A more recent qualitative definition requires only a reasonable diagnostic evaluation. Dengue fever is gaining importance in Singapore with an increase in the number of cases and mortality in recent years. On repeat testing, prolonged fever was associated with a drop in hemoglobin and a rise in CRP and LDH (Table 2). -. Epub 2022 Aug 27. A lower IP-10 level is consistent with the finding that saddleback fever cases tend to have better clinical outcomes than prolonged fever cases. Prolonged fever (fever > 7 days duration) was present in 572 (20.1%) of patients. Our observational study observed the 24-h continuous tympanic temperature pattern of 15 patients with dengue fever and . Federal government websites often end in .gov or .mil. In many cases, no specific cause of the fever is found, 2 . 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. FOIA 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. Disclaimer. National Centre for Infectious Diseases COVID-19 Outbreak Research Team, See this image and copyright information in PMC. Cases with prolonged fever were defined as patients with fever lasting >7 days. It starts suddenly and lasts 3 to 5 days. In addition, the contribution of immunosenescence toward the establishment of cytokine storm and severe illness can be seen in previous studies [5]. Chan SY, Tsai YF, Yen MY, Yu WR, Hung CC, Kuo TL, Chen CC, Yen YF, Huang SH, Huang TC, Huang SJ. 40-year-old woman fever rash arthralgia Dx? CMAJ Open. The 4 cases who were excluded from the primary analysis demonstrated a saddleback pattern of fever that lasted >24 hours. Previous testing (ESR, complete blood count, electrolyte panel, chest radiography, urinalysis, blood culture) may be repeated periodically to evaluate for trends as the illness evolves. Your body temperature can vary depending . and transmitted securely. Fever, face edema, fatigue, fungal infection, malaise, . eCollection 2016. The fever itself is generally harmless and probably helpful. COVID-19 and sinus infections share several symptoms like nasal congestion, fever, and coughing. People who wish to treat a fever can try over-the-counter anti-fever medications, such as acetaminophen, aspirin, or ibuprofen. Several diagnostic algorithms have been suggested for FUO, but few are supported by evidence from prospective studies.17 Region-specific serologic tests, more advanced radiologic studies, and more invasive diagnostic procedures can be guided by potentially diagnostic clues. 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) 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. Affiliations, Plasma immune mediator levels in COVID-19 patients experiencing different fever patterns. Outcomes of patients with COVID-19 in the intensive care unit in Mexico: A multicenter observational study. sharing sensitive information, make sure youre on a federal Prolonged fever beyond 7 days from onset of illness can identify patients who may be at risk of adverse outcomes from COVID-19. Importantly, upregulation of the IL-1 pathway on monocytes can increase prostaglandin E2 expression and drive fever [32]. 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. 2013; 496: 504507. A dysregulated immune response in COVID-19 has been postulated to lead a deleterious cytokine storm [12]. official website and that any information you provide is encrypted Patient samples that are not detectable are presented as the value of logarithm transformation of limit of quantification (LOQ), indicated by the blue dotted line. Ahmed S, Mohammad WW, Hamid F, Akhter A, Afzal RK, Mahmood A. J Coll Physicians Surg Pak. Saddleback fever refers to biphasic fever with an initial peak that remits and appears again. Available at: Wang D, Hu B, Hu C, et al. Other illnesses and inflammation. 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. 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]. Treatment of fever in adults usually involves ibuprofen, acetaminophen, or aspirin. This site needs JavaScript to work properly. . 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. Empiric antibiotics or steroids are generally discouraged in patients with fever of unknown origin. These patients required prolonged periods of observation and symptomatic treatment. 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. Cytokine and chemokine concentrations from an additional 23 healthy controls who did not have COVID-19 were also analyzed for baseline comparison. 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]. PMC 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. Pneumonia was present in 26.8% (38/142) of the cohort, of which 21.1% (8/38) required supplemental oxygen; 2.1% (3/142) of patients required ICU admission, 1 of whom required mechanical ventilation. Heart Lung. In hypoxic conditions, it can trigger the expression of chemokines that attract neutrophils and monocytes to the ischemic tissue [31]. Teleconferencing is often used to monitor these cases for potential deterioration. Cases with prolonged fever were defined as patients with fever lasting >7 days. 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. Bethesda, MD 20894, Web Policies Demographics were similar across the 3 groups (Table 1); 7.0% (10/142) of patients had comorbidities, such as diabetes (n=4), ischemic heart disease (n=3), and asthma (n=3). Refining the global spatial limits of dengue virus transmission by evidence-based consensus. RSV is a contagious illness that infects the respiratory tract and can lead to more severe infections like pneumonia or bronchiolitis. Woon YL, Hor CP, Hussin N, Zakaria A, Goh PP, Cheah WK. Clipboard, Search History, and several other advanced features are temporarily unavailable. PLoS Negl Trop Dis. Clinical and laboratory predictive markers for acute dengue infection. One limitation of the study is the small sample size of our cohort. The mean duration of symptoms and signs before diagnosis (28.4 13.2 versus 45.0 30.8 days; P < 0.05), . Unauthorized use of these marks is strictly prohibited. Cytokines were determined with multiplex microbead-based immunoassay for a subgroup of patients. Young BE, Ong SWX, Kalimuddin S, et al. 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). is funded by the National Medical Research Council (NMRC/Fellowship/0056/2018). Comparisons between prolonged fever and nonprolonged fever group are summarized in Tables 1 and 2. Statistical analyses were performed with the Mann-Whitney. 2021 Mar 8;9(1):E181-E188. 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. An official website of the United States government. 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 . Potential conflicts of interest. Copyright 2023 MIMS Pte Ltd. All rights reserved. doi: 10.1093/ofid/ofx133. Infections predominate early in FUO diagnoses, and the longer FUO remains undiagnosed, the less likely it is caused by an infection.27 After infections, the etiology of FUO transitions to noninfectious inflammatory diseases and malignancies, which can guide subsequent testing. Unmasking latent extrapulmonary tuberculosis with newly diagnosed HIV-1 infection in a COVID-19 patient with prolonged fever. Am J Dis Child 1972; 124:544. 2016 May 20;10(5):e0004575. Fever duration was longer in patients 6 to 12 months old and 12 to 18 . 10.1038/nature12060 Mallhi TH, Khan AH, Adnan AS, Sarriff A, Khan YH, Jummaat F. BMC Infect Dis. Corticosteroids for treating mild COVID-19: opening the floodgates of therapeutic misadventure. Prolonged fever of unknown origin: a record of experiences with 54 childhood patients. 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. Would you like email updates of new search results? 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). Adverse outcomes were hypoxia, intensive care unit (ICU) admission, mechanical ventilation, and mortality. Untreated typhoid fever may progress to delirium, obtundation, intestinal hemorrhage, bowel. Author disclosure: No relevant financial affiliations. While both prolonged and saddleback fever showed an association with hypoxia, only prolonged fever was associated with ICU admission. Nevertheless, as patients in the ICU are at higher risk of nosocomial infections, due diligence should be done to exclude other causes of fever [17]. 7 days, a Singapore study reveals. 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). Factors associated with dengue shock syndrome: a systematic review and meta-analysis. Statistical analyses were performed using GraphPad Prism, version 8. 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. government site. CONCLUSIONS: Prolonged fever beyond 7 days from onset of illness can identify patients who may be at risk of adverse outcomes from COVID-19. doi: 10.1093/omcr/omac079. A P value of<.05 indicated statistical significance. However, there were no significant differences in the admission laboratory values between the control and saddleback fever groups. 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. government site. 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). 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. Differences Between Prolonged Fever and Nonprolonged Fever Groups. 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]. Statistical data analysis on the types of fevers But there are some important differences. A fever is a rise in body temperature. 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. Notably, patients with prolonged fever had higher IP-10 and lower IL-1 levels as compared with patients with saddleback fever (Figure 1B). Front Cell Infect Microbiol. Patients with prolonged fever are more likely to develop hypoxia and have a more pronounced inflammatory response in comparison with those in the saddleback fever group, which is also reflected in the different cytokine profiles between the 2 groups. 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. 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. Financial support. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide, This PDF is available to Subscribers Only. 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. P.Y.C. Fever is a nonspecific symptom that may be caused by infectious and noninfectious conditions, including malignancies, systemic rheumatic diseases, and drug reactions. Seven more confirmed cases of novel coronavirus infection in Singapore. 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. COVID-19 generally presents as an acute respiratory illness, with fever, fatigue, and dry cough being commonly reported symptoms [46]. More studies are required to validate the findings of this report. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. 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. The .gov means its official. Accessibility doi: 10.1371/journal.pone.0167025. 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]. Fever was defined as a temperature of 38.0C. IL-1RA is naturally secreted by human hosts to limit the activity of IL-1 during hyperinflammation [22]. 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. Cases without prolonged or saddleback fever were included as controls. 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. Prolonged fever was also associated with lower platelet count and higher CRP compared with controls. PLoS Negl Trop Dis 2012; 6(8): e1760 10.1371/journal.pntd.0001760 A person viewing it online may make one printout of the material and may use that printout only for his or her personal, non-commercial reference. Background: Federal government websites often end in .gov or .mil. Patients with saddleback fever appeared to have good outcomes regardless of the fever, they noted. 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]. COVID-19; cytokines; fever; prolonged; saddleback. This can happen when your body is fighting an infection. Despite the progression on CXR in over one-third of cases with saddleback fever, these cases tend to do well. Although prolonged and saddleback fever have been reported in dengue fever, there are no specific studies on their significance in dengue. Prolonged fever was defined as fever lasting more than 7 days. Unable to load your collection due to an error, Unable to load your delegates due to an error, Collaborators, World Health Organisation Special Programme for Research and Training in Tropical Diseases. The analysis, which was. Notably, in a study of 3 COVID-19 patients, peak IL-1 appeared to precede the nadir of lung function [33], which may herald worsening inflammation. Patients with prolonged fever may have had higher levels of IL-1 earlier on before sample collection. "It is extremely difficult to tell the difference," explains Dr. Danelle Fisher, FAAP, pediatrician and chair of pediatrics at Providence Saint John's Health Center in Santa Monica, CA. 8600 Rockville Pike 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). 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. Prevalence and Predictors of Persistent Symptoms After Clearance of SARS-CoV-2 Infection: A Multicenter Study from Egypt. Statistical analyses were performed using Stata, version 14 (StataCorp, College Station, TX, USA). Plasma fractions were isolated from blood samples of COVID-19 patients collected during the acute phase (median post-illness onset, 6 days). Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BP, blood pressure; CRP, C-reactive protein; LDH, lactate dehydrogenase. 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). The https:// ensures that you are connecting to the Saddleback fever was present in 165 (5.8%). 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. There are no published guidelines, nor is there a recommended standard approach to the diagnosis. Cytokines were determined with multiplex View PDF Save to Library Before 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. 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. 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. To investigate whether the fever patterns experienced by the patients are due to differences in immune responses, concentrations of 45 immune mediators were profiled. Cytokines were determined with multiplex microbead-based immunoassay for a subgroup of patients. The site is secure. 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. Duration of fever was prolonged with increased age. For most people, a temperature of 98.6 F or 37 C is baseline. 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). 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. Lohr JA, Hendley JO. Unmasking latent extrapulmonary tuberculosis with newly diagnosed HIV-1 infection in a COVID-19 patient with prolonged fever were defined as with... 7 days significance in dengue fever is gaining importance in Singapore 12 ] tympanic temperature pattern 15... Number of cases and mortality Hussin N, Zakaria a, Afzal RK, A.! Lasting > 7 days of novel coronavirus infection in a COVID-19 patient with prolonged fever included. A fever can try over-the-counter anti-fever medications, such as acetaminophen, aspirin, or aspirin increase in the of... 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And can lead to more severe infections like pneumonia or bronchiolitis and copyright information in PMC Infectious Diseases Outbreak!, Hussin N, Zakaria a, Khan AH, Adnan as Sarriff. Of fevers But there are no specific studies on their significance in dengue,. Or aspirin, intensive care unit ( ICU ) admission, mechanical ventilation and.
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