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G284 Kawasaki disease bpsu survey in great britain and ireland

Introduction Kawasaki disease (KD) is the commonest cause of acquired heart disease in the western world. We report here on the preliminary data for the first year of a 2-year national survey in Great Britain and Northern Ireland. Methods Using standard BPSU methodology, children with Complete KD (for the first year) presenting from January 1st to December 31st 2013 were studied with their treatments and complications. The steering committee reviewed cases that were unclear or incomplete. Results Excluding incomplete KD and incomplete data sets, there were 180 with complete KD (15/month). Peak presentation was in March, boy:girl ratio was 1.8 and 69% were 1 to 4 years old. The highest incidence was in children under 5 years especially in London and East Anglia (5.6 / 100,000) and lowest in the Midlands (2.8/100,000). Highest incidence was in Chinese (21.9/100,000), Black African and Caribbean (14.5/100,000) and Mixed ethnicity (15.3/100,000). 81% saw a GP at median 2 days after fever commencement and admission was median (range) of 2 (0–27) days later. Fever duration was 6 (1–28) days. 97% had rash, usually at the start of fever, which was on the trunk or widespread in 89% and was macular in 75%. Bilateral non-purulent conjunctivitis (91%) occurred at 4 (0–27) days and mucositis (97%) at 5 (0–27) days. Periphery involvement was up to 32 days in 156 (86%). Lymphadenopathy was least common (65%) often after 5 days. The BCG scar was inflamed in 11. CRP ranged from 1–501 mg/l, albumin from 17–45g/l, lowest platelet counts were below 150 × 10^9/l in 14. 31 (22%) had dilated coronary arteries, 9 had pericardial effusion and 12 had ECG abnormalities. Intravenous immunoglobulin (2g/kg) given within 7 days to 95%, but not to 9 complete cases (delayed diagnosis). Second dose was given to 13 children. High dose aspirin (30–50mg/kg) followed by low dose aspirin was given to 92%. 19 had sequelae, 15 with persistence of coronary artery dilation, with no deaths. Conclusions These preliminary results show a high incidence of coronary artery disease with the old guideline for KD and give new data on seasonality, ethnicity and correlation with clinical symptoms.

Cost-effectiveness of diagnostic for malaria in Extra-Amazon Region, Brazil

BackgroundRapid diagnostic tests (RDT) for malaria have been demonstrated to be effective and they should replace microscopy in certain areas.MethodThe cost-effectiveness of five RDT and thick smear microscopy was estimated and compared. Data were collected on Brazilian Extra-Amazon Region. Data sources included the National Malaria Control Programme of the Ministry of Health, the National Healthcare System reimbursement table, laboratory suppliers and scientific literature. The perspective was that of the Brazilian public health system, the analytical horizon was from the start of fever until the diagnostic results provided to patient and the temporal reference was that of year 2010. Two costing methods were produced, based on exclusive-use microscopy or shared-use microscopy. The results were expressed in costs per adequately diagnosed cases in 2010 U.S. dollars. One-way sensitivity analysis was performed considering key model parameters.ResultsIn the cost-effectiveness analysis with exclusive-use microscopy, the RDT CareStart™ was the most cost-effective diagnostic strategy. Microscopy was the most expensive and most effective, with an additional case adequately diagnosed by microscopy costing US$ 35,550.00 in relation to CareStart™. In opposite, in the cost-effectiveness analysis with shared-use microscopy, the thick smear was extremely cost-effective. Introducing into the analytic model with shared-use microscopy a probability for individual access to the diagnosis, assuming a probability of 100% of access for a public health system user to any RDT and, hypothetically, of 85% of access to microscopy, this test saw its effectiveness reduced and was dominated by the RDT CareStart™.ConclusionThe analysis of cost-effectiveness of malaria diagnosis technologies in the Brazilian Extra-Amazon Region depends on the exclusive or shared use of the microscopy. Following the assumptions of this study, shared-use microscopy would be the most cost-effective strategy of the six technologies evaluated. However, if used exclusively for diagnosing malaria, microscopy would be the worst use of resources. Microscopy would not be the most cost-effective strategy, even when structure is shared with other programmes, when the probability of a patient having access to it was reduced. Under these circumstances, the RDT CareStart™ would be the most cost-effective strategy.

Cost effectiveness of OptiMal® rapid diagnostic test for malaria in remote areas of the Amazon Region, Brazil

BackgroundIn areas with limited structure in place for microscopy diagnosis, rapid diagnostic tests (RDT) have been demonstrated to be effective.MethodThe cost-effectiveness of the Optimal® and thick smear microscopy was estimated and compared. Data were collected on remote areas of 12 municipalities in the Brazilian Amazon. Data sources included the National Malaria Control Programme of the Ministry of Health, the National Healthcare System reimbursement table, hospitalization records, primary data collected from the municipalities, and scientific literature. The perspective was that of the Brazilian public health system, the analytical horizon was from the start of fever until the diagnostic results provided to patient and the temporal reference was that of year 2006. The results were expressed in costs per adequately diagnosed cases in 2006 U.S. dollars. Sensitivity analysis was performed considering key model parameters.ResultsIn the case base scenario, considering 92% and 95% sensitivity for thick smear microscopy to Plasmodium falciparum and Plasmodium vivax, respectively, and 100% specificity for both species, thick smear microscopy is more costly and more effective, with an incremental cost estimated at US$549.9 per adequately diagnosed case. In sensitivity analysis, when sensitivity and specificity of microscopy for P. vivax were 0.90 and 0.98, respectively, and when its sensitivity for P. falciparum was 0.83, the RDT was more cost-effective than microscopy.ConclusionMicroscopy is more cost-effective than OptiMal® in these remote areas if high accuracy of microscopy is maintained in the field. Decision regarding use of rapid tests for diagnosis of malaria in these areas depends on current microscopy accuracy in the field.

Serum vascular endothelial growth factor in adult haematological patients with neutropenic fever: a comparison with C‐reactive protein

Vascular endothelial growth factor (VEGF) is considered to be of importance in patients with sepsis. No data are available on VEGF kinetics in haematological patients with neutropenic fever. Forty-two haematological patients were included into this prospective study. Median age was 57 yr (range 18-70). Fifteen patients received therapy for acute myeloid leukaemia and 27 patients received autologous stem cell transplantation for haematological malignancy. Laboratory samples for the determination of C-reactive protein (CRP) and VEGF were collected at the start of fever (d0) and then daily. The median serum VEGF concentrations were low in all study patients. In patients with severe sepsis (n = 5) the median VEGF on d0 was higher than in septic patients without signs of hypoperfusion or hypotension (n = 37) (77 pg/mL vs. 52 pg/mL, P = 0.061). Also on d1 the median VEGF concentration was higher in patients with severe sepsis (82 pg/mL vs. 56 pg/mL, P = 0.048). There were no statistically significant differences in CRP values on any day during the study period between patients with severe sepsis and those without. Time from d0 to the peak VEGF concentration (mean 1.02, SE 0.18 d) was shorter than that to the peak CRP concentration (mean 1.93, SE 0.15 d) (P = 0.002). Compared to CRP, serum VEGF was a more rapid indicator for sepsis in our haematological patients with neutropenic fever. Those with severe sepsis had higher VEGF concentrations than those without on d0 and d1 after the onset of fever. Further studies on VEGF are warranted in haematological patients.

Clinical Experience with Three Combination Regimens for the Treatment of High-risk Febrile Neutropenia

The objective of this study was to compare the safety and efficacy of ceftazidime (2 g every 8 h), piperacillin/tazobactam (4 g/500 mg every 6 h), and meropenem (1 g every 8 h), when combined with amikacin (15 mg/kg once daily), in the empirical treatment of high-risk febrile neutropenic episodes in patients with haematological malignancy. A prospective, comparative study designed in the haematology unit of a university hospital in Turkey. A total of 89 febrile episodes in 60 neutropenic patients were treated; 29 febrile episodes in 23 patients with ceftazidime plus amikacin (group 1), 30 episodes in 25 patients with piperacillin/tazobactam plus amikacin (group 2), and 30 episodes in 25 patients with meropenem plus amikacin (group 3). The 3 groups were comparable in terms of age, sex, underlying malignancy, pretherapy neutrophil counts, duration of neutropenia and types of infections. Neutropenia, since the start of fever, persisted for > or =10 days in all of the episodes in the 3 study groups. Nearly all of the episodes were seen in patients with acute leukaemia. In 25.8% (23/89) of the febrile neutropenia episodes, an aetiologic organism was isolated, with gram-negative bacteria being the most commonly isolated. The success without modification rates were 34.5%, 30% and 36.7% for groups 1, 2 and 3, respectively (P >0.05). After modification with a different class of antimicrobial therapy, the response rates increased to 65.5%, 63.3% and 70% for groups 1, 2 and 3, respectively (P >0.05). The mean duration of treatment and the time to defervescence were also comparable in all groups. In all arms, side effects were minimal. It is concluded that the 3 regimens were equally effective and safe in the empirical treatment of high-risk febrile neutropenic episodes.

Circulating Inflammatory Mediators during Start of Fever in Differential Diagnosis of Gram-Negative and Gram-Positive Infections in Leukopenic Rats

Gram-negative and gram-positive infections have been considered the most important causes of morbidity and mortality in patients with leukopenia following chemotherapy. However, discrimination between bacterial infections and harmless fever episodes is difficult. Because classical inflammatory signs of infection are often absent and fever is frequently the only sign of infection, the aim of this study was to assess the significance of serum interleukin-6 (IL-6), IL-10, macrophage inflammatory protein-2 (MIP-2), procalcitonin (PCT), and C-reactive protein (CRP) patterns in identifying bacterial infections during start of fever in normal and cyclophosphamide-treated (leukopenic) rats following an injection of lipopolysaccharide (LPS) or muramyl dipeptide (MDP) as a model for gram-negative and gram-positive bacterial infections. We found that, compared to normal rats, immunosuppressed animals exhibited significantly higher fevers and lesser production of all mediators, except IL-6, after toxin challenge. Moreover, compared to rats that received MDP, both groups of animals that received an equivalent dose of LPS showed significantly higher fevers and greater increase in serum cytokine levels. Furthermore, in contrast to those in immunocompetent rats, serum levels of IL-6 and MIP-2 were not significantly changed in leukopenic animals after MDP injection. Other serum markers such as PCT and CRP failed to discriminate between bacterial stimuli in both groups of animals. These results suggest that the use of the analyzed serum markers at an early stage of fever could give useful information for the clinician for excluding gram-negative from gram-positive infections.

Neutralization of macrophage inflammatory protein-2 blocks the febrile response induced by lipopolysaccharide in rats

1. This study was aimed to test the hypothesis that macrophage inflammatory protein-2 (MIP-2), a powerful chemotactic cytokine for neutrophils, plays a role in bacterial endotoxin fever. 2. The effect of specific anti-rat MIP-2 antibodies on lipopolysaccharide (LPS)-induced fever was tested. Intraperitoneal injection of LPS resulted in a biphasic fever and a significant increase in serum MIP-2 and prostaglandin (PG) E 2 levels which correlated with the start of fever. Intraperitoneal anti-MIP-2 (500 μg/kg) did not affect the body core temperature of unrestrained rats, but markedly attenuated LPS-induced fever. 3. Treatment with the cyclooxygenase inhibitor ibuprofen (10 mg/kg) resulted in a significant attenuation of LPS-induced fever and a significant decrease of MIP-2 and PGE 2 production. 4. These results indicate that LPS fever in rats is, at least, in part dependent on mechanisms involving neutrophils chemotaxis, and that MIP-2 may be an important mediator in the genesis of fever via prostaglandin-dependent pathways.

Plasma IL-8 and IL-6 levels can be used to define a group with low risk of septicaemia among cancer patients with fever and neutropenia.

The standard therapy for patients with fever and chemotherapy-related neutropenia is hospitalization and infusion of broad-spectrum antibiotics. Early discharge of a defined group of patients at low risk for septicaemia would be of great advantage for these patients. In this study plasma interleukin-8 (IL-8) and interleukin-6 (IL-6) levels measured at start of fever (n = 72) could define a low-risk group of febrile patients with neutropenia due to chemotherapy. For this purpose we collected and analysed data on 72 fever episodes from 53 patients with chemotherapy-related neutropenia, aged between 1 and 66 years. Of the 72 episodes, 18 were classified as bacteraemia and/or clinical sepsis (sepsis group). The IL-6 and IL-8 plasma concentration were significantly increased in patients with chemotherapy-related neutropenia and fever due to bacteraemia versus fever of non-bacterial origin (P = 0.043 and P = 0.022 respectively). Logistic regression analysis, with sepsis as the outcome variable, revealed significant effects of age combined with either IL-6 or IL-8. Sepsis occurrence was lowest for patients <16 years and highest in patients between 16 and 50 years, and was higher in patients with increased IL-6 (P = 0.032) or IL-8 (P = 0.049). No significant effect of leucocyte count, C-reactive protein, sex or underlying malignancy at presentation was detected. The plasma IL-6 and IL-8 levels were fairly strongly correlated (Pearson r = 0.62). Using a cut-off value with 100% sensitivity, both IL-8 and IL-6 could define a low-risk group of neutropenic patients of 28% (CI 15-40%) at the start of the febrile period. Intervention studies are warranted to confirm this result and to investigate whether an early discharge based on IL-8 or IL-6 measurement is safe, increases the quality of life, and results in cost savings.

High serum neopterin and low cytokine values may indicate a non-bacterial etiology for fever of unknown origin in neutropenic patients

ObjectiveTo prospectively evaluate serum neopterin, a marker of cellular immune activation, in relation to blood culture findings and cytokine levels (tumor necrosis factor-α (TNF-α), interleukin (IL)–1 receptor antagonist, interferon-γ (IFN-γ), IL-6, and IL-10) at start of fever in neutropenic patients with hematologic malignancies.MethodsSerum samples were obtained during the first 24 h after start of fever in 27 episodes of febrile neutropenia seen in 22 patients.ResultsNeopterin levels increased significantly at start of fever (time 0) compared to baseline values (samples obtained within 72 h before start of fever). Neopterin levels peaked at 2–4 h after start of fever and returned to baseline levels after 12 h. At start of fever no differences in neopterin values were seen with regard to blood culture findings (i.e. blood-culture-negative (BCN) fever episodes versus Gram-positive bacteria versus Gram-negative bacteremia). In five of seven BCN fever episodes, in patients without other clinical evidence of infection, a high neopterin/low TNF-α value was observed and the correlation (r-value) between neopterin/TNF-α was negative in BCN fever episodes (–0.9; p<0.04), as opposed to the bacteremic episodes, where the correlation was positive (0.7; p<0.04).ConclusionThe results of this study show that febrile neutropenic patients are able to react with increased neopterin values, and that some BCN fever episodes are characterized by high neopterin/low cytokine values which may be due to an occult non-bacterial infection. To prospectively evaluate serum neopterin, a marker of cellular immune activation, in relation to blood culture findings and cytokine levels (tumor necrosis factor-α (TNF-α), interleukin (IL)–1 receptor antagonist, interferon-γ (IFN-γ), IL-6, and IL-10) at start of fever in neutropenic patients with hematologic malignancies. Serum samples were obtained during the first 24 h after start of fever in 27 episodes of febrile neutropenia seen in 22 patients. Neopterin levels increased significantly at start of fever (time 0) compared to baseline values (samples obtained within 72 h before start of fever). Neopterin levels peaked at 2–4 h after start of fever and returned to baseline levels after 12 h. At start of fever no differences in neopterin values were seen with regard to blood culture findings (i.e. blood-culture-negative (BCN) fever episodes versus Gram-positive bacteria versus Gram-negative bacteremia). In five of seven BCN fever episodes, in patients without other clinical evidence of infection, a high neopterin/low TNF-α value was observed and the correlation (r-value) between neopterin/TNF-α was negative in BCN fever episodes (–0.9; p<0.04), as opposed to the bacteremic episodes, where the correlation was positive (0.7; p<0.04). The results of this study show that febrile neutropenic patients are able to react with increased neopterin values, and that some BCN fever episodes are characterized by high neopterin/low cytokine values which may be due to an occult non-bacterial infection.

Endotoxemia in febrile patients with hematological malignancies. Relationship of type of bacteremia, clinical findings and serum cytokine pattern.

The relation between gram-negative bacteremia, endotoxemia and cytokinemia in patients with hematological malignancies was studied. Serum endotoxin and cytokines (tumor necrosis factor-alpha, interleukin-1 receptor antagonist, interferon-gamma, interleukin-6 and interleukin-10) were determined in 24 patients with hematological malignancies. Patients were included at start of fever (n = 18) or during a temperature peak during continuous fever (n = 6; time = 0). Blood was drawn for cultures at time of inclusion. Additional samples were obtained and grouped in two time intervals (1-5 h and 6-12 h after inclusion). Endotoxin was detected in eight patients. Endotoxemia was more common among patients with bacteremia than among non-bacteremic patients (7/12 versus 1/12; p < 0.05). All studied cytokines showed a tendency to higher mean values at time 0 in patients with endotoxemia than in patients without endotoxemia. Significantly higher mean endotoxin values were seen at time 1-5 h in patients with gram-negative bacteremia (n = 6) than in patients without gram-negative bacteremia, and at time 0 in patients with chills (n = 6) compared to those without chills.

Clinical significance of serum cytokine patterns during start of fever in patients with neutropenia

Serum concentrations of tumour necrosis factor alpha (TNF-alpha), interleukin-1 receptor antagonist (IL-1ra), interferon gamma (IFN-gamma), interleukin-6 (IL-6) and interleukin-10 (IL-10) were studied in 31 patients with haematological malignancies during febrile neutropenia. Samples were obtained when blood cultures were performed (time 0) and, when possible, after 2, 4, 6, 12 and 24 h. Increased levels of all cytokines were detected after start of fever with peak values in gram-negative (Gr-) bacteraemias after 2 h (TNF-alpha, IL-1ra and IFN-gamma), 4 h (IL-6) and 6 h (IL-10), respectively. At time 0 the median TNF-alpha value was higher in the Gr- group (80 pg/ml; range 54-516 pg/ml) as compared to both gram-positive bacteraemias (Gr+, 14 pg/ml; range 7-60 pg/ml; P < 0.05) and blood culture negative episodes (BCN, 8 pg/ml; range 0-87 pg/ml; P < 0.05). Furthermore, the peak values of TNF-alpha, IL-1ra, IL-6 and IL-10 during the 24 h study period were significantly and/or numerically higher in the Gr- group in comparison to the Gr+ and BCN groups, respectively. It may be concluded that neutropenic patients have increased levels of both pro- and anti-inflammatory cytokines at start of fever, with the highest values recorded during the first hours in Gr- bacteraemias. Prospective studies will show whether monitoring of serum cytokines may be used as an early diagnostic tool before results of blood cultures are available, which may have important therapeutic implications.

Monitoring of endotoxin, interleukin‐6 and C‐reactive protein serum concentrations in neutropenic patients with fever

Serum endotoxin, interleukin-6 (IL-6) and C-reactive protein (CRP) were serially determined in 26 patients with hematological malignancies and chemotherapy-induced neutropenia who developed fever. Endotoxin in serum was detected in 69% of the patients, with the highest values being recorded in patients with gram-negative (Gr-) bacteremia. High levels of IL-6 were found after start of fever, and in 6/9 patients with Gr- bacteremia levels exceeded 200 ng/l in samples drawn within the first 72 hours. However, only in 2/17 patients with gram-positive bacteremias and blood culture-negative fever episodes did IL-6 exceed this concentration (p < 0.05). High CRP values (exceeding 100 mg/l) did not discriminate between Gr- and non-Gr- episodes (7/9 versus 10/17, respectively). In patients with fever at day 3-5 (n = 15), IL-6 values > 100 ng/l were associated with fever continuing for more than 7 days after start of the episode; contrarily, CRP values did not indicate the persistence of fever. Determination of IL-6 may be a better test than CRP in monitoring the acute response to infection in the neutropenic patient. A combination of high endotoxin and IL-6 values may indicate a Gr- bacteremia. This could have therapeutic implications before results of blood cultures are obtained.

Serum cytokine pattern in neutropenic patients during start of fever – clinical implications

Journal of Immunotherapy with Emphasis on Tumor Immunology: February 1995 - Volume 17 - Issue 2 - p 119

Acute Oral Candidiasis during Febrile Episodes in Immunocompromised Patients with Haematologic Malignancies

To estimate clinical, pathogenic and serological aspects of acute oral candidiasis (AOC) during febril episodes in patients with haematologic malignancies, 23 consecutive patients who developed AOC within 7 days from start of fever were compared with 23 consecutive patients who did not develop AOC. The duration of fever and severe granulocytopenia (less than 0.5 x 10(9)/l) was significantly longer in patients with AOC than in patients without AOC, the median differences between the patients with and without AOC being 4 and 3 days, respectively. Development of AOC could not be correlated to a change in the qualitative composition of the oral microflora. The thrombocyte count was lower in patients with AOC on day 4, whereas no differences were found in leukocyte counts. The prevalences of Candida albicans agglutinin titres greater than or equal to 5 were similar in patients with (24%) and without AOC (33%), and in controls (29%). Seroconversion or a significant increase in the agglutinin titre occurred in 4 patients with AOC and long-lasting fever, who became afebrile after systemic antifungal therapy. It is concluded that AOC is associated with long-lasting fever and decreased bone marrow function as judged by low thrombocyte counts, but not related to specific bacteria in the oral cavity or to an increased occurrence of C. albicans antibodies in the serum.