Ventilator-associated pneumonia and bloodstream infections in intensive care unit cancer patients: a retrospective 12-year study on 3388 prospectively monitored patients.

PURPOSE: Some publications suggest high rates of healthcare-associated infections (HAIs) and of nosocomial pneumonia portending a poor prognosis in ICU cancer patients. A better understanding of the epidemiology of HAIs in these patients is needed. METHODS: A retrospective analysis of all the patients hospitalized for ≥ 48 h during a 12-year period in the 12-bed ICU of the Gustave Roussy hospital, monitored prospectively for ventilator-associated pneumonia (VAP) and bloodstream infection (BSI) and for use of medical devices. RESULTS: During 3388 first stays in the ICU, 198 cases of VAP and 103 primary, 213 secondary, and 77 catheter-related BSIs were recorded. The VAP rate was 24.5/1000 ventilator days (95% confidence interval [CI] 21.2-28.0); the catheter-related BSI rate was 2.3/1000 catheter days (95% CI 1.8-2.8). The cumulative incidence during the first 25 days of exposure was 58.8% (95% CI 49.1-66.6%) for VAP, 8.9% (95% CI, 6.2-11.5%) for primary, 15.1% (95% CI 11.6-18.5%) for secondary and 5.0% (95% CI 3.2-6.8%) for catheter-related BSIs. VAP or BSIs were not associated with a higher risk of ICU mortality. CONCLUSIONS: This is the first study to report HAI rates in a large cohort of critically ill cancer patients. Although both the incidence of VAP and the rate of BSI are higher than in general ICU populations, this does not impact patient outcomes. The occurrence of device-associated infections is essentially due to severe medical conditions in patients and to the characteristics of malignancy.

Differential time to positivity of central and peripheral blood cultures is inaccurate for the diagnosis of Staphylococcus aureus long-term catheter-related sepsis.

OBJECTIVES: Differential time to positivity of cultures of blood drawn simultaneously from central venous catheter and peripheral sites is widely used to diagnose catheter-related bloodstream infections without removing the catheter. However, the accuracy of this technique for some pathogens, such as Staphylococcus aureus, is debated in routine practice. METHODS: In a 320-bed reference cancer centre, the charts of patients with at least one blood culture positive for S. aureus among paired blood cultures drawn over a six-year period were studied retrospectively. Microbiological data were extracted from the prospectively compiled database of the microbiology unit. Data concerning the 149 patients included were reviewed retrospectively by independent physicians blinded to the absolute and differential times to positivity, in order to establish or refute the diagnosis of catheter-related sepsis. Due to missing data, 48 charts were excluded, so 101 cases were actually analysed. The diagnosis was established in 62 cases, refuted in 15 cases and inconclusive in the remaining 24 cases. RESULTS: For the 64 patients with both central and peripheral positive blood cultures, the differential positivity time was significantly greater for patients with catheter-related bloodstream infections due to S. aureus (P<0.02). However, because of the high number of false-negative cases, the classic cut-off limit of 120 min showed 100% specificity but only 42% sensitivity for the diagnosis of catheter-related bloodstream infection due to S. aureus. CONCLUSIONS: These results strongly suggest that despite its high specificity, the differential time to positivity may not be reliable to rule out catheter-related bloodstream infection due to S. aureus.

Factors influencing posaconazole plasmatic concentrations in patients presenting with acute myeloid leukemia.

PURPOSE: The effectiveness of posaconazole (PSZ) prophylaxis on invasive fungal infections, in patients presenting with acute myeloid leukemia (AML), seems to be correlated to its blood plasma concentration. Our goal was to identify the risk factors for underdosing. PATIENTS AND METHODS: We retrospectively reviewed the records of patients treated for AML treated with PSZ, during a 2-year period. Assays<500ng/mL were considered as under dosed. RESULTS: Fifty-nine assays (43 patients) were performed during induction (n=22) or consolidation (n=37) chemotherapy. PSZ treatment was initiated within a median of 3 days before neutropenia with a first assay performed at 8 days (3-28). The median PSZ blood plasma concentration was 375ng/mL (<200-1900). Forty-one (69%) treatment were maintained until the end of neutropenia. One patient presented with candidemia, 9 with possible invasive aspergillosis, without any significant association with underdosing. The univariate analysis showed that co-administration of proton pump inhibitors (PPIs) (P=0.01) and cause of hospitalization (induction chemotherapy vs consolidation, P=0.008) were associated with underdosing, contrary to feeding difficulties (P=0.07) and digestive disorders (P=0.5). The multivariate analysis confirmed the impact of PPI use (P=0.01) and the cause of hospitalization (P=0.003). CONCLUSION: This study highlights the major impact of PPI administration on PSZ blood plasma levels and stresses the risk of non-effective prophylaxis during induction treatment of AML.

Discontinuation of empirical antibiotic therapy in neutropenic acute myeloid leukaemia patients with fever of unknown origin: is it ethical?

Based on recommendations of the ECIL-4, we prospectively evaluated discontinuation of empirical antibiotic therapy in high-risk neutropenic acute myeloid leukaemia patients with fever of unknown origin. Seven patients (median neutropenia duration 30 days) were included. Four of them remained afebrile but quickly recovered from neutropenia. The other three had rapid recurrent fever. Two of these three patients had bacteraemia with susceptible strains and one of them was transferred to the ICU for septic shock. Median duration of sparing of antibiotics for the seven patients was 3 days (2-4). Because of these limited results the study was stopped.

Intravascular catheter-related bloodstream infection caused by Abiotrophia defectiva in a neutropenic child.

Bacteraemia and endocarditis are the most frequently reported clinical infections due to Abiotrophia defectiva species. This species has been rarely implicated in infections in neutropenic patients. We report a rare case of long-term venous catheter-related infection caused by A. defectiva that occurred in a febrile child who had neutropenia and Langerhans' cell histiocytosis.

A retrospective series of gut aspergillosis in haematology patients.

Gut invasive aspergillosis is an extremely rare infection in immunocompromised patients. The goal of this retrospective multicentre study is to report on cases of gut aspergillosis in haematology patients, including clinical presentation, risk factors, and outcome. Twenty-one patients from nine centres were identified. Eight had isolated gut aspergillosis, with no evidence of other infected sites, and 13 had disseminated aspergillosis. Thirteen patients had acute leukaemia. Nine were allogeneic stem cell transplant recipients. Clinical symptoms and imaging were poorly specific. The galactomannan antigenaemia test result was positive in 16/25 (64%) patients, including in four of the eight cases of isolated gut aspergillosis. Five of 21 patients had a dietary regimen rich in spices, suggesting that, in these cases, food could have been the source of gut colonization, and then of a primary gut Aspergillus lesion. The diagnosis was made post-mortem in six patients. The mortality rate in the remaining patients at 12 weeks was 7/15 (47%). Gut aspergillosis is probably misdiagnosed and underestimated in haematology patients, owing to the poor specificity of symptoms and imaging. Patients with a persistently positive galactomannan antigenaemia finding that is unexplained by respiratory lesions should be suspected of having gut aspergillosis in the presence of abdominal symptoms, and be quickly investigated. In the absence of severe abdominal complications leading to surgery and resection of the lesions, the optimal treatment is not yet defined.

European guidelines for antifungal management in leukemia and hematopoietic stem cell transplant recipients: summary of the ECIL 3--2009 update.

In 2005, several groups, including the European Group for Blood and Marrow Transplantation, the European Organization for Treatment and Research of Cancer, the European Leukemia Net and the Immunocompromised Host Society created the European Conference on Infections in Leukemia (ECIL). The main goal of ECIL is to elaborate guidelines, or recommendations, for the management of infections in leukemia and stem cell transplant patients. The first sets of ECIL slides about the management of invasive fungal disease were made available on the web in 2006 and the papers were published in 2007. The third meeting of the group (ECIL 3) was held in September 2009 and the group updated its previous recommendations. The goal of this paper is to summarize the new proposals from ECIL 3, based on the results of studies published after the ECIL 2 meeting: (1) the prophylactic recommendations for hematopoietic stem cell transplant recipients were formulated differently, by splitting the neutropenic and the GVHD phases and taking into account recent data on voriconazole; (2) micafungin was introduced as an alternative drug for empirical antifungal therapy; (3) although several studies were published on preemptive antifungal approaches in neutropenic patients, the group decided not to propose any recommendation, as the only randomized study comparing an empirical versus a preemptive approach showed a significant excess of fungal disease in the preemptive group.

[Severe "malignant" influenza in the light of past history]. / La grippe maligne vue à la lumière du passé.

The first influenza pandemic of the xxist century is due to a novel A (H1N1) strain. The infection, which affects younger patients than seasonal influenza, presents most often under a benign form. But it can rarely and rapidly evolve to pulmonary parenchymal involvement, independently of any bacterial superinfection or co-infection. It becomes a true viral pneumonia, which can evolve to acute respiratory distress syndrome (ARDS). This phenomenon was well described for the three xxth century pandemics, especially for the 1968-1969 one. These cases of "malignant flu" benefitted from the great breakthroughs in medical intensive care made in the previous 15 years. The specificity of these pandemic strains to infect lower respiratory tract is of immunological origin: only patients with little or no immunity to the virus can develop viral pneumonia and ARDS. This is why trivalent vaccination against seasonal flu appears to be somewhat protective against severe presentations of the disease. During winter 2009-2010, an inflow of flu-related ARDS cases is expected in French ICUs. Aggressive oxygenation techniques, high dose and prolonged antiviral treatment, and steroid adjunctive therapy, could be used, adding to the experience acquired during previous pandemics.

[Usefulness of panfungal PCR for the diagnosis of fungal infection in immunocompromised patients]. / Intérêt de l'amplification génique à l'aide d'amorces universelles dans le diagnostic des infections fongiques chez le patient immunodéprimé.

The diagnostic of invasive fungal infection is often difficult because of the low sensitivity of fungal culture from infected tissues. Here we have assessed the ability of a panfungal PCR targeted on the DNA region encoding the RNA genes followed by sequencing of the amplification products to detect and identify fungi from tissue biopsies. This assay allowed us to identify the microorganism responsible for an invasive fungal infection in three of our patients. In two cases, hepatosplenic candidiasis was suspected and Candida albicans DNA was detected from liver biopsies. The third patient was cared for a thymome and developed a manubrium osteitis caused by Scedosporium apiospermum.

[Blackwater fever]. / Fièvre bilieuse hémoglobinurique.

DEFINITION: Blackwater fever is a clinical entity characterized by acute intravascular hemolysis classically occuring after the re-introduction of quinine in long-term residents in Plasmodium falciparum endemic areas and repeatedly using the product. CLINICAL PROFILE: The symptomatology appears brutally with emission of porto-colored urine, icterus, pallor, nausea, fever and acute renal failure. The hemolytic-like anemia is immediately severe. Parasitemia is mild or absent. The mechanism of renal failure is tubular necrosis. QUININE AND SIMILAR MOLECULES: Well known at the start of the 20th century, blackwater fever has become exceptional since 1950, when quinine was replaced by chloroquine. The disease reappeared in 1990, following the re-utilization of quinine because of resistance to chloroquine. Thereafter, several cases have been described with halofantrine and mefloquine, two new molecules similar to quinine (amino-alcohol family). The physiopathogenesis of the disease is not well known, however it would appear that the concomitance of a double sensitivization of the red blood cells to the P. falciparum red blood cells and to the amino-alcohols is necessary to provoke the hemolysis. EVOLUTION: The severity of the clinical picture often requires initial management in intensive care unit. Nowadays, however, prognosis is good and the disease usually regresses without after effects.

Usefulness of a strategy based on bronchoscopy with direct examination of bronchoalveolar lavage fluid in the initial antibiotic therapy of suspected ventilator-associated pneumonia.

OBJECTIVES: To evaluate (a) the routine accuracy of bronchoalveolar lavage by direct examination (BAL-D) in diagnosing ventilator-associated pneumonia (VAP), and (b) the impact of a diagnostic strategy including clinical judgment, bronchoscopy, and BAL-D on the initial diagnosis and appropriateness of treatment when VAP is suspected. DESIGN AND SETTING: Prospective cohort study in two academic ICUs in Paris, France. PATIENTS AND PARTICIPANTS: Mechanically ventilated patients with suspected VAP underwent bronchoscopy with BAL and protected specimen brush (PSB). BAL-D results were available within 2 h, BAL on culture and PSB results after 24 h, and antibiotic susceptibility after 48 h. At each step in the strategy the senior and the resident in charge of the patient were asked their diagnosis and their therapeutic plan on the basis of presently available data. Definite diagnosis of suspected VAP was based on histology, appearance of cavitation, positive pleural fluid culture, results of PSB and BAL culture, and follow-up. MEASUREMENT AND RESULTS: A total of 110 episodes of suspected VAP were studied; 94 definite diagnoses were made (47 VAP, 47 no VAP). Using a threshold 1% of infected cells, BAL-D discriminated well between patients with and those without VAP (sensitivity 93.6%, specificity 91.5%, area under the receiver-operating characteristic curve 0.953). The senior clinical judgment was correct in 71% cases. It was correct in 78% and 94% of cases after airway visualization and BAL-D findings, respectively. After BAL-D the positive and negative predictive values in diagnosing VAP were 90% and 98%, respectively. However, the therapeutic plan was correct in only 65% using clinical judgment (15 untreated patients, 3 ineffective treatment, 15 useless treatment), 66% using airway visualization (14 untreated VAP, 4 ineffective treatment, 14 useless treatment), and 88% using BAL-D results (1 untreated patients, 6 ineffective, 4 useless), according to definite diagnosis and final antibiotic susceptibility testings. CONCLUSIONS: A strategy based on bronchoscopy and BAL-D generally leads to a rapid and appropriate treatment of nosocomial pneumonia in ventilated patients.

[Severe malaria]. / Paludisme grave.

Falciparum malaria remains a major killer in developing countries, particularly for African children. Moreover, France is the leading European country in term of incidence of imported malaria. Parasitized erythrocytes, which can form rosettes or auto-agglutinate, are sequestrated in the deep microvasculature and stick to activated endothelium by the mean of various receptors. Activation of T lymphocytes and macrophages induces secretion of proinflammatory cytokines, including tumour necrosis factor, which contributes to severe disease. However, the pathophysiology of coma remains poorly understood. In nonimmune adults, besides cerebral malaria, pictures of severe sepsis with shock, acute renal failure and respiratory distress syndrome are common. Although chemotherapy of malaria is challenged by the continuing evolution of antimalarial resistance, quinine remains the first-line drug for severe imported disease. In addition, early symptomatic management in the intensive care unit setting is of paramount importance. Prevention of severe imported malaria lays on prophylactic measures during travel, as well as adequate management of uncomplicated disease after return. In developing countries, early and adequate treatment of uncomplicated disease using cheap alternatives to classical compounds should contribute to "roll back" malaria, particularly in sub-Saharan Africa.

Resurgence of blackwater fever in long-term European expatriates in Africa: report of 21 cases and review.

Blackwater fever (BWF) is a severe clinical syndrome, characterized by intravascular hemolysis, hemoglobinuria, and acute renal failure that is classically seen in European expatriates chronically exposed to Plasmodium falciparum and irregularly taking quinine. BWF virtually disappeared after 1950, when chloroquine superseded quinine. We report 21 cases of BWF seen in France from 1990 through 1999 in European expatriates who lived in sub-Saharan Africa. All patients had macroscopic hemoglobinuria, jaundice, and anemia. Acute renal failure occurred in 15 patients (71%), 7 of whom required dialysis. The presumed triggers of BWF were halofantrine (38%), quinine (24%), mefloquine (24%), and halofantrine or quinine (14%). Glucose-6-phosphate dehydrogenase (G6PD) activity was normal in the 14 patients who underwent this test. Low-level P. falciparum parasitemia was found in 8 patients. All 21 patients survived. Our data and 13 cases reported in the literature suggest a resurgence of classic BWF among Europeans living in Africa and a need to discuss attendant therapeutic implications.

Rapid effect of interleukin-2 therapy in human immunodeficiency virus-infected patients whose CD4 cell counts increase only slightly in response to combined antiretroviral treatment.

Combined antiretroviral treatment in some human immunodeficiency virus-infected persons does not lead to a rapid increase in CD4 cell counts, and these patients may remain susceptible to opportunistic infections. A group of 13 patients with CD4 cell counts <200 cells/mm3 after > or =9 months of combined antiretroviral treatment received interleukin (IL)-2 immunotherapy (4.5x106 IU twice daily for 5 days every 6 weeks). After only 3 cycles, their CD4 cell counts increased from 123 cells/mm3 (range, 104-134 cells/mm3) to 229 cells/mm3 (range, 176-244 cells/mm3). A marked increase was noted in the naive CD45RA subpopulation of CD4 T lymphocytes. Furthermore, the magnitude of the CD4 cell count response correlated with the baseline expression levels of the antiapoptotic molecule Bcl-2. This study demonstrates that IL-2 immunotherapy can accelerate the recovery of CD4 lymphocytes in persons whose CD4 cell counts fail to increase rapidly in response to combined antiretroviral treatment.

Comparison of direct examination of three types of bronchoscopy specimens used to diagnose nosocomial pneumonia.

OBJECTIVE: To compare direct examination of bronchial aspirate and plugged telescopic catheter specimens (PTC) with infected cell counts in bronchoalveolar lavage (BAL) specimens for the diagnosis of nosocomial pneumonia. DESIGN: Prospective study of critically ill patients. SETTING: Intensive care unit in a university hospital. PATIENTS: A total of 64 patients hospitalized for >48 hrs with suspected nosocomial pneumonia. INTERVENTIONS: Fiberoptic bronchoscopy with bronchial aspirate and quantitative protected specimen brush, PTC, and BAL cultures. PTC and bronchial aspirate specimens were Gram-stained. BAL specimens for infected cell counts were examined as described previously in the literature. MEASUREMENTS AND MAIN RESULTS: Nosocomial pneumonia was diagnosed by the medical staff based on all available clinical, radiologic, laboratory test, and microbiological data and on the course before and after appropriate therapy. A total of 71% of patients were ventilated, and 70.1% were receiving antibiotics. Nosocomial pneumonia was diagnosed in 54% of the cases. On direct examination, sensitivity (Se) and specificity (Sp) of bronchial aspirate specimens were Se, 82% and Sp, 60%; of BAL with 5% infected cells, Se, 56% and Sp, 100%; of BAL with 3% infected cells, Se, 74% and Sp, 96%; of PTC specimens, Se, 65% and Sp, 76%; and of PTC specimens plus BAL with 3% infected cells, Se, 83% and Sp, 78%. BAL with 3% infected cells was significantly better for predicting nosocomial pneumonia than direct examination of bronchial aspirate or PTC specimens (p = .0012). When the BAL showed 3% infected cells, neither direct examination of bronchial aspirate nor direct examination of PTC specimens was useful (p = .24 and p = .38, respectively). Combined use of direct examination of PTC specimens plus BAL with 3% infected cells markedly improved sensitivity. The total cost of each procedure was taken into account for the final evaluation. CONCLUSIONS: Our data suggest that BAL with 3% infected cells is currently the only test whose predictive value for nosocomial pneumonia is sufficiently high to be of use for guiding the initial choice of antimicrobial class while waiting for quantitative culture results.

Pneumocystis carinii pneumonia requiring intensive care management: survival and prognostic study in 110 patients with human immunodeficiency virus.

OBJECTIVE: To perform a descriptive study of patients with acute respiratory failure secondary to acquired immunodeficiency syndrome-related Pneumocystis carinii pneumonia and to identify variables that are predictive of death within 3 months. DESIGN: Case series study. SETTING: Infectious disease intensive care unit (ICU) in a university hospital. PATIENTS: Detailed clinical, laboratory, and ventilatory data were collected prospectively within 48 hrs of admission and during the ICU stay in 110 consecutive human immunodeficiency virus-infected patients requiring ICU management with or without mechanical ventilation for P. carinii pneumonia-related acute respiratory failure. MEASUREMENTS AND MAIN RESULTS: Continuous positive airway pressure was used initially in 66 (60%) patients. Among the 34 patients (31%) who required mechanical ventilation, including 12 at admission and 22 after failure of continuous positive airway pressure, 76% died. The 3-month mortality rate after ICU admission was estimated at 34.6% (95% confidence interval [CI], 25%-44%). The 1-yr survival rate was estimated at 47% (95% CI, 36%-58%). With successive multiple logistic regression models analyzing the relative prognostic importance of baseline clinical and laboratory tests variables, ventilation variables, and events in the ICU, only delayed mechanical ventilation after 3 days (odd ratio [OR], 6.7; 95% CI, 1.9-23.9), duration of mechanical ventilation of > or = 5 days (OR, 2.8; 95% CI, 1.1-6.9), nosocomial infection (OR, 5.2; 95% CI, 2.1-12.9), and pneumothorax (OR, 5; 95% CI, 1.7-14.7) were predictive of death within 3 months of ICU admission. Among patients with delayed mechanical ventilation on day 3 or later and with a pneumothorax associated or not associated with a nosocomial infection, the predicted probability of 3-month death was close to 100%. CONCLUSIONS: Our data suggest that the most significant predictive factors of death were identifiable during the course of P. carinii pneumonia-related acute respiratory failure rather than at admission and can help in bedside decisions to withdraw intensive care support in such patients.