Febrile neutropenia: practical aspects]

BACKGROUND: Infections are a major cause of mortality in neutropenic patients. They require long hospital stays and highly expensive therapeutic measures. In this review we discuss the practical and pharmaco-economic aspects of the management of febrile neutropenia. PREVENTION AND THERAPY: Prevention of fever of unknown origin (FUO) demands hygienic and antimicrobiotic measures. First-line antibiotic therapy consists of an aminoglycoside combined with an ureidopenicillin or a 3rd-generation cephalosporin. Double beta-lactam antibiotic combinations are equally effective and less toxic, but more expensive. Monotherapy with carbapenems, ceftazidime, or cefepime appear to offer comparable efficacy. Lung infiltrates require immediate treatment with amphotericin B. If the initial therapeutic regime fails, a carbapenem plus a glycopeptide antibiotic and a parenteral antimycotic drug should be applied after 3 to 4 days. The prophylactic or interventional administration of hematopoietic growth factors is only indicated in special high-risk situations. CONCLUSIONS: Using the described therapeutic procedure, the response rate exceeds 90%. Consistent, step-wise escalating administration of antibiotics is essential. More evaluation is needed to determine whether selected patients with febrile neutropenia can be treated on an outpatient basis.     

Ciprofloxacin-induced neutropenia and erythema multiforme

Enrichment of soil with chitin (0.6%) significantly stimulated growth of chitinolytic microorganisms (the relative proportion was increased from 1.7 to 26.5%) and the formation of chitinase in soil. In a soil enriched with chitin and glucose (0.6%), the proportion of chitinolytic microorganisms remained similar to that in the nonenriched soil (1.4%), the enzyme formation was negatively affected.     

Transient elevation of serum thyroid hormone concentration after initiation of replacement therapy in myxedema

Measurements of thyroid hormone concentrations in serum are commonly used to determine the proper dose of hormone replacement. We have noted that early in the course of thyroxine (T4) replacement in myxedema, serum T4 concentrations may be transiently elevated before reaching a lower "steady-state" level. This observation is illustrated in a study of six patients. Serum T4, free thyroxine index, and triiodothyronine (T3) rose to peak concentrations at 2 to 6 weeks, 35% to 120% above the values achieved 4 to 8 months later. Values were transiently in the thyrotoxic range in five of the six patients. This phenomenon is most likely due to a decrease in the metabolic clearance rate of the absorbed hormone associated with hypometabolism. Thus, serum T4 and T3 concentrations during the first 6 months of therapy do not reflect the optimal dose of T4 replacement on a long-term basis.     

Dialysis neutropenia: the role of the cytoskeleton

Dialysis neutropenia is the result of pulmonary sequestration of neutrophils after complement activation by the dialyzer membrane. Increased expression of neutrophil adhesion receptors, such as CD11b/CD18, suggests that neutrophil adhesion to the capillary endothelium is a possible mechanism. An alternative hypothesis is that the complement fragment C5a modulates neutrophil mechanical properties via the cytoskeleton-largely filamentous actin (F-actin)-stiffening them and thereby slowing their passage through the pulmonary capillaries. To investigate this hypothesis, we developed an assay to measure the F-actin content of neutrophils in whole blood using flow cytometry and the stain NBD-phallacidin. We measured neutrophil F-actin content during hemodialysis of patients with polysulfone (N = 6), Hemophan (N = 6), and Cuprophan membranes sterilized with either ethylene oxide (N = 5) or steam (N = 6). Cell counts, neutrophil and monocyte CD11b expression and plasma C5a concentrations were also measured. The results confirm the strong relationship between the degree of neutropenia, increases in CD11b expression and plasma C5a levels reported by previous researchers. Modulation of the F-actin content of neutrophils was also strongly related to C5a levels, indicating that the neutrophil cytoskeleton is active during dialysis. Modeling of cell counts suggests that with Cuprophan a substantial fraction of neutrophils and monocytes are sequestered before they even pass through the dialyzer, suggesting some form of systemic activation of these cells. Evidence for systemic activation was also seen in measurements of F-actin content, but not CD11b expression, a finding that strengthens the case for the involvement of the cytoskeleton in dialysis neutropenia.     

Calcium-dependent neutrophil secretion: characterization and regulation by annexins

To gain direct access to the secretory machinery and study the regulation, mechanisms, and effectors of Ca2+-dependent neutrophil secretion, we developed an efficient and reproducible method of plasma membrane permeabilization using streptolysin O. We confirmed previous studies that permeabilized neutrophils secrete in response to calcium alone, but we also found that the Ca2+ dose-response is biphasic. Secretion is detectable at <1.0 microM Ca2+ and reaches a plateau between 1.0 and 60 to 80 microM. When stimulated with >80 microM Ca2+, secretion is two- to threefold greater than at lower [Ca2+], suggesting that two distinct mechanisms of Ca2+-dependent secretion that differ in their affinity for Ca2+ exist in neutrophils. Although permeabilization allows 100% leak of lactate dehydrogenase, maximum secretion from permeabilized cells is 80% that of f-met-leu-phe-stimulated intact cells, indicating that the essential components of the Ca2+-dependent secretory apparatus are predominantly, if not entirely, membrane bound. Permeabilization causes leakage of 100% of annexins V and VI, but 41% of annexin I and 12% of annexin III are retained. Immunofluorescence microscopy revealed that retained annexins I and III are associated with granule membranes. Addition of soluble annexins I and III to permeabilized cells increased Ca2+-induced secretion up to 15% and 90%, respectively, implying that both annexins participate in this secretory pathway. While annexin V is not required for secretion, it inhibits the low Ca2+-affinity mechanism of secretion.     

Transient global amnesia: memory and metamemory

Twenty patients (mean age 64 years) with a previous episode of transient global amnesia (TGA) were examined to assess the functioning of objective memory (by using the Randt Memory Test), the metamemory capacities (Sehulster Memory Scale), the residual level of retrograde amnesia (Questionnaire of Remote Events), and the level of depression (Geriatric Depression Scale). Patients with residual retrograde amnesia scored significantly lower than non-amnesic ones on indices of both short-term and long-term memory, and for one of three main metamemory components, namely self-rating of memory functioning through comparison with memory functioning of peers (Set3). Age, time interval from TGA attack and TGA duration did not prove to influence memory and metamemory scores. Retrograde amnesia and depression were rather substantially associated (1/5), and this association was found to negatively influence nearly all memory and metamemory scores. Depression level showed a positive correlation with short-term memory functioning in non-amnesics. The different pattern and strength of the relationships between metamemory components and objective memory dimensions observed in amnesics and non-amnesics indicate that metamemory evaluations are more closely related to memory functioning in amnesics than in non-amnesics.     

Beh?et''s disease and chronic neutropenia

This paper reviews the Indian data on age distribution of measles prior to large scale immunization. In metropolitan areas, the median age was about 24 months and virtually all the cases were recorded in children under 5, whereas median age in most of rural studies was < 4-< 5 years and all the persons were not affected until 10 years of age. The situation was in between in other areas. Since less than 10 per cent of the cases occurred before 9 months of age, this age is appropriate for routine measles immunization. The results also suggested the choice of age groups to be immunized during measles mass campaigns; the upper age may be 3 years in metropolitan city, 10 years in rural areas, and 5 years in the rest of the population.     

Simulation of flow in a continuous galvanizing bath: Part II. Transient aluminum distribution resulting from ingot addition

The coupled phenomena of momentum, heat, and mass transfer were simulated in order to predict and to better understand the generation and movement of intermetallic dross particles within certain regions of a typical galvanizing bath. Solutions for the temperature and aluminum concentration can be correlated with the solubility limits of aluminum (Al) and iron (Fe) to determine the amount of precipitated aluminum in the form of Fe₂Al₅ top dross. Software developed by the Industrial Materials Institute of the National Research Council of Canada (IMI-NRC), including k-ε turbulence modeling for heat and mass transfer, was adapted for the simulation of a sequence of operating parameters. Each case was modeled over a period of 1 hour, taking into account an ingot-melting period followed by a nonmelting period. The presence of an ingot significantly changes the temperature distribution and also results in important variations in the local aluminum concentration, since the makeup ingot has a higher aluminum concentration. The simulation showed that during the ingot melting, the total aluminum concentration is higher at the ingot side of the bath than at the strip exit side. The region below the ingot presents the highest aluminum concentration, whereas lower aluminum concentrations were found in the region above the sink roll, between the strip and the free surface. It was shown that precipitates form near the ingot surface because this region is surrounded by a solution at 420 °C, which is lower than the average bath temperature of 460 °C. When no ingot is present, the total aluminum concentration becomes much more uniform and decreases with time at a constant rate, depending on the coating thickness. This information is of major significance in the prediction of the formation of dross particles, which can cause defects on the coated product.     

Postinjury neutrophil priming and activation: an early vulnerable window

BACKGROUND: Generation of extracellular, cytotoxic superoxide anion (O2-) by polymorphonuclear neutrophils (PMNs) contributes to an unbridled inflammatory response that can precipitate multiple organ failure (MOF). Release of O2- is markedly enhanced when activated PMNs have been previously "primed" by inflammatory mediators, such as those expressed after trauma. We therefore hypothesized that PMN priming occurs as an integral part of the early inflammatory response to trauma. METHODS: PMNs were obtained from 17 high-risk patients with torso trauma at 3, 6, 12, 24, 48, and 72 hours after injury, as well as from 10 healthy donors, and the in vitro release of O2- was quantitated with a kinetic, superoxide dismutase (SOD)-inhibitable cytochrome c reduction assay. PMN O2- release was measured in the presence and absence of 1 mumol/L N-formyl-methionyl-leucyl-phenylalanine (fMLP) and after priming and activation with 20 nmol/L platelet-activating factor (PAF) and 1 mumol/L fMLP, respectively. RESULTS: In vitro PMN O2- release was used to determine whether postinjury PMNs were (1) activated in vivo, (2) primed in vivo, or (3) primable in vitro. Unstimulated PMNs from trauma patients spontaneously expressed modest amounts of O2- in vitro from 6 to 48 hours after injury, suggesting endogenous activation. Also, fMLP-activated PMNs collected between 3 and 24 hours after injury expressed more O2- than controls (p < or = 0.02), indicating in vivo, trauma-related priming. Furthermore, postinjury PMNs were maximally primed in vivo (i.e., in vitro exposure to PAF before fMLP activation failed to significantly enhance O2- release) as compared to PMNs treated with fMLP. CONCLUSIONS: These data indicate that major torso trauma (first hit) primes and activates PMNs within 3 to 6 hours after injury. Consequently, we postulate that postinjury priming of PMNs may create an early vulnerable window during which a second hit (e.g., a secondary operation or delayed hemorrhage) activates exuberant PMN O2- release, rendering the injured patient at high risk for MOF.     

Outpatient parenteral antibiotic therapy for fever and neutropenia

OPAT for osteomyelitis is effective, safe, and well-established. There are particular considerations with osteomyelitis, however, that relate to patient selection and the plans of therapy. Orthopedic infections may impose physical considerations that need to be considered. Concomitant medical problems, such as diabetes, must be considered and may be good reasons for hospital care aside from the infection. Further investigations of treatment of osteomyelitis are clearly needed, with OPAT patients being good subjects to study.     

Diagnosis and management of chronic neutropenia during childhood

The approach to the diagnostic evaluation of a patient with neutropenia can be guided largely by clinical history and physical examination and does not always require an extensive laboratory evaluation. Based on the history and bone marrow morphology, most children with chronic neutropenia can be classified and managed. Most patients with chronic neutropenia are free of infections and are able to maintain a normal lifestyle with no or minimal medical intervention. On the other hand, for patients with recurrent or severe infections, careful follow-up and institution of treatment are mandatory. The Food and Drug Administration has approved the use of rhG-CSF in patients with chronic neutropenia. As mentioned previously, the use of colony-stimulating factors has dramatically improved the outcome for many patients with the more severe neutropenia; however, this cytokine is expensive, so treatment should be reserved for more severely affected patients and not given just because the ANC is low. Although concerns exist regarding leukemogenic effects or eventual loss of the progenitor cell compartment driven by the continuous stimulation of rhG-CSF, at this moment, the long-term data available suggest that the chronic administration of rhG-CSF is safe.     

Primary inherited defects in neutrophil function: etiology and treatment

A variety of materials have been employed in rhinoplasty for augmentation and reconstruction. While autogenous tissue remains the mainstay of nasal implants and are the clear choice for structural and augmentation grafting of the nasal tip, limited availability and unpredictable resorption or remodeling have made homologous and synthetic implants important considerations for dorsal augmentation grafting. This section discusses categories of graft materials, their physical properties, harvesting and preparation technique, and advantages and disadvantages. An algorithm for nasal implants for specific indications in support and augmentation is presented.     

Hepatic neutrophil influx: eicosanoid and superoxide formation in endotoxemia

We examined early changes, at 0.5, 1.5, and 3 hr of infusion of a nonlethal dose of Escherichia coli endotoxin (ET) in neutrophil (PMN) sequestration in the liver and accompanying alterations in [1-14C]arachidonic acid metabolism and superoxide anion release by Kupffer and endothelial cells and PMNs. One hundred fifty micrograms ET (268 micrograms/kg) was infused over 3 hr. Shorter infusions delivered proportionally less ET. By 30 min of ET infusion the number of PMNs in the 45 ml/min fraction was 2.41 x 10(7), eightfold higher than that in the NaCl-infused rats, representing 35.90 +/- 3.49% (n = 7) of the total cell yield vs 8.20 +/- 0.20% (n = 4) in NaCl controls. By 90 and 180 min of ET infusion the number of PMNs and their share of the total cell yield increased significantly further. Cells were separated by elutriation, followed by application of a Ficoll-Hypaque gradient, when appropriate. Kupffer cells and PMNs were recovered in the 45 ml/min fraction, endothelial cells in the 23 ml/min fraction. At 30 min of ET infusion the profile of arachidonic acid metabolites released from [1-14C]arachidonic acid-prelabeled nonparenchymal cells upon A23187 stimulation was not different from that of cells of NaCl-infused rats. Infusion of ET for 90 min accentuated PMN infiltration, and resulted in significant modulation of the eicosanoid profile, consisting of a major shift in PGD2/PGE2 to PGE2, and LTB4 and 12-HETE accounting for 34% of the total eicosanoids, compared to 12.9% in time-matched NaCL controls.(ABSTRACT TRUNCATED AT 250 WORDS)