Access to Urgent Care Practices Improves Understanding and Management of Endemic Coccidioidomycosis: Maricopa County, Arizona, 2018-2023.

BACKGROUND: Coccidioidomycosis within endemic regions is often undiagnosed because appropriate testing is not performed. A dashboard was developed to provide information about the prevalence of coccidioidomycosis throughout the year. METHODS: Banner Urgent Care Service has many clinics within Maricopa County, Arizona, a highly endemic region for coccidioidomycosis. All clinic visits and subset analyses for patients with ICD10 codes for pneumonia (J18.*) or erythema nodosum (L52) between 2018-2024 were included. Tabulated were daily frequencies of visits, pneumonia and erythema nodosum coding, coccidioidal testing, and test results. Banner Urgent Care Services' counts of monthly coccidioidomycosis diagnoses were compared to those of confirmed coccidioidomycosis cases reported to Maricopa County Department of Public Health. RESULTS: Monthly frequencies of urgent care coccidioidomycosis diagnoses strongly correlated with public health coccidioidomycosis case counts (r=0.86). Testing frequency for coccidioidomycosis correlated with overall pneumonia frequency (r=0.52). The proportion of pneumonia due to coccidioidomycosis varied between <5% and greater than 45% within and between years. Coccidioidomycosis was a common cause of erythema nodosum (65%, 95% confidence: 45%-67%) and independent of pneumonia. Over half of Banner Urgent Care Services' coccidioidomycosis diagnoses were coded for neither pneumonia nor erythema nodosum. CONCLUSION: Data provided by the coccidioidomycosis dashboard can assist urgent care practitioners in knowing when coccidioidomycosis is prevalent in the community. Patients with exposure to endemic coccidioidomycosis who develop erythema nodosum or pneumonia should routinely be tested for coccidioidomycosis. Data from private healthcare organizations can augment surveillance of diseases important to public health.

Antigenic Relatedness between Mannans from Coccidioides immitis and Coccidioides posadasii Spherules and Mycelia.

Immunoassays for cell wall mannans that are excreted into serum and urine have been used as an aid in the diagnosis of many disseminated fungal infections, including coccidioidomycosis. Antigen-detection immunoassays are critically dependent on the detection of an analyte, such as mannan, by antibodies that are specific to the analyte. The goal of this study was to evaluate the extent of cross-reactivity of polyclonal antibodies raised against Coccidioides spp. Analysis of antigenic relatedness between mannans from C. posadasii and C. immitis spherules and mycelia showed complete relatedness when evaluated by the method of Archetti and Horsfall, which was originally used to study the antigenic relationships between Influenzae virus isolates. In a further effort to validate the suitability of the antigenic relatedness calculation methodology for polysaccharide antigens, we also applied the method of Archetti and Horsfall to published results that had previously identified the major capsular serotypes of Cryptococcus species. The results of this analysis showed that Archetti and Horsfall's antigenic relatedness calculation correctly identified the major cryptococcal serotypes. Together, these results suggest that the method is applicable to polysaccharide antigens, and that immunoassays that detect Coccidioides mannans are likely to have good reactivity across Coccidioides species (inclusivity) due to the species' high level of antigenic relatedness.

Genetic and Other Determinants for the Severity of Coccidioidomycosis: A Clinician's Perspective.

The endemic fungal infection, coccidioidomycosis, occurs after inhalation of one or very few Coccidioides spp. spores. Infections produce diverse clinical manifestations, ranging from insignificant to extremely destructive, even fatal. Approaches to understanding this range of consequences have traditionally categorized patients into a small number of groups (asymptomatic, uncomplicated self-limited, fibro-cavitary, and extra-thoracic disseminated) and then looked for immunologic differences among them. Recently, variants within genes of innate pathways have been found to account, in part, for infections that result in disseminated disease. This discovery raises the very attractive theory that, in patients without severe immunosuppression, much of the disease spectrum can be accounted for by various combinations of such deleterious variants in innate pathways. In this review, we summarize what is known about genetic determinants that are responsible for the severity of coccidioidal infections and how complex innate genetic differences among different people might account for the spectrum of disease observed clinically.

Improving Early Recognition of Coccidioidomycosis in Urgent Care Clinics: Analysis of an Implemented Education Program.

Background: Only 0.2% of coccidioidomycosis (CM) diagnoses were made in patients (pts) with pneumonia (PNA) in urgent care (UC), because they were not being tested for CM. Our objective in this study was to improve CM testing rates. Methods: This was a time series of clinician practice before and after an intervention that occurred at UC clinics in Phoenix and Tucson Arizona. All patients in UC were >18 years old. We included information about CM in periodic educational activities for clinicians. Coccidioidal serologic testing (CST), CST results, and their relation to International Classification of Diseases, Tenth Revision (ICD-10) codes were extracted from medical records. Results: Urgent care received 2.1 million visits from 1.5 million patients. The CST orders per 104 visits increased from 5.5 to 19.8 (P < .0001). Percentage positive CSTs were highest for August, November, and December (17.0%) versus other months (10.6%). Positive CSTs were associated with PNA ICD-10 codes, and, independently, for Erythema nodosum (EN) which had the highest positivity rate (61.4%). Testing of PNA pts increased on first visits and on second visits when the first CST was negative. Yearly rates of PNA due to CM ranged from 17.3% to 26.0%. Despite this improvement, CST was still not done for over three quarters of pts with PNA. This was a noncomparative study. Conclusions: Routine quality improvement activities have significantly but only partially improved rates of testing pts with PNA for CM in UC clinics located in a highly endemic area. Innovative strategies may be needed to improve current practice. Also in our region, EN, independent of PNA, is a strong predictor of CM.

Reactivation of Coccidioidomycosis in a Mouse Model of Asymptomatic Controlled Disease.

The majority of human coccidioidomycosis infections are asymptomatic or self-limited but may have sequestered spherules in highly structured granulomas. Under immunosuppression, reactivation of fungal growth can result in severe disease. B6D2F1 mice asymptomatically infected with C. posadasii strain 1038 were immunosuppressed with dexamethasone (DXM) in drinking water. Treated mice died 16−25 days later, while untreated mice survived (p < 0.001). Flow cytometry of lung granulomas on days 5, 10, 15, and 20 of DXM treatment showed immune cell populations decreased 0.5−1 log compared with untreated mice though neutrophils and CD19+IgD−IgM− cells rebounded by day 20. Histopathology demonstrated loss of granuloma structure by day 5 and increasing spherules through day 20. On day 20, T-cells were nearly absent and disorganized pyogranulomatous lesions included sheets of plasma cells and innumerable spherules. Mice given DXM for 14 days then stopped (DXM stop) survived 6 weeks (9/10). Lung fungal burdens were significantly lower (p = 0.0447) than mice that continued treatment (DXM cont) but higher than untreated mice. Histopathologically, DXM stop mice did not redevelop controlled granulomas by sacrifice, though T-cells were densely scattered throughout the lesions. This demonstrates a mouse model suitable for further study to understand the immunologic components responsible for maintenance control of coccidioidomycosis.

Immunogenetics associated with severe coccidioidomycosis.

Disseminated coccidioidomycosis (DCM) is caused by Coccidioides, pathogenic fungi endemic to the southwestern United States and Mexico. Illness occurs in approximately 30% of those infected, less than 1% of whom develop disseminated disease. To address why some individuals allow dissemination, we enrolled patients with DCM and performed whole-exome sequencing. In an exploratory set of 67 patients with DCM, 2 had haploinsufficient STAT3 mutations, and defects in ß-glucan sensing and response were seen in 34 of 67 cases. Damaging CLEC7A and PLCG2 variants were associated with impaired production of ß-glucan-stimulated TNF-α from PBMCs compared with healthy controls. Using ancestry-matched controls, damaging CLEC7A and PLCG2 variants were overrepresented in DCM, including CLEC7A Y238* and PLCG2 R268W. A validation cohort of 111 patients with DCM confirmed the PLCG2 R268W, CLEC7A I223S, and CLEC7A Y238* variants. Stimulation with a DECTIN-1 agonist induced DUOX1/DUOXA1-derived hydrogen peroxide [H2O2] in transfected cells. Heterozygous DUOX1 or DUOXA1 variants that impaired H2O2 production were overrepresented in discovery and validation cohorts. Patients with DCM have impaired ß-glucan sensing or response affecting TNF-α and H2O2 production. Impaired Coccidioides recognition and decreased cellular response are associated with disseminated coccidioidomycosis.

Natural history of pulmonary coccidioidomycosis: Further examination of the VA-Armed Forces Database.

There are still many limitations related to the understanding of the natural history of differing forms of coccidioidomycosis (CM), including characterizing the spectrum of pulmonary disease. The historical Veterans Administration-Armed Forces database, recorded primarily before the advent of antifungal therapy, presents an opportunity to characterize the natural history of pulmonary CM. We performed a retrospective cohort study of 342 armed forces service members who were diagnosed with pulmonary CM at VA facilities between 1955 to 1958, followed through 1966, who did not receive antifungal therapy. Patients were grouped by predominant pulmonary finding on chest radiographs. The all-cause mortality was low for all patients (4.6%). Cavities had a median size of 3-3.9 cm (IQR: 2-2.9-4-4.9 cm), with heterogeneous wall thickness and no fluid level, while nodules had a median size of 1-1.19 cm (Interquartile range [IQR] 1-1.9-2-2.9 cm) and sharp borders. The majority of cavities were chronic (85.6%), and just under half were found incidentally. Median complement fixation titers in both the nodular and cavitary groups were negative, with higher titers in the cavitary group overall. This retrospective cohort study of non-disseminated coccidioidomycosis, the largest to date, sheds light on the natural history, serologic markers, and radiologic characteristics of this understudied disease. These findings have implications for the evaluation and management of CM.

Coccidioidomycosis (CM), also known as San Joaquin Valley Fever, causes a variety of symptoms including pneumonia. This historical study investigates CM of the lungs in American soldiers with CM in the 1950s, prior to modern antifungals, to better understand the natural history.

Vaccines to Prevent Coccidioidomycosis: A Gene-Deletion Mutant of Coccidioides Posadasii as a Viable Candidate for Human Trials.

Coccidioidomycosis is an endemic fungal infection that is reported in up to 20,000 persons per year and has an economic impact close to $1.5 billion. Natural infection virtually always confers protection from future exposure, and this suggests that a preventative vaccine strategy is likely to succeed. We here review progress toward that objective. There has been ongoing research to discover a coccidioidal vaccine over the past seven decades, including one phase III clinical trial, but for reasons of either efficacy or feasibility, a safe and effective vaccine has not yet been developed. This review first summarizes the past research to develop a coccidioidal vaccine. It then details the evidence that supports a live, gene-deletion vaccine candidate as suitable for further development as both a veterinary and a human clinical product. Finally, a plausible vaccine development plan is described which would be applicable to this vaccine candidate and also useful to other future candidates. The public health and economic impact of coccidioidomycosis fully justifies a public private partnership for vaccine development, and the development of a vaccine for this orphan disease will likely require some degree of public funding.

Controversies in the Management of Central Nervous System Coccidioidomycosis.

Central nervous system infection with Coccidioides spp. is fatal if untreated and complications occur even when therapy is directed by experienced clinicians. We convened a panel of clinicians experienced in the management of coccidioidal meningitis to summarize current controversies and provide consensus for the management of this difficult infection.

Cross-Sectional Study of Clinical Predictors of Coccidioidomycosis, Arizona, USA.

Demographic and clinical indicators have been described to support identification of coccidioidomycosis; however, the interplay of these conditions has not been explored in a clinical setting. In 2019, we enrolled 392 participants in a cross-sectional study for suspected coccidioidomycosis in emergency departments and inpatient units in Coccidioides-endemic regions. We aimed to develop a predictive model among participants with suspected coccidioidomycosis. We applied a least absolute shrinkage and selection operator to specific coccidioidomycosis predictors and developed univariable and multivariable logistic regression models. Univariable models identified elevated eosinophil count as a statistically significant predictive feature of coccidioidomycosis in both inpatient and outpatient settings. Our multivariable outpatient model also identified rash (adjusted odds ratio 9.74 [95% CI 1.03-92.24]; p = 0.047) as a predictor. Our results suggest preliminary support for developing a coccidioidomycosis prediction model for use in clinical settings.

The WOPR family protein Ryp1 is a key regulator of gene expression, development, and virulence in the thermally dimorphic fungal pathogen Coccidioides posadasii.

Coccidioides spp. are mammalian fungal pathogens endemic to the Southwestern US and other desert regions of Mexico, Central and South America, with the bulk of US infections occurring in California and Arizona. In the soil, Coccidioides grows in a hyphal form that differentiates into 3-5 micron asexual spores (arthroconidia). When arthroconidia are inhaled by mammals they undergo a unique developmental transition from polar hyphal growth to isotropic expansion with multiple rounds of nuclear division, prior to segmentation, forming large spherules filled with endospores. Very little is understood about the molecular basis of spherule formation. Here we characterize the role of the conserved transcription factor Ryp1 in Coccidioides development. We show that Coccidioides Δryp1 mutants have altered colony morphology under hypha-promoting conditions and are unable to form mature spherules under spherule-promoting conditions. We analyze the transcriptional profile of wild-type and Δryp1 mutant cells under hypha- and spherule-promoting conditions, thereby defining a set of hypha- or spherule-enriched transcripts ("morphology-regulated" genes) that are dependent on Ryp1 for their expression. Forty percent of morphology-regulated expression is Ryp1-dependent, indicating that Ryp1 plays a dual role in both hyphal and spherule development. Ryp1-dependent transcripts include key virulence factors such as SOWgp, which encodes the spherule outer wall glycoprotein. Concordant with its role in spherule development, we find that the Δryp1 mutant is completely avirulent in the mouse model of coccidioidomycosis, indicating that Ryp1-dependent pathways are essential for the ability of Coccidioides to cause disease. Vaccination of C57BL/6 mice with live Δryp1 spores does not provide any protection from lethal C. posadasii intranasal infection, consistent with our findings that the Δryp1 mutant fails to make mature spherules and likely does not express key antigens required for effective vaccination. Taken together, this work identifies the first transcription factor that drives mature spherulation and virulence in Coccidioides.

Contribution of Biologic Response Modifiers to the Risk of Coccidioidomycosis Severity.

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 of patients ≥18 years old with International Classification of Diseases (ICD-10) codes for CM and AI from 1 October 2017 to 31 December 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 sex was associated with more CM (P = .003), and patients with African ancestry were 3 times more likely than those with European ancestry to develop DCM (P < .001). Comparing CM+/AI+ (n = 138) with CM+/AI- (n = 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.

Mouse Model of a Human STAT4 Point Mutation That Predisposes to Disseminated Coccidiomycosis.

STAT4 plays a critical role in the generation of both innate and adaptive immune responses. In the absence of STAT4, Th1 responses, critical for resistance to fungal disease, do not occur. Infection with the dimorphic fungus, Coccidioides, is a major cause of community-acquired pneumonia in the endemic regions of Arizona and California. In some people and often for unknown reasons, coccidioidal infection results in hematogenous dissemination and progressive disease rather than the typical self-limited pneumonia. Members of three generations in a family developed disseminated coccidioidomycosis, prompting genetic investigation. All affected family members had a single heterozygous base change in STAT4, c.1877A>G, causing substitution of glycine for glutamate at AA626 (STAT4E626G/+ ). A knockin mouse, heterozygous for the substitution, developed more severe experimental coccidioidomycosis than did wild-type mice. Stat4E626G/+ T cells were deficient in production of IFN-γ after anti-CD3/CD28 stimulation. Spleen cells from Stat4E626G mice showed defective responses to IL-12/IL-18 stimulation in vitro. In vivo, early postinfection, mutant Stat4E626G/+ mice failed to produce IFN-γ and related cytokines in the lung and to accumulate activated adaptive immune cells in mediastinal lymph nodes. Therefore, defective early induction of IFN-γ and adaptive responses by STAT4 prevents normal control of coccidioidomycosis in both mice and humans.

FDA Public Workshop Summary-Coccidioidomycosis (Valley Fever): Considerations for Development of Antifungal Drugs.

Coccidioidomycosis is a fungal disease endemic to the southwestern United States, Mexico, and Central and South America. Prevalence rates are increasing steadily, and new endemic areas of Coccidioides are emerging. Standard treatment is often administered for months to decades, and intolerance to medications and treatment failures are common. No new treatments for coccidioidomycosis have been approved in the United States in nearly 40 years. On 5 August 2020, the US Food and Drug Administration convened experts in coccidioidomycosis from academia, industry, patient groups, and other government agencies to discuss the disease landscape and strategies to facilitate product development for treatment of coccidioidomycosis. This article summarizes the key topics concerning drug development for coccidioidomycosis presented by speakers and panelists during the workshop, such as unmet need, trial designs, endpoints, incentives, research and development support, and collaborations to facilitate antifungal drug development.

Δcps1 vaccine protects dogs against experimentally induced coccidioidomycosis.

Coccidioidomycosis is a significant health problem of dogs and humans in endemic regions, especially California and Arizona in the U.S. Both species would greatly benefit from a vaccine to prevent this disease. A live avirulent vaccine candidate, Δcps1, was tested for tolerability and efficacy to prevent pulmonary coccidioidomycosis in a canine challenge model. Vaccine injection-site reactions were transient and there were no systemic effects observed. Six of seven vaccine sites tested and all draining lymph nodes were sterile post-vaccination. Following infection with Coccidioides posadasii, strain Silveira, arthroconidia into the lungs, dogs given primary and booster vaccinations had significantly reduced lung fungal burdens (P = 0.0003) and composite disease scores (P = 0.0002) compared to unvaccinated dogs. Dogs vaccinated once had fungal burdens intermediate between those given two doses or none, but disease scores were not significantly different from unvaccinated (P = 0.675). Δcps1 was well-tolerated in the dogs and it afforded a high level of protection when given as prime and boost. These results drive the Δcps1 vaccine toward a licensed veterinary vaccine and support continued development of this vaccine to prevent coccidioidomycosis in humans.

Demonstration of N,N-Dimethyldithiocarbamate as a Copper-Dependent Antibiotic against Multiple Upper Respiratory Tract Pathogens.

Transition metals are necessary cofactors and structural elements in living systems. Exposure to high concentrations of biologically important transition metals, such as zinc and copper, results in cell toxicity. At the infection site, the immune system deploys metal sorbent proteins (e.g., lactoferrin and calprotectin) to starve pathogens of necessary metals (such as iron), while phagocytes expose engulfed pathogens to high levels of other metals, such as copper and zinc. The opportunistic pathogen Streptococcus pneumoniae (the pneumococcus) encounters macrophages during initial and protracted infections. The pneumococcus employs a copper export pathway, which improves colonization and persistent infection of the nasopharynx and the upper respiratory tract. Because copper is tightly regulated in the host, we instead sought to leverage the localized power of nutritional immunity by identifying small molecules with copper-dependent toxicity (CDT) through a targeted screen of compounds for antibiotic efficacy. We chose to include dithiocarbamates, based on the copper synergy observed in other organisms with 1-(diethylthiocarbamoyldisulfanyl)-N,N-diethyl-methanethioamide (tetraethylthiuram disulfide, disulfiram). We observed CDT of some dithiocarbamates in S. pneumoniae. Only N,N-dimethyldithiocarbamate (DMDC) was consistently toxic across a range of concentrations with copper both in vitro and in vivo against the pneumococcus. We also observed various degrees of CDT in vitro using DMDC in Staphylococcus aureus, Coccidioides posadasii, and Schistosoma mansoni. Collectively, we demonstrate that the compound DMDC is a potent bactericidal compound against S. pneumoniae with antimicrobial efficacy against bacterial and fungal pathogens. IMPORTANCE With the rise of antibiotic resistance, approaches that add new antimicrobials to the current repertoire are vital. Here, we investigate putative and known copper ionophores in an attempt to intoxicate bacteria and use ionophore/copper synergy, and we ultimately find success with N,N-dimethyldithiocarbamate (DMDC). We show that DMDC has in vitro efficacy in a copper-dependent manner and kills pathogens across three different kingdoms, Streptococcus pneumoniae, Coccidioides posadasii, and Schistosoma mansoni, and in vivo efficacy against S. pneumoniae. As such, dithiocarbamates represent a new potential class of antimicrobials and thus warrant further mechanistic investigation.

Clinical and Economic Burden of Valley Fever in Arizona: An Incidence-Based Cost-of-Illness Analysis.

BACKGROUND: Coccidioidomycosis, ie, Valley fever, is an important fungal infection in the Southwest, with half to two thirds of all cases occurring in Arizona. This endemic respiratory disease can range from primary uncomplicated pneumonia to disseminated infection such as meningitis with chronic pulmonary complications. Valley fever diagnoses have risen over recent years and cause substantial morbidity and economic burden in Arizona. METHODS: We estimated the lifetime cost-of-illness associated with all cases of Valley fever diagnosed in 2019 in Arizona. Natural history of the disease was determined from literature and expert opinion and assigned costs from national data sources to determine lifetime direct and indirect costs (work loss). RESULTS: Total lifetime costs of $736 million were estimated for the 10 359 cases of Valley fever diagnosed in Arizona in 2019. Direct costs of $671 million accounted for over 90% of expenditures, with $65 million in indirect costs. Disseminated infection produces the highest economic burden at $1.26 million direct and $137 400 indirect costs per person. The lowest Valley fever lifetime costs were for cases of primary uncomplicated pneumonia with $23 200 in direct costs and $1300 in lost wages. The average lifetime direct costs across all Valley fever manifestations are $64 800 per person diagnosed in Arizona in 2019 and $6300 for indirect costs. CONCLUSIONS: Valley fever is responsible for substantial economic burden in Arizona. Our estimates underscore the value of supporting research into developing more rapid diagnostic tests, better therapies, and ultimately a preventative vaccine to address this important public health problem in Arizona.

TNFα Blockade Inhibits Both Initial and Continued Control of Pulmonary Coccidioides.

Tumor necrosis factor alpha (TNFα) is a pluripotent cytokine that is important in many infections, though its role in Coccidioides infection remains poorly understood. The need to understand TNFα in Coccidioides infection has increased recently with the widespread use of TNFα inhibitors for a wide variety of autoimmune conditions. Here, we couple the newly developed Coccidioides infection model using strain Cp1038 and C57BL/6 × DBA/2J F1 (B6D2F1) mice. B6D2F1 mice develop long-lasting control of Cp1038. Treatment of B6D2F1 mice with anti-TNFα antibodies permits significant fungal proliferation and death. Additionally, we show that antibody treatment limited to the first 2 weeks of infection was sufficient to induce this same loss of fungal control. Importantly, anti-TNFα antibody treatment initiated after fungal control leads to a loss of host control. These results highlight the importance of TNFα in both the initial control of murine Coccidioides and ongoing suppression of the fungal disease.

Vaccine Protection of Mice With Primary Immunodeficiencies Against Disseminated Coccidioidomycosis.

Disseminated coccidioidomycosis (DCM), often a severe and refractory disease leading to poor outcomes, is a risk for people with certain primary immunodeficiencies (PID). Several DCM-associated PID (STAT4, STAT3, IFNγ, and Dectin-1) are modeled in mice. To determine if vaccination could provide these mice protection, mice with mutations in Stat4, Stat3, Ifngr1, Clec7a (Dectin-1), and Rag-1 (T- and B-cell deficient) knockout (KO) mice were vaccinated with the live, avirulent, Δcps1 vaccine strain and subsequently challenged intranasally with pathogenic Coccidioides posadasii Silveira strain. Two weeks post-infection, vaccinated mice of all strains except Rag-1 KO had significantly reduced lung and spleen fungal burdens (p<0.05) compared to unvaccinated control mice. Splenic dissemination was prevented in most vaccinated immunodeficient mice while all unvaccinated B6 mice and the Rag-1 KO mice displayed disseminated disease. The mitigation of DCM by Δcps1 vaccination in these mice suggests that it could also benefit humans with immunogenetic risks of severe disease.