Autosomal Recessive IL-12p40 Deficiency due to a Mutation in the IL12B Gene: Report of a Brazilian Patient with Lymph Node Mycobacterial Infection.

Background: Autosomal recessive interleukin (IL)-12p40 deficiency is a genetic etiology of Mendelian susceptibility to mycobacterial disease (MSMD). It has been described in ∼50 patients, usually with onset at childhood with Bacille Calmette-Guérin (BCG) and Salmonella infections. Case Presentation: A male patient born to consanguineous parents was diagnosed with presumed lymph node MSMD at the age of 13 years after ocular symptoms. A positive history of inborn error of immunity was present: BCG reaction, skin abscess, and recurrent oral candidiasis. Abnormal measurements of cytokine levels, IL-12p40 and interferon-gamma (IFN-γ), lead to the diagnosis of MSMD. Genetic analysis showed a mutation in exon 7 of the IL12B gene. Currently, the patient is alive under prophylactic antibiotics. Conclusion: We report a rare case of IL-12p40 deficiency in a Latin American patient. Medical history was crucial for immune defect suspicion, as confirmed by precision diagnostic medicine tools.

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

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.

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.

Paradoxical manifestations during tuberculous meningitis treatment among HIV-negative patients: a retrospective descriptive study and literature review.

BACKGROUND: Tuberculous meningitis (TBM) is the most frequent, severe, and disabling form of central nervous system (CNS) tuberculosis (TB). TBM paradoxical manifestations are characterized by clinical or paraclinical worsening after 1 month of effective anti-TB treatment in patients who initially responded to treatment despite the use of adjunctive corticosteroids. METHODS: Retrospective descriptive study of consecutive HIV-negative adult patients (≥ 18 years) with definitive TBM who developed a paradoxical manifestation following anti-TB in a tertiary-care hospital in Mexico from 2009 to 2019; we also conducted a literature review of published cases/series of paradoxical manifestations in HIV-negative patients from 1980 to 2020. RESULTS: We detected 84 cases of definitive TBM; 55 (68.7%) HIV-negative patients and 29 (36.3%) HIV-infected patients. Among HIV-negative patients, four (7.3%), three female and one male (19-49 years old), developed a paradoxical manifestation within 4-14 weeks following treatment initiation despite receiving adequate corticosteroid doses; Mycobacterium bovis was isolated from the cerebrospinal fluid of three cases and Mycobacterium tuberculosis in one more. Two patients developed vasculopathy-related cerebral infarctions, one severe basilar meningitis, and hydrocephalus, one more a tuberculoma. Two were treated with intravenous cyclophosphamide, and two with steroids. One of the patients treated with steroids died; patients who received cyclophosphamide had a good clinical response. CONCLUSIONS: This case series illustrates the diverse clinical/radiologic paradoxical manifestations of TBM in HIV-negative patients. Cyclophosphamide may be safe and effective in treating TBM-associated paradoxical manifestations. Specific diagnostic and care protocols for these patients are needed.

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.

Mycobacterium branderi Infection in a Horse with Granulomatous Mesenteric Lymphadenitis.

Although relatively uncommon in horses, infections caused by Mycobacterium spp. may affect the gastrointestinal tract. Mycobacterium branderi is a non-tuberculous Mycobacterium (NTM) that causes respiratory infections in man. Non-tuberculous mycobacteria may also affect horses; however, infection by M. branderi has not yet been reported in this species. This report describes the clinical, pathological, microbiological and molecular findings of M. branderi infection in a horse, causing granulomatous mesenteric lymphadenitis. A 17-year-old Thoroughbred stallion had a 3-month history of chronic diarrhoea, cachexia and ventral and cervical oedema. Necropsy examination revealed severe mesenteric lymphadenomegaly, together with mesenteric lymphangiectasia and diffuse small intestinal mucosal thickening. Microscopically, the mesenteric lymph node had diffuse granulomatous inflammatory infiltration, replacing most of the nodal parenchyma, with multiple acid-fast bacilli within the cytoplasm of macrophages. There was also diffuse lymphangiectasia. Fresh samples of mesenteric lymph nodes yielded no bacterial growth; however, nested polymerase chain reaction products obtained from the mesenteric lymph node samples were consistent with M. branderi. This infection should be included as a differential diagnosis in cases of chronic diarrhoea in horses, especially when granulomatous enteritis and lymphadenitis are also observed.

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.

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.

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.

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).