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Unusual lung diseases 

Unusual lung diseases
Unusual lung diseases

Stephen Chapman

, Grace Robinson

, John Stradling

, Sophie West

, and John Wrightson

Page of

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date: 29 June 2022

Introduction to unusual lung diseases

In continental Europe, there have been registers of rare lung diseases for many years. The term ‘orphan’ lung disease was coined because of the feeling that these diseases have, in the past, tended to be neglected because of their rarity; hence, there is limited knowledge of the conditions and limited available data on which to base clinical practice.

The previous British reporting system (BOLD) has now closed. The BTS Specialist Advisory Group on interstitial and rare lung diseases may continue this initiative in due course.

Alveolar microlithiasis

This is a rare ILD, characterized by the accumulation of numerous and diffuse calcified microliths (round calcium and phosphate hydroxyapatite bodies) in the alveolar space. There is no identifiable abnormality of calcium metabolism. A mutation in the SLC34A2 gene that encodes a type IIb sodium-phosphate co-transporter in alveolar type II cells, resulting in the accumulation and formation of microliths rich in calcium phosphate (due to impaired clearance), is considered to be the cause of the disease. Microliths are occasionally identified in the sputum. At post-mortem, the lungs are heavy and rock hard, often needing a saw to cut them. Fewer than 200 cases are reported.

Clinical features

  • Typically presents in young adults, most commonly in the third and fourth decades of life

  • May be an incidental CXR finding in asymptomatic patients

  • Familial tendency—probable autosomal recessive inheritance

  • Equal sex distribution in sporadic cases, 2:1 ♀ preponderance in familial cases

  • Usually slowly progressive, with progressive breathlessness, hypoxia, respiratory failure, and death

  • CXR and chest CT show fine micronodular lung calcification, predominantly basally or around the hila. It may produce complete radiographic opacification. There is no associated lymph node enlargement. Progressive lung infiltration causes restriction of lung movement and impairs gas exchange, leading to progressive respiratory failure.


  • There is no effective medical treatment

  • Lung transplantation has been successful.

Further information

Francisco M et al. Pulmonary alveolar microlithiasis. State-of-the-art review. Respir Med 2013;107:1–9.Find this resource:

Amyloidosis: pathophysiology and classification


Amyloidosis is the extracellular deposition of low molecular weight protein molecules as insoluble fibrils. More than 20 such proteins have been described in different diseases and circumstances. For classification, see Box 49.1.


The disease is one of abnormal protein folding and is classified by the origin of the precursor proteins that form the amyloid. For example, AL amyloid forms from the light chains of immunoglobulins. In familial forms, genetic missense mutations produce abnormal folding of the protein. Little is known of the specific genetic and environmental factors that lead to the development of this abnormal folding. Despite their different origins, these protein molecules fold into alternative forms that are very similar to each other; in the classic ‘β‎-pleated sheet’ structure, fibrils form in an ordered fashion, with uniformity of fibril structure within the sheet. Substitutions of particular amino acids at specific positions in the light chain variable region lead to destabilization of the light chains, increasing the chance of fibrillogenesis. In certain models, this abnormal folding can be initiated by the addition of ‘amyloid-enhancing factor’, rather like the initiation of crystal formation in a supersaturated solution. Amyloid deposits accumulate in the extracellular space, disrupting normal tissue architecture and leading to organ dysfunction, both directly, and having space-occupying effects. The fibrils may be directly cytotoxic (possibly by promoting apoptosis). The subdivisions of amyloid are largely based on the origin of the amyloid protein and shown in Box 49.1.


The epidemiology is difficult to define accurately, as the disease is often un- or misdiagnosed. The age-adjusted incidence is estimated to be 5–13 per million person years.

Future developments

Anti-amyloid drugs are under investigation, including drugs to stabilize the amyloid precursor proteins in their normal configuration and enhance fibril degradation.

Amyloidosis: lung involvement 1

Clinically significant respiratory tract disease is almost always AL in type, though the presence of a strong family history or chronic inflammatory disease may suggest other types.

Laryngeal amyloidosis

Amyloid causes up to 1% of benign laryngeal disease. May present as discrete nodules or diffuse infiltration and is usually localized, though can be a rare manifestation of systemic (AL) amyloid. Deposits are seen most commonly in the supraglottic larynx (presenting with hoarse voice or stridor). May present with choking and exertional dyspnoea that can be progressive or recurrent.

Tracheobronchial amyloid

is rare (67 worldwide cases reported by the mid 1980s). Macroscopically, is either diffusely infiltrative or ‘tumour-like’. It is associated with tracheobronchopathia osteoplastica (a disorder characterized by the deposition of calcified submucosal airway nodules). It presents after the fifth decade with dyspnoea, cough, and rarely haemoptysis. Airway narrowing can lead to atelectasis or recurrent pneumonia; solitary nodules may lead to investigation for presumed lung cancer. Symptomatic disease is usually localized.

Parenchymal amyloid

is the most frequently diagnosed amyloid respiratory disease. It is usually divided radiologically into solitary/multiple pulmonary nodules (usually localized AL amyloid) or a diffuse alveolar pattern (usually a manifestation of systemic AL amyloid). Parenchymal amyloid lung nodules are usually peripheral and subpleural, may be bilateral, and are more common in the lower lobes, ranging in diameter from 0.4 to 15cm. They may cavitate or calcify. Clinical signs are non-diagnostic; PFTs may show a restrictive defect with reduced transfer factor. The differential diagnosis usually includes fibrosis. Cardiac amyloid may coexist, and distinguishing the contribution to the symptoms of the pulmonary and cardiac disease can be difficult. Median survival with clinically overt lung disease is about 16 months (similar to that of systemic amyloid).

Mediastinal and hilar amyloidosis

are rarely associated with localized pulmonary amyloidosis, and their diagnosis should lead to a search for a systemic cause of amyloid. Amyloid lymphadenopathy can also represent localized AL deposition, in association with B-cell lymphoma.


Rare reports of:

  • Ventilatory failure due to diaphragm or other respiratory muscle involvement

  • Sleep apnoea from macroglossia due to amyloid

  • Exudative pleural effusions.

Clinical features

  • Dyspnoea and cough

  • None—parenchymal disease may be an incidental finding on routine radiography

  • Consider the diagnosis particularly in patients with odd upper airway symptoms and parenchymal involvement or those with unexplained CCF or nephrotic syndrome.


Histological confirmation is usually required. Congo red stain producing ‘apple green’ birefringence in crossed polarized light is the gold standard. Positive histology must lead to immunohistochemistry to determine the fibril type.

  • Histology TBB or occasionally open or VATS biopsy (more likely if investigation for solitary pulmonary nodule)

  • 123I-labelled scintigraphy Radiolabelled serum amyloid P (SAP) localizes to amyloid deposits in proportion to the quantity of amyloid present, therefore allowing identification of the distribution and burden of disease. It is most sensitive for solid organ disease though, in lung disease, is useful for determining the extent of disease in other organs. It is, however, expensive and carries an infection risk, as the SAP component is currently obtained from blood donors

  • HRCT may show nodules or parenchymal disease

  • Laryngoscopy and bronchoscopy may be needed to obtain samples for histology, depending on the clinical presentation

  • PFTs to assess the effect of disease on respiratory function. May show reduced transfer factor and a restrictive pattern. Tracheobronchial involvement may lead to abnormal flow–volume loops due to larger airway obstruction

  • Systemic disease:

    • FBC, biochemistry, and urinalysis (?renal involvement)

    • Investigate for underlying blood cell dyscrasia, e.g. myeloma, Waldenström’s macroglobulinaemia (bone marrow examination, and search for urine and serum monoclonal protein by immunofixation—the clonal proliferation underlying systemic AL amyloid is usually very subtle, and its identification may be difficult)

    • Echo for associated cardiac involvement (when CCF is present; survival is 4–6 months)

    • Thyroid/adrenal function is impaired in up to 10%.

Amyloidosis: lung involvement 2


There are limited clinical trials with which to guide management of respiratory tract amyloid. Management decisions are therefore often made empirically.

  • No treatment may be needed

  • Local measures may be warranted for endobronchial disease, e.g. symptomatic laryngeal disease—endoscopic excision, CO2 laser evaporation (useful for small recurrent lesions), stenting. Steroids have no effect on laryngeal amyloid

  • Tracheobronchial amyloid—management depends on symptoms, and treatment may involve repeated endoscopic resection, YAG (yttrium–aluminium–garnet) laser therapy, and surgical resection. Repeated endoscopic procedures are thought to be safer than repeated open surgery

  • Chemotherapy may be warranted for diffuse parenchymal amyloid if there is objectively measurable disease (prednisolone and melphalan to suppress the underlying blood cell dyscrasia). More intensive chemotherapy has a better clinical response, but there are few trials.

Further information

Blancas-Mejia LM, Ramirez-Alvarado M. Systemic amyloidoses. Annu Rev Biochem 2013;82:745–74.Find this resource:

Gillmore JD, Hawkins PN. Amyloidosis and the respiratory tract. Rare diseases. Thorax 1999;54:444–51.Find this resource:

Hereditary haemorrhagic telangiectasia

(HHT; also referred to as Osler–Weber–Rendu syndrome)

Prevalence: 1 in 5, 000–8, 000.


An autosomal dominant disorder, >80% of all cases of HHT are due to mutations in either ENG or ACVRL1 (endoglin and activin, both TGF-β‎1 receptors). A total of over 600 different mutations is known. It is characterized by the development of abnormal dilated vessels in the systemic circulation, which may bleed, leading to:

  • Recurrent epistaxis

  • GI bleeding

  • Iron deficiency anaemia

  • Other organ involvement, e.g. hepatic (in 30%, commonly asymptomatic), renal, pulmonary, and spinal AVMs.


Careful questioning of family members (does anyone in the family have frequent nose bleeds?) and examination for telangiectasia should reveal those in whom screening should occur.

All those with HHT should be screened for pulmonary AVMs (PAVMs; see Unusual lung diseases pp. [link][link]), and all of their offspring post-puberty and pre-pregnancy. There is increasing penetrance with increasing age (62% at age 16, 95% at age 40). Similarly, the detection of PAVMs in a patient should lead to screening for HHT in family members.

There is no consensus regarding the best screening method, but a combination of the following tests may be used:

  • CXR

  • Supine and erect oximetry

  • CT chest

  • Shunt quantification techniques, e.g. contrast echo, 100% O2 rebreathing.

Screening should continue throughout life (every 5–10y) and during times of enlargement or development of AVMs—post-puberty and pre-pregnancy.


  • Usually involves liaison with ENT and gastroenterology colleagues for symptomatic treatment

  • Iron replacement, transfusions

  • Asymptomatic hepatic AVMs—no treatment usually required

  • Cerebral AVMs (in 15% of HHT patients)—some specialists argue these should be treated prophylactically due to the risk of rupture and bleeding (2%/y, often fatal).

Further information

Shovlin CL, Letarte M. Hereditary haemorrhagic telangectiasa and pulmonary AVMs: issues in clinical management and review of pathogenic mechanisms. Thorax 1999;54:714–39.Find this resource:

Idiopathic pulmonary haemosiderosis

A rare disease of undetermined aetiology, characterized by recurrent episodes of alveolar haemorrhage and haemoptysis (in the absence of renal disease), usually leading to iron deficiency anaemia.


The alveolar space and interstitium contain haemosiderin-laden macrophages, with variable degrees of interstitial fibrosis and degeneration of alveolar, interstitial, and vascular elastic fibres, depending on the chronicity of the condition. Electron microscopy shows damage to the endothelial and basement membranes, but no consistent or diagnostic features have been recognized.

No antibodies have been identified, though serum IgA levels are sometimes raised. With recurrent alveolar haemorrhage, the alveolar blood provokes a fibrotic reaction, with the development of diffuse pulmonary fibrosis.

Iron turnover studies show that the accompanying iron deficiency anaemia is due to loss of iron into the lung through haemorrhage.


is uncertain but likely to be multifactorial. Possible associations include toxic insecticides (epidemiological studies in rural Greece), premature birth, and fungal toxin exposure. The disease has an equal sex incidence in childhood, with twice as many men affected in adulthood.

Most patients present in childhood, with 85% of cases having onset of symptoms before 16y. The actual prevalence is unknown, but a cohort study of Swedish children in the 1960s described an incidence of 0.24 per million children. Familial clustering is reported.

Pulmonary haemosiderosis is associated with RA, thyrotoxicosis, coeliac disease, and autoimmune haemolytic anaemia, suggesting a potential autoimmune mechanism.

Clinical features

The clinical course is very variable and ranges from continuous low-level bleeding to massive pulmonary haemorrhage. The latter may be fatal but is fortunately rare.

  • Continuous mild pulmonary haemorrhage leads to a chronic non-productive cough with haemoptysis, malaise, lethargy, and failure to thrive in children

  • Iron deficiency anaemia is common, as are positive faecal occult blood tests (due to swallowed blood)

  • Generalized lymphadenopathy and hepatosplenomegaly are recognized

  • With an acute bleed, cough and haemoptysis may worsen, and dyspnoea, chest tightness, and pyrexia may develop

  • Chronic bleeding leads to chronic disabling dyspnoea, chronic anaemia, and clubbing (in 25%). Cor pulmonale 2° to pulmonary fibrosis and hypoxaemia may develop.


may be normal. Clubbing, basal crepitations, and cor pulmonale are all recognized, depending on the severity of the resulting lung disease.


The diagnosis is one of exclusion, with no evidence of other organ involvement. The main differential diagnosis is Goodpasture’s syndrome, GPA, SLE, and microscopic polyarteritis.

  • Blood tests Microcytic, hypochromic anaemia, with low iron levels. ANCA, dsDNA, and anti-GBM antibodies should be negative

  • CXR May show transient patchy infiltrates, which worsen during an acute bleed. The apices are usually spared. Progressive disease leads to the development of reticulonodular infiltrates and a ground-glass appearance that is typically perihilar or in the lower zones. Hilar lymphadenopathy may be seen

  • PFTs kCO is transiently elevated during bleeding episodes (≥130% is abnormal), but this is only useful acutely. A restrictive defect with reduced kCO may develop with chronic disease

  • CT chest The changes seen are fairly non-specific, showing a diffuse bilateral infiltrate, with patchy ground-glass change

  • BAL (if done) contains haemosiderin-laden macrophages.


There is no specific treatment.

  • Steroids and immunosuppressive drugs (e.g. cyclophosphamide) may be of benefit during acute bleeding episodes but do not appear to affect the long-term outcome. There are no published data to guide the optimal timing of treatment during the course of disease

  • The iron deficiency anaemia responds to replacement therapy, and blood transfusion may be needed in severe bleeds

  • Lung transplant has been tried.

At routine clinic appointments

  • Check spirometry

  • Measure Hb and serum iron levels

  • Ask about increases in SOB or haemoptysis.


The prognosis is very variable, with some patients showing spontaneous remission, others progressing to death. The duration of disease in the literature ranges from death within days, following an acute severe illness, to survival with cor pulmonale associated with chronic disease after 20y.

Langerhans cell histiocytosis


Pulmonary Langerhans cell histiocytosis (LCH; previously termed pulmonary histiocytosis X or pulmonary eosinophilic granuloma) is a rare condition characterized by infiltration of the lung with histiocytes (Langerhans cells). Pulmonary LCH overlaps with a number of other conditions with similar pathological findings but diverse clinical features. These range from localized infiltration of a single organ (e.g. eosinophilic granuloma of bone) to systemic diseases affecting multiple organs (Letterer–Siwe disease, a multi-organ disease affecting infants and elderly, associated with poor prognosis; also Hand–Schueller–Christian syndrome). Although the isolated pulmonary form most commonly presents to chest physicians, pulmonary manifestations also commonly occur in the systemic forms of the disease.


Rare, it tends to affect young adults aged 20–40y. The vast majority of cases occur in current smokers, usually heavy smokers (tobacco and cannabis). May be more common in men, who tend to present at a younger age than women.


Langerhans cells are involved in antigen presentation and are characterized by the presence of well-demarcated cytoplasmic organelles called Birbeck granules on electron microscopy. The Langerhans cells seen in LCH appear to be monoclonal, although it is unclear if this represents a true neoplastic process. The antigen stimulus for activating Langerhans cells in the lung is unknown, although cigarette smoke is a possible candidate. Langerhans cells are typically organized into granulomata that are located in bronchiolar walls and subsequently enlarge and invade adjacent structures. This results in the radiological appearance of nodules that, at first, cavitate and then become cystic.

Clinical features

Typically exertional breathlessness and cough, sometimes with systemic symptoms (e.g. fever, weight loss). Pneumothorax occurs in at least 10% of patients and may be the presenting feature. Rib lesions may also give rise to chest pain. Around 25% of patients are asymptomatic. Examination is usually normal.


  • CXR Typically diffuse reticulonodular shadowing, sometimes with cystic change; upper and middle lobe predominance. May be normal

  • HRCT Diffuse centrilobular nodules, sometimes with cavitation, and thin- and thick-walled cystic lesions, reflecting lesions of varying age. These are interspersed with normal lung. Upper and middle lobe predominance; costophrenic angles are typically spared. Purely nodular or purely cystic appearances may occur. Unusual manifestations, such as single nodules or large airways involvement, are also described

  • PFTs Variable, ranging from normal to obstructive, restricted, or mixed patterns. Reduced gas transfer and exertional hypoxia are common

  • TBB may yield diagnostic material although is often unhelpful; risk of pneumothorax is unknown although may be increased. Surgical lung biopsy is often preferable

  • BAL Increased total cell counts and pigmented macrophages, reflecting simply the presence of cigarette smoking. Use of antibodies (e.g. OKT6) to detect Langerhans cells in BAL fluid is limited by poor sensitivity

  • Extrathoracic biopsy of involved sites (e.g. bone) may be diagnostic.


Usually based on the combination of clinical and HRCT findings: typically a young adult smoker with cysts and nodules on HRCT. Confirmation by surgical lung biopsy may be considered in atypical presentations such as the finding of solely nodular or cystic disease on HRCT. The appearance of purely cystic disease on HRCT may be confused with emphysema (where cysts lack walls) or LAM (where cysts are present uniformly in all regions of lung, including the costophrenic angles).


  • Severe PHT—may be seen in the absence of significant parenchymal lung involvement; direct disease involvement of pulmonary vessels has been described

  • Manifestations of systemic LCH—particularly diabetes insipidus from pituitary disease, skin involvement, lytic bony lesions, and rarely cardiac or GI disease

  • Lymphoma—may precede, complicate, or coexist with pulmonary LCH

  • Lung cancer—more common, probably as a result of cigarette smoking.


Treatment, other than smoking cessation, is often not required and may be entirely successful with resolution of radiographic abnormalities. Oral corticosteroids may be tried in symptomatic disease, although there is little evidence to support their use; they are usually administered for at least 6 months. Lung transplantation should be considered in patients with severe respiratory failure or PHT. Pulmonary LCH may recur in transplanted lungs. Experimental treatments, such as the use of IL2 and anti-TNF-α‎, may be of benefit in the systemic forms of LCH seen in children.


is variable. Spontaneous improvement is common, although later reactivation of disease may occur. A minority of patients deteriorate rapidly, with respiratory failure and death within months. Overall life expectancy is reduced, with median survival 12–13y from diagnosis. Death is most commonly due to respiratory failure. Poor prognostic factors include reduced FEV1, increased RV, and reduced gas transfer.

Further information

Sundar KM et al. Pulmonary Langerhans cell histiocytosis. Chest 2003;123:1673–83.Find this resource:

Patient support group. Unusual lung diseases

Lymphangioleiomyomatosis (LAM): clinical features

Definition and aetiology

A rare disorder characterized by abnormal proliferation of smooth muscle cells, affecting women of childbearing age, usually in their 30s. The disease is hormone-dependent so can occur in post-menopausal women on oestrogen replacement therapy.

  • Incidence of 1 in 1.1 million population

  • 40% of adult women with tuberous sclerosis (learning difficulties, subungual fibromas, seizures, facial angiofibromas, autosomal dominant inheritance or spontaneous mutation) develop pulmonary changes identical to those of LAM.


Abnormal proliferation of atypical smooth muscle cells (LAM cells) throughout the lung, airways, blood vessels, and lymphatics. There is nodular infiltration, which is initially subtle. Progressive growth causes lymphatic and airway obstruction, leading to cyst formation throughout the lungs. The infiltrating cells stain with antibodies to smooth muscle actin and desmin with HMB-45, an antibody that recognizes an epitope within the protein gp-100 in the melanogenesis pathway. LAM is caused by mutations in the tuberous sclerosis (TSC) genes, resulting in activation of the mTOR complex 1 signalling network. Inactivation of both alleles of TSC2 seems to be necessary.

Clinical features


  • 2° pneumothorax (in two-thirds of patients; occurs due to lung cystic change; recurrence is common)

  • Dyspnoea (in 42%) and cough (in 20%)

  • Haemoptysis (in 14%)

  • Chylothorax (in 12%, thoracic duct leakage as a result of lymphatic obstruction by LAM cells, may be bilateral).

Less common

  • Pleural effusion

  • Chest pain

  • Pulmonary haemorrhage (due to blocked blood vessels and increased intraluminal pressure).

Other organs affected


Angiomyolipoma, a benign tumour, occurs in 50% of LAM patients. Usually diagnosed on CT, these are mostly small and single but can be multiple and larger in tuberous sclerosis. Smaller tumours are usually asymptomatic, but larger ones can cause flank pain and bleeding into the renal tract. Treatment options include tumour resection or embolization. Nephrectomy is not usually required. Screening for these lesions is important, as it allows careful treatment planning in case they become symptomatic.


Lymphadenopathy due to lymphatic obstruction. Occurs in one-third of patients and is usually asymptomatic.


Lymphangioleiomyoma—a cystic mass that enlarges during the day and causes fullness and bloating.

Chylous ascites

can occur in the absence of chylothorax.


Cutaneous swellings, likely due to localized oedema.


May be normal. There may be pulmonary crepitations or signs of pleural effusion. Palpable abdominal masses may be present.


  • PFTs may be normal or show a predominantly obstructive pattern. Rarely restrictive. Decreased TLCO, with a normal or increased TLC

  • CXR may be normal. Lungs may appear hyperinflated, with reticular shadowing and septal lines due to obstructed lymphatics. There may also be a diffuse interstitial infiltrate

  • HRCT shows a characteristic appearance, with multiple cysts throughout the lung of varying size, which are usually small (<1cm) and thin-walled. The adjoining lung parenchyma is normal. There may be pleural effusions

  • CT abdomen to examine for presence of angiomyolipomas and other lymphatic involvement.

LAM: diagnosis and management


Consider particularly in young or middle-aged women with:

  • Recurrent pneumothoraces, especially those with pre-existing dyspnoea or haemoptysis

  • Cystic lung disease, airflow obstruction, or chylous pleural effusions

  • Angiomyolipomas or other retroperitoneal tumours

  • Tuberous sclerosis and respiratory symptoms.

The disease is easily missed in its early stages. The diagnosis can be made on the characteristic CT appearances or with open lung biopsy. TBBs may not be diagnostic. Large retroperitoneal abdominal lymph nodes can also be biopsied.


The course of LAM is variable. Treatment should be aimed at those who are symptomatic and declining.

  • Refer to a specialist centre (Nottingham City Hospital in the UK).

  • Diet Low-fat diet with medium-chain triglyceride supplementation may prevent chylothorax recurrence; no strong evidence for this, difficult diet to follow

  • Bronchodilators may improve airflow obstruction

  • Sirolimus shown to stabilize lung function and improve QoL and is recommended treatment

  • Hormonal manipulation with progesterone has been tried. It may be beneficial in reducing the decline in FEV1 and TLCO, particularly in patients with progressive disease, but there are no large studies. Tamoxifen and oophorectomy have also been tried

  • Avoid oestrogens, i.e. the OCP and HRT

  • Contraception An increase in symptoms and accelerated disease decline are reported in pregnancy. Use the progesterone-only pill

  • Pleural aspiration when required for pleural effusions. For recurrent effusions or chylothoraces, thoracic duct ligation or pleurectomy may be effective. Pleurodesis can be performed, but this is relatively contraindicated if future lung transplant is an option

  • Recurrent pneumothoraces Advise regarding flying and diving. Thoracic surgery may be necessary

  • Avoid air travel, if possible, due to risk of pneumothorax

  • Transplant Single (usually) or double lung, or heart-lung. LAM can recur in the transplanted lung

  • Stop smoking, as this accelerates the rate of decline

  • Influenza vaccine.


is very variable. The condition usually slowly progresses to respiratory failure. At 10y, 55% of patients have MRC grade 3 dyspnoea, 23% are on LTOT, and 10% are housebound. Survival: 70% of patients are alive at 10y, 33% are alive at 15y, and 25% are alive at 20y.

Further information

Henske EP, McCormack FX. Lymphangioleiomyomatosis—a wolf in sheep’s clothing. J Clin Invest 2012;122:3807–16.Find this resource:

Patient support group. Unusual lung diseases

Primary ciliary dyskinesia (PCD)

A rare genetic cause of chronic respiratory disease, usually encountered in adult respiratory clinics as a cause of bronchiectasis. Cilia are found in:

  • The whole length of the upper respiratory tract

  • Brain ventricles

  • Fallopian tube/ductus epididymis.

They are made up of dynein arms, with outer and inner connecting rings, and beat at 14 beats/s. Many gene defects have been identified in PCD, causing a number of cilial abnormalities.

Abnormal cilia do not beat normally, leading to reduced mucociliary clearance, microbiological colonization (which further inhibits cilial action), chronic infection, and the development of bronchiectasis.

The main aim following diagnosis in childhood is the prevention of chronic respiratory disease and bronchiectasis.

Clinical features

  • Autosomal recessive, >200 phenotypes

  • May present with neonatal respiratory distress

  • Situs inversus (in about 30%, as cilia determine the side of the organs. Random organ siting occurs with cilial dysfunction, hence the situs inversus of Kartagener’s syndrome)

  • Nasal blockage/rhinitis

  • Persistent wet cough in childhood

  • Hearing problems/history of glue ear/grommets in childhood

  • Clubbing and signs of chest disease are rare in childhood

  • Wheeze in 20%

  • Infertility due to immotile sperm (sperm tails have same morphological defect as the cilia and do not beat correctly)

  • In adults, the disease usually presents with the clinical signs of bronchiectasis: cough productive of purulent sputum, recurrent chest infections, intermittent haemoptysis.


Saccharin test (see Unusual lung diseases pp. [link][link]). Nasal NO is very low in PCD (possibly because NO mediates ciliary function); this is the most sensitive and specific screening test. Cilial biopsy via the nasal route. Cilia are examined by high-speed digital video where their beat frequency and pattern can be assessed, confirming the diagnosis. Most cases of PCD are diagnosed in childhood. There is an increased frequency in the children of consanguineous marriages.

Consider the diagnosis in:

  • Bronchiectasis

  • Situs inversus

  • Persistent upper and lower respiratory infection from early childhood

  • Infertility—♂ may present in infertility clinics.


A national service for the diagnosis of PCD was set up in 2007, with three centres—London (Royal Brompton), Southampton, and Leicester.

In adults, this includes the treatment of 2° bronchiectasis (see Unusual lung diseases pp. [link][link]), with:

  • Antibiotics

  • Physiotherapy

  • Vaccinations

  • Management of haemoptysis.

Further information

Bush A, Hogg C. Primary ciliary dyskinesia: recent advances in epidemiology, diagnosis, management and relationship with the expanding spectrum of ciliopathy. Expert Rev Respir Med 2012;6:663–82.Find this resource:

Patient support group. Unusual lung diseases

Pulmonary alveolar proteinosis (PAP): pathophysiology and clinical features

PAP, also referred to as alveolar lipoproteinosis, is a rare alveolar filling defect affecting around 3 per million people. There is a limited published literature: five reported case series of ≥10 cases, and only 410 total cases reported.


PAP is due to failure of alveolar macrophages to clear spent surfactant, leading to the filling of alveoli with a phospholipid proteinaceous material. It is thought that the defect has an autoimmune basis and, in the idiopathic form, is due to the presence of antibodies to granulocyte-macrophage colony-stimulating factor (GM-CSF), which cause inhibition of normal alveolar macrophage function, leading to abnormalities of surfactant homeostasis. Defects in GM-CSF signalling have been identified in animal models. Congenital disease is thought to be due to mutations in surfactant gene proteins. Other mechanisms for surfactant accumulation have also been identified:

  • Heavy dust exposure leads to surfactant hypersecretion, which exceeds the lungs’ normal clearance mechanism. Animal models have shown that this condition develops from endogenous lipoid pneumonia, with the accumulation of lipid-laden macrophages, which break down to release surfactant

  • Amphiphilic drugs, e.g. amiodarone, chlorphentermine

  • Lymphoma, leukaemia, and immunosuppression The mechanism is uncertain, but it is thought that the lipoprotein may be generated from degenerating alveolar cells.

Appearances similar to alveolar lipoproteinosis may also be seen in endogenous lipoid pneumonia resulting from bronchial obstruction and are described in surfactant-secreting alveolar cell carcinoma.


The alveoli are filled with a granular acellular eosinophilic PAS (periodic acid–Schiff)-positive deposit. Cholesterol clefts and large foamy macrophages may also be seen. The alveolar architecture is usually well preserved. Surfactant protein can be identified using immunohistochemistry. Electron microscopy shows multiple osmiophilic bodies, consistent with denatured surfactant.


  • Presents aged 30–50 (case reports in children and the elderly)

  • ♂:♀ ≈ 4:1

  • Increased incidence in smokers

  • Rare familial cases reported.

Clinical features

  • Typically presents with breathlessness and a non-productive cough. Examination may be normal, or crackles may be heard on auscultation. Clubbing in one-third

  • May present with superadded infection, causing an apparent acute onset of symptoms, in association with fever

  • Median duration of symptoms before diagnosis is 7 months

  • Opportunistic infection is the major complication, most commonly Nocardia species, fungi, and mycobacteria. This occurs due to impaired macrophage function and impaired host defence due to surfactant accumulation.

PAP: diagnosis and treatment


is usually made on the basis of a characteristic CT appearance, although other tests may also be useful.

  • Raised serum LDH

  • ABGs Hypoxia and increased A–a gradient

  • PFTs Restrictive defect, with reduced lung volumes and transfer factor

  • CXR Bilateral consolidation with thickened interlobular septa. Usually bilateral. The pattern is very variable and, in up to 50%, may be perihilar (bat-wing appearance)

  • CT appearance is characteristic, with airspace shadowing in a geographical distribution, alternating with areas of normal lung, the so-called ‘crazy paving’ pattern. This CT appearance is not specific to alveolar proteinosis but is also seen in lipoid pneumonia and bronchoalveolar cell carcinoma

  • BAL reveals milky washings. Identification of antibodies to GM-CSF in BAL washings is diagnostic. Cytological examination shows a granular extracellular deposit with foamy macrophages and cellular debris

  • Transbronchial/open lung biopsies when CT is not characteristic.


of choice is repeated therapeutic whole lung lavage, which should be performed at a specialist centre. There are no RCTs of this treatment, but there is evidence of efficacy in terms of subsequent improvement of symptoms, physiology, and radiology.

  • The indication for whole lung lavage is usually breathlessness, limiting activities of daily living

  • The procedure is done under general anaesthesia using 100% O2 and one-lung ventilation using a double-lumen tube. Repeated warm saline lavage using a closed circuit continues until the bronchial washing returns are clear—this may take up to 40L lavage. One or both lungs may be treated at a time

  • The response is variable—some patients need only one treatment; others may need multiple treatments, and about 10% fail to respond

  • May be done on bypass if the patient is very hypoxic

  • Characteristic milky lavage fluid is obtained

  • Granulocyte colony-stimulating factor (SC injections) is a novel treatment option (only phase II studies, no RCT yet), which may prevent progression of disease

  • There is no benefit from treatment with steroids, and they may exacerbate opportunistic infections.


with whole lung lavage is generally good. Spontaneous remission occurs in one-third; one-third remains stable, and one-third progresses to respiratory failure and death. There are reports of progression to pulmonary fibrosis (which may be a coincidental occurrence).

Further information

Patel SM et al. Pulmonary alveolar proteinosis. Can Respir J 2012;19:243–5.Find this resource:

Patient website. Unusual lung diseases (USA).

Pulmonary arteriovenous malformations (PAVMs): aetiology and diagnosis


  • PAVMs are abnormal blood vessels replacing normal capillaries, making a direct low-resistance connection between the pulmonary arterial and systemic venous circulations. They vary in size, from tiny clusters of vessels (telangiectasia) to larger, more complex aneurysmal-type sacs

  • The disorder is rare, affecting 1 in 15, 000–24, 000

  • Several genetic susceptibility loci have been identified on Chr 9 and Chr 12. One identified mutation is in the endoglin gene. This modulates signalling via the TGF-β‎ family of growth factors. This gene is also implicated in the development of PPH

  • Subjects with significant PAVMs have low pulmonary vascular resistance, a low mean PAP, and a high cardiac output—due to long-standing adaptive mechanisms to the effects of the shunt, in addition to vascular remodelling effects

  • Most patients present post-puberty, as AVMs probably develop at this time. They probably grow throughout life, especially during puberty and in pregnancy. They may rarely regress spontaneously.


  • Most patients present with an abnormal CXR, classically showing a smooth, rounded intrapulmonary mass, with draining or feeding vessels

  • Mild hypoxaemia An AVM is a direct communication between the pulmonary artery and pulmonary vein. Blood therefore bypasses the pulmonary capillary bed, with reduced oxygenation, which poorly corrects with supplementary O2

  • Orthodeoxia is desaturation on standing, due to an increase in blood flow in the dependent lung areas. 70% of PAVMs are basal, hence the desaturation seen

  • CT identifies all AVMs and can determine those suitable for embolization. Contrast is not required

  • Patients may present with the complications of a PAVM, particularly bleeding or peripheral abscess formation. The absence of a normal filtering capillary bed means small particles can reach the systemic circulation, leading to sequelae, particularly in the cerebral circulation—strokes and cerebral abscesses. These abnormal vessels are also at risk of rupture.

Shunt quantification

  • 100% O2 rebreathing study, a non-invasive method of shunt quantification

  • 99mTC perfusion scan, a tracer study; the size of the shunt can be assessed from the proportion of radiolabelled macro-aggregates reaching the systemic circulation, compared with the total number injected. In a normal study, aggregates accumulate in the kidneys

  • Contrast echo to measure the circulatory transit time of injected echo contrast

  • Angiography at specialist centre only

  • In normal individuals, the anatomical shunt is <2–3.5% of the cardiac output (due to post-pulmonary drainage of bronchial veins into pulmonary vein and drainage into the left atrium).

Clinical features

  • Asymptomatic (50%)

  • Dyspnoea

  • Haemoptysis (10%), probably due to additional bronchial telangiectasia, which can also cause haemorrhage into bronchi or the pleural cavity

  • Chest pain (12%); aetiology is uncertain

  • Clubbing

  • Cyanosis

  • Orthodeoxia

  • Vascular bruits

  • Telangiectasia; 80% of PAVM patients have HHT, and their families should be screened because of the risk of stroke (see Unusual lung diseases p. [link])

  • May present with acute stroke, with focal neurological signs.

PAVMs: management and complications



is usually done with coils, which generate local thrombin, leading to cessation of blood flow in AVM feeding vessels. This results in a reduction in the right-to-left shunt and improvement in hypoxaemia and should be done by an expert in a specialist centre only. The small risk of neurological sequelae and angina/arrhythmias is reduced with operator experience.

60–70% of patients are left with a small persisting shunt following treatment and retain a small risk of abscess formation. Patients are therefore given prophylactic antibiotics for dental and surgical procedures (ensure the patient has a MedicAlert card).

Surgical resection

may be more appropriate than embolization in some cases.

Antiplatelet therapy

(rarely) in individual cases, if ongoing transient ischaemic attacks.


is not advised, as there is no increased survival benefit over medical treatment.


the majority of patients with PAVMs have HHT, and so screening of family members is important.


all patients need regular follow-up, with shunt assessment post-surgical resection or embolization, as removal of one shunt may unmask or provoke the development of others.

♀ patients

should be advised to defer pregnancy until completion of formal assessment because of the risks of growth and rupture of PAVMs in pregnancy (see Complications).


  • PAVM patients never die of respiratory failure in the absence of additional respiratory disease

  • All patients are at risk of stroke and cerebral abscesses

  • Transient ischaemic attack/stroke (in 25%) due to rupture of abnormal capillaries in aneurysms

  • Abscess (in 10%) due to paradoxical emboli, through the right-to-left shunt, and the absence of a filtering capillary bed.


is associated with an increase in size of AVMs, and new ones may develop, with potentially catastrophic consequences. Careful shunt assessment is therefore needed prior to pregnancy, with contraceptive advice prior to specialist assessment. Close liaison between the specialist centre and obstetric team is paramount. AVMs may need embolization in the third trimester to allow safe delivery.

Further information

Shovlin CL. Hereditary haemorrhagic telangiectasis: pathophysiology, diagnosis and treatment. Blood Rev 2010;24:203–19.Find this resource:

Recurrent respiratory papillomatosis

These are essentially warts of the upper respiratory tract, caused by the human papillomavirus (HPV 6 or 11). The virus infects epithelial cells and mucous membranes, similar to that seen in cutaneous and anogenital infection. The infection is most commonly acquired during ororespiratory exposure from the mother during vaginal delivery and typically presents in childhood from 6 months onwards, with signs and symptoms of URTI. It may also present for the first time in adulthood. It is associated with HLA-DR3 and with sexual transmission in adults. Recurrent respiratory papillomatosis is rare (2 per 100, 000), but oral HPV infection is common.

Clinical course

This is variable.

  • May remit spontaneously

  • Progressive voice loss and airway obstruction

  • Most cases are confined to the larynx, although up to 25% of patients subsequently develop extralaryngeal spread to the bronchial tree

  • 1% have malignant change to squamous cell carcinomas.


  • Surgical excision to maintain airway patency

  • Laser therapy—but potential problems of thermal injury, stricture formation, and spread of papillomas

  • PDT reduces recurrence rate, using oral or IV photosensitizing agent, then a laser to destroy photosensitive tissue

  • Microdebrider is now used more commonly

  • Medical treatment—interferon, aciclovir, ribavirin, isotretinoin, and methotrexate have all been tried

    • Interferon alfa as a daily SC injection leads to complete remission in 30–50%, and partial resolution in 30%. One-third recur when treatment is stopped. Adverse reactions are common: flu-like symptoms, deranged LFTs, leucopenia, and alopecia

    • Cidofovir is a nucleoside monophosphate analogue and inhibits viral polymerase. It is given as an intralesional injection. Theoretical side effects include nephrotoxicity and neutropenia but have not been seen in practice.

Further information

Pian T et al. Safety of intralesional cidofovir in patients with recurrent respiratory papillomatosis. Eur Arch Otorrhinolaryngol 2013;270:1679–87.Find this resource: