OVERVIEW: What every practitioner needs to know
Are you sure your patient has diffuse alveolar hemorrhage? What are the typical findings for this disease?
The lung has a dual blood supply: a low-pressure, high-capacitance pulmonary circulation and a high-pressure, low-capacitance bronchial circulation. Bleeding from the pulmonary circulation results in diffuse alveolar hemorrhage (DAH). Although massive hemoptysis is uncommon, DAH can be fatal.
The most common symptoms are cough, malaise, and progressive dypsnea on exertion.
The next most common symptoms are hemoptysis, although not as common as in adults, because children often swallow their sputum.
What other disease/condition shares some of these symptoms?
DAH has multiple causes that share common features of anemia, diffuse alveolar opacities on imaging studies, and hemosiderin-laden macrophages in bronchoalveolar lavage fluid, gastric aspirate, and lung biopsy material. The differential diagnosis of diffuse alveolar hemorrhage includes immune-mediated and non–immune mediated disorders.
Systemic lupus erythematosus
Idiopathic pulmonary capillaritis (PC)
Juvenile idiopathic arthritis
Pulmonary vein atresia/stenosis
Pulmonary venoocclusive disease
Left-sided heart failure
Pulmonary capillary hemangiomatosis
Idiopathic pulmonary hemosiderosis (IPH)
Acute idiopathic pulmonary hemorrhage of infancy (AIPH)
What caused this disease to develop at this time?
In immune-mediated DAH, autoantibodies directed against the microvasculature result in pulmonary hemorrhage. These autoantibodies include antinuclear antibody (ANA), antiglomerular basement membrane antibody (anti-GBM antibody), and antineutrophil cytoplasmic antibody (ANCA); they can often, but not always, be detected in the serum. The pathologic feature of immune-mediated DAH is PC.
Left-sided cardiovascular diseases can cause secondary DAH as a result of pulmonary venous hypertension.
IPH is a diagnosis of exclusion. Many patients thought to have IPH clinically actually have PC when lung biopsy is performed, even when serologic test results are negative.
What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?
Imaging studies: see below
Pulmonary function testing: typically shows restriction, but diffusion is often elevated in acute alveolar hemorrhage
CBC: typically shows microcytic, hypochromic anemia
Erythrocyte sedimentation rate and C-reactive protein: often elevated, more so with capillaritis
Urinalysis: may have hematuria and red cell casts in pulmonary-renal syndromes
Blood urea nitrogen and creatinine levels: may be elevated in pulmonary-renal syndromes
ANA: elevated in autoimmune diseases
Anti-GBM antibody: elevated in Goodpasture syndrome
ANCA: elevated in Wegener granulomatosis (C-ANCA pattern) and microscopic polyangiitis (P-ANCA pattern)
Echocardiogram: useful in looking for cardiovascular causes of DAH
Would imaging studies be helpful? If so, which ones?
Posteroanterior and lateral views of a chest radiograph typically show diffuse alveolar densities. High-resolution computed tomography of the chest typically shows diffuse ground glass densities with septal thickening (Figure 1 and
Confirming the diagnosis
Identification of hemosiderin-laden macrophages (HLMs) in bronchoalveolar lavage, gastric aspirate, or lung biopsy tissue confirms the presence of alveolar hemorrhage and is essential for diagnosis. However HLMs do not reveal the cause of alveolar hemorrhage.
Lung biopsy is strongly encouraged because patients with capillaritis can have negative results on serologic examination. In children, lung biopsy performed by video-assisted thoracoscopic surgery reduces morbidity when compared with conventional open lung biopsy. Lung specimens should be read by a pediatric pathologist with expertise in lung disease (
Figure 3 and Figure 4).
If you are able to confirm that the patient has diffuse alveolar hemorrhage, what treatment should be initiated?
Treatment for IPH
Intravenous (IV) pulse methylprednisolone, 30 mg/kg (maximum 1 g) IV, either weekly for 6-8 weeks and taper, or daily for 3 consecutive days and repeated monthly for 6 months
As an alternative to IV pulse methylprednisone, oral prednisone or prednisolone, 1-2 mg/kg/d for 6-8 weeks, followed by taper to every other day to complete 3-6 months may be considered
Hydroxychloroquine, 10 mg/kg/d orally, is often added to corticosteroid treatment as a steroid-sparing agent
Treatment for Idiopathic PC
For patients with non–life-threatening disease:
Methylprednisolone, 30 mg/kg (maximum 1 g) IV weekly for 6-8 weeks and
Cyclophosphamide, orally, 2 mg/kg/d, or retuximab 375 mg/m
2 IV weekly for 4 weeks
Alternative to cyclophosphamide and retuximab: intravenous immunoglobulin (IVIG), immunomodulatory doses, 2 g/kg, given monthly and/or hydroxychloroquine 10 mg/kg/d orally
For patients with life-threatening disease or impending respiratory failure:
IV pulse methylprednisone and
Oral prednisone, 1-2 mg/kg/d and
Oral cyclophosphamide and
Six cycles of plasmapharesis followed by IVIG given monthly
Low-dose every-other-day prednisone or prednisolone and
Methotrexate, 5-15 mg/m2 once weekly orally, or azathioprine, 1-2 mg/kg/d orally
What are the adverse effects associated with each treatment option?
Serious side effects of corticosteroids include immunosuppression, hypertension, diabetes, cataracts, osteoporosis, myopathy, and adrenal suppression.
Serious side effects of cyclophosphamide include immunosuppression, infertility, and future malignancies.
An uncommon side effect of hydroxychloroquine is retinal damage.
Serious side effects of rituximab include immunosuppression, infusion reactions, bowel perforation, and future malignancies.
Serious side effects of IVIG include headache, aseptic meningitis, anaphylaxis, and pulmonary edema.
Serious side effects of methotrexate include hepatic fibrosis, bone marrow suppression, pulmonary fibrosis, acute renal failure, Stevens-Johnson syndrome, and diarrhea.
Serious side effects of azathioprine include bone marrow suppression, hepatotoxicity, and neoplasia.
What are the possible outcomes of diffuse alveolar hemorrhage?
Uncontrolled pulmonary hemorrhage can lead to life-threatening respiratory failure and even death; more insidious, recurrent episodes of DAH may result in pulmonary fibrosis. Most cases of DAH can be controlled or prevented with aggressive intervention.
What causes this disease and how frequent is it?
DAH syndromes are rare in children. The incidence and prevalence are unknown. The cause is largely unknown, with the exception of the rare case of asphyxiation due to child abuse. There are familial cases of immune-mediated DAH, but the genetic basis of these disorders is unknown.
How can diffuse alveolar hemorrhage be prevented?
Currently, there is no evidence that these diseases can be prevented.
What is the evidence?
Because these disorders are quite rare in children, there is very little evidence to support the management and treatment options recommended. Treatment options for pulmonary capillaritis are based to some extent on adult studies. However, the aggressive intervention recommended for life-threatening pulmonary capillaritis in children is based on experience.
Rasmussen, N, Jayne, DRW, Abramowicz, D. “European therapeutic trials in ANCA-associated systemic vasculitis: disease scoring, consensus regimens and proposed clinical trials”. Clin Exp Immunol. vol. 101. 1995. pp. 29-34. (Expert consensus statement on cyclophosphamide dose and length for ANCA-associated vasculitis.)
Jayne, D, Rasmussen, N, Andrassy, K. “A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic antibodies”. N Engl J Med. vol. 349. 2003. pp. 36-44. (Adult randomized prospective study of 155 patients that showed effectiveness of azathioprine as a steroid-sparing maintenance drug.)
Pagnoux, C, Mahr, A, Hamidou, MA. “Azathioprine or methotrexate maintenance for ANCA-associated vasculitis”. N Engl J Med. vol. 359. 2008. pp. 2790-803. (Adult randomized prospective study of 126 patients that established methotrexate was as effective as azathioprine for maintenance therapy.)
Stone, JH, Merkel, PA, Spiera, R. “Rituximab versus cyclophosphamide for ANCA-associated vasculitis”. N Engl J Med. vol. 363. 2010. pp. 221-32. (Adult randomized prospective noninferiority study in 197 patients that established rituximab was not inferior to cyclophosphamide for remission induction.)
Ongoing controversies regarding etiology, diagnosis, treatment
Acute idiopathic pulmonary hemorrhage of infancy is a unique form of DAH in infants who present acutely with respiratory failure. Early reports linking AIPH to mycotoxins from
Stachybotrys chartarum have not been substantiated, and the true cause of AIPH remains unknown. Whether milk allergy can cause DAH (Heiner syndrome) is controversial. Skeptics doubt the existence of Heiner syndrome.
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- OVERVIEW: What every practitioner needs to know
- Are you sure your patient has diffuse alveolar hemorrhage? What are the typical findings for this disease?
- What other disease/condition shares some of these symptoms?
- What caused this disease to develop at this time?
- What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?
- Would imaging studies be helpful? If so, which ones?
- Confirming the diagnosis
- If you are able to confirm that the patient has diffuse alveolar hemorrhage, what treatment should be initiated?
- What are the adverse effects associated with each treatment option?
- What are the possible outcomes of diffuse alveolar hemorrhage?
- What causes this disease and how frequent is it?
- How can diffuse alveolar hemorrhage be prevented?
- What is the evidence?
- Ongoing controversies regarding etiology, diagnosis, treatment