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Community Acquired Respiratory Viruses and BOS:
What's the Scoop?

Peter M Hopkins, FRACP
Director Queensland Lung Transplant Service
The Prince Charles Hospital, Brisbane, QLD, AUSTRALIA

peter hopkinsLung transplant recipients have a unique predisposition to infection due to a number of factors including diminished cough reflex, abnormal lymphatic drainage, physical impairment of mucociliary clearance, high levels of immunosuppression and exposure to airborne pathogens. One consequence of this continued environmental exposure is a high incidence of respiratory viral infection (RVI) compared to healthy individuals.

A number of viruses have been associated with acute allograft dysfunction including influenza A and B, adenovirus, parainfluenza, respiratory syncytial virus (RSV), human Metapneumovirus (hMPV) and rhinovirus. Clinical manifestations range from mild self-limiting pharyngitis, to the more severe spectrum of bronchiolitis, progression of BOS, viral pneumonitis and acute lung injury with respiratory failure. Respiratory viral infections have been aetiologically linked to the development of BOS through local immune up-regulation or predisposition to acute graft rejection, although no direct causative link has been established.

During a twelve year prospective evaluation period commencing January 2000, lung transplant recipients at the Prince Charles Hospital, Brisbane Australia, underwent nasopharyngeal aspirates (NPA). Patients with symptoms of influenza-like illness were targeted, defined as any combination of sore throat, nasal irritation, low grade fever, myalgia and arthralgia with or without respiratory tract symptoms of cough, dyspnoea or wheeze. Respiratory NPA specimens were obtained in the outpatient department and screened by indirect fluorescent antibody test and PCR for RSV, hMPV, influenza A and B, parainfluenza 1-3 and adenovirus.

All patients with paramyxoviral infection and graft dysfunction (defined as >10 percent decline in FEV1) were hospitalised and nursed in a single room isolation under infection control precautions for droplet transmission. The mainstay of treatment consisted of intravenous ribavirin at a commencing dose of 33mg/kg/day for the first 24 hours then 20mg/kg/day thereafter, with dosing adjusted for renal function if appropriate. Furthermore, patients received an oral prednisolone pulse at 1mg/kg tapering by 5mg per day to baseline, broad spectrum B lactam based antibiotic therapy and nebulised bronchodilators. Steroid therapy was implemented to attenuate production of macrophage inflammatory protein-1 alpha and interleukin-8, along with down regulation of lymphocyte alloreactivity. Intragam P (human immunoglobulin, CSL Limited, Victoria) was administered from day 7 if there was no improvement in allograft function, in a dose of 0.4gram/kg/day for 5 days. Such immunotherapy may neutralise super antigens, down regulate T cell immunity, inhibit complement and have anti-cytokine effects. Patients with adenoviral infection and graft dysfunction received intravenous cidofivir pending renal function and those with influenza oral oseltamivir 75mg twice daily orally.

There were 147 episodes of RVI in 85 patients - parainfluenza 42, RSV 37, hMPV 26, influenza A 26, influenza B 10 and adenovirus 6 cases. Cox proportional hazard modelling was used to assess risk factors for RVI, BOS onset and death following RVI, by comparison with 93 lung transplant recipients with no RVI during the study period. On multivariate analysis risk factors for RVI included pre-existing BOS (HR 3.25, CI 1.64-6.42, p=001) and serum IgA level (HR 0.796, CI 0.622-1.017, p=0.06). Risk factors for developing BOS grade 1 were single lung transplant (HR 2.01, CI 1.36-6.25, p=006), serum IgG (HR 0.827, CI 0.753-0.908, p<0.001) and time to onset post transplant of RSV or hMPV (HR 1.75, CI 1.03-3.00, p=0.04). No other viruses were predictive of BOS onset. Risk factors for death included BOS (HR 51.97, CI 17.94-150.57, p<0.001) and time to RSV or hMPV (HR 2.07, CI 1.17-3.68, p=0.013).

In conclusion, our experience suggests that both RSV and hMPV are predictive of both BOS onset and death post lung transplant despite aggressive treatment protocols. Parainfluenza is less problematic, whilst influenza and adenovirus are relatively benign. Mortality is related to BOS acceleration and a predisposition to invasive fungal infection. Changing epidemiological trends, differing viral phenotypes and patient demographics may account for some geographical differences.

Disclosure Statement: The author has no conflicts of interest to disclose.