Etiology

Most cases of DAH are associated with an underlying immunologic, rheumatologic, or vasculitic disorder but other diagnoses may manifest as recurrent or chronic pulmonary bleeding (Table 400-1).

Table 400-1 CLASSIFICATION OF DIFFUSE ALVEOLAR HEMORRHAGE SYNDROMES

From Susarla SC, Fan LL: Diffuse alveolar hemorrhage syndromes in children, Curr Opin Pediatr 19:314–320, 2007.

Pulmonary hemosiderosis has historically been classified as primary or secondary. Primary pulmonary hemosiderosis (PPH) is described as encompassing the diagnoses of IPH, Goodpasture syndrome (Chapter 511), and Heiner syndrome (cow’s milk hyperreactivity); Goodpasture syndrome (or anti–basement membrane antibody disease) appears to be the most common among these entities as a cause of pulmonary hemorrhage.

Secondary pulmonary hemosiderosis refers to the remaining, diverse group of potential etiologies. Among these are cardiac causes of pulmonary hemosiderosis, such as congestive heart failure, pulmonary hypertension, and mitral valve stenosis. Vasculitic and collagen vascular diseases such as systemic lupus erythematosus (SLE; Chapter 152), rheumatoid arthritis (Chapter 148), Wegener granulomatosis (Chapter 161.4), and Henoch-Schönlein purpura (HSP; Chapter 161.1) are another important group to consider in the differential diagnosis. Coagulopathies are encountered and may be either inherited or acquired. Prematurity is also a recognized risk factor for hemorrhage. Pulmonary hemosiderosis has been well described in association with celiac disease. Postinfectious processes such as hemolytic-uremic syndrome (Chapter 478.4) and immunodeficiency syndromes, including chronic granulomatous disease (CGD; Chapter 124) have also been implicated. Numerous medications, environmental exposures, chemicals, and food allergens have been reported as potential causes.

Trends in disease classification are based on the finding of pulmonary capillaritis. The pathologic appearance of pulmonary capillaritis includes inflammation and cellular disruption of the pulmonary interstitial capillary network. This finding is nonspecific with regard to underlying diagnosis, but pulmonary capillaritis, when present, appears to be an important negative prognostic factor in DAH. Newer classification protocols divide the variable causes of DAH into 3 categories. Disorders with pulmonary capillaritis (including SLE, HSP, drug-induced capillaritis, Wegener granulomatosis, and Goodpasture syndrome) are distinguished from those without pulmonary capillaritis. Those disorders in which the pathologic finding of capillary network disruption is absent are further divided into cardiac (pulmonary hypertension, mitral stenosis) and noncardiac (immunodeficiency, Heiner syndrome, coagulopathy, IPH) etiologies.

Epidemiology

Because of the variety of disorders that can manifest with alveolar hemorrhage as a component, the frequency with which DAH occurs is difficult to quantify. Similarly, the prevalence of IPH is largely unknown. In fact, in many children and young adults who were diagnosed with IPH in the past, the etiology of the hemorrhage might have been discovered if they had been studied with the newer and more advanced diagnostics available today. Estimates of prevalence obtained from Swedish and Japanese retrospective case analyses vary from 0.24 to 1.23 cases per million. In general, the manifestations of IPH are seen before age 10 yr. Nearly 80% of cases occur in this age group. The remaining 20% of cases, which occur in adult patients, are typically diagnosed before age 30 yr. The ratio of affected males to females is 1 : 1 in the childhood diagnosis group, and men are only slightly more affected in the group diagnosed as adults.

Pathology

With repeated episodes of pulmonary hemorrhage, lung tissue appears brown secondary to the presence of hemosiderin. The finding of blood in the airways or alveoli is representative of a recent hemorrhage. Hemosiderin-laden macrophages (HLMs) are seen with recovering, recurrent, or chronic pulmonary hemorrhage. It takes 48-72 hr for the alveolar macrophages to convert iron from erythrocytes into hemosiderin. HLMs may be detectable for weeks after a hemorrhagic event. Other nonspecific pathologic findings include thickening of alveolar septa and hypertrophy of type II pneumocytes. Fibrosis may be seen with chronic disease (Chapter 408).

Pathophysiology

In Goodpasture syndrome, anti–basement membrane antibody (ABMA) binds to the basement membrane of both the alveolus and the glomerulus. At the alveolar level, immunoglobulin G (IgG), IgM, and complement are deposited at alveolar septa. Electron microscopy shows disruption of basement membranes and vascular integrity, which allows blood to escape into alveolar spaces.

Pulmonary hemosiderosis in association with cow’s milk hypersensitivity was first reported by Heiner in 1962. This condition is characterized by variable symptoms of milk intolerance. Symptoms can include grossly bloody or heme-positive stools, vomiting, failure to thrive, symptoms of gastroesophageal reflux, and/or upper airway congestion. Pathologic findings have included elevations of IgE and peripheral eosinophilia as well as alveolar deposits of IgG, IgA, and C3. High titers to cow’s milk protein are also typically found in cow’s milk hypersensitivity.

Alveolar hemorrhage, seen rarely in association with SLE, is often severe and potentially life-threatening. Pathologic vasculitic features may be absent. Some immunofluorescent studies have revealed IgG and C3 deposits at the alveolar septa. A clear link between immune complex formation and alveolar hemorrhage has not been established, however.

In HSP, pulmonary hemorrhage is a rare but recognized complication. Pathologic findings have included transmural neutrophilic infiltration of small vessels, alveolar septal inflammation, and intra-alveolar hemorrhage. Vasculitis is the proposed mechanism for hemorrhage.

Wegener granulomatosis is a rare etiology for hemorrhage in children. Pulmonary granuloma formation (with or without cavitation) and a necrotizing vasculitis may be appreciated. In children, presentations attributable to the upper airway, including subglottic stenosis, may suggest the diagnosis. Results of testing for antineutrophil cytoplasmic antibody (ANCA) are generally positive.

A premature infant’s neonatal course can frequently be complicated by pulmonary hemorrhage. The alveolar and vascular networks are immature and particularly prone to inflammation and damage by ventilator mechanics, oxidative stress, and infection. Pulmonary hemorrhage may be unrecognized if the volume of blood is insufficient to reach the proximal airways. The chest radiographic findings in pulmonary hemorrhage may be appreciated instead as a worsening picture of respiratory distress syndrome, edema, or infection.

A number of additional associated conditions and exposures exist, as outlined previously. These occur infrequently in the pediatric population, and suggested mechanisms for hemorrhage are variable. The diagnosis of IPH is made when there is evidence of chronic or recurrent diffuse alveolar hemorrhage and when exhaustive evaluations for primary or secondary etiologies have negative results. A biopsy specimen should not reveal any evidence of granulomatous disease, vasculitis, infection, infarction, immune complex deposition, malignancy, or any other features of associated primary or secondary conditions.

Clinical Manifestations

The clinical presentation of pulmonary hemosiderosis is highly variable. Symptoms may be reflective of an underlying and associated disease process rather than specifically related to pulmonary hemorrhage. Presentations can vary widely from a relative lack of symptoms to shock or sudden death. Hemorrhage may be significant without remarkable symptomatology. Hemoptysis may not occur. Bleeding may occasionally be recognized from the presence of alveolar infiltrates on a chest radiograph. It should be noted that the absence of an infiltrate does not rule out an ongoing hemorrhagic process.

Because the presence of blood in the lung is typically a source of significant irritation and inflammation, the patient may present after an episode of hemorrhage with wheezing, cough, dyspnea, and alterations in gas exchange, reflecting bronchospasm, edema, mucus plugging, and inflammation. On physical examination, the patient may be pale with tachycardia and tachypnea. During an acute exacerbation, children are frequently febrile. Examination of the chest may reveal retractions and differential or decreased aeration, with crackles or wheezes. The patient may present in shock with respiratory failure from massive hemoptysis. Children in particular may present with symptoms of chronic anemia, such as failure to thrive.

Laboratory Findings and Diagnosis

Pulmonary hemorrhage is associated with a decrease in hemoglobin and hematocrit. The classic finding is a microcytic, hypochromic anemia. The reticulocyte count is elevated. The anemia of IPH can mimic a hemolytic anemia. Elevations of plasma bilirubin are caused by absorption and breakdown of hemoglobin in the alveoli. The serum iron level is reduced. Iron-binding capacity is generally elevated. Any or all hematologic manifestations may be absent in the presence of recent hemorrhage.

White blood cell count and differential should be evaluated for evidence of infection and eosinophilia. A stool specimen can be heme-positive secondary to swallowed blood. Renal and liver functions should be reviewed. A urinalysis should be obtained to assess for evidence of nephritis. A coagulation profile, quantitative immunoglobulins (including IgE), and complement studies are recommended.

Testing for ANCA, antinuclear antibody (ANA), anti–double stranded DNA, rheumatoid factor, antiphospholipid antibody, and anti–glomerular basement membrane antibody (antiGBM) evaluates for a number of primary and secondary etiologies of DAH. An elevated erythrocyte sedimentation rate (ESR) is a nonspecific finding.

Sputum or pulmonary secretions should be analyzed for significant evidence of blood or HLMs. Gastric secretions may also reveal HLMs. Flexible bronchoscopy provides visualization of any areas of active bleeding. With bronchoalveolar lavage, pulmonary secretions may be sent for pathologic review and culture analysis. The ability to perform flexible bronchoscopy will be limited if there are large amounts of blood or clots in the airway. A patient with respiratory failure can be ventilated more effectively through a rigid bronchoscope.

Lung biopsy is warranted when DAH occurs without discernible etiology, extrapulmonary disease, or circulating ABMAs. Pulmonary tissue when obtained should be evaluated for evidence of vasculitis, immune complex deposition, and granulomatous disease.

A chest radiograph may reveal evidence of acute or chronic disease. Hyperaeration is frequently seen, especially during an acute hemorrhage. Infiltrates are typically symmetric and may spare the apices of the lung. Atelectasis may also be appreciated. With chronic disease, fibrosis, lymphadenopathy and nodularity may be seen. CT findings may demonstrate a subclinical and contributory disease process.

Pulmonary function testing will likely reveal primarily obstructive disease in the acute period. With more chronic disease, fibrosis and restrictive disease tend to predominate. Oxygen saturation levels may be decreased. Lung volumes may reveal air trapping acutely and decreases in total lung capacity chronically. The diffusing capacity of carbon monoxide (DLCO) may be low or normal in the chronic phase but is likely to be elevated in the setting of an acute hemorrhage, because carbon monoxide binds to the hemoglobin in extravasated red blood cells.

Treatment

Supportive therapy, including volume resuscitation, ventilatory support, supplemental oxygen, and transfusion of blood products, may be warranted in the patient with pulmonary hemosiderosis. Surgical or medical therapy should be directed at any treatable underlying condition. In IPH, early treatment with systemic corticosteroids is the treatment of choice. Therapy is generally initiated at 2-5 mg/kg/day and decreased to 1 mg/kg every other day after resolution of acute symptoms. Early treatment with corticosteroids appears to decrease episodes of hemorrhage. This therapy may also modulate the neutrophil influx and inflammation associated with hemorrhage, thereby decreasing progression toward fibrotic disease.

The goal of gradually tapering the systemic steroid dose may not be tolerated. In addition, a subgroup of patients may not respond optimally to corticosteroid therapy alone. In these cases, immunosuppressive agents such as cyclophosphamide, azathioprine, and chloroquine have been utilized. The indications for and effectiveness of long-term immunosuppressive therapies is unclear. The numerous potential long-term side effects of corticosteroids and other immunosuppressive agents may limit therapy.

In chronic disease, progression to debilitating pulmonary fibrosis has been described. Lung transplantation has been performed in patients with IPH refractory to immunosuppressive therapy. In one reported case study, IPH recurred in the transplanted lung.

Prognosis

The outcome of patients suffering from DAH is highly dependent on the underlying disease process. Some conditions, such as cow’s milk hypersensitivity, respond well to removal of the offending agent. Other syndromes, especially those with an immunologic mechanism, tend to carry a poor prognosis. In IPH, mortality is often related to massive hemorrhage or, alternatively, to progressive fibrosis, respiratory insufficiency, and right-sided heart failure.

Long-term prognosis in patients with IPH varies among studies. Initial case study reviews suggested an average survival after symptom onset of only 2.5 yr. In this early review, a minority of patients were treated with steroids. A later review reported a 5-yr survival rate of 86%. Whether this improvement in survival is related to primarily overall advances in care or long-term immunosuppressive therapy is not established at this time. Spontaneous remissions have been documented.