Patient information: See related handout on fever of unknown origin in adults, written by the authors of this article. doi: 10.1371/journal.pone.0167025. Cases with prolonged fever were found to have higher levels of anti-inflammatory IL-1RA, pro-inflammatory IL-6, and chemokine interferon- IP-10 compared with controls (Figure 1B). 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. The elevation of circulating IL-1RA may reflect overactive IL-1 activation, which has been reported to associated with severe outcomes in COVID-19 [24]. Conclusions: Careers. 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. A fever is a rise in your body temperature. Cases with prolonged fever were defined as patients with fever lasting >7 days. Comparisons between prolonged fever and nonprolonged fever group are summarized in Tables 1 and 2. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BP, blood pressure; CRP, C-reactive protein; CXR, chest x-ray; ICU, intensive care unit; LDH, lactate dehydrogenase. 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). 2020 Oct 1;180(10):1345-1355. doi: 10.1001/jamainternmed.2020.3539. 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). COVID-19; cytokines; fever; prolonged; saddleback. Extreme poverty first: An argument on the equitable distribution of the COVID-19 vaccine in Peru. Both prolonged fever and saddleback fever were not significantly associated with mechanical ventilation as compared with the control group (Table 1). Careers. 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. The analysis, which was. Statistical data analysis on the types of fevers 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. PMC Accessibility Mallhi TH, Khan AH, Adnan AS, Sarriff A, Khan YH, Jummaat F. BMC Infect Dis. Disclaimer. Among these patients, 12.7 percent had prolonged fever (median interquartile range [IQR], 10 days) while 9.9 percent had saddleback fever, with fever recurring at a median IQR of 10 days. At the time of writing, the mortality rate from COVID-19 in Singapore was 0.09% [36]. 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. Would you like email updates of new search results? Fever of unknown origin is more often an atypical presentation of a common disease rather than an unusual disease. Available at: Wang D, Hu B, Hu C, et al. However, there were no significant differences in the admission laboratory values between the control and saddleback fever groups. 2021 Jan-Feb;50(1):28-32. doi: 10.1016/j.hrtlng.2020.10.013. Clinical and laboratory predictive markers for acute dengue infection. 2022 Oct 31;12:1009894. doi: 10.3389/fcimb.2022.1009894. Khalaf M, Alboraie M, Abdel-Gawad M, Abdelmalek M, Abu-Elfatth A, Abdelhamed W, Zaghloul M, ElDeeb R, Abdeltwab D, Abdelghani M, El-Raey F, Aboalam H, Badry A, Tharwat M, Afify S, Elwazzan D, Abdelmohsen AS, Fathy H, Wagih Shaltout S, Hetta HF, Bazeed SE. Cases without prolonged or saddleback fever were included as controls. A, Heatmap showing the relative concentration of cytokines across patients with different fever patterns. 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. Concentrations of 45 immune mediators in plasma were quantified using a 45-plex microbead-based immunoassay. 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. Treatment. However, there was a proportion of patients from our hospital who displayed 2 patterns of fever: 1 group had fever persisting into the second week of illness, while the second group displayed a saddleback pattern of fever, similar to that previously observed in dengue [11]. This corresponded with a rise in CRP and LDH seen in cases with prolonged fever, which are known to be associated with adverse prognostic factors in COVID-19 [15, 16]. Please enable it to take advantage of the complete set of features! CONCLUSIONS: Prolonged fever beyond 7 days from onset of illness can identify patients who may be at risk of adverse outcomes from COVID-19. Epub 2022 Aug 27. 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. P.Y.C. A fever is a rise in body temperature. 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. doi: 10.1371/journal.pntd.0004575. There was progression of infiltrates on the CXR for 72.2% (13/18) of cases with prolonged fever and 38.5% (5/13) in those with saddleback fever. Plasma immune mediator levels in COVID-19 patients experiencing different fever patterns. Differences Between Prolonged Fever and Nonprolonged Fever Groups. Antibiotics usually aren't prescribed just because a child has a fever that is lasting a long time. We also excluded 4 patients whose fever pattern did not fulfill the case definition for prolonged or saddleback fever. Unmasking latent extrapulmonary tuberculosis with newly diagnosed HIV-1 infection in a COVID-19 patient with prolonged fever. The fever itself is generally harmless and probably helpful. See permissionsforcopyrightquestions and/or permission requests. Copyright 2023 MIMS Pte Ltd. All rights reserved. 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. Clipboard, Search History, and several other advanced features are temporarily unavailable. Risk Factors Associated With Mortality Among Patients With COVID-19 in Intensive Care Units in Lombardy, Italy. Rowe EK, Leo Y-S, Wong JGX, Thein T-L, Gan VC, Lee LK, et al. Author disclosure: No relevant financial affiliations. The .gov means its official. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide, This PDF is available to Subscribers Only. 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, explained Ng and co-authors. The results of this study can be used to optimize placement of patients with COVID-19. Infections predominate early in FUO diagnoses, and the longer FUO remains undiagnosed, the less likely it is caused by an infection.27 After infections, the etiology of FUO transitions to noninfectious inflammatory diseases and malignancies, which can guide subsequent testing. Treatment of fever in adults usually involves ibuprofen, acetaminophen, or aspirin. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BP, blood pressure; CRP, C-reactive protein; LDH, lactate dehydrogenase. 2016 Dec 9;11(12):e0167025. Ministry of Health Singapore. Note that serologic tests are helpful only if there are potentially diagnostic clues and if the patient lives in or has visited an area where the suspected disease is prevalent.15, Chest, abdominal, or pelvic computed tomography (CT) may be useful in the secondary evaluation. Erythrocyte sedimentation rate and C-reactive protein levels should be measured in the initial workup of a patient who has prolonged febrile illness without a clear source. Moreover, cases with prolonged fever also showed significantly higher plasma levels of inflammatory biomarkers such as interleukin (IL)-6 (p<0.01), IL-1RA (p<0.05), and induced protein-10 (IP-10; p<0.001) compared with controls during the early acute disease phase. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China, Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China, Clinical characteristics of coronavirus disease 2019 in China, Epidemiologic features and clinical course of patients infected with SARS-CoV-2 in Singapore, Clinical features and dynamics of viral load in imported and non-imported patients with COVID-19, Singapore 2019 Novel Coronavirus Outbreak Research Team, Investigation of three clusters of COVID-19 in Singapore: implications for surveillance and response measures, Clinical and epidemiological features of 36 children with coronavirus disease 2019 (COVID-19) in Zhejiang, China: an observational cohort study, Pre-exposure prophylaxis to prevent the acquisition of HIV-1 infection (PROUD): effectiveness results from the pilot phase of a pragmatic open-label randomised trial, The pathogenesis and treatment of the cytokine storm in COVID-19, De-isolating COVID-19 suspect cases: a continuing challenge, Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China, Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China, Magnitude and prevention of nosocomial infections in the intensive care unit, Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China, Analysis of clinical features of 29 patients with 2019 novel coronavirus pneumonia, Plasma IP-10 and MCP-3 levels are highly associated with disease severity and predict the progression of COVID-19, Exuberant elevation of IP-10, MCP-3 and IL-1ra during SARS-CoV-2 infection is associated with disease severity and fatal outcome, Interleukin-1 receptor antagonist: role in biology, Biologic activities of IL-1 and its role in human disease, Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study, IL-21 is required to control chronic viral infection, Interferon--induced protein 10 in dengue virus infection, Cytokine and chemokine levels in patients with severe fever with thrombocytopenia syndrome virus, The regulation of seventeen inflammatory mediators are associated with patient outcomes in severe fever with thrombocytopenia syndrome, Overview of the IL-1 family in innate inflammation and acquired immunity, IL-1 and IL-1 recruit different myeloid cells and promote different stages of sterile inflammation, Blocking the interleukin-1 receptor inhibits leukotriene B4 and prostaglandin E2 generation in human monocyte cultures, A dynamic immune response shapes COVID-19 progression, Centers for Disease Control and Prevention. 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). This phenomenon is also observed in other viral fevers, like dengue virus [27] and thrombocytopenia syndrome virus [28, 29], where patients with more severe illness have higher serum levels of IP-10. . Prolonged fever beyond 7 days from onset of illness can identify patients who may be at risk of adverse outcomes from COVID-19. A Two-Year Review on Epidemiology and Clinical Characteristics of Dengue Deaths in Malaysia, 2013-2014. FOIA 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. All Rights Reserved. However, unlike RA, rheumatic . eCollection 2022. . doi: 10.1093/ofid/ofx133. These patients required prolonged periods of observation and symptomatic treatment. In this study, we aim to examine the characteristics of patients who developed these patterns of fever and their correlation to cytokine levels, as well as the association with adverse outcomes in COVID-19. Accessibility -. Ahmed S, Mohammad WW, Hamid F, Akhter A, Afzal RK, Mahmood A. J Coll Physicians Surg Pak. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). 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]. Although DHF and SD were more likely to occur in patients in those with saddleback fever, DSS was not. Although there are more than 200 diseases in the differential diagnosis, most cases in adults are limited to several dozen possible causes. The Author(s) 2020. Coronavirus disease 2019 (COVID-19) situation report101.2020. Fever was defined as a temperature of 38.0C. But normal body temperature can range between 97 F (36.1 C) and 99 F (37.2 C) or more. 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. The https:// ensures that you are connecting to the Methods: Pung R, Chiew CJ, Young BE, et al. Unauthorized use of these marks is strictly prohibited. Epub 2020 Oct 21. Repeat CXR was not performed for cases in the control group and 1 case of saddleback fever. A comprehensive history and physical examination should be performed if there are no localizing signs and symptoms in patients with prolonged febrile illness. -, Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW, Moyes CL, et al. Fever was defined as a temperature of 38.0C or higher. Bethesda, MD 20894, Web Policies and transmitted securely. Influenza (flu) and the common cold are both contagious respiratory illnesses, but they are caused by different viruses. 2013 Jul;23(7):463-7. 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). 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 duration was longer in patients 6 to 12 months old and 12 to 18 . Cases with prolonged fever were defined as patients with fever lasting >7 days. Patient samples that are not detectable are presented as the value of logarithm transformation of limit of quantification (LOQ), indicated by the blue dotted line. eCollection 2017 Summer. . Effects of sericin and egg white on the inflammation of damaged skin in mice. government site. All efforts have been undertaken to anonymize the data. eCollection 2022. Patients with prolonged fever may have had higher levels of IL-1 earlier on before sample collection. The 18F fluorodeoxyglucose has better uptake and is cleared more rapidly than older modalities (e.g., gallium Ga 67 citrate), but it is costly and not widely available.14, Liver, lymph node, or temporal artery biopsy may help establish a definitive diagnosis.3,19 A prospective study of 192 patients found that biopsies produced up to a 35% diagnostic yield (about 10% to 35%), especially if performed later in the evaluation when infection is less likely, and malignancies and noninfectious inflammatory diseases are more common.2 Liver biopsy, with a diagnostic yield between 14% and 17%,5,19 can reveal granulomatous hepatitis and determine its cause, which could be infectious, inflammatory, or neoplastic processes.22,27 Lymph node biopsy is most useful in diagnosing lymphoma, infectious diseases, and granulomatous diseases.19,27 In patients 55 years or older, temporal arteritis causes more than 15% of cases of FUO, so biopsy should be considered.5,15,18, Bone marrow biopsy is diagnostically useful, particularly with neoplasm and infectious disease, especially tuberculosis.19,27 One study of 280 hospitalized febrile patients found that bone marrow biopsy was helpful in reaching a diagnosis in nearly 25% of the 130 patients who underwent biopsy.41 Conversely, bone marrow aspiration and culture have a diagnostic yield of only 0% to 2%.3,5,15,22,41. Coronavirus disease 2019 (COVID-19) situation report101. Comparing the difference between prolonged fever cases and saddleback fever cases, we found an increased IL-1 level and lower IP-10 level on admission. Your comment will be reviewed and published at the journal's discretion. This study aims to examine the prevalence of prolonged and saddleback fever in dengue as well as their associations with dengue severity. However, as the number of patients with prolonged fever requiring ICU admission is small in this cohort, further studies should be done to prove this correlation. Interim guidance for implementing home care of people not requiring hospitalization for coronavirus disease 2019 (COVID-19). 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. 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. Can identify patients who may be at risk of adverse outcomes from COVID-19 PubMed logo registered... An argument on the equitable distribution of the complete set of features efforts have been undertaken anonymize. Examine the prevalence of prolonged and saddleback fever cases, we found an IL-1! Mediators in plasma were quantified using a 45-plex microbead-based immunoassay in COVID-19 patients experiencing different fever patterns (. A fever that is lasting a long time the relative concentration of cytokines across patients prolonged., Khan YH, Jummaat F. BMC Infect Dis can range between 97 F ( 36.1 C ) or.... Prolonged and saddleback fever, DSS was not the common cold are both respiratory! As their associations with dengue severity and physical examination should be performed if there are more than 200 diseases the... 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