To prospectively evaluate infectious complications (IC) in pediatric acute liver failure (PALF) by employing surveillance cultures.

From 2011 to 2013, children with PALF in a tertiary care centre received a standard protocolised management. Prophylactic parenteral antibiotics were used without antifungals. Surveillance cultures of blood, urine, ascites and tracheal aspirates were sent. Biochemical and clinical parameters and outcomes were compared between children with and without IC.

Of the 29 children with PALF admitted during the study period (median age 36 mo, range 12-90 mo), 13.8 % had blood stream infections (BSI) at admission. Organisms were isolated in 8.8 % (12/136) of the blood cultures, 13.7 % (11/80) of the urine cultures, 30.8 % (8/26) of the tracheal aspirates and 7.1 % (1/14) of the ascitic fluid cultures. Gram negative bacteriae (n = 17) were the commonest, followed by fungi (n = 13) and gram positive bacteriae (n = 2). Klebsiella pneumoniae and Candida nonalbicans group were the commonest bacteria and fungi respectively. After admission, fungal BSI and urinary tract infections were diagnosed at a median time of 4 d (range 3-8 d) and 3.5 d (range 3-6 d) respectively. ICs were not associated with other complications and increased mortality but with longer hospital and pediatric intensive care unit (PICU) stay.

In this study BSI was a common finding at admission in PALF. Inspite of prophylactic antibiotics, break through gram negative bacterial and fungal ICs were common. Empirical treatment of IC should include broad spectrum antibiotics. Fungal IC occurred beyond 48 h. Prophylactic antifungals at admission may be considered to decrease their frequency. IC prolongs PICU and hospital stay.

Acute liver failure (ALF) is rare in children but carries high mortality. Infectious complications (IC) in adults are an important cause of mortality; however, there are few data in the pediatric population. The aim of the study was to determine the incidence of IC and their effects on the outcome in children with ALF.

The present study is a retrospective review of the case records of children presenting with ALF to our center. All patients with ALF received antibiotics and antifungal as prophylaxis from day 1 and high-dose acyclovir was given to neonates only (stopped when herpes simplex was ruled out). Biochemical parameters, duration of ventilation and intensive care, overall hospital stay, and patient outcome were compared between patients with IC and non-IC.

A total of 145 children (78 boys), median (range) age 4.22 (1 day-16 years) years, were studied. Thirty-seven of 145 (25%) patients had proven IC. The predominant infections included 14 episodes of bacteremia in 13 patients and lower respiratory tract infection and urinary tract infection in 10 and 8 patients, respectively. IC occurred in patients after a median (range) duration of 16 (0-54) days of admission. Median (range) duration of hospital stay in patients with IC was 38 (1-201) days and was significantly higher than in those without IC (10 [1-74] days), P < 0.0001. Overall mortality was 21% (31), of which 7% (11) was from the IC group and 14% (20) from the non-IC group; the difference was not statistically significant.

Infections were more frequent after 2 weeks of admission. Patients with sepsis had longer hospital stays and prolonged ventilation. Invasive fungal infections were rare in pediatric ALF with adequate doses of antifungal prophylaxis.

To review the incidence, etiologies, pathophysiology, and treatment of acute liver failure (ALF) in children. Emphasis will be placed on the initial management of the multiple organ system involvement of ALF.

MEDLINE search from 1970 to March 2005 was performed. Search headings were as follows: acute liver failure, fulminant liver failure, pediatric liver failure, hepatic encephalopathy, and liver transplantation. Studies written in English were selected. Pediatric studies were emphasized. Adult studies were referenced if there were no pediatric studies available in regard to a specific aspect of liver failure.

Pediatric acute liver failure is a rare but life-threatening disease. The common etiologies differ for given age groups. Management includes treating specific causes and supporting multiple organ system failure. Commonly associated disorders that require initial recognition and treatment include energy production deficiencies (hypoglycemia), coagulation abnormalities, immune system dysfunctions, encephalopathy, and cerebral edema. Criteria used to determine the need for liver transplant are reviewed as well as the difficulties associated with predicting which patients will meet these criteria and how rapidly liver transplant will become the only option. Finally, experimental procedures that may provide additional time for the liver to recover are briefly reported.

Acute liver failure is characterized by a dynamic clinical course associated with high mortality. The main prognostic determinant is the development of extrahepatic complications. Close monitoring is mandatory, and prophylactic measures to avoid complications should be initiated. In case of complications, early and aggressive treatment is indicated. To date, artificial liver support devices are still in the experimental phase. Liver transplantation should be considered in patients with predictors of a poor spontaneous prognosis. Therefore, a transplant center should be contacted in every case of acute liver failure.

Mannan-binding protein is synthesized by the liver and functions in first-line host defence by opsonizing mannose-rich microorganisms due to activation of the classical complement pathway independent of Clq, and by an intrinsic ability to opsonize and mediate phagocytosis. We have investigated whether the increased susceptibility to bacterial infections in patients with cirrhosis could be explained by low plasma concentrations of mannan-binding protein and impaired complement-dependent opsonization. We examined 51 patients with compensated alcoholic cirrhosis, 34 who were decompensated and 16 healthy controls. Irrespective of group, we found a significant correlation (p < 0.05) between plasma mannan-binding protein concentration and deposition of the complement opsonin C4 on mannan from baker's yeast. In contrast to what was expected, this kind of opsonization and plasma levels of mannan-binding protein were significantly increased in the patients with decompensated cirrhosis (p = 0.01 and p = 0.007, respectively). A significant correlation (0 < 0.05) was found between mannan-binding protein and erythrocyte sedimentation rate, fibrinogen and haptoglobin in these patients. Though the correlations were weak (rho = 0.49, rho = 0.48 and rho = 0.40, respectively), the elevated levels of mannan-binding protein in the patients with decompensated cirrhosis may reflect an acute phase reaction. It is concluded that plasma levels of mannan-binding protein are increased in patients with decompensated cirrhosis and that complement-dependent opsonization of mannan does not seem to be compromized in patients with alcoholic cirrhosis.

The present study describes the plasma levels of soluble fibronectin (FN), C3d, the breakdown product of C3 complement and Ba, the breakdown product of properdin factor B, in 30 patients of uncomplicated acute viral hepatitis (AVH), 64 patients of fulminant hepatic failure (FHF) and 29 patients of subacute hepatic failure (SAHF) with different hepatitis viral infections. Aetiological analysis of these patients demonstrated hepatitis B, hepatitis C and hepatitis non-A, non-B, non-C (NANB-NC) infections in 6.7, 13.3 and 80% cases, respectively, of the AVH group; 18.8, 42.2. and 39.0% cases, respectively, of the FHF group; and 31.0, 34.5 and 34.5% cases of the SAHF group. None of them had hepatitis A infection. The analysis of data showed that the plasma FN level was significantly reduced in patients with FHF and SAHF as compared to AVH patients and healthy persons. Fibronectin levels in AVH was comparable to that in the healthy group. Further, the FN level was not dependent on the nature of aetiological virus. The level of C3d in plasma was significantly high in all patients of FHF and SAHF, irrespective of their viral aetiology, compared to the AVH group and the healthy group. Like FN, the C3d level was comparable in the AVH and healthy groups. However, the Ba level was comparable to the normal value in all types of infections including the AVH, FHF and SAHF groups. These findings were used to explain the possible roles of fibronectin and complement in the immunopathogenesis of liver injury in patients of acute liver failure of viral aetiology.

Bacterial infection and bacteraemia have been observed in patients with acute liver failure. The exact source of bacteria and nature of pathophysiological mechanisms explaining the development of infection remain unclear. In the present study, acute liver failure was induced by 90 per cent hepatectomy in the rat. The mesenteric lymph nodes and organs were harvested aseptically for bacteriological culture after sham operation or 90 per cent hepatectomy. Function of the liver and reticuloendothelial system (RES) was assayed; gut oxygen extraction was also measured. Translocation of enteric bacteria occurred 2 h after operation and increased with time following hepatectomy. Overgrowth of Escherichia coli in the distal small intestine started 2 h after operation. RES function decreased immediately after 90 per cent hepatectomy; uptake rates per gram tissue in other organs increased significantly. These results indicate that bacterial translocation occurred early after 90 per cent hepatectomy, associated with a decrease in RES function and gut oxygen extraction, and overgrowth of intestinal bacteria.

To investigate whether selective intestinal decontamination from oral administration of poorly absorbable antibiotics is effective in preventing bacterial infection in patients with acute liver failure, the incidence of nosocomial infection in 34 patients consecutively admitted to hospital between 1985-1990 and treated with either neomycin + colistin + nystatin or norfloxacin + nystatin (group I) was compared to the incidence of infection in 57 patients who did not receive oral, poorly absorbable antibiotics and who were consecutively admitted between 1972-1984 (group II). Patients from groups I and II had similar clinical and laboratory data at hospital admission. Twelve patients from group I and 33 from group II developed bacterial infection during the study period. The probability of infection was significantly different (p = 0.0083) in the two groups: 19% vs. 39% at the 3rd day of admission, 33% vs. 74% at the 7th day, and 48% vs. 78% at the 14th day, respectively. This difference was due to a different rate of infection from enterobacteria. Enterobacteria caused one infectious episode in group I and 24 in group II (p less than 0.001). The incidence of infections caused by other organisms, however, was similar in both groups (15 and 19 episodes, respectively). These results suggest that selective intestinal decontamination is useful in reducing the risk of infection from enterobacteria in patients with acute liver failure.

Total hemolytic complement activity and serum complement protein concentrations were compared in 17 hospitalized patients with normal hepatic function and 16 patients with liver disease due to alcohol (15 patients) or acetaminophen toxicity (one patient). In contrast to the control patients, individuals with hepatic dysfunction had decreased total CH50 levels and low concentrations of total C3, C4, C5, factor B, and the regulatory proteins factor I and beta-1H. These patients also had increased C4d/C4 ratios, indicating classical pathway activation. The level of complement deficiency appears to correlate with either prolongation of the prothrombin time or depression of serum albumin concentration. These results indicate that patients with hepatic disease have severe complement depletion that is probably multifactorial in origin. This impairment in complement function will contribute to the impaired antibacterial host defense of the patient with chronic hepatic disease.

Bacterial infection is a serious and often fatal complication of patients with liver disease and can prove fatal either directly or by precipitation of gastrointestinal bleeding, renal failure, or hepatic encephalopathy. At greatest risk are patients with alcoholic cirrhosis or decompensated chronic liver disease, or cases of acute liver disease who progress to fulminant hepatic failure or subacute hepatic necrosis. Infection appears to be unusual in patients with primary biliary cirrhosis. The site and type of infection is unrelated to the aetiology of the liver disease. Bacteraemia, pneumonia, urinary tract infection and spontaneous bacterial peritonitis are most common but infective endocarditis and meningitis, especially with pneumococci, are easily overlooked. Clinical suspicion of infection must be high as the only indication may be a general deterioration in the patients' clinical state, increasing encephalopathy or renal impairment. In the case of patients with fulminant hepatic failure, infection may precipitate the initial or recurrent encephalopathy and contributes to death in 10% of fatal cases. Spontaneous bacterial peritonitis is now recognized to occur in the absence of clinical features of peritonitis. The PMN content of the ascitic fluid may provide the only indication of infection and is the most readily available screening test. The most common types of organism responsible for all types of infection are Gram-negative enteric and streptococci, especially pneumococci, while infection with anaerobes is rare. Risk factors for infection include decompensated alcoholic liver disease, fulminant hepatic failure, gastrointestinal bleeding, invasive practical procedures and impaired host defence mechanisms against infection. Of the host defence mechanisms, impaired function of the reticuloendothelial system, complement, and PMNs represent the most common and serious defects. Defects of humoral immunity are present in ascitic fluid from patients with cirrhosis and are probably a major reason for development of spontaneous bacterial peritonitis. Diuresis improves these functions and reduces the risk of peritonitis. Treatment of infections even with the appropriate antibiotic is still associated with a high mortality but the use of adjuvant gut sterilization is promising, particularly in cases infected with Gram-negative enteric organisms. Infusions of fresh frozen plasma, blood and cryoprecipitate improve some systemic host defences and may be beneficial in the treatment and reduction of risk of infection.

In an attempt to perform a further investigation on the proposal that an increasing susceptibility to Candida infection in liver injury may be related to unsaturated transferrin level (UIBC) and/or to a total amount of transferrin represented by TIBC, we conducted experimental candidiasis using mice with galactosamine-induced liver injury and investigated the effect of preadministration of transferrin prior to inoculation of Candida albicans. Final mortality was 10% in the mice without liver injury and without transferrin (Group 1) and ones with liver injury and with transferrin (Group 3). By contrast a 50% mortality was given in one only with liver injury (Group 2). The TIBCs in Groups 1 and 3 were significantly higher than that in Group 2. The UIBCs in Groups 2 and 3, although there was no significant difference between them, were significantly lower than that in Group 1. This study confirmed that transferrin (TIBC) may have a direct deterring effect on systemic Candida infection and the decreased TIBC in the liver injury enhances the growth of C. albicans.

In an attempt to evaluate effects of liver injury and roles of iron metabolism on systemic fungal infection, experimental systemic Candida infection was produced in mice with galactosamine-induced liver injury. Survival rate and extent of fungal lesion are compared between mice with liver injury (Group 1) and ones without liver injury (Group 2). Median survival was 7 and 18 days in Group 1 and 2 respectively after 21 days observation. Mortality rate of Group 1 was significantly higher (P = 0.05) than that of Group 2. This difference was reflected to the extent of fungal lesions in that they were extensive and disseminated, involving the multiple organs in Group 1 but predominantly localized to the kidneys in Group 2. UIBC (unbound iron binding capacity) and TIBC (total iron binding capacity), i.e., serum transferrin as well as serum iron levels were significantly lower in Group 1 as compared with those in Group 2. These results indicate that hepatic injury promotes Candida infection in vivo and suggest that increased susceptibility to Candida in the presence of liver injury is, at least partially, attributable to low UIBC and/or TIBC.

Serial ascitic fluid samples were obtained during diuresis in seven patients with portal hypertension-related ascites. The samples were tested for concentrations of total protein, CH100, C3 and C4 as well as for in vitro opsonic activity. These parameters were all found to increase to a statistically significant degree when the initial specimen was compared to the final specimen: total protein = 1.5 vs. 2.7 gm per dl; CH100 = 9.3 vs. 20.2 units per ml; C3 = 13.4 vs. 23.8 mg per dl; C4 = 1.9 vs. 3.6 mg per dl, and opsonic activity = 0.8 vs. 1.9 log kill. This increased opsonic activity resulted in a greater than 10-fold increase in bacterial killing. This study demonstrates that diuresis of patients with cirrhotic ascites increases the concentrations of ascitic fluid complement components and increases the opsonic activity of ascitic fluid and may help protect patients from bacterial infection of their ascites.

Fulminant hepatic failure is an uncommon but dramatic illness with a high mortality. Viral hepatitis or drug toxicity is the usual cause. In the severe forms of the illness the patients, often young and previously healthy, rapidly become profoundly unwell due to extensive hepatic necrosis. Coma is accompanied by a disastrous disturbance of all the synthetic, metabolic and excretory functions of the liver. Management is largely supportive and multisystem complications may demand all the resources of the intensive care unit to allow survival. Systems for temporary hepatic support have aroused interest, based on the assumption that the hepatic lesion is potentially reversible. A number of heroic techniques have been tried and abandoned. Encouraging reports of charcoal column haemoperfusion have yet to be confirmed by controlled clinical trial.

The opsonic activity of 60 ascitic fluids from 47 patients was measured using a standard opsonophagocytic assay. Curve analysis of the opsonic activity compared to the ascitic fluid concentration of total protein, total hemolytic complement, C3 and C4 yielded correlation coefficients of 0.84 (p less than 0.001), 0.84 (p less than 0.001), 0.94 (p less than 0.001) and 0.92 (p less than 0.001), respectively. There appeared to be a threshold of concentration for each protein below which there was no killing of bacteria. Cirrhotic ascites had significantly (all p less than 0.001) lower concentrations of total protein and complement and less opsonic activity than noncirrhotic ascites (including malignant, cardiac and miscellaneous types). Perhaps it is the dilution of crucial antimicrobial proteins below a threshold which predisposes to spontaneous bacterial peritonitis.

We analyzed the clinical and bacteriologic features of 12 episodes of spontaneous bacterial peritonitis (SBP) in 11 children (four boys, median age 5.5 years) with chronic liver disease. All patients had cirrhosis and ascites; four had hypersplenism, and one was asplenic. Symptoms included increasing abdominal distention, pyrexia, abdominal pain, gastrointestinal disturbance, and encephalopathy. Nine had rebound tenderness on abdominal palpation, and 12 had reduced bowel sounds. The most frequent organisms isolated from culture of ascitic fluid were Streptococcus pneumoniae (nine). Klebsiella (two), and Haemophilus influenzae (one); blood cultures grew identical organisms in nine. Seven patients died despite intensive antibiotic therapy. In the 3 months prior to onset of SBP, defective yeast opsonization and reduced serum concentration of C4 were found in all nine children tested; eight had reduced concentration of C3. Functional deficiency of all complement components was present in four tested within 1 to 5 months of the onset. In contrast, only eight of 59 cirrhotic children without SBP had low C3, and eight had defective yeast opsonization, although 35 had low C4 values. Four of the patients with SBP and low C3 and C4 concentrations had normal concentrations at the time of diagnosis of liver disease 2 to 5 years previously. Opsonization of type III pneumococci was reduced in sera from three patients who subsequently developed pneumococcal peritonitis. The incidence of SBP in children with chronic liver disease is similar to that in adults, as are the clinical features. Our observations suggest that complement deficiency induced by chronic liver disease may be important in the pathogenesis of SBP.

Twenty six infants with a congenital immunodeficiency, characterised by failure of their sera to opsonise heat killed bakers' yeast for phagocytosis by normal polymorphonuclear leucocytes, were studied during infancy to determine the frequency of infection and development of atopy. They were compared with controls, matched prospectively for birth date, sex, parental smoking, and atopy and in whom feeding patterns were similar. In 18 of 26 infants the serum defect persisted at age one year. The incidence of infection and atopy, was appreciably greater in the study group than in controls. The 8 children in whom the defect was transient had a similar incidence of infection but a higher incidence of atopy than controls. Eight of 26 mothers and four of 9 fathers tested also had the serum defect, suggesting a strong genetic component. We support the hypothesis that immunodeficiency predisposes to infection and atopy, and that transient immunodeficiency predisposes to atopy.