Alveolar proteinosis in a patient recovering from Pneumocystis carinii
case report with a review of literature.
Pulmonary alveolar proteinosis is a rare lung disorder, which was first reported
as idiopathic condition in 1958. The prevalence of acquired pulmonary alveolar
proteinosis has been estimated to be 0.37 per 100,000 population. The cause of
this condition is not entirely clear. We present alveolar proteinosis in a case
recently treated for pulmonary Pneumocystis carinii infection.
A 25-year-old Caucasian female presented with shortness of breath during
management of acute pancreatitis. She had a heart-transplant six years ago, a
distal pancreatectomy secondary to pancreatitis two years ago, chronic renal
failure secondary to Prograft taken for six years to suppress transplant rejection,
and a more recent history of Pneumocystis carinii
infection treated in the
preceding 21 days with augmented doses of Bactrim (Trimethoprim,
Sulfamethoxazole). She had bilateral pleural effusions with radiological and
clinical features suspicious for interstitial lung disease. Cytopathologic evaluation
of broncho-alveolar lavage (BAL) showed hyaline alveolar casts admixed with
amorphous debris and scant chronic inflammatory cells, consistent with alveolar
proteinosis. GMS and PAS stains were negative for P. carinii
. Direct Fluorescent
Antibody (DFA) test for P. carinii
performed on the BAL specimen in our
Microbiology Lab had been repeatedly negative.
Cytopathological findings in bronchoalveolar lavage, with clinical differential
diagnosis of interstitial lung disease, were diagnostic. Pulmonary alveolar
proteinosis after recent treatment for P. carinii
infection suggests a relationship of
Pulmonary alveolar proteinosis is an accumulation of abundant extra cellular
periodic acid-Schiff (PAS) positive proteinaceous material in alveolar spaces. It
was first described as an idiopathic condition in 1958 . This material
represents surfactant distending the alveolar space. Papanicolaou-stained
smears of bronchoalveolar lavage (BAL) fluid show characteristic hyaline
globular alveolar casts which are green, or orange, or centrally orange with a
green rim . The globules may show scant cells “hugging” the periphery, which
appear to be imprints of the pulmonary alveoli with occasional carry-over of
pneumocytes lining the alveoli. Electron microscopy demonstrates whorled
myelin figures characteristic of surfactant .
A 25-year-old Caucasian female with a history of heart transplant, presented with
shortness of breath. Twenty one days prior to her presentation, she had P. carinii
pneumonia for which she was treated with augmented doses of Bactrim
(Trimethoprim, Sulfamethoxazole). She also noticed a progressive lower
extremity edema, pleuritic chest pain, dry cough, and chills. She was diagnosed
as chronic renal failure and was started on hemodialysis as an outpatient. During
hemodialysis, she experienced abdominal pain radiating to the back. She
presented to the emergency room with acute respiratory distress syndrome and
acute pancreatitis secondary to a stone in the pancreatic duct. She was admitted
and shortly after, she required intubation because of decreased oxygen
saturation. A chest X-ray showed increased interstitial markings, suggestive of
interstitial lung disease. Bilateral pleural effusions were also noted and attributed
to the chronic renal failure with fluid overload. Recurrence of P. carinii
was also considered a possibility. BAL was performed as part of a diagnostic-
treatment protocol and 15 cc of cloudy pinkish fluid was sent for cytopathologic
evaluation. Two Papanicolaou (PAP) stained SurePathTM preparations were
The PAP stained SurePath preparations showed characteristic globular alveolar
casts of amorphous material which stained green, orange, and centrally orange
with a green rim (Figure 1). This material was PAS positive and was resistant to
diastase (Figure 2). GMS stain (Figure 3) did not show the characteristic crushed
ping-pong ball like structures with central to eccentric dots (Figure 3 a, b)
observed in the frothy casts associated with P. carinii
pneumonia (Figure 3 c, d).
Oxygen saturation improved after BAL procedure. Three days later she was
extubated, and was discharged within a week. Apart from a hysterectomy for
severe cervical dysplasia six months after this event, she has had an uneventful
healthy course. Currently she is alive and well.
Although pulmonary alveolar proteinosis is usually difficult to differentiate
clinically and radiologically from interstitial lung disease, it can be recognized in
BAL. BAL fluid in alveolar proteinosis is usually opaque on gross appearance.
Proper interpretation of BAL in these cases spares the patient an open lung
biopsy. This is especially important for debilitated or transplant patients, because
pulmonary alveolar proteinosis may be amenable to treatment by a simple
The globular alveolar casts of pulmonary alveolar proteinosis should be
distinguished from foamy alveolar casts of P. carinii
in BAL specimens. In
alveolar proteinosis the globular structures are hyaline as compared to foamy in
P. carinii. The globular extra cellular hyaline material is PAS (diastase resistant)
positive (Figure 2). The morphological details should be scrutinized under higher
magnification, especially at the periphery of these casts. The foamy casts in P.
show distinct dark dots in individual vacuoles even in PAP stained
preparations. If the details cannot be appreciated in PAP stained preparations,
special stain such as GMS are helpful (Figure 3). P. carinii
demonstrate characteristic crushed “ping-pong” ball-like GMS stained dark P.
cysts-structures in the frothy casts (Figure 3 c,d). They are not present in
the hyaline casts of alveolar proteinosis (Figure 3 a,b).
As demonstrated in humans and mouse models, ultrastructurally the alveolar
spaces in pulmonary alveolar proteinosis show numerous lamellar bodies with a
structural resemblance to myelin. These lamellar bodies are similar to the
surfactant present in type II pneumocytes. It is hypothesized that hyperplasic and
hypertrophic type II pneumocytes produce increased amounts of lamellar bodies
and develop into mononucleated giant balloon cells . When they rupture, these
mononucleated giant cells liberate numerous myelinoid structures, lipid droplets,
and many electron dense amorphous acicular crystals which are closely
associated with the extracellular membranous material.
Pulmonary alveolar proteinosis occurs in three clinically distinct forms: idiopathic,
, and secondary
pulmonary alveolar proteinosis has been an enigmatic acquired
disorder since its initial description . The exact etiology of this variant is not
entirely clear but appears to be multifactorial, comprising the combined effect of
infectious, environmental and hereditary factors.
form comprises of a heterogeneous group of disorders  caused
by mutations in the genes encoding surfactant protein B or C or the C chain of
the receptor for granulocyte-macrophage colony-stimulating factor (GM-CSF) [7,
Most of the studies report the congenital form of alveolar proteinosis. One
possible explanation for this form revolves around surfactant. Normally,
surfactant is inactivated by mechanical and biologic processes and converted
into small, surface-inactive aggregates. Approximately 70 to 80 percent of the
small aggregates are taken up by alveolar type II pneumocytes, transported to
phagolysosomes, and reused or catabolized. Alveolar macrophages internalize
and catabolize the remaining surfactant pool, a process critically dependent on
GM-CSF. Some patients with alveolar proteinosis have shown to have genetic
defects rendering the GM-CSF receptor ineffective. The interruption of GM-CSF
signaling in the alveolar macrophage, for example, by targeted ablation of the
gene encoding GM-CSF or its receptor in mice or, presumably, by neutralizing
anti- GM-CSF auto antibodies in humans, causes accumulations of eosinophilic
lipoproteinaceous material and large, foamy macrophages in the alveoli .
pulmonary alveolar proteinosis develops in association with
conditions involving functional impairment or reduced numbers of alveolar
macrophages. Such conditions include some hematologic malignancies,
pharmacologic immune suppression, inhalation of inorganic dust (e.g., silica) or
toxic fumes, and certain infections .
The relationship of pulmonary alveolar proteinosis with recently treated P. carinii
infection has not been specifically stressed previously. However, one case from a
series describing spectrum of morphological changes in alveolar spaces,
associates co-trimoxazole (Trimethoprim, Sulfamethoxazole) treated P. carinii
pneumonia with alveolar proteinosis. Ultra structural examination of alveoli in
case number 5 of this study showed lamellar-body-like structures resembling
those of alveolar proteinosis . Our case was also recently treated for P. carinii
infection with Bactrim (Trimethoprim, Sulfamethoxazole, co-trimoxazole). The
patient improved after BAL and was discharged.
This case suggests a link between treated P. carinii
infection and pulmonary
alveolar proteinosis in this immunocompromised heart transplant patient. The
treated P. carinii organisms may lead to accumulation of lamellar-body-like
structures in alveolar spaces with resultant alveolar proteinosis, which if
diagnosed correctly could be treated with appropriate therapy including relatively
simple procedure such as BAL. Similar reports have linked pulmonary alveolar
proteinosis with Mycobacterium avium -intracellulare  and also with active P.
carinii infection as well as other opportunistic infections . The later report also
stresses the connection between immunosuppressed patients and pulmonary
In summary, this case highlights the importance of differentiating P. carinii
infection from alveolar proteinosis with emphasis on correct differentiation of the
frothy globular casts in P. carinii infection from the hyaline globular casts in
alveolar proteinosis. Correct interpretation of BAL would facilitate proper
management and clinical recovery. A relationship between Bactrim treated
and Pulmonary Alveolar Proteinosis should be considered during the
List of abbreviations
PAP, Papanicolaou stain; BAL, Broncho Alveolar Lavage; GMS, Grocott
Methanamine Silver; GM-CSF, granulocyte–macrophage colony-stimulating
factor; PAS, periodic acid-Schiff; PCP, Pneumocystis carinii
Competing interests are not present in this case.
PK, Cytopathology fellow, collected all the data, participated in cytological
VS, Conceptual organization, cytological-histological evaluation, and manuscript
1. We would like to thank Dr. Basil Varkey for reviewing the manuscript and his
2. Due to the archival nature of the case and only one patient involved as well as
the absence of any potentially identifying patient information, the Institutional
Review Board at the Medical College of Wisconsin, Milwaukee, did not require
patient authorization for this case report.
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Characteristic Features Pulmonary Alveolar
Appearance of the
Dark central dots in the
cyst-like structures by
fungal stains ( GMS,
Characteristic globular alveolar casts of amorphous cyanophilic to acidophilic
debris (a) are admixed with relatively scant cells (b). Some hyaline globules
demonstrate two tone staining (c). The globules of variable sizes range in shapes
and dimensions corresponding with alveolar spaces. Occasional pneumocytes
may be seen “hugging” the periphery of globules (arrow in d). This is different
from the frothy appearance of casts associated with P. carinii
show individual vacuoles with central to eccentric dots. (Bronchoalveolar lavage;
The extra-cellular globular hyaline material is homogeneously PAS positive after
diastase (a, b) without any organisms, as compared to the presence of
organisms in P. carinii associated frothy alveolar casts (see figure 3).
Bronchoalveolar lavage; Periodic-Acid Schiff (PAS) stained SurePath PrepTM)
The hyaline globules in the amorphous material do not show any organisms with
GMS stain (a,b). Compare this with appearance of PCP in positive control (c,d),
which shows frothy casts with the characteristic crushed ping-pong ball like
organisms (c) with small central to eccentric dots (arrow in d). (Bronchoalveolar
lavage; Gomori-Silver Methanamine (GMS) stained SurePath PrepTM).
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