ELIZABETH C. HERSCH, COL, MC, USA, AND C. ROBERT, OH, LTC, MC, USA. There was no difference in types of diagnoses for those who met the strict 1991 definition compared with those who received a diagnosis in less than three weeks.10 Therefore, FUO may be assumed when no reasonable diagnosis is reached after an appropriate inpatient or outpatient investigation.2,6,1017 Table 1 compares the evolution of the definition of FUO.2,3,6,7,1017, Other subtypes of FUO are nosocomial, neutropenic, and human immunodeficiency virusassociated.7 These subtypes have different approaches to evaluation and are beyond the scope of this article.17, The etiologies of FUO have changed over time because of shifting disease patterns and new diagnostic techniques.14 There are more than 200 diseases in the differential diagnosis.4,15,17 In multiple case series, however, the etiology of FUO is limited to several dozen causes, and patients often have an atypical presentation of a common disease.2,6,18. Copyright 2023 American Academy of Family Physicians. Cases with prolonged fever were defined as patients with fever lasting >7 days. Woon YL, Hor CP, Hussin N, Zakaria A, Goh PP, Cheah WK. If there are no potentially diagnostic clues, the patient should undergo a minimum diagnostic workup, including a complete blood count, chest radiography, urinalysis and culture, electrolyte panel, liver enzymes, erythrocyte sedimentation rate, and C-reactive protein level testing. Would you like email updates of new search results? Repeat CXR was not performed for cases in the control group and 1 case of saddleback fever. Fever was defined as a temperature of 38.0C. Front Cell Infect Microbiol. Our cohort only had 1 mortality, and this may be reflective of the overall low mortality rate in Singapore. Would you like email updates of new search results? We wish to thank members of the Singapore Immunology Network Wilson How, Norman Leo Fernandez, Olaf Rtzschke, and Bernett Lee for their assistance with the multiplex microbead-based immunoassays and data analyses. Please enable it to take advantage of the complete set of features! official website and that any information you provide is encrypted Cytokines were determined with multiplex View PDF Save to Library In addition, in comparison with other parameters such as respiratory rate, heart rate, or blood pressure, fever is easy to detect and readily identifiable as a risk factor for severe disease. 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. Bookshelf A person viewing it online may make one printout of the material and may use that printout only for his or her personal, non-commercial reference. Those with prolonged fever had a median duration of fever (interquartile range [IQR]) of 10 (9-11) days for prolonged fever cases, while fever recurred at a median (IQR) of 10 (8-12) days for those with saddleback fever. Outcomes of COVID-19 Among High-Risk Individuals: A Study Comparing Febrile and Afebrile Presentation. government site. MeSH The authors have declared that no competing interests exist. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BP, blood pressure; CRP, C-reactive protein; LDH, lactate dehydrogenase. -, Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW, Moyes CL, et al. Another 4 patients were excluded from the primary analysis as they had a saddleback pattern of fever that lasted >24 hours; 12.7% (18/142) of cases had prolonged fever and another 9.9% (14/142) had saddleback fever. The global distribution and burden of dengue. Those with prolonged fever had a median duration of fever for 10 days (IQR 9-11 days) for prolonged fever cases, while fever recurred at a median of 10 days (IQR 8-12 days) for those with saddleback fever. Saddleback fever cases were also found to have higher pro-inflammatory IL-1, T-cell-activating mediators IL-21 and IL-22, and chemokine stromal cellderived factor 1 (SDF-1) compared with controls (Figure 1B). 2022 Jul 26;2022(7):omac079. Ng DH, Wong JG, Thein TL, Leo YS, Lye DC. History and physical examination alone are often sufficient to diagnose uncomplicated infectious causes of fever . 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]. official website and that any information you provide is encrypted Search dates: November 28, 2011; February 8, 2012; and April 18, 2014. In hypoxic conditions, it can trigger the expression of chemokines that attract neutrophils and monocytes to the ischemic tissue [31]. Concentrations of 45 immune mediators in plasma were quantified using a 45-plex microbead-based immunoassay. The findings of the study are useful for informing the optimal placement of patients with COVID-19, the researchers pointed out. However, unlike RA, rheumatic . Other illnesses and inflammation. 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). Prolonged fever lasting more than 7 days after illness onset can help physicians identify patients at high risk for adverse outcomes from COVID-19, according to a study. For most people, a temperature of 98.6 F or 37 C is baseline. doi: 10.1371/journal.pntd.0002412. Confirmed imported case of novel coronavirus infection in Singapore; multi-ministry taskforce ramps up precautionary measures.2020. Singapore reported its first imported case of COVID-19 in a traveler from Wuhan on January 23, 2020, followed by its first locally transmitted case on February 7, 2020 [2, 3]. Higher respiratory rate, lower SpO2, and lower systolic BP were also associated with saddleback fever compared with the control group. Emadi A, Chua JV, Talwani R, Bentzen SM, Baddley J. 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. An official website of the United States government. An official website of the United States government. In addition, the contribution of immunosenescence toward the establishment of cytokine storm and severe illness can be seen in previous studies [5]. Search life-sciences literature (41,164,937 (41,164,937 The most common subgroups in the differential are infection, malignancy, noninfectious inflammatory diseases, and miscellaneous. and transmitted securely. P.Y.C. Seven more confirmed cases of novel coronavirus infection in Singapore.2020. Some children also may have a sore throat, runny nose or cough along with or before the fever. Ying-Hao P, Yuan-Yuan G, Hai-Dong Z, Qiu-Hua C, Xue-Ran G, Hai-Qi Z, Hua J. PLoS One. Prolonged fever of unknown origin: a record of experiences with 54 childhood patients. If there is no clear source of infection, then further testing should follow. Dengue fever is an acute febrile illness with a duration of 2-12 days. Nature. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (. Unmasking latent extrapulmonary tuberculosis with newly diagnosed HIV-1 infection in a COVID-19 patient with prolonged fever. Unauthorized use of these marks is strictly prohibited. Background: In patients who have a fever of unknown origin with an elevated erythrocyte sedimentation rate and/or C-reactive protein levels, and who have not received a diagnosis after initial evaluation, 18F fluorodeoxyglucose positron emission tomography scan with or without computed tomography may be useful in reaching a diagnosis. We conducted a hospital-based casecontrol study of patients admitted for COVID-19 with prolonged fever (fever>7 days) and saddleback fever (recurrence of fever, lasting <24 hours, after defervescence beyond day 7 of illness). eCollection 2013. 2021 Mar 8;9(1):E181-E188. Untreated typhoid fever may progress to delirium, obtundation, intestinal hemorrhage, bowel. is funded by the National Medical Research Council (NMRC/Fellowship/0056/2018). This suggests that in patients with prolonged fever, close monitoring for deterioration should be instituted, while patients with saddleback fever who remain well and do not require supplemental oxygenation are unlikely to require close monitoring in the hospital. The differences in cytokine and chemokine profiles among [the three groups] suggest that different immunological responses could result in the differences in the clinical phenotype observed, said Ng and co-authors. A comprehensive history and physical examination should be performed if there are no localizing signs and symptoms in patients with prolonged febrile illness. In health, body temperature is regulated around a set point of 37 1C, and a circadian temperature rhythm exists in which the highest temperature of each day occurs around 6 p.m. Home or community isolation facilities are commonly used globally for less sick patients such that hospital beds are free up to cater for sicker patients. Risk Factors Associated With Mortality Among Patients With COVID-19 in Intensive Care Units in Lombardy, Italy. 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. Although there are more than 200 diseases in the differential diagnosis, most cases in adults are limited to several dozen possible causes. -. In contrast, cases with saddleback fever showed no significant change upon repeating their laboratory tests. Interestingly, there are also higher plasma levels of IL-1RA in patients with prolonged fever compared with control patients. If noninvasive diagnostic tests are unrevealing, then the invasive test of choice is a tissue biopsy because of the relatively high diagnostic yield. Copyright 2023 MIMS Pte Ltd. All rights reserved. Sixty-nine percent of them were male with a median age of 34 years. Ministry of Health Singapore. But normal body temperature can range between 97 F (36.1 C) and 99 F (37.2 C) or more. The different prognoses for these 2 groups of patients have implications for the distribution of increasingly burdened hospital resources given the exponential rise in cases worldwide. Patients with prolonged fever had higher induced protein -10 and lower interleukin-1 levels compared with those with saddleback fever at the early acute phase of disease. FOUR TYPES OF FEVERS - Read online for free. Oxford University Press is a department of the University of Oxford. PMC This corroborated well with our findings of increased hypoxia in patients with prolonged fever. Mallhi TH, Khan AH, Adnan AS, Sarriff A, Khan YH, Jummaat F. BMC Infect Dis. eCollection 2017 Summer. Duration of fever was calculated from the date of first symptom onset to the date of defervescence (defined as temperature <37.5C for at least 24 hours) during the hospital admission. Federal government websites often end in .gov or .mil. doi: 10.1371/journal.pone.0167025. Elevated lactate dehydrogenase levels can be indicative of infectious and malignant causes of FUO, including malaria, lymphoma, and leukemia.15,21 Measurement of ferritin levels may also be helpful.33 An elevated ferritin level in prolonged febrile illness may indicate malignancy (especially myeloproliferative disorders) and other noninfectious inflammatory diseases, such as systemic lupus erythematosus or temporal arteritis.21,33 One study established a ferritin level of 561 ng per mL (1,261 pmol per L) as the optimal cutoff value to predict that FUO was due to a noninfectious cause.22 Extreme elevation of ferritin levels (greater than 1,000 ng per mL [2,247 pmol per L]) can point to adult Still disease.34 Infection is the most common reason ESR is extremely elevated, but if there is no evidence of infectious causes, clinicians should consider malignancy, renal disease, and inflammatory disorders if the ESR is 100 mm per hour or greater.29. COVID-19 generally presents as an acute respiratory illness, with fever, fatigue, and dry cough being commonly reported symptoms [46]. 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. Murthy S, Archambault PM, Atique A, Carrier FM, Cheng MP, Codan C, Daneman N, Dechert W, Douglas S, Fiest KM, Fowler R, Goco G, Gu Y, Guerguerian AM, Hall R, Hsu JM, Joffe A, Jouvet P, Kelly L, Kho ME, Kruisselbrink RJ, Kumar D, Kutsogiannis DJ, Lamontagne F, Lee TC, Menon K, O'Grady H, O'Hearn K, Ovakim DH, Pharand SG, Pitre T, Reel R, Reeve B, Rewa O, Richardson D, Rishu A, Sandhu G, Sarfo-Mensah S, Shadowitz E, Sligl W, Solomon J, Stelfox HT, Swanson A, Tessier-Grenier H, Tsang JLY, Wood G; SPRINT-SARI Canada Investigators and the Canadian Critical Care Trials Group. Mucosal bleeding, anorexia, diarrhea, abdominal pain, nausea or vomiting, lethargy, rash, clinical fluid accumulation, hepatomegaly, nosocomial infection, leukopenia, higher neutrophil count, higher hematocrit, higher alanine transaminase (ALT) and aspartate transaminase (AST), higher creatinine, lower protein and prolonged activated partial thromboplastin time (APTT) were significantly associated with prolonged fever but not platelet count or prothrombin time (PT). 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. 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. All authors: no reported conflicts of interest. Previous testing (ESR, complete blood count, electrolyte panel, chest radiography, urinalysis, blood culture) may be repeated periodically to evaluate for trends as the illness evolves. All efforts have been undertaken to anonymize the data. Coronavirus disease 2019 (COVID-19) situation report101. In one review, an ESR of 100 mm per hour or greater had a high specificity for malignancy (96%) and infection (97%), and its positive predictive value was 90%.29 A normal ESR has a high negative predictive value for temporal arteritis.28,30 An ESR that is not elevated has no diagnostic value and does not rule out neoplastic or other disorders.27 CRP level is a sensitive marker for infection and inflammation, but it is not sensitive enough to discriminate between disease processes.28 However, a more recent prospective study found that the chance of establishing a diagnosis was higher in patients who had an elevated CRP level and ESR.15, Procalcitonin is a newer marker specific for bacterial infection. Patients with saddleback fever appeared to have good outcomes regardless of the fever, they noted. 2016 Dec 9;11(12):e0167025. Clinical characteristics and analysis of risk factors for disease progression of patients with SARS-CoV-2 Omicron variant infection: A retrospective study of 25207 cases in a Fangcang hospital. Epub 2022 Aug 27. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. This content is owned by the AAFP. Grasselli G, Greco M, Zanella A, Albano G, Antonelli M, Bellani G, Bonanomi E, Cabrini L, Carlesso E, Castelli G, Cattaneo S, Cereda D, Colombo S, Coluccello A, Crescini G, Forastieri Molinari A, Foti G, Fumagalli R, Iotti GA, Langer T, Latronico N, Lorini FL, Mojoli F, Natalini G, Pessina CM, Ranieri VM, Rech R, Scudeller L, Rosano A, Storti E, Thompson BT, Tirani M, Villani PG, Pesenti A, Cecconi M; COVID-19 Lombardy ICU Network. In addition, IP-10 has also been reported to be associated with increased viral load, lung injury, ICU admission, and mortality [21]. Notably, patients with prolonged fever had higher IP-10 and lower IL-1 levels as compared with patients with saddleback fever (Figure 1B). Unable to load your collection due to an error, Unable to load your delegates due to an error. 40-year-old woman fever rash arthralgia Dx? 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. Shivering, shaking, and chills Aching muscles and joints or other body aches Headache Intermittent sweats or excessive sweating Rapid heart rate and/or palpitations Skin flushing or hot skin Feeling faint, dizzy, or lightheaded Eye pain or sore eyes Weakness Loss of appetite Fussiness (in children and toddlers) However, ESR does not help discriminate between active autoimmune disease and infection, and malignancies and noninfectious inflammatory diseases can cause an elevated ESR and CRP level. Both prolonged (27.8% vs 0.9%, p <0.01) and saddleback fever (14.3% vs 0.9%, p= 0.03) were associated with hypoxia compared to controls. eCollection 2016 May. 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. 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