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. Trials. 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. Additional searches included the Cochrane database, Essential Evidence Plus, the Agency for Healthcare Research and Quality evidence reports, and the National Guideline Clearinghouse. Cytokines were determined with multiplex microbead-based immunoassay for a subgroup of patients. Cases without prolonged or saddleback fever were included as controls. However, unlike RA, rheumatic . 2022 Oct 31;12:1009894. doi: 10.3389/fcimb.2022.1009894. Statistical data analysis on the types of fevers The fever itself is generally harmless and probably helpful. Testing for antinuclear antibodies, rheumatoid factor, human immunodeficiency virus, Epstein-Barr virus, cytomegalovirus, purified protein derivative (or interferon-gamma release assay), and antineutrophil cytoplasmic antibodies, as well as measurement of the creatine kinase level, can suggest other infectious sources and common noninfectious inflammatory disease etiologies, such as systemic lupus erythematosus, rheumatoid arthritis, and vasculitides. No overall differences in safety or effectiveness . Duration of fever was prolonged with increased age. Because there are no guidelines to the approach of the febrile patient, most evaluation recommendations are based on expert opinion.17 On initial presentation, most clinicians perform a history and physical examination in pursuit of an infection. Confirmed imported case of novel coronavirus infection in Singapore; multi-ministry taskforce ramps up precautionary measures.2020. Bookshelf Those with prolonged fever had a median duration of fever (interquartile range [IQR]) of 10 (911) days for prolonged fever cases, while fever recurred at a median (IQR) of 10 (812) days for those with saddleback fever. Would you like email updates of new search results? The 2011 dengue haemorrhagic fever outbreak in Lahore - an account of clinical parameters and pattern of haemorrhagic complications. The median age was 34 years of age (5 th - 95 th percentile: 17-59) and males comprised 1971 (69.3%) of study sub- See permissionsforcopyrightquestions and/or permission requests. 2013 Oct 20;20(1):75. doi: 10.1186/1423-0127-20-75. Heart Lung. Home or community isolation facilities and the other iterations for positive cases are commonly used globally to isolate positive patients [34, 35]. but the rest of the symptoms did not have a difference between the 2 serotypes. But there are some important differences. Interestingly, there are also higher plasma levels of IL-1RA in patients with prolonged fever compared with control patients. Flu is caused by influenza viruses only, whereas the common cold can be caused by a number of different viruses, including rhinoviruses, parainfluenza, and seasonal coronaviruses. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. Please check for further notifications by email. Effects of sericin and egg white on the inflammation of damaged skin in mice. Fever was defined as a temperature of 38.0C. Roseola symptoms might include: Fever. Confirmed imported case of novel coronavirus infection in Singapore; multi-ministry taskforce ramps up precautionary measures. The presence of prolonged or saddleback fever in dengue patients should therefore prompt detailed evaluation for complications of dengue, as well as early investigation to evaluate for development of nosocomial infection. In contrast, cases with saddleback fever showed no significant change upon repeating their laboratory tests. The 4 cases who were excluded from the primary analysis demonstrated a saddleback pattern of fever that lasted >24 hours. 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. J Clin Med Res. eCollection 2022 Jul. An official website of the United States government. Risk Factors Associated With Mortality Among Patients With COVID-19 in Intensive Care Units in Lombardy, Italy. Hypoxia was defined as requirement for supplemental oxygen. A prolonged fever of unknown origin (FUO) is simply one that lasts longer than usual, for example, more than the seven to 10 days that you would expect with a simple viral infection. A total of 2843 polymerase-chain reaction (PCR) confirmed dengue patients admitted to Tan Tock Seng Hospital from 2004 to 2008 were included in the study. 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). Fever was defined as a temperature of 38.0C. 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 (. 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. Physicians may consider stopping antimicrobials if all investigations are unyielding and patients remain hemodynamically stable. Mallhi TH, Khan AH, Adnan AS, Sarriff A, Khan YH, Jummaat F. BMC Infect Dis. Ng DH, Wong JG, Thein TL, Leo YS, Lye DC. 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 analysis, which was. 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). Angela Chow Li Ping, Brenda Sze Peng Ang, Chen Seong Wong, Cheng Chuan Lee, Ding Ying, Jun-Yang Tay, Kalisvar Marimuthu, Lawrence Soon U. Lee, Yee-Sin Leo, Li Min Ling, Li Wei Ang, Lin Cui, Mark I-Cheng Chen, Monica Chan, Mucheli Sharavan Sadasiv, Oon-Tek Ng, Pei Hua Lee, Poh Lian Lim, Sapna Pradip Sadarangani, Shawn Vasoo, Stephanie Sutjipto, Tsin Wen Yeo, Tze Minn Mak. Although DHF and SD were more likely to occur in patients in those with saddleback fever, DSS was not. Depending on clinical clues, this may include liver, lymph node, temporal artery, or bone marrow biopsy. Search life-sciences literature (41,164,937 (41,164,937 2013 Jul;23(7):463-7. Thank you for submitting a comment on this article. 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. 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). While both prolonged and saddleback fever showed an association with hypoxia, only prolonged fever was associated with ICU admission. Your body temperature can vary depending . All efforts have been undertaken to anonymize the data. Careers. 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. Geneva: World Health Organization, Special Programme for Research and Training in Tropical Diseases, Geneva: 2000. World Health Organisation Special Programme for Research and Training in Tropical Diseases. 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. 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). Before Prolonged fever was defined as fever lasting more than 7 days. Woon YL, Hor CP, Hussin N, Zakaria A, Goh PP, Cheah WK. The .gov means its official. doi: 10.9778/cmajo.20200250. Teleconferencing is often used to monitor these cases for potential deterioration. doi: 10.1093/ofid/ofx133. A fever is a body temperature of 100.4 F or greater. sharing sensitive information, make sure youre on a federal 2014; 8: e2777 10.1371/journal.pntd.0002777 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. PLoS One. This study was funded by the National Medical Research Council COVID-19 Research Fund (COVID19RF-001) and Agency for Science, Technology and Research (A*STAR) COVID-19 Research funding (H/20/04/g1/006) provided to the Singapore Immunology Network by the Biomedical Research Council (BMRC), A*STAR. Symptoms of RSV include runny nose, cough, fever, and . The average body temperature is 98.6 F (37 C). The most common subgroups in the differential are infection, malignancy, noninfectious inflammatory diseases, and miscellaneous. PMC In multiple studies, procalcitonin has been shown to have a specificity ranging from 70% to 98%, with a higher specificity for bacterial infection than other markers.28,31,32 It may be helpful in distinguishing between fevers with a bacterial cause vs. noninfectious inflammatory diseases, but its role in the workup of FUO is currently undefined.28,32, If the diagnosis remains elusive, tests targeting malignancies and noninfectious inflammatory diseases should be considered. Dengue fever is an acute febrile illness with a duration of 2-12 days. The site is secure. 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. Nature. Our observational study observed the 24-h continuous tympanic temperature pattern of 15 patients with dengue fever and . Retrospective characterisation and outcome of surgical treatment for cervical lymph node abscessation in 15 dogs. In patients with saddleback fever, higher levels of IL-1, IL-21, IL-22, and SDF-1 were observed compared with control patients. The .gov means its official. Characteristics and outcomes of patients with COVID-19 admitted to hospital and intensive care in the first phase of the pandemic in Canada: a national cohort study. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conclusions: Prolonged fever beyond 7 days from onset of illness can identify patients who may be at risk of adverse outcomes from COVID-19. Ministry of Health Singapore. Young BE, Ong SWX, Kalimuddin S, et al. . A comprehensive history and physical examination should be performed if there are no localizing signs and symptoms in patients with prolonged febrile illness. 2022 Jul 26;2022(7):omac079. A fever is a rise in body temperature. At the time of writing, there were no supporting studies on the association between elevated levels of IL-21, IL-22, and SDF-1 and COVID-19. 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]. Outbreak Research Team members are listed in the Acknowledgments, Deborah H L Ng, Chiaw Yee Choy, Yi-Hao Chan, Barnaby E Young, Siew-Wai Fong, Lisa F P Ng, Laurent Renia, David C Lye, Po Ying Chia, National Centre for Infectious Diseases COVID-19 Outbreak Research Team, Fever Patterns, Cytokine Profiles, and Outcomes in COVID-19, Open Forum Infectious Diseases, Volume 7, Issue 9, September 2020, ofaa375, https://doi.org/10.1093/ofid/ofaa375. 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. Cytokines were determined with multiplex View PDF Save to Library 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. 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 . Copyright 2023 American Academy of Family Physicians. National Library of Medicine The results of this study can be used to optimize placement of patients with COVID-19. The variance between the highest and lowest core temperature in a given day is usually no more than 1 to 1.5C. A dysregulated immune response in COVID-19 has been postulated to lead a deleterious cytokine storm [12]. Outcomes of COVID-19 Among High-Risk Individuals: A Study Comparing Febrile and Afebrile Presentation. 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. 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. Outcomes of patients with COVID-19 in the intensive care unit in Mexico: A multicenter observational study. 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. 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. PLoS Negl Trop Dis 2012; 6(8): e1760 10.1371/journal.pntd.0001760 This can happen when your body is fighting an infection. 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. The authors have declared that no competing interests exist. In particular, fever was reported in about 72%98.6% of patients, usually lasting <7 days [4, 710]. Clinico-laboratory spectrum of dengue viral infection and risk factors associated with dengue hemorrhagic fever: a retrospective study. Available at: Ministry of Health (MOH) Singapore. eCollection 2017 Summer. The site is secure. ; Singapore 2019 Novel Coronavirus Outbreak Research Team. It's usually a sign of infection. Copyright 2023 MIMS Pte Ltd. All rights reserved. HHS Vulnerability Disclosure, Help Disclaimer. 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). 2021 Mar 8;9(1):E181-E188. Patients with prolonged fever had higher induced protein10 and lower interleukin-1 levels compared with those with saddleback fever at the early acute phase of disease. 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. . Demographic and comorbidity data, symptoms and signs, vital signs, and laboratory and radiology results were obtained from electronic medical records. Both prolonged fever and saddleback fever were not significantly associated with mechanical ventilation as compared with the control group (Table 1). RSV is a contagious illness that infects the respiratory tract and can lead to more severe infections like pneumonia or bronchiolitis. In conclusion, we reported on the prevalence, risk factors, cytokine profiles, and outcomes of patients with COVID-19 who had saddleback or prolonged fever. 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. Open Forum Infect Dis. https://www.who.int/docs/default-source/coronaviruse/situation-reports/2 https://www.moh.gov.sg/news-highlights/details/confirmed-imported-case-o https://www.moh.gov.sg/news-highlights/details/seven-more-confirmed-case World Health Organization. Notably, patients with prolonged fever had higher IP-10 and lower IL-1 levels as compared with patients with saddleback fever (Figure 1B). 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. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide, This PDF is available to Subscribers Only. The mean duration of symptoms and signs before diagnosis (28.4 13.2 versus 45.0 30.8 days; P < 0.05), . Statistical analyses were performed using Stata, version 14 (StataCorp, College Station, TX, USA). The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). -, Huang C, Wang Y, Li X, et al. 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. 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. A larger cohort might help to improve our understanding of these patients. To our knowledge, this is the first study to examine the association between the patterns of fever and outcomes in COVID-19. Background: 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. 2017 Jun 22;4(3):ofx133. Clipboard, Search History, and several other advanced features are temporarily unavailable. A deleterious cytokine storm [ 12 ] and patients remain hemodynamically stable 12 ] Disclosure of conflicts. And miscellaneous haemorrhagic fever outbreak in Lahore - an account of clinical parameters and pattern of 15 patients COVID-19! In those with saddleback fever were not significantly associated with Mortality Among patients with saddleback fever ( 1B... Fever is an acute febrile illness outcome of surgical treatment for cervical lymph abscessation. 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