Medical Mycology, 2019, 57, S46–S55

doi: 10.1093/mmy/myy037
Review Article

Review Article
Coccidioidomycosis in Latin America
Rafael Laniado-Laborı́n1,∗ , Eduardo G. Arathoon2 , Cristina Canteros3 ,

Downloaded from https://academic.oup.com/mmy/article/57/Supplement_1/S46/5300138 by guest on 26 January 2021

Raquel Muñiz-Salazar4 and Adrián Rendon5
1
Facultad de Medicina y Psicologı́a, Universidad Autónoma de Baja California, 2 Asociación de Salud Integral,
Hospital General San Juan de Dios, Guatemala, 3 Servicio Micosis Profundas, Departamento Micologı́a, INEI-ANLIS
“Dr Carlos G. Malbrán,” República Argentina, 4 Escuela de Ciencias de la Salud, Universidad Autónoma de Baja
California and 5 CIPTIR, Hospital Universitario de Monterrey UANL, Mexico
∗
To whom correspondence should be addressed. Rafael Laniado-Laborı́n MD, MPH, Tel: +52 +664 686–5626;
E-mail: rlaniado@uabc.edu.mx
Received 18 November 2017; Revised 24 April 2018; Accepted 15 May 2018; Editorial Decision 6 May 2018

Abstract
Coccidioidomycosis is a highly prevalent systemic mycosis in Latin America and has been reported (human
and zoonotic cases) in México, Guatemala, Honduras, Colombia, Venezuela, Brazil, Paraguay, Bolivia, and
Argentina. The incidence of coccidioidomycosis in Latin America is unknown due to lack of clinical awareness
and limited access to laboratory diagnosis. Coccidioidomycosis is as prevalent in Mexico as in the endemic
regions of the United States. The number of cases reported in Brazil and Argentina has progressively
increased during the last decade, including areas that were not considered as endemic. Genetic studies
have shown that the prevalent species in Latin America is Coccidioides posadasii. Coccidioides immitis
has been reported sporadically in indigenous cases from Mexico and Colombia. Coccidioidomycosis and
tuberculosis share some risk factors such as immunosuppression and residing in areas endemic for these
conditions, so their coexistence in the same patient is not uncommon in Latin America. In most regions,
clinical diagnosis of coccidioidomycosis is based on direct sputum examination and histopathology results
from biopsies or autopsies. This would explain why primary coccidioidomycosis is rarely diagnosed, and
most cases published are about chronic pulmonary or disseminated disease.
Key words: coccidioidomycosis, Latin America, epidemiology, tuberculosis.

Introduction Coccidioidomycosis in Mexico

The enormous geographic and climatic diversity of Latin Amer-
ica provides a great diversity of ecosystems that allow the de-
velopment of different microorganisms, including pathogenic
fungi. Coccidioidomycosis is a systemic mycosis that has
been reported in many Latin American countries. The re-
gion has a high proportion of rural population dedicated to
agricultural work, exposed to diverse habitats for fungi, be-
ing therefore exposed to inhalation (or transcutaneous in-
oculation) of Coccidioides arthroconidia. Coccidioidomycosis
has an important impact on public health; however, despite
the reporting of clinical cases in several countries of the re-
gion, clinical and epidemiological information is scarce and
fragmentary.
Coccidioidomycosis (CM) is the most prevalent of the systemic
mycosis in Mexico. CM was first diagnosed in Mexico by Dr.
Gastón Madrid, who reported a case in 1945.1 The patient was
referred due to the possible diagnosis of tuberculosis (TB) to the
80-bed TB sanatorium in Hermosillo, the capital of Sonora, a
state that shares the United States (U.S.)–Mexico border with
Arizona. Bacteriology for TB in this patient was negative despite
the clinical and radiological features suggestive of TB. A fungal
culture was ordered and Coccidioides spp. was isolated from the
sputum. Three years later, Madrid reported a series of coccid-
ioidomycosis cases diagnosed in the region.2 A few years later3
Coccidioides spp. was isolated for the first time in Mexico, in
the soil from a snake burrow in the outskirts of Hermosillo. In

S46 
C The Author(s) 2019. Published by Oxford University Press on behalf of The International Society for Human and Animal

Mycology. All rights reserved. For permissions, please e-mail:journals.permissions@oup.com

Laniado-Laborı́n et al.
1974, Madrid publishes the book Coccidioidomycosis, the only
monograph on CM published to date in Mexico.4
Infection by Coccidioides sp. is as prevalent in Mexico as in
the endemic regions of the United States.5 The first skin sur-
veys with coccidioidin were carried out in Sonora from the late
1940s to the early 1970s, at different sites in the state. Rates of
infection were high all over the state and ranged from 64% to
90% in adults; in children, the rate was reported at 16%.5 In
1966 González-Ochoa reported the first national survey on coc-
cidioidomycosis infection; rates were significantly higher in the
northwestern states (Baja California, Sonora, Sinaloa, and Chi-
huahua) of the country with rates that ranged from 30% to more
than 50%.6 These high rates of infection have been corroborated
in later surveys with coccidioidin and spherulin.7,8
The endemic regions in Mexico are characterized by a dry
climate, alkaline soil, summers with very high temperatures (up
to 50◦ C), and annual precipitation indexes as low as 10 cm; this
combination of environmental factors facilitates the spread of
Coccidioides spores in the air. The high prevalence of infection
in the semi-arid northwestern region of Mexico correlates well
with the evidence from the United States, where the highest rates
of disease are found also in California and Arizona, states with
large desert regions that are likely to serve as ecological niches
for Coccidioides.9
The prevalent species in Mexico is Coccidioides posadasii;10
the only isolates of Coccidioides immitis have been found in
Baja California, a state located in the most northwestern re-
gion of the country; no geographical overlap of the species has
been reported.11 The clinical burden of disease in Mexico is cur-
rently unknown.12 CM was a reportable disease in Mexico up
to 1994, with an average of 1500 cases reported per year; since
1995 there are no data on the clinical burden of CM, when the
disease was eliminated from the national epidemiological reg-
istry for reportable diseases. From 1988 through 1994 the mean
incidence of CM in Mexico was 0.8 per 10.5 The states (all of
them northern states, located in the U.S.–Mexico border) with
the highest rates of clinical cases were Nuevo León, Tamaulipas,
Chihuahua, Baja California, and Sonora.9
An important barrier for the clinical diagnosis in Mexico is
the lack of access to laboratory mycological diagnosis. There are
just a few centers in the country (some of them dedicated to basic
research more than to clinical diagnosis) with the capability and
biosafety standards for culture and identification of Coccidioides
and/or serological diagnosis. In most regions, clinical diagnosis is
based on direct sputum examination and histopathology results
from biopsies or autopsies. This would explain why primary
coccidioidomycosis is rarely diagnosed, and most cases published
are about chronic pulmonary or disseminated CM.
The literature on the interrelationship of diabetes mellitus and
coccidioidomycosis suggest that these patients may experience
severe, progressive, and complicated coccidioidal infections.13
Diabetes is one of the main causes of death in Mexico; the
S47
prevalence of diabetes in the country, according to the latest na-
tional survey is 9.4%;14 severe forms of CM have been reported
in diabetics in Mexico for more than 30 years.15 Tuberculosis
and CM share the same risks factors and its coexistence is also
a common clinical finding in Mexico.16 The coexistence of CM
and human immunodeficiency virus (HIV) has also been re-
ported in Mexico,17 although not with the frequency that should
be expected based on the prevalence of HIV in the country.
Travelers from nonendemic areas should be aware of the po-
tential risk of infection when visiting endemic areas in Mexico.
Downloaded from https://academic.oup.com/mmy/article/57/Supplement_1/S46/5300138 by guest on 26 January 2021
An example of this risk would be an outbreak that included 21
serologically confirmed CM cases (17% attack rate) among a
church group from Washington State in the United States. The
group had just stayed for 6 days at an orphanage in Tecate, Mex-
ico, a town in the Sonoran Desert adjacent to the U.S.–Mexico
border to build a church.18
A group of clinicians and microbiologist from Baja Califor-
nia, Sonora, and Nuevo León have founded the Mexican Coc-
cidioidomycosis Study Group in 2014. The first objective of the
group was to develop the Mexican Guidelines for the Diagno-
sis and Treatment of Coccidioidomycosis; they were published in
the journal of the National Infectious Diseases Society in 2015.19
Funding has been an issue for the regular meeting of the group.
Coccidioidomycosis Research in México
Coccidioidomycosis in humans (Table 1)
The first molecular study on CM in Mexico was reported in
2004; it dealt with the development of a conventional nested
and a real-time polymerase chain reaction (PCR) assay specific
for the identification of C. posadasii DNA by targeting a gene
coding for the antigen 2/proline-rich antigen (Ag2/PRA). The
study included 120 clinical strains isolated from 114 patients
and three formalin-fixed paraffin embedded specimens during a
10-year period (1991–2002) in Monterrey, Mexico. The samples
were amplified using two microsatellite loci (GAC and 621);20 all
strains were correctly identified as C. posadasii, whereas DNA
from related members of the family Onygenaceae tested nega-
tive. Also, specific DNA was amplified by conventional nested
PCR from three microscopically spherule-positive formalin-fixed
tissue samples and identified as C. posadasii, whereas 20 human
tissue samples tested positive for other dimorphic fungi tested
negative.21 This assay is used directly in clinical samples,22,23 as
well in clinical isolates and formalin-fixed tissues.24–28
In 2007, Castañon-Olivares analyzed 56 clinical isolates of
Coccidioides spp. from Mexican patients by real-time PCR using
TaqMan probes to amplify single nucleotide polymorphisms
(SNPs) in four target sequences loci (proline 157, proline 174,
hexokinase 149, and glucose-synthase 192). In total, 54 isolates
identified as C. posadasii and two as C. immitis. Only proline
157, proline 174, and glucose-synthase 192 gave consistent
results on SNP differentiation between the two species, while
Table 1. Molecular studies of Coccidioides spp. performed in clinical, environmental and animal samples from México.
S48

Year of
Year of samples
publication Molecular marker Samples Number/Type collection Geographic origin samples Specie identification Citation

Human
2004 Ag2/PRA 120 clinical strains 1991–2002 Nuevo León C. posadasii (100%) [21]
2 Microsatellites 3 FFPE
2007 SNPs (proline 157, proline 46 clinical isolates No data Baja California, CDMX, Coahuila, Coccidioides spp. [11]
174, hexokinase 149 and Nuevo León
glucose-synthase 192
2012 Ag2/PRA 54 FFPE tissue 1982–2010 Baja California C. posadasii (83%) [26]
U region C. immitis (17%)
2013 Ag2/PRA 32 clinical isolates No data Baja California, Campeche, CDMX, C. posadasii (100%) [25]
AFLP Durango, Nuevo León, Torreón.
2014 Ag2/PRA 154 clinical isolates 1957–2010 Baja California, Chihuahua, Coahuila, CDMX, C. posadasii (82%) [24]
8 Microsatellites Durango, Edo. De México, Guerrero, C. immitis (18%)
U region Michoacán, Nuevo León, San Luis Potosı́,
Sinaloa, Sonora, Tamaulipas, Zacatecas.
2015 U region 3 clinical isolates 2015–2010 Baja California C. posadasii (100%) [31]
2016 U region 1 clinical isolate 2016 Baja California C. posadasii [33]
2017 Ag2/PRA 1 clinical isolate 2017 Mexico City C. posadasii [22]
RAPD

Environmental isolates
2012 ITS2 (nested PCR) 32 soil samples 2006–2010 Baja California Valle de las Palmas Zorra (SJZ) Coccidioides spp. [37]
2013 ITS2 (nested PCR) 5 soil samples 2009 Baja California (Valle de las Palmas) Coccidioides spp. [36]
2015 IT2 (nested PCR) 11 soil samples 2012–2013 Baja California (Valle de las Palmas) C. posadasii (82%) [38]
9 Top soil C. immits (18%)
2 Burrows
2014 Ag2/PRA 4 isolated culture No data Coahuila C. posadasii (100%) [24]
8 Microsatellites from soil samples
U región
2014 ITS2 (nested PCR) 10 soil 2011 Baja California (Valle de las Palmas) Coccidioides spp. [39]

Animal samples
2014 Ag2/PRA 1 isolated culture from 1957 Sinaloa C. posadasii [24]
8 Microsatellites dog
U región
2016 U region 3 FFPE tissue from dogs 2010–2015 Monterrey C. immitis [40]
2017 Ag2/PRA 1 FFPE tissue from cattle 2014 Baja California C. immitis Muñiz-Salazar
(2017)
unpublished

FFPE, formalin-fixed paraffin-embedded; PCR, polymerase chain reaction; SNP, single-nucleotide polymorphism.
Medical Mycology, 2019, Vol. 57, No. S1

Downloaded from https://academic.oup.com/mmy/article/57/Supplement_1/S46/5300138 by guest on 26 January 2021

Laniado-Laborı́n et al.
hexokinase 149 gave negative results in 34 samples. Clinical
isolates were from sputum, cerebrospinal fluid, bronchoalveolar
lavage, pus or tissues, and the tip of a ventriculoperitoneal shunt
catheter and patients clinically diagnosed with coccidioidomyco-
sis in Baja California, Coahuila, Nuevo León, and Mexico City.
González-Becuar in 2012,26 analyzed a total of 129 formalin-
fixed tissue samples with histopathology diagnosis of CM. The
samples were obtained from the collection of the pathology lab-
oratory from the Tijuana General Hospital from 1982 through
2010. In total, 54 (83%) samples identified as C. posadasii, and
11 (17%) as C. immitis, which distributed in five haplotypes for
C. posadasii and three for C. immitis.
In 2013, Duarte-Escalante25 analyzed 32 clinical isolates
from Mexico (Mexico City, Durango, Torreon, Baja California,
Nuevo Leon, and Campeche) and Argentina. All isolates were
identified as C. posadasii. Also, the study reported a high genetic
variability in the isolates from México (0.5011 ± 0.0382) and
Argentina (0.3951 ± 0.0503). A small but significant genetic
differentiation between countries (P = .0001) was detected, sug-
gesting that there is a single genetic population in Latin Amer-
ica. This is the first study in Mexico, which explores the genetic
structure of Coccidioides using the molecular marker amplified
fragment length polymorphism (AFLP).
In 2014, Luna-Isaac et al.24 used nine-microsatellites,
Ag2/PRA and Umeyama region to establish the predominant
Coccidioides species in Mexico, to delineate the current geo-
graphical locations of both species, and to identify a possible
correlation between clinical symptoms and a specific genotype.
One hundred sixty isolates (155 clinical, four environmental,
and one animal) recovered from culture collections of different
institutions in Mexico stored from 1957 and 2010. The pre-
dominant species was C. posadasii (82%). Among 28 C. immitis
strains, 14 unique multilocus genotypes and six clones were ob-
served. While 126 C. posadasii strains showed 29 unique multi-
locus genotypes and 16 clones. Finally, based solely on the size
scores of microsatellite locus 621, which was the most commonly
used to discriminate between species, 28 samples identified as C.
immitis (416–426 bp) and 126 as C. posadasii (399 bp). Inter-
estingly, samples 5233, 5234, M60 09, M61 09, and TJ3835
showed sequences and fragment sizes that corresponded to C.
posadasii using U region that identified as C. immitis based on
the Ag2/PRA and 621 loci. This situation has been observed by
Tintelnot et al.29 who identified one strain of Coccidioides as one
species using restriction fragment length polymorphism (RFLP)
and as another using U region. That strain was previously iden-
tified as C. immitis and postulated to be a hybrid genotype of
both species. Neafsey et al.30 suggest that sexual reproduction
between the two species could occur, causing the hybridization
and introgression of genomic fragments from one species into
the genome of another. On the other hand, Luna-Isaac et al.24
reported the correlation between genotype and clinical presenta-
tion was not significant (P > .05). However, 83% of C. immitis
S49
isolates were associated with cutaneous dissemination, suggest-
ing this species exhibits a higher tendency to disseminate to the
skin, while C. posadasii was related to all forms of clinical pre-
sentation. It is important to highlight that this is the only study
on the genetic structure of Coccidioides in Mexico.
Recently, clinical cases have used molecular markers to
identify species of Coccidioides. In 2015, Moreno-Coutiño31
reported six Mexican male cases, residents of Tijuana Baja
California—three of them with primary pulmonary infection and
further cutaneous dissemination, and three cases of primary cu-
Downloaded from https://academic.oup.com/mmy/article/57/Supplement_1/S46/5300138 by guest on 26 January 2021
taneous coccidioidomycosis. Half of the cases were identified as
C. posadasii using U region.32 In 2016, Arce et al.33 reported a
primary cutaneous coccidioidomycosis caused by C. posadasii in
a male patient 41 years of age, a native and resident of Tijuana,
Baja California, who for 27 years worked as a surveyor in this
region. Recently, Fernández22 reported the case of a Mexican
HIV+ patient with a probable endogenous reactivation of coc-
cidioidomycosis. A direct microscopic examination using potas-
sium hydroxide (KOH) on a sample taken from the cheek nodule
revealed the presence of spherules. The fungus was isolated, and
its identity was confirmed by phenotypic and molecular methods
(Ag2/PRA).
Coccidioidomycosis in environmental
samples (Table 1)
The screening of environmental samples has had low effective-
ness, mainly because of the weak characterization of Coccid-
ioides ecological niche. Coccidioides spp. has been identified
from airborne and soil samples by culture and molecular assays.
The first environmental report of Coccidioides was by Laniado-
Laborin et al.34 who isolated Coccidioides from one air sample
in Tijuana. The most studied site in Mexico is Valle de Las Pal-
mas in Baja California. The interest to study this site is because a
CM outbreak occurred in 1996 when a Washington State church
group traveled to VDP to build an orphanage.35 As mentioned,
after they returned to the United States, 17% (21/126) serologi-
cal cases of coccidioidomycosis were confirmed.
A total of 108 soil samples from Baja California has been ana-
lyzed, mainly from Valle de las Palmas (101 samples); 54% of the
isolated strains are identified as Coccidioides spp. amplifying the
internal transcribed spacer (ITS) region. Most of the soil samples
were from heteromyid latrines, and in a lower frequency from
topsoil, heteromyids’ active burrows and large mammal dens.
No Coccidioides spp. has been found in soils collected in Ense-
nada, Baja California. Luna-Isaac24 reported the molecular iden-
tification of four soil isolates as C. posadasii (M47–06, M49–06,
M50–06, and M51–06), sheltered in the culture collection of the
Universidad Nacional Autónoma de México (UNAM), but the
collection date is unknown.
Romero-Olivares36 constructed a Dikarya-specific gene li-
brary for the ITS region of nuclear ribosomal DNA in order
S50
to determine the diversity of the mycobiota in Baja California.
Although this assay was able to identify species like Penicillium
dipodomyicola, Coprinellus radians, Alternaria spp., among oth-
ers, it was not able to identify Coccidiodes. Thus, a nested PCR
was used to determine this species.37 The most recent work ana-
lyzes the ITS region by a metagenomic approach in a 454 Roche
pyrosequencer.38 The objective was to identify environmental
factors determining fungal community structure in two differ-
ent microhabitats, burrows (influenced by rodent activity), and
topsoil and were compared in winter and summer. Differences
in composition between microhabitats were mainly correlated to
significant differences in environmental factors, such as moisture
and clay content in topsoil samples, and temperature and electri-
cal conductivity in burrow samples. Overall, the fungal commu-
nity structure (dominated by Ascomycota and Basidiomycota)
was less variable between seasons in burrow than in topsoil sam-
ples. Similarly, 13 Coccidioides spp. went undetected by pyrose-
quencing. However, a nested PCR approach revealed its higher
prevalence in burrows.
The last study reported until now in Valle de las Palmas was
performed during 2010–2011by Catalan-Dibene.39 DNA was
extracted directly from 24 soil samples to amplify the ITS2 re-
gion of rDNA.37 A 170 bp amplicon was recovered from 15
out of 24 samples; however, just 10 samples were confirmed
as Coccidioides spp. The rest of the sequences corresponded
to members of the genus Aphanoascus (A. Canadensis and A.
pinarensis) and Penicillium.
Coccidioides in animals (Table 1)
The available published studies on animal CM in Mexico are
scarce; heteromyids, prairie dogs, dogs, and cattle are the only
species reported. Consequently, the actual prevalence of CM
infection in domestic and wild mammals in Mexico is unknown.
In 2014, Catalan-Dibene39 detected antibodies against Coc-
cidioides in two species of heteromyids (Peromyscus maniculatus
and Neotoma lepida) sampled in Valle de las Palmas, Baja Cali-
fornia.
Ramirez-Romero40 analyzed 765 dog biopsies with a pre-
sumptive diagnosis of neoplasm between April 1, 2010, and
March 31, 2015, from Monterrey, Nuevo Leon. In total, three
cases of CM were found (3/765 = 0.39%). The presumptive
diagnoses in these cases were osteosarcoma, lymphoma, and
neurofibroma, respectively. Molecular analysis of formalin-fixed
paraffin-embedded (FFPE) positive samples amplifying the U re-
gion32 showed C. posadasii in one of these cases.
Sera from urban dogs and wild rodents (prairie dogs) were
tested employing the Ouchterlony double immunodiffusion tech-
nique, with coccidioidin produced at UNAM as an antigen.
One hundred domestic dog sera were tested, and three (3%)
tested positive for anti-Coccidioides antibodies; of 158 sera from
prairie dogs, 113 (71.5%) tested positive.
Medical Mycology, 2019, Vol. 57, No. S1
Only a few studies of CM in cattle have been reported in Mex-
ico. Six cases of CM in beef (3) and dairy (3) cattle slaughtered
and inspected in 1995 and 1996 were reported in Mexicali, Baja
California. The identification was performed just by histopatho-
logical analysis. After that, there are no reports in this area until
2017, when a post-mortem examination in 1 out of 319 cattle
slaughtered at Mexicali, using histopathological and molecular
(Ag2/PRA) testing identified C. immitis (Muñiz-Salazar unpub-
lished data).
Downloaded from https://academic.oup.com/mmy/article/57/Supplement_1/S46/5300138 by guest on 26 January 2021
Coccidioidomycosis and tuberculosis:
Differential diagnosis
CM and tuberculosis (TB) share very similar pathogenic mech-
anisms: they usually start with a primary lung infection that
may lead to a chronic condition in which they may present the
same symptoms and radiologic manifestations.41–45 In endemic
regions for both diseases, the clinicians may face quite a chal-
lenge when considering these two infections in the differential
diagnosis. Support from specialized TB and mycology labora-
tories is needed but, even when this is available, confirmation
of either (or both) infection can be difficult. In the following
section, we present a clinical approach for the differential diag-
nosis of tuberculosis and/or coccidioidomycosis in Monterrey,
Mexico.
Diagnostic work-up for TB and CM
Monterrey is located close to the United States–Mexican bor-
der, an endemic region for coccidioidomycosis;43 also it is one
of the cities with the highest incidence of TB in Mexico.46 Clin-
ical guidelines and recommendations to diagnose CM47,48 or
TB44,49 are readily available; in individual cases, the diagnosis
of either disease can be straightforward in some cases but in
others, it can be extremely complicated. Due to this difficulty,
a number of diagnostic modalities may be needed. Cultures are
still considered as the gold standard tests for both infections, but
their sensitivity is far from perfect, creating the need for com-
plementary methods to support the diagnosis.44,47 Diagnosis of
TB is based on the initial finding of acid-fast bacilli (AFB) ei-
ther in sputum or bronchoalveolar lavage (BAL) stains and the
posterior isolation of Mycobacterium tuberculosis in culture; in
the past decade, molecular methods have improved the rapid
diagnosis of TB, and nowadays they are widely used and rec-
ommended as the preferred initial tests.44 On the other hand,
diagnosis of CM based on sputum microscopy and culture is
much less sensitive. BAL stains and culture also lack sensitiv-
ity but bronchoscopy is usually indicated in severe cases when
a specific diagnosis is urgently needed.47 Serodiagnosis is not
recommended for TB44 but can be very useful for the diagnosis
of CM.47,49 Several tests are commercially available for clinical
laboratories but others need to be sent to reference laborato-
ries. Serology is probably the most commonly ordered diagnostic
Laniado-Laborı́n et al.
test, but their results must be interpreted judiciously since mis-
interpretation can lead to false positive or negative diagnosis; a
positive serology test by itself does not make the CM diagnosis
and a negative one does not rule out the disease, mainly in the
most seriously ill patients.47 Skin testing, when available, can
also be used to detect either infection, but they are not useful
for the diagnosis of the disease.44,47 Interferon-gamma release
assays (IGRAs) for the detection of TB infection, are basically
interpreted in a similar way than the tuberculin test but with a
higher sensitivity and specificity.44 However, as mentioned, skin
tests and IGRA tests do not distinguish active disease from latent
infection.
Frequently, a combination of clinical data, radiologic presen-
tation, and results of diagnostic tests should be used in order to
make a specific diagnosis.44,47 Guideline algorithms for the diag-
nosis of TB or CM are designed to search for a specific diagnosis,
either TB or CM, but they do not consider into their algorithms
the possibility of the other infection.44, 47–49 Complicating mat-
ters even more, the two infections may and do coexist.50 Even
though we try to be aligned with international recommenda-
tions, we must adapt them to our local needs and resources.
A modified algorithm for the differential diagnosis when fac-
ing a patient in whom TB or cocci are possible is shown in
Figure 1.
The approach suggests to first rule out TB since this infec-
tion is more common and is contagious. We begin the diagnostic
work-up with the sputum smear for AFB. If AFB is positive, we
start treatment for TB, while we wait for the diagnosis to be con-
firmed by the cultures. If AFB is negative, a molecular test is per-
formed: if positive, TB is diagnosed, if negative, a bronchoscopy
is performed. TheBAL is simultaneously tested for TB and cocci
with stains, cultures, and molecular TB tests. Any positive test is
considered a definite diagnosis. Transbronchial biopsies are per-
formed mainly on those with interstitial infiltrates or on those
with no cavities. For those with stains and negative molecular
tests, we order skin test for both diseases. Negative results may
help to rule out any of the two infections. Positive results are
carefully considered since they do not confirm active disease. In
some cases, Cocci serology is also sent to a reference laboratory.
For patients in which results are all negative and cultures are still
being processed, we may prescribe empirical therapy if the clin-
ical conditions deserve it. Empirical therapy is chosen analyzing
all the available data for each case on an individual basis. In
most cases, the empirical treatment prescribed is for presumed
TB. According to the clinical response and the cultures results,
treatment is further adjusted. For those patients with HIV infec-
tion, diabetes or on any kind of immunosuppressive therapy, an
earlier more aggressive diagnostic approach is used including in-
vasive procedures to obtain tissues for histopathology study and
cultures. Thereare no data to support if our approach is better or
worse compared to the one used in other centers with different
epidemiology and different resources.
S51
Coccidioidomycosis in Central America
Coccidioidomycosis is an endemic fungal infection found in cer-
tain arid and semi-arid regions of Central America.51 Reports
of its presence in the region are scarce, and documented reports
of autochthonous human CM are found in only two countries,
Guatemala and Honduras.
Two early attempts to investigate the presence of disease in
Central America using coccidioidin skin test surveys exist. The
first one by Andrade in 1945,52 included 1200 persons, children,
and adults in Guatemala City. A second study in 1950 included
Downloaded from https://academic.oup.com/mmy/article/57/Supplement_1/S46/5300138 by guest on 26 January 2021
500 persons in the Canal Zone of Panama.53 The reactivity to
the coccidioidin in both studies was less than 1% of the subjects
tested.
A few years later in 1951, the first human case of CM in Cen-
tral America,54 was documented, by two pathologists from Costa
Rica who received lymph node tissue belonging to a 53-year-old
truck driver born in Nacaome, Honduras, and who lived and
worked for the last 24 years in the Comayagua Valley. In 1946,
he developed a cough, chest pain, hemoptysis, night sweats, and
weight loss. In 1950 he traveled to Costa Rica, developing at that
time bilateral supraclavicular lymphadenopathy, with a bloody
purulent discharge. Spherules were documented in the purulent
secretion and in sputum. A chest X-ray suggested mediastinal
lymphadenopathy. Tuberculin test and CM skin tests were re-
active. He received intramuscular colloidal copper, with little
improvement.
It should be mentioned that in 1959, a dog from Nicaragua
was diagnosed with coccidioidomycosis in Norway, after its
arrival,55 raising the possibility of human coccidioidomycosis
there.
Nine years after the first human case from Honduras was
found, two veterinarians reported several infected animals with
coccidioidomycosis in Guatemala. Two bulls56 and seven dogs,57
none of them came from the endemic areas documented later.
Also, during the same year (1960), the first human case in
Guatemala was documented by Eduardo Pérez-Guisasola,58 and
the clinical findings were described by Garcı́a Valdés.59
The patient was a 16-year-old black male, who lived in
Gualán Zacapa, part of the Motagua Valley. His chest X-ray
showed pulmonary infiltrates and skin and bone dissemination.
Pérez-Guisasola, during the next 6 years, found and documented
six more persons with the disease.60 Based on the climatic char-
acteristics of Guatemala, and the region where the patients lived,
Pérez-Guisasola proposed the Motagua Valley, an arid region in
the western part of the country, as the potential endemic area. He
carefully described the clinical, microbiologic and epidemiologic
origin of the infected persons. Patient number one, was 34-year-
old 9-month pregnant female, from Guatemala City (outside
the endemic zone), with disseminated disease. Patient number
two was a 64-year-old diabetic female from Salamá (near to an
endemic zone) with disseminated disease. Patient number three
S52
Figure 1. Flow chart for the usual approach used at the University Hospital of Monterrey in patients whose differential diagnosis includes chronic Coccidioidomy-
cosis or TB. (Tb: tuberculosis; CM: coccidioidomycosis; broncho: bronchoscopy)
was a 19-year-old military recruit, stationed in Teculután (Mo-
tagua Valley) with primary coccidioidomycosis that progressed
to chronic pulmonary disease. Patient number four was a 64-
year-old male carpenter from Quetzaltenango, outside the en-
demic zone, who traveled to the endemic zone, and had dissem-
inated disease. Patient number five was a 20-month old male
with disseminated disease, living in Rı́o Hondo in the endemic
zone. Finally, patient number six was a 24-year-old Mayan male
from Chicojom, Baja Verapaz (near to an endemic area) with
disseminated disease.
In 1967, Ruben Mayorga, based on the previous reports,
decided to perform a skin test survey of the Motagua Valley61–63
and other areas in search of reactive responders. He included
7725 school children; 9734 subjects were from Guatemala and
991 from Nicaragua. He classified his results in five study areas,
designated from A to E; the first four areas were located in
Guatemala and the last area, E, was located in Nicaragua. Area
A, with the highest concentration of reactive results (42.4%),
corresponded to the endemic area of the Motagua river. Areas B
to D were in the surrounding areas, outside the Motagua Valley,
with less than 4% reactivity.
Phylogenetic analysis of C. posadasii isolates from
Central America
Recently,64 five genomes from Guatemala were analyzed to-
gether with 81 genomes from other regions (26 C. immitis
Medical Mycology, 2019, Vol. 57, No. S1
Downloaded from https://academic.oup.com/mmy/article/57/Supplement_1/S46/5300138 by guest on 26 January 2021
and 60 C. posadasii). Of the C. posadasii isolates, three ma-
jor clades were clearly separated and well supported by the
bootstrap analysis: one clade included all isolates from Arizona;
another included four Guatemala isolates and the third clade,
contained nearly all other non-Arizona isolates. There was a
fifth Guatemalan isolate included in the non-Arizona clade. This
isolate was included in the Texas-Mexico-South America clade
and came from an HIV-infected migrant worker, who aban-
doned his antiretroviral treatment and probably was infected
while crossing the border in Texas. He died from disseminated
coccidioidomycosis, shortly after he returned to Guatemala. This
initial work demonstrates that C. posadasii is found in Central
America and is part of a different clade. Phylogenetically it is the
youngest clade, probably originated from the Arizona clade.
There are approximately six new cases of coccidioidomycosis
documented yearly in Guatemala, mostly in HIV-infected in-
dividuals. In Honduras there are only sporadic cases reported.
Based in the number of persons reactive to coccidioidin found in
the endemic areas, these numbers should be higher, but due to
the lack of awareness and mycological skills in the region, a sig-
nificant number of persons with CM probably are not diagnosed.
Epidemiology of coccidioidomycosis in Argentina,
South America
Although this mycosis was described initially in Buenos Aires,
Argentina in 1892,65–67 the number of CM cases reported in
Laniado-Laborı́n et al.
Table 2. Epidemiological studies in Coccidioidomycosis performed
in South America.
Country Period Cases reported (n) Infection rate∗ (%)
Colombia 1958–2015 5 3–13
Venezuela 1948–2014 114
Brazil 1978–2015 829
Paraguay 1950–1967 3 15–44
Bolivia 1948 1 ...
Argentina 1892–2015
∗
Infection rate in each country varies according to the geographical area of the
country.
South America is much lower than those diagnosed in North
America, and the real incidence is unknown perhaps because it
is not a reportable disease, because it may be misdiagnosed as
tuberculosis, which is very endemic, and also because there is
a high percentage of subclinical cases. However, available data
suggest that its prevalence is increasing in some areas of South
America.68–70
As in North America, the geographical endemic areas for
CM in South America are characterized by arid and semi-arid
areas with sandy, alkaline soils and extreme temperatures in
Colombia, Venezuela, Brazil, Paraguay, Bolivia, and Argentina.
In Colombia, five cases were reported from 1958 to 2015 and
low infection rate was detected using coccidioidin skin tests (3–
13%).71 Venezuela reported 114 cases from 1948 to 2004 and
an infection rate of about 50% in major endemic areas of this
country.72
The area that has most recently been described as endemic for
CM is the northeast of Brazil, where the first autochthonous case
was reported in 1978 in a patient from Bahia.73 Epidemiological
studies show autochthonous cases in Ceará, Bahia, Piauı́, and
Maranhão.70 In 2016 the Brazilian Ministry of Health reported
829 hospitalizations due to CM (incidence 7.12/1000 hospital
admissions).69 In the state of Ceara in Brazil, a coccidioidin skin
survey showed a prevalence of infection of 26.4%.74
In the southernmost areas of South America coccidioidomy-
cosis is endemic in the west of Paraguay, southeast of Bolivia,
and in the arid geographic areas from the province of Jujuy to
the province of Rı́o Negro in Argentina.68,75,76
Both Paraguay and Bolivia report only occasional cases; how-
ever in the northwest of Paraguay, the infection rate has been
reported as high as 44% in aboriginal population and oil com-
pany employees.75 Table 2 summarizes the epidemiological stud-
ies performed in South America using the coccidioidin skin test.
In Argentina, epidemiological studies revealed highest infec-
tion rates in Catamarca province, with values about 40% of
reactors. Other areas with high infection rates were described
in the northwest of Córdoba (34%); the west of Santiago del
Estero (19.8%); and La Rioja (19.13%); all of these provinces
are adjacent to Catamarca.
S53
Only a small number of CM cases had been reported in
Argentina before the year 2000, despite the large extent of the
endemic area. In 2009 the first retrospective review of all CM
cases reported in the country documented 128 cases from the
original case reported by Posadas in 1892 to the year 2009.
11–46
From 1892 through 1939 only six cases were registered; between
26
1940 and 1999, 59 more cases were reported, and finally, the
remaining 63 cases (49% of total cases) were reported from
2–40 2000 to 2009, with the Catamarca province having the highest
number of cases.68 The National Mycology Network reported
Downloaded from https://academic.oup.com/mmy/article/57/Supplement_1/S46/5300138 by guest on 26 January 2021
48 new CM human cases from 2010 through 2015. Almost
50% of these cases occurred in patients who lived or visited a
geographic region in the Central Valley of Catamarca. Annual
disease incidence rates in this province increased from historical
values below 0.5/100 000 to 2/100 000 inhabitants from 2000
to 2009;68 incidence from 2010 to 2015 is reported between 1
and 2 cases/100 000 inhabitants.
Probably the dramatic changes in the ecosystem that occurred
between the years of 1973 and 2007 in the central valley of
Catamarca (an increase of 4 times the urbanized areas and 38
times the cultivated areas) was a factor in the increase of CM
in the region.77 Coccidioides has been isolated from the soil in
Argentina (Province of Cordoba).78
In addition, increased diagnosis capability could be a factor
in this incidence increase because the Reference National My-
cology Laboratory of Argentina has provided reagents for CM
immunodiffusion tests to the laboratories of the laboratory net-
work since the year 2000.79
With respect to zoonotic CM, data collected by the Refer-
ence National Mycology laboratory registered only three cases
before to 2005 in dogs from Catamarca. In 2005, an increase in
the number of CM cases in dogs was reported in this province.
Animals showed fever, cough, and lameness and osteomyelitis
lesions. Up to 2014, the total number of canine CM cases in
Catamarca Province was 86. All cases were confirmed by detect-
ing anti-Coccidioides antibodies by immunodiffusion test with
titer >1:4 plus clinical and radiological findings. Figure 2 shows
the evolution of reported dog and human cases by year from
1997 to 2014 in Catamarca Province.
Coccidioides posadasii is the most prevalent etiological agent
of CM in South America68,70 ; there have been two reports
of C. immitis cases in South American patients, one from
Venezuela80 and the other by Argentina,81 but in these cases,
it was impossible to exclude travel by the patients to regions
where C. immitis is prevalent. In 2015, Coccidioides immitis
DNA has been detected in a specimen from a patient from
Pinto, Colombia (the patient never traveled abroad). Although
this species is primarily found in California, it has been re-
ported in other geographical areas as shown by this case from
Colombia; there is the possibility that C. immitis endemic ar-
eas may be extending from the formerly proposed geographical
borders.71
S54
20
18
dog human
16
Number of reported cases
14
12
10
8 13. Santelli AC, Blair JE, Roust LR. Coccidioidomycosis in patients with diabetes
6 mellitus. Am J Med. 2006; 119: 964–969.
4 14. Encuesta Nacional de Salud y Nutrición de Medio Camino 2016, Secretarı́a de
2
0
year
Figure 2. Evolution of reported dog and human cases from 1997 to 2014 in
Catamarca Province, Argentina∗ . (*Data obtained from the Reference National
Laboratory for Mycology of Argentina.)
Coccidioidomycosis is a highly prevalent systemic mycosis in
Latin America and has been reported in México, Guatemala,
Honduras, Colombia, Venezuela, Brazil, Paraguay, Bolivia, and
Argentina. However, despite the reporting of clinical cases in
several countries of the region, clinical and epidemiological in-
formation is scarce and fragmentary. The incidence of CM in the
region is unknown, mainly due to lack of clinical awareness and
limited access to a laboratory. Clinical training in this condition
and the strengthening of the network of mycology laboratories
in the region is necessary to adequately characterize this mycosis
in the region.
Declaration of interest
The authors report no conflicts of interest. The authors alone are
responsible for the content and writing of this paper.
References
1. Madrid GS. Coccidioidomicosis. Prensa Médica. 1946; 6: 1033–1035.
2. Madrid GS. Las micosis pulmonares. 1a parte. Rev Mex Tuber Ap Resp. 1948;
9: 32–55.
3. Sotomayor C, Madrid GS, Torres EA. Aislamiento de Coccidioides immitis del
suelo de Hermosillo, Sonora México. Rev Latinoamericana Microbiol. 1960; 3:
237–238.
4. Madrid GS. Coccidioidomicosis. Talleres de Impresión y Editorial. Hermosillo,
Mexico. Primera Edición, 1974.
5. Ajello L. Comparative ecology of respiratory mycotic disease agents. Bacteriol
Rev. 1967; 31: 6–24.
6. González-Ochoa A. La coccidioidomicosis en México. Rev Invest Salud Pública
(Mex). 1966; 26: 245–262.
7. Fredrich BE. A skin test survey of valley fever in Tijuana, Mexico. Soc Sci Med.
1989; 29: 121–127.
8. Padua A, Martinez-Ordaz VA, Velasco-Rodriguez VM, Lazo-Saenz JG, Cicero
R. Prevalence of skin reactivity to coccidioidin and associated risk factors in
subjects living in a northern city of Mexico. Arch Med Res. 1999; 30: 388–
392.
9. Baptista Rosas RC, Riquelme M. Epidemiologı́a de la coccidioidomicosis en
México. Rev Iberoam Micol. 2007; 24: 100–105.
10. Bialek B, Kern J, Hermann T et al. PCR assays for identification of Coccidioides
posadasii based on the nucleotide sequence of the antigen 2/proline-rich antigen.
J Clin Microbiol. 2004; 42: 778–783.
Medical Mycology, 2019, Vol. 57, No. S1
11. Castañon-Olivares LR, Guereña-Elizalde D, González-Martı́nez MR, Licea-
Navarro AF, González-González GM, Aroch-Calderon A. Molecular identifi-
cacion of Coccidioides isolates from Mexican patients. Ann NY Acad Sci. 2007;
1111: 326–335.
12. Castañon-Olivares LR, Aroch-Calderon A, Bazan-Mora E, Córdova-Martı́nez
E. Coccidioidomicosis y su escaso conocimiento en nuestro paı́s. Rev Facultad
Med UNAM. 2004; 47: 4.
Salud, México, 2016.
15. Forsbach-Sánchez GB, Fuentes-Pensamiento R. Coccidioidomicosis pulmonar
crónica progresiva en una paciente con diabetes mellitus II. Rev Inv Clin. 1985;
Downloaded from https://academic.oup.com/mmy/article/57/Supplement_1/S46/5300138 by guest on 26 January 2021
37: 49–51.
16. Castañeda-Godoy R, Laniado-Laborı́n R. Coexistencia de tuberculosis y coccid-
ioidomicosis: presentación de dos casos clı́nicos. Rev Inst Nal Enf Resp Mex.
2002; 15: 98–101.
17. Laniado-Laborı́n R. Coccidioidomicosis. Más que una enfermedad regional. Rev
Inst Nal Enf Resp Mex. 2006; 19: 301–330.
18. Gabe LM, Malo J, Knox KS. Diagnosis and management of coccidioidomycosis.
Clin Chest Med. 2017; 38: 417–433.
19. Mendoza-Mendoza A, Acuña-Kaldman M, Álvarez-Hernandez G et al. Guı́a del
Grupo Mexicano de Diagnóstico y Tratamiento de la coccidioidomicosis. Enf
Inf Microbiol. 2015; 35: 18–31.
20. Fisher MC, White TJ, Taylor JW. Primers for genotyping single nucleotide poly-
morphisms and microsatellites in the pathogenic fungus Coccidioides immitis.
Mol Ecol. 1999; 8: 1082–1084.
21. Bialek R, Kern J, Herrman T et al. PCR assays for identification of Coccidioides
posadasii based on the nucleotide sequence of the antigen 2/proline-rich antigen.
J Clin Microbiol. 2004; 42: 778–783.
22. Fernández R, Arenas R, Duarte-Escalante E et al. Diagnosis of coccidioidomy-
cosis in a non-endemic area: inference of the probable geographic area of an
infection. Rev Iberoamericana Micol. 2017; 34: 237–240.
23. Brilhante RSN, Cordeiro RA, Rocha MFG et al. Coccidioidal pericarditis: a
rapid presumptive diagnosis by an in-house antigen confirmed by mycological
and molecular methods. J Med Microbiol. 2008; 57: 1288–1292.
24. Luna-Isaac J, Muñiz-Salazar R, Baptista-Rosas R et al. Genetic analysis of the
endemic fungal pathogens Coccidioides posadasii and C. immitis in Mexico. Med
Mycol. 2014; 52: 156–166.
25. Duarte-Escalante E, Zuniga G, Frias-De-Leon MG et al. AFLP analysis reveals
high genetic diversity but low population structure in Coccidioides posadasii
isolates from Mexico and Argentina. BMC Infect Dis. 2013; 13: 411.
26. González-Becuar CG. Identificación de Coccidioides spp. en muestras de tejidos
parafinizados utilizando tres tipos de marcadores moleculares. Ensenada, Baja
California, México: Universidad Autónoma de Baja California; 2012 (Thesis).
27. Canteros C, Toranzo A, Suárez-Alvarez R et al. Genetic characterization of the
fungus involved in the first case of coccidioidomycosis described by Alejandro
Posadas in 1892. Medicina (Buenos Aires). 2009; 69: 215–220.
28. Canteros CE, Vélez H A, Toranzo AI et al. Molecular identification of Coc-
cidioides immitis in formalin-fixed, paraffin-embedded (FFPE) tissues from a
Colombian patient. Med Mycol. 2015; 53: 520–527.
29. Tintelnot K, De Hoog GS Antweiler E et al. Taxonomic and diagnostic mark-
ers for identification of Coccidioides immitis and Coccidioides posadasii. Med
Mycol. 2007; 45: 385–393.
30. Neafsey DE, Barker BM, Sharpton TJ et al. Population genomic sequencing of
Coccidioides fungi reveals recent hybridization and transposon control. Genome
Res. 2010; 20: 938–946.
31. Moreno-Coutiño G, Arce-Ramı́rez M, Medina A et al. Coccidioidomicosis
cutánea: Comunicación de seis casos mexicanos. Rev Chil Infect. 2015; 32:
339–343.
32. Umeyama T, Sano A, Kamei K et al. Novel approach to designing primers for
identification and distinction of the human pathogenic fungi Coccidioides immitis
and Coccidioides posadasii by PCR amplification. J Clin Microbiol. 2006; 44:
1859–1862.
33. Arce M, Ramı́rez V, Castañeda R, Castañón-Olivares L. Primary cutaneous
coccidioidomycosis due to Coccidioides posadasii. Dermatol Rev Mex. 2016;
60: 520–525.
Laniado-Laborı́n et al.
34. Laniado-Laborin R, Cardenas-Moreno RP, Álvarez-Cerro M. Tijuana: zona
endémica de infección por Coccidioides immitis. Salud Pública de México. 1991;
33: 235–239.
35. Cairns L, Blythe D, Kao A et al. An outbreak of coccidioidomycosis in Washing-
ton State residents returning from Mexico. Clin Infect Dis. 2000; 30: 61–64.
36. Romero-Olivares AL, Baptista-Rosas RC, Escalante AE, Bullock SH, Riquelme
M. Distribution patterns of Dikarya in arid and semiarid soils of Baja California,
Mexico. Fungal Ecol. 2013; 6: 92–101.
37. Baptista-Rosas RC, Catalán-Dibene J, Romero-Olivares AL et al. Molecular
detection of Coccidioides spp. from environmental samples in Baja California:
linking Valley Fever to soil and climate conditions. Fungal Ecol. 2012; 5: 177–
190.
38. Vargas-Gastelum L, Romero-Olivares AL, Escalante AE et al. Impact of sea-
sonal changes on fungal diversity of a semi-arid ecosystem revealed by 454
pyrosequencing. FEMS Microbiol Ecol. 2015; 91: fiv044.
39. Catalan-Dibene J, Johnson SM, Eaton R et al. Detection of coccidioidal antibod-
ies in serum of a small rodent community in Baja California, Mexico. Fungal
Biol. 2014; 118: 330–339.
40. Ramirez-Romero R, Silva-Perez RA, Lara-Arias J et al. Coccidioidomycosis in
biopsies with presumptive diagnosis of malignancy in dogs: report of three cases
and comparative discussion of published reports. Mycopathologia. 2016; 181:
151–157.
41. Drutz DJ, Catanzaro A. Coccidioidomycosis. Part I. Am Rev Respir Dis. 1978;
117: 559–585
42. Dritz DJ, Catanzaro A. Coccidioidomycosis. Part II. Am Rev Respir Dis. 1978;
117: 727–771
43. Twarog M, Thompson GR, III. Coccidioidomycosis: recent updates. Semin
Respir Crit Care Med. 2015; 36: 746–755.
44. Lewinsohn DM, Leonard MK, LoBue PA et al. Official ATS/IDSA/CDC Clinical
practice guidelines: diagnosis of tuberculosis in adults and children. Clin Infect
Dis. 2017; 64: 111–115.
45. Welsh O, Vera-Cabrera L, Rendon A, Gonzalez G, Bonifaz A. Coccidioidomy-
cosis. Clin Dermatol. 2012; 30:573–591.
46. Official Mexican TB statistics [Cifras oficiales de tuberculosis en
Mexico]. Available at: http://www.cenaprece.salud.gob.mx/programas/interior/
micobacteriosis/tuberculosis/cifras oficiales.html.
47. Malo J, Luraschi-Monjagatta CM, Wolk D, Thompson RA, Hage C. Update on
the diagnosis of pulmonary coccidioidomycosis. Ann Am Thorac Soc. 2014; 11:
243–253.
48. Neil M, Ampel. The diagnosis of coccidioidomycosis. F1000 Med Rep. 2010,
2: 2.
49. Ammara Mushtaq. Updates in tuberculosis diagnosis in the USA. Lancet Infect
Dis. 2017; 17: 147–148.
50. Cadena J, Hartzler A, Hsue G, Longfield RN. Coccidioidomycosis and tubercu-
losis coinfection at a tuberculosis hospital: clinical features and literature review.
Medicine (Baltimore). 2009; 88: 66–76.
51. Fisher M. C, Koenig G. L, White T. J et al. Molecular and phenotypic descrip-
tion of Coccidioides posadasii sp., previously recognized as the non-California
population of Coccidioides immitis. Mycologia. 2002; 94: 73–84.
52. Andrade M. Investigation of coccidioidomycosis in Guatemala City, using the
coccidioidin skin test. Doctoral thesis, Facultad de Medicina, Universidad de San
Carlos de Guatemala, 1945. [in Spanish]
53. Tucker HA. Histoplasmin, tuberculin, and coccidioidin sensitivity on the Isthmus
of Panama; preliminary report of 500 patients. Amer J Trop Med. 1950; 30: 865–
870.
54. Castro A, Trejos A. Constatación del primer caso centroamericano de coccid-
ioidomicosis Nota Previa. Confirmation of the first Central American case of
coccidiodomycosis. Rev Med Costa Rica. 1951; 10: 89–90 [in Spanish].
55. Nordstoga K, Lindquist K, Strande A. Coccidioidomycosis: report of a case in a
dog. Nordisk Veterinaermedicin.1959; 11: 461–468.
56. Ferri AG, Correa WM, Villagrán E. Coccidioidomicosis en bovinos en
Guatemala. Coccidiodomycosi in bovines in Guatemala. V Congreso Cen-
troamericano de Patologı́a. Diciembre, 1960 [in Spanish].
57. Correa WM, Ferri AG, Rosales LF. Coccidiodomycosis in the dog. Revista de la
Facultad de Med Vet y Zoot. Guatemala 1 [in Spanish].
S55
58. Pérez-Guisasola E, Rosal JE. Human cocciodioidomycosis in Guatemala my-
cologic, histopatholocic diagnosis and biologic confirmation of the first case.
Revista del Colegio Médico de Guatemala. 1960; XI: 290–294 [ in Spanish].
59. Garcı́a Valdés A., Close de León J., Rivera LJ. Coccidioidomicosis comunicación
del primer caso humano en Guatemala. Coccidioidomycosis comunication of the
first human case in Guatemala. Revista del Colegio Médico de Guatemala.1960;
XI: 284–289 [ in Spanish].
60. Pérez Guisasola E. Actual status of coccidiodomycosis in Guatemala. Estado ac-
tual de la coccidioidomicosis en Guatemala. Doctoral thesis. Facultad de Medic-
ina, Universidad de San Carlos de Guatemala, 1967 [ in Spanish].
61. Pérez-Guisasola E, ed. Coccidioidomycosis in Guatemala, 1967. Guatemala: Uni-
versidad de San Carlos de Guatemala. 1971.
62. Mayorga R. Coccidioidomycosis in Central America. In: Ajello L, ed. Coccid-
Downloaded from https://academic.oup.com/mmy/article/57/Supplement_1/S46/5300138 by guest on 26 January 2021
ioidomycosis. Tucson: University of Arizona Press, 1967.
63. Mayorga RP, Espinoza H. Coccidioidomycosis in Mexico and Central America.
Mycopathol Mycol Appl. 1970; 41: 13–23.
64. Engelthaler DM, Roe CC, Hepp CM et al. 2016. Local population structure and
patterns of Western Hemisphere dispersal for Coccidioides spp., the fungal cause
of valley fever. mBio. 7: e00550–16.
65. Posadas A. Un nuevo caso de micosis fungoidea con psorospermias. Cı́rculo Med
Argent. 1892; 5: 585–587.
66. Fisher MC, Koenig GL, White TJ et al. Biogeographic range expansion into
South America by Coccidioides immitis mirrors New World patterns of human
migration. Proc Natl Acad Sci U S A. 2001; 98: 4558–4562.
67. Brown J, Benedict K, Park BJ, Thompson GR. Coccidioidomycosis: epidemiol-
ogy. Clin Epidemiol. 2013; 5: 185–197.
68. Canteros CE, Toranzo A, Ibarra-Camou B et al. Coccidioidomycosis in Ar-
gentina, 1892–2009 Rev Argent Microbiol. 2010; 42: 261–268.
69. Giacomazzi J, Baethgen L, Carneiro LC et al. in association with the LIFE pro-
gram. The burden of serious human fungal infections in Brazil. Mycoses. 2016;
59: 145–150.
70. Cordeiro R, de A, Brilhante RS, Rocha MF et al. Twelve years of coccidioidomy-
cosis in Ceará State, Northeast Brazil: epidemiologic and diagnostic aspects.
Diagn Microbiol Infect Dis. 2010; 66: 65–72.
71. Vianna H, Passos HV, Santana AV. Coccidioidomycosis: report of the 1st case
in a native of Brazil. Rev Inst Med Trop Sao Paulo. 1979; 21: 51–55.
72. Martı́nez-Méndez D, Semprun-Hernández N, Hernández-Valles RC. Coccid-
ioidomicosis: estado actual de la endemia en Venezuela. Invest Clı́n [online].
2015; 564: 411–420.
73. Colombo AL, Tobón A, Restrepo A, Queiroz-Telles F, Nucci M. Epidemiology
of endemic systemic fungal infections in Latin America. Med Mycol. 2011; 49:
785–798.
74. Martins M dos A, de Araújo Eda M, Kuwakino MH et al. Coccidioidomycosis
in Brazil: a case report. Rev Inst Med Trop Sao Paulo. 1997; 39: 299–304.
75. Diógenes MJN, Jamacuru WF, Silva MAB, Carvalho FF. Inquérito epi-
demiológico com esferulina em Jaguaribara – CE, Brasil, 1993. Ann Bras Derm.
1995; 70: 525–529.
76. Negroni R. Evolución de los conocimientos sobre aspectos clı́nico-
epidemiológicos de la coccidioidomycosis en las Américas. Rev Argent Microbiol.
2008; 40: 246–256.
77. Laniado-Laborin R. Expanding understanding of epidemiology of coccid-
ioidomycosis in the Western hemisphere. Ann NY Acad Sci. 2007; 1111: 19–
34.
78. Rubinstein H, Marticorena B, Masih D et al. Isolation of human fungi from
soil and identification of two endemic areas of Cryptococcus neoformans and
Coccidioides immitis. Rev Inst Med Trop Sao Paulo. 1989; 31: 12–16.
79. Johnson SM, Carlson EL, Pappagianis D. Coccidioides species determination:
does sequence analysis agree with restriction fragment length polymorphism?
Mycopathologia. 2015; 179: 373–379.
80. Koufopanou V, Burt A, Taylor JW. Concordance of gene genealogies reveals
reproductive isolation in the pathogenic fungus Coccidioides immitis. Proc Natl
Acad Sci U S A. 1997; 94: 5478–5482.
81. Canteros CE, Vélez H A, Toranzo AI et al. Molecular identification of Coc-
cidioides immitis in formalin-fixed, paraffin-embedded (FFPE) tissues from a
Colombian patient. Med Mycol. 2015; 53: 520–527.