AMERICAN JOURNAL OF CLINICAL PATHOLOGY
Vol. 34, No. 4, October, 1060, pp. 365-370
Printed in U.S.A.
FATAL PNEUMOCYSTIS PNEUMONIA IN AN ADULT
REPORT OF A CASE
C. D. ANDERSON, M.D., AND H. J. BARRIE, B.M., B.CH.
Department of Pathology, University of Toronto, Toronto, Canada
Neonatal pneumonia caused by Pneumocystis carinii has been well recognized in
Europe for some years7 and the pertinent
literature has been recently summarized by
Gajdusek.3 A case was reported in the United
States in 19562 and there have been several
cases from Canada. 1 • 5 The parasite has
been observed in the lungs of a 9J^-monthold boy suffering from hypogammaglobulinema,6 and in adults with cytomegalic
inclusion disease4 and liodgkin's disease.7
We are not aware of any reports of deaths
in adults being caused primarily by infection
with Pneumocystis. This paper deals with
such an instance, a 36-year-old man whose
lungs became so full of the parasite that he
suffocated. The case provided us with an
opportunity of studying the histopathology
of this condition in lungs other than neonatal.
R E P O R T O F CASE
Clinical History
0 . Y., a 36-year-old Japanese man, was
admitted to the Toronto General Hospital
on December 12, 1958, complaining of difficulty in breathing for approximately 6
weeks.
He had been well until March 1958, at
which time he had a 5-day illness characterized by fever, chills, headache, and mild
nonproductive cough. He recovered from
this episode but had similar illnesses in
May, July, and September, each lasting
approximately 1 week. In late October,
7 weeks before admission to the hospital,
he developed sharp pain in the front of the
chest when breathing deeply, and first noted
moderate dyspnea on exertion. Three days
later, he became febrile and developed
Received, March 14, 1960; revision received,
April 2S; accepted for publication June 1.
Dr. Anderson is Fellow, and Dr. Barrie is Professor.
*
drenching night sweats. These symptoms
progressed until admission, by which time
his pain radiated to his epigastrium on
inspiration, and dyspnea limited activity to
ascending 1 flight of stairs.
He had lost approximately 7 lb. since his
first symptoms in March. Except for a vague
story of polyarthralgia with some of the
early febrile episodes, there were no other
symptoms. He was a carpenter and had no
known exposure to dusts, and there was no
known contact with tuberculosis or other
infectious diseases.
Physical examination revealed that the
patient was thin, but normally developed.
There was no clubbing of the fingers or
cyanosis. His temperature was 99.5 F., blood
pressure 100/58, and pulse rate 84 per min.
He was orthopneic and expansion of his
chest was decreased bilaterally. The pulmonary fields were resonant, no rales were
present, but breath sounds were almost
bronchial in quality over the apices.
His concentration of hemoglobin was 84
per cent, erythrocyte sedimentation rate
65 mm. in 1 hr., and white blood cell count
14,400 per cu.mm., with normal differential.
The x-ray film of the chest revealed widespread patchy consolidation, with some
sparing of the upper lobe of the right lung,
and was thought to indicate an inflammatory
process, possibly sarcoidosis. Serum calcium was 10.8 Gm. per ml. LE cells were
not observed. Specimens of sputum were
negative for common pathogens, tubercle
bacilli, and fungi, and the results of blood
cultures were also negative. Skin tests with
coccidioidin, blastomycin, histoplasinin, and
toxoplasmin were negative, but the reaction
to old tuberculin was positive. Brucella
agglutination was positive to 1:100. Electrophoresis of serum protein revealed slight
elevation of alpha-2 globulin fraction.
Bronchoscopy was performed, and the
smears of material removed were reported as
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ANDERSON AND BARRIE
normal. Bone marrow was normal, but
biopsy of a scalene lymph node revealed
nonspecific inflammatory changes.
While in the hospital, the patient became
steadily more dyspneic, and evanescent
rales and friction rubs were heard. He had
a low-grade fever that was not affected by
therapy with Chloromycetin, or antituberculous triple chemotherapy, but it responded
to closes of prednisone, 100 mg. per day.
The patient's condition continued to deteriorate, however, and he died of respiratory insufficiency on the twelfth day of this
therapy, 6 weeks after admission to the
hospital.
Necropsy Findings
Gross findings. There were dense pleural
adhesions bilaterally. The lungs were fully
expanded, and the weights of the right and
left lungs were, respectively, 1035 and
865 Gm. There were a few subpleural emphysematous blebs over the anterior portions, the remainder of the lungs being rubbery in consistency. Examination of the
interior revealed that the lungs were airless,
except for cystic areas in the anterior portions of the upper lobes. Most of the parenchyma was gray, although there were dull
red regions in both of the upper lobes. The
bronchi, blood vessels, and hilar lymph
nodes were normal. There were no other
abnormalities in the various organs, except
for the liver, which manifested slight nodularity. The weight of the liver was 1425 Gm.,
and that of the spleen 125 Gm.
Microscopic findings. The intra-alveolar
material in Pneumocystis pneumonia has a
characteristic appearance. The last 2 words
are so frequently coupled in descriptions of
sections that their impact is negligible, but
their use on this occasion is amply justified,
as may be confirmed by comparing our
illustrations with all of the previously described cases. The foamy material filling the
air spaces is recognizable at a glance (Figs. 1
to 3). In our case, none of the sections from
either lung was free from this substance,
and, as has been described, it often had a
central area that stained dark red with
eosin, and also a paler periphery of looser
texture. The periodic acid-Schiff (PAS)
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stain colors the mucoid envelopes of the
protozoa, and with this stain, under high
power, the difference in these 2 zones was
observed to be caused by differences in
compression of the organism. Many of the
envelopes seemed to be empty, but, in others,
small dots or bars of nuclear material were
frequently visible (Fig. 3). In the center,
where compression was greatest, the outlines
of individual organisms were not recognizable. With Gomori's silver methenamine
method, the main mass of PAS-positive
debris was not impregnated with silver, but
isolated intact organisms stained well.
Changes in the pulmonary tissue were not
uniform, there being 3 chief types of change.
The various types occurred in different
lobules of the lung, but all of the sections
examined revealed all 3 types of change,
so that there seemed to be no preferential
site where the changes could be thought to
be of longer standing than others.
The first appearance (Fig. 4) was as
though the air spaces, even as far as the
alveolar sacs, had been injected solidly with
the protozoa. The interalveolar spurs were
recognizable and intact, and the alveolar
walls were thin and without any swelling
of the epithelial cells. The capillaries were
compressed and empty, and, because of
this, the endothelial nuclei were approximated, thereby resulting in the septums
manifesting a cellular appearance. This
"injected" arrangement occupied less of the
lung than the second.
In the second appearance or arrangement,
the air spaces contained fewer parasites,
and the alveolar sacs and interalveolar spurs
were distinguishable only with difficulty.
The air spaces, consisting chiefly of atriums
and alveolar ducts, were separated from each
other by partitions whose thickness was
partly caused by folding of the interalveolar
spurs, but mostly by a striking edema of the
alveolar walls. This edema, by widely separating the components of the alveolar walls,
provided them with the appearance of an
engineer's "exploded" drawing of a component. This appearance can be distinguished easily in Figures 1 and 2, and Figure
5 is an illustration of 1 of the "exploded"
alveolar walls lined on 1 side by a bar of
F I G S . 1 and 2 (upper left and upper right). Characteristic foamy appearance of Pneumocystis
carinii in the air spaces. Notice the paucity of cellular infiltration. Hematoxylin and eosin. Respectively, X 240 and X 390.
F I G . 3 (lower left). The small dots and bars can be distinguished inside the envelopes, and the
arrow in the top right corner indicates a histiocyte t h a t contains organisms. Hematoxylin and
eosin. X 975.
F I G . 4 (lower right). Pneumocystis cells distending alveolar sacs. Interalveolar spurs arc recognizable. Hematoxylin and eosin. X 400.
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ANDERSON AND BARRIE
greatly swollen epithelial cells. This bar is
separated, by a space, from a tightly contracted capillary, and this, by another space,
from swollen mesenchymal cells and possibly
some histiocytes.
The next set of capillaries is coiled and
dilated and may belong to a folded spur.
The epithelium covering the lower surface
of the spur has degenerated into a structureless membrane. This "exploded" view of the
alveolar walls made it relatively easy to
study the relations of the protozoa to the
epithelial cells and to interstitial histiocytes.
With the hematoxylin and eosin stain, no
parasites were visible in the epithelial cells,
or even in the occasional intra-alveolar giant
cells. With the periodic acid-Schiff stain,
parasites were recognizable in some of the
giant cells, in some of the intra-alveolar
histiocytes, and in rare histiocytes present
in the tissue spaces of the alveolar walls.
Approximately 1 in 10 of the epithelial cells
contained clots or bars of PAS-positive
material in their cytoplasm. This "exploded"
picture of the alveolar wall was occasionally
blurred as a result of infiltration with
mononuclear cells, but this was not conspicuous. In rare instances, the thickened
wall had been over-run with isometric
fibroblasts. Even more rarely, there were
some intra-alveolar polyps of cellular connective tissue.
The third type of change observed in the
lungs was apparently caused by obstruction
of the mouths of the atriums by hyaline
membranes. In the affected lobules, the
number of parasites in the air spaces was
very few; hypertrophy of the epithelium
was slight. In the collapsed periphery of the
lobules, the alveolar capillaries were still
recognizable as a result of their enormous
dilatation with blood (Fig. 6). These collapsed lobules accounted for less than one
fifth of the pulmonary tissue in any one
section. There was negligible fibrosis of the
collapsed portions.
Apart from the 3 simple types of change
just described, there were no abnormalities.
The perivascular lymphatics were free from
parasites or infiltrations of lymphocytes,
and the pulmonary vessels were thin-walled
and manifested no thickening of the intima.
The bronchi were tightly contracted -and
empty, except for a little mucin, but
streamers of mucin and entangled parasites
projected into many of the bronchioles from
the alveolar ducts. Examination of neither
the alveolar ducts nor the respiratory bronchioles revealed any ectasia, and the cysts
observed in the gross study were probably
caused by interstitial air derived from
terminal rupture of some of the alveolar
walls. The walls of many of the alveolar
ducts had a gelatinous semiliquefied appearance.
Examination of the liver revealed a mild
cirrhosis of uncertain origin, the portal
tracts being joined by long delicate bands of
mature collagen. Extremely few of the
lobules were split by fibrous tissue. No parasites were visible in Kupffer cells. Dilatation
of the intrahepatic radicles of the portal
vein and thickening of the splenic pulp
suggested that there had been some portal
hypertension. No parasites were observed
in the spleen. The only extrapulmonary parasites observed were in the sinuses of a hilar
node. They were difficult to distinguish in
the hematoxylin and eosin stains, because
of coincident vacuolation of the cytoplasm
of the histiocytes resulting from erythrophagocytosis, but the organisms could be
recognized with the periodic acid-Schiff
stain.
DISCUSSION
We could find no evidence that the Pneumocystis infection in this man was secondary
to some other disease. None of the hypertrophied epithelial cells contained inclusions
to suggest the presence of cytomegalic
inclusion disease. The only other evidence
of disease was the mild cirrhosis, but there
were negligible changes in the plasma proteins, and we do not know how this could
have predisposed to infection by Pneumocystis. The therapy with prednisone was of
too short duration to have been related
causally. The high titer of agglutinins in his
serum for Brucella abortus was of some
interest, and it is almost certain that he had
been exposed to that organism. The occasional polyps of intra-alveolar fibrosis
observed in the lungs were probably the
Oct. I960
PNEUMOCYSTIS INFECTION
369
FIG. 5 (left). Two alveolar ducts separated by a partition of alveolar wall and folded infcralveolar
spurs. Extreme edema isolates the components of the partition. A giant cell lies in the alveolar duct in
the lower part of the field. Hematoxylin and eosin. X 400.
Fir.. 6 (right). There is more folding of the pulmonary structure and the alveolar capillaries are greatly
distended with blood. Hematoxylin and eosin. X 250.
result of mild intercurrent attacks of partly
unresolved bronchopneumonia, but could
hardly be held to take precedence to the
Pneumocystis infection in explaining the
man's recurrent severe respiratory symptoms
during the year prior to death.
If one can draw a parallel between the
clinical course of a disseminated pulmonary
infection with a fungus, such as Histoplasma, and that of an infection by the
protozoan Pneumocystis, the time-span in
this case of a year for the infection to run its
course would be acceptable.
in order to compare the histopathology of
these 2 diseases, one has only to underline
the relative inertia of the tissues to Pneumocystis.
According to Vanek and his associates,7
this parasite never undergoes intracellular
development, although it has been observed
in the cytoplasm of phagocytes. Even
phagocytosis, however, is negligible. Alveolar
histiocytes usually engulf any foreign material in the air spaces, however inert chemically, but the mucoid envelopes of Pneumocystis seem, for the most part, to be
untouchable; in the portions of lung already
described as seeming to be "injected" with
the parasites, there was no cellular reaction
in the alveolar walls.
The edema causing the so-called "exploded" alveolar walls might well be a
terminal phenomenon, for this appearance
is common to many forms of injury of the
alveolar wall.
The lobules that were collapsed at
necropsy had apparently been keeping the
man alive until the collapse was induced in
them by formation of hyaline membranes
over the mouths of the atriums. It is possible that hyperventilation of these few areas
was responsible for the formation of hyaline
membranes.
Thus, there was little that one could com-
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ANDERSON AND BARRIE
pare with the cellular interstitial and intraalveolar exudate that is common in histoplasmosis, and, of course, the organisms in
the latter disease seem to have a strong
chemotaxis for histiocytes and are rarely
observed not phagocytized. In our case of
Pneumocystis infection, the number of
alveolar walls with infiltration of lymphocytes was extremely small. The parasites
just seem to have gone on proliferating in
the lung until insufficient air spaces remained.
We have no clue as to where the infection
started. The uniform involvement of both
lungs was remarkable, and the streamers of
mucin and organisms projecting into the
small bronchi provided a clue as to the route
of spread. The mucoid envelopes seemed to
be breaking up in the bronchioles, but
fortunately the slides of the material removed at bronchoscopy were still available
and review of them revealed that the organisms could be recognized. They consisted
chiefly of empty envelopes without central
chromatin dots, and, because of their faintly
staining character, they were inconspicuous.
They were PAS-positive, but no material
was available for impregnation by means of
the method with silver methenamine. From
our experience with the sections of lung, we
doubt that the impregnation with silver
would have helped to demonstrate the
envelopes. The demonstration of organisms
in the bronchial secretion, however, is of
obvious importance in the future diagnosis
of this condition.
SUMMARY
Necropsy of a 36-year-old man revealed
that he had suffered from almost solid filling
of his lung with Pneumocystis carinii. The
patient had been ill for 10 months, with
increasingly frequent attacks of fever, chills,
and cough, and he had no intercurrent
disease, except a slight degree of cirrhosis.
Microscopic examination of the lungs
revealed little reaction other than severe
edema, swelling, and separation of the components of the alveolar walls. Only few
organisms were observed in the cytoplasm
of histiocytes in the lung and in the sinuses
of a hilar lymph node.
Review of material collected during antemortem bronchoscopy revealed recognizable
parasites.
SUMMARIO l.\T INTERL1NGUA
Le necropsia de un patiente mascule de
36 annos de etate revelava que ille habeva
suffrite de un quasi solide replenation pulmonar con Pneumocystis carinii. Ille habeva
essite malade durante 10 menses, con progressivemente plus frequente attaccos de
febre, algor, e tusse. Nulle morbo intercurrente esseva presente, excepte un leve
grado de cirrhosis.
Le examine microscopic del pulmon
monstrava pauc reaction altere que sever
edema, tumescentia, e separation del componentes ab le pariete alveolar. Solmente
pauc organismos esseva observate in le
cytoplasma de histiocytos pulmonare in le
sinos de un hilar nodo lymphatic.
Le revista de material colligite per
bronchoscopia ante morte develava le presentia de recognoscibile parasites.
Acknowledgment.
T h e authors wish to thank
D r . E . J . M a l t b y for the use of his clinical notes on
this case.
REFERENCES
1. BERDNIKOFF, C : Fourteen personal cases of
Pneumocystis carinii pneumonia. Canad. M .
A. J . , 80: 1-5, 1959.
2.
D A U Z I E H , G., W I L L I S , T . , AND B A R N E T T , R
N.:
Pneumocystis carinii pneumonia in an infant.
Am. J . Clin. P a t h . , 26: 7S7-793, 1956.
3. GAJDUSEK, D. C : Pneumocystis
carinii—ctiologic agent of interstitial plasma cell pneumonia of premature and young infants.
Pediatrics, 19: 543-565, 1957. '
4. HAMI'EHL, H . : Pneumocystis infection and
cvtomegalv of the lungs in the newborn and
adult. Am. J. Path., 32: 1-13, 1956.
5. H E N D R Y , J., AND M Y E R S , R . F . :
carinii pneumonia.
831-S34, 1959.
Pneumocystis
Canad. M . A. ,)., 8 1 :
6. M C K A Y , E . , AND RICHARDSON, J . :
Pneumocystis
carinii pneumonia associated with hypogammaglobulinaemia. Lancet, 2 : 713-715,
1959.
7. V A N E K , J . , J I R O V E C , O., AND L U K E S , J . : I n t e r -
stitial plasma cell pneumonia in infants.
Ann. paediat., 180: 1-21, 1953.