Hrev_master [page 110] [Emergency Care Journal 2024; 20:12903] Emergency Care Journal 2024 volume 20:12903 Abstract An advisory committee of Italian experts conducted a national, cross-sectional, web-based survey in June 2024 to describe the cur- rent management of fever and associated symptoms in different settings, including primary care, emergency departments, and hos- pital wards in pediatric and adult patients. The survey covered two domains: participants’ features and questions about the main drugs prescribed to treat fever and associated symptoms. A total of 832 questionnaires were analyzed. Paracetamol was the most pre- scribed drug to treat fever. Most participants were influenced by related symptoms when choosing the most appropriate drug. Almost all participants selected the oral route as their preferred one. This survey provides a current state of fever management among physicians in different settings throughout Italy. It high- lights a trend in treating fever with antipyretics at appropriate doses and evaluating pain through validated scales. Introduction Fever and associated symptoms are a challenging issue in both adults and children. They represent common reasons for primary care visits and hospital admissions.1 Fever is caused by a disrup- tion of thermal homeostasis and thermal setpoint caused by pyro- genic cytokines. It is an essential part of the inflammatory response to avoid the reproduction of bacteria and viruses and boost the immunological response.2 As a result of a defensive mechanism, fever should not be treated directly and drastically; instead, the main focus should be on the underlying cause. Although most fevers are viral in origin, approaching a febrile patient is always a concern, and there is a significant gap between current practice and scientific evidence.3 Overtreatment is common, often due to “fever phobia.”4 A wide range of symptoms may be associated with fever, including headache, muscle ache, sweating, chills, loss of appetite, and fatigue.5 Their treatment and relief with antipyretics are strictly connected to the management of pain in different age groups.3 Not assessing appropriately for pain leads to underestimation and sub- sequent undertreatment. Patients who are non-verbal or who have mental impairments are at higher risk. Standardized reliable assessment scores stratified by age are available but not always sufficient if used alone.6 An overall approach should be adopted, including the patient’s quality of life, sleep pattern, social relations, and daily activities to ensure appropriate management. Correspondence: Antonio Gatto, Department of Pediatrics, Fondazione Policlinico “A. Gemelli”, IRCCS. Largo Gemelli 8, 00168 Rome, Italy. E-mail: antonio.gatto@policlinicogemelli.it Tel.: 06.30154475 – Fax: 06.3383211 Key words: fever, antipyretics, pain scales. Conflict of interest: the authors declare that they have no conflict of interest. Funding: none. Contributions: all authors have participated in the preparation of the manuscript, all authors have read and approved the final manuscript. Ethics approval and consent to participate: this study was approved by the Ethics Committee of Fondazione Policlinico Universitario A. Gemelli IRCCS of Rome (#ID6662), and conducted according to the Helsinki Declaration of Human Rights. Participants in the study pro- vided their informed consent before starting the survey upon their free and voluntary assent. Consent for publication: participants in the study provided their con- sent before starting the survey upon their free and voluntary assent. Availability of data and materials: the datasets generated during and/or analyzed during the current study are available from the cor- responding author upon reasonable request. Received: 6 August 2024. Accepted: 12 October 2024. Early view: 8 November 2024. This work is licensed under a Creative Commons Attribution 4.0 License (by-nc 4.0). ©Copyright: the Author(s), 2024 Licensee PAGEPress, Italy Emergency Care Journal 2024; 20:12903 doi:10.4081/ecj.2024.12903 Publisher's note: all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. Management of fever and associated symptoms in children and adults: an Italian national survey Antonio Chiaretti,1 Ignazio Grattagliano,2 Francesco Carlomagno,3,4,5 Massimo Magi,6 Luigi Carbone,7 Silvia Zecca,8,9 Claudia Bondone,10 Antonio Gatto,11 Lorenzo Di Sarno,1 Francesco Franceschi12 1Department of Pediatrics, Fondazione Policlinico "A. Gemelli", IRCCS, Università Cattolica del Sacro Cuore, Rome; 2Italian College of General Practitioners and Primary Care (SIMG), Florence; 3ASL (Local health company) Naples 3 South; 4SIMEUP (Italian Society of Pediatric Emergency Medicine), National Treasurer; 5National Fimp PUER Area Manager (Prevention, Urgency, Emergency Managers); 6Italian Federation of General Practitioners, CEO Nusa Services, Castelfidardo (AN); 7Department of Emergency and Internal Medicine Tiber Island-Gemelli Island Hospital, Rome; 8Family Care Pediatrician; 9National Secretary FIMP (Italian Federation of Pediatrician); 10Department of Pediatric Emergency, Regina Margherita Children's Hospital, Città della Salute e della Scienza, Turin; 11Department of Pediatrics, Fondazione Policlinico “A. Gemelli”, IRCCS, Rome; 12Department of Emergency Medicine, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Largo Gemelli, Rome, Italy Non -co mmerc ial us e o nly As with the management of other conditions7, and despite a remarkable body of evidence,8, a standardized treatment of fever and associated symptoms cannot be recognized yet in adults or children. The primary goal of this nationwide survey is to provide an overview of the current management of fever and associated symptoms in various healthcare settings, including primary care, emergency departments, and hospital wards for pediatric and adult patients. Materials and Methods Potential items for the online questionnaire were identified by an advisory board of Italian experts, either primary care or hospi- talists, who are among the authors of the present paper. All pos- sessed extensive knowledge of current literature and expertise on this topic, with some specializing in adult patients and others in pediatric care. Therefore, the items used for this survey resulted from discrepancies or gaps in literature and clinical practice that were collectively deemed relevant by the advisory board. This study is a national, cross-sectional, web-based survey. The ques- tionnaire was distributed in June 2024 to 2000 physicians nation- wide, with half primary care physicians and the other half hospital- ists, including emergency physicians and ward physicians. Pool selection was assumed to provide a valid representative sample of the hospital and the territory. To boost the return rate, four reminder emails were sent along the planned time frame. Participants in the study provided their informed consent before starting the survey upon their free and voluntary assent on the first page. One thousand one hundred forty recipients did not provide informed consent and were excluded from the study. The enroll- ment flow chart is shown in Figure 1. The estimated time to complete the questionnaire was 5 min- utes. The questions were created with multiple-choice answers. For some questions, a free-text answer was requested. Overall, the questionnaire was composed of 11 items. Please take note of the following information: The survey included two main areas: i) Basic information on the participant, such as gender and current role (resident, hospital doctor, emergency doctor, primary care). Participants were also asked to specify if they are members of a medical group practice and the estimated number of patients they treat for fever per year; ii) Questions about the primary medications prescribed for treating fever and associated symptoms. This included details about dosage, reported side effects, and the use of scales to evaluate pain when it was associated with fever. The whole survey document is included in a supplementary file. The survey detailed the symp- toms associated with fever, including fatigue, warmth, headache, loss of appetite, muscle aches, chills, sweating, nausea, irritability, and arthralgia. The survey was created with no personal identify- ing information requested from the participants, using an available online application, the SurveyMonkey platform. Statistical analysis Descriptive statistics were performed using IBM SPSS for Windows (Version 24.0, IBM Corp). Comparison analyses for cat- egorical variables (survey items) between independent groups (participants’ current positions) were performed using the Chi- square test. Statistical significance was considered at p<0.05. Results A total of 832 questionnaires were analyzed, of which 717 were fully completed and 115 partially completed. The descriptive characteristics of the participants are reported in Table 1. The answers were stratified according to their current positions. The figures showing the responses according to the current positions of the contributors are reported in Figures 2 and 3. When asked to express the estimated number of patients with fever treated per year, most participants (38, n=289) referred 400-800 patients, whereas minor amounts referred less than 400 patients (22%, n=168) and more than 1200 (22%, n=168). Article Figure 1. The survey enrollment flow chart. Table 1. Characteristics of participants. Characteristics of Participants n (%) p 1. Current position Adult emergency department physician 23 (3) Pediatric emergency department physician 23 (3) Adult primary care physician 323 (39) Pediatric primary care physician 335 (40) Hospital pediatrician 119 (14) Resident 9 (1) Total 832 (100) 2. Member of medical group practice Yes 353 (43) < 0.00001 No 464 (57) Total 817 (100) 3. Gender Female 401 (51) < 0.00001 Male 385 (49) Prefer not to answer 3 (0) Total 789 (100) 4. Estimated number of patients with fever visited per year <400 168 (22) < 0.00001 400-800 289 (38) 801-1200 141 (18) >1200 168 (22) Total 766 (100) [Emergency Care Journal 2024; 20:12903] [page 111] Non -co mmerc ial us e o nly Paracetamol was the most prescribed drug to treat fever (84%, n=645, p<0.00001), followed by the association paracetamol- ibuprofen (8%, n=62) and ibuprofen (7%, n=50) as shown in Figure 4. Associated symptoms influenced most participants (86%, n=656) in choosing the most appropriate drug. Almost everyone (95%, n= 763) preferred the oral route (Figure 4). The preferred dose was 1000-3000 mg in 24 hours for paracetamol and 600-1200 mg in 24 hours for ibuprofen. Most physicians, particularly pedia- tricians, preferred to prescribe medication based on the patient’s weight. Many respondents (70%, n=507) reported that neither drug consistently caused adverse effects. Ibuprofen was associated with adverse effects in a small percentage of cases (25%, n=180) and paracetamol in an even smaller percentage (2%, n=18). Pain was assessed by scales continually, frequently, rarely, and never respec- tively, in 16, 38,36, and 10% of cases. The full data on drug choice are reported in Table 2. Discussion Fever is a nearly universal phenomenon; it is safe to say that practically everyone has had a fever at one time or another and its physiology has been extensively studied.9 There is no universally shared threshold for fever, since body temperature changes by indi- vidual, daytime, and way of assessment. On the basis of daily tem- perature fluctuations, a morning temperature >37.2°C or an after- noon temperature of >37.7°C could be considered fever.10,11 A con- ventional threshold of temperature >37.8°C or >38°C is frequently used.12,13 When handling a febrile patient most healthcare providers consider infection as a first hypothesis, and rightly so. However, it should be considered that any condition that promotes the release of pyrogenic cytokines by monocytes will result in fever. Besides infection, these conditions include activity, inflammation, increased metabolism, injury, and exposure to toxins.14 Since fever Article Figure 2. Drugs most prescribed to treat fever and associated symptoms according to the current position of participants. Figure 3. Preferred route of administration according to the current position of participants. [page 112] [Emergency Care Journal 2024; 20:12903] Non -co mmerc ial us e o nly Article Table 2. Drug choice to treat fever. Drug choice n (%) p 1. Drug most prescribed to treat fever and associated symptoms Paracetamol 645(84) <0.00001 Ibuprofen 50(7) Paracetamol/Ibuprofen association 62(8) Other 7(1) Total 764(100) 2. Influence of associated symptoms on drug choice Yes 656(86) 0.008 No 107(14) Total 763(100) 3. Route of administration preferred Oral - oral suspension, drops, tablets 725(95) < 0.00001 Intramuscular 0(0) Rectal 23(3) Intravenous 15(2) Total 763(100) 4. Dose of paracetamol administered to treat fever 1000 mg in 24 hours 34(5) < 0.00001 1000-3000 mg in 24 hours 292(39) Less than 1000 mg in 24 hours 12(2) mg/Kg in pediatric patients 402(54) Total 740(100) 5. Dose of ibuprofen administered to treat fever Less than 600 mg in 24 hours 41(6) < 0.00001 600-1200 mg in 24 hours 244(33) 1200-1800 mg in 24 hours 71(10) mg/Kg in pediatric patients 373(51) Total 729(100) 6. Drug most associated with adverse effects Paracetamol 18(2) 0.06 Ibuprofen 180(25) None 507(70) Both 19(3) Total 724(100) 7. Use of scales to assess pain Always 115(16) <0.00001 Frequently 276(38) Rarely 257(36) Never 73(10) Figure 4. Drugs most prescribed for treating fever. Other includes non-steroidal anti-inflammatory drugs (NSAIDS), corticosteroids, and homeopathic products. [Emergency Care Journal 2024; 20:12903] [page 113] Non -co mmerc ial us e o nly is a main item of a complex immunological defensive system it should not be treated straight away, rather the temperature should be analyzed along with clinical conditions to find the underlying cause. An increasing number of point-of-care tools may integrate physical examination to assess objectively the clinical scenario.15 “Fever phobia” can sometimes lead to frequent, unnecessary visits to the emergency room or clinic, resulting in unplanned doctor vis- its, inappropriate treatments, and unexpected financial costs.16 During the SARS-CoV-2 pandemic, emergency department and primary care visits dropped to low numbers without distinctions among pathologies,17,18 but are now rising again. Since managing fever and associated symptoms in adult and pediatric patients is a main issue in emergency and primary care, we developed a survey to provide current data on this topic in the Italian Health Service. In line with other studies19,20 paracetamol was the preferred drug to treat fever and associated symptoms (p<0.00001), partly considering the side effects of NSAIDs. Ibuprofen is the only other antipyretic recommended in febrile children.13 In a recent system- atic review, Narayan et al.21 stated that there is little evidence sup- porting the superiority of paracetamol or ibuprofen to treat fever in children since both drugs are effective and safe. According to inter- national guidelines the choice of the drug should rely on the child’s characteristics, while the alternate use of the two drugs is contro- versial. Alternating therapy might be more effective than monotherapy in reducing body temperature, but the benefit appears modest and probably not clinically relevant.22 Most physicians in this survey stated that associated symptoms influence their drug choice. Fever is a part of a complex immuno- logical defensive mechanism, so therapy is not aimed simply at reducing it but rather at managing fever-related symptoms. In adults, fever therapy has not shown a significant reduction in mor- tality.23 The oral route of drug administration was the most selected. Analyzing the stratification of answers according to current posi- tions, most emergency physicians selected the intravenous route. In emergency settings, a peripheral intravenous line is routinely placed to obtain a blood sample and administer intravenous fluids when needed. This is probably why the intravenous administration of antipyretics was preferred in this setting. Yet, this widespread practice deserves special attention. As widely reported in the liter- ature, this route is not more effective than the oral one and should not be preferred due to its cost and invasiveness. It should be lim- ited to patients who cannot tolerate oral medications, when a faster effect is desired, or when drugs are poorly absorbed by the gas- trointestinal tract. 24 Few family pediatricians still chose the rectal route. A recent French study showed that parents and healthcare providers use paracetamol suppositories also for non-vomiting or older chil- dren.19 This may be explained by the practical nature of supposito- ries and by some disadvantages of the oral formulation, such as poor taste, short storage time after opening, and transportability issues. Roughly half of the physicians, many of whom were pediatri- cians, dosed the drugs according to the patient’s weight. The more frequent daily dose for adults was 1000-3000 mg for paracetamol and 600-1200 mg. While this responded to prescription standards for paracetamol, it was underdosed for ibuprofen. Underdosing of ibuprofen is in line with what Milani et al.25 reported in more than 60% of children presenting to the Emergency Department. Although most responders reported no adverse effects associated with antipyretic drugs, concerns about the toxicity of non-steroidal anti-inflammatory agents probably underlays underdosing of oral ibuprofen. A list of adverse effects of ibuprofen is reported in the supplementary file. The argument on which is the most effec- tive antipyretic persists.26 A recent meta-analysis stated that ibuprofen is marginally more effective than paracetamol for fever reduction, but only focused on children under 2 years.27 The clini- cal implications of these findings are unclear. As previously men- tioned, antipyretics are used in febrile children with the therapeutic goal of improving the patient’s overall comfort. Because discom- fort was not universally recorded as an inclusion criterion in this study and data on pain outcomes were largely lacking, it was diffi- cult to assess any clinical impact.27,28 Pain assessment through scales is important to appropriately treat pain. In this survey pain evaluation by scales was performed always or frequently in more than 50% of cases, in line with the data of a recent survey among pediatricians by Marseglia et al.29 Interestingly in our survey emergency physicians reported a high rate of use of algometric scales. Our study had several limitations and strengths. The first one is intrinsic to the nature of the survey that is based on self-report- ing. Furthermore, the survey was not targeted to a specific popula- tion, including residents, hospitalists, and family doctors. Yet, this study is one of the few surveys that investigated fever management in hospitals and in outpatient clinics. Another limitation is that we did not get information on how the purported relevance of associated symptoms determined the drug choice. Since in the open-ended section, many participants indicated that they would prefer ibuprofen in the presence of an inflammatory condition, we can assume that this might apply to the wider number of those who did not justify their criteria of choice. A final notable limitation is that there was no prespecified threshold to define fever. As a consequence, we could not assess whether participants would treat mild fever or febricula (tempera- ture < 38°C) We believe that most of them would probably choose not to treat this condition, but we do not have enough data to con- firm this assumption. Conclusions This nationwide survey provides a current state of the manage- ment of fever and associated symptoms by physicians working in different settings in Italy. It highlights a trend towards treating fever with antipyretics at appropriate doses and evaluating pain through validated scales. References 1. Doria M, Careddu D, Iorio R, et al. Paracetamol and Ibuprofen in the Treatment of Fever and Acute Mild-Moderate Pain in Children: Italian Experts' Consensus Statements. Children (Basel) 2021;8:873. 2. Mackowiak PA. Fever: blessing or curse? A unifying hypothe- sis. Ann Intern Med 1994;120:1037-40. 3. Bakalli I, Klironomi D, Kola E, Celaj E. The management of fever in children. Minerva Pediatr (Torino) 2022;74:568-78. 4. Chiappini E, Parretti A, Becherucci P, et al. Parental and med- ical knowledge and management of fever in Italian pre-school children. BMC Pediatr 2012;12:97. 5. Ames NJ, Powers JH, Ranucci A, et al. A systematic approach for studying the signs and symptoms of fever in adult patients: the fever assessment tool (FAST). Health Qual Life Outcomes 2017;15:84. 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The effects of COVID- 19 outbreak on pediatric emergency department admissions for acute wheezing. Pediatr Pulmonol 2022;57:1167-72. 18. Ojetti V, Covino M, Brigida M, et al. Non-COVID diseases during the pandemic: where have all other emergencies gone? Medicina (Kaunas) 2020;56:512. 19. Bertille N, Fournier-Charrière E, Pons G, et al. Enduring large use of acetaminophen suppositories for fever management in children: a national survey of French parents and healthcare professionals' practices. Eur J Pediatr 2016;175:987-92. 20. Holgersson J, Ceric A, Sethi N, et al. Fever therapy in febrile adults: systematic review with meta-analyses and trial sequen- tial analyses. BMJ 2022;378:e069620. 21. Narayan K, Cooper S, Morphet J, Innes K. Effectiveness of paracetamol versus ibuprofen administration in febrile chil- dren: A systematic literature review. J Paediatr Child Health 2017;53:800-7. 22. Trippella G, Ciarcià M, de Martino M, Chiappini E. Prescribing controversies: an updated review and meta-analy- sis on combined/alternating use of ibuprofen and paracetamol in febrile children. Front Pediatr 2019;7:217. 23. Ovtcharenko N, Oczkowski S. In hospitalized adults with fever, fever therapy does not reduce mortality or serious adverse events. Ann Intern Med 2022;175:JC127. 24. McCarthy K, Avent M. Oral or intravenous antibiotics? Aust Prescr 2020;43:45-48. 25. Milani GP, Benini F, Dell'Era L, et al. Acute pain management: acetaminophen and ibuprofen are often under-dosed. Eur J Pediatr 2017;176:979-82. 26. Franceschi F, Saviano A, Carnicelli A, et al. Treatment of fever and associated symptoms in the emergency department: which drug to choose? Eur Rev Med Pharmacol Sci 2023;27:7362-9. 27. Tan E, Braithwaite I, McKinlay CJD, Dalziel SR. Comparison of Acetaminophen (Paracetamol) With Ibuprofen for Treatment of Fever or Pain in Children Younger Than 2 Years: A Systematic Review and Meta-analysis. JAMA Netw Open 2020;3:e2022398. 28. Hay AD, Costelloe C, Redmond NM, et al. Paracetamol plus ibuprofen for the treatment of fever in children (PITCH): ran- domised controlled trial. BMJ 2008;337:a1302. 29. Marseglia GL, Alessio M, Da Dalt L, et al. Acute pain manage- ment in children: a survey of Italian pediatricians. Ital J Pediatr 2019;45:156. Article [Emergency Care Journal 2024; 20:12903] [page 115] Online supplementary Materials The survey document and its 2 domains. Supplementary figure 1. member of medical group practise according to current position of participants. Supplementary figure 2. gender according to current position of participants. Supplementary figure 3. number of patients with fever treated per year according to current position of participants. Supplementary figure 4. influence of associated symptoms on drug choice according to current position of participants. Supplementary figure 5. prescribed dose of paracetamol to treat fever according to current position of participants. Supplementary figure 5. prescribed dose of paracetamol to treat fever according to current position of participants. Supplementary figure 7. drug most associated with adverse effects according to current position of participants. Supplementary figure 8. use of scales to assess pain according to current position of participants. Non -co mmerc ial us e o nly