Research Article: In Vivo Persistence of Human Rhinoviruses in Immunosuppressed Patients

Date Published: February 2, 2017

Publisher: Public Library of Science

Author(s): Ilka Engelmann, Anny Dewilde, Mouna Lazrek, Mathilde Batteux, Aminati Hamissi, Ibrahim Yakoub-Agha, Didier Hober, Dong-Yan Jin.


Several species of the genus Enterovirus cause persistent infections in humans. Human rhinovirus (HRV) infections are generally self-limiting but occasionally persistent infections have been described. This study aimed to identify persistent HRV infections and investigate the clinical and virologic characteristics of patients with persistent infections. From January 2012 to March 2015, 3714 respiratory specimens from 2608 patients were tested for respiratory viruses by using a multiplex reverse transcription–polymerase chain reaction. A retrospective study was performed. Patients with at least two specimens positive for HRV/enterovirus taken 45 days or longer apart were identified and the HRV/enteroviruses were typed. Patients with persistent infection were compared to patients with reinfection and patients with cleared infection. Phylogenetic analysis of the viral protein(VP)4/VP2 region was performed. 18 patients with persistent HRV/enterovirus infection were identified. Minimum median duration of persistence was 92 days (range 50–455 days). All but one patients with persistence were immunosuppressed. Immunosuppression and hematologic disorders were more frequent in patients with persistence (n = 18) than in patients with reinfection (n = 33) and with cleared infection (n = 25) (p = 0.003 and p = 0.001, respectively). In conclusion, this retrospective study identified HRV persistence in vivo which occurred mainly in immunosuppressed patients.

Partial Text

Human rhinoviruses (HRV) are classified into three species (A, B and C) within the genus Enterovirus of the family Picornaviridae [1,2]. HRVs mainly cause upper respiratory tract infections. However, they can also cause lower respiratory infection and are associated with exacerbations of chronic pulmonary diseases [3], such as asthma [4], chronic obstructive pulmonary disease [5] and cystic fibrosis [2,6].

565 patients had two or more specimens tested (Fig 1). Of these, 111 patients had 2 or more specimens that were tested positive for HRV/enterovirus (HRV++), 74 patients had a specimen that tested positive for HRV/enterovirus followed by a specimen that tested negative for HRV/enterovirus (HRV+-), 46 patients had a specimen that tested negative for HRV/enterovirus followed by a specimen that tested positive for HRV/enterovirus (HRV-+) and in 334 patients all specimens were tested negative for HRV/enterovirus (HRV–) (Fig 1). The details of the distribution of these patient groups with regard to the total number of specimens tested per patient is shown in S2 Table. Of the 111 patients that had 2 or more specimens that tested positive for HRV/enterovirus (HRV++), 55 patients had repeated detection of HRV/enterovirus in respiratory specimens taken at least 45 days apart. Specimens of 52 patients were available for typing. Typing was successful in 137 of 139 (98.6%) specimens from 52 patients. Of these, 77 were HRV-A (56.2%), 28 were HRV-B (20.4%), 30 were HRV-C (21.9%) and 2 were Coxsackievirus A21 (1.5%). One patient, in whom the second specimen was untypeable, was excluded from further analysis. Phylogenetic analysis of the VP4/VP2 region of the 136 HRV/enterovirus positive specimens of the other 51 patients is shown in Fig 2.

In the present study, we have systematically searched for HRV/enterovirus persistence and identified 18 patients with persistent HRV/enterovirus infection. To our knowledge, this is the largest case series of persistent HRV/enterovirus infections so far published. Most patients in this study were hospitalized (54/76, 71.1%) and immunosuppression was frequent (47/76, 61.8%). All but one patients with persistent infection were immunosuppressed, and immunosuppression was associated with HRV/enterovirus persistence (p = 0.003, Table 1). The only patient with persistent infection who was not immunosuppressed suffered from cystic fibrosis. To our knowledge there is only one other report of HRV persistence in a cystic fibrosis patient, namely a HRV-A infection in a 43 year-old-patient [28]. In contrast, our patient had an infection with HRV-B69. Hematologic disorders were the underlying condition in most patients with HRV/enterovirus persistence and statistically associated with persistence (p = 0.001, Table 1). Interestingly, a recent study found HRV persistence in 8 paediatric hematopoietic stem cell transplant recipients [29]. In our study, 10 of the 18 patients (55.6%) with persistent infection were stem cell transplant recipients, 1 child and 9 adults. This population of highly immunosuppressed patients seems to be predisposed for HRV/enterovirus persistence. The minimum median duration of HRV/enterovirus persistence in our patients was 92 days, ranging from 50 to 455 days. To our knowledge, a longer duration of persistence has so far only been described twice [23,28].




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