Donor-derived endemic mycoses after solid organ transplantation: A review of reported cases.

BACKGROUND: Donor-derived endemic mycoses are infrequently reported. We summarized the clinical characteristics and outcomes of these infections to provide guidance to transplant clinicians. METHODS: Multiple databases were reviewed from inception through May 31, 2023 using endemic fungi as key words (e.g., Coccidioides, histoplasma, blastomyces, talaromyces, paracoccidioides). Only donor-derived infections (DDI) were included. RESULTS: Twenty-four cases of DDI were identified from 18 published reports; these included 16 coccidioidomycosis, seven histoplasmosis, and one talaromycosis. No cases of blastomycosis and paracoccidiodomycosis were published. The majority were male (17/24,70.8%). Half of the cases were probable (12/24, 50%), seven were possible (29.2%), and only five were proven DDI (20.8%). Donor-derived coccidioidomycosis were observed in kidney (n = 11), lung (n = 6), liver (n = 3), heart (n = 2) and combined SOT recipients (1 KP, 1 KL) at a median time of .9 (range .2-35) months after transplantation. For histoplasmosis, the majority were kidney recipients (6 of 7 cases) at a median onset of 8 (range .4-48) months after transplantation. The single reported possible donor-derived talaromycosis occurred in a man whose organ donor had at-risk travel to Southeast Asia. Collectively, the majority of donors had high-risk exposure to Coccidioides (9/11) or Histoplasma sp. (6/6). Most donor-derived endemic mycoses were disseminated (18/24, 75%), and mortality was reported in almost half of recipients (11/24, 45.8%). CONCLUSION: Donor-derived endemic mycoses are often disseminated and are associated with high mortality. A detailed evaluation of donors for the potential of an undiagnosed fungal infection prior to organ donation is essential to mitigate the risk of these devastating infections.

Coccidioides undetected in soils from agricultural land and uncorrelated with time or the greater soil fungal community on undeveloped land.

Coccidioidomycosis is a typically respiratory fungal disease that, in the United States, occurs primarily in Arizona and California. In California, most coccidioidomycosis cases occur in the San Joaquin Valley, a primarily agricultural region where the disease poses a risk for outdoor workers. We collected 710 soil samples and 265 settled dust samples from nine sites in the San Joaquin Valley and examined how Coccidioides detection varied by month, site, and the presence and abundance of other fungal species. We detected Coccidioides in 89 of 238 (37.4%) rodent burrow soil samples at five undeveloped sites and were unable to detect Coccidioides in any of 472 surface and subsurface soil samples at four agricultural sites. In what is the largest sampling effort undertaken on agricultural land, our results provide no evidence that agricultural soils in the San Joaquin Valley harbor Coccidioides. We found no clear association between Coccidioides and the greater soil fungal community, but we identified 19 fungal indicator species that were significantly associated with Coccidioides detection in burrows. We also did not find a seasonal pattern in Coccidioides detection in the rodent burrow soils we sampled. These findings suggest both the presence of a spore bank and that coccidioidomycosis incidence may be more strongly associated with Coccidioides dispersal than Coccidioides growth. Finally, we were able to detect Coccidioides in only five of our 265 near-surface settled dust samples, one from agricultural land, where Coccidioides was undetected in soils, and four from undeveloped land, where Coccidioides was common in the rodent burrow soils we sampled. Our ability to detect Coccidioides in few settled dust samples indicates that improved methods are likely needed moving forward, though raises questions regarding aerial dispersal in Coccidioides, whose key transmission event likely occurs over short distances in rodent burrows from soil to naïve rodent lungs.

Coccidioidomycosis Seroincidence and Risk among Military Personnel, Naval Air Station Lemoore, San Joaquin Valley, California, USA1.

We conducted a retrospective cohort study that tested 2,000 US military personnel for Coccidioides antibodies in a disease-endemic region. The overall incidence of seroconversion was 0.5 cases/100 person-years; 12.5% of persons who seroconverted had illnesses requiring medical care. No significant association was found between demographic characteristics and seroconversion or disease.

Universal Lifelong Fungal Prophylaxis and Risk of Coccidioidomycosis in Lung Transplant Recipients Living in an Endemic Area.

BACKGROUND: Lung transplant recipients residing in the endemic region are vulnerable to severe morbidity and mortality from Coccidioides. As infection risk persists beyond the first posttransplant year, investigations evaluating extended prophylaxis durations are needed. The purpose of this study is to assess the incidence of coccidioidomycosis among lung transplant recipients receiving universal lifelong azole antifungal prophylaxis. METHODS: Patients receiving transplants from 2013-2018 and initiated on azole antifungal prophylaxis at a lung transplant center in Arizona were included and followed through 2019 or until death, second transplant, or loss to follow-up. Recipients who died or received treatment for coccidioidomycosis during the transplant admission, or who had received a previous transplant, were excluded. The primary outcome was proven or probable coccidioidomycosis with new asymptomatic seropositivity assessed secondarily. RESULTS: A total of 493 lung transplant recipients were included, with 82% initiated on itraconazole prophylaxis, 9.3% on voriconazole, and 8.5% on posaconazole. Mean age at transplant was 62 years, 77% were diabetic, and 8% were seropositive for Coccidioides pretransplant. After a median follow-up of 31 months, 1 proven infection and 1 case of new asymptomatic seropositivity (1/493 each, 0.2% incidence) occurred during the study period. The single coccidioidomycosis case occurred 5 years posttransplant in a patient who had azole prophylaxis stopped several months prior. Although within-class switches were common throughout the study period, permanent discontinuation of azole prophylaxis was rare (1.4% at end of follow-up). CONCLUSIONS: Universal lifelong azole prophylaxis was associated with a low rate of coccidioidomycosis among lung transplant recipients residing in endemic regions.

Coccidioidomycosis in patients with various inflammatory disorders treated with tumor necrosis factor α inhibitors.

Coccidioides fungi are found primarily in the southwestern United States and are the cause of coccidioidomycosis. Tumor necrosis factor α inhibitors (TNFIs) are therapies for autoimmune and inflammatory conditions; their association with coccidioidomycosis is not well characterized. We aimed to determine the prevalence and characteristics of coccidioidomycosis among TNFI recipients with different inflammatory disorders at a tertiary care center. We retrospectively reviewed the electronic health records of patients at our institution from April 4, 2010 to December 17, 2017, who received TNFIs (infliximab, etanercept, adalimumab, certolizumab pegol, or golimumab) and had positive culture, pathologic, and/or serologic results for coccidioidomycosis. Among 1770 patients identified who received TNFIs, 49 (2.8%) had proven or probable coccidioidomycosis. Of these 49, 28 (57%) were men, 47 (96%) were White, and 42 (86%) had pulmonary coccidioidomycosis. The most common TNFIs used were adalimumab, infliximab, and etanercept. Coccidioidomycosis was identified in 25 of 794 patients with rheumatologic disorders (3.1%), 18 of 783 patients with inflammatory bowel disease (IBD) (2.3%), and six of 193 patients with dermatologic disorders (3.1%) (P = .34). There was no difference in coccidioidal infections among recipients of any particular TNFI agents. A minority of patients (7/49, 14%) had an extrapulmonary infection, and the majority of these (6/7) had IBD. Our study shows a low prevalence of coccidioidomycosis in TNFI recipients, even within the Coccidioides-endemic area. Persons with IBD were disproportionately represented among those with extrapulmonary coccidioidomycosis. Treatment with azoles was effective. LAY SUMMARY: Among 1770 patients who received tumor necrosis factor α inhibitors, 49 (2.8%) had newly acquired coccidioidomycosis over a 7-year period. Dissemination occurred in 14.3%, but disproportionately among those with underlying inflammatory bowel disease. All patients recovered with medical management.

Interleukin-8 Receptor 2 (IL-8R2)-Deficient Mice Are More Resistant to Pulmonary Coccidioidomycosis than Control Mice.

The pathology of human coccidioidomycosis is granulomatous inflammation with many neutrophils surrounding ruptured spherules, but the chemotactic pathways that draw neutrophils into the infected tissues are not known. We previously showed that formalin-killed spherules (FKS) stimulate mouse macrophages to secret macrophage inflammatory protein 2 (MIP-2), which suggested that CXC ELR+ chemokines might be involved in neutrophil recruitment in vivo To test that hypothesis, we intranasally infected interleukin-8R2 (IL-8R2) (Cxcr2)-deficient mice on a BALB/c background with Coccidioides immitis RS. IL-8R2-deficient mice had fewer neutrophils in infected lungs than controls, but unexpectedly the IL-8R2-deficient mice had fewer organisms in their lungs than the control mice. Infected IL-8R2-deficient mouse lungs had higher expression of genes associated with lymphocyte activation, including the Th1 and Th17-related cytokines Ifnγ and Il17a and the transcription factors Stat1 and Rorc Additionally, bronchial alveolar lavage fluid from infected IL-8R2-deficient mice contained more IL-17A and interferon-γ (IFN-γ). We postulate that neutrophils in the lung directly or indirectly interfere with the development of a protective Th1/Th17 immune response to C. immitis at the site of infection.

Coccidioidomycosis (Valley Fever) in Primary Care.

Primary pulmonary coccidioidomycosis (valley fever) is caused by inhaling airborne spores of the fungus Coccidioides immitis or Coccidioides posadasii. Residing in or traveling to areas endemic for Coccidioides is required for the diagnosis; no person-to-person or zoonotic contagion occurs. The incidence of coccidioidomycosis is increasing in endemic areas, and it has been identified as the cause of as many as 17% to 29% of all cases of community-acquired pneumonia in some regions. Obtaining a travel history is recommended when evaluating patients with community-acquired pneumonia. Diagnosis usually relies on enzyme immunoassay with immunodiffusion confirmation, but these tests may not be positive for one to three weeks after disease onset. Antifungal agents are not recommended for treatment unless the patient is at risk of or shows signs of complicated or disseminated infection. When antifungals are used, fluconazole and itraconazole are most commonly recommended, except during pregnancy. Treatment may continue for as long as three to 12 months, although lifetime treatment is indicated for patients with coccidioidal meningitis. Monitoring of complement fixation titers and chest radiography is recommended until patients stabilize and symptoms resolve. In patients who are treated with antifungals, complement fixation titers should be followed for at least two years.

A Review of Coccidioidomycosis in California: Exploring the Intersection of Land Use, Population Movement, and Climate Change.

California has seen a surge in coccidioidomycosis (valley fever), a disease spread by the Coccidioides immitis fungus found in soil throughout the state, particularly in the San Joaquin Valley. We reviewed epidemiologic studies in which outbreak and sporadic cases of coccidioidomycosis were examined, and we considered the possible relationship of these cases to environmental conditions, particularly the state's increasing aridity, drought, and wildfire conditions. Most of the studies we reviewed pertained to cases occupationally acquired in construction, military, archeological, and correctional institutional settings where workers were exposed to dust in C. immitis-endemic areas. A few reviewed outbreaks in the general population related to dust exposure from natural disasters, including an earthquake-associated landslide and a dust storm that carried particles long distances from endemic areas. Although many of California's coccidioidomycosis outbreaks have been occupationally related, changing demographics and new, immunologically naïve populations in dry, endemic areas could expose the general population to C. immitis spores. Given the high rate of infection among workers who, for the most part, are healthy, the general population, including some elderly and immunocompromised individuals, could face additional risk. With climate-related events like drought and wildfires also increasing in endemic areas, research is needed to address the possible associations between these phenomena and coccidioidomycosis outbreaks.

Concomitant Central Nervous System Toxoplasmosis and Seronegative Disseminated Coccidioidomycosis in a Newly Diagnosed Acquired Immune Deficiency Syndrome Patient.

Opportunistic infections (OIs) are a significant cause of morbidity and mortality in immunosuppressed patients and may be due to bacteria, virus, protozoa, or fungi. Toxoplasmosis is a common cause of central nervous system infection in human immunodeficiency virus (HIV) patients. Coccidioidomycosis is a relatively common fungal infection that may lead to disseminated disease and fungemia in immune-compromised hosts living in endemic regions. This single-patient case report documents the presentation, diagnosis, management, and outcome of concomitant central nervous system toxoplasmosis and diffuse miliary pneumonia with fungemia due to disseminated seronegative Coccidioides immitis in a 33-year-old male patient recently diagnosed with chronic advanced HIV. Impaired cellular immune function, such as defects in the IL-12/IFN-γ pathway or T-helper IL-17-mediated response, is associated with increased severity of coccidioidomycosis. Fungemia and acute respiratory distress syndrome are both associated with very high mortality in coccidioidomycosis. In HIV hosts, negative Coccidioides serology can be seen in up to 25% of cases and therefore other diagnostic modalities should be initiated promptly and simultaneously. This case demonstrates simultaneous OI in the setting of advanced acquired immune deficiency syndrome and emphasizes the need for early diagnosis of HIV and OI in order to ensure prompt initiation of antiretroviral therapy, prophylactic, and therapeutic medications.

Coccidioidomycosis in solid organ transplant recipients.

PURPOSE OF REVIEW: The purpose of the review is an update of diagnosis and treatment of coccidioidomycosis infection in solid organ transplant (SOT) patients. Endemic fungal infections continue to be a cause of serious morbidity and mortality in transplant recipients. RECENT FINDINGS: In transplant patients there are recommendations regarding screening in areas that are endemic for coccidioidomycosis. This screening involves serologic testing and chest imaging. In endemic areas pretransplant seropositivity varies from 1.4 to 5.6%. In immunocompromised patients with elevated complement fixation titers, evaluation of cerebrospinal fluid is recommended even in the absence of symptoms. Although coccidioidomycosis can be a self-limited disease in immunocompotent patients, all SOT patients should be treated regardless of severity. This may include intravenous amphotericin B in severe cases and fluconazole therapy in milder episodes. In those SOT recipients with evidence of prior coccidioidomycosis, lifelong secondary prophylaxis with fluconazole given risk of recurrent disease. SUMMARY: Coccidioidomycosis continues to be a cause of serious morbidity and mortality in transplant recipients but with proper screening and treatment can be successfully managed.

The Utility of Screening for Coccidioidomycosis in Recipients of Inhibitors of Tumor Necrosis Factor α.

BACKGROUND: Tumor necrosis factor α inhibitors (TNFi) are commonly used to treat immune-mediated disorders, but they are associated with an increased risk of mycobacterial and fungal infections. We compared the outcomes of TNFi recipients screened for asymptomatic coccidioidomycosis with those of unscreened patients to compare the development of symptomatic coccidioidomycosis and to describe its outcomes for patients with abnormal coccidioidal screenings. METHODS: We searched electronic health records from 4 September 2010 through 26 September 2016 for all patients receiving a TNFi for dermatologic, rheumatologic, or gastroenterologic diagnoses, then categorized patients by whether or not they had undergone coccidioidal serologic testing for screening or diagnostic purposes. RESULTS: A total of 2793 patients had a TNFi prescribed. Of those, 1951 met the inclusion criteria: 1025/1951 (52.5%) never had coccidioidal screening; 925/1951 (47.4%) had serologic screening either before beginning TNFi therapy or annually, or both after beginning a TNFi. Symptomatic coccidioidomycosis developed in 35/1025 (3.4%) unscreened patients. Of those screened, 861/925 (93.1%) had negative serologic tests, of which 11/861 (1.3%) subsequently developed symptomatic coccidioidomycosis; 36/925 (3.9%) had coccidioidomycosis at screening (7, probable infection; 11, possible infection; 18, asymptomatic seropositive result); and 17 had only positive findings for immunoglobulin M antibodies and did not meet the definition for coccidioidomycosis. The unscreened cohort was more likely to have symptomatic coccidioidomycosis than the screened cohort (35/1025 vs 11/861, P < .01). CONCLUSIONS: Screening for asymptomatic coccidioidomycosis within a Coccidioides-endemic area allowed for identifying and managing asymptomatic coccidioidomycosis before patients began TNFi therapy. Less symptomatic infection developed in the screened than the unscreened cohort.

Occupational Coccidioidomycosis in a heavy equipment operator.

This article describes a case of Coccidioidomycosis pneumonia in an individual who worked in the McKittrick Oil Field, Kern County, California, for 15 days during an approximate 1-month period in 2016. Coccidioidomycosis is caused by inhaling spores of Coccidioides immitis (C. immitis), a soil fungus endemic in regions of California, most notably the San Joaquin Valley. In California, Kern County has the highest incidence rate of Coccidioidomycosis, and the McKittrick Oil Field lies within the most highly endemic part of Kern County. The affected individual, who resided in a nonendemic state, traveled to Kern County to operate heavy equipment and also perform some laborer tasks. He experienced substantial exposure to soil dust without wearing adequate respiratory protection. Consideration of the relative amounts of soil dust exposure due to the individual's oil field work vs. ambient air permits a conclusion that his infection was work-related. In addition to respiratory protection, some measures needed to reduce soil dust exposure during construction work in areas endemic for C. immitis are discussed.

A point-source outbreak of Coccidioidomycosis among a highway construction crew.

Coccidioidomycosis is an infection caused by inhaling spores of the soil fungus Coccidioides immitis (hereafter termed Cocci). Cocci is endemic in certain areas of California. When soil containing the fungus is disturbed, as during earth-moving activities, respirable Cocci spores can become airborne and be inhaled by persons in the vicinity. This article describes a cluster of seven Cocciodioidomycosis cases among a highway construction crew that occurred in June/July 2008 in Kern County, CA, which is among the most highly endemic regions for Cocci in California. The exposures spanned no more than seven work days, and illness developed within two to three weeks of the exposures. Given the common source of exposure (soil dust generated at the work site) and the multiple cases occurring close in time, the cluster can also be termed a "point-source outbreak." The contractor was not informed of the infection risk and did not take adequate precautions against dust exposure. Appropriate engineering/administrative controls and respiratory protection are discussed.

Immune Reconstitution Inflammatory Syndrome in Patients with AIDS and Disseminated Coccidioidomycosis: A Case Series and Review of the Literature.

Coccidioidomycosis causes substantial morbidity and mortality in endemic areas, and dissemination is frequent in patients with impaired cellular immunity such as AIDS. Immune reconstitution inflammatory syndrome (IRIS) is paradoxical clinical worsening after initiation of antiretroviral therapy (ART) in a patient with HIV and a simultaneous opportunistic infection (OI). Immune reconstitution inflammatory syndrome has been well described for a host of mycobacterial, viral, and fungal OIs and malignancies such as Kaposi sarcoma. To date, only 3 cases of IRIS due to coccidioidomycosis have been reported in the literature. At our institution, we report 4 cases of IRIS in HIV-infected patients with disseminated coccidioidomycosis. Unfortunately, all 4 patients died of worsening coccidioidal infection after initiating ART. The optimal timing of ART in patients with AIDS and coccidioidomycosis remains to be elucidated.

Coccidioidomycosis among persons undergoing lung transplantation in the coccidioidal endemic region.

BACKGROUND: Coccidioidomycosis, an endemic fungal infection, is more likely to be symptomatic and severe among those receiving allogeneic transplants. While several case series have been published for various transplanted organs, none has described the incidence and outcomes in those receiving lung transplants within the coccidioidal endemic region. METHODS: Patients receiving a heart-lung, single-lung, or bilateral-lung transplantation at the University of Arizona between 1985 and 2009 were retrospectively reviewed. RESULTS: Coccidioidomycosis occurred post transplantation in 11 (5.8%) of 189 patients. All but one patient was diagnosed with pulmonary coccidioidomycosis and only one had a history of prior coccidioidomycosis. Two patients received transplants from donors found to have coccidioidomycosis at the time of transplantation and one death was directly attributed to coccidioidomycosis. The risk of developing active coccidioidomycosis was significantly higher if the patient did not receive some type of antifungal therapy post transplantation (P<.001). CONCLUSION: Within the coccidioidal endemic region, post-transplantation coccidioidomycosis was a definable risk among lung transplant recipients. Use of antifungals appeared to reduce this incidence of disease. Almost all cases resulted in pulmonary disease, suggesting that the lung is the primary site of infection.

Risk Factors for Disseminated Coccidioidomycosis, United States.

Of 150,000 new coccidioidomycosis infections that occur annually in the United States, ≈1% disseminate; one third of those cases are fatal. Immunocompromised hosts have higher rates of dissemination. We identified 8 patients with disseminated coccidioidomycosis who had defects in the interleukin-12/interferon-γ and STAT3 axes, indicating that these are critical host defense pathways.

Clinicopathologic and Histopathologic Renal Abnormalities in Dogs with Coccidioidomycosis.

BACKGROUND: We observed evidence of protein-losing nephropathy in some dogs with coccidioidomycosis, suggestive of immune complex glomerulonephritis (ICGN). The goal of this study was to understand the prevalence of renal histopathologic lesions and proteinuria in dogs with coccidioidomycosis. HYPOTHESIS: Biochemical and histopathological evidence of glomerular lesions is present in dogs with coccidioidomycosis. ANIMALS: Hundred and fifty-six dogs with naturally occurring coccidioidomycosis. METHODS: Retrospective case series. Clinical information and results of clinicopathologic testing were retrieved from the University of California, Davis Veterinary Medical Teaching Hospital (VMTH). Microscopic sections of renal tissue procured from necropsy of dogs with coccidioidomycosis were examined to evaluate the nature and distribution of lesions. RESULTS: A total of 156 dogs with coccidioidomycosis were identified; 87 dogs had serum biochemistry and a urinalysis performed, 17 had urine protein:creatinine ratios (UPCs), and 24 had renal tissue available for histopathology. Eleven (13%) of the 87 dogs were azotemic, 55 (63%) were proteinuric (of which 14 [25%] had clinically relevant proteinuria defined as ≥3+ or ≥500 mg/dL), and 14 dogs had UPC ≥0.5 (range, 0.5-21.5, median 4.2). Thirteen (54%) of 24 dogs had renal histopathologic lesions suggestive of ICGN. Seven of these dogs had urinalyses performed; 5 (71%) had clinically relevant proteinuria as described above. Two dogs (33%) with normal glomeruli had granulomatous nephritis, 1 of which had intralesional Coccidioides spherules. CONCLUSIONS AND CLINICAL IMPORTANCE: Coccidioidomycosis should be considered as a possible contributor to glomerular disease in dogs. Whether similar lesions occur in other mammalian hosts, including humans, warrants further investigation.

Coccidioidomycosis Transmission Through Organ Transplantation: A Report of the OPTN Ad Hoc Disease Transmission Advisory Committee.

Donor-derived coccidioidomycosis has caused unexpected morbidity and mortality in transplant recipients. All proven or probable reports of donor-derived coccidioidomycosis to the Disease Transmission Advisory Committee between 2005 and August 2012 were reviewed. Six reports of proven or probable coccidioidomycosis were discovered. In four of six, the infection was first detected at autopsy in the recipient. In two cases it was first identified in the donor. Twenty-one recipients received organs from these six donors. Transmission occurred in 43% at a median of 30 days posttransplant with a mortality rate of 28.5%. Eleven recipients received preemptive antifungals, seven did not receive treatment, and treatment information was not reported for three recipients. Five of seven who did not receive prophylaxis/treatment died and all 11 who received early therapy survived. Six deaths occurred 14 to 55 days after transplant, with a median of 21 days. For exposed recipients, donor-derived coccidioidomycosis is a significant cause of morbidity and mortality. Evidence of infection in one recipient should prompt immediate evaluation for treatment of all other recipients from the same donor as preemptive treatment was effective. Further studies are needed to decide whether all donors from endemic areas should have routine serologic screening.