Rudolph's Pediatrics, 22nd Ed.

CHAPTER 517. Pulmonary Vasculitis Syndromes

Paul Rosen

Vasculitis affecting the lung is exceptionally uncommon in children. The presentation may vary from mild, chronic respiratory symptoms to an acute, catastrophic, life-threatening pulmonary hemorrhage. When symptoms are indolent, diagnosis may be delayed by months or years. Early, aggressive treatment is imperative in cases of pulmonary vasculitis. Cumulative lung damage due to ongoing inflammation can lead to pulmonary fibrosis.

EPIDEMIOLOGY

The epidemiology of pulmonary vasculitis is varied, depending on the underlying disease process. (Vasculitic diseases are discussed in more detail in Chapter 203.) In general, the autoimmune diseases affect females more than males in adulthood. In childhood, the gender discrepancy may be less. Some vasculitic syndromes can affect African Americans and Asians with greater frequency and with greater severity of disease than Caucasians. Age of onset in children is variable as well. For example, the mean age of onset of Wegener granulomatosis (WG) in children is 13 years, with reports of patients presenting before their first birthday.1

PATHOPHYSIOLOGY

Vasculitis signifies blood vessel wall inflammation. Neutrophils infiltrate the vessel walls and damage the endothelial cell layer. Vessel walls thicken and result in luminal narrowing. Fibrinous thrombi may further occlude capillary blood flow.2 Over several weeks to many months, inflammation of the blood vessel wall leads to fibrosis. Simultaneously, inflammation involves the pulmonary interstitium and leads to fibrosis. The end result is destruction of normal lung architecture with decreased gas-exchange capacity.2

The etiology of the diseases that result in pulmonary vasculitis is unknown. The collagen vascular and granulomatous diseases are felt to be complex genetic conditions. Numerous genes, most of which are currently undefined, may lead to a predisposition to develop a specific autoimmune condition. Environmental factors, such as exposure to viruses, may serve as triggers to set off the cascade of autoimmunity.

CLINICAL FEATURES AND DIFFERENTIAL DIAGNOSIS

A child with pulmonary vasculitis may present with indolent symptoms, including fatigue, fever, weight loss, failure to thrive, pallor, decreased appetite, or irritability. Respiratory symptoms may include cough, dyspnea, chest tightness, or hemoptysis. Some present with acute symptoms, including massive pulmonary hemorrhage, that can result in respiratory failure and cardiovascular collapse. The slow, indolent presentation of mild intermittent respiratory symptoms as seen in the case of pulmonary capillaritis can lead to misdiagnosis (atypical asthma) and delayed diagnosis (Fig. 517-1).3 The child presenting with frank hemoptysis secondary to bleeding of medium-or large-sized vessels is generally diagnosed more promptly. The possibility of pulmonary vasculitis should be raised in any child who has the triad of respiratory symptoms, anemia, and bibasilar infiltrates on chest x-ray.4

FIGURE 517-1. Pulmonary capillaritis. Chest radiograph of a 3-year-old girl with pulmonary vasculitis shows bibasilar patchy opacities. (Courtesy of Amisha J. Shah, Pittsburgh, PA.)

Symptom presentation also varies, depending on the size of the vessels involved and the pathophysiological mechanism affecting the vessels. The differential diagnosis of small-and medium-vessel vasculitis includes Wegener granulomatosis, Churg-Strauss syndrome (CSS), microscopic polyangiitis (MPA), and polyarteritis nodosa.5 Large-vessel vasculitis may be due to Takayasu arteritis or Behçet disease.6 In many patients, the underlying disease process causing pulmonary vasculitis is unknown, but as the illness evolves, the pattern of organ involvement allows more definitive diagnosis. Diagnostic uncertainty may also be due to the overlap of the vasculitic and autoimmune disorders.

Wegener granulomatosis is suggested by the triad of inflammation of the upper respiratory tract, the lower respiratory tract, and the kidney (see Fig. 517-2),7 as discussed in Chapter 203. The triad associated with CSS includes asthma, eosinophilia, and necrotizing vasculitis. CSS is exceedingly rare in the pediatric population. Like Wegener, CSS may involve the kidneys and cause inflammation of the sinuses, the joints, and the skin. CSS is more likely to cause cardiac conduction delays and gastrointestinal hemorrhage.7 In microscopic polyangiitis, the kidneys are affected most commonly, while pulmonary vasculitis occurs in less than one third of cases. When the lung is affected, the inflammation affects small vessels.7

FIGURE 517-2. Wegener’s granulomatosis. Axial high-resolution computerized tomographic image of a 15-year-old girl shows left upper lobe perihilar thick-walled nodule with central cavitary change (green line). Smaller nodules are seen in bilateral lung fields. (Courtesy of Amisha J. Shah, Pittsburgh, PA.)

DIAGNOSTIC EVALUATION

A complete list of diagnostic studies to be considered in a vasculitis patient is listed in Table 517-1. The diagnostic approach varies, depending upon the symptom presentation.

The initial evaluation of suspected vasculitis includes evaluation of inflammatory markers such as white blood cell count, platelet count, sedimentation rate, and C-reactive protein in those with an indolent or acute presentation. Evidence of other organ involvement should include evaluation of renal function and liver function. If systemic lupus erythematosus is suspected and a serum antinuclear antibody test is positive, then testing should be done for other antibodies such as double-stranded DNA, Ro, La, ribonuclear protein, and Smith. Evaluation of serum antineutrophil cytoplasmic antibodies (ANCAs) is also useful. These antibodies are directed against antigens in the cytoplasm of neutrophils and monocytes. Cytoplasmic-ANCA (c-ANCA) is usually directed against proteinase 3 (PR3). Perinuclear-ANCA (p-ANCA) is directed against myeloperoxidase (MPO). The ANCA-associated vasculitides include Wegener granulomatosis, Churg-Strauss syndrome, and microscopic polyangiitis.5 Adult Wegener’s patients have a positive ANCA in 90% of cases (usually c-ANCA). Over half of the adult patients with Churg-Strauss syndrome and microscopic polyangiitis have a positive ANCA (usually p-ANCA).7

EKG and echocardiogram should be considered to evaluate cardiac rhythm and function. Computerized tomography (CT) of the sinuses may demonstrate inflammatory infiltration in cases of Wegener granulomatosis. Ophthalmologic examination can demonstrate uveitis. An audiogram may demonstrate sensorineural hearing loss.

In a patient who presents with hemoptysis, the initial workup includes a hemoglobin and reticulocyte count to check for anemia and a chest x-ray to identify evidence of bleeding in the lung. If the x-ray is unrevealing, a CT scan may show pulmonary infiltrates and pulmonary nodules. In most cases, the findings are bilateral. Other radiographic findings may include atelectasis; mediastinal lymphadenopathy; and in longstanding disease, calcification.6 If the clinical picture is uncertain, bronchoscopy may be utilized to prove bleeding in the lung. Hemosiderin-laden macrophages may be found in the bronchial alveolar lavage fluid, especially in the setting of chronic bleeding.4 In Wegener granulomatosis, bronchoscopy may demonstrate upper airway disease such as bronchial stenosis, inflammatory lesions, and ulcerations.5 Once pulmonary hemorrhage is established, a tissue diagnosis should be sought. Transbronchial biopsy specimens may be insufficient to make a diagnosis of vasculitis. Video-assisted thoracoscopic or open-lung biopsy offers the greatest chance of finding histopathologic evidence of pulmonary vasculitis. If suspected pulmonary vasculitis is one component of a systemic disease, then open-lung biopsy can be deferred. Tissue diagnosis may be pursued with biopsy of involved skin, sinus, or kidney.

Table 517-1. Diagnostic Workup for Suspected Pulmonary Vasculitis

If an exhaustive workup for pulmonary hemorrhage is negative for an autoimmune disease and lung pathology shows no evidence of vasculitis, one must consider the diagnosis of idiopathic pulmonary hemosiderosis (IPH). Pathological findings may include bland hemorrhage, well-preserved pulmonary architecture, and minimal or no interstitial inflammation.8 The etiology of IPH is poorly understood. The hemorrhage in IPH may be due to a combination of factors such as autoimmunity, capillary fragility, allergy, genetic predisposition, environmental exposure to fungal toxins, and defective iron metabolism (see Fig. 517-3).8

FIGURE 517-3. Idiopathic pulmonary hemosiderosis. Axial high-resolution computerized tomographic image of a 14-year-old boy shows two pneumatocele cavities in right lung (blue lines). There is an area of ground-glass opacification seen peripherally (red line) with associated changes of bronchiectasis. Interlobular septal thickening is also present. (Courtesy of Amisha J. Shah, Pittsburgh, PA.)

TREATMENT

Treatment for pulmonary vasculitis starts with stabilization of the patient. Presentation with hypoxia, respiratory distress, and ongoing bleeding is an emergent situation that may require mechanical ventilation and blood transfusion. Less acute presentation may just require oxygen supplementation and close monitoring. Once the diagnosis of pulmonary vasculitis has been confirmed, the cornerstone of treatment is aggressive immunosuppressive therapy, as detailed in Chapter 203. In most cases, the treatment consists of high-dose corticosteroids and cyclophosphamide.5 The family must be educated regarding the side effects of immunosuppression. Administration of live vaccines is contraindicated. Annual influenza vaccination is encouraged. Pneumocystis carinii pneumonia prophylaxis should be initiated. The child should be supplemented with calcium and vitamin D while on steroids. Menstruating girls should be given leuprolide while taking cyclophosphamide to reduce the risk of infertility. Male patients should consider sperm banking. Cyclophosphamide therapy requires close monitoring for leukopenia and hemorrhagic cystitis. Less toxic agents such as methotrexate, azathioprine, or mycophenolate mofetil are used for maintenance therapy.7

Complications may arise from both ongoing inflammation and resulting fibrosis and from the cytotoxic therapies used to treat vasculitis. Patients may experience chronic fatigue, dependence on oxygen supplementation, and gradual deterioration in lung function. The main complications from the treatments include opportunistic infections and drug toxicity.

PROGNOSIS

The implementation of aggressive therapies has reduced mortality rates significantly in pulmonary vasculitis. In adult patients with Wegener granulomatosis, what was once a 1-year mortality rate of 80% is now 10%. Although remission is achieved in 90% of patients, relapse occurs in greater than 50% of patients undergoing standard treatment.5 In children with IPH, the mortality rate remains significant.9 Case series report 3- to 5-year mortality rates of 15% to 33%.8