Assessing complement blockade in patients with paroxysmal nocturnal hemoglobinuria receiving eculizumab.

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by intravascular hemolysis, which is effectively controlled with eculizumab, a humanized monoclonal antibody that binds complement protein 5 (C5). The residual functional activity of C5 can be screened using a 50% hemolytic complement (CH50) assay, which is sensitive to the reduction, absence, and/or inactivity of any components of the classical and terminal complement pathway. Little data exist on complement blockade during treatment. From 2010 to 2012, clinical data, hemolysis biomarkers, complement assessment, and free eculizumab circulating levels were systematically measured immediately before every injection given to 22 patients with hemolytic PNH while receiving eculizumab therapy. During the study, 6 patients received ≥1 red blood cell transfusion. Lack of detectable CH50 activity (defined by CH50 ≤ 10% of normal values) was found in 184 samples (51%) and was significantly associated with lower lactate dehydrogenase levels (P = .002). Low levels of circulating free eculizumab (<50 µg/mL) correlated with detectable CH50 activity (CH50 > 10%; P = .004), elevated bilirubin levels (P < .0001), and the need for transfusions (P = .034). This study suggests that both CH50 activity and circulating free eculizumab levels may help physicians to manage PNH patients receiving eculizumab.

Early Lung Computed Tomography Scan after Allogeneic Hematopoietic Stem Cell Transplantation.

A lung computed tomography (CT) scan is essential for diagnosing lung diseases in hematopoietic stem cell transplantation (HSCT) recipients. As a result, lung CT scans are increasingly prescribed in the early phase after allogeneic HSCT, with no assessment of the added value for global patient management. Among 250 patients who underwent allogeneic HSCT in our center over a 2-year period, we evaluated 68 patients who had at least 1 lung CT scan within the first 30 days post-transplantation. The median interval between allogeneic HSCT and lung CT scan was 8.5 days. Patients who underwent an early lung CT scan were more immunocompromised and had a more severe course. Fever was the main indication for the CT scan (78%). The lung CT scan was abnormal in 52 patients, including 17 patients who had an abnormal pre-HSCT CT scan. A therapeutic change was noted in 37 patients (54%) within 24 hours after the lung CT scan. The main changes included the introduction of corticosteroids (n = 23; 62%), especially in patients with a normal CT scan (89%). In univariate models, we found that a normal pretransplantation CT scan (P = .002), the absence of either dyspnea (P = .029) or hypoxemia (P = .015), and a serum C-reactive protein level <10 mg/L (P = .004) were associated with a normal post-HSCT lung CT scan. We found that the association of these variables could predict the normality of early post-HSCT lung CT scans. Pretransplantation lung CT scans are useful for the interpretation of subsequent lung CT scans following allogeneic HSCT, which are frequently abnormal. Early post-HSCT lung CT scans are helpful in patient management, but prescriptions could be more targeted.

Pre-transplant prognostic factors of long-term survival after allogeneic peripheral blood stem cell transplantation with matched related/unrelated donors.

Mobilized peripheral blood has become the predominant stem cell source for allogeneic hematopoietic cell transplantation. In this retrospective single center study of 442 patients with hematologic malignancies, we analyzed prognostic factors for long-term survival after peripheral blood stem cell transplantation from HLA-matched related or unrelated donors. To account for disease/status heterogeneity, patients were risk-stratified according to the Disease Risk Index. Five-year overall survival was similar after transplants with matched related and unrelated donors (45% and 46%, respectively; P=0.49). Because donor age ≥60 years impacted outcome during model building, we further considered 3 groups of donors: matched unrelated (aged <60 years by definition), matched related aged <60 years and matched related aged ≥60 years. In multivariate analysis, the donor type/age group and the graft CD34(+) and CD3(+) cell doses impacted long-term survival. Compared with matched unrelated donor transplant, transplant from matched related donor <60 years resulted in similar long-term survival (P=0.67) while transplant from matched related donor ≥60 years was associated with higher risks for late mortality (hazard ratio (HR) 4.41; P=0.006) and treatment failure (HR: 6.33; P=0.009). Lower mortality risks were observed after transplant with CD34(+) cell dose more than 4.5×10(6)/kg (HR: 0.56; P=0.002) and CD3(+) cell dose more than 3×10(8)/kg (HR: 0.61; P=0.01). The Disease Risk Index failed to predict survival. We built an "adapted Disease Risk Index" by modifying risks for myeloproliferative neoplasms and multiple myeloma that improved stratification ability for progression-free survival (P=0.04) but not for overall survival (P=0.82).

Alveolar and blood T lymphocyte profiles in Pneumocystis jirovecii-positive patients: effects of HIV status.

BACKGROUND: There are substantial differences in the risk evaluation, clinical presentation, and outcome of Pneumocystis pneumonia between human immunodeficiency virus (HIV)-positive and HIV-negative immunocompromised patients. To compare the host immune defenses against Pneumocystis jirovecii, the blood and alveolar lymphocyte profile was explored in these 2 populations. METHODS: The total, CD3(+), CD4(+), and CD8(+) T-lymphocyte counts were measured in the blood and alveoli of immunocompromised patients with a P. jirovecii DNA detected in their bronchoalveolar lavage samples, according to their HIV status. RESULTS: In blood and alveoli, the CD4(+) and CD8(+) T-lymphocyte counts were higher and lower, respectively, in the HIV-negative group. The threshold for initiating prophylaxis in HIV-positive persons, 200 CD4(+) T cells/µL, was not pertinent for HIV-negative patients. The P. jirovecii burden correlated with the blood CD4(+) T-cell counts in the HIV-positive but not in the HIV-negative group. Nevertheless, whatever the HIV status, a correlation was observed between alveolar CD4(+) T cells and the P. jirovecii burden. CONCLUSIONS: The T-lymphocyte profile was different between HIV-positive and HIV-negative patients with P. jirovecii, suggesting a distinct pathogenesis. Alveolar CD4(+) T cells could be critical to explain the development of Pneumocystis pneumonia but may also be important for evaluation of disease risk, mostly among HIV-negative immunocompromised patients.

Cellular and cytokine changes in the alveolar environment among immunocompromised patients during Pneumocystis jirovecii infection.

Limited data exist on the cytokine and cellular changes in the alveolar environment in immunocompromised patients during Pneumocystis jirovecii infection. A cellular and a cytokine analysis were performed on bronchoalveolar lavage (BAL) samples from three groups of patients, i.e., an initial study group of 64 immunocompromised P. jirovecii-positive individuals and two control groups of P. jirovecii-negative patients who had been or not immunosuppressed (65 patients). The results were related to alveolar dilution as determined by urea measurement. Compared with non-infected groups, P. jirovecii-infected patients had a lower level of alveolar macrophages (AM), particularly those with high burdens of P. jirovecii. Alveolar macrophages over-expressed the Dectin-1 receptor, which was largely implicated in P. jirovecii clearance. The alveolar CD8+T and CD4+T lymphocyte counts were increased and an inverse correlation was observed between the alveolar CD4+ cell count and the P. jirovecii burden. Although the alveolar IL-6 level was considerably increased, alveolar IL-17, IL-10, TNF-α, TGF-ß concentrations of P. jirovecii patients were not different from the control groups. Changes in the pulmonary environment were also highlighted during P. jirovecii colonization. Our study suggests that there is a correlation between the P. jirovecii burden in the alveolus (from colonization to a high P. jirovecii burden), and the degree of impairment of the alveolar immune response.

Human Leukocyte Antigen Sensitization in Solid Organ Transplantation: A Primer on Terminology, Testing, and Clinical Significance for the Apheresis Practitioner.

The human leukocyte antigen (HLA) system is an important immunologic barrier that must be considered for successful solid organ transplantation. Formation of donor-specific HLA antibodies in solid organ transplantation is an important cause of allograft injury and may contribute to recipient morbidity and mortality. Therapeutic plasma exchange is often requested to lower HLA antibody levels prior to or after transplantation and for management of HLA antibodies in the context of organ rejection. In this review, we summarize the current terminology, laboratory testing, and clinical significance of HLA sensitization in the solid organ transplant population. Furthermore, to illustrate applications of HLA testing in clinical practice, we summarize our own lung and kidney institutional protocols for managing HLA antibodies in the peri-transplant setting.

Young Sprague Dawley rats infected by Plasmodium berghei: A relevant experimental model to study cerebral malaria.

Cerebral malaria (CM) is the most severe manifestation of human malaria yet is still poorly understood. Mouse models have been developed to address the subject. However, their relevance to mimic human pathogenesis is largely debated. Here we study an alternative cerebral malaria model with an experimental Plasmodium berghei Keyberg 173 (K173) infection in Sprague Dawley rats. As in Human, not all infected subjects showed cerebral malaria, with 45% of the rats exhibiting Experimental Cerebral Malaria (ECM) symptoms while the majority (55%) of the remaining rats developed severe anemia and hyperparasitemia (NoECM). These results allow, within the same population, a comparison of the noxious effects of the infection between ECM and severe malaria without ECM. Among the ECM rats, 77.8% died between day 5 and day 12 post-infection, while the remaining rats were spontaneously cured of neurological signs within 24-48 hours. The clinical ECM signs observed were paresis quickly evolving to limb paralysis, global paralysis associated with respiratory distress, and coma. The red blood cell (RBC) count remained normal but a drastic decrease of platelet count and an increase of white blood cell numbers were noted. ECM rats also showed a decrease of glucose and total CO2 levels and an increase of creatinine levels compared to control rats or rats with no ECM. Assessment of the blood-brain barrier revealed loss of integrity, and interestingly histopathological analysis highlighted cyto-adherence and sequestration of infected RBCs in brain vessels from ECM rats only. Overall, this ECM rat model showed numerous clinical and histopathological features similar to Human CM and appears to be a promising model to achieve further understanding the CM pathophysiology in Humans and to evaluate the activity of specific antimalarial drugs in avoiding/limiting cerebral damages from malaria.