Genetic Analysis of Korean Adult Patients with Nontuberculous Mycobacteria Suspected of Primary Ciliary Dyskinesia Using Whole Exome Sequencing

Purpose@#Nontuberculous mycobacteria (NTM) is ubiquitous in the environment, but NTM lung disease (NTM-LD) is uncommon. Since exposure to NTM is inevitable, patients who develop NTM-LD are likely to have specific susceptibility factors, such as primary ciliary dyskinesia (PCD). PCD is a genetically heterogeneous disorder of motile cilia and is characterized by chronic respiratory tract infection, organ laterality defect, and infertility. In this study, we performed whole exome sequencing (WES) and investigated the genetic characteristics of adult NTM patients with suspected PCD. @*Materials and Methods@#WES was performed in 13 NTM-LD patients who were suspected of having PCD by clinical symptoms and/or ultrastructural ciliary defect observed by transmission electron microscopy. A total of 45 PCD-causing genes, 23 PCDcandidate genes, and 990 ciliome genes were analyzed. @*Results@#Four patients were found to have biallelic loss-of-function (LoF) variants in the following PCD-causing genes: CCDC114, DNAH5, HYDIN, and NME5. In four other patients, only one LoF variant was identified, while the remaining five patients did not have any LoF variants. @*Conclusion@#At least 30.8% of NTM-LD patients who were suspected of having PCD had biallelic LoF variants, and an additional 30.8% of patients had one LoF variant. Therefore, PCD should be considered in patients with NTM-LD with symptoms or signs suspicious of PCD.

Nontuberculous mycobacterial pulmonary disease in a 16-year-old female patient with bronchiectasis

Nontuberculous mycobacterial (NTM) pulmonary disease generally occurs in old people with underlying lung disease. However, unlike adults, NTM infections in children with normal immunity are rare, and they occasionally manifest as lymphadenitis. We herein present a rare case of NTM pulmonary disease in a girl who is the youngest patient reported in Korea. A 16-year-old female was brought to the hospital because of dyspnea on exertion, fever, and productive cough. The patient had bronchiectasis. She underwent Fontan operation for right isomerism, double outlet right ventricle, pulmonary stenosis, and had been taking prophylactic antibiotics for asplenia. NTM were found in the sputum and bronchoalveolar lavage fluid by acid fast bacillus (AFB) staining and culture, which were identified as Mycobacterium avium. The treatment started with azithromycin, ethambutol and rifampicin. After 6 months of treatment, respiratory symptoms improved and the sputum AFB culture became negative. She is currently on medication with above-mentioned drugs for 10 months without any adverse effects. This case suggests that NTM pulmonary disease should be suspected and properly treated especially in children and adolescents with underlying lung disease.

Treatment of Isoniazid-Resistant Pulmonary Tuberculosis / 결핵

Treatment of Isoniazid-Resistant Pulmonary Tuberculosis / 결핵및호흡기질환

Tuberculosis (TB) remains a threat to public health and is the leading cause of death globally. Isoniazid (INH) is an important first-line agent for the treatment of TB considering its early bactericidal activity. Resistance to INH is now the most common type of resistance. Resistance to INH reduces the probability of treatment success and increases the risk of acquiring resistance to other first-line drugs such as rifampicin (RIF), thereby increasing the risk of multidrug-resistant-TB. Studies in the 1970s and 1980s showed high success rates for INH-resistant TB cases receiving regimens comprised of first-line drugs. However, recent data have indicated that INH-resistant TB patients treated with only first-line drugs have poor outcomes. Fortunately, based on recent systematic meta-analyses, the World Health Organization published consolidated guidelines on drug-resistant TB in 2019. Their key recommendations are treatment with RIF-ethambutol (EMB)-pyrazinamide (PZA)-levofloxacin (LFX) for 6 months and no addition of injectable agents to the treatment regimen. The guidelines also emphasize the importance of excluding resistance to RIF before starting RIF-EMB-PZA-LFX regimen. Additionally, when the diagnosis of INH-resistant TB is confirmed long after starting the first-line TB treatment, the clinician must decide whether to start a 6-month course of RIF-EMB-PZA-LFX based on the patient's condition. However, these recommendations are based on observational studies, not randomized controlled trials, and are thus conditional and based on low certainty of the effect estimates. Therefore, further work is needed to optimize the treatment of INH-resistant TB.

Treatment of Isoniazid-Resistant Pulmonary Tuberculosis / 결핵및호흡기질환

Tuberculosis (TB) remains a threat to public health and is the leading cause of death globally. Isoniazid (INH) is an important first-line agent for the treatment of TB considering its early bactericidal activity. Resistance to INH is now the most common type of resistance. Resistance to INH reduces the probability of treatment success and increases the risk of acquiring resistance to other first-line drugs such as rifampicin (RIF), thereby increasing the risk of multidrug-resistant-TB. Studies in the 1970s and 1980s showed high success rates for INH-resistant TB cases receiving regimens comprised of first-line drugs. However, recent data have indicated that INH-resistant TB patients treated with only first-line drugs have poor outcomes. Fortunately, based on recent systematic meta-analyses, the World Health Organization published consolidated guidelines on drug-resistant TB in 2019. Their key recommendations are treatment with RIF-ethambutol (EMB)-pyrazinamide (PZA)-levofloxacin (LFX) for 6 months and no addition of injectable agents to the treatment regimen. The guidelines also emphasize the importance of excluding resistance to RIF before starting RIF-EMB-PZA-LFX regimen. Additionally, when the diagnosis of INH-resistant TB is confirmed long after starting the first-line TB treatment, the clinician must decide whether to start a 6-month course of RIF-EMB-PZA-LFX based on the patient's condition. However, these recommendations are based on observational studies, not randomized controlled trials, and are thus conditional and based on low certainty of the effect estimates. Therefore, further work is needed to optimize the treatment of INH-resistant TB.

Diagnostic Performance of the GENEDIA MTB/NTM Detection Kit for Detecting Mycobacterium tuberculosis and Nontuberculous Mycobacteria With Sputum Specimens

The GENEDIA MTB/NTM Detection Kit (GENEDIA MTB/NTM; Green Cross Medical Science Corp., Chungbuk, Korea) is a multiplex real-time PCR assay used for differential identification of Mycobacterium tuberculosis complex (MTBC) and nontuberculous mycobacteria (NTM). While the importance of differential identification of MTB/NTM is recognized, there is limited data on the performance of GENEDIA MTB/NTM assay to date. A total of 687 consecutive sputum specimens were cultured and analyzed with the GENEDIA MTB/NTM and GENEDIA MTB assays. Nineteen specimens (2.8%) were MTBC-positive, and 69 (10.0%) were NTM-positive based on mycobacterial culture. All specimens showed concordant results for MTBC using both assays, with a kappa value of 1.00, overall sensitivity of 63.2% (12/19), and specificity of 100% (668/668). The overall NTM sensitivity and specificity were 23.2% (16/69) and 99.7% (616/618) for GENEDIA MTB/NTM. The association between NTM-positivity using GENEDIA MTB/NTM and the diagnosis of NTM pulmonary disease was not statistically significant. In conclusion, the two real-time PCR assays showed similar diagnostic performance for MTBC detection. However, the sensitivity for NTM detection was lower than that for MTBC detection.

Treatment of Mycobacterium avium Complex Pulmonary Disease / 결핵및호흡기질환

The pathogen Mycobacterium avium complex (MAC) is the most common cause of nontuberculous mycobacterial pulmonary disease worldwide. The decision to initiate long-term antibiotic treatment is difficult for the physician due to inconsistent disease progression and adverse effects associated with the antibiotic treatment. The prognostic factors for the progression of MAC pulmonary disease are low body mass index, poor nutritional status, presence of cavitary lesion(s), extensive disease, and a positive acid-fast bacilli smear. A regimen consisting of macrolides (clarithromycin or azithromycin) with rifampin and ethambutol has been recommended; this regimen significantly improves the treatment of MAC pulmonary disease and should be maintained for at least 12 months after negative sputum culture conversion. However, the rates of default and disease recurrence after treatment completion are still high. Moreover, treatment failure or macrolide resistance can occur, although in some refractory cases, surgical lung resection can improve treatment outcomes. However, surgical resection should be carefully performed in a well-equipped center and be based on a rigorous risk-benefit analysis in a multidisciplinary setting. New therapies, including clofazimine, inhaled amikacin, and bedaquiline, have shown promising results for the treatment of MAC pulmonary disease, especially in patients with treatment failure or macrolide-resistant MAC pulmonary disease. However, further evidence of the efficacy and safety of these new treatment regimens is needed. Also, a new consensus is needed for treatment outcome definitions as widespread use of these definitions could increase the quality of evidence for the treatment of MAC pulmonary disease.

Diagnosis of pulmonary tuberculosis

The incidence and prevalence of pulmonary tuberculosis (TB) in South Korea remain high despite the fact that South Korea is a high-income country, and pulmonary TB is an important public health issue in terms of both morbidity and mortality. Thus, rapid diagnosis and management of active pulmonary TB are crucial for effective TB control, which can help to prevent the transmission of TB and the occurrence of new TB cases. However, because the clinical and radiological presentations of pulmonary TB may occasionally be nonspecific, identification of causative microorganisms using laboratory tests is the most important diagnostic method. Recently-developed microbiological and molecular techniques are commonly employed in current clinical practice. In particular, advances in liquid culture system, line probe assays, and Xpert MTB/RIF assay have reduced the identification time and facilitate the identification of drug-resistance TB. However, as various tests have both advantages and limitations, physicians should be aware of the principles underpinning the tests when interpreting the results. Thus, the clinical and radiological characteristics of pulmonary TB and several diagnostic laboratory tests that we describe below will aid physicians in diagnosing pulmonary TB efficiently.

Mycobacterium shimoidei Pulmonary Disease: The First Case in Korea

Mycobacterium shimoidei is a nontuberculous mycobacterium (NTM), and is rarely reported as a pathogen causing the NTM pulmonary disease. We describe here the case of a 52-year-old male with symptoms such as chronic cough and a history of pulmonary tuberculosis. Radiologic studies revealed a cavitary lesion in the left upper lobe of his lung. Sputum culture was positive for NTM, which was later identified as M. shimoidei using 16S rRNA and hsp65 sequencing. The patient's symptoms, radiologic evidence, and positive culture results together substantiate that this is the first case of M. shimoidei pulmonary disease from Korea.

Treatment of Mycobacterium Abscessus Pulmonary Disease / 대한내과학회지

Mycobacterium abscessus is the second most important pathogen in pulmonary disease caused by nontuberculous mycobacteria (NTM), following Mycobacterium avium. Mycobacterium abscessus is classified into three subspecies: M. abscessus subsp. abscessus, M. abscessus subsp. massiliense, and M. abscessus subsp. bolletii. Mycobacterium abscessus is the most difficult to treat NTM due to its resistance to many antibiotics. Treatment should include an initial regimen of 2–3 injectable and oral antibiotics for several weeks or months, followed by inhaled amikacin and 1–3 oral antibiotics, depending on the subspecies and drug susceptibility patterns, including macrolide susceptibility. The continuation phase should be continued for a minimum of 12 months after culture conversion. Suitable injectable antibiotics include amikacin, imipenem, cefoxitin, and tigecycline, while oral antibiotics include macrolides (azithromycin or clarithromycin), clofazimine, linezolid, and moxifloxacin. Surgery can be a useful adjunctive therapy for some patients with refractory disease. However, the overall treatment prognosis is still unsatisfactory. Therefore, novel and more effective interventions are required for the treatment of M. abscessus pulmonary disease.

Diagnosis of pulmonary tuberculosis

The incidence and prevalence of pulmonary tuberculosis (TB) in South Korea remain high despite the fact that South Korea is a high-income country, and pulmonary TB is an important public health issue in terms of both morbidity and mortality. Thus, rapid diagnosis and management of active pulmonary TB are crucial for effective TB control, which can help to prevent the transmission of TB and the occurrence of new TB cases. However, because the clinical and radiological presentations of pulmonary TB may occasionally be nonspecific, identification of causative microorganisms using laboratory tests is the most important diagnostic method. Recently-developed microbiological and molecular techniques are commonly employed in current clinical practice. In particular, advances in liquid culture system, line probe assays, and Xpert MTB/RIF assay have reduced the identification time and facilitate the identification of drug-resistance TB. However, as various tests have both advantages and limitations, physicians should be aware of the principles underpinning the tests when interpreting the results. Thus, the clinical and radiological characteristics of pulmonary TB and several diagnostic laboratory tests that we describe below will aid physicians in diagnosing pulmonary TB efficiently.

First Isolation of Mycobacterium virginiense From a Human Pulmonary Specimen

No abstract available.

Treatment of Mycobacterium Abscessus Pulmonary Disease / 대한내과학회지

Mycobacterium abscessus is the second most important pathogen in pulmonary disease caused by nontuberculous mycobacteria (NTM), following Mycobacterium avium. Mycobacterium abscessus is classified into three subspecies: M. abscessus subsp. abscessus, M. abscessus subsp. massiliense, and M. abscessus subsp. bolletii. Mycobacterium abscessus is the most difficult to treat NTM due to its resistance to many antibiotics. Treatment should include an initial regimen of 2–3 injectable and oral antibiotics for several weeks or months, followed by inhaled amikacin and 1–3 oral antibiotics, depending on the subspecies and drug susceptibility patterns, including macrolide susceptibility. The continuation phase should be continued for a minimum of 12 months after culture conversion. Suitable injectable antibiotics include amikacin, imipenem, cefoxitin, and tigecycline, while oral antibiotics include macrolides (azithromycin or clarithromycin), clofazimine, linezolid, and moxifloxacin. Surgery can be a useful adjunctive therapy for some patients with refractory disease. However, the overall treatment prognosis is still unsatisfactory. Therefore, novel and more effective interventions are required for the treatment of M. abscessus pulmonary disease.

Bronchiectasis and Recurrent Respiratory Infections with a De Novo STAT1 Gain-of-Function Variant: First Case in Korea

Bronchiectasis is a chronic disease characterized by airway infection and inflammation, leading to permanent dilation of the bronchi. Evaluation of underlying etiology is important in managing young bronchiectasis patients with recurrent infections caused by unusual pathogens. The signal transducer and activator of transcription 1 (STAT1) protein plays a key role in STAT signaling and immune system regulation. Heterozygotes for gain-of-function (GOF) alleles of the STAT1 gene usually display autosomal dominant chronic mucocutaneous candidiasis (CMC) and a wide range of clinical features, such as bronchiectasis. Here, we report on a patient with CMC and bronchiectasis with various types of infections who carried a pathogenic variant of the STAT1 gene. The 24-year-old female presented with recurrent respiratory bacterial and nontuberculous mycobacterial infections complicated by severe bronchiectasis and CMC. Whole-exome sequencing revealed a c.800C>T (p.Ala267Val) heterozygous mutation in the STAT1 gene. Further analysis by Sanger sequencing of STAT1 from the patient and her parents revealed the patient had a de novo occurrence of the variant. This is the first report of a Korean patient with a GOF pathogenic variant in STAT1. Physicians should be aware of the existence of this variant as a genetic factor associated with CMC and bronchiectasis complicated by recurrent infection.

Changing Epidemiology of Nontuberculous Mycobacterial Lung Diseases in a Tertiary Referral Hospital in Korea between 2001 and 2015

This study investigated the changes in the major etiologic organisms and clinical phenotypes of nontuberculous mycobacterial lung disease (NTM-LD) over a recent 15-year period in Korea. The increase of number of patients with NTM-LD was primarily due to an increase of Mycobacterium avium complex (MAC) lung disease (LD). Among MAC cases, the proportion of M. avium increased compared with M. intracellulare, whereas the incidence of M. abscessus complex and M. kansasii LD remained relatively stable. The proportion of cases of the nodular bronchiectatic form increased compared with the fibrocavitary form of NTM-LD.

Recommendations for Optimizing Tuberculosis Treatment: Therapeutic Drug Monitoring, Pharmacogenetics, and Nutritional Status Considerations

Although tuberculosis is largely a curable disease, it remains a major cause of morbidity and mortality worldwide. Although the standard 6-month treatment regimen is highly effective for drug-susceptible tuberculosis, the use of multiple drugs over long periods of time can cause frequent adverse drug reactions. In addition, some patients with drug-susceptible tuberculosis do not respond adequately to treatment and develop treatment failure and drug resistance. Response to tuberculosis treatment could be affected by multiple factors associated with the host-pathogen interaction including genetic factors and the nutritional status of the host. These factors should be considered for effective tuberculosis control. Therefore, therapeutic drug monitoring (TDM), which is individualized drug dosing guided by serum drug concentrations during treatment, and pharmacogenetics-based personalized dosing guidelines of anti-tuberculosis drugs could reduce the incidence of adverse drug reactions and increase the likelihood of successful treatment outcomes. Moreover, assessment and management of comorbid conditions including nutritional status could improve anti-tuberculosis treatment response.

Down-Regulation of Serum High-Mobility Group Box 1 Protein in Patients with Pulmonary Tuberculosis and Nontuberculous Mycobacterial Lung Disease / 결핵및호흡기질환

BACKGROUND: Recently, increased levels of high-mobility group box 1 protein (HMGB1) have been identified in various inflammatory conditions and infections. However, no studies have evaluated the HMGB1 level in nontuberculous mycobacterial (NTM) lung disease, and compared it to mycobacterial lung disease. METHODS: A total of 60 patients newly diagnosed with NTM lung disease, 44 culture-positive pulmonary tuberculosis (TB) patients, and 34 healthy controls, were included in this study. The serum HMGB1 concentrations were quantified using HMGB1 enzyme-linked immunosorbent assay kits. RESULTS: Serum HMGB1 level in patients with pulmonary TB or NTM lung disease, was significantly lower than that of the healthy controls. In addition, the serum HMGB1 level in TB patients was significantly lower than patients with NTM lung disease. However, the levels in NTM patient subgroups did not differ according to the causative species, disease progression, and disease phenotype. CONCLUSION: Although low levels of serum HMGB1 has the potential to be a marker of mycobacterial lung disease, these levels were unable to differentiate disease progression and disease phenotype in NTM lung diseases.

Progression of Tuberculous Pleurisy: From a Lymphocyte-Predominant Free-Flowing Effusion to a Neutrophil-Predominant Loculated Effusion / 결핵및호흡기질환

No abstract available.

Multidrug-Resistant Tuberculous Mediastinal Lymphadenitis, with an Esophagomediastinal Fistula, Mimicking an Esophageal Submucosal Tumor

Mediastinal tuberculous lymphadenitis rarely mimics esophageal submucosal tumor, particularly in the case of multidrug-resistant tuberculosis (MDR-TB). Herein, we report the case of a 61-year-old woman who visited a local hospital complaining of odynophagia. An initial esophagogastroduodenoscopy revealed an esophageal submucosal tumor, and subsequent chest computed tomography showed subcarinal lymphadenopathy with an esophagomediastinal fistula. The patient was then referred to Samsung Medical Center, and a second esophagogastroduodenoscopy showed deep central ulceration, as well as a suspicious fistula in the esophageal submucosal tumor-like lesion. A biopsy examination of the ulcerative lesion confirmed focal inflammation only. Next, an endobronchial, ultrasound-guided lymph node biopsy was performed, and TB was confirmed. The patient initially began a course of isoniazid, rifampicin, ethambutol, and pyrazinamide. However, after a drug sensitivity test, she was diagnosed with MDR-TB, and second-line anti-TB medications were prescribed. She recovered well subsequently.

Broncho-Pleural Fistula with Hydropneumothorax at CT: Diagnostic Implications in Mycobacterium avium Complex Lung Disease with Pleural Involvement

OBJECTIVE: To determine the patho-mechanism of pleural effusion or hydropneumothorax in Mycobacterium avium complex (MAC) lung disease through the computed tomographic (CT) findings. MATERIALS AND METHODS: We retrospectively collected data from 5 patients who had pleural fluid samples that were culture-positive for MAC between January 2001 and December 2013. The clinical findings were investigated and the radiological findings on chest CT were reviewed by 2 radiologists. RESULTS: The 5 patients were all male with a median age of 77 and all had underlying comorbid conditions. Pleural fluid analysis revealed a wide range of white blood cell counts (410-100690/microL). The causative microorganisms were determined as Mycobacterium avium and Mycobacterium intracellulare in 1 and 4 patients, respectively. Radiologically, the peripheral portion of the involved lung demonstrated fibro-bullous changes or cavitary lesions causing lung destruction, reflecting the chronic, insidious nature of MAC lung disease. All patients had broncho-pleural fistulas (BPFs) and pneumothorax was accompanied with pleural effusion. CONCLUSION: In patients with underlying MAC lung disease who present with pleural effusion, the presence of BPFs and pleural air on CT imaging are indicative that spread of MAC infection is the cause of the effusion.