SARS and H5N1

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suggesting thathumansmight have acquired theinfection have withSARS-CoV, remarkable sequencehomology isolated from civet catsandothergameanimalsinChina Coronaviruses fulfilled theKoch’s postulatesfor causation. whichisanRNAvirusthathas associated coronavirus, Severe syndrome acuterespiratory is causedby the SARS- netdatgte.O hs,774diedfrom SARS. these, Of infected altogether. 8,096personswere November 2002andJuly 2003, Between oftheworld. andotherparts Canada, Vietnam, Singapore, andspread toHongKong, China, Province, The 2002–03SARSepidemicsbeganinGuangdong SEVERE ACUTE RESPIRATORYSEVERE ACUTE SYNDROME DECLARATION OFINTERESTS World HealthOrganisation(WHO) severe syndrome-associated acuterespiratory coronavirus (SARS-CoV), (SARS), seve ribonucleic acid(RNA), reaction (RT-PCR), randomisedcontrolled trial(RCT), (NA), neuraminidase immunoglobulin G(IgG), resolution computedtomography (HRCT), high haemagglutinin(HA), bronchiolitis obliteransorganisingpneumonia(BOOP), LIST OF ABBREVIATIONS KEYWORDS preventing large-scaleoutbreaks for SARSandH5N1. andprompt isolationofsuspectedcasesare themainstays in and markets, farms, soundinfection control measures inhospitals, potentially infected Minimisinghumancontactwith animals, medical community needstostay vigilant. andthe Health Organisationhasconsistently warnedofaH5N1pandemic, The World accidentsandcontactwithgameanimals. related tolaboratory since, afew smallpockets ofoutbreak have occurredSARS were broken inJuly 2003, Whileallknown chainsofperson-to-persontransmission hospital settings. althoughinfection control measures have beenfound tobeeffective in infection, Novaccinehasyet beenapproved for either are highfor bothconditions. Treatment remains andthemortalities supportive been proven effective by RCTs. nonehas orpostulated tobeuseful, agentshaveimmunomodulatory beentried, Althoughvariousantiviraland progressing rapidly tosevere pneumoniaand ARDS. Both SARS-CoVandH5N1beginwithanon-specificinfluenza-like illness, withsporadictransmissiontohumans. populationsin in bird andpoultry Asia, TheH5N1virusappears tobeendemic delicacy. animals consumedasaculinary SARS-CoV couldbetransmittedtohumansfrom civet catsandothergame Molecularstudiessuggestthat modern high-speedinternationaltransportation. facilitatedby They bothhave thepotentialtocauseglobalpandemics, millennium. have arisenin Asia attheturnof pathogenic avian influenza A H5N1virus, ABSTRACT and H5N1 Newly infections –SARS emergedrespiratory S E 1 1 P P ntdCrsinHsia,HongKongSAR, Hospital, United Christian MChu, CM A p APER R i APER d S e - m C o i o V l o

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t r a n s m i s s i o n Acute respiratory distressAcute respiratory syndrome (ARDS), No conflictofinterests declared. 2 nvriyDprmn fMdcn,Uiest fHn og HongKongSAR University ofHongKong, ofMedicine, University Department reverse-transcriptase polymerase chain re syndrome acuterespiratory nosocomial transmission. may explaintheriskof duringpyrexia, particularly stool, Prolonged viralshedding and from thenasopharynx Kong. aresidential complexinHong outbreak in Amoy Gardens, transmission mightalsohave contributedtoalarge-scale Airborne faeces are possiblecontributorstoitsspread. Fomites and detectable instoolfor prolonged periods. ViralRNAisalso human mainly by droplet transmission. associated coronavirus appears tospread from human-to- Severe syndrome- acuterespiratory from theseanimals. >8C,rgr yli,mlie n edce Mild Chestradiography could anddiarrhoea may occur. present, andheadache. malaise, coughmay symptoms includingadry alsobe respiratory myalgia, rigor, (>38°C), Itbeginsasaninfluenza-like illnesswithfever 2–10 days. The incubationperiodfor SARSappears torangefrom C l i n i c a l

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© 2006Royal CollegeofPhysicians ofEdinburgh f e a t Published online Published u Correspondence to to Correspondence r Department of Medicine and Medicine of Department J RCollPhysicians Edinb Geriatrics, United Christian United Geriatrics, e Hospital, 130 Hip Wo Street, Kwun Street, Wo Hip 130 Hospital, Tong, Kowloon, HONG KONG HONG Kowloon, Tong, s tel. tel. fax. fax. e-mail e-mail (852) 3513 4822 3513 (852) (852) 3513 5548 3513 (852) [email protected] April 2006 April CM Chu, CM 2006; 36: 245–248 245

CME CM Chu, KWT Tsang

be normal initially, but a HRCT scan of the thorax usually Treatment shows ground glass infiltrates or frank consolidation in the lungs. Diagnosis can be difficult at this stage because the The mainstay of treatment is provision of supportive care. clinical features are non-specific. Epidemiological clues may Many patients develop ARDS and will require intensive prompt the clinician to suspect the diagnosis, e.g. travel to care and mechanical ventilation. The latter should be of epidemic areas, contact with known patients, contact with the pressure-controlled mode to minimise barotrauma, suspect animals, laboratory accident, clustering of cases. particularly in light of the presence of spontaneous Peripheral lymphopenia is common on presentation. pneumomediastinum in SARS. Antiviral agents, including Other common laboratory features include ribavirin and lopinavir/ritonavir,have been used during the thrombocytopenia, raised aminotransferases, creatine SARS epidemics, but no RCTs were conducted to prove kinase, and lactate dehydrogenase. their efficacy. Corticosteroids were included in many regimens published in the literature with some dramatic The majority of patients will progress,in the second week, responses although RCT data are lacking. Other modes with persistence or recurrence of fever, onset of of therapy that have been tried, or postulated to be useful, respiratory distress,worsening of radiological findings,and include: interferons, convalescent plasma, pentaglobulin, desaturation. Some patients, probably 30–40% of cases, nelfinavir, glycyrrhizin, and small interfering RNAs. Animal progress relentlessly to ARDS. Viral load peaks at around studies and randomised double-blind placebo-controlled 7–10 days, which may explain the high risk of nosocomial trials are required to examine their therapeutic transmission. Clinical deterioration occurs despite a potentials. A vaccine available in the mainland of China substantial drop in viral load after ten days. Spontaneous has begun phase I clinical trials although safety data and pneumomediastinum and pneumothorax, unrelated to other results remain unpublished. mechanical ventilation, may complicate the course of illness. A significant proportion of patients will require HIGHLY PATHOGENIC AVIAN INFLUENZA A intubation and mechanical ventilation for ARDS, although (H5N1) VIRUS success has been reported with non-invasive ventilation under strict personal and environmental protection. The Epidemiology case fatality rates in severely affected countries range from 7 to 17%. Old age, presence of co-morbid diseases, Influenza virus subtype H5N1 has caused outbreaks of and high viral load are poor prognostic factors. disease in poultry in Hong Kong, southern China, Japan, Southeast Asia (Cambodia, Indonesia, Malaysia, Philippines, CME Lung specimens, obtained by biopsy or autopsy, generally Laos,Taipei,Thailand,Vietnam), Republic of Korea, Russia, show diffuse alveolar damage with hyaline membrane Croatia, Kazakhstan, Romania,Turkey, Iraq, Nigeria, Egypt, formation, with varying degree of organisation. India, Niger, and Albania. Of great concern is the Bronchiolitis obliterans organising pneumonia-like increasing number of sporadic avian-to-human changes have also been reported and this may explain the transmissions of H5N1. In 1997, an outbreak of H5N1 anecdotal response of SARS to corticosteroids. influenza occurred in poultry in Hong Kong and infected 18 humans, with 6 deaths. The outbreak was probably Diagnosis terminated by massive culling of 1·5 million poultry. Another two cases of H5N1 human infection were Owing to the non-specific nature of the disease, initial described in Hong Kong in 2003, having acquired the diagnosis, particularly in the absence of epidemiological disease in mainland China. Since 2003, an increasing linkage, could be difficult and requires careful exclusion of number of human cases have been reported from other viral and bacterial infections. Epidemiological clues Southeast Asian countries (Indonesia, Vietnam, Thailand, and the lack of response to treatment targeted at common Cambodia and China). At the time of writing, a total of respiratory pathogens are helpful in making the correct 177 cases with 98 deaths have been described. diagnosis. Viral RNA can often be detected by RT-PCR in nasopharyngeal aspirate, stool, and urine, but the sensitivity H5N1 virus and its transmission is variable and multiple, repeated testing might be necessary. Viral culture is of lower yield than RT-PCR. Seroconversion Influenza viruses are RNA viruses with a segmented is regarded as the gold standard to diagnose SARS-CoV genome and they display marked antigenic diversity. infection, but a significant fourfold rise in IgG might take Influenza A viruses are classified by subtypes of surface more than 60 days, and therefore is not useful for acute glycoproteins, the HA and NA. Aquatic birds are natural management. The presence of an epidemiological link, reservoirs of influenza A, with 16 HA and 9 NA subtypes. radiographic deterioration within 48 hours of admission, Human infections are commonly associated with three HA myalgia, lymphopenia, and elevated alanine transferase subtypes (H1–H3), although avian influenza of other classifies a patient as high risk for SARS. Obviously, RT-PCR subtypes (H5N1, H9N2, H7N7, and H7N3) have and seroconversion cannot be relied upon solely for the occasionally caused human diseases. Because of the initial isolation of suspect cases and acute management. inefficient proof-reading by influenza viral RNA

polymerase, new influenza viral variants with amino acid Treatment substitutions in HA and NA can be produced, and genetic re-assortment between human and avian influenza viruses The first line of defence against H5N1 infection remains can produce new strains with pandemic potentials. As infection control measures to reduce its spread among influenza virus can be transmitted before the onset of animals, and hospital control measures to avoid symptoms, it is likely to spread more rapidly and widely nosocomial outbreaks. Recent H5N1 isolates in than SARS which is less contagious before symptom onset. Southeast Asia are highly resistant to the M2 inhibitors (amantidine and ramitidine) and, therefore, these agents So far, most cases of avian influenza infection in humans are not recommended for treatment of H5N1 infection. were acquired through direct contact with sick or dead These isolates are susceptible in vitro to neuraminidase poultry. Human-to-human transmission of H5N1 has inhibitors such as oseltamivir and zanamivir. However,the been suggested in several household clusters and in one optimal dose and duration of treatment are uncertain. case of child-to-mother transmission. Intimate Clinical application of oseltamivir, hailed to be the ‘best unprotected contact was implicated. Serological surveys defence’ does not really show significant efficacy from the in Vietnam and Thailand show no evidence of Vietnamese or Thai experience. Oseltamivir-resistant asymptomatic infections among contacts. The risk of isolates have been reported in oseltamivir-treated nosocomial transmission to healthcare workers remains patients with H5N1 infection. very low, even under poorly protected conditions. The aforementioned findings suggest that transmission of the Corticosteroids have been tried in some H5N1 patients virus to human remains very inefficient. but their use did not appear to be beneficial. Interferon- alpha may have antiviral and immunomodulatory Clinical and laboratory features properties, but will have to be tested in future RCTs. No licensed vaccine is available for H5N1, although this is an Most reported patients have an initial influenza-like area of active research. illness with high fever (>38°C) and lower respiratory tract symptoms such as dyspnoea. Upper respiratory CONCLUSION symptoms are only sometimes present. Diarrhoea, vomiting, abdominal pain, and pleuritic pain have also Severe acute respiratory syndrome-associated been reported. Two patients have been reported to coronavirus and H5N1 are two newly emerged present with encephalopathy with readily isolated H5N1 respiratory viruses that could cause severe pneumonia virus from their cerebrospinal fluid. Almost all patients with a rapid downhill course. No specific treatment is CME develop pneumonia with respiratory distress, proven to be effective. Minimising unprotected contacts tachypnoea, and radiological consolidation. Rapid with infected animals and human beings, quarantine of progression to ARDS and multi-organ failure with contacts, and prompt isolation of infected individuals are ensuing death occurs in 50–80% of cases. Old age, the mainstays in preventing outbreaks of these infections. delayed hospitalisation, presence of pneumonia, and lymphopenia are risk factors for severe disease. Similar KEYPOINTS to SARS, common laboratory findings include leukopenia, lymphopenia, thrombocytopenia, and elevated • Both SARS and avian influenza A (H5N1) virus have aminotransferases. Diffuse alveolar damage is invariably pandemic potential. found on autopsy. Reactive haemophagocytosis has been • Severe acute respiratory syndrome and H5N1 both described in the bone marrow and other organs, believed begin as influenza-like illnesses. Epidemiological to result from the ‘cytokine storm’ provoked by the information is important for making the diagnosis. H5N1 virus on macrophages. • H5N1 virus appears to be endemic in bird and poultry populations; SARS-CoV-like viruses have been isolated Diagnosis in game animals (e.g. civet cats). • Severe acute respiratory syndrome and H5N1 The clinical and laboratory features of H5N1 disease are infections often progress rapidly to multi-focal non-specific. Epidemiological link, such as contact with pulmonary consolidation and ARDS, with significant sick or dead poultry in an area known to be affected by mortality. H5N1, is of vital importance. • Treatment is supportive and no antiviral drug has been shown, by RCT, to reduce the mortality of either Rapid presumptive diagnosis of H5N1 can be afforded by infection. immunofluorescence using H5-specific monoclonal • Minimising unprotected human contact with infected antibodies or by RT-PCR of H5-specific RNA on animals and humans, and appropriate quarantine nasopharyngeal aspirates. Viral culture from clinical measures are the mainstays in preventing outbreaks of specimens and H5-specific serological testing allow a SARS and H5N1 infection. definitive, albeit retrospective diagnosis.

REFERENCES respiratory syndrome. N Engl J Med 2003; 349(25):2431–41. 4 Beigel JH, Farrar J, Han AM et al. Writing Committee of the World 1 Tsang KW,Ho PL, Ooi GC et al. A cluster of cases of severe acute Health Organization (WHO) Consultation on human Influenza respiratory syndrome in Hong Kong. N Engl J Med 2003; A/H5.Avian influenza A (H5N1) infection in humans. N Engl J Med 348(20):1977–85. 2005; 353(13):1374–85. 2 Peiris JS, Chu CM, Cheng VC et al. HKU/UCH SARS Study Group. 5 Ho PL, Chau PH, Yip PS et al. A prediction rule for clinical Clinical progression and viral load in a community outbreak of diagnosis of severe acute respiratory syndrome. Eur Respir J coronavirus-associated SARS pneumonia: a prospective study. 2005; 26(3):474–9. Lancet 2003; 361(9371):1767–72. 3 Peiris JS, Yuen KY, Osterhaus AD, Stohr K. The severe acute

found black and parched, just as if they had been indurated in smoak’. The king had warned his subjects that smoking tobacco ‘impaired the body’ and was ‘injurious to the lungs’.

After presenting the evidence, Paulli regarded those who willingly purchased ‘sickness and death’ to be ‘infatuated and hood-winked’. In conclusion, he stated,‘If any champion for the interests of tobacco should ask me whether I would have the Pope, the Emperor, and all the Kings, Electors, Princes, and Dukes in Europe, prohibit and discharge the

CME use of tobacco? I answer, that such a revolution is really to be wished for’.

Paulli clearly showed his concern for ‘INJURIOUS TO THE LUNGS’ summary of the arguments for and public health; ‘what is more frequent against tobacco smoking, and than for people of all denominations Warnings against the harmful effects ‘impartially considered’ its use to spend the whole of the day of smoking tobacco are not new. They ‘upon the principles of medicine smoaking tobacco in ale-houses and were being made by physicians over and chymistry’. taverns?’ Not any more in Scotland,Dr three hundred years ago. Although Paulli! It has taken a long time but many during the seventeenth century Paulli was particularly impressed by some of the ‘Princes’ are now listening. regarded tobacco to be a remedy for ‘James the Sixth of England’ who had On Sunday 26 March 2006, Scotland all ills, others argued fiercely against it. ‘disputed publickly against the use of became the first part of the UK to ban Simon Paulli was professor of botany, tobacco, giving instances of persons smoking in enclosed public places. anatomy and surgery at Copenhagen, who used it who were afflicted with and physician to Christian IV of incurable disorders of the breast … John Dallas, Denmark. In 1665, he published a after whose death, the lungs were Rare Books Librarian, RCPE