Plasma immune mediator levels in COVID-19 patients experiencing different fever patterns. 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]. 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. Dengue hemorrhagic fever (DHF), dengue shock syndrome (DSS) and severe dengue (SD) were significantly more likely to occur in patients with prolonged fever. doi: 10.1371/journal.pntd.0004575. Young BE, Ong SWX, Kalimuddin S, et al. Fevers usually don't need treatment. Search for other works by this author on: Singapore Immunology Network, Agency for Science, Technology and Research, Department of Biological Sciences, National University of Singapore, National University of Singapore Graduate School for Integrative Sciences and Engineering, National University of Singapore, Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, National Centre for Infectious Diseases COVID-19 Outbreak Research Team. Accessibility . 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. Conclusions: The results of these microbiological investigations were also collected and analyzed. CMAJ Open. . Patients were categorized as having prolonged fever (lasting >7 days), saddleback fever (defined as recurrent fever which lasts for <24 hours, after defervescence beyond day 7 of illness), or controls if their fever was 7 days. The median age was 34 years of age (5 th - 95 th percentile: 17-59) and males comprised 1971 (69.3%) of study sub- 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. The 2011 dengue haemorrhagic fever outbreak in Lahore - an account of clinical parameters and pattern of haemorrhagic complications. Sixty-nine percent of them were male with a median age of 34 years. 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). The .gov means its official. eCollection 2017 Summer. Interim guidance for implementing home care of people not requiring hospitalization for coronavirus disease 2019 (COVID-19). COVID-19 and sinus infections share several symptoms like nasal congestion, fever, and coughing. 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. eCollection 2022 Jul. Methods 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). The Significance of Prolonged and Saddleback Fever in Hospitalised Adult Dengue. 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. National Library of Medicine 8600 Rockville Pike Our observational study observed the 24-h continuous tympanic temperature pattern of 15 patients with dengue fever and . 2022 Jul 26;2022(7):omac079. eCollection 2022. A, Heatmap showing the relative concentration of cytokines across patients with different fever patterns. In addition, as these patients with saddleback fever tend to do well, there is also no need for repeat laboratory testing or CXR, as the results are unlikely to change management or clinical outcomes. 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. Clipboard, Search History, and several other advanced features are temporarily unavailable. 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). A P value of<.05 indicated statistical significance. This apparent difference in IL-1 between prolonged fever cases and saddleback fever cases may have occurred due to dynamic immune response and the time point of sample collection. Ministry of Health Singapore. Plasma fractions, MeSH government site. 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 (. Demographic and comorbidity data, symptoms and signs, vital signs, and laboratory and radiology results were obtained from electronic medical records. Human immunodeficiency virus and appropriate region-specific serologic testing (e.g., cytomegalovirus, Epstein-Barr virus, tuberculosis) and abdominal and pelvic ultrasonography or computed tomography are commonly performed. In this study, saddleback fever was defined as temperature >37.5C with defervescence of at least one day, followed by a second peak lasting at least one day. Published by Oxford University Press on behalf of Infectious Diseases Society of America. 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. 2022 Oct 31;12:1009894. doi: 10.3389/fcimb.2022.1009894. Adverse outcomes were hypoxia, intensive care unit (ICU) admission, mechanical ventilation, and mortality. Patients who tested positive were not discharged until they had 2 negative PCR tests 24 hours apart [13]. A comprehensive history and physical examination should be performed if there are no localizing signs and symptoms in patients with prolonged febrile illness. Plasma immune mediator levels in COVID-19 patients experiencing different fever patterns. 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. 8600 Rockville Pike Over- or under-reporting of the onset of fever before admission could affect the number of patients found to have prolonged or saddleback fever. PLoS Negl Trop Dis 2012; 6(8): e1760 10.1371/journal.pntd.0001760 2015 Sep 30;15:399. doi: 10.1186/s12879-015-1141-3. 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. Comparisons between prolonged fever and nonprolonged fever group are summarized in Tables 1 and 2. Additional microbiological investigations, such as blood and urine cultures, influenza and respiratory viral multiplex PCR, dengue NS1 and serology, were ordered at the discretion of the primary treating clinician. 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., The hospital-based case-control study included 142 patients who were admitted to the NCID with COVID-19. In one study of patients with FUO, chest and abdominal CT had high sensitivity (82% and 92%, respectively) and were recommended if the initial evaluation was unrevealing.15 CT specificity ranged from 60% to 70%, consistent with other case series.15,16 Echocardiography is recommended if there are clinical indications of endocarditis.5,20 Venous Doppler ultrasonography is indicated for suspected thromboembolism.20 Magnetic resonance imaging of the aortic arch and great vessels of the neck was shown to be helpful when vasculitis was suspected.36, Nuclear imaging studies are noninvasive, image the whole body, and can localize a potential infectious or inflammatory cause for FUO.5,14,19,3740 Recently, 18F fluorodeoxyglucose positron emission tomography technology has been evaluated for guiding further invasive testing, especially in patients who have an elevated ESR or CRP level.14,37 The 18F fluorodeoxyglucose is taken up by inflammatory and cancer cells because of their high rate of glucolysis.14,18,37 Several studies examining this method in patients with FUO found diagnostic yields ranging from 16% to 69%,15,37,38 with a high positive predictive value (93%) and negative predictive value (100%).39,40 A hybrid of CT and 18F fluorodeoxyglucose positron emission tomography has a higher diagnostic yield (sensitivity of 56% to 100%; specificity of 75% to 81%18). Adverse outcomes were hypoxia, intensive care unit (ICU) admission, mechanical ventilation, and mortality. Am J Dis Child 1972; 124:544. Higher heart rate and respiratory rate and lower oxygen saturation (spO2), systolic and diastolic blood pressure (BP) were associated with prolonged fever compared with controls (Table 1). 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. Pediatrics 1975; 55:468. National Library of Medicine Repeat CXR was not performed for cases in the control group and 1 case of saddleback fever. Confirmed imported case of novel coronavirus infection in Singapore; multi-ministry taskforce ramps up precautionary measures. 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. Seven more confirmed cases of novel coronavirus infection in Singapore. Some children also may have a sore throat, runny nose or cough along with or before the fever. 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. 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. 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. Methods: 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. There were no deaths in our study. 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) Out-of-hospital cardiac arrest and in-hospital mortality among COVID-19 patients: A population-based retrospective cohort study. 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. 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]. 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. Cases with saddleback fever were defined as patients with recurrence of fever lasting <24 hours, after defervescence, beyond day 7 of illness. ELIZABETH C. HERSCH, COL, MC, USA, AND C. ROBERT, OH, LTC, MC, USA. Fever was defined as a temperature of 38.0C or higher. Treatment of fever in adults usually involves ibuprofen, acetaminophen, or aspirin. Untreated typhoid fever may progress to delirium, obtundation, intestinal hemorrhage, bowel. Effects of sericin and egg white on the inflammation of damaged skin in mice. A larger cohort might help to improve our understanding of these patients. McClung HJ. Laboratory Results for Prolonged and Saddleback Fever. Cases with prolonged fever were also more likely to require ICU admission compared with controls (11.1% vs 0.9%; P = .05). This circadian rhythm may differ among individuals but should be consistent in each person . Although prolonged and saddleback fever have been reported in dengue fever, there are no specific studies on their significance in dengue. In particular, fever was reported in about 72%98.6% of patients, usually lasting <7 days [4, 710]. Disclaimer. Prolonged fever of unknown origin: a record of experiences with 54 childhood patients. Unauthorized use of these marks is strictly prohibited. The fever itself is generally harmless and probably helpful. Fever of unknown origin (FUO) in adults is one of the most vexing clinical conditions for clinicians and patients. Affiliations, Plasma immune mediator levels in COVID-19 patients experiencing different fever patterns. Before 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. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (. Unauthorized use of these marks is strictly prohibited. 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 was defined as a temperature of 38.0C. The author(s) received no specific funding for this work. Cytokine and chemokine concentrations from an additional 23 healthy controls who did not have COVID-19 were also analyzed for baseline comparison. PLoS One. Bookshelf Two of these patients were admitted to the ICU, which may suggest another phenotype of patients who are at higher risk of adverse outcomes. 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. Normal body temperature can vary depending on the individual, the time of day, and even the weather. If the diagnosis remains elusive, 18F fluorodeoxyglucose positron emission tomography plus computed tomography may help guide the clinician toward tissue biopsy. 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. All authors: no reported conflicts of interest. 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. This corroborated well with our findings of increased hypoxia in patients with prolonged fever. In addition, IP-10 has also been reported to be associated with increased viral load, lung injury, ICU admission, and mortality [21]. 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. 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. 2013; 496: 504507. 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 . 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). Disclaimer. 40-year-old woman fever rash arthralgia Dx? When there are no clear localizing signs or symptoms, clinicians should expand on the patient's symptoms and historical information, looking for potentially diagnostic clues to guide the evaluation (Table 4).1720,25,27 This is a continuous, iterative process.1921 Potentially diagnostic clues lead to a diagnosis in 62% of patients, although clues can be misleading because they are found in 97% of patients.1517, If no potentially diagnostic clues are found, a minimum diagnostic workup should be performed. Ahmed S, Mohammad WW, Hamid F, Akhter A, Afzal RK, Mahmood A. J Coll Physicians Surg Pak. eCollection 2013. To our knowledge, this is the first study to examine the association between the patterns of fever and outcomes in COVID-19. eCollection 2016 May. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Fever, face edema, fatigue, fungal infection, malaise, . Viruses, bacteria, fungi, and parasites can cause infections. IL-1RA is naturally secreted by human hosts to limit the activity of IL-1 during hyperinflammation [22]. -. Prolonged fever beyond 7 days from onset of illness can identify patients who may be at risk of adverse outcomes from COVID-19. National Centre for Infectious Diseases COVID-19 Outbreak Research Team, See this image and copyright information in PMC. Clin Pediatr (Phila) 1977; 16:768. 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. 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. 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. PLoS Negl Trop Dis. Cases with prolonged fever were also more likely to require ICU admission compared with controls (11.1% vs 0.9%; P=.05). Prolonged fever is associated with adverse outcomes in dengue viral infection. 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. 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 analysis, which was. 2020 Oct 28;21(1):897. doi: 10.1186/s13063-020-04819-9. Age-appropriate or potentially diagnostic clueguided cancer screening should be performed (e.g., colonoscopy in patients 50 years or older). Pung R, Chiew CJ, Young BE, et al. Never give a child aspirin, as this increases the risk of . Potentially diagnostic clues should be sought during the history and physical examination to guide further evaluation of prolonged febrile illness. 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). Prolonged fever beyond 7 days from onset of illness can identify patients who may be at risk of adverse outcomes from COVID-19. 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. official website and that any information you provide is encrypted There were no significant changes in laboratory findings when repeated at the point of fever, except for a rise in platelet and lymphocyte counts (Table 2). 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