The Challenge of Diagnosing Lyme Disease

Lyme disease is on the rise. The 30,000 cases reported annually to the Centers for Disease Control and Prevention by state health departments represent only a fraction of the cases diagnosed and treated around the country. About half the cases occur in people under the age of 21, and boys from 5 to 9 years old are the most commonly affected group, possibly because they spend a good deal of time outdoors.

A recent article in The New York Times about a child who was treated for Lyme disease and did well, offering a reassuring message about relatively straightforward cases of the infection, drew more than 700 reader comments, many of them angrily denouncing the author and predicting medical complications to come for her son. Some responses reflect the frustrations of people who feel they have struggled for years with persistent and recalcitrant symptoms from the infection.

The condition can be challenging to treat, in part because it is not always easy to get the diagnosis right the first time around. The biggest problem is that there is no reliable biomarker for Lyme, no way to test, unequivocally, for the presence of the bacteria, Borrelia burgdorferi, which are transmitted by tick bite and cause the disease.

You can make a diagnosis of acute Lyme disease by seeing the characteristic rash, erythema migrans, which at its most classic looks like a target. But it doesn’t always look like that, and it can be hidden in the hair, and it doesn’t show up nearly as clearly on darker-skinned people. “A large number of affected patients don’t have the rash,” said Dr. Lise Nigrovic, a pediatric emergency physician at Boston Children’s Hospital.

The blood tests we have don’t test directly for the bacteria, but instead test for the body’s antibody response. When you hear people talk about sending a “Lyme test” or a “Lyme titer,” what they are sending is a two-tiered test, looking to see whether the body is making antibodies to that bacteria. For that reason, the test will be negative early on during the infection, because it takes time for the immune system to mount this defense.

So the Lyme test is not helpful in the earliest stages of infection — which is when you would ideally like to start treatment. Not only that, it takes a while to get the results.

“For me as an emergency room physician, none of the tests come back in rapid enough time to make a decision,” Dr. Nigrovic said. She makes treatment decisions on the basis of symptoms, such as meningitis or swollen joints, she said, and that also means deciding how aggressively to pursue alternative diagnoses — for example, deciding whether a swollen knee needs to be surgically drained or looking for other possible infections: “In my world, it’s like, O.K., do I tap the knee, let the orthopedist take the kid to the O.R. when it’s probably just Lyme?”

And the increase in Lyme should remind us that ticks can carry other infections as well.

If a different infection is actually causing the symptoms, starting antibiotics for Lyme can mean partially — that is, inadequately — treating something else that could be potentially dangerous. The acute presentation of Lyme includes facial nerve palsy, fainting and swollen joints, especially the knee, but also meningitis, with fever, headache and stiff neck.

“If you recall a tick bite, that’s an important thing to take into account,” Dr. Nigrovic said. So it’s routine to ask about that, in an emergency room or a doctor’s office. Even so, she said, in a study that she and her colleagues published this year, only one out of five children who end up diagnosed with Lyme could recall a tick bite. The nymphal stage ticks that transmit Lyme are so small, she said, that often they are not noticed. “If they don’t recall being bitten by a tick, we really should think about Lyme disease anyway if they’re in an endemic area.”

[Read Wirecutter’s recommendations for insect repellents.]

Dr. Nigrovic works to educate medical personnel in endemic areas, like New England and the upper Midwest, to think about the diagnosis. “If you do have Lyme, you want to have it diagnosed early,” she said. Doctors need to think about it, to send the test, and to bear in mind that if the test is negative, it may be too early in the infection for antibody to be present, so the child may need to be retested. Medical people not working in endemic areas may be less likely to consider the diagnosis — so parents need to be sure that any recent travel is part of the conversation.

And it’s not enough to say that you should always send the test, and that a doctor who doesn’t is somehow missing something.

Lyme titers can be negative early in infection, when the bacteria are present, and they can also be positive when there are no bacteria present.

For people with long-term or perplexing symptoms, who may get a Lyme titer done as part of a check-all-the-boxes work-up, a false positive may draw attention away from the need to diagnose some other serious disease like multiple sclerosis, lupus or rheumatoid arthritis.

A study published in February using data from the Air Force health system concluded that “Lyme disease serological tests were overused in a large health care system, and positive results were frequently misinterpreted, leading to misdiagnosis and widespread antibiotic misuse.”

The study examined all the positive Lyme serologies from 2013 to 2017 across the entire Air Force — including service members, retirees and their families in the United States. The researchers were able to review 212 tests, questioning whether the patients met any of the following four criteria: they continued to be symptomatic but never developed the long-term positive antibody, called IgG; they had no travel history to areas with Lyme; they had no specific symptoms; they were retested within 30 days and were negative.

Of the 212 cases, 113 met at least one of those criteria and 80 met two or more, suggesting that many of the patients did not really have Lyme disease.

To raise the issue of false positives is not in any way to doubt or blame patients, said the study’s lead author, Dr. Bryant Webber, assigned to the United States Air Force School of Aerospace Medicine, which is part of the Air Force Research Laboratory.

“We should feel great sympathy for people experiencing chronic debilitating symptoms,” Dr. Webber said. “We have to figure out why.”

The key takeaway, Dr. Webber said, was that with a disease that has great geographic heterogeneity, it’s very important that clinicians think carefully about how to use — and interpret — the test. This brings up some basic epidemiologic concepts, the sensitivity of the test (how many people who have the infection will test negative) and also the specificity (how many people who don’t have the infection will test positive).

The positive predictive value of a screening test is the probability that someone who has a positive test actually does have the infection — that is, that a positive is a true positive. And the problem is that for any screening test, the positive predictive value depends on the prevalence of the infection.

In a high prevalence area, where 10 percent of the population might have Lyme, Dr. Webber said, the positive predictive value of the test might be 85 percent, while in a low prevalence area, where only 0.1 percent of the population is infected, the positive predictive value of the test might drop to 5 percent. “And this is the exact same test done by the exact same laboratory, the exact same technicians rating the immunoblots.”

So the challenge for doctors is that it’s really important to have an appropriate index of suspicion, to think of Lyme and ask the exposure questions and treat when the clinical story is right. It’s important to send the test and explain to parents what the complexities of interpreting the test can be — but it’s also really important not to decide on Lyme too quickly and thereby miss another diagnosis.

“We really do need improved diagnostics for Lyme,” Dr. Webber said.

When a case is not clear cut enough to warrant treatment just on the basis of symptoms, Dr. Nigrovic said, an emergency room doctor who sends the test needs to explain the importance of follow-up; children need to be seen by their regular doctors to discuss the lab results, and may need to be retested later on, even if the test is negative.

“There are unanswered questions, we really have to invest in good high quality research,” Dr. Nigrovic said. “If we apply science and invest resources, I think we’re going to solve this and really help improve human health.”

Most important, be vigilant about prevention. Use protective clothing. Use insect repellent. “If you’re in a Lyme endemic area, do tick checks at the end of the day,” Dr. Webber said. “The Lyme ticks have to be attached for 48 hours to transmit the Borrelia.”

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