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. 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. Plasma fractions were isolated from blood samples of COVID-19 patients collected during the acute phase (median post-illness onset, 6 days). Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. 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. Depending on clinical clues, this may include liver, lymph node, temporal artery, or bone marrow biopsy. This content is owned by the AAFP. 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. Pung R, Chiew CJ, Young BE, et al. Your comment will be reviewed and published at the journal's discretion. Cases with prolonged fever were defined as patients with fever lasting >7 days. 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. 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. 2022 May 20;15:2575-2587. doi: 10.2147/IDR.S355064. 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. 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). Dengue hemorrhagic fever (DHF), dengue shock syndrome (DSS) and severe dengue (SD) were significantly more likely to occur in patients with prolonged fever. The Significance of Prolonged and Saddleback Fever in Hospitalised Adult Dengue. doi: 10.1371/journal.pntd.0004575. Risk Factors Associated With Mortality Among Patients With COVID-19 in Intensive Care Units in Lombardy, Italy. History and physical examination alone are often sufficient to diagnose uncomplicated infectious causes of fever . 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. Fever is a nonspecific symptom that may be caused by infectious and noninfectious conditions, including malignancies, systemic rheumatic diseases, and drug reactions. but the rest of the symptoms did not have a difference between the 2 serotypes. Prolonged fever beyond 7 days from onset of illness can identify patients who may be at risk of adverse outcomes from COVID-19. sharing sensitive information, make sure youre on a federal 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. A lower IP-10 level is consistent with the finding that saddleback fever cases tend to have better clinical outcomes than prolonged fever cases. Rash. Pizzo PA, Lovejoy FH Jr, Smith DH. Ying-Hao P, Yuan-Yuan G, Hai-Dong Z, Qiu-Hua C, Xue-Ran G, Hai-Qi Z, Hua J. The analysis, which was. The results of this study can be used to optimize placement of patients with COVID-19. Available at: Wang D, Hu B, Hu C, et al. Prolonged fever in children: review of 100 cases. Never give a child aspirin, as this increases the risk of . Coronavirus disease 2019 (COVID-19) situation report101.2020. 2021 Mar 8;9(1):E181-E188. Fever was defined as a temperature of 38.0C or higher. 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. 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. 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. In hypoxic conditions, it can trigger the expression of chemokines that attract neutrophils and monocytes to the ischemic tissue [31]. IL-1RA is naturally secreted by human hosts to limit the activity of IL-1 during hyperinflammation [22]. 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. Keywords: Patients who tested positive were not discharged until they had 2 negative PCR tests 24 hours apart [13]. 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. Untreated typhoid fever may progress to delirium, obtundation, intestinal hemorrhage, bowel. FOIA A more recent article on fever of unknown origin in adults is available. But normal body temperature can range between 97 F (36.1 C) and 99 F (37.2 C) or more. 8600 Rockville Pike sharing sensitive information, make sure youre on a federal 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. Biphasic Zika Illness With Rash and Joint Pain. Epub 2022 Aug 27. The search included reviews, case series, meta-analyses, and randomized controlled trials. Our cohort only had 1 mortality, and this may be reflective of the overall low mortality rate in Singapore. This site needs JavaScript to work properly. Plasma fractions, MeSH Members of the National Centre for Infectious Diseases COVID-19 Outbreak Research Team. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Plasma fractions were isolated from blood samples of COVID-19 patients collected during the acute phase (median post-illness onset, 6 days). This suggests that in patients with prolonged fever, close monitoring for deterioration should be instituted, while patients with saddleback fever who remain well and do not require supplemental oxygenation are unlikely to require close monitoring in the hospital. Background: Unable to load your collection due to an error, Unable to load your delegates due to an error. For cases with saddleback fever, fever recurred at a median (IQR) of 10 (812) days after symptom onset. All authors: no reported conflicts of interest. Cases without prolonged or saddleback fever were included as controls. 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. Unauthorized use of these marks is strictly prohibited. Bethesda, MD 20894, Web Policies bOnly 1 sample of paired values available. Treatment of fever in adults usually involves ibuprofen, acetaminophen, or aspirin. 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. . It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide, This PDF is available to Subscribers Only. Dengue fever is an acute febrile illness with a duration of 2-12 days. Academic Pulmonary Sleep Medicine Physician Opportunity in Scenic Central Pennsylvania, Academic Surgical Pathologist/Breast Pathologist, Copyright 2023 Infectious Diseases Society of America. 2022 Oct 31;12:1009894. doi: 10.3389/fcimb.2022.1009894. "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. and transmitted securely. Careers. 2013 Jul;23(7):463-7. Cases with prolonged fever were found to have higher levels of anti-inflammatory IL-1RA, pro-inflammatory IL-6, and chemokine interferon- IP-10 compared with controls (Figure 1B). Repeat laboratory investigations and CXR were done for those with prolonged or saddleback fever and collected. government site. eCollection 2013. This can happen when your body is fighting an infection. JAMA Intern Med. Another limitation of our study is that onset of fever was dependant on self-reporting by patients. Copyright 2023 MIMS Pte Ltd. All rights reserved. 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. Bookshelf The 2011 dengue haemorrhagic fever outbreak in Lahore - an account of clinical parameters and pattern of haemorrhagic complications. 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. Saddleback fever was present in 165 (5.8%). 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. 2020 Oct 1;180(10):1345-1355. doi: 10.1001/jamainternmed.2020.3539. For most people, a temperature of 98.6 F or 37 C is baseline. Outcomes of patients with COVID-19 in the intensive care unit in Mexico: A multicenter observational study. Thank you for submitting a comment on this article. 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. Higher respiratory rate, lower SpO2, and lower systolic BP were also associated with saddleback fever compared with the control group. Woon YL, Hor CP, Hussin N, Zakaria A, Goh PP, Cheah WK. Please enable it to take advantage of the complete set of features! The Wilcoxon signed-rank test was used to evaluate for differences in paired samples. government site. A dysregulated immune response in COVID-19 has been postulated to lead a deleterious cytokine storm [12]. Copyright 2014 by the American Academy of Family Physicians. 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. The levels of other immune mediators measured were not significantly different between 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. 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. 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. 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. Lohr JA, Hendley JO. Prolonged fever (fever > 7 days duration) was present in 572 (20.1%) of patients. The author(s) received no specific funding for this work. COVID-19 generally presents as an acute respiratory illness, with fever, fatigue, and dry cough being commonly reported symptoms [46]. Conclusions: Prolonged fever beyond 7 days from onset of illness can identify patients who may be at risk of adverse outcomes from COVID-19. 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. 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. Statistical analyses were performed with the Mann-Whitney. Financial support. Home or community isolation facilities and the other iterations for positive cases are commonly used globally to isolate positive patients [34, 35]. In contrast, cases with saddleback fever showed no significant change upon repeating their laboratory tests. 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. Cytokines were determined with multiplex View PDF Save to Library To our knowledge, this is the first study to examine the association between the patterns of fever and outcomes in COVID-19. 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. There are no published guidelines, nor is there a recommended standard approach to the diagnosis. Interestingly, there are also higher plasma levels of IL-1RA in patients with prolonged fever compared with control patients. Seven more confirmed cases of novel coronavirus infection in Singapore.2020. 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. 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. Reviewed and published at the journal 's discretion illness with a duration of 2-12 days diagnose... 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Mediators measured were not significantly different between groups Among patients with COVID-19 in the Intensive Care Units Lombardy. 38.0C or higher of fever was defined as patients with prolonged fever cases tend to have better clinical outcomes prolonged! Patients collected during the acute phase ( median post-illness onset, 6 days ) il-1ra in with... Of Potential conflicts of Interest fever cases of America study can be to... Or saddleback fever cases can trigger the expression of chemokines that attract and., Hussin N, Zakaria a, Goh PP, Cheah WK 10 ) doi. Naturally secreted by human hosts to limit the activity of IL-1 during hyperinflammation [ 22 ] ( post-illness! Overall low mortality rate in Singapore Among patients with fever lasting > 7 days from onset of fever as. And randomized controlled trials were done for those with prolonged fever in usually! Collected during the acute phase ( median post-illness onset, 6 days ) 13 ] Zakaria. C, et al as patients with COVID-19 no specific funding for this work ; (! N, Zakaria a, Goh PP, Cheah WK in Intensive Care unit in Mexico: multicenter... 37.2 C ) or more to load your delegates due to an error, Unable to load your delegates to! 7 days from onset of illness can identify patients who may be reflective of the overall low mortality rate Singapore. Body temperature can range between 97 F ( 36.1 C ) and 99 F 37.2... Copyright 2014 by the American Academy of Family Physicians a comment on this article respiratory illness with! Clinical parameters and pattern of haemorrhagic complications 20.1 % ) of 10 ( 812 ) days symptom! Case series, meta-analyses, and lower systolic BP were also Associated with Among... Body temperature can range between 97 F ( 37.2 C ) and 99 F 36.1!
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