GATA2 variants in patients with non-tuberculous mycobacterial or fungal infections without known immunodeficiencies

ABSTRACT Introduction Haploinsufficiency of the hematopoietic transcription factor GATA2 is associated with a broad spectrum of diseases, including infection susceptibility and neoplasms. We aimed to investigate GATA2 variants in patients with non-tuberculous mycobacterial (NTM) and/or fungal infections (FI) without known immunodeficiencies. Method We performed GATA2 genotyping in patients with NTM and/or FI. Results Twenty-two patients were enrolled (seventeen FI, four NTM and one with both infections). The pathogenic variant NG_029334.1:g.16287C>T was found in one patient (4.5%) and two asymptomatic offsprings. We also found the likely-benign variant NG_029334.1:g.12080G>A (rs2335052), the benign variant NG_029334.1:g.16225C>T (rs11708606) and the variant of uncertain significance NG_029334.1:g.16201G>A (rs369850507) in 18.2%, 27.3%, and 4.5% of the cases, respectively. Malignant diseases were additionally diagnosed in six patients. Conclusion Although detected in 45.4% of the patients, most GATA2 variants were benign or likely benign. Identifying a pathogenic variant was essential for driving both the patient's treatment and familial counseling. Pathogenic variants carriers should receive genetic counseling, subsequent infection prevention measures and malignancies surveillance. Additionally, case-control genotyping should be carried out in Brazil to investigate whether the observed variants may be associated with susceptibility to opportunistic infections and/or concurrent neoplasms.

El costo de la belleza: Comunicación de seis casos clínicos con infección por micobacterias atípicas secundario a inyecciones intradérmicas y reacción a un dermoimplante de origen desconocido / The cost of beauty: six cosmetological clinical cases due to atypical mycobacterial infection secondary to intradermal injections plus reaction to foreign dermal implant

Resumen Comunicamos seis casos de mujeres quienes, tras la aplicación mediante mesoterapia con plasma rico en plaquetas, así como de un material de relleno intradérmico de origen desconocido, desarrollaron una infección en los sitios de inyección asociada a Mycobacterium massiliense, así como granulomas con reacción a cuerpo extraño. Aunque los cultivos fueron negativos, se logró la identificación del microorganismo por extracción de ADN de tejidos blandos obtenido por biopsia y posterior secuenciación del producto obtenido. Debido a la gran similitud en los cultivos de M. massiliense con la especie relacionada Mycobacterium abscessus, y a que tienen diferente respuesta terapéutica, las técnicas moleculares de diagnóstico son una opción real a considerar para administrar en forma precoz el tratamiento específico contra el patógeno y evitar la progresión de la infección.

We report six cases of female patients who, after the application by mesotherapy with platelet-rich plasma, as well as of an intradermal filler material of unknown origin, developed infection at the injection sites associated to Mycobacterium massiliense, as well as granuloma with reaction to foreign body. Although the cultures were negative, the identification of the microorganism was achieved by extraction of soft tissue DNA obtained by biopsy and sequencing the obtained product, with which the therapy was redirected against the particular species. Due to the great similarity in the culture between M. massiliense with the related species M. abscessus, to the required time for its growth, and to the different therapeutic response of each strain, molecular diagnostic techniques are a real option to consider to administer in an early way the appropriate treatment against the pathogen and prevent infection progression.

Cutaneous Atypical Mycobacterial Infection in a Body Scrubber (“Ddaemirri”) / 대한피부과학회지

No abstract available.

Autophagy in Mycobacterium abscessus Infection

Autophagy is a self-degradative process that removes misfolded or aggregated proteins, clears damaged organelles, as well as eliminates intracellular pathogens playing a role in innate immunity. Mycobacterium abscessus (M. abscessus) has been reported as a causative organism in nearly 80% of the rapid growing mycobacteria (RGM) pulmonary disease. The strain exhibits two different colony types: the smooth (S) one which is considered wild-type and the rough (R) one which is the mutated strain. In accordance to the colony morphology, the S and R types display varying autophagic responses in the host cells with the R type inducing elevated autophagy compared to the S type. The major difference in the autophagy could be based on the bioactive molecules exposed on the surface of the S and R types. Though autophagy has a vital role to play in the clearance of intracellular pathogens, very little is known on the autophagy induced by M. abscessus. It has been known that the intracellular pathogens employ different strategies to evade the autophagic pathway and to survive within the host cells. This review summarizes the most up-to-date findings on autophagy induced by M. abscessus morphotypes and how M. abscessus evades the autophagic machinery to divide and thrive inside the host cells. In addition, the prospects of autophagic machinery in devising new anti-infective strategies against mycobacterial infection is also been discussed.

Autophagy in Mycobacterium abscessus Infection

Autophagy is a self-degradative process that removes misfolded or aggregated proteins, clears damaged organelles, as well as eliminates intracellular pathogens playing a role in innate immunity. Mycobacterium abscessus (M. abscessus) has been reported as a causative organism in nearly 80% of the rapid growing mycobacteria (RGM) pulmonary disease. The strain exhibits two different colony types: the smooth (S) one which is considered wild-type and the rough (R) one which is the mutated strain. In accordance to the colony morphology, the S and R types display varying autophagic responses in the host cells with the R type inducing elevated autophagy compared to the S type. The major difference in the autophagy could be based on the bioactive molecules exposed on the surface of the S and R types. Though autophagy has a vital role to play in the clearance of intracellular pathogens, very little is known on the autophagy induced by M. abscessus. It has been known that the intracellular pathogens employ different strategies to evade the autophagic pathway and to survive within the host cells. This review summarizes the most up-to-date findings on autophagy induced by M. abscessus morphotypes and how M. abscessus evades the autophagic machinery to divide and thrive inside the host cells. In addition, the prospects of autophagic machinery in devising new anti-infective strategies against mycobacterial infection is also been discussed.

Incidence of active mycobacterial infections in Brazilian patients with chronic inflammatory arthritis and negative evaluation for latent tuberculosis infection at baseline - A longitudinal analysis after using TNFa blockers

Several studies point to the increased risk of reactivation of latent tuberculosis infection (LTBI) in patients with chronic inflammatory arthritis (CIAs) after using tumour necrosis factor (TNF)a blockers. To study the incidence of active mycobacterial infections (aMI) in patients starting TNFa blockers, 262 patients were included in this study: 109 with rheumatoid arthritis (RA), 93 with ankylosing spondylitis (AS), 44 with juvenile idiopathic arthritis (JIA) and 16 with psoriatic arthritis (PsA). All patients had indication for anti-TNFatherapy. Epidemiologic and clinical data were evaluated and a simple X-ray and tuberculin skin test (TST) were performed. The control group included 215 healthy individuals. The follow-up was 48 months to identify cases of aMI. TST positivity was higher in patients with AS (37.6%) than in RA (12.8%), PsA (18.8%) and JIA (6.8%) (p < 0.001). In the control group, TST positivity was 32.7%. Nine (3.43%) patients were diagnosed with aMI. The overall incidence rate of aMI was 86.93/100,000 person-years [95% confidence interval (CI) 23.6-217.9] for patients and 35.79/100,000 person-years (95% CI 12.4-69.6) for control group (p < 0.001). All patients who developed aMI had no evidence of LTBI at the baseline evaluation. Patients with CIA starting TNFa blockers and no evidence of LTBI at baseline, particularly with nonreactive TST, may have higher risk of aMI.

Two Cases of Cutaneous Mycobacterium abscessus Infection after Mesotherapy / 대한피부과학회지

No abstract available.

Relationship between peripheral blood T lymphocyte subsets and nutrition status of patients with nontuberculosis mycobacteria lung disease / 实用医学杂志

Objective To explore the impact of peripheral blood CD4 + T cells on nutritional status of patients with non-tuberculosis mycobacteria (NTM) lung disease. Methods A retrospective analysis was performed including 78 patients with NTM lung disease from January 2008 to December 2012 in Guangzhou Chest Hospital, who were divided into cellular immunocompromised group with 43 cases and control group including 35 cases and then the impact of malnutrition on cellular immune function decline was explored. Results Peripheral blood CD4+T cells were positively correlated with CD3+T cells, CD8+T cells, CD4+/CD8+T cell ratio in all of the included patients(P0.05). Compared with those in control group, TLC count was obviously lower while there were more patients with bronchiectasis in cellular immunocompromised group, which indicated statistical significance (P < 0.05). Conclusions Most of NTM patients are associated with malnutrition and NTM patients of cellular immunocompromised are associated with bronchiectasis easily and obvious reducing of TLC, but CD4+T cells and serum proteins levels are not necessarily correlated. The severity of NTM is commonly caused by such factors as basic pathologic change, cellular immunization, nutrition and infection.

A Case of Mycobacterium marinum Infection Diagnosed by PCR Amplification and Direct Sequencing / 대한피부과학회지

Mycobacterium marinum is an atypical mycobacterium (ATM) and is an uncommon cause of skin and soft tissue infections associated with contact with contaminated water. Diagnosis is often delayed when only a conventional identification method is used. PCR amplification and direct sequencing is recently available method for rapid identification of ATM. We report a case of M. marinum infection identified by PCR and sequencing. A 56-year-old female was referred for multiple erythematous nodules on both forearms which appeared two months ago. Skin biopsy showed suppurative granulomatous inflammation, and AFB culture showed nontuberculous Mycobacteria. PCR and sequencing were performed, and the obtained sequences were compared to the database using BLAST. The sequences of 16S rRNA and rpoB could not differentiate between M. marinum and M. ulcerans, showing 100% homology to both. Identification was possible using the sequences of the tuf and hsp65 genes, showing both 100% homology to M. marinum, while 99.8%, 99.7% to M. ulcerans. The patient was treated with clarithromycin, rifampicin, and ethambutol for 6 months.

Immunological Mechanisms by Which Concomitant Helminth Infections Predispose to the Development of Human Tuberculosis

Helminthic infections afflict over 1.5 billion people worldwide, while Mycobacterium tuberculosis infects one third of the world's population, resulting in 2 million deaths per year. Although tuberculosis and helminthic infections coexist in many parts of the world, and it has been demonstrated that the T-helper 2 and T-regulatory cell responses elicited by helminths can affect the ability of the host to control mycobacterial infection, it is still unclear whether helminth infections in fact affect tuberculosis disease. In this review article, current progress in the knowledge about the immunomodulation induced by helminths to diminish the protective immune responses to bacille Calmette-Guerin vaccination is reviewed, and the knowledge about the types of immune responses modulated by helminths and the consequences for tuberculosis are summarized. In addition, recent data supporting the significant reduction of both M. tuberculosis antigen-specific Toll-like receptor (TLR) 2 and TLR9 expression, and pro-inflammatory cytokine responses to TLR2 and TLR9 ligands in individuals with M. tuberculosis and helminth co-infection were discussed. This examination will allow to improve understanding of the immune responses to mycobacterial infection and also be of great relevance in combating human tuberculosis.

Infección protésica mamaria por Mycobacteriumfortuitum en una paciente con lupus eritematoso sistémico / Breast implant infection by Mycobacterium fortuitum in a patient with systemic lupus erythematosus

In recent decades there has been an increase in the number of breast implants for reconstruction and cosmetic purposes. Infection is a severe complication mostly caused by Staphylococcus aureus or coagulase-negative staphylococci. Mycobacteria are an infrequent cause of infection in this type of surgery. We describe a case of Mycobacterium fortuitum infection in a patient with lupus, subjected to a prosthetic replacement. These patients are more prone to unusual opportunistic infections. Treatment always requires both removal of prosthetic material and antibiotic therapy.

En las últimas décadas se ha producido un incremento en el número de colocaciones de implantes mamarios para reconstrucciones y fines estéticos. La infección es una complicación seria y en su mayoría es producida por Staphylococcus aureus o Staphylococcus coagulasa-negativa. Las micobacterias son una causa infrecuente de infección en este tipo de cirugías. Describimos el caso de una infección de un implante mamario por Mycobacterium fortuitum en una paciente lúpica sometida a un recambio protésico. Este tipo de pacientes es más propenso a padecer infecciones oportunistas. El tratamiento siempre requiere retiro del material asociado a antibioterapia.

A Case of Mycobacterium chelonae Infection with Foreign Body Granuloma after Injection of Filler / 대한피부과학회지

Although injectable soft-tissue augmentation materials are extremely well-tolerated, undesirable effects sometimes occur. Whereas minor adverse events such as erythema, edema or bruising are generally reversible, the formation of foreign body granuloma, atypical mycobacterial infections or tissue necrosis may cause serious irreversible damages and disfigurement. We present here the case of a 50-year-old woman with an indurated painful nodule and patch on the right cheek, and this occurred after an unlicensed nonspecialist injected filler of unknown ingredients. The histopathologic findings showed granulomatous inflammation composed of lymphocytes, histiocytes and multinucleated giant cells with a Swiss cheese appearance. Although any acid-fast bacilli were not observed on Ziehl-Neelsen staining, the mycobacterial culture demonstrated an ivory-colored wet colony that was identified as M. chelonae by polymerase chain reaction-restriction fragment length polymorphism. The patient was treated with 1 g of clarithromycin for seven weeks, and the lesion improved considerably.

A Case of Tenosynovitis Due to Mycobacterium intracellulare in a Patient with Rheumatoid Arthritis / 감염과화학요법

Nontuberculous mycobacteria are ubiquitous organisms that are frequently present in the water, soil and animal reservoirs. Nontuberculous mycobacterial infections of the musculoskeletal system are rare and usually associated with predisposing factors, such as prior joint disease, trauma, use of intraarticular or oral corticosteroids, or an immunocompromised state. A sixty five-year-old patient with rheumatoid arthritis was hospitalized due to swelling on the left wrist. M. intracellulare was cultured from the aspirated joint fluid. The patient was successfully treated with clarithromycin, ethambutol, and rifampin. We report this case with review, emphasizing high suspicion for nontuberculous mycobacterial infection in patients with predisposing risk factors.

A Case of Tenosynovitis Due to Mycobacterium intracellulare in a Patient with Rheumatoid Arthritis / 감염과화학요법

Nontuberculous mycobacteria are ubiquitous organisms that are frequently present in the water, soil and animal reservoirs. Nontuberculous mycobacterial infections of the musculoskeletal system are rare and usually associated with predisposing factors, such as prior joint disease, trauma, use of intraarticular or oral corticosteroids, or an immunocompromised state. A sixty five-year-old patient with rheumatoid arthritis was hospitalized due to swelling on the left wrist. M. intracellulare was cultured from the aspirated joint fluid. The patient was successfully treated with clarithromycin, ethambutol, and rifampin. We report this case with review, emphasizing high suspicion for nontuberculous mycobacterial infection in patients with predisposing risk factors.

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.

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.

A Case of Mediastinal Tuberculous Abscess and Lymphadenitis after Bone Marrow Transplantation / 감염

After bone marrow transplantation (BMT), recipients can be complicated by infectious or non-infectious chest lesions such as mycobacterial infections or post- transplant lymphoproliferative disorders (PTLDs). BMT recipients usually face a lot of risks of mycobacterial infection because they have severely impaired cell- mediated immunity as a result of their underlying disease, chemotherapy, radiotherapy, acute or chronic graft-versus-host diesase (GVHD) and their treatment. We report a case of mediastinal tuberculous abscess and lymphadenitis after BMT, which mimicks PTLDs. 20 months before admission, BMT was performed on a 41 year-old woman who was diagnosed as chronic myelocytic leukemia. She showed acute and chronic GVHD with several infections of bacteria or viruses after BMT. In endemic area of tuberculosis such as Korea, PTLDs should be differentiated from pulmonary tuberculosis and tuberculous lymphadenitis.

The Usefulness of Serologic Diagnosis for Tuberculosis with Two Rapid Immunochromatographic Assay Devices / 결핵

BACKGROUND: Many diagnostic tests have developed to diagnose tuberculosis and other mycobacterial diseases but the diagnosis of tuberculosis relies largely on radiological findings and acid-fast staining of sputum and/or culture. Recently, new serologic diagnostic methods, which are safe and easy to use have been introduced into Korea. In this study, the usefulness of serologic diagnosis for tuberculosis and the disease pattern induced variation of the test were evaluated. METHODS: Serological assay was performed upon 108 patients with two test kits, the ICT tuberculosis and the BioSign(TM) TB, which are based upon a rapid immunochromatographic assay technique, capable of being interpreted within 15 minutes. The case groups consisted of 61 patients with active pulmonary tuberculosis(36 patients), extrapulmonary tuberculosis(3 patients), or both (22 patients). Control groups consisted of 47 patients with inactive old pulmonary tuberculosis (17 patients), nontuberculous pulmonary disease(16 patients) and nonpulmonary cardiac disease(14 patients). RESULTS: The diagnostic sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of the ICT tuberculosis were 64.3%, 91.5%, 90.0% and 68.3% respectively. The diagnostic sensitivity, specificity, PPV and NPV of the BioSign(TM) TB were 76.5%, 95.3%, 94.1% and 78.8% respectively. Differences in sensitivity were not significant between patients with previous history of tuberculosis or patients without prior history of tuberculosis. The ICT tuberculosis test showed higher sensitivity in pulmonary tuberculosis patients (76.5%) than extrapulmonary tuberculosis patients (33.3%). There was no difference in sensitivity between patients with or without cavitary lesion by chest X-ray. CONCLUSION: Considering high specificity and PPV, serologic diagnosis using a rapid immunochromatographic assay device is another helpful diagnostic method in the diagnosis of tuberculosis, when combined with previous diagnostic methods such as chest X-ray, microbiologic study but it has limitation in terms of confirming the diagnosis for tuberculosis as the only diagnostic method because of relatively low sensitivity and NPV.

Ocorrência de infecções pulmonares devidas ao Mycobacterium Kansasii, em São Paulo, Brasil / Pulmonary disease due to Mycobacterium Kansasii in Säo Paulo, Brasil

No período de 1984 a 1985, foram identificados, através de cultura de escarro e testes laboratoriais especializados, na Região dos municípios de Santo André, São Bernardo, Säo Caetano e Diadema, em São Paulo, 9 casos de infecção pulmonar, causada pelo Mycobacterium Kansasii. Pelo fato de algumas microbactérias causarem quadros pulmonares semelhantes ao da tuberculose e por ser o diagnóstico destas infecções, sob o ponto de vista clínico, radiológico e histológico, insuficiente para diferenciar as doenças pulmonares causadas pelos bacilos álcool-ácido resistentes, recomenda-se a realização de exames bacteriológicos completos, em diferentes áreas do Estado, em pacientes com suspeita de tuberculose, em pacientes positivos ao exame bacterioscópico e naqueles com resposta desfavorável ao tratamento específico para tuberculose (AU).