Int J Clin Exp Med 2015;8(10):18130-18136
www.ijcem.com /ISSN:1940-5901/IJCEM0007906
Original Article
Massive cryptogenic hemoptysis undergoing pulmonary
resection: clinical and pathological characteristics and
management
Xiao-Dong Xia1, Le-Ping Ye1, Wei-Xi Zhang1, Cheng-Yun Wu1, Sun-Shun Yan1, Hai-Xia Weng1, Jie Lin1, Hui Xu1,
Yue-Feng Zhang2, Yuan-Rong Dai1, Liang Dong3
Department of Respiratory Medicine, The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou
325027, Zhejiang, China; 2Department of Thoracic Surgery, The Second Affiliated Hospital, Wenzhou Medical
University, Wenzhou 325027, Zhejiang, China; 3Department of Respiratory Medicine, Qilu Hospital, Shandong
University, Jinan, 250021, Shandong, China
1
Received March 12, 2015; Accepted May 25, 2015; Epub October 15, 2015; Published October 30, 2015
Abstract: Massive cryptogenic hemoptysis is a common presenting symptom and cause of hospitalization for respiratory diseases, and represents a challenging condition in the clinical. This study aimed to analyze the clinical and
pathologic data and management of patients with massive cryptogenic hemoptysis. We retrospectively reviewed 12
patients with massive cryptogenic hemotysis in our hospital between January 2003 and December 2012. Bronchoscopy showed submucosal vascular abnormalities in 4 patients. Of 6 patients managed with conservative measures,
bleeding was completely controlled in 2 patients. Of 10 hemoptysis patients, three were controlled by bronchial
arterial embolization, and seven by surgery. Pathological examination showed a superficial dysplastic, tortuous
and dilated bronchial artery under the bronchial epithelium in 4 patients, and bronchiole dilation in 2 patients, indicating Dieulafoy’s disease of the bronchus and bronchiectasis. No malignance developed within the follow-up. In
conclusion, Dieulafoy’s disease of the bronchus and bronchiectasis should be suspected in patients with massive
cryptogenic hemoptysis. BAE and surgical treatment should be considered in case that massive hemoptysis could
not be controlled by conservative management.
Keywords: Cryptogenic hemoptysis, Dieulafoy’s disease, bronchus, outcome
Introduction
Massive hemoptyis is a life-threatening condition that can lead to airway compromise and
death [1, 2]. Commonly, the etiology of hemoptysis is related to lung neoplasm, bronchiectasis, and tuberculosis [3]. While hemoptysis is
usually identified with the currently available
diagnostic tools such as computed tomography
(CT) scan and fibroptic bronchoscopy, 5-20% of
cases remain classified as cryptogenic [4]. It
represents a challenge to identify the etiology
of cryptogenic hemoptysis and manage the
patient with massive cryptogenic hemoptysis in
emergency. Up to now, multidisciplinary approach, such as medical management especially
together with bronchial artery embolization,
has been effectively applied to the treatment of
massive hemoptysis, and surgical treatment
has seldom been employed [5].
In this study, we retrospectively reviewed patients with massive cryptogenic hemoptysis
who underwent pulmonary resection in the past
10 years, to analyze their clinical and pathologic aspects and evaluate the management of
these patients.
Materials and methods
Subjects
This study was conducted between January
2003 and December 2012 in a tertiary university hospital in Wenzhou, China. The study protocols were approved by Ethics Committee of
Wenzhou Medical College (Wenzhou, China),
and all participants gave signed consent. All
consecutive patients presenting with massive
hemoptysis were included. Hemoptysis was
considered as massive for bleeding of 200 ml
or more per 24 h, or bronchial blood loss caus-
Massive cryptogenic hemoptysis
Table 1. Bleeding sites in lung area in 12 patients with massive cryptogenic hemoptysis
Lobe
Right upper
Right middle
Right lower
Left upper
Lingula
Left lower
Number
2
2
3
2
1
2
Management of hemoptysis
Figure 1. CT scans showing the alveolar infiltrate and
ground glass opacity in right upper lobe.
Figure 2. Bronchoscopic image showing a small,
sessile, non pulsating nodular lesion about 7 mm in
diameter and 1 mm high at the beginning of right upper anterior bronchus.
ing airway or hemodynamic compromise [6]. To
exclude any identifiable cause of hemoptysis,
medical history, physical examination, chest
X-rays, CT-scan and fiberopetic bronchoscopy
were performed. During the study period, 112
patients with massive hemoptysis (76 males
and 36 females) were admitted to the respiratory intensive care unit or thoracic surgery unit,
12 (11 males and 1 female) of whom were
regarded as cryptogenic.
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All patients received conservative management initially in a uniform manner as follows.
Strict bed rest and lateral decubitus toward the
site of bleeding were maintained. Controlled
humidified oxygen-air mixture therapy was
administered. Antibiotics were prescribed in
patients with suspected bacterial infections.
Agents including vasoconstrictive drug vasopressin, antifibrinolytic drug tranexamic acid
and reptilase were administered intravenously.
Blood count, biochemistry, clotting test and
arterial blood gas analysis were performed.
Sputum specimens were submitted for microscopic study and culture of bacteria, acid-fast
bacilli and fungi examination. Chest X-ray and
CT-scan were performed as soon as possible.
Fiberoptic bronchoscopy was performed to
identify the location of the bleeding and a possible etiology in 10/12 patients for failure of
hemorrhage control or as an emergency. In
case of recurrent hemoptysis, bronchial arteriography associated with bronchial arterial
embolization was performed with a Seldinger
technique. If all the means of treatment
described above failed or airway compromise
might happen, an emergency surgical treatment was applied when the site of bleeding
was localized. After surgery, the lung samples
were handled by the same pathologist.
Data collection
Demographic data and information concerning
age, sex, smoking status, risk factors for hemorrhage, comorbid condition, hospital outcome
and prognosis were collected from the patients.
Analysis of outcome
Immediate control of bleeding, recurrences,
and results of management were analyzed.
Int J Clin Exp Med 2015;8(10):18130-18136
Massive cryptogenic hemoptysis
Table 2. Demography of massive cryptogenic hemoptysis patients operated
No.
1
2
3
4
5
6
7
Sex/age
M/31
F/34
M/21
M/44
M/85
M/63
M/56
Smoke (No. of Localization of
Type of pulmonary
Pathological FollowBAE
Outcome
pack-years)
hemoptysis lobe
resection
findings
up
Yes (15)
RML
Yes
lobectomy
Lived
Dieulafoy
84
No (0)
RLL
Yes
lobectomy
Live
Bronchiectasis
49
Yes (5)
RML
Yes
lobectomy
Lived
Dieulafoy
73
Yes (20)
LLL
No
lobectomy
Lived
Unidentified
26
Yes (40)
LUL+
Yes
lobectomy
Lived
Dieulafoy
20
Yes (10)
Lingula
No
pneumonectomy
Lived
Dieulafoy
70
Yes (30)
RUL RUL
Yes
lobectomy
Lived
Bronchiectasis
34
RUL, right upper lobe; RML, right middle lobe; RLL, right upper lobe; LUL, left upper lobe; LLL, left lower lobe.
After discharge, the follow-up were conducted
in the outpatient department or by direct phone
contact until December 2012 at intervals of 2
week, 3 month and every year.
Statistical analysis
Data were analyzed using the SPSS version 12
statistical analysis package (SPSS Inc., Chicago, IL, USA). Examined data were expressed
as the mean ± SD and assessed using the
t-test if appropriate. P < 0.05 was accepted as
statistically significant.
Results
Demographic and clinical presentation
During the 10-year study period, 112 patients
were referred to our hospital for massive
hemoptysis. In these patients, the most commonly identifiable etiology for hemoptysis included brochiectasis in 50 patients (44.6%),
tuberculosis in 16 patients (14.3%), lung cancer in 5 patients (4.5%), bacterial pneumonia in
25 patients (22.3%), and aspergilosis in 4
patients, (3.6%). In 12 of 112 patients, the etiology remained cryptogenic, including 11 male
and 1 female. The mean age was 44.67 ± 17.70
years (range 21-85 years) with a mean smoking
consumption of 18.50 ± 11.15 pack-years
(range 5-40 years). The volume of bleeding was
estimated at 446.67 ± 177.73 mL per day
(range 230-800 mL) upon admission to our
unit.
Chest X-ray, CT-scan, fiberoptic bronchoscopy
and angiographic findings
In all 12 patients with cryptogenic hemoptysis,
chest X-ray and CT-scan showed a single lobar
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alveolar infiltrate and ground glass opacities
(Figure 1). Fibrotic bronchoscopy showed submucosal vascular abnormalities, dilated submucosal vessel, or nodules about 5 mm in
diameter and 1 mm high above the surface in 4
patients (Figure 2). The site of bronchial bleeding was located to left side in 5 patients, right
side in 7 patients. The upper lobes were
involved in 4 patients, middle lobe and lingula
in 3 patients, and lower lobes in 5 patients
(Table 1).
Outcomes
Conservative measures were used in 6 patients
with massive cryptogenic hemoptysis, but complete control of bleeding was obtained in 2
patients. Hemoptysis was uncontrolled in 4
patients treated with terlipressin, 1 of them
had respiratory compromise immediately and 3
of them received BAE secondarily. A first-line
bronchial arteriograghy was attempted in 6
patients, with 3 patients receiving several
embolizations. Hypervascularisation of bronchial arteries was found with the presence of
bronchial artery tortuosity in 7 patients, and
retrograde of bronchial-to-pulmonary artery
shunting in 2 patients. BAE was performed in 9
patients, leading to cession of bleeding in 3
patients but not in other 6 patients (Table 2;
Figure 3).
A total of 7 patients received surgery during
hospitalization because of persistent hemoptysis despite the conservative treatment or BAE.
The type of pulmonary resection was performed
after confirmation of a localized lesion (Table
3). All these 7 patients undergoing emergency
resection survived in long term and had no
obvious complications.
Int J Clin Exp Med 2015;8(10):18130-18136
Massive cryptogenic hemoptysis
Figure 3. Schema showing management and outcomes of patients with massive cryptogenic hemoptysis in this
study.
Follow-up
Table 3. Type of pulmonary resection
Type of pulmonary resection
Pneumonectomy
Lobectomy
Number
Side/lobe
(%)
2
Right = 2 (1 died)
6
RUL = 1, RML = 1, RLL = 2
LUL + Lingula = 1, LLL = 1
Pathological findings
For 7 patients with persistent hemoptysis,
pathological examination showed a superficial
dysplastic bronchial artery in the submucosa
and a tortuous and dilated bronchial artery
under the bronchial epithelium (Figure 4). Four
patients were diagnosed as Dieulafoy’s disease, and 2 patients as brochiectasis. No evidence for chronic bronchial or other vascular
disease was observed in 1 patient. No microorganisms such as bacteria, mycobacteria and
fungi were identified in all 7 patients.
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Follow-up data were available for 12
patients, with a mean duration of
46.42 ± 23.90 months (range 11 to
84 months) after discharge. Hemoptysis recurred at a similar rate in
patients treated by conservative
management and in those by BAEs
(n = 4/6 vs. 6/9; P = 0.98). No recurrence happened in all hemoptysis patients treated by surgery. No lung cancer developed in all patients
undergoing pulmonary resection.
Discussion
This study aimed at characterizing the clinical
spectrum and the management in patients with
massive cryptogenic hemoptysis. In a case
series of Chinese patients with massive hemoptysis, the most frequent causes were tuberculosis, brochiectasis, lung cancer, necrotizing pneInt J Clin Exp Med 2015;8(10):18130-18136
Massive cryptogenic hemoptysis
Figure 4. Pathological findings of lung tissues. Left: dysplastic; Right: a tortuous and dilated bronchial artery under
the bronchial epithelium. Scale bar: 50 µm.
umonia and arteriovenous malformation [7].
Most of these conditions could be diagnosed
by the combined use of a chest computed
tomography (CT) scan, fiberoptic bronchoscope
and bronchial artery embolization (BAE). Although CT scan is the efficient approach to identify the cause and localization of hymoptysis,
this imaging technique has several limitations
[6]. In patients with pulmonary parenchymal
diffused with bleeding and bronchial mucosal
abnormalities, it might become difficult for CT
scan, and fiberscopy appears to be the complementary approach. However, the timing of a
diagnostic bronchoscopy in massive hemoptysis remains controversial, because the presence of large mount of blood in bronchial tree
makes the optical exploration hard. In this case
series, despite extensive diagnostic tools, no
precise cause was found in 12 out of 112
patients (10.7%) with massive hemoptysis and
they were considered as massive cryptogenic
hemoptysis. Recent studies showed that up to
25% of patients presenting with hemoptysis
are classified as cryptogenic [8-10].
In our study, 11 out of 12 patients with massive
cryptogenic hemoptysis were males, in a high
proportion of smokers. These data are consistent with the results of previous studies showing that patients with cryptogenic hemoptysis
had a high proportion of smoking, varying
between 42% and 72% of the studied population [11, 12]. Smoking-induced inflammatory
changes and a remarkable proliferation capacity of the bronchial vessels may be responsible
for the hemoptysis [13-15].
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Hemoptysis is a common symptom for referral
to pulmonologist. Although massive hemoptysis is considered a life threatening condition
that requires urgent and effective management, there is no definitely consensus on the
cutoff volume for the expectorated blood [6].
While it was recommended that massive
hemoptysis should be defined as any hemoptysis that is more than 100 ml per day or causes
airway compromise, the volume of > 200 ml
per day was proposed as the better predictor
for massive hemoptysis [8, 16, 17].
Massive hemoptysis is associated with a high
mortality of 10-15% in spite of intensive care
[10, 18]. An integrated approach for the management of massive hemoptysis including conservative measures, BAE and surgery is suggested [9]. Vasopressin is one of the extensively
drugs in patients with moderate and massive
hemoptysis. Previous studies reported that the
efficacy of vasopressin to stop bleeding ranged
from 27% to 60% [19]. In our case series, we
used this drug to control bleeding as the main
conservative measure, we achieved poor success rate in our cohort, and similar to the previous results that only 2 out of 12 patients of
cryptogenic hemoptysis were controlled [20].
Recently, BAE is regarded as the first-line nonsurgical treatment of massive hemoptysis [9].
Although the efficacy and safety of BAE has
been established in massive hemoptysis,
recurrence of hemoptysis after BAE occurred in
5-30% of patients [21]. Failure of BAE may be
due to incomplete embolization, recanalization
of the embolized vessels, technique skill, revas-
Int J Clin Exp Med 2015;8(10):18130-18136
Massive cryptogenic hemoptysis
cularisation of underlying inflammation and disease progression. Furthermore, less information was reported for BAE in cryptogenic hemoptysis. In case that life-threatening hemoptysis
continues to occur despite BAE, emergency
surgery should be attempted [22]. Our series
showed that 7 of 12 patients with massive
cryptogenic hemoptysis received surgery.
Several limitations should be acknowledged in
our study. First, although it was conducted in a
referral centre with an extensive medical experience of massive hemoptysis, our experiences
with BAE and surgery is limited. Next, no data
on BAE and surgical treatment for mild or moderate cryptogenic hymoptysis were collected
and analyzed.
In this series of case, our study demonstrated
that Dieulafoy’s disease of the bronchus and
bronchiectasis were the main pathological
abnormality for massive cryptogenic hemoptysis. Dieulafoy’s disease of the bronchus is a
vascular anomaly characterized by the presence of a dysplastic artery in the submucosa
[23]. It was reported that the disease accounted for up to 55% of cryptogenic massive hemoptysis [22]. However, Dieulafoy disease of bronchus is under diagnosed for lack of pathological
procedure. If bronchoscopy showed a nodule
with a small, sessile, non pulsating nodular
lesion, often with a white cap and apparently
normal mucosa, Dieulafoy’s disease of the
bronchus should be taken into account [23].
Nevertheless, it is difficult to diagnose this condition because bleeding in the bronchial tree
makes the image obscure. At present, the
pathogenesis of Dieulafoy’s disease of the
bronchus remains unclear. In our series of
case, we described the pathologic investigation
of this lesion after a surgical lung resection.
The pathological examination of a part of the
resected lung lobe revealed a dilated, hypertrophic and tortuous bronchial artery coiling
around the bronchus and reaching to the submucosa, consistent with previous report [24].
In summary, we analyzed the etiologies of massive cryptogenic hemoptysis and found that
Dieulafoy’s disease of the bronchus and bronchiectasis are the main pathological abnormality. Multidisciplinary approach remains as the
cornerstone for the management and exploration of massive cryptogenic hemoptysis. BAE
and surgical treatment should be considered in
case that massive hemoptysis could not be
controlled by conservative management.
Interestingly, two cases with bronchiectasis
were confirmed in patients with massive cryptogenic hemoptysis after surgical pathology.
Although high-resolution computed tomography (HRCT) has been regarded as the gold standard for the diagnosis of bronchiectasis, there
was no evidence of bronchiectasis on HRCT
using 1 mm slices at 5 mm intervals in all our
cases. It is well known that conventional HRCT
can miss small areas of bronchiectasis.
Multildector CT (MDCT) using 1 mm contiguous
slices could improve diagnostic accuracy of
bronchiectasis compared with conventional
HRCT [25]. Therefore, MDCT is recommended
for the identification of the cause of cryptogenic hemoptysis.
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Disclosure of conflict of interest
None.
Address correspondence to: Dr. Xiao-Dong Xia, Department of Respiratory Medicine, The Second
Affiliated Hospital, Wenzhou Medical University,
Wenzhou 325027, Zhejiang, China. E-mail: xia_xiao_
[email protected]; Dr. Liang Dong, Department of
Respiratory Medicine, Qilu Hospital, Shandong
University, Jinan 250021, Shandong, China. E-mail:
[email protected]
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