Long-term Health Effects of Antipyretic Drug Use in the Ageing Population: A Systematic Review


 Background: It is unclear whether fever suppression is beneficial or harmful in the long term in the elderly, due to different immune profile and body temperature compared to the young. Our objective was to determine the long-term health effects of antipyretic treatment in the elderly during infections.Methods: A systematic review was carried out using PubMed, Embase and Cochrane CENTRAL databases. Studies with a sample age ≥60 years investigating any antipyretic drug during infections, comparing with any other drug/therapy/placebo/none were included. Studies in which these drugs were used in roles other than antipyresis were excluded. Databases were searched from their inception until the date of last analysis (27/03/2021). Primary outcome was the onset or worsening of chronic inflammatory diseases. Secondary outcomes were fever reduction, length of hospital stay, patient satisfaction, mortality, laboratory parameters indicative of morbidity, and progress to complications. The Risk of Bias (ROB) was assessed for each study type with the respective ROB formats– Cochrane’s ROB tool for RCTs, ROBINS-I tool for observational studies, Joanna Brigg’s critical appraisal tool for case series and the Cochrane handbook prescribed domains for case reports. Narrative synthesis was performed because high heterogeneity rendered meta-analysis impossible.Results: Of 11481, 17 studies (2 RCTs, 7 observational, 1 case series and 7 case reports) were included. No studies investigated the primary outcome and patient-reported outcomes.The Risk-of-bias of the studies was unclear to high. Fever reduction was significant in the RCTs, in the antipyretic group. BP drop was significant in five studies, in the antipyretic group. Morbidity indicators and length of stay were available only in studies that reported adverse events. Mortality was significant for these drugs in one observational study. The certainty of evidence (GRADE) was low to very low for all outcomes, including fever reduction and mortality. Discussion/Conclusions: There is insufficient evidence regarding the long-term benefit or harm from fever suppression with antipyretics during infections in the elderly. Systematic review registration: This study was funded by the Taylor’s University Ageing Flagship Program and the protocol was registered on PROSPERO (registration number: CRD42020160854)

The data from these studies was extracted to personalised data extraction forms (38) of the Cochrane Effective Practice and Organisation of Care (EPOC) (supplementary material). Full-text screened studies, when excluded, were done so with explanation in these forms. Table 1 provides the characteristics of included studies including the study design, number of participants, interventions, outcomes assessed, and the risk of bias.
Totally, there were 25,722 participants from 17 studies.
The interventions in these studies were acetaminophen and its derivatives, and NSAIDs, compared between themselves, external cooling, with placebo or not compared at all.
A meta-analysis was not possible as the data could not be pooled. This was because, i) the study designs were heterogenous ii) the outcomes were measured at different time points, using various techniques and were reported in heterogenous ways and iii) some studies used comparison between interventions, and others did not. Therefore, a narrative synthesis was conducted, following the guidelines of the Cochrane Consumers and Communications Group (44) (Supplementary material) and the ESRC methods programme (45). The results were synthesised accordingly, and the review reported, in keeping with the PRISMA (64) and the SWiM protocol extension for narrative synthesis (65) (Supplementary material). To assess the certainty of evidence, the guidelines adapting the GRADE assessment for narrative synthesis (43) was followed. The nal ndings were represented in a summary of ndings table.

Grouping by study types
The studies were grouped according to the study design as their natural similarities rendered well for comparing effects. Below is a summary of all included studies according to the study type.

RCTs
Both the RCTs compared the antipyretic drugs among themselves and with placebo for e cacy of fever reduction. They also reported the adverse events.
Cunietti's study included participants with simple self-limiting upper respiratory tract bacterial/viral infections.

Observational studies
Four of the ve prospective observational studies focused on the cardiovascular effects along fever reduction from intravenous antipyretics. Furthermore, Krajcova's study investigated the mechanism of hypotension by observing cardiac output related measurements. Cantais' and Lee's studies investigated mortality from antipyretics. Lee further sought to compare the effect of antipyretic therapy between sepsis and non-sepsis groups. They also incorporated fever temperature ranges and investigated for association of mortality and antipyretic therapy.
Both the included retrospective observational studies investigated mortality from antipyretics and external cooling, comparing those who developed sepsis with those who did not.
All the included observational studies were conducted on ICU patients.

Case series and reports
The case series reported Steven Johnson syndrome and toxic epidermal necrolysis from antipyretics during viral infections. The case reports reported on adverse events from antipyretics taken for common conditions such as u and upper respiratory tract infections. The adverse evets reported were pneumonitis, hypotension, eosinophilia, xed drug eruption, SJS/TEN and aseptic meningitis.

Risk of bias (ROB)
The two RCTs had unclear ROB, due to unavailability of the full text and original publication and all the other studies had high ROB due to their study designs and some due to confounding and missing data. (Table 1)  No study investigated the primary outcome, onset/worsening of chronic in ammatory disease from antipyretic use. We could nd no study that investigated patient satisfaction from use of these drugs either.
Fever reduction: Antipyretics were bene cial in reducing fever as seen in the included  (50,53). The case series did not contribute to this outcome and only one case report mentioned that "fever reduced" after paracetamol (60). Heart rate was also measured in four studies and showed a trend towards reduction after the administration of antipyretics, although the degree of reduction did not reach statistical signi cance (47,49,50,58). One study found a non-statistical signi cant trend towards reduction in peripheral resistance and cardiac output from antipyretic drugs (49).  A mean 51.5 days resulted from the antipyretic treatment adverse effects in the case series (56). Case reports yielded a mean 4 days from the adverse effect of these drugs (57)(58)(59)(60)(61)(62)(63). The observational study that reported the length of stay did not assess the effect of treatment on it (53). The details of laboratory markers in uenced by antipyretic drugs was provided in the case reports of adverse events (56-63). Detailed laboratory readings from these studies are provided in the supplementary material

Adverse events
Adverse events were reported in the RCTs, the case series and all the case reports. Altogether, 18 episodes of adverse effects were reported in 10 studies (47, 48, 56-63), including mild transitory effects, hypotension, Steven Johnson syndrome/toxic epidermal necrolysis, aseptic meningitis, pneumonia, and xed drug eruption. All the case reports con rmed causality of the adverse events.

Discussion
Though the primary objective of this study was to assess the long-term effects of fever suppression, we did not restrict the follow-up period of the study for inclusion as we were also interested in the immediate effects, which were our secondary outcomes of interest. The period of observation in included studies ranged from 2 hours to 4 months. Only two studies had follow-ups long enough to assess long term effects but neither made any comment nor observation of such effects. The reviewed literature offers some insight into the widely variable role of fever during infections in humans. In this study, we could not nd any evidence regarding the chronic in ammatory disease onset or worsening from fever suppression but identify it as a knowledge gap considering many immunological studies addressing this phenomenon (30,32,66). While in common infections, which are self-limiting, pharmacological antipyresis use is bene cial in reducing the temperature and alleviating the symptoms (47,48,60), the same bene t was not appreciated in sepsis or critical illness (49)(50)(51)(52)(53)(54)67).
Physical cooling appeared not to have bene t, except in those who were sedated and were suffering severe sepsis (50,53,54,67), where some bene ts like decrease of energy expenditure, reduction of fever and heart rate were observed (50). There was a strong association of mortality with antipyretic therapy at high fever range in sepsis (67). The reason behind the ndings was postulated by some authors as possibly resulting from the difference in the role fever plays in different subjects during different infection episodes with varying severity. Fever is protective in some and harmful in others (53). The available meta analyses regarding active fever management compared to less active intervention yielded no supporting evidence for such intervention even in physiologically compromised individuals (68).The best recommendation so far seems to be that each case must be regarded for immune compromise and organ damage before recommending or refuting antipyresis (69). They also recommend watching out for organ dysfunction and presence of acute brain pathologies/coma/cardiac arrest before deciding the regimen. The recommendation is permissive fever management in the absence of such pathologies or organ compromise, where the temperature is below 41 o C. However, this recommendation is not based on high quality evidence and is generalised to all cases with fever in the ICU and needs further investigation.
Hypotension appeared to be an adverse effect of note following the administration of antipyresis, as it was reported in seven of the included studies (47,(49)(50)(51)(52)61). The mechanism of development of hypotension was postulated by the study authors as probably resulting from loss of peripheral resistance and decreased cardiac output (49). Other adverse events, like pneumonitis, anaphylactoid reaction, SJS/TEN, xed drug eruption and aseptic meningitis were rare but adequately reported in seven studies (56-60, 62, 63). The length of stay and morbidity indicators were available but were of little consequence.
Earlier systematic reviews investigating the effect of antipyretic treatment on sepsis either found insu cient evidence for any robust estimate to be made regarding mortality from such treatment, or favourable evidence for fever reduction (67, [70][71][72][73]. However, they did not consider the elderly speci cally and did not include non-randomised studies.
This review focussed on elderly people and included all study types. The reviewers decided early on to include case series and reports. While it is desirable to conduct a systematic review and meta-analysis of RCTs for their methodological superiority, a study aiming to assess the adverse effects of a drug may not nd much evidence in them. The ethical/practical issues associated with conducting such studies make it necessary to include observational studies. The evidence is more likely to be better represented in anecdotal reports such as case series and case reports where the real-world situation is depicted better. The inclusion population for RCTs is usually very restricted, making the inclusion of case series, case reports and observational studies imperative, to be able to get more generalisable evidence. However, the inherent limitations of these reports mandate a cautious approach in their assessment and incorporation into the body of evidence.
In the end, with the scarce ndings on elderly population were similar to those in previous systematic reviews on general population.

Assessment of large studies
There were three large studies in this review (53)(54)(55) which incidentally compared antipyretic drug with external cooling. Lee et. al. compared these in septic and non-septic patients whereas Ye's and Zhang's study compared them only in septic patients. All three studies investigated mortality only. Forest plots of these studies (Figs. 2, 3 and 4) show that there may be slightly more mortality in the antipyretic drug group when compared to non-treatment in the septic patients, although, this was not statistically signi cant. All three studies, however, show a signi cant increase in mortality from antipyretic therapy in general (combining external cooling and drugs) against non-treatment in the septic patients. However, this effect seems to result mostly from the external cooling than drugs. The certainty of evidence on mortality from these three studies is low as they are observational studies and have a glaring confounding factor that cannot be ruled out -that the sicker patients may have been given antipyretic therapy compared to those who were less sick, automatically increasing the mortality. Thus, even considering the large studies included in this review, it is not possible to recommend or deter treatment of fever with antipyretic drugs in the elderly during infections.
Thus, while in the individual studies, we found signi cant effect of the antipyretic drugs on fever reduction, mortality, and development of hypotension, when the ndings were synthesised systematically, their certainty turned out to be low or very low.

Strengths and Limitations
The strength of this study is that it considered a wide range of study designs, including case reports and case series, allowing for the review to be close to realworld clinical situations and cover a broad base with regard to aetiology. The review faced challenges in procurement of full text from Reiner's study and original publication of Cunietti's. Poblete's study was also lacking in explicit information separately for the elderly. We had to work with partial data that was available. Furthermore, the primary outcome of interest was not evaluated and reported in any study. We emphasise this as a research gap and advise a study assessing the long-term effect of antipyretic drugs in the elderly. As a review looking at the harmful effects from an intervention, narrative synthesis creates limitation in our ability to quantitatively compare the effect. This could not be avoided due to the heterogeneity of measures and study types. However, narrative synthesis when conducted systematically as done here, adhering meticulously to the framework followed by rigorous quality assessment of the evidence, provides an overall picture about the outcomes, which is reliable to a great extent.

Future research
With this review, the question of long-term effect of antipyretic treatment in the elderly during infections was identi ed as a research gap and considering the proclivity of such practice in general population, we need to investigate this in the future. We identi ed issues in the conduct of investigations that may be responsible for such confusion on the subject. The population of aging adults has not been the focus of any quality study. This is essential as the immunological phenomena changes with age and what applies to the younger population may not be applicable in the aged. Furthermore, none of the studies conducted a long enough follow up to observe long-term effect of the acute disease with fever or the effect of antipyretics. This again, is an important factor to consider, as the elderly tend to suffer from chronic in ammation as already demonstrated, and drugs can be major modulators of the immune system. Such studies with long enough follow up period and of su cient sample size need to be conducted. There are a few confounders that the studies need to take care of. For example, most studies did not differentiate between pharmacological antipyresis and external cooling. This is a aw as the mechanism of temperature reduction by these two methods and the body's response to them are entirely different. Similarly, it would be better to separate the population based on seriousness and aetiology of their illness for the study. The adverse events that develop from such drugs are amply available in case reports and series and such data need to be used for immunological research to identify the exact mechanism behind them to guide in whom such treatment must be avoided. Immunological studies also need to investigate the connection between fever and chronic in ammation as the latest pandemic has given rise to interesting observations such as absence of fever and presence of chronic comorbidities leading to increased mortality from the infection (74,75). We need to examine these factors through extensive observational studies and use the results to plan RCTs to evaluate the exact relevance of antipyretic treatment in the elderly.
Furthermore, we also require physiological and immunological studies to identify the role of fever is sepsis in the elderly and what exactly happens during an antipyretic treatment.

Conclusions
In summary, this systematic review and narrative synthesis of long-term health effects of fever treatment with antipyretic drugs during infections in the elderly could not nd su cient evidence for any rm conclusion. Speci cally, no evidence was available for the association between fever suppression and chronic in ammatory disease. The evidence regarding fever reduction and mortality were of low quality and those regarding hemodynamic alterations, length of stay and adverse events of very low certainty. Future high-quality studies with su cient follow up period, addressing this question are warranted, considering how common the use of antipyretics is in the elderly and how easily this population suffers from the effects of acute in ammatory diseases.

Declarations
Funding: Taylors University ageing agship program. The funders had no role in design or execution of the study Con icts of interest: The authors declare no con ict of interest Authors' contributions: SM conceived and designed the study, performed the research, analyzed the data and wrote the paper EvdW designed the study, analyzed the data and contributed to paper writing MM conceived the study and performed the research GV conceived the study and analyzed the data LNM designed the study, analyzed the data and contributed to paper writing Forest plot showing mortality odds ratio of antipyretic drugs against external cooling in sepsis patients.

Figure 3
Forest plot showing mortality odds ratio of antipyretic drugs against external cooling in non-sepsis patients.

Figure 4
Forest plot showing mortality odds ratio of antipyretic drugs against non-therapy in sepsis patients.

Supplementary Files
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