Comparative Analysis of Single and Combined Antipyretics Using Patient-Generated Health Data: Retrospective Observational Study.

Fever is one of the most common symptoms in children and is the physiological response of the human immune system to external pathogens. However, effectiveness studies of single and combined antipyretic therapy are relatively few due to lack of data. In this study, we used large-scale patient-generated health data from mobile apps to compare antipyretic affects between single and combination antipyretics. We aimed to establish combination patterns of antipyretics and compare antipyretic affects between single and combination antipyretics using large-scale patient-generated health data from mobile apps. This study was conducted using medical records of feverish children from July 2015 to June 2017 using the Fever Coach mobile app. In total, 3,584,748 temperature records and 1,076,002 antipyretic records of 104,337 children were analyzed. Antipyretic efficacy was measured by the mean difference in the area under the temperature change curve from baseline for 6 hours, 8 hours, 10 hours, and 12 hours after antipyretic administration in children with a body temperature of ≥38.0 ℃ between single and combination groups. The single antipyretic and combination groups comprised 152,017 and 54,842 cases, respectively. Acetaminophen was the most commonly used single agent (60,929/152,017, 40.08%), and acetaminophen plus dexibuprofen was the most common combination (28,065/54,842, 51.17%). We observed inappropriate use, including triple combination (1205/206,859, 0.58%) and use under 38 ℃ (11,361/206,859, 5.50%). Combination antipyretic use increased with temperature; 23.82% (33,379/140,160) of cases were given a combination treatment when 38 ℃ ≤ temperature < 39 ℃, while 41.40% (1517/3664) were given a combination treatment when 40 ℃ ≤ temperature. The absolute value of the area under the curve at each hour was significantly higher in the single group than in the combination group; this trend was consistently observed, regardless of the type of antipyretics. In particular, the delta fever during the first 6 hours between the two groups showed the highest difference. The combination showed the lowest delta fever among all cases. Antipyretics combination patterns were analyzed using large-scale data. Approximately 75% of febrile cases used single antipyretics, mostly acetaminophen, but combination usage became more frequent as temperature increased. However, combination antipyretics did not show definite advantages over single antipyretics in defervescence, regardless of the combination. Single antipyretics are effective in reducing fever and relieving discomfort in febrile children.

Park YR ，Kim H ，Park JA ，Ahn SH ，Chang S ，Shin JW ，Kim M ，Lee JH ... -  《JMIR mHealth and uHealth》

Postvaccination Fever Response Rates in Children Derived Using the Fever Coach Mobile App: A Retrospective Observational Study.

Postvaccination fever is a mild adverse event that naturally improves without complications, but is highly prevalent and can be accompanied by febrile convulsions in some cases. These adverse effects may cause parents to delay or avoid vaccinating their children. This study aimed to identify postvaccination fever patterns and the ability of antipyretics to affect changes in these patterns from data collected from a mobile app named Fever Coach. Data provided by parents of feverish children derived from a mobile app, Fever Coach, were used to identify postvaccination fever patterns according to vaccinations and the use of antipyretic drugs. We selected single vaccination records that contained five or more body temperature readings performed within 48 hours of vaccination, and we analyzed postvaccination fever onset, offset, duration, and maximum body temperature. Through observing the postvaccination fever response to vaccination, we identified the effects of antipyretic drugs on postvaccination fever onset, offset, and duration times; the extent of fever; and the rate of decline. We also performed logistic regression analysis to determine demographic variables (age, weight, and sex) involved in relatively high fevers (body temperature ≥39°C). The total number of Fever Coach users was 25,037, with 3834 users having entered single vaccination records, including 4448 vaccinations and 55,783 body temperature records. Most records were obtained from children receiving the following vaccinations: pneumococcus (n=2069); Japanese encephalitis (n=911); influenza (n=669); diphtheria, tetanus, and pertussis (n=403); and hepatitis A (n=252). According to the 4448 vaccination records, 3427 (77.05%) children had taken antipyretic drugs, and 3238 (89.15%) children took antibiotics at body temperatures above 38°C. The number of children taking antipyretics at a body temperature of 38°C was more than four times that of those taking antipyretics at 37.9°C (307 vs 67 cases). The number of instances in which this temperature threshold was reached was more than four times greater than the number when the temperature was 37.9°C. A comparative analysis of antipyretic and nonantipyretic cases showed there was no difference in onset time; however, offset and duration times were significantly shorter in nonantipyretic cases than in antipyretic cases (P<.001). In nonantipyretic cases, offset times and duration times were 9.9 and 10.1 hours shorter, respectively, than in antipyretic cases. Body temperatures also decreased faster in nonantipyretic cases. Influenza vaccine-associated fevers lasted relatively longer, whereas pneumococcus vaccine-associated fevers were relatively short-lived. These findings suggest that postvaccination fever has its own fever pattern, which is dependent on vaccine type and the presence of antipyretic drugs, and that postvaccination temperature monitoring may ease fever phobia and reduce the unnecessary use of antipyretics in medical care.

Ahn SH ，Zhiang J ，Kim H ，Chang S ，Shin J ，Kim M ，Lee Y ，Lee JH ，Park YR ... -  《JMIR mHealth and uHealth》

Combined and alternating paracetamol and ibuprofen therapy for febrile children.

Health professionals frequently recommend fever treatment regimens for children that either combine paracetamol and ibuprofen or alternate them. However, there is uncertainty about whether these regimens are better than the use of single agents, and about the adverse effect profile of combination regimens. To assess the effects and side effects of combining paracetamol and ibuprofen, or alternating them on consecutive treatments, compared with monotherapy for treating fever in children. In September 2013, we searched Cochrane Infectious Diseases Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; EMBASE; LILACS; and International Pharmaceutical Abstracts (2009-2011). We included randomized controlled trials comparing alternating or combined paracetamol and ibuprofen regimens with monotherapy in children with fever. One review author and two assistants independently screened the searches and applied inclusion criteria. Two authors assessed risk of bias and graded the evidence independently. We conducted separate analyses for different comparison groups (combined therapy versus monotherapy, alternating therapy versus monotherapy, combined therapy versus alternating therapy). Six studies, enrolling 915 participants, are included. Compared to giving a single antipyretic alone, giving combined paracetamol and ibuprofen to febrile children can result in a lower mean temperature at one hour after treatment (MD -0.27 °Celsius, 95% CI -0.45 to -0.08, two trials, 163 participants, moderate quality evidence). If no further antipyretics are given, combined treatment probably also results in a lower mean temperature at four hours (MD -0.70 °Celsius, 95% CI -1.05 to -0.35, two trials, 196 participants, moderate quality evidence), and in fewer children remaining or becoming febrile for at least four hours after treatment (RR 0.08, 95% CI 0.02 to 0.42, two trials, 196 participants, moderate quality evidence). Only one trial assessed a measure of child discomfort (fever associated symptoms at 24 hours and 48 hours), but did not find a significant difference in this measure between the treatment regimens (one trial, 156 participants, evidence quality not graded). In practice, caregivers are often advised to initially give a single agent (paracetamol or ibuprofen), and then give a further dose of the alternative if the child's fever fails to resolve or recurs. Giving alternating treatment in this way may result in a lower mean temperature at one hour after the second dose (MD -0.60 °Celsius, 95% CI -0.94 to -0.26, two trials, 78 participants, low quality evidence), and may also result in fewer children remaining or becoming febrile for up to three hours after it is given (RR 0.25, 95% CI 0.11 to 0.55, two trials, 109 participants, low quality evidence). One trial assessed child discomfort (mean pain scores at 24, 48 and 72 hours), finding that these mean scores were lower, with alternating therapy, despite fewer doses of antipyretic being given overall (one trial, 480 participants, low quality evidence) Only one small trial compared alternating therapy with combined therapy. No statistically significant differences were seen in mean temperature, or the number of febrile children at one, four or six hours (one trial, 40 participants, very low quality evidence). There were no serious adverse events in the trials that were directly attributed to the medications used. There is some evidence that both alternating and combined antipyretic therapy may be more effective at reducing temperatures than monotherapy alone. However, the evidence for improvements in measures of child discomfort remains inconclusive. There is insufficient evidence to know which of combined or alternating therapy might be more beneficial.Future research needs to measure child discomfort using standardized tools, and assess the safety of combined and alternating antipyretic therapy.

Wong T ，Stang AS ，Ganshorn H ，Hartling L ，Maconochie IK ，Thomsen AM ，Johnson DW ... -  《-》

Cochrane in context: Combined and alternating paracetamol and ibuprofen therapy for febrile children.

Health-care professionals frequently recommend fever treatment regimens for children who either combine paracetamol and ibuprofen or alternate them.However, there is uncertainty about whether these regimens are better than using single agents and about the adverse effect profile of combination regimens. To assess the results and side effects of combining paracetamol and ibuprofen, or alternating them in consecutive treatments, compared with monotherapy for treating fever in children. In September 2013, we searched Cochrane Infectious Diseases Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; EMBASE; LILACS and International Pharmaceutical Abstracts (2009-2011). We included randomized controlled trials that compared alternating or combined paracetamol and ibuprofen regimens with monotherapy in children with fever. One review author and two assistants independently screened the searches and applied the inclusion criteria. Two authors assessed risk of bias and graded the evidence independently. We conducted various analyses for different comparison groups (combined therapy versus monotherapy, alternating therapy versus monotherapy and combined therapy versus alternating therapy). Six studies, enrolling 915 participants, are included. Compared to administering a single antipyretic alone, administering combined paracetamol and ibuprofen to febrile children can result in a lower mean temperature at 1 hour after treatment (mean difference -0.27 ∘C, 95% confidence interval -0.45 to -0.08, two trials, 163 participants, moderate quality evidence). If no further antipyretics are given, combined treatment probably also results in a lower mean temperature at 4 hours (mean difference -0.70 ∘C, 95% confidence interval -1.05 to -0.35, two trials, 196 participants, moderate quality evidence), and in fewer children remaining or becoming febrile for at least 4 hours after treatment (relative risk 0.08, 95% confidence interval 0.02 to 0.42, two trials, 196 participants, moderate quality evidence). Only one trial assessed a measure of child discomfort (fever, associated symptoms at 24 and 48 hours), but did not find a significant difference in this measure between the treatment regimens (one trial, 156 participants, evidence quality not graded). In practice, caregivers are often advised to initially provide a single agent (paracetamol or ibuprofen), and then provide a further dose of the alternative if the child;s fever fails to resolve or recurs. Giving alternating treatment in this manner may result in a lower mean temperature at 1 hour after the second dose (mean difference -0.60 ∘C, 95% confidence interval -0.94 to -0.26, two trials, 78 participants, low quality evidence), and may also result in fewer children remaining or becoming febrile for up to 3 hours after it is given (relative risk 0.25, 95% confidence interval 0.11 to 0.55, two trials, 109 participants, low quality evidence). One trial assessed child discomfort (mean pain scores at 24, 48 and 72 hours), finding that these mean scores were lower, with alternating therapy, despite fewer doses of antipyretic being given overall (one trial, 480 participants, low quality evidence) Only one small trial compared alternating therapy with combined therapy. No statistically significant differences were seen in mean temperature or in the number of febrile children at 1, 4 or 6 hours (one trial, 40 participants, very low quality evidence). In all the trials, there were no serious adverse events that were directly attributed to the medications used. There is some evidence that both alternating and combined antipyretic therapies may be more effective at reducing temperatures than monotherapy alone. However, the evidence for improvements in measures of child discomfort remains inconclusive. There is insufficient evidence to decide which of combined or alternating therapy might be more beneficial. Future research needs to measure child discomfort using standardized tools, and assess the safety of combined and alternating antipyretic therapies.

Wong T ，Stang AS ，Ganshorn H ，Hartling L ，Maconochie IK ，Thomsen AM ，Johnson DW ... -  《-》

The antipyretic efficacy and safety of propacetamol compared with dexibuprofen in febrile children: a multicenter, randomized, double-blind, comparative, phase 3 clinical trial.

Choi SJ ，Moon S ，Choi UY ，Chun YH ，Lee JH ，Rhim JW ，Lee J ，Kim HM ，Jeong DC ... -  《BMC Pediatrics》