Sites of infection

Evidence of hemodynamic instability were seen in the form of tachycardia (n = 43), hypotension (septic shock) (n = 21), and tachypnea (n = 23).

Laboratory investigations

CRP was done in 131 episodes. Values were <1 xss=removed>3 in 51 episodes, 20,000–50,000/mm3 in 45 episodes, and >50,000/mm3 in 54 episodes.

Profile of microorganisms

Blood cultures were done in 147 of the 150 episodes. There were 45 positive blood cultures, i.e., 30.6% of patients had a microbiologically defined infection. Most of the isolates were gram negative organisms (n = 36; 80%). Three isolates were purely fungal – 6.7%. Two more fungal isolates occurred – in combination with pseudomonas. [Table 2] shows the profile of microorganisms isolated from the blood.

Profile of microorganisms isolated in blood culture

Treatment details

One hundred and twenty-seven episodes were initially treated with first-line antibiotics, 19 episodes with second-line antibiotics and 4 episodes with third-line antibiotics based on the severity of infection. Eventually, 127 episodes received first line, 47 episodes received the second line, and 28 episodes received third-line antibiotics as per institutional protocol. Antifungals were given in 29 episodes (19.3%). 24 among them were empirical and the rest based on positive culture reports. Intensive supportive care in the form of inotropes or mechanical ventilation was required in 17 episodes (11.3%). Inotropes were required in 15 episodes of septic shock – dopamine/adrenaline/noradrenaline. Ventilation support was required in six episodes (4%) of whom one survived and 5 expired.

Outcome of infection

One hundred and thirty-six (90.6%) episodes resolved without sequelae. Twelve patients (8%) died (One of them had varicella with hepatitis and coagulopathy). Two patients survived with sequelae – one with perforation peritonitis requiring colostomy and one with persistent empyema requiring decortication. Overall, induction mortality (12 out of 227-5.3%) was mainly accounted for by infections.

Chemotherapy had to be withheld on 47 episodes. The median duration of withholding chemotherapy was 6.85 days.

Outcome of induction chemotherapy

Of the 227 patients, 208 patients (91.6%) attained remission at the end of 4 weeks of induction chemotherapy. 12 patients (5.3%) expired during induction. 6 patients (2.7%) did not attain remission at the end of 4 weeks of induction chemotherapy. One patient (0.4%) was given an extended induction for 6 weeks as an individualized decision based on multiple factors.

Analysis of risk factors for infection or outcome

We analyzed four factors using Chi-square test to assess whether they predict an increased risk of infection – age, gender, risk group, number of drugs received during induction chemotherapy. However, there was no statistically significant association.

CRP, blood culture positivity, and platelet count were assessed with respect to the outcome of infection using Fisher's exact test. None of the factors showed a statistically significant association with outcome of infection.

Analysis of factors affecting mortality

Mortality was assessed using Fisher's exact test with respect to the following factors: Age, risk, number of drugs used in induction chemotherapy, number of episodes of infection, tachypnea, tachycardia, hypotension, CRP, and platelet count. The only factors found to be significantly associated with mortality were tachycardia (P < 0 class="i" xss=removed>P < 0 class="i" xss=removed>P < 0>

Discussion

Our study was done to assess the incidence of infections during induction chemotherapy in children with ALL and to assess the clinical profile, laboratory parameters, microbiological profile, and the outcome of infections. The induction phase was selected to study the infection profile because this is the phase during which chance of infection is highest both due to the immunosuppressive nature of disease and the chemotherapy regimen used. In a study by Bakhshi et al., 166 of 222 (74.7%) episodes of infections in ALL occurred during induction and intensification/consolidation phase of chemotherapy and only 56 episodes (25.3%) occurred during maintenance phase of chemotherapy.[1]

Our study was done over a period of 1½ years and included 227 patients. 51.5% of patients developed at least one episode of infection during induction. The risk group or the induction protocol (4 drugs versus 3 drugs) did not affect the rates of infection though we would have expected a higher rate of infection with the 4 drug regimen. The most common focus of infection was lower respiratory tract (25%, n = 35) followed by GIT (20%, n = 30). Around one-third of patients had no definite focus of infection. In the previously quoted study by Bakhshi et al., pulmonary infections were the most common site of infection (27.3%), followed by HEENT (22.9%), gastrointestinal tract, blood, urinary tract and connective tissue, with a higher incidence of infections during the intensive phases of chemotherapy.[1] In a study from Egypt which included both ALL and AML patients during induction chemotherapy, oral mucositis was the most frequently detected site of infection (52%), followed by skin (34%), GIT, and lower respiratory tract infections.[2]

The danger signs noted in these episodes were tachycardia (28.6%), hypotension (14%), and tachypnea (15%). The presence of these danger signs had a statistically significant association with mortality. Hence, the occurrence of any of these signs during an episode of infection should alert the clinician regarding the severity of infection.

CRP levels were more than 1 mg/dL in 80% of episodes with 22% episodes having a CRP level more than 9 mg/dL. However, the CRP levels did not correlate with the outcome of infection or mortality. Another laboratory parameter analyzed was the platelet count. Studies have shown that presence of thrombocytopenia in sepsis is associated with increased mortality and poorer outcomes.[3],[4] In our study, low platelet count did not show a statistically significant association with the outcome of infection (P = 0.058) or mortality (P = 0.062). However, the P values showed a trend toward significance. A statistical significance could not be reached probably due to the small sample size.

Around one-third of patients had a positive blood culture (30.6%) with 80% of the isolates being gram negative organisms. Nearly 7% of isolates were fungal. Microbiological data from various other oncology centers in India also show a predominance of Gram-negative organisms which was observed in our study as well.[5],[6],[7],[8],[9] Further analyses did not show a significant correlation between blood culture positivity and laboratory parameters such as CRP or the outcome of infection.

Infections were the major cause of mortality during induction in our series. In an analysis of mortality in children with ALL from PGI Chandigarh by Marwaha et al., the induction mortality during the period 1998–2006 was 10% (n = 40) of which 20 had died of infection.[10] Large cooperative groups have also published data pertaining to their TRM and have shown that the major cause of TRM is infections and especially so during the induction period. In UK ALL 2003 trial, sepsis was the most common cause of TRM and risk of infection-related mortality was higher during induction.[11] In an analysis of the St. Jude experience of deaths during induction therapy and first remission of acute leukemia in childhood, infection was the most common cause of death. Fourteen died during disease remission induction: 11 died of infection, and 3 died of noninfectious causes.[12] Similar results have also been published by the Austrian BFM group and NOPHO group.[13],[14]

Conclusions

Infections were a major cause of morbidity and mortality in pediatric ALL during induction chemotherapy, in our series. Around half of the patients had at least one episode of infection; Gram-negative organisms were the predominant isolates in blood culture. Most infections respond well to standard antibiotic regimens.

Conflict of Interest

There are no conflicts of interest.

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Publication History

Article published online:
23 June 2021

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