29/11/2020 Diagnostic approach to the adult with cystic lung disease - UpToDate

Authors: Anupam Kumar, MD, Robert M Kotloff, MD

Section Editor: Talmadge E King, Jr, MD
Deputy Editors: Helen Hollingsworth, MD, Geraldine Finlay, MD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Oct 2020. | This topic last updated: Feb 03, 2020.

INTRODUCTION

Cystic lung diseases represent a heterogenous group of disorders that share in common the
radiographic feature of multiple air-filled lucencies surrounded by discrete walls.

Conditions that are commonly referred to as diffuse cystic lung diseases include
lymphangioleiomyomatosis (LAM), pulmonary Langerhans cell histiocytosis (PLCH), Birt-Hogg-
Dubé syndrome (BHD), and lymphoid interstitial pneumonia (LIP), although the differential
diagnosis can at times expand to encompass other extremely rare etiologies [1,2].

An approach to the diagnosis of diffuse cystic lung disease in adults will be reviewed here. The
clinical manifestations, evaluation, and management of the individual causes of diffuse cystic
lung disease are discussed in greater detail separately. (See "Sporadic
lymphangioleiomyomatosis: Clinical presentation and diagnostic evaluation" and "Pulmonary
Langerhans cell histiocytosis" and "Birt-Hogg-Dubé syndrome" and "Lymphoid interstitial
pneumonia in adults".)

DEFINITION

Cysts and parenchymal lucencies that mimic cystic disease are typically defined by their
appearance on high resolution computed tomography ( table 1).

Cysts — A pulmonary cyst is defined as a "round parenchymal lucency or low-attenuating area

with a well-defined interface with normal lung" [3]. (See 'Parenchymal lucencies that may
mimic cysts' below.)

Parenchymal lucencies that may mimic cysts — Causes of lung parenchymal lucencies that
may mimic cysts but do not fit the definition of true cystic lung disease include bullae, blebs,
bronchiectasis, cavities, and pneumatoceles ( table 1).
https://www-uptodate-com.ezproxy.javeriana.edu.co/contents/diagnostic-approach-to-the-adult-with-cystic-lung-disease?search=HYPERSENSITIVE NEUMONITI… 1/20
29/11/2020 Diagnostic approach to the adult with cystic lung disease - UpToDate

● Emphysema – Areas of emphysema appear as polygonal or rounded low-attenuation

areas. A central dot representing the pulmonary artery contained within the secondary
pulmonary lobule can sometimes be seen [3]. Emphysematous areas, by definition, lack
walls. However, this distinction may be difficult to discern, as interlobular septa
surrounding emphysematous areas of lung may be misinterpreted as walls (
image 1A-B). Some forms of atypical emphysema present as lucencies that are
indistinguishable from cysts. Conversely, in advanced stages, cystic lung disease may
coalesce into larger areas of low attenuation that mimic emphysema ( image 1A-B).

● Bulla – The term bulla refers to a region of focal lucency that is >1 cm in diameter,
bounded by a thin wall (<1 mm) and usually accompanied by adjacent emphysema. Bullae
can be isolated and vary in size, sometimes filling the hemithorax ( image 2 and
image 3). A bleb is a type of subpleural bulla; the term bleb is now discouraged.

● Honeycombing – Honeycombing represents the advanced, destructive phase of a variety

of fibrotic lung disorders that lead to enlarged airspaces with thick fibrous walls. On high
resolution computed tomography (HRCT), honeycombing appears as clustered hypolucent
areas ranging in diameter from 0.3 to 1.0 cm (but occasionally as large as 2.5 cm), with
well-defined, often thick walls ( image 4 and image 5) [3]. Honeycombing areas tend
to be subpleural, stacked together in contiguous rows and sharing common walls.
Associated radiologic features such as architectural distortion, subpleural reticular
changes, and traction bronchiectasis further aid in distinguishing honeycombing due to
pulmonary fibrosis from cystic lung disease.

● Bronchiectasis – Bronchiectatic cysts (also known as "cystic bronchiectasis") can be

differentiated from cystic lung disease based on their continuity with an airway, tendency
to form clusters ( image 6), and associated findings of tram lines and signet or
Cabochon ring sign. (See "High resolution computed tomography of the lungs", section on
'Bronchiectasis'.)

● Cavitary lung disease – Pulmonary cavities are typically thick-walled (>4 mm) gas-filled
spaces often within an area of consolidation, mass, or nodule and may be filled with other
contents in addition to air (eg, fluid, debris, mycetoma ( image 7)) [4].

● Pneumatoceles – Pneumatoceles are a type of thin-walled parenchymal cyst ( image 8).

They most commonly arise in the setting of acute bacterial pneumonia, typically in
children, but can also result from Pneumocystis jirovecii pneumonia ( image 9), chest
trauma, or barotrauma from mechanical ventilation. While usually few in number,
pneumatoceles can occasionally be numerous and in such cases, can be confused with the

https://www-uptodate-com.ezproxy.javeriana.edu.co/contents/diagnostic-approach-to-the-adult-with-cystic-lung-disease?search=HYPERSENSITIVE NEUMONITI… 2/20

29/11/2020 Diagnostic approach to the adult with cystic lung disease - UpToDate

more diffuse cystic lung diseases. Notably, pneumatoceles are typically asymptomatic and
often disappear following resolution of the inciting event.

CAUSES OF CYSTIC LUNG DISEASE

The majority of adults with cystic lung disease have one of four underlying diseases:
lymphangioleiomyomatosis (LAM), pulmonary Langerhans cell histiocytosis (PLCH), Birt-Hogg-
Dubé syndrome (BHD), or lymphoid interstitial pneumonia (LIP).

A separate category of cystic lung disease is associated with infectious etiologies; these
patients typically present with acute onset of symptoms with fever and/or chills. Often the
lung cysts are pneumatoceles that are caused by the infection (eg, coccidioidomycosis,
hyperimmunoglobulinemia E syndrome, Pneumocystis jirovecii, recurrent respiratory
papillomatosis, staphylococcal pneumonia) [5-12]. (See 'Parenchymal lucencies that may
mimic cysts' above.)

Less common causes of diffuse cystic lung disease are listed in the table ( table 2). Examples
include pulmonary amyloidosis [13], Ehlers Danlos syndrome type IV [14], fire-eater's lung
(pneumatoceles) [15,16], hypersensitivity pneumonitis [17,18], lymphomatoid granulomatosis
[19], neurofibromatosis [20], congenital pulmonary airway (cystic adenomatoid) malformation,
invasive mucinous adenocarcinoma [21], smoking related small airways injury [22], and
Proteus syndrome [23]. (See "Overview of amyloidosis" and "Clinical manifestations and
diagnosis of Ehlers-Danlos syndromes", section on 'Vascular EDS' and "Pulmonary
lymphomatoid granulomatosis" and "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical
features, and diagnosis", section on 'Other manifestations' and "Congenital pulmonary airway
(cystic adenomatoid) malformation" and "Common causes of hoarseness in children", section
on 'Papillomatosis' and "PTEN hamartoma tumor syndromes, including Cowden syndrome",
section on 'Proteus-like syndrome' and "Hypersensitivity pneumonitis (extrinsic allergic
alveolitis): Clinical manifestations and diagnosis", section on 'Other processes caused by
inhalation of organic agents'.)

SUSPECTING AN ETIOLOGY FOR CYSTIC LUNG DISEASE

Patients with cystic lung disease may be asymptomatic, with radiographic abnormalities
incidentally discovered on computed tomography (CT) obtained for other reasons, or may
present with respiratory symptoms, most commonly dyspnea or cough. However, none of

https://www-uptodate-com.ezproxy.javeriana.edu.co/contents/diagnostic-approach-to-the-adult-with-cystic-lung-disease?search=HYPERSENSITIVE NEUMONITI… 3/20

29/11/2020 Diagnostic approach to the adult with cystic lung disease - UpToDate

these features is specific for a particular cystic lung disease. Importantly, the history,
examination, and CT findings together guide the diagnostic evaluation.  

Clinical history — A detailed clinical history can help to narrow the differential diagnosis of
diffuse cystic lung disease. As examples, underlying systemic disease, such as tuberous
sclerosis complex or Sjögren syndrome, can direct attention to possible
lymphangioleiomyomatosis or lymphoid interstitial pneumonia, respectively, while a family
history of renal cancer or pneumothorax, might raise suspicion for Birt-Hogg-Dubé syndrome.

Age, sex, and ethnicity

● Lymphangioleiomyomatosis – Lymphangioleiomyomatosis (LAM) is a disorder that

almost exclusively affects females; reported cases of LAM in males have, with one
exception, occurred in association with tuberous sclerosis complex (TSC) [24,25].
Symptoms typically develop in the third and fourth decades of life [26]. In the United
States, Caucasians comprised 87 percent of patients enrolled in the National Heart, Lung,
and Blood Institute LAM Registry, with those of African descent accounting for 6 percent
and those of Asian descent accounting for 4 percent of enrolled patients [26]. (See
"Sporadic lymphangioleiomyomatosis: Clinical presentation and diagnostic evaluation".)

● Pulmonary Langerhans cell histiocytosis – Pulmonary Langerhans cell histiocytosis

(PLCH) most commonly affects young adults, typically between the ages of 20 to 40. Sex
distribution is equal to slightly female-predominant [27]. Reliable figures on racial
distribution are lacking, though Caucasians comprise the overwhelming majority of cases
documented in the literature. (See "Pulmonary Langerhans cell histiocytosis".)

● Birt-Hogg-Dubé syndrome – Lung cysts are seen in up to 84 percent of patients with Birt-
Hogg-Dubé syndrome (BHD) and appear at a median age of 30 to 40 years [28-30]. Up to
one-third of patients present with a spontaneous pneumothorax, with a median age of
occurrence of 38 years [31]. However, the earliest and often overlooked manifestation of
the disease is the development of cutaneous fibrofolliculomas on the midface, which can
be seen beginning in the third decade of life. There does not appear to be a particular
gender predilection, and data on racial distribution are insufficient to allow comment. (See
"Birt-Hogg-Dubé syndrome".)

● Lymphoid interstitial pneumonia – Demographic information is not helpful in

supporting a diagnosis of lymphoid interstitial pneumonia (LIP).

Smoking — The nearly universal association of PLCH with current or former cigarette

smoking is well established [27]. Thus, PLCH is an exceedingly unlikely diagnosis in a never-

https://www-uptodate-com.ezproxy.javeriana.edu.co/contents/diagnostic-approach-to-the-adult-with-cystic-lung-disease?search=HYPERSENSITIVE NEUMONITI… 4/20

29/11/2020 Diagnostic approach to the adult with cystic lung disease - UpToDate

smoker with cystic lung disease.

Among five patients with BHD syndrome, cigarette smoking was associated with more severe
cystic changes and recurrent pneumothoraces [32], but in a large single family cohort,
cigarette smoking had no correlation with the size or number of cysts [33].

Family history — A family history of lung disease or extrapulmonary findings is often

present in patients with BHD and TSC-LAM, but not PLCH or LIP.

BHD is inherited in an autosomal dominant pattern and often affects multiple family members
[34]. As such, eliciting a careful family history of spontaneous pneumothorax, lung cysts (often
misdiagnosed as bulla or emphysema), renal neoplasms, and fibrofolliculomas can provide
important clues to the diagnosis. In one study of 114 consecutive patients presenting with
spontaneous pneumothorax, seven patients had a family history of pneumothorax and six of
these were found to have BHD [35]. (See "Birt-Hogg-Dubé syndrome".)

Patients with TSC-LAM may have a family history of intellectual disability, seizures, or
cutaneous angiofibromas. (See "Tuberous sclerosis complex: Genetics, clinical features, and
diagnosis".)

Pulmonary manifestations — The most common respiratory symptoms associated with

these disorders are cough and dyspnea. Patients may also present with a spontaneous
pneumothorax or pleural effusion.

Pneumothorax — Pneumothorax is a frequent manifestation of cystic lung disease, and

may be the initial event calling attention to its presence. The prevalence of spontaneous
pneumothorax is highest in LAM patients, in the range of 50 to 60 percent [26,36]. Reported
frequencies of pneumothorax among patients with BHD and PLCH are 24 to 38 percent and 16
percent, respectively [37,38]. Pneumothorax is an uncommon manifestation of LIP, likely
reflecting the paucity of cysts present in this disease.

Pleural effusion — Chylous effusions develop in roughly 10 percent of patients with LAM

[36]. The combination of diffuse cystic lung disease on high resolution CT and chylous effusion
is most often due to LAM, although lymphoma is a rare mimic of this combination. Pleural
effusion is unusual in other forms of cystic lung diseases.  

Extrapulmonary manifestations — Presence of extrapulmonary manifestations can provide

important clues to distinguish between the various cystic lung diseases. Careful history (eg,
abdominal swelling, polyuria, polydipsia) and examination of the skin (manifestations of TSC
and BHD), together with imaging of the abdomen may identify extrapulmonary
manifestations to support an underlying etiology for a specific cystic lung disorder.
https://www-uptodate-com.ezproxy.javeriana.edu.co/contents/diagnostic-approach-to-the-adult-with-cystic-lung-disease?search=HYPERSENSITIVE NEUMONITI… 5/20
29/11/2020 Diagnostic approach to the adult with cystic lung disease - UpToDate

● LAM – Manifestations associated with LAM include (see "Sporadic

lymphangioleiomyomatosis: Clinical presentation and diagnostic evaluation", section on
'Non pulmonary'):

• Renal angiomyolipomas (AMLs; approximately 30 percent) ( image 10)  

• Chylous ascites (10 percent)

• Lymphangioleiomyomas (up to 40 percent)

• Cutaneous manifestations of TSC, such as malar angiofibromas, hypopigmented

macules (ash-leaf spots), Shagreen patches, and periungual fibromas

• Neurologic manifestations of TSC, including cognitive impairment, seizures,

subependymal giant cell astrocytomas, cortical glioneuronal hamartomas, and
subependymal nodules

● PLCH – Extrapulmonary involvement is seen in approximately 20 percent of patients with

PLCH [27] (see "Clinical manifestations, pathologic features, and diagnosis of Langerhans
cell histiocytosis", section on 'Clinical manifestations'):

• Cystic bone lesions (7 percent)

• Diabetes insipidus (8 percent)

• Rarely, skin lesions (brown papules and eczema) and generalized lymphadenopathy
[27]

● BHD – In addition to pulmonary involvement, BHD is associated with renal and cutaneous
manifestations:

• Renal neoplasms: most commonly hybrid oncocytic tumors (50 percent), followed by
chromophobe renal cell carcinomas (35 percent), clear cell renal cell carcinomas (9
percent), and renal oncocytomas (5 percent). (See "Birt-Hogg-Dubé syndrome",
section on 'Kidney tumors'.)

• Cutaneous lesions: 85 percent have fibrofolliculomas ( picture 1) [31]. (See "Birt-

Hogg-Dubé syndrome", section on 'Cutaneous lesions'.)

● LIP – Although LIP is a disorder confined to the lungs, it is associated with a wide variety
of underlying systemic autoimmune diseases and immunodeficiency in the majority of
cases. Most common among these is Sjögren syndrome, present in 25 to 50 percent of LIP
cases ( image 11) [37,39]. For this reason, patients presenting with cystic lung disease

https://www-uptodate-com.ezproxy.javeriana.edu.co/contents/diagnostic-approach-to-the-adult-with-cystic-lung-disease?search=HYPERSENSITIVE NEUMONITI… 6/20

29/11/2020 Diagnostic approach to the adult with cystic lung disease - UpToDate

should be queried about the presence of dry eyes and dry mouth. Patients with
immunodeficiency (eg, common variable immunodeficiency, HIV) often have a history of
infection. (See "Clinical manifestations of Sjögren's syndrome: Extraglandular disease".)

RADIOGRAPHIC FEATURES

High resolution computed tomography (HRCT) of the chest is the cornerstone of the
evaluation of patients with cystic lung disease. HRCT permits detailed characterization of the
appearance and distribution of the cysts and identification of accompanying features. It is
often sufficiently characteristic to suggest a presumptive diagnosis or, at the very least, to
narrow the list of possibilities. Importantly, HRCT features are not pathognomonic and need to
be interpreted in a clinical context so that further diagnostic testing can be selective.

The value of HRCT was highlighted in one retrospective study of HRCT performed in the
evaluation of diffuse cystic lung disease [40]. A suspected radiographic diagnosis was correct
in 70 to 80 percent of cases when HRCT was reviewed by radiologists or pulmonologists with
expertise in cystic lung disease.

Appearance and distribution of cysts — Typical HRCT features of cysts are described for the
following diseases:

● Lymphangioleiomyomatosis (LAM) – Parenchymal cysts associated with LAM are

typically profuse and evenly distributed throughout both lungs ( image 12) [41]. They
are thin-walled and round, display limited variability in size and shape, and lack internal
structures such as vessels or septae.

● Pulmonary Langerhans cell histiocytosis (PLCH) – The cystic lesions of PLCH are
irregularly and bizarrely shaped, have prominent walls, and tend to involve the upper
lobes with relative sparing of the costophrenic angles ( image 13) [42]. Intervening lung
may be normal or have multiple small nodules.

● Birt-Hogg-Dubé syndrome (BHD) – The cysts associated with BHD are thin-walled, often
lentiform in shape (lens-shaped), basilar predominant, and distributed in subpleural
regions and abutting the mediastinum ( image 14). Intervening lung is normal. A study
employing quantitative methods to compare the CT features of LAM and BHD found
significant differences in all parameters examined; BHD cysts were quantitatively less
numerous, larger, and less circular in shape and demonstrated a lower-medial lung zone
predominance [41]. Another study comparing CT features of BHD, LAM, and LIP found

https://www-uptodate-com.ezproxy.javeriana.edu.co/contents/diagnostic-approach-to-the-adult-with-cystic-lung-disease?search=HYPERSENSITIVE NEUMONITI… 7/20

29/11/2020 Diagnostic approach to the adult with cystic lung disease - UpToDate

that patients with BHD were significantly more likely to have elliptical paramediastinal
cysts or a disproportionate number of paramediastinal cysts [43].

● Lymphoid interstitial pneumonia (LIP) – Thin-walled cysts may be seen in the majority
of patients with LIP. These cysts are typically few in number and are most often seen in
areas of ground glass ( image 15) but may occur as an isolated finding [44,45]. They are
often perivascular in distribution, vary in size ranging from 1 to 30 mm in diameter, and
may have internal septae.  

Nodules — Multiple nodules should alert the physician to PLCH, although nodules can also be
found in LIP and tuberous sclerosis complex (TSC)-LAM.

● PLCH – Radiographic abnormalities in PLCH typically begin as upper lobe nodules [46].
These nodules later cavitate and ultimately form cystic lesions ( image 16) [42,47]. It is
important to note that as the disease evolves, nodules and cystic lesions can coexist, and
this combination may permit a radiographic diagnosis of PLCH with a high degree of
confidence [42,48].

● LIP – Ill-defined centrilobular nodules and subpleural nodules can be seen in patients with
LIP ( image 17) [44,49]. In patients with Sjögren syndrome, the presence of nodules
along with cysts should raise suspicion for concurrent lymphoma or amyloidosis [50].

● TSC-LAM – In some patients with TSC-LAM and less commonly in sporadic LAM, multiple
lung nodules accompany the cystic changes. These nodules usually represent multifocal
micronodular pneumocyte hyperplasia (MMPH). The nodules of MMPH range in size from
2 to 14 mm and can be either solid or of ground glass attenuation. They tend to behave in
an indolent fashion; in one series of 32 cases, there was no change in nodule number or
size during a mean follow-up period of 2 +/- 1.1 years [51]. (See "Tuberous sclerosis
complex associated lymphangioleiomyomatosis in adults", section on 'Multifocal
micronodular pneumocyte hyperplasia'.)

Ground glass opacities — The combination of cysts and ground glass opacities is a common
radiographic presentation of LIP; septal thickening and nodules may also be present. Ground
glass opacities are usually not a feature of the other diffuse cystic lung diseases, although
ground glass opacities have been described on CT scans of patients with PLCH and a
concurrent smoking-related disorder, such as respiratory bronchiolitis/desquamative
interstitial pneumonia [52]. (See "Respiratory bronchiolitis-associated interstitial lung disease",
section on 'Imaging'.)

https://www-uptodate-com.ezproxy.javeriana.edu.co/contents/diagnostic-approach-to-the-adult-with-cystic-lung-disease?search=HYPERSENSITIVE NEUMONITI… 8/20

29/11/2020 Diagnostic approach to the adult with cystic lung disease - UpToDate

Pleural effusion — Among the diffuse cystic lung diseases, pleural effusion is most likely to
be due to LAM. Chylous pleural effusions occur in approximately 10 percent of patients with
LAM and can be unilateral or bilateral ( image 18). Pleuritis from a systemic rheumatic
disease is an uncommon cause of an effusion in LIP. Presence of pleural effusion in patients
with LIP should also prompt evaluation for lymphoma, particularly when seen in association
with large nodules and/or consolidative opacities [53]. (See "Sporadic
lymphangioleiomyomatosis: Clinical presentation and diagnostic evaluation", section on 'Chest
computed tomography'.)

Intra-abdominal features — A number of intra-abdominal features can help determine the

cause of diffuse cystic lung disease in patients with LAM or BHD.

● Lymphangioleiomyomatosis – LAM is associated with a number of intra-abdominal and

pelvic features.

• In particular, renal angiomyolipomas ( image 10) are demonstrated on abdominal

imaging in 30 percent of individuals with sporadic LAM and 80 percent of those with
TSC-LAM [54]. The imaging characteristics of renal AML and indications for
percutaneous needle or surgical biopsy are discussed separately. (See "Renal
manifestations of tuberous sclerosis complex", section on 'Diagnosis'.)

Angiomyolipomas may also occasionally be seen within the liver ( image 19).

• Lymphangioleiomyomas are another characteristic feature of LAM, occurring in

approximately 16 percent. They are most often located in the retroperitoneum but
may extend into, or arise in, the pelvis or mediastinum. (See "Sporadic
lymphangioleiomyomatosis: Clinical presentation and diagnostic evaluation", section
on 'Lymphangioleiomyomas'.)

• Other findings on abdominal imaging in patients with LAM include ascites, thoracic
duct dilatation, and lymphadenopathy [54].

● Birt-Hogg-Dubé – Renal neoplasms are found on abdominal imaging performed for

screening purposes in up to 27 percent of patients with BHD [55]. These tumors are
bilateral in approximately 50 percent of cases and multifocal in 65 percent. CT or magnetic
resonance imaging (MRI) with contrast are the imaging procedures of choice. (See "Birt-
Hogg-Dubé syndrome", section on 'Kidney tumors'.)

DIAGNOSTIC APPROACH

https://www-uptodate-com.ezproxy.javeriana.edu.co/contents/diagnostic-approach-to-the-adult-with-cystic-lung-disease?search=HYPERSENSITIVE NEUMONITI… 9/20

29/11/2020 Diagnostic approach to the adult with cystic lung disease - UpToDate

The majority of patients with diffuse cystic lung disease have one of four disorders:
lymphangioleiomyomatosis (LAM), pulmonary Langerhans cell histiocytosis (PLCH), Birt-Hogg-
Dubé syndrome (BHD), or lymphoid interstitial pneumonia (LIP). Other rare causes of diffuse
cystic lung disease are listed in the table ( table 2). Our diagnostic approach starts with
review of the clinical and radiographic features to narrow down the diagnostic possibilities,
followed by focused testing to confirm the diagnosis ( algorithm 1). The typical clinical,
laboratory, and radiographic features and diagnostic criteria for each of the four main causes
of diffuse cystic lung disease are summarized in the table, along with commonly employed
confirmatory diagnostic studies ( table 3).  

A characteristic constellation of clinical, laboratory, and radiographic features is often

sufficient to establish a diagnosis without need for a surgical lung biopsy. In those cases
where uncertainty remains and confirmation is essential for management (eg, progressive
disease, anticipated initiation of sirolimus in LAM), histopathologic evaluation is typically
necessary. In some cases, a period of observation is also appropriate (eg, Sjögren syndrome is
suspected).

When pursuing a tissue biopsy, the least invasive method is selected. As an example, a
lacrimal gland or lip biopsy may confirm a diagnosis of Sjögren syndrome, a skin biopsy can
establish a diagnosis of BHD, while bronchoalveolar lavage or transbronchial lung biopsy can
provide a diagnosis in PLCH or LAM, respectively.

Laboratory testing — Focused laboratory testing can be helpful in suspected LIP, LAM, and
BHD, as described in the following sections ( algorithm 1). As the differentiation between
cystic lung disease and emphysema can be difficult, we often obtain testing for alpha-1
antitrypsin deficiency, although the yield of such testing is low. (See "Clinical manifestations,
diagnosis, and natural history of alpha-1 antitrypsin deficiency", section on 'Laboratory
testing'.)

On occasions when the clinical and high resolution computed tomography findings do not
allow differentiation among the four main causes of cystic lung disease, some experts test
more broadly and obtain testing for antinuclear antibody, anti-Ro/SSA and anti-La/SSB
antibodies, rheumatoid factor, and vascular endothelial growth factor-D (VEGF-D), as well as
genetic testing for the folliculin (FLCN) and tuberous sclerosis complex (TSC1 and TSC2) genes,
and rarely for inheritable causes of bronchiectasis (eg, primary ciliary dyskinesia and cystic
fibrosis). This approach is unproven and may be associated with increased cost to the patient.

Serologic studies — For patients with a known or suspected systemic rheumatic disease

that might be associated with LIP, especially Sjögren syndrome, we usually obtain or review

https://www-uptodate-com.ezproxy.javeriana.edu.co/contents/diagnostic-approach-to-the-adult-with-cystic-lung-disease?search=HYPERSENSITIVE NEUMONIT… 10/20

29/11/2020 Diagnostic approach to the adult with cystic lung disease - UpToDate

serologic studies such as the antinuclear antibody, anti-Ro/SSA and anti-La/SSB antibodies,
and a rheumatoid factor. (See "Clinical manifestations of Sjögren's syndrome: Extraglandular
disease", section on 'Autoantibodies'.)

If common variable immunodeficiency is suspected as a cause of LIP, serum immunoglobulin

levels are measured or reviewed. Similarly, if a patient has risk factors for HIV infection, we test
for HIV. (See "Clinical manifestations, epidemiology, and diagnosis of common variable
immunodeficiency in adults", section on 'Immunoglobulin levels' and "Screening and
diagnostic testing for HIV infection".)

Serum levels of vascular endothelial growth factor-D (VEGF-D) are elevated above the upper
limit of values in many patients with sporadic and TSC LAM, compared with healthy volunteers
or individuals with other cystic lung disease [56,57]. A level of VEGF-D above 800 pg/mL is
highly specific for LAM and, in a patient with compatible radiographic features, is considered
diagnostic [57-59]. Notably, VEGF-D levels below this threshold do not exclude the diagnosis.
This test is only available at specialized laboratories; its diagnostic value in LAM is described in
greater detail separately. (See "Sporadic lymphangioleiomyomatosis: Clinical presentation and
diagnostic evaluation", section on 'Vascular endothelial growth factor-D'.)

Genetic testing — For patients without characteristic skin fibrofolliculomas or

trichodiscomas, genetic testing may help with the diagnosis of BHD, which is caused by
germline mutations in the FLCN gene. FLCN mutation analysis is available as a diagnostic test
and detects mutations in 81 to 88 percent of patients with BHD [31,34]. However,
deletion/duplication analysis (ie, copy number analysis) may be necessary, if FLCN gene
sequence analysis does not identify a pathogenic variant. (See "Birt-Hogg-Dubé syndrome",
section on 'Genetic testing'.)

Genetic testing for tuberous sclerosis complex (TSC1 and TSC2) genes, and for heritable
causes of bronchiectasis (eg, primary ciliary dyskinesia and cystic fibrosis) is of unproven value
but may be warranted in those in whom TSC or inheritable bronchiectasis is suspected. (See
"Genetic testing".)  

Bronchoscopy — Bronchoscopy with bronchoalveolar lavage (BAL) and/or transbronchial lung

biopsy (TBLB) may be helpful in selected patients, such as those with suspected LAM or PLCH
and insufficient clinical or laboratory features to be confident in the diagnosis ( algorithm 1).

● Lymphangioleiomyomatosis – TBLB with immunohistochemical staining for human

melanoma black (HMB)-45 has been shown to identify LAM smooth muscle cells in 60 to
86 percent of cases, particularly when reviewed by a pathologist with expertise in LAM [59-
62]. The yield from transbronchial biopsy may correlate with cyst profusion, low DLCO,

https://www-uptodate-com.ezproxy.javeriana.edu.co/contents/diagnostic-approach-to-the-adult-with-cystic-lung-disease?search=HYPERSENSITIVE NEUMONIT… 11/20

29/11/2020 Diagnostic approach to the adult with cystic lung disease - UpToDate

and low FEV1 [59]. BAL is not helpful in the diagnosis of LAM, except to exclude other
processes. The role of biopsy in patents with suspected LAM is discussed separately. (See
"Sporadic lymphangioleiomyomatosis: Clinical presentation and diagnostic evaluation",
section on 'Choosing transbronchial or surgical lung biopsy'.)

● Pulmonary Langerhans cell histiocytosis – The presence of ≥5 percent CD1a-positive

cells in BAL is considered strongly suggestive of PLCH but is poorly sensitive. BAL and
TBLB together may yield a diagnosis in approximately 50 percent of patients [60]. Other
patients will require video assisted surgical lung biopsy to confirm the presence of
Langerhans cells positive for S-100 protein and CD1a. (See "Pulmonary Langerhans cell
histiocytosis", section on 'Flexible bronchoscopy' and "Pulmonary Langerhans cell
histiocytosis", section on 'Lung biopsy'.)

● Lymphoid interstitial pneumonia – BAL demonstrates lymphocytosis in approximately

30 percent of patients with LIP, but this is a nonspecific finding also seen in diseases such
as sarcoidosis and hypersensitivity pneumonitis. Bronchoscopy is otherwise of limited
value as TBLB does not provide an adequate sample size for the differentiation of
interstitial pneumonias. (See "Lymphoid interstitial pneumonia in adults", section on
'Bronchoalveolar lavage'.)

● Birt-Hogg-Dubé – There is no role for BAL or TBLB in suspected cases of BHD since there
are no distinctive histologic features.

Surgical lung biopsy — The decision to proceed with a surgical biopsy (typically video-
assisted thoracoscopic surgery [VATS]) is dependent on multiple factors including a suspected
diagnosis with pathognomonic histopathology, the cystic burden, opportunity, need for
therapy, and risk. We typically proceed with surgical lung biopsy when the diagnosis remains
in question following clinical, radiographic, and laboratory evaluation; when diagnostic
confirmation is required in order to initiate therapy; and in the absence of contraindicating
factors such as marginal lung function or significant pulmonary hypertension.

As the cystic changes in LIP tend to be nonprogressive, we are more likely to observe patients
with known systemic rheumatic disease without a biopsy unless ground glass opacities or
nodules are present, such that systemic glucocorticoids would be warranted for LIP, or the
nodular opacities are concerning for lymphoma or infection.  

Sometimes, surgical lung biopsy is obtained at the opportune time of surgical treatment for a
pneumothorax (eg, patients with mild or nonprogressive disease).

https://www-uptodate-com.ezproxy.javeriana.edu.co/contents/diagnostic-approach-to-the-adult-with-cystic-lung-disease?search=HYPERSENSITIVE NEUMONIT… 12/20

29/11/2020 Diagnostic approach to the adult with cystic lung disease - UpToDate

VATS biopsy is generally definitive for diagnosis of LAM, PLCH, and LIP (or follicular
bronchiolitis). In contrast, surgical lung biopsy is not appropriate in cases of confirmed BHD
since there are no specific histologic features associated with cysts in this disorder. Certain
rare causes of cystic lung disease may not be associated with specific histopathology (eg,
neurofibromatosis). However, biopsy may be indicated, if an alternate or coexistent pathology
is suspected (eg, LAM, lymphoma).  

Less commonly, lung biopsy may be the best option to establish or exclude worrisome
etiologies, such as metastatic cancer (eg, invasive adenocarcinoma, sarcoma, colorectal
cancer), amyloidosis, light chain deposit disease, and non-Langerhans histiocytosis ( table 2
).

The characteristic histopathologic features of LAM, PLCH, and LIP are described separately.
(See "Sporadic lymphangioleiomyomatosis: Clinical presentation and diagnostic evaluation",
section on 'Definitive pathologic diagnosis' and "Pulmonary Langerhans cell histiocytosis",
section on 'Lung biopsy' and "Interstitial lung disease associated with Sjögren syndrome:
Clinical manifestations, evaluation, and diagnosis", section on 'Lymphoid interstitial
pneumonia'.)

Skin biopsy — In a patient with compatible HRCT, confirmation of BHD is achieved by skin
biopsy showing fibrofolliculomas, obviating the need for genetic testing for a folliculin gene
mutation. (See 'Genetic testing' above.)

SUMMARY AND RECOMMENDATIONS

● Cystic lung diseases represent a diverse group of disorders that share in common the
radiologic feature of multiple air-filled lucencies surrounded by discrete walls (≤2 mm
thickness). Diffuse cystic lung disease must be distinguished radiographically from
emphysema, honeycombing, cystic bronchiectasis, pulmonary cavities, and
pneumatoceles. (See 'Definition' above.)

● The four most common cystic lung diseases are lymphangioleiomyomatosis (LAM),
pulmonary Langerhans cell histiocytosis (PLCH), Birt-Hogg-Dubé syndrome (BHD), and
lymphoid interstitial pneumonia (LIP). Other rare causes of cystic lung disease are listed in
the table ( table 2). (See 'Causes of cystic lung disease' above.)

● The manifestations of cystic lung disease are typically not specific for a particular disorder.
Patients may present with cysts incidentally discovered on computed tomography (CT)
obtained for other reasons. Alternatively, they may present with nonspecific cough or

https://www-uptodate-com.ezproxy.javeriana.edu.co/contents/diagnostic-approach-to-the-adult-with-cystic-lung-disease?search=HYPERSENSITIVE NEUMONIT… 13/20

29/11/2020 Diagnostic approach to the adult with cystic lung disease - UpToDate

dyspnea or with pneumothorax or a pleural effusion. (See 'Suspecting an etiology for

cystic lung disease' above.)

● A detailed history with attention to demographics (age, sex, and ethnicity), smoking
history, and family history (eg, features of tuberous sclerosis complex [TSC] or BHD) is
important in the initial assessment. A careful search for extrapulmonary features,
including cutaneous, pleural, and intra-abdominal manifestations, can provide insight into
the diagnosis ( table 3). (See 'Suspecting an etiology for cystic lung disease' above.)

● High resolution computed tomography (HRCT) is an essential component of the

evaluation process and often can differentiate between the various cystic lung diseases,
especially when reviewed by an expert radiologist. (See 'Radiographic features' above.)

● Our diagnostic approach starts with review of the clinical and radiographic features to
narrow down the diagnostic possibilities, followed by focused testing to confirm the
diagnosis ( algorithm 1). (See 'Diagnostic approach' above.)

● Laboratory assessment can be used to establish a diagnosis of LAM (serum levels of

vascular endothelial growth factor-D level ≥800 pg/mL) and can help identify patients with
a systemic rheumatic disease that would increase the likelihood of LIP. For patients
without characteristic skin fibrofolliculomas, genetic testing for folliculin (FLCN) gene
variants may be indicated for patients with suspected BHD. (See 'Laboratory testing'
above.)

● When tissue confirmation is required in patients with suspected LAM or PLCH,

bronchoscopy with transbronchial lung biopsy and appropriate immunostaining (ie,
human melanoma black [HMB]-45 for LAM; CD1a antigen for PLCH) may be diagnostic in
some cases. Bronchoalveolar lavage (BAL) showing CD1a antigen staining of 5 percent or
more cells is considered supportive of PLCH. (See 'Bronchoscopy' above.)

● For patients without a clear diagnosis despite the above evaluation, particularly in the
setting of progressive disease, surgical lung biopsy can be used to provide a definitive
diagnosis of disorders associated with specific histopathology (LAM, PLCH, LIP). A lung
biopsy is not indicated in disorders not associated with specific histopathology (eg, BHD)
unless an alternate or co-existent process is suspected. (See 'Surgical lung biopsy' above.)

● Skin biopsy of a folliculoma may be diagnostic in BHD or prompt genetic testing for
folliculin variants for confirmation. (See 'Skin biopsy' above.)

Use of UpToDate is subject to the Subscription and License Agreement.

https://www-uptodate-com.ezproxy.javeriana.edu.co/contents/diagnostic-approach-to-the-adult-with-cystic-lung-disease?search=HYPERSENSITIVE NEUMONIT… 14/20

29/11/2020 Diagnostic approach to the adult with cystic lung disease - UpToDate

REFERENCES
1. Gupta N, Vassallo R, Wikenheiser-Brokamp KA, McCormack FX. Diffuse Cystic Lung
Disease. Part II. Am J Respir Crit Care Med 2015; 192:17.

2. Gupta N, Vassallo R, Wikenheiser-Brokamp KA, McCormack FX. Diffuse Cystic Lung

Disease. Part I. Am J Respir Crit Care Med 2015; 191:1354.

3. Hansell DM, Bankier AA, MacMahon H, et al. Fleischner Society: glossary of terms for
thoracic imaging. Radiology 2008; 246:697.

4. Woodring JH, Fried AM, Chuang VP. Solitary cavities of the lung: diagnostic implications of
cavity wall thickness. AJR Am J Roentgenol 1980; 135:1269.

5. Venkata C, Ghafoor S, Venkateshiah SB. A 35-year-old man with recurrent pneumonias,

eczema, coarse facial features, and cystic lung lesions. Chest 2008; 133:1026.

6. Freeman AF, Kleiner DE, Nadiminti H, et al. Causes of death in hyper-IgE syndrome. J
Allergy Clin Immunol 2007; 119:1234.

7. Sadikot RT, Andrew AC, Wilson JD, Arnold AG. Recurrent respiratory papillomatosis with
pulmonary cystic disease in a child, following maternal genital warts. Genitourin Med
1997; 73:63.

8. Dancey DR, Chamberlain DW, Krajden M, et al. Successful treatment of juvenile laryngeal
papillomatosis-related multicystic lung disease with cidofovir: case report and review of
the literature. Chest 2000; 118:1210.

9. Thompson GR 3rd. Pulmonary coccidioidomycosis. Semin Respir Crit Care Med 2011;
32:754.

10. Ooi A, Iyenger S, Barlow CW, Tsang GM. Aggressive Staphylococcal pneumonia: from
multiple cavities to pneumatocole and giant bullae formation. Heart Lung Circ 2005;
14:115.

11. Caksen H, Oztürk MK, Uzüm K, et al. Pulmonary complications in patients with
staphylococcal sepsis. Pediatr Int 2000; 42:268.

12. Gonzalez BE, Hulten KG, Dishop MK, et al. Pulmonary manifestations in children with
invasive community-acquired Staphylococcus aureus infection. Clin Infect Dis 2005;
41:583.

https://www-uptodate-com.ezproxy.javeriana.edu.co/contents/diagnostic-approach-to-the-adult-with-cystic-lung-disease?search=HYPERSENSITIVE NEUMONIT… 15/20

29/11/2020 Diagnostic approach to the adult with cystic lung disease - UpToDate

13. Zamora AC, White DB, Sykes AM, et al. Amyloid-associated Cystic Lung Disease. Chest
2016; 149:1223.

14. Dowton SB, Pincott S, Demmer L. Respiratory complications of Ehlers-Danlos syndrome

type IV. Clin Genet 1996; 50:510.

15. Franquet T, Gómez-Santos D, Giménez A, et al. Fire eater's pneumonia: radiographic and
CT findings. J Comput Assist Tomogr 2000; 24:448.

16. Gentina T, Tillie-Leblond I, Birolleau S, et al. Fire-eater's lung: seventeen cases and a
review of the literature. Medicine (Baltimore) 2001; 80:291.

17. Lynch DA, Newell JD, Logan PM, et al. Can CT distinguish hypersensitivity pneumonitis
from idiopathic pulmonary fibrosis? AJR Am J Roentgenol 1995; 165:807.

18. Franquet T, Hansell DM, Senbanjo T, et al. Lung cysts in subacute hypersensitivity
pneumonitis. J Comput Assist Tomogr 2003; 27:475.

19. Lee JS, Tuder R, Lynch DA. Lymphomatoid granulomatosis: radiologic features and
pathologic correlations. AJR Am J Roentgenol 2000; 175:1335.

20. Ueda K, Honda O, Satoh Y, et al. Computed tomography (CT) findings in 88

neurofibromatosis 1 (NF1) patients: Prevalence rates and correlations of thoracic
findings. Eur J Radiol 2015; 84:1191.

21. Rogers C, Kent-Bramer J, Devaraj A, et al. Rapidly Progressive Cystic Lung Disease. Am J
Respir Crit Care Med 2018; 198:264.

22. Gupta N, Colby TV, Meyer CA, et al. Smoking-Related Diffuse Cystic Lung Disease. Chest
2018; 154:e31.

23. Irion KL, Hocchegger B, Marchiori E, et al. Proteus syndrome: high-resolution CT and CT
pulmonary densitovolumetry findings. J Thorac Imaging 2009; 24:45.

24. Schiavina M, Di Scioscio V, Contini P, et al. Pulmonary lymphangioleiomyomatosis in a

karyotypically normal man without tuberous sclerosis complex. Am J Respir Crit Care Med
2007; 176:96.

25. Adriaensen ME, Schaefer-Prokop CM, Duyndam DA, et al. Radiological evidence of
lymphangioleiomyomatosis in female and male patients with tuberous sclerosis
complex. Clin Radiol 2011; 66:625.

https://www-uptodate-com.ezproxy.javeriana.edu.co/contents/diagnostic-approach-to-the-adult-with-cystic-lung-disease?search=HYPERSENSITIVE NEUMONIT… 16/20

29/11/2020 Diagnostic approach to the adult with cystic lung disease - UpToDate

26. Ryu JH, Moss J, Beck GJ, et al. The NHLBI lymphangioleiomyomatosis registry:
characteristics of 230 patients at enrollment. Am J Respir Crit Care Med 2006; 173:105.

27. Vassallo R, Ryu JH, Schroeder DR, et al. Clinical outcomes of pulmonary Langerhans'-cell
histiocytosis in adults. N Engl J Med 2002; 346:484.

28. Schmidt LS, Linehan WM. Molecular genetics and clinical features of Birt-Hogg-Dubé
syndrome. Nat Rev Urol 2015; 12:558.

29. Marciniak SJ, Johnson SR. Pneumothorax and the biology of Birt-Hogg-Dubé syndrome.
Thorax 2020; 75:442.

30. Chu L, Luo Y, Chen H, et al. Mesenchymal folliculin is required for alveolar development:
implications for cystic lung disease in Birt-Hogg-Dubé syndrome. Thorax 2020; 75:486.

31. Toro JR, Pautler SE, Stewart L, et al. Lung cysts, spontaneous pneumothorax, and genetic
associations in 89 families with Birt-Hogg-Dubé syndrome. Am J Respir Crit Care Med
2007; 175:1044.

32. Ayo DS, Aughenbaugh GL, Yi ES, et al. Cystic lung disease in Birt-Hogg-Dube syndrome.
Chest 2007; 132:679.

33. Skolnik K, Tsai WH, Dornan K, et al. Birt-Hogg-Dubé syndrome: a large single family
cohort. Respir Res 2016; 17:22.

34. Toro JR, Wei MH, Glenn GM, et al. BHD mutations, clinical and molecular genetic
investigations of Birt-Hogg-Dubé syndrome: a new series of 50 families and a review of
published reports. J Med Genet 2008; 45:321.

35. Torricelli E, Occhipinti M, Cavigli E, et al. The Relevance of Family History Taking in the
Detection and Management of Birt-Hogg-Dubé Syndrome. Respiration 2019; 98:125.

36. Johnson SR, Tattersfield AE. Clinical experience of lymphangioleiomyomatosis in the UK.
Thorax 2000; 55:1052.

37. Cha SI, Fessler MB, Cool CD, et al. Lymphoid interstitial pneumonia: clinical features,
associations and prognosis. Eur Respir J 2006; 28:364.

38. Mendez JL, Nadrous HF, Vassallo R, et al. Pneumothorax in pulmonary Langerhans cell
histiocytosis. Chest 2004; 125:1028.

https://www-uptodate-com.ezproxy.javeriana.edu.co/contents/diagnostic-approach-to-the-adult-with-cystic-lung-disease?search=HYPERSENSITIVE NEUMONIT… 17/20

29/11/2020 Diagnostic approach to the adult with cystic lung disease - UpToDate

39. Strimlan CV, Rosenow EC 3rd, Weiland LH, Brown LR. Lymphocytic interstitial
pneumonitis. Review of 13 cases. Ann Intern Med 1978; 88:616.

40. Gupta N, Meraj R, Tanase D, et al. Accuracy of chest high-resolution computed

tomography in diagnosing diffuse cystic lung diseases. Eur Respir J 2015; 46:1196.

41. Tobino K, Gunji Y, Kurihara M, et al. Characteristics of pulmonary cysts in Birt-Hogg-Dubé

syndrome: thin-section CT findings of the chest in 12 patients. Eur J Radiol 2011; 77:403.

42. Abbott GF, Rosado-de-Christenson ML, Franks TJ, et al. From the archives of the AFIP:
pulmonary Langerhans cell histiocytosis. Radiographics 2004; 24:821.

43. Escalon JG, Richards JC, Koelsch T, et al. Isolated Cystic Lung Disease: An Algorithmic
Approach to Distinguishing Birt-Hogg-Dubé Syndrome, Lymphangioleiomyomatosis, and
Lymphocytic Interstitial Pneumonia. AJR Am J Roentgenol 2019; :1.

44. Johkoh T, Müller NL, Pickford HA, et al. Lymphocytic interstitial pneumonia: thin-section
CT findings in 22 patients. Radiology 1999; 212:567.

45. Silva CI, Flint JD, Levy RD, Müller NL. Diffuse lung cysts in lymphoid interstitial
pneumonia: high-resolution CT and pathologic findings. J Thorac Imaging 2006; 21:241.

46. Yousem SA, Colby TV, Chen YY, et al. Pulmonary Langerhans' cell histiocytosis: molecular
analysis of clonality. Am J Surg Pathol 2001; 25:630.

47. Brauner MW, Grenier P, Mouelhi MM, et al. Pulmonary histiocytosis X: evaluation with
high-resolution CT. Radiology 1989; 172:255.

48. Kim HJ, Lee KS, Johkoh T, et al. Pulmonary Langerhans cell histiocytosis in adults: high-
resolution CT-pathology comparisons and evolutional changes at CT. Eur Radiol 2011;
21:1406.

49. Johkoh T, Ichikado K, Akira M, et al. Lymphocytic interstitial pneumonia: follow-up CT

findings in 14 patients. J Thorac Imaging 2000; 15:162.

50. Baqir M, Kluka EM, Aubry MC, et al. Amyloid-associated cystic lung disease in primary
Sjögren's syndrome. Respir Med 2013; 107:616.

51. Muzykewicz DA, Black ME, Muse V, et al. Multifocal micronodular pneumocyte
hyperplasia: computed tomographic appearance and follow-up in tuberous sclerosis
complex. J Comput Assist Tomogr 2012; 36:518.

https://www-uptodate-com.ezproxy.javeriana.edu.co/contents/diagnostic-approach-to-the-adult-with-cystic-lung-disease?search=HYPERSENSITIVE NEUMONIT… 18/20

29/11/2020 Diagnostic approach to the adult with cystic lung disease - UpToDate

52. Vassallo R, Jensen EA, Colby TV, et al. The overlap between respiratory bronchiolitis and
desquamative interstitial pneumonia in pulmonary Langerhans cell histiocytosis: high-
resolution CT, histologic, and functional correlations. Chest 2003; 124:1199.

53. Sirajuddin A, Raparia K, Lewis VA, et al. Primary Pulmonary Lymphoid Lesions: Radiologic
and Pathologic Findings. Radiographics 2016; 36:53.

54. Avila NA, Kelly JA, Chu SC, et al. Lymphangioleiomyomatosis: abdominopelvic CT and US
findings. Radiology 2000; 216:147.

55. Pavlovich CP, Grubb RL 3rd, Hurley K, et al. Evaluation and management of renal tumors
in the Birt-Hogg-Dubé syndrome. J Urol 2005; 173:1482.

56. Young LR, Vandyke R, Gulleman PM, et al. Serum vascular endothelial growth factor-D
prospectively distinguishes lymphangioleiomyomatosis from other diseases. Chest 2010;
138:674.

57. McCormack FX, Gupta N, Finlay GR, et al. Official American Thoracic Society/Japanese
Respiratory Society Clinical Practice Guidelines: Lymphangioleiomyomatosis Diagnosis
and Management. Am J Respir Crit Care Med 2016; 194:748.

58. Hirose M, Matsumuro A, Arai T, et al. Serum vascular endothelial growth factor-D as a
diagnostic and therapeutic biomarker for lymphangioleiomyomatosis. PLoS One 2019;
14:e0212776.

59. Gupta N, Finlay GA, Kotloff RM, et al. Lymphangioleiomyomatosis Diagnosis and
Management: High-Resolution Chest Computed Tomography, Transbronchial Lung
Biopsy, and Pleural Disease Management. An Official American Thoracic Society/Japanese
Respiratory Society Clinical Practice Guideline. Am J Respir Crit Care Med 2017; 196:1337.

60. Harari S, Torre O, Cassandro R, et al. Bronchoscopic diagnosis of Langerhans cell

histiocytosis and lymphangioleiomyomatosis. Respir Med 2012; 106:1286.

61. Meraj R, Wikenheiser-Brokamp KA, Young LR, et al. Utility of transbronchial biopsy in the
diagnosis of lymphangioleiomyomatosis. Front Med 2012; 6:395.

62. Koba T, Arai T, Kitaichi M, et al. Efficacy and safety of transbronchial lung biopsy for the
diagnosis of lymphangioleiomyomatosis: A report of 24 consecutive patients.
Respirology 2018; 23:331.

Topic 112259 Version 5.0

https://www-uptodate-com.ezproxy.javeriana.edu.co/contents/diagnostic-approach-to-the-adult-with-cystic-lung-disease?search=HYPERSENSITIVE NEUMONIT… 19/20

29/11/2020 Diagnostic approach to the adult with cystic lung disease - UpToDate

https://www-uptodate-com.ezproxy.javeriana.edu.co/contents/diagnostic-approach-to-the-adult-with-cystic-lung-disease?search=HYPERSENSITIVE NEUMONIT… 20/20