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Frontiers in Cellular and Infection... 2023Nocardiosis is an infectious disease caused by that primarily affects immunocompromised hosts. is a common opportunistic pathogen that causes disease in humans,...
Nocardiosis is an infectious disease caused by that primarily affects immunocompromised hosts. is a common opportunistic pathogen that causes disease in humans, including pulmonary and extrapulmonary infection. spp. infection is uncommon, and infection with and is even rarer. A 59-year-old immunocompetent woman with risk factors for environmental exposure developed nocardiosis and presented to the hospital with a cough, shortness of breath, hemoptysis, and a back abscess. An enhanced computed tomography (CT) of the chest revealed partial destruction of the right lung, as well as consolidation of the right upper lobe. Rare pathogens and were detected by metagenomic next-generation sequencing (mNGS) from abscess on the back and lung puncture tissue, respectively. She was treated with a combination of antibiotics and was finally discharged with a good prognosis. In this case, we present a patient who was successfully diagnosed with and infection using mNGS. This importance of using mNGS in pathogen detection and the effective use of antibiotics in treating patients with long-term rare infections is highlighted in this report.
Topics: Female; Humans; Middle Aged; Mycobacterium abscessus; Abscess; East Asian People; Nocardia; Nocardia Infections; Anti-Bacterial Agents; Lung
PubMed: 37655298
DOI: 10.3389/fcimb.2023.1229298 -
Clinical Infectious Diseases : An... Aug 2023Nontuberculous mycobacteria (NTM) cause pulmonary (PNTM) and extrapulmonary (ENTM) disease. Infections are difficult to diagnose and treat, and exposures occur in...
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.
Topics: Humans; Female; Male; Mycobacterium Infections, Nontuberculous; Nontuberculous Mycobacteria; Lung; Lung Diseases; Oregon
PubMed: 37083882
DOI: 10.1093/cid/ciad214 -
American Journal of Physiology. Lung... Mar 2024Early-life respiratory virus infections have been correlated with enhanced development of childhood asthma. In particular, significant numbers of respiratory syncytial...
Early-life respiratory virus infections have been correlated with enhanced development of childhood asthma. In particular, significant numbers of respiratory syncytial virus (RSV)-hospitalized infants go on to develop lung disease. It has been suggested that early-life viral infections may lead to altered lung development or repair that negatively impacts lung function later in life. Our data demonstrate that early-life RSV infection modifies lung structure, leading to decreased lung function. At 5 wk postneonatal RSV infection, significant defects are observed in baseline pulmonary function test (PFT) parameters consistent with decreased lung function as well as enlarged alveolar spaces. Lung function changes in the early-life RSV-infected group continue at 3 mo of age. The altered PFT and structural changes induced by early-life RSV were mitigated in mice that have previously been shown to have reduced immune cell accumulation associated with a persistent Th2 environment. Importantly, long-term effects were demonstrated using a secondary RSV infection 3 mo following the initial early-life RSV infection and led to significant additional defects in lung function, with severe mucus deposition within the airways, and consolidation of the alveolar spaces. These studies suggest that early-life respiratory viral infection leads to alterations in lung structure/repair that predispose to diminished lung function later in life. These studies outline a novel finding that early-life respiratory virus infection can alter lung structure and function long-term. Importantly, the data also indicate that there are critical links between inflammatory responses and subsequent events that produce a more severe pathogenic response later in life. The findings provide additional data to support that early-life infections during lung development can alter the trajectory of airway function.
Topics: Humans; Infant; Animals; Mice; Respiratory Syncytial Virus Infections; Lung; Pneumonia; Lung Diseases; Respiratory Syncytial Virus, Human; Mice, Inbred BALB C
PubMed: 38290164
DOI: 10.1152/ajplung.00300.2023 -
Communications Biology Dec 2023SARS-CoV-2 infection can cause persistent respiratory sequelae. However, the underlying mechanisms remain unclear. Here we report that sub-lethally infected K18-human...
SARS-CoV-2 infection can cause persistent respiratory sequelae. However, the underlying mechanisms remain unclear. Here we report that sub-lethally infected K18-human ACE2 mice show patchy pneumonia associated with histiocytic inflammation and collagen deposition at 21 and 45 days post infection (DPI). Transcriptomic analyses revealed that compared to influenza-infected mice, SARS-CoV-2-infected mice had reduced interferon-gamma/alpha responses at 4 DPI and failed to induce keratin 5 (Krt5) at 6 DPI in lung, a marker of nascent pulmonary progenitor cells. Histologically, influenza- but not SARS-CoV-2-infected mice showed extensive Krt5+ "pods" structure co-stained with stem cell markers Trp63/NGFR proliferated in the pulmonary consolidation area at both 7 and 14 DPI, with regression at 21 DPI. These Krt5+ "pods" structures were not observed in the lungs of SARS-CoV-2-infected humans or nonhuman primates. These results suggest that SARS-CoV-2 infection fails to induce nascent Krt5+ cell proliferation in consolidated regions, leading to incomplete repair of the injured lung.
Topics: Mice; Humans; Animals; COVID-19; Influenza, Human; SARS-CoV-2; Lung; Gene Expression Profiling
PubMed: 38092883
DOI: 10.1038/s42003-023-05626-z -
Journal of Virology Sep 2023The continued evolution and emergence of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have resulted in challenges to vaccine and antibody...
The continued evolution and emergence of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have resulted in challenges to vaccine and antibody efficacy. The emergence of each new variant necessitates the need to re-evaluate and refine animal models used for countermeasure testing. Here, we tested a recently circulating SARS-CoV-2 Omicron lineage variant, BQ.1.1, in multiple rodent models including K18-human ACE2 (hACE2) transgenic, C57BL/6J, and 129S2 mice, and Syrian golden hamsters. In contrast to a previously dominant BA.5.5 Omicron variant, inoculation of K18-hACE2 mice with BQ.1.1 resulted in substantial weight loss, a characteristic seen in pre-Omicron variants. BQ.1.1 also replicated to higher levels in the lungs of K18-hACE2 mice and caused greater lung pathology than the BA.5.5 variant. However, in C57BL/6J mice, 129S2 mice, and Syrian hamsters, BQ.1.1 did not cause increased respiratory tract infection or disease compared to animals administered BA.5.5. Moreover, the rates of direct contact or airborne transmission in hamsters were not significantly different after BQ.1.1 and BA.5.5 infections. Taken together, these data suggest that the BQ.1.1 Omicron variant has increased virulence in rodent species that express hACE2, possibly due to the acquisition of unique spike mutations relative to earlier Omicron variants. IMPORTANCE As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to evolve, there is a need to rapidly assess the efficacy of vaccines and antiviral therapeutics against newly emergent variants. To do so, the commonly used animal models must also be re-evaluated. Here, we determined the pathogenicity of the BQ.1.1 SARS-CoV-2 variant in multiple SARS-CoV-2 animal models including transgenic mice expressing human ACE2 (hACE2), two strains of conventional laboratory mice, and Syrian hamsters. While BQ.1.1 and BA.5.5 infection resulted in similar levels of viral burden and clinical disease in hamsters and the conventional strains of laboratory mice tested, increases in lung infection were detected in hACE2-expressing transgenic mice, which corresponded with greater levels of pro-inflammatory cytokines and lung pathology. Taken together, our data highlight important differences in two closely related Omicron SARS-CoV-2 variant strains and provide a foundation for evaluating countermeasures.
Topics: Animals; Cricetinae; Humans; Mice; COVID-19; Disease Models, Animal; Lung; Mesocricetus; Mice, Inbred C57BL; Mice, Transgenic; SARS-CoV-2; Viral Load; Virulence
PubMed: 37676002
DOI: 10.1128/jvi.00628-23 -
JCI Insight Apr 2024BACKGROUNDPersistent cough and dyspnea are prominent features of postacute sequelae of SARS-CoV-2 (also termed "long COVID"); however, physiologic measures and clinical...
BACKGROUNDPersistent cough and dyspnea are prominent features of postacute sequelae of SARS-CoV-2 (also termed "long COVID"); however, physiologic measures and clinical features associated with these pulmonary symptoms remain poorly defined. Using longitudinal pulmonary function testing (PFT) and CT imaging, this study aimed to identify the characteristics and determinants of pulmonary long COVID.METHODSThis single-center retrospective study included 1,097 patients with clinically defined long COVID characterized by persistent pulmonary symptoms (dyspnea, cough, and chest discomfort) lasting for 1 or more months after resolution of primary COVID infection.RESULTSAfter exclusion, a total of 929 patients with post-COVID pulmonary symptoms and PFTs were stratified as diffusion impairment and pulmonary restriction, as measured by percentage predicted diffusion capacity for carbon monoxide (DLCO) and total lung capacity (TLC). Longitudinal evaluation revealed diffusion impairment (DLCO ≤ 80%) and pulmonary restriction (TLC ≤ 80%) in 51% of the cohort overall (n = 479). In multivariable modeling regression analysis, invasive mechanical ventilation during primary infection conferred the greatest increased odds of developing pulmonary long COVID with diffusion impairment and restriction (adjusted odds ratio [aOR] = 9.89, 95% CI 3.62-26.9]). Finally, a subanalysis of CT imaging identified radiographic evidence of fibrosis in this patient population.CONCLUSIONLongitudinal PFTs revealed persistent diffusion-impaired restriction as a key feature of pulmonary long COVID. These results emphasize the importance of incorporating PFTs into routine clinical practice for evaluation of long COVID patients with prolonged pulmonary symptoms. Subsequent clinical trials should leverage combined symptomatic and quantitative PFT measurements for more targeted enrollment of pulmonary long COVID patients.FUNDINGNational Institute of Allergy and Infectious Diseases (AI156898, K08AI129705), National Heart, Lung, and Blood Institute (HL153113, OTA21-015E, HL149944), and the COVID-19 Urgent Research Response Fund at the University of Alabama at Birmingham.
Topics: Humans; COVID-19; Male; Female; Middle Aged; Retrospective Studies; SARS-CoV-2; Aged; Post-Acute COVID-19 Syndrome; Lung; Respiratory Function Tests; Tomography, X-Ray Computed; Dyspnea; Cough
PubMed: 38652535
DOI: 10.1172/jci.insight.177518 -
Microbes and Infection 2023Since the realization that the lungs are not sterile but are normally inhabited by various bacterial species, studies have been conducted to define healthy lung...
Since the realization that the lungs are not sterile but are normally inhabited by various bacterial species, studies have been conducted to define healthy lung microbiota and to investigate whether it changes during lung diseases, infections, and inflammation. Using next-generation sequencing, we investigated bacterial microbiota from whole lungs in two rat strains (previously shown to differ in gut microbiota composition) in a healthy state and during pulmonary infection caused by the opportunistic fungus Aspergillus fumigatus. No differences in alpha diversity indices and microbial composition between DA and AO rats before infection were noted. Fungal infection caused dysbiosis in both rat strains, characterized by increased alpha diversity indices and unchanged beta diversity. The relative abundance of genera and species was increased in DA but decreased in AO rats during infection. Changes in lung microbiota coincided with inflammation (in both rat strains) and oxidative stress (in DA rats). Disparate response of lung microbiota in DA and AO rats to pulmonary fungal infection might render these two rat strains differentially susceptible to a subsequent inflammatory insult.
Topics: Rats; Animals; Aspergillus fumigatus; Lung; Pneumonia; Microbiota; Inflammation
PubMed: 37479024
DOI: 10.1016/j.micinf.2023.105186 -
Current Opinion in Microbiology Feb 2024The respiratory tract microbiome (RTM) is a microbial ecosystem inhabiting different niches throughout the airway. A critical role for the RTM in dictating lung... (Review)
Review
The respiratory tract microbiome (RTM) is a microbial ecosystem inhabiting different niches throughout the airway. A critical role for the RTM in dictating lung infection outcomes is underlined by recent efforts to identify community members benefiting respiratory tract health. Obligate anaerobes common in the oropharynx and lung such as Prevotella and Veillonella are associated with improved pneumonia outcomes and activate several immune defense pathways in the lower airway. Colonizers of the nasal cavity, including Corynebacterium and Dolosigranulum, directly impact the growth and virulence of lung pathogens, aligning with robust clinical correlations between their upper airway abundance and reduced respiratory tract infection risk. Here, we highlight recent work identifying respiratory tract bacteria that promote airway health and resilience against disease, with a focus on lung infections and the underlying mechanisms driving RTM-protective benefits.
Topics: Humans; Lung; Oropharynx; Respiratory Tract Infections; Pneumonia, Bacterial; Microbiota
PubMed: 38277901
DOI: 10.1016/j.mib.2024.102428 -
Journal of Controlled Release :... Aug 2023Acute lung injury (ALI)/ acute respiratory distress syndrome (ARDS) is a devastating inflammatory lung disease with a high mortality rate. ALI/ARDS is induced by various... (Review)
Review
Acute lung injury (ALI)/ acute respiratory distress syndrome (ARDS) is a devastating inflammatory lung disease with a high mortality rate. ALI/ARDS is induced by various causes, including sepsis, infections, thoracic trauma, and inhalation of toxic reagents. Corona virus infection disease-19 (COVID-19) is also a major cause of ALI/ARDS. ALI/ARDS is characterized by inflammatory injury and increased vascular permeability, resulting in lung edema and hypoxemia. Currently available treatments for ALI/ARDS are limited, but do include mechanical ventilation for gas exchange and treatments supportive of reduction of severe symptoms. Anti-inflammatory drugs such as corticosteroids have been suggested, but their clinical effects are controversial with possible side-effects. Therefore, novel treatment modalities have been developed for ALI/ARDS, including therapeutic nucleic acids. Two classes of therapeutic nucleic acids are in use. The first constitutes knock-in genes for encoding therapeutic proteins such as heme oxygenase-1 (HO-1) and adiponectin (APN) at the site of disease. The other is oligonucleotides such as small interfering RNAs and antisense oligonucleotides for knock-down expression of target genes. Carriers have been developed for efficient delivery for therapeutic nucleic acids into the lungs based on the characteristics of the nucleic acids, administration routes, and targeting cells. In this review, ALI/ARDS gene therapy is discussed mainly in terms of delivery systems. The pathophysiology of ALI/ARDS, therapeutic genes, and their delivery strategies are presented for development of ALI/ARDS gene therapy. The current progress suggests that selected and appropriate delivery systems of therapeutic nucleic acids into the lungs may be useful for the treatment of ALI/ARDS.
Topics: Humans; Acute Lung Injury; COVID-19; Respiratory Distress Syndrome; Lung; Anti-Inflammatory Agents
PubMed: 37330013
DOI: 10.1016/j.jconrel.2023.06.018 -
The Journal of Clinical Investigation Oct 2023Secondary lung infection by inhaled Staphylococcus aureus (SA) is a common and lethal event for individuals infected with influenza A virus (IAV). How IAV disrupts host...
Secondary lung infection by inhaled Staphylococcus aureus (SA) is a common and lethal event for individuals infected with influenza A virus (IAV). How IAV disrupts host defense to promote SA infection in lung alveoli, where fatal lung injury occurs, is not known. We addressed this issue using real-time determinations of alveolar responses to IAV in live, intact, perfused lungs. Our findings show that IAV infection blocked defensive alveolar wall liquid (AWL) secretion and induced airspace liquid absorption, thereby reversing normal alveolar liquid dynamics and inhibiting alveolar clearance of inhaled SA. Loss of AWL secretion resulted from inhibition of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel in the alveolar epithelium, and airspace liquid absorption was caused by stimulation of the alveolar epithelial Na+ channel (ENaC). Loss of AWL secretion promoted alveolar stabilization of inhaled SA, but rescue of AWL secretion protected against alveolar SA stabilization and fatal SA-induced lung injury in IAV-infected mice. These findings reveal a central role for AWL secretion in alveolar defense against inhaled SA and identify AWL inhibition as a critical mechanism of IAV lung pathogenesis. AWL rescue may represent a new therapeutic approach for IAV-SA coinfection.
Topics: Mice; Animals; Humans; Influenza, Human; Lung Injury; Coinfection; Pulmonary Alveoli; Lung; Influenza A virus
PubMed: 37581936
DOI: 10.1172/JCI163402