Infections

Both donors and recipients can be the source of post-transplantation infections, which can also occur following exposure to community or nosocomial microorganisms (Fishman, 2009; Green & Michaels, 2012). Prophylactic treatments for viruses such as cytomegalovirus (CMV) and fungi, e.g. Pneumocystis, have limited some opportunistic infections following transplantation (Fishman, 2009).

A growing number of publications have reported outbreaks of post-transplant Pneumocystis jirovecii pneumonia (PJP), with onset occurring in most studies beyond 6 months’ prophylaxis. CMV and allograft rejection had been repeatedly reported as probable risk factors for PJP, but this has now been proven in an extensive systematic review and meta-analysis (Hosseini-Moghaddam et al., 2018). Extended prophylaxis targeting recipients with allograft rejection or CMV infection may reduce the risk of PJP.

Transplanted organs can be a reservoir for the transmission of viruses, e.g. hepatitis B and C viruses, herpes simplex virus (HSV) and HIV, as well as antimicrobial resistant microorganisms (Fishman, 2009). Common recipient-derived pathogens include Mycobacterium tuberculosis; viruses such as hepatitis B or C, and HIV; latent viral infections (HSV and varicella zoster virus (VZV)); endemic fungi (Histoplasma capsulatumCoccidioides immitisParacoccidioides braziliensis), and parasites (e.g. Strongyloides stercoralisTrypanosoma cruzi). HIV-infected patients maintained on highly active antiretroviral therapy (HAART) have been treated successfully following kidney or liver transplantation (Fishman, 2009).

Cytomegalovirus (CMV) infection is the most common opportunistic infection in kidney transplant recipients, occurring in around 8% of patients. Risk factors for the development of CMV include donor seropositivity (particularly if the recipient is seronegative), use of induction immunosuppression (using T-cell depleting antibodies), simultaneous pancreas-kidney (SPK) transplantation, older donors (>60 years), concurrent infection from other viruses and the presence of allograft rejection (Nett et al., 2004; Karuthu & Blumberg, 2012).

In a single-centre, prospective, randomised trial, the incidence of CMV and 3-year efficacy and safety outcomes of everolimus were compared with those of mycophenolate sodium (MPS) in a steroid-free regimen based on low-exposure tacrolimus. The everolimus group presented with a lower incidence of CMV events (18.6% vs 50%, p=0.001), with no differences observed in BPAR, graft loss, or estimated glomerular filtration rate. The regimen effectively prevented acute rejection while demonstrating a more favourable safety profile (de Sandes-Freitas et al., 2018.)

Although the use of mTOR inhibitors is associated with lower incidence of CMV infections, its effect on viral load had not been investigated. In another study, 273 CMV-seropositive kidney transplant patients were randomised to receive anti-thymocyte globulin plus everolimus (n=81), basiliximab plus everolimus (n=97), or basiliximab plus mycophenolate (n=95). All patients received tacrolimus and corticosteroids. Pre-emptive CMV therapy based on a weekly pp65 antigenemia test was given during the first 6 months and blinded weekly CMV DNAemia was compared among the groups. The proportion of patients with undetectable CMV DNAemia was higher in the anti-thymocyte globulin plus everolimus group (23.4%) versus basiliximab plus everolimus (56.7%) versus basiliximab plus mycophenolate (22.1%) (p<0 .001). The proportion of patients with CMV DNAemia below 5000 copies/mL was higher in patients receiving everolimus (74.1% vs 83.5% vs 50.0%, p= 0.000), respectively. The data suggest that mTOR inhibitors (everolimus) reduce the incidence of CMV infection by limiting CMV viral replication (Basso et al., 2018).

Table 7: The effects of CMV viral replication and load of different immunosuppressive regimens (Basso et al., 2018).

The effects of CMV viral replication and load of different immunosuppressive regimens

The risk factors for infection following transplantation are the dose, duration and sequence of immunosuppressive therapies used. Specifically, risk factors are use of induction therapy; high-dose corticosteroids; plasmapheresis; a high rejection risk; early graft rejection or graft dysfunction; and active or latent infection of donor or recipient. In addition, technical complications during transplantation such as anastamotic leak; bleeding; poor healing of wound infection; prolonged intubation or stay in intensive unit care; and surgical, vascular or urinary catheters, are also risk factors for infection (Fishman, 2009).

Figure 21 outlines the timeline of post-transplant infections.

The timeline of post-transplant infections (Fishman, 2009).

Figure 21: The timeline of post-transplant infections (Fishman, 2009).

Comprehensive American Society of Transplantation (AST) guidelines on infectious diseases are available (American Society of Transplantation Infectious Diseases Guidelines 3rd Edition, 2013). The British Transplantation Society guidelines for the prevention and management of CMV disease after solid organ transplantation have been published (British Transplantation Society, 2015).