Viral respiratory infections in very low birthweight infants at neonatal intensive care unit: prospective observational study

Introduction

Viral respiratory infections (VRIs) are very common in childhood representing between 65% to 80% of hospital admissions, during the first 2 years of life.1 2 Many of these viruses colonise the nasopharynx without symptoms3 4 or may be associated with mild upper respiratory infections. In addition to the classical viruses such as respiratory syncytial virus (RSV), influenza and rhinovirus (hRV), other species like metapneumovirus (hMPV), coronavirus (CoV) or bocavirus (hBoV) are relevant agents causing VRI and associated morbidity, mainly in susceptible infants.5–10

Very low birthweight (VLBW) infants are highly vulnerable to respiratory infections. However, there is a real gap of knowledge about the role of VRI in the preterm infant during neonatal intensive care unit (NICU) admission.11–17 First, the prevalence is unknown because in the clinical suspicion of infection routine, virus search is not included, and this search is limited to RSV18 19 ignoring the role of other viruses. VLBW infants usually do not develop classical signs of cold. Instead, they present with non-specific clinical features like apnoeas, need for increased respiratory support or feeding difficulties. In other words, clinical signs that mirror bacterial infection in these patients. This is the reason for the widespread use of antibiotics when facing these clinical courses which potentially lead to microbial resistance. On the other hand, failure to identify these VRIs carries the risk of transmission to other infants with the appearance of outbreaks.

Second, VRI may potentially worsen the clinical course in a given infant. VRIs associate inflammatory mechanism that, together with the effect of mechanical ventilation and oxygen therapy-derived lung damage, could be determinants in the progression towards chronic lung disease.20 21 In fact, Gagneur11 reported increased respiratory support and oxygen supply for longer periods in neonates and older infants with CoV respiratory infections. Bennett13 found a 52% prevalence of VRI among infants below 33 weeks of gestation. Hospital stay, mechanical ventilation and duration of oxygen therapy were longer, and the prevalence of bronchopulmonary dysplasia (BPD) was higher in positive infants. González-Carrasco,14 in a cohort of preterm and term newborns, found a 22% prevalence of VRI, the infants below 32 weeks being particularly vulnerable.

Finally, the relevance of the asymptomatic carriers might be crucial.3 4 Spreading time of respiratory viruses could last for several weeks, specially in infants.22 23

Our purpose is to report about a systematic VRI surveillance study in VLBW infants during NICU admission, with a focus on the prevalence, the type of viruses associated with VRI, the clinical features heralding viral infection and the impact of VRI on morbidity.

Methods

Results

During the study period, 224 infants below 32 weeks of gestation were eligible for the study. A total of 151 infants met inclusion criteria. Four infants who died within the first 7 days after birth were excluded (figure 1). The mean gestational age and birth weight of the remaining 147 that form the study population were 28 (2.1) weeks and 1099 (319) grams, respectively. Forty five per cent of the study infants were male.

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At least one positive NPA was found in 56 infants (38% of study cohort). Seven babies suffered more than one VRI episode. Demographics and other relevant clinical data of infants who became positive and negative are displayed in table 1.

The variety of viruses that were identified is displayed (figure 2), the most frequently isolated types being hRV (58%) and adenovirus (31%). Mean shedding time was 13 days (range 2–48 days), without significant differences between the most frequently isolated viruses (hRV 14 (2–43) days; adenovirus 10 (3–30) days). Positive NPA occurred in clusters during the autumn and winter seasons. Only one case of positive NPA was found to be eventually related to nosocomial infection (cot-side infant also positive, and related in time).

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Among the 56 infants with positive NPA, 26 had at least a symptomatic episode (table 1). Clinical features presented at the time of NPA collection were: non-specific respiratory clinical signs (increased respiratory workload, tachypnoea, apnoea) in 58% of cases, typical cold features (rhinorrhoea, cough, fever) in 38% and other signs in 4%. Twenty-nine per cent of infants received antibiotics due to clinical suspicion of bacterial sepsis (unspecific clinical condition worsening). As a consequence of clinical deterioration, 12 infants had increased oxygen supply and 4 required mechanical ventilation (two infants invasive ventilation). Postnatal age at first positive NPA ranged between 3 days and 111 days, median 43 days (IQR 28–53).

Among the total VRI episodes (n=64), 38 were caused by hRV and 26 by non-hRV species. Type of virus did not influence the clinical course of the patients who became positive. Asymptomatic infection (hRV 20 (53%); non-hRV 13 (50%); p=1), increased apnoea rates (hRV 6 (16%); non-hRV 9 (37%); p=0.07) or need for mechanical ventilation (hRV 1 (3%); non-hRV 3 (12%); p (insufficient cases)) were comparable among hRV and non-hRV episodes.

VRI was more frequent among infants with BPD (58%) than in infants without BPD (24%) (p=0.001). Cox regression analysis found BPD as an independent risk factor for viral infection (OR 4.12, 95% CI 2.12 to 8.41, p<0.001) and symptomatic infection (OR 3.4, 95% CI 1.03 to 11.05, p<0.04). Kaplan-Meier curves did not show differences between patients with and without BPD in relation to age at onset of VRI (figure 3). Male sex increased significantly the risk of symptomatic infection (OR 3, 95% CI 1.4 to 6.7, p<0.003). Neither birth weight nor gestational age influenced the risk of viral infection or symptomatic infection.

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Discussion

Nosocomial VRIs in the NICU were believed to be anecdotal. This study found that 38% of infants born below 32 weeks of gestation have at least one positive NPA sample during their NICU admission. Nearly 50% of these colonised infants show a variety of clinical signs at the time the NPA is taken.

Systematic VRI surveillance is not an established routine in NICU. During the last decade several reports describe a variable prevalence of VRI in this setting, ranging from 8% to 52%.11–16 In our series, the type of virus that was more frequently isolated was hRV, followed by adenovirus. In spite of the general thought that RSV is the virus most frequently associated with classical respiratory features in the premature infant, studies like ours, in which specific surveillance has been done, have shown a higher prevalence of non-RSV-related aetiology.11–17 Steiner22 found hRV infection in 15% of VLBW infants who showed typical clinical signs of viral respiratory tract infection. Our findings support that clinical features related to upper respiratory tract viral infection are diverse and more importantly, that a significant number of positive infants are free of clinical signs. In addition, VRI may associate non-specific clinical signs that could be interpreted as prematurity-related events or bacterial infection. Therefore, this study supports that the current nosocomial VRI in neonatal facilities is more common than what has been previously recognised and may associate significant disease burden, particularly in the more vulnerable preterm infant.

Shedding of respiratory viruses is long, ranging from 1 week to 6 weeks.13 22 Transmission of respiratory viruses is described as high, either by direct contact or the aerosol route. There is transfer of virus from surfaces to hands during routine activities.26 Therefore, a high index of suspicion and systematic surveillance is needed to avoid epidemic outbreaks in neonatal units. In our study population, 54% of positive infants were asymptomatic and among the babies who showed any abnormal clinical sign, less than 40% presented with the classical features of cold. Other studies also remark that atypical, non-upper respiratory tract viral infection signs, such as increased number of desaturation episodes, apnoea, tachypnoea or respiratory stalemate,11–13 are more frequently shown in the positive preterm infants.

It is noteworthy that almost a third of infants had the first presumption diagnosis of bacterial sepsis so that antibiotics were prescribed. Failure to think about these VRIs has the immediate consequence of unnecessary antibiotic use and prolonged antibiotic treatment duration. Gagneur11 described up to 85% antibiotic prescription in infants with documented VRI compared with those who were not infected. In addition, duration of antibiotic treatment was also significantly longer. Recent studies which searched for a viral aetiology in infants with clinical suspicion of late-onset bacterial sepsis have shown a prevalence of positive viral tests close to 10%.27 28

VRIs associated with higher rates of morbidity. Infants with VRI had more need of supplementary oxygen, reached full enteral nutrition later and, consequently, had longer length of hospital stay, features already described.11–14 It is relevant to note that BPD was shown as an independent risk factor for viral infection in the Cox regression analysis, after adjusting by gestational age and birth weight. Infants with BPD had a fourfold increased risk of VRI, indicating a greater susceptibility to infection in these patients. This finding has only been previously described by Bennett.13 BPD is closely associated with antenatal inflammation, oxygen toxicity and ventilator-induced trauma. Babies with BPD also have a longer hospital stay and more antibiotic prescription, potentially affecting the establishment-promoting microbiota on respiratory mucosa.20 High levels of proinflammatory cytokines which modulate human airway epithelial responses to VRI have been shown in infants with BPD.21 All these factors may alter the immune system that, in addition to the genetic predisposition, could explain the increased susceptibility to VRIs in infants with BPD.20 21

Regarding the clinical expression of VRIs associated to the aetiological agent, our results did not show any difference. We have not found in the literature clearly established data on the clinical features related to hRV infection in the premature infant during NICU admission. So far, the different disease expression of viral infection according to type of agent in this vulnerable population deserves further investigation.

The main limitation of our study is the relatively small sample size. Although this is one of the largest series of premature infants prospectively studied for VRI, the study is not able to reach statistical significance in several aspects. For instance, although hRV was the most frequently identified virus, eventual differences in the clinical outcomes of infected infants according to the type of virus could not be sorted out. Likewise, we could not fully characterise the clinical course associated to the various viruses that were found to cause infection. However, the strengths of this work include an uniform population of preterm infants, the systematic prospective study of all types of respiratory viruses, a large number of samples, and a close and prospective data recording during NICU admission.

In summary, systematic surveillance has allowed us to increase our knowledge about VRI in our clinical setting, in which hRV is the most prevalent. VRIs are frequent and commonly asymptomatic. Given the high contagiousness and easy transfer from contaminated surfaces, strict adherence to hand hygiene measures is essential for staff and families. Identification of an index case should move us to establish appropriate measures to prevent outbreaks. This surveillance should focus on infants with respiratory features, and infants with more subtle clinical signs, such as worsening of baseline respiratory condition or suspected late-onset bacterial sepsis. The potential negative impact on the infant’s outcome is of concern. Special awareness should be kept in infants with BPD, as a particular susceptibility to these infections has been found in this study.

Further studies are needed to characterise viral-type specific clinical features as well as the eventual variable susceptibility in the preterm population. The evolution of infants who suffered VRI early in life should also be addressed in appropriate study designs.