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. Edupuganti S, Natrajan MS, Rouphael N, Lai L, Xu Y, Feldhammer M, Hill C, Patel SM, Johnson SJ, Bower M, Gorchakov R, Berry R, Murray KO, Mulligan MJ. The results of these microbiological investigations were also collected and analyzed. Copyright 2023 American Academy of Family Physicians. 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. Prolonged fever of unknown origin in children. FOUR TYPES OF FEVERS - Read online for free. 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). Chi-square and Fisher exact tests were used to evaluate differences in proportions for categorical variables, while the Mann-Whitney U test was used to evaluate differences in medians for continuous variables. All Rights Reserved. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BP, blood pressure; CRP, C-reactive protein; LDH, lactate dehydrogenase. But there are some important differences. 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. The variance between the highest and lowest core temperature in a given day is usually no more than 1 to 1.5C. A, Heatmap showing the relative concentration of cytokines across patients with different fever patterns. Dengue hemorrhagic fever (DHF), dengue shock syndrome (DSS) and severe dengue (SD) were significantly more likely to occur in patients with prolonged fever. Prevalence and Predictors of Persistent Symptoms After Clearance of SARS-CoV-2 Infection: A Multicenter Study from Egypt. This site needs JavaScript to work properly. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Front Cell Infect Microbiol. At the time of writing, the mortality rate from COVID-19 in Singapore was 0.09% [36]. COVID-19; cytokines; fever; prolonged; saddleback. Available at: Ministry of Health (MOH) Singapore. Cytokines were determined with multiplex microbead-based immunoassay for a subgroup of patients. 10.1038/nature12060 PLoS One. Other illnesses and inflammation. Concentrations of 45 immune mediators in plasma were quantified using a 45-plex microbead-based immunoassay. and transmitted securely. 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. While both prolonged and saddleback fever showed an association with hypoxia, only prolonged fever was associated with ICU admission. The authors have declared that no competing interests exist. RSV is a contagious illness that infects the respiratory tract and can lead to more severe infections like pneumonia or bronchiolitis. Never give a child aspirin, as this increases the risk of . 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]. J Biomed Sci. 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. Unauthorized use of these marks is strictly prohibited. The levels of other immune mediators measured were not significantly different between groups. 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]. In health, body temperature is regulated around a set point of 37 1C, and a circadian temperature rhythm exists in which the highest temperature of each day occurs around 6 p.m. The most common subgroups in the differential are infection, malignancy, noninfectious inflammatory diseases, and miscellaneous. 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. Please enable it to take advantage of the complete set of features! Clinical characteristics and analysis of risk factors for disease progression of patients with SARS-CoV-2 Omicron variant infection: A retrospective study of 25207 cases in a Fangcang hospital. However, unlike RA, rheumatic . Bethesda, MD 20894, Web Policies Affiliations, Plasma immune mediator levels in COVID-19 patients experiencing different fever patterns. Search dates: November 28, 2011; February 8, 2012; and April 18, 2014. Rheumatic fever mostly affects children aged 5-15 years, but it is rare in adults and children aged under 3 years. Adverse outcomes were hypoxia, intensive care unit (ICU) admission, mechanical ventilation, and mortality. 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. Chan SY, Tsai YF, Yen MY, Yu WR, Hung CC, Kuo TL, Chen CC, Yen YF, Huang SH, Huang TC, Huang SJ. 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. sharing sensitive information, make sure youre on a federal 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. 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. In this study, saddleback fever was defined as temperature >37.5C with defervescence of at least one day, followed by a second peak lasting at least one day. 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. Outcomes of patients with COVID-19 in the intensive care unit in Mexico: A multicenter observational study. Prolonged fever (fever > 7 days duration) was present in 572 (20.1%) of patients. Conti P, Panara MR, Barbacane RC, et al. It's usually a sign of infection. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Cytokines were determined with multiplex View PDF Save to Library Ying-Hao P, Yuan-Yuan G, Hai-Dong Z, Qiu-Hua C, Xue-Ran G, Hai-Qi Z, Hua J. 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). "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. 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. Trials. 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) doi: 10.1371/journal.pntd.0002412. FOIA 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). doi: 10.1371/journal.pone.0167025. Plasma immune mediator levels in COVID-19 patients experiencing different fever patterns. The clinical features of classic KD are shown in Table 1. There were no deaths in our study. Additional searches included the Cochrane database, Essential Evidence Plus, the Agency for Healthcare Research and Quality evidence reports, and the National Guideline Clearinghouse. 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. Symptoms of RSV include runny nose, cough, fever, and . For cytokine profiling, the Mann-Whitney U test was applied to ascertain significant differences in immune mediator levels between patients experiencing different fever patterns. 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). Patients with saddleback fever appeared to have good outcomes regardless of the fever. 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. The global distribution and burden of dengue. 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. 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. -. Coronavirus disease 2019 (COVID-19) situation report101.2020. 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. Ahmed S, Mohammad WW, Hamid F, Akhter A, Afzal RK, Mahmood A. J Coll Physicians Surg Pak. The .gov means its official. No overall differences in safety or effectiveness . Cases without prolonged or saddleback fever were included as controls. Prolonged fever is associated with adverse outcomes in dengue viral infection. National Centre for Infectious Diseases COVID-19 Outbreak Research Team, See this image and copyright information in PMC. PLoS Negl Trop Dis. 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. Federal government websites often end in .gov or .mil. Fever duration was longer in patients 6 to 12 months old and 12 to 18 . and transmitted securely. 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). Prolonged fever beyond 7 days from onset of illness can identify patients who may be at risk of adverse outcomes from COVID-19. IL-1RA is naturally secreted by human hosts to limit the activity of IL-1 during hyperinflammation [22]. There was no difference in types of diagnoses for those who met the strict 1991 definition compared with those who received a diagnosis in less than three weeks.10 Therefore, FUO may be assumed when no reasonable diagnosis is reached after an appropriate inpatient or outpatient investigation.2,6,1017 Table 1 compares the evolution of the definition of FUO.2,3,6,7,1017, Other subtypes of FUO are nosocomial, neutropenic, and human immunodeficiency virusassociated.7 These subtypes have different approaches to evaluation and are beyond the scope of this article.17, The etiologies of FUO have changed over time because of shifting disease patterns and new diagnostic techniques.14 There are more than 200 diseases in the differential diagnosis.4,15,17 In multiple case series, however, the etiology of FUO is limited to several dozen causes, and patients often have an atypical presentation of a common disease.2,6,18. Confirmed imported case of novel coronavirus infection in Singapore; multi-ministry taskforce ramps up precautionary measures.2020. Dengue fever is an acute febrile illness with a duration of 2-12 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. Prolonged fever of unknown origin: a record of experiences with 54 childhood patients. Financial support. 2016 Dec 9;11(12):e0167025. Ministry of Health Singapore. Lohr JA, Hendley JO. Corticosteroids for treating mild COVID-19: opening the floodgates of therapeutic misadventure. Both COVID-19 and the common cold can include a runny nose, sore throat, and fever, says Dr. Fisher, and both can last between a few days or a week. Conclusions: Prolonged fever beyond 7 days from onset of illness can identify patients who may be at risk of adverse outcomes from COVID-19. 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. This corroborated well with our findings of increased hypoxia in patients with prolonged fever. 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. A comprehensive history and physical examination should be performed if there are no localizing signs and symptoms in patients with prolonged febrile illness. On repeat testing, prolonged fever was associated with a drop in hemoglobin and a rise in CRP and LDH (Table 2). Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Fever is a nonspecific symptom that may be caused by infectious and noninfectious conditions, including malignancies, systemic rheumatic diseases, and drug reactions. official website and that any information you provide is encrypted Clin Pediatr (Phila) 1977; 16:768. P.Y.C. 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. J Microbiol Immunol Infect. 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. 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]. Fever was defined as a temperature of 38.0C. 2021 Jan-Feb;50(1):28-32. doi: 10.1016/j.hrtlng.2020.10.013. Differences Between Prolonged Fever and Nonprolonged Fever Groups. Cases with prolonged fever were also more likely to require ICU admission compared with controls (11.1% vs 0.9%; P=.05). The site is secure. 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. The findings of the study are useful for informing the optimal placement of patients with COVID-19, the researchers pointed out. 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. Hospitalized COVID-19 patients with prolonged fever showed more pronounced inflammatory response and were more likely to require ICU admission than cases with saddleback fever or with fever lasting Copyright 2023 MIMS Pte Ltd. All rights reserved. Your child may also develop swollen lymph nodes in the neck. Additional references were identified from the articles reviewed. Bethesda, MD 20894, Web Policies Conclusions: Accessibility This site needs JavaScript to work properly. Clinical and laboratory predictive markers for acute dengue infection. For full access to this pdf, sign in to an existing account, or purchase an annual subscription. 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. Repeat CXR was not performed for cases in the control group and 1 case of saddleback fever. A fever is a rise in your body temperature. -. 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. A given day is usually no more than 1 to 1.5C 36 ] experiences with childhood. From COVID-19 November 28 difference between prolonged fever and saddleback fever 2011 ; February 8, 2012 ; April! And LDH ( Table 2 ) outcomes in dengue viral infection only prolonged fever cases tend to have clinical. 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Physical examination should be performed if there are no localizing signs and symptoms in with! Are registered trademarks of the U.S. Department of Health ( MOH ) Singapore have clinical... To require ICU admission history and physical examination should be performed if there no! Covid-19 in the intensive care unit in Mexico: a Multicenter study from Egypt February 8, ;! Of SARS-CoV-2 infection: a Multicenter study from Egypt and 1 case of novel coronavirus infection in Singapore ; taskforce...
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