Respiratory Infections: Deadly and on the Rise

LIFE SCIENCES: BUSINESS & TECHNOLOGY REVIEW

Passengers on Hong Kong's Mass Transit Railway wearing masks to protect against the SARS virus in March 2003; the death toll at the time of this picture was 13 with 530 people infected

By Wilson da Silva

They are deadly, spread fast and are known killers: they’re respiratory infections, and they have long been a major concern to clinicians. But the last decade has also seen a surprising increase in new diseases, and a comeback by older ones: making respiratory infections again a hot topic.

Most notable of late was the emergence of Severe Acute Respiratory Syndrome (SARS), which appeared in southern China and spread to 28 countries within months, eventually infecting 8,096 and claiming 774 lives. The story of SARS is enlightening, for it highlights both the strengths and weaknesses of existing procedures, from infection control and treatment to surveillance and monitoring.

While it was ultimately controlled, and the danger of a global pandemic subsided, the fledgling new organism could have been eliminated altogether – but it wasn’t. Now the world has yet another microbial assassin lurking in the shadows, another deadly respiratory illness that preys on man – in a world already replete with them.

New Killers on the Block

Along with SARS – now known to be caused by a novel coronavirus that jumped to humans from the animal world – the past 15 years has seen the rise of hantavirus, the Hendra and Nipah viruses, metapneumovirus and avian influenza. It has also seen the return of fatal ailments like whooping cough and measles, and the rise deadlier, drug-resistant strains of tuberculosis. And that’s just among rich nations: the developing world has faced the return of old scourges like cholera and the rise of new agents like Ebola.

In all cases, emerging and re-emerging diseases were uncovered thanks to the diligence of health professionals: “Early diseases get picked up because doctors and nurses think, ‘there’s something funny about this’,” said Dr Peter Collignon, a leading clinical microbiologist in Australia and a professor of medicine at Canberra’s Australian National University.

“Even the anthrax attacks in the U.S. – there was a surveillance system in place for bioterrorism, but it didn’t pick it up. It was detected by doctors saying, ‘hey, this doesn’t fit’,” he told Life Sciences Business & Technology Review. “I think that’s the reality of how new emerging diseases are going to be identified. A surveillance system is too blunt to pick it up: if you’re looking at hundreds of thousands of cases, one or two won’t blip on the radar. It only gets noticed when there are large numbers – and by then, to some degree, you’ve missed the boat.”

That’s not to say that surveillance is not important, he added: it’s just not the cure-all some officials think it is. Infection control is like war: the price of peace is eternal vigilance. And vigilance means not just surveillance and monitoring by national, regional and global public health bodies, but an appreciation of the importance of public health itself – a basic medical discipline that grew unfashionable and was marginalised by better-funded fields like chronic disease.

In a world where good public health is often slow to keep pace with rapid industrialisation, and where anyone with an air ticket – and a novel infection – can be a world away within a few hours, more powerful tools are needed to fight the threat of emerging diseases, experts say.

The World Health Organization (WHO) acknowledges as much; at a meeting in The Philippines in April, regional director Dr Shigeru Omi said the International Health Regulations - the internationally-binding legal framework governing the global spread of disease – need an urgent overhaul.

Workers disinfecting the waiting area of a Beijing railway station in May 2003

“These regulations relate to an era when infectious diseases were on the decline," he said. Since they were drafted by the United Nations body more than 30 years ago, the level of risk has risen significantly, driven by population growth, industrialisation and large-scale environmental change, he said. “Microbes evolve, and this process is being accelerated by human activity. Human and animal populations provide many appealing ecological niches, and environmental degradation and change are accelerating the potential for epidemic disease spread.”

The WHO has asked for the power to verify information about disease from official and unofficial sources at its discretion and to strengthen binding protocols to deal with outbreaks. Draft new regulations are currently being discussed, and an intergovernmental panel will meet in Geneva in November to iron out a final draft. This is expected to go before WHO's governing body, the World Health Assembly, in 2005 for approval.

But some public health professionals have gone further, suggesting that the U.N. Security Council, the World Trade Organization and the International Monetary Fund impose sanctions on countries that do not comply with their obligations under the regulations, or those that fail to cooperate with the WHO during a public health emergency. Of course, the topic not often discussed is funding: the WHO’s global surveillance of infectious disease operates on less than the budget of a major metropolitan U.S. hospital: US$82.2 million – a figure that fell 2.3% this year.

Old School Killer 

Looming over every discussion of new respiratory infections is influenza - humanity’s deadliest microbial predator and the one most feared by clinicians. 

“As interesting and exotic as Nipah and SARS may be, influenza still remains far and away the real threat,” said Professor George Rutherford, a former chief epidemiologist for California and head of public health at the University of California, San Francisco. “It has killed millions upon millions of people in the 20th century, and is the only disease that has truly proven capacity for massive epidemic spread and massive mortality.”

Another threat is an infection not usually thought of as respiratory, but which is primarily spread via respiratory secretions: measles. “That truly has the potential for epidemic spread, as happened in 1988-91. There were 16,400 cases in California alone, and this is against a background vaccination rate of 90%,” Rutherford added.

During the 1988-91 outbreak in the Americas, there were 55,622 cases in the United States – mostly children under 5 - and 123 deaths. Ninety percent of those who died were unvaccinated, and cases among unvaccinated Hispanic and African American populations were four to seven times higher than among non-Hispanics. Since 1993, large outbreaks have also occurred where vaccination is refused, such as communities in Utah and Nevada, and in Christian Scientist schools in Missouri and Illinois.

Patients put on face masks as they leave a SARS clinic at Sunnybrook & Women's hospital in Toronto

“It kind of falls off the radar screen from time to time, but where it gets out of control, it is a really big deal,” Rutherford said. “The people who die are infants and adults … and the case fatality rate for adults is about 2%, so it’s not inconsequential. Basically, if you’ve got a vaccine, use it.”

Tuberculosis is still a problem, and especially worrying are the drug-resistant strains. There were almost 16,000 cases in the U.S. in 2001 – down from 26,673 a decade earlier – and 749 deaths. Overall, 7% of reported cases were drug-resistant: one-third of these from New York and California. Worldwide, the WHO estimates that one in three people alive today - about 2 billion - are infected with tuberculosis; 50 million of them with drug resistant strains. There are about 10 million new TB cases every year, and between two and three million deaths.

Not Gone, But Forgotten?

Another respiratory ailment often ignored, and only on the increase thanks to falling vaccination rates, is pertussis or whooping cough. A recent analysis by the Centers for Disease Control and Prevention in Atlanta found more than 11,000 pertussis cases in the U.S. last year – up 12.5% on the previous year and the highest recorded rate in three decades.

“Whooping cough does kill, but it’s a very small percentage of people and usually the very young,” said Collignon. “And yet, whooping cough kills more people than bioterrorism ever has.” 

That’s not to say bioterrorism research is not important, said the Australian clinician: current efforts may actually help detect emerging diseases. “But the fear factor can distort rational allocation of resources. I mean, we desperately need a better vaccine for whooping cough that can be given to newborn children. They have to be at least two months old now.”

The solutions are new and better pharmaceuticals to kill an infection, vaccines to reduce epidemics from spreading, and the design of new drugs that target not just the eradication of a microbe, but interfere with its functions: adhesion, replication, and so on. And of course, good public health practice: clean water, food hygiene standards, and so on – the easiest approach and yet the one most often overlooked. 

Sometimes even a small factor in an otherwise hygienic setting can spread a new disease dramatically, thanks to modern crowded conditions. Take the SARS outbreak: just when Hong Kong doctors thought they had quarantined the disease to a few hospitals, an outbreak at an apartment complex saw more than 300 residents infected within days.

In the April 22 issue of the New England Journal of Medicine, Hong Kong clinicians tell how a single individual – whose faeces was later found to replete with SARS coronavirus – transmitted the illness over five days just by flushing a toilet. 

Dried-out traps in bathroom floor drains in the building allowed an exhaust fan to draw droplets from the drainage pipe into air shafts, from whence the contaminated air plume spread. But Hong Kong researchers, who built a model of the drainage system, also found large numbers of aerosol particles could be circulated just by flushing.

“One wonders if this is a pathway that we just have never noticed before,” said Dr Donald Milton of the Harvard School of Public Health in Boston. Research needs to be reactivated into airborne transmission, a field largely ignored in the past half century: “There's a lot of new technology around in that 50 years, and we ought to be able to make some advances … this was a wake-up call.”

Old School Killer 

Another salient lesson from SARS was how political sensitivities can help the rapid spread of a novel microbe. The reticence of Chinese health officials to report a new pneumonia-like disease in Guangdong province in November 2002 allowed the virus to spread unchecked. SARS did not become an epidemic until three months later, when a hapless Chinese doctor brought the ailment with him on a visit to Hong Kong; all infections outside of Guandong, from Hong Kong and Vietnam to Canada, can be traced to the hotel in which he stayed.

A man wears a surgical mask in a Hong Kong street in May 2003

Even when an outbreak was clearly in progress, precious time was wasted by China’s early refusals to allow WHO experts to travel to Guangdong or visit military hospitals in Beijing where SARS patients were hidden. China has since made a great show of transparency, sacking health officials who oversaw the initial cover-up and opening its doors to WHO inspections.

Then there’s avian influenza virus H5N1. The first known case of direct bird-to-human infection struck in Hong Kong in 1997, infecting 18 and killing six. In December 2003, new cases in poultry were reported in South Korea, Indonesia, Japan, Vietnam, Cambodia, Laos, Thailand and China – and they soon spread to humans.

In this latest outbreak, the highly pathogenic H5N1 virus has infected 34 people in Vietnam and Thailand, killing 23 – a death rate of 67%. This compares with 33% in 1997 Hong Kong outbreak of H5N1, and 73% in an earlier outbreak in Vietnam in January 2004. All those infected appear to have been exposed to live poultry before falling ill, suggesting human-to-human transmission of avian influenza H5N1 is still poor. 

“The good news is there’s no human-to-human transmission, but how long that will last with a rapidly-mutating virus, we don’t know,” Rutherford told Life Sciences Business & Technology Review. “The bad news is that the case fatality rate is very high among people who acquired it from poultry. There’s no immunity to it.”

Public health officials know that a worldwide flu pandemic is long overdue: the last was in 1968, when the so-called ‘Hong Kong flu’ – an influenza A virus H3N2 – killed more than a million people worldwide, including 34,000 in the U.S. The next pandemic would kill an estimated minimum of 89,000 people in the U.S., and 650,000 in industrialised countries – with the toll in the developing world being much, much higher.

Plan of Attack

But there is a bright side, experts point out. Antiviral drugs effective against all strains of flu – such as Glaxo’s Relenza and Roche’s Tamiflu – did not exist during the last global pandemic.

“In addition, the antigens for detecting influenza are much better,” said Rutherford. “The diagnostic techniques have become much more sophisticated – they’re faster and much more definitive, and we have sequencing techniques we didn’t have. Which is one of the reasons SARS got solved so quickly.” 

However, it will not be a cakewalk: “It’s still going to kill a lot of people - there’s a lot more people who are immuno-suppressed [because of HIV/AIDS], and a lot of people using steroids and immuno-suppression drugs. And we still don’t make nearly enough flu vaccine – if you had vaccinate everyone over 50 in the U.S., there wouldn’t be enough.”

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