1. Fungal infections in solid organ transplantation
Dr. Joan Gavaldà
ID Senior Consultant Infectious Diseases Department
Coordinator Antibiotic Resistance Lab VHIR
Exemple de portada 5

2. Transplant Recipient with great efforts dyspnea and a decrease of his PFT
at m + 3.1
PFT, Pulmonary function tests

6. Invasive aspergillosis
Diagnosis:
Invasive aspergillosis
Nodular tracheobronchitis due to Aspergillus fumigatus
Invasive pulmonary aspergillosis
A3 acute rejection
Treatment:
Excision by rigid bronchoscopy, placing a small net distally to the fungal ball to prevent dissemination to the graft
Voriconazole + anidulafungin
Methylprednisolone, 3 pulses of 500 mg daily
Nebulized amphotericin B 25 mg q24h
Valganciclovir 900 mg q24h PO
Transplant medicine: Interdisciplinary approach
PO, by mouth

8. On behalf ESCMID Study Group for Infections in Compromised Hosts
On behalf ESCMID Study Group for Infections in Compromised Hosts. Clin Microbiol Infect. 2014;20 Suppl 7

10. Gavaldà J, et al. ESCMID Study Group for Infections in Compromised Hosts. Invasive fungal infections in solid organ transplant recipients.
Clin Microbiol Infect. 2014;20 Suppl 7:27–48.

11. Invasive Fungal Infections in SOT Recipients
Transplant patients have a significant risk of invasive fungal diseases Caused mainly by Candida spp., Aspergillus spp., and to a lesser extent, Cryptococcus spp. and fungi belonging to the Mucorales order
SOT, solid organ transplant

12. Invasive Candidiasis in SOT Recipients
Most frequent agent of IFD Accounting for half of all IFDs Rate varies according to the organ transplanted, being particularly high in abdominal SOTs First months after the surgery Candidemia peritonitis, UTI, wound or surgical anastomoses infection, or esophagitis Overall survival of up to 60%
IFD, invasive fungal disease; SOT, solid organ transplant; UTI, urinary tract infection

13. Invasive Aspergillosis in SOT Recipients
Incidence ranges from 0.1% to 2.4%
IPA: Most common clinical form
More frequent thoracic SOT
Lung transplant: Invasive tracheobronchitis as single, ulcerative or nodular form to IPA
Mortality:
<10–80%
Lung Tx: Depends on the clinical presentation
UT around <10% / IPA 67–82%
IPA, invasive pulmonary aspergillosis; SOT, solid organ transplant; Tx, treatment; UT: ulcerative tracheobronchitis

14. Treatment IFD SOT

15. Drug Interactions

17. Treatment Invasive Aspergillosis SOT General Principles
Should be initiated early in SOT patients with high suspicion of IA (AIII) Individualized according to SOT recipient, type of IA, and immunosuppression used (AIII) Diagnostic evaluation mandatory in order to confirm IA (AIII) Important to reduce immunosuppression as an adjunct to antifungal treatment, but without jeopardizing graft viability Probably the most important strategy is the reduction of the corticosteroid dose (BIII)
IA, invasive aspergillosis; SOT, solid organ transplant

18. Treatment Invasive Aspergillosis SOT Preferred treatment
Voriconazole AIII ECMID / AST (A I)
IV 4 mg/kg/12 h (loading 6 mg/kg) or 200 mg/12 h PO (loading dose of 400 mg/12 h)
Severe Infections: IV administration recommended
Switched to oral intake in case of Renal Insufficiency
TDM recommended (range 2 and 4 mg/L) (AII)
Consider potential hepatotoxicity and drug interactions –immunosuppressants
Liposomal amphotericin B (3 mg/kg/day) AIII ECMID / AST (A I)
If risk of severe liver toxicity or drug interaction with voriconazole
Be aware Amphotericin B lipid formulations nephrotoxicity

19. Treatment Invasive Aspergillosis SOT Severe disease (pneumonia or disseminated disease
Consider Combination Antifungals Voriconazole + Caspofungin Voriconazole + Anidulafungin at least to ensure therapeutic concentrations of voriconazole (AIII)

20. Treatment Invasive Aspergillosis SOT. Duration
Has not been established It should be maintained until radiological signs disappear Usually a minimum of 6–12 weeks
SOT, solid organ transplant

21. Treatment Invasive Aspergillosis SOT Monitor therapeutic response
Clinical evaluation + CT scan every 7–10 days
A cavitation of lesions indicating necrosis nor a slight increase in lesion volume indicates adverse outcome (AIII)
PCR or GM antigen in plasma or serum should not be used for treatment monitoring (DIII)
CT, computed tomography; SOT, solid organ transplant

22. Lim C, et al Clin Radiol. 2012;67:1179‒1186

23. Lim C, et al Clin Radiol. 2012;67:1179‒1186

25. Treatment Invasive Aspergillosis SOT Rescue treatment
Treatment of patients who are refractory or intolerant to initial therapy
Not well defined. Failure of Therapy
dissemination of the clinical symptoms during treatment
new or increased lesions in the CT scan performed 7–10 days after treatment onset (in the absence of recovery from absolute neutropenia)
Stable Disease: no decrease in lesion size in the CT scan performed at 15–21 days
intolerance to elective therapy
Consider Combination Antifungals or Change

26. IFI Lung Transplantation Treatment Colonization Aspergillus spp.
Colonization must be treated to prevent invasive disease:
Nebulized liposomal amphotericin B 25 mg q24h for 7 days, then 25 mg q72h
Nebulized Amphotericin B lipidic complex 50 mg q24h
In case of intolerance to inhaled lipid formulations of Amphotericin B: Voriconazole (Loading dose 400 mg PO q12h, then 200 mg PO q12h.

27. IFI Lung Transplantation Treatment Invasive Tracheobronchitis Aspergillus spp.
Voriconazole plus nebulized lipid formulations
Bronchoscopy to evaluate the extension of disease and to clear necrotic debris and fungus balls (this should be repeated every week or every 2 weeks).
A high-resolution CT scan should also be performed to rule out parenchymal extension (AIII).

28. When should Aspergillus resistance to antifungals be suspected and what are the recommended methods to assess antifungal drug susceptibility?
Should be suspected in every therapeutic failure and when cryptic species are identified as causative agents of IA
We recommend testing for antifungal resistance in every isolate coming from an IA for epidemiological and antifungal R purposes (AII)
Commercially available test can be used in clinical laboratories to screen for resistance
EUCAST or CLSI reference methods should be used to confirm antifungal R
CLSI, Clinical and Laboratory Standards Institute; EUCAST, European Committee for Antimicrobial Susceptibility Testing; IA, invasive aspergillosis

29. Bliateral Lung Transplant Recipient with Harvest Cultures Donor +
Aspergillus spp.

30. Day + 6

35. Prevention IFD SOT

36. Prevention IFD SOT
Absence of clinical trials and the epidemiological differences in IFDs between different transplant programs lead to lack of definitive recommendations for the prevention of IFD in SOT
TID Experience based Medicine NOT Evidence based Medicine
Reduction in the incidence needs to be analyzed together with other types of measures more important than antifungal prophylaxis
optimization of surgical procedures
proper handling of immunosuppression
environmental control of certain filamentous fungi

37. Prevention IFD SOT
The correct identification of patients at increased risk of fungal infection is the main goal for a proper IFD prevention The election of general prophylaxis versus targeted prophylaxis is based on the type of transplant and clinical risk factors Appropriate prophylaxis consider the effectiveness, safety, minimal side effects and drug interactions

38. Risk Factors IFD SOT Invasive Invasive Candidiasis Aspergillosis
Clinical
Biomarkers
No Biological

39. Risk Factors Invasive Candidiasis in SOT
Poor Pre Transplant health condition Retransplantation Complicated Surgery Complicated Immediate Post Transplant Renal failure Hemodialysis OverImmunossupression

40. Risk Factors Invasive Candidiasis in SOT

41. Risk Factors IA in SOT

42. Prevention IFD in Liver Transplantation
Duration 2- 4 w or end risk factors

43. Prevention Invasive Candidiasis SOT

44. Prevention IFD

45. Nebulized Amphotericin B The Vall d’Hebron Experience

46. Lung Transplantation: Prophylaxis Nebulized CAB Aspergillus Infection
Median
Candida
Aspergillus
Median
Death Related to n
(range)
Mucositis
Infection
(range)
Aspergillus
Follow-up (mo)
n (%)
n (%)
Time to Tx (mo)
Infection, n (%)
No prophylaxis 13
27.5 (4-56)
8 (61.5 %)
7 (53.8 %)
3 IPA
2 UT - 2 T
11.6 (0.3-41)
3 (23.1%)
Prohylaxis
17 (6%)
2 IPA
3 UT - 12 T
280
20.9 (0.7-48)
6 ( )
2 (0.7 %)
(intent to treat)
7 out of the 13 patients who did not receive prophylaxis developed Aspergillus infection. In 3 out of them it was the primary cause of death. Two-thirds of this group has at least one episode of mucositis due to Candida sp.
In contrast, in the prophylaxis group fourteen percent of the patients developed Aspergillosis by intent to treat. In four patients compliance with the prophylaxis was poor. Thus, the real incidence of aspergillosis in the prophylaxis group was about 10%. BUT ONLY two patiens (1.8%) had AN INVASIVE DISEASE AND died related to the disease (1.8%). No patient experienced mucositis due to Candida sp.
Close to half of the patients had some side effects, but most of them were mild. The main secondary effect was mild, easily controlled bronchospasm. In no case was it necessary to withdraw prophylaxis because of side effects. About 15% of the patients did not do well on prophylaxis, 9 had poor compliance and three abandoned voluntarily.
Compliance
177
11 (6.2%)
1 (0.5%)
No compliance 18
5 (27.7 %)
1 (5%)
Monforte V, et al. J Heart Lung Transplant. 2001;20:

47. Lung Transplantation: Prophylaxis Nebulized CAB Aspergillus Infection
Risk Factors
Nebulized CAB independent factor to decrease Aspergillus infection
Odds ratio: 0.13; 95% CI ; P<0.05
CMV disease independent risk factor
Odds ratio: 5.1; 95% CI ; P<0.05
Monforte V, et al. J Heart Lung Transplant. 2001;20:

48. Lung Transplantation: PK of Nebulized CAB
BL (µg/mL)
BAL (µg/mL)
4 h* 30
3.0 ( )
15.8 ( )
12 h 32
2.2 ( )
13.7 ( )
24 h 25
2.1 (1-3.2)
11 (7-15.1)
48 h 15
1.6 ( )
10.6 ( )
7 d 4 ND
*In 5 patients, no serum levels of CAB were detected.
Monforte V, et al. Transplantation. 75(9): , May 15, 2003.

49. Lung Transplantation: Nebulized CAB Distribution
Single Lung Transplant
Double Lung Transplant
This slide shows the distribution of nebulized ampb in a single lung recipient. We can see the predominance to the allograft
Chronic Rejection
Ventilation
Perfusion
Monforte V, et al. Transplantation. 75(9): , May 15, 2003.

50. Can We Use Nebulized LAb as Prophylaxis?
Higher amphotericin B
BAL concentrations?
Alveolar macrophage uptake?
Does interval dosing promote
better compliance?

52. Lung Transplantation Nebulized Ambisome PK
Clinical assay similar to previous study with CAB
Ambisome dose 25 mg
Liposomal Ab
No drug levels in blood were seen.

53. 412 patients, mean follow-up 2.56 years (IQR 1.01–4.65)
22 patients Invasive Aspergillosis (22/412, 5.3%)
1-year cumulative incidence of IA: 3.6%
IPA 15 (3.6%)
Ulcerative Tracheobronchitis 7 (1.7%)
31 NIA: Tb 23; Stent infections 6; native-lung aspergillomas 2
Long term Prophylaxis: Safety
Mild adverse effects 12 (2.9%)
Mild, transitory breathing difficulty 8 (1.9%)
Nausea 3; dizziness in 1 (0.2%)
Discontinuation: 7 (1.7%) due secondary effects; 7 spontaneously

54. Mortality: 11 patients (11/412; 2.7%)
IPA 8 of 15 (53.3%)
UT 1 of 7 (14.3%)
Aspergilloma One patient

56. Prevention IFD in Lung Transplantation

57. Penseu que el mirall de la veritat s’esmicolà a l’origen en fragments petitíssims, i cada un dels trossos recull tanmateix una engruna d’autèntica llum. S. Espriu
Pensate che lo specchio della verità si sbricioli all'origine in frammenti molto piccoli, e ciascuno di essi raccolga un piccolo bagliore di luce autentica. S. Espriu

58. Gràcies
Grazie Mille