Serum Cell-Free DNA-based Detection of Mycobacterium avium Complex Infection.

Rationale: Mycobacterium avium complex (MAC) is the most common cause of nontuberculous mycobacterial (NTM) pulmonary disease (PD), which exhibits increasing global incidence. Current microbiologic methods routinely used in clinical practice lack sensitivity and have long latencies, leading to delays in diagnosis and treatment initiation and evaluation. A clustered regularly interspaced short palindromic repeats (CRISPR)-based assay that measures MAC cell-free DNA (cfDNA) concentrations in serum could provide a rapid means to detect MAC infection and monitor response to antimicrobial treatment. Objectives: To develop and optimize a CRISPR MAC assay for MAC infection detection and to evaluate its diagnostic and prognostic performance in two MAC disease cohorts. Methods: MAC cfDNA serum concentrations were measured in individuals with diagnoses of MAC disease or who had bronchiectasis or chronic obstructive pulmonary disease diagnoses without histories of NTM PD or NTM-positive sputum cultures. Diagnostic performance was analyzed using pretreatment serum from two cohorts. Serum MAC cfDNA changes during MAC PD treatment were evaluated in a subset of patients with MAC PD who received macrolide-based multidrug regimens. Measurements and Main Results: The CRISPR MAC assay detected MAC cfDNA in MAC PD with 97.6% (91.6-99.7%) sensitivity and 97.6% (91.5-99.7%) specificity overall. Serum MAC cfDNA concentrations markedly decreased after MAC-directed treatment initiation in patients with MAC PD who demonstrated MAC culture conversion. Conclusions: This study provides preliminary evidence for the utility of a serum-based CRISPR MAC assay to rapidly detect MAC infection and monitor the response to treatment.

Improvement in Health-Related Quality of Life Following Antibiotic Treatment in Nontuberculous Mycobacterial Pulmonary Disease: Initial Analysis of the NTM-KOREA Cohort.

BACKGROUND: Improving health-related quality of life (HRQOL) has emerged as a priority in the management of nontuberculous mycobacterial pulmonary disease (NTM-PD). We aimed to evaluate HRQOL and its changes after 6 months' treatment in patients with NTM-PD. METHODS: The NTM-KOREA is a nationwide prospective cohort enrolling patients initiating treatment for NTM-PD in 8 institutions across South Korea. We conducted the Quality of Life-Bronchiectasis (QOL-B) at 6-month intervals and evaluated baseline scores (higher scores indicate better quality of life) and changes after 6 months' treatment. Multivariate logistic regression was performed to identify factors associated with improvement in the QOL-B physical functioning and respiratory symptoms domains. RESULTS: Between February 2022 and August 2023, 411 patients were included in the analysis. Baseline scores (95% confidence interval [CI]) for physical functioning and respiratory symptoms were 66.7 (46.7-86.7) and 81.5 (70.4-92.6), respectively. Among 228 patients who completed the QOL-B after 6 months' treatment, improvements in physical functioning and respiratory symptoms were observed in 61 (26.8%) and 71 (31.1%) patients, respectively. A lower score (adjusted odds ratio; 95% CI) for physical functioning (0.93; 0.91-0.96) and respiratory symptoms (0.92; 0.89-0.95) at treatment initiation was associated with a greater likelihood of physical functioning and respiratory symptom improvement, respectively; achieving culture conversion was not associated with improvement in physical functioning (0.62; 0.28-1.39) or respiratory symptoms (1.30; 0.62-2.74). CONCLUSIONS: After 6 months of antibiotic treatment for NTM-PD, HRQOL improved in almost one-third, especially in patients with severe initial symptoms, regardless of culture conversion. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov identifier: NCT03934034.

Treatment of Nontuberculous Mycobacterial (NTM) Pulmonary Infection in the US Bronchiectasis and NTM Registry: Treatment Patterns, Adverse Events, and Adherence to American Thoracic Society/Infectious Disease Society of America Treatment Guidelines.

Among 1038 participants with pulmonary Mycobacterium avium complex and 120 with Mycobacterium abscessus enrolled in the US Bronchiectasis and NTM Research Registry, less than half received antibiotic therapy in the 24 months before registry enrollment, of which less than half were guideline based. Adverse effects occurred in 21% of therapy recipients, of whom 33% discontinued therapy.

Evaluation of Mycobacterium Avium Complex Pulmonary Disease Treatment Completion and Adherence to ATS/IDSA Guidelines.

BACKGROUND: Nontuberculous mycobacteria are environmental organisms that cause infections leading to chronic, debilitating pulmonary disease, among which Mycobacterium avium complex (MAC) is the most common species. METHODS: We described patterns of macrolide-based multidrug antibiotic therapies for MAC pulmonary disease (MAC-PD) in US Medicare beneficiaries with bronchiectasis between January 2006 and December 2014. MAC therapy was defined as a multidrug regimen containing a macrolide plus ≥1 other drug targeting MAC-PD (rifamycin, ethambutol, fluoroquinolone, or amikacin) prescribed concomitantly for >28 days. RESULTS: We identified 9189 new MAC therapy users, with a mean age (standard deviation) of 74 (6 years) at the start of therapy; 75% female and 87% non-Hispanic white. A guideline-based regimen (a macrolide, ethambutol, and rifamycin, with or without amikacin) was prescribed for 51% of new MAC therapy users at treatment start, of whom 41% were continuing guideline-based therapy at 6 months, and only 18% at 12 months. Of all new MAC therapy users, by 18 months only 11% were still receiving MAC treatment, 55% had discontinued therapy, and 34% were censored owing to death or the end of the study period. CONCLUSIONS: Overall, nearly half of new MAC therapy users were prescribed a non-guideline-recommended macrolide-based therapy, including regimens commonly associated with promoting macrolide resistance. Treatment discontinuation was common, and once discontinued, only a few beneficiaries resumed therapy at a later time. Our study adds important data to the current literature on treatment patterns for MAC-PD among older US populations. Future research should examine treatment patterns using more contemporary data sources.

Epidemiology of Pulmonary and Extrapulmonary Nontuberculous Mycobacteria Infections at 4 US Emerging Infections Program Sites: A 6-Month Pilot.

BACKGROUND: Nontuberculous mycobacteria (NTM) cause pulmonary (PNTM) and extrapulmonary (ENTM) disease. Infections are difficult to diagnose and treat, and exposures occur in healthcare and community settings. In the United States, NTM epidemiology has been described largely through analyses of microbiology data from health departments, electronic health records, and administrative data. We describe findings from a multisite pilot of active, laboratory- and population-based NTM surveillance. METHODS: The Centers for Disease Control and Prevention's Emerging Infections Program conducted NTM surveillance at 4 sites (Colorado, 5 counties; Minnesota, 2 counties; New York, 2 counties; and Oregon, 3 counties [PNTM] and statewide [ENTM]) from 1 October 2019 through 31 March 2020. PNTM cases were defined using published microbiologic criteria. ENTM cases required NTM isolation from a nonpulmonary specimen, excluding stool and rectal swabs. Patient data were collected via medical record review. RESULTS: Overall, 299 NTM cases were reported (PNTM: 231, 77%); Mycobacterium avium complex was the most common species group. Annualized prevalence was 7.5/100 000 population (PNTM: 6.1/100 000; ENTM: 1.4/100 000). Most patients had signs or symptoms in the 14 days before positive specimen collection (ENTM: 62, 91.2%; PNTM: 201, 87.0%). Of PNTM cases, 145 (62.8%) were female and 168 (72.7%) had underlying chronic lung disease. Among ENTM cases, 29 (42.6%) were female, 21 (30.9%) did not have documented underlying conditions, and 26 (38.2%) had infection at the site of a medical device or procedure. CONCLUSIONS: Active, population-based NTM surveillance will provide data for monitoring the burden of disease and characterize affected populations to inform interventions.

Validity of Diagnosis Code-Based Claims to Identify Pulmonary NTM Disease in Bronchiectasis Patients.

Nontuberculous mycobacteria infection is increasing in incidence and can lead to chronic, debilitating pulmonary disease. We investigated the accuracy of diagnosis code-based nontuberculous mycobacteria lung disease claims among Medicare beneficiaries in the United States. We observed that these claims have moderate validity, but given their low sensitivity, incidence might be underestimated.

Preliminary validation of the NTM Module: a patient-reported outcome measure for patients with pulmonary nontuberculous mycobacterial disease.

INTRODUCTION: Nontuberculous mycobacteria (NTM) cause chronic, debilitating pulmonary disease. Patient-reported outcomes provide measures of symptoms, functioning and treatment response. Here we describe the preliminary validation of the recently developed NTM Module. METHODS: The study population included Northwest NTM Biobank patients in whom Mycobacterium avium complex (MAC) was isolated and who had ever met the 2007 American Thoracic Society/Infectious Diseases Society of America pulmonary disease criteria. The NTM Module was administered at enrolment and 12 months; a subset also completed the Quality of Life Questionnaire-Bronchiectasis (QOL-B). The NTM Module generates four domain scores (0-100; higher scores indicate better functioning) reflecting NTM-specific symptoms (NTM Symptoms, Body Image, Digestive Symptoms and Eating Problems). We described patient characteristics and mean scores, and evaluated psychometric properties, including response to treatment at 12 months, for each domain. RESULTS: Overall, 203 patients with pulmonary MAC disease were included. Average enrolment scores ranged from 76 (NTM Symptoms) to 84 (Eating Problems). Ceiling effects were observed for Body Image (26% of participants) and Eating Problems (52%). Internal consistency (Cronbach's alpha) ranged from 0.67 (Digestive Symptoms) to 0.89 (Eating Problems). The intraclass correlation for test-retest reproducibility (n=27) ranged from 0.72 (Body Image) to 0.94 (Eating Problems). Patients starting treatment (n=35) had statistically significant increases in scores for NTM Symptoms (+5, p=0.04), Digestive Symptoms (+7, p=0.002), Body Image (+7, p=0.03) and QOL-B Respiratory Symptoms (n=25, +10, p=0.006). NTM Symptoms scores increased by 15 points (p=0.002) in the 16 patients with scores ≤80 at enrolment. CONCLUSION: The NTM Module generally performs well as a valid patient-reported outcome for pulmonary MAC disease and was responsive to MAC treatment.

Comparative risks of chronic inhaled corticosteroids and macrolides for bronchiectasis.

INTRODUCTION: Non-cystic fibrosis (CF) bronchiectasis ("bronchiectasis") is a chronic airway disease for which little data exist to inform treatment decisions. We sought to compare the risks of respiratory infections in chronic users of inhaled corticosteroids (ICSs) versus macrolide monotherapy. METHODS: We identified a cohort of US Medicare enrollees with a bronchiectasis diagnosis (International Classification of Diseases, Ninth Revision, Clinical Modification code 494.0 or 494.1) between 2006 and 2014, excluding CF. We defined chronic new use as the first ≥28-day prescription of ICS therapy or macrolide monotherapy. We compared the characteristics of the exposure cohorts using standardised mean differences (SMDs) and computed a propensity score (PS) to account for treatment differences. The risks of acute exacerbation, hospitalised respiratory infection, all-cause hospitalisation and mortality were compared using PS decile-adjusted Cox regression models. RESULTS: We identified 83 589 new users of ICSs and 6500 new users of macrolides from 285 043 included Medicare enrollees with bronchiectasis. The crude incidence of hospitalised respiratory infection was 12.6 (ICS therapy) and 10.3 (macrolide monotherapy) per 100 patient-years. The PS-adjusted HRs comparing ICS with macrolide new users were 1.39 (95% CI 1.23-1.57) for hospitalised respiratory infection, 1.56 (95% 1.49-1.64) for acute exacerbation and 1.09 (95% 0.95-1.25) for mortality. INTERPRETATION: Among patients with bronchiectasis, the use of ICSs was associated with an increased risk of hospitalised respiratory infections compared with macrolide monotherapy.

Surveillance of Extrapulmonary Nontuberculous Mycobacteria Infections, Oregon, USA, 2007-2012.

Limited data are available describing extrapulmonary nontuberculous mycobacteria (NTM) infections in the general population. We describe results from statewide population-based laboratory surveillance in Oregon, USA, during 2007-2012. We defined a case of extrapulmonary NTM infection as >1 isolate from skin/soft tissue, disseminated sites, lymph node, joint, or other sites. The annual incidence of extrapulmonary NTM infection (other than Mycobacterium gordonae) was stable, averaging 1.5 cases/100,000 population. Median age of the 334 patients was 51 years, and 53% of patients were female. Half of cases were caused by M. avium complex, but rapid-growing NTM species accounted for one third of cases. Most extrapulmonary NTM infections are skin/soft tissue. Compared with pulmonary NTM infection, more extrapulmonary infections are caused by rapid-growing NTM species. the designation of NTM as a reportable disease in Oregon in 2014 will result in better detection of changes in the incidence and patterns of disease in the future.

Disseminated Nontuberculous Mycobacteria in HIV-Infected Patients, Oregon, USA, 2007-2012.

We determined disseminated nontuberculous mycobacteria incidence in the HIV-infected population of Oregon, USA, during 2007-2012 by using statewide laboratory surveillance. We identified 37 disseminated nontuberculous mycobacteria cases among 7,349 patients with median annual incidence of 110/100,000 HIV person-years and the highest incidence in those with CD4 counts <50 cells/mm3 (5,300/100,000 person-years).

Hepatitis A and B immunity and vaccination in chronic hepatitis B and C patients in a large United States cohort.

BACKGROUND: Hepatitis A and B vaccines are effective in preventing superinfection and sequelae in patients with chronic hepatitis B or C. We describe immunity and vaccination against hepatitis A and B in chronic hepatitis patients from the US Chronic Hepatitis Cohort Study. METHODS: We identified chronic hepatitis B and C patients with healthcare utilization during 2006-2008 and 12 months of enrollment. We used electronic laboratory records to determine immunity and medical and billing records for vaccination history. Immunity against hepatitis A was defined by positive hepatitis A antibody or documented vaccination. Immunity against hepatitis B was defined as hepatitis B surface antibody level ≥10 mIU/mL or core antibody positive, or by documented vaccination. RESULTS: Among 1635 chronic hepatitis B patients, 978 (59.8%) were immune or vaccinated against hepatitis A, 122 (7.5%) had negative hepatitis A antibody tests, and 535 (32.7%) had no testing or vaccination record. Among 5328 chronic hepatitis C patients, 2998 (56.3%) were immune or vaccinated against hepatitis A, 659 (12.4%) had negative hepatitis A antibody tests, and 1671 (31.4%) had no testing or vaccination record. Additionally, 3150 (59.1%) chronic hepatitis C patients were immune or vaccinated against hepatitis B, 1003 (18.8%) had a negative test result, and 1175 (22.1%) were neither tested for nor vaccinated against hepatitis B. CONCLUSIONS: Approximately 40% of chronic hepatitis B and C patients are susceptible to or have no documented immunity or vaccination against hepatitis A or hepatitis B. Clinicians should consider antibody testing and vaccination for this vulnerable population.

Antibody response to influenza A(H1N1)pdm09 among healthcare personnel receiving trivalent inactivated vaccine: effect of prior monovalent inactivated vaccine.

BACKGROUND: Few data are available on the immunogenicity of repeated annual doses of influenza A(H1N1)pdm09-containing vaccines. METHODS: We enrolled healthcare personnel (HCP) in direct patient care during the autumn of 2010 at 2 centers with voluntary immunization. We verified the receipt of A(H1N1)pdm09-containing monovalent inactivated influenza vaccine (MIIV) and 2010-2011 trivalent inactivated vaccine (TIV). We performed hemagglutination inhibition antibody (HI) assays on preseason, post-TIV, and end-of-season serum samples. We compared the proportion of HCPs with HI titer ≥ 40 against A(H1N1)pdm09 per receipt of prior-season MIIV, current-season TIV, both, or neither. RESULTS: At preseason (n = 1417), HI ≥ 40 was significantly higher among those who received MIIV (34%) vs those who did not (14%) (adjusted relative risk [ARR], 3.26; 95% confidence interval [CI], 2.72-3.81). At post-TIV (n = 865), HI ≥ 40 was lower among HCP who received MIIV and TIV (66%) than among those receiving only TIV (85%) (ARR, 0.93 [95% CI, .84-.997]). At end-of-season (n = 1254), HI ≥ 40 was 40% among those who received both MIIV and TIV and 67% among those receiving only TIV (ARR, 0.76 [95% CI, .65-.88]), 52% among those who received MIIV only, and 12% among those receiving neither. CONCLUSIONS: HCP immunization programs should consider effects of host immune response and vaccine antigenic distance on immunogenicity of repeated annual doses of influenza vaccines.

Antiviral therapy for chronic hepatitis B virus infection and development of hepatocellular carcinoma in a US population.

BACKGROUND & AIMS: Antiviral therapy could reduce the risk of hepatocellular carcinoma (HCC) among persons with chronic hepatitis B virus (HBV) infection. We evaluated the relationship between therapy for chronic HBV infection and HCC incidence using data from a longitudinal study of patients at 4 US healthcare centers. METHODS: We analyzed electronic health records of 2671 adult participants in the Chronic Hepatitis Cohort Study who were diagnosed with chronic HBV infection from 1992 through 2011 (49% Asian). Data analyzed were collected for a median of 5.2 years. Propensity-score adjustment was used to reduce bias, and Cox regression was used to estimate the relationship between antiviral treatment and HCC. The primary outcome was time to event of HCC incidence. RESULTS: Of study subjects, 3% developed HCC during follow-up period: 20 cases among the 820 patients with a history of antiviral HBV therapy and 47 cases among the 1851 untreated patients. In propensity-adjusted Cox regression, patients who received antiviral therapy had a lower risk of HCC than those who did not receive antiviral therapy (adjusted hazard ratio, 0.39; 95% confidence interval, 0.27-0.56; P < .001), after adjusting for abnormal level of alanine aminotransferase. In a subgroup analysis, antiviral treatment was associated with a lower risk of HCC after adjusting for serum markers of cirrhosis (adjusted hazard ratio, 0.24; 95% confidence interval, 0.15-0.39; P < .001). In a separate subgroup analysis of patients with available data on HBV DNA viral load, treated patients with viral loads >20,000 IU/mL had a significantly lower risk of HCC than untreated patients with viral loads >20,000 IU/mL. CONCLUSIONS: In a large geographically, clinically, and racially diverse US cohort, antiviral therapy for chronic HBV infection was associated with a reduced risk for HCC.

Risk factors for hepatitis C infection among Vietnam era veterans versus nonveterans: results from the Chronic Hepatitis Cohort Study (CHeCS).

Research suggests that Vietnam era veterans have a higher prevalence of hepatitis C virus (HCV) than other veterans and nonveterans. However, the reasons for this are unclear, since this research has been conducted among Department of Veterans Affairs (VA) patients and most veterans do not use the VA. The current study compares HCV risk factors between the Vietnam era veterans and nonveterans seen in 4 large non-VA systems to explain this disparity. A total of 4,636 HCV patients completed surveys in 2011-2012. Vietnam era veterans were defined as those who served in the military any time between 1964 and 1975. Bivariate tests followed by logistic regressions, and multivariable modeling were conducted to study risk factors among Vietnam era veterans and nonveterans. Since few veterans were female (~2 %), they were excluded. Among male respondents (N = 2,638), 22.5 % were classified as Vietnam era veterans. Compared to nonveterans, these patients were older (p < 0.001), more educated (p < 0.001), less often foreign born (p = 0.009), more often married (p < 0.001), less often employed, and less likely to have a history of drug abuse treatment (p < 0.001). Comparison of specific risk factor differences for HCV infection by veteran status suggested that while injection drug use approached statistical significance (nonveterans = 46.1 % vs. Vietnam era veterans = 41.4 %, p = 0.06), only reported sex with men was significant (nonveterans = 2.4 % vs. Vietnam era veterans = 0.6 %, p = 0.013). In multivariate logistic regression controlling for age, education, country of birth, marital status and study site, no HCV risk factor was associated with Vietnam era veteran status. However, veterans were more likely to report "other" exposures were the source of infection than nonveterans (p < 0.001). While Vietnam era veterans seen in non-VA facilities do not report a higher prevalence of common HCV risk factors, such as injection drug use, they are more likely to report "other" exposures, typically associated with military service, as the source of HCV infection.

Noninvasive serum fibrosis markers for screening and staging chronic hepatitis C virus patients in a large US cohort.

BACKGROUND: Liver biopsy remains critical for staging liver disease in hepatitis C virus (HCV)-infected persons, but is a bottleneck to evaluation, follow-up, and treatment of HCV. Our analysis sought to validate APRI (aspartate aminotransferase [AST]-to-platelet ratio index) and FIB-4, an index from serum fibrosis markers (alanine aminotransferase [ALT], AST, and platelets plus patient age) to stage liver disease. METHODS: Biopsy results from HCV patients in the Chronic Hepatitis Cohort Study were mapped to an F0-F4 equivalent scale; APRI and FIB-4 scores at the time of biopsy were then mapped to the same scale. RESULTS: We identified 2372 liver biopsies from HCV-infected patients with contemporaneous laboratory values for imputing APRI and FIB-4. Fibrosis stage distributions by the equivalent biopsy scale were 267 (11%) F0; 555 (23%) F1; 648 (27%) F2; 394 (17%) F3; and 508 (21%) F4. Mean APRI and FIB-4 values significantly increased with successive fibrosis levels (P < .05). The areas under the receiver operating characteristic curve (AUROC) analysis distinguishing severe (F3-F4) from mild-to-moderate fibrosis (F0-F2) were 0.80 (95% confidence interval [CI], .78-.82) for APRI and 0.83 (95% CI, .81-.85) for FIB-4. There was a significant difference between the AUROCs of FIB-4 and APRI (P < .001); 88% of persons who had a FIB-4 score ≥2.0 were at stage F2 or higher. CONCLUSIONS: In a large observational cohort, FIB-4 was good at differentiating 5 stages of chronic HCV infection. It can be useful in screening patients who need biopsy and therapy, for monitoring patients with less advanced disease, and for longitudinal studies.

Baseline characteristics and mortality among people in care for chronic viral hepatitis: the chronic hepatitis cohort study.

BACKGROUND: The Chronic Hepatitis Cohort Study (CHeCS), a dynamic prospective, longitudinal, observational cohort study, was created to assess the clinical impact of chronic viral hepatitis in the United States. This report describes the cohort selection process, baseline demographics, and insurance, biopsy, hospitalization, and mortality rates. METHODS: Electronic health records of >1.6 million adult patients seen from January 2006 through December 2010 at 4 integrated healthcare systems in Detroit, Michigan; Danville, Pennsylvania; Portland, Oregon; and Honolulu, Hawaii were collected and analyzed. RESULTS: Of 2202 patients with chronic hepatitis B virus (HBV) infection, 50% were aged 44-63 years, 57% male, 58% Asian/Pacific Islander, and 13% black; and 5.1% had Medicaid, 16.5% Medicare, and 76.3% private insurance. During 2001-2010, 22.3% had a liver biopsy and 37.9% were hospitalized. For the 8810 patients with chronic hepatitis C virus (HCV) infection, 75% were aged 44-63 years, 60% male, 23% black; and 12% had Medicaid, 23% Medicare, and 62% private insurance. During 2001-2010, 38.4% had a liver biopsy and 44.3% were hospitalized. Among persons in care, 9% of persons with HBV and 14% of persons with HCV infection, mainly those born during 1945-1964, died during the 2006-2010 five-year period. CONCLUSIONS: Baseline demographic, hospitalization, and mortality data from CHeCS highlight the substantial US health burden from chronic viral hepatitis, particularly among persons born during 1945-1964.

Consistency of influenza A virus detection test results across respiratory specimen collection methods using real-time reverse transcription-PCR.

In our prospective cohort study, we compared the performance of nasopharyngeal, oropharyngeal, and nasal swabs for the detection of influenza virus using real-time reverse transcription-PCR assay. Joint consideration of results from oropharyngeal and nasal swabs was as effective as consideration of results from nasopharyngeal swabs alone, as measured by sensitivity and noninferiority analysis.