Coccidioides in lung transplant: case report

Abstract

A middle-aged woman was hospitalised for generalised, painful skin lesions 6 weeks after a successful double-lung transplant. She had end-stage lung disease associated with chronic obstructive pulmonary disease due to alpha-1 antitrypsin deficiency, and she had been treated with itraconazole for 16 months because of lung infection associated with Malbranchea spp. Results of a skin biopsy of the initial lesion on her arm showed non-specific dermal inflammation, presumably due to reactivation of the Malbranchea spp infection. Follow-up cervical lymph node biopsy and culture showed Coccidioides posadasii/C. immitis. A detailed review of her travel history showed a 4-month stay in Arizona as a teenager that she barely remembered. Coccidioides spp were likely misidentified as Malbranchea spp owing to similar morphological characteristics. Dosages of immunosuppressive medications were reduced, and antifungal therapy was changed to posaconazole. Her skin lesions resolved.

Background

This case highlights the importance of obtaining a detailed travel history and evaluating risk exposure for solid-organ transplant patients receiving immunosuppressive medications. Minimising immunosuppression is essential for decreasing the risk of reactivation of chronic, latent infections. Communication between microbiology laboratory staff and clinicians is essential for accurate diagnosis, especially of infections caused by rare pathogenic organisms such as Malbranchea spp.

Case presentation

A middle-aged woman was hospitalised for generalised, painful skin lesions 6 weeks after a successful double-lung transplant. Two years before the lung transplant, she was diagnosed with end-stage lung disease secondary to chronic obstructive pulmonary disease due to alpha-1 antitrypsin deficiency. On pretransplant evaluation, she presented with shortness of breath with findings of nodular opacities on chest radiographs. Follow-up chest CT showed nodular scarring and stable, advanced emphysema. She underwent bronchoscopy with biopsy, and the results were positive for Malbranchea spp. There was no known other immunosuppressive disease or therapy in the past. Voriconazole was initially administered but was switched to itraconazole owing to drug intolerance. She received treatment with itraconazole for about 16 months. Clinical improvement ensued. Sputum cultures showed negative findings. She became asymptomatic for the rest of the wait for the transplant.

She had an uncomplicated double-lung transplant and was discharged after 2 weeks of hospitalisation. She was maintained on mycophenolate mofetil, tacrolimus and prednisone. Six weeks after the transplant procedure, dark, tender skin nodules developed on her left upper extremity that spread to her trunk and lower extremities accompanied by persistent fever.

Investigations

The results of a skin biopsy of the initial lesion on her arm showed non-specific dermal inflammation. Chest radiographs showed normal findings. QuantiFERON-TB Gold Plus test results were indeterminate. Serological test results were negative for Histoplasma spp, Blastomyces spp and Coccidioides spp. Transbronchial biopsy on histopathology showed non-necrotising granulomatous inflammation with fungal yeast. A cervical lymph node biopsy was also performed with fungal culture consistent with Coccidioides posadasii/C. immitis. A detailed review of the patient’s travel history showed a 4-month stay in Arizona as a teenager that she barely remembered. No information regarding the travel history of the donor to an endemic area was obtained.

Treatment

The patient was hospitalised, and empiric therapy with liposomal amphotericin B was started owing to the clinical suspicion of reactivation of fungal infection. Immunosuppression was minimised. Empiric therapy of liposomal amphotericin B was transitioned to oral posaconazole after a few days and continued indefinitely.

Outcome and follow-up

The skin lesions and symptoms resolved after a few days of treatment.

Discussion

Coccidioidomycosis is caused by Coccidioides spp, which are dimorphic fungi found in soil. These organisms are prevalent in the southwestern region of the USA and northern Mexico. In transplant patients, other potential sources of infection can include donor transmission or reactivation. No cases of human-to-human transmission have been reported. Several studies have shown that the incidence of coccidioidomycosis ranges from 4% to 8% in transplant patients in highly endemic regions.¹

Infection is usually due to inhalation of spores. Inside the body, the spores develop into spherules that eventually release endospores, and these endospores travel to other parts of the body via the hilar lymph nodes.^{2 3} The most common presentation of coccidioidomycosis is acute pulmonary infection. However, as many as 60% of patients can be asymptomatic. Non-specific symptoms, such as sore throat, cough, fever, pleuritic pain and headache, usually develop within 1–4 weeks after exposure. Signs may include pulmonary nodules or other abnormalities on chest radiographs.^4–6 Dissemination can be common, and in a case series,⁷ dissemination affected 75% of immunocompromised renal transplant patients. Common post-transplant extrapulmonary manifestations involve the skin, blood and joints. Diagnosis of coccidioidomycosis is based on clinical, radiological signs suggestive of infection and (1) identification of coccidioidal spherules in affected tissue with biopsy or cytological analysis, (2) positive culture result for Coccidioides spp in any bodily fluid or (3) positive serological test result for Coccidioides spp.

Immunocompromised patients, such as solid-organ transplant patients receiving immunosuppressive medications, have inadequate T-cell function that is associated with release of endospores. Poor immune response predisposes the patient to a greater risk of dissemination to the skin, bones, joints or meninges. Hence, minimising immunosuppression is essential to mitigating the risk of reactivation in patients with chronic, latent infections. According to the review by Blair and Logan of papers published from 1960 through 2000 transplant patients, common post-transplant extrapulmonary manifestations involve the skin, blood, urine and joints. Diagnosis of coccidioidomycosis is based on clinical and radiological signs suggestive of infection and (1) identification of coccidioidal spherules in affected tissue with biopsy or cytological analysis, (2) positive culture result for Coccidioides spp in any bodily fluid or (3) positive serological test results for Coccidioides spp. Immunocompromised patients, such as solid-organ transplant patients receiving antirejection medications, have inadequate T-cell function that is associated with release of endospores. Poor immune response predisposes the patient to a greater risk of dissemination to the skin, bones, joints or meninges. Hence, minimising immunosuppression is essential to mitigating the risk of reactivation in patients with chronic, latent infections. According to the review by Blair and Logan⁸ of papers published from 1960 through 2000 about coccidioidomycosis in solid-organ transplant patients, most cases of post-transplant coccidioidomycosis were due to reactivation of a previous infection. Most infections developed during the first year after transplant, and incidence decreased in the following years. Notably, even a short visit to an endemic area places solid-organ transplant patients at high risk of infection.⁹ Vikram et al⁹ noted that lung transplant recipients had the highest risk of donor-derived coccidioidomycosis because the lungs are the primary site of infection. Donor-derived infection can be presumed when the recipient has not travelled to an endemic area but proving donor-derived infection can be difficult for transplant recipients who reside in endemic areas. Obtaining a detailed travel history and performing serological tests to screen for Coccidioides spp before transplant are essential for patients and donors who have been to endemic areas. No data indicate the best approach for coccidioidomycosis screening and prophylaxis in non-endemic areas.¹⁰ However, organ donors and recipients with active infection should always be treated before transplant. Treatment should continue until resolution of symptoms, radiographical abnormalities and abnormal serological results (at least fourfold reduction of the complement fixation titre).¹¹

Notably, various assays (eg, enzyme immunoassay, complement fixation test and immunodiffusion) are commonly not sensitive diagnostic tests, especially for immunocompromised patients. Blair et al¹² reviewed the serological test results of patients with symptomatic coccidioidomycosis, and immunosuppressed patients had lower seropositivity rates for all tests, especially during the first year of symptoms. Use of multiple assays was recommended to improve detection because excessive reliance on a single negative test result could delay diagnosis and appropriate treatment for symptomatic patients.

Post-transplant treatment and long-term prophylaxis with fluconazole (400 mg/day) or itraconazole (400 mg/day) are effective methods of controlling reactivation.^{11 13} Posaconazole (400 mg/day) is another option.¹⁴ It is 200-fold more active against Coccidioides spp than fluconazole, with notable in vitro fungicidal activity. It can be given as a salvage therapy to patients with pulmonary coccidioidomycosis that does not respond to standard therapy. To prevent reactivation, lifetime immunosuppressive therapy should be strongly considered for the subset of patients who have active infection after transplant.¹⁵ The role of combination antifungal therapy is still unclear.

Coccidioides spp can be confused for Malbranchea spp because they have similar sporulation patterns, colonies, mycelial appearances, arthroconidial sizes and spaces that separate arthroconidia.¹⁶ However, Malbranchea spp are typically non-pathogenic, and isolation from humans is hardly seen. Malbranchea spp. has rarely been reported in the literature as a cause of respiratory infection in immunocompetent or immunosuppressed hosts.^{17 18} In contrast, Coccidioides spp are typically considered pathogenic and are more commonly reported in the literature. Microscopically, Coccidioides spp have endospores within spherules that appear different from those of Malbranchea spp. Identification can also be confirmed with DNA testing. Hence, communication between microbiology laboratory staff and clinicians is also essential for accurate identification of unusual organisms and diagnosis of disease.

The number of solid-organ transplants is increasing, and this case shows the importance of obtaining a thorough travel and exposure history from patients before organ transplant. Achieving the minimal but optimal level of immunosuppression in transplant patients is critical to minimising risk of reactivation of latent infections.

Learning points.

• Evaluations of travel history and risk exposure are critical for transplant patients.

• Minimising immunosuppression is essential to decreasing risk of reactivation of long- term, latent infections.

• Communication between microbiology laboratory staff and clinicians is essential for accurate diagnosis, especially of diseases caused by unusual organisms.

• Caution when diagnosing fungal infections based solely on morphological appearance.

• Correlation of cultures with other laboratory tests (eg, serological and molecular tests) and consideration for other organisms with similar morphologies are critical to accurate diagnosis.