What Is Known
- Infliximab is a commonly prescribed and highly effective drug for several pediatric diseases, such as Inflammatory bowel disease and juvenile idiopathic arthritis.
- The drug is usually infused over 2 to 3 hours.
- In adults, an accelerated infusion time of 1 hour is safe.
What Is New
- Three retrospective studies and 1 prospective study (including 4 children) have investigated the safety of accelerated infliximab infusions in children.
- None of these studies report an increase in infusion reactions after accelerating infusion time.
- There is insufficient evidence to draw firm conclusions about the safety of accelerated infliximab infusions in children.
Infliximab (IFX), a TNF-alpha inhibitor, is a commonly prescribed drug for several pediatric diseases, such as inflammatory bowel disease (IBD) and juvenile idiopathic arthritis (JIA). Its route of administration is intravenous, and it is administered with a 4- to 8-week interval in an inpatient setting. The drug is usually infused over 2 to 3 hours followed by an 1 hour observation period for the risk of infusion reactions (IR) (1). Although this drug is highly efficacious, the repetitive inpatient administrations are both costly and time consuming for patients, parents and health care. If infusion duration could be shortened to 1 hour, patient's quality of life could be improved (2) and costs could be saved (3,4). Accelerated infusions have been, however, hypothesized to increase risk of IR, for instance by increasing the risk of complement activation-related pseudo allergy or cytokine release syndrome (5). A meta-analysis on the safety of rapid IFX infusions—compromising 13 147 standard infusions and 8497 rapid infusions—in mostly adult patients published in 2013 did not confirm this hypothesis and demonstrated the safety of rapid infusions in patients who had previously tolerated 3 standard infusions (6). Only 2 studies with pediatric patients were, however, included in this meta-analysis and both also included adolescents and adults. Moreover, several pediatric studies have been conducted after this publication. Although these studies suggest a similar effect on incidence of IR in children, most of these studies are small in number or miss a comparison group. In order to safely change the infusion protocols for pediatric patients, more data about the safety of rapid IFX infusions in pediatric patients are needed. This systematic review (SR) aimed to answer the following question: “Does the incidence of IR increase after short (≤1 hour) IFX infusions, compared with the incidence of IR after standard infusions in children ages 0–18 years?”.
The search was conducted in December 2018 with the help of a clinical librarian (J.D.) in the PubMed, Embase (Ovid), Cochrane Library, CINAHL (EBSCO) and Web of Science databases. Inclusion criteria were studies describing the number of IR after rapid IFX infusion, defined as an infusion time of up to 1 hour in children ages 0 to 18 years for any disease. Exclusion criteria were studies whose full text was unavailable and articles not written in English, French, German, Spanish, Italian or Dutch. We did not restrict our search to a certain period of time.
The search terms are shown in the supplementary material (Supplemental Digital Content, http://links.lww.com/MPG/B865). The titles and/or abstracts were screened independently by 2 reviewers (E.W. and J.O.) to identify potentially eligible studies. The full texts of these potentially eligible studies were then retrieved and independently assessed for eligibility by the same reviewers. Any disagreements were resolved through discussion with a third reviewer (B.K.).
To extract data from the included studies, a standardized, pre-piloted form was used. Extracted data included: number of patients, number of infusions, number of different treatment groups, definition and classification of IR, and patient characteristics: sex, age, diagnosis, concomitant immunomodulators or corticosteroids, premedication, number of standard infusions before starting with rapid infusions, dose of IFX, brand of IFX (eg, Remsima/Remicade/Inflectra). Data were extracted by 2 reviewers (E.W. and J.O.).
To assess methodological quality, we planned to use the ROBINS-II tool for prospective observational studies, the Cochrane Collaboration's tool for Randomized Controlled Trials and no quality assessment in case of retrospective studies as the latter are known for high risk of bias and assessing methodological quality would not be of additional value.
We planned to perform a meta-analysis if at least 2 prospective studies were included and if individual patient data could be obtained. We chose not to include retrospective studies in the meta-analysis, because of the high risk of reporting bias and bias by unreported confounders.
After removal of duplicates, 997 records were identified. After title/abstract screening, 927 studies were excluded and 70 full text articles were checked (Fig. 1). Reasons for exclusion were different patient populations (eg, no children or age unspecified) (n = 48), no original research (n = 5), different study design (not about rapid infusions or IR) (n = 3) and no full texts (eg, conference abstracts or letter to the editor) (n = 10). One study included patients ages 2 to 28 years old and 1 included patients ages 6 to 21 years old, but despite efforts to contact the authors, the data on children only could not be retrieved (7,8). These studies were, therefore, not included. Finally, 4 studies, including a total of 498 patients were included in this SR: 3 retrospective studies including 494 children (4,9,10), and 1 prospective study including 4 children (11). Study characteristics are shown in Table 1.
The risk of bias was not assessed, as we only included 1 prospective study that consisted of only 4 children.
The definitions used by the studies included to define IR are shown in Table 1. A total of 347 standard infusions and 3703 rapid infusions were studied. The rates of IR per infusion of all studies included, are summarized in Table 2. The rate of IR per patient reported by the studies included ranged from 0% to 15% of patients (reported 95% CIs ranged from 0% to 42%) in the standard groups, and from 0% to 10% of patients in the rapid groups (reports 95% CIs ranged from 0% to 33%). Of the 3 studies that compared a rapid group to a standard group, none reported a clinically significant difference between groups. No meta-analysis could be performed as we only found 1 fully prospective study, including 4 children.
Details about usage of premedication (PM) and concomitant immunomodulators (CT) are displayed in Table 3. The number of patients using PM and CT differed between the standard and rapid group in 2 studies. Presence of antibodies against IFX were measured in a subset of patients in 1 study, and none of the studies reported IFX trough levels.
In this SR, we described the incidence of IR after a standard IFX infusion, lasting 2 to 3 hours, and after a rapid infusion, defined as 1 hour or less, in pediatric patients. Although we could not properly compare the incidence rates, none of the included studies reported a statistically significant difference in IR between the 2 infusion protocols. Overall, the reported rate of IR in children receiving rapid IFX infusions was low: reported incidences ranged from 0% to 2% of infusions, which is comparable to incidences of 1.4% to 8.5% previously reported in studies on standard IFX infusions in pediatric patients (12–14). Reducing the infusion time could be of benefit both for patients and guardians, who would have to spend less time in the hospital, and for health care as it saves costs and shortens the admission time per patient.
The results of the studies included are in line with the results from a previously published meta-analysis, which even showed a pooled relative risk of 0.45 (95% CI 0.25–0.80; P = 0.007) in favor of the rapid infusions (6). Patients included in this meta-analysis were mostly adults and all received 3 to 4 standard infusions without any adverse events before they could enter into the rapid infusion protocol. As both adult and pediatric studies were only cohort studies and not randomized trials, one could argue that the superiority of rapid infusions was the result of selection bias, as participants only received fast infusions after tolerating the first few regular infusions. This argument is not, however, supported by a recent study on IR in 226 children with IBD, which reported that the first infusion reaction on average happens at the sixth infusion (13).
The strength of the current SR is the thorough search strategy and to the best of our knowledge, all of the studies on the safety of accelerated IFX infusions in children were included in this SR. Unfortunately, all but 1 study had a retrospective design, which is prone to several types of bias; the selection bias mentioned above, and reporting bias potentially leading to underestimation of the number of reported IR. In addition, retrospective studies are at risk for confounding. In literature, usage of premedication (PM) and concomitant immunomodulators (CT) have been described as protective factors against IR (15), and presence of antibodies against IFX (ATI), among others, has been described as a potential risk factor. In half of the studies included in this SR, the number of patients on CT and PM were not equally distributed between the standard and rapid groups, and presence of ATI was only reported in a subset of patients in 1 study. This may have biased the outcomes, although the unequal distributions in use of CT and PM were not skewed to favor 1 treatment. In addition, the relevance of PM for the development of IR has not been confirmed in a number of recent studies (7,13). Also, the included studies used different definitions of IR: some reported acute IR only, whereas another study also reported delayed IR. Therefore, it is still not possible to draw a firm conclusion on the safety of accelerated IFX infusions.
A noninferiority randomized trial is needed to answer our research question. In such a trial, the usage of PM and CT could be standardized and presence of ATI could be measured. Also, more importantly, reporting of IR could be protocolized. It would, however, be difficult to perform such a trial, as a large sample size of approximately 500 participants per arm would be needed to reach a power of 80%.
In conclusion, this SR shows that there is insufficient evidence to conclude whether the rate of IR changes after shortening infusion time from 2 or 3 hours to 1 hour in children receiving IFX. The consistent finding of no increase in IR in all studies and the low rate of observed IR does suggest that there is no important difference in IR between standard and rapid infusions. A noninferiority randomized trial should be performed to prove this statement.
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