Journal of Asthma, 46:1001–1005, 2009Copyright C© 2009 Informa Healthcare USA, Inc.ISSN: 0277-0903 print / 1532-4303 onlineDOI: 10.3109/02770900903281207

ORIGINAL ARTICLE

Loss of Asthma Control in Inner City Children with Asthmaafter Withdraw of Asthma Controller Medication

Kenny Y. C. Kwong, M.D.,1,∗ Tricia Morphew, M.S.,2 Peter Huynh, M.D.,3 Lyne Scott, M.D.,3Nasser Radjal, M.D.,1 and Grace Dale, P.N.P.3

1Division of Allergy-Immunology, Department of Pediatrics, Harbor-UCLA Medical Center, Torrance, California2The Asthma and Allergy Foundation of American, Southern California Chapter, Los Angeles California

3Division of Allergy, Immunology, Department of Pediatrics, Los Angeles County + University of Southern California, Medical Center,Los Angeles, California

To determine what percentage of inner-city children with asthma would lose asthma control when taken off asthma controllers, a retrospectiveanalysis was performed on inner-city asthmatic children who achieved asthma control in an asthma specific disease management program. Oncedisease control was achieved patients had stepwise reduction of asthma controllers based on the National Asthma Education and Prevention Program(NAEPP) Expert Review Panel (EPR) 2 guidelines. In patients who were taken off all controllers, probability of maintaining asthma control at thefirst visit after cessation of these medications was significantly lower compared to patients kept on inhaled corticosteroids. We conclude that cessationof asthma controllers in previously well controlled inner-city asthmatic children results in loss of asthma control in a significant number of thesepatients. Data support recommendations from national asthma guidelines to step down controller therapy, but clinical monitoring is important toreduce impairment due to loss of control.

Keywords asthma; children; control; controllers; withdraw; loss

IntroductionLong-term asthma controller medications remain the stan-

dard of care to achieve and maintain control for children withpersistent asthma. Benefits of these medications usually out-weigh risks, yet long-term exposure to some of these, espe-cially inhaled corticosteroids, are associated with side effectsincluding growth velocity reduction (1–4). The 2007 Na-tional Asthma Education and Prevention Program (NAEPP)Expert Review Panel (EPR) 3 asthma guidelines recommendthat children with persistent asthma be treated with con-troller therapy until asthma control is achieved. Reductionof controller (step down) is advocated when asthma con-trol is maintained for a period of time (4). However, to date,most asthma guidelines have no pragmatic recommendationsregarding duration of long-term controller medications andwithdrawal of controllers if asthma control is maintained forextended periods of time.

Small studies designed specifically to withdraw asthmacontroller medications following stepwise reduction haveshown large number of patients who remain asymptomaticafter cessation of therapy. These range from 45% to 85% inadults and up to 40% in children (5–13). However, these num-bers are in contradistinction to results of large multi-centeredstudies. In both the CAMP and PEAK studies, asthmatic chil-dren had significant improvement in asthma impairment andrisk when placed on inhaled corticosteroids (ICS). When ICS

*Corresponding author: K.Y.C. Kwong, Division of Allergy-Immunology, Department of Pediatrics, Harbor-UCLA Medical Cen-ter, 1000 West Carson Street, Torrance, California 90509; E-mail:kkwongusc@yahoo.com

were withdrawn, these patients had a similar degree of asthmasymptoms compared to patients who were placed originallyon placebo (14,15). It is unclear whether ICS were weanedin stepwise fashion while patients were in asthma control.

In this real world retrospective study inner asthmatic chil-dren in asthma control had asthma controllers reduced ina stepwise fashion according to the 1997 NAEPP ERP 2guidelines. A significant number of these patients who main-tained asthma control long term were able to have asthmacontrollers withdrawn. The outcome of the study was time toloss of asthma control in these patients.

MethodsStudy Population

Patients included in this study were inner-city childrenwith asthma followed up in an asthma-specific disease man-agement program (Breathmobile) using one fixed and fourmobile asthma clinics at Los Angeles County (LAC) + Uni-versity of Southern California (USC) Medical Center be-tween January 1998 through June 2007. Patients were diag-nosed with mild, moderate, or severe persistent asthma byan asthma specialist based on NAEPP EPR 2 criteria. Pa-tients who met all of the following criteria were enrolled: (1)asthma patients 3 to 18 years of age engaged in program ≥365 days; (2) had two or more follow-up visits during year 1with at least one visit during the second half of year 1 (182to 365 days post entry); (3) had at least one visit during thefirst half of the subsequent year (year 2) (366 to 548 dayspost entry); (4) had at least one visit during the second halfof year 2 (549 to 730 days post entry); (5) had assessment ofbaseline asthma severity; and (6) had assessment of asthma

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1002 K. Y. C. KWONG ET AL.

control at all visits during year 1. Patient consent was notrequired as this was a retrospective analysis of clinical data.The study was reviewed and approved by the InstitutionalReview Board at LAC+USC Medical Center.

Asthma Control and Asthma Controller Withdrawal GroupsPatients with persistent asthma were prescribed asthma

controllers following NAEPP ERP 2 guidelines. ICS aloneor in combination with long-acting bronchodilators (LABA)and/or leukotriene receptor antagonists (LTRAs) were avail-able to all patients without restriction. Which combinationsused was left to the discretion of the individual provider.Once asthma control was achieved for 3 months, controllerswere stepped down sequentially, and in certain patientscontrollers were stopped entirely. Asthma control was de-fined as (1) Day time symptoms less than or equal to twoepisodes per week. (2) Night time symptoms less than 2times per month. (3) Forced expiratory flow volume in 1 sec-ond (FEV1) ≥ than 80% of predicted or ≥ 80% of optimumfor patient. (4) Rescue β2-agonist (independent of exerciseprophylaxis/exercise-induced symptoms) less than or equalto twice a week during daytime and less than twice a monthat night. (5) No acute asthma exacerbations (self-reported),defined as a severe asthma exacerbation requiring systemicsteroid rescue since last visit; and (6) no ED visits and orhospitalization (self-reported) since the last visit. Day andnight symptoms and β2-agonist use were based on a 4-weekrecall.

Asthma control maintenance was evaluated in three patientgroups: GRP1, weaned off all asthma controller medication(n = 84, 17.7%); GRP2, weaned to LTRA only (n = 35,7.4%); GRP3, not weaned, i.e., remained on therapy thatincluded ICS (& compliant) (n = 355, 74.9%). The obser-vation start point for each group was defined as follows:GRP1—visit, patient weaned off anti-inflammatory medica-tion; GRP2—visit, patient weaned to LTRA only; GRP3—visit, patient first achieved asthma control (remained on

therapy that included ICS). Assessment of medication step-down and asthma control status was evaluated across subse-quent visits where therapy and control were continuouslymonitored. No patients were weaned to LABA alone asmono-therapy as LABAs were always used in combinationwith ICS.

Outcome analyzed was time to loss of asthma control afterstepping down to LTRA only and cessation of ICS therapy.

ResultsStudy Population

The study population was predominately Hispanic. A totalof 51 patients weaned to LTRA only within 2 years of pro-gram entry (GRP2) were slightly younger at baseline than pa-tients completely weaned off anti-inflammatory medications(GRP1) and those who remained on therapy that included ICS(GRP3) (mean 6.2 years vs. 8.7 and 8.1 years, respectively)(Table1). Among all patients, only 7.8% had mild persistentdisease on treatment initiation (6.0% GRP1, 11.4% GRP2,and 7.9% GRP3). Majority of patients weaned to LTRA onlyhad moderate persistent disease severity at baseline (74.3%).Relatively few had severe persistent disease on treatmentinitiation (14.3% of 35) compared to patients weaned com-pletely off anti-inflammatory medications (46.4% of 84) andthose not weaned (GRP3) (52.4% of 355). Gender and eth-nicity distributions were similar between treatment groups.Season marking the observation start point was also simi-lar between groups, although weaning off anti-inflammatorymedications (GRP1) occurred more often in the spring andweaning to LTRA only (GRP2) more often in the summer.

Loss of Asthma ControlThere was increasing probability of loss of asthma control

after achieving asthma control with subsequent visits in allthree groups. Compared to patients who were not weanedoff ICS patients who had complete withdrawal of all asthma

Table 1.—Characteristics of patients in each therapy group: GRP1 weaned off anti-inflammatory medication, GRP2 weaned to LTRA only, GRP3 not weaned, i.e.,remained on therapy that included ICS.

GRP 1 (a) Weaned offanti-inflammatory meds

GRP 2 (a) Weaned toLTRA only

GRP 3 (a) Notweaned

Test of GRPdifferences (χ2 test)

N = 84 N = 35 N = 355 p valueAge at baseline – mean (SD) 8.7 (3.6) 6.2 years (2.8) 8.1 years (3.1)

2–4 years 13.1% 37.1% 15.5% < 0.0015–11 years 64.3% 60.0% 73.2%12–18 years 22.6% 2.9% 11.3%

Female sex 39.3% 40.0% 36.4% = 0.835Hispanic ethnicity 84.5% 91.4% 89.3% = 0.223African American ethnicity 10.7% 2.9% 4.5%Underlying disease severity (baseline):

Mild persistent 6.0% 11.4% 7.9% = 0.001Moderate persistent 47.6% 74.3% 39.7%Severe persistent 46.4% 14.3% 52.4%

Morbidity (year prior) (b):School absenteeism (any) 17.9% 14.3% 32.7% = 0.004ED visits (any) 25.0% 37.1% 36.6% = 0.125Hospitalizations (any) 10.7% 20.0% 13.2% = 0.396

Season (a):Winter 21.4% 20.0% 23.1% = 0.454Spring 35.7% 17.1% 30.1%Summer 22.6% 34.3% 22.5%Fall 20.2% 28.6% 24.2%

(a) Observation start date: GRP1 — Visit weaned off anti-inflammatory medication. GRP2 – Visit weaned to LTRA only. GRP3 – Visit first achieve asthma control.[Observation end date: Up to two years from date patient entered program (baseline visit).]

(b) Morbidity due to asthma related symptoms year prior to program entry (baseline visit).

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Table 2.—Maintenance of asthma control to first return visit after weaned off anti-inflammatory medications (GRP1), weaned to LTRA only (GRP2), compared tovisit after patient first achieved control and remained on controller therapy that included ICS (GRP3).

Odds ratios (likelihood maintain asthma controlTreatment group to next visit after start point (a))

GRP2 Weaned GRP1 (weaned) vs. GRP 2 (LTRA only)GRP1 Weaned to LTRA only GRP3 Not weaned GRP3 (not weaned) vs. GRP 3 (not weaned)

% of patients in strata who maintain asthmaSTRATA: control to next visit after start point (a) OR (95% CI), p value OR (95% CI), p valueOverall 71.4% 77.1% 83.9% 0.48 (0.3, 0.8), p = 0.009 0.65 (0.3, 1.5), p = 0.306Age (y) at baseline

2–4 54.5% 84.6% 80.0% 0.30 (0.1, 1.2), p = 0.082 1.38 (0.3, 7.1), p = 0.7045–18 74.0% 72.7% 84.7% 0.52 (0.3, 0.9), p = 0.033 0.48 (0.2, 1.3), p = 0.149

GenderFemale 72.7% 71.4% 85.3% 0.46 (0.2, 1.1), p = 0.094 0.43 (0.1, 1.5), p = 0.191Male 70.6% 81.0% 83.1% 0.49 (0.2, 1.0), p = 0.043 0.86 (0.3, 2.7), p = 0.802

Underlying severityMild persistent *100% *75.0% 75.0% * Not evaluated * Not evaluatedModerate persistent 82.5% 80.8% 83.7% 0.92 (0.4, 2.3), p = 0.859 0.82 (0.3, 2.4), p = 0.715Severe persistent 56.4% *60.0% 85.5% 0.22 (0.1, 0.5), p < 0.001 *0.26 (0.0,1.6), p = 0.144

Season at start pointWinter 77.8% *71.4% 86.6% 0.54 (0.2, 2.0), p = 0.349 0.39 (0.1, 2.2), p = 0.290Spring 70.0% *100% 84.1% 0.44 (0.2, 1.1), p = 0.087 * Not evaluatedSummer 78.9% 91.7% 83.8% 0.73 (0.2, 2.5), p = 0.619 2.13 (0.3, 18), p = 0.486Fall 58.8% 50.0% 81.4% 0.33 (0.1, 1.0), p = 0.048 0.23 (0.1, 0.9), p = 0.033

* Not evaluated (or) review results with caution due to limited number of patients in strata (<10 patients).(a) Observation start point: GRP1 — Visit weaned off anti-inflammatory medication. GRP2 – Visit weaned to LTRA only. GRP3 – Visit first achieve asthma control (remain on therapy

that includes ICS).

controllers had significantly higher risk of losing asthma con-trol by the first return visit. Probability of maintaining asthmacontrol at first visit was not significantly different betweenpatients kept on ICS and those weaned to LTRA as mono-therapy (Table 2, Figure 1). Of the patients who were com-pletely taken off asthma controller medications those whowere male, between the ages of 5 to 18 years of age, and whohad severe persistent asthma at initial evaluation were morelikely to lose asthma control at first visit compared to similarpatients kept on ICS (Table 2).

Only patients weaned to LTRA only or completely takenoff all asthma controller during the fall had higher probabilityof losing asthma control at the first return visit compared tosimilar patients kept on ICS (Table 2, Figure 2).

DiscussionIn this retrospective study of inner-city asthmatic children

treated in a real-world setting, we demonstrated that patientswho were weaned completely off all asthma controllers hadan almost twofold risk of losing asthma control by the firstreturn visit. However, weaning to LTRA alone did not sig-nificantly increase risk of loss of asthma control by first visitcompared to those patient kept on ICS. At the end of 1 yearonly approximately 40% of patients with complete termina-tion of asthma controllers were likely to be still in controlcompared to approximately 50% of those left on LTRA and60% of those kept on ICS.

Results are similar to those reported by other investiga-tors. A total of 67% of older asthmatics had worseningof bronchial reactivity on cessation of budesonide therapy(9). In a pediatric study, 19 of 40 children taken off budes-onide had to have the ICS restated by the second return visit(5). The range of patients remaining asymptomatic after ICSwithdrawal is large from 25% to 100% (5–12). It is unclearwhy there exists such a large discrepancy. Perera followedasthmatic children for up to 121 months after cessation of

ICS therapy with 78% of these patients remaining asymp-tomatic (8). These patient may have had less severe base-line asthma severity, thereby allowing easier disease control;However, up to 94% of patients had repeated courses of sys-temic steroids. Patients were also kept on maintenance ICSfor longer periods of time (9–18 months), whereas someother studies including ours stepped down therapy usuallyafter 3 months of asthma control (6,12). Finally many pheno-types of asthma have a waxing and waning character. There-fore, some patients may have been experiencing improve-ments in asthma symptoms during cessation of ICS therapyserendipitously.

The probability of maintaining asthma control at first re-turn visit was slightly but significantly higher in patientskept on LTRA than patients completely weaned off con-trollers. Baseline characteristics of these patients (GRP2)were significant in having more patients 2 to 4 years andmilder baseline asthma severity. LTRAs may, therefore, con-fer slightly more long-term protection against loss of asthmacontrol when ICS are withdrawn, although this interpretationmust be made with caution as the sample size in GRP2 wassmall (n = 35).

Termination of asthma controllers or weaning to LTRAonly in the fall season was associated with loss of asthmacontrol more than other seasons. This is consistent with theseasonal differences in asthma severity and risk of exac-erbations found in many studies (16, 17). Viral infectionshave been implicated to be a predominant cause of asthmaexacerbations in young children in the fall and winter andLTRAs have been suggested to protect these patients againstvirally induced wheezing (18–20). While patients weanedto LTRA alone in this study had slightly better probabilitymaintaining asthma control compared with those completelytaken off controllers, this effect was not seen during the fallseason, suggesting that LTRAs may not have conferred pro-tection against virally induced loss of asthma control. This

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Figure 1.—Unadjusted cumulative probability patient’s asthma maintained after weaning off anti-inflammatory medications or stepping down therapy to LTRAonly compared to paitents who remained on controller therapy that included ICS (p = .229). Observation start point: GRP 1 — Visit weaned off anti-inflammatorymedication, GRP 2 — Visit weaned to LTRA only; GRP 3 — Visit first achieve asthma control (remain on therapy that includes ICS).

interpretation is to be taken with extreme caution as againsample size for group 2 was small and no viral studies wereperformed.

Some investigators have used other markers to predictwhich patients are likely to remain asymptomatic after con-trollers are stopped. These include urinary eosinophil proteinX, sputum and blood eosinophils, and fractionated exhalednitric oxide (5, 10, 21). Combinations of clinical criteriahave also been shown to be effective studies in determin-ing which patients can maintain asthma control after ter-mination of asthma controllers compared to use of these

inflammatory markers (6). Results of this study support thisstrategy as stepwise reduction was based entirely on clinicalparameters recommended by 1997 NAEPP ERP 2 guidelines.Further they support the 2007 NAEPP ERP 3 guidelines instill recommending chiefly clinical criteria to guideline step-wise reduction of controller therapy.

Interpretation of these results must be made with cau-tion. GRP1(weaned off all controllers) and GRP2 (weanedto LTRA alone) were compared to patients who achievedasthma control and not weaned off ICS (GRP3). It is notclear how much controller reduction had taken place in these

Figure 2.—Adjusted cumulative probability patient’s asthma maintained after weaning off anti-inflammatory medications or stepping down therapy to LTRA onlycompared to patients who remained on controller therapy that included ICS (p = .229). Estimates presented for patients whose start point occurred during thesummer (averaged across adjustment factors). Observation start point: GRP 1 — Visit weaned off anti-inflammatory medication; GRP 2 — Visits weaned to LTRAonly; GRP 3 — Visit first achieve asthma control (remain on therapy that includes ICS)

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patients. Ideally the control group should contain patientswho were weaned to the lowest doses of ICS and kept atthat dose to determine if very low doses of ICS protectedagainst loss of asthma control compared to LTRA alone andcessation of all controllers. Despite this shortcoming, ourdata is consistent with other studies. For instance, in adultstreated with budesonide to achieve asthma control, 67% ofpatients who had their ICS discontinued had deteriorationof airway hyperactivity compared to 26% of those kept onICS (9). This was not feasible in this study as the majorityof providers in the program tried to discontinue ICS whencontrol was maintained for extended periods of time.

This was a real-world observation and patients were treatedwith combinations of ICS, LABA, and LTRA. Differentbrands of ICS were also used, but equivalent doses weregenerally used for similar asthma severity in accordance withNAEPP ERP 2 recommendations. The choice of which brandof ICS to use was left to the discretion of each providerand availability from the patient’s health plan. It is unclearwhether brand of ICS played any role in ability of patients tosuccessfully maintain asthma control when controller med-ication was terminated. Similarly, it is uncertain if certaincombinations of ICS and LABA or LTRA were superior inthis respect.

This study, despite its shortcomings, shows that a signifi-cant number of asthmatic patients may be taken off controllermedication and maintain long-term control of their asthma.In juxtaposition, a large number also lose control and may be-come at risk for asthma-related morbidity. Taken together thissupports 2007 NAEPP ERP 3 recommendations that whileasthma controllers should be gradually reduced to minimizepotential of long-term side effects, real-time assessment ofasthma control is needed to identify those patients who losedisease control.

AcknowledgmentThe authors would like to thank the Breathmobile and

Allergy-Immunology clinic physicians and the nursing, res-piratory therapy, and patient financial staff of the Allergy-Immunology Division at LAC+USC Medical Center for tak-ing care of all the asthmatic children in this study.

This study was funded in part by Merck (investigator ini-tiated grant).

Declaration of InterestKYC Kwong has research grants from Merck. In addi-

tion, KYC Kwong has received speaking honorarium fromGenetech, Novartis Sepracor and Phadia. The other authorsdeclare no conflict of interest.

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