mycelial forms of coccidiodes spp. in parasitic phase

ARTICLE
Mycelial forms of Coccidioides spp. in the parasitic phase
associated to pulmonary coccidioidomycosis
with type 2 diabetes mellitus
B. Muñoz-Hernández & M. A. Martínez-Rivera &
G. Palma Cortés & A. Tapia-Díaz &
M. E. Manjarrez Zavala
Received: 6 November 2007 /Accepted: 3 March 2008 / Published online: 30 May 2008
# Springer-Verlag 2008
Abstract Pulmonary coccidioidomycosis shares character-
istics with other pulmonary pathologies. In tissue, spherules
containing endospores are markers of Coccidioides immitis
and C. posadasii infection. Mycelial forms presenting
without classical parasitic structures are often misdiag-
nosed. The study was performed at the National Institute of
Respiratory Diseases (INER) of Mexico between September
1991 and June 2005 and analyzed the association between
cases, controls, and risk factors, including co-morbidity. A
case was defined as any patient who presented mycelial forms
and a control as any patient who presented only spherules or
no parasitic forms. All patients (n=44) with pulmonary coc-
cidioidomycosis were diagnosed by culture, histopathology,
cytology, and immunology. Type 2 diabetic patients with
pulmonary coccidioidomycosis were four times more likely
than non-diabetics to develop parasitic mycelial forms (95%
confidence interval [CI], 0.85–20.10; P<0.01). We formulat-
ed a comprehensive definition based on the results as follows:
patients with pulmonary coccidioidomycosis with an evolu-
tion longer than 8 months, cough, hemoptysis, radiological
evidence of a cavitary lesion, and type 2 diabetes mellitus,
develop parasitic mycelial forms of Coccidioides spp. Based
on microscopic images of patient specimens, we propose
incorporating mycelial forms into the parasitic phase of
Coccidioides spp. in patients with type 2 diabetes mellitus
and chronic and cavitary pulmonary coccidioidomycosis.
Introduction
Coccidioides immitis and C. posadasii are etiologic agents
of coccidioidomycosis [1, 2].
Major endemic zones are in North America where there
are arid and semi-arid climates, such as the northern
Mexican states Sonora, Chihuahua, Coahuila, and Nuevo
Leon and the southwestern United States California,
Arizona, New Mexico, Nevada, Utah, and Texas [1–3].
Coccidioides spp. enters the lungs through the airways and
causes an infection that is usually benign. However, the
infection is sometimes severe and lethal, particularly in
immunocompromised patients. Elderly persons are at greater
risk of developing severe pulmonary disease, while dissem-
inated infection is more frequent in black patients and
pregnant women [1, 3–9]. Transplant patients on immuno-
suppressive therapy or with human immunodeficiency virus
(HIV) infection are at higher risk of developing severe and
progressive coccidioidomycosis [10–13].
Eur J Clin Microbiol Infect Dis (2008) 27:813–820
DOI 10.1007/s10096-008-0508-4
The experiments comply with the current laws of Mexico.
B. Muñoz-Hernández :G. Palma Cortés :M. E. Manjarrez Zavala
Laboratorio de Micología Médica,
Departamento de Investigación en Virología,
Instituto Nacional de Enfermedades Respiratorias (INER),
Calzada de Tlalpan 4502,
CP 14080 México, D. F., México
M. A. Martínez-Rivera
Escuela Nacional de Ciencias Biológicas,
Instituto Politécnico Nacional (IPN),
Prolongación de Carpio S/N, Casco de Santo Tomas,
A. Tapia-Díaz
Departamento de Investigación en Farmacología,
Instituto Nacional de Enfermedades Respiratorias (INER),
Calzada de Tlalpan 4502,
M. E. Manjarrez Zavala (*)
Calzada de Tlalpan 4502, Sección XVI,
e-mail: e_manjarrez@yahoo.com

Coccidioides spp. is a dimorphic fungus that forms
arthroconidia during its mycelial phase while growing in
soil. Inhalation of arthroconidia by a susceptible host
initiates the parasitic phase. The arthroconidia transform
into endospore-containing spherules, which are classically
found in Coccidioides spp. infected tissue, although
parasitic mycelial structures have been identified in some
cases [1, 14, 15]. These non-classic mycelial structures of
Coccidioides spp. have been observed in human tissue or
fluid since 1946. [14–23]. When fungal structures are
examined, hyphae can be found in up to 50% of specimens
[15]. Parasitic mycelial forms have been observed mainly in
specimens from lung tissue, sputum, cerebrospinal fluid,
and nervous tissue [14–20].
Parasitic mycelial forms of Coccidioides spp. are less
frequently observed in pleural fluid, fungus ball, and gastric
lavage product [21–23]. Pulmonary coccidioidomycosis
shares clinical manifestations with other pulmonary pathol-
ogies, including other mycoses, neoplasia, and tuberculosis
[15, 24, 25]. Diagnosis of pulmonary coccidioidomycosis is
a multidisciplinary effort.
The aim of the present study was to evaluate first, the
association between the development of mycelial cells as
parasitic forms of C. immitis or C. posadasii and concomitant
pathologies, clinical, and epidemiological data in patients
referred to the National Institute of Respiratory Diseases
(INER), a tertiary level care center, and second, the signifi-
cance of microscopic findings during the parasitic phase.
Materials and methods
Study type
The study population comprised patients with chronic
pneumopathy referred to the INER of Mexico, without a
definite diagnosis or with a misdiagnosis (usually tubercu-
losis). The patients were followed from September 1991 to
June 2005 in order to detect all new cases of pulmonary
coccidioidomycosis with parasitic mycelial forms.
In this study we include prospective as well as retrospective
analysis. It included elements of cohort, case, and control
studies (ambipective studies). A case was defined as any
patient who presented with mycelial forms; hyphae or hyphae
and spherules (H-HS). A control was defined as any patient
who presented only with spherules or in whom no parasitic
forms were observed (S-NO). However, Coccidioides spp.
was isolated from all case and control specimens.
During analysis, H-HS cases (25 out of 44) were
compared with S-NO controls in whom only spherules
developed (16 out of 19), or in whom it was not possible to
identify any parasitic form microscopically (3 out of 19).
Diagnosis was made by culture. In some patients, immu-
noserology, cutaneous reaction, histopathology, or cytology
were also performed. The study inclusion criterion was
isolation of Coccidioides spp. (44 out of 44). Information
obtained from medical records included clinical back-
ground and risk factors, which served as a basis for
epidemiological analysis. We analyzed gender; age; occu-
pation; socioeconomic status; place of residence; visits to
coccidioidomycosis endemic areas; and clinical issues,
including admittance and final diagnoses; clinical manifes-
tations; disease evolution time; concomitant diseases; radio-
logical studies: X rays and computed axial tomography
(CAT); and microbiological studies.
Coccidioidomycosis diagnosis
Most microscopic examinations were performed on sputum
and bronchial lavage or brushing specimens, and, in a
smaller proportion, secretions from fistulae, lung tissue,
lymph node, and skin. Specimens were sent to the
pathology and mycology laboratories and immediately pro-
cessed. Direct examination with 15% potassium hydroxide
was performed. All specimens were cultured in Sabouraud
agar and mycobiotic agar at 28° until mycelia grew.
Serological tests were performed to identify anti-Coccidioides
spp. antibodies included capillary precipitation, gel immu-
nodiffusion, complement fixation reaction, and enzyme-
linked immunosorbent assay (ELISA). Cellular immune
response was evaluated with a coccidioidin sensitivity test.
To rule out tuberculosis, Mycobacterium tuberculosis was
traced by smear with Ziehl-Neelsen stain or auramine-
rhodamine fluorescence and cultured in Lowenstein-Jensen
medium. Pathology evaluations included cytology and
histopathology using Gomori methenamine silver (GMS),
periodic acid Schiff (PAS), hematoxylin and eosin (H-E),
and Papanicolaou smear stains.
Statistical analysis
Simple, bivariate, and stratified analyses were performed to
measure associations between H-HS forms of Coccidioides
spp. and the mentioned risk factors. Complete data were
obtained from 43 patients. Rates and risks were calculated
for intermediate significance tests with 95% confidence
intervals (CI), and Chi-squared, Mantel-Haenszel, and
Student’s t tests were performed. Excel (Microsoft) and
SPSS v.10.0 software was used (SPSS, Chicago, IL, USA).
Results
Eighty-six percent of the patients were male and 14% were
female. Seventy-nine percent of patients were between 25
and 64 years (mean age 38 years old). Seventy-five percent
814 Eur J Clin Microbiol Infect Dis (2008) 27:813–820

of the patients were employed in a capacity that involved
exposure to soil. Thirty-two percent of the patients were
illiterate or had an incomplete elementary education. Nearly
27% of the patients had attended senior high school.
Approximately 86% of the patients lived or worked in
coccidioidomycosis-endemic areas (Table 1). Due to a high
rate of Mexican migration to the US, we investigated how
many patients lived in or visited endemic areas in the
southern US. Eight of the cases and four of the controls
had, in fact, spent time in those areas. Although most
patients lived in or had visited coccidioidomycosis-endemic
areas, it was not associated with a higher risk of presenting
parasitic mycelial forms. The study population included
patients who were of low socioeconomic status, and 56%
had inadequate housing. The average income was US$150
per month. Patients had been admitted with a presumptive
diagnosis, including coccidioidomycosis (10 out of 44),
aspergillosis (8 out of 44), histoplasmosis (4 out of 44),
acquired immunodeficiency syndrome (AIDS; 4 out of 44,
and tuberculosis (40 out of 44). After appropriate laboratory
and radiological analyses, the final diagnoses were as
follows: in 44 patients, pulmonary coccidioidomycosis
was demonstrated by fungal culture; 41 patients presented
with coccidioidomycosis as the sole pulmonary pathology,
and only 3 patients presented with pulmonary coccidioido-
mycosis associated with tuberculosis. Six of those patients
presented fistulae in the chest with purulent drainage. In
addition, a disseminated form of the infection was observed
in 3 patients who presented with skin lesions. Clinical
manifestations (i.e., cough, hemoptysis, fever, dyspnea and
weight loss) and radiological findings were nonspecific,
although they were compatible with coccidioidal infection.
Chest radiology and CAT revealed a colonized cavitary
lesion, nodules, micronodules, fibrous strands, lung opacity
and, in some patients, pleural effusion, granuloma (cocci-
dioidoma), empyema, and hydropneumothorax (Table 2).
Mean body mass index (BMI) and evolution time of
coccidioidomycosis were significantly different in cases
Table 1 Demographic data of patients with pulmonary coccidioidomycosis, September 1991 to June 2005, INER, Mexico
Demographic variable Cases Controls Total
Number Percentage Number Percentage Number Percentage
Age in years
< 25 1 2.3 6 14.0 7 16.3
25–44 14 32.6 7 16.3 21 48.8
45–64 9 20.9 4 9.3 13 30.2
> 65 1 2.3 1 2.3 2 4.7
NS – – 1 – 1 –
Total 25 58.1 19 41.9 44 100.0
Sex
Male 19 43.2 19 43.2 38 86.0
Female 6 13.6 – – 6 14.0
NS – – – – – –
Total 25 56.8 19 43.2 44 100.0
Stay in endemic area
Yes 21 48.8 16 37.2 37 86.0
No 4 9.3 2 4.7 6 14.0
NS – – 1 – 1 –
Total 25 58.1 19 41.9 44 100.0
Occupation with soil exposure
Yes 19 43.2 14 31.8 33 75.0
No 6 13.6 5 11.4 11 25.0
NS – – – – – –
Total 25 56.8 19 43.2 44 100.0
Education
None 7 20.5 4 11.8 11 32.3
Elementary 2 5.9 1 2.9 3 8.8
Junior high-school 7 20.5 2 5.9 9 26.5
Senior high-school 5 14.7 4 11.7 9 26.5
College 2 5.9 – – 2 5.9
NS 2 – 8 – 10 –
Total 25 67.6 19 32.4 44 100.0
NS, not specified
Eur J Clin Microbiol Infect Dis (2008) 27:813–820 815

and controls. Cases had higher BMI, although they were
not obese (mean 24.46 vs. 20.1, P<0.05). Mean evolution
was 2.5 years for cases and 8 months for controls (P<0.05).
The most frequent concomitant disease was type 2
diabetes mellitus, which affected 52.5% of the patients;
27.5% of the patients were anemic and malnourished and
10% had AIDS. Two controls and 1 case with type 2 diabetes
mellitus had concomitant lung tuberculosis (Table 3). There
was a positive association between type 2 diabetes mellitus
and Coccidioides spp. infection with development of hyphae,
and those patients were four times more likely than non-
diabetics to develop mycelial forms 95% CI, 0.85–20.10;
P<0.05. Data analysis included housing conditions, living
with animals, and smoking habits. Smoking habits was the
only risk factor that revealed statistical significance in a Chi-
squared test for trend on different exposure strata (X2
=5.092,
P<0.05 of diabetics developing mycelial infection).
The biological products analyzed (25 out of 44) contained
the following parasitic mycelial forms of Coccidioides spp.:
1. Septate mycelium with different forms
2. Hyphae forming pleomorphic, ovoid and barrel-shaped
arthroconidia
3. Thin chains of oval and spherical cells
4. Germination and filamentation of spherule with endo-
spores and spores (Figs. 1 and 2)
Those mycelial forms occurred with or without spherules.
In the 1 case of coccidioidoma, parasitic mycelial structures
were associated with spherules containing endospores.
Discussion
Coccidioides immitis and C. posadasii produce pulmonary
infection with clinical manifestations that can be confused
with other pulmonary pathologies, such as tuberculosis,
histoplasmosis, blastomycosis, cryptococcosis, and asper-
gillosis [15, 24, 25]. Mexico has large endemic areas of
coccidioidomycosis. INER of Mexico is a tertiary level care
center that is not located in a coccidioidomycosis-endemic
area. The number of patients with coccidioidomycosis that
are registered at INER was not representative of the total
incidence of coccidioidomycosis in the country during the
present study period. However, INER has specialists to
perform proper coccidioidomycosis diagnostics.
Table 2 Radiological studies of patients with pulmonary coccidioidomycosis
Radiology H-HS S-NO Total
Colonized cavity 25 100.0 10 55.5 35 81.3
Nodules and micronodules 21 84.0 15 83.3 36 83.7
Fibrous traces 15 60.0 8 44.4 23 53.5
Lung opacity 14 56.0 13 72.2 27 62.8
Coccidioidoma 1 4.0 0 0 1 2.3
H, hyphae; HS, hyphae and spherules; S, spherules, NO, no parasitic forms observed
Table 3 Comorbidity of patients with pulmonary coccidioidomycosis
Comorbidity H-HS S-NO Total
Type 2 diabetes mellitus 16b
40.0 5 12.5 21 52.5
Malnutrition and anemia 4 10.0 7 17.5 11 27.5
AIDS 2 5.0 2 5.0 4 10.0
PTB c
– 2 5.0 2 5.0
Cardiopathy, gout, and lymphopenia 2 5.0 – – 2 5.0
Missinga
1 3 – 4 –
Total 25 60.0 19 40.0 44 100
H, hyphae; HS, hyphae and spherules; S, spherules; NO, no parasitic form observed; AIDS, acquired immunodeficiency syndrome; PTB,
pulmonary tuberculosis
a
Information was not given
b
16 with chronic type 2 diabetes mellitus
c
1 case included in type 2 diabetes mellitus, the patient presented pulmonary coccidioidomycosis, diabetes, and PTB

The present study demonstrates that for every 5 patients
that were referred to INER, only 1 had been previously and
correctly diagnosed with pulmonary coccidioidomycosis. This
suggests that there is under-reporting of 78% in pulmonary
coccidioidomycosis patients in primary and secondary care
centers, despite the fact that clinical records show that those
patients have visited or lived in coccidioidomycosis-endemic
areas [15]. Such under-reporting is related to the fact that
clinical manifestations of coccidioidomycosis are very
similar to those of pulmonary tuberculosis. Coccidioido-
Fig. 2 Filamentation and ger-
mination of Coccidioides spp. in
biological specimens.
a Filamentation of a spherule in
fistula thoracic discharge 72 h
after obtaining the specimen at
room temperature (Lactophenol
cotton blue stain, ×100). b The
same event in pulmonary tissue
(PAS stain, ×100). c Filamenting
enlarged spore in lung tissue
(GMS stain, ×105).
d Germinating spherule in lung
tissue (PAS stain, ×103).
e Spore-forming septate hypha
in lung tissue (PAS stain, ×100).
The arrows indicate the start of
germination or filamentation
Fig. 1 Parasitic mycelial forms
in diabetic patients with chronic
and cavitary pulmonary
coccidioidomycosis.
a Filamenting spores and spher-
ules with endospores in lung
tissue (GMS stain, ×40). b Thin
septate hyphae, forming a chain
of ovoid, spherical, and barrel-
shaped arthroconidia in sputum
(PAS stain, ×100). c Septate
hyphae, some forming barrel-
shaped arthroconidia and a
spherule with endospores in
lung tissue (PAS stain, ×60).
d Mycelium with septate hyphae
forming arthroconidia in sputum
(GMS stain, ×60). e Thin septate
hyphae forming an ovoid and
spherical arthroconidia chain in
sputum (GMS stain, ×100).
f Ovoid and spherical cell chain
in sputum (GMS stain, ×40).
g Chain of cells resembling a
rosary in sputum (GMS
stain, ×40)

mycosis mycology and histopathologic diagnostics are
often not used in Mexico. Thus, coccidioidomycosis is
often misdiagnosed.
The association between the evolution time of coccidi-
oidomycosis and the presence of parasitic mycelial forms
suggests that chronicity is an essential factor in the
development of mycelial forms. Calderón and Garcidueñas
[7, 8] reported similar results. We observed patients with a
long evolution of the disease and those with greater weight
than the controls developed hyphae. All patients with
mycelial forms presented cavitary lesions (Table 2).
The process of dimorphism in Coccidioides spp. is not
well known. Klotz et al. [26] have described the critical role
of CO2 in this process. It is essential for the development
for endosporulating spherules in Coccidioides immitis (CO2
partial pressure 20–80 mm). Similar CO2 partial pressure is
found in normal host tissues and it allows parasitic phase
development. Among the most relevant risk factors that
favor the development of pulmonary coccidioidomycosis
are concomitant pathologies that affect a patient’s immune
status, the most frequent being type 2 diabetes mellitus
(Table 3). Other authors have described an increased
propensity toward pulmonary fungal diseases and these
patients were more likely to have cavitary lung disease than
their non-type 2 diabetic counterparts [27–29]. In this study,
patients with type 2 diabetes mellitus and a smoking habit
had a greater chance of developing parasitic mycelial forms
of Coccidioides spp. (Figs. 1, 2). An association between
parasitic mycelial forms of C. immitis and C. posadasii and
gender was not supported by the present study. However,
only 6 women were included in the present study, they
presented mycelial forms, and had type 2 diabetes mellitus.
Mononuclear and polymorphonuclear leukocytes (PML)
are found in sites of C. immitis infection. The defensive role
that macrophages and PML play for the clearance of fungal
infection is well known, and they affect the rate of
conversion of arthroconidia to spherules. However, they
do not participate in fungal dimorphism [30]. The tissue
damage results from fungal toxins (virulence factors) and
host response. Macrophages and PML limit infection by
phagocytosis, granuloma formation, and/or production of
factors inducing fibroblast proliferation.
We observed, in the only case of coccidioidoma, that
there was plentiful mycelial growth. In pulmonary cavities
O2/CO2 interchange is not efficient, and CO2 partial
pressure will be near 0 mmHg due to tissue damage [31].
This condition could lead to mycelial growth as shown in
Fig. 1d. This effect is probably found in coccidioidoma.
Studies of dendritic cell activity in patients with type 2
diabetes revealed that hyperglycemia inhibits the matura-
tion of the dendritic cells and modifies the production and
function of chemical mediators, such as pro-inflammatory
cytokines, which results in a deficient inflammatory
response for controlling coccidioidomycosis. Additionally,
smoking produces a decrease in the mucociliary transport
mechanisms and TNFα levels, with alteration of the
inflammatory response [32–37]. Each of these events may
favor chronic pulmonary coccidioidomycosis and facilitate
development of parasitic mycelial forms.
The Coccidioides spp. dimorphism is a very complex
event. Indeed, there are different factors related to it, one of
which is ornithine decarboxylase (ODC). This enzyme has
been described in Coccidioides immitis [38]. The ODC
gene is constitutive during the parasitic cell cycle and plays
a key role in the morphogenesis [38, 39]. ODC catalyzes
polyamine (putrescine, spermidine, and spermine) biosyn-
thesis from arginine and ornithine. Polyamines play an
important role in dimorphic transition in differential
methylation/demethylation pattern DNA. The microenvi-
ronment determines mycelial growth or the development of
endosporulating spherules [38, 40–43].
Another enzyme involved is arginase. This is released from
spherules during the parasitic cycle of C. posadasii and
contributes to host tissue damage, which exacerbates the
severity of coccidioidal infection and enhances the virulence
of this human respiratory pathogen [42]. The mycelial phase
has been reported to tolerate a broad pH range, from pH 2 to
12. Arginase leads to an alkaline microenvironment [42, 43].
In conclusion, the coexistence of parasitic mycelial and
spherules forms from Coccidioides spp. in type 2 diabetes
and other coccidioidal infections described with this
parasitic form is an adaptive response that depends on
host–parasite interaction.
The present study demonstrated the high frequency:
76% (16 out of 21) of parasitic mycelial forms of
Fig. 3 Mycelial forms during the parasitic phase of Coccidioides spp.
in diabetic patients with chronic and cavitary pulmonary coccidioido-
mycosis. It is also observed in patients with central nervous system
infection. A Typical cycle of the parasitic phase. Formation of
spherules with endospores. B Development of mycelial forms. a
Endospores are released. b–d Spores in different filamentation stages.
The mycelial forms can form (cd) typical barrel-shaped arthroconidia
and (c1) spherical arthroconidia. These arthroconidia can regenerate
mycelial forms (B) and/or spherules with endospores (A)

Coccidioides spp. was observed only in those patients who
suffered chronic type 2 diabetes mellitus (Table 3). Indeed,
there is a possibility of misdiagnosis in that the parasitic
mycelial forms of Coccidioides spp. can be confused with
hyphae of Aspergillus spp. or other hyphomycetes [15].
Observation of mycelial structures and radiological images
are frequently erroneously interpreted as aspergilloma.
Parasitic mycelial forms do not identify Coccidioides spp.
(Figs. 1, 2). However, due to the high frequency with
which mycelial forms were observed in the present study,
it is important to emphasize their presence and search for
the classical parasitic forms of spherules containing endo-
spores when diagnosing Coccidioides spp. infection.
Based on observations of mycelial structures in the
present study, as well as those reported by various authors
in coccidioidal infection in the lung and central nervous
system [1, 14–23], we propose that mycelial forms should
be incorporated into the parasitic phase of the Coccidioides
spp. life cycle (Fig. 3). All illustrated parasitic mycelial
forms were observed in specimens from patients with
chronic cavitary pulmonary coccidioidomycosis concom-
itant with type 2 diabetes mellitus. It is significant to
mention that both spherules with endospores (Fig. 3A) and
mycelial forms (Fig. 3B) were present in those patients.
Indeed, we propose increasing the effort to identify
mycelial forms in patients with coccidioidal infection in
the lungs and central nervous system, in accordance with
reported data [15–21].
Analysis of clinical and mycological findings allowed us
to develop a sensitive operational definition that accounted
for all of the recorded cases. That is, any patient presenting
pulmonary coccidioidomycosis, with an evolution longer
than 8 months, that includes cough, hemoptysis, radiological
evidence of cavitary lesion, and type 2 diabetes mellitus, is
likely to develop parasitic mycelial forms of Coccidioides
spp.
Acknowledgements We thank Rubén López Martínez for his
tireless mission in teaching medical mycologists in Mexico. We are
grateful to Miguel Angel Escamilla González for the illustration of the
parasitic life cycle.
Martínez-Rivera MA is fellow of the EDD/IPN and COFAA/IPN
programs.
The ethics and scientific committees revise and approve the protocol.
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