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.