Idiopathic Pulmonary Haemorrhage, Is It Really Idiopathic?

ABSTRACT

Idiopathic pulmonary haemorrhage (IPH) is a rare cause of haemoptysis that most commonly presents in children. By definition, this condition is idiopathic in nature, however, exclusion of autoimmune capillaritis creates a diagnostic challenge. If autoimmunity is present, treatment is with immunosuppression. We present a 4‐year‐old girl with the classic clinical triad of IPH with haemoptysis, bilateral pulmonary infiltrate on chest radiography and iron deficiency anaemia. Her clinical course was complicated by frequent relapses in symptoms and critical pulmonary haemorrhage despite standard treatment for IPH. Successful remission of disease was induced with rituximab despite the absence of serological or lung biopsy evidence of autoimmune capillaritis.

We present a 4‐year‐old girl with the classic clinical triad of idiopathic pulmonary haemorrhage (IPH) with haemoptysis, bilateral pulmonary infiltrate on chest radiography and iron deficiency anaemia. Successful remission of disease was induced with rituximab despite the absence of serological or lung biopsy evidence of autoimmune capillaritis.

1. Introduction

Haemoptysis is a rare but potentially life‐threatening problem in children. The most common causes are acute pneumonia or tracheobronchitis [1]. Others include bronchiectasis, congenital heart disease, arteriovenous malformation, foreign body inhalation, malignancy, coagulopathy, or diffuse alveolar haemorrhage [1].

IPH is a diagnosis of exclusion. The clinical triad is haemoptysis, bilateral pulmonary infiltrate on chest radiography, and iron deficiency anaemia [2]. In adults, lung biopsy and serological studies are undertaken to exclude autoimmune capillaritis, however, this differentiation in children creates a diagnostic challenge.

2. Case Report

A previously well 4‐year‐old girl presented with 1 week of mild haemoptysis during intercurrent illness with sore throat. The patient was Australian born, had history of atopic eczema and iron deficiency anaemia diagnosed at 12 months. There was no other relevant past medical history.

On examination, the patient was pale, afebrile, heart rate 125 beats per minute, blood pressure 100/50 mmHg, respiratory rate 24 breaths per minute, oxygen saturations 98% in room air. Weight 15.1 kg (15th percentile), height 106 cm (75th percentile). There was no clubbing or chest wall deformity. There was tonsillar erythema without exudate, chest clear on auscultation, systolic cardiac murmur, no organomegaly, rash or arthritis.

Investigations showed microcytic anaemia (haemoglobin 39 g/L), mean corpuscular volume 55 fL (77–96), ferritin 2 mcg/L (20–310). Coagulation profile, platelet count, erythrocyte sedimentation rate, renal/liver function normal. Faecal/urine microscopy negative. Chest radiography was normal.

The patient was commenced on oral amoxicillin/clavulanate and iron replacement. She continued to have daily haemoptysis over 3 months. Haemoglobin incremented to 75 g/L and remained stable.

Further investigations included: Immunoglobulin E (IgE) 637 units/L (< 200), antinuclear antibody 1:160, cow's milk specific IgE 1.45 (0–0.34), erythrocyte sedimentation rate 27 mm/h (0–7). Thyroid function, immunoglobulin levels, antineutrophil cytoplasmic antibodies (ANCA), rheumatoid factor, glomerular baseline membrane, coeliac antibodies, and interferon gamma release assay tests negative.

Flexible bronchoscopy showed punctate mucosal lesions in large airways, with blood‐stained lavage fluid. Cytology showed haemosiderin laden macrophages and Perl's stain was strongly positive. Lower airway fluid was negative for bacterial and mycobacterial culture.

Spirometry and transthoracic echocardiography were normal. Chest computed topography (CT) demonstrated bilateral ground glass opacity in keeping with pulmonary haemorrhage (Figure 1).

FIGURE 1.

Chest radiography with right sided pulmonary infiltrate and chest CT with contrast demonstrating pulmonary haemorrhage.

Treatment was continued with iron, tranexamic acid, and exclusion of cow's milk. Haemoptysis and anaemia escalated to necessitate red cell transfusion. Intravenous monthly methylprednisolone 15 mg/kg/day for 3 doses induced remission. On withdrawal of steroid, relapse was observed. Thoracoscopic lung biopsy was performed. Introduction of azathioprine induced stabilisation and was continued as monotherapy (Figure 2).

FIGURE 2.

Lung biopsy demonstrating alveolar haemorrhage, without capillaritis or immune complex deposition.

At 11 years, there was a recurrence of symptoms culminating in severe anaemia, haemodynamic instability, and type 1 respiratory failure. Treatments included intravenous methylprednisolone, antibiotics for bacterial infection, and change from azathioprine to mycophenolate. Repeat autoimmune serology did not reveal underlying diagnosis, and total Ige and cow's milk IgE had reduced into the expected range.

Given the severity of pulmonary haemorrhage and side effects with long term steroid use, rituximab 375 mg/m² weekly for 2 doses was commenced based on guidelines used for treatment of pulmonary capillaritis [2]. Disease activity measured by haemoptysis, chest radiography, anaemia, and lung function improved in line with B cell depletion. The patient has remained on maintenance mycophenolate and ceased steroid treatment.

At 6 months, she received a third dose of rituximab, remained clinically well, and returned to school for the first time in 12 months.

3. Discussion

IPH is a rare condition that predominantly presents in children. Most alternative causes for haemoptysis can be excluded based on history, examination, and microbiological investigation. In contrast, exclusion of autoimmunity is challenging.

There are several autoimmune conditions that present with haemoptysis. Pulmonary haemorrhage may be the initial presentation of autoimmune disease without other features, and autoantibodies may be absent in early disease. A case series showed that 25% of patients with IPH progress to formal autoimmune diagnosis [3]. To further complicate the matter, there are varying rates of antibody positivity in IPH, which has been reported as up to 92% [3]. The value of repeating serological tests in those with IPH may be revealing, albeit not in our case.

The place of lung biopsy is controversial in the diagnosis of IPH in children [3]. The risk of biopsy must be weighed with the potential to change management. The most common cause of autoimmune pulmonary haemorrhage is pulmonary capillaritis with cellular infiltrate and/or immune complex deposition [3]. Systemic vasculitis can be ANCA positive or negative, anti‐glomerular basement membrane disease (GBM), or serology positive connective tissue disease [3]. Autoimmune pulmonary haemorrhage can occur without capillaritis due to bland haemorrhage or diffuse alveolar damage, which can result in incorrect conclusions being drawn from lung biopsy [3].

Given the severity of our patient's condition, treatment was commenced for autoimmune pulmonary haemorrhage. Published data on the treatment of IPH is limited to small case series. Chin et al. surveyed 88 physicians caring for 274 patients with IPH focusing on treatment [4]. Corticosteroids were the most used agents for treatment of exacerbations, however, the route and dose regime varied significantly. For maintenance therapy, most respondents used corticosteroids, many used hydroxychloroquine (64%), azathioprine (37%), and cyclophosphamide (16%) as adjunctive treatment [4]. Rituximab treatment has recently been described in two cases of IPH without capillaritis [5] but is otherwise not described in the literature to date.

This case highlights an approach to haemoptysis, with a focus on the autoimmune causes of pulmonary haemorrhage. Exclusion of autoimmune aetiology may be difficult however, when first line treatment for IPH fails, immunosuppression should be considered.

Ethics Statement

The authors declare that appropriate written informed consent was obtained for the publication of this manuscript and accompanying images.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.