The rapid emergence of severe acute respiratory syndrome (SARS) due to SARS-coronavirus (CoV) in 2003 took the world by surprise (1-3). By the end of the epidemic in July 2003, 8,096 cases were reported in 29 countries and regions with a mortality of 774 (9.6%) (4). The viral kinetics of patients hospitalized with SARS-CoV appeared like an inverted v-shaped curve over time, with the nasopharyngeal viral loads peaking on day 10 of illness onset whereas many patients progressed to respiratory failure around the same time of the illness (5,6). About 50% of patients required supplemental oxygen whereas 25% would need intensive care support during the second week of the illness (3,7,8). Except for re-emergence at small scales in late 2003 and early 2004 in South China after resumption of wild animal trading activities in markets (9,10), SARS-CoV has fortunately not returned to the community. However the emergence of the Middle East Respiratory Syndrome (MERS) due to MERS-CoV in the Arabic Peninsula and neighboring countries in the Middle East since 2012 has created concern of another severe respiratory infection with a potential for global outbreak (11-13).
This article reviews the clinical lessons learnt from the clinical management of the SARS outbreak in Hong Kong and the subsequent progress in hospital infection control, in addition to research of the ward environmental airflow and the safety of common respiratory therapies. The clinical lessons and research findings may facilitate our preparedness for managing other emerging severe acute respiratory infections.
Lessons learnt from SARS and progress
General medical wards with crowding and inadequate ventilation are not suitable for managing highly infectious diseases
Prior to the outbreak of SARS, most of the hospital wards in HK were designed as general wards without proper partition between beds whereas few isolation facilities were available. Beds were separated by mobile curtains and the distance between beds often fell short of 1 m due to heavy clinical load. Such medical ward design was clearly not ideal in managing highly infectious diseases such as SARS. Following admission of the index patient (a visitor of Hotel M), who presented with community acquired pneumonia (CAP) to a general medical ward at the Prince of Wales Hospital (PWH) on 4th March 2003, 138 patients [many of whom being healthcare workers (HCWs)] were hospitalized with SARS within 2 weeks following exposure to the index case (2,3). This super-spreading event was thought to be related to a combination of the use of salbutamol via a jet nebulizer for its muco-ciliary clearance effect to the index case who had non-productive cough and dyspnoea, overcrowding of beds, and poor ventilation in the hospital ward (3,14). During early Apr 2003, exhaust fans were installed on the windows in the corners of every medical ward as a temporary measure in order to improve the ward ventilation.
A nosocomial outbreak of seasonal influenza A (H3N2) occurred in the same old medical ward setting in 2008 at PWH when a patient hospitalized with acute exacerbation of chronic obstructive pulmonary disease (COPD) was given non-invasive positive pressure ventilation (NPPV) for treatment of hypercapnic respiratory failure despite implementation of droplet and contact precaution (15). Several patients located in the same bay of the COPD patient and some in the distant bays of the same medical ward were infected with the same strain of H3N2 influenza virus in the following week. The nosocomial outbreak was related to imbalanced airflow in the ward due to different HEPA filter fan rates, allowing exhaled air from the patient who was receiving NPPV to be blown towards other bays of the same ward. Following infection outbreak investigation including examination of ward airflow and computer fluid dynamics analysis, this case was an example of how seasonal influenza could possibly be converted from droplet into airborne transmission through NPPV and imbalanced environmental airflow (15).
After the outbreak of SARS, the HKSAR Government injected substantial funding to improve the medical ward environment and upgrade facilities in the public hospitals in preparation for emerging infectious diseases including influenza pandemic. Nowadays there are more than 1,400 isolation beds with double-door and negative pressure in the public hospitals in HK. Bigger isolation rooms with 16 air changes per hour (ACH) at the Princess Margaret Hospital are more effective than smaller isolation rooms with 12 ACH at PWH in removing exhaled air and preventing room contamination but at the expense of relatively more noise and electricity consumption (16). In addition, there is adequate supply of personal protective equipment such as N95 masks, eye shields, gowns, etc. on the isolation wards. The improvement in hospital ward environment and infection control measures has facilitated management of infectious diseases in HK.
Risk factors for super-spreading events within hospitals
Super-spreading events of SARS occurred in hospitals in HK (3), the mainland of China (1), Canada, and other countries (17,18). Globally 1,706 healthcare workers were infected while providing care to the SARS patients at close distance in 2003 (4). A case control study involving 124 medical wards in 26 hospitals in Guangzhou and HK has identified 6 independent risk factors of super-spreading nosocomial outbreaks of SARS: minimum distance between beds <1 m, performance of resuscitation, staff working while experience symptoms, SARS patients requiring oxygen therapy or NPPV whereas availability of washing or changing facilities for staff was a protective factor (19). Procedures reported to present an increased risk of SARS transmission include tracheal intubation, non-invasive ventilation, tracheotomy and manual ventilation before intubation (20). Following the outbreak of SARS, hospital beds on the general wards in HK have been separated at least 1 m apart. HCWs have also developed very good infection control habits (e.g., wearing surgical masks before entering any general ward on duty and maintaining good infection control measures such as hand hygiene, droplet and contact precautions when managing patients with influenza or pneumonia, and upgrading to airborne precaution as appropriate for aerosol-generating procedures).
Exhaled air dispersion distances/directions of common respiratory therapies
To improve our understanding of the risks of various respiratory therapies when managing patients with respiratory due to infectious diseases, we have examined the exhaled air dispersion during application of various respiratory therapies on a high fidelity human patient simulator using the laser visualization technique and smoke particles as markers (20,21).
Oxygen therapy via Hudson mask (22,23) and nasal cannula (16) can disperse exhaled air of patients to 0.4 m lateral to the center of the mask and 1 m towards the end of the bed respectively whereas a jet nebulizer, driven by air or oxygen at 6 L/min, can disperse exhaled air >0.8 m laterally from the patient (24).
NPPV via different brands of face masks and single circuit can disperse exhaled air between 0.4 and 1 m (21,25). Both higher inspiratory pressures and use of a whisper swivel device (to facilitate carbon dioxide removal) can increase the exhaled air leakage and isolation room contamination during NPPV (25). During resuscitation, addition of a viral-bacterial filter during manual ventilation by bagging may reduce the exhaled air leakage forward but it increases the sideway leakage (26).
Patients hospitalized with influenza or pneumonia are often required to wear protective masks to prevent nosocomial infection. Normal cough produces a turbulent jet about 0.7 m towards the end of the bed from the recumbent subject. N95 mask is more effective than surgical mask in reducing expelled air leakage forward during patient’s coughing but there is still significant sideway leakage to 15 cm (27). Thus for practical purpose and taking into account patient’s comfort and compliance, we would recommend putting patients on the surgical masks for infection control purpose.
Use of antiviral therapy, convalescent plasma, and immuno-modulating agents
Ribavirin, a nucleoside analogue, was widely used for treating SARS patients (2,3,5,6,8,17,18). However, it was later known that ribavirin had no significant in vitro activity against SARS-CoV (28,29), and it caused significant haemolysis in many patients (3,17,18,30).
Lopinavir and ritonavir in combination is a boosted protease inhibitor regimen widely used in the treatment of human immunodeficiency virus (HIV) infection. In vitro activity against SARS-CoV was demonstrated for lopinavir and ribavirin at 4 and 50 µg/mL, respectively whereas inhibition of in vitro cytopathic effects was achieved down to a concentration of 1 µg/mL of lopinavir combined with 6.25 μg/mL of ribavirin (31). A retrospective review has shown that the addition of lopinavir 400 mg/ritonavir 100 mg (LPV/r) as initial therapy was associated with lower overall death rate (2.3% vs. 15.6%) and intubation rate (0% vs. 11%) than a matched historical cohort that received ribavirin alone as the initial anti-viral therapy (32). Other reported beneficial effects include a reduction in corticosteroid use, fewer nosocomial infections, a decreasing viral load and rising peripheral lymphocyte count. However, the outcome of a subgroup that had received LPV/r as rescue therapy after receiving pulsed methylprednisolone treatment for worsening respiratory symptoms was not better than the matched cohort (32).
Type I IFNs are produced early as part of the innate immune response to virus infections. There are in vitro and limited animal and observational data that IFN, particularly early use, has efficacy against SARS (33-37). In experimentally infected cynomolgus macaques, prophylactic treatment with pegylated IFN-α significantly reduced viral replication and excretion, viral antigen expression by type 1 pneumocytes and pulmonary damage, compared with untreated macaques, whereas post-exposure treatment with pegylated IFN-α yielded intermediate results (38). Use of IFN-α 1 plus corticosteroids was associated with improved oxygen saturation, more rapid resolution of radiographic lung opacities and lower levels of CPK in SARS patients in Canada (39). These findings support clinical testing of approved IFNs for the treatment of SARS.
During the second week of SARS illness when patients progressed to more severe pneumonia and hypoxemia, there was evidence of bronchiolitis obliterans organizing pneumonia radiologically (3,8,40) and histopathologically (41) in some cases and the progression of the pulmonary disease was mediated by the host inflammatory response (5). Intravenous administration of rescue pulsed methylprednisolone (MP) appeared to suppress cytokine-induced lung injury (3,8,30). Systemic corticosteroids significantly reduced interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), and IFN-γ inducible protein-10 (IP-10) concentrations from 5 to 8 days after treatment in 20 adult SARS patients at PWH (42). Induction of IP-10 is thought to be a critical event in the initiation of immune-mediated lung injury and lymphocyte apoptosis (43).
The use of rescue pulsed MP during clinical progression was associated with favorable clinical improvement in some patients with resolution of fever and lung opacities within 2 weeks (3,8,30). However, a retrospective analysis showed that the use of pulsed MP was associated with an increased risk of 30-day mortality (adjusted OR 26.0, 95% CI: 4.4 to 154.8) (44). In addition, complications such as disseminated fungal disease (45) and avascular necrosis of bone occurred following prolonged corticosteroid therapy (46). With the rescue pulsed MP approach, avascular necrosis of bone was found in 12 (4.7%) patients after screening 254 patients using magnetic resonance imaging at PWH. The risk of avascular necrosis was 0.6% for patients receiving <3 g, and was 13% for those receiving >3 g prednisolone-equivalent dose (47).
A randomized placebo-controlled study conducted at PWH showed that plasma SARS-CoV RNA concentrations in the second and third weeks of illness were higher in patients given initial hydrocortisone (n=10) than those given normal saline (n=7) during early clinical course of illness (48). Despite the small sample size, our data suggest that pulsed MP given in the earlier phase might prolong viraemia and thus it should only be given during later phase for rescue purpose.
Convalescent plasma, donated by patients including HCWs at PWH who had recovered from SARS, contained high levels of neutralizing antibody and appeared clinically useful for treating other SARS patients (49,50). Among 80 non-randomised patients with SARS who were given convalescent plasma at PWH, the discharge rate at day 22 was 58.3% for patients (n=48) treated within 14 days of illness onset compared to 15.6% for those (n=32) treated beyond 14 days (50). Convalescent plasma with high antibody titre of >1:160 was given to 20 critically ill patients with infection due to H1N1pdm09 in HK, and treatment was associated with reduced mortality (crude mortality 20% vs. 55% in controls) and more rapid virus clearance than other critically ill patients given oseltamivir alone (51).
In summary, the major outbreak of SARS in 2003 has taught us many invaluable lessons and led to subsequent improvement of the medical ward environment, better infection control facilities and measures, in addition to advances in knowledge and experience such as use of antiviral agents and immuno-modulating agents in handling emerging severe acute respiratory infections. Clinicians should be aware of air leakage from the various respiratory therapies and adopt strict infection control measures during resuscitation of patients with severe acute respiratory infections in order to prevent nosocomial outbreaks. Carefully designed clinical trials are required to determine the optimal timing and dosage of any antiviral agents, convalescent plasma, and immuno-modulating agents (52) in the treatment of the possibly immune-mediated lung injury in SARS and newly emerged infection such as MERS.
Disclosure: The author declares no conflict of interest.
- Zhong NS, Zheng BJ, Li YM, et al. Epidemiology and cause of severe acute respiratory syndrome (SARS) in Guangdong, People’s Republic of China, in February, 2003. Lancet 2003;362:1353-8. [PubMed]
- Tsang KW, Ho PL, Ooi GC, et al. A cluster of cases of severe acute respiratory syndrome in Hong Kong. N Engl J Med 2003;348:1977-85. [PubMed]
- Lee N, Hui D, Wu A, et al. A major outbreak of severe acute respiratory syndrome in Hong Kong. N Engl J Med 2003;348:1986-94. [PubMed]
- WHO. Summary of probable SARS cases with onset of illness from 1 November to 31 July 2003. Available online: http://www.who.int/csr/sars/country/table2003_09_23/en
- Peiris JS, Chu CM, Cheng VC, et al. Clinical progression and viral load in a community outbreak of coronavirus-associated SARS pneumonia: a prospective study. Lancet 2003;361:1767-72. [PubMed]
- Cheng VC, Tang BS, Wu AK, et al. Medical treatment of viral pneumonia including SARS in immunocompetent adult. J Infect 2004;49:262-73. [PubMed]
- Hui DS, Wong KT, Antonio GE, et al. Severe acute respiratory syndrome: correlation between clinical outcome and radiologic features. Radiology 2004;233:579-85. [PubMed]
- Hui DS, Sung JJ. Severe acute respiratory syndrome. Chest 2003;124:12-5. [PubMed]
- Wang M, Yan M, Xu H, et al. SARS-CoV infection in a restaurant from palm civet. Emerg Infect Dis 2005;11:1860-5. [PubMed]
- Che XY, Di B, Zhao GP, et al. A patient with asymptomatic severe acute respiratory syndrome (SARS) and antigenemia from the 2003-2004 community outbreak of SARS in Guangzhou, China. Clin Infect Dis 2006;43:e1-5. [PubMed]
- Zaki AM, van Boheemen S, Bestebroer TM, et al. Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. N Engl J Med 2012;367:1814-20. [PubMed]
- Memish ZA, Zumla AI, Al-Hakeem RF, et al. Family cluster of Middle East respiratory syndrome coronavirus infections. N Engl J Med 2013;368:2487-94. [PubMed]
- Guery B, Poissy J, El Mansouf L, et al. Clinical features and viral diagnosis of two cases of infection with Middle East Respiratory Syndrome coronavirus: a report of nosocomial transmission. Lancet 2013;381:2265-72. [PubMed]
- Wong RS, Hui DS. Index patient and SARS outbreak in Hong Kong. Emerg Infect Dis 2004;10:339-41. [PubMed]
- Wong BC, Lee N, Li Y, et al. Possible role of aerosol transmission in a hospital outbreak of influenza. Clin Infect Dis 2010;51:1176-83. [PubMed]
- Hui DS, Chow BK, Chu L, et al. Exhaled air dispersion and removal is influenced by isolation room size and ventilation settings during oxygen delivery via nasal cannula. Respirology 2011;16:1005-13. [PubMed]
- Hsu LY, Lee CC, Green JA, et al. Severe acute respiratory syndrome (SARS) in Singapore: clinical features of index patient and initial contacts. Emerg Infect Dis 2003;9:713-7. [PubMed]
- Booth CM, Matukas LM, Tomlinson GA, et al. Clinical features and short-term outcomes of 144 patients with SARS in the greater Toronto area. JAMA 2003;289:2801-9. [PubMed]
- Yu IT, Xie ZH, Tsoi KK, et al. Why did outbreaks of severe acute respiratory syndrome occur in some hospital wards but not in others? Clin Infect Dis 2007;44:1017-25. [PubMed]
- Tran K, Cimon K, Severn M, et al. Aerosol generating procedures and risk of transmission of acute respiratory infections to healthcare workers: a systematic review. PLoS One 2012;7:e35797. [PubMed]
- Hui DS, Hall SD, Chan MT, et al. Noninvasive positive-pressure ventilation: An experimental model to assess air and particle dispersion. Chest 2006;130:730-40. [PubMed]
- Hui DS, Ip M, Tang JW, et al. Airflows around oxygen masks: A potential source of infection? Chest 2006;130:822-6. [PubMed]
- Hui DS, Hall SD, Chan MT, et al. Exhaled air dispersion during oxygen delivery via a simple oxygen mask. Chest 2007;132:540-6. [PubMed]
- Hui DS, Chow BK, Chu LC, et al. Exhaled air and aerosolized droplet dispersion during application of a jet nebulizer. Chest 2009;135:648-54. [PubMed]
- Hui DS, Chow BK, Ng SS, et al. Exhaled air dispersion distances during noninvasive ventilation via different Respironics face masks. Chest 2009;136:998-1005. [PubMed]
- Chan MT, Chow BK, Chu L, et al. Mask ventilation and dispersion of exhaled air. Am J Respir Crit Care Med 2013;187:e12-4. [PubMed]
- Hui DS, Chow BK, Chu L, et al. Exhaled air dispersion during coughing with and without wearing a surgical or N95 mask. PLoS One 2012;7:e50845. [PubMed]
- Tan EL, Ooi EE, Lin CY, et al. Inhibition of SARS coronavirus infection in vitro with clinically approved antiviral drugs. Emerg Infect Dis 2004;10:581-6. [PubMed]
- Ströher U, DiCaro A, Li Y, et al. Severe acute respiratory syndrome-related coronavirus is inhibited by interferon- alpha. J Infect Dis 2004;189:1164-7. [PubMed]
- Sung JJ, Wu A, Joynt GM, et al. Severe acute respiratory syndrome: report of treatment and outcome after a major outbreak. Thorax 2004;59:414-20. [PubMed]
- Chu CM, Cheng VC, Hung IF, et al. Role of lopinavir/ritonavir in the treatment of SARS: initial virological and clinical findings. Thorax 2004;59:252-6. [PubMed]
- Chan KS, Lai ST, Chu CM, et al. Treatment of severe acute respiratory syndrome with lopinavir/ritonavir: a multicentre retrospective matched cohort study. Hong Kong Med J 2003;9:399-406. [PubMed]
- Cinatl J, Morgenstern B, Bauer G, et al. Treatment of SARS with human interferons. Lancet 2003;362:293-4. [PubMed]
- Hensley LE, Fritz LE, Jahrling PB, et al. Interferon-beta 1a and SARS coronavirus replication. Emerg Infect Dis 2004;10:317-9. [PubMed]
- Sainz B Jr, Mossel EC, Peters CJ, et al. Interferon-beta and interferon-gamma synergistically inhibit the replication of severe acute respiratory syndrome-associated coronavirus (SARS-CoV). Virology 2004;329:11-7. [PubMed]
- Morgenstern B, Michaelis M, Baer PC, et al. Ribavirin and interferon-beta synergistically inhibit SARS-associated coronavirus replication in animal and human cell lines. Biochem Biophys Res Commun 2005;326:905-8. [PubMed]
- Chen F, Chan KH, Jiang Y, et al. In vitro susceptibility of 10 clinical isolates of SARS coronavirus to selected antiviral compounds. J Clin Virol 2004;31:69-75. [PubMed]
- Haagmans BL, Kuiken T, Martina BE, et al. Pegylated interferon-alpha protects type 1 pneumocytes against SARS coronavirus infection in macaques. Nat Med 2004;10:290-3. [PubMed]
- Loutfy MR, Blatt LM, Siminovitch KA, et al. Interferon alfacon-1 plus corticosteroids in severe acute respiratory syndrome: a preliminary study. JAMA 2003;290:3222-8. [PubMed]
- Wong KT, Antonio GE, Hui DS, et al. Thin-section CT of severe acute respiratory syndrome: evaluation of 73 patients exposed to or with the disease. Radiology 2003;228:395-400. [PubMed]
- Tse GM, To KF, Chan PK, et al. Pulmonary pathological features in coronavirus associated severe acute respiratory syndrome (SARS). J Clin Pathol 2004;57:260-5. [PubMed]
- Wong CK, Lam CW, Wu AK, et al. Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome. Clin Exp Immunol 2004;136:95-103. [PubMed]
- Jiang Y, Xu J, Zhou C, et al. Characterization of cytokine/chemokine profiles of severe acute respiratory syndrome. Am J Respir Crit Care Med 2005;171:850-7. [PubMed]
- Tsang OT, Chau TN, Choi KW, et al. Coronavirus-positive nasopharyngeal aspirate as predictor for severe acute respiratory syndrome mortality. Emerg Infect Dis 2003;9:1381-7. [PubMed]
- Wang H, Ding Y, Li X, et al. Fatal aspergillosis in a patient with SARS who was treated with corticosteroids. N Engl J Med 2003;349:507-8. [PubMed]
- Hong N, Du XK. Avascular necrosis of bone in severe acute respiratory syndrome. Clin Radiol 2004;59:602-8. [PubMed]
- Griffith JF, Antonio GE, Kumta SM, et al. Osteonecrosis of hip and knee in patients with severe acute respiratory syndrome treated with steroids. Radiology 2005;235:168-75. [PubMed]
- Lee N, Allen Chan KC, Hui DS, et al. Effects of early corticosteroid treatment on plasma SARS-associated Coronavirus RNA concentrations in adult patients. J Clin Virol 2004;31:304-9. [PubMed]
- Soo YO, Cheng Y, Wong R, et al. Retrospective comparison of convalescent plasma with continuing high-dose methylprednisolone treatment in SARS patients. Clin Microbiol Infect 2004;10:676-8. [PubMed]
- Cheng Y, Wong R, Soo YO, et al. Use of convalescent plasma therapy in SARS patients in Hong Kong. Eur J Clin Microbiol Infect Dis 2005;24:44-6. [PubMed]
- Hung IF, To KK, Lee CK, et al. Convalescent plasma treatment reduced mortality in patients with severe pandemic influenza A (H1N1) 2009 virus infection. Clin Infect Dis 2011;52:447-56. [PubMed]
- Hui DS, Lee N, Chan PK, et al. Adjunctive therapies and immunomodulatory agents in the management of severe influenza. Antiviral Res 2013;98:410-6. [PubMed]