Anne Bergeron

Pulmonary Arterial Hypertension in Patients Treated by Dasatinib

Background— The French pulmonary hypertension (PH) registry allows the survey of epidemiological trends. Isolated cases of precapillary PH have been reported in patients who have chronic myelogenous leukemia treated with the tyrosine kinase inhibitor dasatinib. Methods and Results— This study was designed to describe incident cases of dasatinib-associated PH reported in the French PH registry. From the approval of dasatinib (November 2006) to September 30, 2010, 9 incident cases treated by dasatinib at the time of PH diagnosis were identified. At diagnosis, patients had moderate to severe precapillary PH with functional and hemodynamic impairment. No other incident PH cases were exposed to other tyrosine kinase inhibitors at the time of PH diagnosis. Clinical, functional, or hemodynamic improvements were observed within 4 months of dasatinib discontinuation in all but 1 patient. Three patients required PH treatment with endothelin receptor antagonist (n=2) or calcium channel blocker (n=1). After a median follow-up of 9 months (min-max 3–36), the majority of patients did not demonstrate complete clinical and hemodynamic recovery, and no patients reached a normal value of mean pulmonary artery pressure (⩽20 mm Hg). Two patients (22%) died at follow-up (1 of unexplained sudden death and 1 of cardiac failure in the context of septicemia, respectively, 8 and 12 months after dasatinib withdrawal). The lowest estimate of incident PH occurring in patients exposed to dasatinib in France was 0.45%. Conclusions— Dasatinib may induce severe precapillary PH fulfilling the criteria of pulmonary arterial hypertension, thus suggesting a direct and specific effect of dasatinib on pulmonary vessels. Improvement is usually observed after withdrawal of dasatinib.

The Prognosis of Acute Respiratory Failure in Critically Ill Cancer Patients

Abstract: Acute respiratory failure (ARF) in patients with cancer is frequently a fatal event. To identify factors associated with survival of cancer patients admitted to an intensive care unit (ICU) for ARF, we conducted a prospective 5-year observational study in a medical ICU in a teaching hospital in Paris, France. The patients were 203 cancer patients with ARF mainly due to infectious pneumonia (58%), but also noninfectious pneumonia (9%), congestive heart failure (12%), and no identifiable cause (21%). We measured clinical characteristics and ICU and hospital mortality rates. ICU mortality was 44.8% and hospital mortality was 47.8%. Noninvasive mechanical ventilation was used in 79 (39%) patients and conventional mechanical ventilation in 114 (56%), the mortality rates being 48.1% and 75.4%, respectively. Among the 14 patients with late noninvasive mechanical ventilation failure (>48 hours), only 1 survived. The mortality rate was 100% in the 19 noncardiac patients in whom conventional mechanical ventilation was started after 72 hours. By multivariable analysis, factors associated with increased mortality were documented invasive aspergillosis (odds ratio [OR], 2.13; 95% confidence intervals [CI], 1.05-14.74), no definite diagnosis (OR, 3.85; 95% CI, 1.26-11.70), vasopressors (OR, 3.19; 95% CI, 1.28-7.95), first-line conventional mechanical ventilation (OR, 8.75; 95% CI, 2.35-35.24), conventional mechanical ventilation after noninvasive mechanical ventilation failure (OR, 17.46; 95% CI, 5.04-60.52), and late noninvasive mechanical ventilation failure (OR, 10.64; 95% CI, 1.05-107.83). Hospital mortality was lower in patients with cardiac pulmonary edema (OR, 0.16; 95% CI, 0.03-0.72). Survival gains achieved in critically ill cancer patients in recent years extend to patients requiring ventilatory assistance. The impact of conventional mechanical ventilation on survival depends on the time from ICU admission to conventional mechanical ventilation and on the patients response to noninvasive mechanical ventilation. Abbreviations: ARDS = acute respiratory distress syndrome, ARF = acute respiratory failure, BAL = bronchoalveolar lavage, HSCT = human stem-cell transplant, ICU = intensive care unit, MV = mechanical ventilation, NIMV = noninvasive mechanical ventilation.

Polymerase chain reaction for diagnosing pneumocystis pneumonia in non-HIV immunocompromised patients with pulmonary infiltrates.

RATIONALE Pneumocystis jiroveci polymerase chain reaction (PCR) has higher sensitivity than conventional stains but cannot distinguish colonization from infection. METHODS We compared P jiroveci PCR and conventional stains in HIV-uninfected immunocompromised patients. RESULTS Among the 448 patients, 296 (66%) patients had hematologic malignancies; 72 (16.1%), bone marrow transplants; 44 (9.8%), solid tumors; 21 (4.7%), renal transplants; and 15 (3.4%) were taking immunosuppressants for systemic diseases. Diagnostic strategy consisted of BAL in 351 patients and induced sputum (IS) in 97 patients. Conventional pneumocystic pneumonia (PCP) stain was positive in 39 (8.7%) patients, including 34 with positive PCR. In addition, PCR was positive in 32 patients, including 21 with complete follow-up, of whom 14 were diagnosed with probable or definitive PCP (a 36% increase). PCR was 87.2% sensitive and 92.2% specific; positive and negative predictive values were 51.5% and 98.7%, respectively. Sensitivity and negative predictive value were 100% on IS. CONCLUSIONS In HIV-uninfected immunocompromised patients with acute pulmonary infiltrates, P jiroveci PCR correlates with clinical evidence of PCP. A negative PCR allows withdrawing anti-PCP therapy.

Cytokine profiles in idiopathic pulmonary fibrosis suggest an important role for TGF‐β and IL-10

Modulation of cytokine expression represents a potentially useful approach for the treatment of idiopathic pulmonary fibrosis (IPF). To identify potential targets for such intervention, semi-quantitative reverse transcriptase-polymerase chain reaction was used to compare the expression of messenger ribonucleic acids (mRNAs) coding for 17 cytokines in lung tissue obtained from patients with IPF at the time of diagnosis and control subjects. Some cytokines were also studied at the protein level by immunohistochemical techniques. mRNAs coding for all of the cytokines evaluated were detected in both control and fibrotic lung samples. Only transforming growth factor (TGF)‐β and interleukin (IL)-10 mRNAs were quantitatively increased in lung biopsies from patients with IPF compared with those of controls, results confirmed at the protein level by immunohistochemistry. Although mRNAs for platelet-derived growth factor (PDGF)-BB and keratinocyte growth factor (KGF) were expressed in similar amounts in lungs from patients with IPF and controls, localised accumulation of both factors was also observed in IPF. Hyperplastic alveolar epithelial cells were a prominent source of cytokines, where IL-10, PDGF-BB and KGF were present in increased amounts, although increased accumulation in fibroblasts, smooth-muscle cells and matrix components was also observed (PDGF-BB, TGF‐β). These results offer new insights into the cytokines produced in the lung in idiopathic pulmonary fibrosis and suggest that modulation of the production of transforming growth factor‐β and interleukin-10 may represent a potentially useful therapeutic strategy for this disabling disease.

Disseminated adenovirus infections after allogeneic hematopoietic stem cell transplantation: incidence, risk factors and outcome

We analyzed the factors and outcome of patients with disseminated adenovirus infection (dAdV) after allogeneic hematopoeitic stem cell transplantation (HSCT). Thirty patients with dAdV were identified among 620 allogeneic HSCT recipients. Primary diseases were leukemia (n=17), Fanconi anemia (n=12) or others (n=1). Source of stem cells was unrelated in 28 and related in 2 patients. The graft consisted of peripheral blood (n=3), bone marrow (n=12) and unrelated cord-blood (UCB, n=15). Risk factors for dAdV in unrelated HSCT recipients were previous Fanconi disease (p=0.03) and GVHD (p=0.02) in children, and cord blood source of stem cells (p=0.029) and GVHD (0.024) in adults.

Breakthrough Disseminated Aspergillus ustus Infection in Allogeneic Hematopoietic Stem Cell Transplant Recipients Receiving Voriconazole or Caspofungin Prophylaxis

ABSTRACT Aspergillus ustus is an uncommon clinical species which is poorly susceptible to antifungals. We report two cases of A. ustus infections that occurred in allogeneic stem cell transplant recipients while they were receiving either voriconazole or caspofungin. Prolonged use of these new antifungal agents may increase the risk of the emergence of resistant organisms.

Palivizumab Treatment of Respiratory Syncytial Virus Infection after Allogeneic Hematopoietic Stem Cell Transplantation

Among 40 allogeneic stem cell transplant recipients who developed symptomatic respiratory syncytial virus infection, including 22 patients with lower respiratory tract infection, 19 received palivizumab (9 of whom had upper respiratory tract disease). Palivizumab did not prevent progression to lower respiratory infection and had no impact on the overall survival rate.

Polyomaviruses KI and WU in Immunocompromised Patients with Respiratory Disease

Polyomaviruses KI (KIPyV) and WU (WUPyV) were recently identified, mainly in respiratory specimens from children. Among 200 patients with respiratory disorders admitted to Saint Louis Hospital, Paris, France, KIPyV was detected in 8% and WUPyV in 1%. KIPyV was significantly more frequent among human stem cell transplant patients (17.8% vs. 5.1%; p = 0.01).

Use and Limits of (1-3)-β-d-Glucan Assay (Fungitell), Compared to Galactomannan Determination (Platelia Aspergillus), for Diagnosis of Invasive Aspergillosis

ABSTRACT This study was undertaken to examine the performance of the Fungitell β-glucan (BG) assay, to compare it with that of the galactomannan (GM) test for the diagnosis of invasive aspergillosis (IA) in patients with hematological malignancies, and to examine the rates of false-positive BG and GM test results due to β-lactam antibiotics among sera of patients with Gram-positive or Gram-negative bacteremia and selected sera with false-positive results from the GM test. Serum samples from 105 patients with proven (n = 14) or probable (n = 91) IA, 97 hematology patients at risk for invasive fungal infections, 50 healthy blood donors, and 60 patients with bacteremia were used to study the sensitivities and specificities of the assays. The GM test was more specific than the BG assay (97% versus 82%, respectively; P = 0.0001) and the BG assay was more sensitive than the GM test (81% versus 49%, respectively; P < 0.0001) for IA diagnosis. The study of 49 separate batches of β-lactam antibiotics showed high and very similar rates of false-positive results for the GM and BG assays (29 and 33%, respectively; P = 0.82) but with an almost complete lack of concordance between the 2 assays. For patients with bacteremia, the rate of false-positive results was much higher with the BG test than with the GM test (37% versus 2%, respectively; P < 0.0001), with no significant difference between Gram-positive and Gram-negative bacteremia. In conclusion, the BG test may be useful for the diagnosis of IA because of its high sensitivity in comparison with the GM test, but the overall benefit of this assay remains limited because of its inadequate specificity and its cost.

Active Chronic Sarcoidosis is Characterized by Increased Transitional Blood B Cells, Increased IL-10-Producing Regulatory B Cells and High BAFF Levels

Background Sarcoidosis is a multisystemic disease of unknown etiology characterized by a disproportionate Th1 granulomatous immune response in the organs involved. Plasmatic hypergammaglobulinemia and B cell accumulation in granulomatous lesions suggest the possible role of humoral immune responses in the pathogenesis of sarcoidosis. The purpose of this study is to describe B cell peripheral compartment in sarcoidosis. Methodology/Principal Findings We analyzed blood B cell subsets and BAFF levels in 33 patients with chronic sarcoidosis (active sarcoidosis n = 18; inactive sarcoidosis n = 15) and 18 healthy donors. Active chronic sarcoidosis patients had significantly less circulating memory B cells (p<0.01), more transitional (p<0.01) and increased numbers of IL-10-producing regulatory B cells (p<0.05) compared with healthy donors and patients with inactive sarcoidosis. BAFF serum levels were significantly higher in patients with active sarcoidosis (p<0.01 versus healthy donors and inactive sarcoidosis patients) and strongly correlated with serum hypergammaglobulinemia (r = 0.53, p<0.01) and angiotensin converting enzyme levels (r = 0.61, p = <0.01). Conclusions/Significance These data show that there is an altered B cell homeostasis in active sarcoidosis and suggest BAFF antagonist drugs as potential new treatments of this disease.