Coccidioidomycosis Exposure Assessed by Skin Testing and Environmental Factors in Baja California, Mexico

1. Introduction

Coccidioidomycosis (CM) is an infection caused by fungi of the genus Coccidioides, characterized by a wide clinical spectrum ranging from asymptomatic disease to severe, life-threatening illness. After the United States, Mexico has the second-highest number of reported human cases worldwide, with most cases concentrated in the states of Sonora and Baja California [1,2]. According to national surveillance records, Mexico documented 2,425 hospital discharges for CM from 2013 through 2023, of which 338 (13.94%) occurred in Baja California [2]. This state is therefore the second-largest contributor to national case burden.

Historically, estimates of Coccidioides exposure in Mexico have relied on the intradermal skin test (ST) with coccidioidin or spherulin. A positive skin test (ST+) indicates prior exposure to the antigen rather than active infection [3]. In Baja California, these tests have been reported almost exclusively in the city of Tijuana, where positivity rates of 10% were documented in 1991 [2], 27.5% in 2010 among the general population [4], and 10% in pediatric populations in 1999 [5]. However, these studies did not include other regions of the state, leaving substantial gaps in understanding the geographic distribution of exposure.

Environmental surveillance in 2012 [6] and 2015 [7] detected Coccidioides spp. DNA in soil samples from Valle de las Palmas using nested PCR targeting ITS regions, indicating that the fungus was present in that area at least transiently. In 2016, a coccidioidin-ST was conducted to assess exposure among populations with varying levels of exposure: (1) 273 university students who attended classes in Valle de las Palmas but lived elsewhere, among whom 18 (6.6%) tested positive [8]; and (2) 10 residents of Valle de las Palmas, of whom 6 (60%) were positive [9]. These findings suggest that although Coccidioides may be present in the environment, duration and intensity of exposure strongly influence immune sensitization and ST reactivity.

Given the increasing number of CM cases in Baja California and the limited availability of statewide data on population-level exposure, more comprehensive epidemiologic studies are necessary to better understand risk patterns. This study aimed to estimate exposure to Coccidioides in Baja California using the coccidioidin-ST and to evaluate the association of this exposure with environmental variables that influence fungal growth, survival, and dispersal.

2. Materials and Methods

2.1. Population and Sampling

Participants were recruited from nine regions of Baja California: Ensenada (Ensenada municipality), Mexicali (Mexicali), Plan Libertador (Rosarito), San Felipe (San Felipe), Vicente Guerrero (San Quintín), Valle de las Palmas (Tecate), and the communities of El Niño, Terrazas del Valle, and La Morita (Tijuana) (Figure 1). A nonprobability sampling strategy was used. State health institutions collaborated by providing facilities and mobilizing residents for coccidioidin-ST. Surveys were conducted between 2016 and 2022. Each attendee received an explanation of the study objectives and was informed that individuals of any age, sex, or respiratory symptom status were eligible, provided they had no major immunodeficiencies and were not undergoing chemotherapy. Individuals who voluntarily agreed to participate provided written informed consent under approval by the National Bioethics Commission (CONBIOÉTICA-02-CEI-001-20170526) [10]. For minors, consent was obtained from a parent or legal guardian.

Sociodemographic data (age, sex, residence, travel history) and clinical information (current or chronic underlying conditions, respiratory symptoms within the past 3 months, history of prior skin testing, and any adverse reactions to coccidioidin-ST) were collected through structured interviews.

2.2. Antigen

Coccidioidin was produced by the Institute of Epidemiological Diagnosis and Reference (INDRE) of the National Ministry of Health [11,12,13].

2.3. Application

Each participant received an intradermal injection of 0.1 mL of coccidioidin using a hypodermic syringe. The antigen was administered into the mid-third of the volar surface of the nondominant forearm. After injection, participants were asked to remain on site for 15 minutes to monitor for immediate adverse effects.

2.4. Interpretation of Intradermal Test Results

Coccidioidin-ST results were evaluated between 48 and 72 hours after application. The injection site was assessed for reaction characteristics. Presence or absence of erythema was noted; if induration was present, it was measured in millimeters. A reaction with an induration diameter ≥5 mm was classified as positive (coccidioidin-ST+), indicating prior exposure to Coccidioides.

2.5. Environmental Parameters

Twenty-four variables were analyzed, including 19 bioclimatic indicators derived from recent meteorological reanalysis datasets [14]; climate classification [15]; two topographic variables (slope and elevation) [16]; and predominant land use and vegetation [17] surrounding each locality. Differences between high- and low-positivity groups were assessed using the nonparametric Mann–Whitney U test [18], implemented with the wilcox.test function in R (R Foundation for Statistical Computing, Vienna, Austria; RRID:SCR_001905), to identify environmental variables significantly associated with Coccidioides exposure [19].

2.6. Statistical Analysis

Statistical analyses were performed using Stata version 18 (StataCorp LLC, College Station, TX, USA; RRID:SCR_012763). Categorical variables were compared using the chi-square test. Associations between locality and coccidioidin-ST+ status were evaluated by calculating odds ratios (ORs) with 95% confidence intervals in Stata.

3. Results

A total of 521 persons received coccidioidin-ST during 2016–2022; however, only 416 returned for test interpretation. The spatial distribution of the evaluated population was as follows: Ensenada (n=11; 2.64%), Mexicali (106; 25.48%), Plan Libertador (37; 8.89%), San Felipe (30; 7.21%), Vicente Guerrero (74; 17.78%), La Morita (37; 8.89%), El Niño (11; 2.64%), Terrazas del Valle (47; 11.29%), and Valle de las Palmas (63; 15.14%).

Among participants, 66.2% were female and 33.8% male. Ages ranged from 6 months to 86 years (mean 38.5 years; median 37.5 years); nearly half (49%) were 19–40 years old. Most participants (85.6%) reported no travel to Sonora, California, and/or Arizona (USA). Domestic work was reported by 22.4%; 66.2% denied allergies; 47.9% reported no chronic underlying disease; and 58.7% had not experienced respiratory illness within the previous 3 months. Most tests were administered in 2019 (23.8%) and 2020 (32.6%). Overall, 31.9% (133/416) were coccidioidin-ST+; 41.3% had indurations 5–15 mm, and indurations >20 mm were observed in all localities (Figure 2).

Bivariate analysis showed no significant associations between coccidioidin-ST+ and age, travel history, underlying diseases, or recent respiratory illness. Significant differences were observed in the absence of allergies, in the sampling years 2017 and 2019, and among persons reporting domestic work (Table 1).

Because the number of participants varied across regions, associations between coccidioidin-ST+ individuals and locality were based on the proportion of positive cases in each area (Figure 3). Using San Felipe (lowest positivity) as the reference group, higher odds of exposure to Coccidioides spp. were observed in Valle de las Palmas (OR 6.25, 95% CI 2.12–18.43; p=0.001) and La Morita (OR 5.88, 95% CI 1.85–18.72; p=0.003) (Table 2). Based on the most recent subnational survey in Mexico (2011), which reported an average positivity of 29.5% across endemic and non-endemic states [4], study localities were categorized as low-positivity (≤30%) or high-positivity (>30%), as shown in Table 2.

Environmental comparisons between high- and low-positivity groups revealed significant differences in three abiotic variables: annual precipitation, precipitation during the wettest month, and elevation. Descriptive values for these variables across localities are shown in Table 3. High-positivity localities were characterized by annual precipitation of 243.22–310.75 mm, wettest-month precipitation of 55.16–78.77 mm, and elevations of 125.02–276.44 m above sea level (Figure 4).

4. Discussion

Because the sampling was nonprobabilistic, some selection bias was unavoidable. Although the sample is not fully representative of all localities, the findings provide valuable insights into exposure patterns within the participating populations and align with the study objectives.

Among the 133 coccidioidin-ST+ individuals, a larger, though not statistically significant, proportion reported no underlying diseases or immunodeficiencies, indicating that most participants likely had maintained immune function. This pattern supports the interpretation that coccidioidin-ST+ reflects prior exposure, often in the context of subclinical or asymptomatic infection. However, the remaining proportion of participants includes individuals with conditions associated with immunosuppression, such as HIV infection, diabetes, autoimmune diseases, and the use of immunosuppressive therapies for cancer, lymphomas, or leukemias, who may be at increased risk for severe or disseminated disease. In this study, 27% of participants reported chronic underlying conditions, primarily diabetes and hypertension, which may impair immune responses and potentially reduce the likelihood of a detectable skin-test reaction despite prior exposure to Coccidioides. This finding suggests that a substantial proportion of the population has been exposed to Coccidioides, often with subclinical or asymptomatic infection. The observed positivity underscores the need for community education, risk-reduction strategies, and consideration of protective measures in high-risk environments, particularly among vulnerable populations.

The higher frequency of coccidioidin-ST+ among individuals without travel to recognized endemic areas in Mexico or the United States supports the likelihood of local, autochthonous transmission within Baja California. Additionally, the higher proportion of coccidioidin-ST+ among persons without recent respiratory illness may reflect asymptomatic infection or misclassification of mild symptoms as other acute respiratory conditions, such as influenza or COVID-19. In 2024 alone, Baja California documented more than 400,000 respiratory cases [20], none of which underwent differential diagnosis for CM. Over the 2013–2023 period, only 338 CM cases were reported, supporting the interpretation that CM remains underrecognized and likely underdiagnosed in the region. Similar concerns regarding underrecognition and limited surveillance have been raised in other endemic settings [21].

Some significant associations, such as higher coccidioidin-ST+ among participants without allergies and among specific sampling years or occupational groups, should be interpreted with caution, as they may reflect underlying sampling patterns rather than true epidemiologic differences.

Baja California has a predominantly arid climate, with regional variability influenced by latitude, topography, altitude, and Pacific Ocean dynamics [22]. Although climate type did not differ between groups, the four localities with the highest positivity shared the BSks subtype (cold semi-arid steppe climate with winter precipitation). These areas were also characterized by induced or cultivated grasslands, which are atypical within the natural vegetation of Baja California. Nonetheless, these grasslands may create microenvironments that promote moisture retention and increase soil coverage, thereby creating conditions conducive to the survival of Coccidioides.

Overall, the localities with higher exposure, such as Valle de las Palmas, La Morita, Plan Libertador, and El Niño, were characterized by greater environmental moisture, intermediate elevations (125–276 m), and increased annual and wettest-month precipitation. These patterns are consistent with regional atmospheric processes, in which moisture-laden westerly winds from the Pacific rise over the Sierra Juárez, cool, and precipitate on the western side of the peninsula.

The environmental profile identified—BSks climate, induced grasslands, mountainous terrain, intermediate elevation, and seasonal precipitation—resembles patterns described in endemic regions of the United States, including Kern County in California; Pima and Maricopa counties in Arizona; Benton and Walla Walla counties in Washington; and Washington County in Utah [23,24,25], where climatic and geographic conditions similarly influence fungal ecology and transmission dynamics.

La Morita and El Niño, located on the eastern edge of Tijuana, are characterized by high population mobility, including migrant populations, maquiladora workers, as well as limited urban infrastructure and socioeconomic vulnerability [26]. Such conditions increase exposure to dust and disturbed soil [27,28,29], potentially amplifying the risk of Coccidioides exposure in these communities.

Taken together, these findings suggest that exposure to Coccidioides in Baja California is shaped by the interaction of environmental and social determinants. This underscores the importance of strengthening clinical awareness, incorporating environmental risk indicators into surveillance strategies, and improving diagnostic capacity to better characterize and address the burden of CM in the region.

5. Conclusions

This study identified a high proportion of coccidioidin-ST positivity (31.9%) in Baja California, indicating substantial exposure to Coccidioides and a heterogeneous distribution across localities. Higher exposure was observed in areas characterized by semi-arid climates, intermediate elevations (125–276 m), and increased precipitation, supporting the role of environmental conditions in shaping transmission patterns.

Although the nonprobabilistic sampling design limits generalizability, the findings provide relevant insight into exposure patterns in understudied regions. The discrepancy between high levels of exposure and the relatively low number of reported cases suggests that CM remains underrecognized and likely underdiagnosed in the state.

These results highlight the importance of strengthening epidemiologic surveillance and improving clinical awareness, particularly in populations with increased vulnerability due to underlying conditions or social determinants. Incorporating environmental risk indicators into surveillance and prevention strategies may facilitate early detection and more effective targeting of high-risk areas. Further studies using probabilistic designs and integrating clinical and environmental data are needed to characterize transmission dynamics better and inform evidence-based public health interventions.