Chronic diseases are placing an increasingly heavy burden on the healthcare systems of both development and emerging countries. Together with renewed prevention strategies based on systematic and coordinated approaches, clinical laboratories will have an essential role to play with the advent of new biomarkers and the development of e-health systems.

Chronic diseases are acknowledged to be one of the biggest challenges for healthcare systems. Traditionally, chronic diseases were non-communicable. Using World Health Organization (WHO) data [1], they consisted of four major groups – cardiovascular diseases, cancers, chronic respiratory diseases and diabetes, as well as some neuropsychiatric disorders and arthritis. More recently, an increase in survival rates for infectious and genetic diseases has led to expanding the definition to certain communicable diseases (such as HIV/AIDS) as well as genetic disorders like cystic fibrosis.

Attention to chronic diseases has been growing, largely due to three factors:
1. Ageing populations.
2. Early detection, or ‘secondary prevention’.
3. E-health – the possibility offered by sophisticated at-home monitoring and timely treatment.

Ageing populations
The elderly are far more susceptible to chronic disease. In the US, some 10% of the beneficiaries of Medicare, almost all with chronic disease, account for three-quarters of its budget. [2] Per capita spending is 3-10 times more for older adults with chronic diseases than those without. [3] In Europe, the EU Council has noted the “enormous burden” posed by chronic diseases and also warned that the next decade (2011-2020) will see this grow further due to an ageing population. [4]

Early detection
The early detection of chronic disease has been revolutionized by virtue of innovative and ever-faster diagnostic techniques in clinical laboratories. Clinical laboratories have, for some years, taken the lead in reducing the gap between the evolution of a chronic disease and interventional treatment, both at home and in the hospital.

In 2007, a report by the influential Milken Institute think-tank made a powerful argument to include prevention and early detection, rather than treatment alone, in the US debate on funding healthcare. The Milken report was titled ‘An Unhealthy America: The Economic Burden of Chronic Disease’. [5] It was one of the most ambitious attempts to quantify the reduction in case burden that could be achieved by such strategic reorientation: a drop by as many as 40 million cases of chronic diseases in the year 2023, in the US alone. At the time of the report’s launch, former US Surgeon General Richard Carmona noted the biggest problem with the present healthcare system was that it waited for people to get sick and then treated them at high cost.
   
The story is similar in Europe. Though EU-wide statistics do not yet exist, in the UK, half of hospital bed day use is accounted for by only 2.7% of all medical conditions, most of which are chronic diseases. [6] The EU Commission has called for technology-driven strategies to permit both early detection and timely monitoring of chronic disease – and do this in the context of healthy ageing.

As in the US, much European thinking about managing the burden of chronic disease involves e-Health, especially in the context of structured programmes of home care for patients. In January 2007, a major EU Commission study called “Healthy Ageing: Keystone for a Sustainable Europe” [7] approvingly highlighted a Swedish program called ‘Preventive Home Visits’ as leading to both a decrease in GP visits and lower mortality. It called for promoting and using such best-of-class practices across the EU.

E-health and clinical laboratories
All such plans essentially consist of remote acquisition of patient data using lower skilled and mobile personnel. They transfer the data in real- or near real-time for remote interpretation at a clinical laboratory, followed by consultation with a physician (e.g to modify dosage/change medicines), or to transfer the patient for intervention at a hospital.

The role of the clinical laboratory in e-Health is already advanced in telepathology. Though some telepathology efforts have aimed at remote manipulation of diagnostic equipment, the more proven approach has been to transmit images from a slide. Such systems have been in use since the mid-1990s, especially in sparsely populated areas such as parts of Canada and the north-western US, and in Norway and Sweden. France’s RESINTEL was, however, one of the first systems to establish that telepathology was at least as reliable as a physical slide examination, in a transatlantic pilot project. [8]

The largest application for telepathology has so far been in cytology. Nevertheless, microbiologists have been remotely interpreting gram stains, and hematologists have reported success with blood films.

Biomarkers: promises and challenges
The next frontier is likely to be biomarkers – pre-symptomatic signals of early disease states, detectable in blood/serum. In 2011, an article by 61 healthcare experts from Europe, the US, Brazil, Russia, India, China and some other countries called for a systemic approach to combat chronic disease, with a roadmap “for predictive, preventive, personalized and participatory (P4) medicine.” [9] The core of the proposal is to systematically identify biomarkers, which would then (progressively) be used to chart out a matrix of co-morbidities, disease severity and progression – including the critical trigger signals which predict the occurrence of abrupt transitions in the stages of a chronic disease.
   
The authors of the above paper cite an in-depth study on the clinical impact of telemedicine in four major chronic diseases – diabetes, asthma, heart failure and hypertension, [10] and propose that continuous monitoring of individual clinical histories and their development would be a key source of primary data, to build up a robust and extensive knowledge management infrastructure.

The role of clinical laboratories in much of the above system – from biomarker discovery to the monitoring of patients – is evident.  At the moment, tests on the bulk of approved biomarkers (such as Oncotype DX and Trofile) are conducted in large reference laboratories. However, a great deal of research is also being directed at tests for use at home or at point-of-care; for example, CRP (C-reactive protein) and the hormone prolactonin are biomarkers which differentiate between bacterial and viral pneumonia in less than an hour, and reduce the use of precautionary antibiotics.

Nevertheless, there is still some way to go before biomarkers and systemic/personal approaches to medication and treatment of chronic disease become commonplace. Most barriers are regulatory [see box on this page], and are a consequence of the relative novelty of biomarkers – and their potentially sweeping impact.

In the light of this, the challenge for clinical laboratories will be to develop acceptable technical standards for the use of biomarkers, jointly with regulators and manufacturers. Clearly, given the massive challenge posed by chronic diseases in the decades ahead, any serious solution will have to involve a combination of biomarker-based personalized medicine, at-home care and clinical laboratories.

References
1. http://www.who.int/nmh/Actionplan-PC-NCD-2008.pdf
2. Berk ML, Monheit AC. The Concentration of Health Expenditures: An Update. HealthAffairs 1992; 11 (4): 145–149.
3. Fishman P, et al. Chronic Care Costs in Managed Care. Health Affairs 1997; 16 (3): 239–247.
4. http://www.consilium.europa.eu/uedocs/cms_Data/docs/pressdata/en/lsa/118282.pdf
5. http://www.milkeninstitute.org/healthreform/pdf/AnUnhealthyAmericaExecSumm.pdf
6. Chronic Disease management – a compendium of information, UK Department of Health, May 2004
7. http://ec.europa.eu/health/archive/ph_information/indicators/docs/healthy_ageing_en.pdf
8. http://pubmedcentralcanada.ca/pmcc/articles/PMC2579163/pdf/procascamc00009-0625.pdf
9. http://genomemedicine.com/content/3/7/43#B46
10. Pare G, Moqadem K, Pineau G, St-Hilaire C. Clinical effects of home telemonitoring in the context of diabetes, asthma, heart failure and hypertension: a systematic review. J Med Internet Res 2010 (12:e21).
11. http://ec.europa.eu/research/health/pdf/biomarkers-for-patient-stratification_en.pdf
12. http://www.phgfoundation.org/file/3998/

Simmering concerns about respiratory disease pandemics flared up again in mid-February after the death of a patient in Britain due to infection by a new coronavirus. The virus is part of a family which also includes the one that caused the deadly SARS (severe acute respiratory syndrome) crisis.

To recall, in the space of just seven months from November 2002, SARS spread from Hong Kong to over 37 countries, infecting over 8,000 people and killing 775. Its mortality rate was close to that of the 1918 Spanish flu outbreak – billed the ‘Mother of all Pandemics’, and 100 times more than typical influenza epidemics. SARS has since faded away, but the virus is probably lying dormant; it can also infect cats and dogs.

SARS, bird flu and swine flu
SARS outgunned the H5N1 influenza strain which also emerged out of Asia in 1997; this was largely due to the inability of the latter, best known as ‘bird flu’, to spread between people.

In 2009, another influenza strain, Type A/H1N1, involving a cocktail of genes from pigs, birds and humans, was identified in Mexico. By June, the World Health Organization (WHO) had declared the disease (dubbed ‘swine flu’) as a Level 6 pandemic , but this was due to the speed of its spread rather than mortality, which was less than the common flu.

The new coronavirus
The numbers infected by the new coronavirus are small, just 12, so far. However, the virus has some troubling characteristics. Unlike swine flu, mortality is high, and typically accompanied by pneumonia and renal failure. Of the 12 infected so far, six have died, according to the WHO. Of equal concern is the possibility of  human-to-human transmission, as opposed to bird flu.

This time, the new virus has its origins in the Middle East, with Saudi Arabia and Jordan accounting for seven infections and five deaths. In November 2012, the WHO reported cases from within one Saudi Arabian family. However, it was impossible to determine if the patients were infected separately but simultaneously (during travel), or whether the disease had spread between them. Europe hosts the remaining cases – one in Germany and four in Britain, including the Birmingham fatality. While the German patient had been in Qatar, in Britain, rather than the victim, it was his father who had travelled to the Middle East. Since then, the father is reported to have infected yet another family member. Prof. John Watson, head of the Respiratory Disease Unit at the British Health Protection Agency (HPA), noted that this suggested “that person-to-person transmission has occurred.”

Nevertheless, British health officials have been quick to ward off panic. The Birmingham victim is reported to have had a weakened immune system placing him in a vulnerable risk group. The HPA’s Deputy Chief Executive Dr. Paul Cosford has underlined that the disease appears “very difficult to catch.” Prof. Wendy Barclay of Imperial College London adds: “We’re an incremental step closer to worrying, but it isn’t a worry where we need to say there is a pandemic coming.”

Getting it right
These are reassuring words for the public, but hardly so for clinical laboratories. If any of the above assumptions are (or turn out to be) wrong, the challenge for labs will be herculean – as demonstrated during the SARS crisis. Indeed, Prof. Barclay’s statements were reported four days before the new virus took its first casualty in Britain.

Though coronaviruses are fragile (they are easily destroyed by detergents and survive outside a host organism for only a day or so), the severity of illnesses like SARS compel authorities to err on the side of caution – including enforcing quarantine (with its disturbing legal implications). The nature of such a response, in turn, places inordinately heavy demands on labs to get their diagnoses right, and be ready to ramp up scale exponentially. Complicating matters further is the fact that coronaviruses are a large family. Other than SARS, they also include the virus which causes the common cold.

Though several diagnostic tests have emerged since the SARS crisis, each has its limitations. Enzyme-linked immunosorbent assays (ELISA) detect antibodies to SARS reliably, but only 21 days after the onset of symptoms. Immunofluorescence assays (IFA) take half the time but require an immunofluorescence microscope and highly skilled staff. Polymerase chain reaction (PCR) tests are extremely specific, but less sensitive: though positive results strongly indicate SARS infection, negative results do not necessarily mean its absence.

Guidelines for respiratory disease epidemics
The WHO’s laboratory guidelines for SARS hint at the magnitude of the challenge of any new respiratory disease epidemic. Above all, its recommendations on interpreting results are cumbersome. Positive PCR requires at least two different clinical specimens from a patient, or the same specimen collected on two or more days, or two different assays or repeat PCR using the original clinical sample on each occasion of testing.

For ELISA and IFA testing, the WHO specifies a negative antibody test on acute serum, followed by a positive antibody test on convalescent serum, or an over four-fold rise in antibody titre between the acute and convalescent phase
sera, which must be tested in parallel.

So far, evidence of the origin of the new Middle Eastern coronavirus is sketchy. Genetic sequencing at a Dutch laboratory has established that the virus is not the one which causes SARS. Since then, phylogenetic analysis has shown its closest relatives are bat coronaviruses from Hong Kong.

Labs: frontline defence and court of last resort
A Health Canada study titled ‘Learning from SARS’ is an excellent evaluation of the role of laboratories – above all, that of lab personnel, during the crisis. One conclusion was that though the country’s Winnipeg-based National Microbiology Laboratory (NML) was “not designed for an epidemic response”, its personnel (and those from labs across the country) managed to quickly and effectively move into crisis management mode.

The study highlighted the unique role of laboratories as both a ‘first-line’ defence against a new threat as well as a ‘court of last resort’ to improve testing – in terms of diagnosis, surveillance, and response to epidemics.

One priority, according to the Health Canada study, is to standardize testing protocols and share data, to “see the whole picture” of an evolving epidemic. This, it argued, required laboratory information systems (LIS) that are “agile, modular, and rapidly modifiable for special purposes“, a lesson which has relevance for LIS designers even today. On its part, the WHO has mentored an international network of laboratories to identify best practices from the SARS
experience. This will clearly have a bearing on preparations for any new epidemic.

The impact of air travel
The challenge of respiratory system viruses is emphasized by the huge numbers of air travellers. Though little research has been done on the role of airplanes in respiratory epidemics, circumstantial evidence is strong. When SARS struck, 16 of 120 people on a single flight from Hong Kong to Beijing developed the disease, from just one index case. Conversely, the fall in air travel after the September 2011 US terror attacks sharply reduced flu incidence during the year.

Today, of some 8 million air passengers aloft every day, over 1 million cross international borders, just like the victims of the new virus in Britain and Germany. This is an area clearly in need of official attention. Indeed, in March 2003, the WHO recommended screening airline passengers for SARS but its impact was minimal, and questionable. Given the massive number of air travellers, it is clear that any new respiratory epidemic will first grow by leaps and bounds before any meaningful steps can be devised to control it.

The promise of biosensors
Some experts believe that airports should be provided with the means (and the authority) to screen passengers in an impending epidemic, for alternative causes. During the SARS crisis, such eliminative tests – even in a sophisticated setting like the US – were “ordered at the discretion of local clinicians”, diagnosed on “the basis of local interpretations” and many “were never reported to CDC.”

Today, at least one handheld, biosensor-based kit for diagnosing influenza A and B and respiratory syncytial viruses (RSV) – without having to send samples to the lab – is close to market. Deploying such devices at airports ought to be the next step, given the potential threat from the new Middle Eastern coronavirus as well as others that may arise in the future.

This would free laboratories to concentrate on their main task – to identify and confirm genuine, high-risk cases and direct their expertise to what Health Canada billed as their role as a ‘court of last resort’: to quickly master new diagnostic techniques and ensure a quicker response to containing epidemics.

Pertussis (whooping cough) has been a significant cause of morbidity and mortality in young children since the first epidemic was described in 1578. Currently in the West even when infants suffering from the disease are hospitalized and appropriately treated, around 1% still die, and in less developed countries the mortality rate in infants is as high as 4%. However, following the isolation of the causative organism Bordetella pertussis over a century ago, years of research and development resulted in the introduction of an effective vaccine in the 1940s.
The whole cell vaccine used heat-killed bacteria combined with diphtheria and tetanus toxoids to give the classical DPT vaccine, usually given to infants three times during their first year of life with further booster doses twice during childhood. The advent of this vaccine did not prevent the three to five year pertussis epidemic cycle, but it elicited a strong immune response and the total number of cases plummeted in immunized populations. There were some common side-effects, including swelling, mild fever and pain, but these were trivial compared with the high risk of children contracting pertussis if they were not immunized. Sadly, though, very dubious research linked cases of SIDS and encephalopathy with use of whole cell pertussis vaccine, and the popular press eagerly disseminated this dangerously misleading information. Parents began to exercise their so-called ‘freedom of choice’ based on a dearth of unbiased information and stopped having their children immunized, so in the 1990s a new acellular vaccine (DPaT) with fewer side effects gradually replaced the classical DPT.
Now cases of pertussis have more than tripled in the last five years in much of the globe, and the resulting whooping cough epidemic is the worst for 50 years. While it is possible that a more virulent strain of bacterium has evolved, the most likely explanation is that the ‘new’ vaccine is not as effective as its predecessor. Indeed a recent robust study from Australia compared incidence of pertussis in 40,694 children who were immunized in 1998 with either DPT or DPaT (both vaccines were still in use at that time). Significantly higher rates of pertussis were found in the children who had received the latter vaccine.
The suggested solution to the pertussis epidemic is to extend immunisation programmes to cover pregnant women as well as all those who come in contact with young infants. Wouldn’t reintroducing the old vaccine be simpler?