Human mesenchymal stromal cells inhibit Mycobacterium avium replication in clinically relevant models of lung infection.

INTRODUCTION: Novel therapeutic strategies are urgently needed for Mycobacterium avium complex pulmonary disease (MAC-PD). Human mesenchymal stromal cells (MSCs) can directly inhibit MAC growth, but their effect on intracellular bacilli is unknown. We investigated the ability of human MSCs to reduce bacterial replication and inflammation in MAC-infected macrophages and in a murine model of MAC-PD. METHODS: Human monocyte-derived macrophages (MDMs) were infected with M. avium Chester strain and treated with human bone marrow-derived MSCs. Intracellular and extracellular colony-forming units (CFUs) were counted at 72 hours. Six-week-old female balb/c mice were infected by nebulisation of M. avium Chester. Mice were treated with 1×106 intravenous human MSCs or saline control at 21 and 28 days post-infection. Lungs, liver and spleen were harvested 42 days post-infection for bacterial counts. Cytokines were quantified by ELISA. RESULTS: MSCs reduced intracellular bacteria in MDMs over 72 hours (median 35% reduction, p=0.027). MSC treatment increased extracellular concentrations of prostaglandin E2 (PGE2) (median 10.1-fold rise, p=0.002) and reduced tumour necrosis factor-α (median 28% reduction, p=0.025). Blocking MSC PGE2 production by cyclo-oxygenase-2 (COX-2) inhibition with celecoxib abrogated the antimicrobial effect, while this was restored by adding exogenous PGE2. MSC-treated mice had lower pulmonary CFUs (median 18% reduction, p=0.012), but no significant change in spleen or liver CFUs compared with controls. CONCLUSION: MSCs can modulate inflammation and reduce intracellular M. avium growth in human macrophages via COX-2/PGE2 signalling and inhibit pulmonary bacterial replication in a murine model of chronic MAC-PD.

Evaluation of a novel ELISA test using synthetic mycolic acid antigens for serodiagnosis of non-tuberculous mycobacterial (NTM) infections.

The diagnosis of non-tuberculous mycobacteria (NTM) is a particular challenge in people with cystic fibrosis. Current standard diagnostic approaches rely on serial sputum culture, which is resource demanding, dependent on patient expectoration and may be compromised by excessive decontamination, conventional bacterial overgrowth and masking by concomitant oral and nebulised antibiotics. An alternative rapid, reliable and inexpensive diagnostic method is therefore urgently needed. Serum of patients with Mycobacterium abscessus infection and chronic suppurative lung disease without NTM infection was tested against an array of novel synthetic mycolic acids, identical or similar to natural components of mycobacterial cell walls, and glycopeptidolipid (GPL)-core antigen, which has previously been investigated in Mycobacterium avium pulmonary infection. Diagnostic accuracy of individual antigens and combination of various antigens were calculated. An ELISA using individual trehalose dimycolates and GPL-core antigen was able to effectively distinguish serum from infected and non-infected individuals with a specificity of 88% and a sensitivity of up to 88%, which increased to 88% sensitivity and 93% specificity by combining several antigens in the test. These results suggest synthetic mycolic acid antigens, used individually or in combination with GPL-core antigen could be successfully used to distinguish patients with M. abscessus infection from disease controls.

Genome-wide association study of non-tuberculous mycobacterial pulmonary disease.

BACKGROUND: The prevalence of non-tuberculous mycobacterial pulmonary disease (NTM-PD) is increasing in South Korea and many parts of the world. However, the genetic factors underlying susceptibility to this disease remain elusive. METHODS: To identify genetic variants in patients with NTM-PD, we performed a genome-wide association study with 403 Korean patients with NTM-PD and 306 healthy controls from the Healthy Twin Study, Korea cohort. Candidate variants from the discovery cohort were subsequently validated in an independent cohort. The Genotype-Tissue Expression (GTEx) database was used to identify expression quantitative trait loci (eQTL) and to conduct Mendelian randomisation (MR). RESULTS: We identified a putatively significant locus on chromosome 7p13, rs849177 (OR, 2.34; 95% CI, 1.71 to 3.21; p=1.36×10-7), as the candidate genetic variant associated with NTM-PD susceptibility. Its association was subsequently replicated and the combined p value was 4.92×10-8. The eQTL analysis showed that a risk allele at rs849177 was associated with lower expression levels of STK17A, a proapoptotic gene. In the MR analysis, a causal effect of STK17A on NTM-PD development was identified (ß, -4.627; 95% CI, -8.768 to -0.486; p=0.029). CONCLUSIONS: The 7p13 genetic variant might be associated with susceptibility to NTM-PD in the Korean population by altering the expression level of STK17A.

Mediastinal tissue friability-An unreported complication from Mycobacterium chimaera infection post-cardiac surgery.

Mycobacterium chimaera can cause disseminated infection following cardiac surgery with cardiopulmonary bypass and contaminated heater-cooler devices. We discuss a 41-year-old man with a disseminated M. chimaera infection following surgery for a type A aortic dissection. His presentation included cachexia and dorsalgia with a work-up revealing vertebral osteomyelitis with an epidural abscess, bone marrow, and pulmonary infiltration, and fluid collection around his aortic graft. He received 1 month of antibiotics before the explantation of infected foreign material, mediastinal debridement, and aortic reconstruction. Complications included septic shock, respiratory and renal failure, mediastinitis, and four distal aortic anastomotic dehiscences from friable tissue and persistent infection.

Idiopathic facial aseptic granuloma-A diagnostic challenge in pediatric dermatology.

Idiopathic facial aseptic granuloma is a distinct, benign lesion that presents in very young children and is characterized by a painless facial nodule that usually appears on the cheek. It is typically characterized by a prolonged course but heals spontaneously or in response to antibiotic treatment. The challenge is to diagnose this entity correctly, ideally based on clinical acumen, to avoid surgical intervention with facial sutures and the resultant scarring and unnecessary treatment interventions. In this article, we discuss three cases of idiopathic facial aseptic granuloma to raise awareness and highlight the diagnostic challenges and possible link to childhood rosacea.

Prevalence of Nontuberculous Mycobacterial Pulmonary Disease, Germany, 2009-2014.

We analyzed routine statutory health insurance claim data to determine prevalence of nontuberculous mycobacterial pulmonary disease in Germany. Documented prevalence rates of this nonnotifiable disease increased from 2.3 to 3.3 cases/100,000 population from 2009 to 2014. Prevalence showed a strong association with advanced age and chronic obstructive pulmonary disease.

US Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fibrosis: executive summary.

Non-tuberculous mycobacteria (NTM) are ubiquitous environmental organisms that can cause chronic pulmonary infection, particularly in individuals with pre-existing inflammatory lung disease, such as cystic fibrosis (CF). Pulmonary disease (PD) caused by NTM has emerged as a major threat to the health of individuals with CF, but remains difficult to diagnose and problematic to treat. In response to this challenge, the US Cystic Fibrosis Foundation (CFF) and the European Cystic Fibrosis Society (ECFS) convened a panel of 19 experts to develop consensus recommendations for the screening, investigation, diagnosis and management of NTM-PD in individuals with CF. PICO (population, intervention, comparison, outcome) methodology and systematic literature reviews were employed to inform draft recommendations, which were then modified to achieve consensus and subsequently circulated for public consultation within the USA and European CF communities. We have thus generated a series of pragmatic, evidence-based recommendations as an initial step in optimising management for this challenging condition.

Non-tuberculous mycobacteria: a retrospective review of Scottish isolates from 2000 to 2010.

There is growing recognition of the clinical importance of non-tuberculous mycobacteria (NTM), a group of versatile opportunistic bacterial pathogens. We describe the characteristics of NTM isolates in Scotland over an 11-year period using data held by the Scottish Mycobacteria Reference Laboratory. American Thoracic Society microbiological criteria were used to evaluate the clinical significance of isolates. Data presented include analysis of trends across time, species/body site associations, gender and age differences, geographical variations and the association between cystic fibrosis and Mycobacterium abscessus. We emphasise the need for standardised reporting criteria for NTM isolates to ensure optimal surveillance of NTM disease.

Septic Mycobacterium Avium Intracellulare Extensor Tenosynovitis of the Wrist.

Mycobacterium avium intracellulare (MAI) infections of the hand, wrist, and upper extremity are rare, but potentially devastating atypical mycobacterial infections that can affect tendon, bone, and other soft tissues of the musculoskeletal system. We present an immunocompromised patient presenting with acute swelling and pain in the dorsum of the hand and wrist that underwent a wrist extensor tenosynovectomy with intraoperative cultures revealing infection with MAI. The patient developed severe progression of the infection with osteomyelitis of the distal forearm and carpal bones, multiple subsequent extensor tendon ruptures, and dorsal skin necrosis. The infection was eradicated with a combination of surgical treatment and antibiotic therapy. The case is discussed in context of the prior scant literature of infectious tenosynovitis of the hand, wrist, and upper extremity caused by MAI. This case report and literature review outline recommendations for diagnosis and effective treatment of MAI.

Hepatitis B Virus Reactivation and Mycobacterial Infections Associated With Ustekinumab: A Retrospective Study of an International Pharmacovigilance Database.

Background: Reports were recently published on hepatitis B virus reactivation (HBVr), tuberculosis (TB), and atypical mycobacterial infection (AMI) in patients with ustekinumab treatment. However, the literature is limited to case reports and series. The study was aimed to investigate their relationships by using an extensive population-based database. Methods: Using the United States Food and Drug Administration Adverse Event Reporting System (FAERS) database, we collected all cases of HBVr, TB, and AMI between 1 January 2009 and 30 September 2021, for ustekinumab and other drugs. Disproportionality was analyzed using the reporting odds ratio (ROR), which was considered significant when the lower limit of the 95% confidence interval (95% CI) was >1. Results: Of the 18,760,438 adverse cases reported to FAERS for all drugs, 56,581 cases had been exposed to ustekinumab. Adverse events of HBVr, TB, and AMI were reported in 21, 210, and 20 cases, respectively. The ROR for HBVr with ustekinumab was 2.33 (95% CI, 1.52-3.58), for TB was 5.09 (95% CI, 4.44-5.84), and for AMI was 2.09 (95% CI, 1.35-3.24). In the ustekinumab exposure group, no death occurred in patients with HBVr, but one patient experienced life-threatening liver failure. For those with TB, 24 cases experienced hospitalization and 2 deaths occurred. No death occurred in patients with AMI but eight experienced hospitalization. Conclusion: We identified positive signals between ustekinumab exposure and HBVr, TB, and AMI in FAERS. Although these complications are rare, clinicians using ustekinumab should be aware of the risks.

Sweet Syndrome precipitated by Mycobacterium abscessus in a Laotian Man with Autoantibodies to Interferon Gamma.

Autoantibodies to interferon γ, part of the first line of defense in the human immune response, constitutes a rare form of an acquired immunodeficiency in HIV-uninfected adults that can predispose to disseminated atypical mycobacterial infection. Particularly, this has been described in people of Southeast Asian origin. In this case report, we describe a previously healthy, Laotian man who presented with skin lesions consistent with Sweet syndrome that were later found to be precipitated by disseminated atypical mycobacterial disease. Extensive immunological workup revealed the patient to have autoantibodies to interferon γ, rendering him susceptible to this infection. Our report demonstrates a complex case with a multilayered diagnosis, while inviting perspective from multiple specialties. This enigmatic case emphasizes the importance of a broad differential with special attention to demographics while demonstrating the difficulty in treating certain atypical infections that are inherently multidrug resistant.

Non-tuberculous mycobacterial lung disease in patients with bronchiectasis: perceived risk, severity and guideline adherence in a European physician survey.

BACKGROUND: Patients with bronchiectasis are at increased risk of developing non-tuberculous mycobacteria lung disease (NTM-LD), and published guidelines recommend regular testing for NTM infection in this patient population. OBJECTIVE: This study aimed to survey physicians managing patients with bronchiectasis to understand the perceived risk of NTM to their patients, perceived disease severity and frequency of testing for NTM. METHODS: The study comprised an online survey of hospital-based physicians in the UK, Germany, Italy, France and the Netherlands. The target group were hospital-based physicians who had managed at least 10 adult patients with bronchiectasis over the preceding 12 months. RESULTS: In total, 280 physicians completed the survey. Most (87%) thought their patients to be at particular risk of NTM, although it was perceived as a moderate risk versus other respiratory pathogens. Most perceived NTM-LD to impact patient morbidity (84%), and 61% indicated that NTM-LD significantly impacted mortality. 68% of all respondents did not test for NTM prior to initiating macrolide monotherapy, despite guidelines recommending testing. The perceived risk of and screening for NTM varied among countries. CONCLUSIONS: The study demonstrates that physicians understand the risk of NTM-LD and associated morbidity in patients with bronchiectasis; however, a minority do not perceive that NTM-LD significantly affects mortality. Greater awareness of the need to test for NTM infection before initiating macrolide monotherapy for bronchiectasis is essential due to potential emergence of drug-resistant NTM.

Mycobacterial Infections With Ruxolitinib: A Retrospective Pharmacovigilance Review.

BACKGROUND: Ruxolitinib is a selective Janus kinase inhibitor (JAKI) 1/2 approved for the treatment of myelofibrosis (MF) and polycythemia vera (PV). These patients may be at risk for developing opportunistic infections. We assessed the number of patients that developed typical (Mycobacterium tuberculosis [MTB]) and atypical mycobacterial infections (AMI) while on treatment with ruxolitinib by utilizing the United States Food and Drug Administration (FDA) adverse events reporting system (FAERS). MATERIALS AND METHODS: This is a retrospective study utilizing FAERS, a pharmacovigilance database. We queried FAERS for cases of MTB and AMI secondary to ruxolitinib between January 1, 2011 and December 31, 2018. Disproportionality signal analysis was done by calculating the reporting odds ratio (ROR). ROR was considered significant when the lower limit of 95% confidence interval (CI) was > 1. RESULTS: There were 91 reported cases of MTB associated with ruxolitinib compared with 4575 cases from all other drugs. The ROR was significant at 9.2 (95% CI, 7.5-11.4). There were 23 reports of AMI with ruxolitinib compared with 1287 reported with all other drugs. The ROR was significant at 8.3 (95% CI, 5.5-12.6). Twelve (13.2%) patients with MTB and 8 (34.8%) with AMI died. CONCLUSION: Patients on ruxolitinib are at increased risk of developing MTB and AMI. Clinicians should be aware of this risk and consider screening patients for latent MTB prior to initiating ruxolitinib.

The effects of sildenafil on ciliary beat frequency in patients with pulmonary non-tuberculous mycobacteria disease: phase I/II trial.

RATIONALE: Pulmonary non-tuberculous mycobacterial (PNTM) disease has increased over the past several decades, especially in older women. Abnormal mucociliary clearance and abnormal nasal nitric oxide (nNO) have been associated with PNTM disease in other patient cohorts. Mucociliary clearance can be affected by NO-cyclic guanosine monophosphate signalling and, therefore, modulation of the pathway may be possible with phosphodiesterase inhibitors such as sildenafil as a novel therapeutic approach. OBJECTIVE: To define ex vivo characteristics of PNTM disease affected by sildenafil. METHODS: Subjects with PNTM infections were recruited into an open-label dose-escalation trial of sildenafil. Laboratory measurements and mucociliary measurements-ciliary beat frequency, nNO and 24-hour sputum production-were collected throughout the study period. Patients received sildenafil daily during the study period, with escalation from 20 to 40 mg three times per day. MEASUREMENTS AND MAIN RESULTS: Increased ciliary beat frequency occurred after a single dose of 40 mg sildenafil and after extended dosing of 40 mg sildenafil. The increase ciliary beat frequency was not seen with 20 mg sildenafil dosing. There were no changes in sputum production, nNO production, Quality of Life-Bronchiectasis-NTM module (QOL-B-NTM) questionnaire or the St George's Respiratory Questionnaire during the study period. CONCLUSION: Sildenafil, 40 mg, increased ciliary beat frequency acutely as well as with extended administration.

A rare case of pulmonary mycobacteriosis caused by rifabutin resistant Mycobacterium celatum and review of the literature.

The present case demonstrates an atypical pulmonary mycobacteriosis that mimicked classical symptoms and radiology findings for tuberculosis. While T-SPOT Test and PCR analyses proved negative for tuberculosis, microscopic sputum evaluation showed acid-fast bacilli and Mycobacterium celatum was found in culture. Uniquely, in our case M. celatum was resistant to rifabutin. Therefore, after not responding to combination treatment including rifabutin, our patient was treated with ethambutol, clarithromycin and protionamide. Classical risk factors for atypical mycobacteriosis such as immunodeficiency (including medication-induced), preexisting pulmonary disease or multimorbidity were not present. We conclude that the high age of the patient (92 y) may have been the main contributing factor for the infection.

British Thoracic Society Guideline for the management of non-tuberculous mycobacterial pulmonary disease (NTM-PD).

The full guideline for the management of non-tuberculous mycobacterial pulmonary disease is published in Thorax. The following is a summary of the recommendations and good practice points. The sections referred to in the summary refer to the full guideline.