Extracorporeal membrane oxygenation for paediatric refractory hypoxic respiratory failure caused by adenovirus in Shanghai: a case series

Adenovirus (Adv) may cause rapidly progressive, life-threatening illness with multiple organ involvement in both immunocompetent and immunocompromised individuals. Patients with severe Adv infection develop refractory hypoxemia and/or acute respiratory distress syndrome (ARDS) [1, 2]. Extracorporeal membrane oxygenation (ECMO) has been used as a salvage therapy in severe Adv patients with ARDS and refractory hypoxic respiratory failure (RHRF) who respond poorly to conventional therapy [3‐5]. In 2014, Prodhan and colleagues reviewed the Extracorporeal Life Support Organization (ELSO) registry from 1998 to 2009 and found that the hospital survival rate was 38% (62/163) in children requiring ECMO support for Adv infection. Among neonates (<31 days of age), the survival at hospital discharge was only 11% (6/54) [5]. Recently, Ramanathan et al. [6] analysed 25 years of ELSO registry data of those in all age groups who needed ECMO due to severe Adv pneumonia. The in-hospital mortality rate was 58%, with no significant improvement from 1992 to 2016. This outcome strongly indicated that ECMO as rescue therapy was not satisfactory.

In recent years, outbreaks of Adv infection in children have occurred in China [7, 8]. In 2019, the China Health and Health Commission issued expert recommendations for the prevention and treatment of Adv pneumonia in children (http://​www.​nhc.​gov.​cn/​yzygj/​s7653p/​201906/​ab8ec27548ea48f7​93734e8d09c8d42c​/​files/​68cc1dca88f34d56​92a40347d31b4852​.​pdf). This retrospective case series study was undertaken to describe our experience with cases of severe Adv pneumonia with RHRF requiring ECMO from January 2017 to August 2020 in a paediatric intensive care unit (PICU) in Shanghai.

In total, 88 patients with severe Adv pneumonia were admitted to the PICU from January 2017 to August 2020. Among them, 18 children with Adv type 7 (Adv-7) pneumonia complicated by RHRF and mechanical ventilation treatment failure were included in this series. Eleven (61.1%) patients were diagnosed with ARDS. The median age was 19 (9.5, 39.8) months, and 9 patients were male. The baseline pre-ECMO demographics are presented in Tables 1 and 2. The radiologic characteristics of Adv pneumonia are shown in Fig. 1.

We found that the hospital survival rate was 72.2% in children with severe Adv pneumonia who received ECMO support. We found that patients with RHRF with a PaO₂/FiO₂ <61 mmHg, an OI >43, or respiratory failure for more than 9 days had worse outcomes than their counterparts.

In paediatric patients, both PaO₂/FiO₂ and the OI were important variables to evaluate native lung function. To date, the ECMO mode and appropriate initial time of Adv pneumonia need further investigation. Indications for ECMO are currently based on data from adult patients. The OI had the best discriminatory value for mortality risk, with an area under the receiver operator curve of 0.747. An OI≥20, representative of severe paediatric ARDS, appears to be an appropriate cut-off point, as mortality increased from <23% in those with moderate paediatric ARDS to >40% in those with severe paediatric ARDS. Additionally, subjects with an OI>20 exhibited 40% mortality [10]. The current multicentre Extracorporeal Membranous Oxygenation for Severe ARDS study highlights the importance of time from intubation to ECMO [13]. Similar to a previous study [5], our research also showed that nonsurvivors exhibited a lower PaO₂/FiO₂ and higher OI before ECMO as well as longer times from intubation and RHRF confirmation to ECMO than survivors.

ECMO has been used as a salvage therapy for intractable hypoxia in patients with Adv pneumonia [3‐6]. Based on the database of the ELSO registry, Ramanathan et al. [6] reported that patients with Adv pneumonia receiving ECMO had higher in-hospital mortality than those receiving ECMO for other infectious aetiologies. Among 321 paediatric severe Adv pneumonia patients treated with ECMO, 158 patients died, with an in-hospital mortality rate of 49.2% (158/321) [6]. According to our previous research, renal replacement therapy decreased in-hospital mortality in patients complicated with ARDS [14]; the mechanism involved cytokine clearance, and fluid management improved the outcome. Capillary leakage leads to impaired tissue perfusion and hypoxia, which trigger positive fluid balance and are associated with adverse outcomes [12]. In this group of patients, CRRT assisted with fluid management during the ECMO period. During the research period, due to early CRRT intervention, the conditions of 10 Adv pneumonia patients improved and they were able to avoid ECMO therapy. Moreover, we maintained the tidal volume above 3 ml/kg to prevent alveolar collapse during ECMO support. We also monitored dynamic pulmonary compliance during the ECMO period to prevent diffuse alveolar collapse as well as a complete lack of oxygenation in the native lung.

Severe Adv pneumonia has a high mortality rate and is associated with a higher risk of death in infants and young children. In the present study, 5 patients died. Viral virulence and immunocompetent/immune-compromised status have been well described in Adv infection [1, 15]. The innate immune response has been shown to play an important role in the host response to Adv infection [16]. Initial inflammation in Adv pneumonia presents as neutrophilic interstitial infiltrate, followed by the appearance of monocytes and lymphocytic infiltrate, and finally the release of cytokines such as IL-6 and IL-8 [17]. It has been suggested that Adv infection in an immunocompetent individual could result from the inhibition of cytokine production, suppression of T cell function, and inhibition of major histocompatibility complex (MHC) expression by virulent strains, such as HAdV-3 and HAdV-7 [18]. In our research, the nonsurvival group had a higher CD4+ T cell ratio than the surviving group at admission, and one week later, the CD4+ T cell ratio obviously decreased in the nonsurvival group. This could be explained by the following: first, neutrophil activation and accumulation in tissue caused the spread of inflammation; soon after, immune suppression occurred, worsening the outcome. A variety of modes of action have been proposed to explain the beneficial effects of the administration of intravenous immunoglobulin (IVIG), including its interactions with T cell function and antigen-presenting cell maturation/presentation and the general "calming" of inflammatory reactions. At doses higher than those required for replacement therapy, IVIG is being administered for the treatment of certain bacterial and viral infectious diseases [19]. It has been reported that some IVGg batches have significant activity against Adv, so patients are treated with IVIG [20]. Since cidofovir is not available, IVIG is used in many critically ill patients despite the lack of controlled trials.

There were several limitations to our study. First, only 18 patients received ECMO support in our retrospective analysis, which affected the power of the conclusion. Second, although all the surviving patients were followed regularly, long-term follow-up data are absent. To date, three of the patients developed complicated bronchiolitis obliterans, and one patient developed motor retardation, requiring rehabilitation therapy. The overall performance and cerebral performance data are incomplete. However, based on our experience, it was likely that ECMO support combined with other salvage therapies had beneficial effects on cardiopulmonary function in patients with severe Adv pneumonia.

Our data provide insight into ECMO rescue in those with severe Adv pneumonia. Patients with a PaO₂/FiO₂ <61 mmHg or OI >43 and hypoxic respiratory failure for more than 9 days before the initiation of ECMO had worse outcomes.