Diffuse alveolar hemorrhage (DAH) is a life-threatening condition characterized by hemoptysis, anemia, and diffuse alveolar infiltrates. The diagnosis of DAH is generally established by BAL along with radiology and serology in the appropriate clinical setting. Renal biopsy and lung biopsy may be required if vasculitis or anti-GBM disease is being considered to guide the therapy and prognosticate the disease. The majority of cases of DAH are caused by vasculitis, which may be primary idiopathic small vessel vasculitis, primary immune-complex mediated, or secondary. Coagulation disorders, drugs, inhaled toxins, or transplantation are other known causative factors. In our series, the most common cause of DAH was vasculitis. DAH has traditionally been linked to systemic vasculitides.12 Quadrelli et al. characterized 39 patients with DAH of proven immunological etiology, the most frequent being ANCA-related vasculitides (74%), mainly granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). In their series, these two diseases accounted for a similar number of cases (14 GPA vs. 13 MPA). Alexandre et al. found that ANCA-related vasculitides were the most common cause of immune-related DAH (~ 73%).13 AAV was the most common cause in our study, followed by anti-GBM disease, SLE vasculitis, and one case of unclassifiable vasculitis.
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are a group of systemic diseases marked by inflammation and necrosis of small and medium-sized arteries, and one of the most common symptoms is pulmonary involvement. The damage to the alveolar basement membrane resulting from the widespread injury of the pulmonary capillaries promotes the extravasation of red blood cells into the pulmonary alveolar spaces. DAH affects approximately 7–45% of GPA and 10–30% of MPA patients but is uncommon in EGPA patients. The severity of the disease varies from life-threatening to milder types, with associated renal impairment occurring in up to 97% of cases.14 The frequency of DAH was 8–36%, and 57% of the patients showed anti-proteinase-3 (PR3) antibodies, according to a systematic analysis by West et al., which comprised nine studies with a total of 207 patients.15 ANCA antibodies were found to be positive in 13 cases in our study. DAH is the most common and the most severe form of pulmonary manifestation of anti-GBM disease. The molecular and nephritogenic properties of anti-GBM antibodies that bind to renal glomeruli and alveolar-capillary basement membranes are responsible for causing glomerulonephritis and DAH, respectively.16 The exact pathogenesis of DAH in SLE is not fully understood. Diffuse alveolar bleeding, interstitial inflammation, and alveolar hemorrhage without vasculitis are the histopathology findings mentioned. Other reports, on the other hand, have revealed pulmonary vasculitis, with evidence pointing to pulmonary capillaritis and microangiitis as the source of DAH in SLE patients.17
The nonimmune causes include infections, APLA syndrome, PAH, idiopathic pulmonary hemosiderosis, and miscellaneous. The main infections that induce DAH in immunocompromised people include cytomegalovirus, adenovirus, invasive aspergillosis, Mycoplasma, Legionella, and Strongyloides. Influenza A (H1N1), dengue fever, leptospirosis, malaria, and Staphylococcus aureus infection are the most common infectious diseases that cause DAH in immunocompetent patients.18 Infection was implicated as the aetiology in ten of our cases, with two cases of Klebsiella pneumonia and one each of cytomegalovirus, Escherichia coli, tuberculosis, Candida, Aspergillus, mucormycosis, and Acinetobacter baumannii. All these cases were confirmed by microbiological studies. In one case, the causative agent could not be elucidated. One mortality seen in this group was due to mucormycosis.
Hemoptysis is a leading sign of DAH and may develop over days to weeks; however, it may be initially absent in up to one-third of DAH cases.6 The prevalence of hemoptysis is highly variable in different series, from 59.0–96.3%. Therefore, the absence of hemoptysis should not exclude this diagnosis.19 The symptoms of DAH, other than hemoptysis, are nonspecific and include fever, chest pain, cough, dyspnea, and respiratory failure. Non-pulmonary signs and symptoms accompany the underlying systemic disease.6 In the present study, hemoptysis was present in only 61.7% (n = 29) of cases of DAH.
Typical pulmonary lesions of DAH on chest X-rays include bilateral, reticular, or nodular opacities. Chest computed tomography is indispensable in characterizing the pattern and extent of pulmonary disease.20 Ground-glass opacities and consolidation were the most common CT findings in our cases. Although MR has been used to confirm lung hemorrhage, it is probably of limited use in most clinical settings.9, 21
Our study had three cases of idiopathic pulmonary hemosiderosis (IPH) confirmed by lung biopsy. Idiopathic pulmonary hemosiderosis is a diagnosis of exclusion and is an uncommon disease of childhood manifesting with the triad of recurrent hemoptysis, diffuse parenchymal infiltrates on chest radiographs, and iron deficiency anemia.22 The age of presentation is bimodal, with frequency peaks in children less than five years of age and adolescents 11 years or older.22 The diagnosis of IPH is based on the clinical picture, radiological findings on the chest X-ray and CT scan, demonstration of HLM in BALF, and exclusion of other diseases by appropriate serological, microbiological, and radiological tests.23 One case was of a 35-year-old female with Lane-Hamilton syndrome who presented with hemoptysis and, upon evaluation, was found to have chronic diarrhea with raised serum anti-tissue transglutaminase antibody levels. The duodenal biopsy revealed villous atrophy, BALF showed numerous HLMs, and a subsequent lung biopsy confirmed the findings of hemosiderosis (Fig. 4). Only 16 cases of Lane-Hamilton syndrome affecting adults have been reported in the literature thus far.24 Deposition of immunocomplexes (including food allergens) in the alveolar-capillary basement membrane and cross-reaction between antireticulin antibodies and alveolar basal membrane antigens are implicated in the pathogenesis.25, 26
In patients with evidence of DAH and renal involvement, a kidney biopsy may be considered to identify the etiology and guide the therapy.27 In a study by Fatma et al. on 15 cases of DAH associated with renal diseases, 13 underwent a kidney biopsy, of which ten showed crescentic pauci-immune glomerulonephritis.28 In our study, 11 out of 14 cases were diagnosed as crescentic glomerulonephritis, highlighting the utility of renal biopsy as an adjunctive tool in such cases.
Treatment of the cases was based on the underlying etiology. Patients with immune DAH were managed aggressively by immunosuppressive therapy, including steroids, cyclophosphamide, rituximab, intravenous immunoglobulins, and plasmapheresis. Established standard treatment regimens include corticosteroids and immunosuppressive therapy, but these can be detrimental when DAH is due to infection. Plasma exchange improves renal function in patients with ANCA-associated vasculitis. Rituximab can be used as an alternative or in addition to cyclophosphamide to treat AAV and SLE-associated DAH.12 In contrast, patients with nonimmune DAH were managed conservatively such as antibiotics and antifungals for infections. Hence, the prognosis for diffuse alveolar hemorrhage depends primarily on the classification proposed by us.
The main limitation of the study is that it is a retrospective study. Because the disease is rare, the sample size for proper calculation of risk factors is small, so the multivariate analysis may fail to give proper odds ratio in such a setting. A multicenter prospective study may throw more light on this disease.