AATD is an underdiagnosed genetic condition attributable to an inherited mutation in the α1-antitrypsin protease inhibitor of the proteolytic enzyme elastase, with an increased risk of pulmonary and hepatic disease.1 Individuals with AATD commonly present in the fourth or fifth decade of life with symptoms of dyspnea and cough with or without sputum production. AATD may also involve other organs and present with liver cirrhosis, panniculitis, or granulomatosis with polyangiitis.2,3 AATD classically produces a panlobular emphysema disproportionally affecting the lung bases, in contrast to COPD related to tobacco smoke, which typically affects the upper lobes.3 In the United States, the prevalence of AATD has been reported to be 1 in 5097 individuals and is responsible for 1% to 2%of COPD cases.2,4

1. A Woman With Dyspnea and Bronchiectasis
Leonard Riley, MD; Mark Brantly, MD; Ali Ataya, MD
A 41-year-old woman with an 8–pack-year history of tobacco use presented for progres-
sivecoughanddyspneaof4years’duration.Hercoughwasproductiveofyellow-greenspu-
tumandtreatedwithantibioticsonmultipleoccasions,whichprovidedsomealleviationof
her symptoms. She had no history of neonatal respiratory distress, nasal congestion, per-
sistent urticaria, joint laxity, or illicit drug use. She denied a family history of liver cirrhosis,
chronicobstructivepulmonarydisease(COPD),orcysticfibrosis.Examinationrevealedscat-
tered wheezes and rhonchi on auscultation. Pulmonary function testing demonstrated a
severe obstruction with a forced expiratory volume at 1 second (FEV1) of 0.79 L (28% of
predicted),forcedvitalcapacity(FVC)of1.64L(47%ofpredicted),FEV1:FVCratioof48%,
and a reduced diffusing capacity for carbon monoxide of 8.74 mL/min per mm Hg (23.75%
of predicted), which was consistent with emphysema. Chest radiography followed by
computed tomography (CT) of the chest showed lower lobe predominant emphysema
and bronchiectasis (Figure).
Diagnosis
α1-Antitrypsin deficiency (AATD)
What to Do Next
B. Assess serum α1-antitrypsin level and genotype
The key to the correct diagnosis in this case is the severe ob-
structivepatternonpulmonaryfunctiontesting,CTofthechestdem-
onstrating lower lobe predominant emphysema and bronchiecta-
sis, and presentation during the fourth decade of life.
Bronchoscopy with bronchoalveolar lavage and transbron-
chial biopsy may be reasonable in pursuit of an infectious or ciliary
dyskinesiaetiologyrelatedtothispatient’sbronchiectasisbutisun-
likely to provide a unifying diagnosis with her emphysema. Inhaled
nasal nitric oxide and ciliary dyskinesia genetic testing can be used
toevaluateforciliarydyskinesia,buttheabsenceofneonatalrespi-
ratorydistress,year-rounddailycoughandnasalcongestionbegin-
ning before age 6 months, and situs inversus makes this diagnosis
unlikely. A diagnosis of cystic fibrosis is also unlikely, given the
Figure. Computed tomography of the chest. Left, Transverse view. Right, Coronal view.
WHAT WOULD YOU DO NEXT?
A. Order bronchoscopy with
bronchoalveolar lavage and
transbronchial biopsy
B. Assess serum α1-antitrypsin level
and genotype
C. Order inhaled nasal nitric oxide
and ciliary dyskinesia genetic
testing
D. Assess sweat chloride and cystic
fibrosis genetic screening
Clinical Review & Education
JAMA Clinical Challenge
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2. distribution and severity of this patient’s bronchiectasis and em-
physema(predominantlyupperlobesincysticfibrosisvslowerlobes
in AATD) without extrapulmonary manifestations or family history.
Discussion
AATD is an underdiagnosed genetic condition attributable to an
inherited mutation in the α1-antitrypsin protease inhibitor of the
proteolytic enzyme elastase, with an increased risk of pulmonary
and hepatic disease.1
Individuals with AATD commonly present in
the fourth or fifth decade of life with symptoms of dyspnea and
cough with or without sputum production. AATD may also involve
other organs and present with liver cirrhosis, panniculitis, or granu-
lomatosis with polyangiitis.2,3
AATD classically produces a panlobu-
lar emphysema disproportionally affecting the lung bases, in con-
trast to COPD related to tobacco smoke, which typically affects the
upper lobes.3
In the United States, the prevalence of AATD has
been reported to be 1 in 5097 individuals and is responsible for 1%
to 2% of COPD cases.2,4
The World Health Organization, American Thoracic Society,
European Respiratory Society, and the COPD Foundation recom-
mend testing of all individuals with COPD for AATD. However,
there is significant cost associated with testing more than an
estimated 174 million persons globally, and there is low uptake of
this recommendation in clinical practice.3,5-7
Testing for AATD
should be strongly considered when symptoms of emphysema
occur in younger patients (<50 years), when there is a rapid
decline in FEV1, or when there is a strong family history of COPD
or liver cirrhosis.3,5,6
Common pathologic allele variations for α1-antitrypsin prote-
ase inhibitor are named the “Z” allele and “S” allele.2
The allelic
homozygous variation PI*ZZ accounts for approximately 95% of
AATD and significantly increases the risk for severe lung disease.2
According to the National Heart, Lung, and Blood Institute Regis-
try of AATD, which is composed of 97.3% of patients with PI*ZZ
genotype, the mean FEV1:FVC ratio is 43%, with 83.9% individu-
als reporting shortness of breath.8
One study showed that bron-
chiectasis was a common phenotype in 95% of patients with
PI*ZZ genotype; however, only 27% had symptoms of regular
sputum production.9
As directed by the Global Initiative for Chronic Obstructive
Lung Disease (GOLD) guidelines for COPD, treatment for AATD
follows conventional therapy and includes inhaled long-acting
muscarinic agonists, long-acting β-agonists, and corticosteroids.
An option for additional therapy specifically for AATD is purified
α1-antitrypsin infusion, termed “augmentation therapy.”10
Mul-
tiple studies conducted to evaluate the efficacy of augmentation
therapy suggest that it may slow the decline of lung function
evaluated by pulmonary function testing or CT densitometry.1,2
Definitive randomized studies are lacking; however, based on
concordant observational studies the American Thoracic Society
recommends augmentation therapy for individuals with estab-
lished airflow obstruction.6
Patient Outcome
Testingrevealedaserumα1-antitrypsinlevelof18mg/dL(3.3μmol/L)
(reference range, 100-300 mg/dL [18.4-55.2 μmol/L]) with a PI*ZZ
genotype.Thepatientwasprovidedcounselingonavoidanceofto-
baccosmokeaswellasotherinhaledirritantsandmaintainingpneu-
mococcal and influenza immunizations. She initiated GOLD-
directedbronchodilatortherapyandaugmentationtherapy,andher
symptoms and results of pulmonary function testing have im-
proved over the last 6 years.
ARTICLE INFORMATION
Author Affiliations: Division of Pulmonary, Critical
Care, and Sleep Medicine, Department of Internal
Medicine, College of Medicine, University of Florida,
Gainesville.
Corresponding Author: Ali Ataya, MD, Division of
Pulmonary, Critical Care and Sleep Medicine,
University of Florida, 1600 SW Archer Rd, M452,
Gainesville, FL 32610 (AliAtaya@gmail.com).
Section Editor: Mary McGrae McDermott, MD,
Senior Editor.
Published Online: July 5, 2019.
doi:10.1001/jama.2019.8606
Conflict of Interest Disclosures: None reported.
Additional Contributions: We thank the patient for
providing permission to share her information.
Submissions: We encourage authors to submit
papers for consideration as a JAMA Clinical
Challenge. Please contact Dr McDermott at
mdm608@northwestern.edu.
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