The Burden of Respiratory Syncytial Virus Infection in Adults and Reproductive-Aged Women

Why Characterize Disease Burden in a Non-Pediatric Population?

Although RSV vaccine discussion has focused on childhood infection, for several reasons, it may be important to better understand and characterize RSV disease burden in women of childbearing age. First, RSV disease is increasingly recognized as a significant contributor to adult respiratory illnesses worldwide.⁵ Although pregnant women may receive an RSV vaccine to protect her child, other more direct benefits to the mother may be realized. Pregnancy is considered an immunologically attenuated state, and RSV infection during pregnancy is associated with more severe disease and adverse outcomes (e.g., fever, respiratory distress, preterm labor, hospitalization).⁶ As a result, an RSV vaccine could improve maternal as well as infant outcomes and should be considered as part of cost/benefit analyses when planning vaccine introduction. Second, family members, including the mother, may be the source for neonate exposure to RSV; therefore, disease prevalence and modulation of that prevalence in an adult population is germane to this discussion. Third, recent data suggest the possibility of vertical RSV transmission during the prenatal period. When vertical transmission is induced in animal models, specific long-lasting alterations in immunologic and pulmonary functions have been demonstrated in the offspring of mothers acquiring the infection prenatally. Last, the degree of disease burden in adults may influence the timing of RSV vaccination, in that, if the burden is deemed low, the vaccine may be intentionally delayed to later in the third trimester to optimize antibody transfer and newborn protection.

To better understand and characterize RSV disease burden in adults, women of childbearing age, and pregnant women, we performed a literature search using English-language articles identified in the PubMed and Google Scholar databases, with additional resources identified by extraction from references within those documents. Keywords or phrases searched, used separately or in combination were: respiratory syncytial virus, RSV, epidemiology, adult respiratory disease, and pregnancy.

RSV Biology

Human RSV is a member of the Paramyxoviridae family. It is a single stranded RNA virus that has 10 genes encoding 11 proteins. Two of these proteins, F and G, are particularly important for virus attachment and syncytia formation on target host cells. These 2 surface proteins are also the primary target antigens currently being investigated for both active and passive host immunologic protection. RSV is a virus that causes respiratory tract infections with a wide clinical spectrum. Outbreaks of RSV infections occur between fall and spring in temperate climates and tend to last up to 5 months. RSV isolates can be divided into 2 groups: group A and group B, based on antigenic and genetic characteristics. These 2 groups coexist in the human population, with group A being more prevalent. Most studies have not found significant clinical differences between both subtypes.⁷

Complications of RSV Infection in Adults

The majority of RSV cases in the adult population are presumed to represent reinfection with this pathogen because primary acquisition in childhood is so common. Although most cases manifest clinically as mild to moderate upper respiratory disease, more severe complications have been recognized to occur. A prospective study in the United States of hospitalized adults with acute respiratory infections during the influenza season showed an RSV PCR prevalence rate of 8.7% in adults 50–64 years old.¹³ Most of these individuals had at least 2 preexisting chronic comorbidities (e.g., congestive heart failure, chronic obstructive pulmonary disease, obesity) identified. In a multi-institutional study in France that examined adults hospitalized with influenza-like illness, 4% were RSV-positive by multiplex reverse transcription-PCR.¹⁴ Although the majority of these subjects were elderly, making it difficult to compare to a reproductive-age population, there was a 57% complication rate.¹⁴ Pneumonia was identified in 44%, ICU admission was required for 15%, and the in-hospital case fatality rate was 8%. Luchsinger et al. studied 356 Chilean adults with community-acquired pneumonia and found an RSV prevalence of 13.4% by multiple detection methods including serology.¹⁵ In 2 reviews of RSV disease and its complications in adults, experts noted that RSV accounts for between 2%–5% of adult pneumonia cases annually with an increase to 5%–15% of cases during the RSV season.^6,16 In the United States, it is estimated that between 11,000–17,000 adults die of RSV-related infection annually with 10-fold more admitted to the hospital with respiratory compromise. Han et al. reported the annual economic burden in the United States of adult inpatient care related to RSV approximated $150–680 million, with actual health care cost being much higher if non-pneumonia and outpatient cases were included in this calculation.¹⁷ There are no similar cost estimates for other developed or low- to middle-income countries, but this will be an important consideration when planning for future interventions such as the introduction of RSV vaccines.

RSV in Reproductive-Aged Women and Pregnancy

Even fewer data on RSV are available in women of childbearing age or related to pregnancy.^18–24 In 2 different phase-2 clinical trials in healthy women 18–35 years old that looked at the potential for RSV vaccine use in reproductive-aged women, investigators reported a 10%–15% Western blot RSV positivity rate at baseline, likely representing previous or recent exposures.^18,19 Interestingly, in both of these vaccine trials, which spanned 2 RSV transmission seasons, there was Western blot evidence of new RSV infection in 21% and 22%, respectively, in the placebo-arm study participants, unrelated to clinical symptomatology. In a study focused on influenza in rural Nepal, Chu et al. found a 2% RSV PCR positivity rate in pregnant or recently postpartum women with fever and acute respiratory symptoms.²⁰ Similarly, Chaw et al., in another prospective observational study of symptomatic pregnant women in Mongolia during the influenza season, noted a 2.4% RSV positive rate using a point-of-care immunoassay test.²¹ Both of these latter 2 studies were limited by a primary focus on influenza-related symptoms, missed testing times, and other study design issues. In conjunction with a prospective maternal influenza vaccine trial, Madhi et al. retrospectively studied the incidence of RSV positivity by PCRin HIV-negative and HIV-positive South African gravidas and postpartum women.²² Women presenting with respiratory illness from mid-pregnancy until 24 weeks postpartum underwent oral/nasal/pharyngeal swab sampling. The incidence of RSV associated illness (cases per 1000 person-months) during pregnancy in 2011 was 1.7 and 6.6 for HIV-negative and HIV-positive women, respectively. The incidence postpartum was identical for these 2 study populations at 2.3. The authors made additional observations, including the fact that RSV infection during pregnancy did not appear to be associated with any adverse pregnancy outcomes compared to the non-RSV infected groups. They expressed that their study likely underestimated the overall prevalence of RSV due to the focus on influenza-related disease, the variable incidence over RSV seasons (they noted the incidence in pregnancy in 2012 was 5.3 for HIV-negative pregnant women), and the fact that most RSV cases were identified during unsolicited medically attended visits which likely missed cases of milder disease. Hause et al. performed an outpatient, cross-sectional, surveillance study in pregnant women in their second and third trimesters in Houston, Texas. Of 81 subjects who presented with acute respiratory illness symptoms during the RSV season, 10% were identified to have RSV using tandem competitive-PCR.²³

Regarding pregnancy complications associated with RSV infection, and despite the observations mentioned by Madhi et al.²² in the study by Chu et al.,²⁰ of 7 patients with acute respiratory symptoms, fever, and RSV positivity, 2 (29%) experienced preterm birth. Given the very small numbers, statistical analysis comparing these subjects to the non-RSV infected study population (preterm birth rate 13%) was not possible. In a recent U.S. tertiary care center case report series, Wheeler et al. reported on 3 cases of symptomatic RSV infection during the antepartum period, with 2 of these patients requiring hospitalization and intubation for respiratory failure.⁶ Both of these patients had other comorbidities including smoking and preexisting asthma.

In an international study examining RSV infection in pregnant women from high-income countries who were hospitalized, 48% were severe enough to require prolonged hospitalization and 38% were subsequently diagnosed to have pneumonia. The majority of these RSV cases were detected in the third trimester, and one-third had a preexisting health condition, most commonly asthma. Among women who did not deliver during that admission, there was a 29% preterm birth rate.²⁴ Limitations to this study, as is the case with most other studies on this topic, were the small number of patients sampled for RSV, a restriction to hospitalized patients only, and a study design that focused on influenza in pregnancy.

Although tangential in nature, data on influenza in pregnancy, another common viral pathogen, show that pregnant women are 7 times more likely to be hospitalized and 2 times more likely to die compared to non-pregnant women of reproductive age.²⁵ Lastly, and also tangential, pregnant women with pneumonia due to various pathogens, have an increased risk for several adverse pregnancy outcomes, including low birth weight, preterm birth and cesarean delivery.²⁶ As RSV continues to be investigated in this patient population, these types of adverse events need to be carefully monitored.

A novel concern is the concept of vertical transmission of RSV. Using a rodent model, investigators have recently reported evidence of RSV vertical transmission from mother to fetus, with persistence of infection in the offspring after birth.^27,28 These exposed and infected newborn pups showed evidence of prolonged altered viral immunity, dysregulation of neurotrophic pathways, and, most importantly, airway hyper-reactivity with RSV reinfection. Using human specimens, Fonceca and colleagues recently reported rescue of infectious RSV from cord blood mononuclear cells in 26 of 45 (57.7%) samples, with increases in recovery during winter months.²⁹ These findings await confirmation, but suggest another avenue of RSV pathogenesis that might be interrupted by preventing maternal disease via vaccination.