Late Infectious Complications after Liver Transplantation in Children

Infectious complications in children after liver transplantation are a major cause of morbidity and mortality. Most of the lifethreatening infections are seen in the first few months after the operation and are related to their stay in the intensive care unit, invasive monitoring, anastomotic leaks and higher levels of immunosuppressive medications. Infections that happen after six months of liver transplant operation are considered as late infections. True incidence of the type of infections is difficult to establish as most of these patients are usually not managed in the liver transplant centre and the data may not be always provided to the transplant centre by local hospitals. Hence this subject has been only a matter of few research publications [1].


Introduction
Infectious complications in children after liver transplantation are a major cause of morbidity and mortality. Most of the lifethreatening infections are seen in the first few months after the operation and are related to their stay in the intensive care unit, invasive monitoring, anastomotic leaks and higher levels of immunosuppressive medications. Infections that happen after six months of liver transplant operation are considered as late infections. True incidence of the type of infections is difficult to establish as most of these patients are usually not managed in the liver transplant centre and the data may not be always provided to the transplant centre by local hospitals. Hence this subject has been only a matter of few research publications [1].
After 6 month we can divide liver transplant recipients into three groups, in term of their risk to acquire infections: Group 1: patients with good allograft function and low immunosuppression (comprising about 80% of the patient population). This group usually have very low risk of infections. Most common infections in this group of patients are communityacquired and include respiratory viruses: e.g., influenza, parainfluenza, respiratory syncytial virus, human metapneumovirus, swine flu virus, coronaviruses. The common bacterial infections are Streptococcus pneumoniae (drug resistant), Haemophilus influenzae, MRSA, Mycobacterium tuberculosis. Gastrointestinal pathogens -Noravirus, Rotavirus, Compylobacter, Salmonella. Rarely atypical organisms such as Mycoplasma and Legionella. Paediatirc liver transplant recipients particularly young children who are unable to receive live vaccines before transplant are also prone to vaccine-preventable diseases-variciella, measles and mumps. Second category of patients (Group 2, about 10-15% of patient population), who have on going biliary complications secondary to anastomotic strictures or cholangiopathies secondary vascular problems are more likely to get infections due to endogenous flora coliforms, enterococci and emerging carbapenem resistant enterobacteraceae (CRE). Invasive procedures like cholangiography, percutaneous or endoscopic predispose further these patients to environmental pathogens like Pseudomonas hence it is important to consider the antibiotic cover for this type of organisms when using empiric antimicrobial therapies. Patients with recurrent cholangitis are exposed to repeated courses of antibiotics which make them prone to fungal infections. Hence antifungal cover depending on local epidemiology should be considered when response to standard antimicrobials is less than optimal. Third category of patients (Group 3, about 2-5% of patient population) who have difficult to treat allograft rejection requiring higher levels of immunosuppresion and or use of biological agents like mono or polyclonal antibodies. This group can present with severe opportunistic infections involving-P jiroveci, Cryptococcus neoformans, Nocardia and invasive fungi such as Aspergillus, Mucor and other molds. Reactivation of viruses-Herpes group: CMV, HSV encephalitis, EBV and Herpes zoster.
Treating physicians should also keep in mind travel associated pathogens, specific exposures to uncommon pathogens related to work, recreational activities and pets. We evaluated the incidence, risk factors and pathogens for late IC in 181 paediatric LTR between 2004 to 2008 at King's College Hospital, London. Follow-up end points were 2-year, death or retransplantation. Overall incidence of late infections was 21.4% (39/181); predominant infections were due to viruses 19%, most common viral infection was due to cytomegalovirus (CMV) 10.4%, followed by respiratory tract viruses i.e. influenza, Swine flu, rhinovirus, adenovirus & gastrointestinal virus-noravirus. One patient each had cholangitis due to Candida albicans, bacteraemia (E.faecium), conjunctivitis (S aueus) and diarrhoea (Compylobacter).

Late Cytomegalovirus (CMV) Infection in Liver Transplant Recipients
Although late CMV infection is well studied in adult LTR but there is paucity of data in paediatric patients. The risk factors for late CMV infection described are prolonged antiviral prophylaxis, recurrent rejection while on antiviral prophylaxis and increased immunosuppression especially use of antilymphocyte products Annals of Reviews and Research [2]. Late CMV presentation can manifest as non-specific viral syndrome (fever, leukopenia, atypical lymphocytosis & thrombocytopenia) or involvement of visceral organ (common sites include the gastrointestinal tract, liver, and lungs) and the site of involvement varies according to the type of transplant. This is the first centre we analysed highest number of pedaitric LTR for late CMV complications. The overall 1 st CMV infection after transplant was in 51%, 67%, 66% 10% in D-R+, D+R-, D+R+ & D-R-respectively. The overall incidence of late CMV infection in three high risk group (D-R+, D+R-, D+R+ excluding low risk patients D-R-) was 18/131 (13.7%). Most of these patients were young and had late post-transplant complications. Late rejection was seen in 25% of patients mainly in D+R-& D-R+ group. The most important finding was, D-R+ group showed very high rate of hepatitis (36%) on liver biopsies in comparison to 15 % in other two groups.
The anti CMV prophylaxis protocol included IV ganciclovir 5mg/kg twice daily for 2 weeks for D+R-starting at day 7 posttransplant, followed by CMV DNA monitoring till patient is discharged or when symptomatic for other groups. Late CMV disease was present in 5/131 (3.8%) patients. Less than 2% patients required the second line treatment with foscarnet. Late CMV infection was associated with increased morbidity but no mortality. Antiviral prophylaxis only delays the onset of viral replication, and therefore, it does not prevent the development of a primary infection, which is relatively common after prophylactic therapy has been completed [3]. In a study of 67 high-risk CMV liver transplant recipients (9 patients on oral ganciclovir, 58 patients on valganciclovir for 92 days), primary CMV disease was observed in 2%, 25%, 27%, 27%, and 29% of patients at 1, 3, 6, 12, and 24 months, respectively, after antiviral prophylactic therapy was stopped with similar incidences between the two treatment groups [2].
Patient who develop allograft rejection during prophylaxis are at an increased risk for developing delayed-onset CMV disease after cessation of prophylaxis, which has led to increased mortality [4][5][6]. Risk of delayed onset CMV disease could be prevented by minimization of immunosuppression or by prolonging CMV prophylaxis i.e., 6 months instead of 3 months. However, these measures are associated with risk of; graft rejection, drug toxicity, increased cost, emergence of drug resistance [7]. In adult patient's antiviral prophylaxis has been proven to be of benefit as without antiviral therapyrisk of CMV infection was reported to be 44-65%, in high risk CMV LT-recipients during first 12 month [8,9]. Meta-analysis on prophylaxis with ganciclovir or valganciclovir vs placebo showed significant reduction of -CMV infection, CMV disease & mortality in solid organ transplant recipients. Few other studies have reported improved survival and reduction of biopsy proven rejection [10,11].
However, there is no consensus on duration of antiviral prophylaxis. Prolonged duration of treatment could result in ganciclovir resistance. Resistance should be suspected if viral load persists while on antivirals, this could be confirmed by testing for genotypic mutations within the viral genes UL97 and/or UL54. Ganciclovir-resistant CMV disease was reported in up to 7% of high risk CMV recipients while none in CMVseropositive recipients in a group of solid organ transplant recipients [12]. Ganciclovir resistant patients could be treated with foscarnet or cidofovir with or without immunoglobulin and reducing immunosuppression [13]. Other antiviral agents that could become available are oral maribavir, CMX-001, artesunate, and everolimus [14]. Increased understanding, as well as the use of newer diagnostic tests, antiviral therapy, and preventative strategies, have led to marked improvements in the prevention and management of many of the complications associated with post-transplant CMV infections in children.

Influenza Infection
The 2 nd most common late viral infection was respiratory virus influenza. Reported incidence in SOT recipients is 2-4%. In our data of 181 LTR 3% were admitted to hospital because of influenza infection. It is mainly upper respiratory tract (RT) disease, lower RT disease is estimated to occur in 1-5% of LTR. Parainfluenza & influenza were associated with high morbidity and mortality in very young LTR [15]. Oseltamivir is an effective agent with protective efficacy of 75% [16]. It is very important to consider early diagnosis and treatment for influenza infection in SOT recipients as it reduces the severity of influenza, shorten duration of viral shedding, reduce the frequency of lower RT complications e.g. bronchiolitis and pneumonia. Prevention is the most important strategy for influenza management-all LTR should have annual vaccine, 6 months after transplant surgery, if used before that immune response to vaccination could be suboptimal [17,18].

Carbapenem resistant Enterobacteriaceae (CRE)
Excessive use of antibiotics has led to emergence of multidrug resistant gram-negative bacteria. The emerging problems with the CRE is becoming an issue in LTR, because of not only it is harboured in gut for long but can spread rapidly to other patients if stringent infection control precautions are not followed. We encountered an outbreak of infection with Carbapenem resistant Enterobacteriaceae (CRE) in our unit lately. A very stringent infection control protocol including; quarantine of all new admission from other hospitals in to single rooms till results of screening swabs (rectal swabs) are negative for CRE [19][20][21] hand hygiene, environmental cleaning, and antibiotic stewardship helped to control the outbreak. Further continuation of active surveillance prevented the silent dissemination of these superbugs in this immunosuppressed population.

Conclusion
In conclusion the late infections after transplantation requiring hospital admission are not uncommon. Most severe infections occur in patients with biliary complications and during