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Summary: Human genetic studies of critical COVID-19 pneumonia have revealed the essential role of type I interferon-dependent innate immunity to SARS-CoV-2 infection. Conversely, an association between the HLA-B∗15:01 allele and asymptomatic SARS-CoV-2 infection in unvaccinated individuals was recently reported, suggesting a contribution of pre-existing T cell-dependent adaptive immunity. We report a lack of association of classical HLA alleles, including HLA-B∗15:01, with pre-omicron asymptomatic SARS-CoV-2 infection in unvaccinated participants in a prospective population-based study in the United States (191 asymptomatic vs. 945 symptomatic COVID-19 cases). Moreover, we found no such association in the international COVID Human Genetic Effort cohort (206 asymptomatic vs. 574 mild or moderate COVID-19 cases and 1,625 severe or critical COVID-19 cases). Finally, in the Human Challenge Characterisation study, the three HLA-B∗15:01 individuals infected with SARS-CoV-2 developed symptoms. As with other acute primary infections studied, no classical HLA alleles favoring an asymptomatic course of SARS-CoV-2 infection were identified.

Lower respiratory tract infections (LRTIs) present a significant global health burden, exacerbated by the rise in antimicrobial resistance (AMR). The persistence and evolution of multidrug-resistant bacteria intensifies the urgency for alternative treatments. This review explores bacteriophage (phage) therapy as an innovative solution to combat bacterial LRTIs. Phages, abundant in nature, demonstrate specificity towards bacteria, minimal eukaryotic toxicity, and the ability to penetrate and disrupt bacterial biofilms, offering a targeted approach to infection control. The article synthesises evidence from systematic literature reviews spanning 2000–2023, in vitro and in vivo studies, case reports and ongoing clinical trials. It highlights the synergistic potential of phage therapy with antibiotics, the immunophage synergy in animal models, and the pharmacodynamics and pharmacokinetics critical for clinical application. Despite promising results, the article acknowledges that phage therapy is at a nascent stage in clinical settings, the challenges of phage-resistant bacteria, and the lack of comprehensive cost-effectiveness studies. It stresses the need for further research to optimise phage therapy protocols and navigate the complexities of phage–host interactions, particularly in vulnerable populations such as the elderly and immunocompromised. We call for regulatory adjustments to facilitate the exploration of the long-term effects of phage therapy, aiming to incorporate this old-yet-new therapy into mainstream clinical practice to tackle the looming AMR crisis.

Abstract Introduction Long-term treatment of pulmonary sarcoidosis with glucocorticoids has been associated with toxicity and other adverse events, highlighting the need for alternative therapies. The goal of this study was to evaluate the efficacy and safety of repository corticotropin injection (RCI, Acthar® Gel) in patients with pulmonary sarcoidosis and to validate endpoints for use in future clinical trials. Methods In this multicenter, randomized, placebo-controlled trial, subjects received subcutaneous RCI (80 U) twice weekly or matching placebo through 24 weeks in a double-blind treatment phase, followed by an optional 24-week open-label extension. Efficacy was measured by glucocorticoid tapering, pulmonary function tests, chest imaging, patient-reported outcomes, and a novel sarcoidosis treatment score (STS). Safety was assessed by adverse events, physical examinations, vital signs, clinical laboratory abnormalities, and imaging. The study was terminated early due to low enrollment caused by the COVID-19 pandemic, thereby precluding statistical analysis. Results Fifty-five subjects were randomized to receive either RCI (n = 27) or placebo (n = 28). Mean STS at week 24 showed greater improvement with RCI (1.4) compared with placebo (0.7). At week 48, those who remained on RCI had an STS of 1.8 compared with 0.9 in those who switched from placebo to RCI. More subjects in the RCI group discontinued glucocorticoids at week 24 compared to the placebo group. Glucocorticoid discontinuation was comparable at week 48 for those who switched from placebo to RCI and those who continued RCI. Similar trends in favor of RCI over placebo were observed with the other efficacy endpoints. No new or unexpected safety signals were identified. Conclusions RCI was safe and well tolerated, with trends in efficacy data suggesting greater improvement with RCI compared to placebo in patients receiving standard-of-care therapy for pulmonary sarcoidosis. The study also provided validation of efficacy endpoints that may be used in larger trials for pulmonary sarcoidosis. Trial registration ClinicalTrials.gov identifier: NCT03320070. Graphical Abstract

Summary: Background: While vaccines have established utility against COVID-19, phase 3 efficacy studies have generally not comprehensively evaluated protection provided by previous infection or hybrid immunity (previous infection plus vaccination). Individual patient data from US government-supported harmonized vaccine trials provide an unprecedented sample population to address this issue. We characterized the protective efficacy of previous SARS-CoV-2 infection and hybrid immunity against COVID-19 early in the pandemic over three-to six-month follow-up and compared with vaccine-associated protection. Methods: In this post-hoc cross-protocol analysis of the Moderna, AstraZeneca, Janssen, and Novavax COVID-19 vaccine clinical trials, we allocated participants into four groups based on previous-infection status at enrolment and treatment: no previous infection/placebo; previous infection/placebo; no previous infection/vaccine; and previous infection/vaccine. The main outcome was RT-PCR-confirmed COVID-19 >7–15 days (per original protocols) after final study injection. We calculated crude and adjusted efficacy measures. Findings: Previous infection/placebo participants had a 92% decreased risk of future COVID-19 compared to no previous infection/placebo participants (overall hazard ratio [HR] ratio: 0.08; 95% CI: 0.05–0.13). Among single-dose Janssen participants, hybrid immunity conferred greater protection than vaccine alone (HR: 0.03; 95% CI: 0.01–0.10). Too few infections were observed to draw statistical inferences comparing hybrid immunity to vaccine alone for other trials. Vaccination, previous infection, and hybrid immunity all provided near-complete protection against severe disease. Interpretation: Previous infection, any hybrid immunity, and two-dose vaccination all provided substantial protection against symptomatic and severe COVID-19 through the early Delta period. Thus, as a surrogate for natural infection, vaccination remains the safest approach to protection. Funding: National Institutes of Health.

Rationale Nontuberculous mycobacterial (NTM) diseases are difficult-to-treat infections, especially in lung transplant (LTx) candidates. Currently, there is a paucity of recommendations on the management of NTM infections in LTx, focusing on Mycobacterium avium complex (MAC), M. abscessus and M. kansasii. Methods Pulmonologists, infectious disease specialists, LTx surgeons and Delphi experts with expertise in NTM were recruited. A patient representative was also invited. Three questionnaires comprising questions with multiple response statements were distributed to panellists. Delphi methodology with a Likert scale of 11 points (5 to −5) was applied to define the agreement between experts. Responses from the first two questionnaires were collated to develop a final questionnaire. The consensus was described as a median rating >4 or

Abstract Background Little is known about the impact of the ecosystem disruption and its contribution on the non-tuberculosis mycobacteria (NTM) diseases (cases) rate in Florida (FL), a state with a high prevalence of NTM in the United States. We aimed to evaluate the epidemiological distribution of NTM in FL and identify its association with extreme weather events. Methods We used OneFlorida Clinical Research Consortium dataset and extracted data on NTM cases using ICD codes 9- CM 031.0 and ICD-10 A31 during 2012–2018. The number of hurricanes during the study period which affected FL were extracted data from the National Hurricane Center (NHC) and the National Oceanic and Atmospheric Administration (NOAA). Results Prevalence of NTM gradually increased during the study period. The rate was 2012: 14.3/100,000, 2015; 20.1/100,000 and 2018; 22.6/100,00 except in 2014 where there was an 8% decrease. The incidences were 2012; 6.5/100,00, 2015; 4.9/100,000 and in 2015; 5.4/100,000. Geographical analysis demonstrated a gradual expansion of the NTM cases in Alachua, and Marion Counties throughout the study period. Notably, the 2018 heat map showed higher prevalence of NTM in the northwestern, panhandle region of FL which had been absent in the heat maps for years 2012–2018. High number of the hurricanes was associated with the higher number of the new cases of NTM infection for years 2012, 2016–2018, while the lower number of the hurricanes was associated with the lower number of the new cases of NTM infection for years 2014–2015. Conclusion The current study found the prevalence rates of NTM disease in FL rose from 2012 to 2018. A higher prevalence was seen following the hurricanes.

BackgroundProgressive pulmonary fibrosis is a serious complication in subjects with sarcoidosis. The absence of reliable, non-invasive biomarkers that detect early progression exacerbates the difficulty in predicting sarcoidosis severity. To potentially address this unmet need, we evaluated a panel of markers for an association with sarcoidosis progression (HBEGF, NAMPT, IL1-RA, IL-6, IL-8, ANG-2). This panel encompasses proteins related to inflammation, vascular injury, cell proliferation, and fibroblast mitogenesis processes.MethodsPlasma biomarker levels and biomarker protein expression in lung and lymph nodes tissues (immunohistochemical studies) from sarcoidosis subjects with limited disease and progressive (complicated) sarcoidosis were performed. Gene expression of the protein-coding genes included in this panel was analyzed using RNAseq in sarcoidosis granulomatous tissues from lung and lymph nodes.ResultsExcept for IL-8, plasma levels of each biomarker—eNAMPT, IL-1RA, IL-6, ANG-2, and HBEGF—were significantly elevated in sarcoidosis subjects compared to controls. In addition, plasma levels of HBEGF were elevated in complicated sarcoidosis, while eNAMPT and ANG-2 were observed to serve as markers of lung fibrosis in a subgroup of complicated sarcoidosis. Genomic studies corroborated HBEGF and NAMPT among the top dysregulated genes and identified cytokine-related and fibrotic pathways in lung granulomatous tissues from sarcoidosis.ConclusionThese findings suggest HBEGF, eNAMPT, and ANG-2 may serve as potential novel indicators of the clinical severity of sarcoidosis disease.

Abstract Background The coronavirus disease 2019 (COVID-19) pandemic caused by the SARS-Cov2 virus has become the greatest health and controversial issue for worldwide nations. It is associated with different clinical manifestations and a high mortality rate. Predicting mortality and identifying outcome predictors are crucial for COVID patients who are critically ill. Multivariate and machine learning methods may be used for developing prediction models and reduce the complexity of clinical phenotypes. Methods Multivariate predictive analysis was applied to 108 out of 250 clinical features, comorbidities, and blood markers captured at the admission time from a hospitalized cohort of patients (N = 250) with COVID-19. Inspired modification of partial least square (SIMPLS)-based model was developed to predict hospital mortality. Prediction accuracy was randomly assigned to training and validation sets. Predictive partition analysis was performed to obtain cutting value for either continuous or categorical variables. Latent class analysis (LCA) was carried to cluster the patients with COVID-19 to identify low- and high-risk patients. Principal component analysis and LCA were used to find a subgroup of survivors that tends to die. Results SIMPLS-based model was able to predict hospital mortality in patients with COVID-19 with moderate predictive power (Q 2 = 0.24) and high accuracy (AUC > 0.85) through separating non-survivors from survivors developed using training and validation sets. This model was obtained by the 18 clinical and comorbidities predictors and 3 blood biochemical markers. Coronary artery disease, diabetes, Altered Mental Status, age > 65, and dementia were the topmost differentiating mortality predictors. CRP, prothrombin, and lactate were the most differentiating biochemical markers in the mortality prediction model. Clustering analysis identified high- and low-risk patients among COVID-19 survivors. Conclusions An accurate COVID-19 mortality prediction model among hospitalized patients based on the clinical features and comorbidities may play a beneficial role in the clinical setting to better management of patients with COVID-19. The current study revealed the application of machine-learning-based approaches to predict hospital mortality in patients with COVID-19 and identification of most important predictors from clinical, comorbidities and blood biochemical variables as well as recognizing high- and low-risk COVID-19 survivors.

Summary: Noncoding RNAs are important regulators of mucoinflammatory response, but little is known about the contribution of airway long noncoding RNAs (lncRNAs) in COVID-19. RNA-seq analysis showed a more than 4-fold increased expression of IL-6, ICAM-1, CXCL-8, and SCGB1A1 inflammatory factors; MUC5AC and MUC5B mucins; and SPDEF, FOXA3, and FOXJ1 transcription factors in COVID-19 patient nasal samples compared with uninfected controls. A lncRNA on antisense strand to ICAM-1 or LASI was induced 2-fold in COVID-19 patients, and its expression was directly correlated with viral loads. A SARS-CoV-2-infected 3D-airway model largely recapitulated these clinical findings. RNA microscopy and molecular modeling indicated a possible interaction between viral RNA and LASI lncRNA. Notably, blocking LASI lncRNA reduced the SARS-CoV-2 replication and suppressed MUC5AC mucin levels and associated inflammation, and select LASI-dependent miRNAs (e.g., let-7b-5p and miR-200a-5p) were implicated. Thus, LASI lncRNA represents an essential facilitator of SARS-CoV-2 infection and associated airway mucoinflammatory response.

Abstract The Nucleocapsid Protein (N Protein) of severe acute respiratory syndrome Coronavirus 2 (SARS-CoV2) is located in the viral core. Immunoglobulin G (IgG) targeting N protein is detectable in the serum of infected patients. The effect of high titers of IgG against N-protein on clinical outcomes of SARS-CoV2 disease has not been described. We studied 400 RT-PCR confirmed SARS-CoV2 patients to determine independent factors associated with poor outcomes, including Medical Intensive Care Unit (MICU) admission, prolonged MICU stay and hospital admissions, and in-hospital mortality. We also measured serum IgG against the N protein and correlated its concentrations with clinical outcomes. We found that several factors, including Charlson comorbidity Index (CCI), high levels of IL6, and presentation with dyspnea were associated with poor clinical outcomes. It was shown that higher CCI and higher IL6 levels were independently associated with in-hospital mortality. Anti-N protein IgG was detected in the serum of 55 (55%) patients at the time of admission. A high concentration of antibodies, defined as signal to cut off ratio (S/Co) > 1.5 (75 percentile of all measurements), was found in 25 (25%) patients. The multivariable logistic regression models showed that between being an African American, higher CCI, lymphocyte counts, and S/Co ratio > 1.5, only S/Co ratio were independently associated with MICU admission and longer length of stay in hospital. This study recommends that titers of IgG targeting N-protein of SARS-CoV2 at admission is a prognostic factor for the clinical course of disease and should be measured in all patients with SARS-CoV2 infection.

BackgroundThe disproportionate burden of COVID-19 pandemic has become a major concern in the United States (US), but the association between COVID-19 case-fatality rate (CFR) and factors influencing health outcomes at a state level has not been evaluated.MethodsWe calculated COVID-19 CFR for three different waves using COVID Data Tracker from the Centers for Disease Control and Prevention. America's Health Rankings assesses the factors that influence health outcomes to determine state's health rankings. The association between COVID-19 CFR and state health disparities was analyzed by linear regression.ResultsStates with better rankings of Physical Environment were associated with lower CFR for the 1st wave (β = 0.06%, R2 = 0.170, P = 0.003). There was a paradoxical association between the 2nd wave CFR and Clinical Care (β = −0.04%, R2 = 0.112, P = 0.017) and Overall health rankings (β = −0.03%, R2 = 0.096, P = 0.029). For the 3rd wave, states with better rankings of Overall health factors (β = 0.01%, R2 = 0.179, P = 0.002), Social & Economic Factors (β = 0.01%, R2 = 0.176, P = 0.002), Behaviors (β = 0.01%, R2 = 0.204, P < 0.001), and Health Outcomes (β = 0.01%, R2 = 0.163, P = 0.004) were associated with lower CFR. COVID-19 vaccination coverage was also associated with state health rankings (at least one dose: β = −0.13%, R2 = 0.305, P < 0.001; fully vaccinated: β = −0.06%, R2 = 0.120, P = 0.014).ConclusionsThese findings suggested targeted public health interventions and mitigation strategies addressing health disparities are essential to improve inequitable outcomes of COVID-19 in the US.

IntroductionReverse transcription-polymerase chain reaction (RT-PCR) to detect SARS-CoV-2 is time-consuming and sometimes not feasible in developing nations. Rapid antigen test (RAT) could decrease the load of diagnosis. However, the efficacy of RAT is yet to be investigated comprehensively. Thus, the current systematic review and meta-analysis were conducted to evaluate the diagnostic accuracy of RAT against RT-PCR methods as the reference standard.MethodsWe searched the MEDLINE/Pubmed and Embase databases for the relevant records. The QUADAS-2 tool was used to assess the quality of the studies. Diagnostic accuracy measures [i.e., sensitivity, specificity, diagnostic odds ratio (DOR), positive likelihood ratios (PLR), negative likelihood ratios (NLR), and the area under the curve (AUC)] were pooled with a random-effects model. All statistical analyses were performed with Meta-DiSc (Version 1.4, Cochrane Colloquium, Barcelona, Spain).ResultsAfter reviewing retrieved records, we identified 60 studies that met the inclusion criteria. The pooled sensitivity and specificity of the rapid antigen tests against the reference test (the real-time PCR) were 69% (95% CI: 68–70) and 99% (95% CI: 99–99). The PLR, NLR, DOR and the AUC estimates were found to be 72 (95% CI: 44–119), 0.30 (95% CI: 0.26–0.36), 316 (95% CI: 167–590) and 97%, respectively.ConclusionThe present study indicated that using RAT kits is primarily recommended for the early detection of patients suspected of having COVID-19, particularly in countries with limited resources and laboratory equipment. However, the negative RAT samples may need to be confirmed using molecular tests, mainly when the symptoms of COVID-19 are present.

IntroductionAcute kidney injury (AKI) has been associated with an increased mortality rate among hospitalized patients with Coronavirus disease 2019 (COVID-19). The current review aimed to evaluate the symptoms, complications, and treatments performed to manage AKI in patients with COVID-19.MethodsWe searched PubMed/Medline, Web of Science, and Embase for the relevant scientific literature published up to February 1, 2022. The following keywords were used: “COVID-19”, “SARS-CoV-2”, and “Acute kidney injury”.ResultsForty-four studies with a total number of 114 COVID-19 patients with AKI (Mean age: 53.6 years) were included in our systematic review. The most common comorbidities in patients with COVID-19 suffering from AKI were the history of diabetes, hypertension, and hyperlipidemia. Twelve out of the 44 included studies reported a history of chronic kidney disease (CKD) in this group of patients. Focal segmental glomerulosclerosis (FSGS) and acute tubular necrosis (ATN) were the most common pathological evidence. The average length of hospital stay was 19 days, and the average duration of need for mechanical ventilation was 3 days.ConclusionsThe current systematic review shows that AKI frequently complicates the course of COVID-19 hospitalizations and is associated with increased severity of illness, prolonged duration of hospitalization, and poor prognosis. Given the extent of the adverse impact of AKI, early detection of comorbidities and renal complications is essential to improve the outcomes of COVID-19 patients.

IntroductionThe Coronavirus Disease 2019 (COVID-19) pandemic caused by Severe Acute Respiratory Coronavirus 2 (SARS-CoV-2) emerged in late December 2019. Considering the important role of gut microbiota in maturation, regulation, and induction of the immune system and subsequent inflammatory processes, it seems that evaluating the composition of gut microbiota in COVID-19 patients compared with healthy individuals may have potential value as a diagnostic and/or prognostic biomarker for the disease. Also, therapeutic interventions affecting gut microbial flora may open new horizons in the treatment of COVID-19 patients and accelerating their recovery.MethodsA systematic search was conducted for relevant studies published from December 2019 to December 2021 using Pubmed/Medline, Embase, and Scopus. Articles containing the following keywords in titles or abstracts were selected: “SARS-CoV-2” or “COVID-19” or “Coronavirus Disease 19” and “gastrointestinal microbes” or “dysbiosis” or “gut microbiota” or “gut bacteria” or “gut microbes” or “gastrointestinal microbiota”.ResultsOut of 1,668 studies, 22 articles fulfilled the inclusion criteria and a total of 1,255 confirmed COVID-19 patients were examined. All included studies showed a significant association between COVID-19 and gut microbiota dysbiosis. The most alteration in bacterial composition of COVID-19 patients was depletion in genera Ruminococcus, Alistipes, Eubacterium, Bifidobacterium, Faecalibacterium, Roseburia, Fusicathenibacter, and Blautia and enrichment of Eggerthella, Bacteroides, Actinomyces, Clostridium, Streptococcus, Rothia, and Collinsella. Also, some gut microbiome alterations were associated with COVID-19 severity and poor prognosis including the increment of Bacteroides, Parabacteroides, Clostridium, Bifidobacterium, Ruminococcus, Campylobacter, Rothia, Corynebacterium, Megasphaera, Enterococcus, and Aspergillus spp. and the decrement of Roseburia, Eubacterium, Lachnospira, Faecalibacterium, and the Firmicutes/Bacteroidetes ratio.ConclusionOur study showed a significant change of gut microbiome composition in COVID-19 patients compared with healthy individuals. This great extent of impact has proposed the gut microbiota as a potential diagnostic, prognostic, and therapeutic strategy for COVID-19. There is much evidence about this issue, and it is expected to be increased in near future.

Background and Objectives: There is a lack of information regarding the effective duration of treatment necessary to prevent the development of acquired resistance when fluoroquinolones (FQ), and/or pyrazinamide (Z) resistance has occurred in patients with polydrug-resistant tuberculosis and isoniazid resistance. The management of these kinds of patients should be carried out in experienced centers according to drug susceptibility test results, clinical status of the patient and the extensity of the disease. Materials and Methods: We evaluated treatment regimens, treatment outcomes, and drug adverse effects in seven patients with polydrug-resistant tuberculosis, including those with Z and/or FQ resistance in a retrospective analysis Results: Regarding the patients with polydrug-resistant tuberculosis in addition to isoniazid (H) resistance, three had Z, two had FQ, and the remaining two had both Z and FQ resistance. In the intensive phase of the treatment, the patients were given at least four drugs according to drug susceptibility tests, and at least three drugs in the continuation phase. The duration of treatment was 9–12 months. Two of the patients were foreign nationals, and could not be followed up with due to returning to their home countries. Regarding the remaining five patients, three of them were terminated as they completed treatment, and two as cured. No recurrence was observed in the first year of the treatment. The most common, and serious drug side effect was seen for amikacin. Conclusions: In patients with polydrug-resistant TB, if Z and/or FQ resistance is detected in addition to H resistance, the treatment of these patients should be conducted on a case-by-case basis, taking into account the patient’s resistance pattern, clinical condition, and disease prognosis. Close monitoring of the side effects will increase the success rate of the treatment.

Background: The incidence of Mycobacterium avium complex (MAC) increases as immunosuppressed conditions become more common. MAC's standard treatment regimen includes a macrolide, ethambutol, and a rifamycin, among which rifampin and rifabutin are the most commonly used. Although current guidelines recommend initial therapy for MAC with rifampin, it has been theorized to be less efficacious than rifabutin.Methods: We reviewed the relevant scientific literature published up to February 18, 2020. Statistical analyses were performed with Comprehensive Meta-Analysis Software Version 2.0 (Biostat, Englewood, NJ). The pooled frequency with 95% confidence intervals (CI) was assessed using a random-effect model. We considered P

Introduction: The severity of COVID-19 may be correlated with the risk of liver injury development. An increasing number of studies indicate that degrees of hepatotoxicity has been associated with using some medications in the management of COVID-19 patients. However, limited studies had systematically investigated the evidence of drug-induced liver injury (DILI) in COVID-19 patients. Thus, this study aimed to examine DILI in COVID-19 patients.Methods: A systematic search was carried out in PubMed/Medline, EMBASE, and Web of Science up to December 30, 2020. Search items included “SARS-CoV-2”, “Coronavirus,” COVID-19, and liver injury.Results: We included 22 related articles. Among included studies, there was five case report, five case series, four randomizes control trial (RCT), seven cohort studies, and one cross-sectional study. The drugs included in this systematic review were remdesivir, favipiravir, tocilizumab, hydroxychloroquine, and lopinavir/ritonavir. Among included studies, some studies revealed a direct role of drugs, while others couldn't certainly confirm that the liver injury was due to SARS-CoV-2 itself or administration of medications. However, a significant number of studies reported that liver injury could be attributable to drug administration.Discussion: Liver injury in COVID-19 patients could be caused by the virus itself or the administration of some types of drug. Intensive liver function monitoring should be considered for patients, especially patients who are treated with drugs such as remdesivir, lopinavir/ritonavir, and tocilizumab.

Epidemiological data show a worldwide increase in nontuberculous mycobacteriosis. Although it has been partially attributed to the improvement of microbiological methodologies that has allowed a better recovery and identification of nontuberculous mycobacteria (NTM), it is generally accepted that there is a genuine incidence augmentation. The reasons of the increase are likely multifactorial, depending on the nature of the pathogen, the host, and their interaction. Mycobacteria from the Mycobacterium tuberculosis complex has been regarded as pathogenic and NTM as opportunistic and nontransmissible. Nevertheless, few differences have been found in either their phenotypic or genotypic characteristics. The phenomenon of M. tuberculosis adaptation to the human host may be taking place again in NTM as a consequence of human environmental alterations that facilitate the interaction with the pathogen. The current worsening of the immunological status of increasing numbers of individuals, a result of factors such as malnutrition (obesity and diabetes), population aging or the widespread use of immunosuppressive medication, may be allowing the rapid evolution and person-to-person transmission of NTM. It is likely that mycobacteriosis incidence will keep escalating. New measures should be taken to deal with these diseases, including their reportability and the implementation of strain genotyping that would shed light on the NTM dissemination routes from the environment or human hosts.

Background: Cardiomyopathies (CMPs) due to myocytes involvement are among the leading causes of sudden adolescent death and heart failure. During the COVID-19 pandemic, there are limited data available on cardiac complications in patients with COVID-19, leading to severe outcomes.Methods: We conducted a systematic search in Pubmed/Medline, Web of Science, and Embase databases up to August 2020, for all relevant studies about COVID-19 and CMPs.Results: A total of 29 articles with a total number of 1460 patients were included. Hypertension, diabetes, obesity, hyperlipidemia, and ischemic heart disease were the most reported comorbidities among patients with COVID-19 and cardiomyopathy. In the laboratory findings, 21.47% of patients had increased levels of troponin. Raised D-dimer levels were also reported in all of the patients. Echocardiographic results revealed mild, moderate, and severe Left Ventricular (LV) dysfunction present in 17.13, 11.87, and 10% of patients, respectively.Conclusions: Cardiac injury and CMPs were common conditions in patients with COVID-19. Therefore, it is suggested that cardiac damage be considered in managing patients with COVID-19.

Background: Non-tuberculous mycobacteria (NTM), specifically Mycobacterium avium complex (MAC), is an increasingly prevalent cause of pulmonary dysfunction. Clofazimine has been shown to be effective for the treatment of M. avium complex, but there were no published large-scale analyses comparing clofazimine to non-clofazimine regimens in MAC treatment. The objective of this large-scale meta-analysis was to evaluate patient characteristics and treatment outcomes of individuals diagnosed with MAC and treated with a clofazimine-based regimen.Methods: We used Pubmed/Medline, Embase, Web of Science, and the Cochrane Library to search for studies published from January 1, 1990 to February 9, 2020. Two reviewers (SSH and NY) extracted the data from all eligible studies and differences were resolved by consensus. Statistical analyses were performed with STATA (version 14, IC; Stata Corporation, College Station, TX, USA).Results: The pooled success treatment rate with 95% confidence intervals (CI) was assessed using random effect model. The estimated pooled treatment success rates were 56.8% in clofazimine and 67.9% in non-clofazimine groups. Notably, success rates were higher (58.7%) in treatment of HIV patients with disseminated infection.Conclusions: Treatment was more successful in the non-clofazimine group overall. However, HIV patients with disseminated infection had higher treatment response rates than non-HIV patients within the clofazimine group.

IntroductionDiabetes mellitus (DM) is one of the most common comorbidities among patients with coronavirus disease 2019 (COVID-19) which may exacerbate complications of this new viral infection. Metformin is an anti-hyperglycemic agent with host-directed immune-modulatory effects, which relieve exaggerated inflammation and reduce lung tissue damage. The current systematic review aimed to summarize the available evidence on the potential mechanism of action and the efficacy of metformin in COVID-19 patients with DM.MethodsA systematic search was carried out in PubMed/Medline, EMBASE, the Cochrane Controlled Register of Trials (CENTRAL), and Web of Science up to July 30, 2020. The following keywords were used: “COVID-19”, “SARS-CoV-2”, “2019-nCoV”, “metformin”, and “antidiabetic drug”.ResultsFourteen studies were included in our systematic review. Three of them were observational with 6,659 participants. Decreasing insulin resistance, reduction of some inflammatory cytokines like IL-6 and TNF-α, modulation of angiotensin-converting enzyme 2 (ACE2) receptor, and improving neutrophil to lymphocyte ratio are some of the potential mechanisms of metformin in COVID-19 patients with DM. Nine out of fourteen articles revealed the positive effect of metformin on the prognosis of COVID-19 in diabetic or even non-diabetic patients. Moreover, different studies have shown that metformin is more effective in women than men.ConclusionsThe use of metformin may lead to improve the clinical outcomes of patients with mild to moderate SARS-CoV-2, especially in diabetic women. Further observational studies should be conducted to clarify the effects of metformin as a part of the treatment strategy of COVID-19.

Introduction: Until now, there are several reports on cutaneous manifestations in COVID-19 patients. However, the link between skin manifestations and the severity of the disease remains debatable. We conducted a systematic review to evaluate the temporal relationship between different types of skin lesions and the severity of COVID-19.Methods: A systematic search was conducted for relevant studies published between January and July 2020 using Pubmed/Medline, Embase, and Web of knowledge. The following keywords were used: “SARS-CoV-2” or “COVID-19” or “new coronavirus” or “Wuhan Coronavirus” or “coronavirus disease 2019” and “skin disease” or “skin manifestation” or “cutaneous manifestation.”Results: Out of 381 articles, 47 meet the inclusion criteria and a total of 1,847 patients with confirmed COVID-19 were examined. The overall frequency of cutaneous manifestations in COVID-19 patients was 5.95%. The maculopapular rash was the main reported skin involvement (37.3%) commonly occurred in middle-aged females with intermediate severity of the disease. Forty-eight percentage of the patients had a mild, 32% a moderate, and 20% a severe COVID-19 disease. The mild disease was mainly correlated with chilblain-like and urticaria-like lesions and patients with vascular lesions experienced a more severe disease. Seventy-two percentage of patients with chilblain-like lesions improved without any medication. The overall mortality rate was 4.5%. Patients with vascular lesions had the highest mortality rate (18.2%) and patients with urticaria-like lesions had the lowest mortality rate (2.2%).Conclusion: The mere occurrence of skin manifestations in COVID-19 patients is not an indicator for the disease severity, and it highly depends on the type of skin lesions. Chilblain-like and vascular lesions are the ends of a spectrum in which from chilblain-like to vascular lesions, the severity of the disease increases, and the patient's prognosis worsens. Those with vascular lesions should also be considered as high-priority patients for further medical care.

Abstract Objectives Growth hormone‐releasing hormone (GHRH) is a potent stimulator of growth hormone (GH) secretion from the pituitary gland. Although GHRH is essential for the growth of immune cells, the regulatory effects of its antagonist in granulomatous disease remain unknown. Methods Here, we report expression of GHRH receptor (R) in human tissue with sarcoidosis granuloma and demonstrate the anti‐inflammatory effects of MIA602 (a GHRH antagonist) in two in vitro human granuloma models and an in vivo granuloma model using different methods including ELISA, immunohistochemistry, RNA‐seq analysis and flow cytometry. Results MIA602 decreases the levels of IL‐2, IL‐2R, IL‐7, IL‐12, IL‐17A and TNF‐α in an in vitro granuloma model. Further, we show that the anti‐inflammatory effect of MIA602 appears to be mediated by a reduction in CD45+CD68+ cells in granulomatous tissue and upregulation in PD‐1 expression in macrophages. Analysis of the expression of proteins involved in the mitochondrial stage of apoptosis showed that MIA602 increases the levels of caspase‐3, BCL‐xL/BAK dimer and MCl‐1/Bak dimer in the granuloma. These findings indicate that MIA602 may not induce apoptosis. Conclusions Our findings further suggest that GHRH‐R is potentially a clinical target for the treatment of granulomatous disease and that MIA602 may be used as a novel therapeutic agent for sarcoidosis.

Sarcoidosis is a granulomatous inflammatory disease of unknown etiology. Sarcoid like granuloma may develop concurrently or following cancer. Detection of granuloma in mediastinal lymph nodes biopsy in patient with pulmonary nodules may be a concern for undiagnosed lung cancer. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a diagnostic modality of choice for the lung lesions.We discussed A 71-year-old man with history of chronic obstructive lung disease (COPD), who presented with a lung nodule and mediastinal lymphadenopathies. The nodule was 9.9 mm when detected and his endobronchial ultrasound-guided transbronchial fine needle aspiration (EBUS-TBNA) of lymph nodes in station 7 & 4R showed normal lymph node structure. Two years later, his surveillance chest CT scan indicated an increase in the size of the nodule to 15 mm, and PET/CT showed Fluorodeoxyglucose (FDG) avid nodule & mediastinal Lymph nodes. He complained of Shortness of breath after 2–3 climbs of stairs, without any history of cough or fever. He quit cigarette smoking recently and smoked 50 pack years before. He underwent another set of EBUS and was referred for sarcoidosis treatment due to finding non-necrotizing granuloma in 4L and 11L lymph nodes. The patient also underwent another biopsy of the nodule concerning the possibility of cancer sarcoid syndrome. A poorly differentiated lung adenocarcinoma positive for GATA3, positive for P63 and CK7, TTF-1 was reported.Concurrent lung cancer and granulomatous reaction in mediastinal lymph nodes are being reported more often. Recent studies have shown a better survival of patients with diagnosis of cancer and granulomatous findings of sarcoidosis. Performing lung biopsy from any nodular lesion in a patient with sarcoidosis is essential for the differential diagnosis and early therapeutic measures.

Introduction The association between Coronavirus Disease 2019 (COVID-19) and abortion has been debated since the beginning of the COVID-19 pandemic. We aimed to conduct this systematic review to understand better the potential effects of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) on fetal loss in infected mothers presented with abortion following this infection. Methods We included articles published in PubMed/Medline, Web of Science, clinicaltrials.gov, and Embase databases in 2019 and 2020 through a comprehensive search via appropriate keywords, including COVID-19 and abortion synonyms. All studies with the abortion data in COVID-19 confirmed pregnant females were collected. Results Out of 208 potentially relevant articles, 11 articles were eligible to include in the systematic review. The included reports were published because of the following reasons: (1) First-trimester miscarriage; (2) Late miscarriage; (3) complication of COVID-19 infection in pregnancy; (4) COVID-19 disease in artificial pregnancy. First-trimester abortion was found in 5 studies, and second-trimester abortion in 7 studies. Two patients acquired infection during the hospital stay while they were referred for abortion. Reports related to abortion in pregnant females with COVID-19 show that most miscarriages due to COVID-19 in the first trimester were due to placental insufficiency. Conclusions There is an increased risk of abortion in mothers with a positive test result of SARS-CoV-2, which several case reports and case series have identified during the pandemic. Placental inflammation during the viral infection may result in fetal growth retardation and induce abortion. There has not been any consistent evidence of vertical transmission of the virus from mother to fetus, which requires further investigation.

Sarcoidosis is a multi-system disorder of granulomatous inflammation which most commonly affects the lungs. Its etiology and pathogenesis are not well defined in part due to the lack of reliable modeling. Here, we present the development of an in vitro three-dimensional lung-on-chip biochip designed to mimic granuloma formation. A lung on chip fluidic macrodevice was developed and added to our previously developed a lung-on-membrane model (LOMM). Granulomas were cultured from blood samples of patients with sarcoidosis and then inserted in the air-lung-interface of the microchip to create a three-dimensional biochip pulmonary sarcoidosis model (3D BSGM). Cytokines were measured after 48 hours. ELISA testing was performed to measure cytokine response difference between LOMM with 3D BSGM. There were statistically significant differences in IL-1ß (P = 0.001953), IL-6 (P = 0.001953), GM-CSF (P = 0.001953), and INF-γ expressions (P = 0.09375) between two groups. The current model represents the first 3D biochip sarcoidosis model created by adding a microfluidics system to a dual-chambered lung on membrane model and introducing developed sarcoid-granuloma to its air-lung-interface.

Introduction An increased risk of sarcoidosis and sarcoid-like reactions in subjects with a history of malignancy has been suggested. We assessed the incidence and clinical characteristics of cancer patients with biopsies containing sarcoid-like granulomas on cancer metastasis and patient survival. Methods This is a retrospective, multicentre, observational study involving endobronchial ultrasound transbronchial needle aspiration and a melanoma patient dataset at the University of Miami, USA, and a sarcoidosis patient database at Chiba University, Japan. Subjects with a confirmed diagnosis of cancer and who subsequently developed granulomas in different organs were enrolled. The study was registered at Clinicaltrials.gov (NCT03844698). Results 133 patients met the study's criteria. The most common primary cancer sites were the skin (22.5%), breast (20.3%) and lymph node (12.8%). 24 (18%) patients developed sarcoid-like granulomas within 1 year of cancer diagnosis, 54 (40.6%) between 1 and 5 years and 49 (36.8%) after 5 years. Imaging showed possible sarcoid-like granulomas in lymph nodes in 51 cases (38.3%) and lung tissue and mediastinal lymph nodes in 73 cases (54.9%); some parenchymal reticular opacity and fibrosis was found in 5 (3.7%) and significant parenchymal fibrosis in 2 (1.5%) subjects. According to logistic regression analysis, the frequency of metastatic cancer was significantly lower in patients with sarcoid-like granulomas than in controls. Moreover, multivariate Cox proportional hazard analysis showed a significant survival advantage in those with sarcoid-like granuloma. Conclusion Sarcoid-like granulomas are uncommon pathology findings in cancer patients. There is a significant association between the presence of granulomas and reduced metastasis and increased survival. Further study is warranted to understand the protective mechanism involved.

Abstract COVID‐19, caused by a novel coronavirus, is a persistent global pandemic. It is crucial to examine existing reports to effectively summarize and characterize its clinical course. We used a large‐scale meta‐analysis to establish prevalence rates for loss of olfaction and gustation in COVID‐19 positive patients. PubMed/Medline, Embase, and Web of Sciences were searched for articles published until April 30, 2020. Furthermore, to avoid missing papers, more searches were carried out in the reference lists of covered studies. Articles that mentioned olfactory and/or gustatory disorder in patients with COVID–19 were included for further analysis. Articles that did not report the aforementioned information were excluded. Duplicated articles, reviews, and meta‐analysis were excluded as well. The quality of the references was assessed according to the checklist provided by JBI (Joanna Briggs Institute). We used independent extraction of data by multiple observers. The pooled frequency with 95% confidence intervals (CI) was assessed using random effect model. The main outcome measures reported were the pooled frequency of olfaction and pooled frequency of gustation disorder in patients with COVID‐19 calculated using a random effect model weighted by the study population. The 15 included studies had 3,739 participants which all had confirmed COVID–19. Olfactory and gustatory disorders were assessed and a total number of 1,354 and 1,729 were reported to have taste or smell impairment, respectively. The estimated rate of taste disorder in patients with COVID‐19 was 49.0% [95% confidence interval (CI) 34.0–64.0, I2: 96%] (Figure 2). The estimated rate of olfactory disorder in patients with COVID‐19 was 61.0% (95% CI 44.0%–75.0%). Our meta‐analysis demonstrated high rates of taste (49.0%) and smell (61.0%) disorders in patients with confirmed COVID‐19. Results increase the power of recent reports—loss of olfactory and loss of gustation should now routinely be considered in the setting of COVID‐19 infection.

Rationale: The cancer mortality-to-incidence ratio (MIR) can serve as a population-based indicator for cancer care outcomes. In the US, evaluation of lung cancer survival by individual states has not been evaluated.Objective: To assess the association between lung cancer survival by using MIRs and state-level health disparities in the United States.Methods: We calculated 5-year lung cancer MIR averages from 2011 to 2015 using the United States Cancer Statistics (USCS) data. America's Health Rankings (AHR) is a platform using weighted measures in five different categories to calculate annual state health rankings. Five-year averages from 2011 to 2015 of the health uninsured rate and 4-year averages from 2011 to 2014 of health spending per capita were obtained from the U.S. Census Bureau and Centers for Medicare & Medicaid Services. Linear regression analyses were performed to determine the associations between cancer survival value (CSV) = (1 – MIR) × 100% and state health variables.Results: During the study period, the 5-year averages of age-adjusted incidence, mortality rates, and CSVs were 60.3 ± 2.1 per 100,000 population, 43.4 ± 2.1 per 100,000, and 27.9 ± 3.9%, respectively. Among the 50 states, Connecticut had the highest CSV (38.6 ± 1.7%) whereas Nevada had the lowest CSV (18.7 ± 6.5%). Hawaii had the highest health ranking and Mississippi had the lowest ranking in 2016. States with better health rankings, lower health uninsured rates, and higher health spending were significantly associated with higher CSVs (R2 = 0.418, P < 0.001; R2 = 0.352, P < 0.001; R2 = 0.142, P = 0.007, respectively).Conclusions: There are significant differences in lung cancer survival within the United States. Lung cancer survival by using CSV was strongly associated with state health disparities, and it can be an applicable measure to evaluate the state-level health disparities in the United States.

Background: The rapidly evolving coronavirus disease 2019 (COVID-19), was declared a pandemic by the World Health Organization on March 11, 2020. It was first detected in the Wuhan city of China and has spread globally resulting in a substantial health and economic crisis in many countries. Observational studies have partially identified different aspects of this disease. There have been no published systematic reviews that combine clinical, laboratory, epidemiologic, and mortality findings. Also, the effect of gender on the outcomes of COVID-19 has not been well-defined.Methods: We reviewed the scientific literature published from January 1, 2019 to May 29, 2020. Statistical analyses were performed with STATA (version 14, IC; Stata Corporation, College Station, TX, USA). The pooled frequency with 95% confidence intervals (CI) was assessed using random effect model. P < 0.05 was considered a statistically significant publication bias.Results: Out of 1,223 studies, 34 satisfied the inclusion criteria. A total of 5,057 patients with a mean age of 49 years were evaluated. Fever (83.0%, CI 77.5–87.6) and cough (65.2%, CI 58.6–71.2) were the most common symptoms. The most prevalent comorbidities were hypertension (18.5%, CI 12.7–24.4) and Cardiovascular disease (14.9%, CI 6.0–23.8). Among the laboratory abnormalities, elevated C-Reactive Protein (CRP) (72.0%, CI 54.3–84.6) and lymphopenia (50.1%, CI 38.0–62.4) were the most common. Bilateral ground-glass opacities (66.0%, CI 51.1–78.0) was the most common CT scan presentation. The pooled mortality rate was 6.6%, with males having significantly higher mortality compared to females (OR 3.4; 95% CI 1.2–9.1, P = 0.01).Conclusion: COVID-19 has caused a significant number of hospitalization and mortality worldwide. Mortality associated with COVID-19 was higher in our study compared to the previous reports from China. The mortality was significantly higher among the hospitalized male group. Further studies are required to evaluate the effect of different variables resulting in sex disparity in COVID-19 mortality.

COVID-19 is a rapidly evolving pandemic, which represents a multifaceted global threat. Given the economic consequences, most researchers agree that social distancing measures are an effective strategy relative to the cost. Previous studies indicate that community size as well as viral population risk groups should be considered in forming an effective targeted social distancing strategy. The resultant delay in the occurrence of infections in order to support vaccine development has been shown to be an effective policy. However, a return to normalcy from the current situation would require policy intervention that transforms the American economy along with continued targeted social distancing and the use of medical science as a tool to facilitate gradual personal interactions of low-risk individuals. We believe that the adoption of rapid IgG testing would be best suitable for widespread population-level screening as part of a comprehensive plan for incrementally rebuilding the in-person workforce. As such, this crisis represents an opportunity for the United States to increase automation of the manufacturing sector, shrink supply chains, and create higher-level jobs in order to reduce the dependency on other countries for critical supplies. This economic transition to better utilize technology along with reconstruction of the workforce could improve the standard of living for many Americans as well as better prepare the US for future pandemics.

Introduction: The 2019 novel coronavirus (COVID-19) has been declared a public health emergency worldwide. The objective of this systematic review was to characterize the clinical, diagnostic, and treatment characteristics of hospitalized patients presenting with COVID-19.Methods: We conducted a structured search using PubMed/Medline, Embase, and Web of Science to collect both case reports and case series on COVID-19 published up to April 24, 2020. There were no restrictions regarding publication language.Results: Eighty articles were included analyzing a total of 417 patients with a mean age of 48 years. The most common presenting symptom in patients who tested positive for COVID-19 was fever, reported in up to 62% of patients from 82% of the analyzed studies. Other symptoms including rhinorrhea, dizziness, and chills were less frequently reported. Additionally, in studies that reported C-reactive protein (CRP) measurements, a large majority of patients displayed an elevated CRP (60%). Progression to acute respiratory distress syndrome (ARDS) was the most common complication of patients testing positive for COVID-19 (21%). CT images displayed ground-glass opacification (GGO) patterns (80%) as well as bilateral lung involvement (69%). The most commonly used antiviral treatment modalities included, lopinavir (HIV protease inhibitor), arbidiol hydrochloride (influenza fusion inhibitor), and oseltamivir (neuraminidase inhibitor).Conclusions: Development of ARDS may play a role in estimating disease progression and mortality risk. Early detection of elevations in serum CRP, combined with a clinical COVID-19 symptom presentation may be used as a surrogate marker for the presence and severity of the disease. There is a paucity of data surrounding the efficacy of treatments. There is currently not a well-established gold standard therapy for the treatment of diagnosed COVID-19. Further prospective investigations are necessary.

Pulmonary sarcoidosis presents substantial management challenges, with limited evidence on effective therapies and phenotypes. In the absence of definitive evidence, expert consensus can supply clinically useful guidance in medicine. An international panel of 26 experts participated in a Delphi process to identify consensus on pharmacological management in sarcoidosis with the development of preliminary recommendations. The modified Delphi process used three rounds. The first round focused on qualitative data collection with open-ended questions to ensure comprehensive inclusion of expert concepts. Rounds 2 and 3 applied quantitative assessments using an 11-point Likert scale to identify consensus. Key consensus points included glucocorticoids as initial therapy for most patients, with non-biologics (immunomodulators), usually methotrexate, considered in severe or extrapulmonary disease requiring prolonged treatment, or as a steroid-sparing intervention in cases with high risk of steroid toxicity. Biologic therapies might be considered as additive therapy if non-biologics are insufficiently effective or are not tolerated with initial biologic therapy, usually with a tumour necrosis factor-α inhibitor, typically infliximab. The Delphi methodology provided a platform to gain potentially valuable insight and interim guidance while awaiting evidenced-based contributions.

In patients treated with repository corticotrophin injection (RCI) for pulmonary sarcoidosis, effective management of adverse events may improve adherence. However, management of adverse events may be challenging due to limitations in real-world clinical experience with RCI and available published guidelines. We surveyed 12 physicians with a modified Delphi process using three questionnaires. Questionnaire 1 consisted of open-ended questions. Panellists' answers were developed into a series of statements for Questionnaires 2 and 3. In these, physicians rated their agreement with the statements using a Likert scale. Key consensus recommendations included a starting dose of 40 units twice a week for patients with less severe disease, continued at a maintenance dose for patients who responded, particularly those with chronic refractory sarcoidosis. Panellists reached consensus that concomitant steroids should be quickly tapered in patients receiving RCI, but that concomitant use of immunosuppressive medications should be continued. Panellists developed consensus recommendations for adverse event management, and reached consensus that RCI should be down-titrated or discontinued if other interventions for the adverse effects fail or if the adverse effect is severe. In the absence of clinical evidence, our Delphi consensus opinions may provide practical guidance to physicians on the management of RCI to treat pulmonary sarcoidosis.

Background: Signal transducer and activator of transcription 3 (STAT3) is a transcription factor involved in cellular proliferation, apoptosis, and differentiation. Mutations in the STAT3 gene have been associated with dysregulation of the immune system giving rise to primary immunodeficiency syndromes (PID). Clinically, patients may present with very broad manifestations, and its diagnosis is usually very challenging. Proper treatment remains unclear, and limited options are available. Methods: We report an adult male patient with long-standing history of immunodeficiency, who was found to have Mycobacterium abscessus infection. Two-hundred and seven immunogenes were sequenced using next-generation sequencing technology (NGS). Results: A STAT3 heterozygous missense pathologic variant was identified in the patient located in the transactivation domain (TA) of STAT3, associated with a gain of functionality, leading to recurrent bronchopulmonary infections, and involvement of multiple organ systems. Conclusions: Severe cases of autoimmunity should prompt for evaluation of PIDs in the setting of genetic mutations. Anti-IL-6 therapy may benefit patients with STAT3 GOF mutations. These patients should also be screened for lymphoproliferative disorders.

Abstract Background A substantial increase in pulmonary and extra-pulmonary diseases due to non-tuberculous mycobacteria (NTM) has been documented worldwide, especially among subjects suffering from chronic respiratory diseases and immunocompromised patients. Many questions remain regarding the epidemiology of pulmonary disease due to NTM (NTM-PD) mainly because reporting of NTM-PD to health authorities is not mandated in several countries, including Italy. This manuscript describes the protocol of the first Italian registry of adult patients with respiratory infections caused by NTM (IRENE). Methods IRENE is an observational, multicenter, prospective, cohort study enrolling consecutive adult patients with either a NTM respiratory isolate or those with NTM-PD. A total of 41 centers, including mainly pulmonary and infectious disease departments, joined the registry so far. Adult patients with all of the following are included in the registry: 1) at least one positive culture for any NTM species from any respiratory sample; 2) at least one positive culture for NTM isolated in the year prior the enrolment and/or prescribed NTM treatment in the year prior the enrolment; 3) given consent to inclusion in the study. No exclusion criteria are applied to the study. Patients are managed according to standard operating procedures implemented in each IRENE clinical center. An online case report form has been developed to collect patients’ demographics, comorbidities, microbiological, laboratory, functional, radiological, clinical, treatment and outcome data at baseline and on an annual basis. An IRENE biobank has also been developed within the network and linked to the clinical data of the registry. Conclusions IRENE has been developed to inform the clinical and scientific community on the current management of adult patients with NTM respiratory infections in Italy and acts as a national network to increase the disease’s awareness. Trial registration Clinicaltrial.gov: NCT03339063.

Abstract Sarcoidosis commonly affects the lung. Lung transplantation (LT) is required when there is a severe and refractory involvement. We compared post-transplant survival rates of sarcoidosis patients with chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). We also explored whether the race and age of the donor, and double lung transplant have any effect on the survival in the post transplant setting. We analyzed 9,727 adult patients with sarcoidosis, COPD, and IPF who underwent LT worldwide between 2005–2015 based on United Network for Organ Sharing (UNOS) database. Survival rates were compared with Kaplan-Meier, and risk factors were investigated by Cox-regression analysis. 469 (5%) were transplanted because of sarcoidosis, 3,688 (38%) for COPD and 5,570 (57%) for IPF. Unadjusted survival analysis showed a better post-transplant survival rate for patients with sarcoidosis (p

Recurrent tuberculosis (TB) continues to be a significant problem and is an important indicator of the effectiveness of TB control. Recurrence can occur by relapse or exogenous reinfection. Recurrence of TB is still a major problem in high-burden countries, where there is lack of resources and no special attention is being given to this issue. The rate of recurrence is highly variable and has been estimated to range from 4.9% to 47%. This variability is related to differences in regional epidemiology of recurrence and differences in the definitions used by the TB control programs. In addition to treatment failure from noncompliance, there are several key host factors that are associated with high rates of recurrence. The widely recognized host factors independent of treatment program that predispose to TB recurrence include gender differences, malnutrition; comorbidities such as diabetes, renal failure, and systemic diseases, especially immunosuppressive states such as human immunodeficiency virus; substance abuse; and environmental exposures such as silicosis. With improved understanding of the human genome, proteome, and metabolome, additional host-specific factors that predispose to recurrence are being identified. Information on temporal and geographical trends of TB cases as well as studies with whole-genome sequencing might provide further information to enable us to fully understand TB recurrence and discriminate between reactivation and new infection. The recently launched World Health Organization End TB Strategy emphasizes the importance of integrated, patient-centered TB care. Continued improvement in diagnosis, treatment approaches, and an understanding of host-specific factors are needed to fully understand the clinical epidemiological and social determinants of TB recurrence.

The innate immune system plays a critical role in the early detection of pathogens, primarily by relying on pattern-recognition receptor (PRR) signaling molecules. Nucleotide-binding oligomerization domain 2 (NOD2) is a cytoplasmic receptor that recognizes invading molecules and danger signals inside the cells. Recent studies highlight the importance of NOD2′s function in maintaining the homeostasis of human body microbiota and innate immune responses, including induction of proinflammatory cytokines, regulation of autophagy, modulation of endoplasmic reticulum (ER) stress, etc. In addition, there is extensive cross-talk between NOD2 and the Toll-like receptors that are so important in the induction and tuning of adaptive immunity. Polymorphisms of NOD2′s encoding gene are associated with several pathological conditions, highlighting NOD2′s functional importance. In this study, we summarize NOD2′s role in cellular signaling pathways and take a look at the possible consequences of common NOD2 polymorphisms on the structure and function of this receptor.

Abstract Background Tuberculosis (TB) remains a significant global health concern and its diagnosis is challenging due to the limitations in the specificity and sensitivity of the current diagnostic tests. Exosomes are bioactive 30–100 nm vesicles produced by most cell types and are found in almost all human body fluids. Exosomal microRNAs (miRNAs) can transfer biological information between cells and tissues and may act as potential biomarkers in many diseases. In this pilot study, we assessed the miRNA profile of exosomes released from human monocyte-derived macrophages upon infection with Mycobacterium bovis Bacillus Calmette–Guerin (BCG). Methods Human monocytes were obtained from the peripheral blood of three healthy subjects and driven to a monocyte-derived macrophage (MDM) phenotype using standard protocols. MDMs were infected with BCG or left uninfected as control. 72 h post-infection, exosomes were collected from the cell culture medium, RNA was isolated and RNA-seq performed. The raw reads were filtered to eliminate adaptor and primer sequences and the sequences were run against the mature human miRNA sequences available in miRBase. MicroRNAs were identified using an E value

Introduction:Mycobacteria are aerobic non-motile organisms with lipid rich, hydrophobic cell walls that render them resistant to antibiotics. While there are over 150 different species of NTM, Mycobacterium avium complex (MAC) and Mycobacterium abscessus (MAB) are two of the most common culprits of pulmonary infection. MAB has been found to be most common in southeastern United States (Florida to Texas) and the third most rapidly growing NTM infection. It is responsible for chronic lung infections. Mycobacterial cell wall components initiate the interaction between bacteria and host. The reaction between bronchial epithelia and components in the envelope of mycobacterial cell wall is poorly understood.Methods: A lung-on-membrane model was developed with normal human bronchial epithelial (NHBE) cells re-differentiated at the air-liquid interface (ALI) and human endothelial cells on a transwell® polyester membrane. Microparticles from MAB cell walls were developed by an inhouse protocol and added to the ALI side of lung model. NHBE cells were harvested at day 3. RNA was isolated and analyzed with RNASeq. NHBE cells were lysed and protein assay was performed with western blot. We tested whether lung INF-alpha expression would increase in mice treated with intratracheal MAB cell wall particles. A paired t-test is used to compare two population means using GraphPad Prism 7 software.Results: RNAseq analysis identified 1759 differentially expressed genes between NHBE cells challenged with and without MAB microparticles with FDR < 0.5. 410 genes had a 2.5-fold change (FC) or greater. NHBE cells exposure to MAB microparticles significantly enriched the IFN I signaling pathway. Protein overexpression of IFN I family (2′-5′-Oligoadenylate Synthetase 1, Interferon-induced GTP-binding protein Mx1, Interferon-stimulated gene 15) was found in bronchial epithelial cells following exposure to MAB cell wall microparticles. IFN-α protein and gene expressions were significantly increased in mice lung challenged with microparticles in comparison with controls.Conclusion: These data strongly support the role of Type I IFN in cross-talk between NHBE cells and MAB. They also suggest that initiating immune response by NHBE cells may play a central role in innate immunity. Furthermore, this study underscores the importance of mycobacterial cell wall in initiating innate immune response.

Introduction: Hepatic granulomas are common in patients with sarcoidosis, but clinically significant liver disease is uncommon and poorly studied. We aimed to characterize the frequency and clinical course of hepatic sarcoidosis in an ethnically diverse population.Methods: This is a retrospective study including all cases of hepatic sarcoidosis in a single center. The median follow-up time was 49 months (4–121). Cases were identified based on ICD-9 and ICD-10 codes for granulomatous hepatitis, sarcoidosis, and hepatic sarcoidosis. The Chi-square and Wilcoxon-signed rank tests were used as indicated to assess for differences between groups.Results: Of 286 patients with sarcoidosis, 27 had hepatic involvement; 78% were female and 48% African American. The most common pattern of liver tests abnormalities was cholestatic. Ten patients had clinically significant hepatic involvement: cirrhosis in seven (25.9%), portal hypertension in nine (33%), and portal vein thrombosis in one (3.7%). Sex, race, and ethnicity were not associated with an increased risk of hepatic involvement or symptomatic hepatic sarcoidosis. Most patients received medical treatment, most commonly oral glucocorticoids. At the end of the follow-up period, all patients were alive but two had undergone liver transplantation due to complications of hepatic sarcoidosis. Three patients with hepatic sarcoidosis had initially been classified as AMA-negative PBC.Conclusions: Hepatic sarcoidosis was found in 9.4% of patients with sarcoidosis and was clinically significant in 37% of those. Identifying and monitoring hepatic sarcoidosis is crucial given its potential complications.

A subgroup of patients with systemic sclerosis (SSc) develop interstitial lung disease (ILD), characterized by inflammation and progressive scarring of the lungs that can lead to respiratory failure. Although ILD remains the major cause of death in these individuals, there is no consensus statement regarding the classification and characterization of SSc-related ILD (SSc-ILD). Recent clinical trials address the treatment of SSc-ILD and the results may lead to new disease-altering therapies. In this review, we provide an update to the diagnosis, management and treatment of SSc-ILD.

Melanocortin agonists are ancient neuropeptides that have steroidogenesis and anti-inflammatory properties. They activate melanocortin receptors (MCR), a family of five seven-transmembrane G-protein coupled receptors. MC1R and MC3R are mainly involved in immunomodulatory effects. Adrenocorticotropin hormone (ACTH) and alpha-Melanocortin stimulating hormone (α-MSH) reduce pro-inflammatory cytokines in several pulmonary inflammatory disorders including asthma, sarcoidosis, and the acute respiratory distress syndrome. They have also been shown to reduce fibrogenesis in animal models with pulmonary fibrosis. By understanding the functions of MCR in macrophages, T-helper cell type 1, and T-helper cell type 17, we may uncover the mechanism of action of melanocortin agonists in sarcoidosis. Further translational and clinical research is needed to define the role of ACTH and α-MSH in pulmonary diseases.

Background: little is known about the forecasting of new variants of SARS-COV-2 in North America and the interaction of variants with vaccine-derived neutralizing antibodies. Methods: the affinity scores of the spike receptor-binding domain (S-RBD) of B.1.1.7, B. 1.351, B.1.617, and P.1 variants in interaction with the neutralizing antibody (CV30 isolated from a patient), and human angiotensin-converting enzyme 2 (hACE2) receptor were predicted using the template-based computational modeling. From the Nextstrain global database, we identified prevalent mutations of S-RBD of SARS-CoV-2 from December 2019 to April 2021. Pre- and post-vaccination time series forecasting models were developed based on the prediction of neutralizing antibody affinity scores for S-RBD of the variants. Results: the proportion of the B.1.1.7 variant in North America is growing rapidly, but the rate will reduce due to high affinity (~90%) to the neutralizing antibody once herd immunity is reached. Currently, the rates of isolation of B. 1.351, B.1.617, and P.1 variants are slowly increasing in North America. Herd immunity is able to relatively control these variants due to their low affinity (~70%) to the neutralizing antibody. The S-RBD of B.1.617 has a 110% increased affinity score to the human angiotensin-converting enzyme 2 (hACE2) in comparison to the wild-type structure, making it highly infectious. Conclusion: The newly emerged B.1.351, B.1.617, and P.1 variants escape from vaccine-induced neutralizing immunity and continue circulating in North America in post- herd immunity era. Our study strongly suggests that a third dose of vaccine is urgently needed to cover novel variants with affinity scores (equal or less than 70%) to eliminate developing viral mutations and reduce transmission rates.