Long-term use of anti-inflammatory agents in the treatment of cystic fibrosis

Blain Fennell

                INTRODUCTION

Cystic fibrosis (CF) is the most common, inherited disease of Caucasians, with a carrier frequency of 1 in 25-30 individuals.  An autosomal recessive defect, occurring in approximately 1 in 2500-3000 live births based on epidemiological data, the life expectancy of a child born with CF has gradually improved, and is now approaching 32 years.¹ In the lungs of patients with CF, aberrant expression or function of the cystic fibrosis transmembrane conductance regulator (CFTR)  in airway surface and submucosal gland epithelial cells leads to persistent infection at the respiratory epithelial surface. ² Staphylococcus aureus, typable and non-typable Haemophilus influenzae, or Escherichia coli may be intermittently isolated from many patients early in life, but these organisms eventually yield the lung to Pseudomonas aeruginosa, ³ which is infrequently found in patients with other pulmonary disorders.  The isolation of mucoid strains of Pseudomonas aeruginosa from the lung of a patient is virtually pathogneumonic for CF, and its early acquisition is associated with a poorer prognosis.⁴

Although the pulmonary infection contributes to the morbidity of patients with CF, the intense host inflammatory response largely accounts for the progressive, suppurative pulmonary disease that leads to bronchiectasis and eventually respiratory failure, thus shortening the life of the patient.  Inflammation in the CF lung is remarkably compartmentalized, with infection and inflammation primarily contained in the airway lumen, while the alveolar space is relatively spared. Despite the ability of the lung to restrict the location of infection, bronchoalveolar lavage (BAL) and biopsies from patients with CF demonstrate an intense endobronchial inflammatory process characterized by high concentrations of pro-inflammatory cytokines and large numbers of neutrophils, even in patients with early, stable, or clinically mild disease. ^2,5,6,7 More recently, anti-inflammatory agents have also been shown to slow pulmonary deterioration, confirming the concept that the inflammation is damaging rather than protective. ^8-10 Specifically, high-dose Ibuprofen has been shown to affect the course of the disease, especially in younger patients or those with milder disease pulmonary inflammation, but these treatments can have dose-limiting toxicities. ⁹

In this study, we reviewed the use of anti-inflammatory therapy in CF children at the Washington University Pediatric Cystic Fibrosis Center at St. Louis Children�s Hospital and the impact of high-dose ibuprofen on progression of lung disease, specifically focusing on the effect of the anti-inflammatory agent on pulmonary function decline and hospitalization rate.  We also examined the frequency of adverse effects of such agents in this patient population

METHODS

Subjects: Clinical and laboratory data collected from CF patients ages 5 to 18 years and receiving care at the Washington University Pediatric Cystic Fibrosis Center from 1996 to 2002 were included in these analyses.  Patients were eligible for enrollment if they had CF diagnosed according to standard clinical and laboratory criteria.  From medical records, the routine use of anti-inflammatory agents (i.e., ibuprofen, systemic corticosteroids, and inhaled corticosteroids) and inhaled antibiotics (i.e., nebulized tobramycin) were recorded for all patients studied.  A total of 53 CF patients, ranging in age 3 to 18 years, began long-term treatment with high-dose ibuprofen, but only 26 patients received the non-steroidal anti-inflammatory agent throughout the entire length of the study.  The reported reasons for discontinuing ibuprofen were recorded.  The majority of patients were treated with generic ibuprofen preparations.  Using established protocols, blood levels and ibuprofen pharmokinetics were performed by the St Louis Children�s Hospital Clinical Laboratory to establish optimal dosing before patients began regular treatment.  Specifically, daily ibuprofen dose was adjusted to achieve serum concentrations of 50-100 �g/ml.  As controls, data from 45 CF children, ages 5 to 13 years, who did not receive chronic ibuprofen therapy was collected and analyzed in parallel.  The experimental protocol was reviewed and approved by the Washington University Human Studies Committee (IRB).  

Pulmonary function studies: Forced vital capacity (FVC) and forced expiratory volume in one second (FEV₁) were measured using American Thoracic Society guidelines.  The best FEV₁ percent predicted each year, using Morris-Polgar standards, for each patient at least five years of age was used in the analysis. 

Hospitalizations: For each subject, the medical record was reviewed to determine the total number of hospitalizations and intravenous antibiotic administrations that occurred during the time period studied.  The primary and secondary diagnoses at the time of hospitalization were identified, and only hospital admissions for treatment of pulmonary manifestations related to CF were used to determine annual hospitalization rates. 

Laboratory studies: Biochemical abnormalities associated with possible renal, hepatic, or gastrointestinal complications of high-dose ibuprofen use were recorded.  For the purposes of this analysis, abnormal laboratory values were defined by the following: serum creatinine concentration >1.2 mg/dL serum transaminase concentrations aspartate amino transferase (AST) or amino alanine transferase (ALT) >40 U/L, serum total bilirubin level >1.5 mg/dL, and blood hemoglobin level <10 g/dl.

Statistical analysis: All data are reported as the mean + standard error of the mean (SEM).  Statistical analysis for data was determined using 2-tailed Student unpaired t-test or ANOVA.   Group comparisons for antibiotic or anti-inflammatory drug use were made using chi-square analyses.  For all group comparisons, significance was determined at the level of 0.05

Results

Patients

During the period reviewed, 53 patients were treated with high-dose ibuprofen, ranging in age from 3 to 18 years.  Thirty-nine CF patients of similar age and health were not treated with high-dose ibuprofen during this time (Table)(1).

A substantial number (45%) of patients who began the ibuprofen, discontinued its use for various reasons.  Six patients who began therapy were not included in the analysis, because of their transfer from the center, and adequate pulmonary and laboratory data for those individuals were not available. Ibuprofen therapy was discontinued in 1 patient due to non-compliance, and 3 patients stopped the medication for unknown reasons (Table)(4).

There were 2 deaths during the study, one from the ibuprofen-treated group, and the other from the untreated group. 

Pharmacokinetics and Doses of Ibuprofen

As previously established, ⁹ the targeted peak plasma ibuprofen concentration for patients was 50 to 100 μg/ml, which was achieved in all patients treated. The daily dose of ibuprofen ranged from 14.5 to 32.0 mg/kg. The mean daily dose from those patients who ultimately discontinued ibuprofen was not significantly different for those who continued the anti-inflammatory therapy throughout (21.9 � 4.1, and 22.1 � 3.5 respectively). During the seven years of the study, periodic pharmacokinetic studies were repeated to confirm that the dose was adjusted properly for patients in the treatment group.   

Pulmonary Function Studies

Pulmonary function studies were performed regularly on all patients at the center age 5 years or older. We found that the primary outcome measure, FEV₁, was not different between groups regardless of patient age (Figure)(1).

figure

Since previous studies found a greater benefit from high-dose ibuprofen in younger CF patients, we also specifically examined FEV₁ in children under age 13 years at the time of enrollment. Again, we did not detect a significant difference between the groups (Figure)( 2).

figure

Other Outcome Measures

We examined the hospitalization rate for CF patients treated with ibuprofen as compared to the untreated group.  Only 19 percent of the patients who were treated with high-dose ibuprofen were not hospitalized as a result of pulmonary exacerbation or lower respiratory tract infections during the period reviewed, which is not different from CF patients who were not prescribed ibuprofen (21%), and 38 percent of patients in the ibuprofen-discontinued group were not hospitalized during the study (Figure 4 below).

figure

However, there were some patients who had extended or numerous hospital stays during the study, but there was no significant difference in any of these factors was noted among the groups. When evaluating hospitalizations, only respiratory related hospitalizations were included in the hospitalization analysis.

Concomitant Therapies

Besides being prescribed ibuprofen, we examined the use of antibiotics and other anti-inflammatory agents (systemic corticosteroids, inhaled corticosteroids, Tobramycin (TOBI), and rhDNase) frequently used to reduce pulmonary inflammation. There was no statistical significance seen in relation to any of these medications on the study groups (Table 3)

Adverse Effects

Twenty-one patients (45%) discontinued the study drug because of adverse effects (Table)( 4). The primary cause of discontinuing ibuprofen therapy was due to abdominal pain, which accounted for 6 of those patients who discontinued use of the drug. There was, however, no baseline assessment to determine the true impact that ibuprofen had on these patients.  There were 3 patients who discontinued treatment due to GI bleeding, one of which was severe and required admission to the intensive care unit for hemodynamic stabilization. Renal failure was another serious adverse effect that was observed (Table)( 4).  We reviewed selected laboratory studies for biochemical evidence of organ toxicity.  The studies selected included serum creatinine, transaminases, and hemoglobin concentrations (Table 2).

There was no statistical difference among the groups in the number of patients who had abnormal laboratory values. Based on these results, high-dose ibuprofen did not appear to be associated with renal or hepatic toxicity. Moreover, there was not an increased incidence of anemia in the treated group, which is related to gastrointestinal blood loss.  Nevertheless, as mentioned above, severe complications were noted: 2 patients prescribed ibuprofen required aggressive interventions.

Discussion

In our study we retrospectively reviewed the use of anti-inflammatory therapy in CF children at a single center.  There was no statistical difference in the age or gender of patients among the groups.  Pulmonary function tests, (specifically FEV₁ percent predicted) were performed.  No difference was noted in the initial FEV₁ percent predicted in the ibuprofen-treated and the untreated group. FEV₁ percent-predicted mean values were obtained on all patients in the treatment groups over the course of the study.  There was no significant difference in FEV₁ percent predicted or rate of decline at any point in the study.  Ibuprofen dosages were determined for each patient using pharmokinetic studies as determined by guidelines established by Konstan et al.⁹ The laboratory tests used to evaluate patients for evidence of renal and hepatic insufficiencies, as well as potential gastrointestinal hemorrhage revealed no statistical difference among groups, furthermore, patients in all treatment groups were apparently in good health in relation to their disease process.  There were a large number of patients who started taking high-dose ibuprofen, but later discontinued doing so for various reasons.  The main reason for stopping ibuprofen was abdominal pain, but this reason was not well documented for pre- or post-treatment severity.  This study may be too small to predict whether ibuprofen use or CF is the primary cause of abdominal pain in these patients.

There was a case where a patient treated with ibuprofen experienced severe gastrointestinal bleed, in which required a blood transfusion and admission to the intensive care unit.  After ibuprofen was discontinued, the patient�s anemia ceased, and no further hemorrhage was noted.  Another patient developed renal failure, and ibuprofen was also discontinued in this patient.  After the patient stopped taking the ibuprofen, the patient�s renal function returned to normal. There was no difference in the annual hospitalization rates for patients in the ibuprofen-treated and the untreated groups. 

Pulmonary inflammation in cystic fibrosis is responsible for much of the morbidity and mortality in this disease. Several anti-inflammatory agents have been used, such as alternate-day systemic corticosteroids, which were found to improve pulmonary function in treated patients. ¹⁰ Improved pulmonary function was transient, however, returned to previous rates of decline seen before the medication was administered. ¹¹ However, systemic corticosteroids have been associated with substantial side effects involving growth impairment that persisted after the medication was discontinued.  ¹¹

High-dose ibuprofen has been shown to decrease inflammation.  In the original studies, routine use of high-dose ibuprofen resulted in a slower progression of lung disease and lower incidence of hospitalization.  This was most evident in younger patients and those patients with mild lung disease. In addition, fewer side effects were noted, and they did not occur more frequently in the ibuprofen-treated group than in the placebo group. ⁹ The reported use of systemic anti-inflammatory drugs including high-dose ibuprofen, in 111 CF centers across the United States was 13%, which is considerably lower than the experience at Washington University Pediatric Cystic fibrosis Center at St. Louis Children�s Hospital which is 86% in the reviewed patients.  Nevertheless, despite apparent efficacy of high-dose ibuprofen, it has not gained favor at most CF centers, with only 8 percent of eligible patients being prescribed the medication.  The main reason cited for hesitation in prescribing high-dose ibuprofen in CF centers was safety concern. ¹² In our review, we did not find a difference in increased frequency of side effects in patients. Nevertheless, 2 patients had severe adverse reactions that required aggressive medical interventions.

In conclusion, high-dose ibuprofen did not result in a significant decrease in the rate of decline in pulmonary function in our CF center population.  With the increased use of other anti-inflammatory agents it is likely that these other drugs are having an impact and ibuprofen is not exhibiting an additive effect.  We did not establish compliance with the use of ibuprofen, and it is possible that the inconsistent use of ibuprofen may underestimate its effect.  A systematic long-term prospective study in the use of high-dose ibuprofen may be indicated to establish that these factors were not present.

References

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