Hoffmann Claire V, Le Meur Yannick, Moal Marie-Christine, Grall-Jézéquel Anne, Le Nan Nathan, Papon Nicolas, Nevez Gilles, Le Gal Solène
CHU de Brest, Laboratoire de Parasitologie-Mycologie, Brest, France; Univ Brest, Univ Angers, Infections Respiratoires Fongiques, Brest, France.
CHU de Brest, Service de néphrologie et transplantations rénales, Brest, France; Université de Brest, UMR1227, Lymphocytes B et Autoimmunité, Inserm, Labex IGO, Brest, France.
Lancet Microbe. 2025 Sep;6(9):101146. doi: 10.1016/j.lanmic.2025.101146. Epub 2025 Jul 29.
Pneumocystis pneumonia (PCP) case clusters involving solid organ transplant (SOT) recipients have been reported worldwide. Mycophenolic acid, an immunosuppressant used to prevent rejection in SOT recipients that targets the inosine 5'-monophosphate dehydrogenase (IMPDH) protein, has been hypothesised to exert selective pressure on Pneumocystis jirovecii, with the missense mutation G1020A (Ala261Thr) in the impdh gene a possible marker of such selective pressure. The aim of this study was to test the hypothesis that SOT recipients harbour P jirovecii with mutations in the impdh gene and are infected with specific P jirovecii strains.
In this retrospective, multicentre, cross-sectional study of nationally representative, individual-level data, we included SOT recipients, regardless of the organ transplanted, involved or not in a PCP case cluster, and non-SOT recipients (control group) without mycophenolic acid exposure, diagnosed with PCP from 26 French and one Swiss secondary health-care centres. We included patients aged 18 years or older for whom archival P jirovecii DNA extracts were available in sufficient quantity and quality. P jirovecii specimens were characterised using a multilocus sequence typing method including impdh gene analysis. The primary outcome of this study was the detection of the G1020A (Ala261Thr) mutation in the impdh gene. A multivariable logistic regression was done to assess the relation between this mutation and the following variables retrieved from medical records: age, mycophenolic acid exposure at the time of PCP diagnosis, involvement in a PCP case cluster, PCP prophylaxis, and clinical outcome.
58 SOT recipients (44 treated with mycophenolic acid) and 59 non-SOT recipients (control group; not treated with mycophenolic acid) diagnosed with PCP between Jan 1, 2001, and Dec 31, 2021, were enrolled. The G1020A (Ala261Thr) mutation was detected in P jirovecii specimens from 40 (68·9%) SOT recipients (37 treated with mycophenolic acid) and in none of the P jirovecii specimens from the patients in the control group. The multivariable analysis showed that the allele characterised by the G1020A mutation was associated with mycophenolic acid exposure at the time of PCP diagnosis (adjusted odds ratio 73·61 [95% CI 17·41-455·70]; p<0·0001) and involvement in a PCP case cluster (12·77 [1·58-171·90]; p=0·029), whereas it was not associated with age, PCP prophylaxis, and clinical deterioration. A second missense mutation, G1020T (Ala261Ser) was identified in P jirovecii specimens from three SOT recipients (two treated with mycophenolic acid). Two specific multilocus genotypes (MLG-31 and MLG-34) of P jirovecii associated with Ala261Thr and Ala261Ser substitutions in IMPDH, respectively, were detected only in SOT recipients (38 patients with MLG-31 and three patients with MLG-34).
SOT recipients in this study were primarily infected with specific P jirovecii strains with mutations in the impdh gene, which might confer a selective advantage as both the G1020A (Ala261Thr) and G1020T (Ala261Ser) are associated with mycophenolic acid resistance in other fungi. Mycophenolic acid selective pressure might explain the maintenance and circulation of these P jirovecii strains within this patient population, and consequently their potential involvement in PCP case clusters.
French Speaking Society for Transplantation, and Chiesi.
全球范围内均有关于实体器官移植（SOT）受者发生肺孢子菌肺炎（PCP）病例聚集的报道。霉酚酸是一种用于预防SOT受者排斥反应的免疫抑制剂，其作用靶点为肌苷5'-单磷酸脱氢酶（IMPDH）蛋白，据推测，该药物会对耶氏肺孢子菌施加选择性压力，而impdh基因中的错义突变G1020A（Ala261Thr）可能是这种选择性压力的一个标志。本研究的目的是验证以下假设：SOT受者体内携带impdh基因发生突变的耶氏肺孢子菌，且感染的是特定的耶氏肺孢子菌菌株。
在这项回顾性、多中心、横断面研究中，我们纳入了来自法国26个和瑞士1个二级医疗保健中心的SOT受者（无论移植的器官是什么，无论是否参与PCP病例聚集）以及未接触霉酚酸的非SOT受者（对照组），这些患者均被诊断为PCP。我们纳入了年龄在18岁及以上且有足够数量和质量的存档耶氏肺孢子菌DNA提取物的患者。使用包括impdh基因分析在内的多位点序列分型方法对耶氏肺孢子菌标本进行特征分析。本研究的主要结局是检测impdh基因中的G1020A（Ala261Thr）突变。进行多变量逻辑回归分析，以评估该突变与从医疗记录中获取的以下变量之间的关系：年龄、PCP诊断时的霉酚酸暴露情况、参与PCP病例聚集情况、PCP预防措施以及临床结局。
纳入了2001年1月1日至2021年12月31日期间诊断为PCP的58例SOT受者（44例接受了霉酚酸治疗）和59例非SOT受者（对照组；未接受霉酚酸治疗）。在40例（68.9%）SOT受者（37例接受了霉酚酸治疗）的耶氏肺孢子菌标本中检测到G1020A（Ala261Thr）突变，而对照组患者的耶氏肺孢子菌标本中均未检测到该突变。多变量分析显示，以G1020A突变特征的等位基因与PCP诊断时的霉酚酸暴露情况相关（调整后的比值比为73.61 [95%置信区间17.41 - 455.70]；p<），与参与PCP病例聚集情况相关（12.77 [1.58 - 171.90]；p = 0.029），而与年龄、PCP预防措施以及临床病情恶化无关。在3例SOT受者（2例接受了霉酚酸治疗）的耶氏肺孢子菌标本中鉴定出另一个错义突变G1020T（Ala261Ser）。仅在SOT受者中检测到与IMPDH中Ala261Thr和Ala261Ser替代分别相关的两种特定的耶氏肺孢子菌多位点基因型（MLG - 31和MLG - 34）（38例患者为MLG - 31，3例患者为MLG - 34）。
本研究中的SOT受者主要感染的是impdh基因发生突变的特定耶氏肺孢子菌菌株，由于G1020A（Ala261Thr）和G1020T（Ala261Ser）在其他真菌中均与对霉酚酸的耐药性相关，因此这些突变可能赋予了选择性优势。霉酚酸的选择性压力可能解释了这些耶氏肺孢子菌菌株在该患者群体中的维持和传播，以及它们因此可能参与PCP病例聚集的情况。
法语区移植学会和奇西制药公司。
