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Concept: Fever

288

Background Acetaminophen is a common therapy for fever in patients in the intensive care unit (ICU) who have probable infection, but its effects are unknown. Methods We randomly assigned 700 ICU patients with fever (body temperature, ≥38°C) and known or suspected infection to receive either 1 g of intravenous acetaminophen or placebo every 6 hours until ICU discharge, resolution of fever, cessation of antimicrobial therapy, or death. The primary outcome was ICU-free days (days alive and free from the need for intensive care) from randomization to day 28. Results The number of ICU-free days to day 28 did not differ significantly between the acetaminophen group and the placebo group: 23 days (interquartile range, 13 to 25) among patients assigned to acetaminophen and 22 days (interquartile range, 12 to 25) among patients assigned to placebo (Hodges-Lehmann estimate of absolute difference, 0 days; 96.2% confidence interval [CI], 0 to 1; P=0.07). A total of 55 of 345 patients in the acetaminophen group (15.9%) and 57 of 344 patients in the placebo group (16.6%) had died by day 90 (relative risk, 0.96; 95% CI, 0.66 to 1.39; P=0.84). Conclusions Early administration of acetaminophen to treat fever due to probable infection did not affect the number of ICU-free days. (Funded by the Health Research Council of New Zealand and others; HEAT Australian New Zealand Clinical Trials Registry number, ACTRN12612000513819 .).

Concepts: Clinical trial, Statistics, Mathematics, Estimator, Intensive care medicine, Interquartile range, Placebo, Fever

209

Bats are sources of high viral diversity and high-profile zoonotic viruses worldwide. Although apparently not pathogenic in their reservoir hosts, some viruses from bats severely affect other mammals, including humans. Examples include severe acute respiratory syndrome coronaviruses, Ebola and Marburg viruses, and Nipah and Hendra viruses. Factors underlying high viral diversity in bats are the subject of speculation. We hypothesize that flight, a factor common to all bats but to no other mammals, provides an intensive selective force for coexistence with viral parasites through a daily cycle that elevates metabolism and body temperature analogous to the febrile response in other mammals. On an evolutionary scale, this host-virus interaction might have resulted in the large diversity of zoonotic viruses in bats, possibly through bat viruses adapting to be more tolerant of the fever response and less virulent to their natural hosts.

Concepts: Bacteria, Evolution, Severe acute respiratory syndrome, Mammal, Fever, Bat, Viral hemorrhagic fever, Natural reservoir

171

Elevation of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) is prominent in acute dengue illness. The World Health Organization (WHO) 2009 dengue guidelines defined AST or ALT ≥ 1000 units/liter (U/L) as a criterion for severe dengue. We aimed to assess the clinical relevance and discriminatory value of AST or ALT for dengue hemorrhagic fever (DHF) and severe dengue.

Concepts: Malaria, Liver function tests, Aspartate transaminase, Alanine transaminase, Fever, Dengue fever, World Health Organization, EC 2.6.1

170

The mosquito Aedes aegypti is one of the most important disease vectors because it transmits two major arboviruses, dengue and yellow fever, which cause significant global morbidity and mortality. Chemical insecticides form the cornerstone of vector control. The organophosphate temephos a larvicide recommended by WHO for controlling Ae. aegypti, however, resistance to this compound has been reported in many countries, including Brazil.

Concepts: Malaria, Mosquito, Yellow fever, Fever, Aedes aegypti, Aedes, Dengue fever, Insecticide

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Abstract. Acute and convalescent serum samples were collected from febrile inpatients identified at two hospitals in Moshi, Tanzania. Confirmed brucellosis was defined as a positive blood culture or a ≥ 4-fold increase in microagglutination test titer, and probable brucellosis was defined as a single reciprocal titer ≥ 160. Among 870 participants enrolled in the study, 455 (52.3%) had paired sera available. Of these, 16 (3.5%) met criteria for confirmed brucellosis. Of 830 participants with ≥ 1 serum sample, 4 (0.5%) met criteria for probable brucellosis. Brucellosis was associated with increased median age (P = 0.024), leukopenia (odds ratio [OR] 7.8, P = 0.005), thrombocytopenia (OR 3.9, P = 0.018), and evidence of other zoonoses (OR 3.2, P = 0.026). Brucellosis was never diagnosed clinically, and although all participants with brucellosis received antibacterials or antimalarials in the hospital, no participant received standard brucellosis treatment. Brucellosis is an underdiagnosed and untreated cause of febrile disease among hospitalized adult and pediatric patients in northern Tanzania.

Concepts: Participation, Hospital, Blood type, Physician, Brucellosis, Fever, Blood culture, Received Pronunciation

168

Genistein, the major isoflavone in soybean, was recently reported to exert beneficial effects in metabolic disorders and inflammatory diseases. In the present study, we investigated the effects and mechanisms of a dietary concentration of genistein on the inflammatory response in lipopolysaccharide (LPS)-treated RAW 264.7 macrophages. Our results demonstrated that genistein effectively inhibited the LPS-induced overproduction of tumor necrosis factor-alpha (TNF-α) and interleukin 6 (IL-6), as well as LPS-induced nuclear factor kappa B (NF-κB) activation. In addition, the data also showed that genistein prevented LPS-induced decrease in adenosine monophosphate-activated protein kinase (AMPK) phosphorylation. These effects were obviously attenuated by an AMPK inhibitor. Taken together, our results suggest that the dietary concentration of genistein is able to attenuate inflammatory responses via inhibition of NF-κB activation following AMPK stimulation. The data provide direct evidence for the potential application of low concentrations of genistein in the prevention and treatment of inflammatory diseases.

Concepts: Immune system, Inflammation, Adenosine triphosphate, Interleukin, Enzyme inhibitor, Fever, Tumor necrosis factor-alpha, AMP-activated protein kinase

168

The occurrence of dengue haemorrhagic fever (DHF) is thought to result from a complex interplay between the virus, host genetics and host immune factors. Existing published data are not consistent, in part related to relatively small sample sizes. We set out to determine possible associations between dengue virus (DEN-V) NS3 specific T cells and cytokine and chemokine levels and the pathogenesis of severe disease in a large cohort of individuals with DHF.

Concepts: Immune system, DNA, Sample size, Virus, Ribavirin, Fever, Dengue fever, Dengue

168

OBJECTIVES: To assess whether the flowcharts and discriminators of the Manchester Triage System (MTS) can be used as indicators of alarming signs of serious febrile illness to predict the risk of hospitalization for febrile children who present at the emergency department (ED). STUDY DESIGN: Observational study, which included 2455 children (<16 years) who came to the ED of a university hospital with fever as their main complaint (May 2007-July 2009). Alarming signs for serious febrile illness were matched with MTS flowcharts and discriminators. At triage, the percentage of alarming signs positive was calculated. The diagnostic ability of the percentage of alarming signs positive to identify children at risk of hospitalization was assessed by calculating positive and negative likelihood ratios. RESULTS: Thirty percent of children had at least 1 alarming sign positive at triage. Twenty-three percent were hospitalized. Positive likelihood ratios of hospitalization were 5.0 (95% CI: 3.9-6.5) for children with >20% of alarming signs positive at triage and 12.0 (95% CI: 5.2-27.6) for those with >40% of alarming signs positive. Negative likelihood ratios were 0.8 (95% CI: 0.8-0.8) and 1.0 (95% CI: 0.9-1.0), respectively. CONCLUSIONS: By alternatively using the flowcharts and discriminators of the MTS as alarming signs, rather than urgency classifiers, the MTS can function as a simple, readily available tool to identify febrile children at risk of hospitalization early in the care process. This knowledge may help to improve ED throughput times as well as admission and discharge management at pediatric EDs.

Concepts: Scientific method, Hospital, Fever, 0, Integer, Triage

167

Zika virus is a mosquito-borne flavivirus that is related to dengue virus and transmitted primarily by Aedes aegypti mosquitoes, with humans acting as the principal amplifying host during outbreaks. Zika virus was first reported in Brazil in May 2015 (1). By February 9, 2016, local transmission of infection had been reported in 26 countries or territories in the Americas.* Infection is usually asymptomatic, and, when symptoms are present, typically results in mild and self-limited illness with symptoms including fever, rash, arthralgia, and conjunctivitis. However, a surge in the number of children born with microcephaly was noted in regions of Brazil with a high prevalence of suspected Zika virus disease cases. More than 4,700 suspected cases of microcephaly were reported from mid-2015 through January 2016, although additional investigations might eventually result in a revised lower number (2). In response, the Brazil Ministry of Health established a task force to further investigate possible connections between the virus and brain anomalies in infants (3).

Concepts: Disease, Infection, Mosquito, Yellow fever, Fever, Aedes aegypti, Aedes, Dengue fever

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BACKGROUND: Healthcare claims databases have been used in several studies to characterize the risk and burden of chemotherapy-induced febrile neutropenia (FN) and effectiveness of colony-stimulating factors against FN. The accuracy of methods previously used to identify FN in such databases has not been formally evaluated. METHODS: Data comprised linked electronic medical records from Geisinger Health System and healthcare claims data from Geisinger Health Plan. Subjects were classified into subgroups based on whether or not they were hospitalized for FN per the presumptive “gold standard” (ANC <1.0x109/L, and body temperature >=38.30C or receipt of antibiotics) and claims-based definition (diagnosis codes for neutropenia, fever, and/or infection). Accuracy was evaluated principally based on positive predictive value (PPV) and sensitivity. RESULTS: Among 357 study subjects, 82 (23%) met the gold standard for hospitalized FN. For the claims-based definition including diagnosis codes for neutropenia plus fever in any position (n=28), PPV was 100% and sensitivity was 34% (95% CI: 24–45). For the definition including neutropenia in the primary position (n=54), PPV was 87% (78–95) and sensitivity was 57% (46–68). For the definition including neutropenia in any position (n=71), PPV was 77% (68–87) and sensitivity was 67% (56–77). CONCLUSIONS: Patients hospitalized for chemotherapy-induced FN can be identified in healthcare claims databases–with an acceptable level of mis-classification–using diagnosis codes for neutropenia, or neutropenia plus fever.

Concepts: Medicine, Health insurance, Positive predictive value, Negative predictive value, Thermoregulation, Hyperthermia, Fever, Febrile neutropenia