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Highlights of this month...
Serious fungal infections such as Invasive Aspergillosis (IA) are notoriously difficult to diagnose early and thus treatment is difficult and often unsuccessful with high morbidity and mortality. New antifungal drug classes are being actively developed but there is still a need for alternate treatment strategies as there will always be the threat of resistance developing and of course some of the barriers to successful treatment may be common to a single mode of attack.
Genetic susceptibility to fungal infection by Aspergillus
is being investigated and Overton et.al.
(2017) recently identified multiple genetic weaknesses in the immune systems of people with fungal asthma (SAFS) and Allergic Bronchopulomonary Aspergillosis (ABPA Overton et.al.
Reducing genetic susceptibilities in these patients using immunotherapy is therefore a strategy worth investigating and this new review by Posch et.al.
discusses the options. The review concludes that some progress has been made in the development of immunotherapies for this purpose and that they should be possible but we need to know a lot more about the risks and benefits before becoming too optimistic about their use in the clinic.
Spread of antifungal resistance
Resistance to antifungal drugs is an increasing problem in clinics worldwide as doctors attempts to treat serious fungal infections. Evidence is accumulating
that one source of resistant strains is environmental and is caused by the exposure of Aspergillus
strains to agricultural fungicides that are closely related to the triazole drugs used in clinics.
We issued a Press Release
on this subject this month after a group in Ireland detected strains of Aspergillus fumigatus
that were resistant to several antifungal drugs used in the clinic on tulip bulbs imported from the Netherlands
. The assumption is that the use of fungicides as pesticide when growing the bulbs for export has led to the acquisition of resistance in fungi growing in soil surrounding the bulbs. It isn't difficult to imagine many people coming into contact with bulbs contaminated in this way and this could well be one route via which resistant to antifungal medication is spread, and indeed one way that patients who own gardens may become infected. Given the amount of international trade in grown products it is also easy to postulate many more routes of contamination and spread.
There have been 82 new articles & reviews uploaded in June. Some of the highlights are:
Triazole antifungal drugs such as voriconazole and itraconazole can occasionally shorten the QTc interval of the normal cardiac rythmn and thus disrupt normal heart function. The authors of this study noted that the new antifungal drug isavuconazole has the opposite effect on QTc interval, prolonging instead of shortening.
A case is described where a patient who was experiencing shortened QTc interval while being treated with voriconazole was switched to isavuconazole whereupon their QTc interval normalised.
Aspergillus fumigatus (AF) and Pseudomonas aeruginosa (PA) are the most
prevalent fungal and bacterial pathogens isolated from the CF airway,
respectively. Co-colonisation with both pathogens was comparable with persistant colonisation with PA in terms of clinical outcomes (e.g. lung function, exacerbations, hospitalisations etc.). Intermittant colonisation or colonisation with AF alone was associated with better outcomes. This study emphasises the clinical signification of co-colonisation of these micro-organisms.
This trial was a randomized, double-masked
trial to determine the optimal treatment for filamentous fungal
keratitis using 323 fungal ulcer cases at the Aravind Eye Care System, India. Enrolled cases were
randomized to receive topical natamycin or voriconazole.The authors concluded: "Fungal keratitis that is smear-positive despite being pretreated with
appropriate antifungal agents appears to be a risk factor for worse
outcomes, likely a result of initial ulcer severity and treatment
failure. These patients may benefit from more aggressive multimodal
therapy at a tertiary centre."
Fungal endocarditis is an extremely debilitating fungal infection most prevalent in the immunocompromised and intravenous recreational drug users. Most patients present with constitutional symptoms, which are
indistinguishable from bacterial endocarditis, hence a high index of
suspicion is required for pursuing diagnosis. Diagnosis of fungal
endocarditis can be very challenging: most of the time, blood cultures
are negative or take a long time to yield growth. Fungal endocarditis
mandates an aggressive treatment strategy. A medical and surgical
combined approach is the cornerstone of therapy.
ABPA is a common infection in people with cystic fibrosis with nearly one in eleven patients affected though as several clinical features of ABPA overlap with those of CF it is thought that ABPA in CF is underdiagnosed. This review suggests that diagnosis of ABPA in CF patients should be sought in those with evidence
of clinical and radiologic deterioration that is not attributable to
another etiology, a markedly elevated total serum IgE level (while off
steroid therapy) and evidence of A. fumigatus sensitization.
of ABPA involves the use of systemic steroids to reduce inflammation and
modulate the immune response. In patients who do not respond to
steroids or cannot tolerate them, antifungal agents should be used to
reduce the burden of A. fumigatus allergens. Recent studies suggest that
omalizumab may be an effective option to reduce the frequency of ABPA
exacerbations in patients with CF.
Chronic necrotizing pulmonary aspergillosis (CNPA) is a form of chronic
pulmonary aspergillosis (CPA) and affects immunocompetent or mildly
immunocompromised persons with underlying pulmonary disease. These
conditions are associated with high morbidity and mortality and often
require long-term antifungal treatment. The long-term prognosis for
patients with CNPA and the potential complications of CNPA have not been
well documented. The aim of this study was to review published papers
that report cases of CNPA complications and to highlight risk factors
for development of CNPA.
The authors show growth of three fungal species (Penicillium brevicompactum, Aspergillus versicolor and Stachybotrys chartarum) on wallpaper, commonly used to decorate family homes. Those three species produced at least four different mycotoxins, one at levels >100mg/m2 of wallpaper.
The authors showed that air currents similar to those in a normal busy building could release variable amounts of allergen and mycotoxin into the air with up to 15% of one of the species toxins made airborne.
The most part of the aerosolized toxic load is found in particles whose
size corresponds to spores or mycelium fragments. However, some toxins
were also found on particles smaller than spores that are easily
respirable and can deeply penetrate into human respiratory tract.
This is a first step to assessing the risk to health caused by the growth of moulds in damp buildings.
A case of azole-resistant invasive aspergillosis in a female bottlenose
dolphin, who failed to respond to voriconazole and posaconazole therapy.
As intravenous therapy was precluded, high dose posaconazole was
initiated aimed at achieving trough levels exceeding 3 mg/l.
Posaconazole serum levels of 3-9.5 mg/l were achieved without
significant side-effects. Follow-up bronchoscopy and computed tomography
showed complete resolution of the lesions.
Leucocyte populations in the sinonasal mucosa of cats with and without
upper respiratory tract aspergillosis were compared using
immunohistochemistry and computer-aided morphometry.
Importantly, the inflammatory profile in affected cats was not
consistent with the T helper (Th)1 and Th17 cell-mediated response that
confers protective acquired immunity against invasive aspergillosis in
dogs and people and in murine models of the infection. This finding may
help to explain the development of invasive aspergillosis in
systemically immunocompetent cats.
As such he coordinates and runs all of the wide range of trials we
are conducting at NAC and there are many more to come. Azad introduces
some of these trials in this talk and also talks about the importance of
patient and carer input into the setting up and running of each trial
and how they can be involved.
We already have patient volunteers for one or two trials we are
running but will need more for each new trial, so we will be setting up a
group of prospective volunteers in order that we advance our research
and the development of new drugs and diagnostic techniques as quickly as
possible. It seems that we will be able to wrk with patients &
carers from all over the country by using Skype to allow them to
participate in meetings from their own home.
Graham Atherton then went on to talk about setting up a a 'Patient priorities' project with the European Lung Foundation.
We are also running a successful Skype meeting every week
! We are a chatty group of 8 - 12 most weeks but we can accomodate up to 24. If you have a computer or phone that has APP's you will be able to install Skype and join in - instructions at the link below. Skype at 11am BST every Thursday
. Instructions will change over the next few weeks so go to http://www.nacpatients.org.uk/content/skype-group
for the latest information.
Aspergillosis Community (National Aspergillosis Centre) normally meets on the first friday of each month at the Altounyan Suite, North West Lung Centre, Manchester at 1.30pm BST/GMT. If you can't make it in person, you are welcome to listen in to our live Facebook broadcast.
If you want a text reminder when each meeting is approaching (UK only) then send us an email at email@example.com with your mobile phone number.