Immunological and Inflammatory Biomarkers of Susceptibility and Severity in Adult Respiratory Syncytial Virus Infections

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Eligibility and Exclusion Criteria

Inclusion

Human RSV studies in adults

Severity of RSV infection assessed

Biological marker investigated

Studies written in English, French, Spanish, Italian, or Portuguese

Exclusion

Studies in animal models

In vitro studies

Studies exclusively in children

Studies of treatment, diagnostics, or epidemiology of RSV infection

Absent definition of disease severity

Studies without a definitive RSV diagnosis

Studies focusing on viral characteristics

Literature reviews

Abbreviation: RSV, respiratory syncytial virus.

Figure 1.

Systematic review articles included.

RESULTS

Humoral Immunity

Antibodies are a central component of the immunological repertoire and are associated with protection from infection from numerous respiratory pathogens. Several studies have investigated the association between RSV infection, disease severity, and antibody titers. Particular attention has been given to humoral immunity in elderly and comorbid populations, due to the higher prevalence of severe disease in these groups.

Following natural RSV infection serum immunoglobulin G (IgG) levels are known to increase. Falsey et al found that 79% of adults >65 years old had a greater than 4-fold increase in RSV-specific serum IgG compared to 64% of adults <50 years old [9], indicating that the humoral immune response of older adults (>65 years) appears intact in response to natural infection. Although older adults (>65 years) can respond to infection, a low baseline antibody titer (the lowest third of preinfection neutralizing antibody titers) is associated with an increased susceptibility to symptomatic infection. Luchsinger et al observed that a lower RSV serum neutralizing antibody titer at hospital admission amongst adults with community acquired pneumonia (CAP) was associated with an increased likelihood of the CAP being RSV associated (RSV A 8.1 vs 8.9 and RSV B 9.3 vs 10.4; P < .02 for both) [10]. Other reports also show an inverse correlation between anti-RSV neutralizing antibody levels in the serum and RSV-associated hospitalization in the elderly population [11, 12]. Walsh et al indicated a strong association between RSV infection and low serum neutralizing antibody titers (odds ratio [OR], 5.89; confidence interval [CI], 1.69–20.57; P = .006) in elderly and high-risk adults (those with symptomatic cardiopulmonary disease) [13]. The importance of neutralizing antibody in protection from RSV has been supported by a human infection challenge study, which showed that infected healthy young adults had slightly lower serum microneutralizing antibody (MNA) prior to challenge than those who remained uninfected (MNA titers, 9.5 log₂ versus 10.6 log₂; P = .04). The same study also found lower serum RSV F protein IgG titers (15.2 log₂ versus 16.4 log₂; P = .02) in those infected than in those who did not become infected with the virus [14]. Notably, in these young adults, not all infected subjects showed a rise in antibody levels in the serum. Serum antibody levels and neutralizing antibody titers increase after RSV infection [15, 16] but this increase is short lived, with an approximately 2-fold decrease in microneutralization titers every 6 months [16]. Interestingly, study participants who did not become infected had a significantly slower decline in antibody over time. This rapid antibody decay, following transient increases post-RSV infection, may reflect the “immune amnesia” described with RSV, which permits rapid reinfection even with antigenically similar viruses [6, 17]. In an RSV challenge study by Lee et al, 8 (67%) of the 12 participants who became infected had a ≥ 4-fold rise in serum anti-F antibodies and 7 (58%) had ≥ 4-fold rises in anti-G antibodies [14]. RSV challenge studies have also provided supportive evidence for the important role of mucosal antibody in RSV prevention, where nasal IgA levels (but not serum IgG) are particularly associated with protection (OR, 1.9; CI, 1.2–3.4; P < .05) [15].

In addition to conferring protection from infection, trends have been observed between lower neutralizing antibody titers and the severity of an RSV infection (P = .07) [18]. By contrast, RSV challenge studies in young adults indicate that once an infection occurs, antibody levels have little impact on disease severity [15, 19]. However, such challenge studies result in mild disease with limited lower airway symptoms and may incompletely reflect the spectrum of natural disease severity. In addition to demonstrating the role of neutralizing antibodies to RSV protection, Walsh et al noted that chronic pulmonary disease was particularly associated with RSV infection (OR, 3.97 independent of other factors), indicating that underlying pulmonary health is an important contributor to severity of RSV infections [13]. Nasal IgA has been reported to inversely correlate with peak nasal RSV load during natural infection, where RSV G-specific antibodies were most closely correlated [20]. Similarly, Cherukuri et al reported that elderly adults with high titers of RSV F-specific nasal IgA were protected from severe RSV illness [11].

Studies have also investigated the association of age with anti-RSV antibody levels. Some studies have demonstrated that nasal RSV F-specific IgA titers were similar between young and older adults [11], as were serum RSV-specific IgG levels when measured by immunoassay or MNA [9]. Conversely, other studies have observed decreased MNA titers in older age, despite sustained total RSV antibody levels [9, 21]. A further study investigated viral, humoral, and mucosal immunity in protection against natural RSV infection in 1284 prospectively enrolled participants from 4 groups: (1) healthy adults >65 years old, (2) healthy adults 19–40 years old, (3) adults with symptomatic cardiopulmonary conditions, and (4) nursing home residents. Symptomatic RSV infections (from mild upper-respiratory illness to pneumonia) were observed in 67 participants, of which 5 were hospitalized [22]. These RSV-infected subjects had significantly lower preinfection titers of nasal IgA (r = 0.58–0.76; P = .0001) and serum IgG against RSV F, Ga, and Gb proteins (r = 0.54–0.80; P = .0001) and lower serum neutralizing antibody titers. This study could not determine a specific antibody titer predictive of protection from symptomatic RSV infection, although subjects with antibody titers in the highest quartile were approximately 3 times less likely to develop a symptomatic infection [22].

Together, these studies indicate that antibody, particularly IgA in respiratory secretions, provides some protection against RSV infection but may do little to influence disease severity. RSV prefusion F antibodies have recently been implicated as important markers of protection in infants [23] but there is a noted lack of data regarding their role in protection from infection in adults. Neutralization is the main functional test performed in these studies, though other antibody effector functions, including antibody-dependent cellular cytotoxicity, are under studied and may contribute to preventing RSV infection or limiting disease severity. Boosting of antibodies against RSV following infection is short lived, possibly reflecting immune amnesia following infection.

Cellular Immunity

In addition to antibody-mediated protection against RSV infection, the contribution of cellular immunity to protection against infection and in limiting disease severity have also been studied. Although not covered in depth by this review, in vitro studies have demonstrated that antigen presentation of peptides from most RSV proteins can drive T-cell cytotoxicity, with peptides from M2 and SH considered immunodominant [24, 25].

Interferon gamma (IFN-γ) production in response to the RSV F protein by peripheral blood mononuclear cells (PBMCs) and T cells from elderly donors was significantly lower than from young adults (1250 ± 420 vs 180 ± 80 spot-forming cells/10⁶ peripheral blood mononuclear cells; P < .001) [11]. RSV-specific CD8⁺ T cells were also less abundant in elderly relative to younger adults [11, 26, 27]. This decreased frequency and function of RSV-specific T cells in older age may contribute to disease severity and potentially the rate of viral clearance in elderly persons. The central role of cellular immunity was supported by RSV challenge studies, which examined the cytotoxic CD8⁺ T-cell responses in 49 healthy adult volunteers, half of whom had serial bronchoscopies and bronchoalveolar lavage (BAL) for the collection of cells [28]. Interestingly, those patients with greater pre-RSV challenge BAL CD8⁺ RSV-specific T-cell levels had less severe infections and a lower viral load (P = .0142; r = −0.691) [28]. CD8⁺ RSV-specific T cells were less frequent in the blood and no significant correlation was observed between these circulating T cells and RSV severity or viral load, highlighting the importance of collecting samples from the site of disease. There was, however, no significant correlation between CD8⁺ RSV-specific T cells in baseline BAL and susceptibility to infection, indicating that CD8⁺ T cells within the airway may not be a crucial contributor to preventing infection but act to limit disease severity. In addition, this study showed that even in those participants with mild infection scores there was still marked airway inflammation on bronchoscopy, which was maintained after resolution of symptoms in some cases. Interestingly, in the study by de Bree et al, where 31 healthy controls were compared to 9 chronic obstructive pulmonary disease (COPD) patients, it was found that RSV-specific CD8⁺ T cells were undetectable in the blood of the COPD patients [27].

The relative anergy of PBMCs and T cells from elderly volunteers to RSV proteins/epitopes [11, 29] may be a feature of inflammaging, associated with chronic inflammation [30]. Indeed, RSV-specific T cells have been reported to transition to a T helper 2 (Th2) phenotype with age, in addition to increasing T regulatory cell (Treg) frequencies [31]. The combination of these factors may significantly impede the antiviral immune response to RSV in elderly persons, thereby contributing to severity.

Viral Load

Human infection challenge studies have documented infection rates between 50% and 80% of volunteers exposed, with close temporal and scalar associations between measures of viral load in the upper respiratory tract and symptoms of disease [19, 28, 32–35]. Whilst these studies of healthy young adults provide unique insights into RSV pathophysiology, correlates of protection, and predictors of disease severity, the ability to extend the findings of such studies to at-risk groups remains questionable.

Studies of natural infection in adults have observed that peak nasal viral load was not significantly different between hospitalized and outpatient-managed RSV cases [20, 36]. However, the duration of viral shedding was significantly longer in hospitalized cases compared to outpatients (13.1 vs 9.8 days; P = .003) [20]. Amongst hospitalized patients, those requiring mechanical ventilation for respiratory failure had significantly higher peak viral loads; indeed, high RSV load represented an independent risk factor for respiratory failure in multivariable analyses [36, 37].

Further studies that perform detailed longitudinal quantification of RSV to define peak viral load, the kinetics of viral clearance, and progression of symptoms in at-risk adult patients are needed before the findings of RSV challenge studies can be confidently extended to these groups. However, the available data on viral load in naturally infected at-risk patients indicates that viral load is indeed a correlate of disease severity. Conducting challenge studies in at-risk groups has not yet been done. Such studies raise ethical and volunteer safety questions that require close consideration but would offer unique insights to disease pathogenesis in this population.

The Innate Inflammatory Response

In addition to the adaptive humoral and cellular immune responses, innate immune responses may protect against infection and contribute to RSV clearance; conversely, an overexuberant response may contribute to disease pathogenesis [6]. Comparing adults (≥21 years old) hospitalized with RSV infection to outpatient-managed cases, nasal levels of interleukin-6 (IL-6; OR, 2.2; CI, 1.2–4.2; P = .01) and macrophage inflammatory protein 1α (MIP-1α; OR, 9.1; CI, 0.95–87.6; P = .06) were higher in the hospitalized cohort, where increased IL-6 levels remained associated with severe disease after multivariable analysis [20]. Sputum samples from stable COPD patients, taken over a 2-year period, demonstrated that 32.8% of patients tested positive for RSV at some point during the study [38]. Interestingly, those patients from whom >50% of samples were RSV-positive (18 patients) had a faster decline in respiratory function (measured by forced expiratory volume in 1 second, FEV₁) during the study period, and elevated levels of inflammatory cytokines (IL-6, IL-8, and myeloperoxidase [MPO]) in the airway [38]. This study raises the possibility of chronic RSV infection (or greatly diminished viral clearance) in this at-risk COPD population, as previously suggested [39, 40].

DISCUSSION

This review highlights the importance of local mucosal immunity in protection against RSV disease. No study was identified that investigated BAL specimens from older adults or comorbid groups, resulting in a significant gap in our knowledge of lower airway immunity to RSV in these populations [41]. However, the probable reason for such studies not yet having been undertaken is that routine lower airway sampling is clinically challenging and bronchoscopy can be harmful to at-risk adults. Community cohort studies have been undertaken that do include frail elderly and at-risk populations. Their characteristics have been tabulated (Table 2).

Table 2.

Study Characteristics

Author, year	Prospective Study	Natural Infection	Healthy Controls/ Younger Adults Included	High-Risk/ Comorbid Adults Included	Older Adults Included
Falsey et al, 1999 [9]	Yes	Yes	Yes	Yes (nursing home-eligible but living in the community)	Yes
Cherukuri et al, 2013 [11]	Yes	No	Yes	No	Yes
Falsey and Walsh, 1998 [12]	Yes	Yes	Yes	Yes (nursing home-eligible but living in the community)	Yes
Walsh et al, 2004 [13]	Yes	Yes	Yes	Yes (underlying symptomatic cardiopulmonary conditions)	Yes
Lee et al, 2004 [14]	Yes	No	Yes	No	No
Habibi et al, 2015 [15]	Yes	No	No	No	No
Falsey et al, 1992 [18]	Yes	Yes	No	Yes (nursing home residents)	Yes
Bagga et al, 2015 [19]	Yes	No	Yes	No	No
Walsh et al, 2013 [20]	Yes	Yes	Yes	Yes	Yes
Walsh and Falsey, 2004 [22]	Yes	Yes	Yes	Yes (CHF/COPD)	Yes
Jozwik et al, 2015 [28]	Yes	No	Yes	No	No
Duncan et al, 2009 [36]	Yes	Yes	Yes	Yes	Yes
Lee et al, 2015 [37]	Yes	Yes	Yes	Yes	Yes
Wilkinson et al, 2006 [38]	Yes	Yes	No	Yes (all patients had COPD)	Yes

Author, year	Prospective Study	Natural Infection	Healthy Controls/ Younger Adults Included	High-Risk/ Comorbid Adults Included	Older Adults Included
Falsey et al, 1999 [9]	Yes	Yes	Yes	Yes (nursing home-eligible but living in the community)	Yes
Cherukuri et al, 2013 [11]	Yes	No	Yes	No	Yes
Falsey and Walsh, 1998 [12]	Yes	Yes	Yes	Yes (nursing home-eligible but living in the community)	Yes
Walsh et al, 2004 [13]	Yes	Yes	Yes	Yes (underlying symptomatic cardiopulmonary conditions)	Yes
Lee et al, 2004 [14]	Yes	No	Yes	No	No
Habibi et al, 2015 [15]	Yes	No	No	No	No
Falsey et al, 1992 [18]	Yes	Yes	No	Yes (nursing home residents)	Yes
Bagga et al, 2015 [19]	Yes	No	Yes	No	No
Walsh et al, 2013 [20]	Yes	Yes	Yes	Yes	Yes
Walsh and Falsey, 2004 [22]	Yes	Yes	Yes	Yes (CHF/COPD)	Yes
Jozwik et al, 2015 [28]	Yes	No	Yes	No	No
Duncan et al, 2009 [36]	Yes	Yes	Yes	Yes	Yes
Lee et al, 2015 [37]	Yes	Yes	Yes	Yes	Yes
Wilkinson et al, 2006 [38]	Yes	Yes	No	Yes (all patients had COPD)	Yes

Abbreviations: CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease.

Table 2.

Study Characteristics

Author, year	Prospective Study	Natural Infection	Healthy Controls/ Younger Adults Included	High-Risk/ Comorbid Adults Included	Older Adults Included
Falsey et al, 1999 [9]	Yes	Yes	Yes	Yes (nursing home-eligible but living in the community)	Yes
Cherukuri et al, 2013 [11]	Yes	No	Yes	No	Yes
Falsey and Walsh, 1998 [12]	Yes	Yes	Yes	Yes (nursing home-eligible but living in the community)	Yes
Walsh et al, 2004 [13]	Yes	Yes	Yes	Yes (underlying symptomatic cardiopulmonary conditions)	Yes
Lee et al, 2004 [14]	Yes	No	Yes	No	No
Habibi et al, 2015 [15]	Yes	No	No	No	No
Falsey et al, 1992 [18]	Yes	Yes	No	Yes (nursing home residents)	Yes
Bagga et al, 2015 [19]	Yes	No	Yes	No	No
Walsh et al, 2013 [20]	Yes	Yes	Yes	Yes	Yes
Walsh and Falsey, 2004 [22]	Yes	Yes	Yes	Yes (CHF/COPD)	Yes
Jozwik et al, 2015 [28]	Yes	No	Yes	No	No
Duncan et al, 2009 [36]	Yes	Yes	Yes	Yes	Yes
Lee et al, 2015 [37]	Yes	Yes	Yes	Yes	Yes
Wilkinson et al, 2006 [38]	Yes	Yes	No	Yes (all patients had COPD)	Yes

Author, year	Prospective Study	Natural Infection	Healthy Controls/ Younger Adults Included	High-Risk/ Comorbid Adults Included	Older Adults Included
Falsey et al, 1999 [9]	Yes	Yes	Yes	Yes (nursing home-eligible but living in the community)	Yes
Cherukuri et al, 2013 [11]	Yes	No	Yes	No	Yes
Falsey and Walsh, 1998 [12]	Yes	Yes	Yes	Yes (nursing home-eligible but living in the community)	Yes
Walsh et al, 2004 [13]	Yes	Yes	Yes	Yes (underlying symptomatic cardiopulmonary conditions)	Yes
Lee et al, 2004 [14]	Yes	No	Yes	No	No
Habibi et al, 2015 [15]	Yes	No	No	No	No
Falsey et al, 1992 [18]	Yes	Yes	No	Yes (nursing home residents)	Yes
Bagga et al, 2015 [19]	Yes	No	Yes	No	No
Walsh et al, 2013 [20]	Yes	Yes	Yes	Yes	Yes
Walsh and Falsey, 2004 [22]	Yes	Yes	Yes	Yes (CHF/COPD)	Yes
Jozwik et al, 2015 [28]	Yes	No	Yes	No	No
Duncan et al, 2009 [36]	Yes	Yes	Yes	Yes	Yes
Lee et al, 2015 [37]	Yes	Yes	Yes	Yes	Yes
Wilkinson et al, 2006 [38]	Yes	Yes	No	Yes (all patients had COPD)	Yes

Abbreviations: CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease.

There is a relative paucity of data on biomarkers that indicate severity, duration of illness, or susceptibility to symptomatic RSV infection in adults. However, existing data highlight some protective pathways for further analysis, particularly sustained high-titer anti-RSV neutralizing antibodies, RSV-specific IgA, and CD8⁺ T cells in the respiratory tract. Associations have been noted between high viral load and disease severity in natural infection and RSV challenge studies, indicating that viral load may be a correlate of disease severity. However, this association is incomplete and is influenced to some degree by preexisting immunity and underlying health. Age and comorbidities (particularly respiratory and cardiovascular) have been documented to influence the severity of an RSV infection [13], where a possible decline in cellular immunity with age may permit higher infection rates and/or severity in elderly persons (Table 3). Elevated levels of inflammatory mediators (including IL-6, IL-8, and MPO) in the airway of chronic/extended or recurrent RSV infection are associated with faster lung function decline in COPD patients. If chronic airway inflammation is present at baseline (eg, in COPD patients), then the immune and inflammatory response to RSV may be particularly debilitating but unpredictable.

Table 3.

Summary of RSV Biomarkers for Infection Severity and Susceptibility for Infection in Adults

Systemic Markers	Airway Markers
Infection severity
Low RSV neutralizing antibody titer in serum [18] (trend P = .07)	Low levels of RSV CD8⁺ T cells in BAL [28] (P = .0142, r = −0.691)
	High levels of IL-6 in airway [38] (P < .001)
	High levels of IL-8 in airway [38] (P < .001)
	High levels of MPO in airway [38] (P < .001)
	High viral load [28] (P = .003); [33] (P < .05); [34, 35] (P = .0340); [37] (P = .011)
	Viral shedding in nasal secretions for longer [20] (13.1 vs 9.8 days; P = .003)
	Low levels of IgA to RSV Ga and Gb in nasal mucosa [20] (Ga P = .003; Gb P < .0001); [34] (P = .03)
	Higher levels of nasal IL-6 [20] (OR, 2.2; CI, 1.2–4.2; P = .01) and MIP-1α (OR, 9.1; CI, .95–87.6; P = .06)
Susceptibility for infection
Low RSV neutralizing antibody titer in serum [10] (P ≤ .028); [12] (RSV A P = .008 and RSV B P = .01); [13] (P = .018); [14] (P = .04)	Low IgA to RSV F, Ga, and Gb proteins in nasal secretions [22] (r = 0.58–0.76; P = .0001)
Low IgG to F, Ga, and Gb RSV protein levels in serum [22] (r = 0.54–0.80; P = .0001); [14] (only F protein P = .02)	Low IgA to RSV in nasal mucosa [15] (P < .05); [19] (P = .292)
	Low IgA to RSV F protein in nasal mucosa [15] (P < .05)

Systemic Markers	Airway Markers
Infection severity
Low RSV neutralizing antibody titer in serum [18] (trend P = .07)	Low levels of RSV CD8⁺ T cells in BAL [28] (P = .0142, r = −0.691)
	High levels of IL-6 in airway [38] (P < .001)
	High levels of IL-8 in airway [38] (P < .001)
	High levels of MPO in airway [38] (P < .001)
	High viral load [28] (P = .003); [33] (P < .05); [34, 35] (P = .0340); [37] (P = .011)
	Viral shedding in nasal secretions for longer [20] (13.1 vs 9.8 days; P = .003)
	Low levels of IgA to RSV Ga and Gb in nasal mucosa [20] (Ga P = .003; Gb P < .0001); [34] (P = .03)
	Higher levels of nasal IL-6 [20] (OR, 2.2; CI, 1.2–4.2; P = .01) and MIP-1α (OR, 9.1; CI, .95–87.6; P = .06)
Susceptibility for infection
Low RSV neutralizing antibody titer in serum [10] (P ≤ .028); [12] (RSV A P = .008 and RSV B P = .01); [13] (P = .018); [14] (P = .04)	Low IgA to RSV F, Ga, and Gb proteins in nasal secretions [22] (r = 0.58–0.76; P = .0001)
Low IgG to F, Ga, and Gb RSV protein levels in serum [22] (r = 0.54–0.80; P = .0001); [14] (only F protein P = .02)	Low IgA to RSV in nasal mucosa [15] (P < .05); [19] (P = .292)
	Low IgA to RSV F protein in nasal mucosa [15] (P < .05)

Abbreviations: BAL, bronchoalveolar lavage; CI, confidence interval; IgG, immunoglobulin G; IL, interleukin; MIP-1α, macrophage inflammatory protein 1α; MPO, myeloperoxidase; OR, odds ratio; RSV, respiratory syncytial virus.

Table 3.

Summary of RSV Biomarkers for Infection Severity and Susceptibility for Infection in Adults

Systemic Markers	Airway Markers
Infection severity
Low RSV neutralizing antibody titer in serum [18] (trend P = .07)	Low levels of RSV CD8⁺ T cells in BAL [28] (P = .0142, r = −0.691)
	High levels of IL-6 in airway [38] (P < .001)
	High levels of IL-8 in airway [38] (P < .001)
	High levels of MPO in airway [38] (P < .001)
	High viral load [28] (P = .003); [33] (P < .05); [34, 35] (P = .0340); [37] (P = .011)
	Viral shedding in nasal secretions for longer [20] (13.1 vs 9.8 days; P = .003)
	Low levels of IgA to RSV Ga and Gb in nasal mucosa [20] (Ga P = .003; Gb P < .0001); [34] (P = .03)
	Higher levels of nasal IL-6 [20] (OR, 2.2; CI, 1.2–4.2; P = .01) and MIP-1α (OR, 9.1; CI, .95–87.6; P = .06)
Susceptibility for infection
Low RSV neutralizing antibody titer in serum [10] (P ≤ .028); [12] (RSV A P = .008 and RSV B P = .01); [13] (P = .018); [14] (P = .04)	Low IgA to RSV F, Ga, and Gb proteins in nasal secretions [22] (r = 0.58–0.76; P = .0001)
Low IgG to F, Ga, and Gb RSV protein levels in serum [22] (r = 0.54–0.80; P = .0001); [14] (only F protein P = .02)	Low IgA to RSV in nasal mucosa [15] (P < .05); [19] (P = .292)
	Low IgA to RSV F protein in nasal mucosa [15] (P < .05)

Systemic Markers	Airway Markers
Infection severity
Low RSV neutralizing antibody titer in serum [18] (trend P = .07)	Low levels of RSV CD8⁺ T cells in BAL [28] (P = .0142, r = −0.691)
	High levels of IL-6 in airway [38] (P < .001)
	High levels of IL-8 in airway [38] (P < .001)
	High levels of MPO in airway [38] (P < .001)
	High viral load [28] (P = .003); [33] (P < .05); [34, 35] (P = .0340); [37] (P = .011)
	Viral shedding in nasal secretions for longer [20] (13.1 vs 9.8 days; P = .003)
	Low levels of IgA to RSV Ga and Gb in nasal mucosa [20] (Ga P = .003; Gb P < .0001); [34] (P = .03)
	Higher levels of nasal IL-6 [20] (OR, 2.2; CI, 1.2–4.2; P = .01) and MIP-1α (OR, 9.1; CI, .95–87.6; P = .06)
Susceptibility for infection
Low RSV neutralizing antibody titer in serum [10] (P ≤ .028); [12] (RSV A P = .008 and RSV B P = .01); [13] (P = .018); [14] (P = .04)	Low IgA to RSV F, Ga, and Gb proteins in nasal secretions [22] (r = 0.58–0.76; P = .0001)
Low IgG to F, Ga, and Gb RSV protein levels in serum [22] (r = 0.54–0.80; P = .0001); [14] (only F protein P = .02)	Low IgA to RSV in nasal mucosa [15] (P < .05); [19] (P = .292)
	Low IgA to RSV F protein in nasal mucosa [15] (P < .05)

Abbreviations: BAL, bronchoalveolar lavage; CI, confidence interval; IgG, immunoglobulin G; IL, interleukin; MIP-1α, macrophage inflammatory protein 1α; MPO, myeloperoxidase; OR, odds ratio; RSV, respiratory syncytial virus.

There are limitations with this review. The initial search did not identify some articles known to the authors and was conducted in October 2016, with literature on the subject constantly being updated. We have attempted to include the relevant studies that this search missed and those that were more recently published, but some may have been omitted.

In conclusion, additional studies are needed to improve our understanding of RSV pathogenesis in specific at-risk populations, including the frail elderly and those with respiratory comorbidities. It would be of particular interest to determine the kinetics of viral clearance and the anti-RSV immune response in the upper and lower airways of such populations. Examples of some specific research questions have been tabulated (Table 4). Filling such fundamental knowledge gaps appears crucial to understanding RSV pathogenesis and the development of successful anti-RSV therapies in vulnerable adult populations.

Table 4.

Future Research Options

Limitations With Current Research	Possible Future Research Options
Challenge studies have previously been only in young healthy adults	Challenge studies in older adults and comorbid populations
Mainly upper airway studies have been performed in the observational groups	Lower airway sampling in infected adults is needed with comparison between upper and lower airway biomarkers
Virus has been found at multiple timepoints in the same patient. It is not known if this is RSV recurrence or chronic infection	Genotyping of RSV found in the same patient at multiple timepoints may confirm if infection with a new strain is occurring or if the virus is not being cleared
Viral clearance is poorly understood	Investigate which host or virologic factors influence the rate of viral clearance and disease severity, eg, the kinetics of viral clearance and antiviral immune responses
	Investigate the role of prefusion F antibodies in disease susceptibility in adults
	Investigate why is infection severe in some populations and mild in others and are the kinetics of viral clearance distinct between these groups

Limitations With Current Research	Possible Future Research Options
Challenge studies have previously been only in young healthy adults	Challenge studies in older adults and comorbid populations
Mainly upper airway studies have been performed in the observational groups	Lower airway sampling in infected adults is needed with comparison between upper and lower airway biomarkers
Virus has been found at multiple timepoints in the same patient. It is not known if this is RSV recurrence or chronic infection	Genotyping of RSV found in the same patient at multiple timepoints may confirm if infection with a new strain is occurring or if the virus is not being cleared
Viral clearance is poorly understood	Investigate which host or virologic factors influence the rate of viral clearance and disease severity, eg, the kinetics of viral clearance and antiviral immune responses
	Investigate the role of prefusion F antibodies in disease susceptibility in adults
	Investigate why is infection severe in some populations and mild in others and are the kinetics of viral clearance distinct between these groups

Table 4.

Future Research Options

Limitations With Current Research	Possible Future Research Options
Challenge studies have previously been only in young healthy adults	Challenge studies in older adults and comorbid populations
Mainly upper airway studies have been performed in the observational groups	Lower airway sampling in infected adults is needed with comparison between upper and lower airway biomarkers
Virus has been found at multiple timepoints in the same patient. It is not known if this is RSV recurrence or chronic infection	Genotyping of RSV found in the same patient at multiple timepoints may confirm if infection with a new strain is occurring or if the virus is not being cleared
Viral clearance is poorly understood	Investigate which host or virologic factors influence the rate of viral clearance and disease severity, eg, the kinetics of viral clearance and antiviral immune responses
	Investigate the role of prefusion F antibodies in disease susceptibility in adults
	Investigate why is infection severe in some populations and mild in others and are the kinetics of viral clearance distinct between these groups

Limitations With Current Research	Possible Future Research Options
Challenge studies have previously been only in young healthy adults	Challenge studies in older adults and comorbid populations
Mainly upper airway studies have been performed in the observational groups	Lower airway sampling in infected adults is needed with comparison between upper and lower airway biomarkers
Virus has been found at multiple timepoints in the same patient. It is not known if this is RSV recurrence or chronic infection	Genotyping of RSV found in the same patient at multiple timepoints may confirm if infection with a new strain is occurring or if the virus is not being cleared
Viral clearance is poorly understood	Investigate which host or virologic factors influence the rate of viral clearance and disease severity, eg, the kinetics of viral clearance and antiviral immune responses
	Investigate the role of prefusion F antibodies in disease susceptibility in adults
	Investigate why is infection severe in some populations and mild in others and are the kinetics of viral clearance distinct between these groups

Presented in part: RESCEU General Assembly Meeting, Oxford, United Kingdom, 20–22 June 2018.

Notes

RSV infection was identified definitively on a diagnostic test of a body fluid including polymerase chain reaction (PCR), viral culture, or antigen test. Severity of RSV infection was considered appropriate when authors stated their definition or used at least 1 of the following terms: lower-respiratory tract infection; admission or hospitalization due to RSV infection; moderate or severe bronchiolitis; and pneumonia or the need for respiratory support (noninvasive or mechanical ventilation). Biomarkers were defined as any traceable biological parameter/substance that was measurable. Further classification into different groups was performed in order to regroup the broad diversity of markers identified in the literature.

Notes

RESCEU Investigators. Harish Nair, Harry Campbell (University of Edinburgh); Peter Openshaw, Jadwiga Wedzicha (Imperial College London); Philippe Beutels (Universiteit Antwerpen); Louis Bont (University Medical Centre Utrecht); Andrew Pollard (University of Oxford); Eva Molero (Synapse); Federico Martinon-Torres (Servicio Galego de Saude); Terho Heikkinen (Turku University Central Hospital); Adam Meijer (National Institute for Public Health and the Environment); Thea Kølsen Fischer (Statens Serum Institut); Maarten van den Berge (Academisch Ziekenhuis Groningen); Carlo Giaquinto (Fondazione PENTA for the Treatment and Care of Children with HIV-ONLUS); Michael Abram (AstraZeneca); Bing Cai, Charles Knirsch (Pfizer); Antonio Gonzalez Lopez, Ilse Dieussaert, Nadia Dermateau, Sonia Stoszek (GlaxoSmithKline); Scott Gallichan, Alexia Kieffer, Clarisse Demont (Sanofi Pasteur); Arnaud Cheret, Sandra Gavart, Jeroen Aerssens, Veronique Wyffels, Matthias Cleenewerck (Janssen); and Robert Fuentes, Brian Rosen (Novavax).

Acknowledgment. We thank Professor Andrew Pollard at University of Oxford for his support while writing this review.

Financial support. This work was supported by the European Union Horizon 2020 Framework and the European Federation of Pharmaceutical Industries and Associations Innovative Medicines Initiative (grant number 116019 to RESCEU); and the UK National Institute for Health Research (grants to Biomedical Research Centre and Health Protection Research Unit in Respiratory Infections, Imperial College, London; and Senior Investigator award to P. O.).

Supplement sponsorship. This supplement is sponsored by RESCEU (REspiratory Syncytial Virus Consortium in EUrope).

Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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