Autoimmune pulmonary alveolar proteinosis and idiopathic pulmonary haemosiderosis: a dual pathology

Abstract

Pulmonary alveolar proteinosis (PAP) is a rare pulmonary condition which leads to excessive accumulation of proteinaceous material within the alveoli. Idiopathic pulmonary haemosiderosis (IPH) is another orphan lung disease and results in recurrent alveolar haemorrhage. This case study describes a case of these two rare pathologies occurring together. A man in his 50s presented with a 6-week history of haemoptysis and worsening dyspnoea. A CT scan of the thorax showed multifocal, bilateral ground glass opacification with a wide differential diagnosis. Full autoantibody screen including myositis panel and coeliac screen were negative. Bronchoscopy with bronchoalveolar lavage and tissue from a transbronchial lung cryobiopsy were non-diagnostic. Tissue from a video-assisted thoracoscopic surgery biopsy confirmed a diagnosis of PAP with IPH as a second separate pathology. The association of IPH and PAP has not previously been described. We discuss these conditions and postulate how and if they may be related.

Background

Pulmonary alveolar proteinosis (PAP) is a rare syndrome characterised by the accumulation of alveolar surfactant and dysfunction of alveolar macrophages (AM) resulting in defective gas exchange.¹ Symptoms include worsening dyspnoea, cough, haemoptysis, weight loss and night sweats, but approximately one-third of patients will be asymptomatic.^{2 3}

PAP can be classified into three types: primary, secondary and congenital. Primary PAP includes autoimmune PAP (aPAP) which constitutes 90% of cases⁴ and hereditary PAP which is due to a mutation in the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor.^{5 6} aPAP is characterised by the presence of IgG autoantibodies to GM-CSF.¹ GM-CSF autoantibodies bind to pulmonary GM-CSF with high affinity and specificity and neutralise GM-CSF functional activity.⁷ GM-CSF plays an essential role in surfactant haemostasis. Secondary PAP accounts for 10% of cases and is caused by conditions affecting either the function or quantity of AM such as infections (Nocardia, Cytomegalovirus, Mycobacterium, pneumocystis pneumonia, HIV), haematological disorders (myelodysplastic syndrome, acute myeloid leukaemia, acute lymphocytic leukaemia, chronic myeloid leukaemia, Hodgkin’s lymphoma) and inhalation of dusts or fumes (eg, silica) and malignancies (eg, melanoma).⁸ Congenital PAP comprises surfactant production disorders, usually caused by mutations in genes encoding surfactant proteins or proteins involved in lung development.⁴

Idiopathic pulmonary haemosiderosis (IPH) is a rare lung disease of uncertain aetiology which is characterised by a triad of haemoptysis, iron deficiency anaemia and pulmonary infiltrates on imaging and results in recurrent alveolar haemorrhage.⁹ However, this classic presentation is infrequent, and patients can present with a multitude of other symptoms including fever, fatigue, dry cough, chest pain and dyspnoea shortness.¹⁰ It usually presents in children but can also rarely present in adults.¹¹ The gold standard for diagnosis is a biopsy demonstrating haemosiderin laden macrophages.¹¹ This current case report describes a case of these two rare lung pathologies occurring together.

Case presentation

A man in his 50s, who was an ex-smoker, presented with a 6-week history of worsening dyspnoea and haemoptysis. He quantified his haemoptysis as being approximately 5 mL on most days over the proceeding weeks. His medical history was significant for ischaemic heart disease, type 2 diabetes, cardiomyopathy, hypercholesteremia and a raised body mass index. He previously worked as a carpenter. He had a CT scan of the thorax which showed multifocal ground glass opacification most confluent in the lower lobes bilaterally with a wide differential including interstitial lung disease, atypical pneumonia, vasculitis and haemorrhage (figure 1A). Examination on admission revealed that he had fine bibasal crackles. He was not clubbed. He was hypoxic with PaO₂ of 8.6 kPa on arterial blood gas analysis. Review of his recent CT scan then prompted further investigations.

Figure 1.

(A) CT scan of the thorax, December 2016: multifocal ground-glass opacification throughout both lungs, most confluent within the lower lobes bilaterally. This has a wide differential and can relate to infection (with atypical organisms within the differential), interstitial lung disease, hypersensitivity pneumonitis or vasculitis/pulmonary haemorrhage. Malignancy can rarely produce these appearances. (B) CT scan of the thorax, May 2018: 1 year post diagnosis. Mild improvement with no convincing evidence for disease progression.

Investigations

Bloods including an autoantibody screen, antineutrophilic cytoplasmic autoantibodies, coeliac screen and myositis panel were negative. An echocardiogram and cardiac catheterisation excluded valvular heart disease and pulmonary hypertension as a cause of pulmonary haemorrhage. Bronchoscopy with bronchoalveolar lavage (BAL) was carried out and was suggestive, but not diagnostic, of alveolar haemorrhage with scattered haemosiderin laden macrophages. The BAL on this occasion was noted to be slightly blood stained. The patient then proceeded to cryoprobe-assisted transbronchial biopsy of the right middle and lower lobe. This was suggestive of chronic inflammation and intra-alveolar haemorrhage but was overall non-diagnostic.

The patient then proceeded to video-assisted thoracoscopic surgery (VATS). Tissue from VATS of the right upper and lower lobes not only confirmed a diagnosis of likely IPH but also diagnosed PAP as a second separate pathology (figure 2). The dual diagnosis was confirmed by two independent pathologists and multiple multidisciplinary discussions. Serum GM-CSF autoantibody level was 53.3 µg/mL confirming a diagnosis of aPAP.

Figure 2.

Pathology slides following video-assisted thoracoscopic surgery (VATS) procedure of right lower and upper lobes. (A) Pathology slide post VATS procedure showing fresh alveolar haemorrhage (see arrow) (H&E; ×10 magnification). (B) Pulmonary haemosiderosis shows intraluminal haemosiderin-laden macrophages in alveolar lumina (H&E; ×20 magnification). (C) Perl’s iron stain showing the iron within the intra-alveolar macrophages.

Differential diagnosis

On initial presentation, the differential diagnosis for haemoptysis and dyspnoea included malignancy especially given that this man was an ex-smoker. This was ruled out following a review of his CT-thorax and bronchoscopy which did not show any endobronchial lesions. Further causes of haemoptysis include infection which was raised as a possible differential on the CT scan. The patient however did not have infective symptoms and cultures from bronchoscopy with BAL grew normal respiratory flora. Finally, vasculitis was considered as a differential and so a full autoantibody screen was carried out which was normal. This then prompted more invasive investigations such as a cryoprobe-assisted transbronchial lung biopsy and the VATS procedure to elucidate this patient’s symptoms.

Treatment

The patient’s haemoptysis was controlled with 20 mg prednisolone initially and was then tapered to 10 mg. This controlled his symptoms without the need for more invasive treatment. He was assessed for long-term oxygen therapy and remains on ambulatory oxygen currently.

Outcome and follow-up

The patient is alive and continues to be monitored in both the centre where he was initially diagnosed and a centre that specialises in rare lung diseases. His most recent pulmonary function tests (PFTs) were largely normal, although his carbon monoxide transfer factor has dropped from 106% predicted in May 2019 to 85% predicted on most recent PFTs in January 2020. His serum GM-CSF autoantibodies have been repeated on several occasions and remain positive.

Discussion

Disruption in the function or quantity of AM and ineffective surfactant catabolism leading to excessive surfactant derived phospholipids and protein components within the alveoli and distal airways leads to PAP.^{1 12 13} This results in impairment of gas exchange and respiratory insufficiency. Furthermore, ineffective AM function increases the risk of secondary infections and pulmonary fibrosis is a further risk factor later.1 2 12 14 A diagnosis of PAP requires a compatible history, typical radiological findings such as a chest X-ray showing a ‘butterfly’ or ‘bat wing’ pattern or CT evidence of ground glass opacification in geographical pattern termed ‘crazy paving pattern’.¹ Serum autoantibodies to GM-CSF should be tested as the sensitivity and specificity in aPAP approaches 100%.¹⁵ A tissue diagnosis from either BAL or lung biopsy may also be required.

Whole lung lavage (WLL) is the gold standard treatment of PAP and involves washing the affected lungs with normal saline.¹³ The use of exogenous GM-CSF either inhaled or subcutaneously has also been considered as a treatment for aPAP when used either alone or in conjunction with WLL.^{16 17} Rituximab has also been shown to be an effective, safe treatment for aPAP.^18–20 The treatment of secondary cases of PAP involves treatment of the underlying disease or causative factor.

The exact pathogenesis of IPH is unknown although autoimmune, genetic (there are case reports in siblings), environmental (eg, toxins, pesticides) and allergic (eg, allergy to cow’s milk) mechanisms have all been proposed.9 11 21 22 IPH is usually responsive to steroids which can reduce bleeding and prevent progression to fibrosis. Furthermore, those with IPH often have secondary autoimmune conditions such as coeliac disease which supports an autoimmune mechanism of pathogenesis.⁹ Resistant or progressive disease may require treatment with agents like azathioprine or cyclophosphamide.

The association of IPH and PAP has not previously been described in the literature. It is generally advised to avoid corticosteroids in PAP as they can worsen severity and increase the risk of opportunistic infections through suppression of B-cell function and inhibition of catabolism and phagocytosis by AM.²³ It is not clear why the use of steroids in this case did not exacerbate the patients underlying PAP. However, what is clear is that with the use of steroids, the patient’s symptoms and radiology improved.

Like the process described for intraplaque haemorrhage in atherosclerotic plaques,^24–26 AM are responsible for the repeated clearance of excess blood generated in IPH.²⁷ One potential hypothesis that could link IPH and PAP is that, as a result of IPH, the iron filled AM become dysfunctional and therefore are unable to carry out the task of surfactant clearance leading to PAP. This would be consistent, however, with a secondary form of PAP and so should not be associated with auto antibodies to GM-CSF as seen in this case. It is known that auto antibodies to GM-CSF exist, although in lower concentrations, in other pulmonary diseases and in healthy subjects. It is also certainly a possibility that this man presents with two rare lung pathologies that are unrelated.

In conclusion, the above case report describes a case of two rare lung pathologies occurring in the same patient. Treatment with steroids improved the patient’s symptoms. A potential mechanism underlying the association of these two conditions has been hypothesised but it is also possible that there is no association between the two diseases and that this is truly an exceptionally rare case.

Learning points.

• This case report highlights the pathophysiology and diagnostic features of two rare lung diseases.

• It highlights the importance of thorough investigation and the value of a biopsy when a lung disease is not easily explained.

• Although steroids are contraindicated in pulmonary alveolar proteinosis, as it increases the risk of opportunistic infections, steroids in this case did help control the patient’s symptoms.