Measles crept into Utah and Arizona in June, with reports trickling into local health departments of patients coming to doctors and saying their children had just recovered from full-body rashes, and parents telling pediatricians that their whole family had just recovered from measles.

But because patients would decline testing, there were no official cases in the outbreak until August 8, when the Mojave County, Arizona, Department of Public health received a report about a 10-year-old boy who lived in a tightly knit community that spans the border of northern Arizona and southern Utah.

That outbreak has grown to more than 600 reported cases and is now the most active in the US. The Arizona-Utah cases will almost certainly be important to determining whether the US has lost its measles elimination status, meaning it’s stopped the routine transmission of the virus within its borders for over a year. The meeting to make that determination is now set for November.

The US Centers for Disease Control and Prevention tasked one of its disease detectives with using molecular evidence – clues buried deep in the genomes of the measles viruses that infected patients – to learn more about when the outbreak really started and how large it actually is.

The number of reported measles cases in the US jumped last year to 2,267, the highest total in more than three decades. Transmission has not slowed, with cases topping 1,700 in just the first four months of this year as the virus spreads through communities that have turned away from vaccination.

Tracing the origins of an outbreak

Almost as soon as the Utah outbreak was confirmed, health officials suspected that the true number of patients was bigger than they knew.

Most disease outbreaks are undercounted because doctors may miss diagnoses of unfamiliar diseases and patients may not seek medical care for religious or cultural reasons. Both factors seemed to be at play in this outbreak.

Measles has not circulated widely in the US in 30 years, so many doctors have never seen a case. Additionally, the community where measles is spreading has been the home of a sect of the Fundamentalist Church of Jesus Christ of Latter-Day Saints, a group that had a charismatic leader named Warren Jeffs who sowed distrust in vaccines.

The measles vaccine is highly effective. Two doses prevent disease roughly 97% of the time. Because the virus is so contagious, lingering in air for up to two hours after a person leaves the room, high vaccination coverage in an area, more than 95%, is needed to stop it from spreading. But misinformation campaigns and a lack of trust in public health officials have caused population-level protection against the virus to plummet.

Public health departments working to combat the outbreak wondered whether it might be possible to estimate when it really started, as well as its true size, by looking at how the genome of the virus had changed over time, according to Dr. Annie Wang, an Epidemic Intelligence Service officer who was assigned to Arizona’s Pima County Health Department during the outbreak.

EIS officers are a group of highly trained public health specialists who are often assigned to state and local public health departments to help with outbreak investigations. Wang presented their investigation into the outbreak Tuesday during the CDC’s annual EIS conference.

This technique for tracing the origins of an outbreak relies on knowing how quickly viruses develop mutations, or changes, in their genetic material as they pass from person to person. The measles virus is relatively stable and changes very little during transmission. But even this relatively steady virus does develop small changes as it circulates; they just take extra effort to find.

Instead of studying the small part of the measles genome that’s usually used to identify what strain it is, Wang explained, she and her colleagues needed to sequence the entire genome of the virus, or its complete set of blueprints. They did this for viruses sampled from 165 patients.

They were able to use that information to determine, essentially, the birthdate of the virus that gave rise to the Arizona and Utah outbreak, Wang said.

Those early infections probably started at least six weeks – and maybe as many as 14 months – before the 10-year-old boy was diagnosed, she said, though she added that they couldn’t pinpoint the geographic location of the earliest case because they used only viruses sampled in the Utah and Arizona outbreak. There were also sizable measles outbreaks in West Texas and South Carolina last year, as well as in Mexico and Canada.

If the location of that first infection is in the US, however, the research could lend significant weight to the idea that measles has been continually transmitting in the country for longer than a year, the threshold for determining elimination.

Wang and her team also estimated that the Arizona/Utah outbreak has been at least 6.5 times larger than the number of known cases.

More evidence for silent spread

There are other clues that much of the spread of measles in the US is going unreported, too.

A separate EIS investigation of measles in wastewater from Oregon found that the virus was detected 100 times between October and February, in 23 of 24 monitored counties. Oregon had six reported cases of measles during that time, but all of these were outside the areas that were being monitored for the virus.

“The number and spread of detection suggests measles is more widespread than the six reported cases that we have,” Dr. Jeffrey Tamucci, an EIS officer assigned to the Oregon Public Health Authority, said in a conference presentation.

“It begs the question, why are there missing clinical cases? Is it a sick person that does not seek care? A patient being diagnosed with other illnesses? Providers not testing those with clinically compatible symptoms? Or something else?” Tamucci said. “We don’t know for sure. We’re still trying to figure that out.”

Elimination status at risk

The CDC is at work on a nationwide analysis, similar to the one done in Arizona and Utah, looking at genomic data, said Dr. Noel Brewer, a distinguished professor of public health at the University of North Carolina.

“The data from states is useful but has important limitations that include not characterizing the connection to outbreaks in other states,” Brewer said, adding that he was aware of the data from Arizona and Utah. Another state is also doing a genomic analysis, he said.

Brewer chairs the committee that will certify the CDC’s report and give its opinion on measles elimination status to the Pan American Health Organization, or PAHO, which will make the ultimate determination this fall. The committee was convened by the nonprofit Task Force for Global Health and funded by the CDC.

Brewer expects the CDC’s report by the end of June and expects that the data will be convincing and definitive.

“Whether or not forensic epidemiology unearths a smoking gun linking the cases, measles is now widely present across the US and showing no signs of ending anytime soon,” he said.

In early April, CDC scientists published the first large batch of data from advanced genetic sequencing of roughly 1,000 measles viruses that were circulating in the US last year. The agency will use that information to try to determine whether the measles outbreaks in Texas, Arizona and Utah, as well as the outbreaks in South Carolina, Florida and Washington, are linked or the result of separate introductions from outside the US.

“Looking at the larger dataset from the US, Canada, and elsewhere, it’s pretty clear that what is happening in Utah and Arizona is closely connected to prior outbreaks in the US with clear links to e.g., Texas, New Mexico, and other places,” said Dr. Kristian Andersen, an evolutionary biologist at the Scripps Research Institute who is not involved in the effort to analyze the sequences but is closely following it.

“The larger outbreak in South Carolina, Washington and other places sit on a separate clade, but is also clearly caused by endemic transmission within the US (and Canada) and not from ‘immigration’ or other people traveling into the country as we have heard from HHS officials,” Andersen said in an email. (CNN)

Update news