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Hi everyone.

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Welcome to Febrile, a cultured podcast
about all things infectious disease.

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We use consult questions to dive into
ID clinical reasoning, diagnostics

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and antimicrobial management.

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I'm Sara Dong, your host
and a Med Peds ID doc.

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Today's episode of Below the Belt
is led by a team from Australia.

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First up, we have Dr. Morgan Hui.

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Morgan is a basic physician's trainee
with an interest in infectious diseases.

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He is currently working as
an ID registrar at Peninsula

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Health in Melbourne, Australia.

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Hi, it's Morgan.

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Very keen to be here today.

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Dr. Jonathan Darby is an infectious
diseases and general medicine physician.

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He is the head of General Medicine
at St. Vincent's Hospital, Melbourne,

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and an Associate Professor at
the University of Melbourne.

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Hi.

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It's great to be here with you today.

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Dr. Max Olenski is an infectious diseases
and general medicine physician with

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an interest in tropical medicine and
infections in immunocompromised hosts.

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He is the current Perioperative
Medicine Unit Clinical Lead at Peninsula

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Health  and a Sessional Academic
with Monash University in Melbourne.

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Hi, it's Max Olenski here.

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Thanks so much for having us today.

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Really excited for this podcast.

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Dr. Catriona Halliday is the Principal
Hospital Scientist in charge of

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the Clinical Mycology Reference
Lab at the University for Clinical

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Pathology and Medical Research and
New South Wales Health Pathology

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based at Westmead Hospital in Sydney.

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She is actively involved in teaching
both scientific and medical staff in

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medical mycology, and has a strong
interest in culture independent tests to

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aid in the rapid diagnosis of invasive
fungal infections and antifungal

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drug susceptibility surveillance.

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Hi, it's Catriona Halliday,
and nice to be here too.

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Wonderful.

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Thank you guys so much for coming.

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We are just gonna quickly start by
asking you to share a little piece

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of culture, because we call Febrile
everyone's favorite cultured podcast.

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So really just sharing a little
something non-medical that you like,

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whether that's pop culture or hobbies,
um, or other interests that you have.

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So what have you guys
been enjoying recently?

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I had the pleasure of going to see
recently for International Women's

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Day, I went to see the RBG: Of Many,
One, um, production about  Ruth Bader

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Ginsburg's life, which was fantastic.

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It's one woman show, I think it's tour of
the states, uh, and it's come back time

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and time again in, in, uh, Australia.

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That's cool.

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I haven't seen that.

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I was gonna say that in recent
times, my daily routine has, uh,

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incorporated the New York Times puzzles.

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I, I sort of churn through
them every morning while I'm

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having my morning coffee.

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And also I've been doing the
cryptid crossword of late to try

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and get my creative juices flowing.

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Excellent.

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Love a good puzzle.

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Uh, Morgan.

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Uh, since Covid, I think I've been
picking up golf after lockdown.

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Um, not that I play well, but
it's enjoyable to get outdoors.

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And then in the same vein, uh, I've
been watching a lot of golf, YouTube,

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especially being between studying.

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It's very easy watching.

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Um, and it's just something to turn my
brain off at night, which is quite good.

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Yeah, the turning your brain
off is usually a, a common

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theme on people's suggestions.

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Um, and rounding us out, Jonathan.

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Well, I saw you like travel and food.

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So yesterday at weekend Australian time,
I said to my kids, I'm gonna cook dinner,

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and they requested bao buns, so I made
bao buns yesterday, which was good fun.

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Labor of love takes most of the day,

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a lot of work.

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was very nice.

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Yeah, very nice.

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Amazing.

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I love it.

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Well, thank you guys for sharing.

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Um, all right, well, Morgan is
in charge today and is gonna

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take us through the case.

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So I'll hand it over.

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Thank you.

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So today, our case involves a 49-year-old
male who presents to the renal outpatient

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department with a four month history of a
slow growing, painless right elbow lesion.

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He's adherent with his immunosuppression
and a systems review is unrevealing.

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His past medical history includes a
renal transplant in 2017 for primary

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focal segmental glomerular sclerosis.

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His pre-transplant assessment
did not reveal any infections for

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which prophylaxis was afforded.

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His early post-transplant course was
complicated by pulmonary aspergillosis

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and he was treated with a six month
course of voriconazole with clinical,

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biochemical, and radiological resolution.

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At the time of seeing him, he has a stable
allograft function, currently on low dose

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prednisolone, everolimus, and tacrolimus,
and his comorbidities include well

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controlled hypertension, dyslipidemia,
steroid induced osteoporosis, and GORD

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(gastro-oesophageal reflux disease).

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On examination his vitals
were normal alongside a normal

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cardio respiratory exam.

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His abdominal examination revealed
a non-tender right lower quadrant

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mass underlying a hockey stick scar,
consistent with a renal allograft.

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He has a 1.5 centimeter non-tender mobile
lump on the lateral aspect of his right

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elbow, not tethered to the underlying skin
without notable discoloration, overlying

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skin changes, induration, nor sinus.

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There were no other masses on
examination of his lymph node stations.

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At this point, is there anything
else that you'd want to ask our

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patients and what differentials
do you think that you'd entertain?

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Thanks Morgan.

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So just to summarize, this is a
middle aged gentleman who's a renal

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allograft recipient with stable
function on immunosuppression.

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His post-transplant course was
complicated in the early stages, uh,

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with pulmonary aspergillosis, but he
seems to have recovered from that with

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therapy, uh, and presents now with an
incidental painless lump on his elbow.

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Some important questions
that come to mind really are

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clarification  surrounding exposures.

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Um, for instance, what he does for work,
what sort of hobbies he has, um, has

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he had any animal contact, or, a little
bit more about his sexual history.

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Uh, what else is important
would be, um, whether there are

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other locoregional infections or
constitutional symptoms of note.

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The differential diagnosis for a painless
lump in a transplant recipient  runs the

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gamut from a foreign body reaction to
things like a lipoma or other soft tissue

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neoplasms, and this includes lymphoma.

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But considering this is through
the lens of an infectious disease

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approach, I think it's important to
entertain various sorts of infections.

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And likewise, we'd entertain things
like run of the mill bacterial

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skin, soft tissue infections,
like a furuncle or carbuncle.

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But syphilis and cat scratch disease
also appear amongst the differentials.

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Considering a significant history,
fungal etiologies need to be entertained,

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and this includes disseminated
aspergillosis alongside sporotrichosis,

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and, um, more rare things like
mucormycosis or rhizopus infection.

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Um, and then the fine print would be
things like mycobacterial infection, viral

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or parasitic infections, things like TB
or non tuberculous mycobacteria (NTM),

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um, or cysticercosis or trichinellosis
but those sort of things would really

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come to, uh, the fore if his, um,
exposure history was compatible.

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So taking our case a bit further, his
social history revealed that the patient

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immigrated from the Philippines to
Australia 18 years previously, where he

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returns to visit family and friends every
six to 12 months, but not in recent times.

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He's in a long-term heterosexual,
monogamous relationship and works in

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maintenance at an aged care facility.

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He's a sporadic gardener with
no additional epidemiological

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exposures, and does not report any
recent animal nor insect contact,

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nor recent locoregional infections.

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He consumes no alcohol nor smokes tobacco.

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On further history when pressed, he thinks
that he might have had the onset following

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a seamlessly innocuous traumatic injury
against a doorknob without skin breach,

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and no set associated systemic upset.

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His routine lab results were
unremarkable with white cell count,

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LFTs, and inflammatory markers within
normal limits, a stable renal function

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compared to previous, a non-reactive
RPR and a negative QuantiFERON

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gold with a good mitogen response.

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Ultrasound sonography of the lesion
revealed two small circumscribed

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ovoid masses suggestive of
reactive lymphadenopathy.

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This was clinically corroborated
upon surgical review and was resected

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en bloc with tissue set up for
histopathological assessment alongside

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routine mycobacterial and fungal cultures.

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No organisms were seen from the Gram and
Zeihl-Neelson stains, nor subsequently

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cultured . However, filamentous fungi
were noted on fluorescent staining.

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Histopathological examination revealed
multinucleated giant cells, and possible

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copper penny, aka Medlar bodies.

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In addition, there was a suggestion of
a brown micro colony of hyphal elements

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with suspicion for an underlying deep
mycosis, and the specimen was sent for

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further culture and identification.

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I guess, now, what do you think
is meant by deep mycoses and

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how are they differentiated?

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Yeah.

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Thanks for that update,
Morgan, on the case.

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Um, to, to just take a step back.

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This was a subcutaneous lesion
and it, it didn't have any changes

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on the skin, which would make us
think of an inoculation injury.

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But we were certainly taken by the
history of his previous Aspergillus

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infection in the lung and wondered if
this was a site of disseminated infection.

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And there is, as you've pointed out, Max,
a broad differential in a immunosuppressed

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transplant patient with any lesion.

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But it was an unusual site.

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It was an unusual appearance with
relatively few other additional

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symptoms, just that he brought this
mass like lesion to our attention.

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And so to be honest, I hadn't
really used the term deep mycosis

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in clinical practice before.

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Um, I know it's, uh, been raised
here and has been talked about in, in

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some literature, but really when we
think about these lesions, we have a

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broad differential from, from fungal
to atypical mycobacteria to other

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organisms which may be indolent and
slow growing in a transplant patient.

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But this suggestion here with the, the
pigmented nature of the fungal elements

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certainly makes us concerned about
a group of fungi,  which we classify

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in the dematiaceous mould group.

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Um, this is an unusual finding, so
this doesn't happen every day where

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you find this on a biopsy and sometimes
has been found in further other

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organ  sites such as brain or lung
or subcutaneous skin and soft tissue.

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So the, the overarching term we
would sort of use for this would

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be a phaeohyphomycosis, if it
is related to a pigmented mold.

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Actually had to look up the
word "phaeo", 'cause I've always

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wondered where that came from.

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And, and that's, uh, Greek word for dusky.

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So gray or, or black forming.

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And this is thought to be the
melanin in  this group of  fungal

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infections' structure that
causes that, that appearance.

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So there's a few terms we use here.

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And then the other term that
we would consider is this term

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of chromoblastomycosis, where a
chronic infection, usually due

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to inoculation but it could be
dissemination in an appropriate host

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such as this with dissemination.

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Um, there is a well-known entity in
the tropics where these patients have

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a crusted verrucous like lesion on
the skin with chromoblastomycosis.

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And there's a range of specific
species which are fairly geographically

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distinct depending on where  a
patient may have spent time.

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And so with this individual, whilst
living in residential suburban

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Australia, we did note that his
history is from the Philippines and

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traveling back and forth there fairly
frequently with some sparse gardening.

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So we were concerned about this
family of organisms from that basic

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microbiological description before we
had a formal culture and identification

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from our mycology reference laboratory.

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The next step in his workup was
the sterile tissue was sent to

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a diagnostic mycology laboratory
for specialized fungal cultures.

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Uh, from here, Catriona will take
us through exactly what happens

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in the lab to get our diagnosis.

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Thanks very much Morgan, and thank
you Jon for that nice history and

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my, I've now learned what phaeo
means in the phaeohyphomyosis.

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I've got a case at the
moment, so that's good.

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Um, okay.

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So when the sample was sent to us for
culture, we already knew that there were

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fungal elements  seen histologically

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.
When we receive samples in the fungal
lab, it's really important that any

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tissue samples aren't actually ground up.

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We, we just make them into small pieces
and put them onto the various agar and,

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um, we don't grind them up because if
this fungus was likely to be, or we

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sometimes we don't even know if it will
be, a mucormycete, this particular group

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of fungi are really, really fragile.

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Um, and grinding would destroy
the hyphae and, and so the

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organism would be non-viable.

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So as a rule,  no tissue samples are
ground up in a mycology laboratory.

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So these, sterile pieces of tissue were
put onto a variety of different media.

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00:13:31,897 --> 00:13:36,227
We usually use a couple of different
media,  a very general purpose media

229
00:13:36,227 --> 00:13:41,117
with no antibiotics such as Sabouroud
dextrose agar,  and then we use more

230
00:13:41,297 --> 00:13:46,412
nutritious media such as a Sabouraud
dextrose agar base, which might

231
00:13:46,412 --> 00:13:50,342
have something like brain, heart
infusion and  some antibiotics like

232
00:13:50,402 --> 00:13:55,812
chloramphenicol and gentamicin in them
to suppress any bacterial  growth.

233
00:13:56,692 --> 00:14:01,752
So following inoculation, we then  use
plates, but some labs do use slopes.

234
00:14:02,122 --> 00:14:05,422
The plates, we seal them with
parafilm, and then we put them in an

235
00:14:05,422 --> 00:14:10,372
incubator at 30 degrees, rather than
35 degrees, which is what would be

236
00:14:10,372 --> 00:14:12,442
used for most of the bacterial growth.

237
00:14:13,112 --> 00:14:17,222
And 30 degrees, I think most fungi
are environmental organisms and

238
00:14:17,282 --> 00:14:20,432
they just do better for growing
at a slightly lower temperature.

239
00:14:21,042 --> 00:14:26,137
We keep these plates for four weeks
and look at them every couple of days.

240
00:14:26,137 --> 00:14:30,577
And so the reason they're para
filmed is, is both to, to keep the

241
00:14:30,907 --> 00:14:35,117
lids closed,  but also  prevents
dehydration when they're put in the

242
00:14:35,117 --> 00:14:37,397
incubators for, for quite a long time.

243
00:14:38,727 --> 00:14:40,707
So that's the reason we
use that lower temperature.

244
00:14:40,797 --> 00:14:45,877
And,  in this particular case, after
about 10 days, we noticed a  small amount

245
00:14:45,877 --> 00:14:50,647
of growth of a, of a dark gray fungus
growing directly out of that tissue.

246
00:14:51,487 --> 00:14:55,537
So as soon as we get positive
culture, we would then always work

247
00:14:55,537 --> 00:14:57,187
in a biological safety cabinet.

248
00:14:57,477 --> 00:15:02,517
We would then put that organism and
subculture it onto a general purpose

249
00:15:02,517 --> 00:15:05,247
Saboroud agar with no antibiotics in it.

250
00:15:05,787 --> 00:15:12,097
And we'll also prepare a slide culture by
inoculating a potato dextrose agar plate.

251
00:15:12,277 --> 00:15:18,157
In order to identify fungi in the
conventional way, you, you really

252
00:15:18,157 --> 00:15:22,697
need to see how those fungi are
growing  in their natural state.

253
00:15:22,727 --> 00:15:26,897
And so for that, you, you can
use macroscopic appearance, but

254
00:15:26,897 --> 00:15:29,807
the macroscopic appearance can
change depending on the media

255
00:15:29,807 --> 00:15:33,197
that you might be using, how much
light there might be exposed, you

256
00:15:33,197 --> 00:15:34,547
know, to, and things like that.

257
00:15:34,967 --> 00:15:39,807
The macroscopic appearance can be a bit of
a guide, but that microscopic appearance

258
00:15:39,807 --> 00:15:45,657
is what we need to identify something to
the genus and ideally the species level.

259
00:15:46,557 --> 00:15:49,557
So you need to use a media
such as potato dextrose agar

260
00:15:49,887 --> 00:15:52,017
to encourage  that sporulation.

261
00:15:52,767 --> 00:15:56,627
Other media that could be used for
microscopy to prepare slide cultures

262
00:15:56,957 --> 00:16:00,857
is cornmeal agar, which is probably
a little bit less nutritious and

263
00:16:00,857 --> 00:16:02,567
more encouraging of sporulation.

264
00:16:03,692 --> 00:16:10,072
So in this particular case,
again,  we grew a very gray,

265
00:16:10,132 --> 00:16:13,142
velvety fungus with radial grooves.

266
00:16:13,192 --> 00:16:18,332
It changed and became a bit darker
with age on the Sabourouds plate.

267
00:16:18,362 --> 00:16:22,882
And there was  a bit of a dark,
exudate or,  droplets forming

268
00:16:22,882 --> 00:16:24,532
directly outta that colony.

269
00:16:25,102 --> 00:16:29,452
The reverse of the colony was also
dark, so the fact that it was dark

270
00:16:29,452 --> 00:16:33,412
on the reverse as well as on the
surface suggests that the organism

271
00:16:33,442 --> 00:16:37,397
does contain melanin, which fits
with what we've seen histologically.

272
00:16:38,902 --> 00:16:42,172
Unfortunately the microscopic
appearance of this fungus from the

273
00:16:42,172 --> 00:16:44,152
slide culture was not very helpful.

274
00:16:44,152 --> 00:16:45,292
We just got hyphae.

275
00:16:45,292 --> 00:16:49,742
We didn't see any conidia forming,
and so if you don't see conidia

276
00:16:49,742 --> 00:16:54,992
forming out of that hyphae, we can't
identify it using conventional methods.

277
00:16:55,622 --> 00:16:59,572
Fortunately, we have the ability
to overcome this problem and

278
00:16:59,602 --> 00:17:04,442
perform DNA sequencing, which is,
is actually now considered the gold

279
00:17:04,442 --> 00:17:06,902
standard for identification of fungi.

280
00:17:07,922 --> 00:17:13,092
There's a couple of different barcoding
genes for fungal identification that

281
00:17:13,092 --> 00:17:20,602
we rely upon,  the internal transcribed
space region, as well as  some organisms

282
00:17:20,602 --> 00:17:25,352
might identify better with  something
like the elongation factor gene.

283
00:17:25,352 --> 00:17:30,342
But for this particular case,  we
used DNA sequencing of the internal

284
00:17:30,342 --> 00:17:37,602
transcribed spacer region as well as the
D1/D2 region of the 28S ribosomal DNA.

285
00:17:38,182 --> 00:17:39,742
We did two different PCRs.

286
00:17:39,802 --> 00:17:44,062
We sent that  pCR product off the
sequencing and ran  the sequence

287
00:17:44,062 --> 00:17:50,432
results against  gen bank data
databases using a, a BLASTn algorithm.

288
00:17:50,972 --> 00:17:55,172
And I'd never had encountered
the answer that we got.

289
00:17:55,412 --> 00:18:01,942
But the answer we did get from
both the ITS sequencing was  99.4%

290
00:18:02,002 --> 00:18:07,572
identity to an organism called
Falciformispora lignatalis.

291
00:18:07,792 --> 00:18:11,527
And I might have butchered that
pronunciation, but I'm happy

292
00:18:11,527 --> 00:18:12,817
for someone else to correct it.

293
00:18:13,357 --> 00:18:17,197
Um, and then the next closest match
was another species within that

294
00:18:18,307 --> 00:18:23,767
Falciformispora, uh, species, but it
was further away at only 96% identity.

295
00:18:24,097 --> 00:18:26,917
So we were pretty confident
that the organism we'd come

296
00:18:26,917 --> 00:18:29,737
across was this F.lignatalis.

297
00:18:32,152 --> 00:18:36,472
We did try and do antifungal
susceptibility testing for this patient,

298
00:18:36,472 --> 00:18:41,032
but again, with antifungal susceptibility
testing, you must have sporulation

299
00:18:41,092 --> 00:18:46,252
and, uh, we didn't manage to induce
sporulation and therefore we weren't

300
00:18:46,252 --> 00:18:50,272
able to perform antifungal susceptibility
testing in this particular case.

301
00:18:50,712 --> 00:18:53,952
Was it far enough away to call
it catrionelis or not quite?

302
00:18:57,967 --> 00:19:01,387
It makes me feel better that you
also doubt your pronunciation

303
00:19:02,047 --> 00:19:02,377
like,

304
00:19:02,487 --> 00:19:06,117
never come across this organism before
and I'm yet, but I, and I haven't

305
00:19:06,117 --> 00:19:07,917
even come across that genus before.

306
00:19:08,247 --> 00:19:08,517
So,

307
00:19:08,967 --> 00:19:09,657
Thank you.

308
00:19:09,657 --> 00:19:10,587
Thank you so much.

309
00:19:10,857 --> 00:19:15,117
Uh, I guess what do we make of this
and the significance of this organism?

310
00:19:15,187 --> 00:19:17,117
Would we call it a deep mycosis?

311
00:19:17,137 --> 00:19:17,437
Yeah.

312
00:19:17,437 --> 00:19:20,737
And is it how this syndrome
typically manifests itself?

313
00:19:22,212 --> 00:19:25,632
Um, well, as we've said already,
uh, this is an unusual organism

314
00:19:25,692 --> 00:19:29,382
and I think it's been implied as
well that the world of mycology is

315
00:19:29,382 --> 00:19:33,002
forever changing and it is difficult
to keep up with this  kaleidoscopic

316
00:19:33,002 --> 00:19:35,282
landscape of fungal nomenclature.

317
00:19:35,762 --> 00:19:39,692
But this syndrome is indeed, um,
consistent with what we call mycetoma.

318
00:19:40,112 --> 00:19:45,632
And whilst I am no budding mycologist,
uh, I have done my research and we'll

319
00:19:45,632 --> 00:19:47,162
talk a little bit about mycetoma now.

320
00:19:47,472 --> 00:19:50,662
It is a chronic  granulomatous
subcutaneous infection caused

321
00:19:50,662 --> 00:19:54,202
by several species of fungi as
well as soil inhabiting bacteria.

322
00:19:54,652 --> 00:19:58,702
Which is endemic within this so-called
mycetoma belt, um, which spans

323
00:19:58,702 --> 00:20:01,912
from 15 degrees south to 30 degrees
north of the equator and really

324
00:20:02,092 --> 00:20:03,172
within the tropics of the world.

325
00:20:03,862 --> 00:20:06,952
Sporadic cases have been reported
worldwide, including in temperate regions,

326
00:20:06,982 --> 00:20:08,332
and it's really quite rare in Australia.

327
00:20:08,332 --> 00:20:11,582
And when it does occur, it occurs in
the northern states and territories,

328
00:20:11,912 --> 00:20:13,232
which approach the tropics.

329
00:20:14,087 --> 00:20:18,107
We make a distinction between
actinomycetoma and eumycetoma,

330
00:20:18,377 --> 00:20:21,137
the former being caused by soil
inhabiting bacteria, and the latter

331
00:20:21,137 --> 00:20:22,727
from fungis, such as in this instance.

332
00:20:23,117 --> 00:20:27,627
And the typical presentation is usually
with the triad of tumour, uh, sinus

333
00:20:27,627 --> 00:20:31,497
tracts, uh, and macroscopic grains,
which are essentially colonies or

334
00:20:31,527 --> 00:20:33,237
aggregates of the infectious organism.

335
00:20:34,017 --> 00:20:38,037
Uh, it can extend to adjacent structures
including bone, muscle, lymphatics.

336
00:20:38,217 --> 00:20:41,487
And the classic description from
a long, long time ago was that of

337
00:20:41,487 --> 00:20:45,507
Madura foot, named after a region
in India called Madura, where people

338
00:20:45,507 --> 00:20:49,037
would've stepped on this, these fungal
organism, and it was quite disfiguring.

339
00:20:49,247 --> 00:20:53,597
Risk factors as you might gather are
typically environmental or related to

340
00:20:53,597 --> 00:20:57,257
occupation, and thus it had previously
been known or sometimes is known as

341
00:20:57,257 --> 00:21:01,997
an implantation mycosis, uh, and risk
factors also included, such as in this

342
00:21:01,997 --> 00:21:05,517
instance, states of immunocompromised,
whether they be inherited or acquired.

343
00:21:06,942 --> 00:21:10,822
The main age for this sort of syndrome
is in the thirties and typically occurs

344
00:21:10,822 --> 00:21:14,992
in males with changing epidemiology
based on an itinerant population

345
00:21:14,992 --> 00:21:16,342
in other regions around the world.

346
00:21:16,952 --> 00:21:20,902
It usually involves the, the feet,  as
an implantation mycosis where  workers

347
00:21:20,902 --> 00:21:24,362
might be not wearing shoes and
exposed to thorns and other  things

348
00:21:24,417 --> 00:21:27,542
within the soil,  and less likely
to occur in parts of the torso,  the

349
00:21:27,542 --> 00:21:28,802
arms and other parts of the body.

350
00:21:29,702 --> 00:21:33,452
Common organisms for mycetoma
itself, or eumycetoma I should say.

351
00:21:33,702 --> 00:21:37,152
Madurella mycetomatis, which is the,
the classic one, but it's worthwhile

352
00:21:37,152 --> 00:21:40,602
noting that eumycetoma itself is
the minority of cases of mycetoma.

353
00:21:40,602 --> 00:21:45,902
It's 35% of cases of mycetoma  across
the board and within eumycetoma,

354
00:21:45,936 --> 00:21:49,689
Madurella mycetomatis, uh,
accounts for 75% of eumycetoma.

355
00:21:50,449 --> 00:21:54,109
Followed by Falciforma species such
as the other ones that Katrina had

356
00:21:54,109 --> 00:21:58,574
identified as being similar  to
the Falciforma lignatalis which

357
00:21:58,574 --> 00:21:59,564
was identified in this case.

358
00:22:00,014 --> 00:22:02,414
And they tend to differ by
local epidemiology including

359
00:22:02,474 --> 00:22:05,054
climate, vegetation, rainfall,
and, and different soil types.

360
00:22:05,974 --> 00:22:09,004
Little is known about the incubation
period between inoculation and clinical

361
00:22:09,004 --> 00:22:12,634
manifestations, given that many patients
do don't recall a specific predisposing

362
00:22:12,634 --> 00:22:13,894
injury, such as in this instance.

363
00:22:14,414 --> 00:22:17,624
It's worth noting that there are atypical
presentations that typically affect

364
00:22:17,624 --> 00:22:21,474
immunocompromised hosts, whereby the
classic triad might not be present.

365
00:22:21,894 --> 00:22:25,824
There are numerous case reports, uh,
out there that highlight a link with

366
00:22:25,824 --> 00:22:28,964
the tropics in transplant recipients
or those who are immunocompromised.

367
00:22:29,384 --> 00:22:33,894
For instance, patients who have migrated
from their country of origin to a place

368
00:22:33,894 --> 00:22:37,434
that is not within the Mycetoma belt,
and some 40 years later receiving a

369
00:22:37,434 --> 00:22:41,124
transplant and then having this fungus
identified from various parts of the body.

370
00:22:41,464 --> 00:22:44,494
But there's yeah, um, really
quite interesting cases out there.

371
00:22:44,701 --> 00:22:49,841
So beyond clinical suspicion, if someone
came in with a  similar presentation, how

372
00:22:49,841 --> 00:22:53,146
would you go about diagnosing mycetoma?

373
00:22:53,666 --> 00:22:57,651
Uh, it's hard not to have a talk like this
without saying that clinical impression

374
00:22:57,651 --> 00:22:59,271
and an index of suspicion are paramount.

375
00:22:59,601 --> 00:23:00,381
Uh, and they are.

376
00:23:00,471 --> 00:23:03,651
Um, so the presence of that triad
are certainly things that would give

377
00:23:03,651 --> 00:23:07,661
you an indication,  but beyond that,
in terms of clinching the diagnosis,

378
00:23:07,661 --> 00:23:11,491
it's  a composite of growing the
organism, and pursuing culture.

379
00:23:12,081 --> 00:23:15,991
Whether that be with a fine needle
aspirate of the growth, wherever

380
00:23:15,991 --> 00:23:18,991
it may be on the body, uh, with
subsequent inoculation under plates.

381
00:23:19,381 --> 00:23:22,291
I might ask you at this instance,
Catriona, I know you mentioned that you

382
00:23:22,381 --> 00:23:25,761
would tend to culture these only at 30
degrees, but from my reading, sometimes

383
00:23:25,761 --> 00:23:29,301
these get inoculated at both 30 degrees
and uh, 37 degrees for a number of

384
00:23:29,301 --> 00:23:34,191
weeks because different organisms within
this eumycetoma syndrome tend to grow

385
00:23:34,371 --> 00:23:35,871
predominantly different, uh, temperatures.

386
00:23:35,871 --> 00:23:36,651
Is that fair to say?

387
00:23:36,711 --> 00:23:38,251
Or something you don't always do?

388
00:23:38,811 --> 00:23:40,936
Yeah, it is a fair enough question.

389
00:23:40,936 --> 00:23:46,696
I guess we're guided by
standards for recommending what

390
00:23:47,266 --> 00:23:49,036
conditions we do grow fungi at.

391
00:23:49,486 --> 00:23:55,196
And certainly the guideline we used is
the CLSI guideline, which the people in

392
00:23:55,196 --> 00:23:58,646
the states would be very well aware of
and, and they make the suggestion that

393
00:23:58,766 --> 00:24:02,786
whilst you can put things at two different
temperatures and some, some labs do put

394
00:24:02,786 --> 00:24:04,256
things at two different temperatures.

395
00:24:05,156 --> 00:24:09,056
Every time you put more and more
plates out, you dilute how much

396
00:24:09,056 --> 00:24:12,716
sample you actually have to be
able to try and, and grow things.

397
00:24:12,716 --> 00:24:16,156
So for fungal work, the
general recommendation is  you

398
00:24:16,216 --> 00:24:17,716
can just use 30 degrees.

399
00:24:18,136 --> 00:24:21,051
Uh, but, you've gotta remember,
there's also plates that get set up

400
00:24:21,051 --> 00:24:24,501
for bacterial cultures, and there's
no reason why many of these fungi

401
00:24:24,621 --> 00:24:30,011
wouldn't actually grow on some of the
bacterial plates as well, and that is

402
00:24:30,011 --> 00:24:31,631
incubated at the higher temperature.

403
00:24:31,631 --> 00:24:36,281
So we have in my own lab times when we,
we get something growing, but it's also

404
00:24:36,281 --> 00:24:38,111
growing on the bacterial plates as well.

405
00:24:39,371 --> 00:24:40,361
Great, thanks for that.

406
00:24:40,991 --> 00:24:44,921
So, beyond culture, the other things that
are    in establishing a diagnosis include

407
00:24:44,921 --> 00:24:48,941
histopathology with evidence of chronic
granulomatous reaction,  and  possibly

408
00:24:48,941 --> 00:24:53,361
the presence of a grain,  which  given how
rare it is, ought to be discussed directly

409
00:24:53,361 --> 00:24:55,461
with  histopathology  at your own lab.

410
00:24:55,731 --> 00:24:58,971
Um, given that this has not seen a
great deal, and indeed when we returned

411
00:24:58,971 --> 00:25:03,181
to the histopathologist and asked them
was that bunch of fungi you saw in a

412
00:25:03,181 --> 00:25:05,761
conglomerate consistent with a grain,
and when they look through textbook,

413
00:25:05,791 --> 00:25:07,251
they confirm that indeed was the case.

414
00:25:07,821 --> 00:25:10,371
So, uh, good have good
relationships with the various

415
00:25:10,371 --> 00:25:11,471
disciplines around the hospital.

416
00:25:12,676 --> 00:25:16,426
And imaging is used sometimes to
determine extent of disease, whether

417
00:25:16,426 --> 00:25:20,526
it's invading in surrounding tissues,
uh, but also to suggest whether

418
00:25:20,526 --> 00:25:23,806
or not, there may be improvements
to help guide duration of therapy.

419
00:25:23,806 --> 00:25:27,106
I might ask Catriona, just lastly,
is there anything in particular,

420
00:25:27,146 --> 00:25:28,706
you would say about sensitivities?

421
00:25:28,736 --> 00:25:31,766
Um, I know we weren't unable to
achieve sporulation in this instance,

422
00:25:31,766 --> 00:25:35,166
but given this is , this was a rare
fungus and something you hadn't quite

423
00:25:35,166 --> 00:25:39,276
encountered before, clinically, um,
or at a lab level, if you were even

424
00:25:39,276 --> 00:25:43,096
able to achieve sporulation, would
there be much to be gleaned from

425
00:25:43,156 --> 00:25:44,756
undertaking sensitivity testing?

426
00:25:45,746 --> 00:25:47,281
Yeah, so definitely.

427
00:25:47,371 --> 00:25:52,501
We would, uh, try and do susceptibility
testing on any fungus that grew from a,

428
00:25:52,591 --> 00:25:54,571
um, and was deemed to be significant.

429
00:25:55,131 --> 00:25:59,046
In  this particular case, we, because
we couldn't get s sporulation, we

430
00:25:59,066 --> 00:26:00,866
couldn't do susceptibility testing.

431
00:26:01,606 --> 00:26:05,776
If we had been able to do susceptibility
testing, all we would be able to give

432
00:26:05,776 --> 00:26:09,796
would be a value of, of what the,
in minimal inhibitory concentration

433
00:26:09,916 --> 00:26:12,316
was for that particular isolate.

434
00:26:12,646 --> 00:26:16,701
Um, but that can often give clinicians
some confidence that whatever drug

435
00:26:16,701 --> 00:26:21,346
they've decided to treat with, you
know, is likely to be effective or not.

436
00:26:21,616 --> 00:26:25,426
There's certainly no break points
available for any of these unusual fungi.

437
00:26:25,636 --> 00:26:31,726
We, we really only have break points
available for one organism and one

438
00:26:31,726 --> 00:26:36,046
drug for Aspergillus fumigatus with
voriconazole, but, and we don't really

439
00:26:36,046 --> 00:26:38,566
have breakpoint for anything else, so
we are really only gonna be able to

440
00:26:38,566 --> 00:26:42,766
give you a number, which may give you
confidence as to which drug can be used.

441
00:26:43,456 --> 00:26:43,756
Uh.

442
00:26:44,051 --> 00:26:48,281
From my experience with testing
other dematiaceous fungi which grow

443
00:26:48,401 --> 00:26:52,921
in, you know, from cases like this,
quite often itraconazole is actually

444
00:26:52,921 --> 00:26:56,941
really a, um, it suggests that it
is quite an effective drug against

445
00:26:56,941 --> 00:27:00,001
these dark, slow growing molds.

446
00:27:00,031 --> 00:27:00,121
Uh, so.

447
00:27:01,836 --> 00:27:07,656
I'm not a clinician, but that is kind of
my experience in the lab side of things.

448
00:27:07,806 --> 00:27:11,826
As you say, I think as clinicians we
quite enjoy, uh, MICs that are low

449
00:27:11,826 --> 00:27:14,946
numbers, but appreciate that these
are just environmental cutoffs and

450
00:27:15,036 --> 00:27:18,096
uh, it really comes down to trying
to pick what you think is gonna

451
00:27:18,096 --> 00:27:19,646
be the most, um, effective agent.

452
00:27:21,716 --> 00:27:28,191
I think it'd be worth emphasizing that
the biopsy is ideally an excisional

453
00:27:28,191 --> 00:27:33,741
biopsy because it's unusual to get
either histological diagnosis or an

454
00:27:33,741 --> 00:27:35,466
effective culture on either an FNA.

455
00:27:36,216 --> 00:27:40,056
Um, sometimes a core biopsy, but in this
instance, we were fortunate enough to

456
00:27:40,056 --> 00:27:44,646
have the surgical team perform a full
excision, and I think that's really led

457
00:27:44,646 --> 00:27:47,496
to a, an expedited diagnosis in this case.

458
00:27:47,747 --> 00:27:49,497
I completely agree with that, Jon.

459
00:27:49,517 --> 00:27:52,727
And it's the same as if we'd have
to go down the path of using, if we

460
00:27:52,727 --> 00:27:55,187
hadn't managed to grow it, if we'd
gone down the path of having to

461
00:27:55,187 --> 00:27:58,097
use PCR directly from the specimen.

462
00:27:58,397 --> 00:28:03,417
Your, um, ability to get a, a positive
meaningful result from a fine needle

463
00:28:03,417 --> 00:28:07,072
aspirate is, is quite, quite a lot
lower than it would be if you get

464
00:28:07,072 --> 00:28:09,832
a nice, proper tissue specimen.

465
00:28:10,715 --> 00:28:14,535
Jon, how did you go on to choose your
antifungal therapy in this instance?

466
00:28:14,998 --> 00:28:18,988
Yeah, so that was obviously a
little bit complicated in the

467
00:28:18,988 --> 00:28:23,428
sense that we didn't have the full
susceptibility data to guide us.

468
00:28:23,698 --> 00:28:28,918
And in these type of infections,
there's no prospective randomized

469
00:28:28,918 --> 00:28:32,068
clinical trials to determine
the most effective drug therapy.

470
00:28:32,938 --> 00:28:38,608
But we're used to dealing in these, let's
call it gray zones, for the theme today.

471
00:28:38,818 --> 00:28:44,248
Um, in ID where we have to treat
based on what's being reported to work

472
00:28:44,458 --> 00:28:46,048
and what we have familiarity with.

473
00:28:46,648 --> 00:28:51,518
I think the surgical adjunctive therapy
is really important in these cases.

474
00:28:51,518 --> 00:28:54,008
If we can get local control
with the surgical excision,

475
00:28:54,008 --> 00:28:55,028
then that should be emphasized.

476
00:28:56,093 --> 00:29:00,863
However, we still wanted to pursue some
antimicrobial therapy in this case.

477
00:29:01,823 --> 00:29:04,553
Just recalling the case that
it is a transplant patient

478
00:29:04,553 --> 00:29:06,593
on tacrolimus and everolimus.

479
00:29:07,013 --> 00:29:12,173
There are a lot of drug, drug drug
interactions to consider and reviewing,

480
00:29:12,788 --> 00:29:15,668
you know, all of the literature in
the past, a lot of the cases have been

481
00:29:15,668 --> 00:29:19,838
treated perhaps in more resource limited
settings with ketoconazole, which we would

482
00:29:19,838 --> 00:29:22,158
rarely use  in our setting currently.

483
00:29:22,518 --> 00:29:26,028
Um, and then itraconazole has certainly
been used as Catriona alluded to.

484
00:29:26,868 --> 00:29:31,428
Many of the newer studies where there
have been MICs reported, have reported

485
00:29:31,518 --> 00:29:35,743
low values to the newer triazole,
such as voriconazole or posaconazole.

486
00:29:36,393 --> 00:29:39,573
We did have some experience with
voriconazole in the past with this

487
00:29:39,573 --> 00:29:45,013
patient, but perhaps given that that was
not that long ago, in a time interval,

488
00:29:45,283 --> 00:29:50,193
we considered a, a new agent perhaps
being a better option  to switch to.

489
00:29:50,613 --> 00:29:52,893
So we decided to use posaconazole.

490
00:29:53,793 --> 00:29:58,263
This certainly had some significant drug
interactions and really reviewing this

491
00:29:58,263 --> 00:30:02,043
carefully with our nephrology colleagues
and looking at the drug interactions.

492
00:30:02,658 --> 00:30:08,078
There's a significant interaction with
the cytochrome P450 enzyme subset, 3A4.

493
00:30:08,598 --> 00:30:15,688
And so we had to look at that and the
posaconazole was expected to significantly

494
00:30:15,688 --> 00:30:19,168
interact with tacrolimus so that the
initial dose of the tacrolimus had

495
00:30:19,168 --> 00:30:23,458
to be about a third of the baseline
dosing, and the everolimus had to

496
00:30:23,458 --> 00:30:25,978
be about 50% of the baseline dosing.

497
00:30:26,398 --> 00:30:31,918
So the treatment was certainly
initiated in close consultation

498
00:30:31,948 --> 00:30:33,148
with the nephrology team.

499
00:30:33,488 --> 00:30:37,538
We did that at a time when they were
ready and able to do drug levels

500
00:30:37,808 --> 00:30:41,498
quite frequently, and the tacrolimus
actually had to come down further.

501
00:30:41,858 --> 00:30:49,098
So this particular patient was on
0.5 milligrams bd, which eventually

502
00:30:49,098 --> 00:30:54,048
went down to 0.05 milligrams BD
in a step by sequential fashion,

503
00:30:54,078 --> 00:30:55,698
as the levels stayed very high.

504
00:30:56,298 --> 00:31:01,398
So whilst we look at reports of
what is expected, it's a lesson that

505
00:31:01,398 --> 00:31:04,428
you always have to individualize
these drug drug interactions.

506
00:31:04,938 --> 00:31:08,678
There was no ongoing imaging
really for this particular site

507
00:31:08,708 --> 00:31:11,678
'cause we could clinically feel
it and palpate it very nicely.

508
00:31:11,678 --> 00:31:18,053
I. Uh, we did review a cerebral image
just for the completeness, uh, because

509
00:31:18,053 --> 00:31:20,753
some of these organisms have been
known to disseminate to the central

510
00:31:20,753 --> 00:31:22,193
nervous system and that was normal.

511
00:31:22,583 --> 00:31:26,453
Uh, and we did repeat his pulmonary
scan, which had the stable pulmonary

512
00:31:26,453 --> 00:31:30,128
nodules from his previous pulmonary
aspergillosis with no change.

513
00:31:30,308 --> 00:31:32,643
So we elected to treat for six months.

514
00:31:32,928 --> 00:31:37,008
Uh, this was in the time where we had
another worldwide epidemic going on

515
00:31:37,008 --> 00:31:40,818
with, with Covid, and so it was quite
challenging in terms of monitoring

516
00:31:40,818 --> 00:31:45,228
and clinic visits, but we were able
to get the patient in and ensure

517
00:31:45,228 --> 00:31:49,828
that he remained symptom free after
successfully completing the treatment.

518
00:31:53,043 --> 00:31:57,483
Thanks to Morgan, John Max and
Catriona for joining Febrile today.

519
00:31:58,023 --> 00:32:01,293
Don't forget to check out the
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520
00:32:01,293 --> 00:32:04,143
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521
00:32:04,143 --> 00:32:08,313
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522
00:32:08,313 --> 00:32:09,633
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523
00:32:10,623 --> 00:32:14,433
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524
00:32:15,033 --> 00:32:18,063
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525
00:32:18,063 --> 00:32:19,563
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526
00:32:19,998 --> 00:32:20,808
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527
00:32:21,138 --> 00:32:22,818
Stay safe and I'll see you next time.