EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Three months after a kidney transplant, a man experienced an internuclear ophthalmoplegia. Magnetic resonance imaging found a punctuate hyperintensity of the brainstem. Afterwards, the patient presented with peripheral facial paralysis. A complete morphologic assessment showed an increase of the brainstem lesion, together with an excavated pulmonary nodule. Combination therapy with high-dose liposomal amphotericin B and voriconazole was begun for the putative aspergillosis. Owing to its atypical clinical presentation and negative detection of Aspergillus galactomannan antigen on sera, a biopsy specimen of the lung lesion was obtained. Histopathological and mycological investigations allowed the diagnosis of mucormycosis owing to Rhizopus microsporus. Accordingly, voriconazole was replaced with posaconazole. After 5 months, regression of the cerebral lesion was noted. Disseminated mucormycosis in solid-organ recipients is uncommon and mycological diagnosis is challenging. Mortality is high and is increased by diagnostic delay. Treating mucormycosis requires surgical debridement and appropriate antifungal therapy (usually intravenous liposomal amphotericin B). This report suggests that a combination of liposomal amphotericin B and posaconazole can be a therapeutic option in patients with a poor prognosis.

Key words : Zygomycosis, Mucorales, Solid-organ transplant

Mucormycosis is a rare, life-threatening, fungal infection that occurs mainly in immunocompromised patients. In solid-organ transplant recipients, dissemination is uncommon; clinical presentation can be nonspecific and mycological diagnosis is difficult.¹ Mortality is usually high and is increased by diagnostic delay.² We report a case of disseminated mucormycosis with cerebral involvement in a kidney transplant recipient, diagnosed early by lung biopsy. Combination therapy of high-dose liposomal amphotericin B (LAmB) and posaconazole (POS) led to a clinical and morphologic remission.

Three months after receiving a second kidney transplant, a 60-year-old man was admitted in our hospital for a biopsy of the graft, owing to progressive deterioration of his renal function in the context of BK virus infection (9 and to 4.5 log/mL in urine and blood by real-time polymerase chain reaction). His medical history was significant for end-stage renal disease secondary to an unlabeled extracapillary glomerulonephritis contracted in 2001 that led to his first kidney transplant in 2004. Seven years later, because he required dialysis treatment again, this second deceased donor graft was performed.

There was no alloimmunization, Epstein-Barr virus and cytomegalovirus serologic status were positive for both the donor and the recipient. Induction therapy included anti-thymocyte globulin together with prednisolone (decreasing dose to 10 mg/d), tacrolimus 4 mg/day (therapeutic target between 8 and 10 ng/mL) and mycophenolate mofetil (1 g twice daily). Anti-infective prophylaxis included cotrimoxazole, then pentamidine isethionate and valganciclovir. After 10 days, rapid recovery of graft function with a nadir creatinine concentration of 90 μmol/L allowed the patient to be discharged from the hospital.

On the day of the biopsy, the patient presented with internuclear ophthalmoplegia. As magnetic resonance imaging found a punctuate hyperintensity of the brainstem (Figure 1A), an ischemic stroke was suspected. However, an embolic origin was discarded after completion of a transthoracic and transesophageal echocardiograms and Holter electrocardiogram.

During the week following, the patient presented with a peripheral left facial paralysis. A new magnetic resonance image revealed an increase in the brain stem lesion with a swollen appearance that could explain the peripheral facial paralysis by compression of the cerebellopontine angle (Figure 1B). Analysis of the cerebrospinal fluid showed a slight increase in protein level (0.48 g/L). Furthermore, as the graft biopsy eventually confirmed BK virus nephropathy, immunosuppressive therapy was stopped, except for low doses of corticosteroids.

A complete morphologic assessment was therefore conducted, revealing a large excavated pulmonary nodule (20 mm in diameter) in the upper right lobe (Figure 2A). Combination therapy with high-dose liposomal amphotericin B (10 mg/kg/d IV) and voriconazole (VRC, 200 mg twice daily, taken orally) was therefore started in light of a probable invasive aspergillosis as a bronchoalveolar sample, grew Aspergillus section Fumigati (direct examination was negative). However, because of the atypical clinical presentation and negative results for detection of Aspergillus galactomannan antigen in blood and cerebrospinal fluid, a computed tomographic-guided transthoracic biopsy of the lung lesion was performed (Figure 2B). Histopathology revealed an extensive tissue necrosis together with large irregular and nonseptate hyphae, leading to a diagnosis of mucormycosis. Mycological cultures using Sabouraud agar slants were positive in a few days for a Rhizopus species (that were identified as Rhizopus microsporus by ITS rDNA sequencing). In light of this disseminated mucormycosis, LAmB was pursued at high doses, and VRC was replaced by POS (400 mg twice daily).

After withdrawing the immunosuppression regimen, the patient was returned to dialysis therapy. Because clinical and radiologic improvements were seen (ie, stabilization of the cerebral lesions and marked regression of the pulmonary lesions), the patient was discharged from the hospital 3.5 months after starting antifungal therapy. At 5 months follow-up, marked regression of the cerebral lesions was confirmed (Figure 1C).

Unfortunately, after 8 months of antifungal therapy, the patient presented again at our hospital with a complex partial seizure. The main cause of this seizure (either a vascular and/or toxic origin) was not completely understood, but magnetic resonance imaging showed an improvement of cerebral lesions and no evidence of new lesions. Unfortunately, despite initial improvement seen with levetiracetam therapy, the patient died.

We report a case of disseminated mucormycosis with cerebral involvement in a renal transplant patient. Despite its increase in recent years,^3,4 mucormycosis remains an uncommon infection.⁵ In a prospective and multicenter TRANSNET study, the 12-month cumulative incidence of mucormycosis was 0.29% in hematopoietic stem cell transplant recipients and 0.07% in solid-organ transplant recipients, which is 10-fold lower than the mean incidence of invasive aspergillosis.⁶ Moreover, its incidence in kidney transplant recipients is even lower compared with other solid-organ transplant recipients.^6,7 Disse-minated mucormycosis, as in the present case, is described mainly in hematopoietic stem cell transplant recipients, the most common presentation in solid-organ transplant patients being pulmonary and rhinosinusitis.^1,5,8

Mucormycosis is an aggressive and angioinvasive fungal infection, responsible for severe morbidity and mortality.² Early and prompt diagnosis is essential, as delayed appropriate antifungal therapy has been associated with a 2-fold increase in mortality compared with early therapy.⁹ Diagnosis remains challenging because (1) clinical and radiologic presentation can be nonspecific—mucormycosis mimics other fungal infections (eg, invasive aspergillosis as illustrated here), (2) mycological cultures of the clinical samples are regularly negative, (3) no antigen-based detection test is available, and (4) no standardized polymerase chain reaction assay has been evaluated in large multicentric studies. Additionally, mucormycosis remains an unusual infection for which most physicians often have only limited experience. In addition, the Mucorales species are inherently resistant to VRC, which is used as first-line therapy of invasive aspergillosis.¹⁰ Taken together, histo-pathologic and/or direct examination of fresh samples is of overall importance, the recovery of large nonseptate hyphae leads to rapid and prompt diagnoses, allowing one to initiate appropriate therapy. It is necessary therefore to maintain a high level of clinical suspicion and take a multidisciplinary approach to establish the microbiological diagnosis.

Treatment of mucormycosis consists of reducing predisposing factors, surgical debridement, and appropriate antifungal therapy with intravenous LAmB at 5 mg/kg/d now being recommended widely.¹⁰ In the present case, immunosuppression was reduced and LAmB was begun at high doses to improve its penetration in the central nervous system,¹¹ but surgical debridement was not feasible owing to brain involvement. Mortality of mucormycosis remains unacceptably high (approximately 40% of solid-organ transplant recipients^1,5) and close to 100% when dissemination, especially to the central nervous system.⁵ Hence, alternative strategies (eg, antifungal combination therapy) are required. At present, only 2 of the currently licensed systemic antifungal drugs—amphotericin B and POS—display in vitro and in vivo activity^12,13 against the Mucorales. The LAmB-POS combination therapy has been mainly investigated as salvage therapy;¹⁴ therefore, clinical data are sparse. Interestingly, 2 studies report a 60% to 79% response rate when POS is given alone or in combination with LamB.^15,16 Moreover, based on promising clinical results¹⁷ and pharmacological data,¹⁸ it has been suggested that POS may be a therapeutic option when treating central nervous system fungal infections. Given the severity of the clinical presentation in our patient and referring to the above-cited arguments, combination therapy (LAmB IV 10 mg/kg/d and POS) was used.

Finally, clinicians must be aware that the finding of a presumed fungal pneumonia on computed tomographic findings, with repetitively negative Aspergillus galactomannan serum antigen, support the diagnosis of unusual fungal infections including some owing to voriconazole-resistant species such as mucormycosis.² Even if it is impossible to distinguish the respective responsibilities of reduced immuno-suppression and early antifungal combination therapy regarding the clinical improvement of our patient, this report suggests that combination therapy relying on high-dose LAmB together with POS could be a treatment option, especially in patients having a poor prognosis—those with disseminated infections and when surgical debridement is not feasible.¹⁹

Volume: 14 Issue: 1 February 2016

FULL TEXT