*The authors are retired.
Correspondence to: Làszlò Bense, MD, PhD, Postängsv 232, 145 52 Norsborg, Sweden; e-mail: email@example.com
To further elucidate the etiology of spontaneous pneumothorax
(SP), a study was made of three nonsmoking patients who had experienced
several episodes of chest radiograph-verified familial SP (FSP) and 11
unaffected relatives, 5 of whom were smokers and 6 of whom were
never-smokers. Fourteen healthy subjects without SP served as a control
group. All three groups underwent the same clinical, laboratory, and
radiologic examinations, including CT scans of the lungs, with the aim
of detecting any changes in the pulmonary parenchyma. Emphysema-like
changes (ELCs) were detected on CT scans in each of the three patients
with FSP. The unaffected relatives of the FSP patients showed no sign
of FSP, but four of the six never-smokers and three of the five
relatives who were smokers displayed pulmonary emphysema and ELCs on CT
scans. No abnormalities were seen on pulmonary CT scans of the 14
control subjects. The present results indicate that ELCs and pulmonary
emphysema may be genetically
condition in which air is present in the intrapleural cavity without a
known cause is called spontaneous pneumothorax (SP). The occurrence of
familial SP (FSP) was first reported by Faber1in 1921.
Family studies2–13 have been published since that time on
a number of cases of FSP. Information on smoking habits in these
reports is sparse. The FSP cases reported in the literature and those
included in the present study provide evidence that at least some of
the SP cases are genetically determined. An autosomal-dominant trait
has been suggested as an explanation for FSP.2,7,9
Attention has been paid to the human leukocyte antigen region on
chromosome 6.10 From their study, Sharpe et
al10 concluded that SP may be linked to the human
leukocyte antigen genes, a possibility supported by Sugiyama et
A number of extrinsic factors (ie, smoking) and intrinsic
factors are involved in the pathogenetic mechanism of this disease.
Among the intrinsic factors that were previously observed, bilateral
bronchial anomalies of a type causing obstruction seem to be a
prerequisite for the occurrence of SP in never-smokers.14
This view is compatible with and supports the role of heredity in
patients with FSP.
In smokers, the rupture of the alveolar wall into cavities of the
pulmonary tissue is referred to as pulmonary emphysema, and in those
who have never smoked, it is referred to as emphysema-like changes
(ELCs).15–16 ELCs have been observed in nonsmoking SP
The overall purpose of the present article is to determine whether ELCs
are considerably more common in FSP-free relatives in a family (with as
many as three verified FSP cases) than among SP-free control subjects
with similar smoking habits and sex and age distributions.
The study was approved by the Ethics Boards of University
Hospitals, Akademiska in Uppsala, Sweden, and the Karolinska Institute
in Stockholm, Sweden. Each subject gave his or her written consent
prior to participation.
The study initially consisted of three members of a family, two
women and one man, who had experienced FSP even though they had never
smoked (Fig 1
). One of the female patients had had at least 20 episodes of FSP
on the left side and 8 on the right side. The other female FSP patient
had had four episodes of FSP on the left side. The female FSP patients
had been operated on because of frequent recurrences of FSP. None of
the female FSP patients had catamenial SP. The male FSP patient had had
one episode of FSP on the right side that had been treated with
Bülau drainage (ie, a seal under water).
Eleven unaffected family members, five smokers and six who had never
smoked, also were included in the study. The FSP patients and the
majority of their relatives complained of an occasional cough but were
free of malignant, inflammatory, and cardiopulmonary disease.
Echocardiography was carried out 10 weeks after this study in one of
the unaffected female relatives who had never smoked. Regurgitation was
observed at the valva tricuspidalis, with a systolic flow (measured by
Doppler echocardiography) of 2.5 m/s. That implied an
approximate systolic pressure of 30 mm Hg in the pulmonary artery.
Four members of the family who were unaffected by FSP
were unable to participate in the study. One man had cerebral paresis,
and three women lived too far away to attend the examinations.
The control group consisted of 10 healthy subjects, who
had been described previously,15–16 and four smokers
(three women and one man) who had respiratory symptoms of COPD. The
latter four subjects were included in order to match the smokers among
the unaffected relatives.
All patients, relatives, and control subjects underwent
chest radiographs and CT scans of the lungs. In the three FSP patients,
CT scans were performed at least 3 years after the latest FSP episode.
Chest radiographs were requirements for subsequent CT scans.
CT scans of the lungs were performed with a helical apparatus (GE High
Speed Helical CT; General Electric; Paris, France) with the subject in
the supine position. The subject was instructed to hold his or her
breath after an ordinary expiration during an exposure time of 5
s. Body mode with 5 mm-thick CT sections, pitch 2, and 5-mm intervals
were used for the whole lung. Two window settings, with optimal
representation of the lung parenchyma and emphysema, were used in all
examinations. The images were examined by an experienced radiologist,
who was not aware of whether the image belonged to a patient or a
The CT scan examination was focused on the detection of the main
variable, that is, the existence of any cavities in the pulmonary
parenchyma, which were expressed as an estimated percentage of the
volume of the right or left lung. They were defined on CT scans as
lesions with a diameter of at least 3 mm and with an attenuation value
of gas, surrounded by pulmonary parenchyma and with no contact with the
Cavities detected in the pulmonary tissue in smokers were referred to
as pulmonary emphysema. Corresponding cavities in those patients and
subjects who had never smoked were referred to as ELCs, because they
were not induced by known emphysema-promoting factors such as smoking
or α1-antitrypsin (AAT) deficiency. The
percentage of distributions of any observed ELC or pulmonary emphysema
within the apical, middle, and basal regions of the lung was recorded
The concentrations of AAT, haptoglobin, and orosomucoid
in the serum were measured by standard methods in all subjects.
In the analysis of significance, Fisher’s Exact Test
The serum haptoglobin, orosomucoid, and AAT concentrations were
checked in the patients 3 years after the last episode of FSP. The
serum haptoglobin and orosomucoid levels were normal in each individual
of the studied groups. The serum AAT concentration was within the
reference range (reference range, 1.0 to 1.7 g/L) in each person,
except a smoker relative whose AAT concentration was 2.0 g/L.
The posteroanterior and lateral chest radiographs revealed nothing
pathologic in the pulmonary tissue or in the pleura in the patients,
the relatives, or the control subjects. The pulmonary emphysema or ELCs
observed on CT scans could not be discerned on chest radiographs.
ELCs were detected on CT scans in each of the three FSP-affected
patients (100%), which is in accordance with our previous findings in
other patients.15–16 The 11 relatives of the three FSP
patients showed no clinical or radiologic signs of FSP. Four of the six
relatives who never smoked (66%) and three of the five relatives who
smoked (60%) showed ELCs and pulmonary emphysema, respectively (see
Thus, 7 of the 11 relatives who had no subjective, clinical, or
radiologic signs of FSP had pulmonary emphysema and ELCs, whereas no
ELC or pulmonary emphysema was found in the control subjects
(p < 0.001 [one-sided Fisher’s Exact Test]; see
Relationship of smoking and age to pulmonary emphysema is
known.17The recent detection18 of pulmonary
emphysema by CT scanning in 44% of healthy smokers who are
approximately 60 years old suggests that emphysema may not be caused
only by smoking. Our CT scan study15 of SP patients
who had never smoked showed ELCs. To our knowledge, there has been no
previous investigation of the pulmonary tissue to determine the
occurrence of ELCs and emphysema in unaffected relatives of patients
who had never smoked but who had FSP.
The present study was designed with the principal aim of detecting ELCs
and pulmonary emphysema in FSP patients who had never smoked and, in
particular, in their relatives whether or not they had ever smoked. The
relatives were compared with matching nonrelated healthy control
subjects, both smokers and never-smokers, with respect to the presence
and intrapulmonary location of the ELCs and pulmonary emphysema.
ELCs were found in the three FSP patients, which is in conformity with
our previous findings in SP patients.15 We did not expect
to find ELCs in the four relatives of the six who had never smoked and
who also were free even from symptoms of FSP, a finding that suggests a
hereditary factor. The third and the seventh families in the third
generation, and their children, strongly support the hypothesis of
hereditary emphysema, because emphysema occurred in the third
generation and, subsequently, in the fourth generation despite the fact
that none of those relatives smoked or were affected by AAT
Pulmonary emphysema was found in three of the five smokers among the
relatives. The nonrelated control subjects who smoked displayed no
pulmonary emphysema despite their smoke exposure, which exceeded that
of the smoker relatives by 72% (measured Brinkman index, 252 vs
The present study indicates that ELCs and pulmonary emphysema may be
genetically determined. Further studies are required to confirm the
results of our investigation in the studied family.
Abbreviations: AAT = α1-antitrypsin;
ELC = emphysema-like change; FSP = familial spontaneous
pneumothorax; SP = spontaneous pneumothorax
The three FSP patients were excluded from
the analysis. p < 0.001 (one-sided Fisher’s Exact Test).
We thank each member of the family anonymously,
according to their wish.
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