Viral infections and atypical bacterial infections, including Mycoplasma pneumoniae and Chlamydia pneumoniae, have been implicated in the development of asthma due to inflammatory damage to airway tissues (1–4). Some studies also suggest that typical bacterial pathogens, such as Streptococcus pneumoniae, may contribute to asthma development through similar mechanisms (3).

In addition to bacterial and viral pathogens, several fungal mold infections such as aspergillosis and infections due to Alternaria spp. and Cladosporium spp. are known to predispose individuals to asthma development or exacerbations, largely due to hypersensitization to fungal antigens (5). A recent study reported an increased incidence of asthma diagnosis or treatment following infection due to Coccidioides, a dimorphic fungus similar to Histoplasma (6). However, data on the incidence of asthma following histoplasmosis are lacking.

Asthma is considered a risk factor for histoplasmosis, possibly due to altered respiratory tract immunity or the frequent use of chronic corticosteroid in asthma management (7,8). Histoplasmosis can also damage airway tissues and trigger a robust inflammatory immune response (9,10). This may predispose patients to later airway hyperreactivity due to mechanisms described in other fungal infections (5,6). We used a large U.S. health insurance claims database to estimate the frequency of new-onset asthma diagnosis or initiation of asthma treatment following histoplasmosis and assess potentially associated factors.

We used the Merative^™ Marketscan^® Commercial/Medicare Database (https://www.merative.com/documents/brief/marketscan-explainer-general), which includes health insurance claims data for over 45 million patients across the United States with employer-sponsored plans including Medicare Supplemental and Medicare Advantage plans. We identified patients diagnosed with histoplasmosis (n=12,832) during January 01, 2018, to June 30, 2023, using International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes (Supplemental Table 1). To improve diagnostic accuracy, we excluded patients with codes listed only on laboratory or imaging claims alone, as these may reflect rule-out diagnoses. The index date was the date the histoplasmosis code was first used during the study window.

We also excluded 7,783 patients whose histoplasmosis code was assigned by an eye care provider, to remove cases of presumed ocular histoplasmosis. We required continuous health plan enrollment for one year before and one year after the histoplasmosis index date, which excluded an additional 2,288 patients due to lack of continuous enrollment. To identify new-onset asthma diagnoses, we excluded 713 patients with a prior asthma diagnosis or an outpatient prescription for a short-acting β₂ agonist (SABA; i.e., albuterol, albuterol sulphate, or levalbuterol), a standard treatment for asthma, within the year before their index date. Finally, we excluded 229 patients who had a histoplasmosis code in the year before the index date to ensure incident case capture (Supplemental figure 1).

Next, we assessed factors associated with an asthma diagnosis code or a new SABA prescription in the year following the histoplasmosis index date. We assessed patient demographics, provider specialty on the index date, histoplasmosis form, presenting symptoms, clinical findings, and other selected comorbid conditions documented within the 90 days before or on the index date, using ICD-10-CM codes (Supplemental Table 1). We assessed bivariable associations using chi-squared tests, Fisher’s exact tests, and t-tests with a significance threshold of p<0.05. Bivariable associations with p-values <0.2 were included in a stepwise multivariable regression model to estimate adjusted odds ratios (aORs) and 95% confidence intervals (95% CIs) for independent associations between key demographic and clinical factors and asthma diagnosis or SABA prescription.

Finally, we constructed several comparison cohorts. These included: 1) patients with healthcare visits for any reason, to estimate asthma incidence among the general population of commercially insured patients; 2) patients with other thermally dimorphic fungal infections, such as blastomycosis or coccidioidomycosis; 3) patients with aspergillosis, a known fungal infection linked to asthma development and exacerbation (5); 4) patients with influenza infection or COVID-19 diagnoses, which are viral infections linked to asthma development and exacerbation in adults (2,11); and 5) patients with pneumonia due to Chlamydia pneumoniae, Mycoplasma pneumoniae, or Streptococcus pneumoniae, which are pathogens associated with asthma development (3). We constructed the cohorts in the same manner as described above (Supplemental Table 2).

Among 1,819 patients with histoplasmosis who met the inclusion criteria, 252 (13.9%, 95% CI:12.3–15.4) had a new asthma diagnosis code (n=93, 5.1%) or a new SABA prescription (n=197, 10.8%) within one year of their index date; n=38 had both a new asthma diagnosis code and a new SABA prescription (Table 1, Figure 1). Of the 93 patients with asthma diagnosis codes, 26 (28%) were classified as mild, 18 (19%) as moderate, 1 (0.4%) as severe, and 58 (62%) were of unspecified severity (Supplemental Table 3). The median time from histoplasmosis to first asthma diagnosis code or new SABA prescription was 130 days (interquartile range [IQR]: 49.5–239.5).

Patients with histoplasmosis had an even sex distribution (50% male, 50% female), with a median age of 57 years (IQR: 43–69). Patients were primarily from the Midwest (51%) and South (38%) census regions (Table 1). Patients with a new asthma diagnosis code or SABA prescription were more likely than those who did not to have been seen at an acute care hospital (40% vs. 33%, p=0.026) or by a pulmonary specialist on the index date (16% vs. 10%, p=0.004). They were also more likely to have pulmonary histoplasmosis (35% vs. 26%, p=0.003), an unspecified histoplasmosis form (19% vs. 13%, p=0.006), or to have been hospitalized on the index date (19% vs. 13%, p=0.006) (Table 1).

Several pulmonary symptoms and clinical findings were more common among patients who had a new asthma diagnosis code or SABA prescription. This included dyspnea (28% vs. 17%, p<0.001), wheezing (3% vs. 1%, p=0.007), chest pain (18% vs. 13%, p=0.04), hypoxemia (7% vs. 3%, p<0.001), acute respiratory failure (3% vs. 1%, p=0.007), and pleural effusion (11% vs. 6%, p=0.008). Most systemic symptoms were not associated with receiving a new asthma diagnosis code or SABA prescription. Diagnoses in the 90 days before the index date that were associated with receiving an asthma diagnosis code or SABA prescription included allergic rhinitis (7% vs. 4%, p=0.045), anxiety disorder (14% vs. 10%, p=0.029), chronic obstructive pulmonary disease (16% vs. 8%, p<0.001), COVID-19 (9% vs. 4%, p=0.009), depression (14% vs. 8%, p=0.009), and pneumonia (18% vs. 11%, p=0.002). Diagnostic procedures including chest computed tomography (44% vs. 32%, p<0.001), spirometry (33% vs. 9%, p<0.001), or nitric oxide expired gas determination (2%. vs. 0.3%, p=0.007) were more common among patients who received a new asthma diagnosis code or SABA prescription; receipt of antifungal treatment was not associated.

In multivariable logistic regression, pulmonary histoplasmosis was independently associated with higher odds of receiving a new asthma diagnosis code or SABA prescription (adjusted odds ratio (aOR)=1.7, 95% CI: 1.3–2.4), as was dyspnea (aOR=1.7, 95% CI: 1.2–2.4) and wheezing (aOR=4.1, 95% CI: 1.3–12.8) (Supplemental Table 3). Other significant predictors included pericarditis (aOR=11.6, 95% CI: 1.0–131.9), COVID-19 (aOR=2.4, 95% CI: 1.0–5.2), and depression (aOR=1.7, 95% CI: 1.1–2.8).

In the comparison cohorts, the proportion of patients with a new asthma diagnosis code or SABA prescription within the year following the index date was 5.8% (95% CI: 5.8–5.9) among the general population, 8.0% (95% CI: 4.9–11.1) among patients with blastomycosis, 12.9% (95% CI: 11.3–14.6) among patients with coccidioidomycosis, and 19.4% (95% CI: 17.3–21.4) among patients with aspergillosis (Figure 1). Among patients with viral infections, the proportion was 9.3% (95% CI: 9.2–9.3) for those with influenza and 11.4% (95% CI: 11.3–11.4) for those with COVID-19. Finally, among patients with bacterial pneumonia, the proportion was 24.5% (95% CI: 20.1–28.9) for those with Chlamydia pneumoniae, 19.5% (95% CI: 18.8–20.3) for those with Mycoplasma pneumoniae, and 25.4% (95% CI: 23.9–26.8) for those with Streptococcus pneumoniae. When restricting the histoplasmosis cohort to patients who also had a diagnosis code for “unspecified pneumonia,” 20.1% (95% CI: 14.5%–25.7%) received a new asthma diagnosis code or SABA prescription.

In this analysis of patients with commercial insurance, nearly 14% of patients diagnosed with histoplasmosis received either a new asthma diagnosis code or a short-acting beta-agonist (SABA) prescription within the following year. This rate was more than twice that of the general population, higher than observed following infections due to influenza and COVID-19, and similar to that observed after coccidioidomycosis. Furthermore, among patients with histoplasmosis and “unspecified pneumonia” diagnoses, the proportion with a new asthma diagnosis code or SABA prescription was similar to that seen with certain bacterial pneumonias, conditions for which associations with new-onset asthma are well described (1–3,5). Although this is an exploratory study not meant to establish causality, these findings suggest that histoplasmosis, particularly when presenting with pulmonary symptoms or pneumonia, may predispose patients to developing inflammation-mediated airway hyperresponsiveness.

Several potential mechanisms could explain this finding (Table 2). One possibility is that Histoplasma capsulatum infection damages airway epithelial cells, leading to persistent inflammation and a cascade of immune responses that promote airway remodeling and hyperreactivity. In allergic bronchopulmonary aspergillosis (ABPA), for example, Aspergillus proteases provoke prolonged T helper 2 (Th2)-skewed immune responses, mucosal inflammation, and structural airway changes, including smooth muscle hyperplasia and goblet cell metaplasia (5,12,13). Histoplasma expresses several orthologous proteins—including heat shock protein 60, 60S ribosomal protein L3, and fructose 1,6-bisphosphate aldolase (14–16), that could act through similar pathophysiologic mechanisms to stimulate Th2 responses and contribute to asthma pathogenesis. Additionally, fungal cell wall components such as β-glucans, chitin, and mannans can serve as potent pathogen-associated molecular patterns, activating innate immune pathways (e.g., Dectin-1, TLR2/4) and promoting chronic airway inflammation (17). Damaged respiratory epithelia may also release alarmins such as IL-25, IL-33, and thymic stromal lymphopoietin (TSLP), which activate group 2 innate lymphoid cells (ILC2s), critical drivers of allergic inflammation and asthma (18). These responses may be further amplified in individuals with predisposing immune profiles. Another contributing factor may be disruption of the airway epithelial barrier following fungal infection, increasing exposure to inhaled allergens and environmental irritants (19). This sensitization could predispose to de novo asthma or exacerbate subclinical disease. Fungal infections may also alter the composition of the lung microbiome, favoring colonization by bacteria associated with airway inflammation and dysregulated immune responses (20). Moreover, certain fungal proteases may activate protease-activated receptors on airway nerves or smooth muscle, triggering bronchospasm and enhancing neuroimmune signaling that promotes airway hyperresponsiveness (21). Latent persistence of Histoplasma in lung tissues or macrophages could provide a chronic source of antigenic stimulation, sustaining inflammation long after the initial infection. This mechanism has been proposed in other fungal-related pulmonary diseases, such as chronic pulmonary aspergillosis and fungal bronchitis (22).

These hypotheses are supported by our findings that receiving a new asthma diagnosis code or SABA was more common in patients with pulmonary histoplasmosis (compared with other histoplasmosis forms), and in those with pulmonary symptoms and findings (e.g., dyspnea, wheezing, and pneumonia) and potentially more severe disease, as indicated by hospitalization. The independent association we observed between pericarditis and asthma diagnosis or SABA also supports the idea that a heightened systemic inflammatory response may contribute to airway dysfunction (10,23). Similarly, a recent study of coccidioidomycosis showed that patients with more severe pulmonary disease were more likely to receive asthma diagnosis codes or SABA prescriptions (6). Further studies are needed to assess whether there are unique processes related to asthma development following dimorphic fungal infection, or if the processes are similar to those in other respiratory infections (3,4,11,24).

Alternatively, our findings might reflect that histoplasmosis unmasked previously undiagnosed asthma, especially among patients with pre-existing Th2-dominant immune profiles. Because the adaptive immune response to Histoplasma typically requires a Th1 response (9), it is possible that histoplasmosis could occur more frequently in patients who have Th2-dominated immune responses and are more likely to develop asthma regardless of histoplasmosis infection. Approximately 75% of asthma diagnoses or SABA prescriptions in our study occurred 49 days or more after the diagnosis of histoplasmosis, suggesting they were not incidental findings during initial histoplasmosis evaluation. However, patients seen by pulmonologists or allergists during histoplasmosis follow-up may have had a higher likelihood of being evaluated for asthma, potentially leading to detection bias.

Somewhat unexpectedly, we found that depression was independently associated with receiving a new asthma diagnosis code or SABA. Psychological stress has been increasingly recognized as a contributor to asthma incidence and exacerbations, possibly through dysregulation of hypothalamic-pituitary-adrenal axis signaling and immune responses (25). However, further studies are needed to assess what, if any, role histoplasmosis plays in the relationship between depression and asthma.

A primary limitation of our study is the reliance on ICD-10 codes, which are subject to misclassification and under-coding of symptoms. Not all patients with ICD-10 codes for asthma had spirometry-confirmed diagnoses; however, prior studies have validated the use of administrative claims data for asthma research (26). We included SABA prescriptions in our study to improve case detection (26); approximately two-thirds of patients in our study met the case definition by having a SABA prescription and no asthma diagnosis code. However, another study limitation is the lack of information about SABA indication. SABAs can also be prescribed for chronic obstructive pulmonary disease or might reflect off-label use for histoplasmosis-related symptoms (e.g., wheezing or dyspnea) during recovery from histoplasmosis. This could have led to an over-estimation of the outcome of interest. Additionally, we may have overestimated new asthma diagnoses in patients with a history of asthma or SABA use >1 year before histoplasmosis diagnosis.

In summary, this retrospective cohort study found that nearly 14% of patients with histoplasmosis received a new asthma diagnosis or SABA prescription. Further studies could shed light on mechanistic drivers of the association between histoplasmosis and subsequent asthma or SABA prescription, and whether they are unique to thermally dimorphic fungal infections or a broader phenomenon seen with other respiratory pathogens. Understanding these mechanisms may help inform strategies to mitigate post-infectious airway disease in affected populations.