Histology of Pulmonary and Bronchiolar Disorders in Connective Tissue Diseases

Cecilia Brambilla, MD; Alexandra Rice, FRCPath; Andrew G. Nicholson, FRCPath

Disclosures

Semin Respir Crit Care Med. 2019;40(2):147-158. 

In This Article

Disorders by Anatomic Compartments

Airways

As stated above, larger airways are rarely biopsied, other than to look for specific features such as cartilage damage in relapsing polychondritis (RP) or the presence of amyloidosis. Surgical lung biopsies are sometimes undertaken to assess the small airways, especially in children where HRCT is less specific, and pathologists should report the various findings in a systematic fashion. Most are nonspecific, with inflammation being either acute, acute and chronic, or chronic, but these should be documented to consider their various clinical associations. Likewise, fibrosis and fibroblastic changes can be seen in many disorders, but it is important for the reports to distinguish between the loose buds of intraluminal granulation tissue that indicate OP and the more established fibrosis of constrictive obliterative bronchiolitis. Elastin van Gieson (EVG) staining is particularly useful in highlighting the damaged airways. The presence of other features such as granulomatous inflammation and eosinophilia also require documentation so the relative likelihood of the changes being CTD-related can then be assessed via multidisciplinary team review.

Spaces preclude the review of all CTDs that affect the airways, but they are frequently involved in rheumatoid arthritis (RA) and SS, with RP also being a primarily airway-centered disease.

In RA there is a wide spectrum of manifestations ranging from bronchiectasis in large airways to nonspecific chronic bronchiolitis, follicular bronchiolitis, constrictive bronchiolitis obliterans, and bronchocentric granulomatosis[1] in the smaller airways (Figure 1). RA often manifests as systemic lymphoid hyperplasia that in the lung causes expansion of the bronchial MALT, with ensuing follicular bronchiolitis causing airway obstruction through compressing the lumens, leading to mainly obstructive lung function and bilateral reticulonodular opacities on HRCT.

Figure 1.

Airways. (A) Follicular bronchiolitis: airway obstruction through compression of the lumens by lymphoid tissue; (B) Constrictive obliterative bronchiolitis: established fibrosis and granulation tissue laid in concentric circles that narrows the airway lumen until it disappears.

Constrictive obliterative bronchiolitis consists of an autoimmune-driven progressive destruction of bronchial respiratory epithelium replaced by granulation tissue laid in concentric circles that narrows the airway lumen until it disappears. It is characterized by the absence of parenchymal infiltrates on chest radiographs, mosaic attenuation on HRCT, poor responsiveness to therapy, and high mortality rates.[2]

Bronchocentric granulomatosis shows palisading granulomatous inflammation destroying and replacing the walls of bronchi or bronchioles, occasionally associated with eosinophils (although those are more prominent when associated with fungal infection).

In SS the same pathogenic mechanism that leads to destruction of lacrimal and salivary glands causing dryness of eyes and mouth (sicca syndrome) applies to submucosal tracheobronchial seromucinous glands. It has been reported that 10 to 20% of patients with SS have pulmonary involvement, either involving the airways, alveolar interstitium, or both.[3] Morphologically there is a heavy lymphoid infiltrate with germinal centers destroying glandular acini, causing impaired airway clearance that leads to bronchitis, bronchiolitis, bronchiectasis, and pneumonia, the last of these likely secondary to the proximal airway damage.

RP is a rare multisystemic disease widely accepted as a complex autoimmune disorder affecting proteoglycan-rich structures and cartilaginous tissues, especially the auricular pinna (cartilage of the nose), tracheobronchial tree, eyes (sclera and cornea), aorta, and heart's connective components. The frequent association with other rheumatologic and hematologic disorders has been extensively reported over time and a concomitant autoimmune disease is present in one-third of patients with RP. The pathogenesis involves an autoimmune response to as yet unidentified cartilage antigens followed by cartilage matrix destruction by proteolytic enzymes.[4] The clinical spectrum may vary from intermittent inflammatory episodes leading to aesthetic deformities to life-threatening cardiopulmonary manifestations, such as valvular regurgitation[5] and progressive fibrosis of the tracheobronchial wall, leading to a fixed tracheobronchial stenosis that might, eventually, progress to tracheobronchomalacia due to irreversible damage and loss of tissue integrity.

Alveolar Interstitium

Interstitial Pneumonias. In 2002, the American Thoracic Society (ATS)/European Respiratory Society (ERS) Consensus classification was published to unify clinical, imaging, and histologic criteria for interstitial pneumonias in an idiopathic setting. This was further reviewed in 2013, with the addition of pleuroparenchymal fibroelastosis (PPFE) as an additional clinicopathologic entity.[6] Since then, it has become well established that the same histological patterns are seen in association with CTDs, and the same diagnostic criteria can be used. However, it is important to recognize that the frequency of the interstitial pneumonias in CTDs differs when compared with idiopathic disease, with usual interstitial pneumonia (UIP) being more common in idiopathic disease and NSIP being more common in CTDs. Also, for individual CTDs, there are differences in the frequencies and combinations of histologic patterns (Table 2). For example, a combination of OP and NSIP is not infrequently seen in patients with polymyositis/dermatomyositis (PM/DM).

Nonspecific Interstitial Pneumonia: NSIP comprises homogenous expansion of the alveolar interstitium by chronic inflammation with (fibrotic NSIP) or without fibrosis (cellular NSIP). First described in the context of ILD in 1994, subsequent publications show that this pattern is most commonly seen in systemic sclerosis, PM, and SS. Data are more conflicting in relation to RA, where some publications report UIP as more common. The difference in prognosis between UIP and NSIP in an idiopathic setting is not seen in patients with associated CTDs, so most cases are not biopsied when fibrosis is present on HRCT. Indeed, the decision to biopsy is usually because there is unexpected longitudinal behavior or suspicion of development of malignancy. It is also been reported that patients with NSIP associated with undifferentiated CTD have a better prognosis than those with idiopathic NSIP or NSIP associated with hypersensitivity pneumonitis (HP).[7][8]

It is interesting that around 20% of patients diagnosed with idiopathic NSIP subsequently manifest with a CTD within the next 5 years, suggesting that some patients with "idiopathic" disease are in fact pulmonary presentation of their CTD.[9]

Usual Interstitial Pneumonia: UIP comprises established fibrosis with a predominantly subpleural and paraseptal distribution, sharp demarcation between normal and abnormal lung, and a mild associated chronic inflammatory cell infiltrate. Varying numbers of fibroblastic foci are present. Honeycomb change is not infrequently seen. This histological pattern is the commonest in an idiopathic setting when it is associated with idiopathic pulmonary fibrosis (IPF). UIP was commonly reported in association with CTDs prior to the recognition of NSIP but, outside of RA, it is now only rarely seen. Indeed, in patients with RA, there is not infrequently coexistent follicular hyperplasia, a finding that should prompt consideration of searching for a CTD in the histology report.[10]

Organizing Pneumonia: OP comprises buds of intraluminal granulation tissue, with interstitial expansion by variable amounts of chronic inflammation. OP is quite a common pattern in patients with PM/DM, often where it coexists with NSIP. When fibrotic, this combination of NSIP and OP is sometimes termed "fibrosing OP" where it is presumed that the OP is incorporating into the interstitium rather than resolving. This is associated with a poorer prognosis and should be noted within the pathology report. Another important consideration with OP is that it may be secondary to other pathologies, for example there may be an underlying vasculitis and EVG staining is very useful in this situation as it highlights the pulmonary vasculature. Also, the OP may not be associated with the CTD, rather be a reflection of therapy, especially when there is coexistent eosinophilia (Figure 2).

Figure 2.

Common pattern of interstitial pneumonias. (A) Fibrosing NSIP: interstitium expanded by chronic inflammation with fibrosis; (B) cellular NSIP: interstitium expanded by chronic inflammation without fibrosis; (C) UIP: coexistence of normal alveoli with fibroblastic foci, fibrosis, and honeycombing; (D) fibrosing OP and (E) OP: buds of intraluminal granulation tissue with interstitial expansion by variable amounts of chronic inflammation. NSIP, nonspecific interstitial pneumonia; OP, organizing pneumonia; UIP, usual interstitial pneumonia.

Diffuse Alveolar Damage: Diffuse alveolar damage (DAD) is the only acute histological pattern in the classification system. When occurring in an idiopathic setting, the clinical disorder is termed an acute interstitial pneumonia, although most cases occur in a secondary setting, typically acute respiratory distress syndrome (ARDS). Rarely, patients with CTDs present with DAD. In its early stages, in the exudative phase, the key pathological feature is the presence of hyaline membranes. After around 7 days, DAD enters its organizing phase when there is mainly OP.

In addition, DAD can occur as an acute exacerbation of established chronic fibrosing disease. Although this is most commonly seen in association with IPF, acute exacerbations are reported with other histological patterns and in association with CTD-related interstitial fibrosis. As with the idiopathic pneumonias, patients present with rapidly progressing respiratory failure and a pattern of DAD on biopsy. This may be superimposed on background interstitial pneumonia or occur de novo. It is important to exclude other causes such as infection and drug reaction.

Lymphoid Interstitial Pneumonia: Lymphoid interstitial pneumonia (LIP) comprises marked interstitial chronic inflammation calling widening of the alveolar walls, typically with no more than mild fibrosis. Not infrequently, there is coexistent diffuse cystic lung disease and some patients may also have coexistent amyloidosis, particularly those with SS. A diagnosis of LIP is extremely rare in an idiopathic setting and its presence on biopsy should prompt investigations in relation to CTDs and also immunodeficiency syndromes, both congenital and acquired.

Desquamative Interstitial Pneumonia and Respiratory Bronchiolitis: Although desquamative interstitial pneumonia (DIP) and respiratory bronchiolitis (RB) patterns remain in the classification of idiopathic ILDs, it is now accepted that the majority of these cases are caused by exposure to cigarette smoke. It seems likely therefore that early cases of DIP/RB in association with CTDs were primarily related to cigarette smoking, although it remains uncertain whether a background CTD might have a synergistic effect, enhancing the likelihood of damage secondary to the exposure. Furthermore, there is a minority of patients with DIP who are never smokers and it may be that CTDs may play a role in such patients.

Hypersensitivity Pneumonitis with Autoimmune Features: HP has not traditionally been associated with CTD, but recent data suggest that some cases of HP have autoimmune features. Given patients with HP and CTD likely have an element of immune dysregulation, this is not unexpected. Adegunsoye et al[11] reviewed the role of autoimmune disease in the progression of patients with HP. Patients were classified as HP with autoimmune features (HPAF) if they had a documented diagnosis of autoimmune disease (scleroderma, SS, idiopathic inflammatory myopathy, systemic lupus erythematosus (SLE) and RA), or if they had at least one CTD-specific symptom and one positive serological test suggestive of autoimmune disease. They reviewed 120 cases of HP, of which 18 had evidence of autoimmune disease which they classified as HPAF. This group comprised predominantly females and showed an increased mortality as compared with patients with HP. However, no difference in histological features was found between the two groups. In an abstract, Sterclova et al[12] reviewed 257 cases of HP of which 50 also had autoimmune features. This group was of a younger age, females, and showed an increased lymphocytosis on bronchoalveolar lavage (BAL).

Interstitial Pneumonias with Autoimmune Features: Diagnosing CTD can be difficult in cases where the lungs are the predominant organ involved and where there is little or absent evidence of a systemic autoimmune disease. It is not uncommon for patients to present with lung disease before systemic features of a CTD are evident. Some patients with an ILD also have nonspecific features of autoimmune disease that fall short of criteria needed for a defined CTD. There has been a lack of consensus criteria to define these patients and a variety of terms such as undifferentiated CTD-related ILD or lung-dominant CTD have been used.

In 2015 a joint ATS/ERS taskforce proposed the term interstitial pneumonia with autoimmune features (IPAF) to describe patients with an ILD and some features of an underlying autoimmune disease but falling short of criteria needed for a defined CTD. The authors grouped these features into three domains (clinical: Raynaud's phenomenon or telangiectasia; serological: high titer antinuclear antibody, antisynthetase antibody, anti-PM/Scl antibody, and anti-MDA-5 antibody; and morphological, radiological, or histological features suggestive of CTD).[13]

Patients are classified as IPAF if they have an ILD, with one or more features from two of the three of these domains but fail to meet the accepted criteria for a classic CTD. In some cases this is a holding category as patients may subsequently manifest diagnostic features of a systemic CTD.

The histological features that are included as part of the morphological domain are essentially those known to be associated with an underlying CTD. These include multicompartmental and overlapping disease patterns (particularly NSIP, LIP, or OP patterns), presence of lymphoid aggregates with germinal centers, or diffuse lymphoplasmacytic infiltrate. Patients with the UIP pattern may also be categorized as IPAF but these patients must have at least one feature from the other two domains. Recent data suggest that histological features are not sufficiently discriminatory and should be interpreted in conjunction with the clinical, serological, and radiological data.[14] There are currently no data on the role of cryobiopsies.

There have been several case series looking at patients who fulfill the criteria for IPAF.[15–18] The spectrum of clinical, serological, and morphological features reported in these studies varies quite significantly. In relation to morphological criteria, the UIP pattern varied between 0 and 50% of patients and the NSIP pattern between 42 and 64% of patients. In one study OP was seen in 20% of patients.[16] Oldham et all[15] found that patients with UIP-IPAF had an equivalent survival to those with UIP-IPF. In contrast, patients with non-UIP-IPAF had a better survival than those with CTD-related ILD as defined by classical criteria. These patients may benefit from immunosuppressive therapies. In the study by Ito et al,[17] 12% of cases went on to develop a definite CTD (predominantly RA), and some authorities have noted that the current definition of IPAF will include some patients with myositis spectrum disease. Kelly and Moua[19] reviewed a cohort of 101 patients defined as having undifferentiated CTD and found 91% met the criteria for IPAF. The commonest pattern was the UIP pattern. IPAF with non-UIP pattern had better survival whereas those with UIP pattern had equivalent survival to IPF.

It is likely therefore that patients defined by current IPAF criteria represent a heterogeneous population with differing pathogenesis and evolution of disease. Some may evolve into a defined CTD whereas others may remain undifferentiated.

Currently IPAF criteria are regarded as a research tool, and they have not been adopted for routine clinical diagnosis. However, there is evidence that identifying and sub-classifying patients who fall into the definition of IPAF may be clinically useful.

Further validation studies and refinement of the criteria will be needed before adopting the term for routine clinical use.

Other Histological Patterns of Interstitial Pneumonia: PPFE was included in the 2013 ATS/ERS updated classification of interstitial pneumonias, and has recently been associated with autoimmune disease. In addition, two pathological diagnoses were included as histological patterns, although there was insufficient evidence for them to be included as clinical entities. Both of these, namely bronchiolocentric interstitial pneumonia and acute fibrinous and organizing pneumonia can be seen in association with CTDs.

Pleuroparenchymal Fibroelastosis: PPFE is a rare relatively new pattern of interstitial pneumonia with upper lobe predominance, which was first described by Amitani et al in 1992[20] and subsequently termed PPFE by Frankel et al in 2004.[21] It was recently included as a rare pattern of IIP in the 2013 ATS/ERS updated classification of idiopathic interstitial pneumonias (IIPs). It is classified as primary or secondary, the latter associated with bone marrow and lung transplantation, fungal infection, radiotherapy, asbestosis, aluminum exposure, and drugs. It has been recognized as a pattern seen in some patients with UIP and HP,[22] and increasingly in patients with autoimmune disease. Rare case reports and small case series describe PPFE or PPFE-like pattern in patients with autoimmune disease including vasculitis, thyroid disease, and CTD.[23–25] A retrospective pathological review by Kinoshita et al[26] of 24 patients with autoimmune disease and ILD found a PPFE pattern in 12/24 cases. It was a minor component in 10 of these 12 cases, the major associated pattern being UIP (50%). However, in two cases PPFE comprised the major pathological pattern (one case of PM/DM and a case of microscopic polyangiitis).

A separate radiological study by Enomoto et all[25] of 113 patients with CTD-ILD found a radiological pattern of PPFE in 21 cases including 6/14 patients with systemic sclerosis and 4/14 patients with SS. In 12 of the 21 cases there were also radiological features of UIP, and indeed surgical lung biopsy in two patients showed UIP and fNSIP patterns. In a third patient however, postmortem histology showed discordant PPFE (upper lobe) and UIP (lower lobe), as has been reported in patients with idiopathic UIP. Multivariate analysis suggested that the presence of PPFE was a risk factor for death, but whether this was confounded by the presence of coexistent UIP was unclear.

The underlying etiology of PPFE pattern is uncertain, but given that it is associated with several disorders including autoimmune disease, it probably represents a pattern of chronic lung injury associated with several conditions rather than a specific entity. This is supported by a few cases in the literature where PPFE appears to have progressed from or coexist with patterns of acute lung injury (Figure 3).

Figure 3.

Rare patterns of interstitial pneumonia. (A) LIP: marked interstitial chronic inflammation calling widening of the alveolar walls, typically with no more than mild fibrosis; (B) DIP: alveolar spaces filled with histiocytes; (CD) PPFE: upper lobe pleural and parenchymal fibrosis highlighted also with EVG special stain. DIP, desquamative interstitial pneumonia; EVG, Elastin van Gieson; LIP, lymphoid interstitial pneumonia; PPFE, pleuroparenchymal fibroelastosis.

Rheumatoid Nodules. Rheumatoid nodules can develop in any part of the body and also in major airways and lung parenchyma as solitary or multiple lesions that usually shrink and resolve by absorption. The nodules are round in shape with a necrotic center surrounded by a capsule of palisading histiocytes in a chronically inflamed granulation tissue. The main differential diagnosis is with necrotizing granulomatous infection and Wegener's granulomatosis (Figure 4).

Figure 4.

Rheumatoid nodule.

Pulmonary Vasculature. There are numerous manifestations of CTDs in the pulmonary vasculature, including pulmonary arterial hypertension, vasculitis and capillaritis, alveolar hemorrhage, veno-occlusive disease, thromboembolic disease, and pulmonary aneurysms.

Pulmonary Arterial Hypertension. Patients with CTD are at increased risk of developing pulmonary hypertension, defined as a resting mean pulmonary artery pressure of 25 mm Hg or more. It is most commonly associated with patients with scleroderma/systemic sclerosis with prevalence ranging between 8 and 12%,[27] but may also be seen in association with SLE and mixed CTD (MCTD) and less commonly with RA, SS, and myositis, and is associated with poorer prognosis. It has been estimated in a recent meta-analysis that the prevalence in SLE is around 8%[28] with significant differences between gender, age, and diagnostic methods, but it can be actually higher in Asian populations in which the disease is more common.[29] Predictive factors of higher incidence are prolonged SLE disease duration (often 5 years), female under the age of 40 years,[30] and the presence of Raynaud's phenomenon, antiphospholipid antibodies (anticardiolipin and lupus anticoagulant), and anti-U1 ribonucleoprotein antibodies.[31]

The pathogenesis is multifactorial and incompletely understood, but involves hypoxia, inflammatory mediators, cytokines, thrombosis, and dysregulation of bone morphogenetic protein receptor 2 (BMPR2).

Several pathologic patterns can be seen including an obliterative vasculopathy, veno-occlusive disease, formation of microthrombi, and pulmonary fibrosis.[31]

At microscopy there is a myxoid thickening of the wall of small arteries with intimal fibroblasts arranged circumferentially with an "onion skin" pattern, medial hypertrophy, and expansion of the adventitia.[32] Capillaritis/vasculitis and plexiform lesions can also accompany SLE-related PH.[31,33] PH may be seen in isolation or in association with ILD.

Vasculitis. Pulmonary vasculitis or capillaritis is a rare manifestation of CTD.

Vasculitis can affect any type of vessels, from capillaries to large elastic arteries, and is commonly classified by the size of the inflamed vessels.

Histological features include chronic and necrotizing vasculitis of large and small arteries and veins. Capillaritis is characterized by a variably dense infiltrate of capillaries within alveolar septa with leukocytoclasis (destruction and loss of capillary structural integrity) and consequent spilling of red blood cells into the alveolar spaces and interstitium. Neutrophil degeneration releases toxic oxygen radicals and proteolytic enzymes, causing additional injury to the capillaries and alveolar hemorrhage.[34] Fibrinoid necrosis of alveolar capillaries may be seen in severe cases and can be highlighted by Martius Scarlet Blue (MSB) stain for fibrin. Histological features of diffuse alveolar hemorrhage (DAH) range from mild hemosiderosis through to marked acute alveolar hemorrhage and capillaritis.

Vasculitis of large and small arteries and veins may also be seen in a variety of CTDs including SLE, RA,[35–37] MCTD, and PM where it is associated with the presence of anti-Jo1 autoantibodies. It can be seen in isolation or combined with PH.

Veno-occlusive Disease. Veno-occlusive disease may rarely be seen in patients with CTD, but its identification is critical as it has important therapeutic and prognostic implications. Histological features of pulmonary veno-occlusive disease (PVOD) can be subtle and may be seen in small interstitial venules as well as large septal veins, and EVG stain is essential to identify these lesions. As well as venous sclerosis, patchy capillary congestion and hemosiderosis are seen and are useful clues to underlying venous obstruction. Secondary features of pulmonary capillary hemangiomatosis (PCH) can develop in patients with CTD-PVOD.[38,39]

Thromboembolic Disease. Thromboembolism may also be seen, particularly in patients with SLE and antiphospholipid syndrome. Acute and reorganizing thrombi and "colander lesions" in pulmonary arteries have familiar features, but patients may also present venous or small vessel thrombosis resulting in histological patterns of PCH and PVOD.

Behcet's Syndrome. A special mention is needed for Behcet's syndrome that in the lungs has the form of a necrotizing vasculitis involving most commonly large vessels, although all types can be interested (small, medium, or large vessels in both arterial and venous systems). It occurs in 8% of the patients with an almost exclusive male predilection. Pulmonary arterial disease is associated with peripheral vascular disease in approximately 75% of patients, typically presenting as thrombophlebitis with superficial or deep vein thrombosis.[40] Most common and severe manifestations are single or multiple pulmonary artery thrombosis and/or aneurysms that might undergo leakage or rupture contributing to mortality. Microscopically larger vessels show transmural, mainly mononuclear, inflammatory infiltrate accompanied by adventitial fibrosis that results in prominent perivascular cuffing. The progressive inflammatory destruction of the media leads to aneurysm formation. Small vessels show leukocytoclastic (necrotizing) vasculitis associated with deposition of IgA and complement.[41] Thrombi, where present, are usually surrounded by an inflammatory infiltrate.[42]

Diffuse Alveolar Hemorrhage. DAH is a rare manifestation of SLE that can occur as bland pulmonary hemorrhage with or without pulmonary capillaritis.[43] At microscopy, the alveolar spaces are filled with erythrocytes and fibrin without inflammation or destruction of alveolar structures.[44] In case a BAL is undertaken, it shows abundant blood and/or hemosiderophages (macrophages containing Perl's positive hemosiderin pigment).[32] For a histologic description of capillaritis, see earlier discussion (Figure 5).

Figure 5.

Vascular changes. (A) Pulmonary hypertension: marked thickening of arterial wall. (B) Capillaritis: mild neutrophilic infiltrate within capillaries with alveolar hemorrhage. (C) Diffuse alveolar hemorrhage: alveolar hemorrhage with preserved architecture. (DE) Capillary hemangiomatosis in PVOD: same case. Proliferation of capillaries highlighted by CD34 immunostain. PVOD, pulmonary veno-occlusive disease.

Pleura

Pleural effusion is a common respiratory manifestation of CTD. The effusion can be small and asymptomatic or large and bilateral causing fever, pleuritic pain, and breathlessness. It is commonly an exudate rather than transudate, and usually it resolves spontaneously but cytological preparations or pleural biopsies might reach the pathologist.

In RA nonspecific chronic inflammation of the pleura is common, but characteristic rheumatoid nodules or a linear granulomatous process may sometimes be seen. The latter is characterized by collections of palisading epithelioid histiocytes replacing the pleural mesothelial surface secondary to the rupture of a rheumatoid nodule in the pleural cavity (Figure 6). Epithelioid histiocytes and necrotic debris might also be present in the cytological preparation of the pleural effusion, suggesting the diagnosis. Occasionally empyema or pyopneumothorax can occur as a result to higher susceptibility to infection of these patients or rupture of a pleural or subpleural rheumatoid nodule.

Figure 6.

Rheumatoid nodule in the pleura. Palisading epithelioid histiocytes replacing the pleural mesothelial surface.

In SLE the effusion might look nonspecific containing neutrophils and lymphocytes but lupus erythematous cells (neutrophils or macrophages with intracytoplasmic remnants of degenerated nuclei) have been described. Antinuclear factors in high titer and positive immunofluorescence are also a feature.

Diaphragm and Chest Wall

Shrinking Lung Syndrome. Shrinking lung syndrome is defined as unexplained progressive dyspnea associated with pleuritic pain, restrictive lung volume reduction, and diaphragmatic elevation[45] with no interstitial, alveolar, or vascular pulmonary disease.[32] Its pathogenesis remains still controversial and it is a rare complication mostly associated with SLE with a prevalence reported between 0.5 and 1.5%,[46,47] although it has been occasionally described also in patients with other CTDs (SS, scleroderma, RA, and undifferentiated connective tissue disorder).[46,48,49]

Myositis. Muscles of the chest wall can also be afflicted by myositis that affects every other muscle in the body but they are rarely biopsied and the diagnosis is mostly clinical. Resulting chest wall and diaphragmatic weakness can lead to aspiration-related change in the lung.

Neoplasms

Patients with CTD have an increased risk of malignancy, which varies depending on the underlying disease. SS is associated with the development of extra-nodal B cell MALT lymphoma, and there is an increased risk of lung cancer in patients with RA, scleroderma, and SLE. Diagnostic criteria are described elsewhere.

Drugs, CTD, and the Lung

Many of the drugs used to treat CTD can have pulmonary toxicity with patterns that overlap with underlying CTD-ILD. These drugs include methotrexate, cyclophosphamide, and tumor necrosis factor α, and the spectrum of associated lung pathology is wide, including acute lung injury, interstitial pneumonitis, OP, NSIP, UIP, and constrictive bronchiolitis. Pulmonary toxicity may be temporally discontinuous with starting the drug or occurs after the drug has been stopped, which makes diagnosis difficult. Patients may be on multiple and novel drugs, and it is important to be aware of the spectrum of patterns of lung injury associated with each of these (pneumotox.com). Biopsy may be performed to determine if a lung disease is primary or drug-related, and the principles for diagnosing drug-related lung disease are well reviewed elsewhere. Of note, histological features suggestive of a drug reaction such as eosinophilia may also be associated with underlying CTD.

CTDs in Children

ILD in children is rare and that secondary to CTD is rarer still; however, it can lead to significant morbidity and mortality. As in adults it may be the initial presentation of systemic disease and pulmonary manifestations are diverse, affecting all compartments of the lung.

Pediatric connective tissue disorders more commonly associated with pulmonary involvement include SLE, systemic sclerosis, juvenile DM, and mixed CTD. Although there is some overlap, different patterns of lung pathology are more frequently seen with certain systemic disorders. Pulmonary involvement is often associated with a specific immune phenotype within these disorders.[50,51]

The pathogenesis is poorly understood and likely multifactorial involving genetic susceptibility, exogenous triggers, immune dysregulation, and abnormal fibrogenesis.

In children with SLE, pleuritis is the most common pulmonary complication, but rarely it may develop acute lupus pneumonitis (often associated with coinfection), alveolar hemorrhage, venous thromboembolism, and pulmonary hypertension. Pulmonary disease is associated with anti-U1 ribonucleoprotein seropositivity.[52–55]

In patients with juvenile DM a small vessel vasculitis is the commonest manifestation but OP, UIP, and ARDS are described. The development of pulmonary complications appears more common in those patients with anti-Jo-1antibody, and rapid disease progression is associated with the presence of melanoma differentiation associated protein 5 (MDA-5) antibody.[51–54]

Children with juvenile systemic sclerosis may develop both interstitial pneumonia and pulmonary hypertension. NSIP is the most common pattern of IIP reported, and it may be the initial manifestation of disease. Pulmonary hypertension is more frequently seen in systemic sclerosis, in contrast to patients with juvenile localized scleroderma in which pulmonary complications are rare.[51–54,56]

Juvenile idiopathic arthritis is the commonest rheumatological disease in childhood. Pulmonary involvement is rare but pleuritis, LIP, chronic bronchiolitis, lipoid pneumonia, alveolar proteinosis, OP, and hypertension have all been reported. In contrast to adults, children with SS and juvenile ankylosing spondylitis rarely develop lung disease.[51–55]

As in adults the pulmonary manifestations of systemic rheumatologic disease may be hard to differentiate from the pulmonary effects of drugs, immunosuppression, and infection, which must be considered in the differential diagnosis.

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