Placebo found equivalent to amoxicillin for treatment of acute bronchitis in Nairobi, Kenya: a triple blind, randomised, equivalence trial.

BACKGROUND: Antibiotic treatment is not recommended for acute bronchitis in immunocompetent patients in industrialised countries. Whether these recommendations are relevant to the developing world and to immunocompromised patients is unknown. DESIGN, SETTING AND PARTICIPANTS: Randomised, triple blind, placebo controlled equivalence trial of amoxicillin compared with placebo in 660 adults presenting to two outpatient clinics in Nairobi, Kenya, with acute bronchitis but without evidence of chronic lung disease. MAIN OUTCOME MEASURE: The primary study end point was clinical cure, as defined by a >or=75% reduction in a validated Acute Bronchitis Severity Score by 14 days; analysis was by intention to treat with equivalence defined as

Validation of a new clinical scoring system for acute bronchitis.

INTRODUCTION: Although several clinical prediction rules exist for lower respiratory tract infection (LRTI), few are for acute bronchitis (acute bronchitis) and most have not been validated in high human immunodeficiency virus (HIV) prevalence settings. METHODS: An Acute Bronchitis Severity Score (ABSS) was developed and validated during a randomized trial of antibiotic treatment for acute bronchitis. Ambulatory adults with productive cough of < or =2 weeks at out-patient respiratory disease clinics in Nairobi, Kenya, were recruited and assessed for clinical response to therapy. The ABSS quantitative ratings of LRTI-associated symptoms, physical signs and sputum Gram stain purulence were assessed using standard psychometric tests. RESULTS: The ABSS was evaluated among 649 cases of acute bronchitis; 129 (20%) were HIV-seropositive. The ABSS had small floor and ceiling effects (1.8/0.2) and demonstrated high internal consistency (alpha-coefficient of 0.66) and internal validity, with a mean inter item total correlation of > or =0.25. Effect sizes from baseline to subsequent follow-up visits were large (>0.5). Wheezing and chest pain were associated with higher ABSS values, whereas irrelevant clinical variables were not. CONCLUSION: The ABSS demonstrated good responsiveness, high internal consistency, good correlation with common respiratory signs and symptoms and high discriminatory validity among patients with acute bronchitis in a high HIV-seroprevalence setting.

Clinical presentation among HIV-infected and non-infected adults with community acquired pneumonia in Nairobi.

SETTING: Risk factors for mortality in hospitalized patients with community-acquired pneumonia (CAP) are well known. There are limited data on prognostic indicators among out-patients. OBJECTIVE: To compare the clinical presentation, outcome and prognostic factors for clinical improvement in human immunodeficiency virus (HIV) infected and non-HIV-infected out-patients with CAP. METHODOLOGY: Adults in Nairobi with CAP were treated with erythromycin as first-line therapy. Clinical symptoms were evaluated using a validated CAP-related symptom score (CSS). Clinical improvement was defined as reduction of baseline CSS by > or = 50%. RESULTS: Of 531 adults enrolled with CAP, 422 (79.5%) completed follow-up. Participants had a mean age (+/- SD) of 33.7 +/- 11.4 years, 274 (51.6%) were male and 193 (37%) were HIV-seropositive with a higher baseline CSS (27 vs. 25, P < 0.006). Overall, 196 of 422 (46%) had clinical improvement by 28 days. Factors independently associated with a longer time to clinical improvement included not being married (adjusted hazard ratio [aHR] 0.66, 95% CI 0.48-0.92) and higher baseline CSS (aHR 1.05, 95% CI 1.03-1.06). CONCLUSIONS: HIV-infected and non-infected patients with CAP responded similarly to out-patient treatment, but HIV-infected patients were more likely to present with severe symptoms. Baseline CSS and marital status were predictive of time to clinical improvement.

Cytokine balance in the lungs of patients with acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) involves an intense inflammatory response in the lungs, with accumulation of both pro- and antiinflammatory cytokines in bronchoalveolar lavage fluid (BALF). Our goal was to determine how the balance between pro- and antiinflammatory mediators in the lungs changes before and after the onset of ARDS. We identified 23 patients at risk for ARDS and 46 with established ARDS and performed serial bronchoalveolar lavage (BAL). We used immunoassays to measure tumor necrosis factor alpha (TNF-alpha) and soluble TNF-alpha receptors I and II; interleukin 1 beta (IL-1 beta), IL-1 beta receptor antagonist, and soluble IL-1 receptor II; IL-6 and soluble IL-6 receptor; and IL-10. We used sensitive bioassays to measure net TNF-alpha, IL-1 beta, and IL-6 activity. Although individual cytokines increased before and after onset of ARDS, greater increases occurred in cognate receptors and/or antagonists, so that molar ratios of agonists/antagonists declined dramatically at the onset of ARDS. The molar ratios remained low for 7 d or longer, limiting the activity of soluble IL-1 beta and TNF-alpha in the lungs at the onset of ARDS. This significant antiinflammatory response early in ARDS may provide a key mechanism for limiting the net inflammatory response in the lungs.

The etiology of community-acquired pneumonia at an urban public hospital: influence of human immunodeficiency virus infection and initial severity of illness.

In a prospective study, the etiology of community-acquired pneumonia (CAP) was investigated among consecutive patients admitted to an academic, urban public hospital in Seattle. The study population was uniquely young, was predominantly male, and had high rates of homelessness, cigarette smoking, alcoholism, injection drug use, and human immunodeficiency virus (HIV) infection. Leading causes of CAP among HIV-negative patients were aspiration, followed by Streptococcus pneumoniae, Legionella species, and Mycoplasma pneumoniae. Among HIV-positive patients, Pneumocystis carinii, Mycobacterium tuberculosis, S. pneumoniae, and M. pneumoniae were the most common etiologic agents. Severe CAP was associated with typical bacterial infections and aspiration pneumonia but not Legionella infection among HIV-negative patients and with Pseudomonas aeruginosa infections among HIV-positive patients. These findings emphasize the need to tailor empirical antibiotic therapy according to local patient populations and individual risk factors and highlight the importance of recognizing underlying HIV infection in patients who are hospitalized with CAP.

Anti-inflammatory treatment of acute and chronic pneumonia.

The inflammatory response to infection is necessary for host defense but can contribute to the systemic toxicity and lung injury that may result from pneumonia. In some settings, adjunctive treatment of lower respiratory infections with anti-inflammatory agents can reduce morbidity. Corticosteroids have a well-documented role in the management of Pneumocystis carinii pneumonia complicating human immunodeficiency virus (HIV) infection. Corticosteroids also were found to reduce systemic symptoms of tuberculosis in a number of older studies, but their role as adjuncts to contemporary antimicrobial therapy are less clear. Corticosteroids also may be effective under some circumstances in the treatment of inflammatory sequelae of respiratory tract infection, such as tuberculous pleurisy, bronchiolitis obliterans organizing pneumonia, or prolonged acute respiratory distress syndrome. Nonsteroidal anti-inflammatory drugs may have limited applications in the modulation of chronic airway inflammation. Strategies targeting specific cytokines have not been effective to date, but remain active areas of investigation.

Septic shock and acute lung injury in rabbits with peritonitis: failure of the neutrophil response to localized infection.

The major goal of this study was to investigate the mechanisms that link the host response to a local infection in the peritoneal cavity with the development of sepsis and lung injury. Rabbits were infected by intraperitoneal inoculation of fibrin clots containing Escherichia coli at 10(8), 10(9), or 10(10) cfu/clot. Physiologic, bacteriologic, and inflammatory responses were monitored, and the lungs were examined postmortem. At a dose of 10(8) cfu/clot the animals had resolving infection, and a dose of 10(9) cfu/clot resulted in persistent infection at 24 h, with minimal systemic manifestations. In contrast, inoculation of 10(10) cfu/clot resulted in rapidly lethal local infection, with septic shock and lung injury. The onset of septic shock was associated with a paradoxical lack of identifiable polymorphonuclear leukocytes (PMN; neutrophils) in the peritoneal cavity. The absence of PMN in the peritoneum was due in part to lysis of intraperitoneal PMN, because the peritoneal fluids contained free myeloperoxidase and induced rapid death of normal rabbit PMN in vitro. Although most animals became bacteremic, only those with a severe systemic inflammation response developed lung injury. These data show that control of an infection in the first compartment in which bacteria enter the host is a critical determinant of the systemic response. Above a threshold dose of bacteria, failure of the local neutrophil response is a key mechanism associated with deleterious systemic responses. Bacteremia alone is not sufficient to cause lung injury. Lung injury occurs only in the setting of a severe systemic inflammatory response and an inadequate leukocyte response at the primary site of infection.

IL-10 enhances the growth of Legionella pneumophila in human mononuclear phagocytes and reverses the protective effect of IFN-gamma: differential responses of blood monocytes and alveolar macrophages.

Legionella pneumophila is a facultative intracellular pathogen that parasitizes human alveolar macrophages and blood monocytes recruited to the lungs. The inhibitory cytokines IL-10, TGF-beta, and IL-4 generally deactivate macrophages and permit enhanced microbial growth in some models of intracellular infection, but their effects on human alveolar macrophages are unknown. We hypothesized that inhibitory cytokines could facilitate the infection of human alveolar macrophages and monocytes by virulent intracellular lung pathogens. Therefore, we tested the effects of IL-10, TGF-beta, and IL-4 in an in vitro model of human alveolar macrophage and monocyte infection with L. pneumophila. We found that unstimulated alveolar macrophages supported over 100-fold greater L. pneumophila growth than did unstimulated monocytes. IL-10 treatment significantly enhanced L. pneumophila growth in monocytes, and completely reversed the protective effect of IFN-gamma against intracellular L. pneumophila replication. IL-10 had similar but less potent effects on alveolar macrophages. In contrast, TGF-beta and IL-4 had no significant effects on L. pneumophila growth in resting or IFN-gamma-activated monocytes or alveolar macrophages. IL-10 blocked TNF-alpha production by infected cells, but exogenous TNF-alpha did not reverse the activating defect in cells cocultured with IFN-gamma and IL-10. Finally, L. pneumophila-infected monocytes produced substantially more IL-10 than did infected alveolar macrophages. In summary, IL-10 significantly enhances the growth of L. pneumophila in human monocytes, reverses the protective effect of IFN-gamma, blocks TNF-alpha secretion, and is secreted by infected monocytes and alveolar macrophages. Induction of IL-10 may be a virulence mechanism that promotes intracellular bacterial replication in human legionellosis.

Use of the medical futility rationale in do-not-attempt-resuscitation orders.

OBJECTIVE: To describe the use of the medical futility rationale in do-not-attempt-resuscitation (DNAR) orders written for medical inpatients. DESIGN: Structured interviews with medical residents. METHODS: Second- and third-year internal medicine residents (n = 44) were telephoned weekly and briefly interviewed about each patient who received a DNAR order in the preceding week. SETTING: Two university-affiliated hospitals: a veterans affairs medical center and a municipal hospital. PATIENTS: One hundred forty-five medical inpatients for whom DNAR orders were written during their hospitalization. RESULTS: Residents stated that the medical futility rationale applied for 91 patients (63%), but this rationale was invoked independent of patient or surrogate choice for only 17 patients (12%). Of the 91 patients for whom futility applied, both quantitative futility (low probability of success) and qualitative futility (poor quality of life if cardiopulmonary resuscitation [CPR] were performed) applied to 45 (49%), quantitative futility alone to 30 (33%), and qualitative futility alone to 16 (18%). Residents report that they discussed resuscitation issues with all communicative patients for whom the medical futility rationale was invoked. Among patients for whom quantitative futility applied, residents' predictions of the probability that patients would survive to hospital discharge after CPR varied from 0% (for 60% of patients) to 75%. For 32% of these patients, residents predicted survival at 5% or more. Logistic regression modeling showed that the presence of organ failure (odds ratio [OR], 8.9; 95% confidence interval [CI], 3.3 to 23.9), the residents' estimates of the probability of surviving CPR (OR, 0.94; 95% CI, 0.88 to 0.99), and nonwhite race (OR, 2.7; 95% CI, 1.1 to 6.3) were associated with the determination of quantitative futility. In one third of the cases where qualitative futility applied, residents made the judgment of qualitative futility without discussing quality of life with communicative patients. Logistic regression modeling showed immobility (OR, 3.2; 95% CI, 1.1 to 9.0) and age > or = 75 years (OR, 0.3; 95% CI, 0.1 to 0.8) to be associated with the determination of qualitative futility. CONCLUSIONS: While residents did not appear to use the medical futility rationale to avoid discussing DNAR issues with patients, we found evidence of important misunderstandings of the concepts of both quantitative and qualitative futility. If the futility rationale is to be applied to withholding or withdrawing medical interventions, practice guidelines for its use should be developed, and education about medical futility must be incorporated into medical school, residency training, and continuing medical education programs.