Laboratory Animals–Original Article

Veterinary Pathology
2018, Vol. 55(6) 905-915
Coccidioidomycosis in Nonhuman Primates: ª The Author(s) 2018
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Pathologic and Clinical Findings DOI: 10.1177/0300985818787306
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Keith Koistinen1, Lisa Mullaney2, Todd Bell1, Sherif Zaki3,

Aysegul Nalca1, Ondraya Frick1, Virginia Livingston1,
Camenzind G. Robinson1, J. Scot Estep4, K. Lance Batey4,
Edward J. Dick Jr.2, and Michael A. Owston2

Abstract
Coccidioidomycosis in nonhuman primates has been sporadically reported in the literature. This study describes 22 cases of
coccidioidomycosis in nonhuman primates within an endemic region, and 79 cases of coccidioidomycosis from the veterinary
literature are also reviewed. The 22 cases included baboons (n ¼ 10), macaques (n ¼ 9), and chimpanzees (n ¼ 3). The majority
died or were euthanized following episodes of dyspnea, lethargy, or neurologic and locomotion abnormalities. The lungs were
most frequently involved followed by the vertebral column and abdominal organs. Microscopic examination revealed granulo-
matous inflammation accompanied by fungal spherules variably undergoing endosporulation. Baboons represented a large number
of cases presented here and had a unique presentation with lesions in bone or thoracic organs, but none had both intrathoracic
and extrathoracic lesions. Although noted in 3 cases in the literature, cutaneous infections were not observed among the 22
contemporaneous cases. Similarly, subclinical infections were only rarely observed (2 cases). This case series and review of the
literature illustrates that coccidioidomycosis in nonhuman primates reflects human disease with a varied spectrum of pre-
sentations from localized lesions to disseminated disease.

Keywords
animals, coccidioidomycosis, Coccidioides, emerging infectious diseases, primates, review

Coccidioidomycosis, also known as valley fever, California
fever, or San Joaquin Valley fever, is a fungal disease that is
endemic within the Western Hemisphere in semiarid regions
known as the Lower Sonoran Life Zone. This zone within the
United States encompasses the southern parts of Texas, Ari-
zona, New Mexico, and much of central and southern Califor-
nia.22,28 Endemic regions outside of the United States include
semiarid regions of Mexico, especially northern Mexico, as
well as smaller endemic foci within Central and South Amer-
ica.28 It is caused by a geophilic dimorphic fungus of which 2
nearly identical species are recognized, Coccidioides immitis
and Coccidioides posadasii. C. posadasii was recently pro-
posed as a new species based on genetic and phenotypic anal-
ysis22 and is generically known as the non-California species.
C. immitis is almost exclusively found in the endemic areas of
California while C. posadasii is found throughout the Lower
Sonoran Life Zone; this geographic distribution can often help
identify the etiologic agent.28
As dimorphic fungi, these organisms change between a
parasitic (spherule) and a saprophytic hyphal (mold/mycelial)
form depending upon their environment. They exist in a sapro-
phytic mycelial form when in the soil, producing arthrospores
(arthroconidia) that are aerosolized when the soil is disturbed
by human activities or natural forces. These arthrospores cause
infection in humans and other mammals by transforming into
pathogenic spherules upon inhalation.37 After reproducing by
endosporulation, the spherules rupture, releasing hundreds of
endospores into the surrounding tissue. These released endo-
spores also mature into new spherules, and the cycle continues
until host control is achieved.25 These spherules can often be
seen on histologic examination of infected tissues.
Cases of coccidioidomycosis in humans are primarily char-
acterized by an acute self-limiting respiratory disease that is
1
United States Army Medical Research Institute of Infectious Diseases, Fre-
derick, MD, USA
2
Southwest National Primate Research Center, Texas Biomedical Research
Institute, San Antonio, TX, USA
3
Infectious Disease Pathology Branch, Centers for Disease Control and Pre-
vention, Atlanta, GA, USA
4
Texas Veterinary Pathology Associates LLC, Spring Branch, TX, USA
Supplementary material for this article is available online.
Corresponding Author:
Keith Koistinen, United States Army Public Health Center, 5158 Blackhawk
Road, Aberdeen Proving Ground, Gunpowder, MD 21010, USA.
Email: keith.a.koistinen.mil@mail.mil
906
generally asymptomatic or subclinical.51 Clinical disease clas-
sically presents as respiratory disease characterized by dys-
pnea, coughing, and respiratory distress. Typical gross
pathological changes include the presence of pulmonary
nodules and cavities throughout the lung tissue, often accom-
panied by thoracic lymph node enlargement.55 In less than 2%
of cases, hematogenous or lymphatic dissemination leads to
chronic, progressive disease18 involving the viscera, skin, soft
tissue, bone, and the central nervous system.1 Risk factors for
dissemination include immunosuppression secondary to human
immunodeficiency virus (HIV) or organ transplantation, ethnic
and sex predispositions, and occupation.1 The incidence of
coccidioidomycosis reported in humans has increased substan-
tially between the years of 1997 and 2011.14
Focal, regional, and systemic cases have been reported in many
species of nonhuman primates (NHPs), exhibiting a course of
disease similar to that seen in humans. These species include
geladas,46 baboons,3,27,48,56 mandrills,33,47 woolly monkeys,46,47
chimpanzees,6,29,30,32,37,39,47,53 macaques,2,8,10,26,41,47 mangabeys,44
guenons,20,47 spider monkeys,20,47 gorillas,4,31,40,47 capuchins,40
squirrel monkeys,47 and lemurs. 9 Nonhuman primates appear to
be particularly vulnerable to arthrospore exposure in known
endemic regions.5,15,18
An overview of the pathology associated with Coccidioides
spp infection in NHPs has not been previously reported. Here
we provide a review of the cases previously described,* and
describe a retrospective series of 22 naturally acquired cases
that were diagnosed at multiple pathology services, including
the United States Army Medical Research Institute of Infec-
tious Disease (USAMRIID), Southwest National Primate
Research Center at the Texas Biomedical Research Institute
(SNPRC), and Texas Veterinary Pathology Associates (TVP).
SNPRC and TVP are located in San Antonio, Texas, which is at
the very eastern boundary of the geographical endemic distri-
bution of C. immitis/C. posadasii.12
Materials and Methods
A search for histologically confirmed cases of coccidioidomy-
cosis within the pathology records at the authors’ respective
pathology services was performed. Search terms included
coccidioidomycosis and Coccidioides. The cases identified
from those search results are presented.
All of the cases in this series were housed for at least a short
time in indoor/outdoor group housed facilities at primate
research centers in San Antonio and southeast Texas. In addi-
tion, all cases were in the endemic area when diagnosed with
coccidioidomycosis with the exception of case 15 that was
temporarily housed in this endemic region for approximately
14 weeks.
The cases originating from SNPRC, San Antonio, Texas,
represent a population of more than 2000 NHPs, comprising
approximately 1500 baboons, 500 macaques, and 150
*References 2–4, 6, 8–10, 20, 26, 27, 29–33, 37, 39–41, 44, 46–48, 53, 56.
Veterinary Pathology 55(6)
chimpanzees. The TVP cases originated from multiple primate
facilities; TVP is a diagnostic pathology company that provides
pathology services to multiple primate facilities in San Antonio
and southeast Texas. The USAMRIID case was a primate
received from one of the normal vendors used for the institute.
Outdoor access when provided to animals in this case series
consisted of enclosures with indoor and outdoor areas or large
multiacre outdoor corrals. All animal care and research were
conducted under an Institutional Animal Care and Use Com-
mittee–approved protocol in compliance with the Animal Wel-
fare Act, Public Health Service (PHS) policy, and other federal
statutes and regulations relating to animals and experiments
involving animals. The facilities where this research was con-
ducted are accredited by the Association for Assessment and
Accreditation of Laboratory Animal Care, International and
adhere to principles stated in the Guide for the Care and Use
of Laboratory Animals, National Research Council, 2011.
Tissues were collected for histologic evaluation as required
for diagnosis and fixed in 10% neutral buffered formalin, pro-
cessed conventionally, embedded in paraffin, cut at 5 mM and
stained with hematoxylin and eosin or other stains, including
periodic acid–Schiff reaction (PAS) and Gomori’s methena-
mine silver stain (GMS) using standard techniques as needed
for diagnosis. When indicated, individual tissues were frozen in
liquid nitrogen and stored at –80 C, fixed in 2% glutaraldehyde
for electron microscopy, placed in normal saline or transport
medium for cytogenetic evaluation, cultured for bacteria and
viruses, or frozen in Optimal Cutting Temperature Compound
(Tissue-Tek) compound for frozen sectioning. Further evalua-
tion using immunohistochemistry was performed as required.
Necropsies were performed by a board-certified pathologist or
trained laboratory animal veterinarian. Histologic evaluation of
tissues was performed by board-certified veterinary
pathologists.
Electron Microscopy
Samples of formalin-fixed tissue from case 15 (Suppl. Table
S1) were retrieved and prepared for electron microscopy.
Briefly, tissues were postfixed in osmium tetroxide, dehydrated
in ethanol, infiltrated in a 1:1 solution of propylene oxide/Epon
resin, and embedded in Epon resin. Embedded tissues were thin
sectioned (*70-nm sections), and sections were mounted on
copper mesh or slot grids with a plastic support film. Sections
were contrasted with uranyl and lead salts prior to observation.
Sections were observed on a JEOL 1011 (Peabody, MA) trans-
mission electron microscope at 80 kV and digital images were
acquired using a Orca HR digital camera (Hamamatsu Corpo-
ration, Bridgewater, NJ) controlled by AMT image acquisition
software.
Immunohistochemistry
For immunohistochemical identification of Coccidioides sp, an
immunoalkaline phosphatase technique using a rabbit polyclo-
nal antibody raised against C. immitis was used. This
Koistinen et al 907

Table 1. Summary of Findings in 22 Cases of Coccidioidomycosis in Nonhuman Primates.

Distribution of Lesions Sex COD Clinical Signsa

Common Name Species Number D T B A C M F M I NR R L U NS GI N NR

Baboon Papio spp 10 7 2 1 5 5 6 3 1 3 3 1 1 3

Cynomolgus macaque Macaca fascicularis 4 3 1 3 1 3 1 1 1 1 1
Japanese macaque Macaca fuscata 2 2 2 0 2 1 1
Rhesus macaque Macaca mulatta 3 3 2 1 2 1 1 2 1 1
Chimpanzee Pan troglodytes 3 3 2 1 3 3
Total 22 8 11 2 1 0 14 8 16 5 1 8 5 2 2 0 2 4

Distribution of lesions: disseminated (D), thoracic (T), bone only (B), abdominal only (A), cutaneous (C); sex: male (M), female (F); cause of death (COD): mycosis
(M), incidental (I), not reported (NR); clinical signs: respiratory (R), locomotor/neurologic (L), none (N), urinary (U), nonspecific (ie, lethargy, weight loss) (NS),
gastrointestinal (GI), not reported (NR).
a
Some animals had more than 1 category of clinical signs.

polyclonal antibody is reactive against Coccidioides sp and,
based on analysis of tissues with known infections, does not
cross-react with Blastomyces, Cryptococcus, Histoplasma, Rhi-
zomucor, or Candida spp.
In addition, a polyfungal analysis was performed using a
polyfungal goat serum that was raised against a shared epitope
of Aspergillus fumigatus, Aspergillus niger, and Aspergillus
flavus. Based on analysis of tissues with known infections, this
goat serum is known to react with Blastomyces, Coccidioides,
Histoplasma, Candida, Fusarium, Apophysomyces, Basidiobo-
lus, Exserohilum, and Microsphaeropsis with variable reactiv-
ity to Zygomycetes. It is not known to cross-react with
Cryptococcus.
Polymerase Chain Reaction
As previously described,43 DNA was purified from paraffin-
embedded tissue, and polymerase chain reaction (PCR) ampli-
fication was performed using a panfungal primer set, ITS3/
ITS4, which amplifies the ITS2 region of the ribosomal DNA,
to identify Coccidioides sp genomic material.
Literature Review
A search of the PubMed and PrimateLit databases was con-
ducted using the following key words: primate, coccidioido-
mycosis, and Coccidioides. In addition, references from the
articles obtained in the initial search were examined to find
other reports not included in the initial database query.
Results
The pathology database search revealed 22 cases: 16 from
SNPRC, 5 from TVP, and 1 from USAMRIID. A summary
of the cases by species is listed in Table 1; Supplemental Table
S1 contains a complete list of the clinical and pathology find-
ings in each case.
The 16 cases found within SNPRC’s records were diag-
nosed sporadically over a period of 30 years and consisted of
10 baboons, 3 chimpanzees, and 3 macaques; males and
females were equally represented. All cases were born at the
facility or originated within endemic regions of the United
States. The 5 cases within TVP’s records were diagnosed in a
period of 10 years and consisted of 5 macaques, 3 rhesus maca-
ques, and 2 cynomolgus macaques. The single case found in
USAMRIID’s records (records that covered a period of 40
years) was a cynomolgus macaque.
Clinical Findings and Gross Lesions
Baboon. Ten cases were discovered in baboons, including cases
7 and 8 that were described in previously published case
reports.3,48 The clinical history was not available for 3 of the
10 baboon cases (cases 2, 8, and 9). Among the 7 cases in
which clinical history was available, 3 developed respiratory
signs (cases 1, 3, and 10), 3 had locomotion deficiencies (cases
4, 6, and 7), and 1 had no observed clinical findings (case 5).
The respiratory signs consisted of coughing (n ¼ 2) or labored
breathing (n ¼ 1). Motor deficiencies included hindlimb par-
esis to paralysis (n ¼ 2) and weakness and reluctance to move
(n ¼ 1). The animal with no observed clinical findings was
euthanized due to reasons unrelated to fungal infection, and
the lesions attributable to fungal infection in this case consisted
of a mass attached to the wall of the right main bronchus, which
extended to the subjacent lymph nodes and lung. These gross
findings were considered incidental and unrelated to the rea-
sons for euthanasia.
Lesions were most commonly noted in thoracic organs and
less often the vertebral column and abdominal cavity. Lesions
in the thoracic organs most commonly included the lungs (n ¼
7), regional lymph nodes (n ¼ 3), heart (n ¼ 2), trachea (n ¼ 1),
and esophagus (n ¼ 1). Gross lesions within the thoracic organs
included adhesions, granulomas, abscesses, ulcers, or masses.
In some cases, the lungs had dark brown to black discoloration
with black to brown fluid that extended throughout all lung
lobes on cut section. In other cases, the lungs were firm,
mottled gray-red-pink, with suppurative exudate expressed
from the airways on cut section. Thoracic lesions were absent
in 3 baboons (cases 4, 6, and 7). Two of these presented with
hindlimb paresis or paralysis, and all 3 had locally extensive
areas of granulomatous inflammation and necrosis that affected
the vertebrae, adjacent soft tissue, and spinal cord. Case 4 had
908
an irregularly thickened thoracic vertebrae. Case 6 lacked pul-
monary lesions and was the only baboon with lesions involving
abdominal viscera, with granulomas in the spleen and associ-
ated lymph nodes.
Chimpanzee. The 3 chimpanzees diagnosed with coccidioido-
mycosis all presented with respiratory signs, including tachyp-
nea. In addition, case 11 also presented with ascites, and this
case was clinically diagnosed as C. immitis/C. posadasii by
fungal culture of a thymic cyst biopsy. Despite itraconazole
treatment, this chimpanzee’s condition continued to decline
and it was euthanized.
The infection was disseminated to multiple organs in all 3
chimpanzees, including the lungs (n ¼ 3), pleura (n ¼ 1),
spleen (n ¼ 3), lymph nodes (n ¼ 3), liver (n ¼ 3), thoracic
lymph nodes (n ¼ 1), diaphragm (n ¼ 1), peritoneum (n ¼ 1),
and kidneys (n ¼ 1). The gross lesions in these organs were as
described above and appeared as granulomas and abscesses. In
addition, excessive fluid was observed in the abdomen (n ¼ 2)
and pericardium (n ¼ 1), and was characterized as clear, ser-
opurulent with fibrin tags, or suppurative.
Macaque. Nine macaques were diagnosed with coccidioidomy-
cosis: 3 rhesus macaques, 4 cynomolgus macaques, and 2 Japa-
nese macaques. Clinical signs varied and body systems affected
included respiratory (n ¼ 2), urinary (n ¼ 2), locomotor/ner-
vous (n ¼ 2), and gastrointestinal (n ¼ 2). The clinical signs in
individual macaques were described as coughing and gagging,
urinary incontinence and rear-limb paresis, open-mouth breath-
ing and collapse, ruptured bladder, bloody diarrhea with blood-
work consistent with renal disease, diarrhea and dehydration,
subcutaneous edema, hindlimb paresis, or incontinence. One
macaque (case 15) had no clinical signs attributable to fungal
infection. One macaque (case 16) was also seropositive for
Trypanosoma cruzi.
The distribution of lesions was limited to thoracic organs in
4 macaques (cases 15, 20, 21, and 22) and was disseminated
(intrathoracic and extrathoracic) in 5 macaques (cases 14, 18,
19, 16, and 17). The specific lesion location was not available
for all animals but was reported in 6 of 9 macaques as affecting
the lungs (n ¼ 5), spleen (n ¼ 2), liver (n ¼ 2), kidneys (n ¼ 3),
or muscle (n ¼ 1). The lung lesions in macaques were
described as having yellow purulent foci (abscesses), nodules
(Fig. 1 and 2), miliary foci, or areas of dark discoloration
(infarction). Subcutaneous and scrotal edema, hydropericar-
dium, and ascites were additional lesions.
Case 15 was administered 1608 plaque-forming units
(PFUs) of monkeypox virus by aerosol and was euthanized at
the end of the study on day 29 postinfection. Clinical signs
attributable to monkeypox were evident by day 4 postinfection,
including pyrexia, lymphadenopathy, and mild cutaneous pox
lesions. Clinical respiratory signs were not observed before or
after monkeypox challenge. Gross examination revealed few
faintly visible resolving pox lesions that consisted of 1- to 2-
mm whitish/brown discolored spots on the skin of the axillary
and inguinal areas. The left lung was diffusely firm, while the
Veterinary Pathology 55(6)
right lung contained few 5- to 10-mm pale firm foci affecting
10% of the apical and diaphragmatic lobes. All examined
lymph nodes were mildly enlarged, and the spleen was mark-
edly enlarged with rounded edges and prominent white pulp on
cut surface. All noted clinical and gross necropsy abnormalities
in this case, except for the lung lesions, were attributable to the
monkeypox infection and were typical for aerosol exposure to
this virus.24
Histopathology
Histologic findings were similar in all organs for all species and
were characterized by multifocal areas of granulomatous
inflammation composed of numerous multinucleate giant cells
admixed with lymphocytes, plasma cells, histiocytes, and
viable and degenerate neutrophils and eosinophils as well as
fungal spherules that were 25 to 30 microns in diameter with a
2- to 3-micron-thick wall. The spherules rarely underwent
endosporulation; endospores filling the spherules were 2 to 5
microns in diameter (Fig. 3). The spherules were often con-
tained within the cytoplasm of the multinucleate giant cells and
were often degenerate. Within pulmonary lesions, the inflam-
matory foci obscured the pulmonary architecture, and the
bronchioles and alveoli were often dilated and filled with
inflammatory cells, cellular debris, edema, and moderate num-
bers of fungal spherules. In some cases, the alveoli were occa-
sionally lined by plump cuboidal pneumocytes (type 2
pneumocyte hyperplasia). Within the bone and associated soft
tissues, the foci of granulomatous inflammation were accom-
panied by necrosis and degeneration of the mature bone.
The distribution was classified as thoracic, disseminated,
bone only, or abdominal based on location of histopathologic
lesions. The definition of disseminated distribution was based
on finding histologic lesions in pulmonary and nonpulmonary
locations, including visceral organs and/or bone. Thoracic dis-
tribution was the most common and was found in 11 cases (7
baboons, 1 cynomolgus macaque, and 3 rhesus macaques).
Disseminated distribution occurred in 8 cases (3 chimpanzees,
3 cynomolgus macaques, and 2 Japanese macaques). Bone only
and abdominal were the least frequent distributions and
occurred in 2 animals (cases 4 and 7) and 1 animal (case 6),
respectively, and all 3 were baboons.
Concomitant findings in some animals included amyloidosis
in 6 animals (2 baboons, 3 rhesus macaques, and 1 cynomolgus
macaque) in varying locations, including kidney, lymphoid
organs, and pancreas. Pyelonephritis and myocardial infarction
were present in another case, and both were considered unre-
lated to mycosis. The gastrointestinal, endocrine, and reproduc-
tive systems did not reveal other lesions attributable to
Coccidioides spp infection, except for those reported above.
Confirmatory Tests
Routine histopathologic examination supported by special
stains, including PAS reaction (Fig. 4), provided a diagnosis
in most cases. Other confirmatory tests used to characterize the
Koistinen et al 909

Figures 1–4. Coccidioides spp infection, thorax and lungs, rhesus macaque. Figure 1. There are several tan to white nodules attached to the
thoracic wall (arrow). Figure 2. The lungs are diffusely congested and contain several white to tan nodules (arrows). Figures 3–4. Cocci-
dioides spp infection, lung, cynomolgus macaque, case 15. Figure 3. Mature spherule that contains endospores. Hematoxylin and eosin.
Figure 4. The cell walls of the fungal spherules as well the endospores are highlighted. Periodic acid–Schiff reaction.

cases in this series included tissue culture, polyfungal immu-
nohistochemistry, agent-specific immunohistochemistry, PCR,
and electron microscopy. Fungal culture was used to confirm
the diagnosis of coccidioidomycosis in 2 chimpanzees from a
biopsy (case 11) and from tissues collected after death (case 13).
Immunohistochemistry was performed on the 15 cases in
which paraffin-embedded tissue was available, using
antibodies specific for Coccidioides spp as well as polyfungal
antibodies. Both methods identified Coccidioides spp in 14 of
the 15 cases (cases 1–13, 15, 19, and 17). Fungal antigen was
located in spherules located within multinucleate giant cells as
well as extracellular free spherules.
PCR testing was conducted on paraffin-embedded tissue
from these 15 cases using Coccidioides sp.–specific primers
910
Figures 5–6. Coccidioides spp infection, lung, cynomolgus macaque, case 15. Transmission electron microscopy. Figure 5. A fungal spherule in
tissue contains numerous endospores. Figure 6. An immature fungal spherule that lacks endospores.
and was positive in 5 cases (cases 2, 3, 12, 13, and 19). The
assay did not distinguish C. immitis and C. posadasii.
Electron microscopy on the lung tissue from case 15 iden-
tified mature and immature spherules that were approximately
15 to 20 microns in diameter and had a 1-micron-thick
electron-dense wall (Fig. 5). Mature spherules contained endo-
spores while immature spherules lacked endospores (Fig. 6).
Literature Review
A search within the PubMed database revealed 79 naturally
occurring cases of coccidioidomycosis in NHPs (48 male, 19
female, 12 not stated) (Table 2). Of these, 3 cases were also
reported above. The most common species affected were maca-
ques (n ¼ 26), chimpanzees (n ¼ 24), and gorillas (n ¼ 8). The
clinical signs were described in 46 cases and affected the
respiratory system (n ¼ 32), skin (n ¼ 5), and vertebrae and/
or neurological system (n ¼ 9) or were nonspecific such as
weight loss (n ¼ 7) or abdominal distension (n ¼ 3).
Twenty-eight reports did not include any gross pathologic
findings because the animal was alive at the time of study
publication, a necropsy was not performed, or findings were
not included in the description. Gross lesions were found in the
lung (n ¼ 21), spleen (n ¼ 10), liver (n ¼ 7), bone (n ¼ 7),
lymph nodes (n ¼ 7), heart (n ¼ 5), esophagus (n ¼ 4), pleura
(n ¼ 4), trachea (n ¼ 3), kidney (n ¼ 3), testis (n ¼ 2), peri-
toneum (n ¼ 2), diaphragm (n ¼ 2), pancreas (n ¼ 1), colon (n
¼ 1), retina (n ¼ 1), brain (n ¼ 1), and meninges (n ¼ 1). The
Veterinary Pathology 55(6)
distribution of lesions was disseminated (n ¼ 39), intrathoracic
(n ¼ 6), bone (n ¼ 2), abdominal (n ¼ 1), ocular (n ¼ 1), or
cutaneous (n ¼ 3).
Of particular note, 3 chimpanzees lacked involvement of the
respiratory system. These had a granulomatous abdominal
mass encasing the pancreas and the abdominal aorta (case
28) and an osteolytic mass incorporating the 11th, 12th, and
13th thoracic vertebra accompanied by clinical neurologic
signs (case 34), as well as bone lesions in the atlas, its corre-
sponding occipital condyle, and a rib, with soft tissue involve-
ment limited to a perforated esophagus (case 15).
Experimental infection of 93 rhesus macaques with Cocci-
dioides was reported in 5 studies published between 1953 and
1966 (Table 3), using aerosolization, intratracheal injection, or
natural exposure.5,7,16–18 The naturally exposed cases were
infected by housing the animal in an area that was known to
be infested.18 When arthrospores were administered via intra-
tracheal injection, all monkeys showed evidence of pulmonary
infiltration. The pulmonary lesions varied from few focal
lesions to extensive pulmonary destruction, and 1 study attrib-
uted the severity of lesions to the administered dose.5 The
disease progressed from minor inflammation of the lungs and
enlarged lymph nodes to necrotic, granulomatous nodules and
lymph node inflammation. Within 15 days of exposure, the
animals developed nodules within the lungs, regional lymph
nodes, liver, and spleen, as well as fibrinous adhesions between
organs. In macaques infected with aerosolized arthrospores, the
gross lesions were consistent with natural cases.7
Koistinen et al 911

Table 2. Naturally Occurring Cases of Coccidioidomycosis in Nonhuman Primates Reported in the Scientific Literature.

Distribution of Lesions Sex COD Clinical Signsa

Common Name Species Number D T B A C NR O M F NR M I NR R L C NS N NR Reference

Baboon Papio spp 4 1 1 2 2 1 1 3 1 1 2 1 3, 27, 47, 56

Baboon (Gelada) Theropithecus 1 1 1 1 1 45
gelada
Mandrill Mandrillus 2 2 2 2 1 1 33, 46
sphinx
Bonnet macaque Macaca radiata 1 1 1 1 1 2
Cebus Cebus 1 1 1 1 1 40
hypoleucus
Celebes Macaca nigra 3 3 1 2 3 2 1 46
Chimpanzee Pan troglodytes 24 15 1 1 1 5 1 14 4 6 11 1 12 8 1 4 13 6, 29, 30, 32, 37, 39,
46, 53
Cynomolgus Macaca 1 1 1 1 1 41
fascicularis
Gorilla Gorilla gorilla 8 5 3 7 1 5 3 3 1 4 4, 31, 40, 46
Guenon Cercopithecus 5 5 1 3 1 4 1 5 20, 46
spp
Japanese macaque Macaca fuscata 17 17 12 5 11 6 14 6 3 26
Lemur Lemur catta 1 1 1 1 1 9
Lion-tailed Macaca silenus 1 1 1 1 1 46
macaque
Rhesus Macaque Macaca 3 1 2 2 1 3 1 1 1 8, 10, 36, 46
mulatta
Sooty mangabey Cercocebus atys 1 1 1 1 1 43
Spider monkey Ateles hybridus 2 2 1 1 1 1 2 20, 46
Squirrel monkey Saimiri spp 1 1 1 1 1 46
Woolly Monkey Lagothrix spp 3 2 1 1 1 1 2 1 3 45, 46
Number 79 39 6 2 1 3 28 1 47 20 12 50 2 26 32 9 5 7 1 33

Common name: Celebes crested macaque (Celebes), cynomolgus macaque (Cynomolgus). Species: Cebus hypoleucus; Cercopithecus diana, nictitans, or neglectus;
Theropithecus gelada; Macaca mulatta; Macaca nigra; Macaca radiata; Macaca silenus; Mandrillus sphinx. Distribution of lesions: disseminated (D), thoracic (T), bone
(B), abdominal (A), cutaneous (C), ocular (O), not reported (NR); sex: male (M), female (F); cause of death (COD): mycosis (M), incidental (I), not reported (NR);
clinical signs: respiratory (R), locomotor/neurologic (L), none (N), urinary (U), nonspecific (ie, lethargy, weight loss) (NS), not reported (NR).
a
Some animals had more than 1 category of clinical signs.

Table 3. Reports of Experimental Infection of Rhesus Macaques With Coccidiodes sp.

Inoculation
Number Route Gross Pathology Histopathology Reference

46 Aerosolized Nodules in lungs (7 days), liver and spleen (15 days) Inflammatory cells and spherules at 7
center of lesions
15 Aerosolized Few lung lesions to extensive pulmonary destruction Large numbers of spherules within 17
(dependent upon dose) lesions
12 Intratracheal Lesions in lung and lymph nodes Spherules and endospores in lesions 5
5 Aerosolized Lesions throughout lungs, kidney, and lymph nodes, adhesions Spherules in lungs 16
5 Natural None Minor changes in lungs 18
exposure
10 Intratracheal Lung lesions Most contained organism 18

Discussion Pulmonary and disseminated histologic lesions consisted of

pyogranulomas or granulomas. There are frequently aggregates
We report 22 natural cases of coccidioidomycosis in NHPs and
of intermixed neutrophils resulting from the initial reaction to
review natural and experimental cases of coccidioidomycosis
the endospores released from matures spherules. The lesion is
in the nonhuman primate literature. As a group, primates
thought to form a granuloma or pyogranuloma as it matures and
appear particularly susceptible.50 The cases were distributed
is composed of the common components of a granulomatous
between males and females of all ages.
reaction, including giant cells.11
912
The clinical signs and pathology observed in the naturally
occurring cases reported here are generally consistent with
those cases that have been described previously in the litera-
ture. Among the cases reported in the literature, overall, the
species with the most reported cases were macaques (n ¼ 34),
chimpanzees (n ¼ 27), baboons (n ¼ 12), and gorillas (n ¼ 8).
All other species had few reports, and almost all involved dis-
seminated disease. The exception was the spider monkey,
which had 2 reported cases, both with lesions confined to the
thorax. Macaques and chimpanzees frequently had dissemi-
nated disease (21/34 and 18/22 with lesions reported, respec-
tively). None of the 12 affected baboons had disseminated
disease, and lesions were confined to the thorax (n ¼ 7), ver-
tebrae and adjacent soft tissue (n ¼ 2), skin and subcutis (n ¼
2), or spleen and associated lymph node (n ¼ 1). The authors
suspect that 1 or both of the baboon cases with cutaneous
involvement27,56 were misdiagnosed as both were diagnosed
in the United Kingdom, and neither had a reported history of
travel to the Americas. The reason that baboons had a differ-
ence in distribution of lesions was not apparent, and the histo-
logic nature of the lesions described in the reports was not
different.
Despite the presence of gross and histologic lesions at post-
mortem examination, no clinical signs attributed to coccidioi-
domycosis were observed in 2 NHPs in our case series, a
cynomolgus macaque (case 15) and a baboon (case 5). Simi-
larly, serologic surveillance studies have shown that many
infections in humans and animals are asymptomatic. In a sur-
vey of dogs in Arizona, 70% of seropositive dogs exhibited no
sign of disease.49 Similarly, 100% of a group of naturally
exposed monkeys developed subclinical infections after being
contained in outdoor housing in a river basin for a year in an
endemic region (Tucson, Arizona). None of these monkeys
exhibited clinical signs, but all were positive by a coccidioidin
skin test and complement fixation test; 40% of the exposed
monkeys had histologic lesions.18 In NHPs housed outdoors
at the California Primate Research Center in 1977 to 1978, 4
of 119 (3%) were seropositive; the seropositive cases were
attributed to a dust storm that affected the area, as there were
no seropositive animals when they were surveyed prior to the
dust storm.2 Approximately 60% of infected humans are
asymptomatic; the remainder can develop manifestations that
range from mild influenza-like illness to pneumonia. Overall,
less than 5% of infected persons have progressive pulmonary
infection or extrapulmonary dissemination of the disease.35
In one of these subclinical cases, case 15, an initial presump-
tive diagnosis was based on the morphologic appearance of
fungal spherules in the tissue section, but additional confirma-
tory testing was performed because this diagnosis was unex-
pected because of the geographic location (Maryland) and the
absence of clinical signs related to fungal infection. The results
all supported the diagnosis of coccidioidomycosis. In this case
in addition to the lung lesions, other nonpulmonary lesions
were noted, but all of these nonrespiratory clinical and gross
necropsy abnormalities were attributable to experimental mon-
keypox exposure.24 The source of infection of this case is
Veterinary Pathology 55(6)
speculated to be inhalation of dust-borne arthrospores while
the animal was temporarily housed in Texas. C. posadasii is
the most likely cause based on the geographical location his-
tory of this primate and the geographic distribution of this
species. Infection of this monkey during this relatively brief
period of exposure (14 weeks) is supported by the findings of
Converse and Reed18 that infection could be established after
aerosol exposure of rhesus macaques to as few as 10 arthros-
pores. This pathogen is considered one of the most virulent and
highly contagious fungal pathogens, and thus it should only be
grown under biocontainment conditions, as infections have
occurred following exposure to arthrospores in the
laboratory.54
Animal models of coccidioidomycosis include mice, 19
rats,21 hamsters,21 guinea pigs,57 dogs,18,23 cattle,38 and pri-
mates.5,7,16–18,36 Since NHPs appear to be particularly suscep-
tible to infection and the disease progression parallels that in
humans, they appear to be a good model of the disease.
Although the mouse is used most extensively as an animal
model due to its rapid disease progression and the availability
of genetically defined animals, it often requires euthanasia to
collect sufficient tissue samples, and its small size makes it
difficult to assess individual organ pathology.15 There are also
substantial pharmacokinetic discrepancies between mice and
humans, complicating the study of vaccines and treatments.52
Both the mouse and the hamster rapidly develop disseminated
disease regardless of the method of inoculation, and death
occurs within 4 weeks of inoculation in 83.3% of hamsters.21
Infection of NHPs via natural as well as experimental infec-
tion closely resembles the course of disease in humans. The
gross lesions in macaques experimentally infected with aero-
solized arthrospores are also consistent with natural cases.7 The
predictable disease progression with both aerosol and intratra-
cheal inoculation makes NHPs good candidates for modeling
infection with C. immitis/C. posadasii. Additional advantages
of using NHPs as a model of coccidioidomycosis include a
slower disease progression and more variations in disease
forms; this may allow the use of fewer animals and lead to
more targeted treatment studies.
Dogs and cats are also affected by this mycotic infection,
and comparisons to the disease in humans and NHPs can be
made. Similar to humans and NHPs, infections in dogs are
predominantly limited to the lungs and associated lymph
nodes. Disseminated infection in dogs has been recognized in
20% of the cases, and locations affected include the bones,
joints, and lymph nodes, with bone being the most common
site. In dogs, in contrast to other species including mice, ham-
sters, humans, and NHPs, the appendicular skeleton is more
often affected than the axial skeleton.25,50 The brain lesions in
dogs are typically granulomatous mass lesions while in
humans, meningeal lesions typically occur. 50 Cats, like
humans, develop cutaneous lesions more commonly than other
domestic species. Dissemination occurs in 50% of feline infec-
tions, and the skin is the most common site of disseminated
infection.25
Koistinen et al
When comparing the disease in NHPs to humans, the dis-
ease in both includes lung cavitation and bone infections nearly
exclusively within the axial skeleton; infection of the appendi-
cular skeleton is rarely reported. However, NHPs do differ
from humans in the usual lack of skin and subcutaneous
lesions, which occur in more than 65% of cases of disseminated
disease in humans.19,26 The Japanese macaque is a notable
exception, as 3 of 17 had a clinical history of cutaneous invol-
vement that was identified by culture to be Coccidioides spp.26
In humans, the skin lesions are often associated with erythema
nodosum,35 which has not been described in animals.
Morphology of the Coccidioides spherules in histological
sections is unique, and a strongly presumptive diagnosis can
be made with histopathology alone. The diagnosis of coccidioi-
domycosis is not always straightforward if there is an absence
of histologically apparent arthrospores; available confirmatory
tests include fungal culture, immunohistochemistry (IHC),
PCR, and in situ hybridization (ISH). C. immitis/C. posadasii
exists in 2 forms: a hyphal form and a spherule form. The
hyphal forms are rare in tissue sections because they develop
at room temperature (25  C). The hyphal form has been
observed in tissues from humans, especially in cases with large
cavitary lesions.42 The spherules are observed in the tissue
phase and only produced in culture under special growth con-
ditions. The presence of misleading Coccidioides elements that
may resemble other pathogens such as Blastomyces dermatiti-
dis or hyphomycetes has been reported in tissues from humans.
These misleading elements include budding cells; branched,
septate hyphae; and moniliform hyphae consisting of chains
of thick-walled arthroconidia.34
Other fungal organisms with similar but distinguishable
morphology include Emmonsia spp, Blastomyces dermatitidis,
and Rhinosporidium seeberi. The major distinguishing factor
of coccidioidal spherules is the formation of thick-walled endo-
spores within the coccidioidal spherule as it matures. B. der-
matitidis does not form endospores but forms broad-based buds
and is smaller than mature coccidioidal spherules. R. seeberi
forms endospores that have thin walls. In addition, rhinospor-
idial sporangia are much larger than coccidioidal spherules.
Emmonsia spp have the closest morphology but do not form
thick-walled endospores and instead form fruiting bodies that
line the interior of the wall and result in a honeycomb pattern;
these are much less distinct than those of Coccidioides spp. In
addition, Emmonsia spp adiaspore walls are thicker than Coc-
cidioides sp.11 Fungal culture, IHC, PCR, and ISH are other
methods to provide an unequivocal diagnosis. Fungal cultures
must be treated with precautions in the laboratory because the
infectious arthroconidia may develop after incubation at room
temperature.25
Attempts to retrieve genomic material from the paraffin-
embedded tissues had poor sensitivity; only 5 of 15 were PCR
positive for Coccidioides spp. The PCR assay used did not
distinguish C. immitis from C. posadasii. The genomes of C.
immitis and C. posadasii only differ by several DNA poly-
morphisms within 2 microsatellite loci,22 and their differentia-
tion requires fresh unfixed material.
913
Serology is the primary method for the antemortem diagno-
sis of coccidioidomycosis in animals, and it uses the same
reagents and controls as for serodiagnosis of the disease in
humans. The relationship of serology results to clinical disease
is not known for NHPs. Seropositive dogs may have clinical or
subclinical disease, but seropositivity of cats correlates well
with the presence of clinical disease.25
Coccidioides spp was found as a contaminant of a primary
rhesus monkey kidney (RhMK) cell culture obtained from a
commercial supplier; the source of this contamination was not
identified.45 It suggests that screening for this organism should
be considered for cell lines derived from NHPs.
In the past decade, the number of reported cases in humans
has increased, but the reason is uncertain. Contributing factors
are thought to include an increased population in the endemic
area, climatic change (drought and increasing temperatures in
the southwestern United States), dust storms, soil disturbance
caused by increased construction activity, growing numbers of
humans who are immunocompromised or have other risk fac-
tors for severe disease, and immigration of previously unex-
posed persons from areas where coccidioidomycosis is not
endemic.13,14
In this report, we have characterized the distribution of coc-
cidioidomycosis in terms of anatomic distribution, types of
clinical signs, and species of NHPs affected by reviewing past
cases in our records as well as those reported in the scientific
literature. We found that as a group, NHPs are particularly
susceptible to disease, and presentation of coccidioidomycosis
parallels disease in humans with presentations from localized
clinical infections to disseminated disease as well as subclinical
infections. A wide variety of NHP species were represented.
Baboons represented a large number of cases in the case series
presented here and had a slightly unique presentation with
absence of disseminated disease. The reason for the differing
presentation in this species is unknown. Cutaneous infections
in NHPs were also observed but had a very uncommon lesion
distribution. Subclinical infection was also observed, albeit in
only a few cases but this may simply reflect the lack of routine
antemortem surveillance for this disease. The presence of sub-
clinical infections has the potential to interfere with experimen-
tal studies performed in NHPs, and consideration for the
presence of this disease for NHPs that are housed, even tem-
porarily, in endemic areas may be warranted. This survey will
provide information to help fill the knowledge gap for the wide
variety and incidence of presentations of this disease in NHPs,
especially if the disease prevalence in other species, including
humans, continues to increase.
Acknowledgements
The authors gratefully acknowledge Jayson Felty and the TxBiomed
library staff and the SNPRC veterinary pathology and clinical staff
and numerous contributions of USAMRIID’s pathology personnel,
including William Aguilar, Neil Davis, Phil Fogle, Angela Grove,
Gale Krietz, and Christine Mech.
914
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Disclaimers
Opinions, interpretations, conclusions, and recommendations are
those of the author and are not necessarily endorsed by the US Army.
Funding
The authors disclosed receipt of the following financial support for the
research, authorship, and/or publication of this article: This investiga-
tion used resources that were supported by the Southwest National
Primate Research Center (grant P51 RR013986) from the National
Center for Research Resources, National Institutes of Health, which
are currently supported by the Office of Research Infrastructure Pro-
grams through P51 OD011133 as well as the Office of Biodefense
Research Affairs (OBRA)/National Institute of Allergy and Infectious
Diseases (NIAID) with interagency agreement (A120-B.11) between
USAMRIID and NIAID. This investigation was conducted in facilities
constructed with support from the Office of Research Infrastructure
Programs (ORIP) of the National Institutes of Health through grants
C06 RR014578, C06 RR015456, and C06 RR016228.
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