The n e w e ng l a n d j o u r na l of m e dic i n e

case records of the massachusetts general hospital

Founded by Richard C. Cabot

Nancy Lee Harris, m.d., Editor Eric S. Rosenberg, m.d., Associate Editor
Jo-Anne O. Shepard, m.d., Associate Editor Alice M. Cort, m.d., Associate Editor
Sally H. Ebeling, Assistant Editor Christine C. Peters, Assistant Editor

Case 15-2007: A 20-Year-Old Woman

with Asthma and Cardiorespiratory Arrest
Michael E. Wechsler, M.D., M.M.Sc., Jo-Anne O. Shepard, M.D.,
and Eugene J. Mark, M.D.

Pr e sen tat ion of C a se

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-

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 1. Timeline of Asthma Therapies.

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
inhalational treatments with nebulized albuterol
(2.5 mg) and nebulized ipratropium (0.5 mg). Her
other asthma medications were salmeterol (one
puff twice daily), fluticasone propionate delivered
as an aerosol (220 μg per puff, at a dose of two
puffs with a spacer adaptor, twice daily), predni-
sone (5 mg every other day), and albuterol with the
use of a metered-dose inhaler (two puffs four times
daily as needed).
The patient had a history of obesity, gastro-
esophageal reflux for which she took esomepra-
zole, depression, wrist fractures after a fall, a pari-
etal skull fracture after an assault, chickenpox, and
pinworms. Childhood vaccinations had been given
but had been delayed because of missed appoint-
ments. She had no allergies to medications. She
was of South Asian, Scottish, and Dutch ancestry.
She had missed many months of school because
of asthma and had left school after the eighth
grade at the age of 15 years. She gave birth to a
child at the age of 19 years and lived with the
child, her mother, and her half-siblings. She told
some caregivers that she smoked cigarettes but
also told many others that she did not smoke. The
patient’s mother and other maternal relatives had
asthma and eczema, and there was a family his-
tory of diabetes mellitus. Her two half-siblings
were healthy; her father’s medical history was not
known.
On physical examination at the urgent care fa-
cility, the patient was in moderate respiratory dis-
tress. The blood pressure was 152/62 mm Hg, the
pulse 120 beats per minute, and the temperature
37.4°C; the respirations were 28 per minute, and
the oxygen saturation was 90 to 91% while the
patient was breathing ambient air. At her request,
a peak-flow measurement was not performed. The
body habitus was cushingoid, and there were dif-
fuse wheezes in both lungs, without rales or rhon-
chi. There was no digital clubbing or cyanosis. The
remainder of the examination was normal. A chest
radiograph revealed consolidation in the right
middle lobe and patchy opacity in the left upper
lobe. A combination solution of albuterol and ip-
ratropium was administered by nebulizer twice,
and she was discharged home while receiving
prednisone (60 mg daily, with instructions to ta-
per the dose), her other medications, and a 5-day
course of azithromycin.
Approximately 8 weeks before admission, the
patient was seen in the emergency room of a local
hospital because of respiratory symptoms. Cla­
rithromycin was prescribed, but the symptoms
worsened; several days later, a chest radiograph
revealed a left-upper-lobe and perihilar infiltrate

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 case records of the massachuset ts gener al hospital
suggestive of pneumonia. Ceftriaxone was pre-
scribed and admission to the hospital was recom-
mended, but she left against medical advice to care
for her child. One week later, she saw her primary
care physician, who prescribed levofloxacin. Three
days later, she was seen at an urgent care facility
because of persistent symptoms. At that time, she
was taking prednisone (30 mg) daily and albuterol
as needed. Prednisone (30 mg) was administered
orally, and a combination of albuterol and ipratro-
pium was given by nebulizer. She was instructed
to take prednisone (60 mg) daily, tapering to a
final dose of 10 mg every other day. A follow-up
visit and an appointment with a pulmonary spe-
cialist were scheduled, but the patient did not keep
the appointments.
During the next weeks, the patient visited emer-
gency departments four or five times because of
acute symptoms of asthma, and she made numer-
ous phone calls to her primary care physician, re-
questing refills of her medications. The physician
became aware that the patient was receiving asth-
ma medications from several different providers.
In the early hours of the morning of admission,
the patient’s mother noted that the patient was
awake and using a nebulizer, as she did frequently.
When her mother next saw her, approximately
2 hours later, the patient was lying on the floor,
unresponsive, without spontaneous respirations
or pulse. The patient’s mother called emergency
medical services (EMS).
On examination by EMS providers, the patient
was cold, cyanotic, and in asystole. The trachea
was intubated, and cardiopulmonary resuscitation
was initiated. Epinephrine (1 mg) and atropine
(1 mg) were administered intravenously; this was
repeated twice without response. The patient was
taken to the emergency room of another hospital,
arriving 25 minutes later while cardiopulmonary
resuscitation was in progress. She remained in
asystolic cardiac arrest, despite aggressive resus-
citation attempts. She was pronounced dead 10
minutes after arrival. The body was transferred to
this hospital, and an autopsy was performed.
Differ en t i a l Di agnosis
Dr. Michael E. Wechsler: May we review the imaging
studies?
Dr. Jo-Anne O. Shepard: Chest radiographs (Fig. 1A
and 1B) obtained 17 months before her death, on
one of the patient’s multiple visits for asthma ex-
acerbations, show pneumomediastinum, with air
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Table 2. Results of Pulmonary-Function Tests.*
Measure Age
7 Yr 11 Yr 18 Yr
actual value (% of predicted value)
FVC (liters) Normal 2.79 (125)
FEV1 (liters) Normal 2.00 (100) 2.49 (96)
FEF25 of FVC (liters/sec) 3.29 (73)
FEF75 of FVC (liters/sec) — (44) 0.62 (46)
FEF25–75 of FVC (liters/sec) 1.45 (56) 1.71 (58)
* FVC denotes forced vital capacity in liters, FEV1 forced expiratory volume in
the first second, FEF25 maximum forced expiratory flow rate when 25% of the
FVC has been exhaled, FEF75 maximum forced expiratory flow rate when 75%
of the FVC has been exhaled, and FEF25–75 maximum forced expiratory flow
rate between 25% and 75% of the FVC exhaled.
tracking into the neck. On the lateral view (Fig. 1B)
there is a tiny anterior pneumothorax. The pneu-
mothorax results from the Macklin effect, in
which a peripheral alveolus ruptures and the air
tracks centrally along the interstitium into the
mediastinum and soft tissues. These features are
typical of asthma. Bilateral focal consolidations
are present, representing pneumonia.
Dr. Wechsler: This case highlights the problem
of asthma-associated morbidity and mortality,
with more than 4000 deaths from asthma occur-
ring annually in the United States.1 This patient’s
multiple hospitalizations and emergency room
visits exemplify the annual 500,000 asthma-related
hospitalizations and 2 million emergency room
visits that account for $16 billion per year spent
for asthma treatment2 and the millions of asthma-
related lost work and school days. This patient
dropped out of school because of the hold that
asthma had on her life.
There are many possible causes of death in a
patient with asthma in whom respiratory failure
develops. Patients with corticosteroid-induced
chronic immunosuppression are predisposed to
life-threatening infections, anaphylaxis, and acute
hypersensitivity reactions; however, this patient did
not have a history or laboratory evidence to suggest
any of these diagnoses, nor did she have any un-
derlying cardiac disease. She did not have a history
of eosinophilia or other major clinical manifes-
tations of eosinophilic pneumonia or the Churg–
Strauss syndrome. She had nearly all the risk fac-
tors for life-threatening asthma and death from
asthma (Table 3), except for aspirin sensitivity and
older age. Although not a consistent cigarette
smoker, she had some history of smoking and
2085
 The n e w e ng l a n d j o u r na l of m e dic i n e

A B

33p9

Figure 1. Radiographic Images.

ICM AUTHOR Wechsler RETAKE 1st
Posterior anterior (Panel A) and lateral (Panel B) chest radiographs obtained 17 months
2nd before the patient’s death
REG F FIGURE Fig 1A,B
show pneumomediastinum (Panel A, large arrows) and an anterior pneumothorax (Panel 3rd B, large arrow). Bilateral
CASE TITLE
focal consolidations (Panels A and B,EMail
small arrows) are consistent with pneumonia.
Revised
Line 4-C
Enon ARTIST: mleahy SIZE
H/T H/T 33p9
FILL Combo
exposure to secondhand smoke both in utero and PLEASE
AUTHOR, egories of both moderate and severe persistent
NOTE:
during childhood. She had not requiredFigure mechani-
has been redrawn and type has
disease. been reset.
Whereas all patients with asthma should
Please check carefully.
cal ventilation, but she had been hospitalized many avoid or control factors that trigger attacks, patients
times. Therefore, I believe that this
JOB: patient
35620 had with persistent asthma should also use controller
ISSUE: 5-17-07
status asthmaticus with resultant fatal asthma. medication daily to control airway inflammation
Why did this patient die from asthma? The (e.g., inhaled corticosteroids) and, as the severity
answer may lie with the treatment plan, the com- increases, escalate therapy appropriately. Asthma
pliance of the patient with the plan, and the inher- guidelines from 2006 focus on maintenance of
ent severity of her disease (so severe that no mea- control, reflecting an understanding that asthma
sure taken could have saved her). Each of these severity “involves not only the severity of the un-
factors must be addressed in this case. derlying disease but also its responsiveness to treat-
ment,” and that “severity is not an unvarying fea-
Dis cus sion of M a nage men t ture of an individual patient’s asthma but may
change over months or years.” 4
To address growing concern about increased asth- Inhaled corticosteroids, which had been in-
ma-related morbidity and mortality, in the late cluded in this patient’s regimen early in her care,
1990s the National Institutes of Health (NIH) for- are the cornerstone of these recommendations.
mulated the National Asthma Education and Pre- There is evidence that inhaled corticosteroids not
vention Program, establishing guidelines for the only improve lung function and symptoms but also
management of asthma.3 The NIH recommended may prevent deaths from asthma.5 Short-acting
stratification of patients according to the severity beta-agonists may be used in the short term to
of asthma (mild intermittent, mild persistent, mod- relieve symptoms; however, if there is poor asth-
erate persistent, and severe persistent disease) and ma control despite the use of inhaled corticoste-
implementation of treatment algorithms. At differ- roids, as in this case, other controller therapies,
ent times, this patient’s condition fell into the cat- such as long-acting beta-agonists, leukotriene

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 case records of the massachuset ts gener al hospital
modifiers, cromolyn, theophylline, or even sys-
temic corticosteroids should be added to the regi-
men. All these medications were prescribed at
various times for this patient, but not on a con-
sistent basis. When the disease is controlled, the
doses or number of controller medications may be
reduced. This patient’s asthma rarely, if ever, ap-
peared to be sufficiently controlled to allow the
tapering of medications.
Patient education is essential at every step of
asthma management, and patients should con-
tinue to monitor their disease subjectively (i.e.,
assessing symptoms) and objectively (using peak-
flow meters or spirometry). Although such ap-
proaches were attempted in this case, they were
unsuccessful.
Managing Severe Asthma
Both the patient and the physician have responsi-
bilities in the management of severe asthma. How-
ever, a major problem in the control of asthma is
that much of the responsibility lies with the pa-
tient.
Adherence to Controller Therapy and Appropriate
Technique
Even if a medication is shown to be effective in
ideal circumstances, as in a clinical trial, its effec-
tiveness in practice requires adherence to a pre-
scribed regimen; for medication to be effective,
patients must take it regularly as it is meant to be
taken. Like this patient, nearly 70% of patients with
severe asthma do not refill prescriptions for in-
haled corticosteroids,6,7 and many use inhalers in-
correctly. Poor adherence to asthma medications
may be due to lack of an immediate benefit, the
patient’s preference for pills rather than inhalers,
suboptimal results because the patient’s technique
of use is suboptimal, cost, inconvenience, and lack
of education by health care providers. Many pa-
tients, like this one, are children or adolescents
who may have problems accepting the facts of their
illness and the necessity for adhering to an oner-
ous treatment regimen. The cost of the medica-
tions may be an issue, since asthma is increasingly
prevalent among economically disadvantaged, in-
ner-city children for whom access to medications
is often a difficulty. Physicians clearly worked with
this patient to maximize adherence and to explain
the importance of taking medications daily.
Adverse effects of medications can also lead to
poor adherence. For example, inhaled corticoste-
roids can cause dysphonia, oral thrush, osteoporo-
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Table 3. Risk Factors for Life-Threatening Asthma and Death from Asthma.
Long duration of asthma
Poor control of asthma
Systemic dependence on corticosteroids
Noncompliance with medication regimen
Psychosocial factors
Poor socioeconomic conditions
Inconsistent medical follow-up
Delayed medical care
Older age
Cigarette smoking
Aspirin sensitivity
Prior hospitalization for asthma
Prior use of mechanical ventilation
sis, cataracts, glaucoma, and adrenal suppression.
None of these complications were apparent in
this case.
Consistent Physician Care
Consistency of health care providers was a problem
in this case, because no single physician could ap-
preciate the full scope of this patient’s multiple
presentations for worsening asthma. During the
last 5 years of her life, she saw many different pri-
mary care doctors, pulmonologists, and allergists.
She went to different clinics and emergency rooms
many times, each time seeing different physicians.
This fragmentation of care could have resulted in
a missed opportunity for one physician to detect
her clinical deterioration during a period of weeks
or months and to provide support.
Education and Warning Signs
Education of patients about triggers and warning
signs of severe attacks is critical to the manage-
ment of severe asthma. This patient knew what
provoked her asthma (e.g., cold air and hot, humid
air), and she avoided going outside in winter. We
do not know whether she had a peak-flow meter
with which to assess the degree of airflow obstruc-
tion or whether she was aware of the severity of her
disease. There was no record of allergy testing.
Other Medical Options
This patient’s physicians had tried virtually all
available therapies to control her disease (Table 1),
including new treatments such as leukotriene-
receptor antagonists. Novel therapies are now avail-
able that might have helped control this patient’s
2087
 The n e w e ng l a n d j o u r na l
asthma. For instance, omalizumab, a monoclonal
antibody against IgE, prevents IgE from binding
to mast cells and other inflammatory cells, thereby
preventing the release of inflammatory mediators.
Its use may permit a lower dose of corticosteroids
and may reduce the frequency of exacerbations,
which, in turn, could reduce the number of outpa-
tient and emergency room visits and hospitaliza-
tions among patients with moderate-to-severe asth-
ma.8,9 Tumor-necrosis-factor (TNF) inhibitors have
also been investigated in asthma. TNF is a proin-
flammatory cytokine affecting adhesion, migra-
tion, activation, and proliferation of many types of
cells. It is increased in the bronchoalveolar-lavage
fluid of patients with asthma, and preliminary data
suggest that TNF inhibitors may significantly im-
prove lung function and symptoms in patients with
severe asthma.10
Factors Contributing to Poor Outcomes
Despite Optimal Medication Regimens
Several factors can result in poor outcomes despite
optimized medication regimens. Exposure to en-
vironmental exacerbating factors such as dust,
smoke, or cockroaches may impair responsiveness
to specific therapies. Caregivers made attempts to
modify the home environment of this patient when
she was a child, but they were unsuccessful. We
do not know whether the issue of environmental
factors had been raised with the patient during re-
cent years or whether she would have been more
compliant as a young adult than her mother had
been during the patient’s childhood.
Coexisting diseases can also impair asthma
outcomes despite optimal medication regimens.
This patient had evidence of gastroesophageal
reflux disease, a condition that may provoke or
worsen symptoms of asthma. She used a proton-
pump inhibitor, but it would have been important
to ascertain that the reflux was adequately con-
trolled and was not contributing to asthma exac-
erbations. Chronic sinusitis and postnasal drip
may also exacerbate asthma. This patient had a
history of multiple episodes of pneumonia, which
resulted in the exacerbation of symptoms, and in-
fection certainly could have contributed to her re-
spiratory failure and death.
Some conditions mimic severe asthma. This
patient’s fleeting pulmonary infiltrates and air-
flow obstruction could suggest diagnoses such as
cystic fibrosis, allergic bronchopulmonary asper-
gillosis, bronchocentric granulomatosis, or the
Churg–Strauss syndrome. She had no history of
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of m e dic i n e
eosinophilia or vasculitis, which are characteristic
of the last three disorders. Although IgE levels may
be elevated in these conditions, IgE testing was not
performed.
Pharmacogenetics and the Efficacy
of Asthma Therapies
This patient may be one of the many patients whose
asthma is unresponsive to current standard ther-
apies. As many as 40% of patients do not have a
response to inhaled corticosteroids,11-13 and per-
haps even a higher proportion do not have a re-
sponse to leukotriene modifiers. Heterogeneity of
the underlying biology may affect responsiveness
to specific therapies. Symptoms may be driven by
perturbations in corticosteroid, leukotriene, IgE, or
beta-adrenergic pathways or even in other pathways
yet to be identified; each of these pathways may be
modulated by different medications, so therapies
should ideally be tailored to the underlying patho-
genesis. Similarly, asthma may be mediated by eo-
sinophils or, in the case of severe asthma, by neu-
trophils. TNF may have a role, and natural killer
cells may be principal effector cells.14 Since it is
currently not possible to identify the specific path-
way involved in a given patient’s asthma, we pre-
scribe on the basis of trial and error — an approach
that, as this case shows, is not always successful.
Pharmacogenetics, the study of how genetic
differences influence variability in therapeutic and
adverse responses to drugs, may predict some of
the heterogeneity of responses to asthma treat-
ments. A mutation in a specific pathway may cause
or prevent a response to a medication aimed at that
pathway or cause an adverse reaction. In asthma,
genetic factors may affect responses to beta-ago-
nists, leukotriene modifiers, and inhaled cortico-
steroids.15 In particular, a common variant in the
gene coding for the 16th amino acid of the beta-
adrenergic receptor is associated with a decline in
lung function and asthma exacerbations in pa-
tients receiving either short- or long-acting beta-
agonists.16-19 Among patients with asthma, this
polymorphism occurs in one sixth of white pa-
tients and up to one quarter of black patients.
Although genetic testing is not routinely avail-
able, caregivers should be aware of the potential
genotype-specific effects of long-acting beta-ago-
nists and their potential association with bad
outcomes, including death, in patients with asth-
ma.20 Although these therapies are helpful for the
majority of patients with asthma, those taking the
long-acting beta-agonists salmeterol or formoterol
 case records of the massachuset ts gener al hospital

have an increased risk of both exacerbations and
asthma-related death, as compared with those not
receiving these medications.21 Although we do not
have any genotypic information for this patient,
we know she took salmeterol, and a pharmacoge-
netically mediated deleterious effect of this long-
acting beta-agonist could have played a role in her
deteriorating condition and death. A large, pro-
spective, genotype-stratified trial investigating
whether long-acting beta-agonists cause such ad-
verse effects, which is currently being conducted
by the Asthma Clinical Research Network of the
NIH, may answer this question.
teristic of fatal asthma.26-31 The gross pathological
features of fatal asthma may be more dramatic
than the microscopical findings. Pneumothorax
may occur as a complication of the disease and is
a potential cause of death; its documentation at
autopsy requires opening the chest under a water
seal. No pneumothorax was found in this patient.
The lungs were hyperinflated, with rounded con-
tours when removed from the body (Fig. 2A). Ex-
A B

Use of Biomarkers in Asthma Control

This patient had a normal forced expiratory vol-
ume in 1 second, but she clearly had severe asth-
ma, as shown by the long duration and frequency
of her symptoms, frequent use of quick-relief in-
halers, and missed work and school. An important
area of asthma research is the use of biomarkers
to assess airway inflammation and guide therapy
for patients with asthma. Adjustment of asthma
medications on the basis of assessment of sputum
eosinophils, exhaled nitric oxide, and airway hy-
perreactivity can reduce asthma exacerbations22-25
and also potentially minimize treatment-related C D
side effects.

DR . MICH A EL E . W ECHSL ER’S

DI AGNOSIS

Fatal asthma.

Pathol o gic a l Dis cus sion E

Dr. Eugene J. Mark: The diagnosis of fatal asthma

falls within the purview of both the hospital pa-
thologist and the forensic pathologist, the latter
because of the possibility that asthma may explain
sudden unexpected death. Factors for the forensic
pathologist to consider in determining whether
asthma was the cause of sudden, unwitnessed
Figure 2. Autopsy Findings.
death include a history of severe attacks, the exis-
The right lung is hyperinflated
AUTHOR in Wechsler
this gross photograph taken before the
tence and location of therapeutic drugs and inhal- ICM
lung was removed from the body (Panel A); a depressed
RETAKE 1st
polygonal lobule
REG F FIGURE 2 a_e 2nd
ers that could have been used by the patient, and (arrow) contrasts
CASE with the hyperinflated adjacent lung. Mediastinal 3rd emphy-
TITLE
gross and microscopical evidence of acute and sema is presentEMail Revised
(Panel B), with bubbles of air in the pericardial
Line 4-C
fat (arrows).
chronic asthma. At autopsy, the common differen- A small bronchus
Enonis filled with mucus and sloughed epithelial
ARTIST: mst SIZE cells (Panel
H/T H/T
C, hematoxylinFILL
and eosin). A terminal bronchiole (Panel 22p3
D, hematoxylin
tial diagnosis of the cause of death includes as- Combo
and eosin) contains hypertrophic
AUTHOR, PLEASE NOTE:(arrow). Numerous eosin-
smooth muscle
phyxia from other causes, anaphylactic reaction, ophils are presentFigure
in thehas
pulmonary interstitium
been redrawn and type has(Panel E, hematoxylin and
been reset.
coexistent pulmonary emboli, and coronary artery eosin). (Photographs in Panels Please
A andcheck carefully. of Dr. Pavan Auluck, De-
B courtesy
disease. partment of Pathology, Massachusetts General Hospital.)
JOB: 35620 ISSUE: 05-17-07
In this case, the autopsy findings were charac-

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 The n e w e ng l a n d j o u r na l of m e dic i n e

amination of a cut section showed that the pa-
renchyma protruded above the cut edge of the
visceral pleura. When left lying on a dissecting
table, the lungs deflated only slowly. In some cases
it may be difficult to inflate the lungs with forma-
lin through the bronchial tree because of bron-
chiolar obstruction, which was the case with this
patient’s lungs. Pneumomediastinum was present,
with interstitial emphysema in fibroadipose tissue
(Fig. 2B). Mucus plugs in bronchi are a frequent
finding; the mucus may protrude from the cut end
of a bronchus.
Microscopically, bronchi and bronchioles were
distended by mucus (Fig. 2C), and lymphocytes,
neutrophils, and mast cells were present in the
bronchiolar mucosa. The bronchial basement mem­
brane was thickened, and airway smooth-muscle
hypertrophy caused bronchiolar narrowing or sub-
total occlusion (Fig. 2D).32 Signs of chronic scar-
ring, resulting in constrictive bronchiolitis, were
present, with small focal scars representing oblit-
erated bronchioles. Eosinophils are an inconsis-
tent finding in fatal asthma33,34; they may be
present in the bronchial lumen, in alveoli, or in
the pulmonary interstitium, as in this case (Fig.
2E).35,36 There were no pulmonary emboli, and
the remainder of the autopsy disclosed no evidence
of coronary artery disease or other abnormalities.
A Physician: The patient’s mother noted that the
patient was using a nebulizer shortly before she
died. Could that have contributed to her death?
Dr. Wechsler: Frequent use of albuterol was un-
likely to have caused her death unless there was
an underlying cardiac abnormality. The frequent
use of nebulized beta-agonists was an indicator of
the poor control of her asthma, which ultimately
caused her death. We attempted a postmortem
analysis of tissue from this patient for evidence
of the deleterious mutation in the beta-adrener-
gic receptor, but we were unable to extract DNA
of sufficient quality.
A nat omic a l Di agnosis
Status asthmaticus with hyperinflated lungs, pleu-
ral and pericardial interstitial emphysema, mucus
plugging, bronchiolar scarring, and eosinophilic
pneumonitis.
Dr. Wechsler reports receiving consulting fees or advisory-
board fees from Genentech, Merck, Pfizer, Tanox, and Critical
Therapeutics and lecture fees from Novartis, Genentech, and
Merck, and serving as an investigator in a trial of a bronchial
thermoplasty system sponsored by Asthmatx. No other potential
conflict of interest relevant to this article was reported.

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