Cell-free DNA profiling informs all major complications of hematopoietic cell transplantation.

Allogeneic hematopoietic cell transplantation (HCT) provides effective treatment for hematologic malignancies and immune disorders. Monitoring of posttransplant complications is critical, yet current diagnostic options are limited. Here, we show that cell-free DNA (cfDNA) in blood is a versatile analyte for monitoring of the most important complications that occur after HCT: graft-versus-host disease (GVHD), a frequent immune complication of HCT, infection, relapse of underlying disease, and graft failure. We demonstrate that these therapeutic complications are informed from a single assay, low-coverage bisulfite sequencing of cfDNA, followed by disease-specific bioinformatic analyses. To inform GVHD, we profile cfDNA methylation marks to trace the cfDNA tissues-of-origin and to quantify tissue-specific injury. To inform infection, we implement metagenomic cfDNA profiling. To inform cancer relapse, we implement analyses of tumor-specific genomic aberrations. Finally, to detect graft failure, we quantify the proportion of donor- and recipient-specific cfDNA. We applied this assay to 170 plasma samples collected from 27 HCT recipients at predetermined timepoints before and after allogeneic HCT. We found that the abundance of solid-organ-derived cfDNA in the blood at 1 mo after HCT is predictive of acute GVHD (area under the curve, 0.88). Metagenomic profiling of cfDNA revealed the frequent occurrence of viral reactivation in this patient population. The fraction of donor-specific cfDNA was indicative of relapse and remission, and the fraction of tumor-specific cfDNA was informative of cancer relapse. This proof-of-principle study shows that cfDNA has the potential to improve the care of allogeneic HCT recipients by enabling earlier detection and better prediction of the complex array of complications that occur after HCT.

Suspected Bronchiectasis and Mortality in Adults With a History of Smoking Who Have Normal and Impaired Lung Function : A Cohort Study.

BACKGROUND: Bronchiectasis in adults with chronic obstructive pulmonary disease (COPD) is associated with greater mortality. However, whether suspected bronchiectasis-defined as incidental bronchiectasis on computed tomography (CT) images plus clinical manifestation-is associated with increased mortality in adults with a history of smoking with normal spirometry and preserved ratio impaired spirometry (PRISm) is unknown. OBJECTIVE: To determine the association between suspected bronchiectasis and mortality in adults with normal spirometry, PRISm, and obstructive spirometry. DESIGN: Prospective, observational cohort. SETTING: The COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) study. PARTICIPANTS: 7662 non-Hispanic Black or White adults, aged 45 to 80 years, with 10 or more pack-years of smoking history. Participants who were former and current smokers were stratified into normal spirometry (n = 3277), PRISm (n = 986), and obstructive spirometry (n = 3399). MEASUREMENTS: Bronchiectasis identified by CT was ascertained using artificial intelligence-based measurements of an airway-to-artery ratio (AAR) greater than 1 (AAR >1), a measure of bronchial dilatation. The primary outcome of "suspected bronchiectasis" was defined as an AAR >1 of greater than 1% plus 2 of the following: cough, phlegm, dyspnea, and history of 2 or more exacerbations. RESULTS: Among the 7662 participants (mean age, 60 years; 52% women), 1352 (17.6%) had suspected bronchiectasis. During a median follow-up of 11 years, 2095 (27.3%) died. Ten-year mortality risk was higher in participants with suspected bronchiectasis, compared with those without suspected bronchiectasis (normal spirometry: difference in mortality probability [Pr], 0.15 [95% CI, 0.09 to 0.21]; PRISm: Pr, 0.07 [CI, -0.003 to 0.15]; obstructive spirometry: Pr, 0.06 [CI, 0.03 to 0.09]). When only CT was used to identify bronchiectasis, the differences were attenuated in the normal spirometry (Pr, 0.04 [CI, -0.001 to 0.08]). LIMITATIONS: Only 2 racial groups were studied. Only 1 measurement was used to define bronchiectasis on CT. Symptoms of suspected bronchiectasis were nonspecific. CONCLUSION: Suspected bronchiectasis was associated with a heightened risk for mortality in adults with normal and obstructive spirometry. PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute.

Artificial Intelligence-based CT Assessment of Bronchiectasis: The COPDGene Study.

Background CT is the standard method used to assess bronchiectasis. A higher airway-to-artery diameter ratio (AAR) is typically used to identify enlarged bronchi and bronchiectasis; however, current imaging methods are limited in assessing the extent of this metric in CT scans. Purpose To determine the extent of AARs using an artificial intelligence-based chest CT and assess the association of AARs with exacerbations over time. Materials and Methods In a secondary analysis of ever-smokers from the prospective, observational, multicenter COPDGene study, AARs were quantified using an artificial intelligence tool. The percentage of airways with AAR greater than 1 (a measure of airway dilatation) in each participant on chest CT scans was determined. Pulmonary exacerbations were prospectively determined through biannual follow-up (from July 2009 to September 2021). Multivariable zero-inflated regression models were used to assess the association between the percentage of airways with AAR greater than 1 and the total number of pulmonary exacerbations over follow-up. Covariates included demographics, lung function, and conventional CT parameters. Results Among 4192 participants (median age, 59 years; IQR, 52-67 years; 1878 men [45%]), 1834 had chronic obstructive pulmonary disease (COPD). During a 10-year follow-up and in adjusted models, the percentage of airways with AARs greater than 1 (quartile 4 vs 1) was associated with a higher total number of exacerbations (risk ratio [RR], 1.08; 95% CI: 1.02, 1.15; P = .01). In participants meeting clinical and imaging criteria of bronchiectasis (ie, clinical manifestations with ≥3% of AARs >1) versus those who did not, the RR was 1.37 (95% CI: 1.31, 1.43; P < .001). Among participants with COPD, the corresponding RRs were 1.10 (95% CI: 1.02, 1.18; P = .02) and 1.32 (95% CI: 1.26, 1.39; P < .001), respectively. Conclusion In ever-smokers with chronic obstructive pulmonary disease, artificial intelligence-based CT measures of bronchiectasis were associated with more exacerbations over time. Clinical trial registration no. NCT00608764 © RSNA, 2022 Supplemental material is available for this article. See also the editorial by Schiebler and Seo in this issue.

Airway-Occluding Mucus Plugs and Mortality in Patients With Chronic Obstructive Pulmonary Disease.

Importance: Airway mucus plugs are common in patients with chronic obstructive pulmonary disease (COPD); however, the association of airway mucus plugging and mortality in patients with COPD is unknown. Objective: To determine whether airway mucus plugs identified on chest computed tomography (CT) were associated with increased all-cause mortality. Design, Setting, and Participants: Observational retrospective analysis of prospectively collected data of patients with a diagnosis of COPD in the Genetic Epidemiology of COPD cohort. Participants were non-Hispanic Black or White individuals, aged 45 to 80 years, who smoked at least 10 pack-years. Participants were enrolled at 21 centers across the US between November 2007 and April 2011 and were followed up through August 31, 2022. Exposures: Mucus plugs that completely occluded airways on chest CT scans, identified in medium- to large-sized airways (ie, approximately 2- to 10-mm lumen diameter) and categorized as affecting 0, 1 to 2, or 3 or more lung segments. Main Outcomes and Measures: The primary outcome was all-cause mortality, assessed with proportional hazard regression analysis. Models were adjusted for age, sex, race and ethnicity, body mass index, pack-years smoked, current smoking status, forced expiratory volume in the first second of expiration, and CT measures of emphysema and airway disease. Results: Among the 4483 participants with COPD, 4363 were included in the primary analysis (median age, 63 years [IQR, 57-70 years]; 44% were women). A total of 2585 (59.3%), 953 (21.8%), and 825 (18.9%) participants had mucus plugs in 0, 1 to 2, and 3 or more lung segments, respectively. During a median 9.5-year follow-up, 1769 participants (40.6%) died. The mortality rates were 34.0% (95% CI, 32.2%-35.8%), 46.7% (95% CI, 43.5%-49.9%), and 54.1% (95% CI, 50.7%-57.4%) in participants who had mucus plugs in 0, 1 to 2, and 3 or more lung segments, respectively. The presence of mucus plugs in 1 to 2 vs 0 and 3 or more vs 0 lung segments was associated with an adjusted hazard ratio of death of 1.15 (95% CI, 1.02-1.29) and 1.24 (95% CI, 1.10-1.41), respectively. Conclusions and Relevance: In participants with COPD, the presence of mucus plugs that obstructed medium- to large-sized airways was associated with higher all-cause mortality compared with patients without mucus plugging on chest CT scans.

First wave of COVID-19 in Venezuela: Epidemiological, clinical, and paraclinical characteristics of first cases.

The coronavirus disease 2019 (COVID-19) pandemic has particularly affected countries with weakened health services in Latin America, where proper patient management could be a critical step to address the epidemic. In this study, we aimed to characterize and identify which epidemiological, clinical, and paraclinical risk factors defined COVID-19 infection from the first confirmed cases through the first epidemic wave in Venezuela. A retrospective analysis of consecutive suspected cases of COVID-19 admitted to a sentinel hospital was carried out, including 576 patient cases subsequently confirmed for severe acute respiratory syndrome coronavirus 2 infection. Of these, 162 (28.1%) patients met the definition criteria for severe/critical disease, and 414 (71.2%) were classified as mild/moderate disease. The mean age was 47 (SD 16) years, the majority of which were men (59.5%), and the most frequent comorbidity was arterial hypertension (23.3%). The most common symptoms included fever (88.7%), headache (65.6%), and dry cough (63.9%). Severe/critical disease affected mostly older males with low schooling (p < 0.001). Similarly, higher levels of glycemia, urea, aminotransferases, total bilirubin, lactate dehydrogenase, and erythrocyte sedimentation rate were observed in severe/critical disease patients compared to those with mild/moderate disease. Overall mortality was 7.6% (44/576), with 41.7% (28/68) dying in hospital. We identified risk factors related to COVID-19 infection, which could help healthcare providers take appropriate measures and prevent severe clinical outcomes. Our results suggest that the mortality registered by this disease in Venezuela during the first epidemic wave was underestimated. An increase in fatalities is expected to occur in the coming months unless measures that are more effective are implemented to mitigate the epidemic while the vaccination process is ongoing.

Cytomegalovirus events in high-risk allogeneic hematopoietic-cell transplantation patients who received letermovir prophylaxis.

Letermovir is approved for the prevention of cytomegalovirus (CMV) reactivation and clinical disease in patients undergoing allogeneic hematopoietic-cell transplantation (HCT). However, there is uncertainty about letermovir's ability to prevent clinical events during the period of prophylaxis as well as after the discontinuation of prophylaxis in the post-transplant setting. We performed a retrospective cohort study in CMV-seropositive allogeneic HCT recipients at high risk of CMV events, who received letermovir for primary prophylaxis from November 2017 through December 2019. We analyzed CMV outcomes for these patients during and after prophylaxis was discontinued. Patient outcomes were followed through June 2020. Sixty patients received letermovir for a median of 13 weeks (range, 1-72 weeks). Thirteen (22%) patients had quantifiable CMV DNAemia (reactivation) during letermovir prophylaxis a median of 9 days (range, 1-59 days) after starting letermovir. Five (8%) of these patients discontinued prophylaxis and received preemptive therapy (PET) with valganciclovir; eight (13%) continued letermovir as prophylaxis and CMV DNAemia resolved without PET. Thirteen patients (22%) had post-prophylaxis CMV reactivation a median of 33 days (range, 14-109 days) after letermovir discontinuation. In four (7%) of these patients, CMV DNAemia resolved without PET, and nine (15%) received PET. No patient developed CMV disease. Patients who developed CMV reactivation during prophylaxis did so shortly after initiation of letermovir, and most patients who developed CMV reactivation post-prophylaxis did so within 60 days after discontinuation of letermovir. Letermovir prophylaxis has changed the presentation of CMV infection in high-risk HCT patients.

Use of triazoles for the treatment of invasive aspergillosis: A three-year cohort analysis.

In a 3-year cohort study of adult patients with proven or probable IA, fewer patients initially treated with isavuconazole experienced adverse events compared with voriconazole, but more patients required a change in therapy due to lack of clinical efficacy.

Silent Airway Mucus Plugs in COPD and Clinical Implications.

BACKGROUND: Airway mucus plugs are frequently identified on CT scans of patients with COPD with a smoking history without mucus-related symptoms (ie, cough, phlegm [silent mucus plugs]). RESEARCH QUESTION: In patients with COPD, what are the risk and protective factors associated with silent airway mucus plugs? Are silent mucus plugs associated with functional, structural, and clinical measures of disease? STUDY DESIGN AND METHODS: We identified mucus plugs on chest CT scans of participants with COPD from the COPDGene study. The mucus plug score was defined as the number of pulmonary segments with mucus plugs, ranging from 0 to 18, and categorized into three groups (0, 1-2, and ≥ 3). We determined risk and protective factors for silent mucus plugs and the associations of silent mucus plugs with measures of disease severity using multivariable linear and logistic regression models. RESULTS: Of 4,363 participants with COPD, 1,739 had no cough or phlegm. Among the 1,739 participants, 627 (36%) had airway mucus plugs identified on CT scan. Risk factors of silent mucus plugs (compared with symptomatic mucus plugs) were older age (OR, 1.02), female sex (OR, 1.40), and Black race (OR, 1.93) (all P values < .01). Among those without cough or phlegm, silent mucus plugs (vs absence of mucus plugs) were associated with worse 6-min walk distance, worse resting arterial oxygen saturation, worse FEV1 % predicted, greater emphysema, thicker airway walls, and higher odds of severe exacerbation in the past year in adjusted models. INTERPRETATION: Mucus plugs are common in patients with COPD without mucus-related symptoms. Silent mucus plugs are associated with worse functional, structural, and clinical measures of disease. CT scan-identified mucus plugs can complement the evaluation of patients with COPD.

Pulmonary arterial pruning is associated with CT-derived bronchiectasis progression in smokers.

Loss of small pulmonary arteries measured as the ratio of blood vessel volume in arteries <5 mm2 in cross-section to total arterial blood vessel volume (BV5a/TBVa), with lower values indicating more pruning, was associated with 5-yr progressing CT-derived bronchiectasis in smokers (Odds Ratio (OR) [95% Confidence interval], 1.28 [1.07-1.53] per 5% lower BV5a/TBVa, P = 0.007). Corresponding results in smokers with COPD were: OR 1.45 [1.11-1.89] per 5% lower BV5a/TBVa, P = 0.007. The results support a vascular factor for structural progression of bronchiectasis.

[Results of applying a universal protocol for early detection of hypoacusia in newborn infants for 42 months]. / Resultados de aplicar durante 42 meses un protocolo universal de detección e intervención precoz de la hipoacusia en neonatos.

INTRODUCTION AND OBJECTIVES: We present the results from applying over a period of three and a half years a universal newborn hearing screening programme aimed at the early detection of hearing loss. Our goal has been to diagnose and treat all unilateral or bilateral permanent hearing losses > or =40 dB nHL. METHODS: The detection strategy consists of two screening phases with transient evoked otoacoustic emissions (TEOAE) and one diagnostic phase with auditory brainstem responses (ABR). ABR tests were performed on newborns "not passing" the TEOAE screening, as well as those with risk factors for hearing loss. RESULTS: Of 4568 live newborns (NB), we evaluated 97.6 %. Of these, 3.7 % presented risk factors for hearing loss. The first TEOAE was "passed" in both ears by 91.7 % of the newborns; after the second TEOAE, only 1.3 % of cases were referred to the diagnostic phase. We detected 2.7/1000 cases of severe/profound bilateral hearing loss. CONCLUSIONS: This programme was designed for early application of appropriate treatment. Although it is possible to reach the objectives of screening and diagnosis of newborn hearing loss, the intervention stage is much more complicated. This is because intervention depends on different disciplines that must act in co-ordination, as well as multiple environmental and family factors that are difficult to control. Therapeutic effectiveness still remains our challenge and a motive for discussion in fully justifying early congenital hearing loss screening programmes.

High frequency tympanometry (1000Hz) in young infants and its comparison with otoacoustic emissions, otomicroscopy and 226Hz tympanometry. / Timpanometría de alta frecuencia (1.000Hz) en lactantes y su comparación con otoemisiones acústicas, otomicroscopia y timpanometría de 226Hz.

INTRODUCTION AND OBJECTIVE: In the first 6 months of life, 226Hz tympanometry is considered an ineffective procedure for the diagnosis of otitis media with effusion. With the introduction of universal hearing screening, the use of high frequency 1000Hz (1kHz) tympanometry has been recommended. To optimise the diagnosis of neonatal hearing loss, we present this comparison, from the clinical point of view, of the results of 226Hz and 1kHz tympanometry in infants. MATERIALS AND METHODS: We designed a prospective study of 100 children under 9 months of age proceeding from our hearing screening program. We compare the result of tympanometry with binocular microscopy and transient evoked otoacoustic emissions. RESULTS: The application of transient otoacoustic emissions, otomicroscopy and 226Hz and 1kHz tympanometry has shown its usefulness in the management of otitis media with effusion of young infants, with a similar effectiveness between the 4 tests. CONCLUSION: The joint use of otomicroscopy, transient otoacoustic emissions and 226Hz and 1kHz tympanometry, has allowed us to diagnose otitis media with effusion in young infants more accurately than each test separately. We recommend initial use of 1kHz tympanometry, at least in children younger than 7 months, but in the presence of hearing loss or an unclear result, 226Hz tympanometry is a good diagnostic complement.

[Hamartomatous polyp of the hypopharynx]. / Pólipo hamartomatoso de la hipofaringe.

We present the clinical case of a polyp in the hypopharynx discovered incidentally while performing an upper digestive endoscopy in a middle aged woman. Endoscopic resection was performed, and the histological result was a hamartomatous polyp. We review the diagnosis and treatment of this rare entity.