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. 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. This material may not otherwise be downloaded, copied, printed, stored, transmitted or reproduced in any medium, whether now known or later invented, except as authorized in writing by the AAFP. Confirmed imported case of novel coronavirus infection in Singapore; multi-ministry taskforce ramps up precautionary measures.2020. Adverse outcomes were hypoxia, intensive care unit (ICU) admission, mechanical ventilation, and mortality. A fever is a body temperature of 100.4 F or greater. Available at: Wang D, Hu B, Hu C, et al. Prolonged fever beyond 7 days from onset of illness can identify patients who may be at risk of adverse outcomes from COVID-19. Effects of sericin and egg white on the inflammation of damaged skin in mice. This corroborated well with our findings of increased hypoxia in patients with prolonged fever. Temperature 101F (38.3C) on several separate occasions, Evaluation of at least one week in the hospital, Temperature 101F on several separate occasions, Evaluation of at least three outpatient visits or three days in inpatient care, Temperature 101F documented clinically on several separate occasions, Appropriate initial diagnostic workup (inpatient or outpatient) does not reveal etiology of fever, Tuberculosis (especially extrapulmonary/disseminated), Noninfectious inflammatory disease (10% to 30%), Polymyalgia rheumatica/temporal arteritis, Living conditions (e.g., homeless shelter), Occupational exposures/sick contacts (e.g., with hospitalized patients, children), Cytomegalovirus, Epstein-Barr virus, tuberculosis, Recent travel, especially to areas with endemic diseases (domestic and abroad), Region specific (e.g., Q fever for parts of Europe), Alcoholic hepatitis, cirrhosis, Crohn disease, Characteristic rashes (e.g., erythema multiforme, petechiae), Adenovirus, herpes simplex virus, HIV, meningococcemia, tick-borne illness, Adult Still disease, leptospirosis, systemic lupus erythematosus, Hepato- or splenomegaly; palpable abdominal masses, Alcoholic liver disease, carcinoma, cytomegalovirus, Epstein-Barr virus, leukemia, lymphoma, Inflammatory bowel disease, Lyme disease, systemic lupus erythematosus, Cat-scratch disease, cytomegalovirus, Epstein-Barr virus, HIV. A more recent article on fever of unknown origin in adults is available. COVID-19; cytokines; fever; prolonged; saddleback. 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). Please enable it to take advantage of the complete set of features! Your comment will be reviewed and published at the journal's discretion. 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. On repeat testing, prolonged fever was associated with a drop in hemoglobin and a rise in CRP and LDH (Table 2). Interim guidance for implementing home care of people not requiring hospitalization for coronavirus disease 2019 (COVID-19). 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. -. 2014; 8: e2777 10.1371/journal.pntd.0002777 Your child may also develop swollen lymph nodes in the neck. For full access to this pdf, sign in to an existing account, or purchase an annual subscription. Safety and Efficacy of Imatinib for Hospitalized Adults with COVID-19: A structured summary of a study protocol for a randomised controlled trial. 2022 Jul 26;2022(7):omac079. National Centre for Infectious Diseases COVID-19 Outbreak Research Team, See this image and copyright information in PMC. In conclusion, we reported on the prevalence, risk factors, cytokine profiles, and outcomes of patients with COVID-19 who had saddleback or prolonged fever. 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). Plasma fractions were isolated from blood samples of COVID-19 patients collected during the acute phase (median post-illness onset, 6 days). Background: 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. 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. Factors associated with dengue shock syndrome: a systematic review and meta-analysis. but the rest of the symptoms did not have a difference between the 2 serotypes. 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. Ministry of Health Singapore. Demographic and comorbidity data, symptoms and signs, vital signs, and laboratory and radiology results were obtained from electronic medical records. 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). A P value of<.05 indicated statistical significance. For cases with prolonged fever, investigations were repeated beyond day 7 of illness, and for cases with saddleback fever, investigations were repeated at point of fever recurrence. Teleconferencing is often used to monitor these cases for potential deterioration. 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. One limitation of the study is the small sample size of our cohort. A fever is a rise in your body temperature. 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. Front Cell Infect Microbiol. Fever was defined as a temperature of 38.0C or higher. 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. 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. 10.1038/nature12060 Before Coronavirus disease 2019 (COVID-19) situation report101.2020. Demographic, Clinical, Laboratory, and Radiological Features of Prolonged and Saddleback Fever in COVID-19. 2013 Sep 26;7(9):e2412. Hypoxia was defined as requirement for supplemental oxygen. Cases with saddleback fever were defined as patients with recurrence of fever lasting <24 hours, after defervescence, beyond day 7 of illness. 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. If noninvasive diagnostic tests are unrevealing, then the invasive test of choice is a tissue biopsy because of the relatively high diagnostic yield. Normal body temperature can vary depending on the individual, the time of day, and even the weather. Like RA, rheumatic fever affects the joints. The reference values for the normal ranges of laboratory tests were in accordance with those used by the hospital laboratory. In patients with saddleback fever, higher levels of IL-1, IL-21, IL-22, and SDF-1 were observed compared with control patients. eCollection 2016. P.Y.C. Antibiotics usually aren't prescribed just because a child has a fever that is lasting a long time. Accessibility Importantly, upregulation of the IL-1 pathway on monocytes can increase prostaglandin E2 expression and drive fever [32]. 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. 2016 Dec 9;11(12):e0167025. 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. 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. The mean duration of symptoms and signs before diagnosis (28.4 13.2 versus 45.0 30.8 days; P < 0.05), . Outcomes of COVID-19 Among High-Risk Individuals: A Study Comparing Febrile and Afebrile Presentation. Roseola symptoms might include: Fever. 2016 May 20;10(5):e0004575. 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. FOIA Fever of unknown origin (FUO) in adults is one of the most vexing clinical conditions for clinicians and patients. Keywords: A more recent qualitative definition requires only a reasonable diagnostic evaluation. The variance between the highest and lowest core temperature in a given day is usually no more than 1 to 1.5C. 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. The levels of other immune mediators measured were not significantly different between groups. Available at: Ministry of Health (MOH) Singapore. Home or community isolation facilities and the other iterations for positive cases are commonly used globally to isolate positive patients [34, 35]. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BP, blood pressure; CRP, C-reactive protein; LDH, lactate dehydrogenase. An official website of the United States government. 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. 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. Statistical analyses were performed with the Mann-Whitney U test (*P<.05; **P<.01; ***P<.001). 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. 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. Notably, patients with prolonged fever had higher IP-10 and lower IL-1 levels as compared with patients with saddleback fever (Figure 1B). 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. 2022 May 20;15:2575-2587. doi: 10.2147/IDR.S355064. There are no published guidelines, nor is there a recommended standard approach to the diagnosis. 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). 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]. Although prolonged and saddleback fever have been reported in dengue fever, there are no specific studies on their significance in dengue. CONCLUSIONS: Prolonged fever beyond 7 days from onset of illness can identify patients who may be at risk of adverse outcomes from COVID-19. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. This site needs JavaScript to work properly. Treatment. See permissionsforcopyrightquestions and/or permission requests. Patient information: See related handout on fever of unknown origin in adults, written by the authors of this article. 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). 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. But normal body temperature can range between 97 F (36.1 C) and 99 F (37.2 C) or more. In addition, IP-10 has also been reported to be associated with increased viral load, lung injury, ICU admission, and mortality [21]. 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. The most common subgroups in the differential are infection, malignancy, noninfectious inflammatory diseases, and miscellaneous. Prolonged fever of unknown origin in children. 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. Bookshelf 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. 2022 Dec;55(6 Pt 1):1044-1051. doi: 10.1016/j.jmii.2022.07.009. To our knowledge, this is the first study to examine the association between the patterns of fever and outcomes in COVID-19. Prolonged fever was defined as fever lasting more than 7 days. 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. Cases with prolonged fever were also more likely to require ICU admission compared with controls (11.1% vs 0.9%; P=.05). FOUR TYPES OF FEVERS - Read online for free. ELIZABETH C. HERSCH, COL, MC, USA, AND C. ROBERT, OH, LTC, MC, USA. The differences in cytokine and chemokine profiles among [the three groups] suggest that different immunological responses could result in the differences in the clinical phenotype observed, said Ng and co-authors. For most people, a temperature of 98.6 F or 37 C is baseline. 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. 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. Cytokines were determined with multiplex View PDF Save to Library The clinical features of classic KD are shown in Table 1. 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). In hypoxic conditions, it can trigger the expression of chemokines that attract neutrophils and monocytes to the ischemic tissue [31]. Search dates: November 28, 2011; February 8, 2012; and April 18, 2014. . Before 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. Academic Pulmonary Sleep Medicine Physician Opportunity in Scenic Central Pennsylvania, Academic Surgical Pathologist/Breast Pathologist, Copyright 2023 Infectious Diseases Society of America. A dysregulated immune response in COVID-19 has been postulated to lead a deleterious cytokine storm [12]. 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. bOnly 1 sample of paired values available. PLoS Negl Trop Dis. Saddleback fever was present in 165 (5.8%). 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 ). 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. History and physical examination alone are often sufficient to diagnose uncomplicated infectious causes of fever . eCollection 2017 Summer. Chan SY, Tsai YF, Yen MY, Yu WR, Hung CC, Kuo TL, Chen CC, Yen YF, Huang SH, Huang TC, Huang SJ. Epub 2022 Aug 27. These patients required prolonged periods of observation and symptomatic treatment. Epub 2022 Aug 11. Retrospective characterisation and outcome of surgical treatment for cervical lymph node abscessation in 15 dogs. Cytokine and chemokine concentrations from an additional 23 healthy controls who did not have COVID-19 were also analyzed for baseline comparison. The results of this study can be used to optimize placement of patients with COVID-19. Cases without prolonged or saddleback fever were included as controls. For cytokine profiling, the Mann-Whitney U test was applied to ascertain significant differences in immune mediator levels between patients experiencing different fever patterns. eCollection 2013. Ying-Hao P, Yuan-Yuan G, Hai-Dong Z, Qiu-Hua C, Xue-Ran G, Hai-Qi Z, Hua J. The global distribution and burden of dengue. 8600 Rockville Pike 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 site is secure. 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. 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. Unauthorized use of these marks is strictly prohibited. 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. 7 days, a Singapore study reveals. 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. Recommendations of the Scientific Working Group on Dengue. There were no deaths in our study. Unauthorized use of these marks is strictly prohibited. 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). Cytokines were determined with multiplex microbead-based immunoassay for a subgroup of patients. IL-1RA is naturally secreted by human hosts to limit the activity of IL-1 during hyperinflammation [22]. Cases with prolonged fever were defined as patients with fever lasting >7 days. Careers. Nature. 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]. 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. Fever was defined as a temperature of 38.0C. 2 ) purchase an annual subscription COVID-19 Outbreak Research Team, See this image and copyright information in PMC COL. Mean duration of symptoms and signs Before diagnosis ( 28.4 13.2 versus 45.0 30.8 days ; P lt! Covid-19 patients collected during the acute phase ( median post-illness onset, 6 days ) infection... Accessibility Importantly, upregulation of the manuscript have been reported in dengue fever, higher levels other! Shown in Table 1 size of our cohort Dec 9 ; 11 ( 12 ):.!, vital signs, vital signs, and SDF-1 were observed compared with control patients: e0167025 reviewed and at... Covid-19 were also more likely to require ICU admission compared with control patients ; t just... Was defined as fever lasting & gt ; 7 ( 9 ): e0167025 experiencing fever... [ 12 ] & gt ; 7 ( 9 ): e0004575 authors! 26 ; 7 ( 9 ): omac079 2023 Infectious Diseases COVID-19 Outbreak Team! 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