Cases with prolonged fever were defined as patients with fever lasting >7 days. 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. Prolonged fever beyond 7 days from onset of illness can identify patients who may be at risk of adverse outcomes from COVID-19. This site needs JavaScript to work properly. 8600 Rockville Pike Background: Extreme poverty first: An argument on the equitable distribution of the COVID-19 vaccine in Peru. 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. Sixty-nine percent of them were male with a median age of 34 years. In addition, the contribution of immunosenescence toward the establishment of cytokine storm and severe illness can be seen in previous studies [5]. Prolonged fever was defined as fever lasting more than 7 days. HHS Vulnerability Disclosure, Help Higher respiratory rate, lower SpO2, and lower systolic BP were also associated with saddleback fever compared with the control group. This corroborated well with our findings of increased hypoxia in patients with prolonged fever. Both prolonged fever and saddleback fever were not significantly associated with mechanical ventilation as compared with the control group (Table 1). For cytokine profiling, the Mann-Whitney U test was applied to ascertain significant differences in immune mediator levels between patients experiencing different fever patterns. Cytokine and chemokine concentrations from an additional 23 healthy controls who did not have COVID-19 were also analyzed for baseline comparison. In patients with saddleback fever, higher levels of IL-1, IL-21, IL-22, and SDF-1 were observed compared with control patients. bOnly 1 sample of paired values available. 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). COVID-19 generally presents as an acute respiratory illness, with fever, fatigue, and dry cough being commonly reported symptoms [46]. 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]. Prolonged fever is associated with adverse outcomes in dengue viral infection. 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. Bethesda, MD 20894, Web Policies Home or community isolation facilities and the other iterations for positive cases are commonly used globally to isolate positive patients [34, 35]. Clinicians should perform a comprehensive history and examination to look for potentially diagnostic clues to guide the initial evaluation. Disclaimer. Unable to load your collection due to an error, Unable to load your delegates due to an error. The reference values for the normal ranges of laboratory tests were in accordance with those used by the hospital laboratory. 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. 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. 2017 Jun 22;4(3):ofx133. A more recent article on fever of unknown origin in adults is available. If the diagnosis remains elusive, 18F fluorodeoxyglucose positron emission tomography plus computed tomography may help guide the clinician toward tissue biopsy. Some children also may have a sore throat, runny nose or cough along with or before the fever. 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). Before Published by Oxford University Press on behalf of Infectious Diseases Society of America. Fever is a nonspecific symptom that may be caused by infectious and noninfectious conditions, including malignancies, systemic rheumatic diseases, and drug reactions. History and physical examination alone are often sufficient to diagnose uncomplicated infectious causes of fever . 2021 Mar 8;9(1):E181-E188. Europe PMC is an archive of life sciences journal literature. 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. IL-1RA is naturally secreted by human hosts to limit the activity of IL-1 during hyperinflammation [22]. Teleconferencing is often used to monitor these cases for potential deterioration. Challenges in dengue fever in the elderly: Atypical presentation and risk of severe dengue and hospital-acquired infection. Fever of unknown origin is more often an atypical presentation of a common disease rather than an unusual disease. A more recent qualitative definition requires only a reasonable diagnostic evaluation. Cytokines were determined with multiplex microbead-based immunoassay for a subgroup of patients. A, Heatmap showing the relative concentration of cytokines across patients with different fever patterns. In patients with a prolonged febrile illness, a minimum diagnostic workup should be performed before classifying the disease process as a fever of unknown origin. Cases with prolonged fever had a median duration of fever (IQR) lasting 10 (912) days. [Open Forum Infect Dis 2020;7:ofaa375]. 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. Mallhi TH, Khan AH, Adnan AS, Sarriff A, Khan YH, Jummaat F. BMC Infect Dis. Demographic, Clinical, Laboratory, and Radiological Features of Prolonged and Saddleback Fever in COVID-19. In contrast, cases with saddleback fever showed no significant change upon repeating their laboratory tests. One review found that noninvasive procedures led to most of the diagnoses, whereas of the invasive procedures, biopsies had the highest diagnostic yield.4, Other recommended blood tests at this phase include cryoglobulins (elevated in endocarditis, systemic lupus erythematosus, leukemias, and lymphomas),15,35 complement studies, serologic tests, peripheral smear, serum protein electrophoresis, and thyroid function studies. A lower IP-10 level is consistent with the finding that saddleback fever cases tend to have better clinical outcomes than prolonged fever cases. 2020 Oct 1;180(10):1345-1355. doi: 10.1001/jamainternmed.2020.3539. 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. Careers. Similar fever patterns are observed in COVID-19 with unclear significance. 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. Young BE, Ong SWX, Kalimuddin S, et al. 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. For cases with saddleback fever, fever recurred at a median (IQR) of 10 (812) days after symptom onset. Seven more confirmed cases of novel coronavirus infection in Singapore. An official website of the United States government. Copyright 2023 American Academy of Family Physicians. The levels of other immune mediators measured were not significantly different between groups. 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. Blue and red represent low and high concentrations, respectively. Statistical data analysis on the types of fevers Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. 2020 Oct 28;21(1):897. doi: 10.1186/s13063-020-04819-9. Hypoxia was defined as requirement for supplemental oxygen. PMC eCollection 2022. 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. Ahmed S, Mohammad WW, Hamid F, Akhter A, Afzal RK, Mahmood A. J Coll Physicians Surg Pak. 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. These patients required prolonged periods of observation and symptomatic treatment. Fever was defined as a temperature of 38.0C. A P value of<.05 indicated statistical significance. Notably, patients with prolonged fever had higher IP-10 and lower IL-1 levels as compared with patients with saddleback fever (Figure 1B). 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. Differences Between Prolonged Fever and Nonprolonged Fever Groups. We also excluded 4 patients whose fever pattern did not fulfill the case definition for prolonged or saddleback fever. RSV is a contagious illness that infects the respiratory tract and can lead to more severe infections like pneumonia or bronchiolitis. Common causes of FUO are listed in Table 2.6,1523 Typical subgroups used in the differential for classical FUO are infection (20% to 40%), malignancy (20% to 30%), noninfectious inflammatory diseases (10% to 30%), miscellaneous (10% to 20%), and undiagnosed (up to 50%).1,46,1418,2224 Noninfectious inflammatory diseases commonly include connective tissue diseases, vasculitides, and granulomatous diseases.16,17 In developed countries, the noninfectious inflammatory diseases and undiagnosed groups comprise a higher proportion of FUO cases.5,10,15,17 Underdeveloped countries have higher rates of infection and neoplasm.6,24 Drug fever is implicated in 1% to 3% of FUO cases16 (Table 320,21,25,26 ). 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). Would you like email updates of new search results? The search included reviews, case series, meta-analyses, and randomized controlled trials. Despite the progression on CXR in over one-third of cases with saddleback fever, these cases tend to do well. In addition, IP-10 has also been reported to be associated with increased viral load, lung injury, ICU admission, and mortality [21]. 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. 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. 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. There are no published guidelines, nor is there a recommended standard approach to the diagnosis. 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. 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). 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. Our observational study observed the 24-h continuous tympanic temperature pattern of 15 patients with dengue fever and . Keywords: 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. 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. 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. 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. Huy NT, Van Giang T, Thuy DH, Kikuchi M, Hien TT, Zamora J, Hirayama K. PLoS Negl Trop Dis. eCollection 2013. Interim guidance for implementing home care of people not requiring hospitalization for coronavirus disease 2019 (COVID-19). Dengue hemorrhagic fever (DHF), dengue shock syndrome (DSS) and severe dengue (SD) were significantly more likely to occur in patients with prolonged fever. Outcomes of COVID-19 Among High-Risk Individuals: A Study Comparing Febrile and Afebrile Presentation. The different prognoses for these 2 groups of patients have implications for the distribution of increasingly burdened hospital resources given the exponential rise in cases worldwide. Financial support. Thank you for submitting a comment on this article. 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 was defined as a temperature of 38.0C or higher. But there are some important differences. A larger sample size may help to identify if prolonged and saddleback fever could be used as predictors for adverse outcomes such as ICU admission, mechanical ventilation, or death. At the time of writing, the mortality rate from COVID-19 in Singapore was 0.09% [36]. J Microbiol Immunol Infect. 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. This content is owned by the AAFP. HHS Vulnerability Disclosure, Help The Author(s) 2020. Dengue fever is an acute febrile illness with a duration of 2-12 days. FOIA A dysregulated immune response in COVID-19 has been postulated to lead a deleterious cytokine storm [12]. 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. 2021 Jan-Feb;50(1):28-32. doi: 10.1016/j.hrtlng.2020.10.013. CMAJ Open. 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. 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. There were no deaths in our study. 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. J Biomed Sci. 7 days, a Singapore study reveals. 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. 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. McClung HJ. Conclusions: Prolonged fever beyond 7 days from onset of illness can identify patients who may be at risk of adverse outcomes from COVID-19. A fever may be caused by a virus, bacteria, fungus, blood clot, tumor, drug, or the environment. Home or community isolation facilities are commonly used globally for less sick patients such that hospital beds are free up to cater for sicker patients. 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Your comment will be reviewed and published at the journal's discretion. ; Singapore 2019 Novel Coronavirus Outbreak Research Team. This site needs JavaScript to work properly. Prolonged fever of unknown origin in children. In general, fever is defined as a temperature > 38C (100.4F). Murthy S, Archambault PM, Atique A, Carrier FM, Cheng MP, Codan C, Daneman N, Dechert W, Douglas S, Fiest KM, Fowler R, Goco G, Gu Y, Guerguerian AM, Hall R, Hsu JM, Joffe A, Jouvet P, Kelly L, Kho ME, Kruisselbrink RJ, Kumar D, Kutsogiannis DJ, Lamontagne F, Lee TC, Menon K, O'Grady H, O'Hearn K, Ovakim DH, Pharand SG, Pitre T, Reel R, Reeve B, Rewa O, Richardson D, Rishu A, Sandhu G, Sarfo-Mensah S, Shadowitz E, Sligl W, Solomon J, Stelfox HT, Swanson A, Tessier-Grenier H, Tsang JLY, Wood G; SPRINT-SARI Canada Investigators and the Canadian Critical Care Trials Group.