Is chronic fatigue syndrome caused by a virus? An emphatic"no."

Chronic fatigue syndrome (CFS) is an illness characterized by disabling fatigue of at least 6 months. Chronic fatigue syndrome/myalgic encephalomyelitis have an estimated prevalence of 42/10,000 in the United States, with annual direct medical costs of $7 billion. The etiology of the condition has been hotly debated. It is unlikely that CFS can be understood through only one etiological mechanisms. Rather, CFS is a complex illness which is best explained in terms of a multifactorial cognitive behavioral model. This model proposes that CFS is precipitated by life events in vulnerable individuals, such as those who are genetically predisposed, prone to distress, high achievement, and over or under activity. A self-perpetuating cycle where physiological changes, illness beliefs, reduced and inconsistent activity, sleep disturbance, medical uncertainty and lack of guidance interact to maintain symptoms.

CFS has been linked in two independent studies to infection with xenotropic murine leukemia virus-related virus (XMRV) and polytropic murine leukemia
virus (pMLV). Although the associations were not confirmed in subsequent studies by other investigators, patients continue to question the consensus of the scientific community in rejecting the validity of the association. A blinded analysis of peripheral blood from a rigorously characterized, geographically diverse population of 147 patients with CFS and 146 healthy subjects by the investigators describing the original association revealed no evidence of either XMRV or pMLV infection. More than likely the earlier conclusion regarding virus as a cause was due to contamination in the lab with the XMRV which seems to be a combination of two other particles dating from the mid-1990s.

Should we be measuring more often? Lactate levels are frequently elevated in critically ill patients and correlate well with disease severity. Elevated lactate levels are prognostic in prehospital, emergency department, and intensive care unit settings. A recent study found that in patients with hyperlactatemia on ICU admission, lactate-guided therapy significantly reduced hospital mortality when adjusting for predefined risk factors. As this was consistent with important secondary endpoints, this study suggests that initial lactate monitoring has clinical benefit. A review of the literature reported
that supported blood lactate monitoring as being useful for risk assessment in patients admitted acutely to hospital, and especially the trend, achieved by serial lactate sampling, is valuable in predicting in-hospital mortality.

All patients with a lactate at admission above 2.5 mM should be closely monitored for signs of deterioration, but patients with even lower lactate levels should be considered for serial lactate monitoring. The correlation between lactate levels in arterial and venous blood was found to be acceptable, and venous sampling should therefore be encouraged, as the risk and inconvenience for this procedure is minimal for the patient. Venous assays of lactate are readily available on many blood gas instruments, larger chemistry instruments and even in some POC instruments.

While several new drugs have appeared including quinupristin/dalfopristin, linezolid, tigecycline and daptomycin, these are approved only for certain cases and already resistance has been reported.

Although not directly related to laboratory medicine, I must share this with you:  In a study published in Nature Communications, researchers claim that a gene which emerged sometime between six and one million years ago and that it is THE gene is the definitive difference between humans and other primates. Researchers from the University of Edinburgh in Scotland attribute the split of humanity from apes to the gene miR-941. They say that the gene played an integral role in human development and contributed to humans' ability to use tools and learn languages. The gene is highly active in the regions of the brain that control language learning and decision making, indicating that it may play a significant role in the higher brain. This is the first time that a gene that humans and other primates do not share has been shown to actually have a specific function within the body. Read more.

Being vaccinated each year remains is perhaps the best ways to prevent seasonal influenza. The CDC recommends that everyone 6 months of age and older receive influenza vaccine annually.

Recently the FDA announced the approval of Flucelvax. The manufacturing process for the vaccine is similar to the egg-based production method, but a significant difference is that the virus strains included in the vaccine are grown in cells of mammalian origin instead of in eggs. Cell culture technology has already been in use for several decades to produce other U.S. licensed vaccines.

Advantages of cell culture technology include the ability to maintain an adequate supply of readily available, previously tested and characterized cells for use in vaccine production and the potential for a faster start-up of the vaccine manufacturing process in the event of a pandemic.

The vaccine was tested in a randomized controlled clinical study in the United States and Europe that involved about 7,700 people ages 18 to 49 years who received either Flucelvax or a placebo. The study showed that the vaccine was 83.8 percent effective in preventing influenza when compared to placebo. The use of the vaccine in people older than 49 is supported by antibody responses in about 1,700 adults which showed it to be comparable to an egg-based seasonal influenza vaccine approved by FDA for use in people 18 years and older.  The fact that as of now the cell-cultured vaccine has not been tested on people less than 18, explain why it is not approved for those younger than 18. 

We have all heard of the A, B, AB and O blood types, and some of us spend our working day with these and many other types. These blood types are ancient. Humans and all apes share this trait, inheriting these blood types from a common ancestor at least 20 million years, posits a study recently published online on the website of the Proceedings of the National Academy of Sciences.

But why humans and apes have these blood types is still a scientific mystery. After Karl Landsteiner determined the pattern of the ABO blood group, he realized blood types are inherited. Later, researchers learned ABO blood types are governed by a single gene that comes in three varieties: A, B and O. (People who are type AB inherit an A gene from one parent and a B gene from the other.)

Scientists still have no idea of the utility or function of  these blood antigen. Obviously, people who are type O-the most common blood type-get along fine without them. There are some interesting associations between blood types and disease. In some infectious diseases, bacteria may closely resemble certain blood antigens, making it difficult for antibodies to detect the difference between foreign invaders and the body's own blood. People who are type A, for instance, seem more susceptible to smallpox, while people who are type B appear more affected by some E. coli infections. It has also been shown that serum cholesterol levels are related to blood type.

Over the last hundred years, scientists have also discovered that the ABO blood group is just one of more than 20 human blood groups. The while we don't know the biological function of these antigens, we certainly know that they function to remind us we still have lots to learn.

Recently I was asked to interpret a CEA from a person who had undergone chemotherapy for cancer. The question was what to do about a CEA that was 5.0 and had increased to 13.0 in less than a year. It appeared that these values had NOT been discussed with the patient, but the person had accessed the data without discussing them with the physician.

The question that this raises is are there times when laboratory results should not be given to the patient without the clinician physically present? I asked a friend of mine who was part of a cancer clinic. Here is what she had to say about this dilemma: "At my cancer center, the lab is not allowed to give results directly to the patient. We used to, but the doctors got tired of patients seeing results before they reviewed them. The docs would get frantic calls from patients that had a change in a tumor marker and the doc would not have even seen the result yet! So they instituted the rule that the lab could not give results out directly to the patient. We had a lot of upset patients because they felt that they were their results, their medical record, and they had a right to see them. But at least they weren't getting results without the accompanying explanation from a physician."

This situation is not isolated to one cancer center, but I am sure is to be found in many cancer centers as well as in primary physicians who order PSAs and other tumor markers. It has been my experience that HIV screening results were given before the confirmatory results were available. Think also about genetic testing. 

Without doubt there are many unanswered questions about access to medical records.

The author thanks Deena Davis, point of care supervisor at Deaconess Hospital, Bozeman, Mont., for collaboration on this blog. 

"Redefining Medicine with Apps and iPads" is an article by Katie Hafner that appeared in Science Times. The article shows both a new and innovative technology side of medicine as well as the time-honored, hands-on method. The claims are made that technology is taking away a physician's interaction with his patient and that the majority of medical decisions made today are based on findings from analyzers and instruments with little, if any, regard being given to a physical examination.  

Technology will never "replace" a physician. Computers are only as smart as the people who programmed them. The same can be said for laboratory analyzers, EKG instruments and MRI instruments. They all produce results, but an educated person must decide if those results fit the clinical picture. There is no doubt that sophisticated technology plays a major part in modern medicine. The argument can also be made that more patient lives are saved due to this technology. On the other hand, how many patients are misdiagnosed because the provider believed an erroneous lab (or EKG or MRI or x-ray) result over the presenting symptoms?

Why does it have to be one or the other? Lab results or patient symptoms? Shouldn't a diagnosis be made utilizing all of the information available? The young doctor in the article is utilizing a glorified calculator to determine the dose of saline. When physicians begin to rely on a machine to make the diagnosis medicine (and its patients) will be in an overwhelming amount of trouble.  Do we give up all of the technological advances that have been made to aid in diagnosis just to prevent this from happening? Is there not a middle ground using both clinical acumen and technology?

A recent study of mis-diagnoses in ICU patients found that the number of errors is about 8%. The most common errors were in the diagnosis of infection (pneumonia and aspergillosis) and pulmonary embolism and acute myocardial infarction. From the publications examined, 5863 autopsies (median rate 43%) were analyzed. The prevalence of mis-diagnoses ranged from 5.5%-100% with 28% of autopsies reporting at least one misdiagnosis and 8% identifying a diagnostic error. While it cannot be stated that the mis-diagnosis was the cause of mortality or morbidity, the possibility exists. Thus there is a potential for some 40,000 adult patients in the U.S. may die annually from such an error.

Eradicating the cause is one way to curtail this disease. The most vulnerable stages of Plasmodium (including Plasmodium malariae which is  closely related to Plasmodium falciparum and Plasmodium vivax which are responsible for most malarial infections) development occur in the lumen of the mosquito midgut, a compartment shared with symbiotic bacteria. A strategy that uses symbiotic bacteria to deliver antimalaria effector molecules to the midgut lumen, thus rendering host mosquitoes obstinately resistant to malaria infection. The Escherichia coli hemolysin A secretion system was used to promote the secretion of a variety of anti-Plasmodium effector proteins by Pantoea agglomerans, a common mosquito symbiotic bacterium. These engineered P. agglomerans strains inhibited development of the human malaria parasite Plasmodium falciparum and rodent malaria parasite Plasmodium berghei by up to 98%. The use of an engineered symbiotic bacterium has been shown to interfere with the development of P. falciparum in the mosquito. These findings provide the foundation for the use of genetically modified symbiotic bacteria as a powerful tool to combat malaria. (Reported in the July 16, 2012 issue of the Proceedings of the National Academy of Science)

For example, Verhovsek et al. reviewed seven published studies, totaling 1,888 patients who had sustained a first unprovoked VTE. During 4,500 person-years of follow up, annual rates of recurrent VTE differed statistically significantly: 8.9% in patients with positive D-dimer results and 3.5% in patients with negative D-dimer results.

In a somewhat different approach, Palareti et al. prospectively evaluated 599 patients (301 males) with a previous VTE episode. They were repeatedly examined for D-dimer levels after OAT withdrawal and were screened for inherited thrombophilic alterations. Recurrent events were recorded in 58 subjects (9.7%) during a follow-up of 870.7 patient-years. Altered D-dimer levels at one month after OAT withdrawal were associated with a higher rate of subsequent recurrence in all subjects investigated, especially in those with an unprovoked qualifying VTE event (hazard ratio, 2.43) and in those with thrombophilia (hazard ratio, 8.34). The negative predictive value of D-dimer was 92.9% and 95.8% in subjects with an unprovoked qualifying event or with thrombophilia, respectively.

It would appear that continued OAT significantly reduces VTE in patients who one-to-three months after OAT is stopped have an increased D-dimer.

With regard to the Myriad patent, the BRCA genes are found in each and everyone one of us but certain mutations increase the risk of breast and ovarian cancer considerably. Knowing whether one is at this high risk, may help the patient make a more intelligent decision about what path to take regarding treatment (or not). For a number of years Myriad has been under the gun for the fees it charges for the patent and the fact that currently it does not license  the patent so that other laboratories can perform the test. The case moved from lower courts and after having been set aside and then re-instated, it moved to the Supreme Court which recently set the patent aside. In other words, said it was not valid. Myriad will appeal this 16 year old patent.

In the second case, the Supreme Court rejected two patents on a method for monitoring a patient's blood to determine the best dosage for a particular drug (as we all know, monitoring drug levels as well as glomerular filtration, have been used for decades to determine dosages).

The justices unanimously overturned last month a ruling by an appeals court that allowed the patents for Nestle SA unit Prometheus, with the high court saying that companies could not patent observations about a natural phenomenon. The court wrote: "We conclude that the patent claims at issue here effectively claim the underlying laws of nature themselves. The claims are consequently invalid."

It is thought that one in five women have a genetic ‘switch' that increases cancer risk through epigenetic changes. Recently, a study from Imperial College in London of 1,380 women, 640 of whom went on to develop breast cancer, found a strong association between a modification of a single gene found in white blood cells. This change was due to methylation - the gene switch. The 640 women who developed cancer had higher levels of the methylated gene than those women who were unaffected. The increased level of methylation was found as many as 11 years before the cancer was diagnosed.

It is possible to quantify this methylated gene and as a result it may become possible for a laboratory test to aid in the early diagnosis and treatment of not only breast cancer, but also prostate and other cancers.