Twenty-five years of clinical mycology: what has been done and what should be done

Ref ID: 19345

Author:

Viscoli, C.

Author address:

University of Genova, Italy

Full conference title:

6th Trends in Medical Mycology 2013

Date: 11 October 2014

Abstract:

Remarkable achievements have been obtained in the last 25 years in
invasive fungal infections (IFI) which in my view could be summa-
rized in the following 4D acronyms
“¢ Drugs (for treating and preventing)
“¢ Diagnosis (for tuning treatment)
“¢ Definitions (for understanding each other)
“¢ Description (for describing the IFI clinical syndrome in compro-
mised hosts)
Drugs In 1997, groups of investigators on both sides of the Atlantic
Ocean started the first prospective, randomized, multicenter clinical
trial aimed at testing the efficacy of a new drug (voriconazole) vs,
standard amB in the treatment of invasive aspergillosis (IA).
Interestingly, the study was not steered directly by Pfizer, but was
rather supported externally and was conducted by the EORTC Fungal
Group and by the American Mycosis Study Group (or what was
going to become the MSG). All data were analyzed at the EORTC
Data Center in Brussels, thus ensuring outstanding scientific quality
and total transparency. Despite some pitfalls mainly related to
diagnostic uncertainties, this pioneer study represents a landmark for
clinical mycology and set a precedent for all future studies, including
those which still have to be done. Unfortunately, for reasons that
should be discussed, this example of close collaboration between
industry and scientific community did not become the rule. (1)
Diagnosis In the early nineties, a group of scientists at the Pasteur
Institute in Paris was testing several fungal antigens with the aim of
finding a serological marker for IA, able to partially overcome a
chronic diagnostic gap. Starting from an old latex agglutination test
for the detection of galactomannan, they developed a much more
sensitive ELISA system, that became the widely known galactoman-
nan test (GM), which is now used in many hospitals in the world
(although not without some controversies between supporters and
detractors).(2-4) More or less in the same years advances in radiol-
ogy and computerized technology gave the possibility to French
groups of recognizing the existence of some peculiar radiological
signs very often associated with a diagnosis of proven IA in neu-
tropenic patients with neutropenia.(5-7) Other studies came from
many investigators and everybody started to talk about the halo and
air crescent signs, nodules, wedge-shaped infiltrates as more or less
peculiar of early, intermediate or late IA. Lung CT scan replaced
standard chest-x-ray in the routine examination of lungs in immuno-
compromised patients. Very recently, another French group gave
new insights on this argument.(8)
Definitions Traditional diagnosis of IFI was requiring histological
and/or cultural confirmation of tissue invasion. This was relatively
adequate for candida infections (positive blood cultures) but abso-
lutely inadequate for mold infections. With the availability of antigen
detection tests and CT scan, things became much more complicated,
with a plethora of definitions and big discussions between “œpurists”
(we only want documented infections) and “œinnovators” (in this way
we lose a lot of true infections and, maybe, we also lose patients). At
this point a group of people, led by Ben de Pauw, proposed to start a
long and painful road toward finding an agreement on definitions of
IFI based on different degrees of diagnostic certainty. The main pur-
pose was to be able to compare studies and to design clinical trials.
The “œlong and winding road” has not finished, yet, but, after 2 arti-
cles, a lot of work has been done toward understanding each other.
Again, the EORTC Infectious Disease Group and the MSG were the
leaders of the initiative. (9,10)
Description Before the above mentioned achievements, IFI in immu-
nocompromised hosts were rather mysterious entities, rarely diag-
nosed during life, often treated empirically and often left untreated
because undiagnosed and discovered at autopsy. Only few centers
were aggressive in diagnosis, performing lung biopsies and BAL, and
empiric therapy was the rule. “œThe therapy of a disease you don’t
know if it exists, with a drug you don’t know if it works”, as Ben
was arguing. However, progressively, a process of recognition started,
several pieces of the puzzle were put together and a clinical scenario
became apparent. We learned which patients were more at risk and
when, during the course of their disease. We learned (actually are
still learning) that meaningless symptoms, like cough or thoracic
pain, can become very meaningful in the right patient and that fever
is a poorly sensitive method for suspecting a fungal infection. We
started to be careful about minimal skin lesions and learned that a
neutropenic patient with fever, blackish skin lesions and positive
blood cultures for molds probably has fusariosis. We watched care-
fully at the GM results and radiologists became our best collabora-
tors. A clinical syndrome was described putting together the
following factors in various combinations
“¢ patient-related factors (especially type and status of underlying dis-
ease and type of immunodeficiency),
“¢ clinical presentation (especially respiratory symptoms and skin
lesions),
“¢ radiology (any infiltrate?)
“¢ antigen results.
ª 2013 The Authors
Mycoses © 2013 Blackwell Verlag GmbH, 56 (Suppl. 3), 11-42 doi:10.1111/myc.12122
mycoses
Diagnosis,Therapy and Prophylaxis of Fungal Diseases
The consequence, more obvious for some physicians and less for
others, has been to realize the existence of a more rational way for
using antifungals, not any more a blind and ineluctable intervention
(often based on a “œfear of”) but a responsible and well weighted deci-
sion, based on the recognition of the IFI syndrome. (11)
What should be done (yet or again) Actually many things, some
of which are summarized below:
“¢ We all agree that the EORTC-MSG definitions need to be tuned
up, and the process has started already.
“¢ I look forward (but it is probably an illusion) to reestablish virtu-
ous relationships between the industry and research groups
“¢ I look forward to stop endless reanalysis of old studies, but fresh,
modern new studies.
“¢ Some clinical entities, like for example chronic aspergillosis in
mildly immunocompromised hosts, should be better understood, as
well as the role of fungal organisms in apparently non infectious
respiratory syndromes.
“¢ In terms of diagnostic tools, we need information and experience
about the role of new techniques (e.g. PET-CT)
“¢ We are waiting for an answer about the role of biomolecular
methods in diagnosis and we desperately need biological markers for
Mucor infections.
“¢ The role of combination therapy remains unclear
“¢ Recent news about triazole resistance in Aspergillus are worrisome
and should be better understood in terms of their clinical impact.
“¢ Finally, drugs and diagnostic facilities should be available every-
where in the world. I fully realize that the world has more basic
needs (water, mosquito nets, education, anti-HIV drugs, etc), but dis-
criminations exist in the fungal field, as well.
References
1. Herbrecht, R., et al., Voriconazole versus amphotericin B for pri-
mary therapy of invasive aspergillosis. N Engl J Med, 2002. 347(6):
p. 408-15.
2. Stynen D, et al A new sensitive sandwich enzyme-linked immu-
nosorbent assay to detect galactofuran in patients with invasive
aspergillosis. J Clin Microbiol 1995; 33: 497-500.
3. Verweij PE, et al. Sandwich enzymelinked immunosorbent assay
compared with Pastorex latex agglutination test for diagnosing inva-
sive aspergillosis in immunocompromised patients. J Clin Microbiol
1995; 33:1912-1914.
4. Machetti M, et al Comparison of an enzyme immunoassay and
a latex agglutination system for the diagnosis of invasive aspergillosis
in bone marrow transplant recipients BMT, 1998; 21: 917-921.
5. Caillot, D., et al., Improved management of invasive pulmonary
aspergillosis in neutropenic patients using early thoracic computed
tomographic scan and surgery. J Clin Oncol, 1997. 15(1): p. 139-47.
6. Caillot, D., et al., Increasing volume and changing characteris-
tics of invasive pulmonary aspergillosis on sequential thoracic com-
puted tomography scans in patients with neutropenia. J Clin Oncol,
2001. 19(1): p. 253-9.
7. Heussel, C., et al., Pneumonia in febrile neutropenic patients
and in bone marrow and blood stem-cell transplant recipients: use of
high-resolution computed tomography. J Clin Oncol, 1999. 17(3): p.
796-805.
8. Bergeron A, et al The strategy for the diagnosis of invasive pul-
monary aspergillosis should dependon both the underlying condition
and the leukocyte count of patients with hematologic malignancies
Blood, 2012 ;119: 1831-37.
9. Ascioglu, S., et al., Defining opportunistic invasive fungal infec-
tions in immunocompromised patients with cancer and hematopoi-
etic stem cell transplants: an international consensus. Clin Infect Dis,
2002. 34(1): p. 7-14.
10. De Pauw, B., et al., Revised Definitions of Invasive Fungal Dis-
ease from the European Organization for Research and Treatment of
Cancer/Invasive Fungal Infections Cooperative Group and the
National Institute of Allergy and Infectious Diseases Mycoses Study
Group (EORTC/MSG) Consensus Group. Clin Infect Dis, 2008. 46: p.
1813-1821
11. Maertens, J., et al., Galactomannan and computed tomogra-
phy-based preemptive antifungal therapy in neutropenic patients at
high risk for invasive fungal infection: a prospective feasibility study.
Clin Infect Dis, 2005. 41(9): p. 1242-50.

Abstract Number: BPL

Conference Year: 2013

Link to conference website: NULL

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