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.

Mendelian Susceptibility to Mycobacterial Disease (MSMD): Clinical, Immunological, and Genetic Features of 22 Patients from 15 Moroccan Kindreds.

PURPOSE: The first molecular evidence of a monogenic predisposition to mycobacteria came from the study of Mendelian susceptibility to mycobacterial disease (MSMD). We aimed to study this Mendelian susceptibility to mycobacterial diseases in Moroccan kindreds through clinical, immunological, and genetic analysis. METHODS: Patients presented with clinical features of MSMD were recruited into this study. We used whole blood samples from patients and age-matched healthy controls. To measure IL-12 and IFN-γ production, samples were activated by BCG plus recombinant human IFN-γ or recombinant human IL-12. Immunological assessments and genetic analysis were also done for patients and their relatives. RESULTS: Our study involved 22 cases from 15 unrelated Moroccan kindreds. The average age at diagnosis is 4 years. Fourteen patients (64%) were born to consanguineous parents. All patients were vaccinated with the BCG vaccine, and twelve of them (55%) developed locoregional or disseminated BCG infections. The other symptomatic patients had severe tuberculosis and/or recurrent salmonellosis. Genetic mutations were identified on the following genes: IL12RB1 in 8 patients, STAT1 in 7 patients; SPPL2A, IFNGR1, and TYK2 in two patients each; and TBX21 in one patient, with different modes of inheritance. All identified mutations/variants altered production or response to IFN-γ or both. CONCLUSION: Severe forms of tuberculosis and complications of BCG vaccination may imply a genetic predisposition present in the Moroccan population. In the presence of these infections, systematic genetic studies became necessary. BCG vaccination is contraindicated in MSMD patients and should be delayed in newborn siblings until the exclusion of a genetic predisposition to mycobacteria.

A Novel Homozygous Stop Mutation in IL23R Causes Mendelian Susceptibility to Mycobacterial Disease.

PURPOSE: Mendelian susceptibility to mycobacterial disease (MSMD) is caused by inborn errors of IFN-γ immunity. The most frequent genetic defects are found in IL12 or a subunit of its receptor. IL23R deficiency in MSMD has only been reported once, in two pediatric patients from the same kindred with isolated disseminated Bacille Calmette-Guérin disease. We evaluated the impact of a homozygous stop mutation in IL23R (R381X), identified by whole exome sequencing, in an adult patient with disseminated non-tuberculous mycobacterial disease. METHODS: We performed functional validation of the R381X mutation by evaluating IL23R expression and IL-23 signaling (STAT3 phosphorylation, IFN-γ production) in primary cells (PBMCs, EBV-B cells) and cell lines (HeLa) with or without back-complementation of wild-type IL23R. RESULTS: We report on a 48-year-old male with disseminated non-tuberculous mycobacterial disease. We identified and characterized a homozygous loss-of-function stop mutation underlying IL23R deficiency, resulting in near absent expression of membrane bound IL23R. IL23R deficiency was characterized by impaired IL-23-mediated IFN-γ secretion in CD4+, CD8+ T, and mucosal-associated invariant T (MAIT) cells, and low frequencies of circulating Th17 (CD3+CD45RA-CCR4+CXCR3-RORγT+), Th1* (CD45RA-CCR4-CXCR3+RORγT+), and MAIT (CD3+CD8+Vα7.2+CD161+) cells. Although the patient did not have a history of recurrent fungal infections, impaired Th17 differentiation and blunted IL-23-mediated IL-17 secretion in PBMCs were observed. CONCLUSION: We demonstrate that impaired IL-23 immunity caused by a homozygous R381X mutation in IL23R underlies MSMD, corroborating earlier findings with a homozygous p.C115Y IL23R mutation. Our report further supports a model of redundant contribution of IL-23- to IL-17-mediated anti-fungal immunity.1.

Mycobacterium chimaera infections among cardiothoracic surgery patients associated with heater-cooler devices-Kansas and California, 2019.

BACKGROUND: In 2015, an international outbreak of Mycobacterium chimaera infections among patients undergoing cardiothoracic surgeries was associated with exposure to contaminated LivaNova 3T heater-cooler devices (HCDs). From June 2017 to October 2020, the Centers for Disease Control and Prevention was notified of 18 patients with M. chimaera infections who had undergone cardiothoracic surgeries at 2 hospitals in Kansas (14 patients) and California (4 patients); 17 had exposure to 3T HCDs. Whole-genome sequencing of the clinical and environmental isolates matched the global outbreak strain identified in 2015. METHODS: Investigations were conducted at each hospital to determine the cause of ongoing infections. Investigative methods included query of microbiologic records to identify additional cases, medical chart review, observations of operating room setup, HCD use and maintenance practices, and collection of HCD and environmental samples. RESULTS: Onsite observations identified deviations in the positioning and maintenance of the 3T HCDs from the US Food and Drug Administration (FDA) recommendations and the manufacturer's updated cleaning and disinfection protocols. Additionally, most 3T HCDs had not undergone the recommended vacuum and sealing upgrades by the manufacturer to decrease the dispersal of M. chimaera-containing aerosols into the operating room, despite hospital requests to the manufacturer. CONCLUSIONS: These findings highlight the need for continued awareness of the risk of M. chimaera infections associated with 3T HCDs, even if the devices are newly manufactured. Hospitals should maintain vigilance in adhering to FDA recommendations and the manufacturer's protocols and in identifying patients with potential M. chimaera infections with exposure to these devices.

Mycobacterium chimaera Outbreak Management and Outcomes at a Large Pediatric Cardiac Surgery Center.

BACKGROUND: In 2012, a global outbreak of invasive Mycobacterium chimaera (M. chimaera) infection was identified in patients after cardiopulmonary bypass surgery. Investigations revealed the source to be heater-cooler unit (HCU) exhaust, with point-source contamination discovered at the LivaNova HCU manufacturing plant (London, UK). We report our experience with affected HCUs at a high-volume pediatric cardiac surgery center in the United States. METHODS: A multidisciplinary task force was established for outbreak management, including removing contaminated HCUs from service. Patients identified as exposed to affected HCUs were systematically contacted. A call center was created for patient/family inquiries, and symptomatic patients were assessed using an institutional triage protocol, including laboratory/culture data and infectious diseases consultation. RESULTS: Cardiopulmonary bypass surgeries were performed in 4276 patients (median age: 2.1 years; range: 0-48.4 years) between October 2010 and October 2016. Call center volume was highest in the first 6 weeks after patient notification, totaling 307 calls and yielding 70 clinical patient assessments. Presenting symptoms included fatigue (60%), fever (49%), night sweats (46%), myalgias (34%), and weight loss (24%). Among the 70 assessed patients, echocardiogram (n = 30), cardiac computed tomography (n = 2), cardiac magnetic resonance imaging (n = 1), and pulmonary computed tomography (n = 1) did not reveal abnormalities suggestive of active infection. Infectious diseases consultation occurred in 23 (33%) patients. Acid-fast bacilli blood cultures were obtained in 30 patients; all were negative. CONCLUSIONS: Through a highly coordinated outreach effort, no patients have been found to have M. chimaera infection in the 6 years after exposure to contaminated HCUs. Ongoing vigilance for cases that may yet manifest is needed.

Mycobacterial diseases in patients with inborn errors of immunity.

Clinical disease caused by the agent of tuberculosis, Mycobacterium tuberculosis, and by less virulent mycobacteria, such as bacillus Calmette-Guérin (BCG) vaccines and environmental mycobacteria, can result from inborn errors of immunity (IEIs). IEIs underlie more than 450 conditions, each associated with an impairment of the development and/or function of hematopoietic and/or non-hematopoietic cells involved in host defense. Only a minority of IEIs confer predisposition to mycobacterial disease. The IEIs underlying susceptibility to bona fide tuberculosis are less well delineated than those responsible for susceptibility to less virulent mycobacteria. However, all these IEIs share a defining feature: the impairment of immunity mediated by interferon gamma (IFN-γ). More profound IFN-γ deficiency is associated with a greater vulnerability to weakly virulent mycobacteria, whereas more selective IFN-γ deficiency is associated with a more selective predisposition to mycobacterial disease. We review here recent progress in the study of IEIs underlying mycobacterial diseases.

Inherited GATA2 Deficiency Is Dominant by Haploinsufficiency and Displays Incomplete Clinical Penetrance.

PURPOSE: Germline heterozygous mutations of GATA2 underlie a variety of hematological and clinical phenotypes. The genetic, immunological, and clinical features of GATA2-deficient patients with mycobacterial diseases in the familial context remain largely unknown. METHODS: We enrolled 15 GATA2 index cases referred for mycobacterial disease. We describe their genetic and clinical features including their relatives. RESULTS: We identified 12 heterozygous GATA2 mutations, two of which had not been reported. Eight of these mutations were loss-of-function, and four were hypomorphic. None was dominant-negative in vitro, and the GATA2 locus was found to be subject to purifying selection, strongly suggesting a mechanism of haploinsufficiency. Three relatives of index cases had mycobacterial disease and were also heterozygous, resulting in 18 patients in total. Mycobacterial infection was the first clinical manifestation in 11 patients, at a mean age of 22.5 years (range: 12 to 42 years). Most patients also suffered from other infections, monocytopenia, or myelodysplasia. Strikingly, the clinical penetrance was incomplete (32.9% by age 40 years), as 16 heterozygous relatives aged between 6 and 78 years, including 4 older than 60 years, were completely asymptomatic. CONCLUSION: Clinical penetrance for mycobacterial disease was found to be similar to other GATA2 deficiency-related manifestations. These observations suggest that other mechanisms contribute to the phenotypic expression of GATA2 deficiency. A diagnosis of autosomal dominant GATA2 deficiency should be considered in patients with mycobacterial infections and/or other GATA2 deficiency-related phenotypes at any age in life. Moreover, all direct relatives should be genotyped at the GATA2 locus.

Successful termination of an outbreak of Mycobacterium chimaera infections associated with contaminated heater-cooler devices.

The global outbreak of invasive Mycobacterium chimaera infections associated with heater-cooler devices (HCDs) presented several important and unique challenges. To mitigate the risk of infection, we removed the HCDs from operating rooms (ORs) at our hospital and since that time (4.5 years ago) we have had no new cases.

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.

Mycobacterial infections due to PD-1 and PD-L1 checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors that block programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) have improved outcomes for many cancer subtypes but do exhibit toxicity, in the form of immune-related adverse events. OBJECTIVE: The aim of this study was to investigate the emerging toxicities of PD-1 and PD-L1 inhibitors including acute or reactivation of tuberculosis (TB) and atypical mycobacterial infection (AMI). METHODS: This study was completed as a retrospective review using the US Food and Drug Administration Adverse Events Reporting System (FAERS) for incidence of TB and AMI due to PD-1 and PD-L1 inhibitors compared with other FDA (Food and Drug Administration) approved drugs. The statistical methods included disproportionality signal analysis using the reporting OR (ROR) to compare cases. The 95% Wald CI was reported to assess the precision of the ROR. RESULTS: Out of the 10 146 481 adverse events (AEs) reported to FAERS for all drugs between 1 January 2015 and 31 March 2020, 73 886 AEs were due to the five FDA approved PD-1/PD-L1 inhibitors. Seventy-two cases of TB were due to PD-1/PD-L1 inhibitors. Specifically, 45 cases (62.5%) due to nivolumab, 18 (25%) due to pembrolizumab, 5 (7%) due to atezolizumab and 4 (5.5%) due to durvalumab. There were 13 cases of AMI: 9 (69.3%) due to nivolumab, 2 (15.3%) due to pembrolizumab and 1 (7.7%) each due to durvalumab and atezolizumab. Avelumab was not attributed to any AE of TB or AMI. From analysis of the FAERS database, the calculated ROR for TB due to PD-1/PD-L1 inhibitors was 1.79 (95% CI, 1.42 to 2.26) (p<0.0001) and for AMI was 5.49 (95% CI, 3.15 to 9.55) (p<0.0001). CONCLUSION: PD-1/PD-L1 inhibitors used in the treatment of cancer subtypes is associated with increased TB and AMI risk. Although this complication is rare, clinicians using PD-1/PD-L1 inhibitors should be aware of the risks.

Successful Matched Related Bone Marrow Transplantation in a Patient with Autosomal Dominant Interferon Gamma Receptor 1 Deficiency.

This is a report of a successful bone marrow transplant in an IFN-γR1 patient with progressive mycobacterial infection. PURPOSE: Hematopoietic cell transplant in patients with interferon gamma receptor deficiencies has been fraught with challenges, not the least of which is failure of engraftment and infectious complications. METHODS: This is a report of a successful hematopoietic cell transplant in an actively infected patient of advanced age. RESULTS: This case report shows successful engraftment and resolution of infection posttransplant using a matched related donor in a single institution. CONCLUSION: A successful curative HCT despite persistent, disseminated, nontuberculous mycobacterial infection in a patient with AD-IFNγR1 suggests that this approach, while difficult, may be useful in other patients with otherwise refractory disease.

Mycobacterium senegalense Infection after Implant-Based Breast Reconstruction, Spain.

Bacterial infection is a well-known complication of breast implant surgery. We identified Mycobacterium senegalense, the principal pathogen of bovine farcy of cattle, in a woman after implant-based breast reconstruction. This finding indicates that unusual pathogens should be considered as an etiology of infected breast prostheses.

Prosthetic joint infection due to Mycobacterium bovis 5-years after BCG-instillations.

The Bacillus Calmette-Guerin (BCG) has been used as intravesical immunotherapy for superficial urothelial bladder carcinoma in preventing its recurrence. Prosthetic joint infections due to those instillations are very rare and few practitioners know this side effect. We report the case of a 77-year old male with a medical history of right hip replacement and super- ficial urothelial bladder carcinoma treated with BCG-instillations. He presented with a painful hip joint and extreme difficulty at walking. Because of high suspicion of prosthetic joint infection, a 2-stage arthroplasty was performed. Microbiological culture revealed Mycobacterium bovis so he was kept on antituberculous therapy for twelve months. Remarkable is the delay between the instillations and the acquisition of the prosthetic joint infection. A medical history of BCG instillations should warrant the practitioner for a possible joint infection. There are no current guidelines concerning the therapy.