Infections in allogeneic stem cell transplanted patients : Clinical and immunological aspects

Sammanfattning: In allogeneic haematopoietic stem cell transplantation (HSCT), 30 to 40 % of transplant related mortality is associated with infection complications. This includes invasive bacterial and fungal infection, and interstitial pneumonia (IP), which are two important causes of morbidity and mortality. Incidence, aetiology and risk factors of bacteraemia were studied during the pre-engraftment period after HSCT, as well as mortality and cause of death in 500 patients. Thirty-three percent of the patients had confirmed bacteraemia. Viridans streptococci and coagulase negative staphylococci accounted for approximately 90% of all cases. Significant risk factors included prolonged neutropenia (>1 5 days) and recipients of unrelated grafts. Mortality directly attributable to bacteraemia was low (6%), except in gram-negative infections (3/7). However, the overall 60-day mortality was significantly higher in patients with positive blood cultures, and invasive fungal infections were more frequent in these patients. Thus, bacteraemia during the aplastic phase after HSCT might be a marker for high mortality risk, possibly due to more pronounced immune deficiency, including mucosal damage. Both heat-killed bacteria and cell-free supernatants from viridans streptococcal isolates were potent stimulators of pro-inflammatory cytokines (IL 1beta IL8). No evidence of superantigenic activity could be demonstrated in any of the studied strains, but supernatants from strains isolated from patients with severe sepsis seemed to induce higher production of IL1 beta and IL8 as compared to those from non-severe sepsis cases. Viridans streptococcal virulence factors may therefore play a role for development of severe sepsis. Respiratory tract viral infections are not uncommon, and associated with high morbidity and mortality in HSCT patients. To date, there is no established therapy for treatment of these infections. We studied systemic administration of ribavirin in patients with RSV, Influenza B and parainfluenza infections. Ribavirin therapy was safe, without unexpected side effects, did not affect engraftment and might reduce morbidity and mortality if given before development of pneumonia. However, mortality associated with interstitial pneumonia (IP) is still high (>40%) and the clinical features of this condition are similar regardless of the aetiology. Therefore, we assumed that immunopathogenesis, locally in the lung tissue, might be important for development of IP. Analyses of lung biopsies from HSCT patients with IP showed that the immune response was dominated by activated macrophages and increased production of pro-inflammatory cytokines (II1, TGFbeta) Furthermore, we found Th2-type of immune response, characterised by expression of CD86 co-stimulatory molecule and SDF-1 and eotaxin chemokines, and the cytokines IL4, IL5, IL10 and IL13. There was lower expression of Th1 CD80 co-stimulatory molecule and RANTES, MIP- 1alpha and MIP-10 chemokines and no production of Th1-type of cytokines such as IL2, IFNgamma. Consistently, we detected local production of immunoglobulins (IgM > IgA > IgG), but no evidence of T cell mediated cytotoxicity. These findings were similar between the patients irrespective of aetiology of IP, indicating that impaired adequate immune response may be a possible explanation for the severity of IP. In conclusion, improvement in prevention and treatment strategies regarding both invasive bacterial and fungal infections, as well as IP after HSCT are critical to further increase survival after HSCT Traditional prophylaxis and therapy with antimicrobial agents is mandatory but have limitations. Thus, further investigation and understanding of pathogen-host interactions, immunopathogenesis of infection and pattern of immune reconstitution is necessary in order to design better intervention procedures.