Infliximab is a chimeric monoclonal antibody against tumor necrosis factor-α (TNF-α). It is effective in the treatment of moderate to severe Crohn disease (CD) in adults (1–2). Repeated doses at 8-week intervals are effective as maintenance therapy for adults with CD (3). Although pediatric experience is limited, infliximab appears to be effective in the treatment of CD in children and adolescents (4–9).
Infliximab side effects in adults include acute infections and reactivation of latent tuberculosis (TB), infusion reactions, delayed hypersensitivity reactions, serum sickness and an association with malignancy (3,10). In adults, infusion reactions occur in 3% to 6% of infusions affecting 6% to 32% of patients depending on concomitant use of immunosuppressive medications (3,11,12). Stephens et al. recently reported on 432 infliximab infusions administered to 82 pediatric CD patients, the largest experience to date (7). Infusion reactions occurred in 5.3% of infusions and unusual infections in 4% of patients. In a smaller study comparing children and adults, infusion reactions were less frequent in children than adults (13).
We report our experience with 594 infusions in 111 pediatric inflammatory bowel disease (IBD) patients to further delineate the incidence of complications associated with infliximab in this patient population.
SUBJECTS AND METHODS
We reviewed all infliximab infusions administered to patients with inflammatory bowel disease (IBD) at the Children’s Mercy Hospital between July 1, 1998, and April 14, 2003. Data was obtained from an infliximab infusion database maintained by the section of Pediatric Gastroenterology, hospital pharmacy records and patient charts. Data gathered included age, gender, diagnosis, medications and number of infusions. All immediate symptoms were recorded at the time of the infusion and all immediate and delayed symptoms were recorded in the infusion database. Additionally, any infections other than common viral infections (e.g., upper respiratory infections) were recorded in the patient chart and database at the time of occurrence. The database and charts were reviewed to determine the incidence and type of infusion reactions and the incidence of unusual infections.
Infusions were given in a hospital setting either an inpatient unit or outpatient observation unit. Outpatient infusions were administered in an infusion center with continuous observation by a nurse. According to our standard practice, all patients were premedicated with prednisolone (1 mg/kg to a maximum of 50 mg IV) and diphenhydramine (1 mg/kg to a maximum of 50 mg IV). The same regimen was used in patients re-infused after a previous reaction. Any immediate reactions were treated with additional doses of diphenhydramine and slowing of the infusion rate or discontinuation of the infusion.
Immediate infusion reactions were defined reactions occurring during or within 1 hour after infusion. Symptoms considered immediate reactions included a drop in blood pressure, shortness of breath, oxygen desaturation, fever or any rash, including urticaria. Any symptoms occurring during the infusion were recorded and reported. Delayed reactions were defined as arthralgias or joint stiffness and/or edema occurring more than 1 day post-infusion. Delayed symptoms were recorded and reported. All patients with suspected delayed reactions were evaluated by the physician. Corticosteroid treatment of suspected delayed reactions was initiated at the discretion of the attending physician. The incidence of reactions in males and females and in patients with CD and UC was compared by Fisher’s exact test.
This study was reviewed by the Institutional Review Board of the Children’s Mercy Hospital and granted exempt status.
A total of 111 IBD patients received 594 infusions. There were 88 patients with CD (79%) and 23 with UC (21%). There were 55 males and 56 females. Patients ranged in age from 4 to 20 years with a mean of 13.4 ± 2.9 years. Patients received from 1 to 24 infusions with a mean of 5.4 ± 4.7 infusions/patient. The infusion number distribution is shown in Figure 1. CD patients received a total of 514 infusions and UC patients received a total of 80 infusions. Concomitant immunomodulating medication used included 6-mercaptopurine (6MP) or azathioprine alone in 48%, prednisone with either 6MP or azathioprine in 34%, prednisone alone in 9%, budesonide in 4% (two of the four with 6MP), methotrexate in 2% (one of the two with prednisone) and no medication in 3%.
The mean follow-up from the initiation of infliximab therapy was 19.9 ± 12.9 months (range, 1 to 54 months). A total of nine (seven early and two delayed) infusion reactions occurred. One early reaction occurred in a patient with UC, and all other reactions occurred in patients with CD. No patient with an acute reaction had more than a single reaction despite the continuation of treatments. Neither of the patients with delayed reactions received subsequent infusions. Early reactions consisted of shortness of breath and chest pain in four patients (one with hives, one with flushing, one with oxygen desaturation and one with a decrease in blood pressure), throat tightening and facial numbness in one and a rash in two. Early reactions occurred after the second dose in one patient, the third dose in two, the fourth dose in three and the eleventh dose in one. The patient reacting during the eleventh dose had a blotchy rash only. All reactions responded rapidly to IV diphenhydramine. Delayed infusion reactions occurred in two patients after their second and fifth doses, respectively. Reactions were facial and upper extremity swelling with arthralgia in one, and extremity swelling with neuralgia in the other. Both responded within days to oral prednisone. Medication was discontinued in both after 2 weeks without recurrence of symptoms. In patients with infusion reactions, concomitant immunomodulating therapy with 6MP or azathioprine was used in six patients. Three of these six patients also received prednisone, one received budesonide, one received methotrexate with prednisone and one received no other medication.
In summary, reactions were seen in 8.1% of patients and in 1.5% of total infusions. Reactions occurred in 8% of CD patients and 9% of UC patients. The reaction rates for males versus females for all patients and for patients receiving more than one infusion are shown in Figure 2.
No severe or life-threatening infections were encountered. Three patients developed cutaneous tinea infections; two responded to topical treatment alone and the third to oral griseofulvin and topical treatment. Infliximab infusions were continued after a short course of antifungal treatment without exacerbation or recurrence of infection. Shingles occurred in one patient who was also receiving azathioprine. Infliximab infusions were continued in this patient without recurrence. No other infections were identified.
Infliximab is effective in adults with CD for the short-term treatment of moderate to severe disease and as a maintenance regimen (1,3,14). Use of infliximab for pediatric CD was first reported by Hyams et al. (4). Subsequently, infliximab has been reported to be beneficial in pediatric CD patients with moderate to severe disease as well as refractory and steroid-dependent patients (8,9). Kugathasan et al. reported a response rate of 94% in 15 refractory patients and noted a more prolonged response in those patients treated less than 2 years from diagnosis (5). Stephens et al. found infliximab to have a significant steroid-sparing effect, with 58% of patients becoming completely independent of the need for corticosteroids (7).
The effectiveness of infliximab in patients with UC has not been thoroughly evaluated. We have used it in UC patients who are steroid-dependent and with steroid-resistant acute exacerbations. Mamula et al. reported short-term clinical improvement in nine children with moderate to severe UC (15). In 27 adult UC patients, Su et al. reported a positive clinical response in 83% of steroid-responsive patients but in only 33% of steroid-refractory patients (16). Likewise, Probert et al., in a randomized controlled trial, reported infliximab to be ineffective in patients with steroid-resistant UC (17).
Infliximab therapy has been associated with both infusion reactions and delayed hypersensitivity reactions (3). Infusion reactions have been reported in 3% to 13% of adults receiving infliximab (2,3,10). Human antichimeric antibodies develop in 14% of adults treated with infliximab and are associated with an increased incidence of reactions (3,10). Co-therapy with immunomodulating drugs is associated with a decrease in infliximab reactions (10). Hanauer et al. reported infusion reactions in 8% of patients receiving both steroids and immunosuppressives compared with 20% of patients receiving immunosuppressives alone and 32% of patients receiving neither (3).
Until recently, there has been a lack of information on infliximab reactions in pediatric CD. In the largest previous pediatric series, Stephens et al. reported the side effect that occurred in 82 patients receiving 432 infusions (7). Acute infusion reactions occurred in 5.3% of infusions, and no patient experienced delayed reactions. Crandall and Mackner reported infusion reactions in 8.5% of infusions affecting 38.6% of the patients (18). In our patients, infusion reactions occurred in only 1.5% of infusions and affected 8% of the patients. All patients at our institution are premedicated with intravenous methylprednisolone and diphenhydramine, which may have been responsible for the low reaction rate. The use of this premedication regimen was initiated empirically to decrease the frequency of reactions and has been continued because of an observed low reaction rate. Intravenous hydrocortisone has been associated with decreased human antichimeric antibody formation and a trend towards a decrease in infusion reactions from 25% to 15% (P = 0.06) (19). It is possible that some symptoms that may not be associated with physical changes (e.g., headaches or shortness of breath) were not reported by our patients who frequently sleep through much of the infusion after premedication with diphenhydramine. All early reactions at our institution were mild, responded rapidly to therapy and did not preclude continued use of infliximab. Both patients with a delayed reaction declined further infusions.
In our series, gender was a risk factor for a reaction to infliximab with reactions in 14% of females versus 2% of males. Female gender has previously been found (by stepwise logistic regression analysis) to be a risk factor for reaction to a second infusion in pediatric patients predominantly being treated for inflammatory bowel disease (18). Gender has also been identified as a risk factor in adults (20). An explanation for this association has not yet been identified.
The other major concern with infliximab, as with any immunomodulatory drug, is increased susceptibility to infection. TNF-α has a wide range of immune effects, including production of proinflammatory cytokines, promotion of macrophage differentiation and induction of adhesion molecule expression (21). TNF-deficient mice are particularly susceptible to infections such as Candida (22). Infliximab therapy produces a significant down-regulation in mucosal inflammation with a decrease in both polymorphonuclear cells and T lymphocytes (23). T-cell immunodeficiencies are characterized by opportunistic infections with viruses, Pneumocystis carinii and fungi. However, Cornillie et al. were not able to demonstrate systemic suppression of T-cell density or immunocompetence after a single infliximab infusion (24).
The most common infections associated with infliximab therapy are upper respiratory infections (3,14). Although a number of case reports describe a variety of other infections after infliximab, the most commonly reported infections are tuberculosis, histoplasmosis, Listeria monocytogenes and Herpes zoster (25–27). No serious life-threatening infections were seen in our patients, although one patient developed Herpes zoster or shingles. Upper respiratory infections are not tracked at our institution, so their incidence is not known. We noted three patients with cutaneous fungal infection. All occurred near the time that an infusion was due. Although treatment of each infection delayed the next infusion for 1 to 2 weeks, the infections did not preclude further infusions. There were no recurrences with further therapy. Overall, unusual infections were seen in 3.6% of our patients. This is comparable to the 5% rate reported by Stephens et al. and the 4% to 8% rate reported in adults (3,7,12).
In conclusion, our experience supports the use of infliximab as a safe treatment modality for pediatric IBD with a low incidence of generally mild reactions that respond rapidly to interventions. Severe non-infectious reactions such as delayed hypersensitivity reactions can still occur and may preclude further use of this medication. Reactions appear to be more common in female patients. Although associated serious infections appear to be uncommon, cutaneous fungal infections may represent a new complication amenable to therapy that did not necessitate discontinuation of treatment with infliximab.
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