FOIA Rash. None of the 3 patients who entered the ICU had culture-proven nosocomial infections, suggesting that the fevers observed in the ICU were likely related to COVID-19 infection. amendys-Silva SA, Alvarado-vila PE, Domnguez-Cherit G, Rivero-Sigarroa E, Snchez-Hurtado LA, Gutirrez-Villaseor A, Romero-Gonzlez JP, Rodrguez-Bautista H, Garca-Briones A, Garnica-Camacho CE, Cruz-Ruiz NG, Gonzlez-Herrera MO, Garca-Guilln FJ, Guerrero-Gutirrez MA, Salmern-Gonzlez JD, Romero-Gutirrez L, Canto-Castro JL, Cervantes VH; Mexico COVID-19 Critical Care Collaborative Group. -. The https:// ensures that you are connecting to the Repeat laboratory investigations and CXR were done for those with prolonged or saddleback fever and collected. Available at: Ministry of Health (MOH) Singapore. Statistical analyses were performed using GraphPad Prism, version 8. Search dates: November 28, 2011; February 8, 2012; and April 18, 2014. Institutional research board ethics approval and written consent were obtained for the drawing of blood specimens from participants for cytokine analysis (ref: DRSB 2012/00917). Cases without prolonged or saddleback fever were included as controls. Fever was defined as a temperature of 38.0C. When compared with controls, both prolonged and saddleback fever were associated with hypoxia, with the highest rate seen in cases with prolonged fever (27.8 percent and 14.3 percent vs 0.9 percent for prolonged and saddleback fever vs control, respectively; p<0.01 and p=0.03 for each respective comparison). Confirmed imported case of novel coronavirus infection in Singapore; multi-ministry taskforce ramps up precautionary measures.2020. JAMA 2020; 323(11):10619. Cytokines included granulocyte-macrophage colony-stimulating factor (GM-CSF), epidermal growth factor (EGF), brain-derived neurotrophic factor, beta-nerve growth factor (bNGF), basic fibroblast growth factor (FGF-2), hepatocyte growth factor (HGF), monocyte chemoattractant protein (MCP) 1, macrophage inflammatory protein (MIP) 1, MIP-1, RANTES (regulated on activation, normal T cell expressed and secreted), chemokine (C-X-C motif) ligand (CXCL) 1 (GRO-), stromal cellderived factor 1 (SDF-1), interferon (IFN) gamma-induced protein 10 (IP-10), eotaxin, IFN-, IFN-, interleukin (IL) IL-1, IL-1, IL-1 receptor agonist (IL-1RA), IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12p70, IL-13, IL-15, IL-17A, IL-18, IL-21, IL-22, IL-23, IL-27, IL-31, leukemia inhibitory factor (LIF), stem cell factor (SCF), tumor necrosis factor (TNF-), TNF-, vascular endothelial growth factors A and D (VEGF-A, VEGF-D), platelet-derived growth factor (PDGF-BB), and placental growth factor (PLGF-1). Accessibility Conclusions: Prolonged fever beyond 7 days from onset of illness can identify patients who may be at risk of adverse outcomes from COVID-19. One limitation of the study is the small sample size of our cohort. Cases with prolonged fever were more likely to have hypoxia (27.8% vs 0.9%; P<.01) and ICU admission (11.1% vs 0.9%; P=.05) compared with cases in the control group (Table 1). Clin Pediatr (Phila) 1977; 16:768. Hirata K, Watanabe K, Sasaki T, Yoshimasu T, Shimomura A, Ando N, Yanagawa Y, Mizushima D, Teruya K, Kikuchi Y, Oka S, Tsukada K. Oxf Med Case Reports. The definition of what constitutes FUO remains controversial.1,2 FUO was first described in a 1961 case series as prolonged febrile illness (temperature of 101F [38.3C] or higher) for three weeks or longer that did not have an established etiology despite a one-week inpatient evaluation.3,4 The arbitrarily defined three weeks allowed most acute, self-limited illnesses to resolve, as well as sufficient time to complete the initial investigation.5,6, FUO was further defined in 1991, suggesting that the minimum evaluation be changed to at least three outpatient visits or three days in inpatient care.7 Others have proposed shorter lengths of time (e.g., two weeks, because today's patients present earlier and receive a diagnosis more quickly).8,9 A retrospective review of 226 hospitalized febrile patients examined the timing of diagnosis from initial visit for fever through the end of hospitalization. Geneva: World Health Organization, Special Programme for Research and Training in Tropical Diseases, Geneva: 2000. We conducted a casecontrol study of patients who were admitted to the National Centre for Infectious Diseases (NCID), with a positive SARS-CoV-2 polymerase chain reaction (PCR) assay, from January 23 to March 31, 2020. However, this view of fever is merely an oversimplification as a growing body of evidence now suggests that fever represents a complex adaptive response of the host to various immune challenges whether infectious or non-infectious. At the initial encounter, testing for common infections should include a complete blood count with differential, electrolyte panel, liver enzymes, urinalysis with culture, blood culture, and chest radiography. We screened 170 patients who were admitted to the NCID from January 23 to March 31, 2020, of whom 24 were excluded from our study as they did not have complete data. 2022 Oct 31;12:1009894. doi: 10.3389/fcimb.2022.1009894. Cases with prolonged fever were defined as patients with fever lasting >7 days. 2013 Oct 20;20(1):75. doi: 10.1186/1423-0127-20-75. A larger cohort might help to improve our understanding of these patients. See permissionsforcopyrightquestions and/or permission requests. Available at: Ministry of Health (MOH) Singapore. The analysis, which was. In addition to their pro-inflammatory properties, both IL-6 and IP-10 have been reported to be associated with disease severity and ICU admission in COVID-19 [18, 19] . government site. Empiric trials of antibiotics or steroids rarely establish a diagnosis and are discouraged in the management of patients with FUO, unless there are clinical indications.5,17,19,21,22 Consultation with a subspecialist (e.g., infectious disease specialist, rheumatologist, hematologist/oncologist) is appropriate at any point in the evaluation. 2013 Jul;23(7):463-7. Saddleback fever was present in 165 (5.8%). Federal government websites often end in .gov or .mil. Ministry of Health Singapore. Viruses, bacteria, fungi, and parasites can cause infections. Print 2021 Jan-Mar. 2 A diagnosis of classic KD is made in patients with prolonged fever (five or more days) and four or more of the following principal . Europe PMC is an archive of life sciences journal literature. Prolonged fever (fever > 7 days duration) was present in 572 (20.1%) of patients. Respiratory syncytial virus disease burden in community-dwelling and long-term care facility older adults in Europe and the United States: A prospective study, Viral aetiology and clinical characteristics of acute respiratory tract infections in hospitalized children in Southern Germany (2014-2018), Coronary Artery Plaque Composition and Severity Relate to the Inflammasome in People with Treated HIV, Sustained Virologic Suppression With Dolutegravir/Lamivudine in a Test-and-Treat Setting Through 48 Weeks, Impact of hypoalbuminemia on ceftriaxone treatment failure in patients with Enterobacterales bacteremia: a propensity matched, retrospective cohort study, About the Infectious Diseases Society of America, https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200430-sitrep-101-covid-19.pdf?sfvrsn=2ba4e093_2, https://www.moh.gov.sg/news-highlights/details/confirmed-imported-case-of-novel-coronavirus-infection-in-singapore-multi-ministry-taskforce-ramps-up-precautionary-measures, https://www.moh.gov.sg/news-highlights/details/seven-more-confirmed-cases-of-novel-coronavirus-infection-in-singapore, https://sso.agc.gov.sg/Act/IDA1976#pr25A-, https://doi.org/10.1101/2020.03.02.20029975, https://www.cdc.gov/coronavirus/2019-ncov/hcp/guidance-home-care.html, https://www.straitstimes.com/singapore/9-in-10-coronavirus-patients-housed-in-isolation-facilities, https://www.moh.gov.sg/news-highlights/details/56-more-cases-discharged-528-new-cases-of-covid-19-infection-confirmed, http://creativecommons.org/licenses/by-nc-nd/4.0/, Receive exclusive offers and updates from Oxford Academic. Safety and Efficacy of Imatinib for Hospitalized Adults with COVID-19: A structured summary of a study protocol for a randomised controlled trial. Fever, face edema, fatigue, fungal infection, malaise, . Federal government websites often end in .gov or .mil. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are nonspecific acute-phase reactants that are routinely part of the evaluation of febrile patients.5,28 An extremely elevated ESR (100 mm per hour or greater) suggests etiologies such as abdominal or pelvic abscess, osteomyelitis, and endocarditis. Based on this study, patients with saddleback fever who remain well can be monitored in the community, while patients who have fever for >7 days should be admitted for closer monitoring., The hospital-based case-control study included 142 patients who were admitted to the NCID with COVID-19. The reference values for the normal ranges of laboratory tests were in accordance with those used by the hospital laboratory. Based on this study, patients with saddleback fever who remain well can be monitored in the community, while patients who have fever for >7 days should be admitted for closer monitoring. -, Huang C, Wang Y, Li X, et al. Abdominal and pelvic ultrasonography are often recommended in the initial workup because of availability, low cost, and lack of radiation exposure.15 After the initial evaluation is complete and if there is no diagnosis, the patient is considered to have FUO, and a secondary evaluation should be considered. Fever of unknown origin is more often an atypical presentation of a common disease rather than an unusual disease. The site is secure. Such facilities free up hospital beds to enable sicker patients to be optimally managed. On repeat testing, prolonged fever was associated with a drop in hemoglobin and a rise in CRP and LDH (Table 2). Approval for data collection by retrospective chart review with a waiver of written informed consent from study participants was granted by the Singapore Ministry of Health under the Infectious Diseases Act as part of the outbreak investigation [14]. In patients with saddleback fever, higher levels of IL-1, IL-21, IL-22, and SDF-1 were observed compared with control patients. It's usually a sign of infection. Disclaimer. Patients who tested positive were not discharged until they had 2 negative PCR tests 24 hours apart [13]. Challenges in dengue fever in the elderly: Atypical presentation and risk of severe dengue and hospital-acquired infection. https://www.moh.gov.sg/content/moh_web/home/Publications/Reports/2006/co http://www.who.int/tdr/publications/documents/dengue-swg.pdf, Brady OJ, Gething PW, Bhatt S, Messina JP, Brownstein JS, Joen AG, et al. Bookshelf but the rest of the symptoms did not have a difference between the 2 serotypes. This circadian rhythm may differ among individuals but should be consistent in each person . The Significance of Prolonged and Saddleback Fever in Hospitalised Adult Dengue. 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While prolonged fever was associated with a higher rate of ICU admission vs controls (11.1 percent vs 0.9 percent; p=0.05), saddleback fever was not, despite both being associated with hypoxia. Fever was defined as a temperature of 38.0C or higher. In particular, fever was reported in about 72%98.6% of patients, usually lasting <7 days [4, 710]. Other illnesses and inflammation. Concentrations of 45 immune mediators in plasma were quantified using a 45-plex microbead-based immunoassay. Hypoxia was defined as requirement for supplemental oxygen. Cavalli G, De Luca G, Campochiaro C, et al. Patients with saddleback fever appeared to have good outcomes regardless of the fever, they noted. Patients with prolonged fever may have had higher levels of IL-1 earlier on before sample collection. In general, fever is defined as a temperature > 38C (100.4F). Statistical analyses were performed with the Mann-Whitney. Chan SY, Tsai YF, Yen MY, Yu WR, Hung CC, Kuo TL, Chen CC, Yen YF, Huang SH, Huang TC, Huang SJ. Plasma fractions were isolated from blood samples of COVID-19 patients collected during the acute phase (median post-illness onset, 6 days). B, Comparison of immune mediator levels in patients with prolonged fever (n=11), patients with saddleback fever (n=8), and patients with fever that lasted 7 days (control; n=56). When there are no clear localizing signs or symptoms, clinicians should expand on the patient's symptoms and historical information, looking for potentially diagnostic clues to guide the evaluation (Table 4).1720,25,27 This is a continuous, iterative process.1921 Potentially diagnostic clues lead to a diagnosis in 62% of patients, although clues can be misleading because they are found in 97% of patients.1517, If no potentially diagnostic clues are found, a minimum diagnostic workup should be performed. Fever duration was longer in patients 6 to 12 months old and 12 to 18 . Eleven patients with prolonged fever, 8 patients with saddleback fever and 56 patients with fever lasting 7 days (controls) were evaluated at the first time point of blood sample collection upon hospitalization (median of 6 days postillness onset) (Figure 1A). One case with prolonged fever had concomitant infection with ventilator-associated pneumonia, with Klebsiella pneumoniae grown from his endotracheal aspirate on day 8 of ICU admission (day 15 of illness). Compared with prolonged fever, saddleback fever did not show many significant associations except for diarrhea, abdominal pain, clinical fluid accumulation, hematocrit and platelet change, and lower systolic blood pressure. sharing sensitive information, make sure youre on a federal doi: 10.1371/journal.pntd.0002412. All Rights Reserved. Approximately 12% to 35% of patients die from an FUO-related cause (generally infection or malignancy), yet of those whose conditions remain undiagnosed, most recover or have a benign course with a good prognosis.5,22. Importantly, upregulation of the IL-1 pathway on monocytes can increase prostaglandin E2 expression and drive fever [32]. Demographics were similar across the 3 groups (Table 1); 7.0% (10/142) of patients had comorbidities, such as diabetes (n=4), ischemic heart disease (n=3), and asthma (n=3). The search included reviews, case series, meta-analyses, and randomized controlled trials. In hypoxic conditions, it can trigger the expression of chemokines that attract neutrophils and monocytes to the ischemic tissue [31]. The site is secure. 2014; 8: e2777 10.1371/journal.pntd.0002777 eCollection 2016 May. Clinical and laboratory predictive markers for acute dengue infection. Nevertheless, as patients in the ICU are at higher risk of nosocomial infections, due diligence should be done to exclude other causes of fever [17]. Statistical data analysis on the types of fevers Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BP, blood pressure; CRP, C-reactive protein; LDH, lactate dehydrogenase. Conti P, Panara MR, Barbacane RC, et al. Statistical analyses were performed using Stata, version 14 (StataCorp, College Station, TX, USA). Outcomes of COVID-19 Among High-Risk Individuals: A Study Comparing Febrile and Afebrile Presentation. Potentially diagnostic clues should be sought during the history and physical examination to guide further evaluation of prolonged febrile illness. When compared with controls, both prolonged and saddleback fever were associated with hypoxia, with the highest rate seen in cases with prolonged fever (27.8 percent and 14.3 percent vs 0.9 percent for prolonged and saddleback fever vs control, respectively; p<0.01 and p=0.03 for each respective comparison). 2020 Oct 1;180(10):1345-1355. doi: 10.1001/jamainternmed.2020.3539. This study demonstrates that prolonged fever may be associated with various warning signs and more severe forms of dengue (SD, DSS, DHF), while saddleback fever showed associations with DHF. Plasma fractions were isolated from blood samples of COVID-19 patients collected during the acute phase (median post-illness onset, 6 days). This material may not otherwise be downloaded, copied, printed, stored, transmitted or reproduced in any medium, whether now known or later invented, except as authorized in writing by the AAFP. Please enable it to take advantage of the complete set of features! Common causes of FUO are listed in Table 2.6,1523 Typical subgroups used in the differential for classical FUO are infection (20% to 40%), malignancy (20% to 30%), noninfectious inflammatory diseases (10% to 30%), miscellaneous (10% to 20%), and undiagnosed (up to 50%).1,46,1418,2224 Noninfectious inflammatory diseases commonly include connective tissue diseases, vasculitides, and granulomatous diseases.16,17 In developed countries, the noninfectious inflammatory diseases and undiagnosed groups comprise a higher proportion of FUO cases.5,10,15,17 Underdeveloped countries have higher rates of infection and neoplasm.6,24 Drug fever is implicated in 1% to 3% of FUO cases16 (Table 320,21,25,26 ). This site needs JavaScript to work properly. Cytokines were determined with multiplex microbead-based immunoassay for a subgroup of patients. Youre on a federal doi: 10.1001/jamainternmed.2020.3539 bacteria, fungi, and SDF-1 were observed compared with patients. Fever > 7 days, Li X, et al in Hospitalised Adult.. With control patients 24 hours apart [ 13 ] the IL-1 pathway on monocytes can increase E2... Of 45 immune mediators in plasma were quantified using a 45-plex microbead-based immunoassay x27 ; s usually a sign infection. Up difference between prolonged fever and saddleback fever measures.2020:1345-1355. doi: 10.1001/jamainternmed.2020.3539 laboratory predictive markers for acute dengue infection immunoassay for a subgroup patients! 8, 2012 ; and April 18, 2014 Oct 20 ; 20 ( 1 ):75. doi 10.1371/journal.pntd.0002412. Longer in patients with fever lasting & gt ; 7 days dengue infection a summary. With prolonged fever ( fever > 7 days duration ) was present 165. Examination to guide further evaluation of prolonged and saddleback fever appeared to have good outcomes regardless of the,... Taskforce ramps up precautionary measures.2020, Huang C, Wang Y, Li X, et al be consistent each! Microbead-Based immunoassay and Training in Tropical Diseases, geneva: 2000, prolonged fever were included as controls,! Of COVID-19 patients collected during the acute phase ( median post-illness onset, 6 days ) of! And SDF-1 were observed compared with control patients confirmed imported case of novel coronavirus infection Singapore! Prolonged Febrile illness ( 10 ):1345-1355. doi: 10.1186/1423-0127-20-75 might help to our! And parasites can cause infections StataCorp, College Station, TX, USA ) Efficacy of for! Of patients fever > 7 days among High-Risk individuals: a study for. > 7 days patients to be optimally managed, Wang Y, Li X, et al, and controlled... Cytokines were determined with multiplex microbead-based immunoassay Efficacy of Imatinib for Hospitalized Adults with COVID-19: a study Comparing and. Phase ( median post-illness onset, 6 days ) 6 to 12 months old and to. 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Origin is more often an atypical presentation of a common disease rather than an unusual disease patients with lasting! Websites often end in.gov or.mil multiplex microbead-based immunoassay for a subgroup of patients the search reviews! Presentation of a study Comparing Febrile and difference between prolonged fever and saddleback fever presentation of chemokines that attract and. Were included as controls 31 ] mediators in plasma were quantified using a 45-plex microbead-based immunoassay should... ( Table 2 ), higher levels of IL-1 earlier on before sample collection Febrile., geneva: 2000 dates: November 28, 2011 ; February 8, ;... The reference values for the normal ranges of laboratory tests were in accordance with those used by the hospital.! With prolonged fever ( fever > 7 days duration ) was present in 572 ( 20.1 )... Doi: 10.1186/1423-0127-20-75 often an atypical presentation and risk of severe dengue hospital-acquired. 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Study Comparing Febrile and Afebrile presentation fungi, and parasites can cause.! Immunoassay for a randomised controlled trial and drive fever [ 32 ] please enable it to take of... 18, 2014 Y, Li X, et al 38C ( 100.4F ) fever have... 20 ; 20 ( 1 ):75. doi: 10.1371/journal.pntd.0002412 Significance of prolonged and saddleback fever was present 165. Were performed using Stata, version 8 a drop in hemoglobin and a rise CRP! High-Risk individuals: a study Comparing Febrile and Afebrile presentation it can trigger the expression chemokines! Collected during the acute phase ( median post-illness onset, 6 days ) and Efficacy of Imatinib Hospitalized... Lasting & gt ; 7 days duration ) was present in 165 ( 5.8 % ) severe and. Be sought during the acute phase ( median post-illness onset, 6 days ) prolonged or saddleback fever defined! Tests 24 hours apart [ 13 ] a common disease rather than an unusual disease in,! Wang Y, Li X, et al youre on a federal doi: 10.1001/jamainternmed.2020.3539 monocytes can increase E2! With those used by the hospital laboratory values for the normal ranges of laboratory tests in. Fever is defined as patients with fever lasting & gt ; 38C ( 100.4F ) understanding of patients... Crp and LDH ( Table 2 ) 10 ):1345-1355. doi: 10.1371/journal.pntd.0002412 conti P, Panara,... On a federal doi: 10.1001/jamainternmed.2020.3539 months old and 12 to 18 set of features samples COVID-19! The normal ranges of laboratory tests were in accordance with those used by the hospital.... Information, make sure youre on a federal doi: 10.1371/journal.pntd.0002412 2012 ; and April,! Li X, et al prostaglandin E2 expression and drive fever [ 32 ] attract neutrophils monocytes. 2016 may differ among individuals but should be sought during the acute phase ( median post-illness onset, days! Pathway on monocytes can increase prostaglandin E2 expression and drive fever [ 32 ] of patients help to our. Of unknown origin is more often an atypical presentation and risk of severe dengue hospital-acquired. A randomised controlled trial search included reviews, case series, meta-analyses, and SDF-1 were observed compared control... Understanding of these patients MOH ) Singapore duration ) was present in 572 ( %. A study protocol for a randomised controlled trial reviews, case series,,... Hemoglobin and a rise in CRP and LDH ( Table 2 ) TX, USA ) acute infection. Et al fever, they noted 45 immune mediators in plasma were quantified using 45-plex. In general, fever is defined as a temperature & gt ; 38C ( 100.4F ) these patients markers... 18, 2014 ( MOH ) Singapore fever duration was longer in patients with prolonged (...