Results
One-hundred ninety-nine children undergoing ALL maintenance therapy having baseline characteristics as described in Table 1 were recruited. Median age was 72 months (range – 19-186 months). Male: female ratio was 1.28:1, 55.3% children (n=110) were HR and 44.7% (n=89) children were SR. Ninety-four (47.2%) children received CRT, of which 93 received prophylactic 12 Gy CRT and one child received 18 Gy of CRT due to initial CNS positive status.
Ninety-one (45.7%) children developed a total of 147 episodes of severe infections during maintenance chemotherapy. Respiratory system was the most common site affected (59.3% of children and 55.8%. of episodes with severe infection) (Table 2). Gastrointestinal and central nervous system were the most common non-respiratory systems involved. Febrile neutropenia without any evident focus of infection was second most common presentation (24.1% of children with severe infection and 19% of total episodes of severe infection). Leucopenia (TLC<1000/cumm) was present in 40 episodes (27.2%) and in 35 children (38.5%) with severe infection. Five children required inotrope support while intensive care unit (ICU) admission for ventilator support was needed for 4 children. Three (3.3% of children with severe infection) children succumbed to death during severe infection and two of these deaths were due to respiratory infections. Eight children (8.7%) had culture positive infections, Escherichia Coli and Pseudomonas Aeruginosa being the common organisms. Severe infections were high during the initial months of maintenance phase chemotherapy compared to the later months (Figure 1). This may be due to the more severe immunosuppression resulting from the intensive reinduction and reconsolidation chemotherapy phases preceding the maintenance phase.
Out of the total 91 children, who developed severe infections, 42 children were ≤5 years and 49 children were >5 years of age. Proportion of children with severe infection and with respiratory infection was significantly more in ≤5 years age group compared to the older children (P=0.034, 0.015, respectively), while proportion of children who developed severe infection involving systems other than respiratory system was similar in both age groups (P=0.881) (Table 3). Female children developed significantly more severe infections and also respiratory infections during maintenance phase (P=0.008 and 0.046, respectively) (Table 3). In both SR and HR groups, proportion of children with severe infections, respiratory infections, non-respiratory infection, ICU admission and inotrope requirement were similar (P=0.071, 0.288, 0.066, 0.327, 0.249) (Table 3).
Serum immunoglobulin estimation during maintenance phase revealed hypo-IgM in 172 (86.4%) children and hypo-Ig G in113 (56.8%). (Table 1) In the 6-10 years age group (n=87), 24 (27.6%) children had IgA levels <40 mg/dL and 63 (72.4%) children had normal IgA levels (>40 mg/dL). We could not precisely assess the exact number of children with hypo-IgA in this age group as the cut off for hypo-IgA in this age group was 33 mg/dL, while the lower limit of kit for IgA levels was 40 mg/dL. Among the rest of children (n=112), 80.4% (90) had hypo-IgA and 19.6% (22) had normal IgA levels. One-hundred eighty (90.5%) children had decreased levels of at-least one immunoglobulin class, while 64 (32.1%) children had decreased levels of all three immunoglobulin classes. Proportion of children with hypo-IgG, hypo-IgA hypo-IgM, hypoglobulinaemia of at-least one immunoglobulin class and hypoglobulinaemia of all immunoglobulin classes was significantly high in ≤5 years age group as compared to >5 years age group (P=0.044, <0.001, 0.024, 0.009, <0.001, respectively). For children with hypo-IgA, the difference remained significant even after excluding 6-10 years age group children. (Table 1)
Percentage of children developing severe infections as well as respiratory infections was significantly higher among patients with normal IgG levels compared to those with low IgG levels (P=0.045 and 0.022, respectively) (Table 4). Similarly, non-respiratory infections was significantly higher in a group of children who did not have low levels of any of the immunoglobulin class compared to children who had hypoglobulinaemia of at-least one immunoglobulin class (P=0.039, respectively) (Table 4).
On univariate analysis for factors influencing the occurrence of severe infection during ALL maintenance phase, younger age at the time of recruitment, female gender, age group ≤5 years and normal IgG levels were significantly associated with increased risk of severe infection. Odds ratio (OR) (95% CI) was 0.991 (0.984 – 0.99; P=0.024) for children with older age (in months) at the time of recruitment, 0.587 (0.329 – 1.046; P=0.070) for children in age group >5 years, 2.199 (1.239 – 3.903; P=0.007) for female gender and 0.565 (0.319 – 0.998) (P=0.049) for hypo-IgG. On multivariate analysis, only female gender had significantly increased risk of severe infection [OR. (95% CI) 1.970 (1.088 – 3.566) (P=0.025)] (Table 5).