Alveolar dead-space response to activated protein C in acute respiratory distress syndrome.

We report a complicated case of acute respiratory distress syndrome (ARDS) from severe sepsis, in which we measured the ratio of physiologic dead space to tidal volume (V(D)/V(T)) with volumetric capnography prior to, during, and after therapy with human recombinant activated protein C. Previous studies hypothesized that early in ARDS, elevated V(D)/V(T) primarily reflects increased alveolar V(D), probably caused by pronounced thrombi formation in the pulmonary microvasculature. This may be particularly true when severe sepsis is the cause of ARDS. We repeatedly measured V(D)/V(T) in a 29-year-old man with sepsis-induced ARDS over the course of activated protein C therapy. Treatment with activated protein C resulted in a pronounced reduction in V(D)/V(T), from 0.55 to 0.27. Alveolar V(D) decreased from 165 mL to 11 mL (93% reduction). Activated protein C was terminated at 41 h because of gastrointestinal bleeding. When the measurement was repeated 29 h after therapy was discontinued, V(D)/V(T) had increased modestly, to 0.34, whereas alveolar V(D) had increased to 71 mL, or 43% of the pre-activated-protein-C baseline measurement. Alveolar V(T) rose from 260 mL to 369 mL and decreased slightly after termination of activated protein C (336 mL). Over the course of activated protein C therapy there was a persistent decrease in alveolar V(D) and increase in alveolar V(T), even while positive end-expiratory pressure was reduced and respiratory-system compliance decreased. Thus, improved alveolar perfusion persisted despite signs of alveolar de-recruitment. This suggests that activated protein C may have reduced microvascular obstruction. This report provides indirect evidence that microvascular obstruction may play an important role in elevated V(D)/V(T) in early ARDS caused by severe sepsis.

Reaching the limits of tuberculosis prevention among foreign-born individuals: a tuberculosis-control program perspective.

Analysis of whether assiduous implementation of American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America guidelines for targeted testing and treatment of latent tuberculosis infection could have prevented any of 223 cases of active tuberculosis in foreign-born persons in San Francisco during the period 2002-2003. We report that 62% of these cases were not preventable and conclude that a further reduction in the incidence of tuberculosis among foreign-born persons will be modest without modification of current guidelines.

Adverse events and treatment completion for latent tuberculosis in jail inmates and homeless persons.

BACKGROUND: Recently, a short-course treatment using 60 daily doses of rifampin and pyrazinamide was recommended for latent tuberculosis (TB) infection (LTBI). STUDY OBJECTIVES: To determine the acceptability, tolerability, and completion of treatment. DESIGN: Observational cohort study. SETTING: Five county jails and TB outreach clinics for homeless populations in three cities. PATIENTS: Study staff enrolled 1,211 patients (844 inmates and 367 homeless persons). INTERVENTIONS: Sites used 60 daily doses of rifampin and pyrazinamide, an approved treatment regimen for LTBI. MEASUREMENTS: Types and frequency of drug-related adverse events and outcomes of treatment. RESULTS: Prior to treatment, 25 of 1,178 patients (2.1%) had a serum aminotransferase measurement at least 2.5 times the upper limit of normal. Patients who reported excess alcohol use in the past 12 months were more likely than other patients to have an elevated pretreatment serum aminotransferase level (odds ratio, 2.1; 95% confidence interval, 1.1 to 6.1; p = 0.03). Treatment was stopped in 66 of 162 patients (13.4%) who had a drug-related adverse event. Among 715 patients who had serum aminotransferase measured during treatment, 43 patients (6.0%) had an elevation > 5 times the upper limits of normal, including one patient who died of liver failure attributed to treatment. In multivariate analyses, increasing age, an abnormal baseline aspartate aminotransferase level, and unemployment within the past 24 months were independent risk factors for hepatotoxicity. Completion rates were similar in jail inmates (47.5%) and homeless persons (43.6%). CONCLUSIONS: This study detected the first treatment-associated fatality with the rifampin and pyrazinamide regimen, prompting surveillance that detected unacceptable levels of hepatotoxicity and retraction of recommendations for its routine use. Completion rates for LTBI treatment using a short-course regimen exceeds historical rates using isoniazid. Efforts to identify an effective short-course treatment for LTBI should be given a high priority.

Short-course rifampin and pyrazinamide compared with isoniazid for latent tuberculosis infection: a multicenter clinical trial.

BACKGROUND: Rifampin and pyrazinamide are recommended for treatment of latent tuberculosis infection in adults without HIV infection, but reports of severe hepatotoxicity have raised concerns about its safety. Clinical trials have not compared this treatment with isoniazid in adults without HIV infection. OBJECTIVE: To compare the safety and tolerance of a 2-month regimen of rifampin and pyrazinamide with that of a 6-month regimen of isoniazid for treatment of latent tuberculosis infection. DESIGN: Multicenter, prospective, open-label trial. SETTING: Three urban public health tuberculosis clinics in the United States. PATIENTS: 589 adults with latent tuberculosis infection who met U.S. criteria for treatment. INTERVENTION: Patients were assigned in alternate weeks to receive rifampin and pyrazinamide daily for 2 months (n = 307) or isoniazid daily for 6 months (n = 282). MEASUREMENTS: Primary end points were hepatotoxicity, other adverse events, and percentage of patients who completed treatment. RESULTS: Sixteen of 207 (7.7%) patients assigned to rifampin and pyrazinamide developed grade 3 or 4 hepatotoxicity compared with 2 of 204 (1%) patients assigned to isoniazid (odds ratio, 8.46 [95% CI, 1.9 to 76.5]; P = 0.001). The rifampin plus pyrazinamide regimen was more likely than the isoniazid regimen to be discontinued because of hepatotoxicity (odds ratio, 5.19; P = 0.033). The overall percentage of nonhepatotoxic adverse events was 20% in the rifampin-pyrazinamide group and 16% in the isoniazid group. The proportion of patients who completed the study treatment was 61% and 57%, respectively. CONCLUSIONS: A 2-month regimen of rifampin and pyrazinamide was associated with an increased risk for grade 3 or 4 hepatotoxicity compared with a 6-month regimen of isoniazid. Liver enzymes should be measured routinely during treatment to screen for liver injury and prevent progression to severe toxicity.

Update on the treatment of tuberculosis and latent tuberculosis infection.

Tuberculosis (TB) has emerged as a global public health epidemic. Despite decreasing numbers of cases in the United States since 1992, TB remains a serious public health problem among certain patient populations and is highly prevalent in many urban areas. The responsibility for prescribing an appropriate drug regimen and ensuring that treatment is completed is assigned to the public health program or the clinician not to the patient. The initial prescribed regimen for the treatment of TB usually consists of 4 drugs: isoniazid, rifampin, pyrazinamide, and ethambutol. The minimum length for the treatment of drug-susceptible TB with a rifampin-based regimen is 6 to 9 months. Providing medications directly to the patient and watching him/her swallow the anti-TB drugs, which is termed directly observed therapy, is recommended for all patients diagnosed with TB and can help ensure higher completion rates, prevent the emergence of drug resistant TB, and enhance TB control. There has been renewed interest in the treatment of those with latent TB infection as a TB-control strategy in the United States for eliminating the large reservoir of individuals at risk for progression to TB. The 2 broad categories of persons who should be tested for latent TB infection are those who are likely to have been recently infected (such as contacts to infectious TB cases) and persons who are at increased risk of progression to TB disease following infection with Mycobacterium tuberculosis (eg, human immunodeficiency virus infection and selected medical conditions; recent immigrants to the United States from high TB-burden countries). The preferred regimen for the treatment of latent TB infection is 9 months of isoniazid. There is now renewed interest in and great need for the development of new drugs to treat TB and latent TB infection.

Short-course rifampin and pyrazinamide compared with isoniazid for latent tuberculosis infection: a cost-effectiveness analysis based on a multicenter clinical trial.

Two months of treatment with rifampin-pyrazinamide (RZ) and 9 months of treatment with isoniazid are both recommended for treatment of latent tuberculosis infection in adults without human immunodeficiency virus infection, but the relative cost-effectiveness of these 2 treatments is unknown. We used a Markov model to conduct a cost-effectiveness analysis to assess the impact on life expectancy and costs based on the results of a recent clinical trial that compared the rates of adverse events and completion of the 2 treatment regimens. Compared with no treatment, both regimens increased life expectancy by 1.2 years, but RZ cost 273 dollars more per patient. Sensitivity analyses showed that, assuming equal efficacy between the 2 regimens, there was no threshold completion rate for RZ at which the 2 treatments would be of equal net cost. Under most circumstances, treatment of latent tuberculosis infection with isoniazid is cost-saving than treatment with RZ.

A molecular epidemiological assessment of extrapulmonary tuberculosis in San Francisco.

The epidemiology of extrapulmonary tuberculosis (TB) is not well understood. We studied all cases of extrapulmonary TB reported in San Francisco during 1991-2000 to determine risk factors for extrapulmonary TB and the proportion caused by recent infection. Isolates were analyzed by IS6110-based restriction fragment-length polymorphisms analysis. There were 480 cases of extrapulmonary TB, of which 363 (76%) were culture positive; isolates were genotyped for 301 cases (83%). Multivariate analysis identified young age, female sex, and HIV infection as independent risk factors for nonrespiratory TB (excluding pulmonary, pleural, and disseminated TB). Pleural TB was less common in HIV-seropositive persons and women than were nonrespiratory forms of extrapulmonary TB. Pleural TB is different from other forms of extrapulmonary TB and is associated with the highest clustering rate (35% of cases) of all forms of TB. This high rate of clustering occurs because pleural TB is often an early manifestation of recent infection.

Sarcoidosis following HIV infection: evidence for CD4+ lymphocyte dependence.

BACKGROUND: The chronic granulomatous inflammation of sarcoidosis has been hypothesized to depend on the CD4+ T-helper lymphocyte. HIV infection, which depletes these cells, has been reported to attenuate the manifestations of sarcoidosis. STUDY OBJECTIVES: We asked whether the development of symptomatic sarcoidosis in the context of preexisting HIV infection was dependent on the CD4+ lymphocyte count. DESIGN: We performed a retrospective standardized chart review of all patients who developed granulomatous inflammation following HIV infection at an urban academic referral center. MEASUREMENTS: We identified seven patients with sarcoidosis within this cohort and compared their CD4+ lymphocyte count to that in a cohort of 16 patients in whom similar granulomatous inflammation was found but who did not have sarcoidosis. We then compared our cases to all reported cases using a systematic literature review. RESULTS: The CD4+ lymphocyte count was > 200 cells/ microL in all of our patients with HIV infection when they developed subsequent sarcoidosis. In contrast, specific etiologies for granulomatous inflammation were found in all 10 HIV-infected patients who presented with granulomatous inflammation and a CD4+ lymphocyte count of < 200 cells/ microL, with infectious etiologies found in 8 patients. Similarly, there was relative preservation of the CD4+ lymphocyte count in previously reported cases, with 14 of 19 patients (74%) having an absolute CD4+ lymphocyte count of > 200 cells/ microL. CONCLUSIONS: We conclude that the development of the chronic granulomatous inflammation of sarcoidosis appears to depend on the preservation or restoration of the peripheral CD4+ lymphocyte count and that in most cases the CD4+ lymphocyte count exceeds 200 cells/ microL. Furthermore, alternative specific etiologies of granulomatous inflammation are generally identifiable in HIV-infected patients with peripheral CD4+ lymphocyte counts of < 200 cells/ microL.

An official ATS statement: hepatotoxicity of antituberculosis therapy.

Drug-induced liver injury (DILI) is a problem of increasing significance, but has been a long-standing concern in the treatment of tuberculosis (TB) infection. The liver has a central role in drug metabolism and detoxification, and is consequently vulnerable to injury. The pathogenesis and types of DILI are presented, ranging from hepatic adaptation to hepatocellular injury. Knowledge of the metabolism of anti-TB medications and of the mechanisms of TB DILI is incomplete. Understanding of TB DILI has been hampered by differences in study populations, definitions of hepatotoxicity, and monitoring and reporting practices. Available data regarding the incidence and severity of TB DILI overall, in selected demographic groups, and in those coinfected with HIV or hepatitis B or C virus are presented. Systematic steps for prevention and management of TB DILI are recommended. These include patient and regimen selection to optimize benefits over risks, effective staff and patient education, ready access to care for patients, good communication among providers, and judicious use of clinical and biochemical monitoring. During treatment of latent TB infection (LTBI) alanine aminotransferase (ALT) monitoring is recommended for those who chronically consume alcohol, take concomitant hepatotoxic drugs, have viral hepatitis or other preexisting liver disease or abnormal baseline ALT, have experienced prior isoniazid hepatitis, are pregnant or are within 3 months postpartum. During treatment of TB disease, in addition to these individuals, patients with HIV infection should have ALT monitoring. Some experts recommend biochemical monitoring for those older than 35 years. Treatment should be interrupted and, generally, a modified or alternative regimen used for those with ALT elevation more than three times the upper limit of normal (ULN) in the presence of hepatitis symptoms and/or jaundice, or five times the ULN in the absence of symptoms. Priorities for future studies to develop safer treatments for LTBI and for TB disease are presented.

Clinical implementation of the ARDS network protocol is associated with reduced hospital mortality compared with historical controls.

OBJECTIVE: To assess the impact of implementing a low tidal volume ventilation strategy on hospital mortality for patients with acute lung injury or acute respiratory distress syndrome. DESIGN: Retrospective, uncontrolled study. SETTING: Adult medical-surgical and trauma intensive care units at a major inner city, university-affiliated hospital. PATIENTS: A total of 292 patients with acute lung injury or acute respiratory distress syndrome. INTERVENTIONS: Between the years 2000 and 2003, 200 prospectively identified patients with acute lung injury/acute respiratory distress syndrome were managed by the ARDS Network low tidal volume protocol. A historical control group of 92 acute respiratory distress syndrome patients managed by routine practice from 1998 to 1999 was used for comparison. MEASUREMENTS AND MAIN RESULTS: Patients managed with the ARDS Network protocol had a lower hospital mortality compared with historical controls (32% vs. 51%, respectively; p = .004). Multivariate logistic regression estimated an odds ratio of 0.32 (95% CI, 0.17-0.59; p = .0003) for mortality risk with use of the ARDS Network protocol. Protocol-managed patients had a lower tidal volume (6.2 +/- 1.1 vs. 9.8 +/- 1.5 mL/kg; p < .0001) and plateau pressure (27.5 +/- 6.4 vs. 33.8 +/- 8.9 cm H2O; p < .0001) than historical controls. CONCLUSION: Adoption of the ARDS Network protocol for routine ventilator management of acute lung injury/acute respiratory distress syndrome patients was associated with a lower mortality compared with recent historical controls.

A prospective, multicenter study of laboratory cross-contamination of Mycobacterium tuberculosis cultures.

A prospective study of false-positive cultures of Mycobacterium tuberculosis that resulted from laboratory cross-contamination was conducted at three laboratories in California. Laboratory cross-contamination accounted for 2% of the positive cultures. Cross-contamination should be a concern when an isolate matches the genotype of another sample processed during the same period.

Clinical and radiographic predictors of the etiology of computed tomography-diagnosed intrathoracic lymphadenopathy in HIV-infected patients.

In HIV-infected patients with intrathoracic lymphadenopathy, it is not known whether clinical and radiographic findings are useful in predicting a specific diagnosis. We determined the etiology and predictors of the etiology of computed tomography (CT)-diagnosed intrathoracic lymphadenopathy in HIV-infected patients evaluated from June 1993 through April 1999. Multivariate analyses were performed to determine clinical and radiographic predictors of the three most common diagnoses. Of 318 patients, 110 (35%) had lymphadenopathy on chest CT. Among these 110 patients, tuberculosis/nontuberculous mycobacterial disease ( = 31), bacterial pneumonia ( = 26), and lymphoma ( = 21) were the most common diagnoses. Multivariate analysis identified cough and necrosis of lymph nodes on chest CT as independent predictors of tuberculosis/nontuberculous mycobacterial disease. African-American race, symptoms for 1 to 7 days, dyspnea, and presence of airways disease on chest CT were independent predictors of bacterial pneumonia; symptoms for >7 days, absence of cough, and absence of pulmonary nodules on CT independently predicted lymphoma. Intrathoracic lymphadenopathy is a frequent chest CT finding in HIV-infected patients. Opportunistic infections and lymphoma are the most common causes, and specific clinical and radiographic features can suggest these particular diagnoses.

Tuberculosis treatment outcomes: directly observed therapy compared with self-administered therapy.

Effective treatment of tuberculosis requires adherence to a minimum of 6 months treatment with multiple drugs. To improve adherence and cure rates, directly observed therapy is recommended for the treatment of pulmonary tuberculosis. We compared treatment outcomes among all culture-positive patients treated for active pulmonary tuberculosis (n = 372) in San Francisco County, California from 1998 through 2000. Patients treated by directly observed therapy at the start of therapy (n = 149) had a significantly higher cure rate compared with patients treated by self-administered therapy (n = 223) (the sum of bacteriologic cure and completion of treatment, 97.8% versus 88.6%, p < 0.002), and decreased tuberculosis-related mortality (0% vs. 5.5%, p = 0.002). Rates of treatment failure, relapse, and acquired drug resistance were similar between the two groups. Forty-four percent of patients who received self-administered therapy had risk factors for nonadherence and should have been assigned to directly observed therapy. We conclude that treatment plans that emphasize directly observed therapy from the start of therapy have the greatest success in improving tuberculosis treatment outcomes.

Recurrent tuberculosis in the United States and Canada: relapse or reinfection?

Recurrence of active tuberculosis after treatment can be due to relapse of infection with the same strain or reinfection with a new strain of Mycobacterium tuberculosis. The proportion of recurrent tuberculosis cases caused by reinfection has varied widely in previous studies. We evaluated cases of recurrent tuberculosis in two prospective clinical trials: a randomized study of two regimens for the last 4 months of treatment (n = 1,075) and a study of a twice-weekly rifabutin-containing regimen for human immunodeficiency virus-infected tuberculosis (n = 169). Isolates at diagnosis and from positive cultures after treatment completion underwent genotyping using IS6110 (with secondary genotyping for isolates with less than six copies of IS6110). Of 85 patients having a positive culture after completing treatment, 6 (7.1%) were classified as false-positive cultures by a review committee blinded to treatment assignment. Of the remaining 75 cases with recurrent tuberculosis and genotyping data available, 72 (96%; 95% confidence interval, 88.8-99.2%) paired isolates had the same genotype; only 3 (4%; 95% confidence interval, 0.8-11.2%) had a different genotype and were categorized as reinfection. We conclude that recurrent tuberculosis in the United States and Canada, countries with low rates of tuberculosis, is rarely due to reinfection with a new strain of M. tuberculosis.