More than 1 million apheresis platelet collections are performed annually in the United States. After 2 healthy plateletpheresis donors were incidentally found to have low CD4+ T-lymphocyte counts, we investigated whether plateletpheresis causes lymphopenia. We conducted a cross-sectional single-center study of platelet donors undergoing plateletpheresis with the Trima Accel, which removes leukocytes continuously with its leukoreduction system chamber. We recruited 3 groups of platelet donors based on the total number of plateletpheresis sessions in the prior 365 days: 1 or 2, 3 to 19, or 20 to 24. CD4+ T-lymphocyte counts were <200 cells per microliter in 0/20, 2/20, and 6/20 donors, respectively (P = .019), and CD8+ T-lymphocyte counts were low in 0/20, 4/20, and 11/20 donors, respectively (P < .001). The leukoreduction system chamber’s lymphocyte-extraction efficiency was ∼15% to 20% for all groups. Immunophenotyping showed decreases in naive CD4+ T-lymphocyte and T helper 17 (Th17) cell percentages, increases in CD4+ and CD8+ effector memory, Th1, and regulatory T cell percentages, and stable naive CD8+ and Th2 percentages across groups. T-cell receptor repertoire analyses showed similar clonal diversity in all groups. Donor screening questionnaires supported the good health of the donors, who tested negative at each donation for multiple pathogens, including HIV. Frequent plateletpheresis utilizing a leukoreduction system chamber is associated with CD4+ and CD8+ T-cell lymphopenia in healthy platelet donors. The mechanism may be repeated extraction of these cells during plateletpheresis. The cytopenias do not appear to be harmful.
The aim of this study was to examine the role of cyclooxygenase-2 (COX-2) and downstream signaling of prostanoids in the pathogenesis of pulmonary hypertension (PH) using mice with genetically manipulated COX-2 expression. COX-2 knockdown (KD) mice, characterized by 80–90% suppression of COX-2, and wild-type (WT) control mice were treated weekly with monocrotaline (MCT) over 10 weeks. Mice were examined for cardiac hypertrophy/function and right ventricular pressure. Lung histopathological analysis was performed and various assays were carried out to examine oxidative stress, as well as gene, protein, cytokine and prostanoid expression. We found that MCT increased right ventricular systolic and pulmonary arterial pressures in comparison to saline-treated mice, with no evidence of cardiac remodeling. Gene expression of endothelin receptor A and thromboxane synthesis, regulators of vasoconstriction, were increased in MCT-treated lungs. Bronchoalveolar lavage fluid and lung sections demonstrated mild inflammation and perivascular edema but activation of inflammatory cells was not predominant under the experimental conditions. Heme oxygenase-1 (HO-1) expression and indicators of oxidative stress in lungs were significantly increased, especially in COX-2 KD MCT-treated mice. Gene expression of NOX-4, but not NOX-2, two NADPH oxidase subunits crucial for superoxide generation, was induced by ∼4-fold in both groups of mice by MCT. Vasodilatory and anti-aggregatory prostacyclin was reduced by ∼85% only in MCT-treated COX-2 KD mice. This study suggests that increased oxidative stress-derived endothelial dysfunction, vasoconstriction and mild inflammation, exacerbated by the lack of COX-2, contribute to the pathogenesis of early stages of PH when mild hemodynamic changes are evident and not yet accompanied by vascular and cardiac remodeling.
Introduction We recently discovered that a number of frequent apheresis platelet donors at our donor center had CD4+ T-lymphocyte counts below 200 cells/µL. The cause appears to be repeated extraction of these cells by the Trima Accel Automated Blood Collection System's leukoreduction system chamber. Plateletpheresis at our donor center has been conducted exclusively with this instrument since 2006. How long CD4+ T-cell lymphopenia persists after stopping plateletpheresis is unknown. Whether there are infectious or other complications that could relate to CD4+ T-cell lymphopenia in former donors is also unknown. We therefore investigated the blood counts (including CD4+ T-lymphocyte counts) and medical histories of former platelet donors who had a history of frequent platelet donation but had stopped donating platelets for at least 12 months. Methods We mailed a questionnaire to former frequent apheresis platelet donors who had not donated platelets at our donor center for at least 12 months. Donors who replied to the questionnaire were contacted by phone to schedule a study visit. Frequent platelet donation was defined as 20-24 plateletpheresis sessions in at least one 365-day period starting in 2011. Donors who consented to participate in the study confirmed that they had not donated platelets in the prior 12 months, provided a blood sample for analysis, and completed a health questionnaire that included questions about opportunistic infections and malignancies. Medical records of these donors were also reviewed, where available. Approval for the study was obtained from the Partners HealthCare Institutional Review Board (2017P002880) and all participants provided written informed consent. Results Of 52 former frequent platelet donors identified as eligible to receive a questionnaire, one was known to have died of a myocardial infarction and another had requested not to receive communications from the donor center. Therefore, 50 potential study candidates were mailed a questionnaire. Twelve questionnaires were returned as undeliverable. Five potential study candidates returned the questionnaire but either declined to participate in the study or did not respond when contacted to schedule a study visit. Fourteen former frequent platelet donors elected to participate in the study after receiving the first mailing of the questionnaire. Of these 14 study participants, 6 were female and all were Caucasian. The median age was 65. The most common reason for ceasing platelet donation was a positive HLA antibody test (5 participants) followed by "low white blood cells," "heart trouble," and "inconvenience" (2 participants each). All former donors had tested negative for HIV while donating platelets. There were 2 participants with CD4+ T-lymphocyte counts below 200 cells/µL (Figure 1); one of these participants had prior CD4+ T-lymphocyte counts available for review. These showed that the CD4+ T-lymphocyte count in this former donor had improved slightly since ceasing donation one year earlier (Figure 2). Three study participants had a CD4+ T-lymphocyte count between 200 and 300 cells/µL. A review of prescription medications and medical problems did not identify an etiology for the low CD4+ T-lymphocyte counts. Responses to the health questionnaire showed that no study participant had ever had a severe infection, an infection with an unusual pathogen ("bug"), or thrush. Two former frequent platelet donors had a history of shingles, both of whom had CD4+ T-lymphocyte counts slightly below the normal range (441-2156 cells/µL) at the time of participation in the study. Five former donors had a history of cancer: Two episodes of squamous cell skin cancer (1 participant), papillary thyroid carcinoma (1 participant), glioblastoma (1 participant), basal cell skin cancer (1 participant), and squamous cell skin cancer as well as melanoma in situ (1 participant). Conclusion In our small cohort, there is no evidence that CD4+ T-cell lymphopenia predisposes to opportunistic infections or to malignancies classically associated with immune dysregulation. Plateletpheresis-associated CD4+ T-cell lymphopenia has improved slightly in one former frequent platelet donor a year after ceasing plateletpheresis but the count remains below 200 cells/µL. Frequent plateletpheresis involving a leukoreduction system chamber should be considered in the differential diagnosis of idiopathic CD4+ lymphopenia. Disclosures Gansner: Novimmune SA: Research Funding; UpToDate: Patents & Royalties.
BACKGROUND We recently discovered that 30% of current frequent apheresis platelet donors in a study at our donor center had CD4+ counts below 200 cells/μL. How long CD4+ lymphopenia persists after ceasing plateletpheresis is unknown. Whether there are infectious or other complications in former frequent donors that could relate to CD4+ lymphopenia is also unknown. STUDY DESIGN AND METHODS We mailed a letter to former frequent apheresis platelet donors who had not donated platelets for at least 12 months. Frequent donation was defined as 20 to 24 plateletpheresis sessions in at least one 365‐day period starting in 2011. Donors who expressed interest in the study were contacted to schedule a study visit. Participants in the study provided a blood sample and completed a health questionnaire that included questions about opportunistic infections and malignancies. RESULTS Of 50 potential study candidates who were mailed a letter, 15 participated in the study. There were 2 participants with CD4+ counts below 200 cells/μL, one of whom had prior counts that documented a small improvement with cessation of plateletpheresis. Three participants had counts between 200 and 300 cells/μL. No study participant had a history of an opportunistic infection or a malignancy associated with immune dysregulation. CONCLUSION We detected CD4+ lymphopenia in former frequent apheresis platelet donors who had ceased platelet donation for more than 1 year. There was no evidence that the CD4+ lymphopenia predisposes to opportunistic infections or to malignancies associated with immune dysregulation.
Context Intravascular large B-cell lymphoma (IVLBCL) is a rare non-Hodgkin B-cell lymphoma with a poor prognosis. While typically described as comprising large atypical cells restricted to the lumina of small blood vessels, it can show variability in cell size. Objective To report the clinicopathologic features of the IVLBCL with small cell morphology and discuss the practical implications of our findings. Design We searched our archives for all IVLBCL diagnosed in our institution for the last 25 years (1992–2017). Slides were reviewed independently by two hematopathologists. Results We found a total of 11 cases of IVLBCL. Bone marrow, brain, lymph node, pericardium, small bowel, and fallopian tube and ovary were the organs in which the lymphoma was initially diagnosed. One of the cases initially diagnosed in the marrow showed intrasinusoidal involvement by a small cell lymphoma; the diagnosis was confirmed by random skin biopsies showing intravascular large cells with the same phenotype. Retrospective review of the liver on this case also showed the intrasinusoidal involvement by the disease consisting of small cells. In another case, IVLBCL that was initially diagnosed in a small bowel biopsy was retrospectively found in a breast biopsy, but with small cell morphology. Conclusions Our findings suggest that, in the presence of high clinical suspicion, IVLBCL should be high in the differential diagnosis when lymphoma is predominantly intravascular, even when the tumor cells are small. A timely diagnosis of this entity can be critical. Hence, awareness of a small cell variant of IVLBCL should be increased.
Inflammatory pseudotumors have a diverse etiology, mycobacterial pseudotumor (MP) being one of them. MP is a rare entity; it has been reported infrequently in various organs and is extremely rare in the skin. We report a cutaneous MP in an immunosuppressed liver transplant recipient. The lesion consisted mostly of spindle cells, with small numbers of lymphocytes. Conventional acid-fast bacilli (AFB) stain revealed a large number of acid-fast bacilli within spindled histiocytes and the presence of Mycobacterium avium was determined by polymerase chain reaction. Given that the patient had a prior history of cutaneous squamous cell carcinoma resected and reconstructed in the same area, establishing the diagnosis was challenging. Immunohistochemical staining for lysosome-associated membrane protein was strongly positive, suggesting the presence of numerous mature lysosomes within infected spindle cells. Mycobacterial spindle cell pseudotumors can mimic malignant or benign neoplasms and should be considered in differential diagnosis of spindle cell lesions, especially in immunocompromised patients. Further studies are needed to determine mechanisms that permit the survival of mycobacteria within the lesions and that cause this unusual manifestation of infection.
Intussusception is commonly seen in children but is rare in adults and represents only 5% of all intussusceptions causing 1% of intestinal obstructions. More than 50% of these intussusceptions in adults are due to intestinal neoplasms, including malignant lymphoma, e.g., Burkitt lymphoma. These lymphomas are more common in human immunodeficiency virus (HIV)-positive patients than in the general population. We present a case of a young male who was diagnosed with HIV when he developed intestinal obstruction and intussusception secondary to Burkitt lymphoma. He was managed with surgical resection followed by chemotherapy and antiretroviral treatment. HIV patients presenting with acute abdomen pose a diagnostic challenge to clinicians due to a wide range of differential diagnoses including inflammatory, infectious and neoplastic conditions. In a young HIV patient presenting with acute abdomen, intussusception caused by Burkitt lymphoma should be considered in the differential.
Introduction: Benign Ethnic Neutropenia (BEN) is the most common form of neutropenia worldwide and is usually defined as a neutrophil count under 1.5x103/uL without increased infection risk. BEN has been observed predominantly in individuals of African ancestry as well as in certain Middle Eastern ethnic groups. The discovery of neutropenia during routine laboratory testing, however, may prompt extensive workup for infectious, autoimmune, and hematologic disorders. Identifying a readily available test to diagnose BEN in the appropriate ethnic and clinical setting could preempt unnecessary and invasive testing such as a bone marrow aspiration and biopsy and minimize patient anxiety. The absence of the red blood cell (RBC) Duffy antigen, Fy (a- b-), is thought to be responsible for BEN. As the Duffy antigen is utilized by the parasite Plasmodium vivax to enter the RBC, it has been hypothesized that in West Africa, positive selection for the null allele enabled individuals to be protected against infection and have a survival advantage. Aim: Our study examined whether testing for the Fy phenotype could reliably be used as a clinical assay to identify patients with BEN. Methods: Our cases included patients at the VA CT Healthcare System clinically diagnosed with BEN and controls that were chosen randomly from the pools of patients for whom a CBC and type and screen were checked for any other reason. Both probable BEN cases and controls were tested for the Fy phenotype using standard serologic methods in the blood bank. The Fy phenotype, absolute neutrophil count (ANC), white blood cell count (WBC), hemoglobin level, platelet count, and medical diagnoses were extracted from the medical record. Applicable data were compared statistically using the Mann-Whitney U Test with significance set at p < 0.05. Results: Our study included 32 patients (mean age 54, range 21 to 90) who were clinically identified as probable BEN cases and 50 patients (mean age 68, range 38 to 97) chosen as controls. In the probable BEN group, 28 patients self-identified as African American or Black and 3 declined self-identification. In the control group, 11 patients self-identified as African American or Black, 34 self-identified as White, 2 self-identified as Hispanic, 2 declined self-identification, and 1 self-identified as Native Hawaiian. The majority of probable BEN patients (31 of 32) and only a minority of control patients (6 of 50) were Fy (a- b-). Most study patients were male: 30 of 32 probable BEN patients and all control patients were male. The mean ANC count for Fy(a- b-) probable BEN patients was significantly lower than controls (1.68x103/uL versus 5.46x103/uL, p < 0.0001). Similarly, the mean WBC count for Fy (a- b-) probable BEN patients was significantly lower than the mean WBC for controls (3.72 x 103/uL versus 8.14 x 103/uL, p < 0.0001). Hemoglobin was comparable between Fy(a- b-) probable BEN patients and controls (12.91 g/dL versus 11.68 g/dL, p = 0.0673) as were platelets between Fy(a- b-) probable BEN patients and controls (194x103/uL versus 213x103/uL, p = 0.4354). The only African American patient presumed to have BEN that was not confirmed by Fy testing was found to have concurrent diagnoses that could otherwise explain his neutropenia (HIV/HCV). The remaining confirmed BEN cases did not have an accompanying marrow suppressive hematologic disorder. Five control group patients had potentially marrow suppressive hematologic disorders including myelodysplastic syndrome and acute myeloid leukemia. Conclusions: Readily available serologic testing in the blood bank for Duffy antigen phenotyping can be used to confirm suspected BEN in patients with high clinical suspicion. Further testing is in progress of Fy phenotyping comparing controls with neutropenia for any reason to our proposed BEN population to better determine the positive predictive value. Fy phenotyping to confirm BEN suspicion may help avoid unnecessary and invasive neutropenia testing. In addition, since BEN affects certain ethnic groups (primarily those of African ancestry), these individuals may be unfairly excluded from possible treatment including cytopenia-inducing psychiatric medications like clozapine, myelosuppressive chemotherapy, and clinical trials due to ANC eligibility requirements. Fy phenotyping to confirm clinical suspicion of BEN could be a useful tool to help develop modified guidelines for neutropenia-inducing medication. Disclosures No relevant conflicts of interest to declare.
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