Challenges in Management of Invasive Fungal
Infections in Immunocompromised Patients
Dr Anita Verma MD
Consultant Microbiologist
Department of Medical Microbiology & Institute of Liver Studies, King’s
College Hospital, Foundation, NHS trust, London
1
Conflict of interest
 Educational grant and Speakers – Gilead ,
Astellas
 Investigator and speaker for a study - Pfizer
Challenges in Management of Invasive Fungal
Infections (IFI) in Immunocompromised (IC) Patients
New mycologic challenges in IC pateints
 Know the Changing Epidemiology of IFI
 Nonspecific presentation of IFI
 Inadequate diagnostic methods
 Antifungal prophylaxis – Does it work ?
 Breakthrough Infections while on antifungal therapy
 Refractory to antifungal treatment
3
Background: IFI in Immunocompromised Patients
 IFI incidence is increasing in immunocompromised (IC) hosts
(SOTR & HSCT recipients ) because of
 The pool of IC patients is increasing dramatically
 external pressures from antibiotic usage
 use of newer and more potent chemotherapeutic agents
 their highly compromised immune status
SOTR: solid organ transplants recipients, HSCT recipients : hematopoietic stem cell
Epidemiology of IFI in both SOTR & HSCT Recipients
Increasing incidence of moldinfections
SOTR
HSCT
Invasive candidiasis
53%
28%
Invasive aspergillosis
19%
43%
Cryptococcosis
8%
-
Non-aspergillus molds
8%
-
Endemic fungi (5%)
5%
-
Zygomycosis
2%
-
The Transplant-Associated Infections Surveillance Network (TRANSNET) -23
transplant centers in the US, prospective study from 2001 to 2006: epidemiology
of IFI in both SOTR and HSCT recipients
Clin Infect Dis. 2010, 50:1101–11, Clin Infect Dis. 2010, 50:1091–100.
Invasive Aspergillosis
Type of
IA ,%
Disseminated
Mortality
transplant
range (mean)
aspergillosis, %
rate, %
Liver
1-8 (2)
50-60
92
Lung
3-14 (6)
15-20
74
Heart
1-15 (5.2)
20-35
78
Kidney
0.9 - 0 4 (.7)
9-36
77
Pancreas
1.1 - 2.9 (1.3)
NA
100
Small bowel
0 - 3.6% (2.2)
NA
100
Mortality Of Invasive Aspergillosis in Relation To Underlying Disease
Clin Infect Dis 2001;32:358
100
30
20
10
AIDS
40
leukemia
/lymphoma
50
liver transplant
60
lung /heart
70
kidney transplant
80
bone marrow transplant
90
Inadequate Current diagnostic methods for IFI
>30% Detected on autopsy
 In a case series involving patients with hematologic
malignancy
 IFI high prevalence of IFI 31% detected at autopsy
 77% of the patients’ deaths were related to infection
 This highlighted the inadequacies of current diagnostic
methods for IFI
Haematologica. 2006, 91:986–9
Current limitations of classical and new Diagnostic test
for IFI- Issuses
Conventional methods of Microscopy and culture rarely positive because:
Invasive Candidiasis (IC)
 Patients on antifungal prophylaxis
 Imaging not helpful
 Diagnosis is mainly clinical
Invasive Aspergillosis (IA);
 Initially affects the lungs , easily go unoticed because no clinical
symptoms

Even when recognized early, suitable specimens can be difficult to obtain

In LTR pts with IA - 50% who had Aspergillus in BAL,22 fold at
risk of IA (Singh et al 1997)
Lack of adequate diagnoses makes estimating the prevalence and incidence of
IFI unreliable
Diagnosis: Imaging- Invasive Aspergillosis
 Chest X-ray- nodular lesions, interstistial opacities, cavitary
lesions, or pulmonary embolus pattern, or normal chest x-ray
 CT- valuable when chest –x-ray negative, can reveal disease as
much as 5 days earlier
An 18-month-old girl - Aspergillus isolated from the lung. (a) Chest radiograph
showed a round opacity behind the heart. (b) CT revealed a cavitating nodule in
the left lower lobe.
Nonspecific Presentation In Immunocompromised Patients- Case Scinario

18 yrs M LCH, had BMT

Admitted for Liver transplant - D1 post LTx - Ambisome -5mg/kg x7
days (fullfill criteria highrisk for mold infection)

Persistant Neutropenia

Changed to caspofungin ( half dose because of abnormal LFTS)

D18 post LT - multiple cutaneous lesions

Prior to LTX multiple courses of antifungal

Previous lung Bx before LTx -ve

Skin Biopsy- + hyphae

Culture- Aspergilllus fumigatus

Started on voriconazole + Ambisome

No response x 4 weeks

Immunomodulation- leukocyte infusion

Resolution of skin lesion – negative for mold

However 3 month later relapse of underlying dis (LCH)- BX proven
Wright stain;hyphae
Available Non Culture Methods
Detection of circulating surrogate markers.
1. Serological tests - detect fungal antigens
 Aspergillus galactomannan ELISA
 (1→3)- β-D- glucan
 Mannan & anti-Mannan antibody
2.
PCR-based assays - detect fungal DNA.
3.
Imaging
Serological test:β-D- glucan (BDG)
 Cell wall component of wide variety of fungi (not
zygomycetes or Cryptococcus).
 Indicated for the presumptive diagnosis of IFI
 Sensitive with a good negative predictive value i.e. good for
excluding infection.
 A review of 23 & meta-analyses of 16 studies containing 2979
patients gave a pooled sensitivity of 76.8% & specificity of 85.3%.
(Clin Infect Dis 2011;52(6):750-70. )
 Meta-analysis of 31 studies of IFD: sensitivity (80%) & specificity
(82%) was found by a (excluding Pneumocystis infection). (J Clin
Microbiol 2012; 50(1):7-15. )
ANTIFUNGAL STEWARDSHIP
PRE-EMPTIVE TREATMENT BASED ON BDG+ RISK FACTORS
Intensive care unit (ICU) stay - >9 month
Risk factors for IFI
• ALF of unknown cause
•
•
•
•
•
•
Intra-abdominal bleed,
bowl perf, pancreatitis,
dialysis dependent,
multiple viral infction adeno, CMV, EBV
Augmneted immunosuppression
ICU stay >1year
No pos culture, ?suspected
aspergillosis based on BDG+ risk
factors pre-emptive treatment for
IA
Optimal Antifungal Strategy – no uniform
consensus ?
Invasive Fungal Infections
Issues
Prophylaxis- most effective
Variable practice
Emperical: possible- Serology+ clinical
Pre-emptive: probable infectionserology+ radiology + clinical
Specific Treatment : above + tissue
diagnosis- proven infection-
? Which antifungal
?Duration
? role of combination
therapy
Licensed Antifungals
Anidulafun
Micafungin
Posaconazole
Caspofungin
14
Voriconazole
AmBisome
12
Amphocil
10
Abelcet
Itraconazole
8
Fluconazole
Ketoconazole
6
Terbinafine
Miconazole
4
5-Flucytosine
Griseofulvin
2
Amphotericin B
Nystatin
0
1950
1960
1970
1980
1990
2000 2010
Current Practices- Institutional practices of antifungal prophylaxis
vary widely Survey by Singh etal LTX R
(Am JTransplant 2008:8:426-31)
106 UNOS Approved
Transplant Programmes
91% employed some sort
of Prophylaxis
Antifungal choices
Duration of Prophylaxis
• 67 sites participated
• 70% performed >50 transplants annually
• 72%targeted towards high risk patients
• 28% used universal prophylaxis
• 86% used Fluconazole
• 14% either Ambisome 1mg/kg /or
echinocandins was used mainly for mold
•40% centres till hospital stay
•20% for 1month
•10% fo 3month
•Remainder for varied duration
Risk of Antifungal Prophylaxis in Current
Era
 Over one-third of the infections due to non-albicans Candida spp.
 Prior antifungal prophylaxis the only risk-factor for non-albicans
Candida Spp
 Mortality 25 fold higher for cases than for controls (p = 0.0002);
58% for non-C.albicans, and 22.7% for C. albicans infections;
 Azole resistance due to prior fluconazole usuage;Husain et al.,
Transplantation 2003; 27: 2023-2029
Ecological Shift: Candidaemia in a specialist ICU 10 years epidemiology
80
70
2001-05
60
2006-10
50
40
30
20
10
0
20
Refractory to Antifungal Treatment
Invasive candidiasis due to C albicans – Refractory to Fluconazole and Ambisome
Sex/ Underlyi Risk
ng
factors
age
disease
1 M 5 BA, D20
Yr
Post ,
LTx
BP, BL
2 M 16
yr
Bowel
perf, BL,
drains in
situ ,
2yr post
tx
drains in
situ
AntiInitial treatment
fungal
Prophyl
axis
Changed to
Respons Conco
e
mitant
infectio
ns
Flucona Ambisome 3mg/kg + Echinocandin Cleared VRE
zole
fluconazole 12mg/kg x
after
+EBV
6mg/kg 3wks
2wks
x 2wks
Flucona Ambisome 3mg/kg +
Echinocandin Cleared CMV +
zolefluconazole 12mg/kg x
after 10 HSV
400mg 3wks
days
Presentation of Fungal infection –intrabdominal due to C albicans, BA –Biliary atresia, BP- bowel
perforation, LTx – Liver transplant , BL-Biliary leak,
C albicans came back very sensitive MICS value with normal range
21
Breakthrough Infections
‘Cerebral Aspergillosis While on Antifungal therapy
Sex/
age
Liver Presentation of
disease FI after LTx
Site of
FI
1 F 51
PBC
Brain Lesion on
week 11
2 F 50
ALF
(Drug)
Chest infection Lung,
on week 3
Brain
3 M 33
ALF
(POD)
Brain
Anti-fungal
Therapy
Risk
factors
Treatment
Outcome
Ambisome
3mg/kg
Chronic
LF, & RF
Ambisome+
Voriconazole
alive
Caspofungin
PNG, RF
Ambisome+
Voriconazole
*Deceased
Chest infection Lung,
Caspofungin
Acute RF, Ambisome+
Alive
on week 3
Eye,
Re- Tx
Voriconazole
Brain
FI; Fungal infection, ALF; acute liver falure, LF; Liver failure, RF;renal failure, PBC; primary biliary
cirrhosis, PNG; primary nonfunctoning graft, LTx; Liver transplantation
*patient 2 – had 9 month of treatment IA was treated however diedwhile awaiting for 2nd tx - because
of graft failure and bacterial septic shock
22
New Mycologic Challenges
 Refractory to treatment develop breakthrough - needs
further evaluation
 Impaired Host immune system ?Tissue concentration of antifungals
 ? Tolerance
 or Drug-resistant
 Finally, immune-enhancing strategies such as the
 use of growth factors
 and/or white blood cell transfusions
for the prevention and treatment of opportunistic fungal
infections in immunocompromised patients remain an
important area of investigation.
23
Conclusions: Invasive Fungal Infections
Way to improve IFI are
Selective antifungal prophylaxis- risk based

Aggressive diagnostic approach- nonculture methods

High degree of vigilance

Early pre-emptive therapy

Develop less damaging methods of immune suppression

Immunomodulation in very high risk patients
Thank you for your attention