Patients with severe hepatitis are prone to the combination of invasive pulmonary aspergillosis (IPA) due to the low immune function of the body, the use of high doses of glucocorticoids and antibiotics, and imbalance of intestinal microecology. Invasive fungal infections require administration of appropriate antifungal drugs via the parenteral route, but based on the severe hepatic impairment, a trade-off between giving the drugs is needed. In this paper, we focused on a retrospective analysis of 32 patients with half and full doses of injectable voriconazole to observe their efficacy and prognosis.
I. General data From December 2006 to March 2012, 32 patients with heavy hepatitis combined with IPA admitted to the Department of Infectious Diseases of the First Hospital of Soochow University were diagnosed in accordance with the revised criteria of the 10th National Academic Conference on Viral Hepatitis and Liver Diseases in 2000 [1], and the diagnosis of pulmonary aspergillosis was in accordance with the literature criteria [2]. There were 27 males and 5 females, aged 23-72 years, with a mean of (51.0±14.39) years. There were 25 cases in the full dose treatment group and 7 cases in the half dose treatment group. There were no significant differences in demographic characteristics, clinical manifestations, liver function, and prothrombin time among the groups (see Table 1). Among the 32 patients collected, 3 cases were caused by alcoholic cirrhosis, 2 cases were caused by viral hepatitis E, 3 cases were caused by viral hepatitis B combined with drug-related liver damage, 1 case was caused by drug-related liver damage alone, 4 cases were caused by unknown reasons, and the remaining 19 cases were caused by viral hepatitis B. The common clinical manifestations of the 32 patients with Aspergillus pulmonarius infection were fever, cough and sputum, and sputum was mostly rust-colored or The sputum was mostly rust-colored or with blood in it. All patients were seen to have mass-like hyperdense shadow on chest X-ray examination, 21 cases appeared in the right upper lung field, 11 cases appeared in the left lung, among which 5 cases appeared to have irregular cavities, and 1 case of halo sign and crescent-shaped air sign typical of Aspergillus infection in the lung.
The loading dose was 400 mg every 12 hours and the maintenance dose was 200 mg every 12 hours in 25 cases in the full-dose group; the loading dose was unchanged on the first day and the maintenance dose was 100 mg every 12 hours in 7 cases in the half-dose maintenance group; all cases were also given basic support, liver protection and anti-yellowing, promotion of hepatocyte regeneration and improvement of microcirculation. During hospitalization, all cases were given methylprednisolone 1mg/kg/day for immune suppression, anti-infection with corresponding antibiotics and nutritional treatment with femoral vein placement, and artificial liver (plasma replacement) treatment in 13 cases (2 cases in the half-dose group and 11 cases in the full-dose group).
III. Observation items Improvement of clinical symptoms, liver function (TBil, ALT), prothrombin time (PT), chest CT.
IV. Criteria for judging the efficacy Improvement in.
(1) Fever, cough and other symptoms are reduced or disappear;
(2) Laboratory tests: liver function (TBIL, ALT) improved or basically returned to normal, and prothrombin time (PT) index shortened;
(3) Imaging changes: decrease in lesion volume. Deterioration of.
(1) Fever, cough and other symptoms are not reduced or worsened;
(2) Laboratory tests: no significant improvement or improvement in liver function (TBil, ALT) and prolongation of prothrombin time (PT);
(3) Imaging changes: no reduction or enlargement of lesion volume.
V. Statistical treatment The measurement data were expressed as mean ± standard deviation ( ±S), and t-test was used for comparison between two groups, and IBM SPSS 19.0 was used for analysis, and P<0.05 indicated that the difference was statistically significant.
Results
I. Comparison of changes in liver function and PT The changes in serum TBil and ALT and PT after 2 weeks of voriconazole treatment in the two groups are shown in Table 1. liver function in the half-volume group was better than that in the full-volume group after treatment, but the changes in prothrombin time in the two groups were not significant.
Table 1 Changes of TBil, ALT and PT before and after treatment in two groups ( ±S)
Group
Number of cases
TBil(umol/L)
ALT(U/L)
PT(s)
Before treatment
After treatment
Pre-treatment
After treatment
Before treatment
After treatment
Half dose group
7
301.6±177.0
120.3±108.7
101.4±60.0
55.9±27.8
21.4±3.9
21.6±6.1
Full volume group
25
297.6±180.9
296.7±217.3a
112.1±51.3
92.7±49.4 a
21.3±7.1
22.5±6.0
Compared with the full-volume group, aP<0.05.
II. Clinical symptoms and improvement of chest CT ①Clinical symptoms:See Table 2. 60.87%, 70.83%, 61.90% of fever, cough and sputum, lung sternum history straight harrier in the full-volume group; 85.71%, 100.00%, 85.71% in the half-volume group, respectively. The specific clinical manifestations and signs are shown in Table 2. ② Chest CT: see Table 3. The lesion volume in the half-volume treatment group showed a trend of reduction and a tendency of improvement.
Table 2 Changes in clinical manifestations and pulmonary signs before and after antifungal treatment (32 cases)
Clinical manifestations
Full-volume group (n=25)
Before/after treatment
Half-measure group(n=7)
Before/after treatment
Fever
23/9
7/1
Cough and sputum
Rust-colored sputum
21/5
2/0
Sputum with blood in it
2/1
1/0
White mucus sputum
1/1
1/0
Systemic poisoning symptoms
0/0
0/0
Hypoxemia and acid-base imbalance
0/0
0/0
Pulmonary
21/8
7/1
Table 3 Changes in chest CT lesion volume (cm³) before and after treatment in the two groups
Group
Number of cases
1d
1w
2w
Half-volume group
Full volume group
7
23
131±12
132±11
128±11
138±12a
94±7
130±11a
Compared with the full-dose group, aP<0.05
Adverse drug reactions Only one patient in the half-dose group discontinued the drug due to progressive deterioration of liver function, while nine patients in the full-dose group discontinued the drug due to deterioration of liver function. In the full-dose group, 2 patients discontinued the drug due to blurred vision and color vision changes; 9 patients reduced to half-dose treatment due to nausea, vomiting and abdominal distension symptoms.
Discussion
Patients with severe hepatitis have massive hepatocyte necrosis leading to liver failure, a clinical condition that includes hemodynamic changes, renal failure, coagulopathy, metabolic disorders, and a tendency to complicate bacterial or fungal infections. In patients with severe hepatitis, fungal infections in the lung and intestine are the most common sites. Once IPA is complicated in patients with severe hepatitis, the condition can deteriorate rapidly and the morbidity and mortality rate increases, which can be called “terminal infection” and must be given high priority in clinical practice.
Patients with liver failure are prone to multiple complications due to the long hospitalization time, the use of more diagnostic operations such as laparotomy and deep venipuncture, and the long-term combined use of antimicrobials, which significantly increases the chance of invasive fungal infections. To trace the cause of their susceptibility, it is considered to be due to the reduced immune function of patients, which predisposes to intestinal microecological imbalance, and the long-term use of glucocorticoids and antibiotics, which predisposes to further fungal infections or leads to aggravation of IPA.
In 2008, the Infectious Diseases Society of America (IDSA) recommended voriconazole as the drug of choice for the initial treatment of IPA. Compared with amphotericin B deoxycholate, voriconazole has significantly reduced hepatic and renal toxicity, and its hepatotoxicity is dose-dependent and should be reduced in patients with hepatic insufficiency [4]. Toxicity studies with repeated administration suggest that the target organ of voriconazole is the liver. Similar to other antifungal agents, hepatotoxicity occurs in experimental animals at plasma exposures equivalent to those achieved with therapeutic doses in humans.
Voriconazole is primarily metabolized by the liver, with less than 2% of the drug excreted in its original form in the urine. Following administration of radioisotope-labeled voriconazole, approximately 80% and 83% of the radioactivity was recovered in the urine in multiple intravenous and multiple oral dose administrators, respectively. The terminal half-life of voriconazole is dose dependent. Because of the saturable nature of voriconazole metabolism, its pharmacokinetics are nonlinear, with the proportional increase in exposure being much greater than the proportional increase in dose. With regard to the pharmacokinetics of voriconazole, the AUC at half dose maintenance is comparable to that at full dose in people with normal liver function. Therefore, patients with severe hepatitis will have impaired drug metabolism due to massive hepatocyte necrosis, which will increase the burden on the liver, thus causing an excessive AUC and increased toxic reactions.
There are no clinical studies on the application of injectable voriconazole (Weifan) in patients with liver failure. 32 patients with severe hepatitis combined with IPA treated with different doses of antifungal therapy admitted to our department were found to have significantly better liver function after giving half dose of injectable voriconazole (Weifan) compared with the full dose group, and the efficacy was significantly better than that of the full dose group, but there was no significant difference in prothrombin time between the two groups. Patients with severe hepatitis have severe hepatocellular damage, and after the administration of full dose voriconazole, the cumulative concentration of the drug increases and toxicity increases significantly due to the decreased metabolism of the drug by the liver, which further aggravates liver damage and leads to continued deterioration of patients with liver failure and collapse of systemic resistance, and instead deep fungal infection is difficult to control.
According to its pharmacokinetics, patients with liver failure are given half dose of voriconazole whose AUC is comparable to that of normal subjects at full maintenance therapy, which can achieve effective antifungal blood concentration and reduce the toxicity of the drug to the liver. The results of this paper fully suggest that the use of voriconazole should be carefully weighed against the advantages and disadvantages in such a special patient group as liver failure, and that half-dose maintenance therapy with voriconazole for injection (Weifan) is recommended.
In the context of this retrospective study, it is recommended that a large-scale clinical study be conducted to further determine what dose is optimal for the treatment of severe hepatitis, taking into account the patient’s own physical condition, causative factors and drug toxicity, as there may be other factors that may affect its regression due to the small number of cases in this paper.