Invasive pulmonary aspergillosis (IPA) is a major cause of morbidity and mortality in patients who are severely immuno-compromised. Although a relatively low incidence of IPA is reported in patients with liver failure, this condition should be reconsidered as a devastating infectious disease in this population. Early recognition of IPA and prompt antifungal treatment in patient with liver failure may improve the outcome. As noted previously, treatment with glucocorticoid (GC) is established to be a risk factor for IPA, by inhibiting the anti-fungal immune responses of the host. Currently, the Infectious Diseases Society of America (IDSA) recommended voriconazole as the primary agent for treatment of IPA. However, voriconazole is hepatotoxic that is metabolized in the liver by the hepatic cytochrome P450 (CYP) isoenzymes, including CYP2C19, CYP2C9, and CYP3A4.[3,4], The CYP2C19 genetic polymorphism is related to plasma voriconazole concentration, which influence efficacy and safety of anti-fungal drugs. In addition, due to decreased hepatic metabolism of voriconazole in patients with liver dysfunction, therapeutic drug monitoring (TDM) may increase the probability of a successful outcome, and potentially prevent unnecessary drug-related toxicity.
Here, we report a case of IPA in a patient with liver failure who was successfully treated with voriconazole dependent on integrated application of CYP2C19 genotyping and TDM.
The study protocol was approved by the Ethics Committee of the Third Affiliated Hospital of Hebei Medical University, and written informed consent was obtained from the patients.
A 63-year-old female was admitted to our hospital due to fever, cough, and viscous sputum. Thirty-four days previously, the patient developed acute liver failure with total bilirubin (TBIL) 337mmol/L and international normalized ratio (INR) 2.04 after using Chinese herbal medicine for osphyalgia. In an outside hospital, she received a 20-day course of methylprednis-olone by intravenous-to-oral switch route at a gradually reduced daily dose. Liver function and coagulation profiles improved notably. However, the patient presented a new onset of fever with a maximum body temperature up to 38.8°C complicated with respiratory symptoms, such as cough and expectoration of brown-grey colored sputum. She was clinically diagnosed of IPA based upon on chest computed tomography (CT) films, as well as positive isolation of Aspergillus species in the sputum. Further, caspofungin (50 mg daily) and levofloxacin prophylaxis were prescribed for 7 days, but her symptoms did not alleviate. Therefore, she was transferred to the ward of Infectious Disease, the Third Affiliated Hospital of Hebei Medical University.
On admission, physical examination revealed evidence of generalized icterus. Moist crackles were detected on pulmonary auscultation. The laboratory results were as follows: white blood cell 3.36 × 109/L, neutrophils 2.39 × 109/L, lymphocytes 0.5 × 109/L, CD4+ T cells percentage 19.4%, platelets 44 × 109/L, alanine aminotransferase 92U/L, aspartate aminotransferase 55 U/L, TBIL 84.7 μmol/L, direct bilirubin 72.2 μmol/L, alkaline phosphatase 147U/L, glutamyl transpeptidase (GGT) 98U/L, and INR 1.7. Blood inflammatory markers were increased slightly: C-reactive protein 32.3 mg/L, erythrocyte sedimentation rate 22 mm/h, and procalcitonin 0.39ng/mL. Serum 1,3-beta-D-glucan (BDG) test was positive (233.5pg/mL), but galactomannan (GM) test was negative. Thoracic CT scan revealed multifocal bilateral nodular infiltrates and ground glass opacities, in which cavities were also observed [Fig. 1]. The sputum specimens were sent for microbiologic tests. The Aspergillus fumigatus was detected by next-generation sequencing technology (8087 sequence reads) and fungal culture. Other pathogenic microorganisms were excluded.
The genotyping test for CYP2C19 alleles ∗2, ∗3, and ∗17 was performed. The patient carrying CYP2C19∗1/∗2 genotype was identified as intermediate metabolizer. Therefore, intravenous voriconazole was administrated as a loading dose of 200 mg every 12 hours on the first day, followed by maintenance dose of 100 mg every 12 hours [Fig. 2]. However, she started to develop worsening skin rash [Fig. 3], vomiting, and altered state of consciousness following nearly 2days after initiation of voriconazole therapy. On the day 8, the TBIL and GGT levels increased to 179 μmol/L and 167U/L, respectively, while coagulation function was deteriorated again. None of the concomitant administered drugs, except voriconazole, appeared to be potentially hepatotoxic. TDM of the plasma voriconazole trough concentration (Cmin) was performed by two-dimensional liquid chromatography. The plasma Cmin was 16.76 mg/L, which is extremely higher than the recommended therapeutic range (0.5–5 mg/L) [Fig. 2]. Therefore, voriconazole was immediately discontinued, until its plasma Cmin reduced to 0.98 mg/L on the day 28 [Fig. 2]. After 16days of voriconazole discontinuation, symptoms of side effects gradually disappeared and the skin rash began to desquamate [Fig. 3], while the TBIL values declined to 64.2 μmol/L. Synchronously, the patient's body temperature fell to the normal range during this period. On the day 27, a repeat chest CT scan showed that the pulmonary cavity in size was enlarged [Fig. 1]. Under close monitoring, a single dose of voriconazole 100 mg was intravenously applied on the day 29. Plasma Cmin of voriconazole increased to 6.41 mg/L on the day 33, and then decreased to 1.22 mg/L on the day 40 [Fig. 2]. Considering high voriconazole concentration after intravenous infusion, the patient started to be treated with oral voriconazole tablet 200 mg every other day [Fig. 2]. The body temperature and liver function parameters remained normal.
On the day 44, the latest results of chest CT scan showed obvious absorption with cavities and inflammation [Fig. 1]. The patient discharged from the hospital with oral voriconazole tablet 200 mg daily, which was further used on an outpatient basis for 2 months until her recovery from infection. Plasma Cmin of voriconazole fluctuated between 1.5 and 3.2 mg/L [Fig. 2]. The dynamic changes of laboratory parameters together with concentrations of voriconazole during treatment were depicted in Figure 2.
IPA is traditionally regarded as a fatal opportunistic fungal infection that often occurs in immunocompromised patients, such as those with prolonged neutropenia, hematologic malignancies, or solid organ transplantation. It is remarkable that critically ill patients who have advanced liver diseases (cirrhosis or liver failure) are also reported to have increased risk for IPA, carrying a high mortality rate exceeding 70%. In a previous study, the mortality rate was 83% for patients with liver failure who developed IPA. Thus, early diagnosis and therapy of IPA has been proposed to be a main determinant of outcome.
GC is conditionally used for the early stage of liver failure by inhibiting excessive inflammation and immune responses. However, it is reported that prior GC therapy makes approximately 49.1% patients with liver failure more vulnerable to developing IPA. Prolonged GC use (>7days) predisposes patients with liver failure to 18-fold higher risk for IPA. GC impairs the function of neutrophils, T lymphocytes, and monocytes/macrophages, even directly enhancing Aspergillus spp. growth, thereby favoring invasive infection. Thus, it is reasonable to propose that severe lymphopenia following methylprednisolone treatment may be a prominent host factor for IPA in this patient.
Theoretically, both BDG test and GM test were positive in patients with IPA; however, inconsistent results were observed in this case. According to previous studies, the efficacy of the GM test in diagnosis of invasive aspergillosis indicates relatively lower sensitivity (71%) than its specificity (89%). Serum GM test of non-neutropenic patients has limited importance due to its lower sensitivity. If blood malignant patients were excluded from the cohort for analysis, the sensitivity of serum GM test may drop to 22%. Although GM detection in bronchoalveolar lavage fluid is superior to serum specimen for non-neutropenic population, increased risk of pulmonary hemorrhage may limit its use in patients with liver failure.
Treatment of IPA is challenging in patients with severe liver diseases. Although voriconazole is recommended by IDSA as a first-line agent for IPA therapy, this drug displays potential hepatotoxicity that is related to its plasma concentration. Voriconazole is metabolized mainly in the liver by the polymorphic CYP2C19 enzymes. Three different allelic variants including CYP2C19∗2, ∗3, and ∗17 could explain most of the phenotypes associated with voriconazole metabolism.[3,4] A study demonstrated that more frequent CYP2C19∗2 and ∗3 mutations were related to decreased enzyme activity and higher voriconazole concentration in the Chinese population. Thus, patients with liver failure are particularly prone to hepatotoxicity due to abnormal hepatic metabolism of this drug. Since CYP2C19∗1/∗2 genotype associated with intermediate metabolism was observed in this patient, the dosage of voriconazole was reduced by one-half when initiating antifungal therapy.
There is a large body of evidence demonstrating that the plasma Cmin of voriconazole is closely associated with its efficacy and side effects. As a result, the TDM of voriconazole is recommended for patients with liver dysfunction, CYP2C19 mutations, concomitant drug interaction, poor clinical response, voriconazole adverse events, or life-threatening infection. The Chinese Pharmacological Society recommends a rational therapeutic plasma Cmin of voriconazole between 0.5 and 5.0 μg/ mL. A meta-analysis also showed that a voriconazole Cmin of 0.5 mg/L should be considered the lower threshold associated with efficacy. The Cmin > 3.0 mg/L is associated with increased hepatotoxicity, particularly for the Asian population, and > 4.0 mg/L is associated with increased neurotoxicity. In this case, a series of side effects, as a result of extremely high plasma Cmin (16.76 mg/L), occurred following 8-day treatment of voricona-zole. Although discontinuation of voriconazole for 14days, plasma concentration was still above the recommended upper threshold. Of note, a study demonstrated that both conventional dose and halved maintenance dose may be inappropriate in cirrhotic patients (Child-Pugh class B or C) due to high plasma concentration. Thus, plasma concentration of voriconazole should be monitored earlier to avoid adverse effects. Since both liver failure and cirrhosis display distinct pathophysiological characteristics, caution is advised for extrapolating these findings from patients with cirrhosis to those with liver failure. For example, restoration of liver function may alter pharmacokinet-ics of voriconazole. Therefore, dynamic TDM should be considered essential to guide dosage adjustment.
In conclusion, CYP2C19 genotyping combined with TDM will support individualization of voriconazole dosing for patients with severe liver disease, and potentially will minimize toxicity and maximize therapeutic efficacy.
This work was supported by the National Natural Science Foundation of China (No. 81900536).
Caiyan Zhao proposed the study and critically revised the manuscript. Chuan Shen, Ziyue Li, and Wei Wang managed the patient and wrote the paper. Qian Zhao wrote the manuscript and drew the graphs. Yalin Zhao, Lingya Kong, and Jing Xie performed the literature search and revised the manuscript. All the authors approved the final manuscript.
Conflicts of Interest
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