4. NASOPHARYNGEAL MICROBIOTA COMMUNITY COMPOSITION AND BACTERIAL
SUPER-INFECTION DURING RSV INFECTIONS
The interaction between
nasopharyngeal microbiota and RSV in children can be bidirectional. As
discussed above, specific nasopharyngeal microbiota compositions may
modulate RSV severity but, at the same time, RSV-induced infections can
stimulate proliferation of potentially pathogenic microorganisms in the
upper airways and thus favor bacterial superinfections and morbidity
[7,38,39]. RSV infection can promote the invasion of the respiratory
epithelium by non-typeable Haemophilus influenzae andStreptococcus pneumoniae through a variety of mechanisms,
including upregulation of bacterial adhesion protein expression, loss of
epithelial barrier integrity and decrease of bacterial clearance
mechanisms [3,8,40,41]. Using an in vitro and a lung mouse
model of infection, incubation with RSV or purified G protein was shown
to increase Streptococcus pneumoniae adherence to differentiated
ciliated cells of the respiratory epithelium, thus enhancing the
severity of the airway infection and decreasing animal survival
[8,42]. Also detected in these studies were extensive changes in the
pneumococcal transcriptome, with upregulation in the expression of key
pneumococcal virulence genes, including those encoding the pneumococcal
toxin pneumolysin [42]. On the
airway epithelium end, RSV infection upregulated the cellular surface
expression of other known receptors for Streptococcus pneumoniaeand non-typable Haemophilus influenzae , notably the intercellular
adhesion molecule-1 (ICAM-1) and platelet-activating factor receptor
[8]. In clinical practice,
for
infants with RSV bronchiolitis the risk of secondary bacterial
infections (SBI) is present, yet the severity of the resulting bacterial
infection appears to parallel that of the RSV infection (figure 3A). The
low risk of SBI in mild RSV is born out in a study on 1,248 febrile
infants < 60 days of age, from 88 pediatric Emergency
Departments in New York. The rate of SBI was significantly lower in
those with RSV infection (7.0%) than in those without RSV infection
(12.5%) [43]. Additionally, as compared to the RSV-negative
infants, RSV-positive infants had
a lower rate of bacteremia (1.1% vs 2.3) and of urinary tract
infections (UTI) (5.4% vs 10.1%). Similar results were reported in a
retrospective cohort study of < 8-week-old infants, who
presented with fever and a positive RSV antigen test to the Emergency
Department at an urban child facility in Nashville, Tennessee [44].
Buttressing these results is a systematic review of 11 studies on “in-
and out-patients”, < 60 to 90 day old, with
bronchiolitis, reporting no case of bacteremia, yet the rate of UTI
resulting slightly higher in the RSV-positive subgroup (5.1% vs 2.0%)
[45]. These data suggest that,
in nontoxic-appearing infants with
a positive RSV test, full septic evaluations are not necessary, however,
the finding of a low, but clinically relevant rate of urinary tract
infection, probably justifies urine work up [44,45].
Conversely,
the incidence of SBI and
concomitant bacterial pneumonia is more frequently observed (or
diagnosed) in infants with severe RSV bronchiolitis (figure 3B). Out of
127 infants (median age 1.7 months) admitted to the PICU of the Zurich
University Children’s Hospital, 57 were mechanically ventilated
[46]. Tracheal cultures obtained from intubated children within the
first hour of intubation were positive in 25 infants, half of them for
community and half for nosocomial acquired bacteria. Microorganisms
associated with bacterial LRTI included Moraxella catarrhalis ,Haemophilus influenzae type b and Streptococcus
pneumoniae . The incidence of sepsis was 3/127 patient. Despite only
documenting 25 bacterial concomitant infection, antibiotics were
administered to 73/127 infants over the first two days of hospital
admission, namely, to a high proportion of those with negative bacterial
cultures. The authors conclude
that to avoid inappropriate antibiotic prescription, tracheal aspirates
should be investigated microbiologically on a routine basis in this
patient group [46].
The
high frequency of bacterial coinfection in young infants with severe RSV
bronchiolitis was confirmed in the study of the Royal Liverpool
Children’s Hospital [47]. Out of the 165 children (median age 1.6
months) admitted to PICU with RSV bronchiolitis, 70 (42.4%) lower
airway secretions tested positive for bacteria, includingHaemophilus influenzae , Moraxella catarrhalis ,Streptococcus pneumoniae and Staphylococcus aureus[47]. All those with bacterial co-infection were mechanically
ventilated and required ventilatory support for longer than those with
only RSV. Gender, co-morbidity, origin, prior antibiotics, time on
preceding antibiotics, admission oxygen, and ventilation index were not
predictive of positive bacterial cultures
[47]. The risk of prolonged
hospitalization and PICU admission may be even higher in preterm born
infants, hospitalized with RSV disease, if concurrent bacterial
infections are present. Out of a total of 464 infants, median age 2.75
months (range 0.25–96), hospitalized due RSV infection to the Graz
Medical University, 42 (9.1%) were born<37 weeks of
gestational age [48]. Concurrent bacterial infections were detected
in 3.1% of term and 9.5% of preterm infants and the percentage of
those referred to PICU was 5.2% and 23.8% in term and preterm infants
respectively. In all these preterm a diagnosis of pneumonia was made,
and tracheal aspirates were positive for Streptococcus pneumoniaeand Haemophilus influenzae . Mean hospital stay was longer (22.3
days) in preterm infants with bacterial co-infection than in the ones
without it (10.3 days) [48]. Concomitant bacterial infection can
occur also in older children hospitalized with RSV bronchopulmonary
infections as shown in a study performed of 188 pediatric inpatients,
aged up to 5 years, admitted to 2 hospitals in Chiba Prefecture, Japan
[49]. Pathogenic bacteria were isolated from washed sputum bacterial
culture in 43.6% of the children, the three most frequently isolated
being Haemophilus influenzae (43.9%), Streptococcus
pneumoniae (36.6%) and Moraxella catarrhalis (29.3%). Before
admission, 28.7% of the patients received oral antibiotics, most often
macrolides and amoxicillin. Of the Haemophilus influenzae strain
isolated 38.9% were ampicillin-resistant, whilst allStreptococcus pneumoniae strains were penicillin G sensitive,
minimum inhibitory concentration values were 2 µg/ml [49]. Thus, RSV
bronchopulmonary infection in
hospitalized children can often be associated with super-infection by
antimicrobial-resistant bacterial. Prior antibiotic treatment and
Gram-negative pathogen prevalence at nasopharyngeal level can be
associated with more disease severity. A prospective, observational
cohort study, of 136 infants with RSV bronchiolitis enrolled at 24 h of
hospitalization; 104 on the ward and 32 in the PICU [50]. As
compared to an age-matched group of healthy controls, RSV bronchiolitis
infants had more frequent nasopharyngeal colonization withnon-typable Haemophilus influenzae or Moraxella
catarrhalis (Gram-negative bacteria) andStaphylococcus aureus andStreptococcus pneumoniae (Gram-positive bacteria). Higher
proportion of Gram-negative pathogens was associated with higher blood
neutrophil percentages, greater number of nasal wash leukocytes,
increased concentrations of plasma IL-8 and IL-6, a trend towards
increased disease severity and longer need for oxygen. Thus,Staphylococcus aureus , which seems to have a protective role? on
RSV infection, may be detected in the lower airways of young infants
with severe RSV bronchiolitis but its presence does not seem to be
associated with increase disease severity. In this study, 47% (64/136)
of all RSV infants and 75% of those in PICU received antibiotics prior
to sample collection. This common use of antibiotic was associated with
a decreased likelihood of recovering potentially pathogenic bacteria by
culture, but also with enhanced disease severity as defined by clinical
parameters and radiologic findings. Infants treated with antibiotics
prior to hospitalization required oxygen for a longer time and
radiographic lobar consolidation was more frequently identified compared
to those with no prior antibiotics. Atelectasis or lobar consolidation
was associated with higher clinical disease severity scores [50].
The elevated antimicrobial-resistance in bacterial superinfection and
the higher risks of enhanced disease severity highlight the need for
microbiological investigation of airway secretion in this patient
population. Finally, the incidence of Streptococcus pneumoniaecoinfection could be modified following the introduction of seven-valent
pneumococcal conjugate vaccine (PCV7). Weinberger DM et al, evaluating
hospitalization data from community hospitals in 18 U.S.A. states and
comparing the 1992/1993 and 2008/2009 seasons, demonstrated a
significant decline in RSV-coded hospitalizations in children aged
<1 y and 1–2-year-old following PCV7 introduction in 2000
[51]. We could find no data on the effect of the effect of the
subsequent introduction of PCV13.