Article Type : Case Report
Authors : Kumar P, Zhenhui Lee S and Chew EL
Keywords : Pulmonary Alveolar Proteinosis; Chest radiographs; Bronchodilators
Pulmonary Alveolar
Proteinosis (PAP) is a rare syndrome characterised by accumulation of
surfactant lipoproteins in the alveoli. This is caused by decreased clearance
of surfactant, due to autoimmune, congenital or secondary causes. Patients may
be asymptomatic in mild cases, with more severe cases resulting in dyspnoea,
cough, sputum production, and systemic features such as weight loss, fever and
fatigue. Chest radiographs may show lung opacities, nodules or atelectasis. CT
scans may reveal ground glass opacification, and pulmonary function tests may
show reduced diffusion capacity. Though histopathological diagnosis is the gold
standard investigation, the combination of symptoms, clinical signs,
characteristic radiologic findings and diagnostic bronchoscopy lavage findings
are all used in clinical practice when diagnosing PAP. Therapies for PAP depend
on the severity and etiology. Bronchodilators and chest physiotherapy are used
in the treatment of mild PAP. Treatment options for severe cases include
whole-lung lavage, GM-CSF protein administration and rituximab therapy, with
whole-lung lavage being the standard therapy. This case report follows a 63
year-old-man with shortness of breath caused by PAP.
Pulmonary Alveolar
Proteinosis (PAP) is a rare pulmonary syndrome caused by accumulation of excess
non-secreted surfactant proteins trapped in alveoli and terminal airways [1].
This occurs due to insufficient surfactant protein clearance from alveolar
macrophages [2]. Consequently, gas exchange and pulmonary immunity is impaired,
resulting in respiratory symptoms ranging from dyspnoea and cough, to
respiratory failure [1,2]. In 1958, Rosen and colleagues first described PAP as
a disorder with periodic acid-Schiff (PAS) positive proteins filling the
alveoli [3]. Epidemiological studies since then have suggested that PAP has a male
predilection and typically causes respiratory disease in young to middle aged
patients [4].
A 63-year-old male presented to our hospital with a
6-month history of worsening shortness of breath. Over this time, the shortness
of breath had progressed from occurring on exertion to occurring at rest. Due
to this, the patient’s exercise tolerance had significantly reduced. The
patient did not report cough, sputum production, chest pain, fever, weight
loss, night sweats or fatigue. His past medical history included chronic
obstructive pulmonary disease, hypertension, gastroesophageal reflux disease
and arthritis.
On review, the pulse was 78 beats/min, blood pressure
138/60 mmHg; respiratory rate 18 breaths/min, oxygen saturation of 94% on room
air, and the patient was afebrile. Respiratory examination revealed decreased
air entry bilaterally, with air entry greater on the right side of the chest
compared to the left. No additional sounds were audible. Cardiovascular
examination revealed dual heart sounds with an end-systolic murmur radiating to
the carotids. Abdominal and neurological exams were unremarkable.
Laboratory tests were undertaken, with the patient’s
full blood count, electrolyte levels, kidney and liver functions being normal.
Additionally, autoimmune and infectious laboratory panels were all negative. An
arterial blood gas revealed a pH of 7.45, PCO2 of 31mmHg, PO2
of 59mmHg, SaO2 of 89% on room air and an A-a gradient of 51mmg.
A chest radiograph showed opacities in the middle and lower zones of the lungs with no pleural effusion (Figure 1).
Figure 1: CXR - Bilateral symmetrical opacities centrally in middle and lower lung zones.
Figure 2: CT scan - Ground-glass
opacities with thickened interlobular septa and intralobular lines bilaterally.
A CT scan of his chest revealed alveolar opacities in
the upper and lower zones with some mediastinal lymph nodes (Figure 2). The
patient’s pulmonary function test did not indicate airway obstruction or
restriction, and the lung volumes were within normal limits. However, a mild
impairment in gas exchange was evident. A six-minute walk test was performed,
which demonstrated an oxygen saturation drop from 91% to 85% after 3 minutes, a
maximum dyspnoea scale of 2, and a walking distance of 200m. An echocardiogram
showed normal right and left ventricle sizes and systolic function, with
moderate aortic stenosis and a grade 1 mitral regurgitation.
Following this, the patient had a bronchoscopy. This
revealed an inflamed left bronchial tree, mostly in the left upper lobe with
evidence of a non-specific interstitial fibrosis. His left bronchial alveolar
lavage revealed macrophages 33%, lymphocytes 42%, and neutrophils 25% on a
background of amorphous globular debris. There were positive foamy bodies on
PAS stain, with no malignant cells or acid-fast bacilli. His right bronchial
alveolar lavage was unremarkable.
The patient then underwent an elective video assisted thoracoscopic
lung biopsy. Intraoperatively it was noted that the left upper and lower lobes
had adhesions to the chest wall and the fissure was incomplete. Two biopsies
were taken from the upper and lower lobes. His left lower lobe biopsy showed
features suggestive of alveolar proteinosis (Figure 3). His left upper lobe
biopsy was unremarkable.
Figure 3: Histology - Alveolar spaces filled with eosinophilic granular materials (Hematoxylin and eosin stain).
Following these investigations, the patient was referred
to the respiratory outpatient clinic. A GM-CSF antibody test was performed
which was positive, and the patient was formally diagnosed with pulmonary
alveolar proteinosis. As he was clinically symptomatic with a PO2
<70 mmHg and P(A-a)O2 > 40, he was eligible for a whole lung
lavage. Following which, he was noted to have symptomatic improvement lasting
for more than a year. Over the next 3 years, he was continually reviewed in our
outpatient clinic with routine CT scans of his chest to assess for clinical
progression (Figure 4) and whole lung lavage was performed when clinically
indicated.
The estimated prevalence of PAP ranges from 3.7 to 40 cases per million people, varying between countries [2,3,5]. The incidence is reported to be 0.2 cases per million [2]. The rare syndrome affects all ethnic groups and has a male predisposition [5]. Autoimmune PAP is the most common etiology, making up roughly 90% of cases, followed by secondary PAP (4%) and congenital PAP (1%). The remaining 5% of cases is comprised of undetermined PAP-like diseases [4-6].
Figure
4: Post whole
lung lavage CT scan- Reduced ground glass opacities.
Surfactant, a
substance comprised of 90% lipids and 10% proteins, is responsible for reducing
alveolar surface tension and hence preventing airway collapse during
respiration [1]. It is also important for host defence in the lungs [2].
Surfactant is produced and secreted by alveolar type II pneumocytes, with
alveolar macrophages playing a role in the breakdown and clearance of
surfactant through phagocytosis [1,2]. Granulocyte macrophage colony
stimulating factor (GM-CSF) is a cytokine that is relevant to the
pathophysiology of PAP. It is responsible for the terminal differentiation of
macrophages, which is required for alveolar macrophages to be able to
phagocytise surfactant [5,6].
The aetiology of PAP
can be categorised into primary and secondary causes. The most common primary
cause is autoimmune PAP, where patients develop IgG antibodies against GM-CSF.
This results in impairment of alveolar macrophages, leading to accumulation of
surfactant in alveoli [2,5]. The other primary cause is congenital, whereby
there are genetic mutations implicating GM-CSF receptor proteins or surfactant
proteins [2]. Secondary causes of PAP occur due to decreased functional
macrophages. These secondary causes include infections (e.g. nocardia,
cytomegalovirus, mycotuberculosis bacterium), environmental irritants (e.g.
silica, cotton, cement, titanium, and nitrogen dioxide) and, haematological disorders
(e.g. myelodysplastic syndrome, leukemia, and multiple myeloma) [4].
The clinical
presentation of PAP is vague and most often presents as dyspnoea. Occasionally,
it can also present with a cough and gummy white sputum [1]. Systemic features
such as weight loss, fever and fatigue may also be present [7]. On clinical
examination, mild PAP presents asymptomatically. Severe PAP may present with
crackles on auscultation of lungs, clubbing, hypoxemia or cyanosis [6].
Laboratory studies
including serum lactate dehydrogenase (LDH), partial pressure of oxygen (PaO2)
and arterial-alveolar oxygen ratio (A-aPO2) have the utility of
assessing the disease severity of PAP [7]. The sensitivity and specificity of
anti-GM-CSF IgG antibody in the diagnosis of PAP is 92% and 100% respectively
[8]. Chest radiographs may show perihilar alveolar opacities, nodules or
atelectasis, while a CT scan of the chest may reveal ground-glass opacification
in middle or lower lung fields with thickened interlobular septa [6]. Pulmonary
function tests may show reduced diffusion capacity which correlates with the
disease severity of PAP [6-7]. A histopathological diagnosis is the
gold-standard investigation tool in the diagnosis of PAP, with eosinophilic,
granular material and foamy alveolar macrophages in alveoli spaces being
characteristic findings [7].
The management of
PAP is dependent on the severity of the disease. In the mild form of PAP,
physiotherapy and bronchodilators can be used [1,6]. In severe forms of PAP,
patients can undergo whole lung lavage, GM-CSF protein administration or
rituximab therapy as directed by a respiratory physician [1,2,4,5,7]. All
patients with PAP should have regular follow up in the outpatient setting with
pulmonary function tests and chest CT scans [6,7].
Whole lung lavage is
the gold standard treatment for primary and some secondary causes of PAP [4,5].
The invasive procedure is done under general anaesthesia and the patient is
intubated with a double lumen endotracheal tube [1,2]. Whilst one lung remains
ventilated, the other undergoes lavage, with 1-1.5 litres of warmed normal
saline repeatedly introduced to mechanically remove surfactant from the lungs
[1,2,4]. In our respiratory department, patients become eligible for whole lung
lavage if they are symptomatic and hypoxic with an ABG showing PO2<70mmHg
or P(A-a)O2>40mmHg.
GM-CSF therapy is an
alternative treatment strategy for autoimmune PAP which is well tolerated
compared to whole lung lavage, but results in a slower response [1]. The
therapy involves exogenous GM-CSF proteins being inhaled or subcutaneously
administered. Inhaled GM-CSF therapy is an emerging field, which has shown
positive results in early trials with minimal adverse effects. Finally,
immunosuppressive therapy with Rituximab (an anti-B cell monoclonal antibody)
is another potential alternative to whole lung lavage for patients with
autoimmune PAP [2]. Theoretically, the therapy would reduce levels of GM-CSF
autoantibodies. However, more research is required before the effectiveness of
this therapy can be concluded on [5].
PAP is a rare, complicated disease caused by the
failure to degrade surfactant proteins in alveoli, causing dyspnoea, and in
severe cases, respiratory distress. To date, the most effective therapy is
whole lung lavage therapies in combination with chest physiotherapy, resulting
in the mechanical removal of surfactant products from the alveoli, which
provides symptomatic relief for patients.
The author has no relevant affiliations or financial
involvement with a financial interest in or financial with the subject matter
or materials discussed in the manuscript.
Authors declare no conflict of interest.