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Edward H. Livingston, MD, discusses the clinical examination for mononucleosis.
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Edward H. Livingston, MD, discusses the clinical examination for mononucleosis.
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>> Hello, and welcome to JAMAevidence, our monthly podcast focused on core issues and evidence-based medicine. I'm your host, Ed Livingston, and I'm sitting across the table from -- >> Christina Minami, and I'm a general surgery resident at Northwestern University. >> So Christina, when I contacted you a few days ago about helping me with this podcast on mono, what were your thoughts? >> So like when you first asked me to do this podcast, you know, I thought I was absolutely wrong person for this job because all I knew about mono was what I learned in medical school.
And to be perfectly honest, I find it a rather an interesting disease. But, I think, once you had approached me, I went ahead and just did a little digging and found some fascinating tidbits. >> So maybe you're of the same mindset. You might be thinking, is there really anything that I don't already know about mononucleosis? And I think the answer to that question may surprise you. >> So here's the basics. Mononucleosis is a very important disease that all clinicians should know something about.
It's caused by the Epstein-Barr virus and it's so common that by the time any American is five years old, half the population of children will test positive for the virus. >> Mononucleosis is not a particularly severe disease for kids who are younger than five and older adults. Where it's a problem is if the first infection occurs between the ages of about 10 to 20 when patients have a fairly significant disease related to the infection. >> In college-age individuals, the rate of mononucleosis is about 15 per 100-person years and these patients will develop very symptomatic disease.
So this is a very significant problem. >> Mononucleosis is a relatively benign disease and fairly easy to diagnose but it wasn't always that way. [ Music ] The year was 1931. The Great Depression was in full swing, Charlie Chaplin was about to release the movie "City Lights", and an article in JAMA detailing the cases of two young male patients had just been published. >> About a couple of months ago, I started feeling tired.
This didn't make much sense to me because I was never really sick before. But as the weeks went by, I just got more and more tired. And then about a month ago, I started feeling really weak. >> The first patient was 16 years old. He didn't have much strength. He started losing weight and had chills. >> I could feel like a pounding in my chest. The thing that scared me is that I started bleeding in my mouth. I was constantly spitting up blood and my stools had turned black.
When I wake up in the morning, my mouth is full of blood clots. Even though I feel crummy, I still felt good enough to walk to your office today. >> His physician noted that he was really thin and pale. He had a blood pressure of 118/60 but a pulse of 120. His temperature was 100.5. >> What was most remarkable was an awful halitosis. When I examined his mouth, there was bleeding from around his teeth with greyish-white gums. His tonsils were huge and there was obvious foul smelling pus on the tonsils. His tongue was coated with a brownish black film.
He had cervical, axillary, and inguinal adenopathy, although none of those nodes were tender, and he splenic dullness to 3 cm above the left costal margin. I couldn't feel a spleen tip. There was no hepatomegaly. The most notable features on his lab assessment was with his CBC. That showed a platelet count of 80,000. His hematocrit was 40%, he had a white count of 16,000; 4% were neutrophils and 73% were large, atypical lymphocytes.
>> The second patient this physician saw was 22 years old. He had been in good health up until the month prior to his visit, but then he started feeling weak and ill. >> So I noticed that I had a sore throat that just wouldn't go away. I also had some pain in my mouth. And a few days after this all started, I began having some fevers and chills. I never took my temperature, so I don't know how much of a fever I had, but the chills just wouldn't go away.
With time, I just felt more and more weak and I got abdominal cramps. I would also wake up in the middle of the night just sweaty. I didn't feel hungry, just tired all the time. And really, just despite all this, I went to work every day. >> His blood pressure was 85/40 with a pulse of 102 and his temperature was 101. I looked at his mouth. His gums are red and swollen and spongy, and he had enlarged tonsils that were inflamed.
There wasn't any puss. He had really enlarged cervical lymph nodes that were not tender. In the right side of his neck he had one lymph node that was the size of a walnut. There were no axillary or inguinal lymph node enlargements. His liver was tender and could be felt 4 cm below the costal margin and there was splenic dullness extending 2 cm below the left costal margin. The spleen was easily palpable. On lab exam, his white blood cell count was 15,800, 93% lymphoblastics, 6% neutrophils, and 1% eosinophils.
[ Music ] >> The story of these two patients comes from an article in the January 17th, 1931, issue of JAMA describing the difference between acute lymphatic leukemia and infectious mononucleosis. >> The case is instructive because in those days no one knew what either disease was caused by, and the physician involvement in these cases was pretty much limited to establishing a diagnosis. There were no treatments for either disease. >> The first patient had leukemia and died. The second patient had mononucleosis, eventually recovered symptomatically but had abnormal CBC values for months, consistent the very long duration of mononucleosis.
Things have changed a lot. We now know what causes mononucleosis, and CLL is very treatable, with a 90% five-year survival. >> These cases illustrate the difficulties clinicians had before there were any specific tests for mononucleosis or leukemia and the causes of the disease were unknown. >> Nor was there a treatment for either disease. At best, clinicians could try to figure out what disease the patient had and provide them comfort care and counseling as the disease ran its course. >> A year later, the situation improved.
Heterophile antibodies were discovered. These antibodies act as their name implies. Hetero- in Greek means different, something different than one's own, such as heterosexual. Philos in Greek means to be a friend or to love something. So a heterophile is an antibody that's attracted to an antigen different from the antigen that was responsible for the antibody's creation. >> In the case of mononucleosis, the virus that causes the disease results in the generation of antibodies that happened to bind to sheep or horse red blood cells.
>> Heterophile antibodies were discovered in 1932 by Paul and Bunnell at Yale. They tried to figure out how to use heterophilic antibodies clinically. They took serum from a series of hospitalized patients who had a variety of diseases and incubated that serum with sheep red cells. >> In only infectious mononucleosis did they find a very strong agglutination reaction. This resulted in a test for infectious mononucleosis, which eventually evolved into the Monospot test, which continues to be used today. >> Once the heterophile test was available to identify cases of infectious mononucleosis, the disease's clinical features could be better refined.
>> So in the September 7th, 1935, issue of JAMA, McKinley described the clinical and hematologic features of a group of hospitalized university students. The most notable feature in mono was generalized adenopathy with large, non-tender lymph nodes, most prominent in the neck and especially in the posterior cervical lymph node chain, with smaller nodes in the anterior chain. >> Deep cervical lymph nodes tended to be matted into large clumps. There was significant pharyngitis in most cases, although palpable spleens were found. They only occurred in about 40% of the patients.
>> Blood smears were dominated by very atypical lymphocytes. >> McKinley's observations deserve our attention. In 1935, armed only with an imperfect test for mono, he accurately described the main features for the disease that we rely upon today to make the diagnosis. An important conclusion that can be made from McKinley's 1935 JAMA publication is that mono can be diagnosed by careful consideration of a patient's clinical history, physical examination, and simple tests like a blood smear, and maybe even a Monospot test. [ Music ] The discovery of what causes mononucleosis took a long and tortuous path that began with a surgeon in Africa, who noticed his patients had really odd tumors of their jaw.
Those tumors became known as Burkitt's lymphoma, and this is Denis Burkitt describing his experience. >> Now you see, when I got interested in the lymphoma, which now bears my name, it just happened that I was on duty and a certain Dr. Trowel [phonetic] called me into his ward and asked me if I'd see a patient which confused him. And this was the beginning of the whole story. And then shortly afterwards I met another friend, a fellow called George Oettle.
And George said to me, "Denis, this tumor does not occur in South Africa." "Well," I said to myself, "if it's one of the commonest tumors here in Uganda, and it doesn't occur in South Africa, must stop somewhere." And it was largely that, that set me looking at the geography of the tumor, which revealed the fact that it didn't occur where it was cold. It didn't occur where it was dry. It needed a moisture and warmth, and that led on to the whole search for viruses and all that came out of it.
>> Burkitt became interested in the geographic distribution of disease, believing that environmental factors associated with geography could explain diseases and that cures for those diseases could be discovered by understanding the differences in lifestyle and other factors in these geographic regions. Many of our listeners will be familiar with some of his great hypotheses, such as the relationship between diet and diverticular disease and the hygiene hypothesis for appendicitis. [ Music ] Burkitt set out to establish the geographical distribution of these peculiar lymphomas.
He sent out questionnaires to a number of hospitals throughout Africa and found that the tumors were only located in a narrow band of the continent that was about 10 degrees north and 10 degrees south of the equator and traveled down the east coast of Africa to the border between Mozambique and South Africa. >> This became known as the lymphoma belt. Burkitt traveled throughout Africa and eventually visited 57 different hospitals and more detailed observations about the conditions where the disease was found. The tumors were only found in regions that had more than 20 inches of rainfall per year and it never got cooler than 68 degrees Fahrenheit.
He showed these data to an entomologist who suggested that these conditions were necessary for the spread of the vector-borne diseases yellow fever and sleeping sickness, diseases that were transmitted by mosquitoes. >> For this peculiar lymphoma, Burkitt noted that it was co-located in regions in Africa where there were lots of mosquitoes and malaria. Burkitt hypothesized that some form of an infectious disease that existed in these regions caused the lymphoma. [ Music ] >> Burkitt left Africa and returned to England.
Enter Dr. Michael Epstein, a British pathologist who'd been studying viral causes of cancer in chickens. In 1961, he heard a lecture given by Dr. Burkitt about Burkitt's Lymphoma and because of the peculiar geographic findings that Dr. Burkitt described and that those findings suggested an infectious cause of the lymphomas, began work trying to understand what caused Burkitt's Lymphoma. >> Epstein and Yvonne Barr got samples of Burkitt's tumors from Uganda and, after two years of trying, eventually developed cell lines from the tumors. In these cell lines, they found a new form of herpes virus, the types of viruses that cause cold sores and chicken pox.
>> They named the cell lines that they grew from Burkitt Lymphoma tumors as EB cells for Epstein-Barr. And in these cells they found the virus that was responsible for causing the tumors and they named it the EB virus. >> This new virus, the Epstein-Barr virus, and its ability to apparently cause cancer caused much excitement in the scientific community. This observation sparked a great deal of research trying to find a viral cause for cancer and to link this virus to other diseases for which the causes were unknown.
>> One lab doing this work was at the Philadelphia Children's Hospital, run by the husband and wife team of Werner and Gertrude Henle. While they're working with this virus, a technician in their laboratory, Elaine Hutkin, developed a fever, sore throat, and swollen glands in her neck. She also suffered from extreme lethargy. >> Eventually, she developed a skin rash and was diagnosed with infectious mononucleosis. All lab workers had their blood banked when they started working the laboratory so that if they became exposed to anything while working there, the disease could be tracked.
After Elaine developed mononucleosis, they studied her again and found that she had developed antibodies to the Epstein-Barr virus that were not present before she developed mononucleosis. This provided fairly good evidence that the Epstein-Barr virus might cause mononucleosis. >> The Henle team then got a hold of large numbers of blood samples from hospitalized patients with mononucleosis. They related the course of the disease with the presence or absence of the heterophile antibodies and antibodies to Epstein-Barr virus. Their findings were reported in the January 15th, 1968, issue of JAMA.
[ Music ] So Christina, this is a really good place to stop and review the heterophile test sensitivity and specificity. Take a look at the figures in the Henle 1968 publication in JAMA showing that Epstein-Barr virus causes mononucleosis. We're going to post a link to these figures in the show notes to make it easier to see them. Looking at the graphs of the heterophile response in relation to the course of mononucleosis, one can really see how sensitivity and specificity work.
Let's take a sidebar here and review the concepts of sensitivity and specificity of a test when making the diagnosis of a disease. These concepts were discussed in detail in a Rational Clinical Examination article published in the April 12, 2015, issue of JAMA, along with an accompanied podcast that explains all of this. We rely on two mnemonics to try to help understand these concepts. The first one is SPPIN, S-P-P-I-N. If there is a highly specific test and it's positive, you rule the disease in.
In the case of the heterophile test, it is positive pretty much only for mono and nothing else. That means it's a highly specific test and if it's positive, you pretty much know you've made the diagnosis of mono. Things are much less clear for the sensitivity of the heterophile test. It only has a sensitivity of about 70 to 80%. The pneumonic that we use for sensitivity is SNNOUT, S-N-N-O-U-T. If there is a highly sensitive test and it's negative, you can rule out the disease.
The Monospot test is not particularly sensitive. It's only about 70 to 80%. Well, why is that? The reason is it takes about a week to 10 days for the test to become positive when a patient has mono. So that means there's a very substantial time window when a patient has the disease and the test is negative. So it's not a particularly sensitive test and you really can't necessarily rule out the disease.
If it's negative, that's the SNNOUT. What would be a really good test with high sensitivity to illustrate SNNOUT in the case of mono? That would be the VCA test. The viral capsid antigen. That is an antibody test to the antigen that's on the viral particles itself, and that becomes positive almost right away and its sensitivity is about 95% or greater. So SNNOUT, meaning if the VCA is negative, you don't have mono. All right.
So that wraps up our little review of sensitivity and specificity. So let's get back to the issue at hand, the diagnosis of mono. [ Music ] >> So Ed, in the case of mono, how well does actual evidence support findings such as fever, lethargy, sore throat, cervical lymphadenopathy, as being suggestive of a diagnosis of mono? And how good is the mono spot test in establishing the diagnosis? >> For the answer to your questions, let's talk to the author of the Rational Clinical Examination article on mono.
>> My name is Mark Ebell. I'm a family physician and professor in the College of Public Health at the University of Georgia. >> I asked Dr. Ebell when should a clinician suspect that a patient has mono? >> I think you should suspect it in any patient who has a sore throat, especially if they fall into the age range of 15 to 24 years. We'll, sometimes see it at younger ages, but most commonly it's in that adolescent and young adult age range. Typically, patients present with sore throat.
Over 80% have a sore throat and fatigue or malaise. Most of them also have fever. Over 90% have some sort of adenopathy. >> Okay, but those findings could be in a lot of diseases. Remember, in the early 1900s, the big concern was trying to distinguish between mono and CLL. How do you hone in on the diagnosis of mono as opposed to strep or something else like that? >> Well, just based on signs and symptoms, it's challenging. One of the better distinguishing characteristics is that posterior cervical adenopathy, which is relatively uncommon in group A beta-hemolytic strep.
Things like tonsillar enlargement, tonsillar exudate, anterior cervical adenopathy, fever, sore throat, those are all common in both strep and mono. The fatigue tends to be more prominent in mono, so I'd say the posterior cervical adenopathy and the fatigue can be helpful clues. And that's why I think, particularly if you have a patient with sore throat and you're starting to think about mono as a possibility, it's important to check for posterior cervical and perhaps axillary adenopathy. Those are much more specific.
While high percentage have anterior cervical adenopathy, as you know, lots of other things can cause that, whereas the posterior cervical adenopathy significantly increases the likelihood of mono. The likelihood ratios are in the range of three or four. >> So if a patient has posterior cervical adenopathy -- >> People with disease are three times more likely to have that finding than patients without disease. >> In our Rational Clinical Examination articles, we present the ability of a test to establish a diagnosis in terms of likelihood ratio, and we tend not to use sensitivity and specificity.
So Christina, how good are you using likelihood ratios? >> Okay. So we're going to take that as a "I don't have any clue what you're talking about," which is the response that we get from about 95% of physicians who read these articles. So as a consequence, in the November 8, 2015, JAMA Clinical Review podcast, we interviewed Dr. David Simel, and this podcast is called "Using Likelihood Ratios to Understand How Chest Pain Predicts Acute Coronary Syndrome." So the problem with sensitivity is that it tells you what proportion of patients who have a disease have a positive test.
Specificity tells you what proportion of patients who don't have the disease have a negative test. The problem is when you're making a diagnosis, you don't know if the patient has the disease or not. So you need a test that's going to look at the information from the perspective of you having a patient in front of you and not knowing if they have the disease or not. So you need a slightly different measure, and that's what the likelihood ratio accomplishes. And it does so by simultaneously considering whether the patient has the disease or doesn't have the disease, which sensitivity and specificity don't because it separates those two concepts.
Likelihood ratios tell you that if you think someone has a disease and they have some finding, how much that finding increases the probability that they have the disease. It's exactly the perspective you have in clinical medicine when you're trying to figure out what somebody has. Before you can use a likelihood ratio, you have to know what the probability is that someone has a disease. Usually, that's just the prevalence of the disease, but technically, that's called establishing the pretest probability.
For mono, the pretest probability depends a lot on how old the patient is when they present with the symptoms. >> Yet it really has a lot to do with the age group, and I really, like most clinicians, don't really think too much about the diagnosis in people under the age of five or over the age of 25. It rarely does occur, and it may even be more common than we think, just because we don't tend to look for it. So I'd begin with that age range, and then certainly anybody with sore throat in that age range it's a possibility.
I begin to think about testing for it when they have one of the other characteristic signs or symptoms, like they have significant fatigue or they have posterior axillary cervical adenopathy or perhaps there's been an exposure to someone with documented mono. >> Okay, Christina. Tell us how you're going to use this information to make a diagnosis of mono. >> So the prevalence of mono for our high-risk patients, in other words those aged between five and 25, is about 8%. So this means that the pretest probability for someone walking off the street into your clinic is about 8%.
How much this probability is increased by various signs or symptoms of the disease, or particular test, is influenced by this likelihood ratio that you've been talking about. So Ed, I found on your website, JAMAevidence.com, a calculator that helps you convert pretest probabilities and likelihood ratios into post-test probabilities. >> So this is why I love working with surgical residents because they are really quick learners. So now Christina is an expert on this whole concept of likelihood ratios and is going to tell us how to use them.
>> So running the numbers from this Rational Clinical Exam article, if you have a patient you think has mono but they don't have any adenopathy, the likelihood ratio for that is 0.3, which reduces the probability that the patient has the disease from the pretest probability of 8% down to about 2.5%. >> What happens if they have posterior cervical adenopathy? >> If they have posterior cervical adenopathy, that's associated with the likelihood ratio of 3.1. That alone would increase the pretest probability from 8% to 21%.
>> So what about if they have inguinal nodes or axillary adenopathy? >> The presence of those nodes also has the likelihood ratio of about three. So if those are found, the post-test probability of a patient suspected of having mono would be about 21%. >> So what if they have petechiae of their palate? >> The post-test probability of that would be about 32% because the likelihood ratio associated with this finding is 5.3. So the classic symptoms for mono are sore throat, fatigue, stuff like that.
How did that pan out in the Rational Clinical Exam article? >> So those are reasonably sensitive, but not particularly specific. That makes sense because those symptoms can be associated with a large number of diseases. >> Tell me about atypical lymphocytosis and how that affects the diagnosis. >> So atypical lymphocytosis has the likelihood ratio of 11.4. If you find this, there's strong evidence that mono is present. Getting back to our calculator with the pretest probability of 8%, if atypical lymphocytosis is present, the post-test probability is 50%.
You can even be more certain if the proportion of atypical lymphocytes is more than 10% of all lymphocytes. This has the likelihood ratio of 26, giving you a post-test probability of 70%. And if more than 20% of the lymphocytes are atypical, the likelihood ratio is 50 according to a post-test probability of 81%. So a peripheral blood smear with a differential can be a really useful test for making the diagnosis of mono. >> So Christina, and now that you've seen how easy all this is, are you ready to give up surgery to become a pediatrician?
>> Not quite. >> All right. Well, we haven't convinced you. So let's move on to a surgical disease, splenomegaly. This is something we surgeons worry about. Splenomegaly is common with mono. We always associate splenomegaly with mono, but it actually doesn't occur in most of the cases. But it can be an important complication of the disease because of concern for splenic rupture, which would involve people like Christina and me.
>> Well, splenomegaly is a fairly common finding. The studies have been a bit heterogeneous, we see. I think the lower end of the range was somewhere around 20 or 11%, the upper end of the range around 49%. So about a quarter or so of patients have splenomegaly. It probably varies somewhat because it depends on the skill of the examiner in terms of detecting splenomegaly, but it's not uncommon. It's important because if a patient does have splenomegaly or if, as a clinician, you're not confident that you can rule it out, it's wise to counsel them to not engage in any contact sports for about three weeks after the onset of the illness.
But that's a time when they might be at increased risk of a very rare complication, but a serious one, which would be splenic rupture. [ Music ] >> As we mentioned earlier, one of the major purposes of the Rational Clinical Exam Series is to dispel the notions about disease that are not based on fact. This is the case for the relationship between mono and the development of skin rashes that follow the administration of some antibiotics. Parenthetically, I looked at some book chapters on mono and they all have this in them.
Many texts do state that when a patient develops a rash after antibiotics that they might have mono, but that's not really borne out by the literature. >> Yeah, you know, that's been described for a long time, and it's been sort of the conventional wisdom. When we looked at the literature, we found that it may not be quite as clear, and that, at least in the studies that we turned up -- I think there was a study of 173 kids with serologically confirmed mono, and this kind of a fine maculopapular rash was seen in about 30% who'd gotten at least one dose of amoxicillin.
But then we found another study about the same size, where the rash was just as common in kids who hadn't gotten amoxicillin. So it's not completely clear. Some physicians have felt that, you know, if you give a dose of amoxicillin and they develop a rash, it's mono. I don't think we can make that assumption. And I think maybe we've put too much stock in that association in the past. >> So when you suspect mono in a young patient, the best physical findings are palatine petechiae and posterior cervical adenopathy.
If you get a blood smear, lymphocytosis is a great test, but that takes a while to get a result. The Monospot test is performed in the office and can give an answer right away, but it's not perfect. >> Well, Monospot is the classic test, the heterophile antibody test. The problem with it is that in the first week of the illness, it's not uncommon for it to be negative. You can have false negative rates of 20 to 30%. They're higher in relatively younger patients.
So you could have somebody who does have mono and if it's early before they develop a vigorous antibody response, you could have a false negative result if you rely just on the Monospot. It's not the most accurate test, and there are more accurate tests. So if you have a strong clinical suspicion of the disease, or if early in the course you want to confirm it, for example, a competitive athlete where you really want to know for sure do I need to be worried about splenomegaly, there's an IGM VCA, which is a viral capsid antigen test, that's highly accurate.
And that's also accurate quite early in the course of the illness, so that would be a good option. >> So the Monospot is great if it's positive, but not terribly helpful if it's negative. Now there are several diseases that are quite serious that can look something like mono. When you hear hoofbeats, you don't want to think of zebras, but you don't want to miss something that's important when it's present. >> Basically, it's fairly safe to assume that mono is present when patients have the classic presentation for the disease, including fever, sore throat, lethargy, posterior cervical adenopathy, palatine petechiae, and lymphocytosis.
Mono is a self-limiting disease, and one would expect it to go away within a few weeks. >> But if it doesn't, you start to worry about more serious problems. If you're really stuck, you can get the IgM VCA test. That's a test for the viral capsid antigen and is a very specific test for Epstein-Barr virus. If you look at the show notes, we placed a copy of the original manuscripts from the Henle lab that appeared in JAMA in 1968, and you can see that this antigen is present in the blood very early in the course of the disease and lasts for a very long time. It's a pretty good test for mono.
It's not done very much since the diagnosis of mono can be established with a great deal of certainty from the clinical findings previously described. In general, mono is a self-limiting disease, but if it doesn't get better on its own, then you have to worry about other, more serious problems. >> You know, you want to have some follow up with the patient and if they're not responding as you would expect. Typically, patients are doing much better in three to four weeks, and by three months, certainly almost all patients have recovered and gotten back to baseline. And so somebody who they come back in a couple of weeks and they're doing the same or worse, I think that's where you start to get concerned and look for other causes.
Certainly in terms of the differential diagnosis, acute leukemias, acute HIV infection are in the differential, and those are obviously very serious conditions you wouldn't want to miss. And in a patient who has persistent symptoms of lymphocytosis, fatigue, sore throat, a fever, who's not developing a positive test, or perhaps who has a negative IgM VCA test, you'd certainly want to explore those diagnoses further. That's very important, toxoplasmosis, CMV can also cause a mononucleosis-like syndrome and are other things to consider if a patient isn't fitting what you expect in terms of their test results and in terms of the results of the Monospot and other confirmatory tests.
>> So Dr. Ebell, you're a very experienced clinician, and you've done a lot of systematic reviews looking at diagnostic features for a variety of diseases. What'd you learned from writing this Rational Clinical Exam article that you didn't know before? >> Well, I was struck by how helpful the CBC is, particularly early on in the course of the illness, and how fairly simple tests that we kind of take for granted and that we've actually found isn't as helpful as we used to think for things like appendicitis can be quite helpful for diagnosing mono and the likelihood ratios are, you know, I work with these diagnostic meta analyses a lot.
In likelihood ratios of 20, 30, 40, or 50 are really impressive, and you know, very, very strong evidence in favor of the condition. So the other thing I learned was just how inconsistent, and frankly, weak a lot of the literature is. This is a condition -- many of the studies are quite a bit older. They're not as methodologically up to date as we'd like, given our current standards for doing diagnostic test studies. So I think there's room for a large, well-designed study that looks at the association between signs and symptoms and mononucleosis.
Maybe using a better reference standard test than the Monospot, using the VCA IgM and potentially even developing something like the Centor score for strep throat, developing a similar way to combine signs and symptoms to better diagnose mono or to help establish that pretest probability. >> A hundred years ago, physicians were pretty good at making the diagnosis of infectious mononucleosis. They had pegged the constellation of fever, extreme lethargy, sore throat, and adenopathy as being associated with the disease.
One finding that was highly suggestive of mono was a prominent lymphocytosis, especially if there was a great many abnormal lymphocytes. [ Music ] >> That's going to do it for this episode of JAMAevidence. I'd like to thank Dr. Mark Ebell and Dr. Christina Minami for joining me on the program today. More information on this topic is available in the Rational Clinical Examination Series and on our website, JAMAevidence.com, where you can listen to our entire roster of podcasts. Once again, I'm Ed Livingston, and I'll be back soon with another edition of JAMAevidence.
[ Music ]
Segment:0 .
>> Hello, and welcome to JAMAevidence, our monthly podcast focused on core issues and evidence-based medicine. I'm your host, Ed Livingston, and I'm sitting across the table from -- >> Christina Minami, and I'm a general surgery resident at Northwestern University. >> So Christina, when I contacted you a few days ago about helping me with this podcast on mono, what were your thoughts? >> So like when you first asked me to do this podcast, you know, I thought I was absolutely wrong person for this job because all I knew about mono was what I learned in medical school.
And to be perfectly honest, I find it a rather an interesting disease. But, I think, once you had approached me, I went ahead and just did a little digging and found some fascinating tidbits. >> So maybe you're of the same mindset. You might be thinking, is there really anything that I don't already know about mononucleosis? And I think the answer to that question may surprise you. >> So here's the basics. Mononucleosis is a very important disease that all clinicians should know something about.
It's caused by the Epstein-Barr virus and it's so common that by the time any American is five years old, half the population of children will test positive for the virus. >> Mononucleosis is not a particularly severe disease for kids who are younger than five and older adults. Where it's a problem is if the first infection occurs between the ages of about 10 to 20 when patients have a fairly significant disease related to the infection. >> In college-age individuals, the rate of mononucleosis is about 15 per 100-person years and these patients will develop very symptomatic disease.
So this is a very significant problem. >> Mononucleosis is a relatively benign disease and fairly easy to diagnose but it wasn't always that way. [ Music ] The year was 1931. The Great Depression was in full swing, Charlie Chaplin was about to release the movie "City Lights", and an article in JAMA detailing the cases of two young male patients had just been published. >> About a couple of months ago, I started feeling tired.
This didn't make much sense to me because I was never really sick before. But as the weeks went by, I just got more and more tired. And then about a month ago, I started feeling really weak. >> The first patient was 16 years old. He didn't have much strength. He started losing weight and had chills. >> I could feel like a pounding in my chest. The thing that scared me is that I started bleeding in my mouth. I was constantly spitting up blood and my stools had turned black.
When I wake up in the morning, my mouth is full of blood clots. Even though I feel crummy, I still felt good enough to walk to your office today. >> His physician noted that he was really thin and pale. He had a blood pressure of 118/60 but a pulse of 120. His temperature was 100.5. >> What was most remarkable was an awful halitosis. When I examined his mouth, there was bleeding from around his teeth with greyish-white gums. His tonsils were huge and there was obvious foul smelling pus on the tonsils. His tongue was coated with a brownish black film.
He had cervical, axillary, and inguinal adenopathy, although none of those nodes were tender, and he splenic dullness to 3 cm above the left costal margin. I couldn't feel a spleen tip. There was no hepatomegaly. The most notable features on his lab assessment was with his CBC. That showed a platelet count of 80,000. His hematocrit was 40%, he had a white count of 16,000; 4% were neutrophils and 73% were large, atypical lymphocytes.
>> The second patient this physician saw was 22 years old. He had been in good health up until the month prior to his visit, but then he started feeling weak and ill. >> So I noticed that I had a sore throat that just wouldn't go away. I also had some pain in my mouth. And a few days after this all started, I began having some fevers and chills. I never took my temperature, so I don't know how much of a fever I had, but the chills just wouldn't go away.
With time, I just felt more and more weak and I got abdominal cramps. I would also wake up in the middle of the night just sweaty. I didn't feel hungry, just tired all the time. And really, just despite all this, I went to work every day. >> His blood pressure was 85/40 with a pulse of 102 and his temperature was 101. I looked at his mouth. His gums are red and swollen and spongy, and he had enlarged tonsils that were inflamed.
There wasn't any puss. He had really enlarged cervical lymph nodes that were not tender. In the right side of his neck he had one lymph node that was the size of a walnut. There were no axillary or inguinal lymph node enlargements. His liver was tender and could be felt 4 cm below the costal margin and there was splenic dullness extending 2 cm below the left costal margin. The spleen was easily palpable. On lab exam, his white blood cell count was 15,800, 93% lymphoblastics, 6% neutrophils, and 1% eosinophils.
[ Music ] >> The story of these two patients comes from an article in the January 17th, 1931, issue of JAMA describing the difference between acute lymphatic leukemia and infectious mononucleosis. >> The case is instructive because in those days no one knew what either disease was caused by, and the physician involvement in these cases was pretty much limited to establishing a diagnosis. There were no treatments for either disease. >> The first patient had leukemia and died. The second patient had mononucleosis, eventually recovered symptomatically but had abnormal CBC values for months, consistent the very long duration of mononucleosis.
Things have changed a lot. We now know what causes mononucleosis, and CLL is very treatable, with a 90% five-year survival. >> These cases illustrate the difficulties clinicians had before there were any specific tests for mononucleosis or leukemia and the causes of the disease were unknown. >> Nor was there a treatment for either disease. At best, clinicians could try to figure out what disease the patient had and provide them comfort care and counseling as the disease ran its course. >> A year later, the situation improved.
Heterophile antibodies were discovered. These antibodies act as their name implies. Hetero- in Greek means different, something different than one's own, such as heterosexual. Philos in Greek means to be a friend or to love something. So a heterophile is an antibody that's attracted to an antigen different from the antigen that was responsible for the antibody's creation. >> In the case of mononucleosis, the virus that causes the disease results in the generation of antibodies that happened to bind to sheep or horse red blood cells.
>> Heterophile antibodies were discovered in 1932 by Paul and Bunnell at Yale. They tried to figure out how to use heterophilic antibodies clinically. They took serum from a series of hospitalized patients who had a variety of diseases and incubated that serum with sheep red cells. >> In only infectious mononucleosis did they find a very strong agglutination reaction. This resulted in a test for infectious mononucleosis, which eventually evolved into the Monospot test, which continues to be used today. >> Once the heterophile test was available to identify cases of infectious mononucleosis, the disease's clinical features could be better refined.
>> So in the September 7th, 1935, issue of JAMA, McKinley described the clinical and hematologic features of a group of hospitalized university students. The most notable feature in mono was generalized adenopathy with large, non-tender lymph nodes, most prominent in the neck and especially in the posterior cervical lymph node chain, with smaller nodes in the anterior chain. >> Deep cervical lymph nodes tended to be matted into large clumps. There was significant pharyngitis in most cases, although palpable spleens were found. They only occurred in about 40% of the patients.
>> Blood smears were dominated by very atypical lymphocytes. >> McKinley's observations deserve our attention. In 1935, armed only with an imperfect test for mono, he accurately described the main features for the disease that we rely upon today to make the diagnosis. An important conclusion that can be made from McKinley's 1935 JAMA publication is that mono can be diagnosed by careful consideration of a patient's clinical history, physical examination, and simple tests like a blood smear, and maybe even a Monospot test. [ Music ] The discovery of what causes mononucleosis took a long and tortuous path that began with a surgeon in Africa, who noticed his patients had really odd tumors of their jaw.
Those tumors became known as Burkitt's lymphoma, and this is Denis Burkitt describing his experience. >> Now you see, when I got interested in the lymphoma, which now bears my name, it just happened that I was on duty and a certain Dr. Trowel [phonetic] called me into his ward and asked me if I'd see a patient which confused him. And this was the beginning of the whole story. And then shortly afterwards I met another friend, a fellow called George Oettle.
And George said to me, "Denis, this tumor does not occur in South Africa." "Well," I said to myself, "if it's one of the commonest tumors here in Uganda, and it doesn't occur in South Africa, must stop somewhere." And it was largely that, that set me looking at the geography of the tumor, which revealed the fact that it didn't occur where it was cold. It didn't occur where it was dry. It needed a moisture and warmth, and that led on to the whole search for viruses and all that came out of it.
>> Burkitt became interested in the geographic distribution of disease, believing that environmental factors associated with geography could explain diseases and that cures for those diseases could be discovered by understanding the differences in lifestyle and other factors in these geographic regions. Many of our listeners will be familiar with some of his great hypotheses, such as the relationship between diet and diverticular disease and the hygiene hypothesis for appendicitis. [ Music ] Burkitt set out to establish the geographical distribution of these peculiar lymphomas.
He sent out questionnaires to a number of hospitals throughout Africa and found that the tumors were only located in a narrow band of the continent that was about 10 degrees north and 10 degrees south of the equator and traveled down the east coast of Africa to the border between Mozambique and South Africa. >> This became known as the lymphoma belt. Burkitt traveled throughout Africa and eventually visited 57 different hospitals and more detailed observations about the conditions where the disease was found. The tumors were only found in regions that had more than 20 inches of rainfall per year and it never got cooler than 68 degrees Fahrenheit.
He showed these data to an entomologist who suggested that these conditions were necessary for the spread of the vector-borne diseases yellow fever and sleeping sickness, diseases that were transmitted by mosquitoes. >> For this peculiar lymphoma, Burkitt noted that it was co-located in regions in Africa where there were lots of mosquitoes and malaria. Burkitt hypothesized that some form of an infectious disease that existed in these regions caused the lymphoma. [ Music ] >> Burkitt left Africa and returned to England.
Enter Dr. Michael Epstein, a British pathologist who'd been studying viral causes of cancer in chickens. In 1961, he heard a lecture given by Dr. Burkitt about Burkitt's Lymphoma and because of the peculiar geographic findings that Dr. Burkitt described and that those findings suggested an infectious cause of the lymphomas, began work trying to understand what caused Burkitt's Lymphoma. >> Epstein and Yvonne Barr got samples of Burkitt's tumors from Uganda and, after two years of trying, eventually developed cell lines from the tumors. In these cell lines, they found a new form of herpes virus, the types of viruses that cause cold sores and chicken pox.
>> They named the cell lines that they grew from Burkitt Lymphoma tumors as EB cells for Epstein-Barr. And in these cells they found the virus that was responsible for causing the tumors and they named it the EB virus. >> This new virus, the Epstein-Barr virus, and its ability to apparently cause cancer caused much excitement in the scientific community. This observation sparked a great deal of research trying to find a viral cause for cancer and to link this virus to other diseases for which the causes were unknown.
>> One lab doing this work was at the Philadelphia Children's Hospital, run by the husband and wife team of Werner and Gertrude Henle. While they're working with this virus, a technician in their laboratory, Elaine Hutkin, developed a fever, sore throat, and swollen glands in her neck. She also suffered from extreme lethargy. >> Eventually, she developed a skin rash and was diagnosed with infectious mononucleosis. All lab workers had their blood banked when they started working the laboratory so that if they became exposed to anything while working there, the disease could be tracked.
After Elaine developed mononucleosis, they studied her again and found that she had developed antibodies to the Epstein-Barr virus that were not present before she developed mononucleosis. This provided fairly good evidence that the Epstein-Barr virus might cause mononucleosis. >> The Henle team then got a hold of large numbers of blood samples from hospitalized patients with mononucleosis. They related the course of the disease with the presence or absence of the heterophile antibodies and antibodies to Epstein-Barr virus. Their findings were reported in the January 15th, 1968, issue of JAMA.
[ Music ] So Christina, this is a really good place to stop and review the heterophile test sensitivity and specificity. Take a look at the figures in the Henle 1968 publication in JAMA showing that Epstein-Barr virus causes mononucleosis. We're going to post a link to these figures in the show notes to make it easier to see them. Looking at the graphs of the heterophile response in relation to the course of mononucleosis, one can really see how sensitivity and specificity work.
Let's take a sidebar here and review the concepts of sensitivity and specificity of a test when making the diagnosis of a disease. These concepts were discussed in detail in a Rational Clinical Examination article published in the April 12, 2015, issue of JAMA, along with an accompanied podcast that explains all of this. We rely on two mnemonics to try to help understand these concepts. The first one is SPPIN, S-P-P-I-N. If there is a highly specific test and it's positive, you rule the disease in.
In the case of the heterophile test, it is positive pretty much only for mono and nothing else. That means it's a highly specific test and if it's positive, you pretty much know you've made the diagnosis of mono. Things are much less clear for the sensitivity of the heterophile test. It only has a sensitivity of about 70 to 80%. The pneumonic that we use for sensitivity is SNNOUT, S-N-N-O-U-T. If there is a highly sensitive test and it's negative, you can rule out the disease.
The Monospot test is not particularly sensitive. It's only about 70 to 80%. Well, why is that? The reason is it takes about a week to 10 days for the test to become positive when a patient has mono. So that means there's a very substantial time window when a patient has the disease and the test is negative. So it's not a particularly sensitive test and you really can't necessarily rule out the disease.
If it's negative, that's the SNNOUT. What would be a really good test with high sensitivity to illustrate SNNOUT in the case of mono? That would be the VCA test. The viral capsid antigen. That is an antibody test to the antigen that's on the viral particles itself, and that becomes positive almost right away and its sensitivity is about 95% or greater. So SNNOUT, meaning if the VCA is negative, you don't have mono. All right.
So that wraps up our little review of sensitivity and specificity. So let's get back to the issue at hand, the diagnosis of mono. [ Music ] >> So Ed, in the case of mono, how well does actual evidence support findings such as fever, lethargy, sore throat, cervical lymphadenopathy, as being suggestive of a diagnosis of mono? And how good is the mono spot test in establishing the diagnosis? >> For the answer to your questions, let's talk to the author of the Rational Clinical Examination article on mono.
>> My name is Mark Ebell. I'm a family physician and professor in the College of Public Health at the University of Georgia. >> I asked Dr. Ebell when should a clinician suspect that a patient has mono? >> I think you should suspect it in any patient who has a sore throat, especially if they fall into the age range of 15 to 24 years. We'll, sometimes see it at younger ages, but most commonly it's in that adolescent and young adult age range. Typically, patients present with sore throat.
Over 80% have a sore throat and fatigue or malaise. Most of them also have fever. Over 90% have some sort of adenopathy. >> Okay, but those findings could be in a lot of diseases. Remember, in the early 1900s, the big concern was trying to distinguish between mono and CLL. How do you hone in on the diagnosis of mono as opposed to strep or something else like that? >> Well, just based on signs and symptoms, it's challenging. One of the better distinguishing characteristics is that posterior cervical adenopathy, which is relatively uncommon in group A beta-hemolytic strep.
Things like tonsillar enlargement, tonsillar exudate, anterior cervical adenopathy, fever, sore throat, those are all common in both strep and mono. The fatigue tends to be more prominent in mono, so I'd say the posterior cervical adenopathy and the fatigue can be helpful clues. And that's why I think, particularly if you have a patient with sore throat and you're starting to think about mono as a possibility, it's important to check for posterior cervical and perhaps axillary adenopathy. Those are much more specific.
While high percentage have anterior cervical adenopathy, as you know, lots of other things can cause that, whereas the posterior cervical adenopathy significantly increases the likelihood of mono. The likelihood ratios are in the range of three or four. >> So if a patient has posterior cervical adenopathy -- >> People with disease are three times more likely to have that finding than patients without disease. >> In our Rational Clinical Examination articles, we present the ability of a test to establish a diagnosis in terms of likelihood ratio, and we tend not to use sensitivity and specificity.
So Christina, how good are you using likelihood ratios? >> Okay. So we're going to take that as a "I don't have any clue what you're talking about," which is the response that we get from about 95% of physicians who read these articles. So as a consequence, in the November 8, 2015, JAMA Clinical Review podcast, we interviewed Dr. David Simel, and this podcast is called "Using Likelihood Ratios to Understand How Chest Pain Predicts Acute Coronary Syndrome." So the problem with sensitivity is that it tells you what proportion of patients who have a disease have a positive test.
Specificity tells you what proportion of patients who don't have the disease have a negative test. The problem is when you're making a diagnosis, you don't know if the patient has the disease or not. So you need a test that's going to look at the information from the perspective of you having a patient in front of you and not knowing if they have the disease or not. So you need a slightly different measure, and that's what the likelihood ratio accomplishes. And it does so by simultaneously considering whether the patient has the disease or doesn't have the disease, which sensitivity and specificity don't because it separates those two concepts.
Likelihood ratios tell you that if you think someone has a disease and they have some finding, how much that finding increases the probability that they have the disease. It's exactly the perspective you have in clinical medicine when you're trying to figure out what somebody has. Before you can use a likelihood ratio, you have to know what the probability is that someone has a disease. Usually, that's just the prevalence of the disease, but technically, that's called establishing the pretest probability.
For mono, the pretest probability depends a lot on how old the patient is when they present with the symptoms. >> Yet it really has a lot to do with the age group, and I really, like most clinicians, don't really think too much about the diagnosis in people under the age of five or over the age of 25. It rarely does occur, and it may even be more common than we think, just because we don't tend to look for it. So I'd begin with that age range, and then certainly anybody with sore throat in that age range it's a possibility.
I begin to think about testing for it when they have one of the other characteristic signs or symptoms, like they have significant fatigue or they have posterior axillary cervical adenopathy or perhaps there's been an exposure to someone with documented mono. >> Okay, Christina. Tell us how you're going to use this information to make a diagnosis of mono. >> So the prevalence of mono for our high-risk patients, in other words those aged between five and 25, is about 8%. So this means that the pretest probability for someone walking off the street into your clinic is about 8%.
How much this probability is increased by various signs or symptoms of the disease, or particular test, is influenced by this likelihood ratio that you've been talking about. So Ed, I found on your website, JAMAevidence.com, a calculator that helps you convert pretest probabilities and likelihood ratios into post-test probabilities. >> So this is why I love working with surgical residents because they are really quick learners. So now Christina is an expert on this whole concept of likelihood ratios and is going to tell us how to use them.
>> So running the numbers from this Rational Clinical Exam article, if you have a patient you think has mono but they don't have any adenopathy, the likelihood ratio for that is 0.3, which reduces the probability that the patient has the disease from the pretest probability of 8% down to about 2.5%. >> What happens if they have posterior cervical adenopathy? >> If they have posterior cervical adenopathy, that's associated with the likelihood ratio of 3.1. That alone would increase the pretest probability from 8% to 21%.
>> So what about if they have inguinal nodes or axillary adenopathy? >> The presence of those nodes also has the likelihood ratio of about three. So if those are found, the post-test probability of a patient suspected of having mono would be about 21%. >> So what if they have petechiae of their palate? >> The post-test probability of that would be about 32% because the likelihood ratio associated with this finding is 5.3. So the classic symptoms for mono are sore throat, fatigue, stuff like that.
How did that pan out in the Rational Clinical Exam article? >> So those are reasonably sensitive, but not particularly specific. That makes sense because those symptoms can be associated with a large number of diseases. >> Tell me about atypical lymphocytosis and how that affects the diagnosis. >> So atypical lymphocytosis has the likelihood ratio of 11.4. If you find this, there's strong evidence that mono is present. Getting back to our calculator with the pretest probability of 8%, if atypical lymphocytosis is present, the post-test probability is 50%.
You can even be more certain if the proportion of atypical lymphocytes is more than 10% of all lymphocytes. This has the likelihood ratio of 26, giving you a post-test probability of 70%. And if more than 20% of the lymphocytes are atypical, the likelihood ratio is 50 according to a post-test probability of 81%. So a peripheral blood smear with a differential can be a really useful test for making the diagnosis of mono. >> So Christina, and now that you've seen how easy all this is, are you ready to give up surgery to become a pediatrician?
>> Not quite. >> All right. Well, we haven't convinced you. So let's move on to a surgical disease, splenomegaly. This is something we surgeons worry about. Splenomegaly is common with mono. We always associate splenomegaly with mono, but it actually doesn't occur in most of the cases. But it can be an important complication of the disease because of concern for splenic rupture, which would involve people like Christina and me.
>> Well, splenomegaly is a fairly common finding. The studies have been a bit heterogeneous, we see. I think the lower end of the range was somewhere around 20 or 11%, the upper end of the range around 49%. So about a quarter or so of patients have splenomegaly. It probably varies somewhat because it depends on the skill of the examiner in terms of detecting splenomegaly, but it's not uncommon. It's important because if a patient does have splenomegaly or if, as a clinician, you're not confident that you can rule it out, it's wise to counsel them to not engage in any contact sports for about three weeks after the onset of the illness.
But that's a time when they might be at increased risk of a very rare complication, but a serious one, which would be splenic rupture. [ Music ] >> As we mentioned earlier, one of the major purposes of the Rational Clinical Exam Series is to dispel the notions about disease that are not based on fact. This is the case for the relationship between mono and the development of skin rashes that follow the administration of some antibiotics. Parenthetically, I looked at some book chapters on mono and they all have this in them.
Many texts do state that when a patient develops a rash after antibiotics that they might have mono, but that's not really borne out by the literature. >> Yeah, you know, that's been described for a long time, and it's been sort of the conventional wisdom. When we looked at the literature, we found that it may not be quite as clear, and that, at least in the studies that we turned up -- I think there was a study of 173 kids with serologically confirmed mono, and this kind of a fine maculopapular rash was seen in about 30% who'd gotten at least one dose of amoxicillin.
But then we found another study about the same size, where the rash was just as common in kids who hadn't gotten amoxicillin. So it's not completely clear. Some physicians have felt that, you know, if you give a dose of amoxicillin and they develop a rash, it's mono. I don't think we can make that assumption. And I think maybe we've put too much stock in that association in the past. >> So when you suspect mono in a young patient, the best physical findings are palatine petechiae and posterior cervical adenopathy.
If you get a blood smear, lymphocytosis is a great test, but that takes a while to get a result. The Monospot test is performed in the office and can give an answer right away, but it's not perfect. >> Well, Monospot is the classic test, the heterophile antibody test. The problem with it is that in the first week of the illness, it's not uncommon for it to be negative. You can have false negative rates of 20 to 30%. They're higher in relatively younger patients.
So you could have somebody who does have mono and if it's early before they develop a vigorous antibody response, you could have a false negative result if you rely just on the Monospot. It's not the most accurate test, and there are more accurate tests. So if you have a strong clinical suspicion of the disease, or if early in the course you want to confirm it, for example, a competitive athlete where you really want to know for sure do I need to be worried about splenomegaly, there's an IGM VCA, which is a viral capsid antigen test, that's highly accurate.
And that's also accurate quite early in the course of the illness, so that would be a good option. >> So the Monospot is great if it's positive, but not terribly helpful if it's negative. Now there are several diseases that are quite serious that can look something like mono. When you hear hoofbeats, you don't want to think of zebras, but you don't want to miss something that's important when it's present. >> Basically, it's fairly safe to assume that mono is present when patients have the classic presentation for the disease, including fever, sore throat, lethargy, posterior cervical adenopathy, palatine petechiae, and lymphocytosis.
Mono is a self-limiting disease, and one would expect it to go away within a few weeks. >> But if it doesn't, you start to worry about more serious problems. If you're really stuck, you can get the IgM VCA test. That's a test for the viral capsid antigen and is a very specific test for Epstein-Barr virus. If you look at the show notes, we placed a copy of the original manuscripts from the Henle lab that appeared in JAMA in 1968, and you can see that this antigen is present in the blood very early in the course of the disease and lasts for a very long time. It's a pretty good test for mono.
It's not done very much since the diagnosis of mono can be established with a great deal of certainty from the clinical findings previously described. In general, mono is a self-limiting disease, but if it doesn't get better on its own, then you have to worry about other, more serious problems. >> You know, you want to have some follow up with the patient and if they're not responding as you would expect. Typically, patients are doing much better in three to four weeks, and by three months, certainly almost all patients have recovered and gotten back to baseline. And so somebody who they come back in a couple of weeks and they're doing the same or worse, I think that's where you start to get concerned and look for other causes.
Certainly in terms of the differential diagnosis, acute leukemias, acute HIV infection are in the differential, and those are obviously very serious conditions you wouldn't want to miss. And in a patient who has persistent symptoms of lymphocytosis, fatigue, sore throat, a fever, who's not developing a positive test, or perhaps who has a negative IgM VCA test, you'd certainly want to explore those diagnoses further. That's very important, toxoplasmosis, CMV can also cause a mononucleosis-like syndrome and are other things to consider if a patient isn't fitting what you expect in terms of their test results and in terms of the results of the Monospot and other confirmatory tests.
>> So Dr. Ebell, you're a very experienced clinician, and you've done a lot of systematic reviews looking at diagnostic features for a variety of diseases. What'd you learned from writing this Rational Clinical Exam article that you didn't know before? >> Well, I was struck by how helpful the CBC is, particularly early on in the course of the illness, and how fairly simple tests that we kind of take for granted and that we've actually found isn't as helpful as we used to think for things like appendicitis can be quite helpful for diagnosing mono and the likelihood ratios are, you know, I work with these diagnostic meta analyses a lot.
In likelihood ratios of 20, 30, 40, or 50 are really impressive, and you know, very, very strong evidence in favor of the condition. So the other thing I learned was just how inconsistent, and frankly, weak a lot of the literature is. This is a condition -- many of the studies are quite a bit older. They're not as methodologically up to date as we'd like, given our current standards for doing diagnostic test studies. So I think there's room for a large, well-designed study that looks at the association between signs and symptoms and mononucleosis.
Maybe using a better reference standard test than the Monospot, using the VCA IgM and potentially even developing something like the Centor score for strep throat, developing a similar way to combine signs and symptoms to better diagnose mono or to help establish that pretest probability. >> A hundred years ago, physicians were pretty good at making the diagnosis of infectious mononucleosis. They had pegged the constellation of fever, extreme lethargy, sore throat, and adenopathy as being associated with the disease.
One finding that was highly suggestive of mono was a prominent lymphocytosis, especially if there was a great many abnormal lymphocytes. [ Music ] >> That's going to do it for this episode of JAMAevidence. I'd like to thank Dr. Mark Ebell and Dr. Christina Minami for joining me on the program today. More information on this topic is available in the Rational Clinical Examination Series and on our website, JAMAevidence.com, where you can listen to our entire roster of podcasts. Once again, I'm Ed Livingston, and I'll be back soon with another edition of JAMAevidence.
[ Music ]
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