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. Similar fever patterns are observed in COVID-19 with unclear significance. Affiliations, Plasma immune mediator levels in COVID-19 patients experiencing different fever patterns. These patients required prolonged periods of observation and symptomatic treatment. Patients with saddleback fever appeared to have good outcomes regardless of the fever. A lower IP-10 level is consistent with the finding that saddleback fever cases tend to have better clinical outcomes than prolonged fever cases. 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. eCollection 2016. Author disclosure: No relevant financial affiliations. 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. 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. Effects of sericin and egg white on the inflammation of damaged skin in mice. Saddleback fever was significantly associated with hypoxia (14.3% vs 0.9%; P=.03) but not ICU admission (0.9% vs 0.0 %; P=1.00) compared with those in the control group. Statistical analyses were performed using GraphPad Prism, version 8. 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 and SD but not DSS. J Clin Med Res. Department of Infectious Diseases, Tan Tock Seng Hospital, Correspondence: Deborah H. L. Ng, MBChB, MRCP(UK), MSc, MPH, Department of Infectious Diseases, Centre for Healthcare Innovation, 18 Jalan Tan Tock Seng, Singapore 308443 (. 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] . Would you like email updates of new search results? This content is owned by the AAFP. Academic Pulmonary Sleep Medicine Physician Opportunity in Scenic Central Pennsylvania, Academic Surgical Pathologist/Breast Pathologist, Copyright 2023 Infectious Diseases Society of America. bOnly 1 sample of paired values available. doi: 10.1371/journal.pntd.0002412. 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. Careers. Accessibility 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. . Data Sources: A PubMed search was completed using the key terms fever of unknown origin, FUO, pyrexia of unknown origin, and inflammatory markers. Clinicians should perform a comprehensive history and examination to look for potentially diagnostic clues to guide the initial evaluation. 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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. Woon YL, Hor CP, Hussin N, Zakaria A, Goh PP, Cheah WK. 2016 Dec 9;11(12):e0167025. eCollection 2022. Recommendations of the Scientific Working Group on Dengue. A fever is a rise in your body temperature. but the rest of the symptoms did not have a difference between the 2 serotypes. Cases who were already on supplemental oxygen or were already in the ICU at the time of satisfying criteria for prolonged or saddleback fever were excluded from the analysis. 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. PLoS Negl Trop Dis. Your body temperature can vary depending . Financial support. Cases with prolonged fever were also more likely to require ICU admission compared with controls (11.1% vs 0.9%; P = .05). 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. Since its first report in Wuhan, China, in December 2019, COVID-19 has rapidly spread, becoming a pandemic with more than 3 million confirmed cases [1]. Clipboard, Search History, and several other advanced features are temporarily unavailable. A standardized template was used for recording daily signs and symptoms, vital signs, and management. Figure 1 outlines a diagnostic approach to patients with prolonged febrile illness and FUO.1,2,47,1520,23,27, Hospitalization may be considered at any time during the evaluation, especially if the patient exhibits signs of a critical illness. Copyright 2023 MIMS Pte Ltd. All rights reserved. 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). Both prolonged (27.8% vs 0.9%; P<.01) and saddleback fever (14.3% vs 0.9%; P=.03) were associated with hypoxia compared with controls. 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. 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 . Laboratory Results for Prolonged and Saddleback Fever. A total of 142 patients were included in the study; 12.7% (18/142) of cases had prolonged fever, and 9.9% (14/142) had saddleback fever. While it has been reported that complications of COVID-19 occur in the second week of illness, the significance of these 2 patterns of fever with regards to the development of complications is unknown [4]. No overall differences in safety or effectiveness . 8600 Rockville Pike The levels of other immune mediators measured were not significantly different between groups. We conducted a hospital-based case-control 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). Duration of fever was prolonged with increased age. Would you like email updates of new search results? Home or community isolation facilities and the other iterations for positive cases are commonly used globally to isolate positive patients [34, 35]. Bethesda, MD 20894, Web Policies This circadian rhythm may differ among individuals but should be consistent in each person . History and physical examination alone are often sufficient to diagnose uncomplicated infectious causes of fever . Conti P, Panara MR, Barbacane RC, et al. Plasma fractions, MeSH Infect Drug Resist. eCollection 2016 May. Please enable it to take advantage of the complete set of features! Search life-sciences literature (41,164,937 (41,164,937 official website and that any information you provide is encrypted Clinico-laboratory spectrum of dengue viral infection and risk factors associated with dengue hemorrhagic fever: a retrospective study. RSV is a contagious illness that infects the respiratory tract and can lead to more severe infections like pneumonia or bronchiolitis. 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. is funded by the National Medical Research Council (NMRC/Fellowship/0056/2018). Cytokines were determined with multiplex microbead-based immunoassay for a subgroup of patients. None had symptoms of urinary tract infection, thrombophlebitis, or Clostridioidesdifficile diarrhea. Conclusions: Prolonged fever beyond 7 days from onset of illness can identify patients who may be at risk of adverse outcomes from COVID-19. COVID-19; cytokines; fever; prolonged; saddleback. 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. eCollection 2022. 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). In addition, IP-10 has also been reported to be associated with increased viral load, lung injury, ICU admission, and mortality [21]. FOIA Similar fever patterns are observed in COVID-19 with unclear significance. Search dates: November 28, 2011; February 8, 2012; and April 18, 2014. Published by Oxford University Press on behalf of Infectious Diseases Society of America. Prolonged fever in children: review of 100 cases. 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. Fever was defined as a temperature of 38.0C. 2017 Jun 22;4(3):ofx133. Nature. Treatment. The most common subgroups in the differential are infection, malignancy, noninfectious inflammatory diseases, and miscellaneous. Other illnesses and inflammation. Accessibility COVID-19 generally presents as an acute respiratory illness, with fever, fatigue, and dry cough being commonly reported symptoms [46]. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Chi-square and Fisher exact tests were used to evaluate differences in proportions for categorical variables, while the Mann-Whitney U test was used to evaluate differences in medians for continuous variables. -. Adverse outcomes were hypoxia, intensive care unit (ICU) admission, mechanical ventilation, and mortality. Results: government site. 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. FOIA Importantly, upregulation of the IL-1 pathway on monocytes can increase prostaglandin E2 expression and drive fever [32]. as they fulfilled overlapping criteria for prolonged and saddleback fever. aInvestigations were repeated at the point at which they satisfied criteria for prolonged or saddleback fever. 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. 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. Although there were no significant differences in white blood cell counts or absolute values of lymphocytes and CRP, we found significant differences in plasma IL-6 and IP-10 levels between the prolonged fever and control patients. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (. Immune mediator levels in Triton X-100 (1%; Sigma Aldrich) inactivated plasma from a subset of patients in all 3 groups were measured using Cytokine/Chemokine/Growth Factor 45-plex Human ProcartaPlex Panel 1 (ThermoFisher Scientific), in accordance with the manufacturers instructions. 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]. The higher levels of IL-1 could initiate the first occurrence of fever, while the pro-inflammatory cytokines IL-21 and IL-22 mediate the activation of T cells and M1 macrophages [25, 26], which drive the recurrence of fever in saddleback fever cases. A lower IP-10 level is consistent with the finding that saddleback fever cases tend to have better clinical outcomes than prolonged fever cases. Viruses, bacteria, fungi, and parasites can cause infections. 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. Like RA, rheumatic fever affects the joints. Meanwhile, the levels of IP-10 in patients with saddleback fever was lower than those with prolonged fever (p<0.001) at a level almost matching that in controls. 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. The variance between the highest and lowest core temperature in a given day is usually no more than 1 to 1.5C. IL-1 is a pyrogenic cytokine that plays a central role in inflammatory diseases like arthralgia [23]. Fever was defined as a temperature of 38.0C or higher. Blue and red represent low and high concentrations, respectively. A more recent article on fever of unknown origin in adults is available. Additional searches included the Cochrane database, Essential Evidence Plus, the Agency for Healthcare Research and Quality evidence reports, and the National Guideline Clearinghouse. National Library of Medicine This site needs JavaScript to work properly. Saddleback fever was present in 165 (5.8%). 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. In patients with saddleback fever, higher levels of IL-1, IL-21, IL-22, and SDF-1 were observed compared with control patients. For most people, a temperature of 98.6 F or 37 C is baseline. 2021 Nov 5;114(8):541-542. doi: 10.1093/qjmed/hcab138. The author(s) received no specific funding for this work. A, Heatmap showing the relative concentration of cytokines across patients with different fever patterns. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide, This PDF is available to Subscribers Only. 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. Both prolonged fever and saddleback fever were not significantly associated with mechanical ventilation as compared with the control group (Table 1). To our knowledge, this is the first study to examine the association between the patterns of fever and outcomes in COVID-19. Prolonged fever is associated with adverse outcomes in dengue viral infection. 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. Pediatrics 1975; 55:468. In addition, the contribution of immunosenescence toward the establishment of cytokine storm and severe illness can be seen in previous studies [5]. Repeat CXR was not performed for cases in the control group and 1 case of saddleback fever. Additional references were identified from the articles reviewed. Prolonged fever was defined as fever lasting more than 7 days. Dengue fever is an acute febrile illness with a duration of 2-12 days. Unable to load your collection due to an error, Unable to load your delegates due to an error, Collaborators, Your child may also develop swollen lymph nodes in the neck. IL-1RA is naturally secreted by human hosts to limit the activity of IL-1 during hyperinflammation [22]. . Data were collected for the remaining 110 patients from this cohort as controls; 57.0% (81/142) of all study subjects were male, and the median age (interquartile range [IQR]) was 42 (3154) years. 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]. Seven more confirmed cases of novel coronavirus infection in Singapore. [The] lower IP-10 level [with saddleback fever] is consistent with the finding that saddleback fever cases tend to have better clinical outcomes than prolonged fever cases, they noted. Fever of unknown origin has been described as a febrile illness (temperature of 101F [38.3C] or higher) for three weeks or longer without an etiology despite a one-week inpatient evaluation. 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. Physicians may consider stopping antimicrobials if all investigations are unyielding and patients remain hemodynamically stable. eCollection 2022 Jul. 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