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.

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.

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.

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.

Host Factors and Outcomes in Hospitalizations for Pneumocystis Jirovecii Pneumonia in the United States.

OBJECTIVE: To assess host factors in pneumocystis jirovecii pneumonia (PCP)-related hospitalizations and compare outcomes between HIV and non-HIV patients. METHODS: Using the National Inpatient Sample database, we identified 3384 hospitalizations with PCP (International Classification of Diseases, Ninth Revision, Clinical Modification code: 136.3) as the primary discharge diagnosis from 2005 to 2014. We evaluated hospitalizations for the following host factors: HIV, malignancies, organ transplantation, rheumatologic diseases, and vasculitides. We compared the prevalence of individual host factors among PCP hospitalizations over time, and compared intervention rates and outcomes between HIV and non-HIV patients with PCP. RESULTS: Among all hospitalizations for PCP, malignancy was the most prevalent host factor (46.0%, n=1559), followed by HIV (17.8%, n=604); 60.7% (n=946) of malignancies were hematologic. The prevalence of HIV among hospitalizations for PCP decreased from 25.1% in 2005 to 9.2% in 2014 (P<.001), whereas the prevalence of non-HIV immunocompromising conditions increased. Compared with HIV patients, PCP patients without HIV had higher rates of bronchoscopy (52.3% vs 26.7%, P<.001) and endotracheal intubation (17.0% vs 7.9%, P<.001), prolonged hospitalizations (11.5 vs 8.7 days, P<.001), higher hospitalization costs (86.8 vs 48.2×103 USD, P<.001) and increased in-hospital mortality (16.0% vs 5.0%, P<.001). After adjusting for age, sex, and smoking status, there was no difference in mortality between non-HIV and HIV patients with PCP (adjusted odds ratio, 1.4; 95% CI, 0.9 to 2.3). CONCLUSION: The epidemiology of PCP has shifted with an increase in the prevalence of non-HIV patients who have higher intubation rates and prolonged hospitalizations compared with matched HIV patients.

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.

Recent advances in the understanding of bronchiolitis in adults.

Bronchiolitis is injury to the bronchioles (small airways with a diameter of 2 mm or less) resulting in inflammation and/or fibrosis. Bronchioles can be involved in pathologic processes that involve predominantly the lung parenchyma or large airways, but, in some diseases, bronchioles are the main site of injury ("primary bronchiolitis"). Acute bronchiolitis caused by viruses is responsible for most cases of bronchiolitis in infants and children. In adults, however, there is a wide spectrum of bronchiolar disorders and most are chronic. Many forms of bronchiolitis have been described in the literature, and the terminology in this regard remains confusing. In clinical practice, a classification scheme based on the underlying histopathologic pattern (correlates with presenting radiologic abnormalities) facilitates the recognition of bronchiolitis and the search for the inciting cause of the lung injury. Respiratory bronchiolitis is the most common form of bronchiolitis in adults and is usually related to cigarette smoking. Currently, the diagnosis of respiratory bronchiolitis is generally achieved based on the clinical context (smoking history) and chest CT findings. Constrictive (obliterative) bronchiolitis is associated with airflow obstruction and is seen in various clinical contexts including environmental/occupational inhalation exposures, transplant recipients (bronchiolitis obliterans syndrome), and many others. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is increasingly recognized and can be associated with progressive airflow obstruction related to constrictive bronchiolitis ("DIPNECH syndrome"). Diffuse aspiration bronchiolitis is a form of aspiration-related lung disease that is often unsuspected and confused for interstitial lung disease. Novel forms of bronchiolitis have been described, including lymphocytic bronchiolitis and alveolar ductitis with emphysema recently described in employees at a manufacturing facility for industrial machines. Bronchiolitis is also a component of vaping-related lung injury encountered in the recent outbreak.

Pulmonary artery hemodynamics are associated with duration of nocturnal desaturation but not apnea-hypopnea index.

STUDY OBJECTIVES: Sleep-disordered breathing and nocturnal hypoxia are prevalent among patients with precapillary pulmonary hypertension (PAH). The rationale for these associations remains unclear and these relationships have not been well studied in other forms of pulmonary hypertension (PH). We hypothesized that severity of sleep-disordered breathing and nocturnal hypoxia are associated with worsening pulmonary hemodynamics, regardless of hemodynamic profile. METHODS: Four hundred ninety-three patients were divided into 4 groups: 1) no PH, 2) postcapillary pulmonary hypertension, 3) PAH, and 4) mixed PAH/postcapillary pulmonary hypertension. The relationship between right heart catheterization measurements and apnea-hypopnea index or the percentage of sleep time spent with oxygen saturation < 90% (T90) was calculated using multiple linear regression. Analysis of variance was used for between-group comparisons. Statistical models were adjusted for known confounders. RESULTS: Apnea-hypopnea index did not differ between hemodynamic subgroups (P = .27) and was not associated with right atrial pressure (.11 ± .19, P = .55), cardiac index (.25 ± 1.64, P = .88), mean pulmonary artery pressure (-.004 ± .09, P = .97), or pulmonary artery occlusion pressure (.16 ± .14, P = .26). While patients with PH had a higher T90 than those without (mean 24.2% vs 11.7%, P < .001), there was no difference in T90 between individual PH subgroups (P = .70). T90 was associated with mean pulmonary artery pressure (.55 ± .10, P < .0001), PVR (1.61 ± .49, P = .001), and right atrial pressure (.50 ± .20, P = .01), but not cardiac index (-.76 ± 1.73, P = .66), or pulmonary artery occlusion pressure (.23 ± .15, P = .13). CONCLUSIONS: Increased PH severity was associated with longer duration of nocturnal hypoxia regardless of hemodynamic subgroup.

Towards establishing a multiple sclerosis biobank in Jordan.

Genome-wide association studies (GWAS) have been a promising approach in unraveling genetic associations to multiple sclerosis (MS), a complex, multifactorial disease. Biobanks are repositories of patient biospecimens and information that can promote GWAS research. However, the success of GWAS and biobanking is dependent on the level of participation of MS patients in genetic research. In order to initiate MS-based biobanking and GWAS research in Jordan, the willingness of MS patients to participate in long-term, genetic research in Jordan and their preferred type of a consent form were investigated. MS patients (289) were recruited for genetic studies. Personal and clinical information were collected from those who enrolled in the study. Approximately 96% of MS patients agreed to participate in genetic studies. The female:male ratio among patients was 2:1 with most patients being diagnosed with relapsing-remitting MS (88%). The mean age of onset was 28.3 years, the mean duration of illness was 6 years, and the mean Expanded Disability Status Scale was 2.8. Relatedness of parents was significantly associated with having secondary-progressive MS. Approximately 85% of the patients preferred open consent with 37% of them preferring to renew their consent. All the patients approved to be recontacted and update their information via accessing their medical files or physicians. These observations support the establishment of a specialized MS biobank in Jordan and pave the way to participate in international large-scale genetic initiatives.

The promoter SNP, but not the alternative splicing SNP, is linked to multiple sclerosis among Jordanian patients.

Multiple sclerosis is a chronic inflammatory autoimmune disease of the human central nervous system. A number of studies with compelling evidence have provided correlation between single nucleotide polymorphisms in interleukin-7 receptor alpha and multiple sclerosis (MS) in several populations. One such variation, rs6897932, is located within the coding region and results in the generation of a soluble receptor, whereas another one, rs11567685, is located in the promoter region and affects gene expression. In this study, we investigated the frequencies of these two SNPs and their association to MS in 200 healthy controls and 200 MS patients based on a simple PCR-RFLP strategy not reported previously. The frequencies of the high risk alleles for both SNPs were in a high range among healthy and MS subjects relative to previous studies. In addition, whereas no association was found between the alternative splicing SNP, rs6897932, and MS, a significant link was found between the promoter SNP, rs11567685, and MS. These results are in contrast to other studies and may have important implications as to the molecular contribution of IL-7Rα in multiple sclerosis.