What Have We Learned in 100 Years? We Must Leapfrog Diagnostics in Emerging Economies

Jun 29, 2022, 10:15 AM by Dan Milner

Laboratory testing has a long history that precedes the development of most modern medicine, and evidence for examining samples from patients in vitro (literally “within glass”; or, outside of the patient) goes back to the ancient Greeks and Chinese. However, the development of the modern laboratory testing approach very closely parallels the founding and development of ASCP and its subsequent sibling organizations. This includes the basic science, the clinical translational approach, personnel standards, workflow, quality, accreditation and, most importantly, patient safety, in close association with continuous quality improvement.

Unfortunately, while modern medicine and the laboratory have co-evolved with alacrity in the United States and other Western countries, many low- and middle-income countries or, better described, emerging economies, have suffered with both high burdens of communicable disease and slow or stagnant economic growth. This combination created a massive amplification of infectious disease and shifted efforts to these areas at an unavoidable cost to many other conditions. With such a heavy infectious disease burden, it would seem logical for emerging economies to be selected as excellent locations for clinical trials, test development and so on. Yet the delay around HIV diagnosis and treatments in Africa, for example, stands as an immovable blemish on the history of global health. Furthermore, the struggle to create both diagnostic testing and treatments that can be effective in primarily poor and underserved populations faces challenges of revenue/reimbursement, leading to a lack of financial motivation for industry to advance progress in these areas. Only when heavy political pressure and public opinion have been overwhelming or, in parallel, when the research interests of Western scientists have aligned with disease burden, could progress be made. The most important lesson from this dark period in medical history is that leapfrogging is a key strategy that we can employ to save lives in emerging economies.

Leapfrogging and the laboratory

We must be clear on how the leapfrogging concept presents with respect to the laboratory. The example of cell phones in Africa (skipping the universal use of landlines) as a truly disruptive innovation is an excellent nonmedical example of leapfrogging.

Consider traditional microbiology, where identification of organisms in the laboratory requires growth from a primary specimen in a culture plate, followed by a series of biochemical or other tests to make the final identification and inform best treatments. This was, and for many organisms remains, the standard of care even in the West. However, three technologies now available create an opportunity to establish a new workflow in microbiology that is financially and scientifically superior.

One of these is low-complexity point-of-care molecular testing. The ability to rapidly (less than two hours) test a patient for the presence of Mycobacterium tuberculosis, HIV, HPV and other microorganisms allows laboratories to utilize PCR-based screening of large populations in areas with high burdens of certain disease or high suspected disease risk. These tests can be run at a fraction of the cost, infrastructure and skilled workforce necessary to run other methods with much greater sensitivity and specificity.

A second tool is mass spectrometry, a reagentless method that can identify many bacteria and fungi within a few minutes from a plate colony. Whereas a series of disconnected biochemical or other tests are put together to finalize an identification of an organism, mass spectrometry compares the collective spectra of an organism against the known organism database to produce an identification almost instantly. This saves considerable time and money when we consider the issues with supply chain in emerging economies and the reagentless process of mass spectrometry. A last example is sequencing of DNA (or RNA) which, although still relatively expensive and reagent-heavy, can provide invaluable data about a single sample, pooled samples or targeted samples that might inform a specific diagnostic answer for literally any organism.

If we consider just these three technologies within the context of the task of setting up a brand-new microbiology laboratory from scratch, we can identify areas with significant room for leapfrogging. While some basic laboratory instruments may always be needed to support microbial culture and evaluation (e.g., microscope, incubator), there are opportunities to consider, for example, whether to purchase all the traditional tools and reagents needed for full biochemistry or to set up a targeted PCR/mass spectrometry/sequencing facility that can, with the appropriate workflow, answer nearly all the microbiological questions we need to care for our patients. With PCR, we can detect a plethora of bacteria and viruses. With mass spectrometry and/or sequencing, we can identify any colony or viral culture we grow. With the addition of a platform that can run automated antimicrobial resistance testing, we can make treatment recommendations for bacteria and some fungi.

This may not seem like much of a difference as described; however, the reagent supply chain for emerging economies is a major barrier to medical care, so, when we consider leapfrogging, any process that can reduce the reliance on supply chain and support a wide range of applications is highly valuable. These include shelf-stable, long-lived reagents that can be purchased in bulk, as well as kits and reagentless approaches. Finally, in locations where patients often must travel great distances to seek out diagnostic services, leapfrogging opportunities that bring accurate and quick laboratory diagnostics closer to the patient have the potential for great impact on a patient and population level.

The case for collaboration

When we consider the paradigm of infectious diseases, we may have missed the big window for impact, but there is still a huge need to create, grow and expand microbiology facilities in the global health setting. Let’s not fail to do so. By contrast, when we consider cancer diagnostics, we have a huge opportunity to leapfrog today. Although many emerging economies are developing cancer care programs that include diagnostics, the majority are in their infancy relative to Western facilities. Moreover, the rapid pace of new cancer treatment and diagnostic developments in Western settings means that these emerging economies will always be behind unless we take a fundamentally different approach.

Pathologists, like all members of the cancer care team, are in short supply in the majority of African countries. In the West, the role of the pathologist has evolved to be a diagnostic mainstay for cancer, but it was not initially as standardized as it is today. There was a long period of opinion-based (as opposed to diagnostic criteria-based) diagnoses, disconnected from care plans, when often pathological consensus was not reached. Many argued over the semantics and attributes of particular diagnoses (some common, others rare), creating discord among pathologists, when all our clinical colleagues wanted to know was, “How do I treat it?” With the patient safety revolution that began in the early 2000s, the emergence of the consensus conference (a daily or weekly meeting of all pathologists in a group to discuss challenging cases) created an internal tool for quality that begat many similar activities, like correlation conferences (e.g., pathology-radiology, clinicopathological, surgical-pathological, cytology-pathology) and, eventually, the very powerful tumor boards. This last activity, which brings together the entire team, and may even include the patient, allows for open discussion about a case and a consensus plan on treatment, creating accountability across the care team for how to proceed. Telepathology is a unique branch of telemedicine in that it is most often conducted peer-to-peer rather than doctor-to-patient; thus, its adoption in Western systems where pathologists are abundant has been slower than the benefits would have suggested. The creation of telepathology access for African pathologists through the ASCP Partners for Cancer Diagnosis and Treatment Initiative in 2015 preceded by five years the acceptance of telepathology by CMS and the FDA in the United States on a massive scale—with the latter only occurring because of the extreme conditions presented by the COVID-19 pandemic. With wider spread telepathology, the digitization of glass slides is becoming more common.

Now consider that artificial intelligence in pathology, which starts with a digital pathology image, has existed for a while but is not widely in use. In the West, this is due to fear—fear of replacement, falling reimbursement, error, litigation, and so on. But in emerging economies, AI, with the promise of 10- to 20-fold productivity increases for pathologists, is an important leapfrogging opportunity that could support pathologists in Africa today. Although some conferences, especially tumor board and correlation conferences, can certainly be valuable in Africa, their impact is limited by the number of personnel (and their very precious time). The use of AI would massively improve diagnostic capabilities in Africa immediately. Should we wait around for the 10 to 15 years it will take for the U.S.-based pathology milieu to fully embrace AI before it is deployed in emerging economies? Or should we start with emerging economies where data can be collected much faster and in a larger volume due to the burden of disease to show the impact?

The mainstay of a complete histological diagnosis is morphological review of a glass slide followed commonly (75% to 95% of the time) by one or more histological stains and, less commonly, by molecular testing. In the evolution of pathology, the bulk of immunohistochemical stains have been related to classification of tumors, which is not specifically related to treatment. In fact, the WHO classification of tumors (the “Blue Books”) does not consider or include treatment as part of the descriptions of tumors; moreover, NCCN guidelines rarely use the complex classifications of the WHO scheme in presenting treatments. Both observations are certainly true historically, but there are current efforts to improve and align diagnostic classification with treatment choices. But why now?

Prognostic markers (features or test results of a tumor that suggest a certain probability of a given outcome) and predictive markers (features or test results of a tumor that predict its behavior or response to treatment) have been around for a while, but the number and use have exploded in the past two decades. This trend is growing so quickly and expansively that it is a struggle for pathologists to keep up—one of the forces driving subspecialization in pathology, which is a form of quality improvement. But, in the last decade, a parallel explosion in available targeted therapies that require specific testing has created an almost impossible situation for pathologists and the laboratory. Why? These targeted therapies are dependent on the result of a test performed by the pathologist and the laboratory on the tumor, but they may be disconnected from the diagnosis or diagnostic classification of the tumor.

In the simplest example, we have breast ductal carcinoma, which, by standard of care, is stained for hormone receptors and HER2. We have done this for so long in pathology that most would argue that “invasive ductal carcinoma, ER+, HER2+” and “invasive ductal carcinoma, ER-, HER2 -” are different tumors. Despite this, the histological diagnosis is “invasive ductal carcinoma.” The predictive or theragnostic markers are ER and HER2. In contrast we have pembrolizumab, an immuno-oncology agent targeting the PD-L1 pathway. “Pembro” has been so effective in so many tumors that it is now widely used for treatment of tumors after performing PD-L1 testing, after MSI testing, and even empirically with no prior testing. We are certainly not creating new classifications of these tumors in this regard. However, what this phenomenon illustrates is that performing testing that determines how a patient should be treated is the most important role of the laboratory. This role is not the same as completely classifying a tumor by a standard criterion. Thus, the pathologist’s role is adapting and evolving very quickly.

Now we turn to emerging economies and, for example, in the case of Africa, find treatment centers that are trying to get basic chemotherapy that, in the West, has been replaced by targeted therapies. The need to leapfrog is very clear. Moving emerging economies toward systems of diagnosis that utilize tools directly related to the treatments that are available and create opportunities for access to targeted therapies should be our primary goal. This requires rethinking what tools are needed in the laboratory and designing a strategy that does not focus solely on classification, but rather includes treatment selection. If we focus on aligning our clinical needs directly with our diagnostic tools, we can bring much needed diagnostics and treatments to emerging economies rapidly with maximum impact.