Stanford Then and Now: An Interview with Stanford's Jose Montoya (Part One)
"Just tell me one thing more--as a matter of personal curiosity," Abbey concluded. "What do you regard as the main principle--the, shall I say the basic idea--which you keep before you when you are exercising the practice of your profession?"
There was a pause while Andrew reflected desperately. At length, feeling he was spoiling all the good effect he had created, he blurted out:
"I suppose--I suppose I keep telling myself never to take anything for granted."
"Thank you, Doctor Manson."
---from "The Citadel" by A.J. Cronin
Today begins the first of a three-part series based on an in-depth interview with Stanford's infectious disease specialist Jose Montoya and my reporting on the history of M.E. at Stanford and in the Bay Area. Montoya is a leading M.E. doctor both internationally and within his institution. For years, Stanford infectious disease specialists rejected M.E. as a real disease and refused to allow M.E. patients to be seen in their clinic. Over a period of a dozen years, beginning in 2004, Montoya turned this major medical institution around, ultimately engaging numerous collaborators from several medical specialties within the medical school and from other institutions to work on M.E. There is little question that today Stanford is among the most vibrant centers of M.E. research. Montoya’s brick by brick approach is largely responsible. Of special interest to M.E. patients have been his investigations into the use of antiviral therapies.
Over the course of a lengthy conversation, Montoya spoke candidly about the science, the politics and the origins of the disease.
1) “Could there be a virus here?”
Jose Montoya is well known within the small but competitive M.E. research field and recognized as one of the top M.E. specialists by patients, as well. Nevertheless, he came to the disease relatively late. He did not see his first M.E. patient until February of 2004, almost fifteen years after M.E.—formerly documented in extremely rare, discrete outbreaks and largely unknown throughout medicine—began its incursion into the population in the early 1980s. California’s major urban centers, both north and south, seemed particularly hard hit.
Montoya’s first encounter with an M.E. sufferer was something of a fluke and, in hindsight, a bit of a miracle. Stanford's infectious disease clinic had a long-standing policy, communicated formally by letter to hundreds of doctors in the Bay Area in the 1980s, that the clinic would not allow such patients to cross the threshold at Stanford. (Infectious disease doctors at UCLA in Los Angeles instituted a similar policy during the same period.) Stanford is a tertiary care center, meaning patients typically are referred to Stanford clinics by their primary or even secondary doctors for specialized care.
Montoya was blithely unaware of his clinic’s policy, which had been laid down by the medical school’s revered infectious disease chief Thomas Merigan years earlier. Perhaps ironically, Merigan was Montoya's mentor during one of the years of his fellowship in infectious disease. Had this policy not been in place, it seems probable Montoya’s interest in M.E. might have been ignited years earlier.
Merigan is now Professor Emeritus at Stanford. In the mid-1980s, he had a multimillion dollar grant, the largest yet devoted to AIDS at that time, to study the efficacy of AZT and interferon in the treatment of that disease. Merigan and his colleagues went on to develop laboratory tests to measure viral load in the disease.
When a primary care doctor called Montoya in 2004 to ask if he would see an M.E. patient, Montoya recalls, “I was not aware that my own division had asked me twelve years earlier not to see these patients!”
Additionally, the referring doctor emphasized to Montoya the severity of this particular case.
"This patient's life had been devastated," Montoya remembers of his first meeting with the patient. "So all I did was listen. And I couldn't put together the life that she had before and the life that she had now. It didn't cross my mind for a second that she could have a psychological illness.
"There were two things that hit me,” he adds. “One, it's very hard for me to bear the pain of suffering. The ultimate reason that I'm in medicine is that I would like to see suffering on earth decreased to a minimum of nothing. When my patients are suffering, I suffer with them. So, when I saw the suffering of this patient--it was so profound. I couldn’t bear to see this.
"And the second part, the intellectual part, was--could there be a virus here?"
The “intellectual part” Montoya describes has continued to be his leading hypothesis: there is a pathogen, an inciting agent, mostly likely a virus, causing M.E. For Montoya, the Holy Grail is the identity of that virus.
Eleven years later in February of 2015, Montoya participated in a CDC conference call, in which he said, “Our work (at the Stanford ME/CFS team) was born as a response to the suffering experienced by millions of patients waiting for an answer from the medical and scientific communities and from the possibility that an infection may play a role as a trigger and/or perpetrator of the disease.” (italics added)
A peek into Montoya's history suggests he is someone who sets high standards for himself and high ideals for his profession. Originally from Cali, Columbia, he earned his medical degree with honors at the Universidad del Valle in Cali in 1985. He left Cali to attend Tulane University in New Orleans where he performed his internship and residency in internal medicine. While at Tulane, Montoya won four awards, two for outstanding achievement as an intern and resident, and two more for teaching. Montoya began his infectious disease fellowship at Stanford in 1991.
He is currently a professor in the Department of Medicine and Division of Infectious Diseases and Geographic Medicine at Stanford Medical School.
By the early 2000s Montoya had earned a reputation as the nation's top toxoplasmosis expert. Toxoplasmosis is a protozoal infection that can spread via cat feces and more rarely via blood transfusions. In immune-compromised people, the infection can pose a deadly threat. He is the director of the National Reference Laboratory for the Diagnosis and Management of Toxoplasmosis in the United States, based at the Palo Alto Medical Foundation. If an MD anywhere in the U.S. suspects toxoplasmosis in a patient, the Centers for Disease Control, the Food and Drug Administration and the NIH all recommend Montoya's lab as the best source for confirmation.
During the 26 years Montoya has been at Stanford, he has received more than twelve awards for excellence in teaching. He was also named among a list of the top 100 Columbians who have excelled abroad in a 2013 edition of 100 Colombianos en el exterior.
Montoya’s bona fides were such that beginning in the 2000s, a national search by Harvard Medical School resulted in a lengthy courtship by Harvard to lure him to Boston. Stanford, hoping to keep Montoya in place, countered Harvard’s overture, offering Montoya an opportunity to found and direct the Immunocompromised Host Service at the medical school. Montoya, who clearly relishes a challenge, chose to remain at Stanford. As head of that service, he addressed infections in cancer patients and transplant recipients. In both cases, patients’ immune systems are frequently overwhelmed. Often, they face a life and death battle with common infections healthy people easily shrug off.
“That’s where I learned to use antivirals long-term—in that world,” Montoya says. “Most infectious disease doctors will use antivirals for flu, genital herpes, shingles for short periods of time.”
When these diseases and other infections re-ignite in cancer patients, it’s a different story.
“Only in cancer are these drugs typically used for long periods.”
Montoya was unafraid to prescribe antivirals in M.E. patients. Many MDs, in contrast, seem to aver antivirals when they meet with M.E. patients despite observing what would be called “opportunistic infections” in AIDS. Montoya was comfortable prescribing antivirals in M.E. for months or longer--indeed, he believed lengthy duration was critical.
Montoya’s first patient in 2004 had “significant and generalized lymphadenopathy” and “very high” levels of IgG and IgM antibodies against three human herpes viruses: cytomegalovirus, HHV6 and Epstein-Barr. Montoya opted to prescribe an antiviral drug to treat these active infections that he soon recognized were common signs in the disease. He chose valganciclovir--trade name “Valcyte”--the only oral drug on the market with activity against all three infections.
“Humans can get infected with up to eight human herpes viruses, including HHV6, HHV7 and HHV8. Valcyte covers them all,” Montoya notes.
The patient had an excellent response.
“Her lymphadenopathy of years quickly disappeared and to our surprise,” Montoya adds, “her cognitive dysfunction and severe fatigue started to improve as well.”
“What follows is fate,” Montoya says. “because I had not seen an M.E. patient in fourteen years at Stanford, and yet, in the next few months, in a totally random way, I saw three more.”
In the first instance, a nurse who was also a nun at Stanford asked Montoya if he would see her M.E.-afflicted niece. The nurse had no idea Montoya had only recently seen his first patient.
“She asked me as a favor,” Montoya says. “So maybe if she had asked me a few years earlier, I might have said, ‘I have nothing to offer.’ But because I had seen the positive response with the antiviral on the very first patient, I said, ‘I will see her.’ And then—totally unrelated—a couple more people with M.E., who did not know each other, walked in. So that would now number four. And after number four, I saw they all responded to the antiviral.”
An excited Montoya presented his success story to his mentor, Stanford infectious disease specialist Jack Remington, the doctor with whom he completed his fellowship at Stanford. Remington responded with dry wit.
“He’s very tough, very rigorous, very severe with me,” Montoya says. “So Jack says, ‘Yes! I’m so excited for you! Good for you! And, next time, give them a pill made of sugar and you will find the same response. Congratulations!”
Montoya recounts the story with obvious affection for Remington, but the senior man’s comments hit their mark.
Montoya’s first article on M.E. appeared in the Journal of Clinical Virology in 2006. It was a pilot study. Montoya avoided the phrase "chronic fatigue syndrome" in the title of the article, understandably so given his institution's long-standing hostility to the disease. Montoya called his paper, “Use of Valganciclovir in patients with elevated antibody titers against HHV6 and EBV who were experiencing central nervous system dysfunction and longstanding fatigue.” Twelve patients took Valcyte for six months in an “open label” trial. All involved, patients and investigators alike, who included infectious disease doctor Andreas Kogelnik, knew the patients were taking Valcyte. “Nine of twelve experienced near-resolution of their symptoms,” the article concluded.
“That’s when I went to the randomized trial,” Montoya says.
In 2013, Montoya published another treatment study in the Journal of Medical Virology. This time, the study design was structured as a double-blind experiment, meaning half of the thirty patients were given Valcyte for six months, then they were switched to Remington’s sugar pill—a placebo—for the remaining six months while the placebo group took Valcyte.
Patients on Valcyte were more than 7-times more likely to be “responders.” They made significant gains in cognitive function and mental fatigue. Improvements in three immune parameters measured, including cytokines, also improved. Interestingly, high IgG antibody counts to EBV and HHV6 were not among those improvements. The finding suggested that Valcyte may have immune modulating, anti-inflammatory properties in addition to targeted action against specific herpes viruses. It’s also possible that Valcyte might inhibit an as yet unidentified virus. Contributors to this paper included Nevada clinician Daniel Peterson, who also treats with Valcyte as well as the anti-herpetic drugs Famvir and Vistide, and microbiologist Darham Ablashi, who co-discovered HHV6 and has studied the virus for decades.
Currently, Montoya is overseeing another clinical trial of Valcyte in patients with elevated antibodies to HHV6 and EBV to continue to study efficacy. But a second goal is to find a biological signature in responsive patients that will help doctors identify those who are likely to respond to the drug.
The late Martin Lerner was another skilled infectious disease specialist who prescribed antivirals for lengthy periods of months and even years, particularly Valcyte. Lerner noted improved cardiac function in patients who stayed on these regimens.
“There is no question,” Montoya says, “in the same way that I didn’t have a doubt that this was a real illness, that there is a group of patients who can get better with the antivirals. We know this is real, that they have the illness, but that’s not the point. They have tried many doctors, many things, and yet when we institute the antivirals, they start a path. And (the recovery path) seems to be unrelated to how long they have been sick. I’ve had patients who’ve been sick for twenty or thirty years who have had that recovery.
“But--they cannot be having PEM! (Post Exertional Malaise). I cannot emphasize that enough!” Montoya continues. "And yet the first thing a patient does when they are better is do what they haven’t done. And then they crash. Many times they’ll say, ‘I just took the dog for a walk for five minutes and that put me to bed for…’ They don’t seem to understand that it’s not the just that five minute walk, it’s everything they did during the day.“And it’s very hard to know what the pattern will be in each patient. Within the same patient the patterns can be different, but between patients, it’s even worse.
Montoya more than once starts his sentence with the phrase, “My dream is…” This time, he says, “I’ve been dreaming of having a group of health care providers in a room and each of us coming out with the wisdom of our experiences and distilling that wisdom. Because (PEM) is going to possibly sabotage the treatment effect of good drugs, because you give the drug, the patient gets better, and then the patient overdoes it and it looks like the drug is not working.
“So, the duration of the illness seems to be irrelevant. And the duration of treatment is extremely important, even essential. But, they cannot be having PEM,” Montoya says. “And the other things is support—they need supportive people around them. “And the other thing,” Montoya adds after a short pause, “they need to stop looking at the Internet for treatment. It’s crazy.”
2. The Periphery
Montoya is a dapper, courteous man with deep-set brown eyes, a sunny smile and a soft if insistent speaking voice. When he talks, it feels as if his passion for his topic is almost too large to be expressed in mere words, which come in a rush. He anticipates and answers questions before they are asked.
My question to him is only half-posed and coming out in a jumble when he mercifully interrupts me. I have asked, “There was a period of at least decades when doctors didn’t see this disease and at some point in the late 1970s and early 1980s, it started to spread. And now perhaps as many as four million people in the U.S. alone are sick. And yet, most research seems to be simply descriptive and I wonder what happened to germ theory and….”
Montoya smiles and surprises me.
“When it’s all dark, I’m alone, I go to those worlds—the world of ‘What is really happening here?’
“My best moment was when I lost an airplane connection. So, they put us in a bus for three hours on a dark night in Colorado in winter. The night was really dark, the snow was really white, and I sat next to a window and for three hours I just went through this process.
"So yes, many of the things that we see are touching the periphery,” he continues. “But you have to be careful how you say it because your colleagues will take offense.
“But a lot of things are touching the periphery. The metabolomics, the proteomics, messenger RNA—it’s touching the periphery.”
In other words, science has yet to identify the root cause of the disease even though scientists continue to peel back new layers of dysregulation and abnormality—all of it the periphery surrounding the central mystery: the cause.
“I think this disease needed to have that phase because of the skepticism. So I think that we are going through an obligatory phase where we have to tell the world with biological data, ‘This is a real disease.’”
“I mean, it was lucky that the Institute of Medicine did the right thing, but the IOM is only a political statement,” he continues in a reference to the February 2015 Institute of Medicine Report on CFS/ME, which concluded that M.E. was a biologically based, severe disease.
“But the science now is such that no matter how peripheral something looks—like the metabolomics study, the (Robert) Naviaux study, it shows that we’re in a hypometabolic state, a hibernating state.” After a short pause and glances exchanged, Montoya adds, “Well--sure!”
He says the last word the way teenagers say “Duh!” precipitating laughter on both sides.
“So you have people talking to the press and saying respectfully, ‘It’s important, it’s important.’ But it actually is important because it’s really showing there is a biology behind the disease.”
“But when you are seeking the central process, the pathophysiology…” I begin to ask in the frustrated manner of one who has been ill for 31 years.
And Montoya interrupts again, with another surprise.
“It’s not, I think, a coincidence that AIDS and M.E. started—exploded—at the same time. Because we know HIV had been in humans for several years. And there was a recent paper published in Nature where they went back to the sera in the 1970s (and found HIV). Even this guy Gaetan Dugas who was accused of being ‘Patient Zero’ was not the earliest virus carrier in the U.S. Clearly HIV was in the U.S. before that.
“I have had this theory even before I knew about M.E.,” he adds. “As a human race, we have had a huge virus infecting us for centuries—the small pox virus. This virus triggers very strong immune responses. I think that as small pox infected hundreds of thousands of humans over centuries, those who survived were selected to have immune responses that were strong and broad—strong and broad. So that at the same time the immune system was addressing small pox threats, it was addressing other viruses indirectly.
“Then, small pox gets eradicated from the surface of the earth and the last human case is in 1978, although the decline began much longer before that date. But, as a consequence, we wipe out an important, strong immunity that was not covering just small pox but other viruses. And it may explain M.E. as well as AIDS. Because there were hundreds of small (M.E.) outbreaks. You have a whole section on this in your book."
I ask, “But common to those early outbreaks was the fact that they were each contained and did not spread outside of the institution. And then, in the 1980s it explodes. I think it has to be a new pathogen.”
And Montoya responds, “Exactly. I’m looking for that ultimately. But I think this theory might explain why (the epidemic) goes up like this,” and Montoya lifts his hand in the air.
“And please quote that,” he adds. “My hope is that people read it and follow it up. It’s interesting. People only hear what they want to hear. It’s interesting how we listen and not hear. I’ve had people who are really smart who say, ‘That’s a Nobel Prize idea.' And others who just…” and he releases a gentle puff of air as if blowing away a lighter-than-air dandelion seed.
More to come...