Fungal infections post LDLT

1. C
FUNGAL INFECTIONS POST
LIVING DONOR LIVER
TRANSPLANT
BY
Yasmine Mahmoud Massoud
Associate Professor of Tropical Medicine,
Faculty of Medicine ASU
Liver Transplant Hepatologist at Ain Shams
Center for Organ Transplantation

2. Agenda
 Timeline of infections after liver transplant
 Definition of IFI, Fungal colonization
 Incidence and burden of IFI
 Most common causative organisms
 Common clinical manifestations of invasive
fungal infections
 Risk factors for Invasive fungal infections
 Diagnosis of fungal infections
 Highlight on treatment of fungal infections
 Antifungal Prophylaxis and it’s limitations
 Take home messages

3. Introduction
• Infection following living-donor liver transplantation (LDLT) is a serious problem
with a high mortality rate reaching 50%. Factors associated with high risk of
acquiring infection post LDLT, include the difficulty of surgery, poor patient’s
condition, and the immunosuppressive drugs.
• Bacterial infections are the most common reaching about 48 %, followed by
fungal infections 22 %, and viral reaching 12 %.
Mohamed F Montasser, Nadia A Abdelkader, Sara M Abdelhakam, Hany Dabbous, Iman F Montasser, Yasmine M
Massoud et al. Bacterial infections post-living-donor liver transplantation in Egyptian hepatitis C virus-cirrhotic
patients: A single-center study World J Hepatol. 2017 Jul 18; 9(20): 896–904.

4. Timeline of infections post liver
transplant

5. Important definitions
Fungal colonization is defined as the presence of fungus before LT without clinical
symptoms or evidence of infection within 3 months of transplantation.
Proven IFI is defined as a positive fungal culture or histological analysis of a tissue
specimen taken from a disease site, or appearance of fungal or hyphal elements in
a biopsy from a sterile site.
Probable and Possible IFIs are defined based on specific host factors, clinical
features of fungal infection, and mycological evidence from culture and
microscopic analysis and indirect tests, such as antigen detection.
According to Invasive Fungal Infections Cooperative Group in Europe and the Mycoses Study Group in the United States (MSG)

6. Incidence and burden of IFI
 IFIs occur in 7–42% of patients post liver transplant
 IFIs are associated with high mortality of 65% to 90% for invasive
aspergillosis and 30% to 50% for candidiasis
 Morbidity and mortality post transplant is attributed to:
• Delay in diagnosis
• Nonspecific clinical features
• Fastidious nature of these organisms
• Lack of consensus on prophylactic regimens
• Rise of antifungal resistant species
Min Liu, Zhijun Zhu and Liying Sun Risk Factors of Invasive Fungal Infection in Recipients After Liver Transplantation: A
Systematic Review and Meta-Analysis: Front. Med., 04 October 2021

7. Causative
organisms
• Candida Species
 Candidiasis is the most frequent fungal infection
encountered after orthotopic liver transplantation and the
leading cause of invasive fungal infection.
 Candida albicans was the most common isolated species
followed by Candida glabrata and Candida tropicalis.
 Antifungal prophylaxis with fluconazole has resulted in a
shift in epidemiology resulting in a shift in infections
towards non-C. albicans species (e.g., Candida glabrata and
Candida krusei
Mark Pedersen and Anil Seetharam Infections after orthotopic liver transplantation. Clinical and
experimental Hepatology Vol 4, Issue 4, P347-360, December 01, 2014

8. Causative
organisms
• Aspergillus
Aspergillus is the second most common fungal
infection after orthotopic liver transplantation
and account for approximately one quarter of
invasive fungal infections after transplant.
Mark Pedersen and Anil Seetharam. Infections after orthotopic liver transplantation.
Clinical and experimental Hepatology Vol 4, Issue 4, P347-360, December 01, 2014

9. Causative
organisms
• Cryptococcus
Cryptococcus neoformans is the third most
common fungal infection after liver
transplantation and most common cause of
meningitis in transplant recipients.
Inhalation of fungal spores can result in
symptomatic pneumonia or asymptomatic
infection often with dissemination to other body
sites, most commonly the central nervous system,
distant organs or involvement of another single
organ (e.g., lymph node)
Mark Pedersen and Anil Seetharam. Infections after orthotopic liver
transplantation. Clinical and experimental Hepatology Vol 4, Issue 4, P347-360,
December 01, 2014

10. Causative
organisms
• Pneumocystis jiroveci
Pneumocystis jiroveci is a well-established
opportunistic pathogen whose incidence is
recognized in immunosuppressed patients after
solid organ transplant. Patient with
pneumocystis infection may present with fever,
shortness of breath, and nonproductive cough
• Wang E.H. Partovi N. Levy R.D. Shapiro R.J. Yoshida E.M.Greanya E.D. Pneumocystis
pneumonia in solid organ transplant recipients: not yet an infection of the past.
Transpl Infect Dis. 2012; 14: 519-525

11. Causative
organisms
• Mucormycosis
 Mucormycoses can cause local infections with
direct extension and rarely angioinvasive or
disseminated infections. The incidence of
infection in liver transplant recipients ranges from
0% to 1.6%.
 Patients with iron overload syndromes, either
from transfusion or hemochromatosis, have
increased risk of mucormycosis,
• Getrikkos G. and Skiada A. et al. Epidemiology and clinical manifestations of
mucormycosis. J Infect Dis. 2012; 54: S23-S34

12. Causative
organisms
• Histoplasma, Blastomyces and Coccidioides
species
Endemic Fungi in certain areas in the US
Endemic mycoses in SOTRs are rare with overall
incidence estimated to be 0.2%
 Outside these regions, cases may represent
remote travel, reactivation, or donor- derived
 Presentation ranges from indolent pulmonary
infection to acute respiratory distress
syndrome(ARDS) and extrapulmonary
dissemination to the skin, osteoarticular system,
CNS and genitourinary system
Scolarici, M.; Jorgenson, M.; Saddler, C.; Smith, J. Fungal Infections in Liver Transplant
Recipients. J. Fungi 2021, 7, 524.

13. Common clinical manifestations of invasive fungal
infections
Organism Clinical manifestations
Candida Intra-abdominal abscesses
Recurrent cholangitis
Peritonitis
Fungemia, pneumonia
Aspergillus Invasive pulmonary Aspergillosis
Brain abscess
Endophthalmitis
Osteomyelitis
Endocarditis
Cryptococcus CNS infection
Focal lesions on imaging
Meningitis, pneumonia

14. Risk factors for Invasive fungal infections
The predisposition of IFI in LTR is influenced by the host factors, environment and fungal factors.
Identification of risk factors for the LTR is very important in order to stratify the antifungal
prophylaxis
Risk factors specific to liver transplant recipients include anastomotic leak, repeat laparotomy,
choledochojejunostomy. hepatic artery thrombosis and bile leaks.
Other factors include Broad-spectrum antibiotic therapy, parenteral nutrition, prolonged
neutropenia, ICU stay, diabetes, high MELD
Ferrarese A, Cattelan A, Cillo U, Gringeri E, Russo FP, Germani G, Gambato M, Burra P, Senzolo M. Invasive fungal infection before and after liver transplantation. World J
Gastroenterol 2020; 26(47): 7485-7496 [PMID: 33384549 DOI: 10.3748/wjg.v26.i47.7485]

15. Risk factors for
Candida and
Aspergillus
FQ: Fluoroquinolone
HLA: Human leukocyte
antigen
CMV: Cytomegalovirus
HD: Hemodialysis
LT: Liver transplant

17. Diagnosis of fungal infections
• Invasive Candidiasis
 The critical step in IC diagnosis is consideration.
 Blood cultures remain the gold standard for diagnosis of candidemia
yet with significant limitations
 Beta-D-glucan (BDG) but positivity may occur in infection with
Aspergillus and Pneumocystis species
 T2 Candida assay has also emerged as a non-culture-based diagnostic
test performed directly on blood to detect the five most common
pathogenic Candida species (C. albicans, C. glabrata, C. parapsilosis, C.
tropicalis, and C. krusei)
 PCR

18. Diagnosis of fungal infections
• Invasive pulmonary aspergillosis
Diagnosis is made with the use of high-resolution computed
tomography (CT).
Early: nodular opacity with surrounding attenuation, or ‘halo sign.
Late: nodular lesions, diffuse pulmonary infiltrates, consolidation, or
ground-glass opacities.

19. Diagnosis of fungal infections
• Disseminated Aspergillosis
Aspergillus infections disseminate beyond the lungs in approximately
50–60% of liver transplant recipients.
Aspergillus galactomannan (GM) sensitivity ranges from 30% to 100%,
with a specificity of approximately 85%.
 β-D glucan (BDG) sensitivity ranges from 50% to 87.5% (thus a good
test to rule out infection).
Combination of the two tests can be useful for identifying false-positive
reactions

20. Diagnosis of fungal infections
Specific Aspergillus PCR assay
Diagnoses invasive aspergillosis with very good outcomes (100%
sensitivity and 89% specificity).
 Quantitative real-time PCR
Diagnoses invasive aspergillosis with sensitivity and specificity values of
67% and 100%, respectively, and can be used to monitor the fungal
response to infection management.
XiaLiu, Zongxin Ling, Lanjuan Li, Bing Ruan Invasive fungal infections in liver transplantation International Journal of Infectious
Diseases Volume 15, Issue 5, May 2011, Pages e298-e304

21. Diagnosis of fungal infections
• Cryptococcal disease should be considered recipients with fever,
headache, subacute mental status changes, or mass lesions in the lungs
or CNS
• Cryptococcal pneumonia
Could be difficult to identify on radiographic characteristics.
Sensitivity of cryptococcal antigen in cases of pneumonia is low.
• Cryptococcal CNS involvement
 Classic signs of meningitis such as nuchal rigidity, photophobia, or
headache could be missing.
 Detection of cryptococcal polysaccharide antigen in CSF and serum by
latex agglutination test

22. Diagnosis of fungal infections
• Pneumocystis jiroveci
 Bilateral interstitial infiltrates are seen in chest X-ray.
 If the microbial burden is high, pneumocystis organisms may be
identified from bronchoalveolar lavage fluid by direct
immunofluorescence using a fluorescein-conjugated monoclonal
antibody or by staining with toluidine blue.

23. Treatment of fungal infections
• The clinical keys of a successful treatment are early diagnosis and early
administration of appropriate antifungal treatment.
 Invasive Candidiasis:
• Echinocandins (caspofungin, micafungin or anidulafungin) are the first
line for empirical, pre-emptive or proven treatment of IC.
• Fluconazole is considered as an oral alternative if the patient is not
critically ill or unlikely for fluconazole-resistant Candida infection.
• L AmpB should be considered if the first two are contraindicated as a
first-line treatment
Ferrarese A, Cattelan A, Cillo U, Gringeri E, Russo FP, Germani G, Gambato M, Burra P, Senzolo M. Invasive fungal infection before and after liver
transplantation. World J Gastroenterol 2020; 26(47): 7485-7496 [PMID: 33384549 DOI: 10.3748/wjg.v26.i47.7485]

24. Treatment of fungal infections
 Invasive Aspergillosis
• Preferably treated with the triazole voriconazole. Alternative treatments
include LAmpB and isavuconazole.
• Voriconazole has improved the prognosis of patients suffering from
breakthrough CNS aspergillosis.
 Pulmonary Invasive Aspergillosis
Echinocandins in combination with voriconazole
voriconazole has been associated with hepatic and renal dysfunction,
therefore therapeutic drug monitoring is essential

25. Treatment of fungal infections
 Cryptococcal meningitis combination of liposomal amphotericin B or
amphotericin B lipid complex and flucytosine (5-FC) for at least 2 weeks
for the induction regimen, followed by fluconazole for 8 weeks for
consolidation therapy, and fluconazole for 6–12 months for
maintenance treatment.

26. Antifungal Prophylaxis
 The main issue with antifungal prophylaxis is the lack of universal
consensus on the choice of antifungals, its duration, and type of
antifungal prophylaxis.
 Risk factors should be organized to classify patients into specific risk
groups: low and high-risk groups.
 Based on that, patients should receive:
• no prophylaxis
• Or targeted prophylaxis
Giannella M, Bartoletti M, Morelli M, Cristini F, Tedeschi S, Campoli C, et al. Antifungal prophylaxis in liver transplant recipients:
one size does not fit all. Transpl Infect Dis. 2016; 18: 538-544

27. Studies from 2014 till
2020 on antifungal
prophylaxis for liver
transplant recipients

28. Antifungal Prophylaxis
The various antifungals used for prophylaxis are azoles (fluconazole, itraconazole),
echinocandins and liposomal amphotericin B (L AmpB)
Fluconazole is the most administered prophylactic agent
Retrospective and prospective studies indicate that LTR with two or more risk factors are at
at substantially higher risk for IFI.
The incidence of IFI (0-4%) in low-risk LTR is too low to warrant systemic prophylaxis
• Verma A, Weigel KS, Dexter SYK, Dhawan A. Evolution in the Management of Invasive Fungal Infections in Liver Transplant Recipients.
OBM Transplantation 2018;2(2):009

29. Preventive strategies and recommendations for invasive fungal
infections in liver transplant recipients
Candida species Aspergillus species Cryptococcus species
 Fluconazole, at least 400 mg daily for 4–
8 weeks after transplantation
 Echinocandins in fluconazole resistant
candida
 Lipid-associated amphotericin B, 1 mg/kg
for 5 days after transplantation
 Lipid-associated amphotericin B, 1–5 mg/kg
 or itraconazole 400 mg daily for 4 weeks
before and after liver transplantation in
patients with high-risk factors, especially those
with two or more risk factors or Echinocandins
High index of suspicion in
severely immunocompromised
individuals
Rational use of antibiotics Rational use of antibiotics Rational use of antibiotics
Selective digestive decontamination
Microbiological surveillance and
prevention of CMV disease
CMV disease prevention CMV disease prevention CMV disease prevention
Targeted therapy with fluconazole, based on
the presence of risk factors

30. Limitations to prophylaxis
 Many studies indicate that prophylaxis for liver transplant recipients
results in a clear but limited reduction in proven IFIs but has no effect
on overall mortality.
 Targeted prophylaxis is usually complicated by:
• Significantly higher proportion of non-C. albicans infection
• Increased potential for antifungal drug resistance
• Drug-associated toxicity
• Drug interactions between azoles and calcineurin inhibitors (CNI)
pose another challenge
• Verma A, Weigel KS, Dexter SYK, Dhawan A. Evolution in the Management of Invasive Fungal Infections in Liver Transplant Recipients. OBM
Transplantation 2018;2(2):009

31. Take home messages
Fungal infections following liver transplant remain an influential cause
of morbidity and mortality despite the low incidence.
Identifying patients at high risk for developing IFI can be of immense
help in decreasing the diagnostic delay and assure appropriate
prophylaxis.
Targeted prophylaxis appears to be superior to the universal approach.
A robust global consensus with stringent guidelines and an antifungal
stewardship are needed to develop an updated standard of care.