A case series of children with adenovirus pneumonia: three-year experiences in a tertiary PICU

We performed a retrospective analysis of prospectively collected data of patients with severe adenovirus pneumonia admitted to a 36-bed PICU in a tertiary university hospital (Shanghai Children’s Hospital, Shanghai Jiao Tong University, China) between July 2016 and June 2019. All patients with pneumonia were initially screened with rapid respiratory virus assay including respiratory syncytial virus, adenovirus, influenza virus and coxsackie virus with nasopharyngeal swab at PICU admission. If rapid assay screen was negative, the deeper respiratory secretions obtained via endotracheal tube or bronchoalveolar lavage collected by bronchoscopy were tested by real-time polymerase chain reaction (RT-PCR). The inclusion criteria were an age of 29 days to 14 years old. Adenovirus pneumonia was confirmed by a positive RT-PCR from respiratory secretions as well as chest X-ray. The exclusion included:1) Patient was hospital acquired adenovirus pneumonia;2) Children had been admitted to other hospital within the last 3 days prior to the present admission; and 3) Children re-admitted to the PICU without 7 days symptom-free period. The study was approved by the ethics committee of Hospital (Approval number: 2016R007-E01). Informed consent was waived because of its retrospective design.

The clinical course of each patient was obtained through computerized medical record database at hospital. Patient outcomes were grouped into two categories: survivors and non-survivors. The primary end point was hospital mortality. Key secondary outcomes included 28-day mortality, length of PICU stay and hospital stay, duration of mechanical ventilation and ventilator parameters, the clusters of therapy strategies: extracorporeal membrane oxygenation [ECMO] applied for refractory shock or refractory hypoxic respiratory failure, continuous renal replacement therapy or renal replacement therapy [CRRT/RRT] applied for fluid overload or acute kidney injury, prone position ventilation applied when the ratio of PaO₂/FiO₂ lower than 150 mmHg, and neuromuscular blockade applied when the ratio of PaO₂/FiO₂ lower than 150 mmHg as well as the peak inspiration pressure higher than 27cmH₂O. And also, the vasoactive and steroids use, IV immunoglobulin, packed red blood cell perfusion, parenteral nutrition and etc. were recorded respectively.

The parameters including age, gender, pediatric risk of mortality III (PRISM III), the ratio of PaO₂/FiO₂, lung dynamic compliance (Cdyn), cardiac index (CI), mean arterial pressure (MAP), co-morbidities, secondary infection pathogen were collected. We also collect blood gas values and transcutaneous saturations. The biochemical parameters for organ functions (total bilirubin [TBIL]; lactic acid [LA]; serum creatinine [sCr]; etc.), Above laboratory indexes were collected from the first test within 24 h PICU admission. The laboratory indexes include white blood cell, platelet counts (PLT), natural kill cell (NK), cytokines and T lymphocytes series at within 24 h and after 7 days PICU admission.

Patient’s characteristics and outcomes were summarized as median (interquartile range, IQR) for variables and percentage for categorical variables. Mann-Whitney U test was used to compare the continuous variables with abnormally distributed data The Fisher’s exact test or chi-square test was used to compare the categorical data. Adjusted odd ratios (ORs) were estimated by multivariate logistic regression models including the variables with significant difference obtained from group comparison. A value of P < 0.05 was considered statistically significant. Data analyses were performed using Statistical analyses were performed using STATA 15.0 MP (College Station, Texas, USA).

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 Fig. 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.

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%) (Table 2).

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 [19]; 2) Fluid overload which was defined as the fluid overload > 10% [fluid overload = (CRRT initial weight-PICU admission weight)/PICU admission weight× 100%] [20, 21]. The indications for ECMO were:1) severe hypoxemia with a PaO2/ FiO2 ratio of < 50 mmHg for > 3 h or < 80 mmHg for > 6 h, or pH < 7.25 and a partial pressure of arterial CO2 of ≥60 mmHg for > 6 h [22]. 2) hypoxemia complicated with cardio dysfunction when cardiac index (CI) less than 2.2 L/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 0.5–2.0 mg/kg.d for 3–5 days), diuretics, and antibiotics if needed (see in Table 2).

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).

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).

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).