PULMONARY MYCOTIC INFECTIONS—Allergic and Immunologic Factors

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OFFICIAL JOURNAL OF THE CALIFORNIA MEDICAL ASSOCIATION
©1954, by the California Medical Association
.
Volume 81 DECEMBER 1954 Number 6
Pulmonary Mycotic Infections
Allergic and Immunologic Factors
EDMUND L. KEENEY, M.D., San Diego
* The mechanisms of immunity and allergy, and the immune antibody must be considered
at play in every infectious disease, must be as two different and distinct antibodies.
comprehended before the pathogenesis of an Skin and serologic tests are important diag-
infection can be appreciated. nostic aids in certain pulmonary mycotic infec-
Immunity, allergy and serology are con- tions-for example, coccidioidomycosis, blasto-
cernedwith specific antigen-antibodyreactions. mycosis, histoplasmosis and moniliasis.
In immunity the principal concern is with the
Clinical expressions ofallergy may appear in
final disposition of antigen (agglutination,
*coccidioidomycosis, histoplasmosis and moni-
lysis, and phagocytosis). In allergy attention is
liasis.
focused upon tissue damage resulting from
antigen-antibody union. In serology interest is Pulmonary mycoses are divided into three
devoted to the presence of antibody as evalu- groups, that is, the endogenous mycoses
ated by certain visible in vitro reactions-pre- (actinomycosis, moniliasis, geotrichosis), the
cipitin, agglutination, opsonization and com- endogenous-exogenous mycoses (cryptococco-
plement fixation tests. sis,aspergillosis,mucormycosis) andtheexogen-
There are two types of allergic reaction- ous mycoses (nocardiosis, coccidioidomycosis,
histoplasmosis, North American blastomycosis).
the immediate oranaphylactic typeandthede-
layed type or the allergic disease of infection. The diagnosis and treatment of the impor-
Neither kind takes part in the mechanism of tant mycotic infections that invade lung tissue
immunity. At this time the allergic antibody are discussed.
To APPRECIATE the pathogenesis of an infectious certain bacterial and viral infections, there is a pau-
disease it is essential to have knowledge concerning city of information of this kind with regard to my-
the mechanisms of natural immunity, acquired im- cotic infections, for they have been less carefully
munity and allergy pertinent to the infection under scrutinized than the bacterial and viral diseases.
consideration. Such data are not available for all In any discussion dealing with immunity and al-
infections but it is helpful. to project accessible in- lergic sensitivity it is imperative to understand what
formation for the better understanding of the infec- is meant by the terms antigen and antibody. Anti-
tious processes that have not as yet been exhaus- gens are substances of protein or polysaccharide
tively studied. Although these data are available for nature which, upon injection into an animal body,
stimulate the formation of antibodies. A molecule
Presented as part of a Panel on Diseases of the Chest before the
Section on General Practice at the 83rd Annual Session of the Cali- to qualify as an antigen must have a molecular
fornia Medical Association, Los Angeles, May 9-13, 1954.
VOL. 81, NO. 6 * DECEMBER 1954 367
weight of 10,000 or more, and possess upon its munity. Although the antibodies responsible for
surface a repetition of certain chemical groupings. eliciting serologic reactions are the same antibodies
These chemical groupings determine the specificity that neutralize the virulent properties of an offend-
of the antigen, and the most important constituent ing microorganism, resistance to infection is not al-
of a group is an acid radical. Any one invading ways due to antibody. However, serologic reactions
microorganism may be likened to a bag filled with do give clues at times to the nature of the potential
an assortment of different antigens. protective activities of antibodies in vivo, and they
An antibody is a plasma globulin molecule. Anti- are of course of great value in providing methods
bodies, except for their ability to react specifically for diagnosing the existence of an infection. The
with antigen, are frequently the same as normal precipitin, the agglutination, and the complement
gamma globulin. The concentration and character fixation tests are used with advantage in the diag-
of antibodies may be assessed by their physicochem- nosis of certain mycotic lung infections. In not a
ical properties; for instance, precipitation by salts, single instance of a fungous infection do these tests
analysis in the ultracentrifuge, and analysis in the measure immunity.
Tiselius electrophoresis cell. The presence of anti- The concepts of the mechanisms of acquired re-
bodies may also be evaluated by a number of sero- sistance (immunity) are fairly simple ones. The
logic reactions. There are five major manifestations offending organism is possessed of ability to over-
of antibody existence to be noted visibly by sero- come the native resistance of the body, and this act
logic reactions: (1) antibodies may precipitate sol- gives the microorganism virulence. The host then
uble antigens (precipitin test); (2) antibodies may acquires antibodies which neutralize the virulence
cause the aggregation of antigens, if the antigen is properties; hence the microorganism is finally at the
in particulate form as part of a bacterial or other mercy of the body's defenses (phagocytic properties
cell (the agglutination test); (3) antibody plus the of leukocytes and macrophages). In this scheme we
component of normal serum known as complement are concerned with a specific antigen-antibody reac-
may cause cells representing antigen to undergo tion, and our attention is directed particularly to-
lysis; (4) antibody may bring about a combination ward the final disposition of the antigen.
of antigen, such as bacteria and other cells, so as to In all infectious diseases it is not always possible
make phagocytosis by leukocytes and macrophages to correlate the presence of antibodies with the im-
much more effective (the opsonization test); (5) mune state. Some other mechanism may function
antibody combined with almost any antigen will ab- as the harbinger of resistance in place of antibody.
sorb complement even though the union be an in- For example, humoral factors other than antibodies
visible one (the complement fixation test). may be acquired and give resistance, and alterations
There is still a tendency to ascribe the various may take place in the phagocytes which enable them
serologic reactions to the activity of a particular to destroy microorganisms more effectively.
kind of antibody. It is not uncommon to see state- The study of allergy also deals with specific anti-
ments in the literature that "precipitating antibod- gen-antibody reactions. In the mechanism of the
ies," "complement fixating antibodies," and "agglu- allergic reaction we are not concerned with what
tinating antibodies" are formed during the course happens to the antigen; we are interested in what
of an infection. Such statements simply infer that happens to the tissue as a result of the antigen-
separate and distinct antibodies are responsible for antibody reaction.
each of the serologic reactions. This is not always As one examines the various manifestations of
thecase. Asingle antigen in pure state produces only allergy in man one becomes aware of the different
one variety of antiboay, and this antibody present types of reactions and the manner in which these
in the serum is capable under proper conditions of reactions are induced in an allergic person. Some
combining with antigento produce avariety of sero- forms of allergic reaction (immediate or anaphylac-
logic reactions. It is not meant to imply, of course, tic type) may be induced by the entrance of a sim-
that only one antibody is produced in the body re- ple antigen into the tissues. Other forms of reaction
sponse to invasion by a microorganism; every mi- (delayed type or allergic reaction of infection) are
croorganism is a mixture of many antigens. dependent upon the entrance of entire infectious
The site of antibody globulin formation in the agents into the body.
body probably depends upon the nature of the anti- In the kind of allergy that is established by ordi-
gen and the route ofentrance into the body. At pres- nary and simple antigens, the subsequent response
ent it is believed that three kinds of cells take part to the same antigen takes place immediately. It is
in the manufacture of antibody: reticuloendothelial allergy of this type that is present in patients with
cells, plasma cells, and lymphocytes. hay fever, asthma, urticaria, eczema, serum disease,
There are loose concepts in the minds of many erythema nodosum, erythema multiforme, migrating
that the measure of antibody concentration (titer) phlebitis, periarteritis nodosa, rheumatic fever and
by serologic tests measures also the degree of im- possibly acute glomerulonephritis. Persons with al-
368 CALIFORNIA MEDICINE
TABLE l.-Endogenous pulmonary mycoses.
Geographical Appearing in Sputum IdentifiedbyCultured
Disease Distribution Organism Source as Growthon-
Actinomycosis Worldwide ActinomycesIsraeli Tonsils,gums "Sulphurgranules" Brewer'sThioglycol-
latemedium,370 C.
Moniliasis Worldwide Candidaalbicans Mouth,skin,va- Buddingyeastcells, Sabouraud's300 C.
gina,gastrointes- Mycelia
tinaltract
Geotrichosis Worldwide Geotrichumsp.(spe- Mouth,gastro- Rectangularand Sabouraud's300 C.
ciesnotidentified) intestinaltract spherical cells
TABLE 2.-Endogenous-exogenous pulmonary mycoses.
Geographical AppearinginSputum IdentifiedbyCultured
Disease Distribution Organism Souree as- Growthon-
Cryptococcosis Worldwide Cryptococcus Soil,skin Buddingyeastcells Sabouraud's300 C.
neoformans with widecapsules
Aspergillosis Worldwide Aspergillusfumigatus Soil,grains, Brokenfragmentsof Sabouraud's30° C.
(attimes, grasses,respira- mycelium. Small,
otherspecies) torytract roundconidia
Mucormycosis Worldwide Mucorcorymbifer Soil,skin, Fragmentsofnon- Sabouraud's300 C.
(attimes,other respiratorytract septatemycelium
species)
lergy of this type have humoral antibodies that may it must be generally conceded that inflammation is
be transferred by means of their serum to normal helpful tothe body in impeding the spread of micro-
individuals. Only certain cells of the body become organisms by calling forth rapidly an accumulation
sensitized and take part in the allergic reaction; for of phagocytes, it does notnecessarily follow that the
example, endothelial cells, smooth muscle cells and exaggerated inflammatory reaction of allergy ampli-
collagen. These manifestations are regarded as char- fies protection. It has been ably demonstrated that
acteristic of the immediate or the anaphylactic type organisms begin to spread before the allergic re-
of allergic reaction. action takes place and, furthermore, the organisms
Inthekind ofallergic reaction which is dependent arespreadwiththerush offluids thataccompanythe
upon invasion by the entire infectious agent there violent inflammation. Thus the milder inflammation
are definite characteristics which separate it from provoked by the antigenic stimulus in nonallergic
the immediate type: The reaction of the tissues to tissue is more protective in its localizing attributes
antigen is delayed; humoral antibodies are not pres- than the intense inflammatory reaction of allergy.
ent; anycell ofthebody may be destroyed following There is, therefore, no evidence at this time to
contact with antigen. This type of allergic reaction, consider the allergic reaction as a part of the mech-
spoken of as the delayed type or the allergy of in- anism of immunity in infectious diseases.
fection, isresponsible forthetissue damage intuber- With these fundamental thoughts in mind with
culosis, coccidioidomycosis, histoplasmosis, blasto- regard to allergy, immunity and serologic reactions,
mycosis, sporotrichosis, moniliasis and many other one is in a better position to appraise the patho-
infectious diseases. The presence of this kind of genesis of infectious diseases. Hence, the signs and
allergy is demonstrated by delayed positive reaction symptoms produced by mycotic infections and the
to skin test with antigenic materials such as tuber- diagnostic significance of serologic and skin reac-
culin, coccidioidin, histoplasmin or blastomyces tionsin these diseases can be more fully appreciated.
vaccine. The pulmonary mycoses may be divided into
What then may be the relationship of allergy to three groups, the endogenous mycoses, the endoge-
immunity? The allergic reaction could be of assist- nous-exogenous mycoses and the exogenous my-
ance to the body in resisting an invading micro- coses.Actinomycosis, caused byActinomycesIsraeli,
organism if the antibody responsible for the allergic moniliasis caused by Candida albicans, and geo-
reaction were also the antibody responsible for trichosis caused byspecies ofGeotrichum are consid-
resisting the invasion and progress of the micro- eredto beendogenous mycoses (Table 1) The fungi
.
organism. However, this possibility has never been responsible for these infections may and do live in
substantiated. It must be concluded at this time that various regions of the human body without becom-
the allergic antibody and the immune antibody are ing parasitic. Actinomyces Israeli may be found in
not the same, but are two different antibodies. tonsillar crypts, in dental scum and about carious
The allergic reaction, whether immediate or de- teeth. Candida species are inhabitants of the normal
layed, might aid resistance to infection if the intense mouth, intestinal tract and vagina, and may be cul-
inflammationproduced bythe allergicreaction could tured fromthese sites in 35 to 40 per cent of normal
restrict the spread of an infectious agent. Although persons. Geotrichum species are frequently isolated
VOL. 81. NO. 6 * DECEMBER 1954 369
TABLE 3.--Exogenous pulmonary mycoses.
Geographical AppearinginSputum IdentifiedbyCultured
Disease Distribution Organism Source as Growthon-
Nocardiosis Worldwide Nocardiaasteroides Soil Granules. Short and Vealinfusionagar
long fragments of (1oglucose).
mycelium Sabouraud's30° C.
Coccidioido- SouthwestU.S.A., Coccidioidesimmitis Soil "Spherules" Sabouraud's300 C.
mycosis NorthernMexico,
Argentina
Histoplasmosis CentralU.S.A.In Histoplasma Soil Smallyeast-likecells Sabouraud's30° C.
otherspecific capsulatum (cottony). Bloodagar
areasofworld 370 C. (yeast-like)
NorthAmerican SoutheastU.S.A., Blastomyces Soil Doublycontoured, Sabouraud's300 C.
Blastomycosis CentralU.S.A., dermatitidis granular,budding Bloodagar370 C.
NorthAmerica cells (yeast-like)
TABLE4.-Mycotlc Infections In which allergyandserologyIn reactions areImportant.
SerologicReactio
Complement
LaboratoryExpressions Precipitin Fixation Agglutination
ofAllergySkinTests Test Test Test
Disease Organism ClinicalExpressionsofAllergy with: Positive Positive Positive
Coccidioido- Coccidioides In primary phase: Morbilliform Coccidioidin: Yes Yes Not
mycosis immitis rash, erythema nodosum, erythema Positive suitable
multiforme, arthralgia, phlyctenu-
larconjunctivitis
Histoplasmosis Histoplasma In disseminated form: Purpura, Histoplasmin: Not Not Not
capsulatum urticaria, erythema Positive evaluated evaluated evaluated
NorthAmerican Blastomyces 0 Blastomycin and blas- Yes Yes Not
Blastomycosis dermititidis tomyces vaccine: suitable
Positive
Moniliasis Candida Asthma, urticaria, eczema CandidinandCandida Yes Not Yes
albicans vaccine: Positive evaluated
from the mouths and the intestinal tracts of patients histoplasmosis, blastomycosis) occur predominately
without disease. The native resistance of the body in certain restricted geographical areas. These three
prevents these microorganisms from becoming in- mycotic infections have certain common character-
vasive. However, native resistance is flexible and in istics. Forexample: Theyoccurmostly intheUnited
certain circumstances these same fungi may sur- States; the gross cultural characteristics of two of
mount all barriers and proceed to invade, multiply the causative organisms (H. capsulatum, B. derma-
and disseminate through the body. In these respects titidis) are similar; the allergic reaction of delayed
the endogenous fungi act in a manner similar to type develops during the course of infection; with
staphylococci and streptococci. moniliasis, they are the only mycotic infections in
There are certain mycotic diseases that may be which a positive reaction to a skin test is a diagnos-
endogenous as well as exogenous and these are: tic attribute; two of the mycoses (coccidioidomy-
cryptococcosis, aspergillosis and mucormycosis cosis, histoplasmosis), with moniliasis, are the only
(Table 2). Cryptococcus neojormans has been iso- mycoses that have clinical manifestations of the
lated from apparently normal skin and soil; species allergic reaction ofimmediatetype duringthe course
of Aspergillus are found in the respiratory passages of infection; two of the mycoses (coccidioidomyco-
of patients with chronic bronchitis and asthma and sis, blastomycosis), withmoniliasis, arethe onlymy-
in soil and on grains and grasses; species of Mucor coses which during the course of infection stimulate
have been isolated fromtherespiratory passages and the production of the immune type of antibody and
skin of normal persons and in soil. they are, therefore, the only mycotic infections in
The endogenous and the endogenous-exogenous which serologic tests are of diagnostic aid (Table
fungi, excepting Actinomyces Israeli and Cryptococ- 4). These similarities are recalled not with the pur-
cus neolormans, become more virulent when the pose of relating the organisms or the infections to
relationship ofthenormalflora ofthebodyandtheir one another but expressly to stimulate a scheme of
environment is altered by the prolonged administra- simple thinking about a subject which somehow or
tion of the wide spectrum antibiotics. other has been made unnecessarily forbidding.
The exogenous fungi (Table 3) survive and mul- The various mycoses in which pulmonary disease
tiply in soil or on plant material. Of the four strictly is an important feature will now be discussed indi-
exogenous mycoses only one, nocardiosis, is rather vidually. No longer do these infections play an un-
evenly distributed throughout the world. The re- important and remote position in medicine and pub-
maining fungous infections (coccidioidomycosis, lic health. Mycotic infections occur with sufficient
370 CALIFORNIA MEDICINE
frequency to justify consideration of them in the borders of the lobules. By crushing the granule be-
differential diagnosis of every difficult and compli- tween two slides and then staining with Gram's
cated pulmonary infection, and even, under certain stain, the Gram-positive branched filaments can be
circumstances, in supposedly benign and simple res-' demonstrated. Thesebranchedfilamentsmake upthe
piratory diseases. interior of the "sulphur granules."
ActinomycesIsraeli is difficultto culture. The spu-
tum should be washed several times with sterile nor-
THE ENDOGENOUS PULMONARY MYCOSES
mal saline solution. Suspected granules should be
ACTINOMYCOSIS
recovered with a bacteriological loop, washed again
The term actinomycosis should refer only to in- in sterile normal saline solution, and then placed in
fections that are caused by the anaerobes Actino- Brewer's thioglycollate medium and incubated at
myces Israeli and Actinomyces bovis. Until the ap- 370 C. Colonies that gradually develop appear as
pearances of the studies of Erikson,"' of England, fluffy discrete masses of variable size suspended in
and later Thompson,28 ofthe Mayo Clinic, it was the the media. Mycelia do not project from the surface.
opinion of the majority of investigators that human A satisfactory antigenic substance, prepared from
and bovine actinomycosis were caused by the same the organism or from the broth in which the organ-
anaerobic microorganism, and depending upon the ism has been grown, has never been isolated. There-
investigator the organism was referred to either as fore, skin tests and serological tests, which would be
Actinomyces bovis or Actinomyces Israeli. How- of doubtful diagnostic value anyway for this infec-
ever, since the appearance of the sixth edition of tion, are not performed.
"Bergey's Manual of Determinative Bacteriology"
Treatment. Treatment for the mostpart is unsat-
in 1948, Actinomyces Israeli has been catalogued as isfactory andconsists of indicated surgical drainage,
the cause of actinomycosis in human beings, and
the administration of potassium iodide to the point
Actinomyces bovis as the etiologic microorganism
of intolerance, and x-ray therapy. There are numer-
of the bovine infection.
ous clinical reports in the literature proclaiming the
Actinomyces Israeli commonly exists as a sapro-
effectiveness of sulfonamides,22 penicillin,19, aureo-
phyte in the oral cavity and has never been isolated mycin7 and chloramphenicol.26 In the majority of
from soil or vegetation. In the mouth the organism
these reported cases surgical measures, iodides, and
is commonly present in and aboutcariousteeth, den-
x-ray therapy supported the sulfonamide and anti-
tal scum, and the crypts of tonsils. From such posi- biotic therapy, and it is, therefore, impossible to
tions, the organisms may be inhaled or aspirated ascribe the entire clinical result to the use of these
into the lungs to incite pulmonary infection.
latter drugs. It must be concluded that necessary
Diagnosis. The primary lesions in pulmonary surgical intervention, adequate x-ray therapy, and
actinomycosis are usually bilateral and basal, but intensive iodide administration are essential ad-
they may occur unilaterally in any portion of the juncts to antibacterial and antibiotic therapy if
lung. In theprimary site a granulomatous process is optimalresults areto be obtained inthe treatment of
induced which usually extends to the mediastinum, this serious pulmonary infection.
pericardium and heart, and/orto the pleura produc-
MONILIASIS
ing pleural pain and occasionally pleural effusion.
Eventually the organism invades directly through Mycologists have replaced the familiar generic
the pleura to the chest wall, giving rise to numerous term Monilia with the name Candida. However, the
draining sinuses. Infrequently the pulmonary infec- term maniliasis, because of its common usage in the
tion will be the result of a spread from the primary medical literature, has been retained in spite of sug-
focus in one or more of the ribs. Rarely in pulmo- gestionsthatcandidosis orcandidasis mightbe more
nary actinomycosis is there a spread to the regional appropriate. There are seven important species in
lymph nodes, but metastasis by the blood stream to the genus Candida and these are: albicans, tropi-
any part of the body may occur. calis, pseudotropicalis, Krusei, parakrusei, stellatoi-
The diagnosis is established in the laboratory by dea, and GuiUiermondi. Only one of these species,
isolating from the sputum the organism in the form albicans, is commonly pathogenic for man.
of characteristic "sulphur granules." These granules Diagnosis. Bronchopulmonary moniliasis is the
vary in size and shape and have a radiating lobu- term employed to designatethat type of Candida in-
lated structure and usually, although not always, are fection of the lungs in which the disease process is
yellow in color. They are best observed with a low limited to the bronchial tree. Infection of this type,
power microscope lens, but occasionally are large which is not at all uncommon, is manifest clinic-
enough to be identified macroscopically or with a ally by the signs and symptoms of ordinary bron-
hand lens. The interior ofthe granule does notstand chitis. The temperature may be normal or only
out sharply, but the clubs of the periphery are very slightly elevated, and the health of the patient not
refractile and appear as irregular lines marking the seriously affected. Pulmonary roentgenograms re-
VOL. 81. NO. 6 * DECEMBER 1954 371
veal slight to moderate peribronchial thickening. culture form on Sabouraud's agar. On Sabouraud's
The infection may disappear spontaneously or be- medium the organism grows as a yeast, but when
come chronic and thereby mimic the symptoms of stab cultures are made in gelatin or corn meal agar
chronic bronchitis of bacterial origin. the mycelial form of the fungus is produced. To
Pulmonary moniliasis is the term for infections of make certain that the organism isolated isthe patho-
the parenchyma of the lungs. While the parenchy- genic species of Candida, it should be tested for
mal is not so common as the bronchial infection, it fermentation reactions. C. albicans will form acid
ismore serious. Pulmonary moniliasis may resemble and gas in glucose, acid and gas in maltose, but
miliary tuberculosis with cough, fever, dyspnea, only acid in sucrose media. Recently a technique
pain in the chest, hemoptysis and night sweats. was described by Weld29 for the rapid identification
There may be signs of pleural thickening. Areas of of C. albicans.
consolidation resembling bronchopneumonia may Treatment. Bronchopulmonarymoniliasis isbest
be scattered throughout two or more lobes and, in- treated with potassium iodide by mouth and sodium
frequently, there may be lobar consolidation. caprylate by aerosol. The official solution of potas-
The diagnosis of bronchopulmonary and pulmo- sium iodide should be given in as large a dose as
nary moniliasis is fraught with difficulties. Isolation can be tolerated by the patient. One milliliter of a
of the organism, particularly if the patient has re- 10 per cent solution of sodium caprylate (New and
ceived antibiotics, is not conclusive. The organism Non-Official Remedies) should be given by aerosol
frequently establishes itself in the bronchial mucous several times daily. Best results are obtained if a
membranes as a secondary invader. A diagnosis total daily dose of 1 gram is reached.
must be made indirectly by excluding all other con- Pulmonarymoniliasis istreated in a manner iden-
ditions, infections and neoplasms that might affect tical to that of bronchopulmonary moniliasis. Gen-
the bronchial and parenchymal tissue, and by re- tian violet should be given intravenously if the pa-
peated demonstration of the organism in the spu- tient is not doing well on iodide and caprylate ther-
tum. Actually there are no indisputable criteria for apy. The dosage is 5 mg. per kilogram of body
establishing the diagnosis short of the impractical weightandmayberepeated daily or every other day
procedure of lung biopsy. for three to seven doses.
Clinical manifestations of allergic reaction of the It is usually advisable before administering potas-
immediate type may develop during the course of a sium iodide to give the patient three to four weeks
C. albicans infection. Bronchial asthma was reported of specific desensitization treatment with C. albicans
by the author14 to have followed a bronchial infec- vaccine. The prolonged use of a C. albicans vaccine
tion. The asthmatic symptoms completely disap- in the management of patients with chronic infec-
peared with the alleviation of the infection. The tions is also advisable.
author'5 has also observed the development of urti-
caria in a patient with cutaneous moniliasis. The GEOTRICHOSIS
author'5 likewise has observed in the past year the
Geotrichosis is a fungous infection due to one or
development of typical allergic eczema in a two-
more species of Geotrichum. There has never been
year-old child one month following the administra-
a careful study of the saprophytic and pathogenic
tion of aureomycin. C. albicaws was isolated from
species of the genus Geotrichum. The organism is
the stools. After the organism was eliminated from
capable of producing lesions in the mouth, intestinal
the gastrointestinal tract the skin became normal.
tract, bronchi and lungs.
Eczematoid dermatitis of the face and certain cases
of miliaria are thought to be allergic reactions to Diagnosis. Bronchitis is probably the most fre-
Candida infections. Vesicular lesions on the hands, quently recognized manifestation of geotrichosis.
referred to as moniliids and similar in appearance Thesymptomsare identicalto those ofchronic bron-
to dermatophytids, are the result of allergic reac- chitis of bacterial origin. The sputum is often gela-
tions to infections occurring elsewhere in the body. tinous; the pulse and temperature are rarely ele-
Agglutinins and precipitins are occasionally pres- vated; and the general health is good. Medium and
ent in the serum of patients with the severe forms of coarse rales are noticeable especially at the lung
Candida infections. However, there are agglutinins bases. Diffuse peribronchial thickening is a nonspe-
for C.albicans in theserum ofmanynormal persons. cific condition observed in pulmonary x-ray films.
Therefore, serologic tests are of doubtful diagnostic Invasion of the parenchyma of the lungs brings
importance. Skin tests are of no value because posi- about signs and symptoms suggestive of pulmonary
tive reactions occur in a large proportion of patients tuberculosis. The temperature is elevated, the pulse
without active infection. accelerated and the leukocyte content of the blood
The laboratory diagnosis of moniliasis is estab- increased. The sputum is mucopurulent and may or
lished by isolating from the sputum budding cells maynotcontain blood. Thephysical findings arenot
and filaments, and by growing the organism in pure specific, but may lead to suspicion of tuberculosis.
372 CALIFORNIA MEDICINE
Pulmonary roentgenograms reveal patches of in- the brain is by way of the blood stream. Crypto-
filtration with or without cavity formation. coccosis, however, may rarely remain confined to
Microscopic examination of the sputum reveals the lung; there are a few reports in the literature
oblong or rectangular cells with rounded ends and attesting this isolation. Of course, it is quite con-
large spherical cells which measure from 4 to 10 ceivable thaf pulmonary cryptococcosis might occur
microns in diameter.Atroomtemperature onSabou- without beingdiagnosed, because few signs or symp-
raud's medium the organism grows rapidly and toms accompany pulmonary involvement, and the
forms a white to cream colored colony with a dry, organism is rarely looked for inthe sputum unless it
mealy surface. Microscopically the hyphae are seen has been previously demonstrated in the cerebro-
to segment into rectangular arthrospores, which spinal fluid. The majority of cases of cryptococcosis
vary in size and roundness of their ends. The rec- of the lungs, therefore, occur in patients who have
tangular cells ordinarily germinate by a germ tube coexisting lesions in other tissues, especially the
from one corner. This is a very characteristic find- central nervous system.
ing in cultures of Geotrichum. It is common, although not unvarying, for pul-
Treatment. Bronchial infections usually respond monary cryptococcosis to be accompanied by only
rather quickly to iodide by mouth. The official solu- meagerlocal and constitutional signs and symptoms.
tion of potassium iodide should be administered in Symptoms when present are those of a cough with
the largest dose that can be given with tolerance. some expectoration, and at times with hemoptysis.
The pulmonary form of the disease should like- Occasionally pleural pain may appear or a small
wisebetreated with iodides, butsuchtherapy should effusion bepresent in thepleural cavity. Rarely does
not be instituted until tuberculosis has been ex- the infection cause disease of clinical severity. Phy-
cluded in the differential diagnosis. If the infection sical signs, if present, are those of bronchitis or of
does not respond to iodide therapy an autogenous consolidation. Pulmonary roentgenograms are help-
vaccine should be prepared and immunization car- ful and important in making a diagnosis. In roent-
ried out. Also in the event that iodides are ineffec- gen appearance the lesions may suggest a tumor, a
tive, neomycin should be administered. Neomycin pyogenic abscess or a hydatid cyst. In addition to
has proven effective in the treatment of Geotrichum these shadows there may be linear markings with
septicemia,' and urinary tract infections.10 It must surrounding woolly shadows, which suggest in turn
be emphasized that neomycin is a toxic antibiotic the findings common in pulmonary moniliasis.
which causes deafness as well as renal damage if The only exacting proof of pulmonary crypto-
administered for more than a short time. coccosis is the finding of the organism in the spu-
tum. Fortunately the Ziehl-Neelsen stain is excellent
for detecting C. neoformans as well as the tubercle
ENDOGENOUS AND EXOGENOUS PULMONARY MYCOSES
bacillus. An India ink preparation of sputum shows
CRYPTOCOCCOSIS up the capsules of the organism brilliantly and thus
The organism responsible for cryptococcosis in aids in their identification. Pulmonary cryptococ-
man was named Torula histolytica by Stoddard and cosis must be differentiated from other chronic lung
Cutler27 in 1916, and thereafter the disease became diseases suchas tuberculosis,unresolved pneumonia,
known as torulosis. There are now grounds for be- pyogenic abscess, bronchitis, bronchiectasis, fibro-
lieving that the organism is not a true Torula but sis, primary and secondary carcinoma, Boeck's sar-
instead a Cryptococcus. The correct name of the coid, hydatid cyst and other mycotic infections.
fungus is Cryptococcus neoformans, and of the dis-
On Sabouraud's media at 300 C. the organism
ease it produces, cryptococcosis. However, reports grows slowly. At first the growth is moist, smooth,
ofmany cases ofthis infection will be found indexed and cream colored. As the culture ages the color
under torulosis.
changes to yellow and then to brown. A portion of
Diagnosis. Clinical manifestations stem from the the culture examined microscopically and in an
central nervous system, the respiratory system, the India ink preparation reveals best the wide typical
lymphatic system, the skin, the mucous membranes capsules. This capsuletakes on a reddish color when
and the bones and joints. Ordinarily a combination thecells are stained by Gram's technique.
of these tissues, rather than just one, is invaded by The antibody response in cryptococcosis is poor
C. neoformans, but the evidence of the involvement and consequently precipitin, agglutination and com-
of other tissues is usually submerged by the more plement fixation tests are of no importance in the
serious signs ofcentral nervous system disease. diagnosis. Withregardto the diagnostic significance
Pulmonary involvement is, in frequency, second of skin tests very little work has been done. The
only to that of the meninges and brain. It is gener- poor antibody response which accompanies this in-
ally considered that the primary lesion in crypto- fection is undoubtedly partially responsible for the
coccosis occurs in the lungs and that metastasis to poor prognosis.
VOL. 81. NO. 6 * DECEMBER 1954 373
Treatment. There is no specific method of treat- green. Microscopic preparations should be made by
ment, butthis does not imply that ahopeless attitude placing asmallportion ofthe aerial growth in lacto-
be assumed. In dealing with a case ofcryptococcosis phenol cotton blue and covering with a cover slip.
chemotherapeutic tests on mice with all promising The characteristic swollen conidiophore bearing the
drugs should be performed. There is always the pos- sterigmata and then the chains of conidia, which
sibility that the specific strain of C. neoformans iso- mayhavebeenpartially brokeninmakingtheprepa-
lated will be susceptible to one of the sulfonamides, ration, can be identified.
to one of the antibiotics, to actidione, or to some Nothing is known concerning the antibody re-
other drug not yet discovered or synthesized. sponse in humans to infection; consequently, sero-
Immunization with a vaccine of C. neoformans logic tests remain unevaluated. Positive skin reac-
should be tried and continued during the entire tions to extracts of Aspergillus species, of the imme-
course of the disease. If possible a weakly encapsu- diate whealing type, occur inpatients with bronchial
lated strain of the organism should be employed in asthma, but the significance of reaction of the de-
the vaccine, since there is evidence that vaccines layed type and its value in the diagnosis of asper-
prepared from the weakly encapsulated strains are gillosis is unappraised.
more immunogenic than vaccines prepared from the Treatment. The official solution of potassium
strongly encapsulated ones.18 iodide should be given orally in the largest doses
Pulmonary lesions that are isolated and not part that can be tolerated. Prognosis is favorable if the
of a generalized infection may heal. However, since infection is limited to the bronchi, but very poor if
the infection is very likely to disseminate, early there is extensive involvement of the parenchyma
excision of the circumscribed lesion is advisable.2 of the lung with/or without abscess formation.
Cryptococcus neolormans thrives in an acid me-
MUCORMYCOSIS
dium, and it does not survive temperatures of 1050
The genus of Mucor, along with Rhizopus, be-
for seven days or of 107° F. for six days. Accord-
longs to the family Mucoraceae. Molds of this fam-
ingly, alkalinization and hyperthermia have been
ily are frequently referred to as the bread molds
suggested aspossiblemethods oftreatment. Attempts
thus. far with alkalinization have met with failure and they are found abundantly in soil, manure and
and hyperpyrexia has not been adequately tried. on fruits and starchy foodstuffs. Human infections
from species ofMucor are rare. Ofthe many species
ASPERGILLOSIS of this genus only a few, notably M. corymbifer, are
Species of Aspergillus are widely distributed in pathogenic.
nature and, for the most part, may be considered Diagnosis. Inmostofthereportedcasesofhuman
as saprophytes. Occasionally some species become infection due to the Mucors only a single organ or
parasitic and produce inflammatory granulomatous system is ordinarily involved. Infection of the lungs
lesions in the skin, the external auditory canal, the is most common, yet there is no clue from the signs
paranasal sinuses, the orbit, the bronchi, the lungs or symptoms offered by the infection that mightlead
and, infrequently, in the bones and meninges. one to suspect infection from Mucor. As in asper-
The disease aspergillosis, which is caused for the gillosis the findings may suggest pulmonary tuber-
most part by Aspergillus fumigatus, is world wide culosis or other mycotic infections.
in distribution and occurs in persons exposed often The diagnosis of mucormycosis is fraught with
to massive doses of the spores; for example, farmers difficulties. Even growth of the fungus on culture of
exposedtodustfromthreshers; fur cleaners employ- the sputum is not unimpeachable evidence of pri-
ing rye flour as a grease remover; and, in France, mary infection. The conidia of Mucor are airborne
the squab feeders who take grain into their mouths and may become laboratory contaminants, and they
to moisten it and, coincidently, inhale spores. may reside as saprophytes in the respiratory pass-
Diagnosis. Primary pulmonary infection is rare ages and on the skin. Characteristic fragments of
and diagnosis is ordinarily made at autopsy. The mycelium must be repeatedly demonstrated in spu-
clinical symptoms and signs may be those of pulmo- tum or from the region where infection is suspected.
nary tuberculosis, or other mycotic infections that Treatment. A specific form oftherapy has never
involve the lungs. There is no clinical characteristic been developed. It is necessary to adapt procedures
that might lead one to suspect the disease process that have been applied to other mycotic infections.
resulting from invasion by Aspergilli.
Direct microscopic examination of sputum re-
THE EXOGENOUS PULMONARY MYCOSES
veals broken fragments of hyphae with many small,
round, dark green conidia. On Sabouraud's agar at NOCARDIOSIS
30° C. the organism grows rapidly, appearing first The term nocardiosis defines infections in man
as a white, cottony growth. As the conidia are pro- produced by one or several of the species of actino-
duced the color of the colony turns to green or dark mycetes included in the genus Nocardia. The actino-
374 CALIFORNIA MEDICINE
mycete in this genus which is of interest to the clini- States. The light, minute arthrospores which are
cian is Nocardia asteroides. This organism is com- readily adapted to widespread dissemination, gain
mon in the soil and it is reasonable to assume that entrance into the human body through the respira-
pulmonary infection is initiated by the inhalation tory tract, or more infrequently into the skin fol-
of contaminated dust particles. The disease is un- lowing trauma. Rodents and other animals in the
common but world-wide in distribution. endemic areas may act as reservoirs for the fungus.
Diagnosis. In the lung the organism produces Diagnosis. The symptoms of primary coccidi-
bronchopneumonia of a caseating type that may be oidomycosis are indistinguishable from those of
followed by cavity formation. The clinical picture, many acute, mild respiratory infections. Actually the
therefore, is frequently confused with that of pulmo- great majority of primary infections are entirely
narytuberculosis. There is atendency for the organ- asymptomatic. When symptoms do occur there may
isms to disseminate via the blood stream with the be gradations of expression. The incubation period
eventual formation of abscesses in many of the or- variesfrom onetothreeweeks.Thereisusuallyfever,
gans, particularly the brain. Death is frequently which ranges from 990 to 1010 F. Pain in the chest
causedbybrainabscess.Oftenthe lesions inthelungs is one of the most typical and suggestive symptoms
are not observed until postmortem examination. of the disease. Headache, backache, night sweats,
Nocardia asteroides undergoes fragmentation in anorexia and sore throat are common symptoms.
the sputum and, being acid-fast, the fragments re- Quite often a morbilliform rash will appear one to
semble tubercle bacilli. However, the long branched two days after the onset of infection. Eight to 14
filaments eventually can be found by careful search. days following the onset of illness, allergic reactions
The organism grows readily on culture media, but such as erythema nodosum, erythema multiforme,
more slowly than bacteria; consequently isolation arthralgia and phlyctenular conjunctivitis may oc-
from sputum by plating is difficult. Pure cultures cur. Usually no abnormality is noted upon examina-
can be obtained by inoculating guinea pigs with tionofthelungs. However, in one out of five patients
sputum. The animals die after four to nine days and some change in the quality ofthe breath sounds may
at autopsy miliary white nodules are observed over be noted. Roentgenograms of the lungs may or may
the omentum and the peritoneal surfaces. notreveal the following: Thin-walled cavitation usu-
There is no evidence that antibodies are formed ally present in the middle or lower lobes, but rarely
asa result ofinfection. Serologic tests, therefore, are above the clavicle; soft infiltrations; enlarged hilar
not employed as a diagnostic aid. Asteroidin, which nodes; and fan-shaped densities radiating out from
is a broth filtrate of Nocardia asteroides, has been
the hilar nodes. If the lung changes present in the
employed as a skin testing substance in the experi-
primary form persist for six or more weeks, the
mental infection of guinea pigs and rabbits. Its use
progressive form of the disease should be suspected.
as a diagnostic aid in human infections has not been
With the progression of the infection the infiltra-
evaluated.
tions increase in size; there is enlargement of the
Treatment. The specific measures of treatment mediastinal nodes; cavities, formerly present. en-
are similar to those for actinomycosis produced by large; cough is pronounced; and the sputum which
Actinomyces Israeli. There is one notable exception. was scanty becomes more profuse and is occasion-
Penicillin is not particularly effective in nocardi- ally tinged with blood. Approximately 0.1 to 1.0
osis. Sulfadiazine, alone or combined with sulfa-
per cent of the primary cases develop into the pro-
merazine, and aureomycin are the drugs of choice.
gressive form of the disease.
COCCIDIOIDOMYCOSIS Laboratory studies are helpful in making a diag-
nosis. There is frequently leukocytosis accompanied
Coccidioidomycosis is aname originated by Dick-
by eosinophilia. The sedimentation rate is elevated
son8' 9of Stanford University for the disease pro-
and ordinarily there is positive reaction to the coc-
duced by the fungus Coccidioides immitis. The or-
ganism produces an acute, usually mild and benign cidioidin skin test. Should a positive reaction to skin
respiratory infection, which is classified as the pri- test occur in a patient with a normal sedimentation
mary type of coccidioidomycosis. Infrequently, the rate it is unlikely that the current illness is due to
infection becomes chronic and disseminates to al- Coccidioides immitis. During the recovery phase of
most any organ, producing therein granulomatous the primary infection the lymphocytes rise to 50 per
lesions, which progress to such an extent that death cent or more of the total white blood cell count and
occurs in 50 per cent of such cases. This chronic the sedimentation rate gradually declines. The pre-
form of the disease is spoken of as progressive or cipitin and complement fixation tests are usually
disseminated coccidioidomycosis. positive, buttheymay benegative in mild infections.
The fungus is present in the dust and soil of the Titers of the precipitin and complement fixation
arid and semi-arid regions of southwestern United tests are high in the progressive form of the disease.
VOL. 81. NO. 6 * DECEMBER 1954 375
Coccidioides immitis grows on Sabouraud's agar nosed where suspicion is alerted and sound mycolo-
as a white, cottony mold which pigments with age. gic methods are used.
Old cultures contain myriad large, thick-walled
Diagnosis. There are two types of benign pulmo-
arthrospores (chlamydospores). When these spores
nary infection, asymptomatic and symptomatic.
are injected into animals they enlarge and become In the asymptomatic lorm the diagnosis is made
spherical. These large spherical cells, referred to as
in retrospect after observing areas of calcification in
"spherules," give rise to endospores by cleavage of
thepulmonaryroentgenograms ofpatients withposi-
their cytoplasm. It is the "spherule" that is found
tive reaction to histoplasmin skin tests. Although
in the sputum of the patient infected with Coccidi-
the patients may have positive reaction to tuberculin
oides immitis. It is usually taught that the "spher-
skin tests it is now generally agreed that pulmonary
ules" are not contagious. However, investigations
calcification occurs twice as frequently in associa-
recently reported by Rosenthal23' 24 indicated that
tion with histoplasmin sensitivity as with tubercu-
it is well to be suspicious of the old dogma that coc-
lin sensitivity. The pulmonary lesions preceding the
cidioidomycosis is never contagious. areas of calcification are infiltrative and difficult to
Treatment. There is no specific form of therapy differentiate from similar lesions occurring in pul-
for coccidioidomycosis and it can only be hoped monary tuberculosis. The diagnosis is established
that by exercising careful nonspecific measures pro- by culturing Histoplasma capsukatum from the spu-
gression and dissemination of the infection can be tum, which isnotalways easily accomplished. In the
prevented. A patient with primary coccidioidomy- event that tubercle bacilli cannot be cultured or
cosis must bekept at absolute bed rest until: (1) the demonstrated by directmicroscopic technique, histo-
physicalsymptoms ofthe infectionhavedisappeared, plasmosis may be suspected. This is especially true
(2) there is evidence from roentgen examination of ifthe reaction to a histoplasmin skin test is strongly
the lungs thatthe lesion has either disappeared or is positive and the tuberculin test is negative or only
regressing, (3) the sedimentation rate has returned mildlypositive.
to normal, (4) the precipitin and complement fixa- In the symptomatic jorm of histoplasmosis the
tion tests are disappearing or absent. clinical course ofthe disease and the roentgenologic
Most of the patients with the progressive form of findings offer a relatively uniform picture. The incu-
the disease die in two to twelve months, but some bation period is from five to 18 days. The onset of
may recover spontaneously. If patient is extremely symptoms is rather sudden, with generalized ma-
sensitive to coccidioidin, that is has a large skin laise, weakness, vague pain in the chest, nonproduc-
reaction to a 1:1,000 or 1:10,000 dilution, desensiti- tivecough and fever (temperature 1020 to 1050 F.).
zation with this antigen should be given a trial: There are a few positive physical findings. During
the early course of the disease pulmonary roent-
HISTOPLASMOSIS genograms revealthelungfieldstobeclear, butlater
disseminated and bilateral lesions varying from fine
The disease histoplasmosis was first discovered
or mottled granular infiltrations to soft miliary nod-
in the Panama Canal Zone by Darling5 -in 1906.
ules are observed. Cavitation rarely occurs. The
Darlingbelieved thecausative organism was a proto-
lesions tend to calcify in from three to five years
zoan and gave it the name Histopklsma capsulatum.
after-the onset of the acute illness. Even after the
De Monbreun6 eventually established that the etio-
acute phase of the illness has disappeared the symp-
logic organism in histoplasmosis is a fungus. He
toms of shortness of breath, cough and fatigue often
suggested that a relatively mild and nonfatal form
persist for months or even years.
of the disease, similar in nature to the primary and
nonfatal form of coccidioidomycosis might exist.7 Thereis some evidence thatthe symptomatic form
Palmer20 and Christie and Peterson,3 together, were may occur in epidemic proportions. Fairly large
principally responsible for the discovery and recog- groups of persons have developed pneumonitis fol-
nition of histoplasmosis of the common benign pul- lowing exposure to the dust of pigeon manure and
monary type. There are surprisingly few instances subsequently Histoplasma capsulatum has been iso-
of progressive histoplasmosis in view of the many lated from the dust.'2 13 Such epidemics simply
cases of primary pulmonary infection. It is tempt- serve to exemplify that histoplasmosis may occur in
ing to speculate that the form of the organism that epidemic proportions if exposure to dust from soil
is inhaled is less virulent than the form that enters contaminated with the organism takes place.
the body through the skin, mucous membranes, and The fungus in its parasitic phase is a small yeast-
gastrointestinal tract. The organism has been iso- like organism ranging in diameter from 2 to 3
lated from the soil and the disease recognized in microns. These yeast-like bodies invade the mono-
diversified regions of the United States. It is now nuclear cells in enormous numbers. In the sputum
the belief that histoplasmosis can exist in any age theyeast-like bodies areextracellular. Cultures taken
group, in widespread localities, and can be diag- from the sputum must be placed on both blood agar
376 CALIFORNIA MEDICINE