Liu Xiaoyan, Su Haibin, Tong Jingjing, Chen Jing, Yang Haozhen, Xiao Long, Hu Jinhua, Zhang Lina
Liver Failure Treatment and Research Center, 302 Hospital of PLA, Xisihuanzhonglu, Beijing, China.
Medicine (Baltimore). 2017 Oct;96(42):e8039. doi: 10.1097/MD.0000000000008039.
Invasive pulmonary aspergillosis is associated with significant morbidity and mortality in patients with liver failure. Voriconazole (VRCZ) is recommended as a primary therapeutic agent for the treatment of invasive aspergillosis and metabolized in the liver. Now, data are still lacking on the safety and appropriate dosage of VRCZ in patients with liver failure. Here, we report a representative case of invasive pulmonary fungal infection in a patient with liver failure who was treated with low-dose VRCZ.
A 21-year-old man, presented with subacute liver failure caused suspected by viral infection, was admitted on June 22, 2014. Liver function was not improved by the treatment of gancicolovir and methylprednisolone. The patient presented with fever, cough, and hyperpyrexia on July 14. Laboratory tests revealed raised neutrophil percentage (82.1%, normal range [NR] 50-70), international normalized ratio (INR) (2.32, NR 0.8-1.2) and levels of serum lactic acid (4.308 mmol/L, NR 0.6-2.2), alanine transaminase (165 U/L,NR 0-40), aspartate transaminase (99 U/L, NR 8-40), and total bilirubin (654 mmol/L, NR 3.4-20.5). Furthermore, CD4+ T cell, CD8+T cell, and B cell count were low (169, 221, and l8/mL, respectively). Sputum smear microscopy for bacteria was negative, but the direct observation for fungal elements was positive. Thoracic CT scan revealed bilateral pulmonary high-density shadow. Sputum cultures were positive 2 days later with the presence of Aspergillus fumigatus.
Therefore, this patient diagnosed with suspected pulmonary a spergillosis.
VRCZ was used on July 15th and its dosage was 400 mg twice on day 1 followed by a maintenance dose of 100 mg twice daily according to drug usage instruction. However, some side effects, such as tremors, lips twitching, and hair loss, occurred. Plasma VRCZ trough concentration was 8.1 mg/mL which was much higher than the recommend level. Therefore, VRCZ dosage was adjusted according to its plasma concentration. VRCZ plasma concentration fluctuated between 2.5 to 4.7 mg/mL when its dosage was 100 mg once daily and side effects disappeared.
VRCZ was administered for 2 months. This patient's symptoms and liver function were improved. A follow-up CT scan performed at the end of VRCZ therapy indicated that the high-density shadow had diminished.
This case demonstrated that low-dose VRCZ (maintenance dose, 100 mg/day) can achieve effective plasma concentration and reduce side effects without liver damage. We believe that VRCZ is safe to be administered in patients with liver failure, but its plasma concentration should be carefully monitored.
侵袭性肺曲霉病在肝衰竭患者中与显著的发病率和死亡率相关。伏立康唑（VRCZ）被推荐作为治疗侵袭性曲霉病的主要治疗药物，且在肝脏中代谢。目前，关于VRCZ在肝衰竭患者中的安全性和合适剂量的数据仍然缺乏。在此，我们报告一例肝衰竭患者侵袭性肺部真菌感染并接受低剂量VRCZ治疗的典型病例。
一名21岁男性，因疑似病毒感染导致亚急性肝衰竭，于2014年6月22日入院。更昔洛韦和甲泼尼龙治疗后肝功能未改善。患者于7月14日出现发热、咳嗽和高热。实验室检查显示中性粒细胞百分比升高（82.1%，正常范围[NR]50 - 70）、国际标准化比值（INR）（2.32，NR 0.8 - 1.2）以及血清乳酸水平（4.308 mmol/L，NR 0.6 - 2.2）、丙氨酸转氨酶（165 U/L，NR 0 - 40）、天冬氨酸转氨酶（99 U/L，NR 8 - 40）和总胆红素（654 mmol/L，NR 3.4 - 20.5）升高。此外，CD4 + T细胞、CD8 + T细胞和B细胞计数较低（分别为169、221和18/mL）。痰涂片细菌镜检为阴性，但真菌成分直接观察为阳性。胸部CT扫描显示双侧肺部高密度影。2天后痰培养阳性，发现烟曲霉。
因此，该患者被诊断为疑似肺曲霉病。
7月15日开始使用VRCZ，根据药物使用说明，第1天剂量为400 mg，每日2次，随后维持剂量为每日2次，每次100 mg。然而，出现了一些副作用，如震颤、嘴唇抽搐和脱发。血浆VRCZ谷浓度为8.1 mg/mL，远高于推荐水平。因此，根据其血浆浓度调整了VRCZ剂量。当剂量为每日1次，每次100 mg时，VRCZ血浆浓度在2.5至4.7 mg/mL之间波动，副作用消失。
VRCZ使用了2个月。该患者的症状和肝功能得到改善。VRCZ治疗结束时进行的随访CT扫描显示高密度影已缩小。
该病例表明低剂量VRCZ（维持剂量，100 mg/天）可达到有效的血浆浓度并减少副作用且无肝损伤。我们认为VRCZ在肝衰竭患者中给药是安全的，但应仔细监测其血浆浓度。
