Diffuse alveolar hemorrhage (DAH) refers to accumulation of intra-alveolar red blood cells originating from alveolar capillaries due to underlying injury to alveolar microcirculation. The clinical picture includes hemoptysis, anemia, hypoxemic respiratory failure with infiltrates on chest X-ray [1,2]. In the absence of infections or any hemodynamic cause for DAH, anti-neutrophil cytoplasmic autoantibodies (ANCAs) must be looked for and ANCA-associated vasculitis (AAV) - mainly microscopic polyangiitis (MPA),Wegener granulomatosis, or Churg-Strauss syndrome should be considered. We report a case of MPA who presented with DAH and was further found to have interstitial lung disease (ILD).

On examination, her heart rate was 142/min, respiratory rate 48/min, blood pressure 102/60 mmHg and SpO2 was 92% on room air. She had severe pallor, grade-3 clubbing, and non-blanchable erythematous papular rash over both feet. Chest examination revealed subcostal and intercostal retractions with fine crepitations audible all over the chest. Hepatosplenomegaly was present. Growth was well preserved. Rest of the systemic examination was normal.

Laboratory Investigations: Blood investigations revealed anemia (hemoglobin 3.3 g/dL), platelets 120×103 /mm3, total leukocyte count of 5400/mm3 with normal differential count. Past and present radiographs showed prominent interstitial reticular shadows in the middle and lower zones (Fig.1). HRCT chest showed diffuse ground glass opacities in bilateral lung fields and interstitial infiltrates with honeycombing especially in the lower zones (Fig.2). Lung function tests showed moderate restriction pattern: forced vital capacity was <64% predicted), and early small airway obstruction (mean peak expiratory flow rate was <70% predicted). Echocardiography revealed mild pulmonary artery hypertension with moderate tricuspid regurgitation. Prussian blue staining of sputum for hemosiderin-laden macrophages was positive with siderophage percentage more than 86 % corresponding to Golde score >100, confirming DAH [1]. Urine microscopy and renal function tests were normal. ANCA was positive by immunoflourescence with a perinuclear staining pattern and ELISA for antimyeloperoxidase ANCA (MPO-ANCA) was positive (2.808, cutoff-0.394).

Fig.1 Chest X-ray shows prominent interstitial reticular shadows due to diffuse alveolar hemorrhage.

Fig.2 HRCT of lungs show bilateral ground glass opacity and interstitial infiltrates with honeycombing especially in the periphery.

Common infections like malaria, enteric fever, tuberculosis were ruled out on investigations. Her ANA and dsDNA were negative. AntiGlomerular Basement Membrane Antibody and Anti Phospholipid Antibody workup were negative. Serology for Human Immunodeficiency Virus, Hepatitis B surface antigen, Hepatitis C and tissue transglutaminase antibodies were negative. Serum IgE levels were normal (150IU/mL). Direct Coombs test was negative. Skin biopsy was unremarkable and did not reveal features of leucocytoclastic vasculitis.

In view of the multisystem involvement and positive serology for MPO-ANCA, a diagnosis of MPA was made. She was started on oral steroids 2 mg/kg/day and supportive therapy. She went into remission on oral steroids. After 6 weeks, daily therapy was shifted to alternate day and then tapered over one year. Simultaneously, azathioprine was added.

She is on regular follow-up for one year. She had one relapse in past year which was managed with short course of steroids. She has remained normotensive, hepatosplenomegaly has regressed, has had no urinary complaints or need for blood transfusions (hemoglobin-13.1g/dL), normal repeat renal functions and, Elisa for MPO-ANCA has returned to normal.

Severe unexplained anemia in a female with progressive dyspnea and alveolar opacities on chest imaging, without hemorrhage elsewhere alerted us to the possibility of DAH. Long history of fever, cough, clubbing, hepatosplenomegaly, led to the possibility of ILD. Absence of cutaneous/mucous telangiectasias clinically ruled out hereditary hemorrhagic telangiectasia. Nonspecific constitutional symptoms, DAH, ILD with sparing of the upper airways, no asthma/eosinophilia with positive MPO-ANCA clinched the diagnosis of MPA.

MPA is a non-granulomatous pauci-immune primary systemic vasculitides which affects small vessels. Kidneys and lungs are the most frequently affected organs. Annual incidence rates of MPA is 2.1-17.5 per million [3]. DAH and ILD have both been reported in MPA [4,5]. However, unlike our case, untreated MPA usually are rapidly progressive and fatal [4]. Though DAH in MPA is usually acute, rarely DAH has been reported as part of chronic MPA in adult patients [6]. The index case had a slow indolent course with frequent exacerbations which has previously not been reported in a child. Incidence of ILD is 7.2% in MPA. Diagnosis of ILD is usually based on radiological evidence on HRCT and/or lung function tests [5]. Generally, lung biopsy is not recommended for diagnosis [1,2]. It is considered if DAH is associated with negative serology and not a part of a systemic disease. Notably our case didn’t have renal involvement in past 10 years [1,2].

Two main mechanisms have been proposed for the development of ILD in patients with small vessel vasculitis. Firstly, the pulmonary fibrosis occurs in response to pulmonary haemorrhage and secondly, the ANCA antigens such as MPO undergo translocation to the surface of neutrophils (possibly in response to proinflammatory cytokines), and subsequent binding of circulating ANCA results in neutrophil degranulation and release of reactive oxygen species, causing injury and consequent fibrosis [7,8].

Treatment typically includes corticosteroids, immunosuppressive agents, and occasionally plasma-pheresis. 90% of patients achieve remission at 6 months. Relapse rates in AAV are 50%; severe organ-threatening damage and treatment-related adverse effects occur in 25% of patients. 10% of those refractory to standard immunosuppressant therapies are at high risk for death [9]. Serial hemoglobin measurement guides on DAH control or progression [1]. Disappearance of ANCA is almost always associated with absence of disease activity [10].

We conclude that DAH should be considered as a differential diagnosis in recurrent unexplained anemia. A high index of suspicion and prompt management can reverse the symptoms quickly.