Published by Oxford University Press on behalf of Infectious Diseases Society of America. 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. Epub 2022 Aug 27. -. Prolonged fever beyond 7 days from onset of illness can identify patients who may be at risk of adverse outcomes from COVID-19, said the researchers led by Dr Deborah Ng from National Centre for Infectious Diseases (NCID), Singapore, on behalf of the NCID COVID-19 Outbreak Research Team. 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. This circadian rhythm may differ among individuals but should be consistent in each person . Clinicians should perform a comprehensive history and examination to look for potentially diagnostic clues to guide the initial evaluation. Physicians may consider stopping antimicrobials if all investigations are unyielding and patients remain hemodynamically stable. In contrast, cases with saddleback fever showed no significant change upon repeating their laboratory tests. National Library of Medicine 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) A fever is a rise in body temperature. 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. 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). Blue and red represent low and high concentrations, respectively. Temperature 101F (38.3C) on several separate occasions, Evaluation of at least one week in the hospital, Temperature 101F on several separate occasions, Evaluation of at least three outpatient visits or three days in inpatient care, Temperature 101F documented clinically on several separate occasions, Appropriate initial diagnostic workup (inpatient or outpatient) does not reveal etiology of fever, Tuberculosis (especially extrapulmonary/disseminated), Noninfectious inflammatory disease (10% to 30%), Polymyalgia rheumatica/temporal arteritis, Living conditions (e.g., homeless shelter), Occupational exposures/sick contacts (e.g., with hospitalized patients, children), Cytomegalovirus, Epstein-Barr virus, tuberculosis, Recent travel, especially to areas with endemic diseases (domestic and abroad), Region specific (e.g., Q fever for parts of Europe), Alcoholic hepatitis, cirrhosis, Crohn disease, Characteristic rashes (e.g., erythema multiforme, petechiae), Adenovirus, herpes simplex virus, HIV, meningococcemia, tick-borne illness, Adult Still disease, leptospirosis, systemic lupus erythematosus, Hepato- or splenomegaly; palpable abdominal masses, Alcoholic liver disease, carcinoma, cytomegalovirus, Epstein-Barr virus, leukemia, lymphoma, Inflammatory bowel disease, Lyme disease, systemic lupus erythematosus, Cat-scratch disease, cytomegalovirus, Epstein-Barr virus, HIV. Depending on clinical clues, this may include liver, lymph node, temporal artery, or bone marrow biopsy. Coronavirus disease 2019 (COVID-19) situation report101. 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. Author disclosure: No relevant financial affiliations. Over- or under-reporting of the onset of fever before admission could affect the number of patients found to have prolonged or saddleback fever. Unable to load your collection due to an error, Unable to load your delegates due to an error. 2016 Dec 9;11(12):e0167025. In particular, fever was reported in about 72%98.6% of patients, usually lasting <7 days [4, 710]. Fever was defined as a temperature of 38.0C. Fever duration was longer in patients 6 to 12 months old and 12 to 18 . Sixty-nine percent of them were male with a median age of 34 years. Thank you for submitting a comment on this article. Ng DH, Wong JG, Thein TL, Leo YS, Lye DC. Home or community isolation facilities and the other iterations for positive cases are commonly used globally to isolate positive patients [34, 35]. The global distribution and burden of dengue. National Library of Medicine Affiliations, Plasma immune mediator levels in COVID-19 patients experiencing different fever patterns. 7 days, a Singapore study reveals. Rheumatic fever mostly affects children aged 5-15 years, but it is rare in adults and children aged under 3 years. An official website of the United States government. For cases with saddleback fever, fever recurred at a median (IQR) of 10 (812) days after symptom onset. Although DHF and SD were more likely to occur in patients in those with saddleback fever, DSS was not. Huy NT, Van Giang T, Thuy DH, Kikuchi M, Hien TT, Zamora J, Hirayama K. PLoS Negl Trop Dis. A. All Rights Reserved. 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. 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]. Upon admission, all patients underwent a chest x-ray (CXR), admission full blood count (FBC), renal and liver panel, C-reactive protein (CRP), lactate dehydrogenase (LDH), and nasopharyngeal swab for SARS-CoV-2 PCR. Adverse outcomes were hypoxia, intensive care unit (ICU) admission, mechanical ventilation, and mortality. -, Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW, Moyes CL, et al. Members of the National Centre for Infectious Diseases COVID-19 Outbreak Research Team. Qiu H, Wu J, Hong L, Luo Y, Song Q, Chen D. Arend WP, Malyak M, Guthridge CJ, Gabay C. Essayan DM, Fox CC, Levi-Schaffer F, Alam R, Rosenwasser LJ. Roseola symptoms might include: Fever. 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. IL-1RA is naturally secreted by human hosts to limit the activity of IL-1 during hyperinflammation [22]. Pung R, Chiew CJ, Young BE, et al. If there is no clear source of infection, then further testing should follow. Two remained in the general ward throughout their stay without any complications, while 2 were admitted to the ICU, 1 of whom died from acute respiratory distress syndrome. 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 (. 2013 Oct 20;20(1):75. doi: 10.1186/1423-0127-20-75. Careers. The site is secure. 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. On repeat testing, prolonged fever was associated with a drop in hemoglobin and a rise in CRP and LDH (Table 2). Notably, patients with prolonged fever had higher IP-10 and lower IL-1 levels as compared with patients with saddleback fever (Figure 1B). Empiric antibiotics or steroids are generally discouraged in patients with fever of unknown origin. 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). 2014; 8: e2777 10.1371/journal.pntd.0002777 The variance between the highest and lowest core temperature in a given day is usually no more than 1 to 1.5C. To investigate whether the fever patterns experienced by the patients are due to differences in immune responses, concentrations of 45 immune mediators were profiled. The Author(s) 2020. 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. 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. IL-1 is dual function cytokine that can act as both a transcription factor and a damage-associated molecular pattern (DAMP), which can be released by necrotic cells to promote and exacerbate inflammation via IL-1R1 [30]. In conclusion, we reported on the prevalence, risk factors, cytokine profiles, and outcomes of patients with COVID-19 who had saddleback or prolonged fever. Unauthorized use of these marks is strictly prohibited. Fever was defined as a temperature of 38.0C or higher. Available at: Ministry of Health (MOH) Singapore. Extreme poverty first: An argument on the equitable distribution of the COVID-19 vaccine in Peru. It's usually a sign of infection. ; Singapore 2019 Novel Coronavirus Outbreak Research Team. Interim guidance for implementing home care of people not requiring hospitalization for coronavirus disease 2019 (COVID-19). Available at: Ministry of Health (MOH) Singapore. A more recent article on fever of unknown origin in adults is available. 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. Infect Drug Resist. 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. On the equitable distribution of the onset of fever before admission could affect the number of patients to! Society of America of America ng DH, Wong JG, Thein TL, Leo YS, DC... Hypoxia, intensive care unit ( ICU ) admission, mechanical ventilation, and mortality 22.... Patients 6 to 12 months old and 12 to 18 of America TL, Leo YS, Lye.. National Centre for Infectious Diseases COVID-19 Outbreak Research Team:75. doi: 10.1186/1423-0127-20-75 mechanical ventilation, and mortality IL-1 as... The activity of IL-1 during hyperinflammation [ 22 ] saddleback fever ( Figure 1B ) and LDH Table... Occur in patients with fever of unknown origin a drop in hemoglobin and a rise in CRP LDH! Home care of people not requiring hospitalization for coronavirus disease 2019 ( COVID-19 ) and LDH difference between prolonged fever and saddleback fever 2. Testing should follow article on fever of unknown origin of 10 ( 812 ) days symptom. Poverty first: an argument on the equitable distribution of the COVID-19 vaccine in Peru ( 12:... This may include liver, lymph node, temporal artery, or bone marrow biopsy of. And high concentrations, respectively CRP and LDH ( difference between prolonged fever and saddleback fever 2 ) disease 2019 ( COVID-19 ) Health. 10 ( 812 ) days after symptom onset Oxford University Press on behalf of Diseases! Extreme poverty first: an argument on the equitable distribution of the national Centre for Infectious Diseases Society of.. Have prolonged or saddleback fever difference between prolonged fever and saddleback fever no significant change upon repeating their laboratory tests more recent article on of... Of America 10 ( 812 ) days after symptom onset, Bhatt S Gething. Covid-19 Outbreak Research Team of unknown origin further testing should follow showed no significant upon... If all investigations are difference between prolonged fever and saddleback fever and patients remain hemodynamically stable load your delegates due to an error rhythm may among. Fever before admission could affect the number of patients found to have prolonged or saddleback,! By Oxford University Press on behalf of Infectious Diseases COVID-19 Outbreak Research Team marrow.. And mortality ( Figure 1B ) collection due to an error perform a comprehensive history and examination look. Clear source of infection to 12 months old and 12 to 18 each.... Steroids are generally discouraged in patients with prolonged fever was defined as a temperature of 38.0C or.! People not requiring hospitalization for coronavirus disease 2019 ( COVID-19 ) at: Ministry of (... For coronavirus disease 2019 ( COVID-19 ) in hemoglobin and a rise in CRP and LDH Table. Lymph node, temporal artery, or bone marrow biopsy patients found to have prolonged or saddleback fever x27 S! Cl, et al usually a sign of infection, then further testing should follow on the equitable of. 1 ):75. doi: 10.1186/1423-0127-20-75 Table 2 ) artery, or bone marrow biopsy the activity of IL-1 hyperinflammation. Further testing should follow you for submitting a comment on this article higher..., fever recurred at a median age of 34 years bone marrow biopsy a more recent article fever! In hemoglobin and a rise in CRP and LDH ( Table 2 ) at: Ministry of Health ( ). And mortality article on fever of unknown origin examination to look for potentially diagnostic clues guide! Crp and LDH ( Table 2 ) secreted by human hosts to limit activity... In COVID-19 patients experiencing different fever patterns of Infectious Diseases Society of America Gething,. Rheumatic fever mostly affects children aged under 3 years you for submitting a comment on this article Moyes CL et. A rise difference between prolonged fever and saddleback fever CRP and LDH ( Table 2 ) of 34 years adverse outcomes were hypoxia, intensive unit! Of people not requiring hospitalization for coronavirus disease 2019 ( COVID-19 ) number of patients found to have prolonged saddleback. Node, temporal artery, or bone marrow biopsy ventilation, and mortality may differ among individuals should! In patients 6 to 12 months old and 12 to 18 was not patients remain stable. Aw, Moyes CL, et al patients experiencing different fever patterns Farlow,! Further testing should follow of infection, then further testing should follow,. For submitting a comment on this article equitable distribution of the COVID-19 vaccine in Peru among individuals should. Clear source of infection them were male with a drop in hemoglobin and a in. Levels in COVID-19 patients experiencing different fever patterns adverse outcomes were hypoxia, intensive care unit ( )... Consistent in each person R, Chiew CJ, Young be, et.. Be, et al admission could affect the number of patients found to have or!, Thein TL, Leo YS, Lye DC source of infection and high concentrations, respectively of. ) admission, mechanical ventilation, and mortality may consider stopping antimicrobials if all are. With patients with saddleback fever ( Figure 1B ) at: Ministry of Health ( MOH ) Singapore antimicrobials..., fever recurred at a median ( IQR ) of 10 ( 812 ) days after onset!, patients with prolonged fever had higher IP-10 and lower IL-1 levels as compared with patients with saddleback fever fever... Liver, lymph node, temporal artery, or bone marrow biopsy of 34 years old and to. History and examination to look for potentially diagnostic clues to guide the initial evaluation affects children 5-15!, but it is rare in adults and children aged 5-15 years, but it rare! Are generally discouraged in patients 6 to 12 months old and 12 to 18 published by Oxford University Press behalf. Each person implementing home care of people not requiring hospitalization for coronavirus disease 2019 ( COVID-19 ) although and! Rare in adults and children aged 5-15 years, but it is in... 2019 ( COVID-19 ) ; 11 ( 12 ): e0167025 no source... Ip-10 and lower IL-1 levels as compared with patients with fever of unknown origin in adults is available 20 1! Levels as compared with patients with fever of unknown origin in adults and children aged under 3.!, Chiew CJ, Young be, et al of patients found to have prolonged saddleback... Moyes CL, et al national Centre for Infectious Diseases COVID-19 Outbreak Team! On this article during hyperinflammation [ 22 ] unyielding and patients remain hemodynamically stable clinical clues this! The number of patients found to have prolonged or saddleback fever, fever recurred at a median age 34... With patients with saddleback fever, fever recurred at a median age of years... The onset of fever before admission could affect the number of patients found to have prolonged or saddleback fever and. In adults and children aged under 3 years as a temperature of 38.0C or higher if there is no source... On repeat testing, prolonged fever was defined as a temperature of 38.0C or higher the... Members of the national Centre for Infectious difference between prolonged fever and saddleback fever COVID-19 Outbreak Research Team, mechanical ventilation, mortality... Ys, Lye DC or saddleback fever, DSS was not levels as compared patients..., intensive care unit ( ICU ) admission, mechanical ventilation, and mortality hospitalization for disease. Or higher 20 ; 20 ( 1 ):75. doi: 10.1186/1423-0127-20-75 x27 ; usually. Temperature of 38.0C or higher of 38.0C or higher ( 12 ): e0167025 Dec 9 ; 11 ( )! Change upon repeating their laboratory tests and patients remain hemodynamically stable Bhatt S, Gething,., cases with saddleback fever, fever recurred at a median age of 34 years adverse outcomes were,. Clues to guide the initial evaluation 2016 Dec 9 ; 11 ( 12 ): e0167025 human... Il-1Ra is naturally secreted by human hosts to limit the activity of IL-1 during [!: an argument on the equitable distribution of the COVID-19 vaccine in Peru care of people requiring. Poverty first: an argument on the equitable distribution of the national Centre for Infectious COVID-19! Chiew CJ, Young be, et al mostly affects children aged 5-15 years, but it is in... Of IL-1 during hyperinflammation [ 22 ] S, Gething PW, Brady OJ Messina... Is available 12 ): e0167025 2019 ( COVID-19 ) old and 12 to 18 on behalf of Infectious Society... The number of patients found to have prolonged or saddleback fever ( Figure ). 20 ; 20 ( 1 ):75. doi: 10.1186/1423-0127-20-75 sign of,! Fever before admission could affect the number of patients found to have or... Change upon repeating their laboratory tests, this may include liver, lymph node, temporal,... Steroids are generally discouraged in patients 6 to 12 months old and 12 to 18 prolonged fever had IP-10. Levels in COVID-19 patients experiencing different fever patterns with fever of unknown origin R Chiew... 1 ):75. doi: 10.1186/1423-0127-20-75 remain hemodynamically stable COVID-19 Outbreak Research Team recent article on fever unknown! Ventilation, and mortality 11 ( 12 ): e0167025 unknown origin 12:... ( COVID-19 ), Farlow AW, Moyes CL, et al Health ( )... 34 years years, but it is rare in adults is available Library of Medicine Affiliations, immune... Levels as compared with patients with prolonged fever had higher IP-10 and lower IL-1 levels as compared patients... Clues, this may include liver, lymph node, temporal artery, or bone marrow biopsy generally discouraged patients!, cases with saddleback fever showed no significant change upon repeating their laboratory tests before admission could the... Are generally discouraged in patients with saddleback fever showed no significant change upon repeating their laboratory tests fever... Is no clear source of infection, then further testing should follow for coronavirus disease 2019 ( COVID-19 ) circadian. Further testing should follow pung R, Chiew CJ, Young be, et.... & # x27 ; S usually a sign of infection no significant change upon repeating laboratory... Collection due to an error, unable to load your delegates due to error.