Case Report: Paracoccidioidomycosis in Solid Organ Transplantation: Disseminated Disease in a Liver Recipient and Literature Review

Abstract.

Paracoccidioidomycosis (PCM) is an endemic systemic mycosis that is of great importance in Latin America. Its occurrence in solid organ transplantation (SOT) is rare, but with high mortality rate. In this report, we describe a case of PCM in a liver transplant recipient 19 months after transplantation. The patient presented with multiple skin abscesses, arthritis, osteolytic lesions, and pulmonary and adrenal involvement. Despite the presence of disseminated disease and the patient’s immunosuppressed condition, the patient responded well to prolonged antifungal treatment with no sequelae, thus suggesting that early diagnosis and correct treatment may lead to favorable outcomes in SOT recipients with PCM.

INTRODUCTION

Paracoccidioidomycosis (PCM) is an endemic systemic mycosis that is important in Latin America, with South America, especially Brazil, accounting for most of the cases.^1–3 Besides the endemic areas, cases related to migration and international travel were also reported in North America, Europe, Africa, and Asia.⁴

The etiological agents of PCM, Paracoccidioides species, more frequently Paracoccidioides brasiliensis and Paracoccidioides lutzii, are acquired by inhalation of fungal spores present in the soil. This occurs mainly in environments with great agricultural activity, although it can occur in endemic areas in any activity involving soil, such as deforestation or highway construction.^2,3,5,6 Most individuals are exposed to the fungus at a young age. After the primary infection, more than 98% of patients remain asymptomatic, and only a very small percentage of patients progress to one of the two clinical forms of the disease: acute/subacute (juvenile) or chronic PCM. Smoking and alcohol consumption increase the risk of progression to PCM disease.^2,6–8

Approximately 5–10% of patients with PCM manifest its signs and symptoms during the first three decades of life or a few weeks to months after contact with fungal spores and then start presenting in an acute/subacute juvenile form. This occurs with generalized lymph node enlargement with or without associated hepatosplenomegaly. Other organs such as the skin, bones, and gastrointestinal tract may also be affected. However, most patients with PCM will manifest the chronic form of the disease with pulmonary disease and ulcerated lesions in the oropharynx and upper respiratory tract, with or without lymph node involvement. This form represents the reactivation of a fungal quiescent focus or exogenous reinfection.^2,7,8

Although rare in solid organ transplant (SOT) patients, PCM is responsible for a reported high mortality rate (33%).⁹ Here, we present a case of disseminated PCM after liver transplantation with significant and rare clinical manifestations associated with immunosuppression. Despite presenting with the disseminated clinical form of PCM, the patient responded well to treatments with no sequelae. This suggests that early diagnosis and proper treatment may prevent unfavorable outcomes in the scenario of chronic PCM infection in SOT.

CASE

A 53-year-old man, who had worked with coffee crops until he was 20 years old and living in southeast Brazil, underwent a liver transplantation because of cirrhosis of alcoholic etiology in March 2014. He was initially treated with tacrolimus, mycophenolate, and methylprednisolone. He developed stenosis of the inferior vena cava 6 months after transplantation that was complicated with de novo hepatopathy and ascites. He was treated with two venous stents and anticoagulation therapy. In July 2015, he presented with edema and intense pain in the right shoulder. At the time, he was using tacrolimus 2 mg twice daily and no trimethoprim–sulfamethoxazole (TMP–SMX) for Pneumocystis jiroveci pneumonia prophylaxis. On physical examination, cutaneous abscesses were detected in the shoulder, scapula, right eyelid, zygomatic region, and scalp; fine aspiration needle biopsy was performed for one of the lesions. MRI of the right shoulder showed arthritis of the acromioclavicular joint and osteolytic lesions in the scapula and clavicle. Direct microscopy of one of the abscess aspirate and histopathology revealed multiple budding yeast forms that were consistent with Paracoccidioides spp. (Figure 1). Paracoccidioides spp. also grew in the culture after 4 weeks. The identification of anti–P. brasiliensis based on double immunodiffusion was negative at diagnosis and throughout treatment. No serology with P. lutzii antigen was performed. Molecular identification was conducted by sequencing the gp43 gene of P. brasiliensis extracted from paraffin-embedded tissue using the para I and para IV primers, as described in the literature.¹⁰ Disseminated disease was confirmed with multiple cutaneous abscesses, lung injury, and significant impairment of adrenal, reticuloendothelial, osteoarticular, and integumentary systems, which were noted on thoracic and abdominal computed tomography (Figure 2). The patient tested negative for HIV-1 and -2 and hepatitis B and C. Amphotericin B complex lipid induction therapy was initiated at 200 mg/day for 20 days, followed by maintenance treatment with TMP–SMX 800/160 mg, twice daily.

Figure 1.

(A) Hematoxylin and eosin stain, scale ×100, epithelioid granuloma with suppurative necrosis. (B) Grocott’s methenamine silver stain: scale ×400. Paracoccidioides spp. and its morphology, rounded structures with multiple budding east cells, resembling the “pilow wheel”. This figure appears in color at www.ajtmh.org.

Figure 2.

(A) Axial thorax computed tomography (CT) showing the enlarged hilar and mediastinal lymph nodes (arrows). (B) Axial CT showing multiple subtle small nodules (arrow). (C,D) Axial CT showing a lytic lesion in the rib (arrow in C) and scapula (arrow in D). (E) Coronal abdominal CT showing right adrenal thickening with peripheral enhancement (arrow).

Six months after initiating the treatment, muscle weakness and a hyperkalemia of 9.25 mEq/L were observed. Hyperkalemic renal tubular acidosis and hypomagnesemia were diagnosed owing to the association between calcineurin inhibitor (tacrolimus) and trimethoprim. The tacrolimus dose was adjusted, thereby normalizing the laboratory parameters and disrupting the patient’s symptoms. The treatment was maintained for 34 months, with suspension after clinical and radiographic control (Figure 3).

Figure 3.

Coronal head computed tomography showing lytic bone lesions with cortical rupture and soft tissue extension before treatment (A, B, and C), with resolution after 30 months of treatment (D, E, and F). (A and D before contrast, B and E after contrast, and C and F bone window).

LITERATURE REVIEW

Brazil is the main endemic area for PCM in Latin America and also has the second highest absolute number of liver transplants (2,017 in 2017) and kidney transplants (5,426 in 2017) worldwide.¹¹ Despite that, reports of PCM in transplant recipients are rare, and clinical form characterization and standard therapeutic approaches are limited. The disease is already well described in patients with HIV in endemic areas, and in this scenario, the presentation may be different than expected, with overlaps of chronic and acute/subacute findings.^11–13 Some cases also reported its association with neoplasia and chemotherapy and immunobiological use.^14–22

To date, 10 cases of PCM after SOT in adults and one case of PCM after hepatic transplantation in children have been described globally, including the present one (Table 1).^23–31 The 11th case of postrenal transplantation PCM was found in an autopsy review, as well as the single case of PCM after lung transplantation in a review of pulmonary infections, both without descriptive data, and therefore, not included in Table 1.³² Among the 11 reported cases, only one occurred immediately posttransplantation, and all the others occurred late posttransplantation, as most commonly observed in endemic infections.³ Paracoccidioidomycosis disease in this specific population might present with faster evolution of adenomegaly, hepatosplenomegaly, digestive manifestations, and cutaneous-mucosal and osteoarticular involvement.³³ Among the previously reported cases, 60% had disseminated disease. Uncommon severe clinical presentations are reported as isolated severe diarrhea leading to death and acute respiratory failure.^24,31 Amphotericin B was used in 50% of reported cases, possibly reflecting the potential severity of disseminated mycosis in immunocompromised recipients. In addition to the antifungal therapy, in some cases, immunosuppression was discontinued during treatment. Four of the 11 patients reported in the literature died, suggesting a much higher lethality than expected in PCM in immunocompetent patients, which is approximately 5%.³⁴

Table 1.

Summary of reported cases of paracoccidiodiomycosis in solid organ transplantation

Cases (first author)	Age (years)	Gender	Country	Transplanted organ	Immunosuppression	Onset after Tx	Diagnostic method	Organs involved	Treatment	Outcome
1. Sugar et al23	64	M	Birth: El Salvador/Travel: Guatemala	Kidney	Azathioprine 50 mg/day + prednisone 10 mg/day	11 years	First episode: TT needle aspiration: direct examination; serologies: CF/ID positive, relapse: FBC/BAL/TBB: direct examination and culture, CF/ID negative	Lungs	First episode: D-AmB(2 grams cumulative dose); relapse: ketoconazole 200 mg/day	Good progression but still on treatment when reported (14 months follow-up)
2. Reis, Moyses, Neto et al24,25	NA	NA	Brazil	Kidney	NA	> 1 year	NA	Pulmonary	Sulfadiazine	Positive response
3. Reis, Moyses, Neto et al24,25	NA	NA	Brazil	Kidney	NA	> 1 year	NA	Mucosa (lesion on the palate)	Sulfadiazine	Positive response
4. Reis, Moyses, Neto et al24,25	NA	NA	Brazil	Kidney	NA	> 1 year	NA	Gastrointestinal tract	None	Postmortem diagnosis
5. Shikanai – Yasuda et al26	29	F	Brazil	Second renal transplant (deceased donor)	Azathioprine (dose not reported) + prednisone 5 mg/day	5 years	FBC/BAL/TBB: direct examination; serologies: CF and IFI negative, CIE positive	Lungs/lymph nodes	D-AmB	Deceased
6. Zavascki et al27	43	M	Brazil	Kidney (deceased donor)	Azathioprine 100 mg/day, cyclosporine 100 mg/day, and prednisone 5 mg/day	14 years	Skin lesion biopsy; sputum direct examination; serology: ID positive	Skin and lungs	D-AmB1 mg/kg (7 days); itraconazole 200 mg/day for 6 months (last follow-up)	Asymptomatic at 6 months of follow-up
7. Pontes et al28	45	M	Brazil	Kidney (live donor)	Tacrolimus, mycophenolate, and steroids (doses not listed)	3 years	Cervical lesion biopsy	Skin and lungs	TMP–SMX for 39 days (without clinical improvement)	Deceased
9. Goes et al29	66	M	Brazil	Kidney	Prednisone 5 mg/day, mesalazine 1.080 mg/day, and tacrolimus 8 mg/day	19 months	Direct mycological examination of bronchial lavage; mucocutaneous lesion biopsies; culture positive.	Oral mucosa, skin, and lungs	Itraconazole, 400 mg daily; because of clinical worsening and liposomal amphotericin B was introduced	Deceased
8. Radisic et al30	57	F	Argentina	Kidney	ATG induction: mycophenolate mofetil 720 mg and methylprednisolone 16 mg/day	2 days	BAL: direct examination; culture negative, ID negative	Lungs	L-AmB (1 mg/kg × 14 days mg); switch to itraconazole 200 mg/day for 11.5 months	Asymptomatic at 32 months of follow-up
10. Lima et al31	3	F	Brazil	Liver	Tacrolimus (3 mg/day)	2 years	Skin lesions, cervical lymph nodes, and liver biopsies	Liver, skin, lymph nodes, and lungs	TMP–SMX (200/40 mg 12 hourly) and D-AmB (1 mg/kg/day) combined treatment for 5 months and after TMP–SMX (100/20 mg 12 hourly) for 6 more months; tacrolimus was withdrawn during treatment	Asymptomatic at 3 years of follow-up
11. Peçanha Pietrobom (present report)	53	M	Brazil	Liver	Tacrolimus (4 mg/day)	19 months	Skin abscess aspirate direct examination and skin biopsies	Skin, lymph nodes, bone, lungs, and adrenal lesions	ABLC 200 mg/day for 20 days followed by TMP–SMX for another 30 months	Asymptomatic at 1 year of follow-up

M = male; F = female; ABLC = amphotericin B lipid complex; ATG = anti-thymocyte immunoglobulin; BAL = bronchoalveolar lavage; CF = complement fixation; D-AmB = amphotericin B deoxycholate; FBC = fiberoptic bronchoscopy; CIE = counterinmmunoelectrophoresis; ID = immunodiffusion; IFI = indirect immunofluorescence; L-AmB = liposomal amphotericin B; NA = not available; TBB = transbronchial biopsy; TMP–SMX = sulfametoxazole–trimethoprim; TT = transthoracic; Tx = transplantation.

DISCUSSION

Posttransplant immunosuppressive therapy has revolutionized medicine, making SOT safe and effective. However, opportunistic infections are among the leading causes of morbidity and mortality after SOT.³⁵ The risk of infection is determined by previous epidemiological and medical histories, intensity of exposure to microbiological agents, and immunosuppression levels.^35–37 Endemic mycoses can occur many years after transplantation by the reactivation of the quiescent focus, new infection through a recent contact, or donor transmission in endemic areas and may be related to immunosuppression after SOT.³⁸ Atypical clinical manifestations of endemic mycoses are expected to occur in this specific group of patients with cellular immunosuppression in a similar way to what we observe for HIV coinfection in patients with the mixed clinical form.^9,12,13 Immunosuppressed kidney transplant recipients have a persistent poor T helper 1 immune response to Paracoccidioides antigen gp43.³³ Although chronic PCM usually manifests in most adults with pulmonary damage and ulcerative mucocutaneous lesions, our patient was observed to be affected with exuberating lesions in soft and bone tissues. Uncommon clinical findings can lead to a delay in diagnosis. Moreover, because of impaired immune activity in transplant recipients, antibody formation may be inadequate, with an even lower sensitivity of serological examinations.³⁸ Molecular techniques and antigen detection could be good options, although they are usually not available for routine diagnosis.^4,38 Therefore, a high degree of suspicion in individuals with a compatible epidemiological history is mandatory, and efforts toward diagnosis and adequate management need to be established. We would suggest collecting secretions and tissues to directly identify fungal structures to enable adequate and early diagnosis, thereby avoiding unfavorable outcomes.

Paracoccidioides spp. is susceptible to most systemic antifungal agents. However, choosing the best therapy is challenging in this specific group of patients because the propensity to drug interactions and toxicities, such as that in our case, is higher. During treatment, special attention should be paid to drug interactions with immunosuppressors to prevent iatrogenic complications. Itraconazole is the drug of choice for PCM. Nevertheless, azole antifungals inhibit the metabolism of calcineurin and mammalian target of rapamycin (mTOR) inhibitors (the major immunosuppressants used in organ transplantation), although simultaneously increasing the concentrations of tacrolimus in the blood. According to Brazilian guidelines for the clinical management of PCM, this combination should be avoided to prevent toxicities, and hence, it was not prescribed in our case.^2,39 In the reported cases, time of treatment varied from 11 to 31 months, but the ideal treatment duration remains unknown because severe forms require longer maintenance therapy and immunosuppression is usually maintained lifelong in SOT recipients.