FlavivirusToday I learned that a number of investigators refuse to share their samples of Zika virus with other laboratories.

There are countless stories about scientists not sharing reagents because they want to be the first to make a discovery. This behavior allows them to publish first, secure more grant funding, garner invitations to speak at meetings, and generally stroke their egos.

This sort of selfish behavior happens all the time in science, but it is particularly offensive at a time when a new virus is spreading rapidly, and we need information about its biology, pathogenesis, and epidemiology to be able to treat and prevent infections. Not sharing reagents means that advances will come more slowly, or perhaps not at all: how do you know which laboratory will make the crucial findings?

Science has enough of a public image problem already. Do we need to make it worse by not sharing materials to work on a virus that has rapidly entered the public’s eye, and about which there are so many unanswered questions?

By keeping reagents to their own laboratories, scientists are being short-sighted and narrow-minded. Will you be pleased when you need a reagent and you can’t obtain it from another source?

Dear fellow scientists: scientific research is not about you and your ego. It is about contributing to human health. Get with the program.

 

Zika virus and microcephaly

FlavivirusThree reports have been published that together make a compelling case that Zika virus is causing microcephaly in Brazil.

An epidemic of Zika virus infection began in Brazil in April 2015, and by the end of the year the virus had spread through 19 states, many in the northeastern part of the country. Six months after the start of the outbreak, there was a surge in the number of infants born with microcephaly. It was not known if most of the mothers had been infected with Zika virus, as results of serological tests, virus isolation, or PCR were not available.

An initial report of 35 Brazilian infants with microcephaly born to women who either resided in or traveled to areas where Zika virus is circulating revealed that 74% of mothers had a rash (one sign of Zika virus infection) in the first or second trimester. At the time of this study no laboratory confirmation of Zika infection was available, but the infants did not have other infections associated with birth defects, including syphilis, toxoplasmosis, rubella, cytomegalovirus or herpes simplex virus.

Yesterday the CDC reported on the analysis of tissues from two infants with microcephaly who died within 20 hours of birth, and two miscarriages, all from the state of Rio Grande do Norte in Brazil. The mothers all had rashes typical of Zika virus infection in the first trimester of pregnancy, but were not tested for infection.

All four specimens were positive for Zika virus RNA by polymerase chain reaction (PCR) done with primers from two different regions of the viral RNA. Staining of tissues with anti-viral antibodies revealed the presence of viral antigens in two of the four samples, in the brain of one newborn and in the placenta from one of the miscarriages.

A second report from the University of Sao Paulo documents ocular abnormalities in Brazilian infants (from the state of Bahia) with microcephaly and presumed Zika virus infection. The mothers of 23 of 29 infants (79.3%) with microcephaly reported signs of Zika virus infection (rash, fever, joint pain, headache, itch, malaise). Of these, 18 (78.3%) had symptoms during the first trimester of pregnancy, 4 (17.4%) during the second trimester, and 1 (4.3%) during the third trimester.

No laboratory results were available to confirm Zika virus infections, but toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus, syphilis, and HIV were ruled out.

Abnormalities of the eye were found in 10 of 29 (34.5%) of infants with microcephaly. These included focal pigment mottling, chorioretinal atrophy, optic nerve abnormalities, displacement of the lens, or a hole in the iris.

These observations suggest that Zika virus infection may also cause lesions of the eye, although confirmation of infection needs to be done to prove causation. This uncertainty is reflected in the title of the article: “Ocular findings in infants with microcephaly associated with presumed Zika virus congenital infection in Salvador, Brazil” (italics mine).

The final paper is, in my opinion, the blockbuster. In this single case report, a 25 year old European woman working in Natal, Brazil, became pregnant in February 2015. In the 13th week of gestation she had fever, muscle and eye pain, and rash. Ultrasound in Slovenia at 14 and 20 weeks revealed a normal fetus.

At 28 weeks of gestation fetal abnormalities were detected, including microcephaly, and the pregnancy was aborted. Autopsy revealed severe brain defects, and 42 to 54 nm virus particles were detected in the brain by electron microscopy.

Infection with a variety of microbes was ruled out, but Zika virus RNA was subsequently detected in brain tissue by PCR.

Here is the clincher – the entire Zika virus genome was identified in brain tissue by next-generation sequencing! Analysis of the sequence revealed 99.7% nucleotide identity with a Zika virus strain isolated from a patient from French Polynesia in 2013, and a strain from Sao Paulo from 2015. These findings agree with the hypothesis that the current Brazilian outbreak was triggered by a virus from Asia.

Up to now there have been few data that strongly link Zika virus infection to congenital birth defects. Of these three new studies, the recovery of a full length Zika virus genome from an infant with microcephaly is the most convincing. Given the rapidity by which new data are emerging, it seems likely that additional evidence demonstrating that Zika virus can cause microcephaly will soon be forthcoming.

I’m amazed that a flavivirus can cause birth defects – when no flavivirus has done so before*. This is a virus spread by mosquitoes, and to which most of the world is not immune. The Zika virus outbreak will surely test our ability to respond rapidly with substantial mosquito control, diagnostics, antivirals, and a vaccine.

Update 2/11/16: A second paper has been published documenting ocular abnormalities in ten infants born to mothers in Brazil who had symptoms consistent with Zika virus infection.

Update 2/12/16: *Japanese encephalitis virus and West Nile virus have been shown to cross the placenta and infect the fetus. Such events must be rare because a larger association with birth defects has not been reported.

On November 13th, five colleagues and I released an open letter to The Lancet and editor Richard Horton about the PACE trial, which the journal published in 2011. The study’s reported findings–that cognitive behavior therapy and graded exercise therapy are effective treatments for chronic fatigue syndrome–have had enormous influence on clinical guidelines for the illness. Last October, Virology Blog published David Tuller’s investigative report on the PACE study’s indefensible methodological lapses. Citing these problems, we noted in the letter that “such flaws have no place in published research” and urged Dr. Horton to commission a fully independent review.

Although Dr. Horton’s office e-mailed that he would respond to our letter when he returned from “traveling,” it has now been almost three months. Dr. Horton has remained silent on the issue. Today, therefore, we are reposting the open letter and resending it to The Lancet and Dr. Horton, with the names of three dozen more leading scientists and clinicians, most of them well-known experts in the ME/CFS field.

We still hope and expect that Dr. Horton will address–rather than continue to ignore–these critical concerns about the PACE study.

****

Dr. Richard Horton

The Lancet
125 London Wall
London, EC2Y 5AS, UK

Dear Dr. Horton:

In February, 2011, The Lancet published an article called “Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomized trial.” The article reported that two “rehabilitative” approaches, cognitive behavior therapy and graded exercise therapy, were effective in treating chronic fatigue syndrome, also known as myalgic encephalomyelitis, ME/CFS and CFS/ME. The study received international attention and has had widespread influence on research, treatment options and public attitudes.

The PACE study was an unblinded clinical trial with subjective primary outcomes, a design that requires strict vigilance in order to prevent the possibility of bias. Yet the study suffered from major flaws that have raised serious concerns about the validity, reliability and integrity of the findings. The patient and advocacy communities have known this for years, but a recent in-depth report on this site, which included statements from five of us, has brought the extent of the problems to the attention of a broader public. The PACE investigators have replied to many of the criticisms, but their responses have not addressed or answered key concerns.

The major flaws documented at length in the recent report include, but are not limited to, the following:

*The Lancet paper included an analysis in which the outcome thresholds for being “within the normal range” on the two primary measures of fatigue and physical function demonstrated worse health than the criteria for entry, which already indicated serious disability. In fact, 13 percent of the study participants were already “within the normal range” on one or both outcome measures at baseline, but the investigators did not disclose this salient fact in the Lancet paper. In an accompanying Lancet commentary, colleagues of the PACE team defined participants who met these expansive “normal ranges” as having achieved a “strict criterion for recovery.” The PACE authors reviewed this commentary before publication.

*During the trial, the authors published a newsletter for participants that included positive testimonials from earlier participants about the benefits of the “therapy” and “treatment.” The same newsletter included an article that cited the two rehabilitative interventions pioneered by the researchers and being tested in the PACE trial as having been recommended by a U.K. clinical guidelines committee “based on the best available evidence.” The newsletter did not mention that a key PACE investigator also served on the clinical guidelines committee. At the time of the newsletter, two hundred or more participants—about a third of the total sample–were still undergoing assessments.

*Mid-trial, the PACE investigators changed their protocol methods of assessing their primary outcome measures of fatigue and physical function. This is of particular concern in an unblinded trial like PACE, in which outcome trends are often apparent long before outcome data are seen. The investigators provided no sensitivity analyses to assess the impact of the changes and have refused requests to provide the results per the methods outlined in their protocol.

*The PACE investigators based their claims of treatment success solely on their subjective outcomes. In the Lancet paper, the results of a six-minute walking test—described in the protocol as “an objective measure of physical capacity”–did not support such claims, notwithstanding the minimal gains in one arm. In subsequent comments in another journal, the investigators dismissed the walking-test results as irrelevant, non-objective and fraught with limitations. All the other objective measures in PACE, presented in other journals, also failed. The results of one objective measure, the fitness step-test, were provided in a 2015 paper in The Lancet Psychiatry, but only in the form of a tiny graph. A request for the step-test data used to create the graph was rejected as “vexatious.”

*The investigators violated their promise in the PACE protocol to adhere to the Declaration of Helsinki, which mandates that prospective participants be “adequately informed” about researchers’ “possible conflicts of interest.” The main investigators have had financial and consulting relationships with disability insurance companies, advising them that rehabilitative therapies like those tested in PACE could help ME/CFS claimants get off benefits and back to work. They disclosed these insurance industry links in The Lancet but did not inform trial participants, contrary to their protocol commitment. This serious ethical breach raises concerns about whether the consent obtained from the 641 trial participants is legitimate.

Such flaws have no place in published research. This is of particular concern in the case of the PACE trial because of its significant impact on government policy, public health practice, clinical care, and decisions about disability insurance and other social benefits. Under the circumstances, it is incumbent upon The Lancet to address this matter as soon as possible.

We therefore urge The Lancet to seek an independent re-analysis of the individual-level PACE trial data, with appropriate sensitivity analyses, from highly respected reviewers with extensive expertise in statistics and study design. The reviewers should be from outside the U.K. and outside the domains of psychiatry and psychological medicine. They should also be completely independent of, and have no conflicts of interests involving, the PACE investigators and the funders of the trial.

Thank you very much for your quick attention to this matter.

Sincerely,

Ronald W. Davis, PhD
Professor of Biochemistry and Genetics
Stanford University

Jonathan C.W. Edwards, MD
Emeritus Professor of Medicine
University College London

Leonard A. Jason, PhD
Professor of Psychology
DePaul University

Bruce Levin, PhD
Professor of Biostatistics
Columbia University

Vincent R. Racaniello, PhD
Professor of Microbiology and Immunology
Columbia University

Arthur L. Reingold, MD
Professor of Epidemiology
University of California, Berkeley

****

Dharam V. Ablashi, DVM, MS, Dip Bact
Scientific Director, HHV-6 Foundation
Former Senior Investigator
National Cancer Institute, NIH
Bethesda, Maryland

James N. Baraniuk, MD
Professor, Department of Medicine,
Georgetown University
Washington, D.C.

Lisa F. Barcellos, PhD, MPH
Professor of Epidemiology
School of Public Health
California Institute for Quantitative Biosciences
University of California
Berkeley, California

Lucinda Bateman, MD
Medical Director, Bateman Horne Center
Salt Lake City, Utah

David S. Bell, MD
Clinical Associate Professor of Pediatrics
State University of New York at Buffalo
Buffalo, New York

Alison C. Bested MD FRCPC
Clinical Associate Professor of Hematology
University of British Columbia
Vancouver, British Columbia, Canada

Gordon Broderick, PhD
Director, Clinical Systems Biology Group
Institute for Neuro Immune Medicine
Professor, Dept of Psychology and Neuroscience
College of Psychology
Nova Southeastern University
Miami, Florida

John Chia, MD
Clinician/Researcher
EV Med Research
Lomita, California

Lily Chu, MD, MSHS
Independent Researcher
San Francisco, California

Derek Enlander, MD, MRCS, LRCP
Attending Physician
Mount Sinai Medical Center, New York
ME CFS Center, Mount Sinai School of Medicine
New York, New York

Mary Ann Fletcher, PhD
Schemel Professor of Neuroimmune Medicine
College of Osteopathic Medicine
Nova Southeastern University
Professor Emeritus, University of Miami School of Medicine
Fort Lauderdale, Florida

Kenneth Friedman, PhD
Associate Professor of Pharmacology and Physiology (retired)
New Jersey Medical School
University of Medicine and Dentistry of NJ
Newark, New Jersey

David L. Kaufman, MD,
Medical Director
Open Medicine Institute
Mountain View, California

Nancy Klimas, MD
Professor and Chair, Department of Clinical Immunology
Director, Institute for Neuro-Immune Medicine
Nova Southeastern University
Director, GWI and ME/CFS Research, Miami VA Medical Center
Miami, Florida

Charles W. Lapp, MD
Director, Hunter-Hopkins Center
Assistant Consulting Professor at Duke University Medical Center
Charlotte, North Carolina

Susan Levine, MD
Clinician, Private Practice
New York, New York
Visiting Fellow, Cornell University
Ithaca, New York

Alan R. Light, PhD
Professor, Department of Anesthesiology and Department of Neurobiology and Anatomy
University of Utah
Salt Lake City, Utah

Sonya Marshall-Gradisnik, PhD
Professor and Co-Director
National Centre for Neuroimmunology and Emerging Diseases
Griffith University
Queensland, Australia

Peter G. Medveczky, MD
Professor, Department of Molecular Medicine, MDC 7
College of Medicine
University of South Florida
Tampa, Florida

Zaher Nahle, PhD, MPA
Vice President for Research and Scientific Programs
Solve ME/CFS Initiative
Los Angeles, California

James M. Oleske, MD, MPH
Francois-Xavier Bagnoud Professor of Pediatrics
Senator of RBHS Research Centers, Bureaus, and Institutes
Director, Division of Pediatrics Allergy, Immunology & Infectious Diseases
Department of Pediatrics
Rutgers – New Jersey Medical School
Newark, New Jersey

Richard N. Podell, M.D., MPH
Clinical Professor
Rutgers Robert Wood Johnson Medical School
New Brunswick, New Jersey

Charles Shepherd, MB, BS
Honorary Medical Adviser to the ME Association
London, United Kingdom

Christopher R. Snell, PhD
Scientific Director
WorkWell Foundation
Ripon, California

Nigel Speight, MA, MB, BChir, FRCP, FRCPCH, DCH
Pediatrician
County Durham, United Kingdom

Donald Staines, MBBS MPH FAFPHM FAFOEM
Professor and Co-Director
National Centre for Neuroimmunology and Emerging Diseases
Griffith University
Queensland, Australia

Philip B. Stark, PhD
Professor of Statistics
University of California, Berkeley
Berkeley, California

Eleanor Stein, MD FRCP(C)
Assistant Clinical Professor
University of Calgary
Calgary, Alberta, Canada

John Swartzberg, MD
Clinical Professor Emeritus
School of Public Health
University of California, Berkeley
Berkeley, California

Ronald G. Tompkins, MD, ScD
Summer M Redstone Professor of Surgery
Harvard University
Boston, Massachusetts

Rosemary Underhill, MB BS.
Physician, Independent Researcher
Palm Coast, Florida

Dr Rosamund Vallings MNZM, MB BS
General Practitioner
Auckland, New Zealand

Michael VanElzakker, PhD
Research Fellow, Psychiatric Neuroscience Division
Harvard Medical School & Massachusetts General Hospital
Boston, Massachusetts

William Weir, FRCP
Infectious Disease Consultant
London, England

Marcie Zinn, PhD
Research Consultant in Experimental Neuropsychology, qEEG/LORETA, Medical/Psychological Statistics
NeuroCognitive Research Institute, Chicago
Center for Community Research
DePaul University
Chicago, Illinois

Mark Zinn, MM
Research consultant in experimental electrophysiology
Center for Community Research
DePaul University
Chicago, Illinois

TWiVOn episode #375 of the science show This Week in Virology, the TWiVziks present everything you want to know about Zika virus, including association of infection with microcephaly and Guillain-Barré syndrome, transmission, epidemiology, and much more.

You can find TWiV #375 at microbe.tv/twiv.

FlavivirusCan Zika virus be sexually transmitted? Perhaps in very rare cases, but the main mode of transmission is certainly via mosquitoes. That’s why I’ve shamelessly stolen a quote on this topic from Dr. William Schaffner of Vanderbilt University:

Mosquito transmission is the highway, whereas sexual transmission is the byway. Sexual transmission cannot account for this sudden and widespread transmission of this virus.

If you just read the news headlines, which many people do, you will think that Zika virus spreads like HIV. But it does not.

Let’s make a clear distinction between sexually transmitted viruses (like HIV – sex is the main mode of transmission, along with contaminated blood), versus sexually transmissible viruses. The latter includes viruses that now and then might be sexually transmitted under certain circumstances, but which normally are transmitted by another route. Zika virus is transmitted among humans by mosquitoes. If sexual transmission occurs, it is very, very rare, given the large number of Zika virus infections that have been documented.

Is Zika virus sexually transmissible?

The first hint of sexual transmission of Zika virus came from the story of two American scientists working in Senegal in 2008, where they were sampling mosquitoes. Between 6-9 days after returning to their homes in Colorado, they developed a variety of symptoms of infection including fatigue, headache, chills, arthralgia, and a maculopapular rash. The wife of one patient had not traveled to Africa, yet she developed similar symptoms three days after her husband. Analysis of paired acute and convalescent sera from all three patients revealed antibodies against Zika virus. The authors of the study do not conclude that transmission from husband to wife was via sexual activity – they suggest it as a possiblity. Their data could not prove sexual transmission.

More recently infectious Zika virus was detected in semen of a French Polynesian male who had recovered from infection. The presence of virus in semen is compatible with sexual transmission, but the patient was not known to have transmitted infection to anyone.

The CDC has concluded that Zika virus was transmitted to an individual in Texas who had sex with a traveler returning from Venezuela. As of this writing I do not know exactly how the CDC came to this conclusion.

What would be needed to prove that Zika virus is sexually transmissible?

Polymerase chain reaction (PCR) is used to diagnose many viral diseases. This assay detects small fragments of viral nucleic acid and can be very specific. However as we are trying to establish for the first time that Zika virus can be transmitted sexually, more than PCR must be done – infectious virus should be recovered from the donor and recipient. A positive PCR result does not mean that infectious virus is present in the sample, only fragments of the genome, which of course would not be infectious. It is important to correlate the presence of infectious virus with sexual transmission.

Not only should infectious virus be recovered from both donor and recipient, but the viral genome sequences should be nearly identical, providing strong evidence for sexual transmission. If the viral genome sequences were substantially different, this result could imply that the infection was acquired from someone else.

Looking for anti-viral antibodies in serum is a good way to confirm virus infection when virus is no longer present. However it is not as specific as PCR or virus isolation, and does not provide information about the genome of the donor and recipient virus.

Sexual transmission of Ebolavirus still remains speculative. There are several suspected cases, and many examples of PCR positive semen samples from men who have recovered from the disease. It’s not easy to prove that a virus can be transmitted sexually, especially when it is a rare event.

Just as we are not sure that Zika virus causes microencephaly, we are not sure if it can be sexually transmitted.

By David Tuller, DrPH

David Tuller is academic coordinator of the concurrent masters degree program in public health and journalism at the University of California, Berkeley.

 

Last week, a commentary in Nature about the debate over data-sharing in science made some excellent points. Unfortunately, the authors lumped “hard-line opponents” of research into chronic fatigue syndrome with those who question climate change and the health effects of tobacco, among others—accusing them of engaging in “endless information requests, complaints to researchers’ universities, online harassment, distortion of scientific findings and even threats of violence.”

Whatever the merits of the overall argument, this charge—clearly a reference to the angry response of patients and advocates to the indefensible claims made by the PACE trial–unleashed a wave of online commentary and protest on ME/CFS forums. Psychologist James Coyne posted a fierce response, linking the issue specifically to the PACE authors’ efforts to block access to their data and citing the pivotal role of the Science Media Centre in the battle.

The Nature commentary demonstrated the degree to which this narrative—that the PACE authors have been subjected to a wave of threats and unfair campaigning against their work and reputations—has been accepted as fact by the UK medical and academic establishment. Despite the study’s unacceptable methodological lapses and the lack of any corroborating public evidence from law enforcement about such threats, the authors have wielded these claims to great effect. Wrapping themselves in victimhood, they have even managed to extend their definition of harassment to include any questioning of their science and the filing of requests for data—a tactic that has shielded their work from legitimate and much-needed scrutiny.

Until recently, complaining about harassment worked remarkably well for the PACE team. Maybe that’s why they tried claiming victimhood again last October, when Virology Blog ran “Trial By Error,” my in-depth investigation of PACE. The series was the first major critique of the trial’s many indefensible flaws from outside the ME/CFS patient and advocacy community. Afterwards, the investigators complained that “misinformation” and “inaccuracies” in my stories had subjected them to “abuse” on social media and could cause them “a considerable amount of reputational damage.”

These claims were ridiculous—an attempt to deploy their standard strategy for dismissing valid criticisms. The PACE authors amplified this error in December, when they rejected Dr. Coyne’s request for data from a PACE paper published in PLoS One as “vexatious.” They had called previous requests from patients “vexatious” without attracting negative comment or attention—except from other patients. But applying the term to a respected researcher backfired, drawing howls from others in the scientific community with no knowledge of ME/CFS—the PACE team’s action was “unforgivable,” according to Columbia stats professor Andrew Gelman, and “absurd,” according to Retraction Watch.

(In fact, the PLoS One data, when ultimately released, will show that the paper’s main claim—that the PACE-endorsed treatments are cost-effective—is based on a false statement about sensitivity analyses, as I reported on Virology Blog.)

How did this theme of harassment and “vexatiousness” become part of the conversation in the first place? Starting in 2011, a few months after The Lancet published the first PACE results, top news organizations began reporting on an alarming phenomenon: Possibly dangerous chronic fatigue syndrome patients were threatening prominent psychiatrists and psychologists who were researching the illness. These reports appeared in, among other outlets, the BMJ, the Guardian, and The Sunday Times of London. The Times headline, a profile of Sir Simon Wessely, a longtime colleague of the PACE authors, was typical: “This man faced death threats and abuse. His crime? He suggested that ME was a mental illness.”

One patient had supposedly appeared at a PACE author’s lecture with a knife. Other CFS researchers had received death threats. Sir Wessely famously said that he felt safer in Afghanistan and Iraq than in the UK doing research into the disease—a preposterous statement that the press appeared to take at face value. News accounts compared the patients to radical animal terrorists.

According to the news reports, the patients objected to the involvement of these mental health experts because they were anti-psychiatry and resented being perceived as suffering from a psychological disorder. Editorials in medical journals and other publications followed the news accounts, all of them defending “science” against these unwarranted and frightening attacks.

In fact, the Science Media Centre orchestrated the story in the first place—not surprising, given its longtime association with the PACE team and its uncritical promotion of the various PACE papers. According to a 2013 SMC report reviewing the accomplishments of the first three years of its “mental health research function”: “Tom Feilden, science correspondent for BBC Radio 4’s Today programme, won the UK Press Gazette’s first ever specialist science writing award for breaking the story the SMC gave him about the harassment and intimidation of researchers working on CFS/ME. The SMC had nominated him for the award.”

It’s great that the SMC not only spoon-fed Feilden the story but was so pleased with the reporter’s hard work that it nominated him for a prestigious award. In a brochure prepared for SMC’s anniversary, Feilden himself thanked the centre for its help in organizing the scoop about the “vitriolic abuse” and the “campaign of intimidation.”

Of course, patients were attacking the PACE study not because they were anti-science or anti-psychiatry but because the study itself was so terrible, as I reported last October. Luckily, a growing number of scientists outside the field, like Dr. Coyne and the top researchers from Columbia, Stanford and Berkeley who signed an open letter to The Lancet demanding an independent review, have now recognized this. How are patients supposed to react when a study so completely ignores scientific norms, and no one else seems to notice or care, no matter how many times it is pointed out?

The PACE study’s missteps rendered the results meaningless. Let’s recap briefly. The investigators changed their primary outcomes in ways that made it easier to report success, included outcome measures for improvement that were lower than the entry criteria for disability, and published a newsletter in which they promoted the therapies under investigation. They rejected as irrelevant their own pre-selected objective outcomes when the results failed to uphold their claims, and used an overly broad definition for the illness that identified people without it. Finally, despite an explicit promise in their protocol to inform participants of “any possible conflicts of interest,” they did not tell them of their work advising disability insurers on how to handle claimants with ME/CFS.

Patients and advocates have raised these and other legitimate concerns, in every possible academic, scientific and popular forum. This effort has been framed by the investigators, The Lancet and the Science Media Centre as a vicious and anti-scientific “campaign” against PACE. The news reports adopted this viewpoint and utterly failed to examine the scientific mistakes at the root of patients’ complaints.

Moreover, the reports did not present any independent evidence of the purported threats, other than claims made by the researchers. There were no statements from law enforcement authorities confirming the claims. No mention of any arrests made or charges having been filed. And little information from actual patients, much less these extremist, dangerous patients who supposedly hated psychiatry [see correction below]. In short, these news reports failed to pass any reasonable test of independent judgment and editorial skepticism.

Despite their questionable scientific methods and unreliable results, the PACE authors have widespread support among the UK medical and academic establishment. So does the Science Media Centre. Media reports, including last week’s Nature commentary, have presented without question the PACE authors’ perspective on patient response to the study. The reality is that patients have been protesting a study they know to be deeply flawed. Sometimes they have protested very, very loudly. That’s what people do when they are desperate for help, and no one is listening. To call it harassment is disgraceful.

Update 2/3/16: After reading some of the comments, I thought it was important to make clear that I don’t doubt the PACE investigators and some of their colleagues might have received very raw and nasty e-mails or phone calls. Perhaps some of these felt threatening, and perhaps they called in the police. (I’ve worked as a reporter for many years and have also received many, many raw and nasty e-mails, so I know it’s not enjoyable—but pissing people off is also part of the job.) The news accounts, however, provided no independent verification of the investigators’ charges. And the point is that, whether or not they have been the recipient of some unpleasant communications, the investigators have repeatedly used these claims to justify blocking legitimate inquiry into the PACE trial.

Correction: I reviewed the three major articles I linked to, not every single article about the issue, so my description of the coverage applies to those three. I originally wrote that the articles contained “no” interviews with actual patients. However, the Sunday Times article did include a short interview with one ME/CFS patient–a convicted child-molester who blamed his crime on fall-out from his illness. I apologize for the mistake, although I leave it to readers to decide if interviewing this person represented a sincere effort on the reporter’s part to present patients’ legitimate concerns.

I also wrote that the articles included no statements from law enforcement confirming the claims of threats. The Guardian article contained this sentence: “According to the police, the militants are now considered to be as dangerous and uncompromising as animal rights extremists.” This statement is vague, anonymous and impossible to verify with anyone in particular, so I don’t view it as an authoritative statement from law enforcement.

TWiV 374: Discordance in B

TWiVOn episode #374 of the science show This Week in Virology, the TWiVniks consider the role of a cell enzyme that removes a protein linked to the 5′-end of the picornavirus genome, and the connection between malaria, Epstein-Barr virus, and endemic Burkitt’s lymphoma.

You can find TWiV #374 at microbe.tv/twiv.

Zika virus

FlavivirusThe rapid spread of Zika virus through the Americas, together with the association of infection with microcephaly and Guillain-Barré syndrome, have propelled this previously ignored virus into the limelight. What is this virus and where did it come from?

History
Zika virus was first identified in 1947 in a sentinel monkey that was being used to monitor for the presence of yellow fever virus in the Zika Forest of Uganda. At this time cell lines were not available for studying viruses, so serum from the febrile monkey was inoculated intracerebrally into mice. All the mice became sick, and the virus isolated from their brains was called Zika virus. The same virus was subsequently isolated from Aedes africanus mosquitoes in the Zika forest.

Serological studies done in the 1950s showed that humans carried antibodies against Zika virus, and the virus was isolated from humans in Nigeria in 1968. Subsequent serological studies revealed evidence of infection in other African countries, including Uganda, Tanzania, Egypt, Central African Republic, Sierra Leone, and Gabon, as well as Asia (India, Malaysia, Philippines, Thailand, Vietnam, Indonesia).

Zika virus moved outside of Africa and Asia in 2007 and 2013 with outbreaks in Yap Island and French Polynesia, respectively. The first cases in the Americas were detected in Brazil in May 2015. The virus circulating in Brazil is an Asian genotype, possibly imported during the World Cup of 2014. As of this writing Zika virus has spread to 23 countries in the Americas.

The virus
Zika virus is a member of the flavivirus family, which also includes yellow fever virus, dengue virus, Japanese encephalitis virus, and West Nile virus. The genome is a ~10.8 kilobase, positive strand RNA enclosed in a capsid and surrounded by a membrane (illustrated; image copyright ASM Press, 2015). The envelope (E) glycoprotein, embedded in the membrane, allows attachment of the virus particle to the host cell receptor to initiate infection. As for other flaviviruses, antibodies against the E glycoprotein are likely important for protection against infection.

Transmission
Zika virus is transmitted among humans by mosquito bites. The virus has been found in various mosquitoes of the Aedes genus, including Aedes africanus, Aedes apicoargenteus, Aedes leuteocephalus, Aedes aegypti, Aedes vitattus, and Aedes furcifer. Aedes albopictus was identified as the primary vector for Zika virus transmission in the Gabon outbreak of 2007. Whether there are non-human reservoirs for Zika virus has not been established.

Signs and Symptoms
Most individuals infected with Zika virus experience mild or no symptoms. About 25% of infected people develop symptoms 2-10 days after infection, including rash, fever, joint pain, red eyes, and headache. Recovery is usually complete and fatalities are rare.

Two conditions associated with Zika virus infection have made the outbreak potentially more serious. The first is development of Guillain-Barré syndrome, which is progressive muscle weakness due to damage of the peripheral nervous system. The association of Guillain-Barré was first noted in French Polynesia during a 2013 outbreak.

Congenital microcephaly has been associated with Zika virus infection in Brazil. While there are other causes of microcephaly, there has been a surge in the number of cases during the Zika virus outbreak in that country. Whether or not Zika virus infection is responsible for this birth defect is not known. One report has questioned the surge in microcephaly, suggesting that it is largely attributed to an ‘awareness’ effect.  Current epidemiological data are insufficient to prove a link of microcephaly with Zika virus infection. Needed are studies in which pregnant women are monitored to see if Zika virus infection leads to microcephaly.

Given the serious nature of Guillain-Barré and microcephaly, it is prudent for pregnant women to either avoid travel to areas that are endemic for Zika virus infection, or to take measures to reduce exposure to mosquitoes.

Control
There are currently no antiviral drugs or vaccines that can be used to treat or prevent infection with Zika virus. We do have a safe and effective vaccine against another flavivirus, yellow fever virus. Substituting the gene encoding the yellow fever E glycoprotein with that from Zika virus might be a good approach to quickly making a Zika vaccine. However testing of such a vaccine candidate might require several years.

Mosquito control is the only option for restricting Zika virus infection. Measures such as wearing clothes that cover much of the body, sleeping under a bed net, and making sure that breeding sites for mosquitoes (standing water in pots and used tires) are eliminated are examples. Reducing mosquito populations with insecticides may also help to reduce the risk of infection.

Closing thoughts
It is not surprising that Zika virus has spread extensively throughout the Americas. This area not only harbors mosquito species that can transmit the virus, but there is little population immunity to infection. Infections are likely to continue in these areas, hence it is important to determine whether or not Zika virus infection has serious consequences.

Recently Zika virus was identified in multiple states, including Texas, New York, and New Jersey, in international travelers returning to the US . Such isolations are likely to continue as long as infections occur elsewhere. Whether or not the virus becomes established in the US is a matter of conjecture. West Nile virus, which is spread by culecine mosquitoes, entered the US in 1999 and rapidly spread across the country. In contrast, Dengue virus, which is spread by Aedes mosquitoes, has not become endemic in the US.

We recently discussed Zika virus on episode #368 of the science show This Week in Virology. You can be sure that we will revisit this topic very soon.

Added 1/28/16 9:30 PM: The letter below to TWiV provides more detail on the situation in Brazil.

Esper writes:

Hi TWIVomics

I hope this email finds you all well and free of pathogenic viruses.

My name is Esper Kallas, an ID specialist and Professor at the Division of Clinical Immunology and Allergy, University of São Paulo, Brazil.

I have been addicted to TWIV since a friend from U. Wisconsin participated in the GBV-C episode (David O’Connor, episode #260). Since then, never missed one episode. After long silent listening, I decided to write for the first time, motivated by the ongoing events in my country, potentially related to the Zika virus.

In the last episode, Emma wrote about events taking place in the small town of Itapetim, State of Pernambuco, Northeastern Brazil, which I will describe a bit later in this email. Before, let me bring some background information on the current situation.

Most believed Zika was a largely benign virus, causing a self-limited disease, clearly described in episode #368. Its circulation was documented after an outbreak became noticed in the State of Bahia (NE Brazil) by a group led by Guilherme Ribeiro, a talented young Infectious Diseases Scientist from Fiocruz (PMID: 26584464, Emerg Infect Dis. 2015 Dec;21(12):2274-6, free access)

However, things started to get awkward around October 2015, when a single hospital in Recife (NE Brazil) and some other practicing Obstetricians and Pediatricians from the region started reporting a mounting number of microcephaly cases in newborns, later confirmed by the national registry of newborns. The numbers are astonishing. The graph below depicts the number of cases per year prior to the surge in 2015. Only this year, 2,975 cases were reported by December 26, the vast majority in the second semester of the year. Cases are concentrated in the Northeast (map), with 2,608 cases, including 40 stillbirths or short living newborns.

Microcephaly, Brazil

In response to the situation, the Brazilian Ministry of Health has declared a national public health emergency (http://portalsaude.saude.gov.br/index.php/cidadao/principal/agenciasaude/20629-ministerio-da-saude-investiga-aumento-de-casos-de-microcefalia-em-pernambuco).

The Brazilian Ministry of Health has been presenting updates every week (see link: http://portalsaude.saude.gov.br/index.php/o-ministerio/principal/leia-mais-o-ministerio/197-secretaria-svs/20799-microcefalia). It is important to observe some imperfections in these numbers: 1. There may be an over reporting after the news made to the big media, suggesting an association between microcephaly and Zika virus. 2. The criterion to consider a microcephaly case has been changed after the current epidemic from 33cm to 32cm; this is because 33cm of head circumference is sitting in the 10th percentile of newborns at 40 weeks of pregnancy and the adjustment would bring the limit to the 3rd percentile, increasing the specificity to detect a true microcephaly case (this may result in an over reporting in the beginning of the epidemic).

The association between Zika virus infection and microcephaly was suspected since the beginning, when Brazilian health authorities ruled out other potential causes, together with the fact that the microcephaly epidemic followed Zika virus spread. Further evidences were the two positive RT-PCR for Zika RNA in two amniotic fluids obtained from two pregnancies of microcephalic fetuses and a stillborn microcephaly case with positive tissues for Zika RNA. In fact, French Polynesia went back to their records and also noticed an increase of microcephaly case reporting, following their epidemic by the same virus strain in 2013 and 2014.

Now, Zika virus transmission has been detected in several countries in the Americas (http://www.paho.org/hq/index.php?option=com_topics&view=article&id=427&Itemid=41484&lang=en).

Although strong epidemiological data suggest the association between Zika virus and the microcephaly epidemic, a causal link between the virus and the disease is still lacking and is limited to few case reports. Many questions still remain. Does the virus damage embryonic neural tissue? What is the percentage of fetuses getting infected when the mother acquires Zika virus during pregnancy? Does the stage of pregnancy interfere with virus ability to be transmitted to the fetus and the development of neurologic effects? Are there other neurological defects related to Zika virus infection? Is there another cofactor involved, such as malnutrition or other concurrent infection? All these questions are exceedingly important to provide counseling to pregnant women and those who are planning to become pregnant, especially in Northeastern Brazil. In fact, Brazilian authorities have been recommending avoiding pregnancy until this situation is further clarified.

The microcephaly epidemic impact is unimaginable. It is a tragedy. These children are compromised for life and the impact on their families is beyond any prediction.

Back to the story sent by Emma. A small town in the North of Pernambuco State, named Itapetim, has almost 14 thousand inhabitants and has reported 11 cases of microcephaly in the past 3 months. This very same town has been suffering from a prolonged drought, since September 2013 when the last reservoir went dry. Perhaps the storage of clean water or the limited resources has led to the best environment for arbovirus spread and the development of microcephaly.

But the Zika virus’s impact may be reaching further. An increase in Guillain-Barré syndrome cases has also been noticed in the Northeast of Brazil, possibly related to the epidemic.

Several groups have been trying to establish animal models to study the interaction of Zika virus with neural tissue. The forthcoming developments are critical to better understand the virus immunopathology and confirm (or refute) the association between the virus infection and neurologic damage in fetuses and in the infected host developing Guillain-Barré syndrome. Many things still shrouded in mystery.

Keep on the good work. I will keep on listening!

Esper

Do you want to learn virology? Every spring I teach a virology course at Columbia University, and this year’s version has just started. I record every lecture and put the videos on YouTube. Here is a link to the playlist: Virology Lectures 2016. Lecture #1, What is a Virus, is embedded below as a teaser.

I strongly believe that the best approach to teaching introductory virology is by emphasizing shared principles. Studying the phases of the viral reproductive cycle, illustrated with a set of representative viruses, provides an overview of the steps required to maintain these infectious agents in nature. Such knowledge cannot be acquired by learning a collection of facts about individual viruses. Consequently, the major goal of my virology course is to define and illustrate the basic principles of animal virus biology.

You can find the complete course syllabus, pdf files of the slides, and reading at virology.ws/course.

My goal is to be Earth’s virology professor, and this is my virology course for the planet.

On episode #373 of the science show This Week in Virology, Vincent speaks with Julius about his long career in virology, including his crucial work as part of the team at the University of Pittsburgh that developed the Salk inactivated poliovirus vaccine.

You can find TWiV #373 at microbe.tv/twiv. Or you can watch the video below.