A mooc of the Institut Pasteur

Risk Factors for IFD:

an evolving scenario

Olivier LORTHOLARY
M.D.; Ph.D. Professor of Infectious Diseases and Tropical Medicine

Université de Paris, Necker Enfants malades Hospital, APHP, IHU

Imagine and Institut Pasteur, CNRS UMR 2000, Paris, France

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 Population-based analysis of Invasive Fungal Diseases (IFDs),
France, 2001-2010

35,876 incident IFD registered

N°1: Candidemia (43.4%)

N°2: Pneumocystis jirovecii pneumonia (26.1%)
N°3: Invasive aspergillosis (23.9%)
N°4: Cryptococcosis (5.2%)
N°5: Mucormycosis (1.5%)

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Invasive aspergillosis 1.8% per 100,000 persons. Mucormycosis 0.12% per 100,000 persons. IFI: invasive fungal infection.
Bitar et al. Emerg Infect Dis 2014;20:1149–55.
 Key cells involved in the protection against fungi

Combined deficiencies!

MEDICAL
MYCOLOGY Netea Nature Rev Microbiol 2008
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 Risks factors for IFDs

Endogenous
GI tract/skin Community
Reactivation

Healthcare

Exogenous
inhalation/skin Travels
trauma

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 Characteristics of 2507 patients with candidemia in Paris

Patients’ characteristics (N=2507)

Male gender 60,3%

Mean age (± sd) years 60 (± 17)

Intensive care unit 48.1%

Malignancy 50.3%
Prior surgery (30 days) 38.7%
Central venous catheter 74%

2571 isolates in 2507 incident episodes

(2424 single, 83 mixed infections)

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 Risk factors of invasive aspergillosis (France)

Male Mean % Proven % Pulm. IA

Risk N=393
Gender Age Yr (n=60) (N=362)
Acute Leukemia 135 0.57 55 +/- 15 15 96
Allo-HSCT 84 0.67 44 +/- 12 13 89
Lymphoprolif. Dis 81 0.62 59 +/- 15 6 96
SOT 34 0.74 54 +/- 11 21 85
Cancer 22 0.82 58 +/- 15 32 91
Syst. Diseases 18 0.33 62 +/- 15 22 89
Resp. Diseases 9 0.78 63 +/- 13 11 100
Others 10 0.55 55 +/- 15 50 70
mean 0.62 54 +/- 15 15 92

Hematological malignancies: 78%

MEDICAL
MYCOLOGY Lortholary O, et al. Clin Microbiol Infect. 2011;17(12):1882-9.
 Who develops cryptococcosis?

• 2125 cases (1985-2001)

• 1644 cases AIDS (77.4%)
• 335 HIV negative:
17.4% SOT
36.8% HM/cancer
20.4% diverse
25.4% None (!)

MEDICAL
MYCOLOGY Dromer, AIDS 2004
  2003–2008, allo HSCT France1
 Mucormycosis prevalence: 0.4% (N=29) 83%

 225 days after allo 0–2693

 23 breakthrough infections
 10 prior post-transplant infection
 89% patients corticosteroids 1 mg/kg

Aspergillosis
TRANSNET
Candidiasis Percentage of IFI
2 3
8% 43%

63% of non-Aspergillus
MEDICAL mold infections 1. Xhaard Clin Microbiol Infect 2012; 2. Park Emerg Infect Dis 2011;
MYCOLOGY in transplant patients
3. Kontoyiannis Clin Infect Dis 2010.
 Emerging hosts/conditions

 Tobacco
 Major role of diabetes
 Emerging entities in hematology: chronic lymphoid malignancies
 Emerging entities in ICU: cirrhosis, alcoholic hepatitis, IAPA, CAPA
 Travel-associated IFD
 Biologics & small molecules-treated patients
 Foreign devices
 Extreme ages
 Adults with primary immune deficiencies

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 Tobacco

 25 studies that reported on the association between

smoking and IFD, encompassing 18,171 participants

 High methodological standards

 The meta-analysis showed a significant association

between smoking and the risk of IFD, with a pooled
risk ratio of 1.41 (95%CI 1.09-1.81; P = 0.008)

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MYCOLOGY Pourbaix, CID 2020
 Diabetes

 41-49% of HSCT recipients with IFD  9% annual increase of mucormycosis

(Neofytos, CID 2009) in diabetes (Bitar EID 2009)
 Independent risk factor of mucormycosis in  23% of 101 pts with mucormycosis
leukemia and/or BMT and SOT in France (2005-2007)
(Kontoyiannis JID 2005, Singh JID 2009)

influences
prognosis

Lanternier, CID 2012

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 Review of influenza-associated pulmonary aspergillosis in ICU
patients and proposal for a case definition: an expert opinion

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 Fungal risk of immunomodulation (1)

 TNF-alpha (cf infra)

 Anti T cell therapy (basiliximab, abatacept) -
 Anti B cell therapy (Rituximab & other IS = PjP)
 Combination lymphocyte depleting agents ±
 IL-1, IL-4, IL-5 + IgE, IL-6, IL-12/23 -
 IL-17: mucocutaneous candidiasis
 Brodalumab 4%
 Secukinumab 1.7%
 Ixekinumab 3.3%
 Immune checkpoint & complement inhibitors -

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 Fungal risk of immunomodulation (2)

 Ibrutinib (BTK inhibitor):

 Phase1 CNS lymphoma 7/18 IA; IA with steroids, PjP cases, cryptococcosis
 Idelalisib (PI3 kinase inhibitor):
 PjP = primary prophylaxis; PjP = 2.5%, duration prophylaxis ≥ 6 mo
 Anti-CTLA4 Ab
 Few IA cases; PjP prophylaxis ?
 BCR-ABL ±
• Jak (Tofacitinib, Ruxolitinib)
• Syk & ALK & Integrin inhibitors
• Venetoclax (BCL2 inhibitor)
• mTOR inhibitors
• Brentuximab (CD30 Ab) NO SIGNAL OF IFD
• Blinatumomab (CD3-CD19 Ab)
• HDAC inhibitors
• Anti-PD1 Ab

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 Primary immune deficiency patients become older

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 CONCLUSION

1 IFD risk depends of the type/magnitude of primary or

secondary immunodeficiency

2 Now, within a particular group, high risk sub-groups are

individualized = prophylaxis?

3
IFD risk factors : an evolutive scenario
(immunosuppression/emerging populations)

4 Immunogenetic investigations in the absence of primary or

secondary immune deficiency

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