Management of Scedosporium apiospermum in a pre- and post-lung transplant patient with cystic fibrosis

Abstract

Although the predominant type of infection seen in the cystic fibrosis lung remains bacterial, fungal organisms are being isolated more frequently and are associated with a high mortality rate in lung transplant recipients. We present a case of a patient with CF with sputum cultures positive for Scedosporium apiospermum prior to a successful lung transplant. She remains without evidence of infection 18 months later following treatment with a combination of triazoles and terbinafine.

1. Introduction

The genus Scedosporium consists of two medically important species: Scedosporium apiospermum and its telomorph, or sexual form, Pseudallescheria apiosperma, and Scedosporium prolificans. It is a ubiquitous, saprophytic mold that can be isolated from a variety of environmental sources including soil, sewage, polluted water, and decaying vegetation. S. apiospermum is one of the most frequently isolated molds found in CF, second only to Aspergillus species. The rate of these fungal infections increases as life expectancy of these patients improves[1]. Scedosporium species have been isolated in 8% of sputum cultures from patients with CF, placing them at higher risk of subsequent infection[2,3]. They are associated with a high mortality rate in lung transplant recipients. As the spectrum of isolated fungal pathogens broadens, novel antifungal protocols may be needed to improve outcomes in immunocompromised patients. We present a case of a patient with CF with sputum cultures positive for S. apiospermum prior to a successful lung transplant. She continues to be without evidence of infection 18 months later following pre- and extended post-lung transplant treatment with a combination of triazoles and terbinafine.

2. Case

A 24-year old woman with CF, diagnosed at the age of 8 months, was found to have a gradual decline in her pulmonary functions. Her FEV1 had decreased from 1.16 (35% of predicted) in 8/2010 to 0.71 (22% of predicted) in 2/2011; oxygen (O₂) saturation was 93% on room air. She was referred for evaluation for bilateral lung transplantation. Sputum culture was obtained as part of pre-transplant workup and revealed two strains of Pseudomonas aeruginosa and Rhizomucor species. Rhizomucor was found to be sensitive to amphotericin B with minimum inhibitory concentration (MIC) of 0.5 ug/ml and resistant to voriconazole with MIC 32 μg/ml. An attempt at sterilization of Rhizomucor with inhaled liposomal amphotericin B was attempted; however, the patient developed significant wheezing and dyspnea after using the medication for one–two weeks. She was then started on oral posaconazole 400 mg twice daily with high fat meals and pancreatic enzymes.

Three weeks later, the patient presented to clinic with fevers to 102 and increased sputum production. Her O₂ saturation was 93% on 4 l oxygen per nasal cannula. Polymerase chain reaction (PCR) performed on nasal secretions revealed Influenza A virus RNA. She was admitted to the hospital and oseltamivir was instituted; additionally, intravenous tobramycin 10 mg/kg daily and intravenous doripenem 750 mg every eight hours were given to treat Pseudomonas from her earlier sputum culture. Computed tomography (CT) scan of the chest showed new bilateral lower lobe and lingular peribronchiolar nodules, extensive bronchial wall thickening, and diffuse bronchiectasis (Fig. 1). The patient was hospitalized for nineteen days with gradual improvement of her respiratory status. Discharge plans included completing a two month course of posaconazole followed by lung transplant evaluation.

Fig. 1.

Computer tomography of chest demonstrates bilateral lower lobe and lingular peribronchiolar nodules.

The patient was seen in clinic one week later. She remained oxygen dependent on at least 2 l oxygen per nasal cannula with poor exercise tolerance. Spirometry at this visit revealed FEV1 of 0.60 (18%). Sputum culture was obtained one week later and revealed rare growth of Pseudomonas and rare S. apiospermum; there was no growth of rhizomucor. Antifungal susceptibility testing for S. apiospermum showed voriconazole MIC levels to be <0.06 mcg/ml; no sensitivity data for posaconazole was available. Although voriconazole was considered to be a better triazole to treat S. apiospermum, posaconazole was continued as voriconazole has no activity against the zygomycetes and there was potential for persistent growth of Rhizomucor. Two weeks later, the patient developed fevers to 101.3, mild left-sided pleuritic chest pain, and increased sputum production. Because of the concern for worsening fungal pneumonia, terbinafine 250 mg once daily was added to voriconazole. Fevers and pleuritic chest pain resolved over the next ten to fourteen days. A CT scan of the chest obtained six weeks later showed a significant decrease in lung nodules with persistent severe bronchiectasis (Fig. 2). Sputum culture obtained three weeks after addition of terbinafine was negative for mold. Due to the severity of her lung disease, she was evaluated by the transplant program and was felt to be an adequate albeit high risk candidate for double lung transplantation.

Fig. 2.

Improvement of lung nodules following three months of combined antifungal therapy with voriconazole and terbinafine.

Two months after initiation of combination treatment of S. apiospermum, a suitable donor was discovered and the patient underwent bilateral lung transplant. Standard immunosuppression protocol was employed. Intraoperative cultures from the native lung along with postoperative bronchial washings revealed S. apiospermum. Because of the variable absorption of posaconazole in a CF patient with pancreatic insufficiency, there was difficulty in regulating tacrolimus drug levels; therefore, antifungal therapy was changed to voriconazole and terbinafine. Liver and renal function studies were monitored closely given the additive toxicities of voriconazole and tacrolimus. She was weaned off oxygen and discharged from the hospital 16 days after admission.

Following transplant, multiple bronchoscopies were performed and remained negative for the growth of bacterial or fungal organisms. Voriconazole was discontinued after six months; bronchoscopy performed nine months after lung transplant remained negative for the growth of mold and terbinafine was discontinued. The patient is now 17 months post-transplant and without evidence of recurrent infection.

3. Discussion

Given the lack of clear reason for the relatively high occurrence of Scedosporium colonization in CF patients, Pihet et al. [4] performed an environmental study on six CF patients colonized by the mold. 164 samples were obtained from their homes and analysis included those from the surface, air, garden soil, and potted plants. Only the group with potted plants showed significant fungal colonization with S. apiospermum isolated from 36/55 samples. These results indicate it may be prudent for CF patients to avoid the presence of potted plants in their homes both before and after lung transplant as they appear to be a natural reservoir for this mold [5]. S. apiospermum is also increasingly being recognized as a significant pathogen, especially in immunocompromised patients, and has been associated with sinusitis, necrotizing pneumonia, and disseminated infections in patients with cystic fibrosis, bronchiectasis, and chronic lung disease [4]. The actual infection rate may be underestimated due to the difficulty of diagnosing this mold as its clinical presentation, radiologic appearance, and septated appearance on histopathology is similar to Aspergillus. This misdiagnosis could be lethal considering that S. apiospermum is almost always resistant to amphotericin B, the agent frequently used in presumptive Aspergillus infections [6].

A major problem in management is that Scedosporium is an opportunistic mold that may cause either benign, asymptomatic colonization or systemic invasive disease in pre-transplant CF patients. Patients may remain asymptomatic despite colonization for several years; however, Scedosporium has the ability to secrete proteases which may degrade host proteins. It releases polysaccharide/protein antigens which can trigger a local immunological reaction similar to allergic bronchopulmonary disease [7]. Compared with other saprophytic molds, however, Scedosporium species are less likely to be colonizers or contaminants in the appropriate high-risk population [8]. Additionally, the organism is capable of adventitious conidiation (generation of spores in tissue) with associated hematogenous dissemination and positive blood cultures [6]. Various case reports suggest S. apiospermum may cause invasive disease in patients with CF. Borghi et al. [5] reported the premature death of a non-transplanted CF patient who developed disseminated disease one year following the initial isolation of S. apiospermum. In lung transplant recipients, Scedosporium species found in bronchoalveolar lavage (BAL) was associated with advanced bronchiolitis obliterans and airway stenosis [9]. There is poor perfusion to the telescoped bronchial anastamosis and the subsequent development of necrotic sloughing of tissue; thus, this area is at high risk for the development of infection because of poor delivery of systemic antifungal agents. Without antifungal prophylaxis, early fungal membranes in the airways are very common [10].

Most concerning is the risk of disseminated disease and death in CF patients following lung transplant due to increased immunosuppression [5]. The main sites of infection are the lungs, sinuses, CNS, and skin [11,12]; ocular infections such as endophthalmitis or chorioretinitis may also occur [13]. Mortality for disseminated Scedosporium infection in solid organ transplant recipients is close to 100% [14]. This high mortality rate is not only caused by an impaired immune system, but is also due to delayed recognition and diagnosis which can cause an increased risk for dissemination.

The standard of care for management of these fungal infections is not well established. Voriconazole is a broad-spectrum triazole agent that is fungicidal for Aspergillus, S. apiospermum, and other molds like Fusarium. Troke et al. looked at 43 patients with S. apiospermum infection; 54% of patients responded to voriconazole with MIC₅₀ of 0.25 μg/ml [12]. Other studies also show a mediocre response rate in which even triazoles gave only a 50% response rate [6].

The triazole posaconazole (MIC90, 2 μg/ml) also shows some activity against these organisms, but the food-dependent absorption in patients with pancreatic insufficiency makes post-lung transplant calcineurin inhibitor levels difficult to control in CF patients [15]. Additionally, higher doses may have to be used for CF patients due to a larger volume of distribution and higher levels of drug excretion [16]. It is imperative that triazole drug levels are checked due to the malabsorption from pancreatic insufficiency seen in CF patients which causes unreliable bioavailability. Our patient required a non-conventional dose of voriconazole, 300 mg twice daily, to achieve a trough above accepted therapeutic MICs. Calcineurin inhibitor levels must also be monitored closely due to interactions with voriconazole [15,17].

Lujik et al. [17] described S. apiospermum infection in a lung transplant recipient with cystic fibrosis. The patient had been noted to have pre-transplant sputum colonization with S. apiospermum; thus, following transplantation she was treated with a six month course of voriconazole. Post-transplant cultures were negative for mold; however, two months later she developed spondylodiscitis and psoas abscess and surgical biopsy revealed S. apiospermum. The patient had resolution of infection with voriconazole and remained on treatment for over three years; lumbar spine relapse occurred over one year later and the patient was restarted on voriconazole. Other case reports describe disseminated S. apiospermum infection after lung transplantation which resulted in patient deaths [18,19].

Although studies have shown poor in vitro potency of terbinafine monotherapy against Scedosporium species (MIC90, >16 ug/ml) the combination of terbinafine with voriconazole or itraconazole when used against S. prolificans in vitro has demonstrated syngergistic activity [9,20]. Although further studies are needed to evaluate in vivo efficacy of combined therapy, two cases of successful treatment of post-lung transplant S. apiospermum infection were reported by Musk et al. [13]. Due to limited response rates of most antifungal agents, alternative strategies such as combination therapy and dosage escalation should be evaluated further.

Because of the low incidence of invasive infections in CF patients with S. apiospermum colonization, however, positive pulmonary cultures should not preclude these patients from transplant evaluation [19]. Close monitoring of clinical status and frequent re-evaluation with bronchoscopy, cultures, and repeat imaging is essential, especially if not improving on polyene antifungal treatment for presumed Aspergillus. In light of the significant morbidity and mortality with this mold infection and unclear antifungal efficacy, it may be most prudent to focus efforts on prevention and minimize environmental exposures.

Funding source and potential conflict of interest

This study was unfunded. There are no conflicts of interest.