Copyright 2023 American Academy of Family Physicians. The https:// ensures that you are connecting to the Concentrations of 45 immune mediators in plasma were quantified using a 45-plex microbead-based immunoassay. 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. 8600 Rockville Pike doi: 10.1371/journal.pntd.0002412. 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, explained Ng and co-authors. Seven more confirmed cases of novel coronavirus infection in Singapore. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BP, blood pressure; CRP, C-reactive protein; CXR, chest x-ray; ICU, intensive care unit; LDH, lactate dehydrogenase. Clinico-laboratory spectrum of dengue viral infection and risk factors associated with dengue hemorrhagic fever: a retrospective study. Careers. 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. 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). The https:// ensures that you are connecting to the All authors: no reported conflicts of interest. 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: 10.9778/cmajo.20200250. 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. Fever is a nonspecific symptom that may be caused by infectious and noninfectious conditions, including malignancies, systemic rheumatic diseases, and drug reactions. 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. 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. However, there were no significant differences in the admission laboratory values between the control and saddleback fever groups. In multiple studies, procalcitonin has been shown to have a specificity ranging from 70% to 98%, with a higher specificity for bacterial infection than other markers.28,31,32 It may be helpful in distinguishing between fevers with a bacterial cause vs. noninfectious inflammatory diseases, but its role in the workup of FUO is currently undefined.28,32, If the diagnosis remains elusive, tests targeting malignancies and noninfectious inflammatory diseases should be considered. CONCLUSIONS: Prolonged fever beyond 7 days from onset of illness can identify patients who may be at risk of adverse outcomes from COVID-19. Duration of fever was calculated from the date of first symptom onset to the date of defervescence (defined as temperature <37.5C for at least 24 hours) during the hospital admission. Saddleback fever refers to biphasic fever with an initial peak that remits and appears again. COVID-19 and sinus infections share several symptoms like nasal congestion, fever, and coughing. Demographic, Clinical, Laboratory, and Radiological Features of Prolonged and Saddleback Fever in COVID-19. Sixty-nine percent of them were male with a median age of 34 years. 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. This study aims to examine the prevalence of prolonged and saddleback fever in dengue as well as their associations with dengue severity. 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. 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). 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. Cases with prolonged fever were also more likely to require ICU admission compared with controls (11.1% vs 0.9%; P = .05). For most people, a temperature of 98.6 F or 37 C is baseline. Another 4 patients were excluded from the primary analysis as they had a saddleback pattern of fever that lasted >24 hours; 12.7% (18/142) of cases had prolonged fever and another 9.9% (14/142) had saddleback fever. Safety and Efficacy of Imatinib for Hospitalized Adults with COVID-19: A structured summary of a study protocol for a randomised controlled trial. Europe PMC is an archive of life sciences journal literature. PLoS Negl Trop Dis. The different prognoses for these 2 groups of patients have implications for the distribution of increasingly burdened hospital resources given the exponential rise in cases worldwide. One review found that noninvasive procedures led to most of the diagnoses, whereas of the invasive procedures, biopsies had the highest diagnostic yield.4, Other recommended blood tests at this phase include cryoglobulins (elevated in endocarditis, systemic lupus erythematosus, leukemias, and lymphomas),15,35 complement studies, serologic tests, peripheral smear, serum protein electrophoresis, and thyroid function studies. Cavalli G, De Luca G, Campochiaro C, et al. For cytokine profiling, the Mann-Whitney U test was applied to ascertain significant differences in immune mediator levels between patients experiencing different fever patterns. 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. [The] lower IP-10 level [with saddleback fever] is consistent with the finding that saddleback fever cases tend to have better clinical outcomes than prolonged fever cases, they noted. 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. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Recommendations of the Scientific Working Group on Dengue. 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. 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. HHS Vulnerability Disclosure, Help A P value of<.05 indicated statistical significance. 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). Confirmed imported case of novel coronavirus infection in Singapore; multi-ministry taskforce ramps up precautionary measures. Concentrations of 45 immune mediators in plasma were quantified using a 45-plex microbead-based immunoassay. The .gov means its official. Before Prolonged fever beyond 7 days from onset of illness can identify patients who may be at risk of adverse outcomes from COVID-19. QJM. 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. Please enable it to take advantage of the complete set of features! Adverse outcomes were hypoxia, intensive care unit (ICU) admission, mechanical ventilation, and mortality. However, there was a proportion of patients from our hospital who displayed 2 patterns of fever: 1 group had fever persisting into the second week of illness, while the second group displayed a saddleback pattern of fever, similar to that previously observed in dengue [11]. aInvestigations were repeated at the point at which they satisfied criteria for prolonged or saddleback fever. Influenza (flu) and the common cold are both contagious respiratory illnesses, but they are caused by different viruses. 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. Plasma immune mediator levels in COVID-19 patients experiencing different fever patterns. Epub 2022 Aug 27. -. Trials. 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. Factors associated with dengue shock syndrome: a systematic review and meta-analysis. The search included reviews, case series, meta-analyses, and randomized controlled trials. In particular, fever was reported in about 72%98.6% of patients, usually lasting <7 days [4, 710]. 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. "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. More studies are required to validate the findings of this report. The Author(s) 2020. Please enable it to take advantage of the complete set of features! and transmitted securely. 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. 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). Prolonged fever of unknown origin in children. Prevalence and Predictors of Persistent Symptoms After Clearance of SARS-CoV-2 Infection: A Multicenter Study from Egypt. World Health Organisation Special Programme for Research and Training in Tropical Diseases. Fever was defined as a temperature of 38.0C. Disclaimer. Interim guidance for implementing home care of people not requiring hospitalization for coronavirus disease 2019 (COVID-19). People who wish to treat a fever can try over-the-counter anti-fever medications, such as acetaminophen, aspirin, or ibuprofen. Epub 2022 Aug 11. 2016 Dec 9;11(12):e0167025. 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