Authors Puebla Neira, D. MD1. Angelova, E. MD2, PhD, Nishi, S. MD1. 1Division of Pulmonary and Critical Care Medicine. 2Department of Pathology. University of Texas Medical Branch 301 University Boulevard Galveston, TX 77555
Case
A 41-year-old male construction worker without significant past
medical history presented to the ER complaining of non-productive cough,
shortness of breath, profound fatigue, unintentional weight loss (15
lbs in one month) and fever worsening over several weeks. He was
admitted to the hospital and diagnosed with multilobar pneumonia based
on initial chest radiography (CXR). He was treated with antibiotics and
3 liters of supplemental oxygen. Computed tomography (CT) of the chest
revealed diffuse ground glass infiltrates predominantly in the lung
bases without evidence of pulmonary embolism (Figure 1). A bronchoscopy
with bronchoalveolar lavage (BAL) was done for cell counts, cultures
and cytopathology (Figure 2).
Figure 1Figure 2
Question
What is the diagnosis?
A. Cryptogenic organizing pneumonia B. Acute respiratory distress syndrome C. Idiopathic pulmonary fibrosis D. Pulmonary alveolar proteinosis E. Idiopathic non-specific interstitial pneumonia
Answer
Answer: D. Pulmonary alveolar proteinosis
Discussion
A high level of suspicion based on the combination of clinical,
laboratory and radiographic data is necessary to diagnose this disease.
Pulmonary alveolar proteinosis is characterized by accumulation of
Periodic acid-Schiff (PAS) positive lipoproteinaceous material in the
distal airspaces1. The lipoproteinaceous material (mostly
surfactant phospholipid and apoproteins) is the result of a variety of
disorders that affect the production and clearance of surfactant. The
etiologies can be autoimmune, hereditary, congenital or secondary to
high level dust exposures, hematologic malignancies or after allogeneic
hematopoietic cell transplantation1 (Table 1).
The clinical presentation is nonspecific. Most patients have
progressive shortness of breath, dry cough that worsens insidiously.
Other symptoms include chest pain, fatigue, joint pain, chills, weight
loss, and hemoptysis. Fever is unusual and should raise the suspicion
of infection. Physical exam findings are not specific and include
rales, digital clubbing and cyanosis (severe cases) 1.
A CXR finding of “bat wing” infiltrates (prominent perihilar region
infiltrates) can be found in this disease although it is not
pathognomonic. HRCT of the chest demonstrates patchy or diffuse
infiltrates (ground glass or consolidation). Often “crazy-paving”
pattern (Figure 4) on CT imaging is found and represents interlobular
septal thickening. Pulmonary function testing can show restrictive
changes with decreased diffusion capacity. Intrapulmonary shunt
physiology results in hypoxemia which can be profound1.
Additionally, GM-CSF auto-antibodies can be elevated, especially in
cases of autoimmune disease. Tissue sampling, either via bronchoscopic
BAL or surgical biopsy is necessary to confirm the presence of
lipoproteinaceous material. BAL fluid in PAP is classically milky in
appearance and shows large amounts of PAS-positive lipoproteinaceous
material1. Treatment depends on the severity of illness.
Mild cases may be observed, while patients who are symptomatic or shown
signs of progressive disease may be treated with whole lung lavage
(WLL). Standard treatment is management of the underlying inciting
trigger and treatment with recombinant GM-CSF subcutaneously if
auto-antibodies are present. Inhaled administration, although not FDA
approved, has also shown benefit, especially in refractory cases such as
our patient2,3 .
Table 1. PAP etiologies1
Autoimmune
Antibodies against GM-CSF
Hereditary
GM-CSF receptor defects
Congenital
Defects in surfactant-related gene variants
Secondary
High level dust exposures
Hematologic malignancies
After allogeneic hematopoietic cell
transplantation
In this patient, the diagnosis of PAP was established based on
clinical, radiologic and cytopathologic evidence. Clinically, he was
found to have polymyositis and significant exposure history associated
with PAP. BAL cytopathology (Figure 2A) showed Romanowsky stained
slides with amorphous proteinaceous aggregates (arrowhead) and (Figure
2B) Papanicolaou stain showed many alveolar macrophages, some with
engulfed amorphous material. The patient’s granulocyte monocyte colony
stimulating factor (GM-CSF) auto-antibody level was high and he was
started on immunosuppressive therapy and subcutaneous recombinant GM-CSF
(sargramostim). He underwent WLL with characteristic clearance of
lipoproteinaceous sediment on each successive lavage (Figure 3), but
required WLL every 3-6 months due to worsening of symptoms and
infiltrates on imaging. Subcutaneous administration of recombinant
GM-CSF was switched to nebulized administration and the patient has not
required WLL since.
Figure 3. Total lung lavage. First fluid obtained (left), last fluid obtained (right). Note the lipoproteinaceous material sediment at the bottom.Figure 4. Crazy paving pattern
References
Trapnell B, Whitsett J, Nakata K. Pulmonary Alveolar Proteinosis. N Engl J Med 2003; 349: 2527-39.
Reed J, Ikegami M, Cianciolo E, et. al. Aerosolized GM-CSF
ameliorates pulmonary alveolar proteinosis in GM-CSF-deficient mice.
American Journal of Physiology-Lung Cellular and Molecular
Physiology 1999; 276(4): L556-L563.
Yamamoto H, Yamaguchi E, Agata H, et. al. A combination therapy of
whole lung lavage and GM‐CSF inhalation in pulmonary alveolar
proteinosis. Pediatr Pulmonol 2008; 43: 828-30.
