TB can persist in lungs despite treatment, researchers find

Date:

September 6, 2016

Source:

NIH/National Institute of Allergy and Infectious Diseases

Summary:
It has been known that the microbe that causes TB, Mycobacterium tuberculosis, can persist
in the lungs even after patient tissue samples test negative for the bacteria. In new research,
scientists have found through the use of positron emission tomography/computerized
tomography scanning that TB lesions can remain in the lungs long after treatment with
antibiotics has been completed.

Patients with active tuberculosis of the lungs, the infectious form of the
disease known as pulmonary tuberculosis (TB), are typically treated with
several medications for a period of six months. However, clinicians currently
lack a definitive way to determine when antibiotics have effectively cured a
patient of the disease. It has been known that the microbe that causes
TB, Mycobacterium tuberculosis, can persist in the lungs even after patient
tissue samples test negative for the bacteria. In new research appearing
in Nature Medicine, intramural researchers at the National Institute of Allergy
and Infectious Diseases (NIAID), part of the National Institutes of Health,
together with NIAID grantees, found through the use of positron emission
tomography/computerized tomography (PET/CT) scanning that TB lesions can
remain in the lungs long after treatment with antibiotics has been completed.
The scientists used PET/CT to examine the lungs of 99 patients with pulmonary TB in South Africa
before, during and after treatment with a typical regimen of TB medications. For tuberculosis,
PET/CT can be used to measure the level of inflammation, or lesions, in affected areas of the lungs.
Previously, NIAID researchers found that PET/CT could be used to successfully predict the
effectiveness of TB drug regimens.
After six months of treatment, PET/CT scans of 76 of the 99 patients showed lung lesions similar to
those seen in untreated pulmonary TB patients. One year after treatment concluded, 50 patients still
showed radiological abnormalities. The investigators found that while most lesions decreased in
severity and size, only 16 of those patients with such abnormalities were fully cleared of TB lesions;
the remaining 34 patients still had significant residual lesions. The researchers also detected TB

genetic material in respiratory samples of saliva and mucus from a substantial number of patients
deemed to be cured of clinical symptoms at the end of treatment.
The findings show that TB bacteria may persist in the lungs even after patients have finished
treatment and are free of clinical symptoms. Although it is unclear how this might affect the risk of
disease relapse, the study results underscore the need for new diagnostic methods and improved TB
treatment strategies, according to the researchers.

HIV not a super-spreader of drug-resistant tuberculosis

Date:

August 9, 2016

Source:

eLife
Summary:
While the human immunodeficiency virus pandemic fuels tuberculosis outbreaks, it does not
drive the development and transmission of multidrug-resistance in TB patients as previously
suspected, according to a study.

While the human immunodeficiency virus (HIV) pandemic fuels tuberculosis

(TB) outbreaks, it does not drive the development and transmission of
multidrug-resistance in TB patients as previously suspected, according to a
study published in eLife.
The findings, from a collaboration between Norwegian, British and Argentinian scientists, also show
that TB drug resistance is not more likely to evolve in HIV-positive patients compared to HIV-negative
patients.
"It is already known that a parallel HIV pandemic amplifies the TB epidemic, with ongoing efforts
around the world to tackle these potentially fatal diseases," says lead author Vegard Eldholm, a
research fellow at the Norwegian Institute of Public Health.
"Among the estimated 1.5 million people who died from TB in 2015, about 200,000 cases involved
multidrug-resistant TB and 400,000 were HIV co-infected. However, it is not clear exactly how much
of an effect HIV has had on drug resistance in the most common form of TB, Mycobacterium
tuberculosis (Mtb)."
To explore the impact of HIV co-infection on Mtb drug resistance, Eldholm and his team analysed the
genomes of 252 TB isolates from patients belonging to the largest outbreak of multidrug-resistant TB
in South America to date.

The isolates were collected from patients with known HIV status from the mid-1990s until 2009. The
team used the genomes to create a time-labelled phylogenic tree, a diagram showing the inferred
evolutionary relationships among the mutations within the sampled patients. They then applied a
new mathematical model optimized for TB to reconstruct how the disease spread among individuals.
Finally, they combined the results of both methods to estimate the length of the TB latent period -the time from infection to infectiousness -- and identify the patients in who TB strains evolved drugresistance mutations.
"We saw no significant differences in the rate at which mutations occur in the genomes of strains in
HIV-positive and negative patients. This suggests that drug resistance is not more likely to evolve in
HIV-positive patients," says co-corresponding author Francois Balloux, Professor of Computational
Systems Biology at University College London.
While the team's reconstruction of disease transmission among individuals did not reveal a
significant impact of HIV co-infection on the ability of patients to transmit TB, their estimates of TB
latency confirm that HIV co-infection accelerates the development of active TB.
"HIV prevents some cells from doing their job in the immune system, meaning the body is unable to
fight off a large number of infections," Eldholm explains.
"The disease therefore provides TB with a pool of susceptible hosts, amplifying the rate of coinfection. Indeed, for this reason, HIV patients at a major hospital in Buenos Aires, Argentina, played
a central role in fueling South America's largest multidrug-resistant TB epidemic in the early 1990s,"
he adds.

Details of mysterious Utah Zika-related death:

Transmission by tears or sweat
Date:
September 30, 2016
Source:
University of Utah
Summary:
The first Zika virus-related death in the continental U.S. occurred in June of this year, but
even now, months later, two aspects of this case continue to puzzle health experts. First, why
did this patient die? It is quite rare for a Zika infection to cause severe illness in adults, much

less death. Second, how did another individual, who visited the first while in the hospital,
become ill from Zika? This second patient did not do anything that was known at the time to
put people at risk for contracting the virus.

The first Zika virus-related death in the continental U.S. occurred in June of
this year, but even now, months later, two aspects of this case continue to
puzzle health experts. First, why did this patient die? It is quite rare for a Zika
infection to cause severe illness in adults, much less death. Second, how did
another individual, who visited the first while in the hospital, become ill from
Zika? This second patient did not do anything that was known at the time to
put people at risk for contracting the virus.
Researchers at the University of Utah School of Medicine and ARUP Laboratories in Salt Lake City
begin to unravel the mystery in a correspondence published online on Sept. 28 in The New England
Journal of Medicine. Details from the two cases point to an unusually high concentration of virus in
the first patient's blood as being responsible for his death. The phenomenon may also explain how
the second patient may have contracted the virus by touching the tears or sweat from the primary
patient, the first such documented case.
"This rare case is helping us to understand the full spectrum of the disease, and the precautions we
may need to take to avoid passing the virus from one person to another in specific situations," says
corresponding author Sankar Swaminathan, M.D., Chief of Infectious Disease and Professor of
Internal Medicine at the University of Utah School of Medicine. He collaborated with coauthors
Robert Schlaberg, M.D., M.P.H., Marc Couturier, Ph.D., and Kimberly Hanson, M.D., M.H.S. from
ARUP Laboratories, and Julia Lewis, D.O. from the University of Utah School of Medicine. "This type
of information could help us improve treatments for Zika as the virus continues to spread across the
world and within our country."
From the letter in NEJM, a story unfolds. Last May, Patient 1, a 73-year-old man, traveled to
southwest Mexico, a Zika-infected area. Eight days after returning, he started having abdominal pain
and fever, and by the time he was admitted to the University of Utah hospital he also had inflamed,
watery eyes, low blood pressure and a rapid heart rate. Despite the medical staff's best efforts to
stabilize him, his condition declined rapidly. During this time, Patient 2 came to visit and reported
wiping away Patient 1's tears and helping to reposition him in the hospital bed. It wasn't long before
Patient 1 slipped into septic shock, and his kidneys, lungs and other organs started to shut down. He
died shortly thereafter.
Even though it's well known that Zika can cause severe brain damage in unborn babies, symptoms
are typically mild in adults. Only nine other Zika-related deaths have been reported worldwide, says
Swaminathan. Despite the odds, tests performed after Patient 1's death revealed that he had Zika.
Patient 1 was initially identified as being potentially infected with Zika virus during validation of a real
time PCR test for Zika virus that is currently under development at ARUP Laboratories, and was

subsequently confirmed as positive by both the Utah Department of Health and the Centers for
Disease Control and Prevention.
Further investigation using Taxonomer, a tool developed by scientists at University of Utah and
ARUP Laboratories, that rapidly analyzes all genetic material from infectious agents in a patient's
sample, showed there were no other infections that explained his illness. It also found that the Zika
virus that infected the patient was 99.8 percent identical to that carried by a mosquito collected from
southwest Mexico, the same region that Patient 1 had visited a few weeks prior.
Seven days after Patient 1's death, Patient 2 was meeting with Swaminathan to talk about what had
happened when the doctor noticed that his visitor had red, watery eyes, a common Zika symptom.
Tests confirmed his suspicion, but in contrast to Patient 1 this patient only had mild symptoms that
resolved within the following week.
Like Patient 1's death, Patient 2's diagnosis was unexpected. The species of mosquito that carries
Zika had not been found in Utah and Patient 2 had not traveled to a Zika-infected area. A
reconstruction of events ruled out other known means of catching the virus.
"This case expands our appreciation for how Zika virus can potentially spread from an infected
patient to a non-infected patient without sexual contact or a mosquito vector," says Couturier. "This
and any future cases will force the medical community to critically re-evaluate established triage
processes for determining which patients receive Zika testing and which do not."
The authors believe that the reason behind the unusual nature of the case lies in yet another
anomaly. Patient 1's blood had a very high concentration of virus, at 200 million particles per milliliter.
"I couldn't believe it," says Swaminathan. "The viral load was 100,000 times higher than what had
been reported in other Zika cases, and was an unusually high amount for any infection." The
observation opens up the possibility that the extraordinary amount of virus overwhelmed the patient's
system, and made him extremely infectious.
Still, what led to the unusually severe infection in the first place remains unknown. Was there
something about Patient 1's biology or health history that made him particularly susceptible? There
were small differences in the virus' genetic material compared to other samples of Zika virus, did
they cause the virus to be exceptionally aggressive?
"We may never see another case like this one," says Swaminathan. "But one thing this case shows
us is that we still have a lot to learn about Zika."
The work was supported by the National Institutes of Health.