Infection prophylaxis in solid organ transplantation : focus on Aspergillus, Cytomegalovirus and Streptococcus pneumoniae

Solid organ transplantation (SOT) can be a life-saving treatment option for patients with terminal organ failure due to insufficiency of heart, lung, liver, kidney, pancreas or small bowel. The evolution of SOT from the early 20th century to this day includes technical advancement and development of surgical methods, accumulation of understanding the transplantation immunology and rejection and finally, the pharmacological innovations related to transplantation and infection. The major challenges in allotransplantation remain to be rejection and compatibility issues since, except for identical twins, foreign tissue will universally be rejected by the host immune system unless efficient immunosuppressive drugs are administered. These drugs predispose the recipients to infection. The aims of this study was to assess different prophylactic measures in preventing SOT-related typical infections. Focus was on Aspergillus, cytomegalovirus (CMV) and Streptococcus pneumoniae. Fungal infections, particularly mold infections such as aspergillosis, are major complications among lung transplant recipients. In study I we retrospectively analyzed the use of antifungals, post-transplant Aspergillus incidence rate and death among 76 consecutive lung transplant recipients in 2002-2010 in Helsinki University Hospital. Nebulized amphotericine B (AmB) lipid complex was administered to all patients as anti-Aspergillus prophylaxis and iv caspofungin was added if the patient was considered to be at high risk for post-transplant aspergillosis (e.g. pre-transplant airway colonization with Aspergillus, mycetoma or a tracheobronchial aspergillosis of the explanted lung). The median follow-up time was 953 days (range 16-2751 days) and the overall cumulative mortality was 14.5%. The incidence rate of post-transplant invasive aspergillosis (IA) was a relatively low 4% and there was no IA during the first 24 months post-transplant. Post-transplant airway colonization with Aspergillus and age >55 years were independent risk factors for death. The results of this study are comparable to the heterogenic pool of other studies on Aspergillus prevention in lung transplant recipients. Prospective, randomized studies are needed. Cytomegalovirus (CMV) remains an essential pathogen in solid organ transplantation. Reactivation or a primary CMV infection can lead to end-stage organ disease, often in the transplanted organ, and cause considerable morbidity and mortality. Preventive measures to control CMV infection post-transplant are recommended. In study II we retrospectively evaluated our strategy in heart transplant recipients at low-risk for CMV (CMV-seropositive recipients, R+). We used a low-dose valganciclovir (VGCV) of 450 mg once daily or a renally adjusted dose of that, as opposed to the generally accepted dose of 900 mg once daily to all patients at risk. The aim of the low-dose strategy was to reduce side-effects, mainly the incidence of leukopenia, and to cut costs. Between 2004-2010 we executed a hybrid CMV strategy of universal prophylaxis with VGCV for three months and pre-emptive strategy for another three months to reduce the incidence of postprophylaxis late-onset CMV disease in one hundred consecutive heart transplant recipients in Helsinki University Hospital. Pre-emptive strategy consisted of testing symptomless patients every two weeks for CMV viremia and start treatment if a predefined threshold was reached (in this case 1000 deoxyribonucleic acid (DNA) copies or 5/50 000 pp65 antigen positive leukocytes in a peripheral blood sample). All patients except one received T-cell depleting induction therapy with antithymocyte globulin. The incidence of CMV disease was relatively low in this study, 4%. Six patients had a breakthrough viremia while on prophylaxis and this was due to either non-compliance or a renally non-adjusted dose of VGCV since kidney function had rapidly recovered over time. There were only two cases of postprophylaxis late-onset CMV disease. The incidence of leukopenia was not particularly low in this study despite the low-dose strategy. All patients were able to accomplish VGCV prophylaxis and at the same time 94% tolerated sulphametoxazole prophylaxis and 99% received mycophenolate mophetil as immunosuppression, both potentially myelotoxic agents as well. No suspicion on VGCV resistance rose since all viremias and diseases reacted promptly to treatment. This study added to the growing evidence that low-dose VGCV is efficacious and safe in low-risk heart transplant recipients. We have continued to use 450 mg VGCV once daily for R+ recipients. Careful monitoring of renal function is encouraged. Vaccination against Streptococcus pneumoniae is recommended for SOT recipients in most guidelines, since invasive pneumococcal disease (IPD) is a considerable threat to both the immunosuppressed and the otherwise healthy. The optimal adult pneumococcal vaccination protocol among the transplant candidates/recipients is not known. Polysaccharide vaccines have not lead to adequate protection in the immunosuppressed and revaccination may lead to hyporesponsiveness. To gain more information on the subject we randomized kidney and liver transplant candidates (135 and 47, respectively) to be administered either a 13-valent pneumococcal conjugate vaccine (PCV13) or a 23-valent pneumococcal polysaccharide vaccine (PPV23) pre-transplant as patients entered the transplant waiting list. The primary endpoint in both studies was whether there was a difference in immunogenicity and safety between the arms four weeks after the primary vaccination. The secondary endpoint was whether the second dose of PCV13 administered in the PCV13 group of both kidney and liver transplant recipients six months after the transplantation was immunogenic and safe. Recipients in the PPV23 arm were scheduled to be revaccinated in 3-5 years as was the recommendation at the time. In patients in dialysis the geometric mean titers (GMCs) in the PCV13 arm were significantly higher for 6/13 common serotypes making it more immunogenic than PPV23 in this group of patients. No such difference was found in the study of liver transplant candidates. At six months post-transplant the serotype-spesific antibodies elicited by the first vaccination had declined to the baseline in both arms in both studies. There was no difference in this between liver and kidney recipients even though 70% of the patients in the liver study received a transplant in less than 3 months. The second PCV13 vaccination restored the seroresponces and was safe. The need for revaccination post-transplant in adult SOT recipients was clearly shown here. We did change our vaccination recommendation against pneumococcus on basis of this study.