Let’s say we’re a team of healthcare professionals in an emergency department, in Germany.

One quiet evening, a person in their early forties comes into the ward. They’re not in terrible condition but they’re clutching their stomach and they’re groaning as they walk through the room, with bags under their eyes.

It’ll be our job to find out what’s wrong and help them! For one thing, we want to help them get better. But what’s more, for infectious diseases and outbreaks, discovering the root of the illness in just one person could stop it from spreading, preventing many more people from falling ill too.

So how do we untangle mysteries like these to find out whether someone is ill and what might be responsible? Like all good science, it means collecting the right kind of evidence and testing our hypothesis. In a medical setting, clinical symptomatology and diagnostic testing are what enable us to do just that.

I’m Pardis Sabeti, and this is Crash Course Outbreak Science! [Theme Music]. In general, diagnosing a patient can take very different routes. If someone comes in with blood oozing from a severed arm, it’s… pretty obvious what’s wrong with them.

But infectious diseases aren’t always as dramatically visible, so it takes a bit more detective work to diagnose them. For these kinds of illnesses, like the one our patient might have, there are two important tools we can use:. Clinical symptomatology and diagnostic testing.

Symptomatology comes first in the diagnosis process, so we’ll start with that too! No prizes for guessing, the name refers to symptoms, the evidence from the patient that hints they have a particular disease. Clinical symptomatology is the study of mapping the symptoms a patient exhibits to the diseases they might have.

The process begins with taking the patient’s history, starting with the obvious: why have they come to the hospital? That often gives us their most immediate symptoms, like whether they have a fever or a cough. We also want to know how long they’ve experienced their symptoms and how severe they are.

Looking even further back, their medical history also provides vital clues. If a patient has asthma, for example, their reaction to a respiratory virus might be particularly strong! Their general history as a person also provides important insights.

Their lifestyle, like what they eat, whether they smoke and whether anyone in their family has had particular illnesses all help give an idea of the patient’s susceptibility to certain diseases. Even their job and the kinds of travelling they do is important! After all, reservoirs for infectious diseases depend on geography, so where a person has been can indicate the kinds of pathogens they could have been exposed to.

Once we have the patient’s history, we’re ready to interpret their symptoms. Actually, in this setting, the word symptom means something a little more specific than we’re used to. It’s the evidence of disease that only the patient themselves experiences and reports to us, like discomfort, chills, or the pain in our hospital patient’s stomach.

We call the other, objectively measurable characteristics signs. Signs include things like the patient’s temperature, blood pressure or a rash. Taking our patient’s temperature would be a helpful sign to record, given their other symptoms.

After recording the particular symptoms and signs from a patient, we’re ready to make an educated guess as to why the patient might be ill. Consider a patient who turns up in mid February with a low fever, a terrible headache and achy muscles in an average US city, who hasn’t done much travelling recently. Given the symptoms, a doctor might suspect this as a case of the flu.

While other diseases also present the same symptoms, the middle of February is peak flu season in the US and the flu spreads more easily in cities. On the other hand, if it was the summer and the patient was an avid hiker in New England presenting a rash, stiff joints and a fever, the doctor might instead suspect that the patient had Lyme disease. Lyme disease is contracted from tick bites, and ticks are found outdoors, fitting the patient’s history.

It’s worth pointing out, at this stage we haven’t drawn any totally firm conclusions yet. Many diseases present with the same symptoms and signs, making them tricky to tell apart. What’s more, a single disease may have variable presentation, meaning that the symptoms and signs they cause vary from patient to patient.

So typically, we can only narrow down the possibilities for which disease might have infected the patient. That list of possible diseases is known as a differential, and the more narrow our list of potential diseases is, the smaller the differential becomes. Once we significantly shrink our differential, diagnostic testing can help us pin down the true suspect.

Fortunately, lots of infectious diseases have a key element that helps guide the design of such tests: the pathogen itself! Detecting the germ that caused the disease, or its remnants, is a surefire way to confirm whether a patient is, or was, infected by it. So specifically, a diagnostic test is a procedure which is designed to confirm or rule out the presence of a specific pathogen inside a patient.

That’s done by taking a sample from the patient, such as saliva, blood, urine or stool, which is then analyzed with biochemistry techniques. Tests come in many different varieties. Some involve identifying the entire microbe itself, by, say, looking for it under a microscope from a patient’s blood sample or even, in the case of some bacteria, attempting to grow it in the lab from a patient sample.

Other times, they involve identifying parts of a pathogen, like genetic material. That’s because when pathogens infect us, they release a bit of their genetic material into our bodies. Since each kind of pathogen has its own specific genome, we can use that to identify them.

For example, Polymerase Chain Reaction or “PCR” tests, aim to replicate those segments of pathogenic DNA from a patient's sample so we have enough segments to detect in a well-equipped laboratory. Other tests might look for certain kinds of proteins on pathogens, known as antigens, from a patient sample like saliva or blood. Antigen tests tend to be faster and simpler to use than genetic techniques.

Finally, tests can also look for antibodies, the proteins that our immune system develops during an infection so it can ready its defenses if it ever shows up again. Antibody tests work really well when we can’t find a pathogen another way. Plus, detecting antibodies can be really helpful when managing an outbreak.

By determining who has already been previously infected, we can chart the course of infections and how it spreads. While all of these tests have their uses, none are perfectly accurate, so we need to understand their limitations. There are two key ways in which we measure the accuracy of diagnostic tests: sensitivity and specificity.

Sensitivity is how often a test correctly reports that a person is sick, when they really are. Imagine there’s 100 people who have a disease. Let’s call it… Hank-itis.

If all of them took a test with a sensitivity of 70%, we’d expect the test to correctly report a positive result for about 70 of them. The other 30 would be incorrectly given a negative result by the test. Specificity is sort of the opposite.

It tells you how often a test correctly gives a negative result for someone who isn’t sick. Now, consider a different group of 100 people and none of them have Hankitis, and all take the same test. If that test had a specificity of 85%, we’d expect about 85 negative results and 15 incorrect positive results.

These can be tricky concepts to take in all in one go, so you might want to pause this video and consider them for a moment! The key thing is that we want tests with both very high sensitivity and specificity. We want to get a positive result when the pathogen is present, and a negative one when it is not.

Sometimes, a more sensitive test is a less specific one and vice versa. But these days, there are a lot of tests that have both! However, some tests with both a high specificity and sensitivity aren’t always the best to use.

For example, even though PCR tests are more specific and sensitive than antigen tests, they require specialized equipment in a lab to use, which might be harder to perform in places like rural areas with less access to specialized healthcare facilities. If we want to be able to test lots of people and stop the spread of a disease during an outbreak we might distribute antigen tests instead, since they can be sent to individuals to be used in their own households, even though they might be less sensitive and less specific. Finally, there’s another crucial factor which determines the kinds of tests we use: speed!

If we’re testing for a disease whose progression is very slow, like tuberculosis, then waiting a week for a result is no big deal. But if we think the patient might have, say, Ebola which quickly worsens over a few days and needs to be treated fast, we want a test that will provide a result within hours. A test’s speed depends on the chemical processes behind it and whether the sample needs to be transported somewhere far away from the patient.

This is particularly important when we need to identify infected people as soon as possible, in case they need to quarantine to stop the spread of a disease during an outbreak. By now, it’s clear, there’s a lot to consider when it comes to symptomatology and diagnostic testing. But with all this, we now have the tools to help our patient!

Let’s go to the Thought Bubble. First off, we take the patient’s history. Prior to this, they had no serious medical conditions, and seemed fit enough to regularly travel abroad for work.

In fact, they flew back from West Africa just last week. When asked for their symptoms, they report a pain in their stomach, dizziness, nausea and recent headaches. The bags under their eyes are from a lack of sleep the previous night.

Our differential is still quite large. So we conduct some tests to record the patient’s signs. We take some blood samples and record their temperature, finding they’re just under 38 degrees Celsius, on the boundary of a fever.

And after an hour or two, one test reports high levels of a certain enzyme which indicates that their liver is acting up. While their blood work was being done, we also recorded a second measurement of their temperature, which reached 39 and a half degrees Celsius, well into fever territory! Considering this sudden fever and their other symptoms, we recall that the patient has recently travelled to West Africa, where an outbreak of Lassa fever was in the news recently.

What’s more, lassa infections frequently affect liver function. We now have a strong guess for the disease that’s troubling our patient, though we’re not certain yet. Confirming a case of lassa fever would be a big deal.

The patient would have to be quarantined to stop others from being infected and kept under close observation, as lassa fever is often deadly. We’d also have to contact everyone the patient had been in contact with, to get them to self-isolate and get tested! Given the importance of getting this diagnosis right, we decide to opt for a highly sensitive and specific test.

Thankfully, there’s a PCR testing facility in the hospital which can test for it in just a few hours, so that's what we do! And sure enough, the test comes back positive for lassa fever. Thanks, thought bubble!

With a confirmed diagnosis, we now have a head start on giving the patient care before their symptoms worsen, improving their odds of survival. And we can set about contacting everyone they’ve been in touch with, to check up on them and tell them to self isolate in case they’re infected. It’s clear that symptomatology and diagnostic tests are powerful tools in helping us diagnose and treat patients, as well as preventing outbreaks.

Thankfully, the hospital in our example was sufficiently equipped to deal with the challenge at hand. But making sure that that's the case is a challenge all of its own. In our next episode, we’ll be looking at healthcare systems more broadly, to understand how they help tackle outbreaks and how we can ensure they help everyone stay healthy.

We at Crash Course and our partners Operation Outbreak and the Sabeti Lab at the Broad Institute at MIT and Harvard want to acknowledge the Indigenous people native to the land we live and work on, and their traditional and ongoing relationship with this land. We encourage you to learn about the history of the place you call home through resources like native-land.ca and by engaging with your local Indigenous and Aboriginal nations through the websites and resources they provide. Thanks for watching this episode of Crash Course Outbreak Science, which was produced by Complexly in partnership with Operation Outbreak and the Sabeti Lab at the Broad Institute of MIT and Harvard— with generous support from the Gordon and Betty Moore Foundation.

If you want to help keep Crash Course free for everyone, forever, you can join our community on Patreon.