Community-Acquired Respiratory Viruses in Transplant Patients: Diversity, Impact, Unmet Clinical Needs

Abstract

Patients undergoing solid-organ transplantation (SOT) or allogeneic hematopoietic cell transplantation (HCT) are at increased risk for infectious complications. Community-acquired respiratory viruses (CARVs) pose a particular challenge due to the frequent exposure pre-, peri-, and posttransplantation. Although influenza A and B viruses have a top priority regarding prevention and treatment, recent molecular diagnostic tests detecting an array of other CARVs in real time have dramatically expanded our knowledge about the epidemiology, diversity, and impact of CARV infections in the general population and in allogeneic HCT and SOT patients. These data have demonstrated that non-influenza CARVs independently contribute to morbidity and mortality of transplant patients. However, effective vaccination and antiviral treatment is only emerging for non-influenza CARVs, placing emphasis on infection control and supportive measures. Here, we review the current knowledge about CARVs in SOT and allogeneic HCT patients to better define the magnitude of this unmet clinical need and to discuss some of the lessons learned from human influenza virus, respiratory syncytial virus, parainfluenzavirus, rhinovirus, coronavirus, adenovirus, and bocavirus regarding diagnosis, prevention, and treatment.

Keywords: bone marrow transplantation; diagnosis; respiratory viruses; solid-organ transplantation; treatment; vaccination.

FIG 1

CARV epidemiology over 5 years in symptomatic children and adults attending a tertiary care center, adapted from reference . HAdV, human adenoviruses; HCoV, human coronavirus (-229E, -OC43, -NL63, and -HKU1); IV-A, influenza virus A; IV-B, influenzavirus B; HMPV, human metapneumovirus; HPIV, human parainfluenzavirus (1 to 4); HRSV, human respiratory syncytial virus (A/B); HRV, human rhinovirus; M.pne, Mycoplasma pneumoniae (for comparison).

FIG 2

Timetable of infectious disease events after allogeneic hematopoietic cell transplantation and solid-organ transplantation. BKPyV, BK polyomavirus; C. difficile, Clostridium difficile; CARV, community-acquired respiratory viruses; CMV, cytomegalovirus; EBV, Epstein-Barr virus; G+, Gram-positive; G−, Gram negative; HAdV, human adenovirus; HBV, hepatitis B virus; HCV, hepatitis C virus; HEV, hepatitis E virus; HHV-6, human herpesvirus-6; HSV, herpes simplex virus; JCPyV, JC polyomavirus; PTLD, posttransplant lymphoproliferative disorder.

FIG 3

Schematic illustration of community-acquired respiratory virus infection and pathogenesis in immunocompetent and immunocompromised patients posttransplant in the allogeneic constellation of lung transplantation and hematopoietic cell transplantation. (Top) Infections with CARVs causing mostly upper- and lower-respiratory-tract infectious disease (RTID) and following lower RTID progression to chronic allograft disease/dysfunction (CLAD) in the allogeneic setting of lung or hematopoietic cell transplantation. (Bottom, left) Relative level and intensity of direct viral cytopathology in the respiratory tract, of the inflammation caused by the innate and adaptive immune response, and of the bacterial superinfection in a patient with no or moderate immunodeficiency. (Bottom, right) The same parameters for allogeneic HCT or lung transplant patients with severe immunodeficiency but including an alloimmune response (rejection), an increased risk of bacterial and fungal superinfection, and progression to bronchiolitis obliterans syndrome (BOS) and CLAD.

FIG 4

Influenza A viral loads and disease outcomes. (A) Viral loads were significantly higher in patients with lower RTID (pneumonia) than in patients with upper RTID both at presentation (day 0) and over the time of follow-up. (B) Viral loads were significantly higher in patients admitted to intensive care units (ICU) versus patients not admitted to ICU at diagnosis (day 0) and over the time of follow-up. (C) Viral loads were significantly lower at presentation in patients who had received influenza vaccine in the same season that infection occurred. (Reproduced from reference with permission of the Infectious Diseases Society of America.)

FIG 5

Immunodeficiency and probability of survival in allogeneic HCT patients presenting with lower RTID caused by human respiratory syncytial virus. Immunodeficiency scoring index (left) and immunodeficiency grading (right) were calculated as indicated in Table 2 for 85 allogeneic HCT recipients diagnosed with HRSV lower RTID and compared for mortality. High-risk individuals, as identified by a high immunodeficiency scoring index (left, score of 7 to 12; red line), had a higher risk for mortality than those having a moderate index (left, score of 3 to 6; green line) or low index (left, score of 0 to 2; blue line) (OR, 10.5; 95% CI, 1.9 to 56.6; P = 0.01). Similarly, individuals with very severe immunodeficiency (right, 2 to 7 criteria; red line) had a higher risk for mortality than those with moderate immunodeficiency (right, 1 criterion, green line) or moderate risk (right, 0 criteria; blue line) (OR, 11.1; 95% CI, 2.8 to 45.1; P < 0.001). Both grading approaches predicted time to mortality, as demonstrated by Kaplan-Meier survival curves. (Reproduced from reference with permission of John Wiley and Sons.)