Olivier Thierry Rutschmann

Diagnosis of pulmonary embolism by multidetector CT alone or combined with venous ultrasonography of the leg: a randomised non-inferiority trial

BACKGROUND Multislice CT (MSCT) combined with D-dimer measurement can safely exclude pulmonary embolism in patients with a low or intermediate clinical probability of this disease. We compared this combination with a strategy in which both a negative venous ultrasonography of the leg and MSCT were needed to exclude pulmonary embolism. METHODS We included 1819 consecutive outpatients with clinically suspected pulmonary embolism in a multicentre non-inferiority randomised controlled trial comparing two strategies: clinical probability assessment and either D-dimer measurement and MSCT (DD-CT strategy [n=903]) or D-dimer measurement, venous compression ultrasonography of the leg, and MSCT (DD-US-CT strategy [n=916]). Randomisation was by computer-generated blocks with stratification according to centre. Patients with a high clinical probability according to the revised Geneva score and a negative work-up for pulmonary embolism were further investigated in both groups. The primary outcome was the 3-month thromboembolic risk in patients who were left untreated on the basis of the exclusion of pulmonary embolism by diagnostic strategy. Clinicians assessing outcome were blinded to group assignment. Analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00117169. FINDINGS The prevalence of pulmonary embolism was 20.6% in both groups (189 cases in DD-US-CT group and 186 in DD-CT group). We analysed 855 patients in the DD-US-CT group and 838 in the DD-CT group per protocol. The 3-month thromboembolic risk was 0.3% (95% CI 0.1-1.1) in the DD-US-CT group and 0.3% (0.1-1.2) in the DD-CT group (difference 0.0% [-0.9 to 0.8]). In the DD-US-CT group, ultrasonography showed a deep-venous thrombosis in 53 (9% [7-12]) of 574 patients, and thus MSCT was not undertaken. INTERPRETATION The strategy combining D-dimer and MSCT is as safe as the strategy using D-dimer followed by venous compression ultrasonography of the leg and MSCT for exclusion of pulmonary embolism. An ultrasound could be of use in patients with a contraindication to CT.

Age-adjusted D-dimer cutoff levels to rule out pulmonary embolism: the ADJUST-PE study.

IMPORTANCE D-dimer measurement is an important step in the diagnostic strategy of clinically suspected acute pulmonary embolism (PE), but its clinical usefulness is limited in elderly patients. OBJECTIVE To prospectively validate whether an age-adjusted D-dimer cutoff, defined as age × 10 in patients 50 years or older, is associated with an increased diagnostic yield of D-dimer in elderly patients with suspected PE. DESIGN, SETTINGS, AND PATIENTS A multicenter, multinational, prospective management outcome study in 19 centers in Belgium, France, the Netherlands, and Switzerland between January 1, 2010, and February 28, 2013. INTERVENTIONS All consecutive outpatients who presented to the emergency department with clinically suspected PE were assessed by a sequential diagnostic strategy based on the clinical probability assessed using either the simplified, revised Geneva score or the 2-level Wells score for PE; highly sensitive D-dimer measurement; and computed tomography pulmonary angiography (CTPA). Patients with a D-dimer value between the conventional cutoff of 500 µg/L and their age-adjusted cutoff did not undergo CTPA and were left untreated and formally followed-up for a 3-month period. MAIN OUTCOMES AND MEASURES The primary outcome was the failure rate of the diagnostic strategy, defined as adjudicated thromboembolic events during the 3-month follow-up period among patients not treated with anticoagulants on the basis of a negative age-adjusted D-dimer cutoff result. RESULTS Of the 3346 patients with suspected PE included, the prevalence of PE was 19%. Among the 2898 patients with a nonhigh or an unlikely clinical probability, 817 patients (28.2%) had a D-dimer level lower than 500 µg/L (95% CI, 26.6%-29.9%) and 337 patients (11.6%) had a D-dimer between 500 µg/L and their age-adjusted cutoff (95% CI, 10.5%-12.9%). The 3-month failure rate in patients with a D-dimer level higher than 500 µg/L but below the age-adjusted cutoff was 1 of 331 patients (0.3% [95% CI, 0.1%-1.7%]). Among the 766 patients 75 years or older, of whom 673 had a nonhigh clinical probability, using the age-adjusted cutoff instead of the 500 µg/L cutoff increased the proportion of patients in whom PE could be excluded on the basis of D-dimer from 43 of 673 patients (6.4% [95% CI, 4.8%-8.5%) to 200 of 673 patients (29.7% [95% CI, 26.4%-33.3%), without any additional false-negative findings. CONCLUSIONS AND RELEVANCE Compared with a fixed D-dimer cutoff of 500 µg/L, the combination of pretest clinical probability assessment with age-adjusted D-dimer cutoff was associated with a larger number of patients in whom PE could be considered ruled out with a low likelihood of subsequent clinical venous thromboembolism. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01134068.

Impact of treatment with human immunodeficiency virus (HIV) protease inhibitors on hepatitis C viremia in patients coinfected with HIV

The impact of human immunodeficiency virus (HIV) protease inhibitors on hepatitis C (HCV) viremia was assessed in 19 patients infected with both HIV and HCV. HIV and HCV RNA levels were measured before and during treatment with protease inhibitors. Before treatment, mean levels of HCV RNA were 5.3 log for HCV RNA and 5.0 log for HIV RNA. CD4 lymphocyte counts were 63/mm3. After 6 weeks of treatment, a mean reduction of 2.1 log10 in HIV RNA (P < .001) and a mean (+/-SE) increase of 73 (+/-21) CD4 and 296 (+/-70) CD8 cells were observed (P < .05). In contrast, both HCV viremia (+0.4 log +/- 0.1) and alanine aminotransferase increased (P < .04). HCV RNA levels returned to baseline after 17 and 32 weeks of treatment. Thus, potent anti-HIV regimens with protease inhibitors may temporarily worsen HCV status despite improvement of HIV parameters.

A placebo-controlled trial of didanosine plus stavudine, with and without hydroxyurea, for Hiv infection

Objective:To explore the short-term effects on surrogate markers for HIV progression of didanosine (ddI) plus stavudine (d4T), with or without hydroxyurea. Design:Randomized, double-blinded, prospective study. Setting:Swiss HIV Cohort Study. Patients:A total of 144 patients (75% antiretroviral-naive) were studied (mean baseline HIV-1 RNA, 4.53 log10 copies/ml; mean CD4 cell count, 370 × 106/l). Intervention:Patients received ddI (200 mg twice daily) plus d4T (40 mg twice daily), with additional hydroxyurea (500 mg twice daily) or placebo. Main outcome measures:The primary endpoint was a reduction of viraemia below 200 copies/ml after 12 weeks. At that time, patients who did not reach the primary endpoint were withdrawn in the hydroxyurea arm, whereas patients in the placebo group had the option of adding hydroxyurea to ddI and d4T. All patients were followed until week 24. Results:After 12 weeks, 54% of the patients randomized to hydroxyurea had viraemia below 200 copies/ml, compared with 28% on placebo (P < 0.001). Using an ultrasensitive assay with a limit of detection of 20 copies/ml, 19% of patients receiving hydroxyurea had viraemia levels below 20 copies/ml, compared with 8% on placebo (P = 0.05). Mean decrease in HIV-1 RNA was 2.3 and 1.7 log10 copies/ml for hydroxyurea and placebo groups, respectively (P = 0.001). Hydroxyurea was found to induce lymphopenia (−124 × 106/l). Increase in CD4 cell counts was +28 × 106/l during hydroxyurea treatment compared with +107 × 106/l on placebo (P = 0.001). Conclusions:Hydroxyurea improved the antiviral activity of d4T and ddI over a 12-week period, but was associated with a smaller increase in CD4 cell counts due to hydroxyurea-induced lymphopenia.

β-Lactam Monotherapy vs β-Lactam-Macrolide Combination Treatment in Moderately Severe Community-Acquired Pneumonia A Randomized Noninferiority Trial

IMPORTANCE The clinical benefit of adding a macrolide to a β-lactam for empirical treatment of moderately severe community-acquired pneumonia remains controversial. OBJECTIVE To test noninferiority of a β-lactam alone compared with a β-lactam and macrolide combination in moderately severe community-acquired pneumonia. DESIGN, SETTING, AND PARTICIPANTS Open-label, multicenter, noninferiority, randomized trial conducted from January 13, 2009, through January 31, 2013, in 580 immunocompetent adult patients hospitalized in 6 acute care hospitals in Switzerland for moderately severe community-acquired pneumonia. Follow-up extended to 90 days. Outcome assessors were masked to treatment allocation. INTERVENTIONS Patients were treated with a β-lactam and a macrolide (combination arm) or with a β-lactam alone (monotherapy arm). Legionella pneumophila infection was systematically searched and treated by addition of a macrolide to the monotherapy arm. MAIN OUTCOMES AND MEASURES Proportion of patients not reaching clinical stability (heart rate <100/min, systolic blood pressure >90 mm Hg, temperature <38.0°C, respiratory rate <24/min, and oxygen saturation >90% on room air) at day 7. RESULTS After 7 days of treatment, 120 of 291 patients (41.2%) in the monotherapy arm vs 97 of 289 (33.6%) in the combination arm had not reached clinical stability (7.6% difference, P = .07). The upper limit of the 1-sided 90% CI was 13.0%, exceeding the predefined noninferiority boundary of 8%. Patients infected with atypical pathogens (hazard ratio [HR], 0.33; 95% CI, 0.13-0.85) or with Pneumonia Severity Index (PSI) category IV pneumonia (HR, 0.81; 95% CI, 0.59-1.10) were less likely to reach clinical stability with monotherapy, whereas patients not infected with atypical pathogens (HR, 0.99; 95% CI, 0.80-1.22) or with PSI category I to III pneumonia (HR, 1.06; 95% CI, 0.82-1.36) had equivalent outcomes in the 2 arms. There were more 30-day readmissions in the monotherapy arm (7.9% vs 3.1%, P = .01). Mortality, intensive care unit admission, complications, length of stay, and recurrence of pneumonia within 90 days did not differ between the 2 arms. CONCLUSIONS AND RELEVANCE We did not find noninferiority of β-lactam monotherapy in patients hospitalized for moderately severe community-acquired pneumonia. Patients infected with atypical pathogens or with PSI category IV pneumonia had delayed clinical stability with monotherapy. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00818610.

Toxicity, efficacy, plasma drug concentrations and protease mutations in patients with advanced HIV infection treated with ritonavir plus saquinavir

Objective:To assess the safety, efficacy and plasma drug levels of the combination of ritonavir plus saquinavir for the treatment of advanced HIV infection. Design:Multicentre pilot study. Patients:Eighteen protease inhibitor-naive patients, with intolerance or contraindication to reverse transcriptase inhibitors, a median CD4 cell count of 12 × 106/l (range, 1–50 × 106/l), and a median HIV viraemia of 5.25 log10copies/ml (range, 4.00–6.13 log10 copies/ml). Methods:Patients received 600 mg twice daily of both ritonavir and saquinavir. Viraemia was measured at baseline and at weeks 5, 9 and 13. Response was defined as a drop of viraemia of more than 1 log10 at week 5. Plasma drug levels were determined after at least 3 weeks of combined treatment: samples were collected before and 1, 2, and 4 h after the morning ingestion of both drugs. The protease gene was sequenced at baseline and under treatment. Results:Among the 16 patients evaluable at week 5, 11 were responders, and among these patients, six remained responders at week 13 (two with undetectable viraemia). Study discontinuations were due to side-effects (n = 4), patient choice (n = 3), protocol violation (n = 1) and death (n = 1). Responders had higher drug levels than non-responders (P < 0.01 for saquinavir, P = 0.04 for ritonavir). In two non-responders, development of multiple new mutations at positions 10, 20, 48, 82, 84 and 90 was observed after 5–13 weeks. Conclusion:The response to ritonavir plus saquinavir in advanced HIV infection is unpredictable. A minority of patients respond with disappearance of HIV viraemia. In other patients, rapid cumulative emergence of protease mutations conferring resistance to treatment cannot always be prevented by good compliance and relatively high plasma drug levels.

Should pulmonary embolism be suspected in exacerbation of chronic obstructive pulmonary disease

Background: The cause of acute exacerbation of chronic obstructive pulmonary disease (COPD) is often difficult to determine. Pulmonary embolism may be a trigger of acute dyspnoea in patients with COPD. Aim: To determine the prevalence of pulmonary embolism in patients with acute exacerbation of COPD. Methods: 123 consecutive patients admitted to the emergency departments of two academic teaching hospitals for acute exacerbation of moderate to very severe COPD were included. Pulmonary embolism was investigated in all patients (whether or not clinically suspected) following a standardised algorithm based on d-dimer testing, lower-limb venous ultrasonography and multidetector helical computed tomography scan. Results: Pulmonary embolism was ruled out by a d-dimer value <500 μg/l in 28 (23%) patients and a by negative chest computed tomography scan in 91 (74%). Computed tomography scan showed pulmonary embolism in four patients (3.3%, 95% confidence interval (CI), 1.2% to 8%), including three lobar and one sub-segmental embolisms. The prevalence of pulmonary embolism was 6.2% (n = 3; 95% CI, 2.3% to 16.9%) in the 48 patients who had a clinical suspicion of pulmonary embolism and 1.3% (n = 1; 95% CI, 0.3% to 7.1%) in those not suspected. In two cases with positive computed tomography scan, the venous ultrasonography also showed a proximal deep-vein thrombosis. No other patient was diagnosed with venous thrombosis. Conclusions: The prevalence of unsuspected pulmonary embolism is very low in patients admitted in the emergency department for an acute exacerbation of their COPD. These results argue against a systematic examination for pulmonary embolism in this population.

Upper-Respiratory Viral Infection, Biomarkers, and COPD Exacerbations

Background Respiratory viruses frequently are recovered in the upper-respiratory tract during acute exacerbations of COPD (AECOPD), but their role as contributing pathogens remains unclear. The usefulness of procalcitonin and C-reactive protein as indicators of the presence or absence of viral infection in this setting also needs to be evaluated. Methods The study was of a prospective cohort of patients with COPD admitted to the ED for AECOPD. Reverse transcriptase-polymerase chain reaction (RT-PCR) for 14 respiratory viruses was performed on nasopharyngeal swabs collected at admission and after recovery in stable condition. Results Eighty-six patients (mean age, 72 years; male, 64%) were included. During AECOPD, upper-respiratory viral infections were detected in 44 (51%) patients: picornavirus in 22, metapneumovirus in seven, coronavirus in eight, influenza A/B in two, parainfluenza in two, and respiratory syncytial virus in three. A dual infection was present in three patients. After recovery, viruses were detected in only eight (11%) of 71 patients (P < .001 compared with AECOPD phase). In five of these patients, no virus had been identified during the initial exacerbation, thus suggesting a new viral infection acquired during follow-up. During AECOPD, procalcitonin and C-reactive protein levels did not differ significantly between patients with or without a proven viral infection. Conclusions Prevalence of upper-respiratory viral infection, as detected from nasopharyngeal swab by RT-PCR, is high in AECOPD and low after clinical recovery, suggesting that AECOPD frequently are triggered by viral infections initiated in the upper-respiratory tract. In our study, serum procalcitonin and C-reactive protein did not discriminate virus-associated exacerbations from others. Trial registration clinicaltrials.gov; Identifier: NCT00448604.

Regression of Kaposi's sarcoma during therapy with HIV-1 protease inhibitors: A prospective pilot study

BACKGROUND Early studies using HIV protease inhibitors (PI) showed regression of Kaposis sarcoma (KS) lesions in some patients. OBJECTIVE Our purpose was to determine prospectively the influence of PI on HIV-related KS. METHODS KS lesions of nine patients with progressive cutaneous disease were prospectively evaluated clinically and by means of epiluminescence microscopy before and during PI therapy. HIV viremia and CD4 cell count were measured in parallel. RESULTS All patients experienced reduction or initial stabilization of KS lesions during the first 4 to 8 weeks of HIV-1 PI therapy. After a median follow-up of 7 months and according to AIDS Clinical Trials Groups criteria, six patients had a partial response, two showed stable disease, and in one noncompliant patient KS progressed, requiring chemotherapy. With epiluminescence microscopy, a reduction in skin surface alterations, lesional size, and color intensity was demonstrated in six of nine patients. PI induced a median decrease in viremia of 1.66 log and a median increase in the CD4 count of 49 cells/mm3. CONCLUSION In this series, HIV PI therapy reduced or stabilized KS. The efficacy of HIV-1 PI in KS may result from the improvement in cellular immunity. These results suggest the use of PI in AIDS-related KS regardless of the level of CD4 lymphocyte count and HIV viremia.

National Survey of Guideline-Compliant COPD Management Among Pneumologists and Primary Care Physicians

The aim of this survey was to investigate guideline-compliant COPD management among pneumologists and primary care physicians (PCPs). A multiple-choice questionnaire was sent out to 1836 PCPs and 863 pneumologists in Germany. The questions focused on the key aspects of current national and international COPD guidelines. Four hundred eighty-six PCPs and 359 pneumologists participated in the study. It was found that pneumologists held the GOLD guideline in high regard (60.4%), while PCPs tended to follow the German National COPD guideline (66.5%). Differences were also found with regard to diagnosis and classification of COPD on the basis of spirometric and clinical criteria. The current GOLD classification of moderate and severe COPD was used by 36.2% and 23.4% of the pneumologists, respectively, and by 32.1% and 20.2% of the PCPs. Although PCPs and pneumologists endorsed educational measures to help patients quit smoking, implementation was still inadequate. The two most important therapeutic goals were to improve quality of life and prevent exacerbations. Except for the criteria for the use of steroids and the implementation of pulmonary rehabilitation measures, treatment of COPD based on severity class was largely in compliance with guidelines. However, appreciably more PCPs than pneumologists incorrectly assessed the evidence-based clinical benefits of various therapeutic measures. The study shows that, despite the popularity of COPD guidelines, deficits exist among pneumologists and PCPs with respect to diagnosis and treatment of COPD and practical implementation of educational measures. These deficiencies in guideline conformity might be best addressed through targeted continuing-education measures.