EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Invasive fungal infection after solid-organ transplantation is known as a severe complication and carries with it a high risk of infection-related mortality. Among patients after heart transplant Aspergillus species most often cause atypical pneumonia. The incidence of invasive aspergillosis after heart transplant has been reported from 3% to 14%. It is the opportunistic pathogen with the highest mortality, ranging from 50% to 80%. Prompt antifungal therapy is crucial, but rapid diagnostic procedures with sufficient sensitivity and specificity are lacking at the moment. We present a rare case of a patient with massive metastasizing invasive aspergillosis within 1 month after heart transplant, undetected before death.

Key words : Invasive aspergillosis, Solid-organ transplant, Heart transplant, Combination therapy

Invasive aspergillosis (IA) is a common life-threatening infection in highly immunocompromised patients with mortality rates between 30% and 90%.¹ Intracranial aspergillosis is a rare pathologic condition, difficult to treat, and often fatal that generally affects immunodepressed patients.² There have been only a few reported survivors, and mortality exceeds 95% in the immunosuppressed host.³

Early diagnosis improves mortality but can be challenging.⁴ The introduction of second-generation triazole voriconazole has played a role in decreasing morbidity and mortality, when compared to amphotericin B,⁵ but concern exists regarding mounting azole resistance,⁶ and mortality remains as high as 30-80%.^7,8 Owing to the suboptimal outcome with antifungal monotherapy, either with azoles or amphotericin B, combination antifungal therapy has become a point of interest. Data from controlled studies regarding antifungal combination therapy for treatment of IA and some results of in vitro studies, animal models, and case reports suggest that antifungal combination therapy with azoles and echinocandins may have additive activity against Aspergillus species.^9-11

Herein, we report a rare case of a patient with massive metastasizing IA within 1 month after heart transplant, undetected before death.

A 61-year-old man underwent orthotopic heart transplant in July 2012 because of its dilatative cardiomyopathy with ejection fraction of 15% and recurrent cardiac decompensation. In November 2011 implantation of a Left Ventricular Assist Device (LVAD, Heartware Inc., Framingham, MA, USA) as bridge to transplant was necessary.

Orthotopic heart transplant passed off without complications, the organ could be implanted within 3 hours of total ischemia. Postoperatively, the patient could be delivered to ICU in hemodynamic stable state with moderate catecholamine infusion. Because of acute on chronic renal failure, continuous renal replacement therapy was initiated. Transesophageal echocardiography always showed a very good cardiac function. As a consequence of elevated infection parameters in combination with fever an empirical antibiotic therapy with ceftazidime and teicoplanin was initiated. The patient could be extubated 6 days after transplant.

One day after extubation, the patient had to be re-intubated due to respiratory decompensation. The situation was accompanied by high need of catecholamine support due to circulatory insufficiency. By pulmonary artery catheter a cardiac index of 3.5 L/min/m² was calculated. Bronchoscopy as well as bronchoalveolar lavage revealed no pathological findings However, with persistently elevated C-reactive protein, procalcitonin, and leucocytes antimicrobiologic therapy was changed to imipenem and caspofungin. During the following days, the hemodynamic situation was stabilized with only mild catecholamine support.

Endomyocardial biopsy 10 days after transplant showed no rejection. Dilatative tracheotomy was performed 6 days after reintubation, 12 days after transplant. With suspicious clinical appearance of the abdomen with distension and insufficient intestinal motility repetitive sonographic examinations were performed, showing no pathologic findings. After an episode of massive vomiting 16 days after transplant, computed tomography of the abdomen detected signs of intestinal perforation, causing an emergent laparotomy. Intraoperatively a localized perforation of the coecum was sewed over. There was no need of resection of intestinum, the abdominal wall could be recapped primarily. According to the clinical situation the antimicrobiologic therapy was adapted with withdrawal of caspofungin, continuation of imipenem and additional administration of metronidazole and teicoplanin. In the further course, the patient was stable, with need of mild catecholamine support; he was always awake and neurologically adequate.

Eight days after laparotomy (23 days after transplant) a burst abdomen was detected, once again leading on to an emergent relaparotomy. A new intestinal perforation was obvious, causing the resection of the ileocecal segment with ileo- and Ascetostoma. The abdominal wall could not be recapped in this situation. During an elective abdominal lavage 3 days later few hepatic lesions were detected and atypically resected.

Five hours after this operation (POD 27 after orthotopic heart transplant), the patient was somnolent and not adequately contactable. Clinical examination showed anisocoria. Computed tomography revealed early signs of ischemic infarction in media and anterior area of both hemispheres (Figure 1A). External ventricular drain was installed because of neurologic impairment of the patient with worsening of the vigilance. Control computed tomography did not yield new effects, particularly no signs of brain incarceration.

Two days later, computed tomography was repeated again and showed global cerebral infarction without the possibility of grey/white matter differentiation, global cerebral edema, and upper incarceration (Figure 1B). Decision was taken not to widen therapy, death took place 1 month after the transplant.

While during the lifetime, all microbiologic examinations of several tissues (liver, appendix, ileum, bronchoalveolar lavage, blood cultures) could not find any pathologic result (beside abdominal Enterococcus faecium and Candida albicans in tracheal secretion), the autopsy findings were quite surprising:

Metastasizing invasive extrapulmonary asper-gillosis with multiple abscess formations in left ventricle, liver, and both kidneys (Figure 2), but not in the lung were found. Neuropathologic results showed massive septic-metastasizing encephalitis caused by IA with hemorrhagic infarction of the greater part of the cerebrum including mesencephalon and basal ganglia (Figures 3A and 3B). Postmortem we received the final result of the histologic examination of liver and intestinal tissue resected while the surgical interventions due to intestinal ischemia and burst abdomen. Invasive aspergillosis already existed at that time (Figure 4). Subsequently, it can be stated that the patient deceased because of central failure of regulatory function caused by septic-metastasizing aspergillus encephalitis.

Invasive aspergillosis is a rare but life-threatening opportunistic infection after solid-organ transplantation. Because of the extremely high mortality, it is crucial to start effective antifungal therapy early. However, early diagnosis of invasive pulmonary or extrapulmonary aspergillosis is still challenging.¹¹ Montoya and associates described a median time of 46 days for onset of invasive pulmonary aspergillosis after a heart transplant, but a median time of 104 days to the first positive culture result.¹² Radiograph or computed tomography in case of invasive pulmonary aspergillosis may show typical nodules, but again, they represent diagnostic procedures with poor sensitivity and only do matter in concern of pulmonary aspergillosis. Further signs of IA were described in some publications, such as fever, acute organ rejection, with patients being cytomegalovirus positive carrying a higher risk of IA.¹³

The presented case illustrates the natural course of a patient who had IA after solid-organ transplant in a dramatic manner. Sufficient diagnostic tools were lacking, and adequate therapy could not be initiated.

The event of acute intestinal perforation even lead the clinicians on a false trail. Caspofungin had been removed early, while believing that acute peritonitis being focus. In our case, pathological examination had been the only diagnostic tool to proof IA, but as mentioned above, these results were not available when patient was alive. Furthermore, the uncommon manifestation of the IA (affecting multiple organs without pulmonal infiltration) constitutes a remarkable fact, which additionally aggravated early diagnosis. Furthermore the abrupt and massive cerebral destruction needs to be mentioned. Computed tomography scan performed immediately after appearance of the first neurologic symptoms could not detect any Aspergillus-like infiltrations, but seemed to show disseminated cerebral ischemia, being rapidly progredient and causing death within a minimum of time.

Early diagnosis must be the main goal for successful treatment of IA. As sufficient diagnostic tools beside positive culture or histopathology are still missing in the moment, early and broad antifungal therapy with that is, voriconazole, maybe even as combination therapy should be considered during the early postoperative course (90 days) after solid-organ transplant.^9,10 As seen in this case, clinical, radiologic, and cultural/histopathologic findings are inadequate for early diagnosis of IA, especially concerning extrapulmonary manifestation. Detection of serum galactomannan as a matter of routine to detect the dynamical development of the antigen, even without clinical suspicion of IA should be discussed and may lead to earlier diagnosis, early, and adequate therapy, and improved outcome of patients with IA.

Volume: 14 Issue: 3 June 2016

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