Diagnostic Yield of 16S Ribosomal Ribonucleic Acid Gene-Based Targeted Metagenomic Sequencing for Evaluation of Pleural Space Infection: A Prospective Study.

Objective: To better understand the microbial profile of complicated parapneumonic effusions and empyema, and to evaluate whether antimicrobial selection would differ if guided by targeted metagenomic sequencing (tMGS) vs conventional cultures (CCs) alone. Patients and Methods: We analyzed the pleural fluid of a cohort of 47 patients undergoing thoracentesis from January 1, 2017 to August 31, 2019, to characterize their microbial profile. All samples underwent 16S ribosomal ribonucleic acid gene polymerase chain reaction, followed by tMGS. Results: Pleural space infection was deemed clinically present in 20 of the 47 (43%) participants. Of those, n=7 (35%) had positive pleural fluid cultures and n=14 (70%) had positive tMGS results. The organisms identified by tMGS were concordant with CCs; however, tMGS detected additional bacterial species over CCs alone. Streptococcus and Staphylococcus species were the most common organisms identified, with Streptococcus intermedius/constellatus identified in 5 patients. Polymicrobial infections were found in 6 of the 20 patients, with anaerobes being the most common organisms identified in these cases. Conclusion: Streptococci and staphylococci were the most common organisms identified in infected pleural fluid. Anaerobes were common in polymicrobial infections. When compared with CCs, tMGS had higher sensitivity than CCs. Targeted metagenomic sequencing identified additional organisms, not identified by CCs, with associated potential management implications.

DIPNECH: pragmatic approach, uncertainties, notable associations, and a proposal for an improved definition.

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare, but increasingly recognized entity that primarily affects middle-aged and elderly women. It is characterized by abnormal proliferation of pulmonary neuroendocrine cells (PNECs) and is considered a preinvasive lesion for carcinoid tumorlets/tumors. Sometimes, DIPNECH is accompanied by constrictive bronchiolitis which usually manifests as chronic cough and/or dyspnea, along with airflow limitation on spirometry. The telltale imaging sign of DIPNECH is the presence of multiple noncalcified pulmonary nodules and mosaic attenuation on CT. However, these clinico-radiologic features of DIPNECH are characteristic but nonspecific; thus, histopathologic confirmation is usually necessary. DIPNECH has an indolent course and only rarely leads to respiratory failure or death; progression to overt neuroendocrine tumor (carcinoid) of the lung occurs in a minority of patients. Of available therapies, somatostatin analogs and mechanistic target of rapamycin inhibitors are the most promising. In this review, we provide an update regarding the diagnosis and management of DIPNECH and describe critical gaps in our understanding of this entity, including the central terms 'diffuse' and 'idiopathic.' We also summarize the inconsistencies in definitions employed by recent studies and discuss the pitfalls of the DIPNECH definitions proposed by the World Health Organization in 2021. In this context, we propose an objective and reproducible radio-pathologic case definition intended for implementation in the research realm and seeks to enhance homogeneity across cohorts. Furthermore, we discuss aspects of PNECs biology which suggest that PNEC hyperplasia may contribute to the pathogenesis of phenotypes of lung disease aside from constrictive bronchiolitis and carcinoid tumorlets/tumors. Finally, we steer attention to some of the most pressing and impactful research questions awaiting to be unraveled.

Outcomes for Elective Open and Thoracoscopic Surgical Lung Biopsies in the United States and Temporal Trends.

Objective: To elucidate the outcomes of surgical lung biopsies (SLBs) performed for indications other than interstitial lung disease (ILD) and stratify outcomes according to procedural approach (open vs thoracoscopic). Patients and Methods: Using the Nationwide Inpatient Sample database (January 1, 2008, through December 31, 2014), we identified elective hospitalizations with International Classification of Diseases, Ninth Revision, Clinical Modification codes for open (33.28) and thoracoscopic (33.20) SLB. We stratified cases by the presence/absence of ILD. Our primary outcome was in-hospital mortality. Results: There were 47,469 hospitalizations for elective SLB (26,540 [55.9%] thoracoscopic) during the study period; 23,930 patients (50.5%) were women, 17,019 (35.9%) had ILD, and the mean ± SD age was 62.6±13.0 years. Over the study period, thoracoscopic increasingly replaced open SLB, and in-hospital mortality declined (3.5% [308 of 8678] in 2008 vs 2.5% [130 of 5215] in 2014; P<.001). Mortality following thoracoscopic SLB was 2.1% (550 of 26,519; 1.9% [214 of 11,513] in ILD and 2.2% [336 of 15,006] in non-ILD), and mean ± SD length of stay was 5.1±6.9 days. Open SLBs had worse outcomes; mortality was 3.7% (782 of 20,914; 3.9% [214 of 5487] in ILD and 3.7% [568 of 15,427] in non-ILD), and mean ± SD length of stay was 8.2±12 days. On multivariable analysis, male sex, advanced age, ILD, and higher comorbidity index correlated with higher mortality. Conversely, lower mortality was observed among individuals with obesity (odds ratio, 0.73; 95% CI, 0.60-0.88) and those who had their thoracoscopic SLBs performed at high-volume centers (top quartile) (odds ratio, 0.73; 95% CI, 0.57-0.94). Conclusion: Surgical lung biopsy is more often performed for non-ILD indications. Interstitial lung disease was an independent predictor of poor outcomes, but the unadjusted outcomes were worse in the non-ILD cohort due to differences in patient characteristics. Thoracoscopic SLBs performed at high-volume centers had superior outcomes.

Isolated Elevation in Lung Residual Volume Is Associated With Airway Diseases.

BACKGROUND: Residual volume (RV) is a derived lung compartment that correlates with air trapping in the context of air flow obstruction on spirometry. The significance of an isolated elevation in RV in the absence of other pulmonary function test (PFT) abnormalities is not well defined. We sought to assess the clinical and radiologic findings associated with isolated elevation in RV. METHODS: We searched our out-patient PFT database at Mayo Clinic (Rochester, Minnesota) from 2016-2018 for adult patients with isolated elevation in RV. We defined isolated elevation in RV as RV ≥ upper limit of normal or ≥ 130% predicted with normal total lung capacity (TLC), spirometry, and diffusion capacity of the lung for carbon monoxide (DLCO). We then matched this high-RV group by age and sex to an equal number of individuals with normal RV, TLC, spirometry, and DLCO (normal-RV group). RESULTS: We identified 169 subjects with isolated elevation in RV on PFTs, with a median age of 73 y; 55.6% were female, and median body mass index was 26.8 (vs 29.8 in the normal-RV group). The median RV was 3.08 L (134% predicted, interquartile range [IQR] 130-141) in the high-RV group and 2.26 L (99% predicted, IQR 90-109) in the normal-RV group (P < .001). Subjects with high RV were more likely to have smoked (54% vs 40%, P = .01) and almost twice as likely to have a maximum voluntary ventilation < 30 times the FEV1 (21% vs 12%, P = .02). Clinically, asthma (21% vs 11%, P = .01) and non-tuberculous mycobacterial lung infections (12% vs 2%, P = .001) were more prevalent in the high-RV group. On chest computed tomography, bronchiectasis (31% vs 15%, P = .008), bronchial thickening or mucus plugging (46% vs 22%, P < .001), and emphysema (13% vs 5%, P = .046) were more common in the high-RV group. CONCLUSIONS: Isolated elevation in RV on PFTs is a clinically relevant abnormality associated with airway-centered diseases.

Incidence, Risk Factors, and Mortality of Clinical and Subclinical Rheumatoid Arthritis-Associated Interstitial Lung Disease: A Population-Based Cohort.

OBJECTIVE: To identify the incidence, risk factors, and outcomes of rheumatoid arthritis-associated interstitial lung disease (RA-ILD) and to assess time trends in the incidence and mortality in RA-ILD. METHODS: We included adult residents of Olmsted County, Minnesota with incident RA between 1999 and 2014. Subjects were followed until death, emigration, or April 30, 2019. ILD was defined as the presence of a radiologist-defined pattern consistent with ILD on chest computed tomography (CT). When chest CT was absent, the combination of chest radiograph abnormalities compatible with ILD and restrictive pattern on pulmonary function testing was considered consistent with ILD. Potential risk factors included age, sex, smoking, obesity, seropositivity, extraarticular manifestations (EAMs), and medications. For survival analysis, we matched RA-ILD patients to RA-non-ILD comparators. The frequency and mortality from clinician-diagnosed RA-ILD from 1999 to 2014 was compared against a cohort from 1955 to 1994. RESULTS: During the 1999-2014 time period, 645 individuals (70% women) had incident RA, were a median age of 55.3 years, and 53% never smoked. Twenty-two patients had ILD before RA, and 51 (67% women) developed ILD during follow-up. The 20-year cumulative incidence of RA-ILD was 15.3%. Ever-smoking (hazard ratio [HR] 1.92), age at RA onset (HR 1.89 per 10-year increase), and severe EAMs (HR 2.29) were associated with incident RA-ILD. The RA-ILD cases had higher mortality than their matched RA comparators (HR 2.42). Incidence of RA-ILD was non-significantly lower from 1999 to 2014 than from 1955 to1994, but mortality was improved. CONCLUSIONS: RA-ILD occurs in nearly 1 in 6 patients with RA within 20 years and is associated with shorter survival. Lack of significant change in RA-ILD incidence over 6 decades deserves further investigation.

Is the combination of bilateral pulmonary nodules and mosaic attenuation on chest CT specific for DIPNECH?

BACKGROUND: Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is characterized by multifocal proliferation of pulmonary neuroendocrine cells. On chest CT, DIPNECH exhibits bilateral pulmonary nodules and mosaic attenuation in most patients. We sought to: (1) assess the specificity of this pattern (i.e., bilateral pulmonary nodules together with mosaic attenuation) for DIPNECH; (2) describe its differential diagnosis; and (3) identify the clinico-radiologic features that may help prioritize DIPNECH over other diagnostic considerations. METHODS: We searched the Mayo Clinic records from 2015 to 2019 for patients with bilateral pulmonary nodules and mosaic attenuation on CT who had a diagnostic lung biopsy. A thoracic radiologist reviewed all CT scans. Chi-square test was used for categorical variables, and odds ratios were utilized to measure the association between certain variables and DIPNECH. RESULTS: Fifty-one patients met our inclusion criteria; 40 (78%) were females and 34 (67%) were never-smokers. Median age was 65 (interquartile range 55-73) years. Lung biopsy was surgical in 21 patients (41%), transbronchial in 17 (33%), and transthoracic in 12 (24%); explanted lungs were examined in 1 (2%). Metastatic/multifocal cancer was the most common diagnosis, and was found in 17 (33%) cases. Bronchiolitis was diagnosed in 12 patients (24%), interstitial lung disease in 10 (20%), and DIPNECH in 5 (10%). Previous diagnosis of an obstructive lung disease (odds ratio 15.8; P = 0.002), and peribronchial nodular distribution on CT (odds ratio 14.4; P = 0.006) were significantly correlated with DIPNECH. Although statistical significance was not reached, DIPNECH nodules were more likely to display solid attenuations (80% vs. 67%, P = 0.45), and were more numerous; > 10 nodules were seen in 80% of DIPNECH cases vs. 52% in others (P = 0.23). Because DIPNECH primarily affects women, we analyzed the women-only cohort and found similar results. CONCLUSIONS: Various disorders can manifest the CT pattern of bilateral pulmonary nodules together with mosaic attenuation, and this combination is nonspecific for DIPNECH, which was found in only 10% of our cohort. Previous diagnosis of an obstructive lung disease, and peribronchial distribution of the nodules on CT increased the likelihood of DIPNECH vs. other diagnoses.

Presenting Clinicoradiologic Features, Causes, and Clinical Course of Exogenous Lipoid Pneumonia in Adults.

BACKGROUND: Exogenous lipoid pneumonia (ELP) develops when lipid-containing substances enter the airways through aspiration or inhalation and incite an inflammatory response. The diagnosis of ELP often is difficult because findings may be nonspecific. The clinical course of ELP has not been well characterized. RESEARCH QUESTION: What are the presenting clinicoradiologic features of ELP, its causative agents, and clinical course? STUDY DESIGN AND METHODS: We searched the Mayo Clinic electronic medical records for patients diagnosed with ELP between 1998 and 2020. Inclusion diagnostic criteria were: (1) lipoid pneumonia (LP) on histopathologic examination, (2) lipid-laden macrophages in BAL fluid, or (3) fatty attenuation of parenchymal opacities on chest CT imaging. Additionally, all patients were required to have a clinician diagnosis of LP in the absence of conditions known to cause endogenous LP. RESULTS: Thirty-four patients were identified. Mean age was 71 years, with no sex predominance; one-half were asymptomatic. The diagnosis was confirmed by lung biopsy (including three lobectomies for suspected malignancy) in 71% of patients, CT scan in 24% of patients, and BAL in 5% of patients. Most patients manifested bilateral parenchymal opacities that commonly involved the lower lobes; fatty attenuation was identifiable in only 41% of patients. A causative substance was identified in 79% of patients, in most cases after the diagnosis was established. Over a median follow-up of 1.2 years, only 20% of patients with chronic respiratory symptoms improved, whereas 50% worsened. Over a median follow-up interval of 1 year, CT scan abnormalities improved or resolved in 33% of patients and progressed in 39% of patients. Patients who deteriorated were older, with a higher prevalence of GI disorders than those who remained stable or improved. INTERPRETATION: ELP often is asymptomatic and may not manifest fatty attenuation on chest CT imaging. Clinical and radiologic abnormalities persist or worsen in most affected patients, even when the causative agent is discontinued.

Constrictive bronchiolitis in diffuse idiopathic pulmonary neuroendocrine cell hyperplasia.

BACKGROUND: Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is characterised by multifocal proliferation of neuroendocrine cells and belongs in the spectrum of pulmonary neuroendocrine tumours. Some patients with DIPNECH develop airflow obstruction but the relationship between the two entities remains unclear. METHODS: We performed a computer-assisted search of the Mayo Clinic's electronic medical records for biopsy-proven cases of DIPNECH. We extracted clinical, pulmonary function, imaging and histopathological data along with treatments and outcomes. RESULTS: Among 44 patients with DIPNECH 91% were female and the median age was 65 years (interquartile range 56-69 years); 73% were never-smokers. Overall, 38 patients (86%) had respiratory symptoms including cough (68%) and dyspnoea (30%); 45% were previously diagnosed to have asthma or COPD. Pulmonary function testing showed an obstructive pattern in 52%, restrictive pattern in 11%, mixed pattern in 9%, nonspecific pattern in 23%, and was normal in 5%. On chest computed tomography scan, 95% manifested diffuse nodules and 77% manifested mosaic attenuation. For management, 25% of patients were observed without pharmacological therapy, 55% received an inhaled bronchodilator, 41% received an inhaled corticosteroid, 32% received octreotide; systemic steroids, azithromycin, or combination chemotherapy was employed in four patients (9%). Of 24 patients with available follow-up pulmonary function tests, 50% remained stable, 33% worsened and 17% improved over a median interval of 21.3 months (interquartile range 9.7-46.9 months). CONCLUSION: DIPNECH occurs mostly in women and manifests diffuse pulmonary nodules and mosaic attenuation on imaging. It is commonly associated with airflow obstruction due to constrictive bronchiolitis, which manifests limited response to current pharmacological therapy.