Pulmonary aveolar proteinosis (PAP) is an extremely rare lung disease (fewer than one case per million of population) in which the alveoli of the lung become congested with a mixture of excess lipo-protein (surfactant derived) material and non-functional macrophages.
Gas exchange, particularly for oxygen can become severely impaired as a result and symptoms include breathlessness, cough and chest pain though some patients present with minimal symptoms or as a result of incidental discovery of the characteristic airspace shadowing on plain chest radiograph or CT.
Since the disease was first described in 1958, there has been a sort of "rule of thirds" with a third of patients having very mild disease with little tendency to progression and little or no need for specific treatment. A third of patients have severe symptoms and incapacity and require treatment and usually eventually resolve. The last third have very severe PAP with severe and progressive incapacity and may respond poorly to treatment and only after prolonged treatment.
Treatment with whole lung lavage
The main treatment of PAP is massive whole lung lavage (WLL) which requires prolonged general anaesthesia and is critically dependant on perfect lung separation by double-lumen endobronchial tube. WLL is a 3-to-5 hour procedure and benefits from technical support from the perfusion department.
In many cases, PAP responds well to a series of WLL procedures but is somewhat unpredictable, so individual patients have a wide range in requirement of WLL episodes before obtaining prolonged (or even permanent) satisfactory remission. WLL is a specialist procedure, in part because of its component elements but mainly because of the extreme rarity of the target illness and the low likelihood of expertise developing except when the caseload is concentrated in a small number of centres worldwide.
Royal Brompton Hospital is certainly such a centre and has one of the largest personal series of PAP in the world (as of May 2008 over 50 patients with PAP treated by 470 episodes of WLL between 1986 and 2008).
Developments in treatment
In the past decade there has been a tremendous increase in knowledge of patho-physiology of PAP and this has encouraging implications for treatment. The central role of Granulocyte Monocyte Colony Stimulating Factor (GMCSF) in the regulation of the normal alveolar macrophage is now understood and therefore the consequences of loss of GMCSF regulation predictably leads to loss of alveolar macrophage participation in surfactant turnover (lipo-protein accumulation in alveoli) and impairment of alveolar host defence (increased risk of opportunistic infection).
The majority of adult patients with PAP have very high concentrations of an IgG antibody to GMCSF circulating and effectively neutralising GMCSF expression. There is much interest in treating PAP with exogenous GMCSF, either by systemic injection or by inhalation of aerosol GMCSF and initial reported (and as yet unreported) results are encouraging.
Status of PAP treatment at Royal Brompton Hospital
The standard approach is to welcome referrals of patients diagnosed or suspected of having PAP. Dr Cliff Morgan works in conjunction with Professor Athol Wells and Dr Elisabeth Renzoni, both consultants in respiratory medicine – interstitial lung disease (ILD), to receive any such referrals.
In all cases the diagnosis is reviewed (original investigations plus repeat / additional as required) and is generally confidently accepted on the basis of history, absence of other positive disease, chest CT and analysis of bronchoalveolar lavage (BAL). This is done in conjunction with colleagues from imaging and histopathology. Only rarely is an open lung biopsy required to make or quantify the diagnosis of PAP.
Treatment is on the basis of any level of functional impairment and is by a programme of WLL treatments in the first instance. The vast majority of patients with PAP should be expected to obtain satisfactory and prolonged remission after between two and six episodes of WLL.
Those with poor response or rapidly relapsing disease are considered for a trial of treatment by inhaled aerosol GMCSF (May 2008 – 4 started, 2 pending) and while initial results are encouraging it is too early to make scientific comment. There are additional options for patients who fail to respond to both these mainstays of treatment, including selective immuno-suppression with Rituximab and antibody clearance with plasmapheresis and the next decade should define the true role of these modalities.
Royal Brompton Hospital is working with international experts in PAP in Europe, USA, Australia and Japan through an initiative of the NIH – Rare Lung Disease Consortium / PAP and also supports the patient support group, based in the USA, the PAP Foundation.
Read our information for patients.
