Urine phospholipid profiling in patients with rheumatoid arthritis and nontuberculous mycobacterial pulmonary disease

ObjectiveTo investigate the early detection of pulmonary non-tuberculous mycobacterial (PNTM) disease by CT before the initiation of molecular-targeted therapeutic drugs in patients with rheumatoid arthritis (RA) and the efficacy and...

Purpose: CA 19-9 is a useful marker for the diagnosis of gastrointestinal cancer including pancreatic cancer. However, there are several previous studies about CA 19-9 elevation in benign lung diseases like emphysema, fibrosis and bronchiectasis. This study evaluates the clinical significance of serum CA 19-9 elevation in cases of pulmonary nontuberculous mycobacterial (PNTM) disease and cases of pulmonary tuberculosis (TB). Methods: Serum CA 19-9 levels in patients with PNTM (n=59) and pulmonary TB (n=36) were measured. Multivariate logistic regression analysis was performed to evaluate the factors related to CA 19-9 elevation in PNTM disease. The sequential changes in serum CA 19-9 before and after treatment were compared between pulmonary TB and PNTM disease. Results: The median CA 19-9 level was higher in patients with PNTM disease than in patients with pulmonary TB (PNTM: 13.80, TB: 5.85, P <0.001). Mycobacterium abscessus (OR 21.78, 95% CI: 1.68, 282.38; P =0.018) and extensive pulmonary lesions in more than three lobes (OR 11.03, 95% CI: 1.03, 117.89, P =0.047) were associated with elevated CA 19-9 levels in PNTM disease. CA 19-9 levels showed a tendency to decrease during successful treatment of PNTM disease but not in pulmonary TB. Conclusion: S erum CA 19-9 level was increased in substantial proportions of the patients with PNTM disease; in this setting, CA 19-9 may be a useful marker for monitoring therapeutic responses. Key words: Carbohydrate antigen 19-9; Nontuberculous mycobacteria; Tuberculosis; Biological marker Abbreviations : PNTM : Pulmonary nontuberculous mycobacterium TB : Tuberculosis CA 19-9 : Carbohydrate antigen 19-9.

Background Because of the low sensitivity of sputum smear and culture, diagnosis of nontuberculous mycobacterium (NTM) pulmonary disease, especially in patients with bronchiectasis, is often difficult. We investigated the usefulness of bronchoscopy for the diagnosis of NTM pulmonary disease including M. avium complex (MAC) and M. abscessus in patients with bronchiectasis and multiple pulmonary nodules on chest computed tomography (CT). Methods We reviewed 48 cases of patients who were performed bronchoscopic bronchoalveolar lavage (BAL) and transbronchial lung biopsy (TBLB) under suspect of NTM pulmonary disease based on CT findings of bronchiectasis and multiple nodules from April 2002 to June 2003. Results Twenty five of the 48 patients (54%; 12 MAC, 14 M. abscessus) were diagnosed as NTM pulmonary disease on the basis of the American Thoracic Society diagnostic criteria for NTM pulmonary disease. Sixteen of the 21 patients (76%; 5 MAC, 11 M. abscessus) with 3 or more positive sputum cultures of NTM were confirmed tissue invasion by TBLB. Five of the 24 patients (21%; 4 MAC, 1 M. abscessus) who could not be diagnosed with sputum cultures were diagnosed by bronchoscopic BAL and TBLB. Conclusion Bronchoscopy is helpful for the diagnosis of NTM pulmonary disease and confirmation of tissue invasion by NTM, not only MAC but also M. abscessus, in patients with bronchiectasis and multiple nodules on chest CT scan.

Nontuberculous mycobacterial pulmonary disease (NTM-PD) prevalence in Japan is among the highest worldwide. COPD and bronchiectasis are common comorbidities among patients with NTM-PD, and it is challenging to treat NTM-PD in patients with these conditions. There are limited data on the incremental burden that NTM-PD adds to underlying COPD or bronchiectasis in Japan. Therefore, the objective of this study was to assess the incremental burden associated with NTM-PD in patients with pre-existing COPD and/or bronchiectasis. This nested case-control study was based on JMDC, Inc. claims data (2015-2020). Patients with COPD and/or bronchiectasis with NTM-PD (cases) were age and sex matched 1:3 to patients with COPD and/or bronchiectasis without NTM-PD (controls), resulting in three mutually exclusive patient groups (COPD, bronchiectasis or both; with or without NTM-PD). Incremental burden of NTM-PD was assessed within each group by comparing hospitalisations during the 1-year period after NTM-PD diagnosis (index) between cases and controls with both univariate analysis and multivariate analysis adjusting for pre-index comorbidities. Univariate analyses in the three patient groups consistently demonstrated incremental hospitalisation burden in cases versus controls (e.g. COPD group: 20% of 492 cases versus 13% of 1476 controls had all-cause hospitalisations; 11% versus 5% had respiratory-related hospitalisations; and 6% versus 2% had COPD-related hospitalisations). Subsequent multivariate analysis further confirmed the findings. The substantial incremental burden of hospitalisation associated with NTM-PD in patients with COPD and/or bronchiectasis highlights the urgent need for appropriate management of NTM-PD in Japan.

<b>Objective:</b> To compare the clinical features between elderly amd non-elderly patients with pulmonary nontuberculous mycobacterial (NTM) disease. <b>Patients:</b> The subjects consisted of 114 patients over 75 years (elderly) and 193 patients under 74 years (non-elderly) with pulmonary NTM disease diagnosed with criteria proposed by ATS between 2008 and 2019. <b>Results:</b> The ratio of males/females was higher in elderly than non-elderly patients. The presence of underlying diseases was more frequent in elderly than non-elderly patients. The detection method frequently involved periodical health examinations in non-elderly patients and bronchoscopy was positively performed for a definite diagnosis. Regarding laboratory findings,&nbsp;the positive response rate of MAC antibody was similar in&nbsp;both patient groups. The causative microorganism was frequently M.intracellulare in elderly patients and M.kansasii in non-elderly patients. Although small nodules with bronchiectasis were frewuntly noted in non-elderly patients as radiological findings, there were no significant differences. Combined chemotherapy including CAM was performed for 55% of elderly patients and 73% of non-elderly patients. However, there were no significant differences in clinical efficacy rates or adverse reactions. <b>Conclusions:</b> Combined chemotherapy was performed for elderly patients with a good&nbsp;performance status (PS) and pulmonary NTM disease, achieving a favorable clinical effect equal in that of non-elderly patients. Therefore, it may be appropriate to actively perform diagnosis and treatment for elderly patients with pulmonary NTM disease showing a good PS.

To highlight recent original research and specialty society guidelines regarding the diagnosis and treatment of nontuberculous mycobacterial (NTM) pulmonary disease. The prevalence of NTM pulmonary disease has risen in recent years. The prevalence of individual NTM species varies geographically, although Mycobacterium avium complex (MAC) and Mycobacterium abscessus complex (MABC) remain among the most commonly encountered in many regions. Diagnosis and treatment of NTM pulmonary disease can be complex but guideline-based recommendations have been published. However, adherence to guideline recommendations is poor. Drug susceptibility testing plays a role with important caveats for treatment. Alternative therapies are being explored with older antimycobacterial drugs like clofazimine, which has demonstrated efficacy and tolerability for treatment-refractory NTM infections, and a novel formulation of amikacin for inhalation which may be better tolerated than parenteral administration. Several studies have shown that patients will have recurrences as high as 48%, and that these are not solely relapses but many cases are reinfections with a new organism. United States and European research registries of patients with non-cystic fibrosis bronchiectasis are expected to provide needed data on clinical characteristics of patients at risk for NTM pulmonary disease. The evidence base for optimal management of NTM pulmonary disease is expanding but notable gaps in the literature remain.

RATIONALE. Nontuberculous mycobacterial pulmonary disease (NTM-PD) has a high treatment burden, long treatment duration, and side effects that can impact quality of life (QOL). Anxiety and depression can be seen in NTM-PD patients, with prevalence of depression ranging 26-38% in patients with NTM-PD in Japan (Kakuta et al, 2020). The NTM Research Consortium has placed a priority on management of mental health challenges for patients with NTM-PD (Henkle et al., 2016). We aimed to describe and explore associations between depression, anxiety, QOL and other aspects of mental health for patients with NTM-PD in a multidisciplinary NTM clinical program. METHODS. During NTM clinic visits, patients completed the Patient Health Questionnaire-8 and Generalized Anxiety Questionnaire-7 to assess depression and anxiety, and were asked questions about current mental health treatment. Those with elevated mental health scores were referred for intervention by the team psychologist. Patients also completed the PROMIS single-item general self-rated health question (1 “Poor” to 5 “Excellent”;Hays et al., 2015), and a single-item QOL question, based on the CF-QOL (0 “Worst” to 10 “Best” in the past 2 weeks;Yohannes et al., 2011). Descriptive and correlational statistics were utilized. RESULTS. Patients with NTM-PD who completed screening (N = 50) were 66.6±9.4 years old (Table 1). Fifty-six percent had elevated (≥5) depression symptoms and 32% had elevated anxiety symptoms. Fifty percent (n = 25) of patients were on psychiatric medications at the time of screening, and 32% (n = 16) were taking medication to manage pain;only 6.0% (n = 3) were engaged in counseling/psychotherapy. Higher depression scores were significantly associated with lower perceptions of QOL (r =-.321, p = .025) and worse perceived general health (r =-.565, p < .001). Similarly, higher anxiety scores were significantly associated with lower perceptions of QOL (r =-.301, p = .035) and worse perceived general health (r =-.342, p = .016). CONCLUSIONS. A substantial proportion of patients with NTM-PD in our program experience depression and anxiety symptoms;these symptoms may affect treatment course, and therefore should be an area of focus. Optimization of quality of life and perceptions of health for patients with NTM-PD may benefit from incorporation of treatment of co-occurring mental health symptoms. Limitations of this QI project are our small, albeit growing, group of patients we have been able to screen during COVID-19, and need for tracking of mental health outcomes as they pertain to treatment/health outcomes.

BackgroundThis study aimed (I) to investigate the clinical implication of computed tomography (CT) cavity volume in tuberculosis (TB) and non-tuberculous mycobacterial pulmonary disease (NTM-PD), and (II) to develop a three-dimensional (3D) nnU-Net model to automatically detect and quantify cavity volume on CT images.MethodsWe retrospectively included conveniently sampled 206 TB and 186 NTM-PD patients in a tertiary referral hospital, who underwent thin-section chest CT scans from 2012 through 2019. TB was microbiologically confirmed, and NTM-PD was diagnosed by 2007 Infectious Diseases Society of America/American Thoracic Society guideline. The reference cavities were semi-automatically segmented on CT images and a 3D nnU-Net model was built with 298 cases (240 cases for training, 20 for tuning, and 38 for internal validation). Receiver operating characteristic curves were used to evaluate the accuracy of the CT cavity volume for two clinically relevant parameters: sputum smear positivity in TB and treatment in NTM-PD. The sensitivity and false-positive rate were calculated to assess the cavity detection of nnU-Net using radiologist-detected cavities as references, and the intraclass correlation coefficient (ICC) between the reference and the U-Net-derived cavity volumes was analyzed.ResultsThe mean CT cavity volumes in TB and NTM-PD patients were 11.3 and 16.4 cm3, respectively, and were significantly greater in smear-positive TB (P<0.001) and NTM-PD necessitating treatment (P=0.020). The CT cavity volume provided areas under the curve of 0.701 [95% confidence interval (CI): 0.620–0.782] for TB sputum positivity and 0.834 (95% CI: 0.773–0.894) for necessity of NTM-PD treatment. The nnU-Net provided per-patient sensitivity of 100% (19/19) and per-lesion sensitivity of 83.7% (41/49) in the validation dataset, with an average of 0.47 false-positive small cavities per patient (median volume, 0.26 cm3). The mean Dice similarity coefficient between the manually segmented cavities and the U-Net-derived cavities was 78.9. The ICCs between the reference and U-Net-derived volumes were 0.991 (95% CI: 0.983–0.995) and 0.933 (95% CI: 0.897–0.957) on a per-patient and per-lesion basis, respectively.ConclusionsCT cavity volume was associated with sputum positivity in TB and necessity of treatment in NTM-PD. The 3D nnU-Net model could automatically detect and quantify mycobacterial cavities on chest CT, helping assess TB infectivity and initiate NTM-TB treatment.

BackgroundSince nontuberculous mycobacterial pulmonary disease (NTM-PD) is common in middle-aged/elderly slender women at risk of osteoporosis, we hypothesized that NTM-PD could be associated with osteoporosis. The study aimed to evaluate the prevalence of osteoporosis in patients with NTM-PD compared with that in the general population and determine the factors associated with osteoporosis in the subjects, including the serum estradiol (E2) and 25-hydroxyvitamin D (25OHD) levels.MethodsWe have recruited 228 consecutive adult patients with NTM-PD from a prospective cohort study at the Keio University Hospital, who had no history of osteoporosis or osteoporosis-associated bone fracture but underwent dual-energy X-ray absorptiometry-based bone mineral density (BMD) evaluation from August 2017–September 2019. The E2 and 25OHD levels were measured in 165 patients with available stored serum samples. We performed multivariable logistic regression analyses for osteopenia and osteoporosis.ResultsOsteoporosis (T-score ≤ − 2.5) and osteopenia (T-score − 1 to − 2.5) were diagnosed in 35.1% and 36.8% of patients with NTM-PD, respectively. Compared with the general population, the proportion of osteoporosis was significantly higher in 50–59-, 60–69-, and 70–79-year-old women with NTM-PD. Multivariable analysis revealed that older age (adjusted odds ratio [aOR] for 1-year increase = 1.12; 95% confidence interval [CI] = 1.07–1.18), female sex (aOR = 36.3; 95% CI = 7.57–174), lower BMI (aOR for 1 kg/m2 decrease = 1.37; 95% CI = 1.14–1.65), and chronic Pseudomonas aeruginosa (PA) infection (aOR = 6.70; 95% CI = 1.07–41.8) were independently associated with osteoporosis. Additionally, multivariable analysis in 165 patients whose serum E2 and 25OHD levels were measured showed that both low E2 levels (< 10 pg/mL) and lower 25OHD levels were independently associated with osteoporosis.ConclusionsMiddle-aged/elderly women with NTM-PD have a higher prevalence of osteoporosis than the general population. BMD screening should be considered in NTM-PD, especially in older females with severe diseases such as chronic PA infection and lower BMI, and low serum E2 and 25OHD levels.

Background:Nontuberculous mycobacterial pulmonary disease (NTM-PD) is a chronic lung infection associated with persistent respiratory symptoms and diminished health-related quality of life (HRQoL). As with other chronic conditions, increased levels of anxiety and depression can impact prognosis and HRQoL.Objectives:To describe the prevalence of anxiety and depression and to identify HRQoL domains that are correlated with mental health in patients with NTM-PD.Design:A cross-sectional observational study of adults with self-reported or clinically confirmed NTM-PD.Methods:Participants with NTM-PD enrolled in two studies (n = 40 interview + surveys and n = 230 completing electronic surveys only) at four U.S. sites. Inclusion criteria were age >18 years, English-speaking, and U.S. residence. In-person enrolled participants met ATS/IDSA criteria and had symptom documentation in medical records; remotely enrolled participants self-reported NTM-PD and symptoms. Data collected included demographics, GAD-7 and PHQ-8 (anxiety and depression screening, respectively), QOL-B Respiratory Symptoms Scale (RSS), selected PROMIS short forms (Fatigue 7a, Cognitive Function 6a, Sleep Disturbance 4a), and Patient Global Impression of Severity of NTM-PD symptoms (PGIS). Interview-only participants completed the GAD-7, PHQ-8, QOL-B RSS, and were evaluated for cognitive functioning using the computerized Symbol Digit Modalities Test (oral version).Results:The study population was predominantly female (57%/91% in the interview/survey studies, respectively) and aged >65 years (50%/77.4%). Overall, 18%/14% screened positive for anxiety and 32%/18% for depression. Participants screening positive for anxiety or depression had significantly lower QOL-B RSS, cognitive function, and sleep scores, and higher fatigue. Fatigue showed the strongest correlation with mental health outcomes, particularly with those screening positive for depression (ρ = 0.644, p < 0.05).Conclusion:Mental health symptoms are strongly correlated with worse HRQoL outcomes in NTM-PD. These findings underscore the need for the implementation of routine mental health screening and interventions in NTM-PD care.

A 45-year-old woman with scleroderma for 15 years duration, rheumatoid arthritis in the past five years, and interstitial pneumonia in the past two years had been followed at OPD. Although sputum had appeared and cough had increased since January 2002, there was no obvious abnormal findings on chest X-ray. Later, as a chest X-ray revealed an infiltrative shadow with cavity in the right lower lung field, we suspected pulmonary tuberculosis and performed the direct smear examination of sputum immediately. As acid-fast bacilli were positive (Gaffky 10) and the polymerase chain reaction (PCR) test was positive for only Mycobacterium avium, we diagnosed the case as pulmonary nontuberculous mycobacterial disease. This case was thought to be pulmonary nontuberculous mycobacterial disease complicated with interstitial pneumonia with collagen vascular disease as a secondary infectious type, and as the cause of the disease, the decrease of the local pulmonary defence mechanism due to pre-existing pulmonary lesions was suspected.

Nontuberculous mycobacterial pulmonary disease (NTM-PD) is widely underdiagnosed, and certain patient groups, such as those with underlying respiratory diseases, are at increased risk of developing the disease. Understanding patients at risk is essential to allow for prompt testing and diagnosis and appropriate management to prevent disease progression. What are the risk factors for NTM-PD that should prompt a physician to consider NTM testing and diagnosis? Electronic searches of PubMed and EMBASE were conducted in July 2021 for the period 2011-2021. Inclusion criteria were studies of patients with NTM-PD with associated risk factors. Data were extracted and assessed using the Newcastle-Ottawa Scale. Data analysis was conducted using the R-based "meta" package. Only studies that reported association outcomes for cases with NTM-PD compared with control participants (healthy populations or participants without NTM-PD) were considered for the meta-analysis. Of the 9,530 searched publications, 99 met the criteria for the study. Of these, 24 formally reported an association between possible risk factors and the presence of NTM-PD against a control population and were included in the meta-analysis. Comorbid respiratory disease was associated with a significant increase in the OR for NTM-PD (bronchiectasis [OR, 21.43; 95%CI, 5.90-77.82], history of TB [OR, 12.69; 95%CI, 2.39-67.26], interstitial lung disease [OR, 6.39; 95%CI, 2.65-15.37], COPD [OR, 6.63; 95%CI, 4.57-9.63], and asthma [OR, 4.15; 95%CI, 2.81-6.14]). Other factors noted to be associated with an increased risk of NTM-PD were the use of inhaled corticosteroids (OR 4.46; 95%CI, 2.13-9.35), solid tumors (OR, 4.66; 95%CI, 1.04-20.94) and the presence of pneumonia (OR, 5.54; 95%CI, 2.72-11.26). The greatest risk for NTM-PD is conferred by comorbid respiratory diseases such as bronchiectasis. These findings could help with identification of patient populations at risk for NTM-PD to drive prompt testing and appropriate initiation of therapy.

To explore nutritional heterogeneity among patients with nontuberculous mycobacterial (NTM) pulmonary disease by identifying nutritional phenotypes using K-means clustering, and to compare nutritional and inflammatory markers, Runyon classification, and comorbidities across phenotypes. A retrospective analysis of 457 patients diagnosed with NTM pulmonary disease was conducted. Nine nutritional and inflammatory indicators were collected: body mass index (BMI), hemoglobin (HGB), lymphocyte count (LY), C-reactive protein (CRP), prealbumin (PAB), albumin (ALB), total protein (TP), triglycerides (TG), and total cholesterol (TC). The candidate clusters were initially evaluated using the elbow method and silhouette scores. In the absence of a distinct inflection point in the elbow method, the solution with the highest silhouette coefficient was regarded as the most compact candidate solution. An exploratory final clustering scheme was then determined by further incorporating bootstrap internal stability analysis and clinical interpretability. Subsequently, nutritional and inflammatory profiles, Runyon classification (Groups I and III), and comorbidity distributions were compared among phenotypes. Ordinal logistic regression analysis was employed to identify factors associated with nutritional phenotype grade. Four nutritional phenotypes were identified: Healthy-Low Inflammation (24.5%), Hyperlipidemic-Well-nourished (18.8%), Lean-Moderate Inflammation (42.5%), and Severely Emaciated-High Inflammation (14.2%). Significant differences existed in nutritional and inflammatory markers (all P<0.001). The Severely Emaciated-High Inflammation type exhibited the lowest BMI, HGB, ALB, and TP levels; highest CRP level; highest proportion of Runyon Group III [mainly represented by the Mycobacterium avium complex (MAC)] infections (67.7%, P=0.011); and more severe comorbidities (malignancy, renal insufficiency; P<0.05). The Healthy-Low Inflammation type displayed optimal nutritional profiles, highest proportion of Runyon Group I (predominated by Mycobacterium kansasii and Mycobacterium marinum) infections (44.6%, P=0.003), and few severe comorbidities. Ordinal logistic regression analysis demonstrated that age ≥ 60 years, malignant tumor, respiratory diseases, and renal diseases were significantly associated with an increased cumulative odds of progressing to a poorer nutritional phenotype grade (all P < 0.05). Nutritional status in patients with NTM pulmonary disease shows significant heterogeneity closely associated with inflammation, bacterial strain type, and comorbidities. The Severely Emaciated-High Inflammation type exhibited the most unfavorable nutritional-inflammatory profile, suggesting that early identification, nutritional assessment, and comprehensive intervention should be strengthened clinically for such patients.

The management of patients with nontuberculous mycobacterial (NTM) disease, especially pulmonary disease (PD), is neither intuitive nor simple. As is often lamented, treatment of NTM PD is typically more complicated and difficult than the treatment of tuberculosis (TB). Complexity begins with the requirement to select patients that meet established diagnostic criteria and who would benefit from therapy. Essentially all patients with NTM PD have respiratory comorbidities, typically bronchiectasis and/or chronic obstructive lung disease which also requires evaluation and treatment. Management of these comorbidities in the presence of NTM PD is critical but presents additional challenges such as symptomatic overlap with NTM PD that obfuscates NTM treatment responses. Likewise, the decision to begin a multidrug mycobacterial regimen must always involve careful risk-benefit assessment on an individual patient basis. In those instances that treatment for NTM PD is not started, continued monitoring and follow-up of patients are essential. For successful treatment outcomes, clinicians managing NTM PD patients must be familiar with the characteristics of individual NTM PD pathogens and especially the nuances and peculiarities of drug susceptibility patterns. For selected pathogens and antibiotics, the avoidance of acquired mutational drug resistance is imperative. Management requires close and ongoing patient monitoring to assess treatment response and drug toxicity. There are multiple impediments to successful NTM PD therapy so that even with optimal management strategies, treatment success can be elusive. In that context, however, adherence to basic management principles will maximize the chances for a successful treatment outcome. Specific recommendations for comprehensive NTM disease management are offered in this chapter.

Treatment for patients with pulmonary nontuberculous mycobacterial (NTM) disease includes long, multi-drug, and toxic medication regimens. Surgical resection is an alternative treatment for patients with localized or refractory NTM infection. Robot-assisted operations have not been performed routinely in this population.