Upon admission, all patients underwent a chest x-ray (CXR), admission full blood count (FBC), renal and liver panel, C-reactive protein (CRP), lactate dehydrogenase (LDH), and nasopharyngeal swab for SARS-CoV-2 PCR. A P value of<.05 indicated statistical significance. Unable to load your collection due to an error, Unable to load your delegates due to an error, Collaborators, All Rights Reserved. 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. Plasma fractions were isolated from blood samples of COVID-19 patients collected during the acute phase (median post-illness onset, 6 days). 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 ). Blue and red represent low and high concentrations, respectively. 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. The Significance of Prolonged and Saddleback Fever in Hospitalised Adult Dengue. Published by Oxford University Press on behalf of Infectious Diseases Society of America. Dengue fever is gaining importance in Singapore with an increase in the number of cases and mortality in recent years. 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). Treatment of fever in adults usually involves ibuprofen, acetaminophen, or aspirin. The fever itself is generally harmless and probably helpful. 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. 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. Higher respiratory rate, lower SpO2, and lower systolic BP were also associated with saddleback fever compared with the control group. Author disclosure: No relevant financial affiliations. 2016 Dec 9;11(12):e0167025. Like RA, rheumatic fever affects the joints. 2022 Aug;14(8):321-326. doi: 10.14740/jocmr4791. Clinico-laboratory spectrum of dengue viral infection and risk factors associated with dengue hemorrhagic fever: a retrospective study. Results: Prolonged fever beyond 7 days from onset of illness can identify patients who may be at risk of adverse outcomes from COVID-19. Demographic and comorbidity data, symptoms and signs, vital signs, and laboratory and radiology results were obtained from electronic medical records. In particular, fever was reported in about 72%98.6% of patients, usually lasting <7 days [4, 710]. 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. But there are some important differences. Fever often occurs in response to infection, inflammation and trauma. 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). -, Huang C, Wang Y, Li X, et al. 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 elevation of circulating IL-1RA may reflect overactive IL-1 activation, which has been reported to associated with severe outcomes in COVID-19 [24]. 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. 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. 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. 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. Cases with prolonged fever were defined as patients with fever lasting >7 days. Self-recorded temperature monitoring for COVID-19 patients at home or community isolation facilities can be used to triage patients who need admission to the hospital. Statistical analyses were performed using GraphPad Prism, version 8. Disclaimer. Over- or under-reporting of the onset of fever before admission could affect the number of patients found to have prolonged or saddleback fever. Lohr JA, Hendley JO. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). [Open Forum Infect Dis 2020;7:ofaa375]. Cytokines were determined with multiplex microbead-based immunoassay for a subgroup of patients. 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. Statistical data analysis on the types of fevers 2013 Jul;23(7):463-7. Unauthorized use of these marks is strictly prohibited. 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. Clin Pediatr (Phila) 1977; 16:768. 2014; 8: e2777 10.1371/journal.pntd.0002777 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. Adverse outcomes were hypoxia, intensive care unit (ICU) admission, mechanical ventilation, and mortality. 7 days, a Singapore study reveals. The reference values for the normal ranges of laboratory tests were in accordance with those used by the hospital laboratory. Blue and red represent low and high concentrations, respectively. 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. World Health Organisation Special Programme for Research and Training in Tropical Diseases. 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). National Library of Medicine CMAJ Open. sharing sensitive information, make sure youre on a federal Coronavirus disease 2019 (COVID-19) situation report101.2020. Disclaimer. Out-of-hospital cardiac arrest and in-hospital mortality among COVID-19 patients: A population-based retrospective cohort study. 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. A fever is a rise in your 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. PLoS Negl Trop Dis 2012; 6(8): e1760 10.1371/journal.pntd.0001760 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. Affiliations, Plasma immune mediator levels in COVID-19 patients experiencing different fever patterns. 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. 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. doi: 10.1371/journal.pone.0167025. eCollection 2016 May. JAMA 2020; 323(11):10619. Your child may also develop swollen lymph nodes in the neck. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are nonspecific acute-phase reactants that are routinely part of the evaluation of febrile patients.5,28 An extremely elevated ESR (100 mm per hour or greater) suggests etiologies such as abdominal or pelvic abscess, osteomyelitis, and endocarditis. Copyright 2023 MIMS Pte Ltd. All rights reserved. JAMA Intern Med. Concentrations of 45 immune mediators in plasma were quantified using a 45-plex microbead-based immunoassay. MeSH 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). 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. Elevated lactate dehydrogenase levels can be indicative of infectious and malignant causes of FUO, including malaria, lymphoma, and leukemia.15,21 Measurement of ferritin levels may also be helpful.33 An elevated ferritin level in prolonged febrile illness may indicate malignancy (especially myeloproliferative disorders) and other noninfectious inflammatory diseases, such as systemic lupus erythematosus or temporal arteritis.21,33 One study established a ferritin level of 561 ng per mL (1,261 pmol per L) as the optimal cutoff value to predict that FUO was due to a noninfectious cause.22 Extreme elevation of ferritin levels (greater than 1,000 ng per mL [2,247 pmol per L]) can point to adult Still disease.34 Infection is the most common reason ESR is extremely elevated, but if there is no evidence of infectious causes, clinicians should consider malignancy, renal disease, and inflammatory disorders if the ESR is 100 mm per hour or greater.29. 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. Differences Between Prolonged Fever and Nonprolonged Fever Groups. eCollection 2013. Fever is a nonspecific symptom that may be caused by infectious and noninfectious conditions, including malignancies, systemic rheumatic diseases, and drug reactions. 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]. Am J Dis Child 1972; 124:544. Although there are more than 200 diseases in the differential diagnosis, most cases in adults are limited to several dozen possible causes. Cases with prolonged fever were also more likely to require ICU admission compared with controls (11.1% vs 0.9%; P = .05). Search dates: November 28, 2011; February 8, 2012; and April 18, 2014. Never give a child aspirin, as this increases the risk of . Ng DH, Wong JG, Thein TL, Leo YS, Lye DC. doi: 10.1371/journal.pntd.0004575. 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 (. Seven more confirmed cases of novel coronavirus infection in Singapore. eCollection 2022. 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. The .gov means its official. Similar fever patterns are observed in COVID-19 with unclear significance. Depending on clinical clues, this may include liver, lymph node, temporal artery, or bone marrow biopsy. Other illnesses and inflammation. In hypoxic conditions, it can trigger the expression of chemokines that attract neutrophils and monocytes to the ischemic tissue [31]. 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. Data were collected for the remaining 110 patients from this cohort as controls; 57.0% (81/142) of all study subjects were male, and the median age (interquartile range [IQR]) was 42 (3154) years. Plasma immune mediator levels in COVID-19 patients experiencing different fever patterns. 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. This content is owned by the AAFP. Patients with prolonged fever may have had higher levels of IL-1 earlier on before sample collection. This circadian rhythm may differ among individuals but should be consistent in each person . 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. In addition, as these patients with saddleback fever tend to do well, there is also no need for repeat laboratory testing or chest X-ray, as the results are unlikely to change management or clinical outcomes, they said. -. Prolonged fever beyond 7 days from onset of illness can identify patients who may be at risk of adverse outcomes from COVID-19. Untreated typhoid fever may progress to delirium, obtundation, intestinal hemorrhage, bowel. Outcomes of interest were hypoxia, admission to the intensive care unit (ICU), need for mechanical ventilation, and mortality. An official website of the United States government. official website and that any information you provide is encrypted Dengue fever is an acute febrile illness with a duration of 2-12 days. Print 2021 Jan-Mar. 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. The search included reviews, case series, meta-analyses, and randomized controlled trials. 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. Fever was defined as a temperature of 38.0C. If noninvasive diagnostic tests are unrevealing, then the invasive test of choice is a tissue biopsy because of the relatively high diagnostic yield. 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