Mahmoud M. Mustafa

Correlation of interleukin-1β and cachectin concentrations in cerebrospinal fluid and outcome from bacterial meningitis

Because interleukin-1 beta (IL-1 beta) and cachectin (tumor necrosis factor) are thought to mediate the bodys response to microbial invasion, we measured IL-1 beta and tumor necrosis factor concentrations in paired cerebrospinal fluid (CSF) samples (on admission to the hospital, CSF1; 18 to 30 hours later, CSF2) from 106 infants and children with bacterial meningitis. In CSF1, IL-1 beta was detected in 95% of samples; the mean (+/- 1 SD) concentration was 944 +/- 1293 pg/ml. Patients with CSF1 IL-1 beta concentrations greater than or equal to 500 pg/ml were more likely to have neurologic sequelae (p = 0.001). Tumor necrosis factor was present in 75% of CSF1 samples; the mean concentration was 787 +/- 3358 pg/ml. In CSF2 the mean IL-1 beta concentration was 135 +/- 343 pg/ml, and IL-1 beta concentrations correlated significantly with CSF2 leukocyte count, with glucose, lactate, protein, and tumor necrosis factor concentrations, and with neurologic sequelae. Tumor necrosis factor was detected in CSF2 specimens of 53 of 106 patients, with a mean concentration of 21 +/- 65 pg/ml. Of the 106 patients, 47 received dexamethasone therapy at the time of diagnosis. These patients had significantly lower concentrations of IL-1 beta and higher glucose and lower lactate concentrations in CSF2, and they had a significantly shorter duration of fever compared with the values in patients not treated with steroids (p less than or equal to 0.002). Our data suggest a possible role of IL-1 beta and tumor necrosis factor as mediators of meningeal inflammation in patients with bacterial meningitis, and might explain, in part, the beneficial effect of dexamethasone as adjunctive treatment in this disease.

Tumor necrosis factor in mediating experimental Haemophilus influenzae type B meningitis.

Tumor necrosis factor (TNF) could possibly be instrumental in mediating injury to the CNS during bacterial meningitis. In CSF of rabbits with meningitis induced with Haemophilus influenzae type b (Hib) lipooligosaccharide (LOS), TNF activity was first detected 45 min after intracisternal (IC) injection of 20 ng Hib LOS and white blood cells (WBC) first appeared 75 min later. The peak TNF activity (45 ng/ml) was observed at 120 min after IC and persisted for 5 h. When 1-2 X 10(7) CFU of Hib was used to induce meningitis, peak CSF TNF activity was comparable with that after 20 ng Hib LOS, but the activity persisted for 14 h. Dexamethasone (DXM) (1 mg/kg per i.v.) given 1 h before or simultaneously with IC Hib LOS reduced significantly TNF activity and meningeal inflammation. Goat anti-human TNF alpha antibodies given IC with 20 ng Hib LOS or 2 X 10(6) CFU of Hib resulted in a significant reduction in CSF TNF concentrations, which was also associated with reduced meningeal inflammation in Hib LOS-inoculated animals. We conclude that TNF participates in mediating meningeal inflammation associated with Hib experimental meningitis, and that DXM, when given before or with Hib LOS, inhibits CSF TNF production and modulates the meningeal inflammatory response.

A pilot study of outpatient management of febrile neutropenic children with cancer at low risk of bacteremia

Febrile neutropenic children with cancer were eligible for outpatient management with intravenous ceftriaxone therapy if they displayed selected low-risk criteria. Nineteen children were enrolled. All patients had sterile blood cultures, and only one of them was hospitalized because of persistent fever. This pilot study suggests that selected children with febrile neutropenia might be successfully managed without hospitalization.

Immune recovery in children with malignancy after cessation of chemotherapy

Purpose: To study longitudinally the extent and recovery of cellular and humoral immune alterations in children with cancer after completion of their therapy. Patients and Methods: Using standard immune assays, cellular and humoral immunity was measured in 43 infants and children with cancer at completion of therapy and every 3 months thereafter for 1 year. There were 17 patients with acute lymphoblastic leukemia. 9 with Hodgkin disease, and 17 with solid nonhematopoietic tumors. All children had received standard childhood immunizations before diagnosis of cancer. Immune assays performed included circulating lymphocyte subpopulations, in vitro antigen-induced responses, and total concentrations of serum immunoglobulin G (IgG), IgM, IgA, and IgG subclasses, and specific antibodies against diphtheria, tetanus, pertussis, and poliovirus types I, II, and III. Results: At completion of therapy, the majority of patients had low circulating lymphocyte subpopulations and antigen-induced responses. Serum antibody concentrations were low in up to 89% of patients regardless of the underlying malignancy. Although improvement occurred during the year of follow-up, 35 of 43 (81%) patients continued to exhibit one or more immune abnormalities 9 to 12 months after cessation of chemotherapy. Younger patients had more persistent alterations. Other risk factors studied (including gender, duration of therapy, and underlying malignancy) did not correlate with the severity of the immune defects. With the exception of poliovirus antibodies, specific antibody titers against common childhood vaccine antigens were deficient at completion of therapy and 9 to 12 months later in a substantial proportion of patients. Conclusion: Children with malignancy have persistent specific and nonspecific immune alterations 9 to 12 months after cessation of chemotherapy. The clinical implications of these in vitro observations are unclear and require further evaluation.

Use of amphotericin B colloidal dispersion in children.

PURPOSE To describe the experience with a new lipid-based amphotericin product (amphotericin B colloidal dispersion or ABCD) in children with fever and neutropenia who are at high risk for fungal infection. PATIENTS AND METHODS Forty-nine children with febrile neutropenia were treated in a prospective, randomized trial comparing ABCD with amphotericin B. An additional 70 children with presumed or proven fungal infection were treated with 5 different open-label studies of ABCD. Patients were registered into these studies for reasons of: 1) failure to respond to amphotericin B; 2) development of nephrotoxicity or preexisting renal impairment; or 3) willingness to participate in a dose-escalation study. Extensive data detailing response and toxicity were collected from each patient. RESULTS In the randomized trial, there was significantly less renal toxicity in the children receiving ABCD than in those receiving amphotericin B (12.0% vs. 52.4% [P = 0.003]). Other adverse symptoms were not significantly different. In the additional open-label studies, although 80% of patients receiving ABCD reported some adverse symptom, the majority of these were infusion related, and nephrotoxicity was reported in only 12% of these patients. CONCLUSIONS ABCD was well-tolerated at doses up to 5 times greater then those usually tolerated with amphotericin B. Renal toxicity was markedly less than expected, and there were no other unexpected severe toxicities. Further randomized studies are needed to further define the role of this and other liposomal products in children.

Value of C-reactive protein determination in the initial diagnostic evaluation of the febrile, neutropenic child with cancer

We studied prospectively the value of administration C-reactive protein (CRP) in the diagnostic evaluation of the child with cancer hospitalized for fever and neutropenia. During a 7-month period 74 patients with malignant disease had 122 hospital admissions because of fever and neutropenia. All patients had a serum CRP obtained 8 to 24 hours after the onset of fever as part of their initial evaluation. There was a borderline correlation between serum CRP concentration and temperature at admission (P = 0.06). Patients with fever without an identifiable source had significantly lower CRP concentrations compared with those having focal or microbiologically documented infection (34.9 +/- 6 vs. 70.2 +/- 12 mg/liter; P = 0.0005). Twelve patients had positive blood cultures, 5 of which were coagulase-negative staphylococci considered to be central venous catheter-related infection or colonization. CRP concentrations were significantly lower in these 5 patients compared with the 7 patients with septicemia caused by other organisms (21 +/- 9 vs. 113 +/- 23 mg/liter; P = 0.01). In distinguishing between septicemic and nonsepticemic children, serum CRP was found to have excellent sensitivity and negative predictive value at concentration limits of 20, 50 and 100 mg/liter. However, both specificity and positive predictive value were low at these respective levels, thus limiting the overall utility of serum CRP in the initial empiric management of the febrile, neutropenic child with cancer.

The changing epidemiology of bacteremia in neutropenic children with cancer

Gram-positive bacteria have been the predominant organisms causing bacteremia in febrile neutropenic cancer patients during the past decade. Recently we have noted an increase in Gram-negative bacteremia in children and adolescents with cancer. Therefore we retrospectively reviewed 153 episodes of bacteremia during a 6-year period to investigate changes in the etiology of bacteremia in pediatric oncology patients. In the early 3-year period (January, 1988, to December, 1990) Gram-positive organisms comprised 73 (74%) of the 99 isolates, and Staphylococcus epidermidis was the most common isolate. In the later 3-year period (January, 1991, to December, 1993) Gram-negative organisms were seen with greater frequency and represented 50% of isolates (P = 0.004). Pseudomonas aeruginosa was the most commonly isolated organism during this period (22% of all isolates). We speculate that the recent utilization of more intensive chemotherapy regimens has caused an alteration in the epidemiology of bacteremia in children and adolescents with cancer which could influence the initial empiric antibiotic regimens and the outcome of such infections.

Evaluation of the safety and efficacy of repeated sedations for the radiotherapy of young children with cancer: a prospective study of 1033 consecutive sedations

PURPOSE A prospective observational study to examine our current practice of either conscious sedation (C.S.) or general anesthetic (G.A.) for children undergoing radiation therapy (we use the term sedation to include both C.S. and G.A.). Specifically, the study examines the reasons for selection of patients, choice of drugs, safety and effectiveness of the procedure, side effects of repeated daily sedation, and compliance of the family with the regimen. METHODS AND MATERIALS Recorded data included patient demographics, sedation technique, time for various stages of the procedure, breathing support required, sedation outcome, and complications. RESULTS One hundred ninety-eight consecutive children underwent 4232 procedures involving either simulation or radiation treatment, an average of 21 procedures each. Seventy-four (37%) required sedation for a total of 1033 procedures, an average of 14 sedations each. For those patients who received sedation, the age ranged from 9 months to 14 years (median, 3.8) and 96% had a mold, (85% of the head and neck). The doctors assessment of the need for sedation was correct 89% of the time. Thirty-seven percent required sedation at the start of treatment, but, even after 30 fractions, 15% still required sedation. Presedation status correlated with successful sedation and treatment (p = 0.0001). Ninety-six percent had some form of i.v. access, usually a portacath (76%); 883 sedations were performed with G.A. and 148 with C.S.; 93% of sedations were completed satisfactorily, 5% with some difficulty, and the patient was unable to be treated in 2%. With G.A., satisfactory sedation was achieved 97% of the time, whereas, with C.S., satisfactory sedation was achieved only 68% of the time. There were no complications for 97% of observations. Not one serious complication occurred. An endotracheal tube was used only twice during G.A. For C.S., the results for chloral hydrate, meperidine, and midazolam were, respectively, at least one complication, 23%, 0%, 5%; satisfactory sedation for treatment, 60%, 60%, 82%; and unable to treat 20%, 13%, 5%. For G.A., only 1 patient was unable to be treated. The median time from start of medication to the end of radiation treatment was a median of 10 min (75% complete within 15 min) for G.A., vs. 30 min (75% complete in 50 min) for C.S. On multivariate analysis, the only significant factor predicting a successful outcome was a G.A. using propofol (odds ratio, 20.6), vs. C.S. using either chloral hydrate, meperidine, or midazolam. (p = 0.0001). CONCLUSION In this study, there were no serious complications of sedation in 1033 procedures. As a result of the study, we developed improved methods for better preparation of the patient and family to try to reduce the need for sedation, and reduce the indications for C.S., while confirming the safety and efficacy of a G.A. with propofol for children needing sedation for daily radiation therapy.

Fatal hemolysis induced by ceftriaxone in a child with sickle cell anemia

A 2-year-old boy with sickle cell anemia had a massive, fatal hemolytic reaction after administration of an intravenous dose of ceftriaxone. Laboratory studies demonstrated the presence of an IgM antibody against ceftriaxone, binding to and destroying the patients erythrocytes by an immune complex mechanism. This rare complication should be considered in the differential diagnosis when hemoglobinuria develops in a child after administration of ceftriaxone or a similar agent.

Comparative study of cefepime versus ceftazidime in the empiric treatment of pediatric cancer patients with fever and neutropenia

Background. In view of the recent trend toward monotherapy in the treatment of bacterial infection, we evaluate the clinical efficacy and safety of cefepime vs. ceftazidime for the empiric treatment of febrile episodes in neutropenic pediatric cancer patients. Methods. In a single site, open label study, 104 neutropenic pediatric cancer patients [96% with absolute neutrophil count (ANC) of <500 neutrophils/mm3] with a median age of 6 years were randomized (1:1) to receive either intravenous cefepime or ceftazidime (50 mg/kg/dose every 8 h; ≤6 g/day) for empiric treatment of fever (temperature >38.0°C occurring at least twice in 24 h, or single >38.5°C). Febrile episodes were classified as either microbiologically or clinically documented infection or fever of unknown origin. Therapy continued until the ANC was ≥1000 neutrophils/mm3 or there was an increasing ANC in low risk patients (maximum duration of treatment, 8 weeks). The primary efficacy endpoints assessed were clinical and microbiologic response to assigned drug therapy. Secondary outcome measures were rate of early discontinuation of study drug and use of concomitant antibiotic therapy to modify initial study drug regimen. Results. Of 68 patients who could be evaluated for efficacy, 74% (26 of 35) of cefepime-treated patients and 70% (23 of 33) of ceftazidime-treated patients responded to treatment. The small number of study patients precluded statistical analysis of results. In a modified intent-to-treat analysis, 59% of the patients treated with cefepime and 47% of ceftazidime-treated patients responded to therapy. Cefepime patients developed fewer new infections than ceftazidime patients (9%vs. 21%, respectively) and early discontinuation of study drug therapy occurred slightly more often in the ceftazidime group. Further, the use of concomitant systemic antimicrobial therapy (mostly vancomycin) occurred less often in the cefepime-treated patients, as compared with the ceftazidime group [35% [17 of 49]vs. 44% (24 of 55), respectively]. No deaths or serious adverse events were considered to be related to study therapy. The most frequent adverse event was rash that was moderate in severity, and it occurred equally in both groups. Conclusion. Cefepime appears to be safe and effective compared with ceftazidime for initial empiric therapy of febrile episodes in neutropenic pediatric cancer patients.