Rook's Textbook of Dermatology

Department of Dermatology and Allergology, Ludwig Maximilian University, Munich, Germany

INTRODUCTION

There are many disorders that affect both the skin and the respiratory system, ranging from common infections and allergies to complex multisystem diseases. This chapter examines the relationship between the two organ systems and discusses selected disorders from amongst the diverse groups of diseases that may affect both (Table 151.1). After a brief discussion of allergic disorders affecting the upper respiratory tract, the chapter focuses on pulmonary involvement in autoimmune disorders, vasculitides, infections and hereditary syndromes. Many of these often complex diseases are described in more detail elsewhere in this book.

Table 151.1 Conditions that affect the skin and respiratory system.

Disease	Respiratory system features or comment
Inflammatory
Sarcoidosis	Pulmonary fibrosis, hilar lymphadenopathy, laryngeal involvement, necrotizing sarcoid granulomatosis
Pulmonary vasculitides	See text (this section)
Systemic sclerosis	Interstitial fibrosis, pneumothorax, pulmonary hypertension
Sjögren syndrome	Decreased secretions, sinusitis, bronchoalveolitis, interstitial lung disease
Lupus erythematosus	Pleuritis, pleural effusion, shrinking lungs syndrome
Mixed connective tissue disease	Fibrosing alveolitis (especially U₁ ribonucleoprotein antibody positive)
Antiphospholipid syndrome	Pulmonary embolism, infarction, thrombosis, haemorrhage
Dermatomyositis	Muscular weakness, pharyngeal dysfunction (aspiration pneumonia), interstitial lung disease, bronchiolitis obliterans
Relapsing polychondritis	Tracheal collapse
Multicentric reticulohistiocytosis	May be associated with bronchial neoplasia, also lung infiltration, pleural effusion
Bullous diseases (epidermolysis bullosa, pemphigus, Stevens–Johnson syndrome, toxic epidermal necrolysis)	Upper respiratory tract involvement; paraneoplastic pemphigus is associated with intrathoracic disease, especially Castleman disease, thymoma
Graft-versus-host disease	Restrictive defect, fibrosis
Pyoderma gangrenosum	Neutrophilic nodules in lung, tracheal involvement
Familial Mediterranean fever	Pleurisy
Infections and infestations
Tuberculosis	Specific skin lesions, erythema nodosum
Mycobacterium avium–intracellulare infection	May disseminate to skin (usually in HIV infection)
Leprosy	Laryngeal involvement
Mycoplasma infection	Causes erythema multiforme (often mucosal)
Dissemination of pulmonary fungal infections	Blastomycosis, coccidioidomycosis, cryptococcosis, aspergillosis, histoplasmosis, melioidosis
Scrub typhus	Pneumonia (common)
Varicella	Pneumonia
Measles	Pneumonia
Larva migrans	Asthma/bronchitis with eosinophilia
Chronic mucocutaneous candidiasis	Bronchiectasis
Whipple disease	Cough, pleural effusion, pulmonary infiltrate, hilar lymphadenopathy
Congenital/inherited
Atopic disease	Asthma, hay fever
Cutis laxa	Emphysema, cor pulmonale
Tuberous sclerosis	Rhabdomyomas
Neurofibromatosis	Kyphoscoliosis, intrathoracic neuromas, lung fibrosis, bullae
Ataxia–telangiectasia	Pneumonia, bronchiectasis, pulmonary fibrosis
Hereditary haemorrhagic telangiectasia	Haemoptysis, dyspnoea, cyanosis due to arteriovenous shunting
α₁-antitrypsin deficiency	Emphysema
Darier disease	Lower lobe fibrosis, laryngeal involvement
Dyskeratosis congenita	Interstitial pneumonia, fibrosis
Lipoid proteinosis	Laryngeal involvement
Riley–Day syndrome	Lung infiltrate, pneumonia
Birt–Hogg–Dubé syndrome	Lung cysts, pneumothorax
Hyper-IgE syndrome	Abscesses, pneumonia
Infiltrations and metabolic
Histiocytoses (Langerhans cell histiocytosis, Rosai–Dorfman disease, haematophagocytic syndrome, necrobiotic xanthogranuloma, sea-blue histiocytosis, others)	Pulmonary nodules and fibrosis, upper respiratory tract infiltration disease, xanthoma disseminatum
Amyloidosis	Cutaneous amyloid deposition secondary to chronic lung disease, lung infiltration in primary amyloidosis
POEMS syndrome	Pleural effusion, bronchospasm
Carcinoid syndrome	Bronchospasm
Hypothyroidism	Laryngeal involvement
Myxoma	Pleurisy
Drugs
Used in respiratory disease, causing rash, phototoxicity	For example co-trimoxazole (drug eruptions), pirfenidone
May cause skin eruptions and respiratory tract disease	For example antibiotic-induced toxic epidermal necrolysis, cisplatin (bronchospasm, pigmentation)
Used for skin disease, respiratory side effects	For example isotretinoin (bronchospasm)
Miscellaneous
Angio-oedema	Upper airway obstruction
Anaphylaxis	Bronchospasm
Pancreatitis	Basal pleural reaction, cutaneous fat necrosis
Yellow nail syndrome	Pleural effusion, bronchiectasis
Mastocytosis	Rhinorrhoea, laryngeal oedema, bronchospasm
Tumours	Metastatic disease, Kaposi sarcoma, lymphomatoid granulomatosis, extensive mycosis fungoides/Sézary syndrome, others

HIV, human immunodeficiency virus; POEMS, polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes.

The mucosa of the upper respiratory tract may be affected by the same processes as the skin in a range of infective and allergic disorders.

Pulmonary disease rarely occurs as a direct consequence of a primary skin disease, except for instances such as metastasis from a primary skin tumour (e.g. melanoma). Similarly, there are relatively few instances in which skin abnormalities occur as a direct consequence of respiratory pathology. Examples include cyanosis due to severe pulmonary disease or intrapulmonary right-to-left shunts, and finger clubbing due to chronic cyanotic lung disease or neoplasm.

Some drugs used for the treatment of pulmonary disease may cause side effects on the skin and vice versa. A very few drugs may cause skin symptoms and respiratory tract disease at the same time (e.g. cisplatin).

AUTOIMMUNE DISORDERS

Amongst autoimmune disorders it is the connective tissue diseases in particular that may affect both organs.

Respiratory disease is the second most common clinical manifestation of systemic sclerosis (see Chapter 56), with a prevalence of between 25% and 90% [1]. Systemic sclerosis is associated with interstitial lung disease and pulmonary vascular disease leading to pulmonary hypertension. In addition, bronchiectases are found in up to 68% of patients on high-resolution computer tomography. Pneumothorax, pleural effusion, respiratory muscle involvement and ‘splinting’ of the chest by sclerotic skin may all occur.

The proportion of patients with systemic lupus erythematosus (SLE) (see Chapter 51) who develop pulmonary disease is similar in reported series (20–90%) [2]. The clinical manifestations involve all compartments of the respiratory tract (pleura, parenchyma, vessels and airways) and can follow an acute or chronic course. Pleuritis, pulmonary hypertension or interstitial lung disease may be present in mixed connective tissue disease [3]. Involvement of the respiratory muscles may lead to diaphragmatic elevation and the ‘shrinking lungs’ syndrome [4]. Pulmonary embolism, haemorrhage, infarction and hypertension as well as thrombosis of the lung vessels may occur in patients with the antiphospholipid syndrome (see Chapter 52) [5].

Relapsing polychondritis (see Chapter 154) [6] is due to autoantibodies against type II collagen, and is a potentially fatal disease. Dyspnoea and inspiratory stridor occur in over 50% of patients as a result of oedema of the respiratory tract mucosa and collapse of the cartilaginous support of the larynx and trachea. Inflamed nasal and auricular cartilages are present in most patients, with nasal obstruction, arthropathy and a high erythrocyte sedimentation rate. Costal cartilage is involved in one-third of cases. The non-cartilaginous lobe of the ear is classically spared in relapsing polychondritis.

In dermatomyositis (see Chapter 53), there are three main mechanisms that provide a link with respiratory disease [7]. Firstly, dermatomyositis may occur as a consequence of bronchial carcinoma. Secondly, muscular weakness due to myositis may affect either the intercostal and thoracic musculature, or the larynx and pharynx – involvement of the latter may lead to aspiration pneumonia as a complication. Finally, interstitial lung disease or bronchiolitis obliterans may occur in dermatomyositis. The lung disease is typically associated with the presence of antiaminoacyl transfer RNA (tRNA) synthetase antibodies, such as the histidyl tRNA synthetase (Jo-1) antibody. The antisynthetase syndrome consists of dermatomyositis (or polymyositis) with interstitial lung disease, arthritis and Raynaud phenomenon [8]. The presence of antisynthetase antibodies is also associated with the clinical entity of ‘mechanics’ hands’ in dermatomyositis, characterized by hyperkeratotic skin on the lateral aspects of the fingers. Dermatomyositis may also indirectly be associated with lung disease as a consequence of treatment – either infection due to immunosuppression, or rarely drug-induced pneumonitis (methotrexate), which may cause diagnostic confusion with pulmonary involvement by the disease itself.

In Sjögren syndrome (see Chapter 55), the frequency of lung involvement varies between 9% and 75%. It can affect the small airways but may also present with interstitial lung disease [9]. Alveolitis can be demonstrated in about 50% of patients but is often asymptomatic.

VASCULITIS

Vasculitis of many types may affect the lung (see Chapter 10). The major pulmonary vasculitides belong either to the group of small-vessel vasculitis or variable-vessel vasculitis [10].

small-vessel vasculitis

Any form of systemic small-vessel vasculitis (SVV) can affect the lung. According to current classifications [10], SVV can be divided into antineutrophil cytoplasmic antibody (ANCA) associated vasculitis and immune complex SVV. The ANCA-associated forms are: granulomatosis with polyangiitis (GPA), eosinophilic GPA (EGPA, formerly the Churg–Strauss syndrome) and microscopic polyangiitis (MPA).

Granulomatosis with polyangiitis [11, 12, 13] This rare disease is characterized by necrotizing granulomatous vasculitis of the upper and lower respiratory tracts, necrotizing glomerulonephritis, and disseminated vasculitis of various organs. ANCAs directed against proteinase 3 are found in 40–95% of cases. Skin lesions are present in 30–60% of patients, including vasculitis with purpura, subcutaneous nodules and ulcers (see Chapter 102). Upper airway disease causes nasal discharge, ulceration and bleeding, and may be associated with oral ulceration. Pulmonary changes are typical with bilateral infiltrates, nodules or cavities. Subglottic or tracheobronchostenosis may also occur. Prognosis is poor in patients with lung or renal disease. Chronic nasal staphylococcal carriage is more frequent in GPA than in healthy controls, and is associated with a poorer prognosis and a higher relapse rate [11]. Diffuse alveolar haemorrhage, due to extensive pulmonary capillaritis, is a life-threatening complication of GPA; it also occurs in MPA, and more rarely in SLE, antiphospholipid syndrome, Behçet disease and secondary to drugs such as D-penicillamine [14].

Eosinophilic granulomatosis with polyangiitis (Churg–Strauss syndrome) [12, 13] This rare condition comprises rhinitis, asthma, pneumonitis, fever, malaise, eosinophilia (usually over 10%) and widespread vasculitis, which may cause skin lesions, neuropathy and cardiac or, less commonly, renal disease. Cutaneous lesions include palpable purpura and nodular lesions and are present in up to 70% of patients (Figure 151.2). ANCAs are not present in all cases of EGPA. They may be helpful in differentiating the disease into two subgroups: one with more vasculitic and one with more eosinophilic manifestations. The latter ANCA-negative subgroup is reported to have endomyocardial involvement and lung infltrates more often [15]. The ANCAs detected in EGPA are directed against myeloperoxidase in 32–92% of cases [11].

Microscopic polyangiitis ANCAs against myeloperoxidase (MPO-ANCA) can be found in up to 80% of patients with MPA [11]. It is a necrotizing form of vasculitis that predominantly affects small vessels: arterioles, venules and capillaries may all be affected. Lung involvement is reported in 20–60% and skin involvement in 40–70% of cases [11]. Common pulmonary clinical symptoms are dyspnoea, cough and haemoptysis. Alveolar haemorrhage can occur in up to a third of MPA patients [16].

Immune complex small-vessel vasculitis Pathognomonic are vessel wall deposits of immunoglobulin and complement factors that predominantly affect the small vessels. Urticarial vasculitis, cryoglobulinaemic vasculitis and IgA vasculitis (Henoch–Schönlein purpura) belong to this subgroup [10]. In urticarial vasculitis, pulmonary involvement is common and comprises pleuritis and obstructive lung disease [17]. In one large series, over 20% of patients with urticarial vasculitis had lung involvement, either chronic obstructive pulmonary disease or asthma. Although it is not clear that these were always causally related to the vasculitis, obstructive pulmonary disease was more frequent in the group of patients with hypocomplementaemia [18], and pulmonary vasculitis was demonstrated in over 50% of patients with lung disease.

Variable-vessel vasculitis

Behçet disease. Behçet disease has been classified amongst the variable-vessel vasculitis group [10], although it also has many features of an autoinflammatory disease (Figure 151.3) [19]. The frequency of lung involvement in Behçet disease shows a wide variation, from <1% to 18%. Pulmonary involvement can be classified into three groups: pulmonary artery aneurysm, parenchymal changes and a subgroup of diverse pulmonary disorders including pleural effusion. Thrombophlebitis may be a marker for an increased risk of pulmonary artery aneurysm as about 80% of patients with this complication also have thrombophlebitis [20].

INFECTIONS

Numerous infections may involve both the respiratory tract and the skin: a selection of these have been listed in Table 151.1. Many viral infections, for example, may cause upper and sometimes lower respiratory tract symptoms in association with either a non-specific exanthem or with erythema multiforme. Mycoplasma infection is particularly associated with Stevens–Johnson syndrome. Psittacosis (ornithosis) may be accompanied by erythema nodosum and erythema multiforme.

Associations between tuberculosis and the skin include non-specific reactions such as erythema nodosum or erythema multiforme, as well as several patterns of specific skin lesions such as lichen scrofulosorum, Bazin disease and papulonecrotic tuberculide (see Chapter 27). Several systemic mycoses (see Chapter 32) are caused by inhalation but may subsequently cause skin lesions, either non-specific reactions including erythema multiforme and erythema nodosum, or specific lesions caused by haematogenous dissemination. Other mycoses may have primary cutaneous lesions with occasional spread to internal organs, including the lung (e.g. sporotrichosis).

NEUTROPHILIC DERMATOSES

Pulmonary and major airway involvement has been described with pyoderma gangrenosum and with neutrophilic dermatoses [29, 30], usually comprising focal, dense neutrophilic infiltrates with scattered radiological opacities. In Sweet syndrome, the principal clinical symptoms of lung involvement are dyspnoea, cough and general malaise. Endobronchial involvement may also occur in eosinophilic states such as the hypereosinophilic syndrome, although cardiac disease is more important in this condition. See also Chapter 49.

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CHAPTER 151
The Skin and Disorders of the Respiratory System

INTRODUCTION

ALLERGIC DISORDERS