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BACKGROUND: Epidemiological trends and clinical relevance of NTM species in Japan following the adoption of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry remain unclear. METHODS: We analyzed the results of mycobacterial culture tests of respiratory specimens collected between January 2017 and December 2021. We assessed the clinical relevance of NTM species by analyzing the proportion of patients diagnosed with NTM pulmonary infection (NTM-PI). We illustrated the incidence and clinical relevance of each NTM species using a two-dimensional scatter plot. Medical chart review and radiological analysis were also performed for less common species. RESULTS: Among 65,368 respiratory specimens tested for acid-fast bacilli, NTM were identified in 12,802 specimens from 3177 patients. The number of incident cases with NTM-PI has continued to increase. Notably, the number of incident cases with M. abscessus species (MABS) was continuously increasing and accounted for 10.6% of all incident cases with NTM-PI. The clinical relevance of the common NTM species, M. avium complex, MABS and M. kansasii, ranged from 57 to 72%. Seven other species exhibited a higher clinical relevance than these common NTM species, with M. shinjukuense (100%) having the highest clinical relevance. On the other hand, 11 species, including M. fortuitum (32.4%), M. xenopi (20.0%), and M. gordonae (22.9%), showed clinical relevance below 50%. CONCLUSIONS: The present study clarified the incidence and clinical relevance of NTM species using a two-dimensional scatter plot, which could serve as a useful tool for clinical decision-making and future epidemiological research.

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OBJECTIVES: To compare the characteristics and prognosis of patients with nontuberculous mycobacterial (NTM) pulmonary disease (PD) with pleuroparenchymal fibroelastosis (PPFE) with those of patients with nodular/bronchiectatic (NB) and fibrocavitary (FC) NTM-PD. METHODS: This multicenter, retrospective, observational study enrolled 32 patients with NTM-PPFE (median age: 70.5 years, 15 females) from six institutions in Japan from January 2003 to December 2018. Their clinical characteristics, and response to therapy were compared with age- and sex-matched cohorts of patients with non-cavitary NB and cavitary NB/FC NTM-PD. RESULTS: Patients with NTM-PPFE had a lower body mass index and a higher standard NTM-PD therapy initiation rate than patients with other NTM-PD types. Sputum culture conversion rates were comparable between groups; however, patients with NTM-PPFE had a higher incidence of treatment-related adverse events, including optic neuropathy associated with high-dose ethambutol therapy, lower percent predicted forced vital capacity values, higher serum Krebs von den Lungen 6 (KL-6) levels, and poorer treatment outcomes than the other groups. Cox regression revealed that NTM-PPFE was an independent risk factor for death/pneumothorax (adjusted hazard ratio: 35.3, 95% confidence interval: 3.90-4692). CONCLUSIONS: NTM-PPFE is a unique NTM-PD phenotype with a poorer prognosis than the NB and FC phenotypes.

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BACKGROUND: Amikacin  liposome inhalation suspension (ALIS) improved sputum culture conversion rate at 6 months for patients with refractory Mycobacterium avium complex pulmonary disease (MAC-PD) in an international phase 3 trial. Patient characteristics and chest high-resolution CT (HRCT) findings associated with ALIS effectiveness are poorly documented. OBJECTIVE: We aimed to clarify ALIS effectiveness for refractory MAC-PD at 6 months, elucidating associated patient characteristics and chest CT findings. METHODS: We reviewed medical records of 12 patients with refractory MAC-PD for whom ALIS treatment was initiated at Toho University Omori Medical Center from November 2021 through September 2022. All patients demonstrated treatment persistence for at least 3 months. They were divided into culture conversion and non-conversion groups using sputum culture conversion status after 6-month ALIS treatment initiation. Clinical and radiological characteristics were compared. RESULTS: Seven of the 12 patients (58.3%) achieved sputum culture conversion within 6 months. The culture conversion group had shorter pre-ALIS initiation treatment duration [21 months (16-25) vs. 62 months (32-69); p = 0.045]; lower cavitary lesion incidence on HRCT (28.6% vs. 100%; p = 0.028); and fewer clarithromycin (CLA)-resistant strains [0/7 (0%) vs. 3/5 (60%); p = 0.045]. Chest HRCT findings improved in 4 of 7 (57.1%) and 1 of 5 (20%) patients in the culture conversion and non-conversion groups, respectively. CONCLUSION: ALIS facilitated sputum culture conversion within 6 months in 58.3% of patients with refractory MAC-PD. Sputum culture conversion was significantly more frequent for CLA-susceptible strains and patients with fewer cavitary lesions. Improved CT findings after ALIS did not always correspond to sputum culture conversion.

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Pulmonary nontuberculous mycobacteria (NTM) disease is an emerging public health challenge that is especially problematic in people with cystic fibrosis (CF). Effective treatment depends on accurate species and subspecies identification and antimicrobial susceptibility status. We evaluated the GenoType NTM-DR VER 1.0 assay using biobanked NTM isolates with whole genome sequence (WGS) data and control isolates (total n=285). Species and subspecies detection sensitivity and specificity were 100 % for all species and subspecies except for two subspecies of M. intracellulare, that demonstrated a small degree of discrepant identification between M. intracellulare subspecies intracellulare and subspecies chimaera. All antimicrobial resistance markers were identified with 100 % sensitivity and specificity. We conclude that the GenoType NTM-DR assay offers a rapid and accurate option for identifying the most frequently encountered pathogenic NTM taxa and drug resistance markers. SUPPORT: Colorado CF Research Development Program and Colorado CF National Resource Centers funded by the Cystic Fibrosis Foundation, NJH Advanced Diagnostics Laboratories, Colorado Advanced Industries Accelerator Grant.

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OBJECTIVE: Mycobacterium avium complex pulmonary disease (MAC-PD) is occasionally complicated by interstitial lung disease (ILD) in clinical practice, but clinical studies are limited. This study aims to elucidate the clinical and imaging characteristics of MAC-PD in patients with ILD. METHODS: We retrospectively analyzed imaging and clinical data from medical records of 54 consecutive ILD patients diagnosed with MAC-PD from 2011 to 2021 at our institution. We compared the imaging and clinical data of these patients with 2218 ILD patients diagnosed at our institution. RESULTS: The mean age of the patients was 74 years, with 25 males and 29 females, and a mean body mass index (BMI) of 20.0 kg/m2. Compared to all ILD patients, ILD-associated MAC-PD had older ages, lower BMI. The most common underlying ILD diagnosis was unclassifiable interstitial pneumonia. MAC-PD imaging classification was nodular-bronchiectatic (NB) type in 17 patients, fibro-cavitary (FC) type in 15 patients, and unclassifiable (UC) type in 22 patients. Many UC types were difficult to diagnose due to the absence of clear findings indicative of MAC infection. Chronic pulmonary aspergillosis complication was 24.1 %. The mean survival of ILD-associated MAC-PD was 55.6 months, shorter than that of regular MAC-PD. The UC type had a shorter survival than the NB type, similar to the FC type. CONCLUSION: MAC-PD associated with ILD frequently complicates chronic pulmonary aspergillosis and has a poor prognosis. The most common imaging type, UC type, particularly has a shorter survival. Careful management is essential for MAC-PD associated with ILD.

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Uncontrolled HIV is associated with a wide range of hematologic abnormalities through direct suppressive effects, opportunistic infections, tumor marrow infiltration, or antiretroviral, antimicrobial, or antitumor therapy. We present a patient with a history of uncontrolled HIV presenting with acute severe thrombocytopenia shortly after starting treatment for disseminated Mycobacterium avium complex (MAC). While the thrombocytopenia was resistant to transfusion and intravenous immunoglobulin (IVIG), it mildly improved with dexamethasone after holding home medications. Etiologies for this patient's thrombocytopenia include uncontrolled HIV infection and medication-induced, likely secondary to rifabutin. We propose a possible combined effect of both factors. Clinicians should be aware of the increased risk of severe, acute medication-induced thrombocytopenia in patients with uncontrolled HIV, given their baseline susceptibility to hematologic abnormalities.

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Nontuberculous mycobacteria are responsible for causing pulmonary as well as extrapulmonary diseases. These organisms are often multidrug resistant and management of these cases poses a therapeutic challenge. Lung cancer has been a prevalent challenge globally with a high mortality rate in affected individuals. Adenocarcinoma poses debilitating outcomes in most patients by inflicting a diagnostic and therapeutic challenge. The concomitant association of adenocarcinoma and Mycobacterium avium complex worsens the prognosis causing a challenge in managing such cases. We present a rare association between adenocarcinoma and pulmonary Mycobacterium avium complex complicating the traditional therapeutic regime. A different approach in the administration of therapy for this unique concomitant association between two debilitating diseases is outlined in the presented report.

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BACKGROUND: The prevalence of nontuberculous mycobacteria pulmonary disease (NTM-PD), particularly caused by Mycobacterium avium complex (MAC), is rising due to improved diagnostics, increased awareness, and more susceptible populations. NTM-PD significantly affects quality of life and imposes substantial economic costs. Understanding its clinical features, risk factors, and treatment challenges is vital for enhancing patient outcomes. PATIENTS AND METHODS: A convenience sample from the University of Connecticut Health Center and Wayne State University involving patients with NTM-PD from 2021 to 2024 was studied retrospectively. Cases were selected to demonstrate typical diagnostic and treatment challenges, followed by a multidisciplinary roundtable discussion to examine patient-centered care strategies. RESULTS: Analysis of six cases pinpointed chronic lung conditions and immunomodulatory therapy as key risk factors. Standard treatment, involving extensive multi-drug regimens, frequently results in poor adherence due to side effects and complex management requirements. The discussions underlined the importance of a customized, interdisciplinary approach to improve treatment effectiveness and patient quality of life. CONCLUSIONS: NTM-PD is an escalating public health issue with notable clinical and economic consequences. Managing this disease effectively demands a comprehensive, patient-centered strategy that includes precise diagnosis, flexible treatment plans, and collaborative care.

This paper focuses on a type of lung disease caused by nontuberculous mycobacteria (NTM), which are bacteria found in the environment. NTM pulmonary disease has become more common due to better diagnostic methods, increased awareness, and a growing number of people with conditions that make them more vulnerable to infections. This disease can seriously affect a person's quality of life and is challenging to treat because it often requires long and complex antibiotic regimens.The authors, who have expertise in pulmonary diseases and infectious diseases, reviewed the medical records of six patients treated for NTM disease at the University of Connecticut Health Center and Wayne State University between 2021 and 2024. Following the submission of case synopses, the authors engaged in a discussion to explore the challenges of managing NTM infections. The discussion focused on identifying the best practices for diagnosis and treatment, emphasizing a patient-centered approach to care.Patients with preexisting lung conditions or those undergoing certain medical treatments are more susceptible to developing NTM lung disease. The treatment often involved multiple drugs, which posed challenges for patients due to side effects and the complexity of the regimen. The findings underscored the importance of a personalized, collaborative approach in treating NTM lung disease to improve patient outcomes and quality of life.

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Pneumatosis cystoides intestinalis (PCI) is an uncommon condition characterized by the presence of a collection of individual gas cysts in the submucosa and subserosa of the intestine. The etiology of PCI is still unclear. We experienced 3 cases with PCI during treatment for pulmonary Mycobacterium avium complex (MAC) infection. Each case was treated conservatively. We believe our case series will highlight the importance of examining the gastrointestinal tract of patients with MAC infection and hopefully elucidate the clinical characteristics of PCI which developed during MAC treatment.

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Infections remain a major concern following bispecific antibody therapy but are not well described in pivotal trials. We present the first well-documented case of a classic but rare opportunistic infection, disseminated Mycobacterium avium complex, in a patient receiving bispecific antibody therapy.

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BACKGROUND: Lung transplant recipients (LTRs) are at risk for Mycobacterium avium complex (MAC) infections, in part due to the presence of structural lung disease pre-transplant and relatively higher levels of immunosuppression post-transplant. There is a lack of data regarding outcomes of LTR with MAC infections pre-transplant. METHODS: This is a single-center retrospective analysis of patients who received lung transplants (LTs) from 2013 to 2020 with 1) evidence of MAC on culture or polymerase chain reaction before or at the time of transplant or 2) granulomas on explant pathology and positive acid-fast bacillus stains with no other mycobacteria identified. Patients were deemed to have MAC pulmonary disease (MAC-PD) if they met the American Thoracic Society/Infectious Disease Society of America criteria. RESULTS: Fourteen patients (14/882, 2%) met inclusion criteria. Seven patients (7/14, 50%) had pre-transplant MAC-PD, four of whom had cavitary disease. None of the 14 patients had smear-positive cultures at the time of transplant. Two patients in our cohort received treatment for MAC before transplant. Thirteen patients were bilateral LTR (13/14, 93%). One single LTR was the sole patient to receive MAC treatment post-transplant. No patients developed MAC-PD after transplant. CONCLUSION: The bilateral LTR in our cohort did not develop MAC-PD despite not receiving MAC treatment post-transplant. It is possible source control was achieved with native lung explantation. Our observations suggest patients may not uniformly require pre- or post-transplant MAC treatment if they are smear-negative and undergo bilateral LT.

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Background: Routine screening for nontuberculous mycobacterial (NTM) lung disease is dependent on sputum cultures. This is particularly challenging in the cystic fibrosis (CF) population due to reduced sputum production and low culture sensitivity. Biomarkers of infection that do not rely on sputum may lead to earlier diagnosis, but validation trials require a unique prospective design. Purpose: The rationale of this trial is to investigate the utility of urine lipoarabinomannan (LAM) as a test to identify people with CF with a new positive NTM culture. We hypothesize that urine LAM is a sensitive, non-invasive screening test with a high negative predictive value to identify individuals with a relatively low risk of having positive NTM sputum culture. Study design: This is a prospective, single-center, non-randomized observational study in adults with CF, 3 years of negative NTM cultures, and no known history of NTM positive cultures. Patients are followed for two year-long observational periods with the primary endpoint being a positive NTM sputum culture within a year of a positive urine LAM result and a secondary endpoint of a positive NTM sputum culture within 3 years of a positive urine LAM result. Study implementation includes remote consent and sample collection to accommodate changes from the COVID-19 pandemic. Conclusions: This report describes the study design of an observational study aimed at using a urine biomarker to assist in the diagnosis of NTM lung infection in pwCF. If successful, urine LAM could be used as an adjunct to traditional sputum cultures for routine NTM screening.

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Antimicrobial resistance poses a significant threat to humanity, and the development of new antibiotics is urgently needed. Our research has focused on thiopeptide antibiotics such as micrococcin P2 (MP2) and derivatives thereof as new anti-infective agents. Thiopeptides are sulfur-rich, structurally complex substances that exhibit potent activity against Gram-positive pathogens and Mycobacteria species, including clinically resistant strains. The clinical development of thiopeptides has been hampered by the lack of efficient synthetic platforms to conduct detailed structure-activity relationship studies of these natural products. The present contribution touches upon efficient synthetic routes to MP2 that laid the groundwork for clinical translation. The medicinal chemistry campaign on MP2 has been guided by computational molecular dynamic simulations and parallel investigations to improve drug-like properties, such as enhancing the aqueous solubility and optimizing antibacterial activity. Such endeavors have enabled identification of promising lead compounds, AJ-037 and AJ-206, against Mycobacterium avium complex (MAC). Extensive in vitro studies revealed that these compounds exert potent activity against MAC species, a subspecies of non-tuberculous mycobacteria (NTM) that proliferate inside macrophages. Two additional pre-clinical candidates have been identified: AJ-024, for the treatment of Clostridioides difficile infections, and AJ-147, for methicillin-resistant Staphylococcus aureus impetigo. Both compounds compare quite favorably with current first-line treatments. In particular, the ability of AJ-147 to downregulate pro-inflammatory cytokines adds a valuable dimension to its clinical use. In light of above, these new thiopeptide derivatives are well-poised for further clinical development.

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Nontuberculous mycobacterial pulmonary disease (NTM-PD) results from opportunistic lung infections by mycobacteria other than Mycobacterium tuberculosis or Mycobacterium leprae species. Similar to many other countries, the incidence of NTM-PD in the United Kingdom (UK) is on the rise for reasons that are yet to be determined. Despite guidelines established by the American Thoracic Society (ATS), the Infectious Diseases Society of America, and the British Thoracic Society, NTM-PD diagnosis and management remain a significant clinical challenge. In this review article, we comprehensively discuss key challenges in NTM-PD diagnosis and management, focusing on the UK healthcare setting. We also propose countermeasures to overcome these challenges and improve the detection and treatment of patients with NTM-PD.

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Lady Windermere syndrome (LWS) is a disease caused by a non-tuberculous Mycobacterium (NTM) that is commonly found in thin women who voluntarily suppress their cough reflex. The NTM that causes this syndrome is Mycobacterium avium complex, an organism commonly present in chlorinated city water and soil. Patients with LWS are tall, lean, elderly white women. We report a case of an immunocompetent 81-year-old thin Puerto Rican female with a recurrent cough since childhood, who was misdiagnosed with tuberculosis (TB) and prophylactically treated. While the patient fitted the clinical picture of NTM pulmonary infection based on symptoms, imaging, and microbiologic findings, her demography and morphologic features were not completely consistent with published findings. The incidence and prevalence of NTM lung disease are rising worldwide due to the aging population, increased use of immunosuppressive medications, and prevalence of chronic pulmonary obstructive disease and bronchiectasis. The goal of this report is to increase awareness of LWS as one of the diagnoses that should be considered in patients presenting with clinical findings resembling TB and bring attention to the different clinical characteristics this patient with LWS possessed.

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Despite the increasing incidence of simultaneous mycobacterial and non-mycobacterial tuberculosis (TB) infection, little literature is available exploring the topic. Here, we present a case of a 22-year-old female diagnosed with pulmonary TB for four months with simultaneous multiple sputum cultures positive for non-tuberculous mycobacteria (NTM). Computed tomography of the chest without contrast reported linear areas of scarring involving both lung apices, more prominent on the left side. The patient completed intensive phase treatment for TB and is currently on isoniazid and rifampin with a referral to an infectious disease specialist for recommendations on treatment of Mycobacterium avium regimen in view of azithromycin allergy (intense cough and rash). While the coexistence of NTM is commonly attributed to colonization, differentiating colonization from disease is crucial considering the long duration of treatment, potential drug toxicity, risk of drug resistance, and significant cost of treatment. Clinical, microbiological, and radiological evidence should be considered for diagnosis of TB and NTM coinfection and expert consultation should be sought in formulating the treatment plan.

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Mycobacterium avium complex pulmonary disease (MAC-PD) has a heterogeneous clinical course. However, immune profiles associated with MAC-PD clinical course are limited. We performed single-cell RNA sequencing of peripheral blood mononuclear cells from 21 MAC-PD patients divided into three clinical courses: group A, spontaneous culture conversion; group B, stable disease without antibiotic treatment; and group C, progressive disease with antibiotic treatment. A lower proportion of NK cells and higher proportion of monocytes were noted in group C compared to combined groups A and B. The proportion of classical monocytes was higher in group C compared to groups A and B, while the proportion of non-classical monocytes decreased. EGR1, HSPA1A, HSPA1B, and CD83 were up-regulated in spontaneous culture conversion group A compared to progressive disease group C. Up-regulation of MYOM2 and LILRA4 and down-regulation of MT-ATP8, CD83, and CCL3L1 was found in progressive disease group C. PCBP1, FOS, RGCC, S100B, G0S2, AREG, and LYN were highly expressed in favorable treatment response compared to unfavorable response. Our findings may offer a comprehensive understanding of the host immune profiles that influence a particular MAC-PD clinical course and could suggest an immunological mechanism associated with the disease progression of MAC-PD.

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Bartonella is a genus of arthropod-borne bacterial pathogens that typically cause persistent infections of erythrocytes and endothelial cells in mammalian hosts. The species that primarily infect humans are Bartonella henselae and Bartonella quintana. Depending on immune status, the clinical presentation of B. henselae may differ, manifesting as cat-scratch disease in immunocompetent individuals or bacillary angiomatosis (BA) and peliosis in immunocompromised patients. The cutaneous manifestations of BA are typically characterized by occasionally painful, angiomatous papules and nodules, often with a chronic, persistent course. Herein, we present a case of biopsy-confirmed B. henselae infection in a 32-year-old HIV-positive female with acquired immunodeficiency syndrome in the setting of disseminated Mycobacterium avium complex infection, an association that has been less frequently described. This case serves as an important reminder to consider uncommon opportunistic infectious etiologies when examining immunocompromised patients, as prompt diagnosis and treatment are essential in this patient population.

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BACKGROUND: The Mycobacterium avium complex (MAC) comprises the most frequent non-tuberculous mycobacteria (NTM) in Central Europe and currently includes twelve species. M. avium (MAV), M. intracellulare subsp. intracellulare (MINT), and M. intracellulare subsp. chimaera (MCH) are clinically most relevant. However, the population structure and genomic landscape of MAC linked with potential pathobiological differences remain little investigated. METHODS: Whole genome sequencing (WGS) was performed on a multi-national set of MAC isolates from Germany, France, and Switzerland. Phylogenetic analysis was conducted, as well as plasmids, resistance, and virulence genes predicted from WGS data. Data was set into a global context with publicly available sequences. Finally, detailed clinical characteristics were associated with genomic data in a subset of the cohort. RESULTS: Overall, 610 isolates from 465 patients were included. The majority could be assigned to MAV (n = 386), MCH (n = 111), and MINT (n = 77). We demonstrate clustering with less than 12 SNPs distance of isolates obtained from different patients in all major MAC species and the identification of trans-European or even trans-continental clusters when set into relation with 1307 public sequences. However, none of our MCH isolates clustered closely with the heater-cooler unit outbreak strain Zuerich-1. Known plasmids were detected in MAV (325/1076, 30.2%), MINT (62/327, 19.0%), and almost all MCH-isolates (457/463, 98.7%). Predicted resistance to aminoglycosides or macrolides was rare. Overall, there was no direct link between phylogenomic grouping and clinical manifestations, but MCH and MINT were rarely found in patients with extra-pulmonary disease (OR 0.12 95% CI 0.04-0.28, p < 0.001 and OR 0.11 95% CI 0.02-0.4, p = 0.004, respectively) and MCH was negatively associated with fulfillment of the ATS criteria when isolated from respiratory samples (OR 0.28 95% CI 0.09-0.7, p = 0.011). With 14 out of 43 patients with available serial isolates, co-infections or co-colonizations with different strains or even species of the MAC were frequent (32.6%). CONCLUSIONS: This study demonstrates clustering and the presence of plasmids in a large proportion of MAC isolates in Europe and in a global context. Future studies need to urgently define potential ways of transmission of MAC isolates and the potential involvement of plasmids in virulence.

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