SEARCH

SEARCH BY CITATION

Keywords:

  • Coccidioidomycosis;
  • fungal infection;
  • immunocompromised patient;
  • infection;
  • liver transplantation

Abstract

  1. Top of page
  2. Abstract
  3. Background
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. References

Coccidioidomycosis is an infection caused by Coccidioides species, which are endemic for the Southwestern United States and parts of Central America and South America. Most infected individuals are asymptomatic or have mild-to-moderate respiratory illness. Coccidioidomycosis is more severe in patients with depressed cellular immunity, such as organ transplant recipients. We retrospectively reviewed charts of 391 liver transplant recipients (mean follow-up, 38.7 months; range, 2–105 months). Before transplantation, 12 patients had a history of coccidioidomycosis and 13 patients had asymptomatic seropositivity. Of these 25 patients, 23 had no active coccidioidomycosis posttransplantation and 2 had reactivated infection. One of 5 patients with indeterminate serology before transplantation died of disseminated coccidioidomycosis shortly after transplantation. De novo coccidioidomycosis developed in 12 patients (3%) who had no evidence of coccidioidomycosis pretransplantation. Of 15 total episodes of posttransplantation coccidioidomycosis, 10 (66%) occurred during the first year. Dissemination was noted in 33% of active coccidioidomycosis after transplantation; two patients (13%) died of coccidioidomycosis. Because most coccidioidal infections occurred in the first posttransplantation year despite targeted antifungal prophylaxis, we recommend a new strategy of universal antifungal prophylaxis for 6–12 months for liver transplant recipients who reside in the endemic area.


Abbreviations: 
EIA

enzyme immunoassay

IgM

immunoglobulin M

MMF

mycophenolate mofetil

Background

  1. Top of page
  2. Abstract
  3. Background
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. References

Coccidioidomycosis is caused by dimorphic fungi of Coccidioides species, which are endemic in certain parts of Southwestern United States, Northern Mexico, Central America and South America. Extrapulmonary infection occurs in 1–5% of individuals with known coccidioidomycosis (1–3). Immunosuppressed patients, such as patients with human immunodeficiency viral infection, solid organ transplant recipients and patients treated with corticosteroids or tumor necrosis factor antagonists, are at increased risk for coccidioidomycosis and severe or disseminated disease (4–6).

In the endemic area of the Southwestern United States, the incidence of coccidioidomycosis in solid organ transplant recipients ranges from 1.4% to 6.9% (7–11). Identified risk factors for active coccidioidomycosis in this patient population include a pretransplantation history of coccidioidomycosis, serologic findings positive for coccidioidomycosis at transplantation and use of high-dose corticosteroids for treatment of acute cellular rejection (12). Some reports have suggested that targeted antifungal prophylaxis in solid organ transplant recipients may decrease the incidence of coccidioidomycosis (7,12,13). Several cases of donor-related transmission of coccidioidomycosis have been documented (12,14–16).

The aim of this study was to update previous observations regarding coccidioidomycosis that we had reported early in the experience of the solid organ transplantation program at our institution (7). Specifically, we sought to determine the incidence of coccidioidomycosis among liver transplant recipients, to assess the efficacy of current prophylaxis and treatment regimens and to identify potential risk factors of coccidioidal infection after liver transplantation.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Background
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. References

Chart review

A retrospective review of medical records was performed for all patients who underwent orthotopic liver transplantation at Mayo Clinic in Arizona between June 6, 1999 and December 2, 2007. Patients who did not survive the surgery were excluded from the review. We recorded details of the transplantation, comorbid conditions, coccidioidal infection (if applicable) (e.g. date of infection; history of coccidioidomycosis; symptoms; extent and outcome of the infection; serologic, microbiologic, histopathologic and radiographic findings), other infections, immunosuppressive treatment, rejection of the organ and outcome of the patient. The Mayo Clinic Institutional Review Board approved our study.

Definitions

We defined the following terms for consistency throughout our study:

  • (i) 
    Confirmed coccidioidomycosis: a case in which either biopsied material showed Coccidioides spherules in direct examination or cultures of clinical specimens grew Coccidioides species.
  • (ii) 
    Highly probable coccidioidomycosis: a case with positive serologic findings, symptoms typical of coccidioidomycosis and radiographic findings (such as, but not limited to, infiltrates, masses, nodules and cavities) characteristic of coccidioidal infection.
  • (iii) 
    Probable coccidioidomycosis: a case with positive serologic findings and either symptoms or a radiographic finding, but not both, characteristic of coccidioidal infection.
  • (iv) 
    Asymptomatic positive serology: a case with positive serologic findings but normal results on radiographic study and no identifiable illness.
  • (v) 
    Disseminated coccidioidomycosis: a case with a biopsy- or culture-proven extrapulmonary site or the presence of miliary pattern on the chest radiograph.
  • (vi) 
    Coccidioidomycosis before transplantation: a case of a diagnosis of coccidioidomycosis made by a medical practitioner and supported by a description of a compatible illness that included 1 or more typical symptoms (e.g. fever, chills, sweats, respiratory symptoms, headache, rash, myalgias, arthralgias and fatigue) and typical findings on laboratory (positive results on serology, microbiology or histopathology) and radiographic (e.g. chest radiographs, computed tomographic scans) studies. This category did not include patients who did not have a formal diagnosis made by a medical professional.

Coccidioidal serology

Patients were routinely screened with serologic testing for coccidioidomycosis, with numerous simultaneous methods at the initial evaluation, on the day of transplantation, at 3 and 12 months posttransplantation, and annually thereafter. Studies are repeated as needed to evaluate symptoms.

Multiple methods were used for identifying coccidioidal antibodies, including enzyme immunoassay (EIA) for immunoglobulin M (IgM) and immunoglobulin G (Meridian Bioscience Test Kit; Meridian Bioscience, Inc., Cincinnati, OH, USA), immunodiffusion for IgM (Meridian Bioscience Test Kit; Meridian Bioscience, Inc.) and immunoglobulin G (Gibson Laboratories Test Kit; Gibson Laboratories, Lexington, KY, USA), and complement fixation test (antigen obtained from the Coccidioidomycosis Serology Laboratory at the School of Medicine, University of California, Davis, Davis, CA, USA). When results were indeterminate, tests were repeated; if necessary, samples were sent to the Coccidioidomycosis Serology Laboratory at the School of Medicine, University of California, Davis, for further clarification.

Coccidioidomycosis prophylaxis

The dose and duration of the coccidioidal prophylaxis after liver transplantation were based on the patient's pretransplantation history of coccidioidomycosis, the results of serologic testing, or the development of active infection posttransplantation, in accordance with previously published protocol (12). Patients with seronegative results who had no history of coccidioidomycosis before transplantation or who did not have coccidioidomycosis after transplantation did not receive coccidioidal prophylaxis. Patients with seronegative results who had a well-documented history of coccidioidomycosis of more than 1 year before transplantation received oral fluconazole (200 mg/day) for 6–12 months. Patients who had positive coccidioidal serologic results at transplantation or had either active infection in the 1 year before transplantation or after transplantation received lifelong prophylaxis of oral fluconazole (400 mg/day).

Noncoccidioidal, antifungal prophylaxis

Various (noncoccidioidal) antifungal prophylaxis regimens were used in the follow-up period, in part reflecting changes to protocol, type of transplantation procedure received, the presence or absence of biliary complications, or patient participation in studies. Nystatin was administered as part of the selective bowel decontamination study in participating patients (study period, September 1999–September 2000; n = 16). Fluconazole (200 mg/day) for 1 month was administered to patients who participated in a multicenter immunosuppression study (study period, November 2002–February 2004; n = 18) or patients who received a living donor organ in accordance with living donor protocol (June 2002–November 2007; n = 46). Patients whose transplantation course was complicated with a bile leak received fluconazole (200 or 400 mg/day), amphotericin B, liposomal amphotericin B, voriconazole or no prophylaxis, as determined on a case-by-case basis.

Pretransplantation evaluation

All liver transplant candidates underwent a multidisciplinary evaluation that included history taking, physical examination and laboratory and radiologic testing. All candidates were carefully interviewed and examined by an infectious-disease specialist, who looked for any history or presence of infection. All identified abnormalities were further evaluated and defined. For instance, any abnormality on chest radiograph (whether active or indeterminate) was further evaluated with chest computed tomography, bronchoscopy, biopsy or other studies and treated as appropriate.

Liver transplant immunosuppression

Standard immunosuppression for liver transplant recipients consisted of tacrolimus with intravenous methylprednisolone, followed by oral prednisone, the dose of which was tapered and discontinued within 4 months. For patients with a serum creatinine value of 2.0 or greater, mycophenolate mofetil (MMF) (1000 mg twice daily) was added to allow lower tacrolimus levels; this dosage was reduced to 500 mg twice daily to accommodate symptomatic intolerance or cytopenia found on a complete blood cell count. Patients with primary biliary cirrhosis and autoimmune hepatitis received low-dose prednisone (5 mg/day). Patients who were not able to tolerate this type of immunosuppression received cyclosporine or sirolimus as determined on a case-by-case basis.

From November 2001 to February 2004, 19 patients participated in a multicenter immunosuppression study in which patients were randomly assigned to receive tacrolimus plus prednisone (n = 4), tacrolimus plus prednisone plus MMF (n = 6) or tacrolimus plus MMF plus daclizumab (n = 9).

Graft rejection

Patients with biopsy-proven acute cellular rejection were treated with three doses of methylprednisolone sodium succinate (3 g total) or, occasionally, with an increase in the dose of immunosuppressive medications as decided on a case-by-case basis. To date, antilymphocyte or anti-IL-2 treatments have not been required.

Statistical analysis

We used simple descriptive statistics for analysis of the data obtained in the study. Fisher exact test was used to assess differences among proportions of various attributes of patients who did or did not have coccidioidomycosis.

Results

  1. Top of page
  2. Abstract
  3. Background
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. References

Between June 6, 1999 and December 2, 2007, 397 patients had liver transplantation performed at Mayo Clinic in Arizona. Of these patients, six died during the procedure and their records were excluded from our study. The average follow-up period after transplantation was 39 months (range, 2–105 months). Characteristics of the patient population are presented in Table 1.

Table 1.  Characteristics of the 391 patients in the study
CharacteristicValue1
  1. CMV = cytomegalovirus; ESLD = end-stage liver disease; MMF = mycophenolate mofetil.

  2. 1Data are presented as number and percentage of patients unless specified otherwise.

  3. 2Other races include Hispanic as self-reported (n = 50), Asian (n = 6), Asian Indian (n = 1) and Middle Eastern (n = 2).

  4. 3Autoimmune process includes primary sclerosing cholangitis (n = 16), primary biliary cirrhosis (n = 14) and autoimmune hepatitis (n = 14).

  5. 4Other causes of ESLD include hepatitis B infection (n = 11), cryptogenic cirrhosis (n = 28), nonalcoholic steatohepatosis (n = 13), hemochromatosis (n = 4), Budd-Chiari syndrome (n = 3), Wilson disease (n = 1), congenital cirrhosis (n = 1), familial amyloidosis (n = 2), fulminant hepatic failure (n = 4), α1-antitrypsin deficiency (n = 3), polycystic liver disease (n = 4), secondary sclerosing cholangitis (n = 2), epithelioid hemangioendothelioma (n = 2), primary hyperoxaluria (n = 2), Alagille syndrome (n = 1), metastatic tumor (n = 2) and vitamin A toxicity (n = 1).

  6. 5Corticosteroid-induced diabetes mellitus was defined as transient elevation of blood glucose levels posttransplantation that required insulin therapy. The condition resolved after corticosteroid therapy was discontinued or the dose decreased.

  7. 6Other types of induction immunosuppression included various combinations of prednisone, tacrolimus, MMF, cyclosporine or rapamune, as decided on a case-by-case basis.

  8. 7The treatment of rejection required only modification of oral immunosuppression.

  9. 8All patients requiring corticosteroid treatment for rejection received methylprednisolone sodium succinate at 1000 mg intravenously every other day for three doses.

Demographics
 Male sex269 (68.8)
 Female sex122 (31.2)
 Age, mean, median (years)51.8, 52.0
Race
 White307 (78.5)
 African American 8 (2.0)
 Native American17 (4.3)
 Other2 59 (15.1)
Etiology of ESLD
 Hepatitis C infection208 (53.2)
 Alcoholic liver disease 49 (12.5)
 Autoimmune process3 44 (11.3)
 Other4 84 (21.5)
 Multiple factors 6 (1.5)
Donor type
 Deceased donor314 (80.3)
 Living donor 77 (19.7)
Cancer history
 Hepatocellular carcinoma 98 (25.1)
 Other liver malignancy 6 (1.5)
 Nonliver solid organ malignancy21 (5.4)
 Hematologic malignancy 4 (1.0)
 Multiple11 (2.8)
Diabetes mellitus
 Pretransplantation105 (26.9)
 Posttransplantation 8 (2.0)
 Corticosteroid induced5115 (29.4)
Induction therapy
 Prednisone/tacrolimus231 (59.1)
 Prednisone/tacrolimus/MMF146 (37.3)
 Daclizumab/tacrolimus/MMF 9 (2.3)
 Other6 5 (1.3)
Rejection
 No rejection227 (70.8)
 Mild732 (8.2)
 Required corticosteroid therapy8 82 (21.0)
CMV status
 Mismatch 63 (16.1)
 Infection 67 (17.1)

Patients with coccidioidomycosis before transplantation

Twelve patients (3%) had a history of coccidioidomycosis before transplantation (Table 2). Of these 12 patients, 11 received posttransplantation coccidioidomycosis prophylaxis per protocol (12). The dosage of fluconazole prescribed for prophylaxis was from 100 to 400 mg daily; 6 of the 11 patients received 400 mg daily. The variability of dosage was due to medication intolerance, decreased renal function, interactions with other medications and noncompliance.

Table 2.  Summary of coccidioidal characteristics and outcomes in patients with coccidioidomycosis before transplantation
Characteristic or outcomeCoccidioidomycosis ≥2 years pretransplantation (n = 5)Coccidioidomycosis <2 years pretransplantation (n = 7)
  1. 1As defined by the presence of a 2.0-cm pulmonary nodule and a complement fixation titer of 1:128. At transplantation, a coccidioidal granuloma was noted on the serosal surface of the explanted liver. No other site of dissemination was identified (methods included bone scan, computed tomography of abdomen and pelvis and cerebrospinal fluid examination).

  2. 2100–200 mg orally daily.

  3. 3200–400 mg orally daily.

  4. 4Manifested by an enlarging pulmonary cavity after stopping prophylaxis, against medical advice (n = 1) and biopsy-proven coccidioidal peritonitis in the patient footnoted above1 (n = 1).

Active coccidioidomycosis at transplantation011
Pulmonary coccidioidomycosis56
Extrapulmonary coccidioidomycosis011
Serologic result with complement fixation,AllNonreactive, 1:128
 range (on day of transplantation)nonreactive(median, nonreactive)
Prophylaxis
 Fluconazole lifelong2253
 Fluconazole for 6–12 months220
 Stopped by patient against medical advice02
 None10
Chest radiograph at transplantation
 No abnormalities42
 Nodule
   ≤1 cm, uncalcified12
   ≤1 cm, calcified10
   >1 cm00
 Cavity03
 Infiltrate00
Coccidioidomycosis postransplantation
 None (seronegative, no symptoms)51
 Positive serologic results, no symptoms04
 Active024

Among these 12 patients, active coccidioidal infection after transplantation was present in 2 patients, both of whom received antifungal prophylaxis. One of the two patients had active coccidioidomycosis at the time of transplantation, manifested by a lung cavity and a complement fixation titer of 1:128. However, he had no clinically evident extrapulmonary infection. Because of his projected imminent demise from underlying cirrhosis and hepatocellular carcinoma, he undertook the transplantation procedure. At explantation, rare coccidioidal granuloma was seen in the liver; the recipient received 400 mg of fluconazole daily. Two and a half years after transplantation, while adherent to prophylaxis, he was found to have numerous, biopsy-proven coccidioidal granulomas throughout the peritoneum.

The other patient had a quiescent coccidioidal cavity at transplantation, but 4 years posttransplantation she stopped taking fluconazole prophylaxis, against medical advice. Several months later, her cavitary lung lesion had enlarged, and she subsequently restarted the antifungal regimen.

Patients with asymptomatic seropositivity at or before transplantation

Eighteen asymptomatic patients had positive (n = 13) or indeterminate (n = 5) coccidioidomycosis serologic results immediately before or on the day of transplantation. Seven (54%) of the 13 patients with seropositive results received azole prophylaxis per protocol (12). None of the 13 had active infection during the follow-up period.

None of the five patients with indeterminate serologic results before transplantation received anticoccidioidal prophylaxis. Four of these patients showed no signs of active infection; however, one patient who had indeterminate serologic results 1 month before transplantation died of overwhelming and disseminated coccidioidomycosis in the first month after transplantation.

Patients with newly diagnosed coccidioidomycosis after transplantation

Of the 391 transplant recipients, 12 (3%) were found to have either confirmed, highly probable, or probable de novo coccidioidomycosis posttransplantation (Table 3). Disseminated disease was observed in 3 (25%) of the 12 patients.

Table 3.  Patients with confirmed, highly probable or probable coccidioidomycosis posttransplantation and residing in an endemic area
CharacteristicInfection status, no. of patients
De novo Infection (n = 12)Reactivation (n = 2)Pretransplantation indeterminate serologic results (n = 1)
  1. 1Sites of dissemination included tendon (n = 1), skin (n = 1), liver (n = 1) and peritoneum (n = 1) and miliary pulmonary involvement (n = 1). No central nervous system coccidioidomycosis was identified in this cohort.

  2. 2The treatment of this patient was stopped because of symptom resolution and the return of serologic results to reference range in the clinical setting of adverse effects due to fluconazole.

  3. 3Patient stopped antifungal therapy against medical advice and his pulmonary cavitation enlarged, after which the medication was resumed with adequate disease control.

  4. 4One patient had indeterminate enzyme immunoassay results for immunoglobulin M and no symptoms, so he received no treatment. The patient subsequently died of disseminated coccidioidomycosis. A second patient never had positive coccidioidal serologic results. The patient died secondary to severe necrotizing pneumonia caused by Pseudomonas species, methicillin-resistant Staphylococcus aureus, Aspergillus species and Coccidioides species.

  5. 5Patient died of severe necrotizing pneumonia caused by Pseudomonas species, methicillin-resistant S aureus, Aspergillus species and Coccidioides species.

Strength of coccidioidomycosis diagnosis
 Confirmed311
 Highly probable710
 Probable200
Location
 Pulmonary area only910
 Disseminated1311
Pretransplantation radiographic findings
 Nodules   
   <5 mm, uncalcified210
   1 cm, uncalcified100
 Calcified lesions100
 Cavity020
 Upper lobe scar100
 Infiltrate000
 No abnormalities801
Timing of the infection
 <6 months711
 6 months–1 year100
 >1 year410
Antifungal treatment
 Fluconazole, 400 mg daily, lifelong910
 Fluconazole, 200 mg daily, lifelong100
 Fluconazole, 200 mg daily, 6 months1200
 Fluconazole, 400 mg daily, stopped by patient after 4 years0130
 None4101
Outcome
 Infection resolved900
 Infection improved220
 Death due to coccidioidomycosis1501
 Death due to other000

Among the 12 patients, 11 (91%) received antifungal treatment and survived. The sole untreated patient had a negative coccidioidal serologic result on numerous occasions. The patient died of an overwhelming sepsis caused by Pseudomonas species and Staphylococcus aureus. Necrotizing pneumonia was found on autopsy and S. aureus, Pseudomonas species, Aspergillus species and Coccidioides species were isolated from the patient's lung tissue.

Of these 12 coccidioidal infections, 7 (58%) occurred in the first 6 months after transplantation (Table 3). All patients lived in the endemic area.

A subgroup analysis was performed to identify potential risk factors for development of coccidioidomycosis in liver transplant recipients (Table 4). When compared with liver transplant recipients who did not have coccidioidomycosis, patients with coccidioidomycosis were not different with respect to sex, race, type of liver transplantation (deceased versus living donor), immunosuppression, etiologic features of liver disease, organ rejection, history of diabetes mellitus and other comorbidities and presence of severe noncoccidioidal infections (including cytomegalovirus disease or hepatitis C).

Table 4.  Distribution of patients with diagnosed coccidioidomycosis and patients without active infection who did not have a pretransplantation coccidioidomycosis history
CharacteristicsCoccidioidomycosis status, no. (%)p-Value
Diagnosed de novo coccidioidomycosis (n = 12)No de novo infection or history of coccidioidomycosis (n = 349)
  1. CMV = cytomegalovirus; ESLD = end-stage liver disease; HCC = hepatocellular carcinoma.

  2. 1Race at high risk for coccidioidomycosis.

  3. 2Included both mild rejection treated with adjustment of immunosuppressant dose and acute rejection requiring pulse corticosteroid therapy.

  4. 3Included patients noted to have chronic kidney disease (n = 21), patients receiving hemodialysis throughout the follow-up period (n = 11), patients with end-stage kidney disease requiring a dual kidney-liver transplantation (n = 11) and patients with pretransplantation hepatorenal syndrome (n = 10).

  5. 4Patients had either hepatitis C or hepatitis B infection as a cause of ESLD.

  6. 5Toxic etiologic factors included alcoholic liver disease and vitamin A toxicity.

  7. 6Autoimmune causes included primary biliary cirrhosis, primary sclerosing cholangitis and autoimmune hepatitis.

  8. 7Of the four patients with diabetes mellitus, three manifested coccidioidomycosis at more than 1 year posttransplantation.

  9. 8Aspergillus infection was seen concurrently with coccidioidal lung infection.

  10. 9Included infections caused by species of Candida (n = 29; peritonitis [n = 12], infection of the graft or biliary tract [n = 8], esophagitis [n = 5], fungemia [n = 3], arthritis [n = 1]), Aspergillus (n = 1, pulmonary infection), Scedosporidium (n = 1, brain abscesses) and Histoplasma (n = 1, disseminated).

  11. 10CMV disease requiring hospitalization (n = 1).

  12. 11Included cytomegalovirus infections (n = 50; viremia [n = 34], gastrointestinal tract infections [n = 10], hepatitis [n = 3], retinitis [n = 2] and pneumonia [n = 1]), herpes simplex infections (n = 8), varicella zoster (n = 8, of which 1 was varicella meningitis) and influenza pneumonia (n = 1).

  13. 12Concomitant infection with fungal, bacterial or viral microorganisms.

  14. 13Recipient had test results negative for CMV and donor had test results positive for CMV.

Male sex10 (83)235 (67) 0.51
African American107 (2)>0.99
Residence in endemic area 12 (100)328 (94) >0.99
Donor type
 Deceased 9 (75)285 (82) >0.99
 Living related or unrelated 3 (25)64 (18)0.49
Prednisone-based maintenance immunosuppression1 (8)40 (11)>0.99
Receipt of daclizumab induction1 (8)7 (2)0.24
Transplant rejection
 Yes2 4 (33)105 (30) 0.77
 No 8 (67)244 (70) >0.99
Kidney disease3053 (15)0.23
ESLD etiologic features
 Infectious4 8 (67)198 (57) 0.81
 Hepatitis C 7 (58)181 (52) 0.77
 Toxic5046 (13)0.38
 Autoimmune61 (8)40 (11)>0.99
 Other 3 (25)65 (19)0.72
Diabetes mellitus47 (33)102 (29) 0.77
Malignancy
 HCC 4 (33)90 (26)0.75
 Solid organ malignancy (non-HCC)1 (8)26 (7) 0.59
 Hematologic malignancy04 (1)>0.99
Infection identified during hospitalization
 None 3 (25)166 (48) 0.41
 Fungal and not coccidioidomycosis18 (8) 32 (9)90.50
 Bacterial 6 (50)91 (26)0.24
 Viral 1 (8)10 66 (19)11>0.99
 Multiple infections12 2 (17)51 (15)0.70
CMV status
 Mismatch131 (8)56 (16)>0.99
 Disease1 (8)65 (19)0.70
Posttransplantation hepatitis C
 Reactivated infection 5 (42)81 (23)0.16

Asymptomatic patients with positive serologic findings

On routine posttransplant screening, 39 patients with negative pretransplantation serologic findings had positive (n = 30) or indeterminate (n = 9) coccidioidal serologic results during follow-up without symptoms of active infection or a radiographic finding that could be attributed to coccidioidomycosis. Four of the 39 patients had more than 1 positive serologic marker; 35 patients had 1 positive or indeterminate serologic marker (primarily, an IgM marker detected through EIA) and were clinically deemed as having a false-positive result. These latter patients did not receive any antifungal treatment. No clinical infection was observed in the 39 patients, and the serologic results became negative without intervention in 27 patients during the follow-up period.

Coccidioidomycosis in donors

Two patients received an organ from a donor with coccidioidal infection. In 1 case, the donor was a 23-year-old construction worker who was ejected from a car in a motor vehicle crash. Family members did not report any known intercurrent illness, and work-up before his death included a normal chest radiograph and normal results on sputum and bronchoscopy cultures. Posttransplantation coccidioidomycosis developed in two recipients of the other organs from the same donor. Our recipient underwent 6 months of fluconazole prophylaxis, and no active infection was observed during the follow-up period. In the other case, the donor had asymptomatic seropositivity, with a complement fixation titer of 1:2 and no active chest radiographic abnormalities. No prophylaxis was given to the transplant recipient, and no coccidioidal infection was found after transplantation.

Discussion

  1. Top of page
  2. Abstract
  3. Background
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. References

Inadequacy of cellular immunity is a well-established risk factor for development of coccidioidomycosis (17). Solid organ transplant recipients require lifelong suppression of cell-mediated immunity to prevent organ rejection, thus increasing their risk of coccidioidal infection or other opportunistic infections (6). This study highlights the serious nature of coccidioidomycosis in the transplant recipient. Among the 15 patients with active infection (12 de novo infection, 2 reactivations and 1 with pretransplantation indeterminate serologic results), 5 had disseminated infection (33%) and 2 (13%) died of active coccidioidomycosis. Therefore, all efforts to limit the effect of this endemic fungal infection are warranted.

Earlier studies have identified several risk factors for the development of coccidioidomycosis posttransplantation. These factors include previous history of coccidioidomycosis, positive coccidioidal serologic results at transplantation and treatment of acute rejection with intravenous corticosteroids (12). In a previous report, 7 of 10 patients with prior history of coccidioidomycosis who never received antifungal prophylaxis after the solid organ transplantation died of disseminated disease (12). Therefore, it is standard to offer prophylaxis to patients with seropositivity or a history of prior coccidioidomycosis.

We initially reported our early experience with targeted prophylaxis for liver transplant recipients who had such risk factors for posttransplantation coccidioidomycosis (7). In the initial report, four patients received targeted prophylaxis and none had reactivated coccidioidomycosis. In addition, de novo coccidioidal infection occurred in 1 of 72 patients (1.4%). At that time, we were unable to identify any patient characteristics that placed the sole patient at increased risk for this infection.

In this study, 12 patients had coccidioidomycosis before transplantation, 11 of whom were asymptomatic at the time of transplantation. Excellent adherence to antifungal prophylaxis continues to predict the lack of active coccidioidomycosis. One of the two patients was not compliant with the posttransplant prophylaxis regimen and had reactivated coccidioidal infection. Except for this one case, no reactivation of the coccidioidomycosis was observed in patients with quiescent infection before transplantation. Our current study supports our initial report, and we continue to advocate the use of and adherence to antifungal prophylaxis for this patient population (6,8,13,18).

The optimal duration of such antifungal (anticoccidioidal) prophylaxis has not yet been established. As reported in other studies (18,19), we observed that nonadherence to antifungal prophylaxis (2 of 12 patients in our study) did not inevitably result in active coccidioidomycosis. However, one recipient with apparently quiescent cavitary lung infection took fluconazole for 4 years, stopped for 1 year, and subsequently had enlargement of the cavitary lesion, which was controlled only with reinstitution of her azole therapy. Although coccidioidal lung nodules and cavities both harbor live fungal organisms, the sputum from patients with cavities are much more frequently culture positive than the sputum from patients with nodules, indicating a greater fungal burden in the cavities (20). We thus speculate the possibility that a lung cavity may be more likely to reactivate than a nodule when prophylaxis is withdrawn.

Treatment of acute cellular rejection has been reported to be a risk factor for coccidioidomycosis in solid organ transplant recipients (6,21). We did not observe this finding in our initial (7) or the present evaluation. In this study, 82 patients required pulsed corticosteroid treatment of acute cellular rejection. Two patients (2%) had pulmonary coccidioidomycosis. No statistically significant association was found between administration of such antirejection therapy and development of coccidioidal illness. However, this cohort did not have any episodes of corticosteroid-resistant rejection and was never treated with antilymphocyte treatments, such as human, monoclonal or chimeric antilymphocyte antibodies or other antirejection regimens. The lack of infection risk seen in this study compared with previous studies may have been due to a lower level of immunosuppression regimens required to reverse the organ rejection.

The liver transplant recipients in our transplantation program have typically resided in and continue to live in the endemic area, putting them at daily risk for de novo infection. In our initial report, 1 (1.4%) of 72 recipients had coccidioidomycosis, compared with 12 (3%) patients in this study (p= 0.70). Within the endemic area, the incidence of de novo coccidioidomycosis in solid organ transplant recipients ranges from 1.4% to 6.9% (7–11).

Past studies have shown that in the absence of coccidioidal prophylaxis, approximately 70% of posttransplantation coccidioidomycosis occurs during the first posttransplantation year (6,9). In this cohort, despite the institution of a targeted prophylaxis program, we had a similar observation, with eight cases (67%) in the first posttransplantation year; seven of those cases were diagnosed within the first 6 months. In the past, it was hypothesized that the coccidioidal infections occurring early in the posttransplantation period were cases of reactivation and that anticoccidioidal prophylaxis would eliminate these early cases of coccidioidomycosis (6). Because our high-risk patients already received antifungal prophylaxis, our results indicate a vulnerability to de novo coccidioidomycosis in the early posttransplantation course. A possible explanation for the preponderance of early posttransplantation coccidioidal infection is simply that the patients are at high risk in this early transplantation period because the doses of immunosuppressive medications are highest during this period.

We sought to identify potential risk factors for de novo coccidioidomycosis in liver transplant recipients but found no statistically significant association with respect to numerous patient and transplantation characteristics (Table 4). Therefore, how to further refine targeted prophylaxis is unclear. As a result, we have changed our strategy from targeted to universal prophylaxis for the first year posttransplantation for patients who remain in the endemic area.

Previously, we have strongly advocated the use of targeted prophylaxis for the prevention of coccidioidomycosis in organ transplantation. Unlike our previous studies and recommendations, with the accumulation of 8 years of experience, we conclude that, despite a program of targeted prophylaxis, coccidioidomycosis continues to plague our transplant recipients, and de novo infection accounts for most active cases. Because most liver transplant recipients in our program continue to reside in the endemic area (and thus are at continual risk of acquisition of coccidioidomycosis), we now propose a new strategy of universal prophylaxis of fluconazole of 6–12 months for such patients after transplantation (Table 5). Patients with a history of recent coccidioidomycosis or positive serologic results at transplantation will still receive fluconazole at 400 mg/day for life; however, all other recipients will receive 6–12 months of fluconazole at 200 mg daily. We hypothesize that the addition of fluconazole to treatment of patients at risk for de novo posttransplant coccidioidomycosis will minimize infection risk at the time of maximum immunosuppression. In addition, because the proposed prophylaxis simplifies the prophylaxis construct by applying one of two doses of fluconazole to all recipients for the first year after transplantation, we hope to see improved adherence to the protocol.

Table 5.  Comparison of old and new (proposed) prophylaxis protocol for coccidioidomycosis posttransplantation
CharacteristicPrevious prophylaxis protocolProposed prophylaxis
Previous history of coccidioidomycosis
 >1 year before transplantationFluconazole 200 mg daily × 6–12 monthsFluconazole 200 mg daily × 6–12 months
 ≤1 year before transplantationFluconazole 400 mg daily, lifelongFluconazole 400 mg daily lifelong
Positive serologic results before or at time of transplantationFluconazole 400 mg daily × 1 year, lifelong. Consider dosage reduction at 1 year if seronegativeFluconazole 400 mg daily × 1 year, lifelong. Consider dosage reduction at 1 year if seronegative
No history of coccidioidomycosis, negative serologic resultsNoneFluconazole 200 mg daily × 6–12 months

How to best approach the care of patients with indeterminate serologic results before transplantation continues to be an unsettled issue. In 11 cases, indeterminate serologic results or an isolated IgM positivity (through EIA) were interpreted as ‘negative’ by the clinician, such that the patients did not receive anticoccidioidal prophylaxis after transplantation. The EIA IgM test has generated controversy in that some investigators have found this test to be falsely positive when not accompanied by positive results for other serologic markers (2,22). Investigators of a recent study argued that the solitary IgM seropositivity with EIA is often a true positive result (23). In this study, one patient with an indeterminate EIA IgM result 1 month before transplantation had an early posttransplantation course complicated by fatal disseminated coccidioidomycosis. As a result, the subsequent policy at our transplantation center has been to consider any and all indeterminate or positive pretransplantation serologic findings as ‘positive’ and to recommend prophylaxis for patients as they proceed into a period of high-level immunosuppression.

Our retrospective study has several limitations. As shown, serologic results can be indeterminate, falsely negative, or falsely positive and can be difficult to interpret. Our program has chosen to administer prophylaxis to patients with positive serologic results even though the possibility of false-positives (e.g. potentially the case in patients with autoimmune causes of hepatitis) is present. There was variability of antifungal regimens and immunosuppression, although in our analysis, we could not identify that the variability in the dosage of fluconazole altered the risk of coccidioidal infections. In addition, some patients participated in immunosuppression studies outside our normal protocols; however, such patients did not have an increased risk of coccidioidal infection.

We conclude that coccidioidomycosis continues to challenge transplantation programs within the endemic area. Prospective organ recipients require multidisciplinary evaluation and careful screening and follow-up after transplantation. In the clinical setting of targeted prophylaxis for patients with known risk factors for posttransplantation, de novo infection accounts for most cases of active coccidioidomycosis, most of which occur in the first 6 months after transplantation. We now propose a new strategy of prophylaxis for the first 6–12 months for all recipients who maintain residence in the endemic area. Future studies should assess the efficacy of and adherence to such a strategy.

Disclosure

  1. Top of page
  2. Abstract
  3. Background
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. References

The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

References

  1. Top of page
  2. Abstract
  3. Background
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosure
  8. References