REVIEW URRENT C OPINION

Emerging respiratory tract viral infections David S. Hui a and Alimuddin Zumla b

Purpose of review This article reviews the clinical and treatment aspects of avian influenza viruses and the Middle East Respiratory Syndrome coronavirus (MERS-CoV). Recent findings Avian influenza A(H5N1) and A(H7N9) viruses have continued to circulate widely in some poultry populations and infect humans sporadically. Sporadic human cases of avian A(H5N6), A(H10N8) and A(H6N1) have also emerged. Closure of live poultry markets in China has reduced the risk of A(H7N9) infection. Observational studies have shown that oseltamivir treatment for adults hospitalized with severe influenza is associated with lower mortality and better clinical outcomes, even as late as 4–5 days after symptom onset. Whether higher than standard doses of neuraminidase inhibitor would provide greater antiviral effects in such patients requires further investigation. High-dose systemic corticosteroids were associated with worse outcomes in patients with A(H1N1)pdm09 or A(H5N1). MERS-CoV has continued to spread since its first discovery in 2012. The mortality rates are high in those with comorbid diseases. There is no specific antiviral treatment or vaccine available. The exact mode of transmission from animals to humans remains unknown. Summary There is an urgent need for developing more effective antiviral therapies to reduce morbidity and mortality of these emerging viral respiratory tract infections. Keywords avian influenza, Middle East Respiratory Syndrome coronavirus, respiratory tract infections, treatment, viral

INTRODUCTION Severe acute respiratory infections (SARIs) such as avian influenza A(H5N1) [1] and A(H7N9) viruses [2] with pandemic potential have continued to circulate widely in some poultry populations and infect humans sporadically. As most humans have no background immunity to these viruses, infection caused by these viruses may lead to severe disease and death. Sporadic human cases of avian A(H5N6) [3], A(H10N8) [4 ] and A(H6N1) [5 ] have also emerged in recent years. The global circulation of oseltamivirresistant seasonal influenza, the emergence of A(H1N1)pdm09 virus in 2009 followed by its continual circulation [6] and the ongoing outbreak of Middle East Respiratory Syndrome coronavirus (MERS-CoV) since its first discovery in 2012 [7] all point to an urgent need for developing more effective antiviral therapies to reduce morbidity and mortality. This article reviews the clinical and treatment aspects of these important and emerging viral SARIs. &

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H5N1 VIRUSES Human cases of the highly pathogenic avian influenza A(H5N1) were first documented in Hong Kong www.co-pulmonarymedicine.com

in 1997 [1]. It re-emerged unexpectedly in 2003 [8] before spreading to other parts of Asia, the Middle East, Europe and Africa. As of 26 January 2015, there have been 413 deaths out of 718 human cases in 16 countries [9]. There was one fatal case in a Canadian tourist who died of meningo-encephalitis in January 2014 in Alberta after visiting Beijing in December 2013 without clear exposure to infected avian sources or environmental contamination [10]. A history of exposure to dead or sick poultry/wild birds occurs in over 60% of cases of human A(H5N1) infection. The incubation period for A(H5N1) infection may range from 2 to 8 days but may be as long as 17 days. a Division of Respiratory Medicine and Stanley Ho Center for Emerging Infectious Diseases, The Chinese University of Hong Kong, Shatin New Territories, Hong Kong and bDivision of Infection and Immunity, University College London, and NIHR Biomedical Research Centre, UCL Hospitals NHS Foundation Trust, London, UK

Correspondence to David S. Hui, Division of Respiratory Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin New Territories, Hong Kong. Tel: +852 2632 3128; fax: +852 2648 9957; e-mail: [email protected] Curr Opin Pulm Med 2015, 21:284–292 DOI:10.1097/MCP.0000000000000153 Volume 21  Number 3  May 2015

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Emerging respiratory tract viral infections Hui and Zumla

KEY POINTS  Avian influenza A(H5N1) and A(H7N9) viruses with pandemic potential have continued to circulate widely in some poultry populations and infect humans sporadically.  Sporadic human cases of avian A(H5N6), A(H10N8) and A(H6N1) have also emerged in recent years.  Observational studies have shown that oseltamivir treatment for adults hospitalized with severe influenza is associated with lower mortality and better clinical outcomes, especially when antiviral treatment has been initiated within 2 days of illness onset but even as late as 4–5 days after symptom onset.  The mortality rates of MERS-CoV infection are high among those with comorbid diseases and the exact mode of transmission from animals to humans remains unknown.  There is an urgent need for developing more effective antiviral therapies to reduce the morbidity and mortality of these emerging respiratory tract viral infections.

The clinical spectrum has ranged from asymptomatic infection or mild influenza-like illness to severe pneumonia, and multiorgan failure. Some of the A(H5N1) human cases have been linked to consumption of dishes made of raw, contaminated poultry blood. However, slaughter, defeathering, handling carcasses of infected poultry and preparing poultry for consumption, especially in household settings, are likely to be important risk factors [11,12]. Among the fatal cases, the median duration from symptom onset to death was 9–10 days (range 6–30 days) [12]. Viral RNA in blood was present in fatal H5N1 cases and was associated with higher pharyngeal viral loads. Nasopharyngeal swab samples, bronchoalveolar lavage and cerebrospinal fluid samples tested positive in the Canadian case for influenza A(H5N1) virus by various molecular testing methods, including sequencing [10]. In addition, low peripheral blood T-lymphocyte counts and high chemokine and cytokine levels have been observed in severe H5N1 infection and these correlated with pharyngeal loads [13]. A new reassortant genotype of H5N1 containing the haemagglutinin and neuraminidase genes from clade 1.1.2 and the internal genes from clade 2.3.2.1 was detected in 2013 and was associated with the highest number of cases (n ¼ 26) and deaths (n ¼ 14) in Cambodia [14 ]. Full viral genome analysis of the fatal case in Canada has shown an HA gene of clade 2.3.2.1c and is a reassortant with an A(H9N2) subtype lineage polymerase basic 2 gene without &

mutations conferring resistance to adamantanes or neuraminidase inhibitors (NAIs) [10]. Human– human transmission has been rare, as a metaanalysis has shown that only 1–2% of more than 12 500 study participants from 20 studies exposed to patients with A(H5N1) infection had sero-evidence for prior A(H5N1) infection [15]. Delay in the delivery of appropriate treatment to patients with influenza A(H5N1) infection in Indonesia was mainly related to delay in diagnosis rather than late presentation to healthcare settings [16]. Age, country, per capita government health expenditure and delay from symptom onset to hospitalization have been identified as the risk factors for mortality related to A(H5N1) infection, emphasizing the importance of early diagnosis, treatment and supportive care [17]. A systematic review has shown that women were at a higher risk of death [odds ratio (OR) 1.75, 95% confidence interval (95% CI) 1.27– 2.44] following A(H5N1) infection, whereas young age, in particular less than 5 years old, was protective (OR 0.44, 95% CI 0.25–0.79) [18].

H7N9 VIRUSES Human infections with a new avian influenza A (H7N9) virus were first reported in China in March 2013 in patients hospitalized with severe pneumonia [19]. There were 134 human cases in the first epidemic wave from January to September 2013, whereas the second wave from October 2013 to October 2014 comprised 306 confirmed cases with 273 hospitalizations. The estimated risk of death (hospitalization fatality risk, HFR) among hospitalized cases of A(H7N9) infection in the second wave was 48% (95% credibility interval: 42–54%), which was slightly higher than the corresponding risk of 36% in the first wave. In the second wave, the HFR was estimated at 36% (95% CI, 28–45) in patients less than 60 years of age but at 59% (95% CI, 51–67) among those aged at least 60 years. The risk of death among symptomatic cases was 0.10 (95% CI, 0.029–3.6) in the second wave and was similar to the estimate in the first wave [20]. As of 26 January 2015, 486 laboratory-confirmed cases of human infection with avian influenza A(H7N9) virus, including 185 deaths, have been reported to WHO and 469 occurred within China [9]. Human cases outside the mainland of China have been confirmed in Hong Kong (n ¼ 12), Taiwan (n ¼ 4) and Malaysia (n ¼ 1) in visitors who developed illness after returning from the mainland of China to their home cities [21,22]. Current data for A(H7N9) infection indicate an incubation period ranging from 2 to 8 days, with an average of 5 days. The WHO currently recommends that an

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Infectious diseases

incubation period of 7 days be used for field investigations and monitoring of patient contacts. The median time from poultry exposure to disease onset was 6 days, whereas the median time from illness onset to hospital admission, acute respiratory distress syndrome (ARDS) development, antiviral therapy and death were 4, 7, 6 and 21 days, respectively [23 ]. Several family clusters have been reported, but there was no sustained human to human transmission [23 ]. Pre-existing comorbid conditions occurred in more than 60% of these cases. The prominent clinical features on admission were those of a severe influenza syndrome with fever, cough, fatigue and dyspnoea, whereas the most striking laboratory findings were marked lymphopenia and thrombocytopenia. Elevated cytokine levels have been observed in patients and the excessive cytokine responses may contribute to the clinical severity of A(H7N9) infection [24,25]. Comparisons of clinical features between human cases of A(H5N1) and A(H7N9) are summarized in Table 1 [23 ,26 ]. Closure of live poultry markets in the mainland of China has tremendously reduced the risk of A(H7N9) infection. An ecologic modelling study estimated that closure of live poultry markets reduced the mean daily number of A(H7N9) virus infections in the four most affected cities by 97–99%

[27]. A retrospective serological study of blood specimens taken in January–May and October– November in 2012 from 1544 individuals who worked in live poultry markets, farms, slaughter houses or kept backyard poultry in Eastern China revealed no evidence of A(H7N9) infection [28].

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Table 1. Comparisons of clinical and epidemiological features between H7N9 and H5N1 [23 ,26 ] &&

Median age (years) Male, %

&

H7N9 (n ¼ 139)

H5N1 (n ¼ 43)

61 (2–91)

26 (19–35)

71%

22 (51%)

Comorbid illness

79/108 (73%)

5/41 (12%)

Urban residence

101 (73%)

19 (44%)

Rural residence

38 (27%)

24 (56%)

82%

29/41 (71%)

Occupational exposure to poultry

9 (6%)

4 (9%)

Visited wet poultry markets

70/107 (65%)

23/41 (56%)

Exposure to sick or dead poultry

63/107 (59%)

16/41 (39%)

NA

21/41 (51%)

Onset of illness to hospitalization (median, days)

4

7

Onset of illness to ARDS (median, days)

7

7.5

Onset of illness to death (median, days)

21

11

34%

70%

Exposure to poultry

Exposure to backyard poultry

Case fatality rate in hospital

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OTHER NOVEL INFLUENZA SUBTYPES The first human case of avian A(H6N1) infection was reported in a 20-year-old lady with pneumonia in Taiwan in May 2013 with subsequent full recovery following treatment with oseltamivir [5 ]. The first human case of avian A(H5N6) was confirmed in a 49-year-old man in Sichuan Province, China in May 2014 with a fatal outcome [3] and another case was confirmed in a 58-year-old man with a history of exposure to live poultry in Guangdong Province in December 2014 [29]. The virus was a reassortant that contained seven genes from A(H5N1) and the NA gene from an H6N6 virus circulating in ducks [30]. China has also confirmed three human infections, two fatal, with avian A(H10N8) viruses that contain the internal genes from A(H9N2), as does A(H7N9) [4 ,31]. Like the A(H7N9) virus, the A(H6N1) and A(H10N8) viruses have low pathogenicity in poultry and are therefore more difficult to detect in birds in contrast to the highly pathogenic A(H5N1) virus. &

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TREATMENT OF INFLUENZA VIRUSES The M2 inhibitors (amantadine and rimantadine) and the NAIs (oseltamivir, peramivir, zanamivir and laninamivir) are the main antiviral agents approved for the prevention of and treatment for influenza. In general, antiviral treatment should be commenced as soon as possible for any patient hospitalized with confirmed/suspected influenza with severe, complicated or progressive illness, and also for outpatients at a higher risk for influenza complications [32]. The M2 inhibitors (adamantanes) are not effective against influenza B viruses and recently circulating influenza A(H3N2) and influenza A(H1N1)pdm09 viruses, which are resistant due to a S31N mutation in the M2 ion channel. However, as some avian influenza A(H5N1) strains are still susceptible [33], combination of an adamantane with an NAI may enhance antiviral activity for susceptible isolates [34 ]. Oseltamivir is effective in reducing mortality (OR, 0.17; P ¼ 0.04) in influenza A(H5N1) infection when given before onset of respiratory failure [35] and may provide some survival benefit (49% reduction in mortality) when treatment is started within 6–8 days after symptom onset [36]. Several observational studies have shown that treatment with oseltamivir for adults &&

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Emerging respiratory tract viral infections Hui and Zumla

hospitalized with severe influenza is associated with lower mortality and better clinical outcomes, especially when antiviral treatment has been initiated within 2 days of illness onset but even as late as 4–5 days after symptom onset [37,38 ]. All H7N9 viruses are amantadine-resistant due to the S31N substitution in the M2 ion channel protein. In patients hospitalized with severe A(H7N9) infection, reduction of viral load following oseltamivir treatment was associated with improved outcome, whereas the emergence of virus resistant to NAIs harbouring a R292K mutation was associated with poor outcomes and lack of response to oseltamivir and peramivir, and reduced susceptibility to zanamivir and laninamivir (50-fold and 25-fold rises in IC50, respectively). Two patients with severe A(H7N9) infection and R292K mutation requiring extracorporeal membrane oxygenation (ECMO) had received systemic corticosteroid treatment, which might have contributed to treatment failure and a fatal outcome [39 ]. The recommended treatment duration of oseltamivir is generally 5 days, but longer treatment is advisable for critically ill patients with respiratory failure with persistent viral replication in the lower respiratory tract despite treatment [32,34 ]. Whether higher than standard dose of NAI would provide greater antiviral effects in such patients requires further investigation. One randomized control trial (RCT) of hospitalized patients (76% being children) revealed no clinical or virological advantages when comparing double-dose oseltamivir with standard dose [40 ]. No additional benefit of higher-dose oseltamivir treatment was observed in adults hospitalized with influenza A, although a faster virologic response was noted in influenza B [41]. However, an RCT of 18 critically ill patients with A(H1N1)pdm09 in Canada found that therapy with a triple dose of oseltamivir was associated with higher proportions of viral clearance at 5 days than standard therapy (78 versus 11%; P ¼ 0.015) [42]. Zanamivir and laninamivir have quite similar profiles of drug susceptibility. One example is that H275Y mutation, which confers high-level resistance to oseltamivir carboxylate and reduced susceptibility to peramivir in N1-containing viruses, does not reduce susceptibility to zanamivir and laninamivir significantly [43]. Intravenous zanamivir was used widely on a compassionate ground during the 2009 pandemic for late treatment of critically ill adults with influenza A(H1N1)pdm09 and those with suspected or proven oseltamivir resistance [44]. There were no drug-related trends in safety parameters and a subset of 93 patients with positive PCR tests at baseline for influenza showed a median decrease in nasopharyngeal viral RNA load &&

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of 1.42 log10 copies/ml after 2 days of treatment [45]. Intravenous zanamivir has been used with a favourable outcome in a patient with severe A(H7N9) infection complicated by pneumonia, which did not respond to oseltamivir initially [46]. Other new antiviral treatment modalities that may be useful for managing severe influenza are outlined in Table 2 [47–57,58 ,59]. &

SYSTEMIC CORTICOSTEROIDS AND OTHER IMMUNE-MODULATING AGENTS FOR SEVERE INFLUENZA Treatment with high-dose systemic corticosteroid was associated with worse outcomes in A(H5N1) patients [12]. Several observational studies have shown that systemic corticosteroid therapy given for influenza A(H1N1)pdm09-asssociated viral pneumonia or ARDS increased the risk of mortality and morbidity (e.g. secondary infections), especially when there was delay or lack of NAI therapy [57]. Systemic corticosteroid therapy might have delayed clearance of A(H7N9)virus and increased the risk of emergence of resistance to NAI in critically ill patients requiring ECMO [39 ]. During the SARS outbreak in 2003, a higher risk of avascular osteonecrosis and prolonged virus shedding were observed in patients who had received high-dose systemic corticosteroid therapy [60,61]. It is therefore advisable to avoid the use of high-dose systemic corticosteroid in severe respiratory viral infections except for the context of clinical trials. Other immunomodulating agents such as acute use of statins, N-acetylcysteine, nitazoxanide, macrolides, peroxisome proliferator-activated receptor agonists, intravenous gammaglobulin (IVIG), celecoxib, mesalazine and the role of plasmapheresis and hemoperfusion as rescue therapy require further investigation [57]. &

MIDDLE EAST RESPIRATORY SYNDROME CORONAVIRUS MERS-CoV has continued to spread within Saudi Arabia since it was first isolated from a patient who died from a severe respiratory illness in June 2012 in Jeddah [7]. The exact source and mode of infection remain unclear. Limited human-tohuman transmission has been reported in hospitals and family cluster outbreaks [62–64]. As of 16 February 2015, there have been 983 confirmed cases of MERS-CoV, with at least 360 deaths [65]. There are some similarities and yet some differences in the clinical and laboratory features between MERS and SARS [66]. Risk factors for developing severe MERS-CoV disease include comorbid illness

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Infectious diseases Table 2. Treatment modalities other than neuraminidase inhibitors for influenza Therapeutic agent(s)

Mechanisms of actions

General comments

Fludase (DAS181)

An inhaled bacterial sialidase which functions by removing sialic acid (Sia) from the surface of epithelial cells, preventing attachment and subsequent infection by respiratory viruses that utilize Sia as a receptor. Its host-directed receptor destroying action is inhibitory for parainfluenza and influenza viruses, including those resistant to & && the adamantanes and NAIs [14 ,34 ].

When delivered topically, it is effective in animal models of lethal influenza due to A(H5N1) and A(H7N9), including the NAI-resistant R292K variant [47].

A phase 2 RCT has shown that inhaled DAS181 reduced pharyngeal viral replication in uncomplicated influenza but did not reduce nasal viral loads or improve clinical outcomes [48]. Favipiravir (T-705; 6-fluoro3-hydroxy-2-pyrazinecarboxamide)

A polymerase enzyme inhibitor active against influenza A, B and C viruses, including strains resistant to current antivirals, and a broad range of other RNA viruses at somewhat higher concentrations [49].

Combinations of favipiravir and NAIs showed additive to synergistic effects in preclinical models [50], but clinical trials have been limited to uncomplicated influenza to date.

Nitazoxanide (NTX)

An oral antiparasitic agent, with immunomodulatory effects, including upregulation of interferon and various interferon-inducible genes, and a specific influenza inhibitory effect related to blockade of HA maturation [51].

A phase 2 RCT reported significant antiviral effects (1.0 log10 reduction in nasal viral loads) with NTX 600 mg twice daily for 5 days and shorter time to alleviation of illness (difference in medians of about 20 h vs. placebo) in acute uncomplicated influenza [52].

Combination of antiviral agents

A triple combination antiviral drug (TCAD) regimen composed of amantadine, oseltamivir and ribavirin was superior to dual and single drug regimens in mice infected with drug-susceptible, low pathogenic A(H5N1) (A/Duck/MN/1525/ 81) and amantadine-resistant 2009 A(H1N1) influenza (A/California/04/09). Amantadine monotherapy had no activity against the amantadine-resistant virus, but showed dose-dependent protection in combination with oseltamivir and ribavirin, suggesting that amantadine’s activity could be restored in the context of TCAD therapy [53].

TCAD therapy resulted in >90% survival in mice infected with both viruses, whereas treatment with dual and single drug regimens resulted in 0% to 60% survival. Furthermore, TCAD therapy provided survival benefit when treatment was delayed until 72 hrs postinfection, whereas oseltamivir monotherapy was not protective after 24 h postinfection [53].

In contrast to combinations of agents with differing mechanisms of action, combining optimal doses of agents with the similar mechanisms of actions (e.g. dual NAIs) does not enhance antiviral activity and may sometimes result in antagonism [54].

One retrospective study of critically ill adults suggested trends towards lower mortality in TCAD recipients than those receiving oseltamivir alone [55].

Host-directed therapies aiming at reducing the unproductive damaging consequence of the host immune response to the pathogen.

Combinations of oseltamivir with prednisolone and sirolimus was associated with shortened liberation of ventilator and ventilator days in patients with severe pneumonia due to A(H1N1)pdm09 [56].

Antivirals combined with host-directed therapies

E.g. Sirolimus, a mammalian target of rapamycin inhibitor may potentially inhibit autophagic cell death and may have positive impact in preventing or speeding recovery from ARDS. Passive immunotherapy

288

Neutralizing antibodies against influenza virus.

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Non-RCTs and case reports suggest that convalescent plasma with neutralizing antibodies appeared useful as add-on therapy for patients with SARS and severe influenza pneumonia including that caused by A(H5N1) [57].

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Emerging respiratory tract viral infections Hui and Zumla Table 2 (Continued) Therapeutic agent(s)

Mechanisms of actions

General comments Exploratory posthoc meta-analysis of studies on SARS-CoV and severe influenza showed a significant reduction in the pooled odds of mortality following convalescent plasma treatment, vs. placebo or no therapy [odds ratio, 0.25; 95% & CI, 0.14–0.45; I(2) ¼ 0%] [58 ]. ARCT reported a mortality benefit in patients with severe A(H1N1)pdm09 illness when hyperimmune globulin was given within 5 days of symptom onset (OR, 0.14; 95% CI, 0.02–0.92; P ¼ 0.04) [59]. Hetero-subtypic anti-HA stem neutralizing antibodies, which appear highly effective in animal models [60], are entering clinical testing.

such as obesity, diabetes, an immuno-compromised state, cardiac disease and pulmonary disease [62,63, 66–68]. One case series in Saudi Arabia has shown that concomitant infections (OR 14.13, 95% CI 1.58–126.09; P ¼ 0.018) and low albumin (OR 6.31, 95% CI 1.24–31.90; P ¼ 0.026) were independent predictors of severe illness requiring intensive care support, whereas age at least 65 years was the only predictor of mortality (OR 4.39, 95% CI 2.13–9.05; P < 0.001) [69]. The rate of secondary transmission among household contacts of patients with MERSCoV infection is about 5% [70 ]. Prolonged viral shedding over 5 weeks has been observed in an asymptomatic healthcare worker after looking after a confirmed and symptomatic case of MERS-CoV infection wearing a surgical mask and gloves [71]. Numerous therapeutic options have been explored for the treatment of MERS-CoV, but there has been no therapy of proven benefit. The use of systemic corticosteroid was associated with significant adverse effects in SARS [60,61] and would not be recommended for MERS-CoV. MERS-CoV is readily inhibited by type I interferons (IFN-a and especially IFN-b) [72,73]. A combination of IFNa2b and ribavirin reduced lung injury and modestly reduced viral replication (

Emerging respiratory tract viral infections.

This article reviews the clinical and treatment aspects of avian influenza viruses and the Middle East Respiratory Syndrome coronavirus (MERS-CoV)...
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