moderate persistent asthma.1 By patient report onthe day of the study visit, 26 patients (8 AfricanAmericans) stated that they used two inhalations ofalbuterol on a regular schedule either once daily(n ⫽ 5), twice daily (n ⫽ 5), three times daily(n ⫽ 8), or four times daily (n ⫽ 8) [African Ameri-cans vs whites, p ⫽ 0.40]. All other patients reportedusing albuterol at two inhalations on an as-neededbasis. Quantification of SABA use during the weekimmediately prior to the study day was not obtained.
Forty percent of participants were using low-doseICS, 14% were using medium-dose ICS, and 2%were using high-dose ICS; one pediatric patient wastreated with prednisone every other day.1 All partic-ipants had been using ICS for at least 3 months, butthe majority had used ICS for ⱕ 2 years. Clinicalcharacteristics were similar between users and non-users of ICS (baseline FEV
Figure 2. Fitted dose/response after cumulative doses of albu-
1 percentage of predicted
[p ⫽ 0.89]; duration of asthma [p ⫽ 0.89]; and fre-
terol (solid line). Open circles represent individual patient re-sponses. Response is percentage of predicted FEV
quency of SABA use [p ⫽ 0.48]). Thirty-two patients
lative doses of albuterol administered from the MDI were 180
were using a theophylline product, and 1 patient was
g, 270 g, 360 g, 450 g, and 540 g; and the cumulative
using cromolyn sodium. Of these 32 patients, 21
doses from the MDI plus nebulizer were 2,770 g (270 g MDI
plus 2,500 g nebulized); 2,860 g (360 g MDI plus 2,500 g
patients were also using an ICS. All participants had
nebulized); 2,950 g (450 g MDI plus 2,500 g nebulized); and
long-standing asthma with an asthma diagnosis for
3,040 g (540 g MDI plus 2,500 g nebulized).
64%, 63%, and 56% of their lives in the age groups
⬍ 20 years, 20 to 45 years, and 46 to 65 years,
whites and African Americans demonstrated no dif-
ference in ED50, but Rmax was 91.9% of predictedFEV1 in whites and 82.4% of predicted in African
Modeled Data
Americans (p ⫽ 0.0004) [Fig 3]. Consistent with ourmodeled data of difference in Rmax between ethnic
Population modeling of the albuterol dose/re-
groups, whites had an absolute improvement in
sponse relationship is shown in Figure 2. A Hill
percentage of predicted FEV
coefficient (␥) of 2 was found to best fit the data and
1 of 26.7% from base-
line after receiving maximum albuterol doses
had lowest objective function value. In preliminary
compared with 16.6% in African Americans
studies, several pharmacodynamic models were fit-
(p ⬍ 0.0003). Using the modeled parameters, two
ted to the albuterol dose vs FEV1 relationship. The
inhalations of albuterol (180 g) would increase
sigmoid Emax model with ␥ ⫽ 2 provided the best fit
percentage of predicted FEV
to the data. Subsequent analyses setting ␥ as a
1 by 11.7% in African
Americans vs 17.5% in whites. Baseline percentage
parameter resulted in unreasonable pharmacody-
namic and variability estimates suggesting that fitting
was not different between
whites and African Americans (65.2 ⫾ 11.4% vs
the sigmoid Emax model with four parameters re-
65.8 ⫾ 8.3%, respectively; p ⫽ 0.81), nor was du-
sulted in overparameterization. Therefore, we set
ration of asthma (p ⫽ 0.31) nor the proportion
2 and fit the model with thee parameters. The
using ICS (p ⫽ 0.61).
modeled parameters, ED50 of 141 g and Emax of24.0%, predict that the standard of administeringtwo inhalations of albuterol (180 g) is sufficient to
Table 2—Population Modeling of Albuterol
produce a 14.4% increase in percentage of predicted
FEV1 from baseline and to reach 60.0% of Emax
(Table 2). There were 40% and 56% variabilities
associated with ED50 and Emax, respectively.
Incorporating gender, age, years diagnosed with
asthma, and current ICS use (yes/no) as covariates
64.3% of predicted FEV1
87.6% of predicted FEV1
for R0, Rmax, and ED50 did not account for signifi-
24.0% of predicted FEV1
cant between-participant variability. Including eth-
nicity as a covariate on Emax decreased the interpa-
tient variability by 1% (p ⬍ 0.05). Modeled data for
Residual error (SD)
3.2% of predicted FEV1
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Table 3—BP and Heart Rate at Baseline and After
Maximal Albuterol Doses*
After Maximal Albuterol
Systolic BP, mm Hg†
Diastolic BP, mm Hg‡
Heart rate, beats/min§
*Data are presented as mean ⫾ SD.
†p ⫽ 0.53.
‡p ⫽ 0.06.
§p ⫽ 0.13.
response to SABAs has been observed to be highlyvariable between patients.3–9 The results of thepresent study support these findings and extendthem to include quantification of the variability in
Figure 3. Fitted dose/response after cumulative doses of albu-
bronchodilator response using a pharmacodynamic
terol in African Americans (solid line) and whites (dotted line).
population model. This is the first study to our knowl-
Open triangles are individual patient responses for African
edge to use population pharmacodynamic modeling to
Americans. Open circles are individual patient responses forwhites. Response is percentage of predicted FEV
characterize the dose/response relationship and vari-
tive doses of albuterol administered from the MDI were 180 g,
ability associated with bronchodilator response after
270 g, 360 g, 450 g, and 540 g; and the cumulative doses
inhaled albuterol in physician-diagnosed asthmatic pa-
from the MDI plus nebulizer were 2,770 g (270 g MDI plus
2,500 g nebulized); 2,860 g (360 g MDI plus 2,500 g
tients with moderate-to-severe persistent disease. With
nebulized); 2,950 g (450 g MDI plus 2,500 g nebulized); and
an Emax of 24% of predicted FEV1 (absolute change
3,040 g (540 g MDI plus 2,500 g nebulized).
in percentage of predicted FEV1 over baseline) andan ED50 of 141 g (dose of albuterol that producedhalf-maximal bronchodilation, ie, 12% [0.5 ⫻ 24%]),
Effect of Nebulized Albuterol After Maximum
these modeled data predict that two inhalations of
Doses From the MDI
albuterol (180 g) would increase the percentage ofpredicted FEV
All participants reached maximum improvement
1 by 14.4%. The results of this study
cannot be applied to the management of acute exacerba-
in FEV1 (⬍ 100 mL change from highest FEV1
tions of asthma, which may have a predominantly
obtained after previous dose) after six inhalations or
inflammatory component. Inflammation is known to
less of albuterol from the MDI (Fig 2). The population-
impair the response to inhaled 
modeled data in Figure 2 demonstrate that addition
2-agonists, which
would result in different 
of nebulized albuterol to maximal doses from an
MDI (from 2,770 to 3,040 g) does not further
Patients were considered stable and enrolled in the
increase bronchodilator response. However, nebu-
study if they had not had an asthma exacerbation
lized albuterol provided additional bronchodilation
requiring treatment with oral steroids, emergency de-
(ⱖ 200 mL)14 in 11 participants (21%) [mean ⫾ SD
partment care, or hospitalization in the past 3 months
improvement, 366.5 ⫾ 126.1 mL; range, 200 to 610
and were not having an acute worsening of their
mL]. After receiving nebulized albuterol, six par-
symptoms (albuterol use for acute symptom control
ticipants had a fall in FEV ⬎
100 mL (range, 3.3
was unchanged over previous days). It is likely that
some patients would be considered as having poorlycontrolled but stable asthma based on their baseline
Adverse Effects
pulmonary function, lack of antiinflammatory therapy,
There was no change from baseline in BP or heart
and regularly scheduled use of inhaled albuterol. Ques-
rate after maximal albuterol doses (Table 3). There
tionnaires currently used to assess asthma stability such
were no complaints of tremor.
as the Asthma Control Test, the Childhood AsthmaControl Test, the Asthma Control Questionnaire, andthe Asthma Therapy Assessment Questionnaire control
index1 were not available at the time this study wasconducted.
Inhaled albuterol is the most extensively used
Bronchodilator response in the present study was
medication for patients with asthma. Bronchodilator
extremely variable (Fig 2). Nevertheless, the results
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of our study clearly show the typical pharmacologic
study, the covariates of gender, ethnicity, age, years
pattern for the bronchodilator response to albuterol
diagnosed with asthma, and current ICS use (yes/no)
(steep increase in response at low doses followed by
did not further explain the variability observed. We
flattening of the response curve at high doses). The
were surprised that ICS use did not influence our
between-subject coefficient of variation for R0 and
findings because corticosteroids increase -adrenergic
Rmax was approximately 16%, and for Emax was
expression and could affect ED50 and Emax.36 How-
56.2% (Table 2). The similar coefficient of variation
ever, only a little over half of patients were using
for R0 and Rmax compared with the large variability
ICS, and 73% were using a low dose. There were no
in Emax suggests that variability associated with
significant differences between ICS users (including
Emax is due to R0, ED50, and Rmax, and that the
the pediatric patient on prednisone) and nonusers
change from baseline (Emax) between individuals is
for baseline FEV1 percentage of predicted nor du-
highly variable. Thus, the Emax 56.2% coefficient of
ration of asthma. In addition, a similar proportion of
variation predicts that certain asthmatics may be
ICS users and nonusers reported albuterol use on a
particularly responsive to the bronchodilator effects
regular schedule (two inhalations once to four times
of albuterol and may experience relief of symptoms
daily). Thus, there were not any obvious clinical
with relatively low doses of inhaled albuterol. This
differences between ICS users and nonusers that
individual variation in bronchodilator responsiveness
would be expected to influence the ED50 or Emax
is clearly evident in Figure 2. However, the variabil-
findings. It is possible that inclusion of participants
ity in the ED50, although high (41%), is not clear
with differing genotypes or haplotypes for genes in
from the graph and indicates that the relationship
the 2-receptor pathway could have contributed to
between the dose of inhaled albuterol to achieve a
variability.37–43 However, a limitation of our study is
targeted reversibility is highly variable.
that we did not collect DNA.
The actual doses of albuterol delivered to the
Additionally, we do not know the extent of prior
lungs of the study participants would be lower
inhaled SABA usage in the week immediately prior
than the doses we used in the pharmacodynamic
to the study day. Twenty-six patients reported regu-
model for the MDI (90 g) and nebulizer (2,500
lar use of albuterol one to four times daily as part of
g). Of the 100 g present in the valve of an
their asthma self-management. Frequent use of in-
albuterol MDI (90 g delivered from the mouth-
haled SABAs and long-acting 2-agonists can induce
piece of the actuator), only 25 to 40 g is delivered
2-receptor desensitization, causing patients to be-
to the patient in an in vitro model when the MDI
come less bronchodilator responsive to additional
is attached to a holding chamber.25–27 Likewise,
SABA doses.44–46 In addition, frequent use is con-
only 400 to 500 g of a 2,500-g dose of albuterol
sidered a marker of airways inflammation and in-
inhalation solution placed in the nebulizer used in
flammatory mediators impair 2-receptor activation
this study is available for inhalation.28 As we did
by 2-agonists.24,31 Thus, the variability in broncho-
not measure the amount of drug available to the
dilator response observed in this study could reflect
patient from the devices, we chose to use the MDI
dysfunction of the 2-receptor induced by overuse of
and nebulizer doses most commonly recognized by
albuterol and the presence of underlying airway
inflammation in some patients.
Patients in this study had a wide range of baseline
While patients included in our study had been
FEV1 values (40 to 80% of predicted FEV1). Base-
nonsmokers for at least the previous year, patients
line FEV1 influences the bronchodilator response to
with ⬍ 5–pack-year history were allowed to partici-
inhaled 2-agonists such that larger doses are re-
pate. Smoking is known to increase responsiveness to
quired in patients with lower baseline values to reach
albuterol and methacholine, and even former smok-
maximum bronchodilation compared with patients
ing increases the risk of having poorly controlled
who have higher baseline values.29 Reasons for this
asthma.47–49 It is possible that the inclusion of a mix
phenomenon could include the presence of endoge-
of former and never-smokers in our study could have
nous functional antagonists acting at the 2-receptor, or
contributed to the variability in bronchodilator
desensitization of the 2-receptor due to either the
action of inflammatory mediators at the receptor
Our data demonstrate an ethnic difference in
or from excessive exposure (due to overuse) to
bronchodilator reversibility in white vs African-
2-agonist drugs.24,30,31 Baseline FEV1 was not in-
American patients with moderate-to-severe, stable
cluded as a covariate in our analysis because it is
asthma. Ethnicity as a covariate accounted for only
included as a parameter in the pharmacodynamic
1% of the variability in Emax (p ⬍ 0.05), but when
bronchodilator response was stratified by ethnicity,
Other studies5,7,8,35 have also noted significant
differences became clinically important. White pa-
interpatient variability in response. In the present
tients achieved a 9.5% higher maximum percentage
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of predicted FEV1 than African-American patients
consistent with a study in hospitalized asthmatics in
(91.9% vs 82.4%, p ⫽ 0.0004), and the pharmacody-
which approximately seven inhalations of albuterol
namic model predicts that African-American pa-
produced maximal bronchodilation and the addition
tients would increase percentage of predicted FEV1
of a single 5.0-mg dose of nebulized albuterol in-
by 11.7%, compared with 17.5% for white patients
creased FEV1 by only 44 ⫾ 8.7 mL.55 Examination
after a standard dose of albuterol (two inhalations of
of individual responses indicates that there are asth-
90 g from an MDI). There was no difference in
matics who benefit with treatment by nebulizer
baseline FEV1 nor duration of asthma to explain this
following maximal MDI dosing (Fig 2). Further
finding, and 50% of the African Americans were re-
research is needed to identify which patients would
ceiving ICS therapy. It is possible that there were
require additional dosing by nebulization.
genetic differences between white and Africans-
Both the asthma and COPD diagnosis and man-
American patients in our study population that influ-
agement guidelines recommend up to a 400-g dose
enced response.41 Our data could have important
of a short-acting inhaled bronchodilator to assess the
clinical implications for 2-agonist treatment in African
degree of bronchodilator response as an indicator of
Americans, in which higher doses of albuterol oradditional or alternative drugs such as anticholinergics
disease severity.1,56 Our findings do not alter this
may be required for sufficient bronchodilation.
recommendation for asthmatics because we found
Three previous studies34,50,51 compared broncho-
that two to four inhalations of albuterol (as predicted
dilator response to albuterol between white and
by the ED50 of 141 g) could increase FEV1
African-American asthmatics. Our data are consis-
percentage of predicted by 12% in patients with
tent with Hardie et al,50 who found that maximum
moderate-to-severe persistent disease. However, af-
bronchodilation in mild asthmatics was lower in
ter maximal bronchodilation was achieved by dosing
African-American compared to white patients after
with the MDI, 21% of our study patients had further
multiple doses of albuterol by MDI following
clinically relevant increases in FEV1 with a 2.5-mg
methacholine-induced bronchoconstriction. Of the
nebulized dose of albuterol. Therefore, our results
other two studies,34,51 one was underpowered to
suggest that if adequate bronchodilation is not
detect a difference between ethnic groups, and the
achieved with the MDI, administration of a nebu-
other was conducted in emergency department
lized dose may be warranted. Nebulized albuterol is
patients (whose clinical features differ from stable
known to cause palpitations, sinus tachycardia, anx-
asthmatics), and patients were not dosed with
iety, tremor, and increased BP.
albuterol to maximal bronchodilation. Differences
A small number of participants had bronchocon-
in response between other ethnic groups have
striction after nebulized albuterol. The formulation
been observed.52,53
of albuterol solution used at the time this study was
The finding from our modeled data that 180 g of
conducted contained 50 g of benzalkonium chlo-
albuterol is sufficient to increase percentage of pre-
ride per 2.5-mg dose. Inhaled benzalkonium chlo-
dicted FEV1 14.4% from baseline and to reach
ride administered in the absence of an SABA is
60.0% of Emax is supported by results from other
known to induce bronchospasm in asthmatics.57,58
studies5,8,11 in which four inhalations (90 g per
However, aside from case reports, there are no
inhalation) or less achieve near-maximal bronchodi-
controlled studies to indicate that the dose of ben-
lation. Studies that found that larger doses were
zalkonium chloride used in albuterol solutions for
required to reach a maximum bronchodilator re-
nebulization approved by the Food and Drug Ad-
sponse included patients with severe bronchocon-
ministration cause clinically relevant bronchocon-
striction, which is known to shift the albuterol dose/
response curve to the right54 (larger doses needed to
Our pharmacodynamic population model of albu-
achieve the same effect), or demonstrated relatively
terol bronchodilator response data is important to
small incremental increases (⬍ 100 mL) in FEV1 at
the practicing clinician because we found that the
higher doses.7,9,11
majority of stable asthmatics with moderate-to-severe
Nebulizer treatment is often used in patients with
asthma having symptoms will achieve a 12% increase
insufficient response to multiple inhalations of albu-
in percentage of predicted FEV1 with two to four
terol from an MDI. Our modeled population data
inhalations of albuterol from their MDI. However,
predict that nebulized albuterol does not add to the
the maximum percentage of predicted FEV1 will
bronchodilator effects from maximal albuterol dos-
vary widely between patients with additional doses.
ing from an MDI as shown by the flat dose/response
Importantly, the reduced bronchodilator response to
curve for all cumulative doses, which include the
albuterol in African-American asthmatics compared
2.5-mg nebulized albuterol dose (2,770 g, 2,860 g,
to whites suggests that African Americans may require
2,950 g, 3,040 g) [Fig 1, 2]. These data are
more aggressive treatment than whites to ensure the
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Case Report of Eosinophilic Gastroenteropathy and a Sandra Roberto A,1, Rómulo Bonilla G, MD,2 Gabriel Pérez G, MD.3 1 Fourth year medical student at the Hospital Universitario de Santander of the Universidad Introduction: Eosinophilic gastroenteropathy is a rare disease characterized by infiltration of eosinophils into one Industrial de Santander in Bucaramanga, Colombia
Malawi HIV and AIDS Monitoring and Evaluation Report 2005-2006 Estimated Population based HIV prevalence per Region Acknowledgements The National AIDS Commission (NAC) is grateful to the following organizations for providing data used to compile this report; all CBOs that reported to district assemblies in the 2005-6 Financial Year; NGOs, FBOs, public sector and private sector institutions that submitted reports to NAC, and District Assemblies during the 2005-2006 Financial Year; District AIDS Coordinators and numerous individuals that assisted in data abstraction from data source institutions, namely: Mr. J. Ghobede (Population Services International) Mrs. Veronica Chirwa, Mr James Gondwe and Mr. J. Zingeni (Ministry of Health, John Snow Incorporated Project); Mr. Chris Moyo and Mr. Naphini (Ministry of Health, HMIS); Dr Felix Salaniponi (Ministry of Health, TB Control Programme); Mr George Bello (Ministry of Health-CHSU); Dr. Eric Schouten (Ministry of Health, HIV Co-ordinator); Professor Tony Harries (Ministry of Health, HIV and AIDS Unit), Tupochele Mtila and Felistas Sibweza (Banja la Mtsogolo), Mrs Kanyuka and Mr. Derick Zanera (National Statistics Office); Mr. Wellington Limbe and Mr Tapson Ndundu (Malawi AIDS Counselling and Rehabilitation Organisation); Mr. D. Runganaikaloo (National AIDS Commission- Financial Management Agency); HIV Sentinel Surveillance Technical Working Group; Dr Kalanda (MASAF); National Health Accounts and HIV Resource Tracking Technical Working Group; and, the Malawi Demographic and Health Survey Steering Committee,
