The panorama of infections in immunocompromised patients and in patients with an increased susceptibility to infections

The main objective of this thesis was to contribute to immunomodulatory interventions that are important for the clinical outcome in patients undergoing haematopoietic stem cell transplantation (HSCT) and in patients with antibody deficiency or increased susceptibility to infections.

Graft-versus-host disease (GVHD), infections, and relapse of the underlying disease are the main complications after allogeneic haematopoietic stem cell transplantation. In study I, we retrospectively examined 179 patients who had undergone HSCT, with the aim of evaluating the effects and kinetics of IgG levels after HSCT. We concluded that IgG levels increased after transplantation throughout the five-year study period. Patients with low IgG levels (< 4 g/L) on two occasions during the first year after HSCT showed a reduced survival rate and an increased incidence of transplant-related mortality compared with patients with normal levels. Persistently low levels of IgG were found to be a risk factor for death after HSCT.

In vivo T-cell depletion with anti-thymocyte globulin is a commonly used strategy for the prevention of GVHD and to avoid rejection after transplantation. In study II, we retrospectively compared 36 patients given Campath as part of the conditioning with a matched cohort of 72 patients receiving thymoglobulin (TMG). The objective was to compare the two different drugs with regard to clinical outcome after HSCT. No differences in transplant related mortality, overall survival, or relapse-free survival were found between the two groups. Furthermore, Campath was associated with less overall acute GVHD but more chronic GVHD. Finally, we noted a trend towards more fungal infections in the patients treated with Campath. In conclusion, TMG and Campath as part of the conditioning appear to result in a similar clinical outcome.

Low serum levels of vitamin D are associated with an increased risk of respiratory tract infections (RTIs). To date, clinical trials with vitamin D against various infections have not been conclusive. Thus, our objective was to investigate whether supplementation with vitamin D could reduce infectious symptoms and antibiotic consumption in patients with antibody deficiency or increased susceptibility to RTI. 140 patients with > 42 days of symptoms from the respiratory tract over a 12-month period prior to inclusion were included in study III. They were randomized to receive vitamin D (4,000 IU) or placebo daily for 1 year. The primary endpoint was an infectious score based on five parameters: symptoms from the respiratory tract, ears and sinuses, malaise, and antibiotic consumption. Secondary endpoints were serum levels of 25(OH)D, microbiological findings, and levels of anti-microbial peptides (AMPs) in nasal fluids. The key message from this study was that vitamin D supplementation reduced symptoms and antibiotic consumption in patients with an increased frequency of respiratory tract infections.

The role of vitamin D in HSCT is not fully understood. To address this issue, we designed a study which included 123 children who were followed retrospectively for up to 8 years after HSCT. The aim of study IV was to determine whether vitamin D levels at baseline were associated with short- and long-term outcome parameters. Vitamin D deficiency was defined as a pre-transplant level of 25(OH)D below 50 nmol/L. We found that the frequency of acute GVHD was higher and that of chronic GVHD lower in patients with sufficient vitamin D levels (> 50 nmol/L) compared with those with vitamin D deficiency. In patients transplanted due to malignancies, overall survival was higher in the group with sufficient vitamin D levels. We also found that relapse was more common in the insufficient-level group. Since vitamin D deficiency was associated with an increased risk of death, relapse, and chronic GVHD, we concluded that baseline vitamin D status appears to influence the clinical course in children undergoing HSCT. However, randomized and placebo-controlled trials will fully clarify this issue.

The main conclusions are that (1) low IgG levels are a risk factor for death after HSCT, (2) TMG and Campath as part of the conditioning before HSCT result in similar outcome, (3) supplementation with vitamin D may reduce disease burden in patients with frequent RTIs, and (4) vitamin D appears to affect the clinical outcome in children undergoing HSCT.

List of scientific papers

I. A-C Norlin, D Sairafi, J Mattsson, P Ljungman, O Ringdén, M Remberger. Allogeneic stem cell transplantation: low immunoglobulin levels associated with decreased survival. Bone Marrow Transplantation. 2008; 41:267-273.
https://doi.org/10.1038/sj.bmt.1705892

II. A-C Norlin, M Remberger. A comparision of Campath and Thymoglobulin as part of the conditioning before allogeneic hematopoietic stem cell transplantation. European Journal of Haematology. 2010; 86:57-66.
https://doi.org/10.1111/j.1600-0609.2010.01537.x.

III. P Bergman, A-C Norlin, S Hansen, R S Rekha, B Agerberth, L Björkhem-Bergman, L Ekström, J D Lindh, J Andersson. Vitamin D3 supplementation in patients with frequent respiratory tract infections: a randomized and double-blind intervention study. BMJ Open. 2012; 2:e001663.
https://doi.org/10.1136/bmjopen-2012-001663

IV. M E A Hansson, A-C Norlin, B Omazic, A-C Wikström, P Bergman, J Winiarski, M Remberger, M Sundin. The role of vitamin D in pediatiric haematopoietic stem cell transplantation. [Manuscript]