Neutropenia with fever

CAUSAL GERMS: Over the last 10 years, hemotology units have seen many changes in the epidemiological pattern of infections in neutropenic patients, with a growing number of infections caused by Gram-positive germs. The number of septicemias due to multiresistant Gram-negative germs (Pseudomonas aeruginosa, Strenotrophomonas maltophilia) has however remained high. IMPACT OF THERAPEUTIC REGIMENS: Improved prognosis in neutropenic patients depends for a large part on careful management of septic episodes. As the risk of septicemia is strongly correlated with the degree of efficacy of antibiotic regimens, susceptibility data must always be examined when developing antibiotic protocols in units caring for neutropenic patients.     

Neutropenia and thrombocytopenia in burns

Two patients are presented who developed a potentially lethal blood dyscrasia after a burn injury. The first developed a neutropenia and the second a thrombocytopenia. The possible causes are discussed. These cases stress the importance of regular monitoring of the complete blood picture in the management of burns patients.     

Neutropenia and fever after aorto-coronary bypasses

Plasma-derived products are often used in cardiac surgery. We report the case of a patient developing an infection due to Parvovirus B19 after coronary artery bypass. Symptoms were fever, asthenia, anemia, and pancreatitis. This infection can be transmitted from plasma-derived product, like fibrin sealant (used for hemostasis during surgery). Parvovirus B19 is resistant to existing virus-inactivating techniques. The patient had to leave our hospital after symptomatic treatment which has significantly increased the length to stay.     

Neutropenia impairs venous thrombosis resolution in the rat

OBJECTIVES: Neutrophil influx is one of the first events in a formed deep venous thrombosis (DVT), but whether these cells are active participants in the resolution process is not clear. This study tests the hypothesis that neutrophils (PMN) are active participants in DVT resolution. METHODS: Thrombosis was induced by inferior vena caval (IVC) ligation in male Sprague-Dawley rats, and rats were sacrificed at 2, 4, or 7 days for evaluation of the thrombus. Neutropenia was induced by rabbit anti-rat PMN serum, and controls received rabbit serum. Venography was performed at the 7-day time point. Immunohistochemical staining was performed to quantify intrathrombus PMNs and monocytes, and the myeloperoxidase (MPO) assay was performed to assess intrathrombus neutrophil activity. Intrathrombus concentrations of kerotinocyte cytokine (KC), macrophage inflammatory protein-2 (MIP-2), gamma interferon inducible protein-10 (IP-10), macrophage inflammatory protein-1 alpha (MIP-1 alpha), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor (TNF)-alpha were quantified by enzyme immunoassay at each time point and normalized to total protein. Total collagen was determined at day 7. RESULTS: Peripheral blood smears showed a 94% PMN reduction at 2 days (P <.05), recovering to 44% of control at 7 days. Intrathrombus PMNs were significantly lower in neutropenic rats at 2 and 4 days, but there were no differences in intrathrombus monocytes. The MPO assay confirmed reduced neutrophil activity at 4 days. Thrombi from neutropenic rats were larger at 2 and 7 days compared with controls. In vivo thrombus area at 7 days as assessed by venography was also greater in neutropenic rats as compared with controls. The intrathrombus KC concentration was increased more than 20-fold in the neutropenic rats at 2 days, but there were no significant differences in other intrathrombus chemokines. Finally, intrathrombus collagen was increased over threefold in neutropenic rats as compared with controls. CONCLUSION: Neutropenia impairs DVT resolution by several measures, most likely by altering normal fibrinolytic activity and thrombus collagen turnover.     

Neutropenia and Plasma Free Radical Reaction Products During Haemodialysis

To determine whether haemodialysis produces an increase in freeradical activity, plasma phospholipid plus free fatty acid (PL+FFA)octadeca-9,11-dienoic acid (18:2(9,11)) and plasma thiobarbituricacid reactivity (TBAR) were measured serially during dialysiswith cuprophan and polycarbonate membranes. Plasma TBAR didnot change significantly during dialysis with either membrane.There was however, an increase in PL+FFA 18:2(9,11) and in themolar ratio of 18:2(9,11) to its parent compound, linoleic acid(18:2(9,12)), with both membranes, although this was most significantwith cuprophan membranes. The administration of heparin to normal controls without dialysisproduces a comparable rise in PL+FFA 18:2(9,11). Haemodialysiswith prostacyclin anticoagulation resulted in no significantchange in PL+FFA 18:2(9,11). The data indicates that the increasein PL+FFA 18:2(9,11) during haemodialysis is due to a heparin-inducedrise in FFA 18:2(9,11) and is not a consequence of increasedfree radical activity. In contrast to animal models of systemic complement activation,we were unable to demonstrate an increase in plasma free radicalactivity during haemodialysis. However, this does not precludea role for free radicals, released by activated neutrophils,in the pathogenesis of pulmonary dysfunction during haemodialysis.     

Neutropenia complicating parenteral antibiotic treatment of infected nonunion of the tibia

Fifty patients with posttraumatic tibial nonunion complicated by chronic refractory osteomyelitis were treated with intravenous antibiotics. Fifteen patients (30%) experienced 18 episodes of leukopenia; seven of these patients became neutropenic and three became severely neutropenic. No patient became neutropenic prior to the 20th day of antibiotic therapy. The classic findings of fever, pruritus, maculopapular rash, and eosinophilia did not correlate with either the onset or the severity of the neutropenia. Neutropenia can develop precipitously. Prevention of neutropenia is difficult in a patient population receiving long-term antibiotic therapy. Regular monitoring of the white blood cell count and differential cell count minimizes the risk of developing prolonged, severe neutropenia with potential complications. No patient in this series had any serious or infectious complication secondary to neutropenia.     

Neutropenia in kidney and liver transplant recipients: Risk factors and outcomes

No studies have directly compared the key characteristics and outcomes of kidney (KTx) and liver transplantation (LTx) recipients with neutropenia. In this single‐center, retrospective, cohort study, we enrolled all adult patients who received a KTx or LTx between 2000 and 2011. Neutropenia was defined as 2 consecutive absolute neutrophil count (ANC) values <1500/mm³ in patients without preexisting neutropenia. The first neutropenia episode occurring during the first year post‐transplantation was analyzed. A total of 663 patients with KTx and 354 patients with LTx met the inclusion criteria. Incidence of neutropenia was 20% in KTx and 38% in LTx, respectively. High‐risk CMV status and valganciclovir (VGCV) use were significant predictors of neutropenia for KTx recipients, but only VGCV use vs nonuse in LTx recipients. Neutropenia was associated with worse survival in KTx recipients (adjusted HR 1.95, 95% CI 1.18‐3.22, P<.01), but not in LTx recipients (adjusted HR 0.75, 95% CI 0.52‐1.10, P=.15). Sixteen acute rejection episodes were associated with preceding neutropenia in KTx recipients (HR 1.77, 95% CI 1.16‐2.68, P=.007) and 24 acute rejection episodes in LTx recipients (HR 1.41, 95% CI 0.97‐2.04, P=.07). Incidence of infection was similar in patients with and without neutropenia among KTx and LTx recipients.     

Neutropenia associated with the use of low-dose methotrexate in a peritoneal dialysis patient.

Sir, We describe a case of neutropenia associated with the use oflow-dose methotrexate in a patient undergoing continuous ambulatoryperitoneal dialysis, who subsequently developed invasive pulmonaryaspergillosis. Case. A 64-year-old man was admitted with fever 23 daysafter starting methotrexate for the treatment of psoriasis,receiving a cumulative dose of 35 mg. Mouth ulceration developed     

On the Mechanisms of Haemodialysis-induced Neutropenia: A Study with Five New and Re-used Membranes

A prospective study was undertaken in 12 haemodialysed patientssuccessively treated on five new as well as re-used dialysermembranes, that is cuprophane, cellulose acetate, polysulphone,polycarbonate, and polyacrylonitrile. A significant reductionof neutrophils occurred with every membrane during their firstuse, which improved only with cuprophane upon re-use. Thrombocytopeniawas noted only when neutropenia reached very low values. Monocytereduction occurred on cuprophane, cellulose acetate and polycarbonate,but did not improve during second use. C₃d accumulation paralleledthe time course of neutropenia only with cuprophane and celluloseacetate. Plasma collected at the extreme of neutropenia inducedaggregation of control and predialysis cells, but did not aggregateautologous dialysed neutrophils collected at 5 min. Our dataindicate that the mechanism linking complement activation toneutropenia is probably triggered by more than one factor.     

Incidence, Risk Factors, and Impact of Severe Neutropenia After Hyperthermic Intraperitoneal Mitomycin C

Background  Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are considered the standard of care for patients with peritoneal dissemination of appendiceal cancer and are increasingly being evaluated for use in patients with carcinomatosis from colon cancer. Mitomycin C (MMC) is one of the most frequently used HIPEC agents in the management of peritoneal-based gastrointestinal malignancies. This study analyzes the incidence and risk factors for developing neutropenia following MMC-HIPEC combined with CRS. Methods  All patients undergoing CRS and MMC-HIPEC for appendiceal cancer between January 1993 and October 2006 were retrospectively reviewed. Logistic regression was used to identify risk factors for the development of neutropenia, defined as an absolute neutrophil count (ANC) <1,000/mm³. Results  One hundred and twenty MMC-HIPEC were performed in 117 patients with appendiceal cancer. The incidence of neutropenia was 39%. Neutropenia occurred in 57.6% of female and 21.3% of male patients (p < 0.0001). Female gender and MMC dose per body surface area (BSA) were independent risk factors for neutropenia on multivariable logistic regression [odds ratio (OR) of neutropenia in females = 3.58 (95% confidence interval, CI: 1.52, 8.43); OR for 5 unit (mg/m²) increase in MMC dose per BSA = 3.37 (95% CI: 1.72, 6.63)]. Neutropenia did not increase the risk of mortality, postoperative infection or length of hospital stay. Conclusion  Neutropenia is a frequent complication associated with MMC-HIPEC. Female sex and MMC dose per BSA are independent risk factors for neutropenia. These differences must be considered in the management of patients undergoing MMC-HIPEC to minimize the toxicity of the procedure.     

Protroca: A Noninterventional Study on Prophylactic Lipegfilgrastim against Chemotherapy-Induced Neutropenia in Nonselected Breast Cancer Patients

BackgroundProtroca evaluated the efficacy and safety of primary and secondary prophylaxis of neutropenia with lipegfilgrastim (Lonquex®) in breast cancer patients receiving neoadjuvant or adjuvant chemotherapy (CT).Patients and MethodsOf the 255 patients enrolled, 248 patients were evaluable for the intent-to-treat (ITT) and 194 patients for the per-protocol set. Primary and secondary end points after lipegfilgrastim treatment were assessed.ResultsNine patients of the ITT set receiving lipegfilgrastim as primary prophylaxis (n = 222) had febrile neutropenia of grade 3–4 (5 patients) or infection of grade 3–4 (4 patients); 1/26 of those receiving secondary prophylaxis had an event. Dose reductions were performed in 9.5% of the patients. Postponement of cancer CT cycles for >3 days occurred in <15% of patients; 10.8% (92/851 AEs) and 8% (2/25 SAEs) of documented adverse events and serious adverse events, respectively, were related to lipegfilgrastim.ConclusionsApplication of lipegfilgrastim was effective as primary and secondary prophylaxis in the prevention of CT-induced neutropenia in breast cancer.     

Incidence, Risk Factors and Clinical Consequences of Neutropenia Following Kidney Transplantation: A Retrospective Study

Neutropenic episodes in kidney transplant patients are poorly characterized. In this retrospective study, neutropenia was experienced by 112/395 patients (28%) during the first year posttransplant. The only factor found to be significantly associated with the occurrence of neutropenia was combined tacrolimus-mycophenolate therapy (p < 0.001). Neutropenic patients experienced more bacterial infections (43% vs. 32%, p = 0.04). Grade of neutropenia correlated with the global risk of infection. Discontinuation of mycophenolic acid (MPA) due to neutropenia was associated with an increased incidence of acute rejection (odds ratios per day 1.11, 95% confidence intervals 1.02–1.22) but not with reduced renal function at 1 year. The time from onset of neutropenia to MPA discontinuation correlated with the duration of neutropenia. Granulocyte colony-stimulating factor (G-CSF) administration was safe and effective in severely neutropenic kidney graft recipients, with absolute neutrophil count >1000/μL achieved in a mean of 1.5 ± 0.5 days. Neutropenia is an important and frequent laboratory finding that may exert a significant influence on outcomes in kidney transplantation. As well as leading to an increased incidence of infection, it is associated with a higher rate of allograft rejection if MPA is discontinued for >6 days (p = 0.02). G-CSF accelerates recovery of neutropenia and may be a good therapeutic alternative for severely neutropenic patients.     

Incidence and Management of Leukopenia/Neutropenia in 233 Kidney Transplant Patients Following Single Dose Alemtuzumab Induction

BackgroundThe purpose of this study was to determine the incidence and management strategies for post-transplant leukopenia/neutropenia in kidney recipients receiving alemtuzumab induction during the first year following transplantation.MethodsWe prospectively identified 233 adult patients who underwent kidney transplantation with alemtuzumab induction at a single institution. The incidence and severity of leukopenia (white blood cell count [WBC] ≤2500/mm³) and neutropenia (absolute neutrophil count [ANC] ≤500/mm³) were evaluated at 1, 3, 6, and 12 months post-transplantation. We determined any association with cytomegalovirus (CMV) infection, graft rejection, and infections requiring hospitalization. We also reviewed interventions performed, including medication adjustments, treatment with granulocyte stimulating factor, and hospitalization.ResultsThe combined incidence of either leukopenia or neutropenia was 47.5% (n = 114/233) with an average WBC nadir of 1700 ± 50/mm³ at 131.0 ± 8.5 days and an average ANC nadir of 1500 ± 100/mm³ at 130.4 ± 9.6 days. No significant difference in graft rejection, CMV infection, or infections requiring hospitalization was found in the leukopenia/neutropenia group vs the normal WBC group (P = .3). The most common intervention performed for leukopenia/neutropenia group was prophylactic medication adjustment. Six patients (5.2%) required a change in >1 medication. The majority of these patients also required granulocyte stimulating factor (61.5%; 32/52), with an average of 2.5 doses given. A total of 25 patients (21.9%) required hospitalization due to leukopenia/neutropenia with an average length of stay of 6 days.ConclusionsKidney transplant patients receiving alemtuzumab induction required significant interventions due to leukopenia/neutropenia in the first year post-transplantation. These results suggest the need for additional studies aimed at defining the optimum management strategies of leukopenia/neutropenia in this population.     

Neutropenia prevents decrease in strength of rat intestinal anastomosis: partial effect of oxygen free radical scavengers and allopurinol

A marked decrease in strength, probably due to local collagenolysis, occurs early after surgery in tissues adjacent to an incisional wound. To examine the role of the neutrophils, antineutrophil serum (ANS) was given to rats before and after a standardized end-to-end ileoileal anastomosis. Preimmune serum (PIS) was given to control rats. The decrease in anastomotic breaking strength, amounting to 55% in the PIS group, did not occur in ANS-treated rats, in which there was a decrease by more than 95% in the number of circulating polymorphonuclear cells. The decrease in tissue strength seems to be partly from oxygen free radicals, since the free radical scavengers superoxygen dismutase (SOD) and catalase prevented approximately 50% of the decrease. The xanthine oxidase inhibitor, allopurinol, prevented approximately 30% of the decrease. This is consistent with oxygen free radicals being partly generated by the neutrophils and partly generated after conversion of tissue xanthine dehydrogenase to xanthine oxidase. In contrast to ANS, SOD and catalase were unable to fully prevent the decrease in breaking strength. Therefore some other factor in addition to oxygen free radicals should be involved. One such factor may be the release of collagenolytic proteinases, e.g., elastase and cathepsin G, from the neutrophils.     

Biosimilar Granulocyte Colony-Stimulating Factor Is Effective in Reducing the Duration of Neutropenia After Autologous Peripheral Blood Stem Cell Transplantation

Background

Autologous peripheral blood stem cell transplantation (APBSCT) is the standard of therapy for patients with multiple myeloma and refractory Hodgkin's and non-Hodgkin's lymphomas. Granulocyte colony-stimulating factor (G-CSF) is widely used to accelerate hematopoietic recovery after transplantation and to reduce the morbidity and mortality associated with prolonged neutropenia. Biosimilar G-CSF is approved for the same indications as the originator G-CSF. This is one of the first reported uses of a biosimilar G-CSF for neutrophil recovery after APBSCT.

Methods

A total of 23 consecutive patients with hematological malignancy (multiple myeloma, Hodgkin's and non-Hodgkin's lymphomas, and acute myelogenous leukemia) were recruited at the Department of Haematooncology and Bone Marrow Transplantation at the Medical University of Lublin. Patients (12 men and 11 women; median age, 47 ± 13 years) received biosimilar G-CSF (Zarzio, Sandoz Biopharmaceuticals) after myeloablative chemotherapy (primarily BiCnU, etoposide, cytarabine, and melphalan or melphalan 140/200 mg/m²) followed by PBSCT. The median number of transplanted CD34+ cells was 4.2 ± 0.8 × 10⁶/kg body wt. G-CSF therapy was started when absolute neutrophil count (ANC) was <0.5 × 10⁹/L and was continued until ANC reached >1.5 × 10⁹/L for 3 consecutive days. Hematopoietic recovery parameters were compared with those in the control group, which consisted of 23 consecutive patients transplanted in the period before the biosimilar G-CSF group and receiving originator G-CSF (Neupogen, Amgen).

Results

The mean duration of treatment with biosimilar and originator G-CSF was 14.4 ± 5.1 and 18.6 ± 11.5 days, respectively (P = .43). The adverse event profile was comparable between the biosimilar G-CSF and originator G-CSF groups, with similar occurrence of neutropenic fever (5 versus 6 patients) and bone pain (7 patients in each group). One patient in the biosimilar group had neutropenic enterocolitis and sepsis. There was no case of death in either group. Granulocyte recovery in the study group was as follows: mean days to ANC >0.5 × 10⁹/L was 13.0 ± 4.0 days; to ANC >1.5 × 10⁹/L, 13.6 ± 4.5 days; and to ANC >1.5 × 10⁹/L, 14.0 ± 4.7 days. Mean duration until platelet recovery >20 × 10⁹/L was 16.1 ± 4.4 days. There were no statistically significant differences between the biosimilar and originator G-CSF groups in hematopoietic recovery parameters.

Conclusions

Biosimilar G-CSF is safe and effective in reducing the duration of neutropenia in patients undergoing myeloablative therapy followed by APBSCT and probably in cost savings in transplantation budgets.     

Neutropenia at the time of subcutaneous port insertion may not be a risk factor for early infectious complications in pediatric oncology patients

Background

The risk of infection associated with subcutaneous port (SQP) placement in patients with neutropenia remains unclear. We reviewed the rate of early infectious complications (< 30?days) following SQP placement in pediatric oncology patients with or without neutropenia [absolute neutrophil count (ANC) < 500/mm³].