Computed tomography appearances of the lung parenchyma in pulmonary hypertension

Abstract

Computed tomography (CT) is a valuable tool in the workup of patients under investigation for pulmonary hypertension (PH) and may be the first test to suggest the diagnosis. CT parenchymal lung changes can help to differentiate the aetiology of PH. CT can demonstrate interstitial lung disease, emphysema associated with chronic obstructive pulmonary disease, features of left heart failure (including interstitial oedema), and changes secondary to miscellaneous conditions such as sarcoidosis. CT also demonstrates parenchymal changes secondary to chronic thromboembolic disease and venous diseases such as pulmonary venous occlusive disease (PVOD) and pulmonary capillary haemangiomatosis (PCH). It is important for the radiologist to be aware of the various manifestations of PH in the lung, to help facilitate an accurate and timely diagnosis. This pictorial review illustrates the parenchymal lung changes that can be seen in the various conditions causing PH.

Introduction

Pulmonary hypertension (PH) is defined as a mean pulmonary artery pressure ≥25 mm Hg, measured by right heart catheterisation,^1,2 although the recent 6th World Symposium on Pulmonary Hypertension have suggested updating this definition, using a cut-off of 20 mm Hg.³ PH can manifest as a complication of many pathophysiological conditions of both cardiac and respiratory origin, and is becoming an increasingly common health issue worldwide.⁴ The development of this complication is almost invariably associated with a poor prognosis and increased mortality.

PH is a disease of the elevated pulmonary arterial pressure with a variety of underlying aetoiologies, which are classified into five groups as per the joint guidelines of the European Society of Cardiology and European Respiratory Society,² Table 1. The groups are regularly updated as the understanding of the distinct patient phenotypes improves. An appreciation of the classification is essential, as some of the groups have targeted management strategies.⁵ These aetiology-based groups consist of pulmonary arterial hypertension and pulmonary veno-occlusive disease (Group 1);left heart dysfunction (Group 2); lung disease and/or hypoxia (Group 3); chronic thromboembolic disease (Group 4); and miscellaneous conditions (Group 5), such as sarcoidosis and pulmonary histiocytosis, Figure 1.

Table 1.

The Classification and Associated Parenchymal Changes in Pulmonary Hypertension

	CT Parenchymal Changes
Group 1
Pulmonary Arterial Hypertension
- Idiopathic	Often normal. Ground glass nodules in a random distribution and centrilobular pattern
- Scleroderma	May be normal. Ground glass nodules in a random / central distribution and centrilobular pattern. Dilated oesophagus.
- PVOD / PCH	Ground-glass opacification/nodularity, mediastinal lymphadenopathy, interlobular septal thickening
Group 2
Left heart dysfunction	Ground glass change, interlobular septal thickening, atelectasis secondary to pleural effusions, dilated LA
Group 3
Hypoxia
- COPD	Centrilobular/paraseptal/pan-acinar emphysema with upper lobe predominance
- ILD(general features)	Peripheral reticular opacification, reticular ground-glass, traction bronchiectasis, fibrosis, honeycombing
- Hypersensitivity Pneumonitisa	Air-trapping, centrilobular nodules, bronchocentric, fibrosis, traction bronchiectasis, chronic changes 1/3 upper zone, 1/3 lower zone, 1/3 uniform
-Scleroderma	NSIP >UIP (air-trapping not typical)
Group 4
Chronic thromboembolic disease	Geographic mosaic attenuation, peripheral scars secondary to infarction, reduced calibre vessels in low attenuating lung, dilated PAs in higher attenuating lung, ± bronchiectasis
Group 5
Miscellaneous conditions
- Sarcoidosis	Peri-lymphatic and subpleural of nodules, upper/middle zone dominance, peri-hila ‘streaming’ fibrosis
- Langerhan’s Cell Histiocytosis	Micro or macro-nodules, costophrenic angle sparing, variable bizarre morphology cysts

COPD, Chronic obstructive pulmonary disease; CTEPH, Chronic thromboembolic pulmonary hypertension; ILD, Interstitial Lung Disease; PCH, Pulmonary capillary haemangiomatosis; PVOD, Pulmonary veno-occlusive disease.

^aCT features may be indistinguishable from other forms of ILD in the chronic phase

Figure 1.

Schematic representation of the pulmonary circulation, illustrating the normal pulmonary vascular bed and the site of pathology in each of the pulmonary hypertension subgroups. CTEPH = chronic thromboembolic pulmonary hypertension, Misc. = Miscellaneous, PAH = pulmonary arterial hypertension, PCH = pulmonary capillary haemangiomatosis, PVOD = pulmonary veno-occlusive disease.

Although chest radiography and echocardiography are the main imaging modalities in the screening of patients for PH,⁶ CT may still be the first investigation to raise the possibility of the diagnosis. It is, therefore, important that the radiologist considers PH in patients presenting with breathlessness and/or reduced gas transfer. CT also plays an important role in the diagnostic workup and assessment of patients.⁶ CT features common to all groups of PH include pulmonary arterial dilatation, right ventricular dilatation, right ventricular thickening, and interventricular septal bowing, Figure 2a/b. These signs should be interpreted in the context of the CT findings within the lung parenchyma. Another sign of PH, in all PH groups, is dilatation of the segmental pulmonary arteries. This is specific for PH when the segmental artery is greater in size than the corresponding bronchus in three or more lobes.⁷ This ‘reverse bronchiectasis sign’ can, in our opinion, be more conspicuous when viewed on lung windows.

Figure 2.

Pulmonary Hypertension. Axial CT demonstrating main pulmonary artery: aortic ratio >1.1 (a). Axial CT (b) demonstrates an RV:LV ratio of >1.0. The RV:LV ratio is calculated as the maximal axial diameter of the right ventricle compared to the maximal axial diameter of the left ventricle. Right ventricular hypertrophy can be subjectively assessed by examining for right ventricular wall thickening (black arrow) and increased RV trabecular. Intraventricular bowing (dotted arrow) and a small pericardial effusion are also present.

Lung parenchymal changes can provide clues to the aetiology of the PH, which in turn may dictate whether referral to specialist centres and further treatment is warranted. In this review, we outline these parenchymal CT features.

Group 1: Pulmonary Arterial Hypertension

Group one is pulmonary arterial hypertension (PAH) and its subtypes. PAH is rare but when present is most likely to be due to idiopathic PAH or PAH associated with connective tissue disease.⁴ All diseases within this group share the same underlying pathophysiology, i.e. a progressive vasculopathy affecting the precapillary arterioles that lead to a reduction in lumen patency and a rise in pulmonary vascular resistance, although the precise trigger for this process can vary between diseases. The incidence of PAH is estimated between and 1.1 and 7.6 cases per million population.^8,9 This group is especially important to identify, as these patients can respond well to vasoactive PH-specific treatment that can improve morbidity and mortality substantially.⁵ Other causes of PAH include familial cases, portal hypertension, HIV and congenital heart diseases. Internationally schistosomiasis is thought to be the largest single cause of PH.¹⁰

The lungs are often normal in idiopathic PAH but ground glass nodules can be seen in Figure 3. The exact aetiology of this is uncertain, but it likely reflects a more complex PAH, where pathologically there is disease in the post-capillary venules as well as the pre-capillary arterioles. In some cases, centrilobular nodules in idiopathic PAH have been attributed to cholesterol granulomas.¹¹ They occur in 33–42% of patients, are often centrilobular but can occur in a random cranio-caudal and central-peripheral distribution.^12,13 These ground glass nodules are not infrequently mistaken for other pathology, including respiratory bronchiolitis interstitial lung disease and sub-acute hypersensitivity pneumonitis.

Figure 3.

Idiopathic PH (IPAH). Multiple centrilobular diffuse ground glass nodules (circle).

Also included in Group one are pulmonary veno-occlusive disease (PVOD) and pulmonary capillary haemangiomatosis (PCH), rare subtypes of PAH. In these conditions, the pathology is centred on the post-capillary venules (rather than the pre-capillary arterioles). PVOD and PCH are associated with a much worse prognosis than other causes of PAH,¹⁴ and the only effective treatment is transplant. We have previously reviewed PVOD in detail,¹⁵ and it is important to emphasise that the early identification of these patients is essential to allow for attempts at appropriate management. Furthermore, if confused for PAH, the traditional PAH vasoactive therapy can lead to fatal pulmonary oedema.^16,17

The radiologist should be aware of the triad of features seen in PVOD and PCH, namely, ground glass nodules, mediastinal lymphadenopathy and interlobular septal thickening.¹² These features are all significantly more likely to be present in PVOD compared to idiopathic PAH. The presence of ground glass nodular opacification is a useful feature, which is present in 87% of PVOD patients compared to 33% of idiopathic PAH patients,¹² Figure 4. When present, they are likely to be more conspicuous than seen in idiopathic PH, but are similarly centrilobular and random in distribution.^12–14 The second feature of the triad is the presence of septal lines. This is common in PVOD and again more conspicuous than the occasional areas of septal thickening seen in idiopathic PAH.^12,14 Although the presence of interstitial septal lines in PVOD and PCH can resemble pulmonary oedema, the left atrium will tend to be of normal size (suggesting the abnormality is not due to left heart disease). Finally, the presence of lymphadenopathy is a specific sign when present, and is a strong indicator of PVOD, rarely seen in PAH,^12,14 Figure 5.

Figure 4.

Pulmonary veno-occlusive disease. Widespread ground glass nodules (circles) in two patients with PVOD.

Figure 5.

Pulmonary capillary haemangiomatosis. Pre-vascular lymphadenopathy (black arrow) and diffuse bilateral ground glass opacification.

PAH can occur in conjunction with connective tissue disease, most commonly scleroderma, in which 8–12% of patients are affected.^13,18,19 PAH due to scleroderma will often manifest with normal lung parenchyma, but again ground glass nodules and septal lines may be seen. These features are more commonly associated in scleroderma with PAH (than in scleroderma without PAH) and may also reflect a more severe form of disease,^20,21 with pathology also partly involving the post-capillary venules as well as the pre-capillary arterioles, Figure 6.The nodules also tend to be centrilobular but may be either randomly distributed or be more centrally located than seen in idiopathic PH. Note should also be made that scleroderma and PVOD can co-exist.¹⁵ Separately, scleroderma can also lead to PH secondary to left heart disease (Group 2) or secondary to an interstitial parenchymal process (Group 3 – discussed below).

Figure 6.

Scleroderma. Subtle ground glass ’texture’ throughout the lung parenchyma (white arrows). Note also the dilated oesophagus (black arrow).

Another cause in Group one is partial anomalous pulmonary venous drainage (PAPVD). This diagnosis can be made on CT, however it may be frequently overlooked.²² This condition is congenital and leads to abnormal drainage of pulmonary venous blood. Rather than following the normal drainage pattern into the left atrium, one or more pulmonary veins drain into the systemic circulation, for example, SVC, IVC or right atrium. If PAPVD is demonstrated, it is also important to look for an associated atrial septal defect.

In summary, the lung parenchyma on CT is often normal in Group one pathologies, particularly in cases of idiopathic PAH. However, it is important to look for parenchymal features that may indicate a diagnosis of PVOD or PCH as this will significantly alter patient management. It is not possible to distinguish between PAH, PVOD or PCH with invasive pressure measurements; it is possible on lung biopsy, but this procedure is high risk in the presence of PH. Consequently, CT plays a vital role.

Group 2: Pulmonary hypertension associated with left heart dysfunction

The most common cause of PH in the developed world is left heart dysfunction,¹² which may be due to atrial, ventricular or valvular dysfunction. However, the overall leading cause is ischaemic heart disease.²³ PH is estimated to occur in approximately 70–80% of patients with congestive cardiac failure^24,25 and up to approximately 75% of patients with aortic stenosis.^26,27 It is more likely in patients with advanced heart failure.²⁸ PH secondary to left heart disease is also seen in Heart Failure with Preserved Ejection Fraction (HF-PEF), which can be challenging to diagnose clinically and, therefore, may not be highlighted as a possibility on the CT request. In PH associated with left heart dysfunction, signs of interstitial oedema may be evident, including ground glass opacification, interlobular septal thickening and pleural effusions, Figure 7. As previously mentioned, these appearances can be similar to those of PVOD and PCH. Auxiliary findings such as left atrial dilatation, left ventricular dilatation and coronary calcification should also be assessed, and in conjunction with echocardiography can aid diagnosis. Analysis of the left atrial area on CT has been shown to correlate with pulmonary arterial pressures on right heart catheterisation.²⁹ Vasoactive PH-specific therapy can precipitate pulmonary oedema in these patients, as a result of increased flow into the pulmonary arteries and should be avoided in this patient group. Given this, these patients do not warrant referral to an expert PH centre.

Figure 7.

Left heart dysfunction. Bilateral pleural effusions, coronary artery calcification (white arrow) and left atrial dilatation are seen on mediastinal windows (a), while lung windows (b) demonstrate septal lines (white arrow).

Group 3: Pulmonary hypertension due to lung diseases and/Or Hypoxia

In this subgroup, the radiologist will most commonly encounter chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD). Other causes include sleep disordered breathing and developmental abnormalities. Group three also includes patients with mixed restrictive and obstructive patterns of disease such as combined pulmonary fibrosis with emphysema (CPFE).

The rates of PH in patients with COPD have been estimated from 18 to 50%^30,31 and are associated with increased COPD exacerbations and hospitalisation.³² COPD can manifest as a wide range of morphological phenotypes on CT images.³³ Centrilobular emphysema can range from scattered areas of lucency separated by large areas of normal lung parenchyma to widespread centrilobular lucencies, with hyper expansion of the secondary pulmonary lobules and gross architectural distortion, Figure 8. In patients with COPD, the use of aorta to main pulmonary artery diameter ratio may also be more effective than the absolute measurement of the main pulmonary artery (MPA).³⁴

Figure 8.

Emphysema. Axial slice through the upper lobes demonstrates confluent emphysema with diffuse centrilobular lucencies and intervening regions of normal lung parenchyma.

Interstitial lung disease can manifest as a variety of parenchymal lung changes dependent upon the aetiology. In a general clinical setting of interstitial lung disease patients, Idiopathic Pulmonary Fibrosis (IPF) has been demonstrated to be the most common cause of PH.³⁵ Usual Interstitial Pneumonia (UIP) is the radiological pattern associated with the clinical diagnosis of IPF, although a UIP pattern can also be seen in other conditions, including connective tissue diseases, chronic hypersensitivity pneumonitis and asbestosis.³⁶ In patients with advanced ILD, the rate of PH has been estimated to range from 29 to 79%.^37,38 These patients have an increased mortality risk.^39–41 The CT appearances of a typical UIP pattern are subpleural basal honeycombing with a craniocaudal gradient of fibrosis.,³⁶Figure 9. Traction bronchiectasis, tractionbronchiolectasis, architectural distortion and volume loss (evident by abnormal positioning of the fissures) will also be demonstrated. If the CT features are not a typical UIP pattern, the overall pattern of disease may also be classified as probable UIP, indeterminate for UIP or an alternative diagnosis – classification and descriptors widely published elsewhere.

Figure 9.

Idiopathic Pulmonary Fibrosis (IPF). Subpleural basal honeycombing, reticulation and traction bronchiectasis.

It is also noteworthy that, when assessing patients with ILD for CT features of PH, some studies have suggested that the ratio of the MPA diameter to the aortic diameter, rather than absolute MPA diameter, is a superior sign of PH.^42,43 However, a larger study has shown that the MPA diameter is effective in the diagnosis of PH in both patients with ILD and without ILD, and correlates with mean pulmonary artery pressure.⁴⁴ The MPA can change enlarge in patients with acute exacerbations and can also enlarge over time.^45,46 Therefore an enlarged MPA can help identify PH in patients with ILD, but the degree of dilation is not necessarily indicative of the severity of PH.

Scleroderma can manifest in Group one as a primary vasculopathy (PAH), but can also manifest in Group three as an interstitial parenchymal process. The pattern of ILD in scleroderma is most commonly non-specific interstitial pneumonia (NSIP) but can also be UIP, Figure 10. Importantly, if ground glass nodules are seen in a patient with scleroderma, this may represent part of the primary vasculopathy and not ‘early interstitial change’. The ground glass nodules in PAH will be centrilobular, as opposed to peripheral subpleural basal reticular ground glass changes often encountered with NSIP.

Figure 10.

Scleroderma and NSIP. Axial slice through the lower lobes demonstrates peripheral reticular ground glass change (arrow) with some traction bronchiolectasis and subpleural sparing.

The exact mechanism by which lung disease causes PH is unclear but is likely to be multifactorial and due to a combination of pulmonary vasculature obliteration and hypoxia-induced vasculopathic changes. Again PH-specific therapy is not indicated in this disease group where it can be ineffective and, in some cases, worsen hypoxia by causing shunting through non-ventilated areas of lung. Given this, it is recommended that patients with likely lung disease-related PH are not routinely referred to an expert PH centre.

Group 4: Chronic thromboembolic pulmonary hypertension

Chronic thromboembolic PH (CTEPH) is an important diagnosis for the radiologist to be aware of. Radiology may be pivotal: if a CTPA is falsely reported as ‘negative for CTEPH’, the condition may not be considered again. There is thought to be a significant under diagnosis, with 71–93% of patients worldwide not identified.⁴⁷ Undiagnosed it may be fatal, yet it is a potentially treatable and curable cause of PH with pulmonary endarterectomy and medial therapy both used.⁴⁸ Following an acute pulmonary embolism, the incidence of CTEPH at 2 years is thought to be approximately 4%.⁴⁹ However, not all patients with CTEPH will have a history of a preceding acute pulmonary embolism and the radiologist should be alert to the diagnosis from a range of referrers.⁵⁰

Chronic thromboembolic disease (CTED) is characterised radiologically by pulmonary arterial webs and occlusions reflecting incompletely cleared thrombotic material. This can lead to PH and progressive right ventricular failure, which is termed CTEPH. The lung parenchyma may demonstrate mosaicism and peripheral infarcts, Figure 11. Acutely infarcts often manifest as peripheral wedge-shaped areas of increased opacification with a broad pleural base and a truncated apex.⁵¹ The natural history of pulmonary infarcts spans a spectrum from the classic wedge-shaped infarcts, to large areas of peripheral ground glass change and eventually irregular peripheral scarring. Infarcts have been reported to be a common finding in CTEPH, occurring in up to 72% of patients.^52–54 If areas of infarction become cavitary, one must consider the possibility of secondary infection.

Figure 11.

Chronic thromboembolic pulmonary hypertension. Chronic pulmonary infarcts in two different patients. In CTEPH, chronic pulmonary infarcts may result in the colloquially termed ‘scruffy lung’ with areas of peripheral scarring.

Mosaicism may manifest in CTEPH as areas of hypoattenuating lung tissue (Figure 12). Like mosaicism in small airways disease, the pathology resides within the regions of low attenuation. However, the mechanism is due to ‘vascular’ rather than ‘airways’ pathology. In CTEPH, there are regions of lung with decreased perfusion (and hence attenuation) secondary to pulmonary arterial occlusion. As a result, the vessels within these regions are reduced in calibre.⁵⁵ In contrast, within the adjacent areas of increased attenuation, dilated segmental/subsegmental pulmonary arteries may be visualised (‘reverse bronchiectasis sign’) secondary to PH, Figure 12. This mosaicism is anecdotally often ‘large and geographic’, in a peripheral and segmental location with sharp margins, rather than the more lobular mosaicism seen in constrictive small airways disease.

Figure 12.

Chronic thromboembolic pulmonary hypertension. Mosaic lung in two different patients. Note the reduced calibre vasculature in the areas of low attenuation (white circle) and the differential size of the segmental pulmonary arteries. Some are enlarged due to pulmonary hypertension (white arrow), whereas others small due to occlusive disease (dotted arrow).

The radiologist should avoid diagnosing CTEPH-related mosaicism on an expiratory scan (evident by inward bowing or flattening of the posterior tracheal membrane). Mild mosaicism on expiratory studies can be considered normal, whereas more conspicuous change can be the result of air-trapping seen in conditions such as constrictive small airways disease or hypersensitivity pneumonitis.

Bronchiectasis is thought to occur in up to 64% of patients with CTEPH, possibly secondary to hypoxia.^56,57 However, in our experience, this is a less frequent occurrence. CT appearances of CTEPH can be mimicked by other disease processes, notably large vessel vasculitis causing concentric narrowing of the pulmonary arteries or peripheral pruning of the pulmonary arterial branches.⁵⁸

Other more novel imaging techniques in the evaluation of patients with CTEPH are dual energy CT and CT lung subtraction iodine mapping. These techniques allow for the perfusion of the pulmonary parenchyma to be evaluated by analysing iodine distribution throughout the lungs and are additive to the conventional CT assessment of the parenchyma, essentially providing an anatomical and functional assessment in one study.⁵⁹ In patients with CTEPH, there may be areas of differential perfusion throughout the lung parenchyma due to arterial obstruction, which can be quantified and used to aid in the diagnosis.⁶⁰ This may be especially useful in ‘distal CTEPH’ where webs and occlusions reside in vessels beyond the proximal segmental level.

Group 5: Pulmonary hypertension associated with miscellaneous conditions

A diverse collection of medical conditions that can result in PH are placed in Group five. Relative to the lung parenchyma, and perhaps the most commonly encountered by radiologists, are sarcoidosis and Langherhan’s cell histiocytosis (LCH). Other causes of PH within this category include congenital metabolic disorders, haematological disorders and tumoural thrombotic microangiopathy.

PH is common in patients with advanced sarcoidosis, estimated at 74%, and is a predictor of poor outcomes.^61,62 There are a number of mechanisms by which sarcoidosis cause PH including destruction of the distal capillary bed by fibrosis, vascular involvement from specific granulomatous changes, pulmonary constriction by vasoactive products and extrinsic compression of the pulmonary arteries by mediastinal adenopathy/fibrosis.

Sarcoidosis has been named as the great mimicker, considering the myriad of manifestations associated with this disease. This moniker is quite apt in the context of lung parenchymal changes in patients with sarcoidosis and there are a wide variety of potential disease manifestations in the lung.⁶³ The typical parenchymal findings associated with sarcoidosis are peri-lymphatic nodules, found in a peri-bronchovascular and subpleural distribution Figure 13^64,65. There is also an upper to mid-lung predilection in most patients^64,65 and air-trapping is a common CT feature, in up to 95% of patients.^66,67 Atypical features include in order of frequency: patchy ground glass opacification; macro-nodules; interlobular septal thickening; airspace consolidation; cavitary lesions and miliary nodules.⁶³ In advanced disease, fibrotic parenchymal changes are evident, with traction bronchiectasis, architectural distortion and paracicatricial emphysema.^63–65 This advanced fibrotic sarcoid is usually centred on the bronchovascular bundles and can be seen ‘streaming from the hila’ Figure 13⁶⁴

Figure 13.

Sarcoidosis. Multiple perilymphatic bronchovascular nodules (a) and end-stage pulmonary sarcoidosis demonstrating fibrosis ‘streaming from the hila’ (b)

Langerhan’s cell histiocytosis (LCH) is a disease predominantly of young adults, strongly associated with smoking and harbours a relatively poor prognosis.^68–70 LCH is frequently associated with PH, occurring in 92–100% of patients with advanced disease.^69,70 Pulmonary manifestations of LCH are characterised by a nodular pattern of disease in the early stages, which can be micro- or macro-nodular, with classical sparing of the costophrenic angles, Figure 14.^71,72 Later in the disease cystic lung disease is predominant, with the characteristic nodules, moving through a cavitary phase and later becoming purely cystic.^72,73 These cysts have been described as bizarre, with varying sizes, shapes and wall thickness.⁷²

Figure 14.

Langerhans Cell Histiocytosis. Microcystic form with small lung cysts (arrow) and scattered random small nodules (circle).

Conclusion

PH is an important diagnosis that all radiologists should consider on CT imaging, particularly CT pulmonary angiography. The changes within the lung vary depending on the cause of PH. This review has outlined the differing parenchymal features seen on CT. Knowledge of these parenchymal features may help the radiologist appropriately identify the cause of PH.