What is the typical course of pulmonary LAM?

Lung function is commonly estimated using a parameter called forced expiratory volume in one second (FEV1), the amount of breath that is expelled in the first second of a vigorous expiratory maneuver. A normal FEV1 for a 65 inch tall, 40 year old female is about 2800 cc. On average, lung function declines by about 100 cc per year in patients with LAM, compared to an average rate of about 30 cc per year for healthy adults. So over 10 years, lung function might decline by about a liter, reaching levels that are about 60% of predicted in a patient with LAM who starts with baseline lung function (FEV1) at the mean for her age and height. The rate of decline in the placebo arm of the MILES trial was about 30% faster than the literature suggests at about 134 cc per year, and the rate of decline in the premenopausal patients (200 cc per year) was 5 fold faster (on average) than the postmenopausal patients (40 cc per year).

How can I make the diagnosis of pulmonary LAM?

In general, the diagnosis of LAM should be made using the least invasive method available. Surgical lung biopsy should be necessary in only about 20% of cases using the algorithms below. It is important to note that some patients may not require a definitive diagnosis. Examples include patients with end stage lung disease who are approaching lung transplant, and patients with tuberous sclerosis. Some patients with very mild cystic change who would not be candidates for therapy because of absence of exercise limitation, lung function impairment or rapid decline may prefer to be followed expectantly rather than assume the risk of an invasive procedure that would not change management regardless of the outcome.

A definite diagnosis of LAM can be based on biopsy of tissue from the thorax or abdomen, or by cytologic analysis of thin needle aspirates or of pleural fluid or ascites. Transbronchial biopsy has a yield of over 50% in patients who have more than mild profusion of cysts.

A clinically confident diagnosis of LAM can be made based on a compatible HRCT showing diffuse thin walled cysts and any one of the following: 1) renal angiomyolipoma (radiographic diagnosis based on fat density, most often), 2) tuberous sclerosis, 3) chylothorax, 4) lymphangiomyoma (radiographic diagnosis, based on hypodense center), 5) serum VEGF-D of ≥800 pg/ml (commercially available here---https://research.cchmc.org/translationalcores/webfm_send/202).

In patients who have typical cystic change on CT but no stigmata of tuberous sclerosis, obtaining a serum VEGF-D and/or an abdominal CT to search for angiomyolipomas or lymphangiomyomas are reasonable next steps. If an effusion is present, a tap can be performed to determine if the fluid is chylous (triglyceride levels typically >110 mg/dl) and if LAM cell clusters are present on cytologic evaluation (including HMB-45 staining). Needle biopsy of thoracic or abdominal nodes can also be considered. Transbronchial biopsy has a yield of >50% predicted and appears to be safe in small series.

Who should be treated with mTOR inhibitor therapy?

In the MILES trial, sirolimus was shown to stabilize lung function in patients who met the enrollment criterion of FEV1<70% predicted, so many LAM experts treat patients with ‘abnormal lung function’ defined by that parameter.

Some physicians offer treatment to patients with significant cystic change and mixed obstructive and restrictive physiology that results in well-preserved FEV1 but a low DLCO, although this practice has not been formally studied in trials. Some physicians would consider treatment in patients with any abnormal lung function parameter, including FEV1, DLCO, FVC, TLC, RV, for those who desaturate to less than 90% with walking, or those who are declining rapidly, even before they reach the lower limit of normal for FEV1 in their age and height group. The goal in the last scenario is to prevent progression of disease to more advanced stages, but this indication has not been evaluated in trials.

Several biomarkers may be useful in the decision of whether to treat with mTOR inhibitors. The most useful biomarker is the historical rate of decline in FEV1. Patients who are consistently declining at annual rates of 75-100 cc or more may be considered for therapy, especially as they approach the lower limit of normal for lung function or as symptoms develop. Patients with elevated baseline serum VEGF-D (>800 pg/ml) progressed more rapidly without treatment and responded better to sirolimus in the MILES trial. Premenopausal patients progressed much more rapidly without treatment (-200 cc FEV1 per yr) than did postmenopausal patients (-40 cc FEV1 per year); an observation that might tilt the scales in favor of treatment in the former, and in favor of watchful observation in older patients with evidence of stability over time.

In case reports and small series, patients with chylous effusions and chylous ascites have been shown to respond to treatment with sirolimus, often with complete resolution. This indication, while very promising, has not been prospectively evaluated in trials.

How should mTOR inhibitor therapy be managed?

It is important that the diagnosis of LAM be established with certainty before mTOR therapy is begun. Patients with a diagnosis of definite LAM and probable LAM based on the European Respiratory Society (ERS) Guidelines typically qualify for treatment without further investigation. In addition, the diagnosis of LAM is considered definite in women with characteristic cystic change on CT of the chest who have a VEGF-D of ≥800 pg/ml. In patients who have possible LAM based on ERS criteria, transbronchial biopsy can be considered to establish the diagnosis before treatment is begun, with a yield of over 50% based on small series. Appropriate vigilance for development of pneumothorax post procedure is required, since the safety of the procedure in LAM has not been established with certainty.

Another basic principle in sirolimus therapy is that the drug is suppressive rather than remission inducing, so continuous therapy is required for sustained benefit. The long-term safety of sirolimus has been evaluated as part of combinatorial regimens in renal failure patients, but less is known about the safety of the drug used as monotherapy in LAM. When facing the prospect of life-long therapy with an immunosuppressive agent, it is critical that the lowest effective dose be sought in each patient. Recent data from Japan suggests that low dose sirolimus, with mean serum levels of 2.16 ng/mL;range,0.8–4.3 ng/mL, provide durable stabilization with fewer side effects than the doses that were used in the MILES study.

Baseline labs that should be obtained prior to starting therapy with mTOR inhibitors include CBC with differential, UA, glucose, creatinine, AST, ALT, serum VEGF-D, and fasting lipid profile. Baseline pulmonary function tests should be obtained, including spirometry, lung volumes, diffusing capacity and 6 minute walk distance. Most patients should be started on 1 mg sirolimus p.o. per day. Two weeks after starting therapy, a sirolimus level, CBC, glucose, creatinine, AST and ALT should be repeated. It is important that sirolimus levels be drawn at the trough point, just prior to the daily dose of sirolimus. In the MILES trial, sirolimus serum levels were targeted to the range of 5-15 ng/ml. However, recent studies suggest that serum levels less than 5 ng/ml are also effective. A sirolimus level, CBC, UA, creatinine, glucose, AST, ALT and fasting lipid profile should then be obtained monthly for the first six months. Spirometry should be obtained every 3-6 months, and lung volumes, diffusing capacity and six minute walk testing every 6-12 months. Plotting pre and post sirolimus FEV1 is useful for determining if the drug has had a durable effect on the trajectory of lung function decline. If stabilization is achieved with 1 mg sirolimus per day, dose escalation may not be necessary. If lung function decline has not been stemmed, the dose should be adjusted upward. Most LAM physicians target serum levels ranging from 1-5 ng/ml, and few push the dose to achieve serum levels greater than 10 ng/ml. It is important to note that many drugs affect the metabolism of mTOR inhibitors, and treatment with antibiotics and anti-seizure medications can greatly affect the daily dose required to maintain serum levels.

Everolimus has been tested in an open label trial in patients with LAM, and appears to be effective. The side effects in that study exceeded those seen in the MILES trial, most likely because the doses used were proportionately higher. In renal transplant patients, 2 mg/d sirolimus and everolimus both produce trough serum concentrations of about 3-8 ng/ml, so assuming equal potency, the conversion factor should be 1:1.

What side effects of mTOR inhibitor should be discussed with patients?

Side effects are largely dose dependent, and have been less frequent in patients who have serum levels of sirolimus of less than 5 ng/ml. All side effects generally abate when the drug is stopped, with the exception of the theoretic risk of latent malignancies. Efforts should be made to avoid interruptions in dosing, such as by choosing antibiotics that do not interfere with metabolism of sirolimus. A notable exception is the need to hold the drug for impending surgery or after accidents or interventions regarding optimal healing, which the drug is known to impede.

The most common side effects are gastrointestinal, including loose stools, dyspepsia and aphthous ulcers. Oral ulcers can be managed with Magic Mouthwash if they are mild or with Orabase if they are more painful.

Elevation of serum cholesterol or triglycerides is common, and can usually be treated with dietary intervention. Therapy with statins can be considered for patients who meet ATP IV guidelines for treatment. Marked elevation of triglycerides is rarely seen, but can precipitate pancreatitis, and can occasionally result in the need to discontinue therapy.

Lower extremity edema can develop, most likely as a manifestation of drug induced lymphedema. Management options include elevation, compressive stockings and gentle, chronic diuresis.

Acne is common, but is usually mild and easily managed with topical agents.

Dysmenorrhea is common in patients on sirolimus. Occasionally, excessive bleeding can result in iron deficiency anemia. Alteration or complete cessation of menses can also occur. In general, however, no specific intervention is required.

Ovarian cysts can occur and persist in patients on sirolimus. Occasionally cysts can become large, and torsion can occur. Although appropriate vigilance is required for newly discovered cysts, knowledge that cysts can occur and persist on sirolimus is most useful for averting unnecessary surgery.

Some patients are allergic to mTOR inhibitors, and can develop rash, anaphylaxis and angioedema.

Sirolimus pneumonitis is a potentially serious development, especially in patients with compromised lung function. This side effect was not seen in the MILES trial and is thought to be rare in patients treated with lower doses of sirolimus. Asian patients may be more susceptible to drug induced lung injury, however. Sirolimus pneumonitis can be subtle, presenting with fever, cough and shortness of breath. Ground glass infiltrates are seen on CT. It can be difficult to differentiate infection from drug induced lung injury. In general, the drug should be held until there is clarity regarding diagnosis and management, especially when symptoms or an oxygen need develops, or the profusion of ground gas is substantial.

Sirolimus inhibits wound healing. Cases of bronchial dehiscence with fatal outcomes at 4-6 weeks post transplant have occurred in patients who were given sirolimus as part of their post operative immunosuppressive regimen. It is not clear that sirolimus is dangerous in listed patients who stop the drug on the date of transplant, since the drug washes out in the weeks before the critical wound healing period begins (2-4 weeks). Everolimus, which has a shorter half-life, would be a good candidate for a clinical trial of mTOR inhibitors for listed patients.

Sirolimus is associated with a risk of skin cancer. Patients on sirolimus should avoid direct sunlight, wear protective clothing and use sunblock.

Development of latent malignancy, especially lymphomas, is a theoretical risk that applies to all immunosuppressive agents. It is unclear whether monotherapy with sirolimus, a mild immunosuppressant at the doses typically used in LAM patients, is associated with an enhanced risk. There have been no reported cases of latent malignancy in LAM patients treated with mTOR inhibitors, although the drug has only been in common use for this indication for about 5 years.

What is pulmonary alveolar proteinosis (PAP)?

PAP is a syndrome - not a single disease, characterized by progressive accumulation of surfactant in pulmonary alveoli that causes restrictive lung impairment, hypoxemic respiratory insufficiency and, in severe cases, respiratory failure and death. PAP was initially described by Rosen in 1958 and is now recognized to occur in a group of heterogeneous diseases usefully classified as Primary PAP, Secondary PAP, and Disorders of Surfactant Production.

Pulmonary surfactant composition, function, and homeostasis

Pulmonary surfactant is comprised of about 90% lipids (mostly phospholipids and a small cholesterol and other neutral lipids) and 10% surfactant proteins (SP-A, SP-B, SP-C, SP-D).

Normally, surfactant comprises a thin layer on the alveolar surface that helps maintain alveolar stability by reducing surface tension at the alveolar wall-liquid-air interface: without surfactant, this surface tension would cause alveolar collapse (as occurs in premature babies with insufficient surfactant production).

Surfactant homeostasis is normally maintained by balanced production of surfactant in alveolar epithelial cells and clearance by these cells and alveolar macrophages, each of which clear about half of the excess/used surfactant. Alveolar macrophages require GM-CSF stimulation for normal surfactant clearance (and other host defense functions).

Pathogenesis

Disruption of surfactant homeostasis results in the development of PAP and can through various mechanisms including 1) reduction in the ability of alveolar macrophages to clear surfactant, 2) reduction in the numbers of alveolar macrophages (and hence reduction in the clearance capacity of the tissue-resident alveolar macrophage population), or abnormal surfactant production (and accumulation).

In Primary PAP (autoimmune PAP, hereditary PAP – see below), the ability of alveolar macrophages to clear surfactant from the alveolar/lung surface is reduced, which results in accumulation of surfactant in alveoli. In autoimmune PAP, very high levels of antibodies against GM-CSF are present in the blood and lungs and completely neutralize the activity of GM-CSF. In hereditary PAP, GM-CSF signaling is disrupted by genetic mutations encoding alpha or beta subunits of GM-CSF receptors.

In Secondary PAP (many diseases), surfactant clearance by alveolar macrophages is also reduced (because either the numbers or functions of these cells are reduced), which results in the accumulation of surfactant in alveoli.

In Disorders of Surfactant Production (multiple diseases), abnormal surfactant production results in surfactant that is dysfunctional and causes parenchymal lung disease, which varies with the gene affected as well as the type of exact mutation within the effected gene(s) – the result is a variable degree of surfactant and significant parenchymal architectural distortion of the alveolar structures.

What diseases are associated with development of PAP syndrome?
Primary PAP

Autoimmune PAP due to high levels of GM-CSF autoantibodies
Hereditary PAP due to CSF2RA mutations
Hereditary PAP due to CSF2RB mutations

Secondary PAP

Hematologic diseases¹
Non-hematologic malignancy²
Immune deficiency and chronic inflammatory syndromes³
Chronic infections⁴
Toxic inhalation syndromes⁵

Pulmonary Surfactant Metabolic Dysfunction Disorders

SFTPB mutations resulting in SP-B deficiency
SFTPC mutations resulting in SP-C dysfunction
ABCA3 mutations resulting in abnormal surfactant production
NKX2.1 mutations resulting in abnormal surfactant production

¹ Includes: acute lymphocytic leukemia, acute myeloid leukemia, aplastic anemia, chronic lymphocytic leukemia, chronic myeloid leukemia, myelodysplastic syndromes, multiple myeloma, lymphoma, Waldenstrom’s macroglobulinemia.

² Includes: adenocarcinoma, glioblastoma, melanoma.

³ Includes: acquired immunodeficiency syndrome, amyloidosis, fanconi’s syndrome, agammaglobulinemia, juvenile dermatomyositis, renal tubular acidosis, severe combined immunodeficiency disease.

⁴ Includes: cytomegalovirus, mycobacterium tuberculosis, nocardia, pneumocystis jirovecii (formerly carinii).

⁵ Includes: dusts (inorganic) – aluminum, cement, silica, titanium, indium; organic dusts – agricultural, bakery flower, fertilizer, sawdust; fumes – chlorine, cleaning products, gasoline/petroleum, nitrogen dioxide, paint, synthetic plastic fumes, varnish.

What is the epidemiology of PAP?

PAP is very rare - probably affecting less than 10,000 people in the United States, and occurs in men, women and children of all ages, ethnic backgrounds, and geographic locations.

Autoimmune PAP – caused by GM-CSF autoantibodies – is the most common type and accounts for about 85-90% of cases. It most commonly occurs in the 20 – 40 year age range but also in children as young as 3 years and the elderly as old as 90 years. Smoking is a known risk factor.

Hereditary PAP – caused by genetic mutations that disruption the function of GM-CSF receptor alpha or beta subunits – is very rare and may account for 5% of cases. It typically presents in children in the 2 – 6 year old age range but can present in adults as old as 35 years.

Secondary PAP – associated with a wide variety underlying clinical conditions or toxic inhalation syndromes – is also very rare and may account for approximately 5% of cases. For many of the associations, the relationship or causality to the clinical condition or exposure is uncertain. The clinical presentation of secondary PAP is determined by the occurrence of the underlying clinical condition or exposure.

Disorders of surfactant production – caused by mutations in genes critical to surfactant production (SFTPB, SFTPC, ABCA3, NKX2.1) – is very rare and may account for approximately 5% of cases. Recessive mutations in these genes result in the production of biochemically and functionally abnormal surfactant, which has widely differing secondary physiological and tertiary anatomical effects on lung structure and function and clinical manifestations – all depending on which gene is affected and the nature of the mutation(s) involved. Various degrees of abnormal alveolar surfactant accumulation can occur (i.e., PAP syndrome) in association with other, typically more significant anatomic, physiologic, and/or clinical abnormalities.

What are the clinical features of PAP?

Clinical Presentation

Primary PAP (autoimmune PAP, hereditary PAP) presents in most patients as exertional dyspnea of insidious onset that progresses over time. A non-productive cough is common. Sputum production occurs in about 5% of patients and when it occurs, sputum is typically whitish frothy material. Hemoptysis and fever are rare unless infection is also present. In severely affected individuals, cyanosis is also present. Digital clubbing is not a feature.

Secondary PAP presents in the clinical context of another underlying disease and thus, the presentation varies depending on the nature, timing of development of the underlying disease. For example, in PAP caused by the development of myelodysplastic syndromes, the presentation can be similar to that of Primary PAP but occurs in the context of the hematologic disease. In contrast, in acute inhalation exposure to significant amounts of respirable silica (e.g., as may occur in sandblasters), acute pulmonary toxicity and can be accompanied by respiratory symptoms such as cough.

Disorders of Surfactant Production present differently and at various ages depending on which gene and specific mutation is affected. Recessive mutations in SFTPB, ABCA3, NKX2.1 can present with respiratory failure at birth. Mutations in ABCA3 can also present as progressive respiratory insufficiency in young children and adolescents. In contrast, SFTPC mutations can present as interstitial lung disease at various ages.

Natural History

Primary PAP usually goes unnoticed until disease progression is advanced – i.e., not until after the amount of surfactant accumulation in alveoli is sufficient to displace enough inhaled air to reduce oxygen uptake to cause exertional (or resting) hypoxemia and dyspnea. This process appears to occur slowly over months to years in many (or most) patients and goes completely unnoticed in the early stages. As surfactant accumulation continues over time, disease severity proceeds from sub-clinical (no symptoms) to mild exertional dyspnea (breathlessness) to more severe exertional dyspnea and, finally, dyspnea at rest.

PAP is frequently diagnosed incorrectly as either asthma in children before a chest x-ray is obtained, or as pneumonia in children or adults after a chest x-ray is obtained. Further, the accurate diagnosis of PAP is usually delayed until after bronchodilators and/or several courses of ‘appropriate’ antibiotics have failed to yield clinical improvement, prompting diagnostic reconsideration and evaluation.

Importantly, the disease severity judged based on presence of highly abnormal chest x-ray findings (see below) is frequently out of proportion – more severe – compared to the patient's symptoms, This discordance of radiological and clinical findings can be very useful diagnostically in the early recognition and accurate diagnosis of PAP and underscores the importance of clinical awareness and a high degree of clinical suspicion.

The natural history of PAP caused by loss of GM-CSF signaling (autoimmune PAP, hereditary PAP caused by CSF2RA/B mutations) includes the development of secondary infections with common as well as opportunistic organisms. In addition, some patients also can develop pulmonary fibrosis by a mechanism that is not defined.

Disease Progression

The clinical course in primary PAP is quite variable and ranges from spontaneous improvement or remission of symptoms to progressive deterioration, respiratory failure, and death. Many individuals continue to have symptoms and require treatment by whole lung lavage (see below). The overall 5-year survival has been reported to be approximately 95% with treatment and about 85% in without therapy.

Secondary Infections

Autoimmune PAP is associated with an increased risk of microbial infection at pulmonary and extrapulmonary sites by a range of common pathogens and opportunistic organisms. Review of the medically literature suggests that, historically, approximately 18% of the mortality associated with PAP is caused by infections. While recent experience suggests that infection-related mortality is far lower than this, serious infections involving either common or opportunistic microorganisms can occur at presentation or any time during the clinical course and require therapy.

How is PAP diagnosed?

The timely and accurate diagnosis of PAP requires a high degree of clinical suspicion. Importantly, while routine clinical practice procedures and tests can establish the presence of PAP syndrome, they cannot identify the disease responsible. For this, an algorithm for differential diagnosis of PAP syndrome and specialized tests are needed. Some of these are currently available through as part of clinical research diagnostic testing programs like the one available at the Translational Pulmonary Science Center Laboratory associated with the Rare Lung Disease Consortium.

Approach to diagnosis

PAP should be suspected in patients with dyspnea of insidious onset and typical radiologic findings – diffuse ground glass opacification and superimposed septal thickening.

The history may be unremarkable except for dyspnea or may identify the presence of intercurrent infection suggested by the presence of fever, purulent sputum, and/or hemoptysis.

The physical examination may be otherwise unremarkable or inspiratory crackles may be present in lateral and dependent portions of the chest. Digital clubbing is not a feature of Primary PAP but may occur in some diseases associated with Secondary PAP or Disorders of Surfactant Production.

Routine laboratory testing usually not usually helpful but may reveal an increase in serum lactate dehydrogenase (LDH). Serum LDH is increased in proportion to disease severity in PAP.

Pulmonary function testing is normal in many patients but may reveal restrictive lung impairment in advanced disease. Importantly, the DLCO is decreased in proportion to disease severity in patients with PAP. Arterial blood gas measurement typically reveals a decrease in PaO2 and widened alveolar-arterial gradient that both decline in proportion to disease severity.

A standardized (American Thoracic Society) six-minute walk test can be helpful in assessing the severity of PAP. At rest, the peripheral capillary oxygen saturation (SpO₂) may be reduced in patients with mild disease but usually falls during the course the tests in patients with clinically significant PAP and is reduced at rest in patients with advanced disease.

The chest x-ray in Primary and Secondary PAP of hematologic origin typically reveals bilateral patchy air space disease that appears similar to pulmonary edema but without the other radiographic signs of left heart failure. Various other patterns can occur including mixed alveolar, interstitial, or nodular infiltrates, and asymmetrical or focal abnormalities. Adenopathy, cardiomegaly, and effusions are not features of PAP and thus, not typically seen in uncomplicated PAP. The chest x-ray in Disorders of Surfactant Production varies depending on the specific disease present. In newborns with SP-B deficiency (SFTPB mutations) or some ABCA3 mutations, the radiographic signs of respiratory distress syndrome are present. In children and adults with other ABCA3 mutations or dysfunctional SP-C (SFTPC mutations), the chest x-ray reveals the presence of interstitial lung disease indicative of parenchymal abnormalities and fibrosis. Notwithstanding, the diagnostic value of the plain chest x-ray is limited by its lack of specificity.

Conventional chest computed tomography (CT) scans in Primary PAP and Secondary PAP of hematologic origin typically show bilateral, diffuse consolidation with poorly defined margins. High-resolution chest CT, which is superior, shows diffuse, patchy areas of ground-glass opacification with sharply-defined, straight and angulated margins representing the boundaries of secondary lobules or lung lobes. Also present in most cases is a ‘lattice’ of fine overlapping lines that form 3- to 10-mm polygonal shapes coinciding with the edges of the ‘geographic’ areas of ground glass opacification. Superimposition of these two patterns gives an appearance that has been described as “crazy paving,” which is characteristic but not diagnostic of PAP. Notably, crazy paving also occurs in hypersensitivity pneumonitis, Pneumocystis jiiroveci pneumonia, minimally invasive adenocarcinoma, lymphangitic carcinomatosis, cardiogenic pulmonary edema, acute lung injury, lipoid pneumonia. Notably, high-resolution chest CT is superior to both conventional CT and chest radiography in the assessment of the pattern and distribution of abnormalities and may demonstrate lesions even when the radiograph is normal. In Secondary PAP caused by toxic inhalation syndromes, the radiographic features of PAP may be accompanied by other radiographic signs related to the specific material inhaled. In Disorders of Surfactant Production, the radiographic features relate more closely to parenchymal lung abnormalities than those of surfactant accumulation and can include radiographic findings of respiratory distress syndrome or interstitial lung disease.

Bronchoscopy with evaluation of bronchoalveolar lavage cytology is helpful in establishing the presence of PAP syndrome as the cause of the clinical, physiologic, and radiographic abnormalities. Importantly, no findings from bronchoscopy, bronchoalveolar lavage, or cytopathology are capable of identifying the specific disease responsible for PAP.

Lung histopathology including examination of specimens obtained by transbronchial biopsy or surgical biopsy are capable of establishing the presence of PAP syndrome. However, lung biopsies are not capable of identifying the specific disease responsible in patients with PAP. Because lung biopsies are associated with increased morbidity and simple blood tests are now available that can identify the specific PAP-causing disease in more than 90% of patients, lung should be used only if the results of other tests are inconclusive and examination of lung parenchyma is needed.

Establishing a diagnosis of PAP syndrome

The typical diagnostic workup of PAP should include a standard medical history – including a detailed review of pulmonary exposures, hematologic problems, and serious infection history, physical examination, pulmonary function testing - including DLCO measurement, a standardized six-minute walk test to measure exercise-induced peripheral capillary oxygen desaturation and exercise-induced dyspnea/fatigue, and, if indicated, a high-resolution chest CT.

Identifying the specific PAP-causing disease

After a diagnosis of PAP syndrome is established, it is important that differential diagnosis be undertaken to identify the specific PAP-causing disease.

In a previously healthy individual with a new diagnosis of PAP syndrome (see above), an abnormal serum GM-CSF autoantibody (GMAb) test (see below) is usually sufficient to establish the diagnosis of autoimmune PAP. This is because 85 – 90% of all cases of PAP are caused by autoimmune PAP and the GMAb test is 100% sensitive and specific for this diagnosis.

When the GMAb test is negative or the measured serum GM-CSF autoantibody concentration is indeterminate (i.e., a value between clearly normal (<3 mcg/ml) and clearly abnormal (>9 mcg/ml)), a functional test to diagnose impaired GM-CSF signaling is useful – such tests include the STAT5 Phosphorylation Index test or the CD11b stimulation Index Test (see below). An abnormal STAT5-PI or CD11b-SI test with an intermediate GMAb Test result can confirm a diagnosis of autoimmune PAP.

When the GMAb test is normal (i.e., GM-CSF autoantibodies are not abnormally increased) and a STAT5-PI or CD11b-SI Test is abnormal (i.e., GM-CSF signaling is impaired), a diagnosis of hereditary PAP due to GM-CSF receptor mutations should be suspected. A variety of additional tests are available to further define the specific mutations responsible including: Serum GM-CSF, GM-CSF Ra, GM-CSF Rb, CSF2RA DNA/mRNA, CSF2RB DNA/mRNA, GM-CSF Clearance Tests (see below).

When the GMAb test is normal and the patient has been diagnosed with an underlying disease known to be associated with PAP, a diagnosis of Secondary PAP may be made. However, In such cases, genetic testing to exclude the presence of a Disorder of Surfactant Production may be needed.

In newborns, children, adolescents, and adults in whom a diagnosis of PAP syndrome has been established and, especially if parenchymal lung disease is also present, genetic testing for Disorders of Surfactant Production is indicated. These tests are available commercially.

For further information on these and other tests to identify surfactant related lung diseases, please contact the RLDC.

Specific blood tests used to identify PAP-causing diseases

• Serum GM-CSF autoantibody (GMAb) Test – measures GM-CSF autoantibody concentration in serum by enzyme-linked immunosorbent assay (ELISA) using polyclonal GM-CSF autoantibody purified from individuals with autoimmune pulmonary alveolar proteinosis (aPAP) as the reference standard. Test results above the critical threshold value have a specificity of 100% and a sensitivity of 100% for a diagnosis of autoimmune PAP.
• Serum GM-CSF concentration (GM-CSF) Test – measures GM-CSF concentration in serum by an enzyme-linked immunosorbent assay (ELISA), using recombinant human GM-CSF as the standard. Serum GM-CSF is elevated in individuals with pulmonary alveolar proteinosis caused by defects in GM-CSF receptor function and in infection. The normal range for serum GM-CSF has not been reported. The sensitivity and specificity of this test for a diagnosis of hereditary PAP has not been reported.
• STAT5 Phosphorylation Index (STAT5-PI) Test – detects GM-CSF receptor signaling in blood leukocytes by measuring the level of GM-CSF stimulated phosphorylation of signal transducer and activation of transcription 5 (STAT5) using flow cytometry. Results are expressed as a STAT5 phosphorylation index (STAT5 PI) calculated as the mean fluorescence intensity (MFI) in stimulated cells minus that of un-stimulated cells divided by the MFI of un-stimulated cells multiplied by 100. The result is reported as ‘detected’ or ‘not detected’ for a normal or abnormal result, respectively. The specificity and sensitivity of this test for detection of GM-CSF signaling have not yet been reported.
• CD11b Stimulation Index (CD1b-SI) Test – detects GM-CSF receptor signaling in blood leukocytes by measuring the increase in cell surface CD11b on blood leukocytes stimulated by GM-CSF using flow cytometry. Results are expressed as a CD11b Stimulation index (CD11b SI) calculated as the mean fluorescence intensity (MFI) of stimulated cells minus that of un-stimulated cells divided by the MFI of un-stimulated cells multiplied by 100. The result is reported as ‘detected’ or ‘not detected’ for a normal or abnormal result, respectively. The specificity and sensitivity of this test for detection of GM-CSF signaling have not yet been reported.
• GM-CSF Receptor Alpha (GM-CSF R a ) Test - determines if GM-CSF receptor alpha is detected by antibody immunofluorescence staining on the surface of leukocytes in heparinized whole blood using flow cytometry. Normal and abnormal results are reported as ‘detected’ or ‘not detected’, respectively. The specificity and sensitivity of this test for detecting the GM-CSF receptor alpha chain has not been reported.
• GM-CSF Receptor beta (GM-CSF R b ) Test - determines if GM-CSF receptor beta is detected by antibody immunofluorescence staining on the surface of leukocytes in heparinized whole blood using flow cytometry. Normal and abnormal results are reported as ‘detected’ or ‘not detected’, respectively. The specificity and sensitivity of this test for detecting the GM-CSF receptor beta chain has not been reported.
• CSF2RA DNA Sequence Analysis (CSF2RA DNA) Test - determines a partial nucleotide sequence of the GM-CSF receptor α chain gene (CSF2RA) by standard methods. Sequence numbering is relative to the first base of the initiation codon (GenBank accession no. NM_006140.3 (alpha chain)).
• CSF2RB DNA Sequence Analysis (CSF2RB DNA) Test - determines a partial nucleotide sequence of the GM-CSF receptor β chain cDNA (CSF2RB) by standard methods. Sequence numbering is relative to the first base of the initiation codon (GenBank accession no. NM_000395 (beta chain)).
• CSF2RA mRNA Sequence Analysis (CSF2RA mRNA) Test - determines a partial nucleotide sequence of the GM-CSF receptor α chain cDNA (CSF2RA) by standard methods. Sequence numbering is relative to the first base of the initiation codon (GenBank accession no. NM_006140.3 (alpha chain)).
• CSF2RB mRNA Sequence Analysis (CSF2RB mRNA) Test - determines a partial nucleotide sequence of the GM-CSF receptor β chain cDNA (CSF2RB) by standard methods. Sequence numbering is relative to the first base of the initiation codon (GenBank accession no. NM_000395 (beta chain)).
• GM-CSF Clearance Test - measures the clearance of exogenously added recombinant GM-CSF by blood leukocytes from the patient maintained in culture media ex vivo. GMCSF is cleared rapidly by normal leukocytes in this assay but not by leukocytes from individuals with hereditary PAP caused by GM-CSF receptor dysfunction. The specificity and sensitivity of this test for a diagnosis of hereditary PAP have not been reported.

Assessing disease severity

The presence or absence of symptoms (dyspnea), signs of infection (fever, hemoptysis), degree of impairment in oxygen uptake at rest and during exercise, are all used to determine the degree of lung impairment/ disease severity in patients with PAP. Specific assessments include pulse oximetry, pulmonary function testing to measure DLCO, six-minute walk testing, and arterial blood gas measurement. A scale of PAP disease severity based on blood gas measurement has been defined by Yoshikazu Inoue as follows:

• Stage 1 – PaO2 > 70 mm Hg, asymptomatic

• Stage 2 – PaO2 > 70 mm Hg, symptomatic (dyspnea, cough)

• Stage 3 – PaO2 < 70 mm Hg

• Stage 4 – PaO2 < 60 mm Hg

• Stage 5 – PaO2 < 50 mm Hg.

How is PAP treated?
Current ‘standard’ therapy

Whole Lung Lavage is currently considered to be the standard therapy for Primary PAP. It is also useful in patients with Secondary PAP of hematologic origin with compromised lung function who require urgent care for PAP. However, it provides little or no benefit in patients with Disorders of Surfactant Production. It is an invasive procedure performed under general anesthesia and separate endotracheal intubation of each lung, in which one lung is mechanically ventilated while the other is infused with large volumes (up to 50 L) of saline to physically “wash out” the accumulated surfactant lipids. While effective, the procedure has not been standardized across institutions with respect to the method (i.e., volume infused, use of mechanical percussion, the end point of an individual lavage procedure), indications for its use, methods for evaluating the treatment effectiveness, or timing of repeated procedures. Notwithstanding, it is widely held among practitioners to improve symptoms, radiographic findings, and gas exchange in PAP patients. Although WLL is safe in the vast majority of individuals, complications can include hypoxemia, pneumonia, sepsis, hydropneumothorax, and acute respiratory distress syndrome. The procedure is not performed in a patient with an active bacterial lung infection, since this can result in sepsis and shock. Bronchoscopic segmental or lobar lavage has been proposed as a safe alternative in patients in whom whole-lung lavage under general anesthesia is considered risky due to severe hypoxemia. Other alternatives include performance in a hyperbaric chamber, and use of complete cardiopulmonary bypass.

In practice, the indications for WLL therapy include dyspnea, exercise intolerance, and a desire to reduce the requirement for supplemental oxygen therapy. Reasonable indications for performing the procedure may include dyspnea limiting activities of daily living, arterial PO2 less than 60 mm Hg while breathing room air, significant desaturation (>5%) on exercise, and a shunt fraction greater than 10% to 12%.

Experimental GM-CSF augmentation therapy

A promising potential therapy currently in clinical research testing for patients with autoimmune is the aerosol administration of recombinant human GM-CSF (rhGM-CSF). Several early or preliminary studies show that inhaled GM-CSF may have a therapeutic effectiveness in between 62 and 95 percent of patients. However, formal toxicology studies have not been previously done to evaluate administration of rhGM-CSF by the aerosol inhalation route. This and other therapeutic approaches are being evaluated by clinical investigators of the Rare Lung Diseases Consortium.

What is Hermansky-Pudlak Syndrome (HPS)?

HPS is a rare autosomal recessive disease that causes oculocutaneous albinism (OCA), bleeding due to platelet dysfunction, and colitis and pulmonary fibrosis in some subtypes. HPS was first described by the Czechoslovakian physicians Hermansky and Pudlak in 1959, and there are now 9 reported genetically distinct subtypes of HPS (denoted HPS-1-9). HPS gene products are ubiquitously expressed and assemble into hetero-oligomeric complexes called BLOCs (biogenesis of lysosome-related organelle complexes), which are critical in trafficking to lysosome-like organelles, such as melanosomes and platelet dense granules.

What is the prevalence of HPS?

HPS is a rare disease, though the overall frequency is not known. However, HPS-1 is concentrated in the northwest section of Puerto Rico, where the frequency is 1 in 1800 due to a founder mutation (a 16-bp duplication in exon 15 of HPS1). HPS has now been reported worldwide, including from India, Japan, the United Kingdom, and Western Europe. More than 1100 individuals have registered with Hermansky–Pudlak Syndrome Network, a not-for-profit patient advocacy and support organization (www.hpsnetwork.org).

What are the clinical features of HPS?

The most common health conditions of people with HPS are albinism, the tendency to bleed easily, and development of pulmonary fibrosis. Kidney and heart problems are less common, but can be related to HPS.

Albinism is generally the first recognized clinical feature of HPS, though the degree of hypopigmentation is variable. Visual acuity can range from mildly decreased to legally blind, and ophthalmologic findings include transillumination of the iris, congenital horizontal nystagmus, strabismus, and impaired dark adaptation.

Bleeding diathesis occurs due to absence of dense granules thereby compromising the secondary phase of platelet aggregation. Bleeding complications vary from mild to severe and may include easy bruising, epistaxis, or prolonged or heavy bleeding with menses, dental procedures, and surgeries. Hemorrhage is a common cause of morbidity in HPS patients, and serious cases have been reported with dental extractions and parturition.

Approximately 15% of people with HPS will develop granulomatous colitis, which resembles Crohn’s disease, and typically presents with abdominal pain and bloody diarrhea. The mechanisms of colitis in HPS are not well understood.

Pulmonary fibrosis has only been observed in individuals with selected HPS subtypes, specifically HPS-1, HPS-2 and HPS-4. Lung histology from affected HPS patients is similar to patterns found in Idiopathic Pulmonary Fibrosis (IPF), including hyperplastic type II alveolar epithelial cells (AECs). In addition, irregular lamellar bodies and lipid accumulation in type II AECs and alveolar macrophages have also been reported in HPS.

The natural history of pulmonary fibrosis in HPS has been reported as variable but universally progressive, with mortality commonly occurring typically in the 4th-5th decades of life, and with an approximate survival of two years after forced vital capacity (FVC) reaches 50% of predicted values. However, the age of death has ranged from 26-61 years, and decline in FVC is not uniform.

How is HPS diagnosed?

HPS diagnostic criteria include tyrosinase-positive OCA and a specific platelet storage pool deficiency. Standard laboratory blood test results are not sufficient to diagnosis of HPS, and examination of platelet dense granules by electron microscopy must be performed by an experienced lab. Contact the HPS Network at info@hpsnetwork.org if more information or assistance is needed. Genetic testing for HPS genes can also be useful in some cases. Because pulmonary fibrosis has only been observed in patients with HPS-1, HPS-2, and HPS-4, it is clinically important to know the HPS subtype.

How is HPS pulmonary fibrosis diagnosed?

Pulmonary fibrosis remains the most serious complication of HPS. Nonproductive cough and progressive dyspnea on exertion are the most common presenting pulmonary symptoms, with a mean age of onset of pulmonary symptoms previously reported of about 35 years, though presentation in late adolescence has also been observed. There is no known gender predominance, and history of tobacco smoking is rare in this population. Pulmonary function tests (PFTs) commonly show a restrictive pattern with reduced DLco. Diagnosis is made by chest HRCT scan, as lung biopsy is generally contraindicated because of bleeding complications.

What are some key aspects of the management and treatment of HPS?

Recommendations for the care of HPS patients have been reviewed in a publication by Seward and Gahl, Pediatrics 2013.

Oculocutaneous Albinism: HPS patients should be provided with vision services, minimize sun exposure through use of sunscreen and also protective clothing, and obtain regular skin exams due to skin cancer risk.

Bleeding: It is recommended that HPS patients avoid taking aspirin, NSAIDs such as ibuprofen or others, and anticoagulants. Use of a medical alert product such as a bracelet or necklace is strongly advised. There are no formal trials, but expert opinion has been to recommend consideration of desmopressin premedication for procedures likely to cause minor bleeding. For more severe bleeding or procedures, a platelet transfusion may be required. Use of a single donor for platelet transfusion is advised whenever possible, as some HPS patients have unfortunately developed significant sensitization that can impact lung transplant considerations in the future.

Granulomatous colitis: Granulomatous colitis in HPS is managed similarly to Crohn’s disease and has been successfully treated with anti-TNF therapy, though surgical resection has been performed as a last resort in some cases.

Pulmonary Fibrosis: For HPS patients with pulmonary fibrosis, supplemental oxygen and other symptomatic care should be provided if needed. There is no established role for the use of steroids or cytotoxic agents. Referral for lung transplantation should be considered, including time for pre-transplant planning with a hematologist regarding management of platelet dysfunction and bleeding risk. Emerging therapies for Idiopathic Pulmonary Fibrosis (IPF) may also have a role in treating HPS patients who have patterns of pulmonary fibrosis similar to that seen in IPF.

Additional information and patient support is available through the HPS Network (https://www.hpsnetwork.org/)

What is Birt-Hogg-Dubé Syndrome (BHD)?

Birt-Hogg-Dubé syndrome (BHD) is an autosomal dominant condition caused by mutations in the folliculin (FLCN) gene, which has tumor suppressive properties. The characteristic clinical manifestations of BHD include formation of hair follicle tumors (fibrofolliculomas), kidney tumors, and lung cysts.¹

Genetics and Pathogenesis:

The BHD gene locus was localized to chromosome 17 in the early 2000’s.^2,3 Subsequent studies have confirmed the tumor suppressor role of FLCN gene.^4-6 Although great strides have been made in the understanding of the tumor suppressor actions of FLCN, the exact mechanism of action still remains unclear. Possible mechanisms suggested by various studies include modulation of the PI3K-AKT-mTOR pathway⁷, alterations in the TGF-beta signaling pathways⁸, dysregulated RhoA signaling and alterations in cell-cell adhesion.^9,10 Similarly, the mechanism by which FLCN deficiency causes formation of pulmonary cysts is not established, but possible involvement of the E-cadherin-LKB1-AMPK pathway has been suggested.¹¹

Clinical Features:

The classic triad of clinical manifestations in BHD consists of fibrofolliculomas, renal tumors, and pulmonary cysts. However, it is important to note that there is significant phenotypic variation in the clinical presentation of BHD, and the involvement of all three organ systems is not necessary to diagnose BHD.¹

 

Pulmonary: Pulmonary involvement is one of the most common phenotypic manifestations of BHD. Pulmonary cysts can be seen in greater than 80% of patients with BHD.¹² These cysts are prone to rupture leading to the development of spontaneous pneumothoraces. Most patients with BHD are asymptomatic from a pulmonary perspective until they develop a spontaneous pneumothorax. Approximately one third of patients with BHD develop a spontaneous pneumothorax, with a mean age in the mid-thirties.¹² Patients with BHD are at a 32-fold higher risk of developing a spontaneous pneumothorax as compared to the normal population.¹³ The other hallmark of pulmonary involvement with BHD is the extremely high rate of recurrence (75%) of pneumothoraces following a sentinel event.¹²

 

Renal: Patients with BHD are at a higher risk (7 times the risk of normal population) of developing renal tumors. The renal tumors in BHD are frequently multifocal, or bilateral, and can have varying histologies.¹³ Approximately one-third of patients with BHD develop renal tumors, with a mean age at diagnosis of 50 years.¹⁴

 

Skin: Fibrofolliculomas appear as raised, dome-shaped, whitish papules, typically seen on the face, neck, and upper trunk. Skin lesions of BHD are seen in greater than 80% of patients.¹⁵

Radiographic Features:

Pulmonary: High-resolution CT (HRCT) chest is the modality of choice to diagnose the pulmonary manifestations of BHD. The characteristic HRCT findings of BHD include the presence of round-lentiform cysts distributed in the basilar, sub-pleural locations, with close proximity to the pulmonary vasculature. The intervening lung parenchyma appears normal on the HRCT.¹ Based on these characteristic HRCT features, an expert radiologist can identify BHD in over 90% of the cases.¹⁶

 

Renal: The characteristic renal findings on imaging include the presence of multiple, often bilateral, renal tumors of various shapes and sizes.¹³

Diagnosis:

The diagnosis of BHD should be suspected in any young patient presenting with a spontaneous pneumothorax, especially in non-smoking individuals with a positive family or personal history of pneumothoraces, skin or kidney tumors. In addition, BHD should be suspected in patients presenting with early onset (age <50 years) multifocal or bilateral renal cancer or renal cancer of mixed chromophobe and oncocytic histology. Multiple sets of diagnostic criteria have been published for BHD.^1,15,17

 

Management:

Pulmonary: Patients should be reassured that BHD typically does not lead to significant lung function impairment and does not progress to respiratory failure. Thus, the major pulmonary management in BHD relates to the management of spontaneous pneumothoraces. Patients should be educated about the signs and symptoms of a spontaneous pneumothorax. Given the high recurrence rate, pleurodesis should be offered following the initial pneumothorax rather than waiting for a recurrence.^1,18

 

Renal: Renal cancer is the most life-threatening manifestation of BHD. Patients with BHD should be screened regularly for renal tumors. It is recommended that screening starts after the age of 20 years with serial scans performed every 3 years. Although the optimal modality of scanning is not well established, MRI tends to be the preferred approach as it provides the most sensitivity (better than ultrasound), and does not suffer from the drawback of radiation exposure (as compared to CT scan). Nephron-sparing surgery is recommended for tumors greater than 3cms in size.¹⁵

References:

1. Gupta N, Seyama K, McCormack FX. Pulmonary manifestations of Birt-Hogg-Dube syndrome. Fam Cancer 2013;12:387-96.
2. Khoo SK, Bradley M, Wong FK, Hedblad MA, Nordenskjold M, Teh BT. Birt-Hogg-Dube syndrome: mapping of a novel hereditary neoplasia gene to chromosome 17p12-q11.2. Oncogene 2001;20:5239-42.
3. Nickerson ML, Warren MB, Toro JR, et al. Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dube syndrome. Cancer Cell 2002;2:157-64.
4. Schmidt LS, Nickerson ML, Warren MB, et al. Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dube syndrome. Am J Hum Genet 2005;76:1023-33.
5. Hasumi Y, Baba M, Ajima R, et al. Homozygous loss of BHD causes early embryonic lethality and kidney tumor development with activation of mTORC1 and mTORC2. Proc Natl Acad Sci U S A 2009;106:18722-7.
6. Vocke CD, Yang Y, Pavlovich CP, et al. High frequency of somatic frameshift BHD gene mutations in Birt-Hogg-Dube-associated renal tumors. J Natl Cancer Inst 2005;97:931-5.
7. Baba M, Furihata M, Hong SB, et al. Kidney-targeted Birt-Hogg-Dube gene inactivation in a mouse model: Erk1/2 and Akt-mTOR activation, cell hyperproliferation, and polycystic kidneys. J Natl Cancer Inst 2008;100:140-54.
8. Hong SB, Oh H, Valera VA, Baba M, Schmidt LS, Linehan WM. Inactivation of the FLCN tumor suppressor gene induces TFE3 transcriptional activity by increasing its nuclear localization. PLoS One 2010;5:e15793.
9. Nahorski MS, Seabra L, Straatman-Iwanowska A, et al. Folliculin interacts with p0071 (plakophilin-4) and deficiency is associated with disordered RhoA signalling, epithelial polarization and cytokinesis. Hum Mol Genet 2012;21:5268-79.
10. Medvetz DA, Khabibullin D, Hariharan V, et al. Folliculin, the product of the Birt-Hogg-Dube tumor suppressor gene, interacts with the adherens junction protein p0071 to regulate cell-cell adhesion. PLoS One 2012;7:e47842.
11. Goncharova EA, Goncharov DA, James ML, et al. Folliculin controls lung alveolar enlargement and epithelial cell survival through E-cadherin, LKB1, and AMPK. Cell Rep 2014;7:412-23.
12. Toro JR, Pautler SE, Stewart L, et al. Lung cysts, spontaneous pneumothorax, and genetic associations in 89 families with Birt-Hogg-Dube syndrome. Am J Respir Crit Care Med 2007;175:1044-53.
13. Zbar B, Alvord WG, Glenn G, et al. Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dube syndrome. Cancer Epidemiol Biomarkers Prev 2002;11:393-400.
14. Pavlovich CP, Grubb RL, 3rd, Hurley K, et al. Evaluation and management of renal tumors in the Birt-Hogg-Dube syndrome. J Urol 2005;173:1482-6.
15. Schmidt LS, Linehan WM. Molecular genetics and clinical features of Birt-Hogg-Dube syndrome. Nat Rev Urol 2015;12:558-69.
16. 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.
17. Menko FH, van Steensel MA, Giraud S, et al. Birt-Hogg-Dube syndrome: diagnosis and management. Lancet Oncol 2009;10:1199-206.
18. Gupta N, Vassallo R, Wikenheiser-Brokamp KA, McCormack FX. Diffuse Cystic Lung Disease. Part II. Am J Respir Crit Care Med 2015;192:17-29.

What is Pulmonary Langerhans cell histiocytosis (PLCH)?

Pulmonary Langerhans cell histiocytosis (PLCH) is rare, progressive, diffuse cystic lung disease primarily seen in young adults. PLCH has a very strong association with smoke exposure, and greater than 90% of patients with PLCH are current/former smokers. While pulmonary involvement is the major cause of morbidity and mortality among patients with PLCH, a small proportion of these patients have disease involvement outside the thoracic cavity characterized by the development of lytic bone lesions, and diabetes insipidus.¹

Etiopathogenesis:

While the exact etiopathogenesis of development of PLCH is not well established, the association with exposure to cigarette smoke is a constant theme among the majority of patients with PLCH. Greater than 90% of patients with PLCH are either current or former smokers at the time of diagnosis.^2,3 The earliest lesion in PLCH is the accumulation of Langerhans’ cells in a peribronchiolar distribution.¹ Langerhans’ cells are differentiated cells of monocyte–macrophage lineage that function as antigen-presenting cells and regulate airway mucosal immunity.⁴ Cigarette smoke, by inducing a variety of cytokines such as granulocyte/ macrophage colony–stimulating factor and transforming growth factor-β, acts as the major factor leading to the recruitment and activation of Langerhans’ cells.^5,6 These activated Langerhans’ cells express abundant co-stimulatory molecules resulting in secondary recruitment of other immune cells and forming cellular nodules. Expression of matrix metalloproteinases, and other destructive enzymes, from these nodules leads to bronchiolar destruction and, ultimately, cyst formation in PLCH.¹

It was believed that PLCH is a polyclonal reactive disease process induced by exposure to cigarette smoke.⁴ However, in recent years disease-causing mutations in the BRAF proto-oncogene, and other mutations in the MAP kinase pathway have been discovered in greater than 50% of cases of PLCH.⁷ The discovery of these mutations has caused a paradigm shift in our understanding of development of PLCH, and PLCH is now considered as an inflammatory neoplastic disorder.¹

Clinical features:

There is wide inter-individual variation in terms of the presenting clinical manifestations of PLCH. Some patients are relatively asymptomatic and the disease is discovered incidentally on chest imaging, while others present with relatively non-specific symptoms of cough and dyspnea on exertion. Constitutional symptoms such as fever, and weight loss may be present in approximately one-fifth of the patients. A small proportion of patients (less than 20%) can present with a spontaneous pneumothorax, or extra-thoracic involvement, typically manifesting as lytic bone lesions or CNS involvement.²

Radiology:

High-resolution CT (HRCT) chest is the most useful non-invasive diagnostic test to diagnose PLCH. The characteristic HRCT findings of PLCH include cystic and/or nodular abnormalities, typically present in the upper and middle lobes with relative sparing of the costo-phrenic angles. Cysts in PLCH, if present, tend to have bizarre, irregular shapes, as opposed to the smooth, round shaped cysts typically seen in the other diffuse cystic lung diseases.⁸

Pathology:

The histopathological features of PLCH range from the detection of bronchiolocentric Langerhans cells in the background of inflammation and smoking related changes such as respiratory bronchiolitis to the formation of stellate, fibrotic scars in the late stages. Immunohistochemical staining for S-100 and CD1a can help identify Langerhans cells o tissue biopsies.¹

Diagnosis:

In the most typical cases of PLCH, an expert radiologist can diagnose PLCH with almost 100% accuracy based on HRCT features alone. However, the diagnostic accuracy of HRCT alone is sub-optimal if the findings are at all atypical.⁸ In these cases, tissue confirmation is usually needed to establish the diagnosis with certainty. In the presence of compatible HRCT findings of PLCH, the presence of one of the following is confirmatory for the diagnosis of PLCH:

1. Detection of greater than 5% CD1a positive cells⁴
2. Histopathological features of PLCH on transbronchial lung biopsy (30-50% diagnostic yield in small case series)^9,10
3. Histopathological features of PLCH via a surgical lung biopsy

Management:

Smoking cessation is the key to successful management of patients with PLCH. In some patients, smoking cessation alone can lead to disease stabilization, or even regression.^11,12 However, the disease continues to progress in a certain proportion of patients even after successful smoking cessation.¹³ No effective treatment exists for this subgroup of patients currently. Cladribine (2-CDA) has shown some promise in the treatment of patients with refractory PLCH,¹⁴ however, this approach has not been studied in a controlled manner, and has a significant adverse effect profile. The discovery of underlying genetic mutations in the MAP kinase pathway has given hope that targeted therapies aimed at disease causing mutations will be effective for patients with PLCH. However, this approach needs to be better studied in controlled trials before widespread use can be recommended.

Other management issues relate to the development of spontaneous pneumothoraces and pulmonary hypertension. Spontaneous pneumothoraces are seen in approximately 15% of patients with PLCH, albeit with a very high recurrence rate (60%). Thus, patients with PLCH should be offered pleurodesis following their initial pneumothorax in order to prevent future events.¹⁵ Patients with PLCH are at a higher risk for development of PLCH, and should undergo periodic monitoring for the development of pulmonary hypertension. The optimal time-interval and modality of this screening need to be better established.¹

References:

1. Gupta N, Vassallo R, Wikenheiser-Brokamp KA, McCormack FX. Diffuse Cystic Lung Disease. Part I. Am J Respir Crit Care Med 2015;191:1354-66.
2. Vassallo R, Ryu JH, Schroeder DR, Decker PA, Limper AH. Clinical outcomes of pulmonary Langerhans'-cell histiocytosis in adults. N Engl J Med 2002;346:484-90.
3. Tazi A, de Margerie C, Naccache JM, et al. The natural history of adult pulmonary Langerhans cell histiocytosis: a prospective multicentre study. Orphanet J Rare Dis 2015;10:30.
4. Vassallo R, Ryu JH, Colby TV, Hartman T, Limper AH. Pulmonary Langerhans'-cell histiocytosis. N Engl J Med 2000;342:1969-78.
5. Tazi A, Bonay M, Bergeron A, Grandsaigne M, Hance AJ, Soler P. Role of granulocyte-macrophage colony stimulating factor (GM-CSF) in the pathogenesis of adult pulmonary histiocytosis X. Thorax 1996;51:611-4.
6. Asakura S, Colby TV, Limper AH. Tissue localization of transforming growth factor-beta1 in pulmonary eosinophilic granuloma. Am J Respir Crit Care Med 1996;154:1525-30.
7. Mourah S, How-Kit A, Meignin V, et al. Recurrent NRAS mutations in pulmonary Langerhans cell histiocytosis. Eur Respir J 2016;47:1785-96.
8. 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.
9. Baqir M, Vassallo R, Maldonado F, Yi ES, Ryu JH. Utility of bronchoscopy in pulmonary Langerhans cell histiocytosis. J Bronchology Interv Pulmonol 2013;20:309-12.
10. Harari S, Torre O, Cassandro R, Taveira-DaSilva AM, Moss J. Bronchoscopic diagnosis of Langerhans cell histiocytosis and lymphangioleiomyomatosis. Respir Med 2012;106:1286-92.
11. Mogulkoc N, Veral A, Bishop PW, Bayindir U, Pickering CA, Egan JJ. Pulmonary Langerhans' cell histiocytosis: radiologic resolution following smoking cessation. Chest 1999;115:1452-5.
12. Schonfeld N, Dirks K, Costabel U, Loddenkemper R, Wissenschaftliche Arbeitsgemeinschaft fur die Therapie von L. A prospective clinical multicentre study on adult pulmonary Langerhans' cell histiocytosis. Sarcoidosis Vasc Diffuse Lung Dis 2012;29:132-8.
13. Elia D, Torre O, Cassandro R, Caminati A, Harari S. Pulmonary Langerhans cell histiocytosis: a comprehensive analysis of 40 patients and literature review. Eur J Intern Med 2015;26:351-6.
14. Grobost V, Khouatra C, Lazor R, Cordier JF, Cottin V. Effectiveness of cladribine therapy in patients with pulmonary Langerhans cell histiocytosis. Orphanet J Rare Dis 2014;9:191.
15. Mendez JL, Nadrous HF, Vassallo R, Decker PA, Ryu JH. Pneumothorax in pulmonary Langerhans cell histiocytosis. Chest 2004;125:1028-32.

What is the typical course of Pulmonary Alveolar Microlithiasis (PAM)?

PAM is a rare, inherited disorder of lung phosphate balance that is associated with small stone formation in the airspaces of the lung. Mutations in the gene SLC34A2 result in loss of a key sodium, phosphate co-transporter (called Npt2b), known to be expressed in distal airway epithelial alveolar type II cells, as well as in the mammary gland, and to a lesser extent in intestine, kidney, skin, prostate and testes. As the disease progresses, the lung fields become progressively more dense (white) on the chest x-ray, lung inflammation and fibrosis, elevated pressures in the lung blood vessels, hypoxia and respiratory failure ensue, usually in middle age. The clinical course of PAM can be highly variable, with some patients remaining asymptomatic for decades, and others progressing more rapidly. There is no effective treatment, and the mechanisms of stone formation, inflammation and scarring are not known.

How can I make the diagnosis of PAM?

PAM is usually diagnosed on the basis of a typical radiological pattern, namely a very fine, sand-like calcific density distributed diffusely involving both lungs, often with basilar predominance. A confident clinical diagnosis can be based on this pattern in many cases, but bronchoscopy with or without biopsy may be helpful. After PAM is diagnosed in a given patient, family members should be screened by chest radiography, and parents should be counseled that future children are also at risk of developing the disease.

How can I treat PAM?

To date, no treatment has been proven to effectively reverse or prevent the progression of PAM. Lung transplantation is an option for end stage disease, but is typically only recommended as a last resort when quality of life is significantly impaired.

What is the typical course of GLA/lymphangiomatosis?

The disorder often causes a variety of general, nonspecific symptoms including fatigue and nausea as well as symptoms more directly related to the chest, including chest pain, wheezing, shortness of breath (dyspnea), chronic cough, and coughing up blood (hemoptysis) or chyle. Chest tightness, recurrent respiratory infections and recurrent pneumonia have also been reported in individuals with diffuse pulmonary GLA/lymphangiomatosis. Some individuals give a history suggestive of asthma but the symptoms may actually be secondary to the GLA/lymphangiomatosis rather than true asthma.

Diffuse pulmonary GLA/lymphangiomatosis is a lung restricted form of the disease can eventually cause compression of nearby structures in the chest, bony destruction leading to the appearance of “holes” in adjacent bones (lytic bone lesions), and other complications such as the accumulation of lymph fluid (chyle) in the space between the lung surface and chest wall (pleural space), a condition known as chylous pleural effusions. A collapsed lung (pneumothorax) can also occur. Some of these complications can be life-threatening e.g. when chylous pleural effusions become large enough to make breathing difficult, and when chyle accumulates in the pericardium.

How can I make the diagnosis of GLA/lymphangiomatosis?

A diagnosis of GLA/lymphangiomatosis is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation, and a variety of specialized tests. Because of the disorder’s rarity and varying presentation in each individual, correct diagnosis can be challenging.

Pulmonary function tests may be used to help diagnose GLA/lymphangiomatosis. Affected individuals often have a restrictive pattern or a mixed restrictive and obstructive lung function pattern. Lymphoscintigraphy can also be used to help obtain define disorders of lymphatic flow or the site of leak. Newer techniques such as heavy T2 weighted MRI, and dynamic contrast enhanced MRI lymphangiography provide much better resolution and definition of lymphatic anatomy and pathology.

A lung biopsy may be used to confirm a diagnosis of diffuse pulmonary GLA/lymphangiomatosis, is not always advisable because it can be associated with complications such as a chylothorax.

Various imaging techniques including plain x-rays, ultrasound, CT scanning and MRI may be used to determine the location, behavior and extent of the disorder. Plain x-rays can reveal infiltrates or chylous effusions.

How can I treat GLA/lymphangiomatosis?

A wide variety of potential therapies have been tried in individuals with GLA/lymphangiomatosis, yet there are no proven treatments.

Excision of affected tissue has been effective in some cases when the disease is localized. However, this is typically not the case in GLA/lymphangiomatosis. When surgery is attempted, diseased lymphatic tissue is often difficult to distinguish from healthy tissue, making it challenging to completely remove all affected tissue. Sclerotherapy has demonstrated good results in some cases. Radiotherapy has also been tried in individuals with GLA/lymphangiomatosis where surgery is not an option.

A variety of drugs have been reported in the medical literature for the treatment of individuals with diffuse pulmonary GLA/lymphangiomatosis, including interferon α2b, glucocorticoids, bisphosphates, thalidomide, rapamycin, propranolol and bevacizumab.

Dietary treatments have generally proven ineffective. Pleural or pericardial drainage may be necessary in some cases. Some individuals have also undergone pleurodesis or surgical removal of part of the pleura to prevent fluid accumulation there. Lung transplantation has been used to treat some patients with severe disease that has not responded to any other therapy, but due to the extensive nature of the disease in the chest, this surgery can be very challenging.