by George Taniwaki

NASA recently celebrated the fifteenth anniversary of the launching of the Chandra X-ray Observatory by releasing several new images. One of the images, shown below, is an amazing composite that reveals in exquisite detail the turbulence surrounding the remnants of the Tycho supernova. (Scroll down to Figure 2, then come back.)

Tycho supernova

The scientific name of the Tycho supernova remnant is SN 1572, where SN means supernova and 1572 refers to the year it was first observed. That’s right, over 400 years ago, in November 1572, many people noticed a new bright object in the sky near the constellation Cassiopeia. Reports at the time indicated that it was as bright as Venus (peak magnitude of –4) meaning it was visible during the day.

SN 1572 is called the Tycho supernova because a Danish scientist named Tycho Brahe published a paper detailing his observations. His paper is considered one of the most important in the history of astronomy, and science in the Renaissance.

Tycho_Cas_SN1572

Figure 1. Star map drawn by Tycho Brahe showing position of SN 1572 (labelled I) within the constellation Cassiopeia. Image from Wikipedia

What people at the time didn’t know was that SN 1572 was about 9,000 light years away, meaning it was unimaginably far away. The explosion that caused it happened long ago but the light had just reached the earth.

(Actually, SN 1572 is fairly close to us relative to the size of the Milky Way which is 100,000 light years across, and extremely close relative to the size of the observable universe which is 29 billion light years across. Space is just really unimaginably large.)

What they also didn’t know was that SN 1572 was probably a Type 1a supernova. This type of supernova is common, and has a very specific cause. It starts with a binary star system. Two stars orbit one another very closely. Over time, one of the stars consumes all of its hydrogen and dies out, leaving a carbon-oxygen core. Its gravity causes it to accrete the gas surrounding it until its mass reaches what is called the Chandrasekhar limit and it collapses. The increased pressure causes carbon fusion to start. This results in a runaway reaction, causing the star to explode.

About a supernova remnant

In the 400 years since SN1572 exploded, the debris from it has been flying away at 5,000 km/s (3100 mi/s). It is hard to see this debris. Imagine a large explosion on the earth that occurs at night.

The debris itself doesn’t generate very much light, but it does produce some. Space is not a vacuum. It is a very thin gas. When electrons from the moving debris of the supernova remnant strike a stationary particle, it gives off a photon (which depending on the energy of the collision, is seen as radio waves, microwaves, visible light, UV, or x-rays). This energy also heats up the remaining particles, releasing additional photons, making them detectable with a very sensitive telescope.

About false color images

The Chandra X-ray Observatory was launched in 1999 from the space shuttle Columbia. As the name implies, it can take digital images of objects in the x-ray range of light. Since humans cannot see in this range, images taken in the x-ray range are often color coded in the range from green to blue to purple.

Often, composite images of space objects are created using telescopes designed to capture photons from different wavelengths. For instance, visible light telescopes like the Hubble Space Telescope often have the colors in their images compressed to black and white. Images from infrared telescopes, like the Spitzer Space Telescope, and ground-based radio telescopes are often given a false color range between red to orange.

Pictures please

All right, finally the results. Below is the most detailed image ever of the Tycho supernova remnant. It is a composite created by layering multiple, long-exposure, high-resolution images from the Chandra X-ray Observatory. The press release says, “The outer shock has produced a rapidly moving shell of extremely high-energy electrons (blue), and the reverse shock has heated the expanding debris to millions of degrees (red and green).

“This composite image of the Tycho supernova remnant combines X-ray and infrared observations obtained with NASA’s Chandra X-ray Observatory and Spitzer Space Telescope, respectively, and the Calar Alto observatory, Spain.

“The explosion has left a blazing hot cloud of expanding debris (green and yellow) visible in X-rays. The location of ultra-energetic electrons in the blast’s outer shock wave can also be seen in X-rays (the circular blue line). Newly synthesized dust in the ejected material and heated pre-existing dust from the area around the supernova radiate at infrared wavelengths of 24 microns (red).”

Tycho2014

Figure 2. Tycho supernova remnant composite image released in 2014. Image from NASA

Compare Figure 2 above to an image of the Tycho supernova remnant that NASA released in 2009 using data from observations made in 2003 shown below. Notice the lack of details. Also notice the large number of stars in the background, some even shining through the dust of the explosion. Apparently, the image above has been modified to eliminate most of these distractions.

These two images dated only a few years apart reveal what is likely remarkable advances in software for manipulating space images. I say that because the hardware in the telescopes themselves, such as optics, detectors, and transmitters probably have not changed much since launch. Thus, any improvements in resolution and contrast between the two images is a result of better capabilities of the software used to process images after the raw data is collected.

A New View of Tycho's Supernova Remnant

Figure 3. Tycho supernova remnant composite image release in 2009. Image from NASA

by George Taniwaki

Your smartphone is more than an addictive toy. With simple modifications, it can become a lifesaving medical device. The phone can already receive and send data to medical sensors and controllers wirelessly. By adding the right software, a smartphone can do a better job than a more expensive standalone hospital-grade machine.

In addition, smartphones are portable and patients can be trained to use them outside a clinical setting. The spread of smartphones has the potential to revolutionize the treatment of chronic conditions like diabetes. This can enhance the quality of life of the patient and significantly increase survival.

Monitoring blood sugar

Type 1 diabetes mellitus is an autoimmune disease in which the body attacks the pancreas and interrupts the production of insulin. Insulin is a hormone that causes the cells in the body to absorb glucose (a type of sugar) from the blood and metabolize it. Blood sugar must be controlled to a very tight range to stay healthy.

A lack of insulin after meals can lead to persistent and repeated episodes of high blood sugar, called hyperglycemia. This in turn can lead to complications such as damage to nerves, blood vessels, and organs, including the kidneys. Too much insulin can deplete glucose from the blood, a situation called hypoglycemia. This can cause dizziness, seizures, unconsciousness, cardiac arrhythmias, and even brain damage or death.

Back when I was growing up (the 1970s), patients with type 1 diabetes had to prick their finger several times a day to get a blood sample and determine if their glucose level was too low or too high. If it was too low, they had to eat a snack or meal. (But not one containing sugar.)

They would also test themselves about an hour after each meal. Often, their glucose level was too high, and they had to calculate the correct does of insulin to self-inject into their abdomen, arm, or leg to reduce it. If they  were noncompliant (forgetful, busy, unable to afford the medication, fearful or distrustful of medical institutions or personnel, etc.), they would eventually undergo diabetic ketoacidosis, which often would require a hospital stay to treat.

BloodGlucoseTestStrip

Figure 1a. Example of blood glucose test strip. Photo from Mistry Medical

InsulinShot

Figure 1b. Boy demonstrating how to inject insulin in his leg. Photo from Science Photo Library

If all these needle pricks and shots sound painful and tedious, they were and still are. There are better test devices available now and better insulin injectors, but they still rely on a patient being diligent and awake.

Yes, being awake is a problem. It is not realistic to ask a patient to wake up several times a night to monitoring her glucose level and inject herself with insulin. So most patients give themselves an injection just before going to bed and hope they don’t give themselves too much and that it will last all night.

Continuous glucose monitoring

Taking a blood sample seven or eight times a day is a hassle. But even then, it doesn’t provide information about how quickly or how much a patient’s glucose level changes after a meal, after exercise, or while sleeping.

More frequent measurements would be needed to estimate the rate at which a patient’s glucose level would likely rise or fall after a meal, exercise, or sleeping. Knowing the rate would allow the patient to inject insulin before the glucose level was outside the safe range or reduce the background dosage if it is too high.

In the 1980s, the first continuous glucose meters were developed to help estimate the correct background dosage of insulin and the correct additional amounts to inject after snacks and meals.

The early devices  were bulky and hard to use. They consisted of a sensor that was inserted under the skin (usually in the abdomen) during a doctor visit and had wires that connected it to a monitoring device that the patient carried around her waist. The sensor reported the glucose level every five to ten seconds and the monitor had enough memory to store the average reading every five to ten minutes over the course of a week.

The devices were not very accurate and had to be calibrated using the blood prick method several times a day. The patient would also have to keep a paper diary of the times of meals, medication, snacks, exercise, and sleep. After a week, the patient would return to the doctor to have the sensor removed.

The doctor would then have to interpret the results and calculate an estimated required background dose of insulin during the day and during the night and the correct amount of additional injections after snacks and meals. The patient would repeat the process every year or so to ensure the insulin dosages were keeping the glucose levels within the desired range.

Today, continuous glucose monitors can measure glucose levels using a disposable sensor patch on the skin that will stay in place for a week. It transmits data to the monitor wirelessly. Using a keypad, the monitor can also record eating, medication, exercise, and sleeping. The monitor can store months of personal data and calculate the amount of insulin needed in real-time. Alerts remind the patient when to inject insulin and how much. They are cheap enough and portable enough that the patient never stops wearing it.

ContinuousGlucoseMonitor

Figure 2. Wireless continuous blood glucose monitor and display device. Image from Diabetes Healthy Solutions

Continuous insulin pump

Also in the 1980s, the first generation of subcutaneous insulin pumps were commercialized. These pumps could supply a low background dose of insulin rather than big spikes provided by manual injections. The first pumps were expensive, bulky, hard to use. By the early 2000s though, insulin pumps became widely available and were shown to reliably reduce the fluctuations in glucose levels seen in patients who relied on manual injections. By providing a low dose of insulin continuously during the day and at night with the ability of the patient to manually apply larger doses after meals, it lowered the average level of glucose while also reducing the incidence of hypoglycemia. Over longer periods it also reduced the incidence of complications commonly seen with diabetes.

InsulinPumpEarlyinsulinpump

Figure 3a and 3b. Early insulin pump (left) and modern version (right). Images from Medtronic

There is one drawback to the continuous insulin pump. It can provide too much insulin at night while the patient is asleep. While sleeping, the patient’s glucose level falls. Since she is not performing blood tests, she will not notice that the insulin pump is set too high. Further, since she is asleep she may not realize that she is in danger, a condition called nocturnal hypoglycemia.

Software to control the pump

Imagine combining the continuous glucose meter with the continuous insulin pump. Now you have a system the mimics the behavior of the human pancreas. Sensors constantly monitor the patient’s glucose level, and anticipate changes caused by activities like eating, sleeping, and exercise.

The key is to use a well-written algorithm to predict the amount of insulin needed to be injected by the pump to keep sugar levels within the acceptable range. Instead of a human, software controls the insulin pump. If the glucose level does not stay within the desired levels, the algorithm learns its mistake and corrects it.

The initial goal of the combined monitor and pump was to predict low glucose levels while a patient was sleeping and suspend the pumping of insulin to prevent nocturnal hypoglycemia. Ironically, the US FDA panel rejected the first application submitted for the device saying that the traditional uncontrolled continuous insulin pump was actually safer than a new device because of the new device’s lack of field experience.

After years of additional studies the combined device, manufactured by Medtronic, was approved for use in the US in 2013. Results of a study involving 25 patients in the UK was published in Lancet Jun 2014. Another trial, involving 95 patients in Australia was published in J. Amer. Med. Assoc. Sept 2013.

CombinedGlucoseMonitorInsulinPump

Figure 4. Combined glucose meter and insulin pump form a bionic pancreas. Image from Medtronic

Better software and smartphones

The Medtronic combined device is proprietary. But several groups are hacking it to make improvements. For instance, researchers led by Z. Mahmoudi and M. Jensen at Aalborg University in Denmark have published several papers (Diabetes Techn Ther Jun 2014Diabetes Sci Techn Apr 2014, Diabetes Techn Ther Oct 2013) on control algorithms that may be superior to the one currently used in the Medtronic device.

Another interesting paper appeared in the New Engl J Med Jun 2014. It reports a study by Dr. Steven Russell of Massachusetts General Hospital and his colleagues. They wrote an app for a smartphone (Apple’s iPhone 4S) that could receive the wireless data from the Medtronic glucose meter and wirelessly control the Medtronic insulin pump.

Smartphones are ideal platforms for use in developing medical devices because they can communicate wirelessly with other devices, have sufficient computing power and memory for even the most complex control tasks, are designed to be easy to program and easy to use, and many people already own one.

Dr. Russell and his colleagues used a machine learning algorithm they had previously developed (J Clin Endocrinol Metab May 2014) to couple the two.

Even though this is a research project, not a commercial product, the results are pretty impressive. The study lasted 5 days, with the first day used to calibrate the algorithm and days 2-5 as the test.

As can be seen in Figure 5, after a day of “training” patients using the bionic pancreas (solid black line) had lower average glucose levels than patients on the standard protocol (solid red line). Further, the variance of their glucose level (black shaded area) was smaller than for patients on the standard protocol (red shaded area). Notice how much better the control is using the bionic pancreas, especially at night.

InsulinNEJM1

Figure 5. Variation in mean glucose level among adults during 5-day study. Image from New Engl J Med

Another measure of quality is the amount of time the patients’ glucose levels were within the desired level of 70 to 120 mg/dl (the green shaded region in Figure 6). Patients with the bionic pancreas (solid black line) spent about 55% of the time within the desired level. They also had fewer incidents of hypoglycemia (pink shaded region) or hyperglycemia (white region on right) than patients using the standard protocol (red line).

Note that even with the bionic pancreas, 15% of the time patients had a glucose level above 180, so there is still plenty of room to improve control.

InsulinNEJM

Figure 6. Cumulative glucose level in adults during day 1 where the bionic pancreas adapted to the patient (dashed line) and days 2-5 (solid black). Image from New Engl J Med

by George Taniwaki

Patients are often frustrated and confused when navigating the healthcare system. Part of the problem is that if you are sick or hurt, it reduces your cognitive abilities. But it also because hospitals are busy places with little funding for improving the user experience. Often the layout of the rooms, the signage, the forms and instructions, and the language used by the staff are not tailored to the needs of patients who are unfamiliar with the system.

Design to reduce patient violence

A significant problem in hospital emergency medical departments (called A&E in Britain, ER in America) is abusive and violent patients. According to the National Audit Office, violence and aggression towards hospital staff costs the NHS at least £69 million a year in staff absence, loss of productivity and additional security.

Some other statistics from the Design Council report: More than 150 incidents of violence and aggression are reported each day within the NHS system. In 2010, the incidence rate of violence and aggression was about 1 per 1000 patients. In 2009, 21% of staff report bullying, harassment, and abuse by patients, 11% report physical attacks by patients.

Working with the National Health Service, a design firm called PearsonLloyd developed some low-cost methods to reduce the incidence of violence and aggression, increase patient satisfaction, improve staff morale, and reduce security costs. They call their program, A Better A&E. The program was pilot tested at St. George’s Hospital in London and Southampton General. For an introduction, see the video below.

BetterAE

Figure 1. Still from video “A Better A&E. Image from Vimeo

Signage and brochure

The program consisted of three parts. First, improved signage was installed that included an estimated wait times along with a brochure that explained why a patient who arrived after you could be seen a doctor before you.

BetterAEbusyBetterAEWait

Figures 2a and 2b. Large screen monitor alternately shows how busy the A&E is and then how long the wait time is for different categories of patients. Images from Design Council report

BetterAEbrochure

BetterAESignage

Figure 3a and 3b. A page from brochure explaining why wait times differ among patients and what to expect at each station. Signage posted at each patient area keyed to the brochure. Images from Dezeen.com

Root cause analysis

The second part of the redesign was the introduction of program to capture information from doctors, nurses, and other staff about factors that led to violent and abusive behavior. The program included root cause analysis and a prominently posted Incident Tally Chart to record the “variables within the system that might hinder the ability of staff to deliver high quality care.”

BetterAEIncidentTally

Figure 4. Incident tally posted where staff can record any events during their shift. Images from Design Council Report

Toolkit and patterns

The final part of the program was to design a toolkit that would take the lessons from the A&E departments of the two pilot hospitals and generalize them so that they could be adopted by any hospital within the NHS system. The toolkit is presented as an easy to use website, http://www.abetteraande.com

Results

Surveys of patients and staff taken after the redesign indicated that both groups saw benefits.

  • 88% of patients felt the guidance solution was clear
  • 75% of patients felt the signage reduced their frustration during waiting times
  • Staff reported a 50% drop in threatening body language and aggressive behavior
  • NHS calculated that each £1 spent on design solutions resulted in £3 in benefits

by George Taniwaki

A new organ preservation method may help increase the number of transplants. It could dramatically increase the survival of patients with end stage liver or heart disease.

Background

The most common organ to be transplanted are kidneys. Part of the reason is that there are lots of patients with kidney failure waiting for a transplant. And part of the reason for that is patients with kidney failure can be placed on dialysis therapy while waiting for a donor organ. This allows them to survive several years while waiting for a donor organ. Patients requiring a replacement for failed hearts, lungs, and livers cannot wait. They must be transplanted quickly. If an organ is not available, they will die.

The other reason kidneys are the most common organ to be transplanted is that donor kidneys can be kept in ice water storage for 24 to 36 hours prior to transplant and still remain viable. This provides time to run crossmatch tests using blood samples from the donor and several possible recipients, contact the best matching patients and their surgeons, get them to the hospital, and transport the donor organ to the hospital. Hearts can only be stored about 4 hours and livers can only be stored about 12 hours. This often is not enough time to prepare for surgery and so the donor organ has to be discarded, unused.

I discuss some of these issues in earlier blog posts. For instance, see my Nov 2010 blog entry and May 2010 blog entry.

New and supercool protocol

In a paper published in Nature Medicine, Jun 2014 (subscription required), Tim Berendsen at University Medical Center in Utrecht, the Netherlands, Bote Bruinsma at Massachusetts General Hospital and Harvard Medical School, and others have developed a new protocol to supercool organs below zero (32 deg F) without freezing them. Their technique was tested on rat livers, but would likely work on human livers and would work with other organs, including kidneys. A good explanation of the process is included in a Jun 2014 press release.

HarvardRatLiver

Figure 1. Supercooled rat liver being perfused with new solution developed by Harvard researchers. Photo from Harvard University

Their technique involves four steps. First, the organ is placed in a vessel while an ice cold solution (usu. about 4 deg C, 39 deg F) is circulated through it, a process called perfusion. The solution contains dissolved oxygen and nutrients such as glucose that help keep the organ alive. This is already the standard procedure for perfusing organs.

What is new, is the perfusion solution and the next steps. The perfusion solution contains PEG-35kD (polyethylene glycol) and other proprietary ingredients (to be commercialized) that act as an antifreeze. This allows the solution and the liver to be carefully cooled to -6 deg C (21 deg F) in a way that avoids the formation of ice crystals that could damage the cells in the liver. The liver can remain perfused in the supercooled condition for up three days and remain viable. Then the liver is carefully warmed to above freezing and prepared for surgery as normal.

HarvardRatLiverChart

Figure 2. Chart showing temperature profile of liver using proprietary perfusion solution and supercooling protocol. Image from Nature Medicine

Extending the viable time for liver transplant from 12 hours to three days would be a huge change. It would allow many more transplants to occur, with a corresponding decrease in the number of patient deaths caused by a shortage of organs. Just as important, by allowing time for multiple crossmatch tests to be conducted, it could potentially improve the matching of organs to patients.

The next steps in the research is to try livers from larger animals and to test the protocol on other organs.

by George Taniwaki

About comment spam

Comment spam is a real problem. Most websites that allow comments (like mine) receive over 100 spam messages that link to unethical or fraudulent websites for each legitimate comment they receive.

Luckily, there are excellent spam filters that identify and remove these annoying click-bait messages. For instance, the service that hosts this blog, WordPress, uses a service called Akismet. These spam filters use pattern recognition to find suspicious messages based on characteristics like message content, sender email address, sender IP address, web page commented on, etc. Suspect messages are tagged as spam and moved to a junk comment folder.

Naturally, in the spam arms race, the creators of spam campaigns need tools to rapidly create comments, ideally a unique one for every blog post, so as to avoid being detected.

The message

I recently received a comment on this blog that reveals how comment spammers create messages. The comment was actually not the intended comment. Rather, the spammer sent me over 300 lines of code they used to create custom-looking comments. Phrases that could be customized were enclosed in curly braces {}. The options for the words in a phrase were separated by vertical pipes |. The curly braces could be nested to allow multiple levels of customization. In fact, the entire comment starts with a curly brace so that different versions of the message could be sent. The spam message generator is partially reproduced below.

Note in particular how many of the characters (highlighted in yellow) are accented or Unicode homoglyphs, meaning they form words that look like English, but will not appear in any dictionary that might be used by a spam filter to detect phrases often used in spam messages. Of special note is that words used multiple times will often have a different glyph replacement in each instance.

{

{ӏ have|I’ve} bеen {surfing|browsing} online mοrе thаn {three|3|2|4} hours todaу, ƴet I
never found any іnteresting article like
yours. {It’s|It іs} pretty worth enoսgh for me. {Іn mу opinion|Personally|In my view}, іf
ɑll {webmasters|site owners|website owners|web owners} аnd
bloggers mаde gooԁ content as ƴou dіd, tҺe {internet|net|web} will bе {much moгe|a lot more} useful than ever beforе.|
I {couldn’t|could not} {resist|refrain fгom} commenting.

{Very wеll|Perfectly|Well|Exceptionally well} written!|
{ӏ wіll|І’ll} {rіght awaʏ|immeԀiately} {tɑke
hold of|grab|clutch|grasp|seize|snatch} уoսr {rss|rss feed} ɑs I {can not|ϲаn’t} {іn finding|fіnd|to find} yοur {email|е-mail} subscription {link|hyperlink} օr
{newsletter|e-newsletter} service. Ɗo {yoս ɦave|yoս’ve} any?
{Please|Kindly} {аllow|permit|lеt} me {realize|recognize|understand|recognise|кnow}
{sߋ tɦat|in orԁer that} I {may juѕt|may|cοuld} subscribe.
Ҭhanks.|

The string of faux-fawning gibberish continues for another 290 lines or so and finally ends with this heart-felt closing.

Thɑnks fоr {greɑt|wonderful|fantastic|magnificent|excellent} {іnformation|info} ӏ wɑs looking for thіs {informatіon|info} for my mission.|
{Hi|Hello}, i tɦink that і saw you visited my {blog|weblog|website|web site|site} {ѕo|thus}
i сame to “return the favor”.{I аm|I’m} {trying to|attempting tߋ} find thіngs to {improve|enhance}
mʏ {website|site|web site}!І suppose its ok to use {some of|a fеw of} уօur ideas!\

I’m somewhat surprised the code above can confuse a spam filter. A pattern recognition algorithm could be designed to detect which forms of phrases, misspellings, and glyph substitutions are most commonly seen in spam rather than in messages typed by honest but error-prone humans.

Anyway, I want to thank this incompetent spammer for providing me with content for this blog post. And of course, thanks for the {kind|wonderful|supporting} message.

For examples of actual blog spam that prey on people who might be persuaded to sell a kidney, see this previous blog post.

by George Taniwaki

I recently received two comments on this blog from what appear to be scam artists seeking to prey on desperate people who might be persuaded to buy or sell a kidney.

I didn’t bother to follow up with either person to learn more about this scam. I say scam because it is illegal to buy or sell organs in nearly every country on earth. Further, nobody will pay for your travel expenses to a developing nation to have a nephrectomy (kidney removal surgery).

Bottom line: Do not respond to messages from strangers offering you money!

The messages

The first message shown below, is short and specifically is targeted at poor people who need money.

Do you want to sell your kidney due to financial problem? If yes you are in the right place of selling your kidney for good money. contact us @ SAWAN NEELU ANGEL’s HOSPITAL Multi specialist Home, J-293,Saket, New Delhi-17 India.. Email Us now:

Very Urgent

 

Dr Ashok kumar
ASN Directo

 

The second message is a bit of a mixed bag. This scam artist starts his pitch with an offer to help poor people desperate for a chance to escape debt. But at the end of his message, makes a stab at conning kidney patients to make a down payment for a transplant.

Good day,

Do you want to buy a Kidney or you want to sell your kidney? Are you seeking for an opportunity to sell your kidney for money due to financial break down and you don’t know what to do, then contact us today and we shall offer you good amount for your Kidney. My name is Doctor Calvin Cien am a Nephrologist in UBTH clinic hospital. Our clinic is specialized in Kidney Surgery and we also deal with buying and transplantation of kidneys with a living an corresponding donor. We are located in Indian, Turkey, Nigeria, USA, Malaysia. If you are interested in selling or buying kidney’s please don’t hesitate to contact us via email.

Best Regards.
Dr. Calvin Cien.

 

For more on how comment spam is created, see this blog post:

Comment spam template (June 2014)

For more on how scams work, see the following blog posts:

The Craigslist counterfeit check scam (June 2013)

Paris scam artists (March 2011)

by George Taniwaki

The human cytomegalovirus (CMV), a member of the Herpesvirus genus, is highly contagious and quite widespread. It is estimated that over two-thirds of all adults have anti-CMV antibodies in their blood and the proportion of the population exposed increases with age.

CMV infection is usually quite mild. Most people who have it don’t even know it. However, it can cause serious illness and death to those who are immunocompromised such as infants, the elderly, patients with HIV infection, and patients who have received a bone marrow or organ transplant. An excellent primer on CMV and its impact on kidney transplants in provided in the J. Amer. Soc. Nephr. Apr 2001.

Because CMV is so common, it is impossible (both mathematically and ethically) to avoid using donor kidneys that are infected, even when transplanting into a patient who tests negative for CMV antibodies.

As can be seen in the table below, the infection risk is lower for patients who test negative for CMV antibodies (possibly because they have a natural immunity to the virus). It is also lower for patients who receive a kidney from a donor who tests negative (since the kidney is less likely to carry the virus). The percentages in each group assumes random distribution of CMV among donor and patient populations.

Level of risk and (% of population) Patient CMV-
Lower risk  (33%)
Patient CMV+
Higher risk (67%)
Donor CMV-
Lower risk (33%)
Lowest risk (11%) Low risk (22%)
Donor CMV+
Higher risk (67%)
High risk (22%) Highest risk (45%)

 

For solid organ transplant recipients, CMV is the most common serious viral infection. Medscape notes that, “CMV infection usually develops during the first few months after transplantation and is associated with clinical infectious disease (e.g., fever, pneumonia, GI ulcers, hepatitis) and acute and/or chronic graft injury and dysfunction.”

The standard procedure to prevent or treat CMV infection is to prescribe ganciclovir, sold under the trade names Cytovene and Cymevene (Roche). Like other antiviral drugs, ganciclovir disrupts the replication of viral DNA.

Unfortunately, this drug has several limitations. First, widespread use of the drug seems to be leading to increased incidence of ganciclovir-resistant CMV infection. Second, the drug can cause serious side effects including hematological (blood) effects such as granulocytopenia (low white blood count), neutropenia (low neutrophil count), anemia (low red blood count), and thrombocytopenia (low platelet count). Third, animal studies showed it to be a potential human carcinogen, teratogen, and mutagen.

image

Figure 1. Replication of long chain of viral DNA by CMV. Image from New Engl. J. Med.

New therapy option

A new drug to prevent or treat CMV called letermovir is currently under investigation. In the New Engl J. Med. May 2014 (subscription required), Roy Chemaly and his coauthors report that among patients receiving hematopoietic stem-cell transplants (bone marrow transplants), use of letermovir significantly reduced the incidence of CMV infection and the level of viral DNA fell as the dose increased. This means the new drug is quite effective. Just as important, it had an acceptable safety profile. Patient taking even the highest dosage  did not report greater side effects than those taking the placebo. Specifically, it showed no hematologic toxicity or nephrotoxicity (kidney damage). An excellent discussion of this breakthrough is provided in an accompanying editorial that appears in the same issue. The editorial also highlights the higher reliability and sensitivity of quantitative polymerase chain reaction (PCR) to measure viral load and predict the onset of symptoms.

Naturally, additional studies will need to be conducted to test letermovir with patients receiving a solid organ transplant. But the initial test results are promising and give hope that within this decade fewer kidney transplant patients will lose their graft or their life due to CMV infection.

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