Early Use of Intrapleural Tissue Plasminogen Activator and Dornase Alfa in Loculated Pleural Effusion Due to Mycobacterium Tuberculosis.

Tuberculosis is a highly infectious respiratory disease due to Mycobacterium tuberculosis (MTb). The most common manifestation of MTb is pulmonary tuberculosis, but some patients can present with extrapulmonary manifestations as their initial presentation. Tuberculous pleurisy and pleural effusion are among the most common extrapulmonary manifestations of MTb. The treatment of pleural MTb is the same as the treatment for pulmonary disease, with a four-drug regimen with rifampin, isoniazid, pyrazinamide, and ethambutol (RIPE) under directly observed therapy (DOT). Drainage of the pleural effusion is usually not recommended in tuberculosis pleural effusion. We present a case of a complex, loculated pleural effusion due to MTb in an otherwise healthy middle-aged male who responded rapidly and completely to an early, short course of intrapleural tissue plasminogen activator and dornase alfa (TPA/DNase) therapy.

Discordance Between Invasive and NonInvasive Oxygen Saturation in Critically Ill COVID-19 Patients.

OBJECTIVES: To investigate discordance in oxy-hemoglobin saturation measured both by pulse oximetry (SpO2) and arterial blood gas (ABG, SaO2) among critically ill coronavirus disease 2019 (COVID-19(+)) patients compared to COVID-19(-) patients. METHODS: Paired SpO2 and SaO2 readings were collected retrospectively from consecutive adult admissions to four critical care units in the United States between March and May 2020. The primary outcome was the rate of discordance (|SaO2-SpO2|>4%) in COVID-19(+) versus COVID-19(-) patients. The odds each cohort could have been incorrectly categorized as having a PaO2/FiO2 above or below 150 by their SpO2: Fractional inhaled oxygen ratio (pulse oximetry-derived oxyhemoglobin saturation:fraction of inspired oxygen ratio [SF]) was examined. A multivariate regression analysis assessed confounding by clinical differences between cohorts including pH, body temperature, renal replacement therapy at time of blood draw, and self-identified race. RESULTS: There were 263 patients (173 COVID-19(+)) included. The rate of saturation discordance between SaO2 and SpO2 in COVID-19(+) patients was higher than in COVID-19(-) patients (27.9% vs 16.7%, odds ratio [OR] 1.94, 95% confidence interval [CI]: 1.11 to 2.27). The average difference between SaO2 and SpO2 for COVID-19(+) patients was -1.24% (limits of agreement, -13.6 to 11.1) versus -0.11 [-10.3 to 10.1] for COVID-19(-) patients. COVID-19(+) patients had higher odds (OR: 2.61, 95% CI: 1.14-5.98) of having an SF that misclassified that patient as having a PaO2:FiO2 ratio above or below 150. There was not an association between discordance and the confounders of pH, body temperature, or renal replacement therapy at time of blood draw. After controlling for self-identified race, the association between COVID-19 status and discordance was lost. CONCLUSIONS: Pulse oximetry was discordant with ABG more often in critically ill COVID-19(+) than COVID-19(-) patients. However, these findings appear to be driven by racial differences between cohorts.

Critically Ill Adults With Coronavirus Disease 2019 in New Orleans and Care With an Evidence-Based Protocol.

BACKGROUND: Characteristics of critically ill adults with coronavirus disease 2019 (COVID-19) in an academic safety net hospital and the effect of evidence-based practices in these patients are unknown. RESEARCH QUESTION: What are the outcomes of critically ill adults with COVID-19 admitted to a network of hospitals in New Orleans, Louisiana, and what is an evidence-based protocol for care associated with improved outcomes? STUDY DESIGN AND METHODS: In this multi-center, retrospective, observational cohort study of ICUs in four hospitals in New Orleans, Louisiana, we collected data on adults admitted to an ICU and tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) between March 9, 2020 and April 14, 2020. The exposure of interest was admission to an ICU that implemented an evidence-based protocol for COVID-19 care. The primary outcome was ventilator-free days. RESULTS: The initial 147 patients admitted to any ICU and tested positive for SARS-CoV-2 constituted the cohort for this study. In the entire network, exposure to an evidence-based protocol was associated with more ventilator-free days (25 days; 0-28) compared with non-protocolized ICUs (0 days; 0-23, P = .005), including in adjusted analyses (P = .02). Twenty patients (37%) admitted to protocolized ICUs died compared with 51 (56%; P = .02) in non-protocolized ICUs. Among 82 patients admitted to the academic safety net hospital's ICUs, the median number of ventilator-free days was 22 (interquartile range, 0-27) and mortality rate was 39%. INTERPRETATION: Care of critically ill COVID-19 patients with an evidence-based protocol is associated with increased time alive and free of invasive mechanical ventilation. In-hospital survival occurred in most critically ill adults with COVID-19 admitted to an academic safety net hospital's ICUs despite a high rate of comorbidities.

Asthma status moderates the relationship between neighbourhood disadvantage and obesity in African American adolescent females.

INTRODUCTION: Significant health disparities exist in asthma and obesity for African American youths. Successful interventions present an opportunity to address these disparities but require detailed study in order to ensure generalizability. This study investigated the intersection of obesity, neighbourhood disadvantage, and asthma. METHODS: Data were extracted from 129 African American females ages 13 to 19 years (mean = 15.6 years [SD = 1.9]). Obesity was measured via body mass index (BMI). Asthma status was based on clinical diagnosis and/or results of the International Study of Asthma and Allergies during Childhood (ISAAC) questionnaire. The concentrated disadvantage index (CDI) assessed neighbourhood disadvantage. RESULTS: Findings showed that 21.5% (n = 28) of participants were clinically defined as having asthma, 76.2% (n = 99) had obesity, and 24.9% (n = 31) were classified without obesity. The mean BMI was 35.1 (SD = 9.1) and the mean CDI was 1.0 (SD = 0.9). CDI and obesity were significantly associated in participants without asthma, but not in those with asthma. Multivariable linear regression results showed a significant interaction between CDI and asthma (t value = 2.2, P = .03). CONCLUSION: In sum, results from this study found that asthma moderated the relationship between neighbourhood disadvantage and obesity.

Step-Down Therapy for Asthma Well Controlled on Inhaled Corticosteroid and Long-Acting Beta-Agonist: A Randomized Clinical Trial.

BACKGROUND: Stepping down therapy when asthma is well controlled on combination inhaled corticosteroids (ICSs) and long-acting beta-agonists (LABAs) is recommended, but it is not known whether lowering the ICS dose or stopping LABA is superior. OBJECTIVE: To evaluate whether step-down therapy with LABA is superior to one without; and, secondarily, to evaluate whether reducing the ICS dose while maintaining LABA is noninferior to remaining on stable-ICS/LABA. METHODS: The study was a randomized, double-masked 3-arm parallel group trial in participants aged 12 years or older. Following an 8-week run-in, 459 participants were randomly assigned to continue medium-dose ICS/LABA, reduced-dose ICS/LABA, or ICS alone (LABA-step-off) and followed for 48 weeks. The primary outcome was time to treatment failure, a composite of health care utilization, systemic corticosteroid use, increase in rescue therapy, decline in lung function, or participant or physician decision. RESULTS: Time to treatment failure did not differ significantly between reduced- ICS/LABA and LABA-step-off (hazard ratio, 1.07; 95.3% CI, 0.69-1.65, P = .76). Nor was there a difference between stable-ICS/LABA and reduced-ICS/LABA (hazard ratio, 1.11; 95% CI, 0.70-1.76; P = .67), but the 10% noninferiority margin was exceeded. Lung function declines and hospitalization rates were significantly greater in the LABA-step-off group. CONCLUSIONS: The 2 step-down regimens did not differ in terms of treatment failure, although stopping LABA was associated with a decline in lung function and more hospitalizations. There was no evidence to support the noninferiority of reduced-ICS/LABA as compared with stable-ICS/LABA.

Treatment with intranasal iloprost reduces disease manifestations in a murine model of previously established COPD.

Pulmonary endothelial prostacyclin appears to be involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). The effect of treatment with a prostacyclin analog in animal models of previously established COPD is unknown. We evaluated the short- and long-term effect of iloprost on inflammation and airway hyperresponsiveness (AHR) in a murine model of COPD. Nineteen mice were exposed to LPS/elastase, followed by either three doses of intranasal iloprost or saline. In the long-term treatment experiment, 18 mice were exposed to LPS/elastase and then received 6 wk of iloprost or were left untreated as controls. In the short-term experiment, iloprost did not change AHR but significantly reduced serum IL-5 and IFN-γ. Long-term treatment with iloprost for both 2 and 6 wk significantly improved AHR. After 6 wk of iloprost, there was a reduction in bronchoalveolar lavage (BALF) neutrophils, serum IL-1ß (30.0 ± 9.2 vs. 64.8 ± 7.4 pg/ml, P = 0.045), IL-2 (36.5 ± 10.6 vs. 83.8 ± 0.4 pg/ml, P = 0.01), IL-10 (75.7 ± 9.3 vs. 96.5 ± 3.5 pg/ml, P = 0.02), and nitrite (15.1 ± 5.4 vs. 30.5 ± 10.7 µmol, P = 0.01). Smooth muscle actin (SMA) in the lung homogenate was also significantly reduced after iloprost treatment (P = 0.02), and SMA thickness was reduced in the small and medium blood vessels after iloprost (P < 0.001). In summary, short- and long-term treatment with intranasal iloprost significantly reduced systemic inflammation in an LPS/elastase COPD model. Long-term iloprost treatment also reduced AHR, serum nitrite, SMA, and BALF neutrophilia. These data encourage future investigations of prostanoid therapy as a novel treatment for COPD patients.

Chronic Binge Alcohol Administration Increases Intestinal T-Cell Proliferation and Turnover in Rhesus Macaques.

BACKGROUND: Alcohol use results in changes in intestinal epithelial cell turnover and microbial translocation, yet less is known about the consequences on intestinal lymphocytes in the gut. Here, we compared T-cell subsets in the intestine of macaques before and after 3 months of chronic alcohol administration to examine the effects of alcohol on intestinal T-cell subsets. METHODS: Rhesus macaques received either alcohol or isocaloric sucrose as a control treatment daily over a 3-month period via indwelling gastric catheters. Intestinal lymphocyte subsets were identified in biopsy samples by flow cytometry. Twenty-four hours prior to sampling, animals were inoculated with bromo-deoxyuridine (BrdU) to assess lymphocyte proliferation. Immunohistochemistry was performed on tissue samples to quantitate CD3+ cells. RESULTS: Animals receiving alcohol had increased rates of intestinal T-cell turnover of both CD4+ and CD8+ T cells as reflected by increased BrdU incorporation. However, absolute numbers of T cells were decreased in intestinal tissues as evidenced by immunohistochemistry for total CD3 expression per mm(2) intestinal lamina propria in tissue sections. Combining immunohistochemistry and flow cytometry data showed that the absolute numbers of CD8+ T cells were significantly decreased, whereas absolute numbers of total CD4+ T cells were minimally decreased. CONCLUSIONS: Collectively, these data indicate that alcohol exposure to the small intestine results in marked loss of CD3+ T cells, accompanied by marked increases in CD4+ and CD8+ T-cell proliferation and turnover, which we speculate is an attempt to maintain stable numbers of T cells in tissues. This suggests that alcohol results in accelerated T-cell turnover in the gut, which may contribute to premature T-cell senescence. Further, these data indicate that chronic alcohol administration results in increased levels of HIV target cells (proliferating CD4+ T cells) that may support higher levels of HIV replication in intestinal tissues.

Serotonin 5-HT2 receptor activation prevents allergic asthma in a mouse model.

Asthma is an inflammatory disease of the lung characterized by airways hyper-responsiveness (AHR), inflammation, and mucus hyperproduction. Current mainstream therapies include bronchodilators that relieve bronchoconstriction and inhaled glucocorticoids to reduce inflammation. The small molecule hormone and neurotransmitter serotonin has long been known to be involved in inflammatory processes; however, its precise role in asthma is unknown. We have previously established that activation of serotonin 5-hydroxytryptamine (5-HT)(2A) receptors has potent anti-inflammatory activity in primary cultures of vascular tissues and in the whole animal in vasculature and gut tissues. The 5-HT(2A) receptor agonist, (R)-2,5-dimethoxy-4-iodoamphetamine [(R)-DOI] is especially potent. In this work, we have examined the effect of (R)-DOI in an established mouse model of allergic asthma. In the ovalbumin mouse model of allergic inflammation, we demonstrate that inhalation of (R)-DOI prevents the development of many key features of allergic asthma, including AHR, mucus hyperproduction, airways inflammation, and pulmonary eosinophil recruitment. Our results highlight a likely role of the 5-HT2 receptors in allergic airways disease and suggest that 5-HT2 receptor agonists may represent an effective and novel small molecule-based therapy for asthma.

Radiology case of the month. Abnormally dilated arteries in an asymptomatic male. RADIOLOGIC DIAGNOSIS: Aortic coarctation. There is narrowing in the region of the aortic isthmus (arrows, Figures 2 and 4). The extent of collateral arterial dilation (arrows, Figures 1 and 3) suggests this to be a hemodynamically significant finding.

A 61-year-old male with a past medical history of chronic, uncontrolled hypertension received a non-contrasted computed tomogram (CT) of the chest and abdomen to investigate for possible Conn syndrome. This noncontrast study showed some areas of nodularity around the vertebral bodies bilaterally and extending into the posterior mediastinal region. A CT of the chest with intravenous contrast, and 3D reconstruction were then obtained.

Streptococcus pneumoniae translocates into the myocardium and forms unique microlesions that disrupt cardiac function.

Hospitalization of the elderly for invasive pneumococcal disease is frequently accompanied by the occurrence of an adverse cardiac event; these are primarily new or worsened heart failure and cardiac arrhythmia. Herein, we describe previously unrecognized microscopic lesions (microlesions) formed within the myocardium of mice, rhesus macaques, and humans during bacteremic Streptococcus pneumoniae infection. In mice, invasive pneumococcal disease (IPD) severity correlated with levels of serum troponin, a marker for cardiac damage, the development of aberrant cardiac electrophysiology, and the number and size of cardiac microlesions. Microlesions were prominent in the ventricles, vacuolar in appearance with extracellular pneumococci, and remarkable due to the absence of infiltrating immune cells. The pore-forming toxin pneumolysin was required for microlesion formation but Interleukin-1ß was not detected at the microlesion site ruling out pneumolysin-mediated pyroptosis as a cause of cell death. Antibiotic treatment resulted in maturing of the lesions over one week with robust immune cell infiltration and collagen deposition suggestive of long-term cardiac scarring. Bacterial translocation into the heart tissue required the pneumococcal adhesin CbpA and the host ligands Laminin receptor (LR) and Platelet-activating factor receptor. Immunization of mice with a fusion construct of CbpA or the LR binding domain of CbpA with the pneumolysin toxoid L460D protected against microlesion formation. We conclude that microlesion formation may contribute to the acute and long-term adverse cardiac events seen in humans with IPD.

Chronic alcohol induces M2 polarization enhancing pulmonary disease caused by exposure to particulate air pollution.

BACKGROUND: Chronic alcohol consumption causes persistent oxidative stress in the lung, leading to impaired alveolar macrophage (AM) function and impaired immune responses. AMs play a critical role in protecting the lung from particulate matter (PM) inhalation by removing particulates from the airway and secreting factors which mediate airway repair. We hypothesized AM dysfunction caused by chronic alcohol consumption increases the severity of injury caused by PM inhalation. METHODS: Age- and sex-matched C57BL/6 mice were fed the Lieber-DeCarli liquid diet containing either alcohol or an isocaloric substitution (control diet) for 8 weeks. Mice from both diet groups were exposed to combustion-derived PM (CDPM) for the final 2 weeks. AM number, maturation, and polarization status were assessed by flow cytometry. Noninvasive and invasive strategies were used to assess pulmonary function and correlated with histomorphological assessments of airway structure and matrix deposition. RESULTS: Co-exposure to alcohol and CDPM decreased AM number and maturation status (CD11c expression), while increasing markers of M2 activation (interleukin [IL]-4Rα, Ym1, Fizz1 expression, and IL-10 and transforming growth factor [TGF]-ß production). Changes in AM function were accompanied by decreased airway compliance and increased elastance. Altered lung function was attributable to elevated collagen content localized to the small airways and loss of alveolar integrity. Intranasal administration of neutralizing antibody to TGF-ß during the CDPM exposure period improved changes in airway compliance and elastance, while reducing collagen content caused by co-exposure. CONCLUSIONS: Combustion-derived PM inhalation causes enhanced disease severity in the alcoholic lung by stimulating the release of latent TGF-ß stores in AMs. The combinatorial effect of elevated TGF-ß, M2 polarization of AMs, and increased oxidative stress impairs pulmonary function by increasing airway collagen content and compromising alveolar integrity.

Effect of bacterial pneumonia on lung simian immunodeficiency virus (SIV) replication in alcohol consuming SIV-infected rhesus macaques.

BACKGROUND: Opportunistic infections in human immunodeficiency virus (HIV)-infected persons have been shown to increase the rate of HIV replication. In populations where prophylaxis against Pneumocystis pneumonia is utilized, bacterial pneumonia is now the leading cause of lower respiratory tract infection in HIV+ patients. Our prior studies have shown that chronic alcohol consumption in demarcated simian immunodeficiency virus (SIV)-infected rhesus macaques increases plasma viral load set point and accelerates progression to end-stage acquired immune deficiency syndrome. While chronic alcohol abuse is well known to increase the incidence and severity of bacterial pneumonia, the impact of alcohol consumption on local and systemic SIV/HIV burden during lung infection is unknown. Therefore, we utilized the macaque SIV infection model to examine the effect of chronic ethanol (EtOH) feeding on SIV burden during the course of pulmonary infection with Streptococcus pneumoniae, the most commonly identified etiology of bacterial pneumonia in HIV+ and HIV- persons in developed countries. METHODS: Alcohol was administered starting 3 months before SIVmac251 inoculation to the end of the study via an indwelling intragastric catheter to achieve a plasma alcohol concentration of 50 to 60 mM. Control animals received isocaloric sucrose. Four months after SIV infection, the right lung was inoculated with 2 × 10(6) CFU S. pneumoniae. RESULTS: Leukocyte recruitment into the lung, pulmonary bacterial clearance, and clinical course were similar between EtOH and control groups. While plasma SIV viral load was similar between groups postpneumonia, chronic EtOH-fed macaques showed a prolonged increase in SIV RNA in bronchoalveolar lavage fluid. Alveolar macrophages isolated from EtOH-fed macaques 1 day post-pneumonia showed greater nuclear factor kappa beta (NF-κB) activation. CONCLUSIONS: This study indicates that chronic EtOH feeding results in enhanced local, but not systemic, SIV replication following pneumococcal pneumonia. Increased NF-κB activity in the setting of chronic EtOH ingestion may play a mechanistic role in this observation.

The acute neutrophil response mediated by S100 alarmins during vaginal Candida infections is independent of the Th17-pathway.

Vulvovaginal candidiasis (VVC) caused by Candida albicans affects a significant number of women during their reproductive ages. Clinical observations revealed that a robust vaginal polymorphonuclear neutrophil (PMN) migration occurs in susceptible women, promoting pathological inflammation without affecting fungal burden. Evidence to date in the mouse model suggests that a similar acute PMN migration into the vagina is mediated by chemotactic S100A8 and S100A9 alarmins produced by vaginal epithelial cells in response to Candida. Based on the putative role for the Th17 response in mucosal candidiasis as well as S100 alarmin induction, this study aimed to determine whether the Th17 pathway plays a role in the S100 alarmin-mediated acute inflammation during VVC using the experimental mouse model. For this, IL-23p19(-/-), IL-17RA(-/-) and IL-22(-/-) mice were intravaginally inoculated with Candida, and vaginal lavage fluids were evaluated for fungal burden, PMN infiltration, the presence of S100 alarmins and inflammatory cytokines and chemokines. Compared to wild-type mice, the cytokine-deficient mice showed comparative levels of vaginal fungal burden and PMN infiltration following inoculation. Likewise, inoculated mice of all strains with substantial PMN infiltration exhibited elevated levels of vaginal S100 alarmins in both vaginal epithelia and secretions in the vaginal lumen. Finally, cytokine analyses of vaginal lavage fluid from inoculated mice revealed equivalent expression profiles irrespective of the Th17 cytokine status or PMN response. These data suggest that the vaginal S100 alarmin response to Candida does not require the cells or cytokines of the Th17 lineage, and therefore, the immunopathogenic inflammatory response during VVC occurs independently of the Th17-pathway.

Inhaled fluticasone propionate impairs pulmonary clearance of Klebsiella pneumoniae in mice.

BACKGROUND: Recent trials demonstrate increased pneumonia risk in chronic obstructive pulmonary disease patients treated with the inhaled corticosteroid (ICS) fluticasone propionate (FP). There is limited work describing FP effects on host defenses against bacterial pneumonia. METHODS: C57BL/6 mice received daily, nose-only exposure to nebulized FP or vehicle for 8 days, followed by pulmonary challenge with Klebsiella pneumoniae. Bacterial burden, phagocytosis, leukocyte recruitment, cytokine expression, nitric oxide release, and survival were measured. RESULTS: Inhaled FP increased bacterial burden in lungs and blood 48 h after infection but affected neither in vivo phagocytosis of bacteria by alveolar macrophages (AM) nor alveolar neutrophil recruitment. AM from FP-treated mice showed impaired expression of infection induced TNF-alpha, IP-10 (CXCL-10), and interleukin 6 (IL-6), and AM also showed a trend towards impaired intracellular pathogen control following in vivo infection. In vitro FP treatment resulted in a dose-dependent impairment of cytokine expression by AM. Furthermore, infection-induced nitric oxide (but not hydrogen peroxide) production was impaired by FP in vivo and in vitro. FP decreased survival in this model. CONCLUSIONS: Exposure to inhaled FP impairs pulmonary clearance of K. pneumoniae in mice, an effect associated with greater systemic bacteremia and death. Decreased AM cytokine and nitric oxide expression parallel the failure to control infection. These results support the study of ICS effects on human pulmonary host defenses.

The impact of alcohol on BCG-induced immunity against Mycobacterium tuberculosis.

BACKGROUND: Alcoholics are at heightened risk for developing active tuberculosis. This study evaluates chronic alcohol consumption in a murine model of vaccination with Mycobacterium bovis Bacille Calmette-Guèrin (BCG) and subsequent pulmonary infection with virulent Mycobacterium tuberculosis. METHODS: BALB/c mice were administered the Lieber-DeCarli liquid ethanol diet or pair-fed the liquid control diet for 3 weeks either before or after subcutaneous vaccination with M. bovis BCG. At least 3 weeks after BCG vaccination, groups of mice on the aforesaid diets were challenged with intratracheal infection with M. tuberculosis H37Rv. Lung mycobacterial burden, and lung and lung-associated lymph node CD4(+) lymphocyte production of tuberculosis-specific interferon (IFN)-γ were assayed. Popliteal lymph node lymphocytes from both dietary regimens undergoing BCG vaccination (in the absence of M. tuberculosis infection) were also evaluated for purified protein derivative-induced IFN-γ production by ELISpot assay. RESULTS: Mice begun on alcohol prior to vaccination with M. bovis BCG demonstrated impaired control of pulmonary challenge with virulent M. tuberculosis, as well as impaired lung CD4(+) and popliteal lymph node T-cell IFN-γ responses. If BCG vaccination was delivered prior to initiation of alcohol feeding, the mice remained protected against a subsequent challenge with M. tuberculosis, and BCG-induced immunity was not impaired in either the lung or the popliteal lymph nodes. CONCLUSIONS: Alcohol consumption blunts the development of the adaptive immune response to M. bovis BCG vaccination, which impairs the control of a secondary challenge with M. tuberculosis, but only if the alcohol exposure is begun prior to BCG vaccination. These results provide insight into mechanisms by which alcohol consumption impairs antimycobacterial immunity, including in response to vaccination and subsequent pathogenic challenge.

Mechanisms of neutrophil accumulation in the lungs against bacteria.

Bacterial lung diseases are a major cause of morbidity and mortality both in immunocompromised and in immunocompetent individuals. Neutrophil accumulation, a pathological hallmark of bacterial diseases, is critical to host defense, but may also cause acute lung injury/acute respiratory distress syndrome. Toll-like receptors, nucleotide-binding oligomerization domain (NOD)-like receptors, transcription factors, cytokines, and chemokines play essential roles in neutrophil sequestration in the lungs. This review highlights our current understanding of the role of these molecules in the lungs during bacterial infection and their therapeutic potential. We also discuss emerging data on cholesterol and ethanol as environmentally modifiable factors that may impact neutrophil-mediated pulmonary innate host defense. Understanding the precise molecular mechanisms leading to neutrophil influx in the lungs during bacterial infection is critical for the development of more effective therapeutic and prophylactic strategies to control the excessive host response to infection.

Focus on: Alcohol and the immune system.

Alcohol abuse suppresses multiple arms of the immune response, leading to an increased risk of infections. The course and resolution of both bacterial and viral infections is severely impaired in alcohol-abusing patients, resulting in greater patient morbidity and mortality. Multiple mechanisms have been identified underlying the immunosuppressive effects of alcohol. These mechanisms involve structural host defense mechanisms in the gastrointestinal and respiratory tract as well as all of the principal components of the innate and adaptive immune systems, which are compromised both through alcohol's direct effects and through alcohol-related dysregulation of other components. Analyses of alcohol's diverse effects on various components of the immune system provide insight into the factors that lead to a greater risk of infection in the alcohol-abusing population. Some of these mechanisms are directly related to the pathology found in people with infections such as HIV/AIDS, tuberculosis, hepatitis, and pneumonia who continue to use and abuse alcohol.

Alcohol's role in HIV transmission and disease progression.

Alcohol use has negative effects on HIV disease progression through several mechanisms, including transmission, viral replication, host immunity, and treatment efficacy. Research with animal models has explored the effect of alcohol intake on several aspects of simian immunodeficiency virus (SIV) disease progression. Data suggest that the increased SIV levels observed in alcohol-consuming animals may represent an increase in virus production as opposed to a decrease in host defense. Results also suggest that changes in nutritional balance and metabolism, as a possible consequence of a proinflammatory state, together with increased virus production in animals consuming alcohol, accelerate SIV and possibly HIV disease progression. Further studies using the animal model are necessary.

Acute alcohol intoxication inhibits the lineage- c-kit+ Sca-1+ cell response to Escherichia coli bacteremia.

Alcohol abuse predisposes the host to bacterial infections. In response to bacterial infection, the bone marrow hematopoietic activity shifts toward granulocyte production, which is critical for enhancing host defense. This study investigated the hematopoietic precursor cell response to bacteremia and how alcohol affects this response. Acute alcohol intoxication was induced in BALB/c mice 30 min before initiation of Escherichia coli bacteremia. Bacteremia caused a significant increase in the number of bone marrow lineage (lin(-))-c-kit(+)Sca-1(+) cells. Marrow lin(-)c-kit(+)Sca-1(+) cells isolated from bacteremic mice showed an increase in CFU-granulocyte/macrophage activity compared with controls. In addition to enhanced proliferation of lin(-)c-kit(+)Sca-1(+) cells as reflected by BrdU incorporation, phenotypic inversion of lin(-)c-kit(+)Sca-1(+)Sca-1(-) cells primarily accounted for the rapid increase in marrow lin(-)c-kit(+)Sca-1(+) cells following bacteremia. Bacteremia increased plasma concentration of TNF-alpha. Culture of marrow lin(-)c-kit(+)Sca-1(+)Sca-1(-) cells with murine rTNF-alpha for 24 h caused a dose-dependent increase in conversion of these cells to lin(-)c-kit(+)Sca-1(+) cells. Sca-1 mRNA expression by the cultured cells was also up-regulated following TNF-alpha stimulation. Acute alcohol intoxication inhibited the increase in the number of lin(-)c-kit(+)Sca-1(+) cells in the bone marrow after E. coli infection. Alcohol impeded the increase in BrdU incorporation into marrow lin(-)c-kit(+)Sca-1(+) cells in response to bacteremia. Alcohol also suppressed the plasma TNF-alpha response to bacteremia and inhibited TNF-alpha-induced phenotypic inversion of lin(-)c-kit(+)Sca-1(+)Sca-1(-) cells in vitro. These data show that alcohol inhibits the hematopoietic precursor cell response to bacteremia, which may serve as one mechanism underlying the impaired host defense in alcohol abusers with severe bacterial infections.