Discussion
In this study from India, during childhood ALL maintenance chemotherapy, 45% children developed 147 episodes of severe infections requiring inpatient treatment and 1.5% of them suffered infection related mortality. Younger children and female patients had significantly higher risk of severe infection. Holmes et al observed 400 febrile episodes among 136 children on Children’s Oncology Group protocol during the maintenance chemotherapy period.9 In a study from Greece by Kostaridou et al , 22 (78%) out of 28 children developed infection, though it was not classified as severe requiring admission.10 We included only infections requiring inpatient care in the present study.
Among the severe infections during maintenance, the system most commonly involved was respiratory system, affected in 59.3% children. This finding was similar to most reports from the developed world. In a study from United Kingdom, Rapson et al observed that pneumonia was the most common infection (70% of all infections) during continuation therapy.11 In a study from Greece by Kostaridouet al also 53% of infection episodes involved respiratory system.10 Luczynski et al from Poland reported 39% of total infections were respiratory infections in children with ALL during maintenance chemotherapy.17 In a study from a middle income country like Egypt, pneumonia was the most common cause of death (33%) in remission during ALL chemotherapy.6In our study also pneumonia was the commonest cause of death, accounting for 66% of maintenance deaths.
There was no difference in the number of children developing severe infections between SR and HR groups in our study, as maintenance treatment protocols were similar for both groups, consisting of vincristine, steroid pulse and similar 6 MP and methotrexate. This may have abolished the difference observed between various risk groups in studies from the developed world.7,11,17
Rapson et al from UK, did not find any significant differences in leukocyte counts, mitotic response to phytohaemagglutinin, and serum immunoglobulin levels among patients treated with intensive continuous therapy who had serious infections and those who did not develop any.11 In our study also regression analysis did not show significant correlation between hypo-IgG, hypo-IgA or hypo-IgM and development of severe infection. Though children with normal IgG levels showed a trend towards severe infection in our study, it did not reach statistical significance in multivariate analysis. Holmes et alfrom USA observed that IgG monitoring and IVIG supplementation did not significantly impact episodes of fever, febrile upper respiratory infection, or positive blood culture rates between groups with IgG levels <500 mg/dL and >500 mg/dL and even in IVIG supplemented group.9 Our observation on association between hypoglobulinaemia and risk of severe infection was similar to this. Their data also suggested that monitoring or supplementation of low IgG is not indicated for infection prophylaxis in ALL patients during maintenance chemotherapy.
In our study 43.2% children had normal IgG levels during maintenance chemotherapy. Many authors have shown that immunoglobulin levels, especially IgG showed a trend towards normalization in post intensive chemotherapy phase during maintenance period, explaining the possible role of deficiency of immunological parameters other than immunoglobulin as the predisposing factor for severe infections during maintenance chemotherapy 9,17,18. Abnormality of T cells, NK cells, and other cytokines have been shown in ALL children undergoing chemotherapy in various studies,10,12,17–24 which also might have contributed to increased risk of severe infections during maintenance chemotherapy. Severe infection pattern seen in our cohort also could be due to any of these other immune abnormalities, but as we didn’t estimate these parameters in our study, a definite conclusion could not be drawn regarding this. Instead of the deficiency of any one particular immune system arm, it may be the combination of deficient immune system parameters which predisposes the ALL children to infections during maintenance chemotherapy.
It has been shown by Van Tilburg et al that decline in levels of serum IgG did not correlate well with decline in levels of IgG antibody to vaccine preventable diseases.8 Children with low IgG may have normal levels of antibody to vaccine preventable diseases or against infections occurred in past and this might have prevented the occurrence of infection in children with hypo-IgG.8 In our study also, through a similar mechanism, ALL children with hypo immunoglobulin levels might have had normal antibody levels against vaccine antigens or past infections.
Younger children (≤5 years) had significantly more number of severe infections in our study compared to the older children, though multivariate analysis could not demonstrate statistical significance. Inaba et al from St Jude Children’s Research Hospital, USA, observed that younger age at diagnosis was associated with significantly increased risk of infection during induction and later part of continuation phase.25 and our observation was also similar. In addition to hypoglobulinaemia, younger children may also have associated deficiency of other immune parameters contributing to their increased susceptibility to severe infection.
The main strength of our study included that it was a prospective study conducted in a tertiary care cancer centre with a fairly large number of ALL children on maintenance chemotherapy (199 children) and nearly equal number of children in each of the six months period of maintenance (58, 52, 47, and 42 in 0-6, 7-12, 13-18 and 19-24 months of maintenance chemotherapy, respectively) could be recruited. A male to female ratio of 1.28:1 observed in our study, was helpful to compare parameters between both genders.
Limitations of the study were that we could not monitor immunity markers other than serum immunoglobulin and both HR and SR groups received similar maintenance chemotherapy, because of which the difference between the risk groups could not be assessed.