfermedades causadas por micobacterias ambientales es creciente, debido a las dificultades diagnósticas y de tratamiento. Objetivos: determinar el comportamiento de la enfermedad pulmonar por especies del complejo Mycobacterium avium intracellulare y la correspondencia con la terapéutica recibida en el Hospital Neumológico Benéfico Jurídico de La Habana, durante el período 2000-2010. Métodos: se realizó un estudio descriptivo retrospectivo, que abarcó 55 pacientes con el diagnóstico de la enfermedad, los cuales cumplieron con los criterios de inclusión-exclusión predefinidos; la tendencia en el registro de diagnósticos se basó en el coeficiente de correlación lineal; en las variables cualitativas y cuantitativas discretas se usaron distribuciones de frecuencia con el cálculo del porcentaje y su respectivo intervalo de confianza de 95 porciento. Resultados: se obtuvo una tendencia decreciente en el diagnóstico de enfermedad pulmonar por especies del complejo Mycobacterium avium intracellulare, el 47,3 porciento de los pacientes estudiados se encontraba entre los 50 y 69 años de edad. La mayor parte del grupo no tenía ocupación de riesgo epidemiológico y la comorbilidad pulmonar se detectó en 97,9 porciento, sobresaliendo la tuberculosis pulmonar. Se comprobó la no correspondencia entre la terapéutica recibida y el régimen recomendado por la American Thoracic Society, en 100 porciento de los pacientes. Conclusión: la instauración de un programa ajustado a las normativas de tratamiento internacionalmente aceptadas, constituye en el Hospital Benéfico Jurídico, una necesidad para la atención a este grupo de enfermos

Introduction: the global concern about diseases caused by environmental mycobacteria is growing since their diagnosis and treatment are difficult. Objectives: to determine the behavior of Mycobacterium avium intracellulare complex pulmonary disease, and the therapeutic match with the treatment given at Benéfico Jurídico Pneumological Hospital, during the 2000-2010 period. Methods: a retrospective descriptive study of 55 patients diagnosed with the disease, who met the previously defined inclusion/exclusion criteria. The diagnostic registration trend was based on the linear correlation coefficient; the qualitative quantitative discrete variables used frequency distributions with percentage calculations and their respective 95 percent confidence intervals (CI). Results: a decreasing trend in the diagnosis of pulmonary disease from Mycobacterium avium-intracellular complex species; 47.3 percent of the studied patients aged 50 to 69 years. Most of the group had no occupation with epidemiological risk, and the pulmonary comorbidity was detected in 97.9 percent of patients, mainly pulmonary tuberculosis. A mismatch between the received therapy and the recommended treatment by the American Thoracic Society (ATS) was proved in 100 percent of patients. Conclusion: the introduction of a therapeutic program adapted to the internationally accepted standards of treatment is a must for the care of this group of patients in Benefico Juridico Hospital

Disease caused by non-tuberculous mycobacteria: diagnostic procedures and treatment evaluation in the North of Buenos Aires Province

Non-tuberculous mycobacteria (NTM) have emerged as pathogens frequently associated to HIV co-infection. The aims of this study were to describe the clinical importance of NTM in patients from the North of Buenos Aires Province and the drug-susceptibility patterns in relation with the therapy used. A total of 23,624 clinical specimens were investigated during the period 2004-2010. Ziehl-Neelsen stain and cultures were used for diagnosis. Molecular and biochemical tests were performed to identify the mycobacteria. TB and mycobacterioses cases were 2 118 and 108 respectively. Sixteen NTM species were found: Mycobacterium avium and Mycobacterium intracellulare as the main causative agents. Infections produced by more than one species at the same time were confirmed (4 cases). Macrolides and fluoroquinolones were the most active in vitro drugs. Treatment evaluation showed that 68.0 % of the cases completed the therapy, 20 % died; and 12 % were relapses. The cases in which the treatment outcome was evaluated received an individual tailor-made therapeutic scheme including those drugs showing in vitro activity and presumed in vivo usefulness. More than a quarter of the patients had HIV co-infection and the majority of the deaths were associated with this co-infection.

Enfermedad causada por micobacterias no tuberculosas: diagnóstico y evaluación del tratamiento en el norte del Gran Buenos Aires. Las micobacterias no tuberculosas (MNT) emergieron como patógenos frecuentemente asociados a la co-infección con el HIV. EL objetivo del estudio fue describir la importancia clínica de las MNT en pacientes de la región norte de la provincia de Buenos Aires y los patrones de drogo-sensibilidad en relación con la terapia empleada. Se investigó un total de 23.624 especímenes clínicos durante, el período 2004-2010. La tinción de Ziehl-Neelsen y los cultivos se utilizaron para diagnóstico. Las micobacterias fueron identificadas mediante pruebas bioquímicas y moleculares. Los casos de tuberculosis y micobacteriosis fueron 2 118 y 108, respectivamente. Se encontraron 16 especies de MNT, siendo las principales, Mycobacterium avium y Mycobacterium intracellulare. En 4 casos se confirmaron infecciones producidas por más de una especie al mismo tiempo. Los macrólidos y las fluoroquinolonas tuvieron mayor actividad in vitro. La evaluación del tratamiento confirmó que el 68 % de los casos completó la terapia; 20 % murió y el 12 % recayó. Los casos en los que se evaluó el tratamiento recibieron un esquema terapéutico individual incluyendo aquellas drogas que mostraron actividad in vitro. Más de un cuarto de los pacientes tuvieron co-infeccion con el HIV y la mayoría de las muertes estuvieron asociadas con esta co-infección.

Diagnóstico molecular de histoplasmosis humana en muestras de sangre entera / Molecular diagnosis of human histoplasmosis in whole blood samples

Se evaluó el uso de sangre entera para el diagnóstico molecular de histoplasmosis utilizando un método artesanal de extracción de ADN fúngico y una PCR anidada que amplifica una porción del gen HcP100 específica de Histoplasma capsulatum. La sangre entera se trató con liticasa, enzima lisante de Trichoderma harzianum y proteinasa K, seguido de una extracción fenólica. Este tratamiento permitió una lisis completa de las células, mostró buen rendimiento en la obtención de ADN y posibilitó la detección de la banda de 210 pb específica de H. capsulatum en la PCR anidada. El límite de detección fue de 0,25-1 levaduras/ml de sangre. El método se evaluó en 31 muestras de sangre de 19 pacientes con diagnóstico microbiológico de histoplasmosis, en 21 muestras de pacientes con otras micosis o infecciones por micobacterias y en 30 controles sanos. La PCR fue positiva en sangre para 17/19 pacientes con histoplasmosis (14/15 inmunocomprometidos y 3/4 sin inmunocompromiso aparente). Las muestras de sangre de los 30 controles sanos y de 20 pacientes con otras patologías fueron negativas, sólo hubo un falso positivo correspondiente a un paciente con infección por Mycobacterium avium-intracellulare. El método presentó 89% de sensibilidad y 96% de especificidad para el diagnóstico de histoplasmosis en sangre entera.

To assess the value of using whole blood samples for the molecular diagnosis of histoplasmosis, we applied an in-house DNA extraction method and a nested PCR targeting a 210 bp specific segment of the Histoplasma capsulatum HcP100 gene. A whole blood volume of 2.5-3 milliliters was centrifuged and the cellular pellet was treated with Trichoderma harzianum lyticase and proteinase K prior to applying a conventional phenol DNA extraction. This procedure allowed complete cell lysis, high DNA yield and specific amplification. The PCR detection limit was 0.25-1 yeast cells/ml of blood sample. The method was assessed on 31 blood samples from 19 patients with microbiological diagnosis of histoplasmosis, 30 healthy persons and 21 patients with other mycoses or mycobacterial diseases. Positive results were obtained in samples from 17/19 patients with histoplasmosis (14/15 immunocompromised and 3/4 without known immunological disorder). Blood samples from the 30 healthy controls and 20 patients with other conditions proved negative; the only false positive result was obtained from a patient with Mycobacterium avium-intracellulare infection. With 89% sensitivity and 98% specificity, this molecular method for detection of the agent in blood shows promising for the rapid diagnosis of human histoplasmosis.

Micobacteriosis pulmonar en pacientes HIV negativos en la ciudad de Buenos Aires, años 2003-2004 / Pulmonary mycobacteriosis in non HIV patients, Buenos Aires City, 2003-2004

La enfermedad provocada por micobacterias ambientales es sospechada fundamentalmente en pacientesHIV positivos o con otras enfermedades de base. En nuestro país no hay información actualizadaacerca de la prevalencia, tratamiento y evolución de esta enfermedad en pacientes inmunocompetentes.Presentamos 10 casos de enfermedad pulmonar por micobacterias ambientales en pacientes inmunocompetentes:diagnóstico clínico-bacteriológico, tratamiento y evolución.

Pulmonary disease,due to Mycobacteria other than tuberculosis, is mainly suspected in HIV + patients, or underlyingother diseases. In our country, there is no updated information on the prevalence of this pulmonarydisease, its treatment and evolution in immucocompetent patients. We present 10 cases of pulmonary diseasedue to Mycobacteria other than tuberculosis in non HIV patients: clinical-bacteriological diagnosis, treatment andevolution.

Enfermedades micobacterianas diseminadas en pacientes con VIH/SIDA. Evaluación de los hemocultivos por método rápido / Disseminated mycobacterial infections in patients with HIV/AIDS. Evaluation of blood cultures

Mil cuarenta hemocultivos correspondientes a 451 enfermos uruguayos con SIDA y diagnóstico clínico de micobacteriosis diseminada fueron evaluados entre 1999 y 2003. Las muestras fueron procesadas en el Centro de Referencia Nacional para Micobacterias (Montevideo, Uruguay), utilizando el sistema de hemocultivos automatizado para micobacterias MB - BacT (BioMérieux). Se detectaron 45 muestras positivas (4,3%) correspondientes a 26 enfermos (promedio 2,3 muestras por paciente). En 10/26 casos se identificó M. avium complex (MAC) y en 13/26 el germen aislado fue M. tuberculosis. El tiempo medio de incubación fue de 12,4 días (intervalo 6-19 días) para MAC y de 22,6 días (intervalo 7-35 días) para M. tuberculosis. El hemocultivo ha demostrado ser la mejor muestra para la confirmación bacteriológica de las enfermedades micobacterianas diseminadas cuando se estudian por lo menos 2 muestras por paciente. La frecuencia de aislamientos de M. tuberculosis y MAC aislados en pacientes con SIDA en Uruguay, corresponde a la de un país con una moderada prevalencia de tuberculosis.

One thousand-forty blood cultures corresponding to 451 Uruguayan patients with AIDS and clinic diagnosis of disseminated mycobacterial infection were evaluated between 1999 and 2003. Samples were processed in the NationalReferenceCenter for Mycobacteria (Montevideo, Uruguay), using the automated blood culture system for mycobacteria MB -BacT (BioMérieux). Forty-five positive samples were detected (4.3%) corresponding to 26 patients with AIDS (average 2.3 samples per patient). In 10/26 patients M. avium complex (MAC) was identified and in 13/26 the isolated germ was M. tuberculosis. The average time of incubation was of 12.4 days (range 6-19 days) for MAC and of 22.6 days (range 7-35 days) for M. tuberculosis. Blood culture has demonstrated to be the best sample for the bacteriological confirmation of the disseminated mycobacterial infections when at least 2 samples by patient are studied. The frequency of isolates of M. tuberculosis and MAC in AIDS patients is according with a moderate prevalence of tuberculosis in Uruguay.

Prevalence of Mycobacterium avium and Mycobacterium tuberculosis in blood cultures of Brazilian AIDS patients after introduction of highly active retroviral therapy

The use of highly active antiretroviral therapy (HAART) for the treatment of HIV infection has been associated with a marked reduction in the incidence of most opportunistic infections. From April 2001 to February 2002, 80 blood samples from patients who were suspected to have disseminated mycobacterial infection, presenting fever and (preferably) a CD4 T cell count < 100.0 cell/mL were investigated. Twelve (15 percent) of the 80 blood cultures were positive for mycobacteria, with Mycobacterium avium being identified in 7 (8.8 percent) samples and M. tuberculosis in 5 (6.2 percent). The TCD4+ count at the time of M. avium bacteremia ranged from 7cells/æL (average of 48.5 cell/æL), while in M. tuberculosis bacteremia it ranged from 50.0 cells/æL (average of 80.0 cell/æL). The prevalence of M. avium bacteremia in our study follows the expected decline in opportunistic infections observed after the introduction of HAART; however, mycobacteremia by M. tuberculosis still indicates a high prevalence of tuberculosis infection in AIDS patients.

Prevalencia de micobacteriosis y de tuberculosis en pacientes de un hospital de referencia de la provincia de Córdoba / Prevalence of mycobacteriosis and tuberculosis in a reference hospital, Cordoba province

Las micobacterias ambientales (MA) constituyen un importante grupo de especies bacterianas que se encuentran en el medio ambiente, pueden colonizar y ocasionalmente producir enfermedad enel hombre. En este trabajo se investigó la frecuencia de casos de micobacteriosis en relación con los de tuberculosis durante un período de diez años (1.991-2.000). Se estudiaron 16.700 muestras de 9.300 pacientes adultos de ambos sexos asistidos en el Hospital Regional de Tuberculosis de la Provincia de Córdoba, por consulta espontánea. Los aislamientos se realizaron por cultivo en los medios de Lowenstein Jensen y Stonebrink. Las colonias de bacilos ácidoalcohol resistentes (BAAR) se identificaron por pruebas bioquímicas y moleculares. El total de casos diagnosticados fue de 716, de los cuales 684 (95,5%) correspondieron a al complejo Mycobacterium tuberculosis y a micobacterias ambientales 32 (4,5%). Los casos de micobacteriosis se definieron por reiterados aislamientos con desarrollo representativo de una micobacteria ambiental, sospecha clínica y radiológica. De los 32 casos de micobacteriosis, el 75% del total correspondió aMycobacterium avium-intracellulare,15,6% a Mycobacterium fortuitum, 3,1% a Mycobacterium kansasii y 6,3% a Mycobacterium chelonae.Los casos de tuberculosis fueron 94,5% de localización pulmonar y 5,5% extrapulmonar.

Environmental mycobacteria (EM) constitute an important group of bacteria species found in the environment. They can colonize and occasionally produce disease in man. Sixteen thousand three hundred samples from 9300 adult symptomatic patients from the Hospital Regional of Tuberculosis in Cordoba were bacteriolocally investigated. The isolations were performed by culture on Lowenstein Jensen and Stonebrink culture media. The colonies of acid fast bacilli (AFB) were identified by biochemical and molecular tests. Among 716 culture positive cases, 684 (95.5%) were due to Mycobacterium tuberculosis complex and 32 to environmental mycobacteria.Serial samples allowed the confirmation of the etiologicalagent in culture and correlated with consistent clinical and radiological abnormalities. Seventy-five percente of these patients were affected by M. avium complex, 15.6% by M. fortuitum, 3.1% Mycobacterium kansasii and 6.3% Mycobacterium chelonae. Among tuberculosis cases, 94.5% and 5.5% had pulmonary and extrapulmonary disease respectively.

Prolonged fever due to Mycobacterium avium complex (MAC) disease in advanced HIV infection: a public health concern.

From March 1997 to June 1998, infectious etiologies of prolonged fever was prospectively investigated in 104 advanced human immunodeficiency virus (HIV) infected patients admitted to Siriraj Hospital. The etiology could be identified in 91 cases (87.5%). Of these, blood cultures from 68 patients yielded mycobacteria and fungi. Mycobacterium avium complex was the most common blood isolate in 24 per cent of the patients; followed by Mycobacterium tuberculosis in 20.2 per cent, Cryptococcus neoformans in 5.8 per cent, Penicillium marneffei in 5.8 per cent. During the course of febrile illness, 79 of the 91 patients (86.8%) exhibited focal lesions. Weight loss, elevated serum alkaline phosphatase were often found to be significantly more associated with MAC bacteremia (P < 0.05). Pulmonary involvement significantly correlated more with M. tuberculosis bacteremia than MAC bacteremia (P < 0.05). No cause could be identified in 13 cases. Mycobacterium blood culture alone established the etiologies in 68 cases (65.4%). Of the 25 patients with disseminated MAC (DMAC) infection, nine patients died during hospitalization. Another three cases died within a few months of appropriate anti-MAC chemotherapy. We concluded that the risk of DMAC infection in advanced AIDS patients in Thailand is high when low CD4 lymphocyte count is established. The prolonged fever resulted from DMAC in advanced HIV infection is warrant to be public health concern. Mycobacterium blood culture is a most valuable tool contributing to the diagnosis of infectious agents in this condition. The guidelines of 1997 USPHS/IDSA should be followed to give chemoprophylaxis against DMAC disease in patients with advanced HIV infection and a CD4 count less than 50 cells/mm3.