Published ahead of print on September 28, 2006, doi:10.1164/rccm.200604-489OC
© 2006 American Thoracic Society doi: 10.1164/rccm.200604-489OC
Chronic Rhinoviral Infection in Lung Transplant RecipientsCentral Laboratory of Virology, Division of Infectious Diseases, Department of Internal Medicine; Department of Pathology; Division of Pulmonary Medicine, Department of Internal Medicine; Clinic of Thoracic Surgery, Department of Surgery, University Hospitals of Geneva, Geneva; Division of Pulmonary Medicine, Department of Medicine; Institute of Microbiology and Division of Infectious Diseases, Department of Pathology, University Hospital of Lausanne, Lausanne; and Division of Pulmonary Medicine, University Hospital, Bern, Switzerland Correspondence and requests for reprints should be addressed to Laurent Kaiser, M.D., Central Laboratory of Virology, Division of Infectious Diseases, University Hospitals of Geneva, Rue Micheli-du-Crest 24, 1211 Geneva 14, Switzerland. E-mail: laurent.kaiser{at}hcuge.ch
Rationale: Lung transplant recipients are particularly at risk of complications from rhinovirus, the most frequent respiratory virus circulating in the community. Objectives: To determine whether lung transplant recipients can be chronically infected by rhinovirus and the potential clinical impact. Methods: We first identified an index case, in which rhinovirus was isolated repeatedly, and conducted detailed molecular analysis to determine whether this was related to a unique strain or to re-infection episodes. Transbronchial biopsies were used to assess the presence of rhinovirus in the lung parenchyma. The incidence of chronic rhinoviral infections and potential clinical impact was assessed prospectively in a cohort of 68 lung transplant recipients during 19 mo by screening of bronchoalveolar lavages. Measurements and Main Results: We describe 3 lung transplant recipients with graft dysfunctions in whom rhinovirus was identified by reverse transcriptase–polymerase chain reaction in upper and lower respiratory specimens over a 12-mo period. In two cases, rhinovirus was repeatedly isolated in culture. The persistence of a unique strain in each case was confirmed by sequence analysis of the 5'NCR and VP1 gene. In the index case, rhinovirus was detected in the lower respiratory parenchyma. In the cohort of lung transplant recipients, rhinoviral infections were documented in bronchoalveolar lavage specimens of 10 recipients, and 2 presented with a persistent infection. Conclusions: Rhinoviral infection can be persistent in lung transplant recipients with graft dysfunction, and the virus can be detected in the lung parenchyma. Given the potential clinical impact, chronic rhinoviral infection needs to be considered in lung transplant recipients.
Key Words: lung transplantation • picornavirus • respiratory virus • rhinovirus • VP1
Human rhinovirus (HRV) is the leading cause of respiratory tract infections and, on average, adults experience one proven rhinoviral infection each year, whereas, in children, it is a more frequent occurrence (1, 2). Consequently, exposure to rhinovirus for persons living in the community is much more frequent than to many other respiratory viruses, and it is probably the most common cause of self-limited upper respiratory diseases. However, the spectrum of its impact in hospitalized patients or those at risk of complications from viral respiratory infections needs to be established. In immunocompetent subjects, rhinovirus clearance is rapid and viral shedding limited to 10 d, on average. In contrast, viral clearance is delayed in subjects with an impaired immune system, and prolonged shedding might occur after the acute phase of any viral infection (3). Although protracted infection for weeks and even months has been well documented after parainfluenza, respiratory syncytial virus, or influenza illnesses (4–6), this has not been established for rhinovirus. In daily clinical practice, rhinovirus is generally not considered, and routinely used virologic investigations are insensitive (7). To bridge the gap between the limited sensitivity of diagnostic tools and the lack of knowledge on the potential impact of this virus in groups of patients at risk of complications, sensitive molecular tools need to be used in large prospective studies. This need is supported by evidence demonstrating that rhinoviral disease is not exclusively limited to the upper respiratory tract, and can also lead to lower respiratory complications (8–14). Immunocompromised hosts might have a higher risk of developing such complications. It has also been shown recently that asthma patients have a relative immunosuppression, characterized by impaired T-helper cell type 1 and interferon responses that are likely to promote rhinoviral infections in vivo (15–17) and subsequent asthma exacerbations. Given the frequency of rhinoviral infections, and the increasing number of transplant recipients living in the community, there is a need to investigate potential complications associated with these infections. Compared with other organ transplant patients, lung transplant recipients are potentially at higher risk of complications, as the transplanted organ itself is directly exposed to rhinovirus. After the observation of a lung transplant recipient in whom rhinovirus was isolated repeatedly over several weeks, we first confirmed that this patient was chronically infected with a single isolate. We then assessed prospectively the incidence of chronic rhinoviral infections and its potential clinical impact in a cohort of lung transplant recipients.
Patients The index case that prompted the present study was identified by routine investigations in our clinical laboratory. To identify additional cases, we used a prospective study to assess the impact of respiratory viruses in lung transplant recipients. In this ongoing study conducted in our two centers, all lung transplant recipients who underwent a bronchoalveolar lavage (BAL) procedure (for routine surveillance, follow-up after rejection, abnormal pulmonary function tests, suspicion of opportunistic infection, nonresponse to wide-spectrum antibiotics, unexplained lower respiratory tract symptoms, or new chest X-ray infiltrate) were screened for the presence of 13 different respiratory viruses by reverse transcription–polymerase chain (RT-PCR) reaction, and for three atypical bacteria, as described previously (18). At the time of the present study, 68 lung transplant recipients, followed by the Geneva–Lausanne transplantation centers from November 2003 to September 2005, were included in the study. The ethics committees of the University Hospitals of Geneva and Lausanne approved the study, and signed informed consent was required for all participants. Real-time qualitative RT-PCR assays used for rhinovirus detection targeted the 5' noncoding region (5'NCR) and were performed using the forward primer 5'-GCA CTT CTG TTT CCC C-3', reverse primer 5'-GGC AGC CAC GCA GGC T-3', and the two probes, 5'-FAM-AGC CTC ATC TGC CAG GTC TA-TAMRA-3' and 5'-VIC-AGC CTC ATC GAC CAA ACT A-TAMRA-3', under conditions described previously (7). All the different steps of the extraction and reverse transcription were conducted in parallel with known positive supernatants of HRV2-infected cells and negative controls. RT-PCR assays for influenza A and B, parainfluenza 1–3, respiratory syncytial virus A and B, enterovirus, human metapneumovirus, coronavirus OC43, 229E, and NL63 were performed as described previously (18). In the present study, all the assays were used as qualitative tools. Cell culture and inhibition assays are described in METHODS in the online supplement. On isolates selected for sequencing, we first sequenced a portion of the 5'NCR region (180 bp) followed by the VP1 surface glycoprotein (800 bp). The 5'NCR is the most conserved region of picornavirus, and the VP1 surface protein contains the receptor-binding site and is the main target of the humoral response against rhinoviruses. The 5'NCR analysis was performed as previously described with minor modifications (7). We adapted the methods described by Ledford and colleagues (19) for the VP1 sequence, taking into account the large genotypic variability of rhinoviruses and the fact that clinical strains are of unknown serotype (see METHODS in the online supplement for details). Sequence alignment was performed with ClustalW version 1.81 and phylogenetic analyses were performed with the Phylip package (20, 21). When clinically indicated, transbronchial biopsies were performed to exclude acute rejection. The procedure and tissue examination were performed according to the International Society for Heart and Lung Transplantation guidelines (22). Two senior pathologists, blinded to any viral RT-PCR results, reviewed the biopsy slides and established a consensus diagnosis. Immunohistochemistry for rhinovirus detection was performed on 3–5 µm tissue sections mounted on silane-coated glass slides. The primary antibodies (anti-human rhinovirus 64 antisera, ATCC VR 1174 AS/GP; LGC Promochem, Molsheim, France) and secondary antibodies (rabbit anti-guinea pig immunoglobulins/HRP no. PO14102-2; DakoCytomation AG, Baar, Switzerland) were used at 1:500 and 1:100 dilution, respectively. An irrelevant, nonimmune guinea pig serum (G9774) diluted to 1:500 was used as a negative control on the lung biopsy that was then revealed by the same secondary antibody.
Index Case Description A 57-yr-old male underwent unilateral lung transplantation for emphysema, with a post-transplantation clinical course mostly marked by repeated respiratory infectious episodes. Under an immunosuppressive regimen of tacrolimus, mycophenolate mofetil, and prednisone, he did not present any acute or chronic rejection. Seven years after transplantation (in January 2001), he developed both upper and lower respiratory tract symptoms, characterized by persistent rhinorrhea, cough, and dyspnea, which prompted iterative respiratory sample collection for viral analysis. His FEV1 dropped from 1.06 to 0.8 L within a period of 5 mo (19% decrease). The first nasopharyngeal sample collected at the onset of symptoms yielded rhinovirus by cell culture. During the following 5 mo, six of eight different nasopharyngeal specimens were observed to be positive by cell culture, despite a 10-d course of oral pleconaril (23). No other respiratory pathogen was identified; screening for atypical bacteria and other respiratory viruses was negative, and multiple antibiotic courses failed to improve his condition. Graft dysfunction and terminal respiratory failure developed, and retransplantation was performed. The postoperative course was marked by persistent respiratory symptoms and bilateral chest X-ray infiltrates, followed by respiratory failure. Pseudomonas aeruginosa pneumonia and pulmonary tuberculosis developed, and were both successfully treated. Nevertheless, the patient's general condition, as well as graft function, declined, and he died 13 mo after the first rhinovirus isolation. During the 6 mo after retransplantation, 12 BAL specimens obtained from the retransplanted lung were available. Among these, 5 were positive for rhinovirus by cell culture, and of the 10 tested by RT-PCR, all but 1 were positive for rhinovirus. A total of 8 of these 12 BAL specimens were also tested by RT-PCR for the presence of 12 different respiratory viruses. All were negative except the last one, which was coinfected with coronavirus 229E. Nine nasopharyngeal specimens were also cultured, and six were positive. Four were also tested by RT-PCR, and all were positive. Only one set of lung biopsies was performed (six fragments containing pulmonary parenchyma without bronchioles) that revealed lung fibrosis and slight inflammatory changes, but with no sign of perivascular lymphocytic inflammation, rejection, or any other specific histologic tissue modifications. In this case, we investigated the presence of rhinovirus on the lung biopsy, using antibodies specifically adapted to the infecting strain after validation on infected HeLa cells (Figure 1). Rhinovirus-positive cells were clearly detected in the parenchyma, as shown in Figure 2.
Virologic Investigations of the Index Case In our index case, rhinovirus was identified either by cell culture and/or by RT-PCR on 18 of 21 upper or lower respiratory specimens sampled during a 1-yr period. We sequenced both the VP1 capsid glycoprotein and a portion of the 5'NCR region of six isolates spanning a period of 11 mo. Sequencing of the 5'NCR revealed only one nucleotide change. Phylogenetic analysis of the VP1 region revealed a very low genetic distance among the six clinical isolates, and showed that these isolates clustered with reference sequences of serotypes 64 and 94 (Figure 3). Very few nucleotide changes were observed over time, and ranged from 5 to 13 nucleotides (0.6–2.3%) and from 2 to 6 (0.8–2.3%) at the amino acid level. To indirectly validate this analysis, we also analyzed the VP1 sequence of two clinical isolates of other patients that clustered closely to the present isolate based on the 5'NCR region (data not shown). The VP1 showed differences ranging from 17.2 to 30.1% at the nucleotide level and from 10.6 to 27.2% at the amino acid level. All these data prove that the patient was infected during the entire study period by the same founder isolate, and was not reinfected by different strains (19).
To assess the presence of neutralizing antibodies in the patient's serum, we tested three isolates (collected at the beginning, middle, and end of the 11-mo follow-up) in the presence of two of the patients' sera collected after 20 and 26 wk of persistent rhinoviral infection. Although these isolates were not neutralized by the patients' sera, they were completely inhibited by antisera directed against rhinoviruses 64 and 94, and only weakly inhibited by the antisera against rhinovirus 22 (the next-closest serotype). This demonstrated that the rhinoviral strain of the patient was serologically closely related to the serotypes 64 and 94, as suggested by our genotypic analysis.
Prospective Study
Case 2 A 57-yr-old man received bilateral sequential lung transplantation for end-stage emphysema and lung fibrosis induced by methotrexate. Immunosuppression consisted of cyclosporine A, mycophenolate mofetil, and prednisone. The first months after transplantation were uneventful. He then experienced a mild but persistent cough and dyspnea, which prompted a BAL procedure that was positive for rhinoviral RNA but remained negative for all other pathogens. Transbronchial biopsies revealed A1B2 rejection (22). At 8 mo after transplantation, he was hospitalized for a severe interstitial pneumonia that necessitated mechanical ventilation for 24 h. At this time, cultures from the BAL fluid obtained in a routine laboratory eventually grew positive for picornavirus and remained negative for any other typical or atypical bacteria. Broad-spectrum antibiotics were prescribed, and the patient recovered slowly, with lung function returning to previous levels in about 8 wk; mild dyspnea (New York Heart Association II) persisted. At 12 mo after transplantation, an acute A3 rejection was sequentially treated with pulses of methylprednisolone, antilymphocytic immunoglobulins, intravenous immunoglobulins, and alemtuzumab. Despite a subsequent profound lymphocytic depression that lasted 6 mo, transbronchial biopsies revealed a persistent A2 rejection pattern. The graft function and the patient's respiratory condition gradually worsened [bronchiolitis obliterans syndrome (BOS) stage III], and he died of respiratory failure 24 mo after transplantation. A total of 6 of 10 BAL and 4 of 8 nasopharyngeal specimens collected during the 15 mo after the first episode of lower respiratory symptoms were positive for rhinovirus, as determined by RT-PCR. All these samples were also tested by RT-PCR for the presence of 12 other respiratory viruses, and were negative. Reinoculation on HeLa cells of the initial samples collected at 7 mo of follow-up isolated rhinovirus, a finding that was confirmed by specific PCR and sequencing on the cell supernatant. A portion of the 5'NCR and the VP1 of the baseline isolate, and those collected 7 and 12 mo later, were then sequenced. Nucleotide changes between these three VP1 sequences ranged between 0.6 and 1% at the nucleotide level and between 1.2 and 1.8% at the amino acid level. Of note, the VP1 was very close to serotype 27, and harbored a phenylanaline at position 152, a genotype naturally resistant to pleconaril (19). During the follow-up period, this patient had 10 transbronchial biopsies that showed histologic signs of acute rejection, graded A0 in two biopsies, A1 in one, A2 in two, A3 in three, A4 in two, and lymphocytic bronchiolitis, graded B1 in two, B2 in two, and B3 in one (Bx in three). The tissue fragments (3.7, on average, per bronchoscopy) contained bronchi and/or bronchioles, as well as parenchyma in most of them. The histologic changes did not differ from the usual modifications that define cellular rejection, but in one biopsy with A4 rejection, a strong tissue eosinophilia was present. In four biopsies, the bronchial columnar mucosa was replaced by squamous metaplasia with hyperplasia of the mucinous cells.
Case 3 After hospital discharge, the patient complained of shortness of breath, dry cough, and clear rhinitis. FEV1 dropped from 2.1 L (96% of predicted value) to 1.91 L (10% decrease), whereas blood panel, chest X-ray, and BAL cultures were noncontributive. Under a treatment of wide-spectrum antibiotics, respiratory symptoms resolved, and FEV1 rose to 2.38 L, but rhinitis persisted. At 6 mo after transplantation, dyspnea reappeared, accompanied by productive cough, and FEV1 dropped back to 1.98 L (17% decrease). BAL cultures were positive for Stenotrophomonas maltophila and Penicillium spp., both considered as contaminants, and biopsies revealed A3 rejection requiring a 3-d course of methylprednisolone. Within 2 wk, the FEV1 rose back to 2.5 L. However, control transbronchial biopsies showed persistent A3 rejection treated with antithymoglobulin. At 11 mo after transplantation, the patient was hospitalized for an acute episode of pericarditis, together with productive cough, rhinitis, and fever. The chest X-ray was noncontributive, blood and BAL cultures were negative for bacteria, and transbronchial biopsies revealed A1 rejection. A total of 4 of 13 BAL and all of 8 nasopharyngeal specimens collected immediately after transplantation and during an 8-mo period were rhinovirus-positive, as determined by RT-PCR; 6 isolates, including the baseline and the last positive isolate at 7 mo, were then sequenced. All BAL specimens were also tested by RT-PCR for 12 other respiratory viruses, and were negative. Similar to the other cases, the VP1 showed only minor changes over time, with less than 1.2% change both at the nucleotide and the amino acid level. This patient underwent eight transbronchial biopsies during the follow-up period; three showed normal lung parenchyma (A0 in three) and five showed vascular lymphocytic infiltrates corresponding to acute rejection grade A1 in one, A2 in two, and A3 in two. Lymphocytic bronchiolitis was graded as B1 in two biopsies and B2 in one (Bx in five). The histologic changes (5.1 tissue fragments, on average, per bronchoscopy) did not differ from the usual modifications, although an unusual number of macrophages were concentrated in the alveolar lumen in three biopsies. BAL and nasopharyngeal specimens obtained at Months 8 and 11 were then negative for rhinovirus, and we observed an improvement in the patient's condition and lung functions. After an additional 8-mo follow-up, her clinical condition did not require any further BAL procedures.
In this study, we describe three lung transplant recipients chronically infected by rhinovirus. The sequences of the VP1 capsid protein from sequential rhinoviral isolates recovered in the respiratory tract confirmed the persistence of a single strain in each of the three cases, and ruled out reinfection by other strains. Two of the three cases had chronic upper respiratory tract symptoms; all had relapsing lower respiratory tract symptoms, and two subsequently died with graft dysfunction. Although these lung transplant recipients had multiple therapeutic interventions, including antirejection therapy, that increased their risk for opportunistic complications, rhinovirus was the only pathogen identified in the majority of the respiratory samples, and the response to broad-spectrum antibiotic treatment was limited. Rhinoviral RNA was identified less frequently in the upper than in the lower respiratory specimens, thus suggesting a potential implication in the production of lower respiratory tract symptoms. Rhinovirus has previously been recognized as a cause of lower respiratory tract symptoms (13, 24–26) and pneumonia (27–29), and is known to replicate at the temperature of the lower airways. It has also been shown that replicative strands, as well as viral antigens, are present in human bronchial epithelia after experimental inoculation of prototypic strains in the upper respiratory tract (12, 30). Because this has not yet been shown after naturally acquired infection, we investigated whether rhinovirus could be identified in the lower respiratory tract of the index case. Using antibodies specifically directed against the infecting strain, we confirmed the presence of interstitial and epithelial cells positive for rhinovirus. This proved that the virus was present in the lower respiratory parenchyma. Despite the presence of few virus-positive cells, the associated histopathologic changes observed on the transbronchial biopsies did not differ, on average, from the usual morphologic modifications that define cellular rejection, and no specific tissue modifications could be identified. Although some studies have revealed significant inflammatory changes of the lower respiratory tract of rhinovirus-infected patients, others have shown limited inflammatory changes in upper or lower respiratory tract biopsies positive for rhinovirus (11, 12, 30, 31), and, as in our case, identified only few, scattered infected cells. In conclusion, taken together, our clinical, virologic, and pathologic observations strongly suggest that rhinovirus contributed to the lower respiratory symptoms, although it is not possible to determine whether it was the main cause, a promoter, or a cofactor of the respiratory complications observed. In two of our three cases, rhinovirus was diagnosed almost exclusively by nucleic acid detection, and, as expected for rhinovirus, isolation by routinely used cell culture failed in most instances (7, 32). In one case, reinoculation of initially culture-negative samples on rhinovirus-sensitive cell lines allowed us to isolate full virions. This strongly emphasizes the need for appropriate diagnostic tools and adapted culture procedures. The detection of nucleic acid raises, however, the question of its significance, as rhinovirus can be detected in young children in the absence of respiratory symptoms. A review of these data suggests that this reflects, in most cases, viral RNA remnants of a recent infection (HRV can be detected up to 6 wk before its disappearance from the nasal mucus of young children) or the preliminary phase of an ongoing illness (33–39). This conclusion is supported by a recent cohort of children screened each week for the presence of picornavirus (40). In this study, the detection of viral RNA preceded the reported illness in 29% of cases, viral shedding persisted for 3 wk in 25% of cases, and, in these immunocompetent children, prolonged shedding for months did not occur. The rate of picornavirus infections considered as asymptomatic was rare—less than one-fifth of all infectious episodes—and the authors caution that this is certainly an overestimation due to underreporting of minor respiratory symptoms. In our cases, given that RNA viruses cannot establish latent infection, and that they are unable to persist at the mucosal surface without degradation, continuous viral RNA detection over months indicates active replication cycles and persistent infection. In two cases, rhinovirus was also isolated repeatedly on cell culture, confirming the production of functional virions. The identification of few nucleotide and amino acid changes in chronic cases also proves that replication cycles have occurred. In nonchronic cases identified in the prospective phase (eight cases), all the 38 BALs performed before the first positive event were HRV negative. At the time of HRV positivity, all had respiratory symptoms, and most were negative for other pathogens, as shown in Table 2. Of the 25 BALs available after the positive episode, only three (12%) were still HRV-positive, and all patients eventually cleared the virus. This confirms that the viral shedding was transient, and that rhinovirus is not a bystander of the lower respiratory specimens of lung transplant recipients. Recently, it has also been shown that identification of rhinoviral RNA in BAL specimens of lung transplant recipients (18) or patients with chronic obstructive pulmonary disease (41) is, in most cases, associated with concomitant respiratory symptoms, and that HRV was very rarely recovered in specimens in a control population without acute respiratory symptoms. Other investigations have also linked viral respiratory tract infections to graft dysfunction and bronchiolitis obliterans syndrome (42–45). All these reports support the hypothesis that respiratory viral infections could promote lower respiratory tract complications and graft dysfunction in lung transplant recipients.
Over a period of 19 mo, approximately 15% of lung transplant recipients studied presented an episode of rhinoviral infection detected in their bronchoalveolar specimens. The majority cleared the infection that was not recovered in subsequent BAL specimens, as discussed previously here. Nevertheless, this infection was persistent in 2 of 10 cases analyzed over a period of 19 mo, thus suggesting that this might be a relatively common event in these highly immunosuppressed subjects. Chronic disease for months or years with other members of the Picornaviridae family, such as enterovirus or poliovirus, is a recognized clinical entity in immunocompromised hosts (23, 46–49). In this regard, our data extend this to rhinovirus, which is structurally and functionally very close to other picornaviruses. Immunity against rhinovirus is characterized by the appearance of specific neutralizing antibodies likely to play a role in viral clearance and protection against reinfection by the same strain (50). The index patient failed to produce neutralizing antibodies against the infecting strain, which could explain why viral clearance failed. The two additional patients identified had profound cellular immunosuppression, and were unlikely to mount any effective immune response either. In this respect, persistent rhinoviral infection could be considered as an opportunistic event in the presence of a failing immune response. Prolonged HRV infections for months have also been described in children with asthma, in whom the cellular immune response can be altered (15–17). In this group of relatively immunosupressed patients, HRV can be detected 6 mo after the initial infection in 25% of cases (36). Finally, as no animal reservoir has been identified, we need to hypothesize the existence of chronic carriers and/or a persisting chain of transmission outside the seasonal outbreaks. The persistent infection documented over several months in the present report suggests also that particular cases could act as a reservoir to sustain transmission. The canyon pocket of the rhinoviral VP1 is the binding site of pleconaril (51), which inhibits viral uncoating and/or attachment. This drug has been used in a few transplant recipients with rhinoviral pneumonia, but proof of its efficacy is still lacking (23). Our index patient was treated with pleconaril, but no benefit to symptoms or viral shedding was observed. We therefore examined the emergence of resistance in the clinical isolate by sequence analysis of the VP1. As described previously here, amino acid substitutions were observed, and likely corresponded to quasispecies emerging during chronic RNA virus infections, but we did not observe any amino acid substitutions considered critical for pleconaril resistance within the drug-binding pocket (19). However, it has been shown that 9% of clinical isolates have a limited sensitivity to pleconaril (52), and that a substantial number of serotypes exhibit intrinsically high 50% effective inhibitory concentration (19), including serotypes 64 and 94, which are closely related to our isolate. Thus, this index case was possibly infected with a naturally drug-resistant strain. The third patient also exhibited a viral genotype considered resistant to pleconaril. These observations, and the selection of a drug-resistant strain while on therapy (53), highlight the challenges facing researchers of new antiviral drugs targeting picornaviruses. We have documented that rhinoviral infection can be persistent in lung transplant recipients. The clinical evolution of our cases, the isolation and the identification of viral RNA in lower respiratory specimens, and the presence of viral antigens in the lower respiratory parenchyma suggest that rhinovirus contributed to the symptoms and to respiratory complications, including chronic graft dysfunction. Therefore, in lung transplant recipients with severe immunosuppression, chronic rhinoviral infection needs to be considered. This might have substantial implications in term of diagnostic procedures, clinical management, and antiviral use, if available.
The authors thank Chantal Gaille and Delphine Garcia for their excellent technical assistance, as well as Rosemary Sudan for editorial assistance.
* These investigators contributed equally to this article.  Supported by grant 3200B0-101670 from the Swiss National Foundation, and by a research fund of the Department of Internal Medicine, University Hospitals of Geneva. This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org Originally Published in Press as DOI: 10.1164/rccm.200604-489OC on September 28, 2006 Conflict of Interest Statement: L.K. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript. J.-D.A. has been reimbursed by Novartis for attending an international conference in 2005 and by AstraZeneca in 2004. He received $2,000 in 2005 and 2006 for speaking at conferences by Roche, Health Care Consulting Switzerland and Actelion. J.-C.P. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript. C.D. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript. T.R. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript. J.G. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript. W.W. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript. P.M. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript. S.Y. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript. L.P. received $25,000 in 2004 and $15,000 in 2005 from Abbot, Dey and Roche Diagnostic, used exclusively for the salary of technicians and reagents. I.L. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript. L.N. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript. C.T. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript. P.M.S. has no financial relationship with a commercial entity that has an interest in the subject of this manuscript. Received in original form April 7, 2006; accepted in final form September 3, 2006
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1-antitrypsin deficiency. The postoperative period was complicated by severe primary graft dysfunction requiring 6 wk of intensive care and a further 3 mo of in-hospital stay. Immunosuppressive regimen consisted of tacrolimus, mycophenolate mofetil (switched to azathioprine after 4 mo), and prednisone. At 4 wk after transplantation, a first BAL was positive for rhinovirus, as determined by RT-PCR. 
and airway responsiveness in asthma. Am J Respir Crit Care Med 2003;168:1091–1094.