Participants characteristics
From 2012 to 2019, there were a total of 958 cases under 5 years of age who suffered from severe CAP in PICU and NICU, from which 12 were not eligible for duration of antimicrobial therapy <48h and 1 was excluded because of imperfect data records. Finally, 945 children were recruited for analysis, including 341 young children aged 2-59 months and 604 infants younger than 2 months. 88 deaths occurred during the investigation, with the overall all-cause mortality being 9.3%. Cochran-Armitage trend test showed that there was no significant difference between age and mortality (Z=0.089, P=.929). The baseline features of participants were demonstrated in Table 1. In infants younger than 2 months, 63% were male. Almost half of the infants were born with low birth weight (41.1%) and most of the dead had underweight (73.5%) or very severe pneumonia (75.5%). 102 infants (16.9%) used mechanical ventilation during hospitalization, including 22 non-survivors (21.6%). In children aged 2-59 months, 54% were male and 62.4% were with very severe pneumonia, answering for more deaths. Young children with underweight accounted for 66.7% of the fatalities and there were only 11 children (3.2%) who used mechanical ventilation. The majority of severe CAP cases aged 0-59 months were hospitalized for 7-14 days.
Comorbidity
In children less than 2 months, most of the patients had >3 diseases simultaneously (74.8%), and it revealed that more comorbidity could significantly increase the risk of death (P <.001). Congenital heart disease (CHD) was the most common comorbidity, but no association was identified between CHD and severe CAP death (31.9% vs 40.8%, P =.296). The secondary was acute respiratory distress syndrome (ARDS), which was statistically related to a high mortality (3.4% vs 20.4%, P <.001). Besides, death was more likely to occur in the cases combined with anemia, pulmonary hypertension, encephalopathy, sepsis, neonatal asphyxia, or gastrointestinal hemorrhage.
In young children aged 2-59 months, mortality was also higher in the patients with >3 combined diseases than that in the patients with less comorbidity (P <.001). Being alike to the young infants, CHD was the most prevalent among the children with severe CAP. Compared with survivors, a higher risk of death could result from severe CAP complicated with pulmonary hypertension.
Antimicrobial treatment and concomitant medications
As shown in Table 1, medications used during hospitalization may also be responsible for the mortality. The vast majority of initial antimicrobial treatment was empirical owing to the difficulty in identifying pathogens, of which monotherapy was the most frequent choice for young infants aged <2 months (93.5%) with 7.6% for mortality, including second-generation cephalosporin (54.3%), carbapenem (29.7%), third-generation cephalosporin (12.7%), other β-lactams (2.5%), and else (0.8%). However, over half of the children aged 2-59 months used ≥2 antimicrobials (72.4%), mainly antiviral drugs plus third-generation cephalosporin (68.2%) or carbapenem (24.5%). Of the 121 cases using the single-drug therapy in this group, third-generation cephalosporin was the most universal choice (50.4%), followed by carbapenem (44.6%), and the mortality was as high as 14.9%, much more than the mortality of children who used ≥2 antimicrobials (9.5%). The multivariate analyses described there was no correlation between antimicrobial regimens and mortality.
In the real world, other medications including antiasthmatic, expectorant, immunotherapy, dietary supplement, and diuretic etc. were also widely employed in children with severe CAP in ICU. Tabulated data pointed out that there was a higher mortality in infants and young children with sedative-hypnotics (40.7% vs 57.1%, P=.02; 48.7% vs 69.2%, P=.018) or furosemide (43.1% vs 79.5%, P=.076; 66.2% vs 97.4%, P<.004). Compared with the survivors, a higher proportion of the dead used corticosteroid despite no significant correlation with death. For the infants <2 months, in contrast, there was a significantly lower percentage of the death in the cases with probiotics (75.7% vs 36.7%, P<.001) or without inhaled corticosteroids (10.3% vs 20.4%, P=.034). More survivors received ambroxol in the age group of 2-59 months (62.6% vs 48.7%).
Microbiological findings
Of the 945 children, 122 patients were detected to have at least 1 pathogen (12.9%) during hospitalization, 78.7% of whom were simple infection. Gram-negative bacteria were the most prevalent pathogens in children with severe CAP in ICU (38.5%), of which the majority was Enterobacteriaceae (48.9%) and Klebsiella pneumoniae (36.2%). Atypical bacteria ranked second (23.8%), followed by virus (20.5%). Gram-positive bacteria were responsible for 18.9% of all pathogens, mainly including staphylococcus (82.6%). Streptococcus pneumoniae and respiratory syncytial virus (RSV) that frequently caused pneumonia in children were rarely detected in severe CAP in ICU. Fisher’s exact tests revealed that Gram-negative bacteria were significantly associated with a higher mortality (35.2% vs 64.3%, P=.028) in ICUs. Although no significant difference was found between the number of pathogens and mortality (P=.1), co-infected patients were more likely to die (19.4% vs 35.7%). (Table 2)
Independent risk factors for severe CAP death
In the infants younger than 2 months, very severe pneumonia (OR: 3.55; 95% CI: 1.39-9.09), BW <1.8kg (OR: 3.92; 95% CI: 1.50-10.23) and mechanical ventilation (OR: 5.06; 95% CI: 1.97-12.95) were identified as independent risk factors for death by the multivariable logistical regression analysis adjusted for co-variants. In addition, when severe childhood CAP was accompanied by anemia (OR: 5.61; 95% CI: 2.36-13.35), neonatal asphyxia (OR: 6.03; 95% CI: 1.57-23.12) or gastrointestinal hemorrhage (OR: 3.73; 95% CI: 1.21-11.48), the mortality would increase. Moreover, sedative-hypnotics (OR: 4.32; 95% CI: 1.76-10.61) was independently associated with a higher risk of death, whereas a lower mortality for probiotics (OR: 0.24; 95% CI: 0.10-0.54). (Table 3)
In the young children aged 2-59 months, the following risk factors were independently associated with a higher risk of death: severe underweight (OR: 4.72; 95% CI: 1.92-11.62); mechanical ventilation (OR:14.43; 95% CI 3.31-62.96); more comorbidity (OR: 10.84; 95% CI: 2.47-47.65); and children with sedative-hypnotics (OR: 4.13; 95% CI:1.50-11.38) showed a higher mortality. (Table 3)