ACUTE CHILDHOOD LEUKEMIA: THE ROLE OF LOW IMMUNITY TO A RANGE OF INFECTIOUS AGENTS

Maria Dalamaga1, Eleni Petridou1,2, Dimitrios Trichopoulos1,2, Andreas Mentis3, Alkistis Skalkidou1, Themistoklis Karpathios4, Maria Kalmanti5, Dimitrios Koliouskas6, Helen Kosmidis7, John Panagiotou8, Fani Piperopoulou9, Fani Tzortzatou10

  1. Department of Hygiene and Epidemiology, Athens University Medical School, 75 M.Asias Str., Athens, 11527, Greece
  2. Department of Epidemiology, Harvard School of Public Health, 677 Huntington Ave., Boston, MA 02115, USA
  3. Diagnostic Services Department, Hellenic Pasteur Institute, 127 Vas. Sofias Avenue, Athens, Greece
  4. Dept. of Paediatrics, "Aglaia Kyriakou" Children’s Hospital, Thivon and Livadias, Athens, Greece 11527
  5. Department of Paediatric Haematology-Oncology, University Hospital of Heraklion, Heraklion, Greece
  6. Department of Paediatric Haematology-Oncology, Ippocrateion General Hospital, Thessaloniki, Greece
  7. Department of Paediatric Haematology-Oncology, A.Kyriakou Children's Hospital, Athens, Greece
  8. Department of Paediatric Haematology-Oncology, Agia Sophia Children's Hospital, Athens, Greece
  9. Second Department of Paediatrics, Aristoteleion University of Thessaloniki, AHEPA General Hospital, Thessaloniki, Greece
  10. Unit of Childhood Haematology-Oncology, First Department of Paediatrics, Athens University Medical School, Agia Sophia Children's Hospital, Athens, Greece

SLIDE 1: TITLE –AUTHORS-SETTING

It has been suggested that acute lymphoblastic leukaemia (ALL) among children may be a rare outcome of a delayed non specific infection in situations of low herd immunity to a relatively wide range of agents.

According to Greaves hypothesis, acute lymphoblastic leukaemia (ALL), and in particular a specific form of it (c-ALL) is a disease of affluent societies involving a rare response to one or more common infections. It is postulated that, for most common infections, the biological norm is to be encountered very early in life, through the mother or other siblings. In most contemporary societies, exposure density of infants and toddlers to infections has been much reduced through improvements in hygiene and changing social conditions. Lack of early exposure may leave the immune system unmodulated, so that late infection with common micro-organisms faces an inappropriately programmed immune system, that may trigger a violent immune response and subsequent clonal expansion.

According to the delayed infection hypothesis, the risk of ALL should increase with reduced frequency of infections in infancy. We have evaluated the delayed infection hypothesis in a case-control study of incident ALL cases in all six paediatric haematology-oncology units and the respective paediatric hospitals in Greece.

SLIDE 2: CASE-CONTROL STUDY

A case control study of 94 incident cases of ALL and an equal number of hospital controls with minor non-infectious conditions, individually matched for age and gender, was undertaken in Greece. To assess past exposures against a range of infectious agents, a battery 10 of serological tests was used. It was hypothesised that newly diagnosed acute lymphoblastic leukaemia cases, in comparison to their controls, would be characterised by a more seronegative spectrum, with the exception of a strongly positive response to a single infectious agent, assumed to trigger ALL. We did not speculate that this triggering agent would have a specific identity or properties, except that the infection with it would be delayed in comparison to the usual time interval, during which this infection usually occurs.

SLIDE 3: Distribution of cases and controls

Slide 3 shows the distribution of the studied cases of childhood leukaemia and their matched controls by sociodemographic factors, that is gender, age, maternal marital status and maternal education.. Birth weight and birth order, two established risk factors of childhood leukaemia as well as house ownership and anaemia during pregnancy, were significant predictors and together with the matching factors formed the core model for subsequent analyses.

SLIDE 4: CORE MODEL

The core model is shown in Slide 4, following application of both conditional and unconditional logistic regression which generated comparable results.

SLIDE 5: Serological results

Slide 5 shows the serological results by case control status. A statistically significant positive association is evident with respect to Parainfluenza, whereas the inverse associations with Mycoplasma and Epstein-Bar virus are suggestive, but statistically non significant.

SLIDE 6: Odds ratios for infectious agents

Slide 6 depicts the mutually adjusted odds ratios, derived from multiple logistic regression, for childhood leukaemia in relation to graded seropositivity for the ten infectious agents studied. There was little evidence for an association of childhood leukaemia with the serology of any of the ten studied infectious agents among the very young children. In contrast, among children five years or older, there was a statistically significant positive association of leukaemia with Parainfluenza and a series of inverse associations with Epstein Barr Virus, Human Herpes Virus-6, Mycoplasma pneumonia and Parvovirus B19.

SLIDE 7: Key messages and conclusions

Among children five years or older, the risk of leukaemia is higher when the low herd immunity for several agents is challenged by late infection from an infectious agent, that, as a rule attacks children at a younger age. These findings strongly support the hypothesis that ALL among children five years and older may have infectious etiological components.


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