First Brazilian Case Report of Unrelated Patients with Identical ISG15 Mutation.

BACKGROUND: ISG15 deficiency is a mixed syndrome of Mendelian susceptibility to mycobacterial infections (MSMD), a rare inherited condition characterized primarily by recurrent infections from low-virulence mycobacteria and monogenic type I interferonopathy. OBJECTIVE: To characterize the laboratory and molecular features of two patients from different families affected by the same ISG15 variant. METHODS: We began with clinical characterization and investigation, assessed IL-12/IFN-γ production, performed genetic characterization through WES and Sanger sequencing, conducted an in silico molecular analysis of the genetic ISG15 variant's protein impact, and utilized RNAseq for transcriptome analysis to understand pathway impacts on ISG15-deficient subjects from unrelated families. RESULTS: A mutation in the ISG15 gene was identified, affecting two patients treated in different hospitals and cities in Brazil (Fortaleza and Sao Paulo), who are also members of unrelated families. Both patients showed low IFN-γ production when stimulated with BCG or BCG + IL-12. ISG15 deficiency presented with two distinct clinical phenotypes: infectious and neurological. It was identified that both patients are homozygous for the variant (c.83 T > A). Furthermore, it was observed that the mutant protein p.L28Q results in an unstable protein with increased flexibility (ΔΔG: -2.400 kcal/mol). Transcriptome analysis revealed 1321 differentially expressed genes, with significant upregulation in interferon pathways, showing higher expression in patients compared to controls. CONCLUSION: This study describes the first reported cases in Brazil of two unrelated patients with the same ISG15 mutation c.83 T > A, exhibiting infectious features such as mycobacterial infections and systemic candidiasis, neurological findings, and skin lesions, without adverse reactions to the BCG vaccine. CLINICAL IMPLICATIONS: Reporting ISG15 gene mutations in Brazilian patients enhances understanding of genetic susceptibilities, guiding effective diagnostics and treatment. Identifying high-risk individuals aids clinical practices, genetic counseling, and influences public health policies. We have identified the first case in Brazil of the same ISG15 variant c.83 T > A that was identified in two unrelated patients with distinct clinical phenotypes, infectious and neurological.

Investigating cutaneous tuberculosis and nontuberculous mycobacterial infections a Department of Dermatology, Beijing, China: a comprehensive clinicopathological analysis.

Background: Cutaneous tuberculosis (CTB) and nontuberculous mycobacteria (NTM) infections present considerable diagnostic and therapeutic challenges. This study aims to provide a comprehensive clinicopathological analysis of CTB and NTM infections. Methods: We conducted a retrospective analysis of 103 patients diagnosed with cutaneous tuberculosis (CTB) and nontuberculous mycobacteria (NTM) infections at a Beijing dermatology department from January 2000 to January 2024. Demographic, clinical, histological, and laboratory finding data were collected. Diagnostic methods and histopathological examination were recorded. Treatment regimens and outcomes were reviewed. Descriptive statistics were used to summarize demographic and clinical data, and continuous variables expressed as means and standard deviations (SD), and categorical variables as frequencies and percentages. Statistical analyses were conducted using SPSS version 25.0. Results: The cohort included 103 patients (40.8% males and 59.2% females), with a mean age of 51.86 years. Common clinical manifestations included nodules (97.1%), erythema (74.8%), and plaques (68.9%). Histological examination revealed hyperkeratosis (68.9%), parakeratosis (23.3%), and extensive neutrophil infiltration (95.1%) were observed. Acid fast bacteria (AFB) stains and nucleic acid tests exhibited respective positivity rates of 39.6% and 52.3%, respectively. Most patients were treated with a combination of three drugs; 77.1% of patients showed improvement, with the cure rate for CTB being 20.0%. Discussion: This study highlights the diverse clinical and histological presentations of CTB and NTM infections, emphasizing the need for comprehensive diagnostic approaches. The variability in treatment regimens reflects the complex management of these infections. Conclusion: The implementation of advanced molecular techniques and standardized treatment protocols is imperative for enhancing diagnostic precision and therapeutic outcomes.

A Unique Case of Cellulitis Secondary to Mycobacterium chelonae in a Patient With Monoclonal Gammopathy of Undetermined Significance.

We report a case of an 84-year-old patient with Monoclonal Gammopathy of Undetermined Significance (MGUS) treated with multiple courses of antibiotics and steroids before being diagnosed with Mycobacterium chelonae infection. It is known that MGUS affects both humoral and cellular immunity with impairment of antibody production, function of T-cells, natural killer (NK) cells, and dendritic cells. This case report demonstrates the need to consider patients with MGUS as immunocompromised and draws attention to the correlation between MGUS and Mycobacterium infections. The delay in diagnosis exemplifies the importance of considering atypical pathogens and involving sub-specialists early in the treatment of infections in patients with a history of MGUS.

Mycobacterium senegalense Infection in Kidney Transplant Patient with Diabetes, Memphis, Tennessee, USA.

Fewer than 30 cases of Mycobacterium senegalense infection have been reported. We report a complicated case of M. senegalense infection in Memphis, Tennessee, in the southeastern United States. The patient's comorbidities of past organ transplant and insulin-dependent diabetes required delicate consideration of those health conditions to guide treatment.

Mycobacterial Infection in Recalcitrant Otomastoiditis: A Case Series and Literature Review.

Otomastoiditis caused by mycobacterial infections is uncommon and recalcitrant. Its clinical presentations, sometimes similar to those of common chronic suppurative otitis media, make diagnosis difficult. This retrospective study analyzed the clinical features, treatment course, and therapeutic outcomes of patients with mycobacterial otomastoiditis. The cases of six patients diagnosed with mycobacterial otomastoiditis or suspected mycobacterial infection between January 2007 and January 2019 in a single tertiary medical center in Taiwan were investigated. Information about predisposing factors, clinical features, culture reports, histopathology, treatment course, and outcomes were collected and analyzed. Relevant literature available in English was also reviewed. One patient was infected with tuberculous mycobacteria, two with suspected tuberculous mycobacteria, and three with nontuberculous mycobacteria. All six patients responded poorly to empiric antibiotic therapy, and diagnosis was not possible at their previous clinics. Five patients underwent tympanomastoidectomies; one was administered antimycobacterial medication without undergoing surgery. Mycobacterial infection was confirmed from a tissue culture or from the histopathology of the specimen, but in two patients, no definitive evidence of tuberculosis was found. Antimycobacterial medication was administered based on clinical suspicion, and improvement was noted. With appropriate therapy, all patients recovered, and no sequelae were observed after treatment. If empiric antibiotic therapy cannot achieve acceptable results, atypical infections, such as mycobacteria, should be considered. Antimycobacterial medication could be administered under clinical suspicion, serving as a diagnosis ex juvantibus. Surgical intervention might help reduce the bacterial load and obtain specimens for accurate diagnosis, but this may be unnecessary if appropriate antimycobacterial medication results in improvement. Early diagnosis and treatment can prevent complications in patients with recalcitrant otomastoiditis.

The reproductive status determines tolerance and resistance to Mycobacterium marinum in Drosophila melanogaster.

Sex and reproductive status of the host have a major impact on the immune response against infection. Our aim was to understand their impact on host tolerance or resistance in the systemic Mycobacterium marinum infection of Drosophila melanogaster. We measured host survival and bacillary load at time of death, as well as expression by quantitative real-time polymerase chain reaction of immune genes (diptericin and drosomycin). We also assessed the impact of metabolic and hormonal regulation in the protection against infection by measuring expression of upd3, impl2 and ecR. Our data showed increased resistance in actively mating flies and in mated females, while reducing their tolerance to infection. Data suggests that Toll and immune deficiency (Imd) pathways determine tolerance and resistance, respectively, while higher basal levels of ecR favours the stimulation of the Imd pathway. A dual role has been found for upd3 expression, linked to increased/decreased mycobacterial load at the beginning and later in infection, respectively. Finally, impl2 expression has been related to increased resistance in non-actively mating males. These results allow further assessment on the differences between sexes and highlights the role of the reproductive status in D. melanogaster to face infections, demonstrating their importance to determine resistance and tolerance against M. marinum infection.

Management of Polypharmacy and Potential Drug-Drug Interactions in Patients with Mycobacterial Infection: A 1-Year Experience of a Multidisciplinary Outpatient Clinic.

In 2022, we opened an outpatient clinic for the management of polypharmacy and potential drug-drug interactions (pDDIs) in patients with mycobacterial infection (called GAP-MyTB). All patients who underwent a GAP-MyTB visit from March 2022 to March 2023 were included in this retrospective analysis. Fifty-two patients were included in the GAP-MyTB database. They were given 10.4 ± 3.7 drugs (2.8 ± 1.0 and 7.8 ± 3.9 were, respectively, antimycobacterial agents and co-medications). Overall, 262 pDDIs were identified and classified as red-flag (2%), orange-flag (72%), or yellow-flag (26%) types. The most frequent actions suggested after the GAP-MyTB assessment were to perform ECG (52%), therapeutic drug monitoring (TDM, 40%), and electrolyte monitoring (33%) among the diagnostic interventions and to reduce/stop proton pump inhibitors (37%), reduce/change statins (14%), and reduce anticholinergic burden (8%) among the pharmacologic interventions. The TDM of rifampicin revealed suboptimal exposure in 39% of patients that resulted in a TDM-guided dose increment (from 645 ± 101 to 793 ± 189 mg/day, p < 0.001). The high prevalence of polypharmacy and risk of pDDIs in patients with mycobacterial infection highlights the need for ongoing education on prescribing principles and the optimal management of individual patients. A multidisciplinary approach involving physicians and clinical pharmacologists could help achieve this goal.

Mycobacterium marinum: A Case-Based Narrative Review of Diagnosis and Management.

Skin and soft tissue infections caused by non-tuberculous mycobacteria are occurring more frequently in recent years. However, chronic skin and soft tissue lesions present a challenge for clinicians, as the diagnostic work-up and definitive diagnosis require knowledge and available laboratory resources. We present here the case of a 66-year-old male patient who presented with painful abscess-like nodules on his right hand and forearm, which worsened after treatment with an anti-TNF-a agent. The fluid specimen taken from the lesion was positive for mycobacteria according to the acid-fast stain. Mycobacterium marinum was identified, first by next-generation sequencing and finally grown on culture, after eight weeks. Acknowledging the complexity of diagnosing and managing infections by non-tuberculous mycobacteria, and especially Mycobacterium marinum, we provide a review of the current epidemiology, clinical characteristics, diagnosis and management of Mycobacterium marinum infection.

Epidemiology, management, and clinical outcomes of extrapulmonary Mycobacterium abscessus complex infections in heart transplant and ventricular assist device recipients.

Nontuberculous mycobacteria are emerging pathogens, yet data on the epidemiology and management of extrapulmonary nontuberculous mycobacteria infections in orthotopic heart transplantation (OHT) and ventricular assist device (VAD) recipients are scarce. We retrospectively reviewed records of OHT and VAD recipients who underwent cardiac surgery at our hospital and developed Mycobacterium abscessus complex (MABC) infection from 2013 to 2016 during a hospital outbreak of MABC linked to heater-cooler units. We analyzed patient characteristics, medical and surgical management, and long-term outcomes. Ten OHT patients and 7 patients with VAD developed extrapulmonary M. abscessus subspecies abscessus infection. The median time from presumed inoculation during cardiac surgery to the first positive culture was 106 days in OHT and 29 days in VAD recipients. The most common sites of positive cultures were blood (n = 12), sternum/mediastinum (n = 8), and the VAD driveline exit site (n = 7). The 14 patients diagnosed when alive received combination antimicrobial therapy for a median of 21 weeks, developed 28 antibiotic-related adverse events, and underwent 27 surgeries. Only 8 (47%) patients survived longer than 12 weeks after diagnosis, including 2 patients with VAD who experienced long-term survival after an explantation of infected VADs and OHT. Despite aggressive medical and surgical management, OHT and VAD patients with MABC infection experienced substantial morbidity and mortality.

Contemporary Pharmacotherapies for Nontuberculosis Mycobacterial Infections: A Narrative Review.

Nontuberculous mycobacteria (NTM) are a group of atypical bacteria that may cause a spectrum of clinical manifestations, including pulmonary, musculoskeletal, skin and soft tissue, and cardiac infections. Antimycobacterial medication regimens for NTM infections require multiple agents with prolonged treatment courses and are often associated with poor tolerance in patients and suboptimal clinical outcomes. This review summarizes NTM pharmacotherapy, including treatment concepts, preferred medication regimens according to NTM species and site of infection, and emerging treatment methods for difficult-to-treat species.

Role of Therapeutic Drug Monitoring in the Treatment of Persistent Mycobacterium abscessus Central Nervous System Infection: A Case Report and Review of the Literature.

A patient presenting with recurrent ventriculoperitoneal shunt infection was found to have Mycobacterium abscessus growing from cerebrospinal fluid (CSF), which remained persistently positive. Therapeutic monitoring of clarithromycin, imipenem, and linezolid in CSF and plasma revealed lower than expected concentrations, prompting alternative therapy and culture clearance on hospital day 42.

Clinically refined epidemiology of nontuberculous mycobacterial pulmonary disease in South Korea: overestimation when relying only on diagnostic codes.

BACKGROUND: There have been reports of increases in the incidence and prevalence of nontuberculous mycobacterial pulmonary disease (NTM-PD) in several countries, but no studies have analyzed claims data using laboratory tests. This study aimed to estimate the nationwide epidemiology and medical treatments of NTM-PD according to laboratory tests run in Korea. METHODS: Using claims data from the Health Insurance Review and Assessment Service, we analyzed patients with nontuberculous mycobacterium (ICD-10: A31) who were diagnosed from Jan 2007 to Jun 2019. The incidence and prevalence of NTM-PD and whether related laboratory tests were performed were analyzed. Diagnostic code-based NTM-PD patients were defined as patients who had NTM as a diagnosis on at least 2 occasions within 180 days. Clinically refined NTM-PD patients were defined as those excluding hospital-diagnosed patients with acid-fast bacilli (AFB) culture rates less than 5%. Laboratory tests included AFB smears, AFB culture, NTM identification, and drug susceptibility tests (DSTs). RESULTS: A total of 60,071 diagnostic code-based NTM-PD patients were evaluated. Clinically refined NTM-PD included 45,321 patients, excluding 14,750 (24.6%) patients diagnosed in hospitals with low AFB culture rates. The annual incidence per 100,000 population increased from 2.9 cases in 2008 to 12.3 cases in 2018. The annual prevalence per 100,000 population increased from 5.3 cases in 2008 to 41.7 cases in 2018. After removing outliers according to the AFB culture rate, a significant decrease in incidence was observed in women younger than 50 years. Among patients with clinically refined NTM-PD, the test rates for AFB culture, NTM identification, and DST were 84.3%, 59.1%, and 40.4%, respectively. From the outpatient clinic, 17,977 (39.7%) patients were prescribed drugs related to NTM treatment, with a median number of prescriptions of 7 (interquartile range (IQR) 3-11) and a median duration from the diagnosis to end of treatment of 330 (IQR 118-578) days. CONCLUSIONS: Although the incidence and prevalence of NTM-PD are on the rise, the recent surge in women 50 years of age is overestimated in patients not adequately tested. In claim-based studies, there may be limitations in estimating the epidemiological data with only the diagnostic codes.

Transmembrane TNF and Its Receptors TNFR1 and TNFR2 in Mycobacterial Infections.

Tumor necrosis factor (TNF) is one of the main cytokines regulating a pro-inflammatory environment. It has been related to several cell functions, for instance, phagocytosis, apoptosis, proliferation, mitochondrial dynamic. Moreover, during mycobacterial infections, TNF plays an essential role to maintain granuloma formation. Several effector mechanisms have been implicated according to the interactions of the two active forms, soluble TNF (solTNF) and transmembrane TNF (tmTNF), with their receptors TNFR1 and TNFR2. We review the impact of these interactions in the context of mycobacterial infections. TNF is tightly regulated by binding to receptors, however, during mycobacterial infections, upstream activation signalling pathways may be influenced by key regulatory factors either at the membrane or cytosol level. Detailing the structure and activation pathways used by TNF and its receptors, such as its interaction with solTNF/TNFRs versus tmTNF/TNFRs, may bring a better understanding of the molecular mechanisms involved in activation pathways which can be helpful for the development of new therapies aimed at being more efficient against mycobacterial infections.

Nontuberculous mycobacterial infection of the knee after arthrocentesis for idiopathic hemarthrosis: A case report.

INTRODUCTION: Nontuberculous mycobacterial (NTM) infections of the musculoskeletal system are uncommon. Such infections are typically acquired by direct inoculation after penetrating trauma, surgical procedures, or needle injections. There are no reported cases of NTM infection after arthrocentesis for idiopathic hemarthrosis of the knee. Here we report a case of NTM infection in the knee that developed after arthrocentesis for idiopathic hemarthrosis of the knee. PRESENTATION OF CASE: The patient was an 85-year-old woman who experienced swelling of the left knee. An arthrocentesis was carried out, and hemarthrosis was found. The patient was referred to our hospital for repeated recurrence of hematoma of the knee. Significant swelling was observed in the suprapatellar sac. Magnetic resonance imaging examination revealed a mass at the suprapatellar sac. Laboratory data showed elevation of inflammatory markers. Debridement was performed under arthroscopy and samples were collected for culture. Although routine microbiological cultures were negative, the patient continued to experience knee swelling and laboratory data showed high C-reactive protein levels. Therefore, open debridement was carried out. At 4 weeks after the first surgical treatment, intraoperative cultures yielded Mycobacterium intracellulare. At this point, we diagnosed septic arthritis of the knee due to NTM infection. The patient showed an excellent prognosis with three-drug medical treatment for 1 year. CONCLUSION: Clinically, diagnosis of septic arthritis due to NTM infection is not easy. Because selection of examination depends on clinical suspicion, NTM infections should be considered for patients with elevation of inflammatory markers after episodes of surgical procedures, and/or needle injections.

Histopathology of laboratory-reared Nothobranchius fishes: Mycobacterial infections versus neoplastic lesions.

Short-lived killifishes of the genus Nothobranchius Peters, 1868 (Cyprinodontiformes) are considered promising model organisms for biomedical research on ageing and tumorigenesis. We conducted histopathological analysis of 411 adult individuals from three Nothobranchius species to study details on spontaneous age-related neoplastic lesions. Light microscopy based on H&E and toluidine blue-stained sections revealed (a) non-proliferative liver changes with pronounced vacuolation of hepatocytes; (b) proliferation of kidney haemopoietic tissue contributing to excretory system damage; (c) proliferation of splenic mononuclear haemoblasts accompanied by reduced erythropoiesis; (d) proliferation of mononuclear cell aggregates in the liver parenchyma; and (e) rare occurrence of hepatocellular adenomas. Ziehl-Neelsen (ZN) staining revealed that the proliferative lesions are a host defence response to mycobacterial infections manifested by activation of the mononuclear phagocytic system and atypical granulomatous inflammatory reaction. 16S rRNA analysis identified three species of Mycobacterium in our samples. Our findings turn attention to lesions which mimic neoplasms by their gross appearance and question the light microscopic interpretation of lesions unless differential ZN staining is included. Beyond the limitations of our morphological approach, the intensity of mycobacterial infections is a challenging opportunity for research into the molecular-genetic background of the mononuclear phagocytic system reaction in Nothobranchius killifish.

Rare enough ? Cardiac Device-related pocket Infection due to Mycobacterium fortuitum.

Nontuberculous mycobacteria are rare causes of cardiac implantable electronic device (CIED)-related infections and may lead to device-related endocarditis, so preventing them is key. We present a case of CIED-related pocket infection due to Mycobacterium fortuitum which highlights the challenges in management of such infections.