Rationale: Two molecular phenotypes of the acute respiratory distress syndrome (ARDS) with divergent clinical trajectories and responses to therapy have been identified. Classification as "hyperinflammatory" or "hypoinflammatory" depends on plasma biomarker profiling. Limited data are available about the differences in the pulmonary biology of the molecular phenotypes. Objectives: To identify differences in the pulmonary biology of ARDS molecular phenotypes Methods: We compared tracheal aspirate gene expression between hyperinflammatory and hypoinflammatory phenotypes in bulk RNA sequencing (RNASeq) from coronavirus disease (COVID-19) and non-COVID-19 ARDS and single-cell RNASeq from non-COVID-19 ARDS. In a subset of subjects, we also compared plasma proteomic data. Measurements and Main Results: In bulk RNASeq analyses, 1,157 genes were differentially expressed (false discovery rate < 0.1) between phenotypes in non-COVID-19 ARDS, and 85 genes were differentially expressed between phenotypes in COVID-19 ARDS. Eighteen genes were reproducibly differentially expressed between phenotypes in both cohorts, including greater expression of IL32, HSPA8, and PPP3CC in hyperinflammatory ARDS. A total of 195 pathways were reproducibly enriched across the two cohorts by gene set enrichment analysis, including greater expression of granulopoiesis, T-cell and IFN signaling, and integrated stress response pathways in hyperinflammatory ARDS. Network analysis of single-cell RNASeq in a third group of patients identified greater T-cell signaling to other immune cells in hyperinflammatory ARDS. Conclusions: Hyperinflammatory and hypoinflammatory ARDS molecular phenotypes have distinct respiratory biology. Hyperinflammatory ARDS is characterized by an increased IFN-stimulated gene expression and T-cell activation in the lungs.

Sarcoidosis is a chronic granulomatous disease, which can affect the central nervous system (CNS) in 5-10% of cases and can mimic other CNS infections. Presence of non-necrotizing granulomas is associated with neurosarcoidosis, while necrotizing granulomas are a histological hallmark of neurotuberculosis. We present a case of necrotizing granulomas in a patient ultimately diagnosed with neurosarcoidosis, highlighting the diagnostic complexity.A 28-year-old female with history of aqueductal stenosis and VP shunt presented with several months of progressive gait ataxia and anterograde amnesia. MRI brain showed diffuse leptomeningeal and subarachnoid enhancement concerning for granulomatous encephalitis. Key tests, including TB QuantiFERON, HIV, Brucella, and Syphilis, were negative. Inflammatory markers were elevated including C-reactive protein (60 mg/L, ULN 5 mg/L) and angiotensin-converting enzyme (77 U/L, ULN 67 U/L). Lumbar punctures revealed lymphocytic pleocytosis, extremely elevated protein, and low glucose. A brain biopsy demonstrated necrotizing granulomas, without bacterial or fungal organisms. Empiric treatment for neurotuberculosis with RIPE therapy was initiated while awaiting AFB and fungal cultures, in addition to high dose steroids in concordance with TB meningitis protocol. Over the course of eight weeks of treatment, the patient's cognition and balance improved. Ultimately, RIPE therapy was discontinued after serial AFB, fungal cultures, and brain tissue AFB were finalized as negative.This case underscores the challenges in differentiating neurosarcoidosis from infectious granulomatous conditions, particularly neurotuberculosis. While necrotizing granulomas suggest neurotuberculosis, this patient's absence of risk factors for TB, negative cultures, cerebrospinal fluid profile, and marked improvement with immunosuppressive therapy supported a diagnosis of neurosarcoidosis. Neurosarcoidosis has a highly variable presentation, most commonly manifesting as cranial neuropathy. However, spinal cord and cerebellar involvement can present as ataxia and cognitive decline. This patient's CT chest showed sub-CM hilar adenopathy, but she lacked other manifestations including ocular, skin, cardiac, muscle, liver or renal involvement. Thus, it is important to recognize that neurosarcoid can be the presenting manifestation of sarcoidosis and occur in isolation.In this case, the patient's unusual biopsy findings prompted initial treatment for neurotuberculosis, but ultimately her presentation was most consistent with chronic lymphocytic meningitis secondary to neurosarcoidosis. Though necrotizing granulomas are rare in neurosarcoidosis, they do not exclude the diagnosis. Clinicians must carefully weigh diagnostic findings against the broader clinical picture, particularly where empiric treatments may initially cloud the diagnosis. Continued monitoring and response to therapy are essential in refining diagnoses and optimizing outcomes in complex cases such as this.

Background Two molecular phenotypes of the acute respiratory distress syndrome (ARDS) with divergent clinical trajectories and responses to therapy have been identified. Classification as “hyperinflammatory” or “hypoinflammatory” depends on plasma biomarker profiling. Differences in pulmonary biology underlying these phenotypes are unknown.Methods We analyzed tracheal aspirate (TA) RNA sequencing (RNASeq) data from 41 ARDS patients and 5 mechanically ventilated controls to assess differences in lung inflammation and repair between ARDS phenotypes. In a subset of subjects, we also analyzed plasma proteomic data. We performed single-cell RNA sequencing (scRNASeq) on TA samples from 9 ARDS patients. We conducted differential gene expression and gene set enrichment analyses, in silico prediction of pharmacologic treatments, and compared results to experimental models of acute lung injury.Findings In bulk RNASeq data, 1334 genes were differentially expressed between ARDS phenotypes (false detection rate < 0.1). Hyperinflammatory ARDS was characterized by an exaggerated innate immune response, increased activation of the integrated stress response, interferon signaling, apoptosis, and T-cell activation. Gene sets from experimental models of lipopolysaccharide lung injury overlapped more strongly with hyperinflammatory than hypoinflammatory ARDS, though overlap in gene expression between experimental and clinical samples was variable. ScRNASeq demonstrated a central role for T-cells in the hyperinflammatory phenotype. Plasma proteomics confirmed a role for innate immune activation, interferon signaling, and T-cell activation in the hyperinflammatory phenotype. Predicted candidate therapeutics for the hyperinflammatory phenotype included imatinib and dexamethasone.Interpretation Hyperinflammatory and hypoinflammatory ARDS phenotypes have distinct respiratory tract biology, which could inform targeted therapeutic development.Funding National Institutes of Health; University of California San Francisco ImmunoX CoLabs; Chan Zuckerberg Foundation; Genentech### Competing Interest StatementThe authors have declared no competing interest.### Funding StatementThis study was funded by the NIH: F32HL151117 (AS), R35HL140026 (CSC), 2R24AA019661-06A1 (CSC), NIH/NHLBI K23HL138461-01A1 (CRL), U19 AI1077439 (DJE, CSC). Additional funding from: UCSF ImmunoX CoLabs, Chan Zuckerberg Foundation 2019-202665, Genentech TSK-020586### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:These studies were approved by the UCSF Institutional Review Board (17-24056, 20-30497), which granted an initial waiver of informed consent to collect TA and blood samples within 48 hours of ICU admission. Informed consent was then obtained from patients or surrogates.I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAll data produced in the present study are available upon reasonable request to the authors

Rationale: Cigarette smoke exposure is associated with an increased risk of developing acute respiratory distress syndrome (ARDS) in trauma, transfusion, and nonpulmonary sepsis. It is unknown whether this relationship exists in the general sepsis population. Furthermore, it is unknown if patients with ARDS have differences in underlying biology based on smoking status. Objectives: To assess the relationship between cigarette smoke exposure and ARDS in sepsis and identify tobacco-related biomarkers of lung injury. Methods: We studied a prospective cohort of 592 patients with sepsis from 2009 to 2017. Plasma cotinine and urine NNAL [urine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol] were measured to categorize smoking status. Plasma biomarkers of inflammation and lung injury were measured, including in a smaller cohort of trauma patients with ARDS to increase generalizability. Measurements and Main Results: Passive and active smoking were associated with increased odds of developing ARDS in patients with sepsis. Among patients with sepsis and ARDS, active cigarette smokers were younger and had lower severity of illness than nonsmokers. Patients with ARDS with cigarette smoke exposure had lower plasma levels of IL-8 (P = 0.01) and sTNFR-1 (soluble tumor necrosis factor 1; P = 0.01) compared with those without exposure. Similar biomarker patterns were observed in blunt trauma patients with ARDS. Conclusions: Passive and active smoking are associated with an increased risk of developing ARDS in patients with pulmonary and nonpulmonary sepsis. Among patients with ARDS, those with cigarette smoke exposure have less systemic inflammation, while active smokers also have lower severity of illness compared with nonsmokers, suggesting that smoking contributes to biological heterogeneity in ARDS.

RATIONALE Cigarette smoke exposure is associated with an increased risk of developing ARDS in trauma, transfusion, and non-pulmonary sepsis. It is unknown whether this relationship exists in the general sepsis population. Furthermore, it is unknown if ARDS patients have differences in underlying biology based on smoking status. OBJECTIVES To assess the relationship between cigarette smoke exposure and ARDS in sepsis and identify tobacco-related biomarkers of lung injury. METHODS We studied a prospective cohort of 592 septic patients from 2009 - 2017. Plasma cotinine and urine NNAL were measured to categorize smoking status. Plasma biomarkers of inflammation and lung injury were measured, including in a smaller cohort of trauma patients with ARDS to increase generalizability. MEASUREMENTS AND MAIN RESULTS Passive and active smoking were associated with increased odds of developing ARDS in patients with sepsis. Amongst septic patients with ARDS, active cigarette smokers were younger and had lower severity of illness than nonsmokers. ARDS patients with cigarette smoke exposure had lower plasma levels of IL-8 (p = 0.01) and sTNFR-1 (p = 0.01) compared to those without exposure. Similar biomarker patterns were observed in blunt trauma patients with ARDS. CONCLUSIONS Passive and active smoking are associated with an increased risk of developing ARDS in patients with pulmonary and non-pulmonary sepsis. Amongst patients with ARDS, those with cigarette smoke exposure have less systemic inflammation, while active smokers also have lower severity of illness compared to nonsmokers, suggesting that smoking contributes to biological heterogeneity in ARDS.

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The immunological features that distinguish COVID-19-associated acute respiratory distress syndrome (ARDS) from other causes of ARDS are incompletely understood. Here, we report the results of comparative lower respiratory tract transcriptional profiling of tracheal aspirate from 52 critically ill patients with ARDS from COVID-19 or from other etiologies, as well as controls without ARDS. In contrast to a "cytokine storm," we observe reduced proinflammatory gene expression in COVID-19 ARDS when compared to ARDS due to other causes. COVID-19 ARDS is characterized by a dysregulated host response with increased PTEN signaling and elevated expression of genes with non-canonical roles in inflammation and immunity. In silico analysis of gene expression identifies several candidate drugs that may modulate gene expression in COVID-19 ARDS, including dexamethasone and granulocyte colony stimulating factor. Compared to ARDS due to other types of viral pneumonia, COVID-19 is characterized by impaired interferon-stimulated gene (ISG) expression. The relationship between SARS-CoV-2 viral load and expression of ISGs is decoupled in patients with COVID-19 ARDS when compared to patients with mild COVID-19. In summary, assessment of host gene expression in the lower airways of patients reveals distinct immunological features of COVID-19 ARDS.

We performed comparative lower respiratory tract transcriptional profiling of 52 critically ill patients with the acute respiratory distress syndrome (ARDS) from COVID-19 or from other etiologies, as well as controls without ARDS. In contrast to a cytokine storm, we observed reduced proinflammatory gene expression in COVID-19 ARDS when compared to ARDS due to other causes. COVID-19 ARDS was characterized by a dysregulated host response with increased PTEN signaling and elevated expression of genes with non-canonical roles in inflammation and immunity that were predicted to be modulated by dexamethasone and granulocyte colony stimulating factor. Compared to ARDS due to other types of viral pneumonia, COVID-19 was characterized by impaired interferon-stimulated gene expression (ISG). We found that the relationship between SARS-CoV-2 viral load and expression of ISGs was decoupled in patients with COVID-19 ARDS when compared to patients with mild COVID-19. In summary, assessment of host gene expression in the lower airways of patients with COVID-19 ARDS did not demonstrate cytokine storm but instead revealed a unique and dysregulated host response predicted to be modified by dexamethasone.

BACKGROUND: Cigarette smoking is associated with an increased risk of developing ARDS. However, whether changes in smoking patterns or processes of care impact this relationship is unclear. RESEARCH QUESTION: Are changes in smoking and resuscitation patterns associated with changes in the relationship between smoking and ARDS? STUDY DESIGN AND METHOD We conducted a prospective cohort study of critically injured adults with blunt trauma from 2005 to 2015. Plasma cotinine, a tobacco biomarker, was measured to categorize patients by smoking status. We used regression to assess the relationship between smoking, resuscitation practices, and ARDS over time. RESULTS: In the overall cohort, active (OR, 1.9; 95% CI, 1.0-3.5; P = .046) and passive (OR, 2.6; 95% CI, 1.4-4.8; P = .002) smoking were associated with an increased risk of developing ARDS in multivariate analyses. In contrast to the dose-response relationship in patients enrolled from 2005 to 2008, passive cigarette smoke exposure was associated with the highest risk of developing ARDS in patients enrolled from 2009 to 2015, suggesting a threshold effect. Packed RBC (pRBC) and fresh frozen plasma (FFP) transfusions were associated with an increased risk of developing ARDS, particularly in active smokers (pRBC: OR, 5.6; P < .001; FFP: OR, 4.5; P < .001) compared with passive smokers or nonsmokers. Blood product transfusion and smoking patterns changed over time. INTERPRETATION: Despite changes in resuscitation and smoking patterns, cigarette smoking remains associated with an increased risk of developing ARDS. However, this relationship changed over time, with passive smokers at particularly increased risk of developing ARDS in later years, which may be related to changes in smoking patterns or transfusion practices over time. These findings highlight the need for additional mechanistic and epidemiologic studies of the effects of low levels of cigarette smoke exposure on lung health.

Background Cigarette smoking is associated with an increased risk of developing ARDS. However, whether changes in smoking patterns or processes of care impact this relationship is unclear. Research Question Are changes in smoking and resuscitation patterns associated with changes in the relationship between smoking and ARDS? Study Design and Methods We conducted a prospective cohort study of critically injured adults with blunt trauma from 2005 to 2015. Plasma cotinine, a tobacco biomarker, was measured to categorize patients by smoking status. We used regression to assess the relationship between smoking, resuscitation practices, and ARDS over time. Results In the overall cohort, active (OR, 1.9; 95% CI, 1.0-3.5; P = .046) and passive (OR, 2.6; 95% CI, 1.4-4.8; P = .002) smoking were associated with an increased risk of developing ARDS in multivariate analyses. In contrast to the dose-response relationship in patients enrolled from 2005 to 2008, passive cigarette smoke exposure was associated with the highest risk of developing ARDS in patients enrolled from 2009 to 2015, suggesting a threshold effect. Packed RBC (pRBC) and fresh frozen plasma (FFP) transfusions were associated with an increased risk of developing ARDS, particularly in active smokers (pRBC: OR, 5.6; P < .001; FFP: OR, 4.5; P < .001) compared with passive smokers or nonsmokers. Blood product transfusion and smoking patterns changed over time. Interpretation Despite changes in resuscitation and smoking patterns, cigarette smoking remains associated with an increased risk of developing ARDS. However, this relationship changed over time, with passive smokers at particularly increased risk of developing ARDS in later years, which may be related to changes in smoking patterns or transfusion practices over time. These findings highlight the need for additional mechanistic and epidemiologic studies of the effects of low levels of cigarette smoke exposure on lung health. Cigarette smoking is associated with an increased risk of developing ARDS. However, whether changes in smoking patterns or processes of care impact this relationship is unclear. Are changes in smoking and resuscitation patterns associated with changes in the relationship between smoking and ARDS? We conducted a prospective cohort study of critically injured adults with blunt trauma from 2005 to 2015. Plasma cotinine, a tobacco biomarker, was measured to categorize patients by smoking status. We used regression to assess the relationship between smoking, resuscitation practices, and ARDS over time. In the overall cohort, active (OR, 1.9; 95% CI, 1.0-3.5; P = .046) and passive (OR, 2.6; 95% CI, 1.4-4.8; P = .002) smoking were associated with an increased risk of developing ARDS in multivariate analyses. In contrast to the dose-response relationship in patients enrolled from 2005 to 2008, passive cigarette smoke exposure was associated with the highest risk of developing ARDS in patients enrolled from 2009 to 2015, suggesting a threshold effect. Packed RBC (pRBC) and fresh frozen plasma (FFP) transfusions were associated with an increased risk of developing ARDS, particularly in active smokers (pRBC: OR, 5.6; P < .001; FFP: OR, 4.5; P < .001) compared with passive smokers or nonsmokers. Blood product transfusion and smoking patterns changed over time. Despite changes in resuscitation and smoking patterns, cigarette smoking remains associated with an increased risk of developing ARDS. However, this relationship changed over time, with passive smokers at particularly increased risk of developing ARDS in later years, which may be related to changes in smoking patterns or transfusion practices over time. These findings highlight the need for additional mechanistic and epidemiologic studies of the effects of low levels of cigarette smoke exposure on lung health.

Accurate and informative microbiological testing is essential for guiding diagnosis and management of pneumonia in patients who are critically ill. Sampling of tracheal aspirate (TA) is less invasive compared with mini-bronchoalveolar lavage (mBAL) and is now recommended as a frontline diagnostic approach in patients who are mechanically ventilated, despite the historical belief that TA was suboptimal due to contamination from oral microbes. Advancements in metagenomic next-generation sequencing (mNGS) now permit assessment of airway microbiota without a need for culture and, as such, provide an opportunity to examine differences between mBAL and TA at a resolution previously unachievable. Here, we engaged shotgun mNGS to assess quantitatively the airway microbiome in matched mBAL and TA specimens from a prospective cohort of critically ill adults. We observed moderate differences between sample types across all subjects; however, we found significant compositional similarity in subjects with bacterial pneumonia, whose microbial communities were characterized by dominant pathogens. In contrast, in patients with noninfectious acute respiratory illnesses, significant differences were observed between sample types. Our findings suggest that TA sampling provides a similar assessment of airway microbiota as more invasive testing by mBAL in patients with pneumonia.

Culture-confirmed bacteremia occurs in only a fraction of pneumonia cases. The degree to which microbial DNA circulates in blood of patients with pneumonia, however, is unknown. Detection of cell-free microbial DNA from plasma is a promising new tool for infectious disease diagnosis. We conducted unbiased metagenomic next-generation sequencing (mNGS) of paired plasma and respiratory fluid from 25 subjects, 18 with pneumonia (four with concurrent bloodstream infections) and seven with non-infectious respiratory illnesses. Cell-free plasma mNGS identified one or more culture-confirmed bacterial or fungal pathogens in 67% of patients with pneumonia, compared to 100% for respiratory mNGS. In two patients who developed probable ventilator-associated pneumonia (VAP), plasma mNGS afforded early detection of the eventual culture-confirmed VAP pathogens. Our findings suggest that in a majority of patients with severe pneumonia, circulating microbial DNA from confirmed respiratory pathogens can be detected in the bloodstream, even in the setting of negative blood cultures.

Culture-confirmed bacteremia occurs in only a fraction of pneumonia cases. The degree to which microbial DNA circulates in blood of patients with pneumonia, however, is unknown. Detection of cell-free microbial DNA from plasma is a promising new tool for infectious disease diagnosis. We conducted unbiased metagenomic next-generation sequencing (mNGS) of paired plasma and respiratory fluid from 25 subjects, 18 with pneumonia (four with concurrent bloodstream infections) and seven with non-infectious respiratory illnesses. Cell-free plasma mNGS identified one or more culture-confirmed bacterial or fungal pathogens in 72% of patients with pneumonia, compared to 100% for respiratory mNGS. In two patients who developed probable ventilator-associated pneumonia (VAP), plasma mNGS afforded early detection of the eventual culture-confirmed VAP pathogens. Our findings suggest that in a majority of patients with severe pneumonia, circulating microbial DNA from confirmed respiratory pathogens can be detected in the bloodstream, even in the setting of negative blood cultures.

BACKGROUND Acute respiratory distress syndrome (ARDS) following trauma is historically associated with crystalloid and blood product exposure. Advances in resuscitation have occurred over the last decade, but their impact on ARDS is unknown. We sought to investigate predictors of postinjury ARDS in the era of hemostatic resuscitation. METHODS Data were prospectively collected from arrival to 28 days for 914 highest-level trauma activations who required intubation and survived more than 6 hours from 2005 to 2016 at a Level I trauma center. Patients with ratio of partial pressure of oxygen to fraction of inspired oxygen of 300 mmHg or less during the first 8 days were identified. Two blinded expert clinicians adjudicated all chest radiographs for bilateral infiltrates in the first 8 days. Those with left-sided heart failure detected were excluded. Multivariate logistic regression was used to define predictors of ARDS. RESULTS Of the 914 intubated patients, 63% had a ratio of partial pressure of oxygen to fraction of inspired oxygen of 300 or less, and 22% developed ARDS; among the ARDS cases, 57% were diagnosed early (in the first 24 hours), and 43% later. Patients with ARDS diagnosed later were more severely injured (ISS 32 vs. 20, p = 0.001), with higher rates of blunt injury (84% vs. 72%, p = 0.008), chest injury (58% vs. 36%, p < 0.001), and traumatic brain injury (72% vs. 48%, p < 0.001) compared with the no ARDS group. In multivariate analysis, head/chest Abbreviated Injury Score scores, crystalloid from 0 to 6 hours, and platelet transfusion from 0 to 6 hours and 7 to 24 hours were independent predictors of ARDS developing after 24 hours. CONCLUSIONS Blood and plasma transfusion were not independently associated with ARDS. However, platelet transfusion was a significant independent risk factor. The role of platelets warrants further investigation but may be mechanistically explained by lung injury models of pulmonary platelet sequestration with peripheral thrombocytopenia. LEVEL OF EVIDENCE Prognostic study, level IV.

BACKGROUND The risk of the acute respiratory distress syndrome (ARDS) is increased in passive and active smokers after blunt trauma. However, the mechanisms responsible, including the role of platelet aggregation, for this association are unknown. METHODS We analyzed 215 patients with severe blunt trauma from a prospective observational cohort at a Level I trauma center between 2010 and 2015. Subjects underwent impedance-based platelet aggregometry in response to platelet agonists arachidonic acid, adenosine diphosphate, collagen, and thrombin receptor activating peptide-6. Acute respiratory distress syndrome within the first 8 days of admission was adjudicated using Berlin criteria. Plasma cotinine was measured to assess cigarette smoke exposure. Regression analyses were used to assess the relationship between (1) platelet aggregation and ARDS and (2) cigarette smoke exposure and platelet aggregation. RESULTS At both 0 hour and 24 hours, impaired platelet aggregation was associated with increased odds of developing ARDS. Cigarette smoke exposure was associated with increased platelet aggregation upon arrival to the emergency department. However, at 24 hours, cigarette smoke exposure was associated with increased impairment in platelet aggregation, reflecting a statistically significant decline in platelet aggregation over the initial 24 hours after trauma. The relationship between this decline in platelet aggregation and ARDS differed by cigarette smoke exposure status, suggesting that impaired platelet activation differentially affects the risk of ARDS in those with cigarette smoke exposure (arachidonic acid, p for interaction: 0.005, collagen p for interaction: 0.02, adenosine diphosphate, p for interaction: 0.05). CONCLUSION Impaired platelet aggregation at 0 hour and 24 hours is associated with an increased risk of developing ARDS after severe blunt trauma. Cigarette smoke–exposed patients are more likely to develop impaired platelet aggregation over the first 24 hours of admission, which may contribute to their increased risk of ARDS. Level of Evidence Prognostic/Epidemiological, level III.

On 25 January 2018, the Food and Drug Administration (FDA) Tobacco Scientific Advisory Committee unanimously voted (with one abstention) that Phillip Morris International (PMI) could not claim their heated tobacco product (HTP) IQOS (I-Quit-Ordinary-Smoking) would reduce the risk of tobacco-related diseases. Regardless, IQOS is already available in over 30 countries, and thus merits scrutiny from the scientific and medical communities. The preclinical and clinical data PMI submitted to FDA indicate that IQOS exposure may be associated with unexpected liver toxicity. We reviewed preclinical studies conducted by PMI scientists1 and clinical studies of 5 and 90 days of exposure to IQOS and IQOS menthol2–5 included in PMI’s Modified Risk Tobacco Product application submitted to the US FDA.Wong and colleagues1 exposed 92 male and 92 female Sprague Dawley rats to up to 90 days of mainstream aerosol from IQOS, mainstream smoke from 3R4F research cigarettes, or room air (sham). After 90 days of exposure, liver weights and blood levels …

Lower respiratory tract infections (LRTIs) lead to more deaths each year than any other infectious disease category. Despite this, etiologic LRTI pathogens are infrequently identified due to limitations of existing microbiologic tests. In critically ill patients, noninfectious inflammatory syndromes resembling LRTIs further complicate diagnosis. To address the need for improved LRTI diagnostics, we performed metagenomic next-generation sequencing (mNGS) on tracheal aspirates from 92 adults with acute respiratory failure and simultaneously assessed pathogens, the airway microbiome, and the host transcriptome. To differentiate pathogens from respiratory commensals, we developed a rules-based model (RBM) and logistic regression model (LRM) in a derivation cohort of 20 patients with LRTIs or noninfectious acute respiratory illnesses. When tested in an independent validation cohort of 24 patients, both models achieved accuracies of 95.5%. We next developed pathogen, microbiome diversity, and host gene expression metrics to identify LRTI-positive patients and differentiate them from critically ill controls with noninfectious acute respiratory illnesses. When tested in the validation cohort, the pathogen metric performed with an area under the receiver-operating curve (AUC) of 0.96 (95% CI, 0.86-1.00), the diversity metric with an AUC of 0.80 (95% CI, 0.63-0.98), and the host transcriptional classifier with an AUC of 0.88 (95% CI, 0.75-1.00). Combining these achieved a negative predictive value of 100%. This study suggests that a single streamlined protocol offering an integrated genomic portrait of pathogen, microbiome, and host transcriptome may hold promise as a tool for LRTI diagnosis.

The scientific evidence supports a specific standard for all combusted tobacco products, with a nicotine level for the standard implemented in a single step. The tobacco companies have already shown that it is technically possible to implement such a standard. In implementing this standard there are substantial risks of adversely affecting risk perceptions, especially among youth, that could lead to increased use of nicotine products not covered by the new standard. Effectively countering these adverse effects needs to be part of the standard and associated public education from the beginning to prevent the tobacco industry from taking advantage of this standard to expand its market resulting in net population harm. Lowering the nicotine delivery of all combusted tobacco products – not just cigarettes – if written and enforced vigorously in a way that anticipates tobacco industry efforts to thwart the intent of the standard, holds promise for improving public health.