Mycobacterium marinum mediates regulation of prostaglandin E2 expression on host immune response through cyclooxygenase pathway.

PURPOSE: Investigate the role of COX signaling in activating the PGE2-EP2 pathway. METHODS: Utilized a marine Mycobacterium infection model in zebrafish. Marine mycobacteria were stained with fluorescein isothiocyanate. The COX inhibitor indomethacin, EP2 receptor inhibitor AH6809, EP4 receptor inhibitor AH23848 and clodronate Liposomes were used to investigate the role of COX, EP2, EP4 and macrophage whether participating in combat marine mycobacterial infection. The expression level of the target gene was detected using real-time fluorescence quantitative PCR instrument. RESULTS: The findings revealed that larvae exposed to the COX inhibitor indomethacin or the EP2 receptor inhibitor AH6809 demonstrated a significantly higher mortality rate due to marine mycobacterium infection than those in the control group. Administration of exogenous prostaglandin E2 (PGE2) rescued the survival of zebrafish infected with marine mycobacteria and treated with indomethacin. Additionally, a significant reduction in survival rate was noted in macrophage-depleted zebrafish infected with marine mycobacteria. CONCLUSION: The host may combat marine mycobacterium infection via COX signaling, which activates the PGE2-EP2 pathway and mediates macrophage resistance.

Beyond the Needle: Unmasking Atypical Mycobacteria in Postvaccination Abscesses in Children.

Introduction: Atypical or nontuberculous mycobacteria (NTM) are an environmental organism responsible for opportunistic infection. Rapid-growing NTM are more commonly associated with hospital-acquired infections. Many of the organisms responsible for diseases in immunocompromised patients and hospital-acquired infections originate from tap water, such as Mycobacterium kansasii, Mycobacterium xenopi, Mycobacterium gordonae, Mycobacterium simiae, Mycobacterium mucogenicum, Mycobacterium fortuitum, Mycobacterium chelonae, and Mycobacterium abscessus. NTM is a rare organism responsible for the injection abscess. Considering low incidents, not much clinical data are available for this condition. Here, we discuss such cases which can be helpful to spread awareness and provide data for future policy makers. Materials and Methods: This was a retrospective study. Data on patients with injection abscess were collected from the last 6 years. Detailed history and clinical examination findings were analyzed. Children with injection abscess were operated and their further management and outcome were studied. Results: A total of 13 cases with confirmed culture of NTM were treated over 6 years. The age ranged from 2½ months to 5¾ years with male:female ratio of 7:6. All patients hailed from the same geographical area. All children were healthy with no history of any long-term or chronic illness, without additional symptoms and had received Bacillus Calmette-Guérin vaccination at birth. The total duration of illness varied from 1 to 5 months, with a mean of 3 months. All patients had a history of intramuscular age-appropriate vaccination as per the national immunization schedule. All patients were followed up to 6 months after intervention and none of our patients developed relapse. Conclusion: Patient who does not respond with optimum treatment should have a high suspicion of such opportunistic infection, which is crucial to their management. Hospital-acquired NTM infections often result from contaminated instruments or fluids. Adherence to strict aseptic precautions, hand hygiene and environmental precautions are the key to preventing these infections. In case of skin and soft tissue infections / abscesses, surgical intervention plays a significant role for managing the patient.

Induction of IL-32 in the immune response of keratinocytes to Mycobacterium marinum infection.

Keratinocytes are the predominant cell type in the skin epidermis, and they not only protect the skin from the influence of external physical factors but also function as an immune barrier against microbial invasion. However, little is known regarding the immune defence mechanisms of keratinocytes against mycobacteria. Here, we performed single-cell RNA sequencing (scRNA-seq) on skin biopsy samples from patients with Mycobacterium marinum infection and bulk RNA sequencing (bRNA-seq) on M. marinum-infected keratinocytes in vitro. The combined analysis of scRNA-seq and bRNA-seq data revealed that several genes were upregulated in M. marinum-infected keratinocytes. Further in vitro validation of these genes by quantitative polymerase chain reaction and western blotting assay confirmed the induction of IL-32 in the immune response of keratinocytes to M. marinum infection. Immunohistochemistry also showed the high expression of IL-32 in patients' lesions. These findings suggest that IL-32 induction is a possible mechanism through which keratinocytes defend against M. marinum infection; this could provide new targets for the immunotherapy of chronic cutaneous mycobacterial infections.

Diagnosis of cutaneous mycobacterial spindle cell pseudotumor in the absence of typical inflammatory cells: A case report.

Mycobacterial spindle cell pseudotumor (MSP) is a non-neoplastic condition that is characterized by spindle-shaped histiocytes colonized by mycobacteria. MSP is most commonly diagnosed in the immunocompromised and, while MSP can occur throughout the body, the most common sites of MSP involvement are the lymph nodes and the skin. To diagnose MSP, histopathological analysis typically demonstrates the presence of inflammatory cells, in addition to spindle cells and the unequivocal mycobacteria, which guides the diagnosis away from potential neoplasms. If properly diagnosed and treated with appropriate antibiotic therapy, patients tend to experience almost complete resolution of their symptoms. MSP is a rare condition; to our knowledge, there have only been 11 documented cases of cutaneous MSP, including the one introduced in this report. Here, we present a unique case of a 50-year-old female on chronic immunosuppressive therapy diagnosed with cutaneous MSP in the absence of inflammatory cells on pathology.

Successful treatment of mycobacterial infection associated hemophagocytic lymphohistiocytosis with etoposide and anti-tuberculous therapy: a case report.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a rare and potentially life-threatening disorder characterized by an exacerbated but ineffective inflammatory response, which can be classified as primary and secondary HLH. HLH associated with Mycobacterium tuberculosis is uncommon. This case report accounted an immunocompetent patient who was confirmed to be Mycobacterium infection, or rather, highly suspected tuberculosis (TB) associated HLH, with a favorable outcome. CASE PRESENTATION: A 36-year-old man presented with persistent fever, pancytopenia, and hyperferritinemia. A bone marrow smear demonstrated hemophagocytosis, and pathological examination of lung biopsy was positive for acid-fast bacilli, which established the diagnosis of Mycobacterium infection and HLH. Then the patient treated successfully with anti-TB therapy, along with 8 weeks of etoposide. CONCLUSION: This case emphasizes that HLH should be kept in mind when clinicians encounter a patient with severe infection presenting with pancytopenia and hyperferritinemia. Given the high mortality, early diagnosis and appropriate therapy can provide patients with a favorable prognosis.

Case Series and Review of the Literature of Mycobacterium chelonae Infections of the Lower Extremities.

Mycobacterium chelonae infections involving the lower extremities are rare clinical entities that present a diagnostic challenge given its diverse clinical presentations ranging from superficial (e.g., cellulitis, painful vesicular lesions) to deep (e.g., tenosynovitis) infections. We present 1 cases of M chelonae infections of the feet diagnosed 6 to 12 months after initial symptoms representing the difficulty of diagnosing this condition. Both cases were successfully managed with aggressive surgical debridement and long durations of antibiotic therapy with long-term care. A comprehensive review of the literature of M chelonae infections of the lower extremities was performed to provide summary data on the presenting symptoms, examination findings, predisposing conditions, and management approaches of this rare, but emerging clinical entity. Our cases and comprehensive review serve to raise awareness of atypical mycobacterial infections, including M chelonae, and advocate for the early consideration of mycobacterial cultures in the diagnostic workup of chronic lower extremity infections especially in the setting of poor initial response to standard antibacterial therapies.

Current Status of the Management of Mendelian Susceptibility to Mycobacterial Disease in Mainland China.

PURPOSE: Although many studies have investigated Mendelian susceptibility to mycobacterial disease (MSMD) worldwide, there is no report of the long-term clinical management and prognosis for MSMD in China. METHODS: This is a cohort study from January 2000 to June 2018. Three hundred and twenty-four patients with bacillus Calmette-Guérin (BCG) infection were diagnosed during this period, and those with MSMD diagnosed by genetic and functional experiments were enrolled in the study. The clinical and genetic characteristics and management of these MSMD patients were summarized. RESULTS: Thirty patients diagnosed with MSMD were followed up. The age at the follow-up end point ranged from 5 to 173 months. Among the patients, IL12RB1 mutations were identified in 22, IFNGR1 mutations in 5, STAT1 mutations in 2, and IFNGR2 mutation in 1. The medium age at onset was 3 months. BCG infection involved multiple organs, including regional infection (8/30; 26.7%) or distant or disseminated infection (22/30; 73.3%). Ten percent (30/324) of patients with BCG infection had a confirmed MSMD diagnosis. Protein expression of IL12RB1 or IFNGR1 was decreased in all patients with IL12RB1 or IFNGR1 mutation, respectively, as indicated by flow cytometry. In addition, 77.8% of patients received rhIFN-γ treatment, which can improve the prognosis of patients with IL12RB1 deficiency. Two patients received stem cell transplantation. Twenty-five patients remained alive at the time of publication. CONCLUSION: MSMD is an important cause of BCG infection. Flow cytometric detection of IL12RB1 and IFNGR1 expression is very useful for rapid MSMD diagnosis. rhIFN-γ therapy is effective in patients with MSMD, particularly improving prognosis in those with IL12RB1 deficiency.

Human immunodeficiency virus-associated tuberculosis care in Botswana: evidence from a real-world setting.

BACKGROUND: Tuberculosis (TB) is among the world's top public health challenges and the leading killer of people with HIV, yet is a treatable disease. This study aimed to assess, in a real-world setting, the implementation of antiretroviral therapy (ART) and Cotrimoxazole preventive therapy (CPT) policy, specific interventions proven to benefit patients in HIV-associated TB care. METHODS: This retrospective cohort study was conducted in Botswana in the Serowe/Palapye district, a largely urban district with a high burden of HIV-associated TB with a high case fatality, at Segkoma and Palapye hospitals and their feeder clinics. Between 1 January 2013 and 31 December 2013, confirmed HIV-positive patients aged ≥15 years with a confirmed TB diagnosis and medical record available were included in the analysis. The Kaplan-Meier method was used to compare time to death for the group of patients on ART and the group of patients not on ART during TB treatment. Cox proportional hazard regression was undertaken to identify predictors of mortality. RESULTS: Of the 300 patients included in the study, 217 (72%) were ART experienced at TB diagnosis. Of these, 86 (40%) had TB within 3 months following ART initiation. Of the 83 (28%) patients who were ART-naïve at TB diagnosis, 40 (48%) were commenced on ART during TB treatment, with 24 (60%) patients commencing within 4 weeks following TB treatment initiation. The overall ART uptake was 84%, while cotrimoxazole preventive therapy uptake was 100%. There were 45 deaths (15%), ART-experienced patients during TB treatment accounted for 30 deaths (30/257; 14%), while those who were not ART-experienced during TB treatment accounted for 15 deaths (15/43; 35%). There was a significant difference in survival time between patients with no ART use during TB treatment and those with ART use during TB treatment (log rank p < 0.001). Patients with no ART use during TB treatment were more likely to die within the first 2 months. CONCLUSION: The implementation of CPT policy is a substantial success. Strengthening the implementation of ART policy could improve survival among HIV-associated TB patients.

Nontuberculous Mycobacterium infection complicated with Haemophagocytic syndrome: a case report and literature review.

BACKGROUND: Non-tuberculous mycobacterial (NTM) infection is usually observed in patients with immunosuppressive conditions. It may also cause unregulated immune responses. While there have been increasing numbers of reported tuberculosis-related HPS (haemophagocytic syndrome), HPS caused by NTM infection is still very rarely reported. CASE PRESENTATION: We report a previously healthy 21-year-old Chinese female with fever, night sweats and fatigue, in whom HPS was diagnosed according to the HLH-2004 criteria. Mycobacterium intracellulare was cultured from her peripheral blood. After treatment with corticosteroid, clarithromycin, rifampicin, ethambutol and amikacin, the patient finally recovered. We also reviewed relevant publications on NTM infection complicated with HPS and found 11 cases, including ours. Clinical presentations, diagnoses and prognoses were analysed and summarized to deepen our understanding of this rare condition. CONCLUSIONS: Most reported NTM-related cases were caused by disseminated infection. The lack of localized symptoms might add to the difficulty involved in making the right diagnosis. While it usually takes time to obtain tissue or blood culture results, granuloma in a bone marrow biopsy might be an early indicator of possible mycobacterial infection. Although treatment varied, the overall prognosis of NTM-related HPS was promising.

Corticosteroid dose and the risk of opportunistic infection in a national systemic lupus erythematosus cohort.

Objective This study investigated whether the incidence of opportunistic infection differed in systemic lupus erythematosus patients who received different doses of corticosteroids. Methods We included patients with diagnosed systemic lupus erythematosus from 1997 to 2010 using Taiwan national health insurance data. The index day for systemic lupus erythematosus patients was 3 months after the systemic lupus erythematosus diagnosis. A non-steroid cohort was matched 4:1 with the steroid cohort according to age, sex and index day. The end of the follow-up period was the day of opportunistic infection diagnosis, 1 year after the index day, or death. Results The overall cumulative incidence of opportunistic infection was 136-fold higher in the steroid cohort than in the non-steroid cohort. The adjusted hazard ratio for developing mycobacterium infection in the steroid cohort was 11, and the adjusted hazard ratio for developing herpes zoster was 43.6 compared to the non-steroid cohort after adjusting for immunosuppressive agents and comorbidities. The adjusted hazard ratio value for opportunistic infection was 1.40 (95% confidence interval (CI) 0.78-2.51) for a daily prednisone-equivalent dose of 7.5-15 mg, 1.72 (95% CI 1.02-2.91) for 15-30 mg, 1.96 (95% CI 1.17-3.28) for 30-60 mg and 2.24 (95% CI 1.26-4.00) for over 60 mg compared with low-dose steroids (<7.5 mg). Conclusion This study confirmed that the risk of opportunistic infection is higher in systemic lupus erythematosus patients treated with steroids in the first 3 months after diagnosis versus those not treated with steroids. Medium and high doses were associated with a higher risk of opportunistic infection compared with low doses. However, there was no controlling for disease activity, making it hard to know if increases in infection were due to disease itself or corticosteroids.

Interstitial Lung Diseases Misdiagnosed as Tuberculosis.

OBJECTIVE: To determine the frequency of misdiagnosis of tuberculosis in interstitial lung disease cases. METHODS: This is a prospective study including patients registered in the interstitial lung disease clinic, Jinnah Postgraduate Medical Center, Karachi, during May-June 2017. Diagnosis of tuberculosis was only confirmed if there was any bacteriological evidence of tuberculosis at the time of diagnosis or if there was improvement in symptoms after treatment in patients diagnosed as having tuberculosis on clinical grounds. RESULTS: Seventy-three patients were included in the study, out of which 53 (72.60%) were females and 20 (27.39%) were males. Tuberculosis was treated before presentation in 28 (38.35%) of interstitial lung disease patients. Except for two silicosis patients who had smear positive tuberculosis, rest of the patients were misdiagnosed as having tuberculosis. CONCLUSION: Interstitial lung diseases are the disorders that are frequently unrecognized and misdiagnosed. More commonly the confusion is with tuberculosis. Thorough knowledge about interstitial lung diseases should be provided to the primary care physicians, especially in countries with high tuberculosis burden, so that to limit maltreatment with anti-tuberculous drugs when they are not needed and early referral to interstitial lung disease clinic.

Mycobacterium chelonae-abscessus Complex Infection After Flatfoot Reconstruction.

Mycobacterium infections involving tuberculosis in the foot are rare but cases are readily available in published studies. Atypical or nontuberculosis mycobacterium foot infections are rare, especially those involving the soft tissue and bone, and have been infrequently reported. To date, no case reports involving atypical mycobacterium infection after elective foot surgery have been reported. We present the case of a 49-year-old female who underwent flatfoot reconstruction, with a resultant Mycobacterium chelonae-abscessus infection and osteomyelitis postoperatively. The patient ultimately underwent hardware removal with multiple debridements. The patient was treated ultimately with a 6-week course of intravenous antibiotics and 5 months of oral antibiotics for the mycobacterium infection and osteomyelitis. At the last follow-up examination, the patient remained healed with a satisfactory outcome. We also provide a literature review of mycobacterium infections in the foot.

Variable agreement among experts regarding Mycobacterium avium complex lung disease.

Data regarding many clinical aspects of pulmonary Mycobacterium avium complex (pMAC) are lacking. Guidelines rely substantially upon expert opinion, integrated through face-to-face meetings, variably weighting individual opinions. We surveyed North American non-tuberculous mycobacteria experts regarding clinical aspects of pMAC using Delphi methods. Nineteen of 26 invited experts (73%) responded, with extensive variability. Convergence could not be reached for most questions. Respondents described extensive uncertainty around specific issues. Findings underscore urgent need for more research.

Disseminated Mycobacterium gordonae and Mycobacterium mantenii infection with elevated anti-IFN-γ neutralizing autoantibodies.

A case of disseminated nontuberculous mycobacteria(l) (NTM) infection in a patient with positive neutralizing anti-interferon-γ (IFN-γ) autoantibodies involving bone, bronchus, systemic lymph nodes, and skin is reported. The causative NTMs were two different strains: Mycobacterium gordonae, which rarely causes true disease, and Mycobacterium mantenii, which is extremely rare. Anti-mycobacterial treatment successfully ameliorated all disseminated lesions. Although the concentration of anti-IFN-γ autoantibodies increased during the pre-treatment period, it gradually decreased after anti-mycobacterial treatment was started.

Novel assay to detect increased level of neutralizing anti-interferon gamma autoantibodies in non-tuberculous mycobacterial patients.

Subjects exposed to non-tuberculous mycobacterium (NTM) species do not always develop an active disease, which likely reflects underlying host susceptibility factors. Recent reports have shown that anti interferon gamma (IFN-γ) neutralizing autoantibodies (IFN-γ Ab) are associated with the development of disseminated NTM in patients without known evidence of immunodeficiency. The purpose of this study is to establish the screening method if subjects have IFN-γ Ab. Whole blood was obtained from patients with disseminated NTM, those with pulmonary NTM, and healthy controls. The neutralizing capacity to IFN-γ activity was assessed as an inhibition of Signal Transducer and Activation of Transcription 1 (STAT-1) phosphorylation in leukocyte after stimulation with exogenous IFN-γ by flow cytometer. The strength of phosphorylation was described as STAT1 phosphorylation index. Antigen capture assay was performed to measure the relative titer of Immunoglobulin-G fraction of IFN-γ Ab. STAT1 phosphorylation by IFN-γ was significantly inhibited in the leukocytes from patients with disseminated NTM compared to that in healthy subjects, while this inhibition was not observed in patients with pulmonary NTM. All subjects with inhibited STAT1 phosphorylation had high titer of Immunoglobulin-G that reacted with IFN-γ in the antigen capture assay. The measurement of STAT1 phosphorylation index in whole blood leukocytes and antigen capture assay are simple and useful method for detection of anti-IFN-γ neutralizing autoantibodies, and is valuable in the pathophysiological diagnosis of disseminated NTM patients without obvious immunodeficiency.

Multifocal Cutaneous Tuberculosis in an Immunocompetent Patient: A Case Report.

Cutaneous tuberculosis is an infection caused by Mycobacteria tuberculosis, the rare Mycobacterium bovis and the bacillus Calmette-Guérin vaccine. This disease has many clinical types with diverse clinical manifestations, mainly includes lupus vulgaris, tuberculosis verrucosa cutis, orificial tuberculosis and scrofuloderma that are difficult to identify. We report a case of cutaneous tuberculosis in a female who presented with disseminated papular and nodular lesions on her face and hands. The results of skin biopsy, PCR, and IGRA test contributed to the diagnosis. All lesions were resolved leaving only superficial scars after 5 months treatment.

Disseminated Nontuberculous Mycobacterium Infection During Treatment of Multiple Myeloma: A Case Report and Review of the Literature.

Multiple myeloma (MM) is a plasma B-cell malignancy characterized by immune dysfunction, with infection representing a major complication. Bacteria, including Streptococcus pneumoniae, are common pathogens in patients with MM, but reports on infections with nontuberculous mycobacteria (NTM) have been limited. We herein report a case of disseminated NTM infection in a patient with MM undergoing treatment with immunomodulatory drugs. At the diagnosis, the patient showed lymphocytopenia and was treated with clarithromycin, rifampicin, and ethambutol; however, culture positivity persisted, and the patient died. The possibility of NTM infection should be considered in cases of unexplained deterioration of the MM patient's general condition.

An analytic feasibility study of the BD MAX™ MDR-TB assay for testing of non-sputum specimens for detection of the Mycobacterium tuberculosis complex (MTBC) and isoniazid (INH) and rifampin (RIF) resistance.

Rapid diagnosis of tuberculosis and drug resistance in extrapulmonary specimens can be challenging. The BD MAX™ multidrug resistant (MDR)-TB assay (BD MAX™) has demonstrated high sensitivity and specificity for the detection of the Mycobacterium tuberculosis complex (MTBC) as well as resistance to INH and Rifampin (RIF) in pulmonary specimens but has not been rigorously assessed in extrapulmonary samples. We evaluated the diagnostic accuracy of the BD MAX™ assay for the detection of MTBC and drug resistance in extrapulmonary specimens spiked with MTBC from the Johns Hopkins strain collection. A total of 1083 tests were performed across multiple sample types, with an overall percent agreement of 94.8% (795/839) for detection of MTBC and 99% (379/383) and 96.4% (323/335) for determination of INH and RIF resistance-conferring mutations, respectively. The BD MAX™ assay provides same day detection of MTBC and drug-resistance results and could be a beneficial diagnostic test in extrapulmonary sample types.

Clinical features of patients presenting with fever of unknown origin caused by non-tuberculous mycobacterium infection.

INTRODUCTION: Although non-tuberculous mycobacterium (NTM) infection accounts for only a small proportion of fever of unknown origin (FUO) cases, it has become a more common etiology in recent years. Therefore, we reviewed FUO patients with underlying NTM infection to better understand its clinical features. METHODOLOGY: The medical records of patients presenting with FUO and diagnosed with NTM infection admitted to Peking Union Medical College Hospital between January 2016 and June 2021 were reviewed. The clinical information of patients whose follow-up data were available were summarized. Specimens submitted for pathogenic identification were processed by mycobacterial culture, acid-fast staining, and mycobacterial nucleic acid detection. IBM SPSS Statistics v22.0 (SPSS, Inc., Chicago, IL, USA) was used for data analysis. RESULTS: Fifty-five FUO patients were diagnosed with NTM infection (55/785; 7.0% of FUO cases). Patients were mostly middle-aged men and had a relatively long disease course. Seven, 29, and 54 patients had previously no respondence to glucocorticoids, immunosuppressants, and multiple antibiotics, respectively; their inflammatory indexes were significantly increased; and there was no obvious risk of immunosuppression in this group, who were likely to be T.SPOT-TB negative (33/41; 80.5%). The most commonly identified NTM was Mycobacterium intracellulare followed by Mycobacterium chelonae/abscessus, Mycobacterium kansasii, and Mycobacterium avium. CONCLUSIONS: Microbiological investigations including culture, acid-fast staining, NTM nucleic acid examination, and next-generation sequencing were performed to confirm the diagnosis of NTM in FUO patients. FUO patients should screen for NTM infections so that this important etiology can be recognized, targeted treatments administered early, and outcomes improved.