Contribution of Biologic Response Modifiers to the Risk of Coccidioidomycosis Severity

Abstract

Background The risk of coccidioidomycosis (CM) as a life-threatening respiratory illness or disseminated CM (DCM) increases as much as 150-fold in immunosuppressed patients. The safety of biologic response modifiers (BRMs) as treatment for patients with autoimmune disease (AI) in CM-endemic regions is not well defined. We sought to determine that risk in the Tucson and Phoenix areas. Methods We conducted a retrospective study reviewing demographics, Arizona residency length, clinical presentations, specific AI diagnoses, CM test results, and BRM treatments in electronic medical records (EMR) of patients >18 years old with International Classification of Diseases (ICD-10) codes for CM and AI from 10/01/2017 to 12/31/2019. Results We reviewed 944 charts with overlapping ICD-10 codes for CM and AI, of which 138 were confirmed to have both diagnoses. Male gender was associated with more CM (p=0.003), and African ancestry was three times more likely than European to develop DCM (p<0.001). Comparing CM+/AI+ (138) with CM+/AI- (449) patients, there were no significant differences in CM clinical presentations. Patients receiving BRMs had 2.4 times more DCM compared to Pulmonary CM (PCM). Conclusions AI does not increase the risk of any specific CM clinical presentation, and BRM treatment of most AI patients does not lead to severe CM. However, BRMs significantly increase the risk of DCM, and prospective studies are needed to identify the immunogenetic subset that permits BRM-associated DCM.

Risk of Coccidioidomycosis Infection Among Individuals Using Biologic Response Modifiers, Corticosteroids, and Oral Small Molecules

“…In a retrospective chart review of 944 individuals with autoimmune disease from the Tucson and Phoenix, Arizona areas, BRMs were associated with a significant increased risk of disseminated coccidioidomycosis. 34 Finally, corticosteroid doses equivalent to >20 mg of prednisone have been noted to suppress cell-mediated immunity, thereby heightening the risk of severe or disseminated coccidioidomycosis. 1 Our study's findings have clinical implications suggesting that for individuals with rheumatic or autoimmune diseases in geographic regions endemic for coccidioidomycosis and treated with BRMs and/or corticosteroids, clinician consideration of regular screening for coccidioidomycosis is warranted.…”

“…Of the 12 patients who were on corticosteroids at the time of being diagnosed with coccidioidomycosis, 7 developed pulmonary disease, and 4 had disseminated disease. In a retrospective chart review of 944 individuals with autoimmune disease from the Tucson and Phoenix, Arizona areas, BRMs were associated with a significant increased risk of disseminated coccidioidomycosis 34 . Finally, corticosteroid doses equivalent to >20 mg of prednisone have been noted to suppress cell‐mediated immunity, thereby heightening the risk of severe or disseminated coccidioidomycosis 1 …”

The Known and Unknown “Knowns” of Human Susceptibility to Coccidioidomycosis

“…In the past two decades, external factors, such as immunocompromised hosts (HIV-AIDS) [11,12] or immunosuppression for medical reasons (transplant recipients [13] and biological response modifiers [14,15]), have been reported in individuals with severe or disseminated disease. Additionally, epidemiologic studies and outbreak reports have supported increased risk associated with occupational exposure associated with agricultural work [16,17], construction [18], and outdoor movie production [18].…”

“…The reported studies have either centered on TNFi [38] or grouped all BRMs together [15,39]. In one review, Blair et al [40] reviewed reports of coccidioidomycosis with various BRMs.…”

“…Mouse studies revealed that blockade of TNF signaling inhibits initial response to infection, leading to dissemination and mortality [47], and impairs control of existing infections, causing breakdown of granuloma and increased fungal burden [47]. Cohort studies involving biologic therapies revealed that inhibition of TNF by monoclonal antibodies or soluble TNF receptors led to an increased risk of coccidioidomycosis [14,15]. TNFi-induced reactivation of controlled disease was originally reported for tuberculosis (TB) [69].…”