OTHER ILD

 

Other ILD

Other ILD
Vasculitis/Diffuse Alveolar Hemorrhage (DAH)
Pulmonary Langerhans Cell Histiocytosis (PLCH)
Eosinophilic Pneumonia
Neurofibromatosis
Lymphangioleiomyomatosis (LAM)

ILD, interstitial lung disease.

Vasculitis/Diffuse Alveolar Hemorrhage

 

Disease Definition

  • Pulmonary vasculitis is characterized by inflammation and necrosis of the vasculature, commonly the capillaries1
  • DAH is the most common manifestation of pulmonary vasculitis. DAH is characterized by the widespread extravasation of red blood cells and collecting in the alveoli1,2
DAH, diffuse alveolar hemorrhage
1. Krause ML et al. Immunol Allergy Clin North Am. 2012;32(4):587-600. 2. Cordier JF et al. Semin Respir Crit Care Med. 2011;32:310-321. 

Clinical Presentation

  • Highly variable1
  • Patients commonly present with nonspecific symptoms that can develop acutely or over time1,2
    • Dyspnea
    • Cough
    • Fever
    • Chest pain
  • A majority of patients (~67%) experience a variable degree of hemoptysis1
  • Anemia – acute or chronic (lasting several weeks) – is common2
1. Krause ML et al. Immunol Allergy Clin North Am. 2012;32(4):587-600. 2. Cordier JF et al. Semin Respir Crit Care Med. 2011;32:310-321.

Clinical Presentation (cont’d)

  • Patients will often have signs and symptoms of a related systemic disorder1
  • Patient presentation can range from being asymptomatic with radiographic abnormalities to severe respiratory failure resulting from impaired oxygen uptake from the alveoli1,2
1. Krause ML et al. Immunol Allergy Clin North Am. 2012;32(4):587-600. 2. Cordier JF et al. Semin Respir Crit Care Med. 2011;32:310-321.

Diagnosis

  • Decreased hemoglobin and/or hematocrit levels without external bleeding in addition to increasing pulmonary alveolar opacities is characteristic of DAH1
  • Identification of the underlying systemic disease causing DAHis crucial2
    • Review of systems including exposure history
    • Past medical history
    • Comprehensive physical exam                                               
1. Cordier JF et al. Semin Respir Crit Care Med. 2011;32:310-321. 2. Krause ML et al. Immunol Allergy Clin North Am. 2012;32(4):587-600.

Diagnosis of DAH

Transbronchial Lung Biopsy
  • Diagnostic gold standard to show alveolar hemorrhage as well as the inflamed capillaries1
  • Histologic confirmation of vascular inflammation is required2
Imaging – CXR and HRCT
  • Nonspecific, varies through disease course1,2
  • Alveolar opacities – focal or diffuse areas of ground glass and/or consolidation1,2
  • Opacities are bilateral, patchy or diffuse, dominant in mid and lower zones ofthe lungs1
  • Pleural effusion is not a feature of DAH  if present, suspect heart or renal failure1
Bronchoscopy with BAL
  • Frequently required to accurately diagnose DAH2
  • Confirms presence of blood in the alveoli and rules out infection2
Laboratory studies
  • Because of nonspecific presentation, comprehensive panels should be done including CBC, coagulation, serum creatinine, and ANCA testing2
ANCA-associated vasculitis; ANCA, antineutrophil cytoplasmic antibody; BAL, bronchoalveolar lavage; CBC, complete blood count; CXR; chest X-ray; HRCT, high-resolution computed tomography; TBBx, transbronchial lung biopsy.
1. Cordier JF et al. Semin Respir Crit Care Med. 2011;32:310-321. 2. Krause ML et al. Immunol Allergy Clin North Am. 2012;32(4):587-600. 

Management of DAH

  • Recommendations for management are disease specific once an underlying cause is identified1
    • Non-immune mediated causes are managed by treating thesystemic disease
    • Immune-mediated cases require immediate administration of high-dose glucocorticoids
  • Supportive care including ventilatory support (eg, oxygen supplementation, mechanical ventilation)1
1. Krause ML et al. Immunol Allergy Clin North Am. 2012;32(4):587-600.

Pulmonary LangerhansCell Histiocytosis

 

Disease Definition

  • Proliferation of monoclonal CD1a-positive Langerhans cells that infiltrate the bronchioles and alveolar interstitium, along with lymphocytes, plasma cells, neutrophils, and eosinophils1,2
1. Lee J. Pulmonary Langerhans Cell Histiocytosis. The Merck Manual Online. Retrieved from The Merck Manuals Online Medical Library Database. Updated May 2018. https://www.merckmanuals.com/professional/pulmonary-disorders/interstitial-lung-diseases/pulmonary-langerhans-cell-histiocytosis. Accessed on August 17, 2018. 2. Suri HS et al. Orphanet Journal of Rare Diseases. 2012;7(16):1-13.

Epidemiology

Rare disease but prevalence and incidence cannot be determined due to lack of population-based studies

74% - 5-year survival

12 years - Median survival

1. Lee J. Pulmonary Langerhans Cell Histiocytosis. The Merck Manual Online. Retrieved from The Merck Manuals Online Medical Library Database. Updated May 2018. https://www.merckmanuals.com/professional/pulmonary-disorders/interstitial-lung-diseases/pulmonary-langerhans-cell-histiocytosis.
 

 
 

Risk Factors

Cigarette smoking plays a primary role
 
Men and women affected equally
 
Patients are at increased risk of cancer

The typical patient is a white smoker and 20 to 40 years old1,2

1. Lee J. Pulmonary Langerhans Cell Histiocytosis. The Merck Manual Online. Retrieved from The Merck Manuals Online Medical Library Database. Updated May 2018. https://www.merckmanuals.com/professional/pulmonary-disorders/interstitial-lung-diseases/pulmonary-langerhans-cell-histiocytosis 2. Suri HS et al. Orphanet Journal of Rare Diseases. 2012;7(16):1-13.

Clinical Presentation

  • Dyspnea
  • Nonproductive cough
  • Fatigue
  • Fever
  • Weight loss
  • Pleuritic chest pain
1. Lee J. Pulmonary Langerhans Cell Histiocytosis. The Merck Manual Online. Retrieved from The Merck Manuals Online Medical Library Database. Updated May 2018. https://www.merckmanuals.com/professional/pulmonary-disorders/interstitial-lung-diseases/pulmonary-langerhans-cell-histiocytosis.

Common Patient Presentations

15%-25%
1. Asymptomatic and radiographic abnormalities are detected on a routine chest X-ray1,2

67%
2. Respiratory symptoms (eg, dry cough, dyspnea) on presentation are linked to systemic symptoms (eg, fever, weight loss)2

10%-20%
3. Spontaneous pneumothorax causes chest pain1,2
 
1. Lee J. Pulmonary Langerhans Cell Histiocytosis. The Merck Manual Online. Retrieved from The Merck Manuals Online Medical Library Database. Updated May 2018. https://www.merckmanuals.com/professional/pulmonary-disorders/interstitial-lung-diseases/pulmonary-langerhans-cell-histiocytosis. 2. Tazi A. Eur Respir J. 2006;27:1272-1285.


 

Diagnosis

Imaging – CXR and HRCT1-3
  • CXR shows bilaterally symmetric nodular opacities in the middle and upper lung fields with cystic changes
  • Lung bases are often spared
  • Diagnosis is confirmed with an HRCT – can differentiate PLCH from other cystic lung diseases (eg, LAM, emphysema)
PFTs1,2
  • Findings are normal, restrictive, obstructive, or mixed depending on when the test is done during the course of the disease
  • Most commonly, the DLCO is reduced
Bronchoscopy / biopsy / BAL1
  • Indicated when imaging and PFTs are inconclusive
  • Finding >5% of CD1a cells in BAL is highly suggestive of disease
Appearance may mimic COPD or lymphangioleiomyomatosis (LAM)1

COPD, chronic obstructive pulmonary disease; DLCO,  diffusing capacity of lung for carbon monoxide; PFT, pulmonary function test
1. Lee J. Pulmonary Langerhans Cell Histiocytosis. The Merck Manual Online. Retrieved from The Merck Manuals Online Medical Library Database. Updated May 2018. https://www.merckmanuals.com/professional/pulmonary-disorders/interstitial-lung-diseases/pulmonary-langerhans-cell-histiocytosis. 2. Tazi A. Eur Respir J. 2006;27:1272-1285. 3. Suri HS et al. Orphanet Journal of Rare Diseases. 2012;7(16):1-13.

Management

  • A majority of patients recover or remain stable without treatment1
  • Primary treatment is smoking cessation – with disease resolving in ~33% of patients2
  • Empiric use of corticosteroids and cytotoxic drugs, although efficacy is unproven1,2
  • Lung transplantation is curative when combined with smoking cessation2
1. Tazi A. Eur Respir J. 2006;27:1272-1285. 2. Lee J. Pulmonary Langerhans Cell Histiocytosis. The Merck Manual Online. Retrieved from The Merck Manuals Online Medical Library Database. Updated May 2018. https://www.merckmanuals.com/professional/pulmonary-disorders/interstitial-lung-diseases/pulmonary-langerhans-cell-histiocytosis

Eosinophilic Pneumonia

 

Disease Definition

Characterized by presence of eosinophils in alveolar spaces, BAL fluid, and/or the interstitium1

Acute1,2
  • Unknown etiology characterized by rapid eosinophilic infiltration of the lung interstitium
  • Can be caused by tobacco exposure, medications, fungal/parasitic infection
Chronic3
  • Acute or subacute illness that recurs
  • May be allergy related

1. Giacomi FD et al. Am J Respir Crit Care Med. 2018;197(6):728-736. 2. Lee J. Acute Eosinophilic Pneumonia. The Merck Manual Online. Retrieved from The Merck Manuals Online Medical Library Database. Updated May 2018. https://www.merckmanuals.com/professional/pulmonary-disorders/interstitial-lung-diseases/acute-eosinophilic-pneumonia. 3. Lee J. Chronic Eosinophilic Pneumonia. The Merck Manual Online. Retrieved from The Merck Manuals Online Medical Library Database. Updated May 2018. https://www.merckmanuals.com/professional/pulmonary-disorders/interstitial-lung-diseases/chronic-eosinophilic-pneumonia.

Epidemiology and Risk Factors

Prevalence and incidence of both acute and chronic eosinophilic pneumonia are unknown

Acute1,2
  • Often affects otherwise healthy patients, usually smokers, men age 20-40
Chronic3
  • Most patients are nonsmokers
  • Patients may have allergy or asthma history

1. Giacomi FD et al. Am J Respir Crit Care Med. 2018;197(6):728-736. 2. Lee J. Acute Eosinophilic Pneumonia. The Merck Manual Online. Retrieved from The Merck Manuals Online Medical Library Database. Updated May 2018. https://www.merckmanuals.com/professional/pulmonary-disorders/interstitial-lung-diseases/acute-eosinophilic-pneumonia. 3. Lee J. Chronic Eosinophilic Pneumonia. The Merck Manual Online. Retrieved from The Merck Manuals Online Medical Library Database. Updated May 2018. https://www.merckmanuals.com/professional/pulmonary-disorders/interstitial-lung-diseases/chronic-eosinophilic-pneumonia.

Clinical Presentation

Acute1
Patient presents with an acute febrile illness (duration < 7 days) and acute respiratory failure requiring mechanical ventilation
  • Nonproductive cough
  • Dyspnea
  • Malaise
  • Myalgias
  • Night sweats
  • Pleuritic chest pain
  • Tachypnea
  • Fever (>38.5°C)
  • Bibasilar inspiratory crackles
  • Rhonchi on forced exhalation
Chronic2
Patient presents with sudden and severe illness characteristic of community-acquired pneumonia
  • Cough
  • Fever
  • Progressive dyspnea
  • Wheezing
  • Night sweats
  • Weight loss if symptoms are recurrent

1. Giacomi FD et al. Am J Respir Crit Care Med. 2018;197(6):728-736. 2. Lee J. Acute Eosinophilic Pneumonia. The Merck Manual Online. Retrieved from The Merck Manuals Online Medical Library Database. Updated May 2018. https://www.merckmanuals.com/professional/pulmonary-disorders/interstitial-lung-diseases/acute-eosinophilic-pneumonia. 3. Lee J. Chronic Eosinophilic Pneumonia. The Merck Manual Online. Retrieved from The Merck Manuals Online Medical Library Database. Updated May 2018. https://www.merckmanuals.com/professional/pulmonary-disorders/interstitial-lung-diseases/chronic-eosinophilic-pneumonia. 4. Marchand E et al. Orphanet Journal of Rare Diseases. 2006;1:11.

Diagnostic Tests

Acute1,2
 
Imaging – CXR and HRCT
  • Bilateral, random, patchy ground-glass or reticular opacities, consolidation opacities, and smooth interlobular septal thickening
  • Small, bilateral, pleural effusions occur in ~67% of patients
CBC
  • Fails to demonstrate significantly elevated eosinophil counts
  • ESR and IgE levels are high but nonspecific
Pleural fluid analysis
  • Marked eosinophilia with high pH
PFTs
  • Restrictive process with reduced DLCO
Bronchoscopy/BAL/biopsy
  • BAL shows high number and percentage (>25%) of eosinophils
  • Biopsy shows eosinophilic infiltration with acute and organizing diffuse alveolar damage – rarely needed
Chronic3,4
 
CXR
  • Bilateral peripheral or pleural-based opacities, most commonly in the middle and upper lung zones
CBC, ESR, iron studies
  • Peripheral blood eosinophilia, high ESR, iron deficiency anemia, and thrombocytosis are present
BAL
  • Usually done to confirm the diagnosis
  • Eosinophilia >40% is highly suggestive of CEP

CEP, chronic eosinophilic pneumonia; ESR, erythrocyte sedimentation rate; IgE, immunoglobulin E.
1. Giacomi FD et al. Am J Respir Crit Care Med. 2018;197(6):728-736. 2. Lee J. Acute Eosinophilic Pneumonia. The Merck Manual Online. Retrieved from The Merck Manuals Online Medical Library Database. Updated May 2018. https://www.merckmanuals.com/professional/pulmonary-disorders/interstitial-lung-diseases/acute-eosinophilic-pneumonia. 3. Lee J. Chronic Eosinophilic Pneumonia. The Merck Manual Online. Retrieved from The Merck Manuals Online Medical Library Database. Updated May 2018. https://www.merckmanuals.com/professional/pulmonary-disorders/interstitial-lung-diseases/chronic-eosinophilic-pneumonia. 4. Marchand E et al. Orphanet Journal of Rare Diseases. 2006;1:11.

Diagnosis of AEP

  1. Acute respiratory illness (duration <1 month)
  2. Pulmonary infiltrates on imaging
  3. Pulmonary eosinophilia (>25% eosinophils in BAL fluid) or eosinophilic pneumonia on lung biopsy
  4. Absence of other specific pulmonary eosinophilic diseases

AEP, acute eosinophilic pneumonia.
1. Giacomi FD et al. Am J Respir Crit Care Med. 2018;197(6):728-736.

Diagnosis of CEP

  1. Respiratory symptoms (duration > 2 weeks)
  2. Alveolar and/or blood eosinophilia
  3. Peripheral pulmonary infiltrates on imaging
  4. Exclusion of any known causes

1. Marchand E et al. Orphanet Journal of Rare Diseases. 2006;1:11.

Management

Acute1,2
  • Systemic corticosteroids; if applicable, remove identified trigger or exposure
  • Prognosis is usually good
  • Patients commonly respond to corticosteroids with full recovery
  • Resolution of symptoms within 24-48h, radiographic abnormalities within 30 d
Chronic3,4
  • Systemic corticosteroids
  • Maintenance therapy: inhaled corticosteroids, oral corticosteroids, or both
  • Failure to respond (within 48h) to steroids suggests another diagnosis
  • Resolution of symptoms and radiographic abnormalities in 14-30 d

1. Giacomi FD et al. Am J Respir Crit Care Med. 2018;197(6):728-736. 2. Lee J. Acute Eosinophilic Pneumonia. The Merck Manual Online. Retrieved from The Merck Manuals Online Medical Library Database. Updated May 2018. https://www.merckmanuals.com/professional/pulmonary-disorders/interstitial-lung-diseases/acute-eosinophilic-pneumonia. 3. Lee J. Chronic Eosinophilic Pneumonia. The Merck Manual Online. Retrieved from The Merck Manuals Online Medical Library Database. Updated May 2018. https://www.merckmanuals.com/professional/pulmonary-disorders/interstitial-lung-diseases/chronic-eosinophilic-pneumonia. 4. Marchand E et al. Orphanet Journal of Rare Diseases. 2006;1:11.

Neurofibromatosis

 

Disease Definition

  • 3 major forms: type 1 (NF1), type 2 (NF2), schwannomatosis1,2
  • NF1 (von Recklinghausen disease) is the most common type and also exhibits thoracic manifestations3
1. Lammert M et al. Arch Dermatol. 2005; 141:71. 2. Evans DG et al. Am J Med Genet A. 2010; 152A:327. 3. Valeyrie-Allanore L et al. Br. J. Dermatol. 2005;153(1): 79-82.

Epidemiology

  • NF1 is an autosomal dominant genetic disorder with an incidence of approximately 1 in 2600 to 3000 individuals1,2
  • Approximately 5% of NF1 patients develop mediastinal tumors3
  • A total of 64 cases of NF-associated diffuse lung disease have been identified4
1. Lammert M et al. Arch Dermatol. 2005; 141:71-74. 2. Gutmann DH et al. Nat Rev Dis Primers. 2017;23;3:17004. 3. Valeyrie-Allanore L et al. Br. J. Dermatol. 2005;153 (1): 79-82. 4. Zamora AC et al. Eur Respir J. 2007;29:210-14.

Diagnosis of NF1

  1. Presence of ≥6 café au lait macules, >5mm in diameter pre-puberty or ≥1.5mm post-puberty
  2. Skin-fold freckling
  3. ≥2 neurofibromas or 1 plexiform neurofibroma
  4. ≥2 iris hamartomas (Lisch nodules)
  5. Optic glioma
  6. Skeletal dysplasia
  7. Affected first-degree relative

1. Gutmann DH et al. Nat Rev Dis Primers. 2017;23;3:17004.

Clinical Presentation of NF-DLD1

80%
Dyspnea
 
32%
Cough
 
5%
Chest pain
 
11%
Asymptomatic

NF-DLD, neurofibromatosis with diffuse lung disease.
1. Zamora AC et al. Eur Respir J. 2007;29:210-14.

Thoracic Manifestations

  • Neurofibroma: well-circumscribed round or elliptic masses in the paravertebral regions or along the nerves’ courses
    • May erode, invade, or destroy adjacent bone; may calcify
  • Focal thoracic scoliosis
  • Posterior vertebral scalloping
  • Enlarged neural foramina
  • Characteristic rib abnormalities – due to bone dysplasia or erosion from adjacent neurofibromas
 
1. Fortman BJ et al. Radiographics. 2001;21(3):601-12.

Thoracic Manifestations (cont’d)

  • Lung Parenchymal Disease1
    • Cysts and bullae formation: upper lobe
    • Diffuse interstitial fibrosis: lower lobe
      • Ground-glass opacification
      • Basilar reticular abnormalities
  • Secondary Pulmonary Arterial Hypertension2
 
1. Shino MY et al. Semin Respir Crit Care Med. 2012;33(5):572-5. 3. Montani D et al. Medicine (Baltimore). 2011;90(3):201-11.

Management

  • Aims at early detection and symptomatic treatment of complications as they occur
  • The decision to obtain testing such as imaging studies depends on the history and physical findings
  • There is no overall treatment for NF1 or any therapeutic agents specifically approved for patients with NF1
1. Gutmann DH et al. Nat Rev Dis Primers. 2017;23;3:17004.

Lymphangioleiomyomatosis (LAM)

 

Disease Definition

  • Characterized by proliferation of atypical smooth muscle cells throughout the chest leading to destruction and infiltration of the lung parenchyma, cystic emphysema, and progressive deterioration of lung function1-3
  • Low-grade, destructive, metastasizing neoplasm that spreads through the lymphatic system1
1. Hancock E et al. Respir Med. 2002;96(1):1-6. 2. Harknett EC et al. QJM. 104(11):971-9. 3. Lee J. Lymphangioleiomyomatosis. The Merck Manual Online. Retrieved from The Merck Manuals Online Medical Library Database. Updated May 2018. https://www.merckmanuals.com/professional/pulmonary-disorders/interstitial-lung-diseases/lymphangioleiomyomatosis.

Epidemiology

  • Rare, affects <1 in 1 million people1,2
  • Occurs exclusively in women aged 20-401,2
  • Prognosis is uncertain because clinical course is variable2,3
    • Median survival is likely >8y from diagnosis
    • Progression may accelerate during pregnancy
1. Harknett EC et al. QJM. 104(11):971-9. 2. Lee J. Lymphangioleiomyomatosis. The Merck Manual Online. Retrieved from The Merck Manuals Online Medical Library Database. Updated May 2018. https://www.merckmanuals.com/professional/pulmonary-disorders/interstitial-lung-diseases/lymphangioleiomyomatosis. 3. Hancock E et al. Respir Med. 2002;96(1):1-6.

Disease Course

  • Slowly progressive and over years often leads to respiratory failure and death
  • Lung function declines 2-3x faster than a healthy person
  • NOT an ILD
1. Harknett EC et al. QJM. 104(11):971-9. 2. Lee J. Lymphangioleiomyomatosis. The Merck Manual Online. Retrieved from The Merck Manuals Online Medical Library Database. Updated May 2018. https://www.merckmanuals.com/professional/pulmonary-disorders/interstitial-lung-diseases/lymphangioleiomyomatosis.

Clinical Presentation1-3

  • Dyspnea
  • Cough
  • Chest pain
  • Hemoptysis
  • Spontaneous pneumothorax is common (36%)
LAM is often confused with other obstructive lung diseases – patients are often diagnosed with asthma, emphysema, or COPD before LAMis suspected1

1. Lee J. Lymphangioleiomyomatosis. The Merck Manual Online. Retrieved from The Merck Manuals Online Medical Library Database. Updated May 2018. https://www.merckmanuals.com/professional/pulmonary-disorders/interstitial-lung-diseases/lymphangioleiomyomatosis. 2. Hancock E et al. Respir Med. 2002;96(1):1-6. 3. Ryu JH et al. Am J Respir Crit Care Med. 2006;173(1):105-11

Diagnosis

Imaging – CXR & HRCT1
  • Multiple, small, diffusely distributed cysts
Lung Biopsy1
  • If HRCT is nondiagnostic
  • Abnormal proliferation of LAM cells with cystic changes
PFTs1,2
  • Obstructive or mixed obstructive and restrictive pattern
  • Increased TLC and RV
  • Reduced PaO2 and DLCO

PaO2, partial pressure of oxygen; RV, residual volume; TLC, total lung capacity
1. Lee J. Lymphangioleiomyomatosis. The Merck Manual Online. Retrieved from The Merck Manuals Online Medical Library Database. Updated May 2018. https://www.merckmanuals.com/professional/pulmonary-disorders/interstitial-lung-diseases/lymphangioleiomyomatosis. 2. Hancock E et al. Respir Med. 2002;96(1):1-6.

Management

  • mTOR inhibitors can stabilize or slow decline in pulmonary function in patients who have progressive disease, with FEV1 <70%
  • Lung transplantation
mTOR, mammalian target of rapamycin
1. Lee J. Lymphangioleiomyomatosis. The Merck Manual Online. Retrieved from The Merck Manuals Online Medical Library Database. Updated May 2018. https://www.merckmanuals.com/professional/pulmonary-disorders/interstitial-lung-diseases/lymphangioleiomyomatosis.