What is Scedosporium and how does infection occur?
Scedosporium apiospermum is found throughout the world in soil and polluted water. Strictly speaking S. apiospermum is the asexual form of a filamentous fungus which when isolated in its sexual form (reproductive form) is called Pseudallescheria boydii. Both forms look different when growing on agar but they are in fact the same mould. So maybe the sexuality of moulds does matter?
Infection occurs after inhalation of spores. This can occur as an opportunistic infection in immunosuppressed patients or following water inhalation after a near-drowning accident (have I told you of my near drowning accident…see blog). S. apiospermum can also colonise without causing infection. Patients most at risk of developing infection with S. apiospermum are immunosuppressed in some way including bone marrow transplant recipients, chronic steroid use, haematological malignancies, chronic granulomatous disease and other organ transplant recipients (especially lung transplants).
Given that the mould is usually acquired through inhalation of spores it is not surprising that respiratory tract infection is the most common clinical presentation of infection; either pneumonia or sinusitis. After inhalation S. apiospermum can potentially invade either locally or through the blood stream. Local invasion from the sinuses can lead to brain abscesses whereas dissemination via the bloodstream can lead to necrotic skin lesions, abscesses and endophthalmitis.
Infection can also occur if contaminated water or soil gets into the eyes, causing keratitis, or into skin and soft tissue following contamination of broken areas of skin due to trauma.
The main problem with diagnosing S. apiospermum is that most people do not think about invasive fungal infections when they are seeing patients as fungi are uncommon; think zebra amongst horses (sorry, just returned from Botswana…great wildlife viewing in Botswana!). It is therefore important to keep an open mind when seeing immunosuppressed patients and to consider that they might have an opportunistic infection even if you don’t know all of the potential pathogens in a given situation. This is how I approach these patients and it helps me from missing potential diagnoses.
Having thought about the diagnosis, the next step is to try and get the appropriate specimens (and decide which tests to ask for and which bottle to place the sample in!). Acquiring the specimen is not always easy, as the infection can be in a place that requires an invasive procedure to take samples. Another difficulty is distinguishing infection from colonisation (any moist site can become colonised without causing infection) when samples are taken from non-sterile sites. Sometimes this is a bit of alchemy but if you are treating an “infection” with the right treatment and it just won’t go away, then consider that it might be colonisation rather than infection. There have been good guidelines produced about the diagnosis of invasive fungal infections by the British Society for Medical Mycology which have been the subject of a previous blog.
The most useful tests to confirm S. apiospermum are histology and culture. However as the differential diagnosis in immunocompromised patients is so broad it is important to look for other common moulds, e.g. Aspergillus spp. and zygomycetes at the same time. Beta-D-glucan is the investigation of choice. Beta-D-glucan is part of the cell wall of many of the moulds and its detection in a sample indicates infection from a mould, however it is not specific to S. apiospermum. Beta-D-glucan detection can help with deciding whether to perform further invasive sampling techniques, such as taking biopsies or bronchoscopies, in patients with a positive test.
The mortality from S. apiospermum in immunosuppressed patients ranges from 40-100% depending on the underlying disease and whether an appropriate antifungal is prescribed. If the laboratory grows S. apiospermum antifungal sensitivity testing must be performed to help guide therapy. The appropriateness of an antifungal can only be assessed by testing whether it is active or not. Antifungal testing like this is usually done by Reference Laboratories, not regular microbiology laboratories, and this can take up to 2 weeks to get a result. At this stage you have the microorganism and based upon this a Microbiologist can choose a “best guess” treatment, which for S. apiospermum is Voriconazole.
Treating S. apiospermum is difficult!
Waiting 2 weeks for a sensitivity result is therefore not possible before starting antifungals, so empirical therapy is initially required. Voriconazole is usually used as the initial empirical therapy for S. apiospermum as this is most likely to be active.
The outcome of treatment and survival from S. apiospermum is influenced by a number of other important factors including: the site of infection, whether the fungal burden can be reduced by surgical resection and the underlying immunosuppression of the patient and whether this can be reversed.
Voriconazole is available both orally and intravenously which, when appropriate, helps to facilitate outpatient therapy during long duration treatment regimens. The main drawbacks to Voriconazole are the need to monitor serum levels every week and the potential for side-effects and interactions with other medications. Voriconazole has lots of interactions as it inhibits cytochrome P450 (an enzyme that interferes with an awful lot of drugs). Trough levels are required to try and maximise response without side-effects or toxicity occurring, the target is 2-5.5 mcg/mL.
Amphotericin B lipid formulations e.g. AmBisome, have been used to treat S. apiospermum but they are much less effective than Voriconazole and have a much higher mortality. These should not be used unless shown to be active on sensitivity testing. Amphotericin B lipid formulations are also only available IV which makes outpatient treatment more difficult.
Echinocandins, Itraconazole and Terbinafine have variable activity against S. apiospermum and should not be used unless the microorganism is definitely known to be sensitive and there is a reason not to use another option. In this case combination therapy may be appropriate e.g. Itraconazole PLUS Terbinafine has shown synergy in vitro but there is limited clinical experience with this combination.
There is no specific duration of therapy; every patient should be managed individually. Treatment should continue until all signs of infection have improved and in some patients with ongoing immunosuppression it may be prudent to continue therapy until their immunosuppression has resolved as they may never fully clear the infection when immunosuppressed. Some patients even warrant life-long therapy. The minimum treatment is 3 months before any further decision about length of therapy is considered.
Our patient was one of the lucky ones and he did slowly start to improve once his Voriconazole levels were optimised. One of the things that helped his case was the multidisciplinary approach that lead to a relatively quick diagnosis and initiation of treatment. However, given that he will always be immunosuppressed due to his bone marrow transplant a decision was made to continue with Voriconazole for the time being and watch his Beta-D-glucan levels regularly to look for possible signs of reactivation. He may well be on life-long therapy. What about resistance… who knows… watch this space…