Respiratory viruses

Epidemiology and risk factors

The seasonality of respiratory virus infections among immunocompromised children is similar to that in the community ( Fig. 21.1 ). Respiratory syncytial virus (RSV) typically circulates in the community from November through March, with peak detection in January. Human metapneumovirus follows a similar pattern although often somewhat later. Influenza epidemiology can vary somewhat from year to year, with typical seasons lasting from December to March. Influenza A tends to be more predominant early in the season and influenza B is often seen later in the season. Up-to-date influenza surveillance data for the United States are published on the Centers for Disease Control and Prevention website ( https://www.cdc.gov/flu/index.htm ), and global surveillance data are maintained by the World Health Organization ( https://www.who.int/influenza/surveillance_monitoring/updates/en/ ).

Parainfluenza viruses (PIVs) vary in seasonality by type. PIV-1 causes croup epidemics in the autumn, generally every other year. PIV-2 infections usually follow the same pattern as PIV-1 and PIV-3 outbreaks, usually occuring in the spring. PIV-3 remains the most common PIV subtype detected in both hospitalized and outpatient studies, but newer molecular epidemiology suggests that either PIV-1 or PIV-4 may be the second most common PIV detected in children, depending on the year. PIV-4 may be detected year-round. Human rhinoviruses (HRVs) and human coronaviruses (HCoVs) are present at moderate levels year-round, although there may be peaks of certain strains over the course of the year.

Exposure to sick contacts is the single most well-described risk factor for respiratory viral acquisition in immunocompromised children. Respiratory viruses are typically transmitted by respiratory secretions through direct contact, via fomites, or by large droplet spread. Entry generally occurs through contact with nasal mucosa or eyes, in contrast to the less permissive oral route. Transmission by small-particle aerosols of RSV has not been proven and, if it occurs, it is an infrequent route. Clinical observations suggest PIVs and human metapneumovirus (HMPV) are transmitted similarly to RSV. Although PIV-1 and PIV-3 have been recovered from air samples collected in the vicinity of infected patients, direct contact and transmission via fomites are likely to be more important. The high initial and subsequent infection rates, as well as outbreaks reported in hematopoietic cell transplant (HCT) recipients in both inpatient and outpatient settings, demonstrate that these viruses spread readily and that a relatively small inoculum is likely able to cause infection.

Epidemiologic patterns of respiratory viral detection in children are roughly similar among HCT recipients, solid organ transplant (SOT) recipients, and oncology patients, although risk factors for viral detection are unique.

Clinical manifestations

In healthy individuals, most respiratory viral infections are associated with self-limited upper respiratory tract symptoms. Notable exceptions include a stronger association between RSV and bronchiolitis in young infants, PIV and laryngotracheobronchitis, and HRVs and reactive airway disease exacerbations. In immunocompromised patients, respiratory viral infections can be associated with prolonged shedding, lower respiratory tract disease, the need for supplemental oxygen, late airflow obstruction, and even death. Prolonged viral shedding can be associated with persistent respiratory symptoms or can be asymptomatic with durations up to 4 weeks (mean). Persistent shedding of PIV in asymptomatic immunocompromised patients for many months has been noted using sensitive molecular detection methods, and prolonged shedding has been described for HMPV, HCoVs, and HRVs. Impairment of T-cell function appears to be commonly associated in children with prolonged shedding; additional risk factors in HCT recipients include initial high viral load, use of steroids, and myeloablative conditioning.

Initial clinical symptoms related to RSV infection in immunocompromised hosts are similar to those in immunocompetent persons. Upper respiratory tract infection may progress to lower respiratory tract disease, with likelihood of progression probably related to immune status. Over 1 to 2 weeks, lower respiratory tract involvement may become evident by increasing respiratory distress, worsening hypoxia, and potentially, the need for assisted ventilation. Children or adults who acquire RSV or HMPV during or shortly after chemotherapy for malignancy may also have severe, life-threatening disease. Recovery after assisted ventilation for RSV and HMPV pneumonia occurs but remains uncommon despite advances in supportive care. The associated respiratory failure in severely immunocompromised patients may result in multiorgan system failure, with high mortality rates in patients requiring mechanical ventilation. ^, Severe and fatal infection attributed to HMPV has been reported in cancer patients, and HMPV is a relatively common cause of acute respiratory infection in children and adults with malignancy, HCT recipients or organ transplant recipients. Risk factors for severe HMPV infection include lymphopenia. ^{, ,} Quantitative bronchoalveolar lavage (BAL) viral load has not been associated with mechanical ventilation or death for RSV, PIV, or HMPV in adult patients after HCT; however, the detection of respiratory virus RNA in serum has been associated with fatal outcomes.

PIV infection with lower respiratory tract disease in immunosuppressed patients, particularly those in the immediate posttransplantation period, may result in a similar clinical picture, although the overall mortality rate may be less than that associated with RSV. ^, Many immunocompromised adults with PIV infection first present with symptoms of mild upper respiratory tract disease, but in contrast to RSV, influenza, and HMPV, detection of PIV-1 and PIV-3 in asymptomatic HCT recipients is relatively common, reported in 6 of 17 (35%) infection episodes in a prospective study. Fewer than half of PIV-infected patients have a fever. In severely immunocompromised patients, such as allogeneic HCT recipients less than 100 days after transplant, PIV-3 is the most common PIV subtype detected, reported in 80% of 544 HCT recipients with PIV. In all PIV-infected transplant recipients, infection may progress to lower respiratory tract disease with more serious disease linked to supplemental oxygen requirement, low monocyte counts, and high-dose steroid use. The detection of PIV in BAL or other lower respiratory tract specimens is associated with decreased survival overall in HCT recipients. Higher pretransplant PIV-3 antibody levels were not protective against severe sequelae. Concomitant infections with other viruses, fungi, or severe graft-versus-host disease are relatively common in adult patients with PIV pneumonitis.

Influenza remains a significant cause of morbidity and mortality in immunocompromised children and adults. In a recent multicenter review of immunocompromised children hospitalized with influenza, immunocompromised children were more likely to present with fever and less likely to present with respiratory distress. They were also less likely to require intensive care but were hospitalized longer. In a study of adult and pediatric HCT and SOT recipients, 22.1% of subjects presented with pneumonia and 66.5% were hospitalized. Prior vaccination was associated with decreased disease severity. Mortality after influenza was 2.9% in adults and 0% in pediatric patients in this study, although higher mortality rates have been previously reported.

With the increased use of molecular diagnostic assays, HRVs and HCoVs are now the most common respiratory viruses detected in immunocompromised patients. HRV can be detected in 20% to 30% of HCT recipients, with progression to lower respiratory tract infection occurring in 17% of patients. ^, Once HRV progresses, mortality rates can be similar to other respiratory viruses, including influenza, PIV, and RSV. In addition to HRVs, other members of the Enterovirus genus, including Enterovirus-D68, can be associated with outbreaks and severe disease. Enterovirus D68 was associated with several hundred cases of severe respiratory illnesses in children in the United States in 2014 and 2018; severe disease was also seen in immunocompromised patients. HCoVs can also be associated with severe disease in the lower respiratory tract and can result in death. Specific considerations for HCT, SOT, and oncology patients are outlined in the following text.

Disease prophylaxis/prevention