Baseline Characteristics
Of 842 patients with pneumonia that requires PICU admission during the study period, 671 cases were community-acquired pneumonia (CAP). Among CAP, 67 with primary adenovirus infection were identified, and adenovirus accounted for 9.99% for all severe CAP admission. The patient enrolment and study profile were shown in Figure 1. Among included patients, the median age was 18 (10, 38.5) months and 40 patients (59.7%) were male. Children aged <24 months accounted for 83.6% (56/67) of all cases. The main characteristics at initial PICU admission between survivors and non-survivors were summarized in Table 1.
Table1. Baseline Characteristics at PICU Admission Between Survivors and Non-survivors
Variables at PICU admission
|
Survivors(n=56)
|
Nonsurvivors(n=11)
|
Total(n=67)
|
p value
|
Age, mo, median (IQR)
|
18(11, 38)
|
20(=7.5, 41.5)
|
18 (10, 38.5)
|
0.889
|
Male gender, n (%)
|
32(57.14%)
|
8(72.7%)
|
40 (59.7%)
|
0.335
|
PRSM III score, median (IQR)
|
13(10, 15)
|
14(11, 18)
|
13(10, 15)
|
0.133
|
days of illness before at PICU admission, median (IQR)
|
9(7,10.5)
|
6(5, 12)
|
9 (6, 11)
|
0.959
|
Laboratory values, median (IQR)
|
|
|
|
|
White blood cell, 109/L
|
6.55 (4.36,12.23)
|
6.11 (4.35, 10.87)
|
6.48 (4.29, 11.96)
|
0.923
|
Platelet, 109/L
|
254 (179, 349.5)
|
258 (148.5, 444.5)
|
258 (178, 353)
|
0.837
|
NK cells, %
|
3.85(2.23,6.57)
|
5(2, 6.9)
|
4.06(2.19, 6.68)
|
0.787
|
pH
|
7.4 (7.33, 7.44)
|
7.33 (7.28, 7.42)
|
7.4 (7.33, 7.44)
|
0.109
|
PaO2, mmHg
|
71 (57, 82.5)
|
73 (65.38, 84.38)
|
72 (57, 84)
|
0.853
|
PaCO2, mm Hg
|
43 (38, 55)
|
52 (44.5, 68)
|
44 (38, 55.5)
|
0.104
|
MAP, mmHg
|
55 (52, 68.25)
|
49 (42.5, 57)
|
55 (51.5, 67)
|
0.171
|
LA, mmol/L
|
1.95(1.38,2.33)
|
2(1.65, 4.25)
|
2 (1.4, 2.6)
|
0.968
|
CI, L/min/m2
|
4.2 (3.9, 5)
|
3.6(3.45, 4.1)
|
4.2 (3.85, 4.85)
|
0.011
|
TBIL ,umol/L
|
4,42(3.2, 5.87)
|
10.85(5.35, 20.22)
|
5.02 (3.29, 6.61)
|
0.069
|
serum creatinine, umol/L
|
32.5 (25.5, 40.88)
|
34.5(29.25, 54)
|
33 (26.25, 42)
|
0.291
|
IQR : interquartile range ; NK cells : natural kill cell; CI: cardiac index; MAP: mean arterial pressure; TBIL; total bilirubin, Lactate: LA
All patients were admitted to PICU for the reasons of fever (100%) and respiratory symptoms consistent with cough (100%) or whoop (65.7%), tachypnea (100%), acute respiratory failure (100%) requiring oxygenation support.
At PICU admission, co-infection (defined as pneumonia caused by adeno virus as well as typical bacteria, mycoplasma pneumoniae and other viruses) was seen in 25.37% (17/67) patients. During the PICU stay, nosocomial infection including VAP and bloodstream infection were seen in 32.84% (22/67) patients, higher morbidity in non-survival (63.6%,7/11) than in survival (26.78%,15/56). Nosocomial infected pathogens were isolated from different specimens including blood, sputum, bronchoalveolar lavage fluid, and hydrothorax. The most frequently isolated pathogens were Acinetobacter baumanii 9 patients (13.4%), Klebsiella pneumoniae in 7(10.5%), mycoplasma pneumoniae in 6 (9.8%), Stenotrophomonas maltophilia in 4 (5.9%), and Candida albicans in 3 (4.5%) (Table2).
Table2. PICU Therapeutic Interventions Between Survivors and Non-survivors
|
Survivors(n=56)
|
Non-survivors(n=11)
|
Total(n=67)
|
p value
|
Median of PICU stay, days
|
11(7.75, 18)
|
15(11, 19.5)
|
11 (8, 18)
|
0.861
|
Median of hospital stay, days
|
22.5 (16, 34.25)
|
17(16, 23.5)
|
22 (16, 31)
|
0.124
|
Co-morbidity, n (%)
|
|
|
|
|
ARDS
|
27(48.21%)
|
9 (81.82%)
|
36(53.73%)
|
0.041
|
Liver dysfunction
|
21(31.34%)
|
10 (90.9%)
|
31 (46.27%)
|
0.001
|
AKI
|
4 (7.14%)
|
5 (45.45%)
|
9 (13.43%)
|
0.001
|
shock
|
42 (75%)
|
10 (90.9%)
|
52 (77.61%)
|
0.247
|
GI dysfunction
|
31 (55.36%)
|
11 (100%)
|
42 (62.69%)
|
0.005
|
PICU and hospital therapies, n (%)
|
|
|
|
|
Invasive Mechanical ventilation
|
51 (91.07%)
|
11 (100%)
|
62 (92.54%)
|
0.303
|
CRRT/RRT
|
11 (19.64%)
|
8(72.73%)
|
19 (28.36%)
|
0.000
|
ECMO
|
6 (10.71%)
|
3 (37.5%)
|
9 (13.43%)
|
0.141
|
Prone positioning, n (%)
|
15 (26.79%)
|
4 (36.36%)
|
19 (28.36%)
|
0.519
|
Neuromuscular blockade, n (%)
|
22 (39.29%)
|
8 (72.73%)
|
30 (44.78%)
|
0.041
|
Vasoactive use
|
48 (85.71%)
|
10 (90.9%)
|
58 (86.57%)
|
0.644
|
diuretics use
|
43 (76.79%)
|
8 (72.73%)
|
51 (76.12%)
|
0.773
|
Steroids use
|
55 (98.21%)
|
11(100%)
|
66 (98.51%)
|
0.655
|
IV immunoglobulin
|
50 (89.29%)
|
10 (90.9%)
|
60 (89.55%)
|
0.872
|
Parenteral nutrition
|
12 (21.43%)
|
10 (90.9%)
|
22 (32.84%)
|
0.000
|
Packed red blood cell perfusion
|
28 (50%)
|
10 (90.9%)
|
38 (56.72%)
|
0.012
|
Nosocomial infenction †, n (%)
|
15 (26.79%)
|
7(63.64%)
|
22(32.84%)
|
0.017
|
bacterial
|
15 (26.79%)
|
7(63.64%)
|
22 (32.84%)
|
|
fungal
|
4 (7.14%)
|
1(9.09%)
|
5 (7.46%)
|
|
† parts of patients complicated with bacteria, mycoplasma pneumoniae or fungi in nosocomial infection or co-infection.
Management And Outcomes
All management decisions were performed by intensivist according to the guideline recommendation [8,16,17], experts’ opinion [18], and routine practice in our PICU. Additional oxygen was utilized in 100% (67cases) patients with 8.96% (6cases) requiring high flow nasal oxygen therapy, and 92.54% (62cases) requiring mechanical ventilation at some period during hospitalization. The indications for CRRT/RRT were:1) AKI which was defined according to the KDIGO criteria[20]; 2) Fluid overload which was defined as the fluid overload >10% [fluid overload = (CRRT initial weight-PICU admission weight)/PICU admission weight×100%][21]. The indications for ECMO were:1) severe hypoxemia with a PaO2/ FiO2 ratio of <50 mmHg for >3 hours or <80 mmHg for >6 hours, or pH <7.25 and a partial pressure of arterial CO2 of ≥60 mmHg for >6 hours[22]. 2)hypoxemia complicated with cardio dysfunction when cardiac index (CI)less than 2.2L/min.m2; and 3) hypoxemia complicated with circulatory dysfunction when persistent lactatemia greater than 4 mmol/L and vasoactive inotropic score (VIS)greater than 50.VIS was calculated as ([(epinephrine+ norepinephrine) ug/kg.min] × 100 + [(dobutamine + dopamine) ug/kg.min] + [milrinone ug/kg.min] ×15. Intravenous neuromuscular blockade was started if the peak inspiratory pressures approximated 28–30 cmH2O, and the patient was hypoxemic and continued to show excessive work of breathing despite adequate sedation[23]. Other cluster therapies included prone positioning, IV immunoglobulin, parenteral nutrition, vasoactive drugs, packed red blood cell perfusion, steroids (methylprednisolone 0.5-2.0mg/kg.d for 3-5 days), diuretics, and antibiotics if needed(see in Table2).
Among the 67 patients with severe adenovirus pneumonia, 11(16.42%) children died in PICU and among them, 10 (14.93%) cases died within 28 day after PICU admission. The overall PICU mortality was 16.42% (11/67), and 28-day mortality was14.93 % (10/67). Patients aged less 2-year old accounted for 72.73% (8/11) of non-survivors.
The median lengths of stay in the PICU and hospital were 11 days (8, 18 days) and 22 days (16, 31 days), respectively (Table 2). The median duration of mechanical ventilation was 5.75 days (3.98, 11.67) in patients required invasive ventilation. In non-survivors, the median ventilator days was longer than that in survivors but without statistical significance (8.48 [4.77, 11.82] days vs. 10.75 [8.17, 19.08] days, p = 0.348). The rate of CRRT and use of neuromuscular blockade, parenteral nutrition, or packed red blood cell perfusion were significantly higher in non-survivors than that in survivors (p< 0.001, p = 0.041, p< 0.001, p = 0.012, respectively; Table 2). Moreover, the ratio of nosocomial infection was higher in non-survivors compared with survivors (63.64 % vs. 26.79 %, p = 0.017; Table 2).
The changes of parameters about ventilator characteristics and blood gas analysis in survivors and non-survivors were shown in Table 3. There were no significant differences in parameters including peak inspiratory pressure (PIP), positive expiratory end pressure (PEEP) and mean airway pressure (MAP) on the initial day, 3rd day and 7th day of invasive ventilation between survivors and non -survivors (all p> 0.05, Table 3). However, the values of Cydn on 3rd day and 7th day of invasive ventilation were significantly lower in non-survivors compared with survivors (p =0.012, p=0.045, Table 3). In addition, the ratio of PaO2/ FiO2 and SaO2 levels displayed a tendency decrease in non-survivors compared with survivors on the 3rd day after receiving invasive mechanical ventilation (p = 0.038, p= 0.008, respectively; Table 3).
Table 3
The changes of parameters about patients receiving invasive mechanical ventilation
Variables
|
D1
|
D3
|
D7
|
Survivor
(n = 56)
|
Nonsurvivor
(n = 11)
|
p-
value
|
Survivors
(n = 56)
|
Nonsurvivor
(n = 11)
|
P
-value
|
Survivor
(n = 56)
|
Nonsurvivor
(n = 11)
|
p-
value
|
PIP,cmH2O
|
21 (19,23.5)
|
25 (21, 27)
|
0.145
|
21.5 (20, 24)
|
24 (20.5, 28)
|
0.377
|
22 (20, 26)
|
23 (21.75, 30)
|
0.27
|
MAP,cmH2O
|
11 (10, 12.5)
|
12 (10.5, 13.5)
|
0.372
|
11.5(9.25, 13)
|
12 (11, 14.5)
|
0.412
|
12 (11.5, 14.5)
|
13 (11, 17.25)
|
0.458
|
PEEP, cm H2O
|
5 (4, 5)
|
5 (4, 5)
|
0.368
|
5 (5, 6)
|
5 (5, 5.5)
|
0.801
|
5 (5, 6)
|
6 (5, 6)
|
0.567
|
Cdyn, cm H2O/kg
|
0.4 (0.32, 0.48)
|
0.33 (0.31, 0.425)
|
0.286
|
0.52 (0.43, 0.55)
|
0.4 (0.31, 0.4)
|
0.012
|
0.5 (0.4, 0.56)
|
0.26 (0.22, 0.34)
|
0.045
|
Tidal volume, ml/kg
|
8 (7.8, 8)
|
7.2 (6.65, 8)
|
0.0029
|
8.3 (8, 8.5
|
8 (7.2, 8.1)
|
0.072
|
8.2 (8, 8.5)
|
7.55 (6.03, 8.35)
|
0.307
|
PaO2/FiO2 ratio, mmHg
|
151 (113, 180).25
|
140 (90, 143.5)
|
0.177
|
185 (139, 224)
|
111 (103,174.5)
|
0.038
|
170 (110, 212)
|
137.5 (89.5, 157.75)
|
0.384
|
Oxygenation index
|
|
|
|
|
|
|
|
|
|
PaCO2, mm Hg
|
44 (35, 50.25)
|
48 (41.5, 57.5)
|
0.138
|
45 (40.5, 48.5)
|
42 (37.5, 55.5)
|
0.727
|
44 (41, 48)
|
58 (43, 69.5)
|
0.305
|
PaO2, mm Hg
|
72 (57, 86.25)
|
73 (58.375, 84.5)
|
0.871
|
78 (72.5, 89.5)
|
78 (72.5, 89.5)
|
0.087
|
77 (55, 90)
|
65 (51.5, 75)
|
0.357
|
SaO2,%
|
95 (92, 96)
|
93 (90.5, 95)
|
0.265
|
96 (95, 97)
|
93 (91.5, 95.5)
|
0.008
|
96.5 (92.25, 98)
|
91 (89, 95.5)
|
0.655
|
D1: initial day of invasive mechanical ventilation; D3: 3 days of ventilation; D7: 7 days of ventilation; PIP: Cdyn: lung dynamic compliance; MAP: mean airway pressure; |
Besides the lower cardiac index (CI) in non-survivors than survivors at PICU admission (Table 1), CD4+ cells percentage showed a higher tendency in non-survivors than that in survivors at PICU admission (p = 0.071, Table 4). There were no significant differences in aspects of white blood cell and platelet count, NK cell, CD4+, CD8+, CD19+ percentage between two groups at PICU admission. During PICU stay, platelet Count was significantly lower in non-survivors at 7 days after PICU admission when compared with survivors (93 [85, 371], vs. 327 [257.75, 443.75]×109/L, p = 0.039; Table 4). In addition, the interleukin 6 (IL-6) and IL-10 were significantly higher in non-survivors than those of survivors at 7 days after PICU admission (p = 0.035, p< 0.01, respectively; Table 4).
Table 4
Changes of blood cell and immunological parameters at PICU admission and 7days after admission
Variables
|
PICU admission
|
7 days after admission
|
|
Survivors(n = 56)
|
Non-survivors (n = 11)
|
P value
|
Survivors(n = 56)
|
Non-survivors(n = 11)
|
P value
|
Hb, g/L
|
101.5 (90, 113.5)
|
100 (100, 109.5)
|
0.699
|
99.5 (95, 106)
|
95 (90, 110)
|
0.457
|
WBC, 109/L
|
6.55 (4.36, 12.23)
|
6.11 (4.35, 10.87)
|
0.923
|
8.78 (5.26, 10.77)
|
4.37 (3.39, 11.69)
|
0.774
|
platlat,109/L
|
254 (179, 349.5)
|
258 (148.5, 444.5)
|
0.837
|
327 (257.75, 443.75)
|
93 (85, 371)
|
0.039
|
NK cells, %
|
3.85 (2.23, 6.57)
|
5 (2, 6.895)
|
0.787
|
3.98 (2.185, 6.01)
|
2.98 (1.02, 8.08)
|
0.812
|
CD19+, %
|
44.02 (30.91, 52.64)
|
42.1 (24.47, 53.55)
|
0.437
|
34.58 (30.13, 45.36)
|
38.58 (24.66, 44.04)
|
0.804
|
CD4+, %
|
25.56(19.5, 31.39)
|
32.48 (23.2, 41.59)
|
0.071
|
27.49 (22.96, 35.48)
|
33.23 (29.82, 38.79)
|
0.489
|
CD8+, %
|
20.02(14.96, 26.75)
|
16.36 (15.34 20.25)
|
0.555
|
20.14 (17.76, 28.28)
|
20.58 (14.23, 22.5)
|
0.614
|
IL-6, ng/L
|
0.1 (0.1, 0.1)
|
0.1 (0.1 ,0.1)
|
0.449
|
0.1 (0.1, 0.1)
|
47.77 (0.1, 239.29)
|
0.035
|
IL-8, ng/L
|
0.1 (0.1, 12.09)
|
0.1 (0.1, 36.39)
|
0.707
|
0.1 (0.1, 0.1)
|
7.15 (3.09, 20.21)
|
0.144
|
IL-10, ng/L
|
0.1 (0.1, 4.05)
|
8.99 (0.1, 32.57)
|
0.855
|
0.1 (0.1, 0.1)
|
18.39 (0.1, 32.74)
|
0.0005
|
IL-2R, ug/L
|
15.31(4.27, 28.78)
|
18.92 (11.38, 33.37)
|
0.459
|
10.25(20.81, 24.32)
|
21.71(16.37 33.43)
|
0.089
|
Multivariate Logistic Analysis
By univariate logistic analysis, the patients were associated with worse outcome of severe adenovirus pneumonia in complicated liver dysfunction due to the adeno virus infection (16.485 [1.745~ 155.705], p = 0.014), AKI (10.833[2.269~51.706], p = 0.003), gastrointestinal dysfunction (0.355 [0.178~0.706], p = 0.003) which was defined according to the European Consensus Definition of acute gastrointestinal injury (AGI)[24], encephalopathy (5.629 [1.333~ 23.774], p=0.019), co-infection & nosocomial infection (15.455 [1.847~129.326], p = 0.012) (Table 5). By multivariate logistic regression analysis, the independently risk factor associated with mortality was liver dysfunction (21.231 [1.696~265.779], p = 0.018) and nosocomial infection (2.574 [0.986~15.671], p=0.05) (Table 5).
Table 5. Logistic analysis of variables independently associated with hospital mortality
Outcome
|
OR
|
St.Err.
|
95%CI
|
P value
|
Univariate logistic regression
|
|
|
|
|
PRISM III
|
1.079
|
0.119
|
0.868~1.342
|
0.690
|
ARDS
|
0.5
|
0.185
|
0.242~1.032
|
0.061
|
Liver dysfunction
|
16.485
|
18.887
|
1.745~155.705
|
0.014
|
AKI
|
10.833
|
8.639
|
2.269~51.706
|
0.003
|
Shock
|
3.333
|
3.644
|
0.391~28.41
|
0.271
|
Gastrointestinal dysfunction
|
0.355
|
0.124
|
0.178~0.706
|
0.003
|
Encephalopathy
|
5.629
|
4.138
|
1.333~23.774
|
0.019
|
Co-infection& nosocomial infection
|
15.455
|
16.751
|
1.847~129.326
|
0.012
|
Multivariate logistic regression
|
|
|
|
|
Liver dysfunction
|
21.231
|
27.376
|
1.696~265.779
|
0.018
|
nosocomial infection
|
2.574
|
0.706
|
0.986~15.671
|
0.05
|