Articles
Invasive aspergillosis in liver transplant recipients in France (2007–21): a nationwide, retrospective, matched case–control study
Coralie Le Hyaric, Cléa Melenotte, François Lefebvre, et al
Lancet Microbe 2026; 7: 101272
https://doi.org/10.1016/j.lanmic.2025.101272
Summary
Background
Invasive aspergillosis is a rare but severe complication of liver transplantation. Incidence varies from 1·2% to 5·6% and mortality is greater than 50%. Few studies have investigated this complication. We aimed to describe cases of, and identify the factors associated with, invasive aspergillosis occurrence and mortality.
Methods
This nationwide, retrospective, matched case–control study included cases of invasive aspergillosis occurring after liver transplantation between Jan 1, 2007, and Dec 31, 2021, matched 1:1 on centre and transplantation period to control individuals without invasive aspergillosis across 15 liver transplantation centres in France. Cases were patients aged 18 years or older who presented with proven or probable invasive aspergillosis. The matched control was the next patient who received a transplant at the same transplantation centre after the case. Cases were retrospectively identified in each centre using the mycology laboratory database and the French Medicalised Information System Programme. Data were retrieved from hospital charts. The primary outcome was the identification of risk factors associated with the development of invasive aspergillosis following liver transplantation. Multivariable analysis using conditional logistic regression with a random effect for study centres was done to establish risk factors.
Findings
Among 14 332 liver transplantations, 196 recipients with invasive aspergillosis (62 [32%] female and 134 [68%] male) were identified and matched with 196 control individuals (54 [28%] female and 142 [73%] male). Invasive aspergillosis occurred at a median of 29 days (IQR 7–173) after liver transplantation. Risk factors for developing invasive aspergillosis were history of chronic kidney disease (adjusted odds ratio 4·13 [95% CI 2·35–7·24]), liver transplantation for acute liver disease (3·41 [1·44–8·06]), post-liver transplantation renal replacement therapy (3·82 [1·96–7·42]), and post-liver transplantation vasopressor support for longer than 24 h (2·82 [1·70–4·68]).
Table 1. Characteristics of cases and controls at time of liver transplantation and post-operative complications in a univariable analysis
| Empty Cell | Cases (n=196) | Controls (n=196) | OR (CI 95%) | p value |
|---|---|---|---|---|
| Age at liver transplantation, years | 54 (10·6) | 53 (11·8) | 1·01 (0·99–1·02) | 0·50 |
| Sex | ||||
| Male | 134 (68%) | 142 (73%) | 1·20 (0·79–1·83) | 0·39 |
| Female | 62 (32%) | 54 (28%) | ||
| BMI at liver transplantation, kg/m2 | 26·6 (5·8) | 26·1 (5·0) | 1·01 (0·98–1·05) | 0·50 |
| High blood pressure | 67/182 (37%) | 73/190 (38%) | 0·98 (0·64–1·49) | 0·92 |
| Diabetes | 65/195 (33%) | 56/196 (29%) | 1·23 (0·81–1·88) | 0·34 |
| Active smoking | 48/185 (26%) | 52/184 (28%) | 0·87 (0·54–1·38) | 0·55 |
| COPD | 23/196 (12%) | 17/196 (9%) | 1·38 (0·72–2·62) | 0·33 |
| Chronic kidney disease | 38/196 (20%) | 14/196 (7%) | 4·43 (1·95–10·06) | 0·0004 |
| Renal replacement therapy | 12/196 (6%) | 3/196 (2%) | 5·50 (1·22–24·81) | 0·027 |
| Neutropenia | 5/193 (3%) | 0/183 | 0·00 (0·00–inf) | 0·99 |
| Systemic steroid use before liver transplantation | 27/196 (14%) | 16/196 (8%) | 1·69 (0·91–3·13) | 0·10 |
| Previous known Aspergillus colonisation or infection∗ | 23/195 (12%) | 2/195 (1%) | 11·50 (2·71–48·78) | 0·0009 |
| Previous liver transplantation | 25/196 (13%) | 13/196 (7%) | 2·00 (1·00–3·99) | 0·050 |
| MELD score >30 | 86/183 (47%) | 46/183 (25%) | 2·55 (1·55–4·17) | 0·0002 |
| MELD score, median (IQR) | 28 (17–39) | 19 (10–30) | 1·06 (1·04–1·08) | <0·0001 |
| Hepatitis B | 16/196 (8%) | 12/196 (6%) | 1·36 (0·63–2·97) | 0·44 |
| Liver transplantation indications† | ||||
| Cirrhosis without acute-on-chronic liver failure | 99/195 (51%) | 126/196 (64%) | 0·59 (0·39–0·88) | 0·010 |
| Acute-on-chronic liver failure§ | 41/195 (21%) | 28/196 (14%) | 1·65 (0·95–2·88) | 0·077 |
| Acute liver disease | 49/195 (25%) | 15/196 (8%) | 4·78 (2·33–9·80) | <0·0001 |
| Acute-on-chronic liver failure 2 and 3 | 19/24 (80%) | 7/16 (44%) | 0·00 (0·00–inf) | 1·00 |
| Acute liver failure | 30/195 (15%) | 8/196 (4%) | 4·67 (1·93–11·27) | 0·0006 |
| Hepatocellular carcinoma | 38/195 (20%) | 68/196 (35%) | 0·42 (0·25–0·70) | 0·0009 |
| Other | 22/195 (11%) | 20/196 (10%) | ·· | ·· |
| Perioperative and post-operative characteristics | ||||
| Liver transplantation from ICU | 91/195 (47%) | 43/190 (23%) | 4·08 (2·31–7·15) | <0·0001 |
| Liver transplantation duration, hours | 6·7 (2·2) | 6·5 (2·0) | 1·11 (0·94–1·30) | 0·22 |
| Cold ischaemia time, min | 450·7 (132·1) | 443·2 (139·2) | 1·00 (1·00–1·00) | 0·71 |
| Red blood cell units during liver transplantation, median (IQR) | 6 (3–10) | 4 (0–8) | 1·11 (1·05–1·16) | <0·0001 |
| Red blood cell units >4 during liver transplantation | 115/182 (63%) | 80/189 (42%) | 2·57 (1·58–4·15) | 0·0001 |
| ICU hospitalisation >7 days after liver transplantation | 146/186 (79%) | 93/188 (50%) | 4·47 (2·55–7·82) | <0·0001 |
| Mechanical ventilation >24 h | 119/188 (63%) | 60/194 (31%) | 4·88 (2·85–8·35) | <0·0001 |
| Vasopressor support >24 h | 96/184 (52%) | 39/195 (20%) | 6·55 (3·47–12·35) | <0·0001 |
| Post-liver transplantation renal replacement therapy | 96/191 (50%) | 26/195 (13%) | 8·78 (4·41–17·49) | <0·0001 |
| Re-operation | 63/196 (32%) | 44/196 (22%) | 1·70 (1·06–2·74) | 0·028 |
| Re-transplantation | 2/196 (1%) | 5/196 (3%) | 0·25 (0·03–2·24) | 0·22 |
| Primary graft dysfunction‡ | 42/192 (22%) | 21/196 (11%) | 2·75 (1·42–5·32) | 0·0027 |
| Rejection | 19/193 (10%) | 20/195 (10%) | 0·95 (0·50–1·81) | 0·87 |
| Bacterial infection¶ | 160/187 (86%) | 105/195 (54%) | 5·62 (3·11–10·13) | <0·0001 |
| Yeast infection¶ | 45/188 (24%) | 10/188 (5%) | 5·13 (2·40–10·93) | <0·0001 |
| Cytomegalovirus infection or disease|| | 53/190 (28%) | 49/194 (25%) | 1·93 (1·24–3·00) | 0·0034 |
| Antimould prophylaxis | 59/196 (30%) | 45/196 (23%) | 1·64 (0·96–2·78) | 0·069 |
| Caspofungin | 33 (56%) | 19 (42%) | ·· | ·· |
| Micafungin | 18 (31%) | 21 (47%) | ·· | ·· |
| Amphotericin B | 5 (9%) | 3 (7%) | ·· | ·· |
| Voriconazole | 3 (5%) | 2 (4%) | ·· | ·· |
| Immunosuppressive regimen | ||||
| Tacrolimus | 172/193 (89%) | 185 (94%) | 0·44 (0·19–1·02) | 0·056 |
| Mycophenolate mofetil | 187/193 (97%) | 189 (96%) | 1·17 (0·39–3·47) | 0·78 |
Screening for colonisation was not systematically done in patients and the absence of colonisation does not imply that the patient was sampled.†
Two indications can be associated in one patient.‡
Primary graft dysfunction was defined as the presence of one or more of the following postoperative laboratory values: bilirubin ≥10 mg/100 mL on day 7, international normalised radio ≥1·6 on day 7, and alanine aminotransferase or aspartate aminotransferase >2000 IU/L within the first 7 days.15§
All patients with acute-on-chronic liver failure, regardless of the stage.¶
Bacterial and yeast infection can occur within 1-year post-transplantation, regardless of the development of invasive aspergillosis.||
Cytomegalovirus infection and disease were grouped into a single variable because it was not possible to retrospectively classify cytomegalovirus syndromes correctly.
Table 2. Invasive aspergillosis characteristics
| Empty Cell | Cases (n=196) |
|---|---|
| Location of invasive aspergillosis | |
| Lower respiratory tract only | 158/196 (81%) |
| Disseminated∗ | 31/196 (16%) |
| Lower respiratory tract | 23/31 (74%) |
| CNS | 19/31 (61%) |
| Cardiovascular system† | 11/31 (36%) |
| Other‡ | 13/31 (42%) |
| Extrapulmonary single-site locations§ | 7/196 (4%) |
| Vascular complications of invasive aspergillosis¶ | 10/195 (5%) |
| Thoracic CT scans | 169/196 (86%) |
| Pleural effusion | 114/169 (68%) |
| Pulmonary condensation | 100/169 (59%) |
| Nodule | 83/169 (49%) |
| Excavated nodules | 6/83 (7%) |
| Ground glass opacities | 73/169 (43%) |
| Halo sign|| | 14/169 (8%) |
| Air crescent sign | 6/169 (4%) |
| Biology at diagnosis | |
| Neutrophils, g/L | 7·3 (3·0–11·7) |
| C-reactive protein, mg/L | 64·0 (27·0–109·6) |
| Creatinine, μmol/L | 114·0 (69·8–186·5) |
| Bilirubin, μmol/L | 49·3 (14·0–160·8) |
| Alanine aminotransferase, UI/L | 86·0 (24·5–214·5) |
| Aspartate aminotransferase, UI/L | 54·0 (24·0–165·0) |
| Albumin <30 g/100 mL | 84/148 (57%) |
| Prothrombin time, % | 69·0% (55·0–85·0) |
| Fibrinogen, g/L | 3·3 (2·2–4·1) |
| Isolation of Aspergillus species | |
| None | 38/196 (19%) |
| Aspergillus fumigatus | 140/158 (89%) |
| Aspergillus flavus | 6/158 (4%) |
| Aspergillus niger | 5/158 (3%) |
| Other Aspergillus spp | 13/158 (8%) |
| More than one Aspergillus spp isolated | 6/158 (4%) |
| Voriconazole MIC >1 μg/μL | 0/47 |
| Positive galactomannan (≥1) in serum | 70/161 (44%) |
| Galactomannan level in serum, index | 2·98 (1·7–4·3) |
| Positive galactomannan (≥1) in bronchoalveolar lavage fluid | 65/97 (67%) |
| Positive Aspergillus fumigatus PCR in serum | 16/32 (50%) |
| Positive Aspergillus fumigatus PCR in bronchoalveolar lavage fluid | 33/44 (75%) |
| Detection of acute septate hyphae in histology | 19/29 (66%) |
| Fungal co-infection | 15/196 (8%) |
| Location of co-infection | |
| Lower respiratory tract | 7/14 (50%) |
| Intra-abdominal infection | 4/14 (29%) |
| Fungemia and/or catheter infection | 2/14 (14%) |
| Disseminated infection | 1/14 (7%) |
| Identified co-infection species | |
| Candida spp∗∗ | 6/15 (40%) |
| Mucorales | 3/15 (20%) |
| Scedosporium apiospermum | 1/15 (7%) |
| Paecilomyces spp | 1/15 (7%) |
| Exophiala spp | 1/15 (7%) |
| Pneumocystis jiroveci | 3/15 (20%) |
Some patients had infection in several locations (each one is counted).†
Cardiovascular infections were: six infectious endocarditis (including two patients with positive heart valve culture), two pericarditis (positive pericardial fluid culture), and two patients with positive myocardial biopsy. For one patient, the information was missing.‡
Other locations were: kidney (four [13%]), skin and soft tissues (four [13%]), liver (three [10%]), and osteoarticular (two [6%]).§
Single-site locations were intra-abdominal (three [43%]), sinus (three [43%]), and osteoarticular (one [14%]).¶
Vascular complications were thrombosis (six [3%] of 194), aneurysm (two [1%] of 195), and disseminated intravascular coagulation (two [1%] of 195).||
Among these patients, one presented with neutropenia.∗∗
Excluding isolation of Candida spp in pulmonary samples other than biopsy.
Table 3. Treatment of invasive aspergillosis
| Empty Cell | Cases (n=196) |
|---|---|
| Antifungal first-line treatment∗ | 187/196 (95%) |
| Length of antifungal treatment, days | 36·0 (21·0–86·0) |
| Treatment duration among patients alive at 3 months | 66·0 (31·3–149·0) |
| Monotherapy | 175/187 (94%) |
| Voriconazole | 96/187 (51%) |
| Isavuconazole† | 19/187 (10%) |
| Other azole‡ | 1/187 (1%) |
| Caspofungin | 25/187 (13%) |
| Micafungin | 12/187 (6%) |
| Amphotericin B | 22/187 (12%) |
| Combined therapy | 12/187 (6%) |
| Azole and echinocandin | 8/187 (4%) |
| Azole and amphotericin B | 3/187 (2%) |
| Echinocandin and amphotericin B | 1/187 (1%) |
| Surgical treatment | 18/196 (9%) |
| Immunosuppressive treatment modification | 78/190 (41%) |
| Drug decrease§ | 37/190 (20%) |
| Tacrolimus | 21/190 (11%) |
| Systemic corticosteroids | 9/190 (5%) |
| Mycophenolate mofetil | 6/190 (3%) |
| Other | 3/190 (2%) |
| Drug discontinuation§ | 48/190 (25%) |
| Mycophenolate mofetil | 24/190 (13%) |
| Tacrolimus | 20/190 (11%) |
| Systemic corticosteroids | 10/190 (5%) |
| Modification of at least two drugs | 17/190 (9%) |
| Secondary prophylaxis | 16/121 (13%) |
| Posaconazole | 7/121 (6%) |
| Itraconazole | 4/121 (3%) |
| Isavuconazole | 3/121 (3%) |
| Voriconazole | 2/121 (2%) |
Nine patients did not receive any treatment, mostly due to death before the results of the investigations.†
Isavuconazonium.‡
The other azole was itraconazole (one [0·5%]).§
Some patients had several drug modifications (each one is counted)
Interpretation
This study identifies three patient populations at risk of invasive aspergillosis after liver transplantation: patients with history of chronic kidney disease, those who have received a transplant for acute liver disease, and those who had a post-operative period marked by organ failure. This identification could lead to new invasive aspergillosis prophylactic strategies.
Funding
None.
