Low Absolute Neutrophil Count Research Articles

Admission Clinical and Laboratory Factors Associated With Death in Children With Cancer During a Febrile Neutropenic Episode

Early identification of children with cancer at risk for death during a febrile neutropenic (FN) episode may increase their possibility for survival. Our aim was to identify at the time of admission, clinical and laboratory variables differing significantly among children who survived or died during a FN episode. In a prospective, multicenter study, children admitted with a high-risk FN episode were uniformly evaluated at enrollment and managed according to a national consensus protocol. Medical charts of children who died were evaluated to determine whether the death could be associated with an infection. Admission clinical and laboratory variables significantly associated with death were identified. A total of 393 (70%) of 561 FN episodes evaluated from June 2004 to December 2005 were classified as high risk for invasive bacterial infection, of which 14 (3.6%) resulted in an infectious-related death. Deaths occurred from 2 to 27 days after admission, and most dying children were admitted with relapse of acute lymphocytic leukemia (36%), hypotension (71%), and a diagnosis of sepsis (79%), compared with surviving children (16%, 20%, and 5% respectively, P < 0.001). Children who died were admitted with lower absolute neutrophil count (P < 0.001) and absolute monocytes count levels (P = 0.008), higher blood urinary nitrogen (P = 0.03) and C-reactive protein values (P < 0.001), and had more positive cultures (79% versus 32%, P = 0.008). We identified early clinical and laboratory findings significantly associated with death occurring at a later stage. Routine evaluation of these variables may prove to be useful in the early identification of children with a high-risk FN episode at risk for death.

Ethnic neutropenia among women of European, African, and Caribbean backgrounds

6587 Background: Black women are less likely than white women to receive complete chemotherapy for cancer. One reason for interruption of chemotherapy may be a patient's low white blood count (WBC) or absolute neutrophil count (ANC). In studies of white blood cell count (WBC) and race, white individuals’ WBC has been considered the standard, and 25–40% of non-Hispanic black individuals have been described as having “benign ethnic neutropenia.”. We therefore studied the prevalence and severity of ethnic neutropenia among women in six ethnic groups and of the association between neutropenia and serum cytokine and C-reactive protein (CRP) levels and neutrophil elastase (ELA2) polymorphisms. Methods: Following IRB approval, each participant provided a blood sample that was tested for WBC with differentials, cytokines and CRP levels, and ELA2 polymorphisms. We compared median WBC and ANC using Kruskal-Wallis tests. We used Fisher's exact tests to analyze association of severe neutropenia with ethnicity, cytokine and CRP levels, and ELA2 polymorphisms. Results: We enrolled 263 women 20–70 years old who had no cancer diagnosis.. As the table shows, median WBC and ANC differed by group; Dominicans had significantly higher median WBCs and ANCs than all other groups. Of 12 women with severe neutropenia (ANC = 1,500), none was Dominican or European-American. Subjects with a common upregulating ELA2 promoter polymorphism (C-199A) had lower ANC counts than other subjects. No associations were found between ANC counts and either cytokines or CRP levels. Conclusions: Median WBC and ANC and severe neutropenia were associated with ethnicity. Mild neutropenia is considered clinically benign, but because severe neutropenia may result in decreased doses or delays in chemotherapeutic treatment for malignancies, ethnic neutropenia and its role in treatment decisions requires further investigation. No significant financial relationships to disclose. [Table: see text]

Success rate and myeloid toxicity of carboplatin desensitization protocol in low grade glioma patients

20012 The effectiveness of carboplatin and vincristine chemotherapy in the treatment of low grade glial tumors is well established. This study was retrospectively designed to investigate the success rate and myeloid toxicity of carboplatin desensitization in a group of patients with carboplatin allergy. A total of 45 patients followed between October 1998-January 2007 with low grade glial tumors were included into study. Patients with severe hypersensitivity reactions (including anaphylaxis) were given 6-step desensitization protocol with gradual increase in concentration of carboplatin over 6 hours. Weekly absolute neutrophil count (ANC) and number of febrile neutropenia episodes of each patient during treatment period were collected from patient files. Among 45 patients, eight were switched to desensitization protocol. They had received a median of 6 courses (range 1–29) of carboplatin before developing their first allergic reaction. A median number of 15 courses of desensitizations (range 3–40) were given to these patients. Desensitization was successful in 6 patients. Age, gender, diagnosis were found to be similar in patients with and without carboplatin allergy. Regarding myeloid toxicity, mean percentage of follow-up weeks with ANC values below 1,500/mm3 in patients with and without desensitization were 0.42±0.04 and 0.21±0.02, respectively (p=0.009). Mean percentage of weeks with ANC values below 500/mm3 were not significant between two groups (p=0.28). However, desensitization protocol was not found to have an impact on number and presence of febrile neutropenia episodes. In conclusion, desensitization protocol might be an alternative to complete scheduled treatment in low grade glioma patients with hypersensitivity to carboplatin. Although, the percentage of low ANC weeks seemed to be statistically higher, insignificance of febrile neutopenia episodes in our patients demonstrated safety of desensitization protocol in terms of myeloid toxicity. No significant financial relationships to disclose.

Associations of ABCB1, ABCC2, and ABCG2 polymorphisms with irinotecan‐pharmacokinetics and clinical outcome in patients with advanced non‐small cell lung cancer

The authors investigated whether ABCB1, ABCC2, and ABCG2 genetic polymorphisms affect pharmacokinetics (PK) of irinotecan and treatment outcome of patients with advanced nonsmall cell lung cancer (NSCLC). Blood samples from 107 NSCLC patients treated with irinotecan and cisplatin chemotherapy were used for genotyping ABCB1 (1236C > T, 2677G > T/A, 3435C > T), ABCC2 (-24C > T, 1249G > A, 3972C > T), and ABCG2 (34G > A, 421C > A) polymorphisms. Genotypes were correlated with irinotecan-PK, toxicity, tumor response, and survival. Among 8 polymorphisms, 3435TT and 2677TT were associated with AUC(SN-38G) and CL(SN-38G). When haplotypes are assigned, 2677TT/3435TT carriers showed significantly lower AUC(SN-38G) (P = .006), whereas 2677GG/3435CC carriers showed significantly higher AUC(SN-38) (P = .039). These findings suggest that 2677TT and 3435TT variants are associated with higher efflux activity. In toxicity, the 2677G/T or A was associated with grade 4 neutropenia. The 2677GG carriers showed significantly lower absolute neutrophil count during the 1(st) cycle (P = .012) as well as entire course of chemotherapy (P = .042). The 3435TT was associated with higher frequency of grade 3 diarrhea (P = .047). In tumor response, ABCC2 -24TT and 3972TT genotypes were associated with higher response rates (P = .031 and P = .048, [corrected] respectively) and longer progression-free survival (P = .010 and P = .019, [corrected] respectively), which was sustained in haplotype analysis. Specific polymorphisms of ABCB1 and ABCC2 can influence disposition and tumor response to irinotecan by regulating transporter activity. These findings may help to individualize irinotecan-based chemotherapy in patients with advanced NSCLC.

Risk Factors of Bloodstream Infection Associated Mortality in Pediatric Patients with Hemato-oncologic Disease

Background: Bloodstream infection is one of the important causes of mortality, and morbidity in pediatric patients with hemato-oncologic disease. The purpose of this stu dy was to identify the risk factors related to mortality in patients who suffered from a bloodstream infection. Methods: We retrospectively reviewed and analyzed the medical records of 133 pediatric patients with hemato-oncologic diseases who had episodes of bloodstream infection documented at Asan Medical Center from June 2002 through May 2005. Results: A total of 288 pathogens were isolated, and there were 17 episodes of polymicrobial infections. Among the episodes of bloodstream infection, 93.4% were caused by bacteria of which 60.1% were gram-positive bacteria, and 33.3% were gram-negative bacteria. Fungal infections accounted for 6.6% of the infections. The main pathogens included Staphylococcus epidermidis (31.3%), Pseudomonas aeru- ginosa (8.3%), and Klebsiella pneumoniae (7.3%). Gram-positive organisms were isolated more frequently than gram-negative organisms, and non-albicans Candida species were documented more frequently than C. albicans in our study. Infection related mortality was 8.3% (11 of 133 patients). The pulmonary infiltration on chest X-ray (CXR) (P=0.001), and a low absolute neutrophil count ( ≤500/μL) (P=0.017) at the time of blood culture were significantly associated with mortality. Gram-negative bacterial infection (especially with Stenotrophomonas maltophilia) and fungal infection often progressed to the septic shock or death. Conclusion: This study revealed that the presence of pulmonary infiltration on a CXR, neutropenia ( ≤ 500/μL), and gram-negative bacterial infection might be important risk factors of mortality in pediatric patients with hemato-oncologic diseases necessitating more aggressive and vigilant supportive care.

The Role of SN‐38 Exposure, UGT1A1*28 Polymorphism, and Baseline Bilirubin Level in Predicting Severe Irinotecan Toxicity

Irinotecan, an anticancer drug, is associated with severe and potentially fatal diarrhea and neutropenia. The objective of this analysis was to evaluate the role of SN-38 exposure, the active metabolite of irinotecan, UGT1A1 genotypes, and baseline bilirubin on the maximum decrease (nadir) in absolute neutrophil counts following irinotecan. This analysis extended the work of a previous study that examined the effect of UGT1A1 genotypes on the incidence of severe neutropenia in 86 advanced cancer patients following irinotecan treatment. Regression analysis showed that the absolute neutrophil count nadir depended on SN-38 exposure (AUC) and UGT1A1*28 homozygous 7/7 genotype. An increased SN-38 AUC and the 7/7 genotype were significantly associated with a lower absolute neutrophil count nadir (R2 = .49). An alternate model suggested that higher baseline bilirubin and the 7/7 genotype were also significantly associated with a lower absolute neutrophil count nadir, although with a lower coefficient of determination (R2 = .31). Based on these findings and other reports, the irinotecan label was modified to indicate the role of UGT1A1*28 polymorphism in the metabolism of irinotecan and the associated increased risk of severe neutropenia. The label modifications also included recommendations for lower starting doses of irinotecan in patients homozygous for the UGT1A1*28 (7/7) polymorphism.

Role of laboratory variables in differentiating SARS-coronavirus from other causes of community-acquired pneumonia within the first 72 h of hospitalization

The Centers for Disease Control and Prevention (CDC) recommend that SARS-coronavirus (SARS-CoV) testing be considered in epidemiologically high-risk patients hospitalized with community-acquired pneumonia (CAP) if no alternative diagnosis is identified after 72 h. The aim of this study was to identify routine laboratory variables that might indicate the need for SARS-CoV testing. Routine hematological/biochemical variables in patients with laboratory-confirmed SARS (2003) were compared with those in consecutive patients hospitalized June–December 2004 with radiologically confirmed CAP. Stepwise logistic regression analyses were performed to identify discriminating variables at baseline and by day 3 of hospitalization. Nasopharyngeal aspiration and antigen detection for influenza virus and respiratory syncytial virus using an immunofluorescence assay (IFA) were routinely performed in patients with CAP. Altogether, 181 patients with CAP (who remained undiagnosed by IFA) and 303 patients with SARS were studied. The mean intervals from symptom onset to admission were 3.1 and 2.8 days, respectively (p > 0.05). The etiological agent of CAP was identified retrospectively in only 39% of cases, the majority being bacterial pathogens. At baseline, age and absolute neutrophil count (ANC) were the only independent discriminating variables (p < 0.0001). Using a value of <4.4 × 109/l as the cutoff for ANC, the sensitivity and specificity of ANC for discriminating SARS were 64 and 95%, respectively (AUC 0.90). By day 3 of hospitalization, age (p < 0.0001), change in ANC (p = 0.0003), and change in bilirubin (p = 0.0065) were discriminating variables. A model combining age <65 years, a change in ANC of >−3 × 109/l, and a change in bilirubin of ≥0 mmol/l had a sensitivity of 43% and a specificity of 95% for SARS (AUC 0.90). There are only a few laboratory features (including lymphopenia) that clearly discriminate SARS from other causes of CAP. Nevertheless, when evaluating epidemiologically high-risk patients with CAP and no immediate alternative diagnosis, a low ANC on presentation along with poor clinical and laboratory responses after 72 h of antibiotic treatment may raise the index of suspicion for SARS and indicate a need to perform SARS-CoV testing.

Periodontitis as a Manifestation of Chronic Benign Neutropenia

A subcategory of chronic neutropenia is chronic benign neutropenia, which is characterized by a prolonged non-cyclic neutropenia as the sole abnormality, with no underlying disease to which the neutropenia can be attributed. Chronic neutropenia is defined as a low absolute neutrophil count for >6 months. In this presentation, periodontitis seems to be the sole manifestation of a juvenile patient with chronic benign neutropenia. A 7-year-old white male presented with periodontitis of the primary dentition and early tooth loss. His medical and dental history was otherwise unremarkable. Suspecting some systemic illness as the underlying cause, the patient was referred for a medical consultation and a series of blood tests. Blood analyses included a complete blood count (CBC), sequential multiple analyzer 24 (SMA 24), glycated hemoglobin levels, and screening for anti-white blood cell antibodies. Blood levels of calcium, vitamin D, dihydroxyvitamin-D, phosphorus, and alkaline phosphatase were also measured. Liver function tests were performed. Following analysis of recent and previous blood test results, a diagnosis of chronic benign neutropenia was assigned. The patient's periodontal condition was treated with scaling and root planing, oral hygiene instruction, and antimicrobial mouthrinses. Three-month recall visits were recommended as a follow-up protocol. This case represents the importance of diagnosing periodontal disease as a possible indicator of underlying systemic disease. When a patient presents with an unusual, generalized form of periodontal disease, screening for systemic disorders is required, as the oral condition may be the first or only manifestation of a systemic abnormality. This case also illustrates the reason for the change in classification of such a condition to periodontitis as a manifestation of systemic disease. This condition was previously classified as prepubertal periodontitis, a disease diagnosis that focused on the patient's age at the onset of the disease rather than the etiology.

Range of Normal Neutrophil Counts in Healthy Zimbabwean Infants

Mother-to-child HIV prevention trials in sub-Saharan Africa use the US National Institutes of Health Division of AIDS (DAIDS) grading scale to monitor hematologic toxicity. A recent study of nevirapine prophylaxis given for 6 months in breast-feeding Zimbabwean infants reported several cases of relative neutropenia in clinically well infants, raising concerns of drug toxicity. However, the DAIDS tables are based on normal blood counts for white infants, although there is evidence that black African infants may have lower absolute neutrophil counts (ANCs) than white infants. To establish normal hematologic values in black Zimbabwean infants and to quantify the apparent prevalence of relative neutropenia in this population, we evaluated HIV-uninfected healthy infants born to HIV-uninfected women at birth, 10 days, 6 weeks, 3, and 4 months of life. A physical examination and blood count were performed at each visit, and an HIV test was performed at the final visit. The ANC values were graded using the DAIDS table. A total of 145 healthy term infants satisfied the inclusion criteria. The mean ANC values for Zimbabwean infants were less than half of the corresponding standard values at all 5 time points (P < 0.0001). Using the DAIDS table in use at the time that the blood was collected, 57% of these healthy infants had relative neutropenia of any grade at birth, followed by 29% at day 10, 53% at 6 weeks, 32% at 3 months, and 37% at 4 months of life. Our data indicate that relative neutropenia exists in healthy black Zimbabwean infants. The guidelines for identifying toxicity were changed in December 2004. However, even by the new DAIDS tables, 43%, 23%, 24%, 42%, and 43% of these healthy babies had relative neutropenia at the time of the 5 visits. Future HIV prevention and treatment trials in sub-Saharan Africa should use normal hematologic values derived from African infants to avoid the overestimation of antiretroviral drug toxicity.

Same day administration of pegfilgrastim with dose dense doxorubicin in early breast cancer patients

671 Background: Pegfilgrastim is indicated to decrease the incidence of febrile neutropenia in patients with non-myeloid malignancies receiving myelosuppressive chemotherapy. In licensing studies, patients received a single dose of pegfilgrastim on day 2 of each chemotherapy cycle, which added an extra visit for day 2 administration. We administered pegfilgrastim to a series of early breast cancer patients on the same day of chemotherapy. We reviewed charts retrospectively to assess both efficacy and safety. Methods: Data on blood counts, toxicity and chemotherapy dosing was collected from July 1, 2003 to May 6, 2005 for all patients with early breast cancer who received sequential or combination doxorubicin, cyclophosphamide and paclitaxel on a 14 day schedule. Herceptin was given with paclitaxel and/or cyclophosphamide in 2 patients. Results: 64 patients with a median age of 50 years (range 22–67 years) were treated. 14 patients had stage I disease, 39 stage II and 11 stage III disease. Forty-one patients were treated postoperatively and 23 preoperatively. 211 cycles of doxorubicin were administered. After administration of doxorubicin, pegfilgrastim 6 mg s.c. was given on the same day. The lowest absolute neutrophil count on day 14 after doxorubicin was 1693/mm3 with no episodes of febrile neutropenia. The highest absolute neutrophil count was 23,671/mm3. The only dose reductions were five doxorubicin doses for grade 1–2 mucositis. Grade 1–2 nausea and vomiting was the most common toxicity seen after doxorubicin. Grade 1 bone pain was the most common side effect seen after pegfilgrastim occurring in 13/64 patients. There was no grade 3 or 4 toxicity of any kind. Conclusion: Pegfilgrastim administered on the same day as doxorubicin on a 14 day schedule was both safe and effective. Side effects were mild and included bone pain most likely attributable to pegfilgrastim. Neither granulocytopenia nor febrile neutropenia were seen and no treatments were delayed or postponed. Pegfilgrastim given on the same day as chemotherapy was effective in maintaining adequate granulocyte counts to allow treatment 14 days later and to avoid infection from granulocytopenia. Toxicity from pegfilgrastim was mild and tolerable. [Table: see text]

Prospective Evaluation of the Relationship of Patient Age and Paclitaxel Clinical Pharmacology: Cancer and Leukemia Group B (CALGB 9762)

To prospectively evaluate the pharmacokinetics and toxicity profile of paclitaxel in relation to patient age in adults > or = 55 years old. Paclitaxel was administered at 175 mg/m2 for 3 hours to 153 patients, 46 of whom were > or = 75 years of age. Pharmacokinetic and toxicity assessments were performed. Data were analyzed by cohort (cohort 1, age 55 to 64 years; cohort 2, age 65 to 74 years; cohort 3, age > or = 75 years). Paclitaxel concentration versus time (AUC) and total-body clearance (CL(tb)) data were available for 122 patients (cohort 1, 46 patients; cohort 2, 44 patients; cohort 3, 32 patients). Mean paclitaxel AUC increased across cohorts (P = .01). Mean (SE) AUCs were 22.4 (2.5) micromol/L x hour, 26.2 (2.8) micromol/L x hour, and 31.7 (5.6) micromol/L x hour for cohorts 1, 2, and 3, respectively. There was a corresponding significant (P = .007) age-related decrease in mean (SE) paclitaxel CL(tb) (cohort 1, 11.0 [0.7] L/h/m2; cohort 2, 9.3 [0.6] L/h/m2; cohort 3, 8.2 [0.6] L/h/m2). Patients in cohort 3 experienced significantly lower absolute neutrophil count nadirs than did younger groups (P = .02). There was also a significant increase in percentage of patients with > or = grade 3 neutropenia across age cohorts (cohort 1, 22%; cohort 2, 35%; cohort 3, 49%; P = .006). However, the increased exposure of patients to paclitaxel and increased neutropenia were not reflected in adverse clinical sequelae such as hospitalization for toxicity (P = .82), receiving intravenous antibiotics (P = .21), or experiencing a temperature more than 38 degrees C (P = .45). Although paclitaxel CL(tb) decreases with increasing patient age, there is great interpatient variability. Cooperative group studies to evaluate the effect of aging on pharmacokinetics are feasible.

Does Early Myeloid Recovery Predict Superior Survival in Children and Young Adults Undergoing Hematopoietic Stem Cell Transplantation?.

Introduction: Slow rate of myeloid recovery at the end of induction chemotherapy reflected by a low absolute neutrophil count (ANC) is highly predictive of relapse in children with ALL (Laughton et al, 2005). Whether rate of myeloid recovery is predictive of outcome post-hematopoietic stem cell transplantation (HSCT) in children and young adults has not been studied.Objective: To explore the association between early ANC recovery and survival in children and young adults undergoing allogeneic and autologous HSCT for leukemia or lymphoma.Methods: Retrospective chart review was performed for all consecutive patients (age 6 months to 21 years) undergoing first HSCT for hematologic malignancies and lymphomas at Mayo Clinic, Division of Pediatric Hematology/Oncology from 1995 to 2004. Day 15 and day 28 ANC were calculated for all patients. The primary end point was 1-year relapse free (RFS) and overall survival (OS). To explore the association between ANC and primary outcome, patients were stratified in 2 groups: ≥ or < than median ANC and Kaplan Meier survival curves were generated for both the groups and compared with the log-rank test. Matched related donor (MRD), matched unrelated donor (MUD) and haploidentical (as one group) and autologous transplantations were analyzed separately.Results: There were a total of 50 patients. 28 received MRD, 2 MUD, 10 haploidentical and 10 autologous. The underlying malignancies were (AML n =25, Biphenotypic Leukemia n=1, ALL n =7, NHL n=3, HD n=7, JMML n=5, CML n=2, CLL n=1). No patient was lost to follow up during that time and data was available for all except (day 28 ANC) for one patient. The 1-year RFS and OS rate was the same; 81% for the MRD, 50% for MUD and haploidentical and 70% for autologous transplant populations, respectively. In patients receiving MRD transplants, higher ANC at either day 15 or day 28 post transplantation was associated with better, albeit statistically non-significant, RFS/OS rates at 1 year (86% for ≥ median (0.68) vs. 76% for < median p=0.44 and 92% for ≥ median (2.2) vs. 72% for < median p= 0.18 respectively). Opposite results were observed for MUD and Haploidentical transplantation group (33% for ANC ≥ median (0.47) at day 15 vs. 66% for < median p=0.28, 43% for ANC ≥ median (1.9) at day 28 vs. 60% for < median p=0.48). For autologous transplant group, higher ANC at day 15 was associated with better, albeit statistically non-significant, RFS/OS rates at 1 year (80% for ANC ≥ median (0.42) vs. 60% for < median p=0.60) while opposite results were observed on day 28 (60% for ANC ≥ median (0.46) vs. 75% for < median p=0.54).Conclusions: Our data generated conflicting findings of the association between ANC and RFS/OS in different patient populations undergoing HSCT. However, our results are limited by the small sample size. Further collaborative studies are needed to explore this association.

Low Absolute Neutrophil Counts in African Infants

Infants of African origin have a lower normal range of absolute neutrophil counts than white infants; this fact, however, remains under appreciated by clinical researchers in the United States. During the initial stages of a clinical trial in Malawi, the authors noted an unexpectedly high number of infants with absolute neutrophil counts that would be classifiable as neutropenic using the National Institutes of Health's Division of AIDS toxicity tables. The authors argue that the relevant Division of AIDS table does not take into account the available evidence of low absolute neutrophil counts in African infants and that a systematic collection of data from many African settings might help establish the absolute neutrophil count cutpoints to be used for defining neutropenia in African populations.

Early Responses to Chemotherapy of Normal and Malignant Hematologic Cells Are Prognostic in Children With Acute Lymphoblastic Leukemia

Improved cure rates for children with acute lymphoblastic leukemia (ALL) have resulted from better relapse prediction, using clinical and laboratory features at diagnosis, and more intensive therapy in high-risk patients. More recently, measurements of the variation in the response of malignant lymphoblasts to chemotherapy in vivo have further improved relapse prediction. It is unknown whether the variation in the response of nonmalignant hematologic cells after chemotherapy correlates with the response of lymphoblasts or risk of relapse. We retrospectively evaluated myelosuppression during induction and consolidation chemotherapy in 227 children uniformly treated for ALL on consecutive Australian and New Zealand Children's Cancer Study Group protocols. The early response to treatment was assessed in a representative subset (n = 62) by determining minimal residual disease (MRD) level by molecular techniques on the end-of-induction bone marrow sample. We found that a slow rate of myeloid recovery at the end of induction chemotherapy, reflected in a low absolute neutrophil count (ANC), was highly predictive of relapse (P < .0001). Additionally, patients with a high end-of-induction MRD level had a high risk of relapse (P = .001). Multivariate analysis confirmed the independent prognostic significance of MRD and ANC at the end of induction chemotherapy (P < .05). There was no significant association between other measures of myelotoxicity and MRD or relapse. We conclude that the responses of normal myeloid cells and malignant lymphoblasts to chemotherapy predict outcome by distinct mechanisms. While these results are promising, their use in the clinical setting needs to be examined in a future randomized controlled trial.

Smoking status affects chemotherapy-induced neutropenia

8097 Background: A regimen of gemcitabine (G) and docetaxel (T) was tested concurrently in 39 patients with breast and 40 with lung cancer, and different toxicity profiles were observed. Multivariate analysis incorporating cancer type, gender, age and prior treatment showed that grade 4 neutropenia was seen more frequently among non-smokers, (p=0.03). Pharmacokinetic effect of smoking status on the clearance of both drugs was examined. G is cleared via renal excretion, and is affected by age and gender, but not by smoking status. T is metabolized by the enzyme cytochrome p450 3A4 (cyp 3A4), whose activity is not associated with smoking status, as demonstrated by measurement of erythromycin breath tests in a separate cohort of 79 sarcoma patients. Interactions between smoking and absolute neutrophil count (ANC) were investigated further. Methods: Charts of 466 patients treated with G and/or T in a single outpatient facility were reviewed. Cohorts were defined by drug dose and regimen. Within each cohort, mean ANC on cycle 1 day 8 was tested for association with smoking status and gender. Results: Compared to non-smokers, smokers had higher ANC after single agent G 800-1200/m2, or after G plus T 100/m2 (p=0.01),** but had lower ANC after single agent T 75 or 100/m2. Smokers treated with G plus T 75/m2 had higher ANC than did those treated with the same dose of T alone (p=0.01).* Gender had no effect on these observations. Conclusions: Smokers have higher ANC when treated with G, either alone or with T, but have lower ANC when treated with T alone. The addition of G to T in smokers results in improved ANC. These associations may be explained on the basis of the increased proliferation rate of myeloid progenitor cells, which has been reported in smokers. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly & Co. Eli Lilly & Co.; Aventis

Neutrophil regeneration precedes healing of tissue destruction, as indicated by serum C‐reactive protein, in children with cancer recovering from neutropenic fever

Aim: To evaluate the relationship between absolute neutrophil count and C‐reactive protein (CRP) in the recovery phase of neutropenic fever among paediatric patients with cancer. Methods: A total of 102 paediatric oncology patients with 177 episodes of fever and neutropenia was studied prospectively in a two‐centre setting. Antimicrobial therapy was discontinued 9 d (mean) post‐initiation with a mean absolute neutrophil count of 1.8 ± 109l‐1 and CRP of 32 mg l‐1. Results: The mean level of CRP below 20 mg l‐1 was reached on day 12. The level of CRP peaked on the day following the commencement of antimicrobial therapy. Throughout the episodes of fever and neutropenia higher levels of CRP were associated with a lower absolute neutrophil count. Following defervescence the pace of marrow recovery as evidenced by an increasing absolute neutrophil count to &lt; 0.2 and &lt; 0.5 ± 109l‐1 was more rapid than the normalization of serum CRP. There was a 2–3 d lag period between absolute neutrophil count exceeding the level of 200 ± 106l‐1 and the return of CRP to a baseline level. All episodes were treated successfully and there were no fatalities. Conclusion: Among patients recovering from neutropenia and fever the signs of marrow recovery remain the key criterion in evaluating the safety of discontinuing antimicrobial therapy, with serum CRP remaining more of an indicator of ongoing tissue repair.

Neutrophil regeneration precedes healing of tissue destruction, as indicated by serum C-reactive protein, in children with cancer recovering from neutropenic fever.

To evaluate the relationship between absolute neutrophil count and C-reactive protein (CRP) in the recovery phase of neutropenic fever among paediatric patients with cancer. A total of 102 paediatric oncology patients with 177 episodes of fever and neutropenia was studied prospectively in a two-centre setting. Antimicrobial therapy was discontinued 9 d (mean) post-initiation with a mean absolute neutrophil count of 1.8 x 10(9) l(-1) and CRP of 32 mg l(-1). The mean level of CRP below 20 mg l(-1) was reached on day 12. The level of CRP peaked on the day following the commencement of antimicrobial therapy. Throughout the episodes of fever and neutropenia higher levels of CRP were associated with a lower absolute neutrophil count. Following defervescence the pace of marrow recovery as evidenced by an increasing absolute neutrophil count to > 0.2 and > 0.5 x 10(9) l(-1) was more rapid than the normalization of serum CRP. There was a 2-3 d lag period between absolute neutrophil count exceeding the level of 200 x 10(6) l(-1) and the return of CRP to a baseline level. All episodes were treated successfully and there were no fatalities. Among patients recovering from neutropenia and fever the signs of marrow recovery remain the key criterion in evaluating the safety of discontinuing antimicrobial therapy, with serum CRP remaining more of an indicator of ongoing tissue repair.

Evidence of early systemic activation and transendothelial migration of neutrophils in neonates with severe respiratory distress syndrome.

Several observations imply that the early inflammatory response involving activated neutrophils, tissue macrophages, and cytokines plays an important role in the pathogenesis of neonatal respiratory distress syndrome (RDS) and progression to bronchopulmonary dysplasia (BPD). The aim of this study was to test the hypothesis that changes in circulating neutrophil number and function and plasma levels of cytokines, consistent with neutrophil activation and migration to the tissues, occur during the early stages of neonatal RDS. For this purpose we measured peripheral blood levels of certain immunological parameters that promote neutrophil activation and transendothelial migration. Twenty preterm neonates with severe RDS and 20 healthy infants matched for gestational age were the subjects. The absolute neutrophil count (ANC), and plasma levels of interleukin-6 (IL-6), granulocyte colony-stimulating factor (G-CSF), and sL-selectin using an enzyme-linked immunosorbent assay (ELISA), neutrophil CD11b expression, and respiratory burst activity (RBA) using flow cytometry, were measured within 24 h after birth. The two groups were comparable regarding perinatal characteristics. None of the neonates studied had any clinical or laboratory evidence of infection by the time of blood sampling. The immunological investigation showed that the RDS neonates had significantly lower ANC (P = 0.032), higher expression of the CD11b on neutrophils (P = 0.0065), and higher G-CSF and IL-6 plasma levels (P = 0.0047 and P < 0.0001, respectively) in comparison to healthy preterm neonates. The neutrophil RBA and plasma sL-selectin levels did not differ significantly between the two groups. We conclude that in neonates with severe RDS, there is evidence of a systemic neutrophil activation early in the course of the disease, supporting the view of a contributing role of activated neutrophils in the pathogenesis of RDS.

Neonatal sepsis workups in infants >/=2000 grams at birth: A population-based study.

Few data are available on the outcome of neonatal sepsis evaluations in an era when intrapartum antibiotic therapy is common. We identified all newborns weighing >/=2000 g at birth who were ever evaluated for suspected bacterial infection at 6 Kaiser Permanente hospitals between October 1995 and November 1996, reviewed their records and laboratory data, and tracked them to 1 week after discharge. We analyzed the relationship between key predictors and the presence of neonatal bacterial infection. Among 18 299 newborns >/=2000 g without major congenital anomalies, 2785 (15.2%) were evaluated for sepsis with a complete blood count and/or blood culture. A total of 62 (2.2%) met criteria for proven, probable, or possible bacterial infection: 22 (.8%) had positive cultures and 40 (1.4%) had clinical evidence of bacterial infection. We tracked all but 10 infants (.4%) to 7 days postdischarge. There were 67 rehospitalizations (2.4%; 2 for group B streptococcus bacteremia). Among 1568 infants who did not receive intrapartum antibiotics, initial asymptomatic status was associated with decreased risk of infection (adjusted odds ratio [AOR]:.26; 95% confidence interval [CI]:.11-.63), while chorioamnionitis (AOR: 2. 40; 95% CI: 1.15-5.00), low absolute neutrophil count (AOR: 2.84; 95% CI: 1.50-5.38), and meconium-stained amniotic fluid (AOR: 2.23; 95% CI: 1.18-4.21) were associated with increased risk. Results were similar among 1217 infants who were treated, except that maternal chorioamnionitis was not significantly associated with neonatal infection. The risk of bacterial infection in asymptomatic newborns is low. Evidence-based observation and treatment protocols could be defined based on a limited set of predictors: maternal fever, chorioamnionitis, initial neonatal examination, and absolute neutrophil count. Many missed opportunities for treating mothers and infants exist.

Treatment of HIV-related neutropenia.

Several studies documenting the association of bacteremia and severity of neutropenia in HIV-infected patients, as well as studies using the colony stimulating factors filgrastim or sargramostim to prevent and treat neutropenia in this patient population, are summarized. Three studies are described in which low absolute neutrophil count was associated with increased incidence of bacterial infections in patients with HIV infection. Two hematopoietic growth factors called colony stimulating factors (filgrastim and sargramostim) are available in the United States, but neither is approved by FDA for the treatment or prevention of neutropenia in HIV-infected patients. Studies have shown both filgrastim and sargramostim to be effective in treating neutropenia in HIV-infected patients without increasing the viral load. In one study, filgrastim use on a daily or intermittent basis was associated with reduction in severe neutropenia or death; in addition, filgrastim-treated patients had fewer bacterial infections, fewer hospital days (both total number of days and days associated only with bacterial infections), and a reduced need for i.v. antimicrobials compared with HIV-infected controls. In another study, neutropenia caused by zidovudine was successfully treated with sargramostim. Both filgrastim and sargramostim show promise in treating and preventing neutropenia in HIV-infected patients. More research is needed to determine the patient population who can best benefit from therapy with these agents and to determine the relative advantages and disadvantages of filgrastim and sargramostim.