User:Dr Ramdip Ray/sandbox/Infections in Liver Transplant recipients

Common Infections in the Liver Transplant recipient Introduction

Liver transplantation has become the standard of care for the majority of patients with End Stage Liver Disease (CLD ), many of those with Acute Liver Failure ( ALF ) and those with unresectable hepatocellular cancer (HCC). With improving rates of survival (90 % at one year 1-3), the focus has shifted from surgical issues to complications that  influence  the quality of life after a successful liver transplant such as infective episodes. Inspite of the fact that liver transplant recipients require much lower doses of immunosuppression, new infections and reactivation of viral infections still cause significant postoperative morbidity and mortality. 1,2 One or more episodes of infection are seen in over 80% of liver transplant recipients in the first year after transplant 4. While most infections are treatable, immunosuppressant medications often blunt the classic response to infections; this alters the clinical picture and delays recognition of these infections and initiation of treatment5. Hence infections surveillance remains a major issue in the first 3 years after transplantation. 6,7

With the advent of better tolerated immunosuppressive medications, thousands of liver transplant recipients are now leading near –normal productive lives in the community. It is therefore imperative that •	Consultants across many specialties in tertiary level hospitals need to be aware of the different profile of infections seen in these recipients. •	Physicians in the community need to be equipped with adequate information to identify and sometimes themselves deal with infections in patients who have a transplanted liver. •	Recurrent viral infection which caused the original liver disease will also need to be dealt with in the late postoperative period. This article attempts to familiarize the physician in the community to identify common new infections in the transplant recipient.

All transplant recipient are an ‘at risk’ population for infection because 67- 80 % of patients will develop an infection within the first year; they must all be monitored for any evidence of infections. In order to deal effectively with these infections, the physician must take into account the following factors : •	The type of infective organism and the seriousness of the exposure •	Source of infection - hospital or community acquired •	Antibiotic prescription practices in the hospital and the community, which influence the patterns of resistance •	The degree of immunosuppression, which is a function of 	Dosage of immunosuppressants 	Pre existing nutritional deficiencies, neutropenia, lymphopenia, splenectomy, use of induction agents, graft function 	Local factors – bile / fluid / pus collections, ischemic tissue including congested segments of the graft 	Co-morbidities – obesity, diabetes mellitus, renal impairment, infections with immunomodulatory viruses ( CMV, HIV etc ) 	ABO incompatible graft The timeline of infections can broadly be categorized into 3 different phases :

Phase 1.

Infections while still in hospital Surgical or technical factors are the usual culprits for these early infections.Preoperative infection/colonization picked up in the preoperative period in those who have prolonged hospital stay may have a dramatic flare in the post operative period in spite of a technically sound operation. Bacterial and fungal (mucormycosis) wound infections, line or catheter related infections, bacterial pneumoniasand pseudomembranous colitis are cause significant morbidity. Prolonged use of antibiotics in sick transplant recipients has added to the problem of emergence of drug resistant strains like MDR-Klebsiella which require toxic medications such as polymixins.

Phase 2.

Infections within the first 3 – 6 months Infections from opportunistic organisms predominate in this period as a result of immunosuppression. The common organisms are: Viruses		Cytomegalovirus (CMV), Herpes simplex and zoster, recurrent Hepatitis B and C Fungi		Aspergillus, Cryptococcus, Histoplasma, and Coccidioides species Bacteria	 Mycobacterium tuberculosis, and less commonly Nocardia and Listeria Some of these infections can be prevented by prophylaxis for common opportunistic infections such as Co-trimoxazole forPneumocystis carinii(jivoveri) pneumonia, antiviral therapy for hepatitis B reinfection of graft, and acyclovir for herpes infection.

Phase 3

Infections beyond 6 months After 6 months the spectrum of infections resembles that of any other healthy member of the society such as influenza, UTI and community-acquired pneumonias. However the likelihood of getting these infections is more as compared to the general population. Herpes zoster, CMV and some fungal infections are more common than in the general community.

Bacteria Since bacteriae are responsible for much of the early morbidity and mortality after liver transplant, it is important to have some insights into : •	The risks factors and pathogenesis •	The changing patterns of antibiotic resistance in the hospital and the community •	The ways and means of preventing and treating them. Biliary interventions, prolonged hospital stay, re-operative surgery and invasive procedures predispose the patient towards these infections8,10,11,12 Common bacterial pathogens that are isolated are : •	Enterococci •	Viridans streptococci •	Staphylococci •	Enterobacteriaceae13-16 Management may vary according to the causal pathogen and the site of infection viz, •	surgical site o	abdominal cavity o	wound infection •	bloodstream •	urinary tract •	respiratory tract.

The incidence of bacterial infection can be reduced by not operating on patients who are already infected. Spontaneous Bacterial Peritonitis (SBP), active lung infections,oesophageal candidiasis are best dealt with preoperatively. MRSA/VRE colonization increases risk of later infection[17-21 ; infection prevention protocols should reduce its incidence and transmission. Surveillance, cohorting, contact isolation and nasal decolonization reduce the incidence of MRSA infection in liver transplant recipients 19,20. 2% intranasal mupirocin and chlorhexidine baths are used for decolonization of MRSA carriers. VRE is often difficult to eradicate and it maybe prudent to discharge these patients from hospital and readmit after a period at home.

Non judicious use of antibiotics in all healthcare settings as well as in transplant recipients has led to infections with some resistant strains, which have repeatedly threatened transplant programsinclude: •	methicillin-resistant S. aureus (MRSA) •	vancomycin/linezolidresistant enterococcus (VRE)14. •	extended-spectrum beta-lactamase (ESBL)-producing Klebsiella pneumonia or Escherichia coli 22

Surgical site infections ( SSIs ) classically manifest with redness, induration, tenderness, purulent collection / discharge, sometimes with fever & leukocytosis, and are seen in about 10% of recipients. Wound infection rates are also a surrogate marker of hospital infection control practices. Higher rates are seen in low volume centres which perform 50 or less transplants in a year 2. Gram-positive cocci ( S. aureus, enterococcus ), and less commonly Gram-negative pathogens ( E coli, Acinetobacterbaumannii,  Pseudomonas aeruginosa ) and fungi ( Candida, Mucormycoses )  are the usual culprits. 1,7,4,12. Surgical debridement is the mainstay of treatment, backed up with appropriate antibiotics guided by the pathogen isolated and the pattern of antibiotic sensitivity. While SSIs cause significant morbidity, they do not affect survival. On the contrary, Intra-abdominal infections are associated with high, graft loss (39% vs 7%), and higher risk of re-transplantation9.A Roux en Y hepaticojejunstomy used for biliary reconstruction ( as opposed to a bile duct-to-duct anastomosis ) predisposes to intra abdominal infections. Enterococci, including VRE, S. aureus including MRSA, Candida species, and Gram-negative bacilli such as Pseudomonas sp., Klebsiella ,Acinetobacter, and Enterobacteriaceae9 are often responsible. The classical features of fever, pain and a rising white cell count may not manifest; imaging is warranted at the slightest suspicion. Sizeable collections at the portashould be percutaneously drained. A plain CT scan is preferred over ultrasound imaging as the CT scan is more sensitive. If bile has been aspirated further intervention directed at the biliary complication should be instituted. Bloodstream infections occur early after transplant and are usually due to enterococci, viridans streptococci and gram-negative bacilli, probably from translocation from the gastrointestinal tract. Resistant strains of Gram negative bacilli are often very difficult to treat and may run a very fulminant course. The classic features of fever with chills / rigors and leukocytosis may not appear in immunosuppressed patients. Increasing tachycardia, worsening acidosis, dramatic fall in white cell count, toxic granules on peripheral smearmay be early pointers. Patient with intra-abdominal collections, longstanding vascular catheters, re-operative surgery, prior treatment for rejectionor renal impairment would be at a higher than usual risk for bloodstream infections. 11,23. If an abdominal CT scan shows no collection, vascular lines should be changed, pneumonia (clinical or radiological evidence) should be treated with physiotherapy, urinary catheters should be removed and retroperitoneal inflammationshould be ruled out(flank tenderness and discolouration).E. coli, K. pneumoniae and P. aeruginosa are the common Gram negative pathogens which cause significant mortality among liver transplant recipients. 23,24. The prevalence of ESBL producing strains is high in India; MDR pathogens have been reported in as high as 62.5% of A. baumannii, 54.2% of Stenotrophomonasmaltophilia, and 51.5% of Pseudomonas sp. isolates11. Outbreaks of carbapenem-resistant Klebsiellainfections require treatment with expensive and potentially nephrotoxic polymixin B, and maystillresult in high mortality rates. Treatment should target removal of the source of infection ( draining collections, removing invasive lines & catheters, aggressive chest physiotherapy ) combined with appropriate culture based antibiotics and withholding CNIs ( Tacrolimus, Sirolimus , Cyclosporine ) and Mycophenolate till the infection has cleared. Mycobacterium tuberculosis infection remains endemic in India and may infect the transplant recipient by reactivation of a dormant infection, although rare cases of nosocomial and donor transmission have been reported. 25,26.The onset can occur within 15 days to several years of after liver transplantation. 27 (mean, 9 months). . 26 Pulmonary tuberculosis manifests in 51–64% of infections, but extrapulmonarydisease is also seen. 26,27 .Anti tubercular regimens need to be modified keeping in mind the hepatotoxicity and interaction of rifampicin with CNIs.

Viruses

Viral infections such as B and C are often responsible for liver diseases that lead on to liver transplantation. Fulminant liver disease can be caused by hepatitis A, B and E. Unless prophylactic treatment is started, recurrence of cirrhosis is possible. Both hepatitis B and C can result in an aggressive course post transplant known as Fibrosing Cholestatic hepatitis. Further both hepatitis A and E can infected a transplanted liver. Usually infection from hepatitis A is not a problem as most of us have been exposed to this virus in young childhood. If the patient is from a population that has not been exposed to the virus, effective vaccine is available and should be used prior to transplantation. There is good evidence that hepatitis E infection can be controlled by ribavirin treatment. A detailed discussion of management of hepatitis B and C infection post transplant is beyond the purview of this chapter and will not be discussed any further. The common viral pathogens of greatest relevance are cytomegalovirus (CMV), herpes simplex virus (HSV), varicella zoster virus (VZV), Epstein-Barr virus (EBV) and human herpes viruses. The incidence of CMVIgG positivity in the general population ranges from 45% to 100%. 28,29, and is >95% in the Indian subcontinent. 30 .This places our population at intermediate risk for CMV disease after a liver transplant. The CMV which remains latent inside cells may be reactivated in transplant recipients during periods of intense immunosuppression. Commonly CMV disease may manifest as fever and bone marrow suppression ( CMV syndrome ). Tissue invasive disease may affect the G I tract causing gastritis or colitis, manifesting as diarrhea and abdominal cramps. Although many organ systems may be involved, CMV hepatitis is a common manifestation in liver recipients presenting with elevated liver enzymes that may be difficult to distinguish from graft dysfunction. A liver biopsy may infrequently be needed and may show the hallmark inclusion bodies with clusters of polymorphonuclear cells. 31,32 The 2 basic approaches to preventing CMV disease are universal prophylaxis and preemptive therapy. With the prophylactic approach, usually 450 mg of valganciclovir is given to all transplant recipients twice daily for 3 months. With the preemptive approach, clinicians assess the risk of CMV infection by monitoring patients with CMV DNA count every 1 to 2 weeks, and treat if the results are positive. It is believed that antiviral prophylaxis significantly decreases the incidence of CMV infection/reactivation and disease. 33,36, but there are concerns that this may only delay the onset of CMV disease in many cases. The risk of CMV infection and disease can be categorized by the pretransplant CMV immunoglobulin G (IgG) status of both the recipient and the donor. . 37,38Patients are routinely tested for CMV serology before and CMV viremia after transplantation The highest risk of CMV infection and disease are in CMV naïve recipients who have a seropositive donor ( CMV D+/R- ), especially if they receive boluses of methylprednisolone to treat Acute Cellular Rejection ( ACR ). Based on the authors’ cumulative experience of over 1400 liver transplants and a study conducted by Wadhawan, Gupta. 39 et al, the following conclusions were drawn which are relevant at least for patients in the Indian subcontinent : •	CMV reactivation is common after LRLT (13%), but the disease is rare (2.9%) without prophylaxis in CMV IgG–positive recipients. •	CMV IgG–positive recipients may not require ganciclovir/valganciclovir prophylaxis if they are systematically monitored. •	The administration of high-dose methylprednisolone for treating acute rejection strongly correlates with CMV reactivation as well as disease. •	CMV DNA levels should be determined 3 weeks after LRLT; when the level is greater than 500 copies/mL, prophylactic treatment may be indicated if the patient is being treated with high-dose methylprednisolone for rejection. •	CMV reactivation and disease did not affect survival in our study cohort (positive recipients) with our center's approach to treatment. In patients with a rise in titers and with unexplained febrile illness, graft dysfunction, cytopenia, or diarrhea, treatment with valganciclovir at a dose of 450 mg twice a day is recommended. We monitor CMV DNA viral load every week and stop therapy once 2 consecutive CMV DNA samples are negative.

Infections with HSV ( oral or genital mucositis, rarely with visceral disease ) or VZV( either chicken pox or shingles ) are less common with the institution of routine prophylaxis with acyclovir / famciclovir in liver transplantation. Varicella vaccine is an attenuated live virus, so it can be administered to susceptible transplant candidates ( Varicella Zoster IgG negative ) usually prior to transplantation.

Infections with Ebstein Barr viruses have not been a common problem after liver transplant in the Indian subcontinent.Symptoms and signs of infection with EBV may resemble those due to CMV. Like CMV,it may be the result of reactivation of latent virus or it may be transmitted from donor to a EBV seronegative recipient .Fever, leukopenia, atypical lymphocytosis, or thrombocytopenia may be indicative of EBV disease. Sometimes the virus may be associated with Post Transplant Lymphoproliferative diseases ( PTLD ) particularly in children.

Fungi

Renal dysfunction ( creatinine > 3mg/dL ), dialysis in the postoperative period, operative time > 11 hrs, re-transplantation, reoperation within 5 days of transplant, hepaticojejunostomy, blood product transfusion > 40 units, prior fungal colonization, CMV infection and Acute Liver Failure predispose transplant recipients to infections with Candida and Aspergillus spp. Cryptococcus neoformans (meningitis, lung disease and cellulitis 40 ) and endemic mycoses due to Histoplasmacapsulatum, Coccidiodesimmitis, and Blastomycesdermatitidis occur less commonly. Candidaalbicans is the most common species, but increasingly other species including  C. parapsilosis, C. tropicalis, C. kefyr, C. guilliermondii,  C. glabrata and C. krusei. 41,45 are being cultured. C. glabrata and krusei are resistant to flucanozole. While oral thrush (mucosaldisease ) is common, much of the morbidity and mortality is the result of invasive candidiasis41 - 47. Overall mortality associated with invasive fungal presentation is as high as 77%44. Clinical studies have shown that fluconazole, itraconazole, or amphotericin B prophylaxis markedly reduced the incidence of invasive candidiasis in liver recipients.Many centres including ours practice a regimen of 4 weeks’ prophylaxis with Fluconazole or least for 1 additional week after discontinuing antibiotics.

Invasive candidiasis is defined as : 1. Direct microscopic evidence of the candida in a specimen obtained from a normally sterile site 2. Recovery of candida by culture of a sample obtained from a normally sterile site in a suspicious clinical setting, or 3. Recovery of Candida species in one or more blood cultures (candidemia)48. Disseminated candidiasis is defined as an episode of candidemia with associated target-like abscesses in the liver or the spleen, or the presence of progressive retinal exudates on ophthalmologic examination48. Antifungal therapy of invasive candidiasis begins empirically with broad spectrum caspofungin(ormicafungin, anidulafungin ) because of emergence of infections by fluconazole resistant strains. This is combined with surgical debridement,removal of potentially infected catheters and withholding/lowering the dose of immunosuppression. Once fungal cultures identify the sensitivity pattern, antifungal therapy can then be directed more appropriately. Aspergillosis causes invasive disease in 1-9.2% of recipients49with high rates of mortality. Aspergillusfumigatuslung infection is the commonest, 49 while other species such as A. niger, A. flavus and A. terreus are less common50. Lung infections may be confirmed when a CT scan shows well-circumscribed lesions with or without the halo sign, air-crescent sign or a cavity. CNS infections with focal lesions on imaging or recovery of aspergillus on fungal cultures 48 are the other ways of this infection being diagnosed. Measuring aspergillus antigens ( e.g. galactomannan) in plasma, bronchoalveolar lavage fluid, or CSF could be useful for diagnosis49 but cross reactivity with piptaz group of antibiotics limits diagnosticaccuracy51,52. The overall incidence of invasive Aspergillosis is low and therefore prophylaxis against aspergillosiscan not be recommended in routine transplants., The American Society of Transplantation recommends the use of a lipid formulation of amphotericin B (3-5 mg/kg per day) or an echinocandin for liver recipients with factors that place them at high risk49; the duration of antifungal prophylaxis is during the initial hospital stay or for 4 wk after liver transplantation49. Voriconazole combined with reduced immunosuppression is the usual management.50 Amphotericin B is now considered as second line therapy53because of nephrotoxicity and echinocandins( caspofungin ) are reserved for salvage therapy for invasive aspergillosis49. Duration of therapy needs to be more then 12 weeks and is guided by the patient’s immune status and the response to treatment. Pneumocystis jiroveci( earlierknown as P carinii which was considered a protozoa ) infections are rare because of routine prophylaxis with trimethoprim-sulfamethoxazole in non-allergic liver transplant recipients. However recipients who receive intense immunosuppression for chronic or recurrent rejection are at risk for pneumocystic infections even a year after transplantation. . 54Treatment with trimethoprim-sulfamethoxazole remains effective in most patients.

Conclusion

Infections are common after liver transplantation with the highest incidence in the first six months after transplantation. In the first month they are usually bacterial infections akin to patients undergoing any major gastrointestinal operation. Subsequently viral infections from CMV, varicella zoster, mycobacterium tuberculosis and cryptococcal meningitis predominate. In the late transplant period infections are similar to what is common in the community but with increased frequency. Surveillance, withholding or reducing immunosuppression and specific antimicrobial therapy allow for successful treatment in most infections.

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