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A 20-year-old woman with asthma was taken to the emergency room of another hos- From the Division of Pulmonary and
pital because of cardiorespiratory arrest. The patient had had severe asthma since Critical Care, Department of Medicine,
Brigham and Women’s Hospital (M.E.W.);
childhood. She was born after a normal pregnancy and delivery to a teenaged, single the Departments of Radiology (J.O.S.) and
mother, who smoked three packs of cigarettes per day during pregnancy and during Pathology (E.J.M.), Massachusetts General
the patient’s childhood. Asthma developed at the age of 4 years, and exacerbations Hospital; and the Departments of Medi-
cine (M.E.W.), Radiology (J.O.S.), and Pa-
occurred frequently thereafter, triggered by cold air, hot humid air, physical activity, thology (E.J.M.), Harvard Medical School
respiratory infections, anxiety, and exposures to paint and to cats and birds that were — all in Boston.
kept in her home or the homes of relatives. Attacks often occurred at night or in the
N Engl J Med 2007;356:2083-91.
early morning. A timeline of medical therapy for asthma is shown in Table 1, and the Copyright © 2007 Massachusetts Medical Society.
results of pulmonary-function tests are shown in Table 2. During testing, the results
improved after bronchodilator therapy. She was followed by pediatricians and spe-
cialists in pulmonary medicine; however, she repeatedly missed outpatient follow-up
appointments and visited emergency rooms on many occasions because of exacer-
bations. She was inconsistent in her use of inhalers and oral medications; she used
inhaled bronchodilators up to 10 times per day when she had symptoms. At the age
of 15 years, she told hospital staff that she rarely took her medications regularly.
Involvement by the Department of Social Services was requested because of non-
compliance with treatment, and the patient’s mother was counseled to stop smok-
ing, but these interventions were unsuccessful. Visiting-nurse assessments of the pa-
tient’s residence for possible allergens were scheduled, but despite multiple attempts,
the assessments were not performed because of the family’s absence from the home.
Oxygen desaturation occurred during some asthma episodes, including an episode
of status asthmaticus at the age of 8 years, with an oxygen saturation of 80% while
the patient was breathing ambient air and had a respiratory rate of more than 50
breaths per minute. She was admitted to this hospital every few months because of
asthma and pneumonia, occasionally to the pediatric intensive care unit. Tracheal
intubation was never required. Peripheral-blood eosinophilia was never documented.
Immunoglobulin E levels were not measured.
Five months before this admission, 1 day after receiving treatment in an emer-
gency room for an asthma flare, the patient was seen at an urgent care facility be-
cause of shortness of breath, cough productive of white sputum, chills, and wheez-
Medications Administered
on Admission (to Emergency
Age Range Medications Taken at Home Department or Hospital)
4–10 yr Metaproterenol Epinephrine (subcutaneous)
Albuterol by nebulizer and metered-dose inhaler Aminophylline (intravenous)
Theophylline Methylprednisolone (intravenous)
Isoetharine by nebulizer
Cromolyn sodium inhaler
Beclomethasone inhaler
Tapered prednisone (5–14 days)
10–15 yr Albuterol by nebulizer and metered-dose inhaler Epinephrine (subcutaneous)
Ipratropium bromide by nebulizer Terbutaline sulfate (subcutaneous
Salmeterol xinafoate inhaler or intravenous)
Fluticasone propionate metered-dose inhaler
Budesonide inhaler
Tapered prednisone (5–14 days)
Montelukast sodium tablets
Beclomethasone inhaler
15–20 yr Albuterol metered-dose inhaler Epinephrine (subcutaneous or in-
Albuterol and ipratropium bromide by nebulizer travenous)
Theophylline Dexamethasone
Salmeterol xinafoate inhaler Terbutaline (subcutaneous or intra-
Fluticasone propionate metered-dose inhaler venous)
Montelukast sodium tablets Magnesium sulfate (intravenous)
Prednisone (5–60 mg daily)
ing of 2 days’ duration, despite around-the-clock were healthy; her father’s medical history was not
inhalational treatments with nebulized albuterol known.
(2.5 mg) and nebulized ipratropium (0.5 mg). Her On physical examination at the urgent care fa-
other asthma medications were salmeterol (one cility, the patient was in moderate respiratory dis-
puff twice daily), fluticasone propionate delivered tress. The blood pressure was 152/62 mm Hg, the
as an aerosol (220 μg per puff, at a dose of two pulse 120 beats per minute, and the temperature
puffs with a spacer adaptor, twice daily), predni- 37.4°C; the respirations were 28 per minute, and
sone (5 mg every other day), and albuterol with the the oxygen saturation was 90 to 91% while the
use of a metered-dose inhaler (two puffs four times patient was breathing ambient air. At her request,
daily as needed). a peak-flow measurement was not performed. The
The patient had a history of obesity, gastro- body habitus was cushingoid, and there were dif-
esophageal reflux for which she took esomepra- fuse wheezes in both lungs, without rales or rhon-
zole, depression, wrist fractures after a fall, a pari- chi. There was no digital clubbing or cyanosis. The
etal skull fracture after an assault, chickenpox, and remainder of the examination was normal. A chest
pinworms. Childhood vaccinations had been given radiograph revealed consolidation in the right
but had been delayed because of missed appoint- middle lobe and patchy opacity in the left upper
ments. She had no allergies to medications. She lobe. A combination solution of albuterol and ip-
was of South Asian, Scottish, and Dutch ancestry. ratropium was administered by nebulizer twice,
She had missed many months of school because and she was discharged home while receiving
of asthma and had left school after the eighth prednisone (60 mg daily, with instructions to ta-
grade at the age of 15 years. She gave birth to a per the dose), her other medications, and a 5-day
child at the age of 19 years and lived with the course of azithromycin.
child, her mother, and her half-siblings. She told Approximately 8 weeks before admission, the
some caregivers that she smoked cigarettes but patient was seen in the emergency room of a local
also told many others that she did not smoke. The hospital because of respiratory symptoms. Cla
patient’s mother and other maternal relatives had rithromycin was prescribed, but the symptoms
asthma and eczema, and there was a family his- worsened; several days later, a chest radiograph
tory of diabetes mellitus. Her two half-siblings revealed a left-upper-lobe and perihilar infiltrate
A B
33p9
asthma. For instance, omalizumab, a monoclonal eosinophilia or vasculitis, which are characteristic
antibody against IgE, prevents IgE from binding of the last three disorders. Although IgE levels may
to mast cells and other inflammatory cells, thereby be elevated in these conditions, IgE testing was not
preventing the release of inflammatory mediators. performed.
Its use may permit a lower dose of corticosteroids
and may reduce the frequency of exacerbations, Pharmacogenetics and the Efficacy
which, in turn, could reduce the number of outpa- of Asthma Therapies
tient and emergency room visits and hospitaliza- This patient may be one of the many patients whose
tions among patients with moderate-to-severe asth- asthma is unresponsive to current standard ther-
ma.8,9 Tumor-necrosis-factor (TNF) inhibitors have apies. As many as 40% of patients do not have a
also been investigated in asthma. TNF is a proin- response to inhaled corticosteroids,11-13 and per-
flammatory cytokine affecting adhesion, migra- haps even a higher proportion do not have a re-
tion, activation, and proliferation of many types of sponse to leukotriene modifiers. Heterogeneity of
cells. It is increased in the bronchoalveolar-lavage the underlying biology may affect responsiveness
fluid of patients with asthma, and preliminary data to specific therapies. Symptoms may be driven by
suggest that TNF inhibitors may significantly im- perturbations in corticosteroid, leukotriene, IgE, or
prove lung function and symptoms in patients with beta-adrenergic pathways or even in other pathways
severe asthma.10 yet to be identified; each of these pathways may be
modulated by different medications, so therapies
Factors Contributing to Poor Outcomes should ideally be tailored to the underlying patho-
Despite Optimal Medication Regimens genesis. Similarly, asthma may be mediated by eo-
Several factors can result in poor outcomes despite sinophils or, in the case of severe asthma, by neu-
optimized medication regimens. Exposure to en- trophils. TNF may have a role, and natural killer
vironmental exacerbating factors such as dust, cells may be principal effector cells.14 Since it is
smoke, or cockroaches may impair responsiveness currently not possible to identify the specific path-
to specific therapies. Caregivers made attempts to way involved in a given patient’s asthma, we pre-
modify the home environment of this patient when scribe on the basis of trial and error — an approach
she was a child, but they were unsuccessful. We that, as this case shows, is not always successful.
do not know whether the issue of environmental Pharmacogenetics, the study of how genetic
factors had been raised with the patient during re- differences influence variability in therapeutic and
cent years or whether she would have been more adverse responses to drugs, may predict some of
compliant as a young adult than her mother had the heterogeneity of responses to asthma treat-
been during the patient’s childhood. ments. A mutation in a specific pathway may cause
Coexisting diseases can also impair asthma or prevent a response to a medication aimed at that
outcomes despite optimal medication regimens. pathway or cause an adverse reaction. In asthma,
This patient had evidence of gastroesophageal genetic factors may affect responses to beta-ago-
reflux disease, a condition that may provoke or nists, leukotriene modifiers, and inhaled cortico-
worsen symptoms of asthma. She used a proton- steroids.15 In particular, a common variant in the
pump inhibitor, but it would have been important gene coding for the 16th amino acid of the beta-
to ascertain that the reflux was adequately con- adrenergic receptor is associated with a decline in
trolled and was not contributing to asthma exac- lung function and asthma exacerbations in pa-
erbations. Chronic sinusitis and postnasal drip tients receiving either short- or long-acting beta-
may also exacerbate asthma. This patient had a agonists.16-19 Among patients with asthma, this
history of multiple episodes of pneumonia, which polymorphism occurs in one sixth of white pa-
resulted in the exacerbation of symptoms, and in- tients and up to one quarter of black patients.
fection certainly could have contributed to her re- Although genetic testing is not routinely avail-
spiratory failure and death. able, caregivers should be aware of the potential
Some conditions mimic severe asthma. This genotype-specific effects of long-acting beta-ago-
patient’s fleeting pulmonary infiltrates and air- nists and their potential association with bad
flow obstruction could suggest diagnoses such as outcomes, including death, in patients with asth-
cystic fibrosis, allergic bronchopulmonary asper- ma.20 Although these therapies are helpful for the
gillosis, bronchocentric granulomatosis, or the majority of patients with asthma, those taking the
Churg–Strauss syndrome. She had no history of long-acting beta-agonists salmeterol or formoterol
have an increased risk of both exacerbations and teristic of fatal asthma.26-31 The gross pathological
asthma-related death, as compared with those not features of fatal asthma may be more dramatic
receiving these medications.21 Although we do not than the microscopical findings. Pneumothorax
have any genotypic information for this patient, may occur as a complication of the disease and is
we know she took salmeterol, and a pharmacoge- a potential cause of death; its documentation at
netically mediated deleterious effect of this long- autopsy requires opening the chest under a water
acting beta-agonist could have played a role in her seal. No pneumothorax was found in this patient.
deteriorating condition and death. A large, pro- The lungs were hyperinflated, with rounded con-
spective, genotype-stratified trial investigating tours when removed from the body (Fig. 2A). Ex-
whether long-acting beta-agonists cause such ad-
verse effects, which is currently being conducted
by the Asthma Clinical Research Network of the A B
NIH, may answer this question.
Fatal asthma.
amination of a cut section showed that the pa- the remainder of the autopsy disclosed no evidence
renchyma protruded above the cut edge of the of coronary artery disease or other abnormalities.
visceral pleura. When left lying on a dissecting A Physician: The patient’s mother noted that the
table, the lungs deflated only slowly. In some cases patient was using a nebulizer shortly before she
it may be difficult to inflate the lungs with forma- died. Could that have contributed to her death?
lin through the bronchial tree because of bron- Dr. Wechsler: Frequent use of albuterol was un-
chiolar obstruction, which was the case with this likely to have caused her death unless there was
patient’s lungs. Pneumomediastinum was present, an underlying cardiac abnormality. The frequent
with interstitial emphysema in fibroadipose tissue use of nebulized beta-agonists was an indicator of
(Fig. 2B). Mucus plugs in bronchi are a frequent the poor control of her asthma, which ultimately
finding; the mucus may protrude from the cut end caused her death. We attempted a postmortem
of a bronchus. analysis of tissue from this patient for evidence
Microscopically, bronchi and bronchioles were of the deleterious mutation in the beta-adrener-
distended by mucus (Fig. 2C), and lymphocytes, gic receptor, but we were unable to extract DNA
neutrophils, and mast cells were present in the of sufficient quality.
bronchiolar mucosa. The bronchial basement mem
brane was thickened, and airway smooth-muscle A nat omic a l Di agnosis
hypertrophy caused bronchiolar narrowing or sub-
Status asthmaticus with hyperinflated lungs, pleu-
total occlusion (Fig. 2D).32 Signs of chronic scar-
ral and pericardial interstitial emphysema, mucus
ring, resulting in constrictive bronchiolitis, were
plugging, bronchiolar scarring, and eosinophilic
present, with small focal scars representing oblit-
pneumonitis.
erated bronchioles. Eosinophils are an inconsis- Dr. Wechsler reports receiving consulting fees or advisory-
tent finding in fatal asthma33,34; they may be board fees from Genentech, Merck, Pfizer, Tanox, and Critical
present in the bronchial lumen, in alveoli, or in Therapeutics and lecture fees from Novartis, Genentech, and
Merck, and serving as an investigator in a trial of a bronchial
the pulmonary interstitium, as in this case (Fig. thermoplasty system sponsored by Asthmatx. No other potential
2E).35,36 There were no pulmonary emboli, and conflict of interest relevant to this article was reported.
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