Additional references were identified from the articles reviewed. 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). Grasselli G, Greco M, Zanella A, Albano G, Antonelli M, Bellani G, Bonanomi E, Cabrini L, Carlesso E, Castelli G, Cattaneo S, Cereda D, Colombo S, Coluccello A, Crescini G, Forastieri Molinari A, Foti G, Fumagalli R, Iotti GA, Langer T, Latronico N, Lorini FL, Mojoli F, Natalini G, Pessina CM, Ranieri VM, Rech R, Scudeller L, Rosano A, Storti E, Thompson BT, Tirani M, Villani PG, Pesenti A, Cecconi M; COVID-19 Lombardy ICU Network. 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. To our knowledge, this is the first study to examine the association between the patterns of fever and outcomes in COVID-19. Differences Between Prolonged Fever and Nonprolonged Fever Groups. 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. 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. Huy NT, Van Giang T, Thuy DH, Kikuchi M, Hien TT, Zamora J, Hirayama K. PLoS Negl Trop Dis. National Library of Medicine But there are some important differences. 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. Clinico-laboratory spectrum of dengue viral infection and risk factors associated with dengue hemorrhagic fever: a retrospective study. Accessibility In one study of patients with FUO, chest and abdominal CT had high sensitivity (82% and 92%, respectively) and were recommended if the initial evaluation was unrevealing.15 CT specificity ranged from 60% to 70%, consistent with other case series.15,16 Echocardiography is recommended if there are clinical indications of endocarditis.5,20 Venous Doppler ultrasonography is indicated for suspected thromboembolism.20 Magnetic resonance imaging of the aortic arch and great vessels of the neck was shown to be helpful when vasculitis was suspected.36, Nuclear imaging studies are noninvasive, image the whole body, and can localize a potential infectious or inflammatory cause for FUO.5,14,19,3740 Recently, 18F fluorodeoxyglucose positron emission tomography technology has been evaluated for guiding further invasive testing, especially in patients who have an elevated ESR or CRP level.14,37 The 18F fluorodeoxyglucose is taken up by inflammatory and cancer cells because of their high rate of glucolysis.14,18,37 Several studies examining this method in patients with FUO found diagnostic yields ranging from 16% to 69%,15,37,38 with a high positive predictive value (93%) and negative predictive value (100%).39,40 A hybrid of CT and 18F fluorodeoxyglucose positron emission tomography has a higher diagnostic yield (sensitivity of 56% to 100%; specificity of 75% to 81%18). Cytokines were determined with multiplex microbead-based immunoassay for a subgroup of patients. HHS Vulnerability Disclosure, Help Keywords: Before official website and that any information you provide is encrypted 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]. Your child may also develop swollen lymph nodes in the neck. 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. Clipboard, Search History, and several other advanced features are temporarily unavailable. 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. Please enable it to take advantage of the complete set of features! Heart Lung. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. 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. 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]. A. 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. 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. Statistical analyses were performed using Stata, version 14 (StataCorp, College Station, TX, USA). Confirmed imported case of novel coronavirus infection in Singapore; multi-ministry taskforce ramps up precautionary measures. A more recent article on fever of unknown origin in adults is available. 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. A comprehensive history and physical examination should be performed if there are no localizing signs and symptoms in patients with prolonged febrile illness. Careers. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. In addition, in comparison with other parameters such as respiratory rate, heart rate, or blood pressure, fever is easy to detect and readily identifiable as a risk factor for severe disease. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (. Institutional research board ethics approval and written consent were obtained for the drawing of blood specimens from participants for cytokine analysis (ref: DRSB 2012/00917). The https:// ensures that you are connecting to the This apparent difference in IL-1 between prolonged fever cases and saddleback fever cases may have occurred due to dynamic immune response and the time point of sample collection. Epub 2022 Aug 27. This site needs JavaScript to work properly. official website and that any information you provide is encrypted Mallhi TH, Khan AH, Adnan AS, Sarriff A, Khan YH, Jummaat F. BMC Infect Dis. Moreover, cases with prolonged fever also showed significantly higher plasma levels of inflammatory biomarkers such as interleukin (IL)-6 (p<0.01), IL-1RA (p<0.05), and induced protein-10 (IP-10; p<0.001) compared with controls during the early acute disease phase. The findings of the study are useful for informing the optimal placement of patients with COVID-19, the researchers pointed out. . 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. 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. Laboratory Results for Prolonged and Saddleback Fever. 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. 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 (. Although DHF and SD were more likely to occur in patients in those with saddleback fever, DSS was not. 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. Concentrations of 45 immune mediators in plasma were quantified using a 45-plex microbead-based immunoassay. Young BE, Ong SWX, Kalimuddin S, et al. 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. There were no deaths in our study. 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. Epub 2020 Oct 21. 2013 Oct 20;20(1):75. doi: 10.1186/1423-0127-20-75. The differences in cytokine and chemokine profiles among control patients with fever7 days, patients with prolonged fever, or patients with saddleback fever at the early acute phase of illness suggest that different immunological responses could result in the differences in the clinical phenotype observed. National Library of Medicine However, ESR does not help discriminate between active autoimmune disease and infection, and malignancies and noninfectious inflammatory diseases can cause an elevated ESR and CRP level. However, it is interesting that there are higher pro-inflammatory IL-1 levels in patients with saddleback fever. 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. 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. Although there are more than 200 diseases in the differential diagnosis, most cases in adults are limited to several dozen possible causes. 2016 Dec 9;11(12):e0167025. 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 Sixty-nine percent of them were male with a median age of 34 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). Cases without prolonged or saddleback fever were included as controls. For most people, a temperature of 98.6 F or 37 C is baseline. More studies are required to validate the findings of this report. Conti P, Panara MR, Barbacane RC, et al. 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. Infect Drug Resist. 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. Prolonged fever of unknown origin: a record of experiences with 54 childhood patients. The median age was 34 years of age (5 th - 95 th percentile: 17-59) and males comprised 1971 (69.3%) of study sub- Additional searches included the Cochrane database, Essential Evidence Plus, the Agency for Healthcare Research and Quality evidence reports, and the National Guideline Clearinghouse. Fever of unknown origin (FUO) in adults is one of the most vexing clinical conditions for clinicians and patients. Nevertheless, as patients in the ICU are at higher risk of nosocomial infections, due diligence should be done to exclude other causes of fever [17]. 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. eCollection 2013. Copyright 2014 by the American Academy of Family Physicians. 2020 Oct 1;180(10):1345-1355. doi: 10.1001/jamainternmed.2020.3539. Symptoms of RSV include runny nose, cough, fever, and . 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. Over- or under-reporting of the onset of fever before admission could affect the number of patients found to have prolonged or saddleback fever. PLoS One. Fever was defined as a temperature of 38.0C or higher. Challenges in dengue fever in the elderly: Atypical presentation and risk of severe dengue and hospital-acquired infection. 2013 Jul;23(7):463-7. Published by Oxford University Press on behalf of Infectious Diseases Society of America. Please enable it to take advantage of the complete set of features! While both prolonged and saddleback fever showed an association with hypoxia, only prolonged fever was associated with ICU admission. If noninvasive diagnostic tests are unrevealing, then the invasive test of choice is a tissue biopsy because of the relatively high diagnostic yield. 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). 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. In contrast, cases with saddleback fever showed no significant change upon repeating their laboratory tests. Interim guidance for implementing home care of people not requiring hospitalization for coronavirus disease 2019 (COVID-19). History and physical examination alone are often sufficient to diagnose uncomplicated infectious causes of fever . Clipboard, Search History, and several other advanced features are temporarily unavailable. 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. Repeat CXR was not performed for cases in the control group and 1 case of saddleback fever. Both prolonged fever and saddleback fever were not significantly associated with mechanical ventilation as compared with the control group (Table 1). Pizzo PA, Lovejoy FH Jr, Smith DH. Patients with saddleback fever appeared to have good outcomes regardless of the fever, they noted. In patients with a prolonged febrile illness, a minimum diagnostic workup should be performed before classifying the disease process as a fever of unknown origin. bOnly 1 sample of paired values available. Refining the global spatial limits of dengue virus transmission by evidence-based consensus. doi: 10.1093/ofid/ofx133. 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. Patient information: See related handout on fever of unknown origin in adults, written by the authors of this article. Never give a child aspirin, as this increases the risk of . 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. Potential conflicts of interest. 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. ELIZABETH C. HERSCH, COL, MC, USA, AND C. ROBERT, OH, LTC, MC, USA. eCollection 2016 May. -, Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW, Moyes CL, et al. McClung HJ. Prolonged fever beyond 7 days from onset of illness can identify patients who may be at risk of adverse outcomes from COVID-19, said the researchers led by Dr Deborah Ng from National Centre for Infectious Diseases (NCID), Singapore, on behalf of the NCID COVID-19 Outbreak Research Team. 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). If the diagnosis remains elusive, 18F fluorodeoxyglucose positron emission tomography plus computed tomography may help guide the clinician toward tissue biopsy. Your comment will be reviewed and published at the journal's discretion. Viruses, bacteria, fungi, and parasites can cause infections. The clinical features of classic KD are shown in Table 1. Am J Dis Child 1972; 124:544. On repeat testing, prolonged fever was associated with a drop in hemoglobin and a rise in CRP and LDH (Table 2). Nature. In addition to their pro-inflammatory properties, both IL-6 and IP-10 have been reported to be associated with disease severity and ICU admission in COVID-19 [18, 19] . Prolonged fever beyond 7 days from onset of illness can identify patients who may be at risk of adverse outcomes from COVID-19. The most common subgroups in the differential are infection, malignancy, noninfectious inflammatory diseases, and miscellaneous. Data Sources: A PubMed search was completed using the key terms fever of unknown origin, FUO, pyrexia of unknown origin, and inflammatory markers. Adverse outcomes were hypoxia, intensive care unit (ICU) admission, mechanical ventilation, and mortality. The results of these microbiological investigations were also collected and analyzed. Prolonged fever is associated with adverse outcomes in dengue viral infection. 2014; 8: e2777 10.1371/journal.pntd.0002777 sharing sensitive information, make sure youre on a federal Statistical data analysis on the types of fevers Conclusions: Prolonged fever beyond 7 days from onset of illness can identify patients who may be at risk of adverse outcomes from COVID-19. Rash. 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. It's usually a sign of infection. Pediatrics 1975; 55:468. ; Singapore 2019 Novel Coronavirus Outbreak Research Team. 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. 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. 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. Demographic, Clinical, Laboratory, and Radiological Features of Prolonged and Saddleback Fever in COVID-19. National Centre for Infectious Diseases COVID-19 Outbreak Research Team, See this image and copyright information in PMC. However, there were no significant differences in the admission laboratory values between the control and saddleback fever groups. Disclaimer. The 4 cases who were excluded from the primary analysis demonstrated a saddleback pattern of fever that lasted >24 hours. 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 ). Unmasking latent extrapulmonary tuberculosis with newly diagnosed HIV-1 infection in a COVID-19 patient with prolonged fever. 2017 Jun 22;4(3):ofx133. The reference values for the normal ranges of laboratory tests were in accordance with those used by the hospital laboratory. 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. 2022 Aug;14(8):321-326. doi: 10.14740/jocmr4791. doi: 10.9778/cmajo.20200250. Cases with saddleback fever were defined as patients with recurrence of fever lasting <24 hours, after defervescence, beyond day 7 of illness. and transmitted securely. Our cohort only had 1 mortality, and this may be reflective of the overall low mortality rate in Singapore. None of the 3 patients who entered the ICU had culture-proven nosocomial infections, suggesting that the fevers observed in the ICU were likely related to COVID-19 infection. The Author(s) 2020. Cavalli G, De Luca G, Campochiaro C, et al. This study aims to examine the prevalence of prolonged and saddleback fever in dengue as well as their associations with dengue severity. The .gov means its official. One limitation of the study is the small sample size of our cohort. 2020 Oct 28;21(1):897. doi: 10.1186/s13063-020-04819-9. Other illnesses and inflammation. 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). Academic Pulmonary Sleep Medicine Physician Opportunity in Scenic Central Pennsylvania, Academic Surgical Pathologist/Breast Pathologist, Copyright 2023 Infectious Diseases Society of America. Prolonged fever beyond 7 days from onset of illness can identify patients who may be at risk of adverse outcomes from COVID-19. An official website of the United States government. Unable to load your collection due to an error, Unable to load your delegates due to an error, Collaborators, Roseola symptoms might include: Fever. Plasma fractions were isolated from blood samples of COVID-19 patients collected during the acute phase (median post-illness onset, 6 days). Outcomes of interest were hypoxia, admission to the intensive care unit (ICU), need for mechanical ventilation, and mortality. eCollection 2022. Erythrocyte sedimentation rate and C-reactive protein levels should be measured in the initial workup of a patient who has prolonged febrile illness without a clear source. Outcomes of patients with COVID-19 in the intensive care unit in Mexico: A multicenter observational study. Conclusions: 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. 4 cases who were excluded from the primary analysis demonstrated difference between prolonged fever and saddleback fever saddleback pattern of fever before admission could affect number... In those with saddleback fever COVID-19, the researchers pointed out Medicine Opportunity. The control and saddleback fever in dengue fever in the admission laboratory values between the control group and case. Ltc, MC, USA of the onset of illness can identify patients who may be at risk severe! 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