The value of rapid diagnostics - a case study of pneumonia
The last two decades have witnessed major changes to the speed and reliability of AMR testing as a result of the introduction of new molecular methods. Over that time, many different molecular AMR diagnostics have become commercially available which make it possible to identify different microorganisms in a patient sample and their susceptibility to different antibiotics. Yet, the turnaround of results remains slow.
The only way the rising level of AMR can be properly addressed is with rapid diagnostics that can provide results within a few hours. Such diagnostics are a vital tool in the move away from the prescription of antibiotics based on clinical symptoms to more precise treatment. This is particularly important because the symptoms for bacterial and viral infections are often indistinguishable. As figure 1 shows several rapid diagnostics are now available for different conditions.
Figure 7.2.1: Types of rapid diagnostics available for infectious diseases(Credit: Peeling, Boeras).
Just how valuable a rapid diagnostic can be to slowing down AMR progression is highlighted by the case study of a new rapid diagnostic developed in Cambridge, England, for pneumonia - one of the leading causes of death in the world. The disease kills around 2.6 million people a year (Conway-Morris). In severe cases of pneumonia the lungs become so inflamed and the tiny air sacs inside the lungs become filled up with so much fluid and pus that patients find it very hard to breathe. In some people this can prove fatal, especially in people over the age of 65 and those with respiratory disorders.
Figure 7.2.2: X-ray of a normal chest (credit: Vilas Navapurkar).
Figure 7.2.3: Xray showing clinical deterioration in chest from patient with pneumonia after 4 or 5 days on a ventilator and escalation of antibiotics. The deterioration is probably linked to antibiotic resistant bacteria (credit: Vilas Navapurkar).
Figure 7.2.4: Challenges in the conventional management of pneumonia (credit: Vilas Navapurkar).
Developed by ICU doctors together with scientists in Cambridge University and Public Health England, the new diagnostic has dramatically cut down on the time it takes to get results. This is critical because one of the greatest challenges in the management of pneumonia is that patients can deteriorate very quickly and the slow rate at which laboratory tests can limit treatment options. This means that doctors often prescribe best-guess antibiotics based on clinical symptoms to start with, followed up with another type of antibiotics if the first course does not work. Sadly, in a significant number of cases, none of the antibiotics will work and in some instances may even cause harm to the patient. The use of 'best guess’ antibiotics also helps to boost the the spread of AMR.
The Cambridge test uses what is known as an array card. It contains tiny wells loaded with DNA sequences that match those of common microbes that cause pneumonia. If a target DNA sequence is present in a patient sample, the array card amplifies it so that it can be detected. The array card is highly customisable. Single targets can be added or modified without having to re-optimise the entire panel.
Figure 7.2.5: Photo of the Cambridge team behind the development of the array card diagnostic for pneumonia. From left to right: Dr Sushmita Sridhar, Dr Nick Brown, Professor Gordon Dougan, Dr Joana Pereira Dias, Dr Mailis Maes, Dr Vilas Navapurkar, Professor Stephen Baker, Dr Josefin Bartholdson Scott, Dr Martin Curran, Dr Sally Forrest, Dr Amelia Soderholm.
The genes targeted on the array card were chosen based on the Cambridge’s team’s local experience with pneumonia and antibiotic resistance. Put together by Martin Curran, Andrew Conway-Morris and Vilas Navapurkar the card includes genes from 52 different respiratory pathogens commonly found in ventilated patients with pneumonia. Many different microbes can cause pneumonia. This includes viruses like SARS-CoV2 and influenza as well as bacteria and fungi. Various factors determine which specific type of organism causes the disease, including where the patient acquired the disease - in the community or in a hospital - and the condition of their immune system.
Figure 7.2.6: Array card (Credit: Vilas Navapurkar).
In order for the test to be carried out, fluid samples are taken from the deepest parts of a patient’s lungs (bronchial lavage) and sent off to the laboratory where they are spun with reagents to separate pathogen genetic material (DNA or RNA) from human genetic material. This is then auto loaded onto a card and inserted into a reading machine, which performs a series of runs, including control checks, which takes about four hours to complete. The readout provided by the machine is presented as a set of curves to show where pathogens have been detected. These curves appear as numerical (Ct or cycle threshold) values. The Ct value measures the level at which a pathogen is detected. The lower the Ct the greater the presence of a pathogen, whereas the higher it is the less pathogen there is. Ct values less than 30 are regarded as significant. Curves higher than 34 indicate the pathogen is bordering on undetectable, while those in the mid 20s indicate a high level of a pathogen. After being checked in the laboratory the results are then checked and entered into the electronic patient record which the clinician can access at a patient’s bedside to work out the appropriate management pathway (Navapurkar email).
Tried out in patients in the adult intensive care unit at Addenbrooke’s Hospital, the diagnostic managed to identify the pathogen responsible for severe pneumonia in patients on ventilators in a minimum of four hours but usually within a day (for results to be available in the electronic patient record). This compares with 61 hours needed to turn around a result using conventional culturing methods. It can also detect bacteria known to cause pneumonia often not picked up with conventional methods.(Navapurkar et al).
Encouragingly the fast turnaround of results from the array card test had a measurable effect on the choices ICU doctors at Addenbrooke’s Hospital made. Over half of the doctors changed their antibiotic prescriptions, with most changes leading to fewer antibiotics being used (Navapurkar et al).
The team also tested the diagnostic method in patients admitted to the ICU with COVID-19. It proved very helpful in picking up secondary bacterial and fungal pneumonia in patients on ventilators. Patients with COVID-19 were found to be highly susceptible to these secondary cases of pneumonia, many of which were caused by hard-to-treat multidrug-resistant bugs.
The array card diagnostic is now integral to the management of all suspected ICU pneumonias including COVID-19 in Addenbrooke’s Hospital. It has proven particularly useful for separating patients who have the virus from those who do not. This has helped to improve safety on the ward and free up beds and nursing staff (Interview).
One of the reasons the card has worked so well in Cambridge is because it helped to improve the working relationship between ICU staff and those in the microbiology department. If other ICUs follow this pattern and develop enhanced multi-disciplinary working mechanics with microbiology colleagues then this will be an important behavioural step forward in the AMR challenge.
Figure 7.2.7: Martin Curran with array card (credit: Vilas Navapurkar).
The new diagnostic test developed in Cambridge is particularly important because despite considerable efforts to reduce and control pneumonia in recent years, including the development of vaccines, the disease remains stubbornly persistent and places a major burden on healthcare services. Worldwide pneumonia is one of the most common infective reasons for admission to intensive care. It is also a frequent complication of hospital stays, being the most common secondary infection patients acquire when in the intensive care unit (ICU). A large proportion of pneumonia acquired in the ICU is linked to mechanical ventilation (Conway-Morris).
For those admitted to intensive care with pneumonia, the risk of dying is high, between 15 and 50 per cent (Li et al). Many who survive are also often left with serious long-term ill-health conditions including reduced physical ability and heart problems. Both the speed and completeness of a patient’s recovery is highly dependent on their age and what type of pathogen caused their infection (Waterer).
Most of those killed by pneumonia are the very young or the elderly. But the condition can strike at any age. A disproportionately large proportion of pneumonia deaths occur in low and middle income countries where it is the commonest cause of death. However, it remains common in higher income countries, where pneumonia is the sixth most common cause of death (Conway-Morris).
Having proven the ability to rapidly identify the pathogen so effective treatment can start sooner, the Cambridge team hopes to roll out the array card system globally. One of its attractions is that it can be modified to incorporate different pathogens in different locations, as well as different resistance genes. This is vital for more precise antibiotic treatment and preventing the spread of antimicrobial resistance.
Click here to see a transcript of the interview with Dr Andrew Conway-Morris and Dr Vilas Navapurkar.
Interview (15 Sept 2020) with Vilas Navapurkar, Andrew Conway-Morris and Gordon Dougan by Lara Marks.Back
Peeling, RW, Boeras, DI (11 July 2016) Diagnostic innovation for antimicrobial resistance.Back
Waterer, G (2017) , 'Recovery from community acquired pneumonia: The view from the top of the iceberg', European Respiratory Journal, 49, 1700571; DOI: 10.1183/13993003.00571-2017.Back