Preemptive treatment of fungal infection: has its time arrived in liver transplantation?

Preemptive treatment of fungal infection based on plasma (1 → 3)β-d-glucan levels after liver transplantation. Akamatsu N, Sugawara Y, Kaneko J, Tamura S, Makuuchi M. Infection 2007;35:346-351.

COMMENTS

A previous “Liver Transplantation Worldwide” column¹ addressed the use of the galactomannan assay to monitor the development of Aspergillus infection in high-risk patients. In this review, Akamatsu et al. explore the question of treating fungal infection on the basis of monitoring by the (1 → 3)-β-d-glucan (BDG) assay. Kelaher² has reported on both assays.

Akamatsu et al. used plasma BDG level measurements to monitor their living donor liver recipients for postoperative fungal infection. The authors state that BDG composes a portion of the cell wall of most fungi, including Candida, Aspergillus, and other yeasts and molds such as Trichosporon, Fusarium, Penicillium, Cephalosporium, and Pneumocystis jiroveci. The authors point out that the BDG is negative for patients with cryptococcosis. Plasma BDG was measured with the Fungitec G test (Seikagaku Kogyo, Tokyo, Japan) once a week for 3 months and then once a month for 1 year. Other body fluids were cultured for fungal surveillance once per week for 1 month following transplantation. All patients received fluconazole for the first 7 postoperative days. When the BDG level was ≥40 pg/mL and after confirmation of a second consecutive positive result, preemptive treatment was started with intravenous fluconazole and trimethoprim-sulfamethoxazole. Preemptive treatment was continued until the BDG level decreased to <20 pg/mL. When a fungal infection was suspected, the final diagnosis of invasive infection was based on histology, antigen assays, and/or cultures.

In the authors' 180 consecutive adult patients with a median follow-up of 19 months (range 1-52), 40 patients had a BDG level > 40 pg/mL occurring postoperatively at a median of 125 days (range 9-393). The duration of preemptive treatment was a median of 18 days (range 9-57). Of the 40 patients receiving preemptive therapy, 14 were diagnosed with fungal infection. In all, 24 patients were diagnosed with invasive fungal infection with an overall mortality from fungal infection of 0.6% (1 patient). Akamatsu et al. conclude that this low mortality rate from fungal infection might indicate the usefulness of monitoring for fungal infection and instituting preemptive therapy.

In another patient population, Maertens et al.³ stated that preemptive antifungal therapy still has a ways to go before it can effectively lower the morbidity rate from posttransplantation fungal infections. Consistent with the results from this Akamatsu review, more study is needed before preemptive treatment of fungal infection can be established as the standard of care in liver transplantation.

Abbreviations

BDG, (1 → 3)-β-d-glucan; HCV, hepatitis C virus; IL, interleukin; TIPS, transjugular intrahepatic portosystemic shunt.

REFERENCES

What Causes Fibrosis Progression in Recurrent Hepatitis C?

Genetic polymorphisms of inflammatory cytokines and liver fibrosis progression due to recurrent hepatitis C. Falleti E, Fabris C, Toniutto P, Fontanini E, Cussigh A, Caldato M, et al. J Interferon Cytokine Res 2007;27:239-246.

COMMENTS

The rate of progression of fibrosis in patients transplanted with recurrent hepatitis C virus (HCV) dictates the quality of life, need for retransplantation, and, ultimately, survival.¹ Slowing the rate would enhance the quality and number of recipient life years and increase the cost effectiveness of liver transplantation. Several factors have been associated with the rate of progression, but are we close to knowing the cause?

Many studies have recently appeared describing clinical factors associated with fibrosis progression in patients transplanted with HCV.^2-10 Increased donor age, type of immunosuppression, and HCV genotype and viral load have been the most influential factors leading to progressive fibrosis. Wali et al.² found that livers from older donors were a powerful determinant of the fibrosis progression rate. Rayhill et al.³ also reported on the association of older donor livers with early fibrosis. Slow tapering of steroids and withdrawal 25 months following liver transplantation, as opposed to rapid tapering and withdrawal 91 days after liver transplantation, have been associated with slower fibrosis progression.⁴ Roche and Samuel⁵ reported that high viral load and infection with HCV genotype 1b, along with other factors, are associated with accelerated recurrent HCV. Several other clinical factors have been associated with the progression of fibrosis. Cotler et al.⁶ reported that posttransplant diabetes mellitus was associated with HCV fibrosis progression. Walter et al.⁷ recently reported in Liver Transplantation on their multivariable analysis showing recipient male gender, antiviral treatment before liver transplantation, and initial immunosuppressive regimen without azathioprine to be associated with progression of fibrosis. Of note, mild to moderate donor liver steatosis was found by Botha et al.⁸ to have no impact on HCV-related cirrhosis. Schmeding et al.⁹ reported that a liver graft from a living donor was not associated with fibrosis progression in HCV recipients. Berenguer et al.¹⁰ conducted a meta-analysis which concluded that HCV progression was independent of the use of tacrolimus or cyclosporine A.

Beyond the clinical factors associated with fibrosis progression, genetic factors could be the cause. In this review, Falleti et al. describe their study on whether single nucleotide polymorphisms that regulate the expression of different cytokines are associated with fibrosis progression in recurrent HCV. These authors investigated the single nucleotide polymorphisms of interferon-γ, interferon-γ receptor-1, interleukin-6 (IL-6), IL-10, IL-18, and tumor necrosis factor-α in 50 consecutive patients transplanted for end-stage liver disease due to HCV with at least a 12-month follow-up period. Patients received either tacrolimus or cyclosporine with corticosteroid tapering that was completed within 6 months in all but 5 patients. The median histologic follow-up period was 54 months (range 12-102). A total of 315 liver biopsies were evaluated from this group of patients (131 as annual biopsies). Of these 50 study patients, 29 experienced recurrent HCV. Each recipient was placed into a low-, intermediate-, or high-producer phenotype category for each cytokine. Interestingly, Falleti et al. found older donor age to be the only clinical variable associated with fibrosis progression. Among the cytokine polymorphisms, only IL-10 was found to be significant. Only 1 of 17 patients identified as low IL-10 producers reached a severe level of fibrosis, whereas a severe level was reached by 20 of 33 intermediate or high IL-10–producing patients. A synergism between intermediate/high interferon-γ producers and low IL-10 producers was also significant. The authors concluded that single nucleotide polymorphisms resulting in high and low producers of phenotypes of both T helper 1 and T helper 2 cytokines appear to modulate the course of recurrent hepatitis C.

At present, this single nucleotide polymorphism profile is merely associated with progressive fibrosis in recurrent HCV. In time, additional genomic research might just help us determine the cause.

REFERENCES

Liver Function Determines Success of Transjugular Intrahepatic Portosystemic Shunt in Treating Hepatic Hydrothorax

The outcome after transjugular intrahepatic portosystemic shunt (TIPS) for hepatic hydrothorax is closely related to liver dysfunction: a long-term study in 28 patients. Wilputte JY, Goffette P, Zech F, Godoy-Gepert A, Geubel A. Acta Gastroenterol Belg 2007;70:6-10.

COMMENTS

Treatment of resistant hydrothorax is controversial. Several reviews have focused on the many available options.^1-3 Because most patients with hepatic hydrothorax are transplant candidates, those on the waiting list must be managed in a fashion that does not prevent them from receiving a liver transplant.

Following initial therapies for ascites (sodium-fluid restriction and diuretics), treatment options for hepatic hydrothorax include thoracentesis, chest-tube placement, pleurodesis with talc administered via thoracoscopy, transjugular intrahepatic portosystemic shunt (TIPS), and, finally, liver transplantation. Thoracentesis carries a risk of bleeding and pneumothorax, especially if multiple interventions are required.² Chest-tube placement can lead to protein and fluid loss and infection, and the tubes are difficult to remove once placed because of the high fluid output.⁴ In a series of 41 patients receiving thoracoscopic surgery with talc pleurodesis, 1 died operatively, 7 had fluid recurrence, and 33 (80%) experienced success.⁵

Other treatment options have been reported. Octreotide, a vasoconstrictor, has been used to treat refractory hepatic hydrothorax with definitive results.⁶ There is a case report of administering terlipressin, another vasoconstrictor drug, and albumin to a patient with hepatorenal syndrome to successfully treat hepatic hydrothorax.⁴ Thoracoscopic pleura or mesh onlay reinforcement to the diaphragm has been reported in 10 patients.⁷ One successful case was treated with nasal continuous positive airway pressure.⁸

In this review, Wilputte et al. review the treatment of hepatic hydrothorax with TIPS, which these authors state has been advocated as the treatment of choice. These authors reviewed 28 patients who underwent TIPS over a 10-year period for treatment of hepatic hydrothorax or refractory ascites associated with hepatic hydrothorax. None had infectious causes for the hydrothorax. During follow-up, 17 patients died after a mean of 173 days because of complications of liver disease. The 30-day mortality was 14.3% because of gastric ulcer bleeding, hepatic bleeding, sepsis, renal failure, or pulmonary edema. The 90-day mortality was 25%, and the 150-day mortality was 53%. A Child score > 10 was a strong predictor of mortality (odds ratio 7.62; confidence interval 2.34-24.83). A positive clinical response to TIPS was observed in 68% of the patients after a mean of 4 months. TIPS was successful in 15 of 20 patients with a Child score < 10 and in only 1 of 8 patients with a Child score > 10 (P < 0.01). Overall, 33% of the patients experienced a TIPS dysfunction requiring 1 or more revisions. Two patients developed intractable hepatic encephalopathy and died of liver failure.

Finally, liver transplantation is an excellent option for patients with cirrhosis with hepatic hydrothorax. Xiol et al.⁹ reported on 28 patients with hepatic hydrothorax who received liver transplants. Of these, 18 received intraoperative intervention with paracentesis, thoracentesis, or both. In addition, 6 patients needed a thoracic tube after transplantation for 2-7 days, and 2 others needed therapeutic thoracentesis. At 1 month after liver transplantation, pleural effusion persisted in 9 patients. After 3 months, only 1 patient had effusion, and this was attributed to cardiac failure. The survival in patients with hepatic hydrothorax was no different when compared to that in a control group.

Management of hepatic hydrothorax in patients on the liver waiting list is troublesome. Survival following liver transplantation has been shown to be no different between patients with and without hepatic hydrothorax. With the knowledge that patients most refractory to TIPS have the worst liver function, we must get these patients to transplantation without undue complications from treatment of their hepatic hydrothorax.

REFERENCES

Intraoperative Hyperglycemia and Liver Transplant Survival

Effect of intraoperative hyperglycemia during liver transplantation. Ammori JB, Sigakis M, Englesbe MJ, O'Reilly M, Pelletier SJ. J Surg Res 2007;140:227-233.

COMMENTS

A report by Langouche et al.,1 reviewed in a previous “Liver Transplantation Worldwide” column,2 concluded that using intensive insulin therapy to maintain normoglycemia during critical illness directly protected the endothelium and inhibited excessive inducible nitric oxide synthase induction, helping prevent organ failure and death. The question was posed whether intensive insulin therapy could improve survival in critically ill liver transplant patients.2

In this report, Ammori et al. evaluate the effect of strict intraoperative glucose control on liver transplant outcomes. These investigators retrospectively reviewed 184 patients who underwent liver transplantation. Elevated intraoperative glucose levels were treated with intravenous insulin bolus or continuous infusion. Strict glycemic control was defined as a mean intraoperative blood glucose < 150 mg/dL; a glucose level ≥ 150 mg/dL was defined as poor control. Sixty recipients (32.6%) had strict intraoperative glycemic control (mean 135 ± 1 mg/dL), whereas 124 (67.4%) had poor control (mean 183 ± 2 mg/dL). Patients with poor control were significantly older and received a significantly greater amount of insulin than the strictly controlled group (24 ± 2 versus 13 ± 3 units). Patients in the strictly controlled group experienced significantly fewer infections (30% versus 48%; P = 0.02) within 30 days of transplantation than the poorly controlled group. Survival in the strictly controlled group, at both 1 year and 2 years, was significantly higher than that in the poorly controlled group (1 year, 91.2% versus 78.1%, and 2 years, 85.9% versus 72.7%; P = 0.05). As the authors point out, poor intraoperative glycemic control either causes the increased risk in postoperative infection and mortality or identifies patients at increased risk. The older age of the patients in the poorly controlled group is a confounder.

A note of caution is sounded by a recent study of intensive insulin therapy during cardiac surgery, which revealed that such therapy does not reduce perioperative death.3 This present review by Ammori et al. is a start in promoting the effectiveness of strict glucose control in the liver transplant population. Prospective randomized studies will strengthen the argument.