The (Not so) Spanish Flu, and How it Became the Deadliest Epidemic in Modern Time.

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I had a little bird,

its name was Enza.

I opened the window,

and in flew Enza.

     ~Children’s rhyme of 1917

In early March 2018 a mess cook at an Army base in Kansas reported to the infirmary complaining of sore throat, headache, and fever. After being checked over, the doctor could find no cause for alarm, and returned him to duty. By lunch time the infirmary was filled with soldiers complaining of similar symptoms, and by the end of the month the number of sick soldiers had grown beyond the capacity of the base hospital and a make-shift infirmary was created using an airplane hanger. By the end of the first month, 38 men had died. Influenza routinely killed 30% of those infected if they were under age 2. This influenza was killing health young men in the twenties. The soldiers were suffering with would become known as the Spanish Flu. You can imagine the worst place to have an infectious disease would be a place where tens of thousands of people were crowded together, as they were in training camps, where they prepared to go to war. The disease would spread to other training camps and eventually overseas.

Laura Spiney, in her book Pale Rider: The Spanish Flu of 1918 and How It Changed the World called the 1918 influenza epidemic, “The greatest wave of death since the Black Death.” A bit dramatic perhaps, but nevertheless accurate. What made this epidemic even more deadly, brought groups of infected and uninfected people together, and greatly helped the spread of this deadly disease, was the denials by those in power that anything was wrong.

In 1917, California Senator Hiram Johnson, an isolationist Progressive-Party-member-turned-Republican, states the first casualty when war comes is truth. At the time, Congress passed a measure, signed into law by President Woodrow Wilson, that made it punishable by up to 20 years in prison to “utter, print, write or publish any disloyal, profane, scurrilous, or abusive language about the government of the United States.” A clear violation of the First Amendment. Yet because Spain was neutral, its press was not under morality laws, so the pandemic they reported on became known as the Spanish flu.

In the cities of Minneapolis, St. Paul, Chicago, Philadelphia, New York, San Francisco, and several others, parades and events considered “important to the war effort” were not cancelled, even though they brought great numbers of people together. When public health experts demanded that such events (parades, rallies, etc.) would help spread the disease, they were reminded of the Morality Law, and the notion that “Fear kills more than the disease.”

The flu pandemic of 1918 to 1919 infected an estimated 500 million people worldwide, and claimed the lives of between 50 and 100 million people. More than 25 percent of the U.S. population became sick, and 675,000 Americans died during this pandemic, more than 10 times the number killed in Vietnam. The 1918 flu was first observed in Europe, the U.S. and parts of Asia before swiftly spreading around the world. By the time the disease had burned itself out, the total number of dead outnumbered those killed in both World Wars.

Why so deadly. Although many people had been exposed to H3N8 virus that had been circulating in the human population for about a decade, the human virus picked up genetic material from a bird flu virus just before 1918, creating a novel virus. The new virus had surface proteins that were very different, thus people’s immune system would have made antibodies, but they would have been ineffective against the virus. The high fatality was brought about by a combination of refusing to warn the public about exposure, refusing to allow newspapers to print stories of the epidemic, the novel makeup of the virus, the opportunistic bacteriological infections that thrived in weakened immune systems of many, and a process known as hypercytokinemia, or cytokine storm. Cytokines are molecules that aid cell-to-cell communication in immune responses and trigger inflammation. It is the overreaction of immune system (like fever and inflammation) that caused the high lethality of this influenza.

While most influenza viruses are dangerous for children, the elderly, or those with compromised immune systems, the 1918 strain was deadliest for those in their 20’s and 30’s in good health with a robust immune systems. The Spanish influenza strain provoked a manic immune response creating a potentially fatal immune reaction with highly elevated levels of various cytokines. In recreating the pandemic of 1918, medical research scientists used reconstructed 1918 influenza virus and injected in mice and monkeys to try to understand why it was so lethal. The animals’ immune systems responded so violently, the lungs filled with blood and fluids, essentially drowning them. Scientists have deduced that what made the Spanish flu so deadly was that it used the body’s own immune system to flood the lungs with fluid, and destroy the lining of the respiratory system, making it much easier for bacteria to infect the lungs. In this case, the healthier you were, the more violent the immune response to the virus.

In the end, the 1918 influenza virus pandemic was due to a combination of a novel virus, an official disregard for honesty to avoid damaging morale and the war effort, a cowardly press that refused to challenge this veil of secrecy that was the government’s propaganda machine. Let us home the government and those at the highest levels of power will treat the next influenza epidemic more honestly and openly.

Could it ever happen again? Could it happen again where a novel influenza virus becomes epidemic then pandemic killing millions? According to an article in The Lancet, flu pandemic like that of 1918-1919 were to break out today, it would likely kill 60-80 million (This is more than the total number of people that die in a single year from all other causes combined). The estimate stems from a new tally of flu deaths from 1918 to 1920 in different countries, which varied widely. To gauge the potential threat from the H5N1 avian influenza currently circulating among birds in Asia and Africa, the researchers reviewed the toll of the most severe previous case from 1918 as a benchmark.

Worried? You should be. If anything, the new estimates may be optimistic, according to epidemiologist Neil Ferguson of London’s Imperial College in an editorial published in The Lancet. High incomes may not protect rich countries as much as some writers have suggested. In 1918 pandemic influenza, being young, fit, and healthy was no protection. Public health researchers and epidemiologists warn that it is not a matter of if the next influenza pandemic strikes, but when.

Meanwhile, national governments slash public health funding and funds needed for health research.

 

The Eradication of Smallpox and the Helper T-Cells

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In May of 1980, the World Health Organization (WHO) pronounced, after two centuries, that the fight against smallpox had ended. This meant that there were no known cases of the disease anywhere on the planet. Many other infectious diseases have returned from the brink of extinction, but few have been so deadly as the only human communicable disease (thus far anyway) to be eradicated.

Most people are familiar with smallpox, if at all, from their history classes or, or films about the conquest of the Americas. But smallpox was not an invention of the Spanish Conquistadors, but something they had naturally grown resistant.

Medical Anthropologists believe that disease began to infect humans starting around the first agricultural settlements of the Old World. Despite such a long history, little evidence exists before 1570 BCE when it appeared in the New Kingdom in Egypt. Many historians believe that the Plague of Athens in 430 BCE and the Antoine Plague that lasted from 165-180 ACE and killed upwards of 7 million people, including the Emperor Marcus Aurelius and hastened the fall of the Roman Empire, were caused by smallpox.

Smallpox made its way to France sometime in the early 700’s. A clergyman writing around the time described the unmistakable symptoms as “a violent fever followed by the appearance of pustules.” He found that if the person lived long enough, the pustules developed scabs, after which the person survived. By the time the disease had reached the rest of Europe, it had spread across Africa and Asia. Smallpox was not a disease of the poor or the aged or the young. It was an equal opportunity killer. And in the Old World, smallpox killed approximately 30% of those who contracted it, while many more were left disfigured or blind. As devastating as smallpox was in the Old World, it was far more destructive in the New World. One significant reason for this great difference was in the immune systems of the two groups.

Helper T-cells are one of the most important cells in that comprise our adaptive immunity, and are a significant part of almost all our adaptive immune responses. Helper T-cells activate cytotoxic T cells that target and kill invading organisms. They also activate B cells that secrete antibodies and macrophages, ingesting and destroying microbes. But a relatively recent discovery is that the American natives possessed a different variant of the Helper T-cell than Europeans. Whereas Europeans maintained an immune response that developed over thousands of years of fighting off bacteria and viruses, the peoples of the Americas had developed an immune system that dealt with the daily concerns of parasitical infection. While their T-cells were better at recognizing invading parasites, combating parasites, they may not recognize many of the organisms the Europeans had adapted to and had brought with them.

The population of the Americas in the pre-Columbian era is estimated to have been between 25 and 60 million people. Of those populations, approximately 95% died as a result of European diseases. At the same time, the Europeans did not have the same kisses as the American natives and were spared the bulk of the infectious disease is of the Americas. With one or two significant exceptions: the reason that the Europeans were immune to so many possible infections in the Americas stems from the fact that Europeans have been caretakers of domesticated animals for several thousand years and had adapted to many common diseases found in domesticated animals that were used for food sources; adapted, but certainly not immune.

The American natives did not possess the same domesticated animals. Cattle, pigs, and horses were absent from the Americas. While the Spanish and Portuguese explorers met with some resistance from natives, the Incas and the Triple Alliance (Aztecs) had largely succumbed to smallpox by the time they arrived. Historians now calculate that the indigenous populations of both American continents were reduced by about 90% from the introduction of smallpox. The Great armies that the conquistadors faced were already greatly weakened by disease. This lesson was not lost on military leaders that would follow (Lord Jeffrey Amherst, the commander-in-chief of British forces in North America during the French and Indian war advocated handing out smallpox affect blankets to his native foes).

This helps explain how a group of fewer than 200 men, over half of which were on foot, manage to defeat an empire, at that time the largest in the world, with a reported standing army of over 70,000.

Today, thanks to the efforts of public health practitioners, medical researchers, and physicians, smallpox is, so far as we know, relegated to a bygone era. In fact, if you were born after 1972, you would not have received a smallpox vaccine. Still, what would happen if smallpox for re-introduced into American society today? The Variola major virus that causes smallpox killed a third of people infected, and was so virulent it claimed the lives of over 300 million people, just in the 20th century alone. Although estimates vary somewhat, the total number of persons killed by smallpox may exceed 2 billion. With an infectious disease so deadly, could ever make a comeback? If smallpox were to make a comeback, there would likely be two possible sources: intentional release, or unintentional release.

The intentional release is the release of the virus by a terrorist or group into a population. The unintentional release is through the thawing of the frozen virus. The residents of a Siberian town lost 40% of its population to smallpox in the 1890’s. The victims had been buried in the upper layers of permafrost along a river, whose banks have begun to erode, due to floodwaters from a warming climate. Russian scientist are concerned that the graves of anthrax-infected cattle can also be found across Russia, including in areas where the ground has thawed two feet deeper than normal. Recently, the thawing of one of the anthrax-killed animals claimed over 100 Reindeer and hospitalized 13 people living in the area. Scientists speculated that the Reindeer were succumbing to the high temperatures, ate the thawed remains of an infected carcass frozen for many years. From there, the infection was passed to the herders.

Regardless of the cause, The Centers for Disease Control and Prevention (CDC)’s Strategic National Stockpile is the nation’s largest supply of life-saving pharmaceuticals for use in a public health emergency severe enough to cause local supplies to run out. The stockpile ensures the right medicines and supplies are available when and where needed to save lives, and this includes, you may be relieved to know, a reported 400 million doses of smallpox vaccine.

On Being a Disease Detective

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Recently, I was asked what a disease detective did. While I considered my response, a situation came to mind from a few years back that captured the process perfectly. The following events are true, the names of been changed to protect the innocent, namely me.

Shifu: This can’t be right, it must be a coincidence.
Oogway: There are NO coincidences.
Shifu: Yes, you said that before.
Oogway: That was no coincidence either. (Kung Fu Panda)

My wife developed a nasty cough one October. Listening to her breath sounds through a stethoscope, I could hear a distinct rattle, indicated fluid of some sort. Her chief complaint was feeling tired, and having a headache. This was just a week after we had completed an outdoor endurance event that involved a great deal of mud, freezing water, and military-style obstacles. It felt fine the day after the event, but by the middle of the next week, started to experience the symptoms. At my urging, she made an appointment with her nurse practitioner. In retrospect, I should have accompanied her to her appointment.

The practitioner explained that she had a cold. She prescribed Tylenol, fluids, and bed rest. Two weeks later, the symptoms had worsened, and she made another appointment. This time the clinician ordered a cardiac stress test. I am uncertain as to her reasoning, however, I believe in being thorough. My wife mentioned having participated in an event that involved mud and water just a few days before the onset of symptoms but was told it had nothing to do with her illness. When I heard this, I was shocked and any respect I had for this practitioner, albeit slight, disappeared. Any good disease detective understands that foundationally, there simply are no coincidences.

Two weeks passed, and the appointment for the cardiac stress test came and went. My wife continued working, but looked and felt run down. Her breathing continued to be labored, and she lacked energy. When the practitioner called and explained that the test had revealed no abnormalities, my wife asked the logical question, “What will they do now?” The response (and I still have difficulty believing this had I not heard it myself) was “What do you mean?”

My wife said, “I still have the symptoms, what are you going to try next?” The nurse said that the practitioner had not made any follow ups or recommendations. At this point, although I knew it might annoy my wife, I called the office back and demanded to speak to the practitioner. Trying to remain calm, I explained that my wife’s symptoms were intensifying, and that I felt fairly strongly that she had a lung infection, most probably Campylobacter, and that she had most probably been infected during the event she had described, now over two months prior. Again, I was told that this was merely a coincidence, and that frankly she did not feel comfortable being questioned by the spouse of a patient. At this point, my patience evaporated. I explained to her that I was not just the spouse of a patent; I was a clinical epidemiologist and an environmental health scientist. Further, I said, I believed allowing a patient suffer for over two months while proffering no answers was ridiculous, and furthermore, to have a patient have to repeatedly ask “What do we do next” for some course of treatment bordered on incompetence. Her demeanor softened, and she then asked what I would recommend. I suggested that, as the primary symptom was breathing related, I would want to see a pulmonologist as soon as possible.

I accompanied her to the pulmonologist office, which conducted a thorough history. When I mentioned the event in October, and explained what we had done for nearly 9 hours, she put a pen down and looked at us. “That is most likely the cause,” she remarked. My wife then repeated what her practitioner had said, that it was just a coincidence. The pulmonologist smiled and said, “There are no coincidences.”

I could not help but smile as I had been saying this for almost three months.

After the pulmonologist conducted a few tests (Peak flow, Diffusion gas), and my wife was given an inhaler, after which peak flow was tested again. Finally, she stepped away from the room while my wife redressed, she asked me what I thought the pulmonologist would say. I said that I thought perhaps she would diagnose a lung infection, probably Campylobacter, which was picked up during the event, which had taken place on a farm that once raised swine. I said that she would most probably be given an antibiotic, most likely Zpac, a corticosteroid dilatator, and a rescue inhaler. The pulmonologist returned and, told us that she believed my wife had picked up a Campylobacter infection from the mud and water during the event. She was surprised that this was not diagnosed months ago, but that it should be relatively easy to treat. She handed my wife three scripts, explaining that the first one was for a medicine called “Azithromycin, or Zpac.” There were also scripts for a corticosteroid, and a rescue inhaler, which could be used as needed.

My wife turned to me and said, “you think you’re so smart don’t you?” My wife now sees a board-certified internist that I vetted. It never ceases to amaze me why people would not keep going to a mechanic who could not fix their car but will continue to see a healthcare provider who cannot seem to properly diagnose their illness. Especially when you give them the answer, not just once, but several times.

As Oogway said, “There are no coincidences.” 

Opinions are Not Facts, and Things are seldom as they first appear.

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“The rise of childhood obesity has placed the health of an entire generation at risk.” ~Tom Vilsack

 Often of late, we hear non-experts make sweeping pronouncements on subjects from healthcare and education to socioeconomics. Seldom do they add anything to the conversation, instead muddying the already perturbed waters. While we certainly cannot fault someone for proffering an opinion, however, we must remember that they are no more than an opinion, or an idea.

Of course, some ideas are more lasting than others, and on rare occasions, these facts have held up to rigorous scientific scrutiny. An example is the Theory of Evolution. It should be noted that the term “theory” used in science means a well-substantiated explanation of the natural world; one based on facts repeatedly confirmed by observation and experiment. This explanation seems to confuse some people, and others, being intellectually dishonest, attempt to imply that a scientific theory is simply a guess. Therefore, it seems that some explanation is needed to outline the steps in the scientific method: Observation, Hypothesis, Experiment, Analyses of Data, Draw Conclusion.

Observation and Hypothesis

A hypothesis is a reasonable guess, based on knowledge or observation, as to how something occurs, or, more frequently, how one variable might effect another (if at all). For example, one hypothesis put forward in the 1970’s was that for many people, the regular use of tobacco products resulted in Cancer of the lungs. The original question may have been something like “Why have medical practitioners seen a drastic increase in lung cancers in the past 20 years.”

After formulating a series of research questions based on observation, the researcher creates a Hypothesis and a Research Question (RQ) that will attempt to address the original question. They then make a testable prediction, test, and then analyze the resulting data. The hypothesis will need to be tested, retested, and tested again before it is accepted as being true.

The research question may have looked like this: Is there a statistically significant association between subjects who smoke tobacco and the development of lung cancer. The RQ was simply a hypothesis (a pretty good one if we are honest). However, hypotheses are proven and disproven all of the time. The use of hypotheses is critical in the scientific method.

Theory

 A scientific theory consists of hypotheses that, after repeated testing, have been shown to be true, at least thus far. Theories in science are one of the pinnacles of provability because the theory must never be shown to have been wrong in its prediction. Scientific theories can and do evolve; this is not indicative that the original theory was incorrect, just incomplete. An example is Newton’s theory of gravity. While Newton could show what gravity did, he did not fully understand why it did it.

Laws

Scientific laws are short, sweet, and always true. They are often expressed in a single statement and rely on a concise mathematical equation.  Laws are accepted as being universally true, and are the cornerstones of science. They must never be wrong (that is why there are many theories and few laws). If a law were ever to be shown false, any science built on that law would also be wrong. For example, E=MC2 has been shown to be true, at least thus far; however, it is not in itself a law, but a central tenet of the Theory of Special Relativity. It is not inconceivable (although the odds are astronomical against) that all space is not the same.

Examples of scientific laws include one of the simplest, yet frequently misunderstood laws, Thermodynamics. Thermodynamics involves the properties of temperature, energy, and entropy. Boyle’s law describes how the pressure of gas increases as the volume of the container decreases, in other words, the force exerted on the container by the compressed gas. Both of these laws can be shown to be true mathematically. While scientific laws describe a formula that explains what will occur, they may not always describe why it will occur. A good example is the Law of Gravity.

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According to Sir Isaac Newton’s Law of Universal Gravity, “Every point mass attracts every single point mass by force pointing along the line intersecting both points. The force is directly proportional to the product of the two masses and inversely proportional to the square of the distance between the point masses.” What this means in plain language is quite a bit simpler: gravitational force is inversely proportional to the square of the separation distance between any interacting objects, the greater the separation distance, the weaker the gravitational forces will exist between them. As two objects are separated from each other, the force of gravitational attraction between them also decreases (Inverse square law). This law accurately predicts what will happen, however, not why. Is gravity simply a result of mass warping space-time as described by Einstein? Is it the result of gravitons (a hypothetical that mediates the force of gravitation in the framework of quantum field theory)? You see how a law explains the what, but not the how (the how is in the theory, which of course begins with a question and, you guessed, a hypothesis).

One theory (which many accept as law) is that obesity is caused by overeating. While a poor diet and large quantities of food poor in nutritional value may lead to overeating, the fact is obesity is a very complex interplay that involves energy consumption, energy expenditure, hormone production, activity, resting metabolic rate, dietary intake, and several other factors including the type of fat a person has and how much of it. But as health science has come to realize, fat is not just fat and obesity has complex causes.

The human body has two major types of fat tissue: white fat and brown fat. In the human body, fat is used for energy, the maintaining of body temperature, regulating hormones, and as a store of energy for later use.

White fat is found around the kidneys and under the skin in the buttocks, thighs, and abdomen and is used to store energy, manufacture and store hormones that control appetite and hunger, and helps regulate appetite. Comprised on a single lipid, white fat has significantly fewer blood vessels (explaining why it appears white), and it is the main form of fat in the body, created from connective tissue. Because white fat is critical in the creation of estrogen, adiponectin, and leptin (hormones that help regulate hunger including leptin), it is a major endocrine gland. White fat also has numerous receptors for glucocorticoids, growth hormones, and important stress hormones including adrenalin, norepinephrine, and cortisol. Finally, white fat also produces inflammatory substances, as adipocytes of obese individuals tend to attract macrophages (part of the immune response), promoting inflammation, and increasing the release of inflammatory factors that influence insulin resistance. In obese persons, large numbers of immune cells infiltrate adipose tissue, promoting a low-grade chronic inflammation, which has been associated with hypertension, heart disease, and metabolic syndrome. Because white fat acts as an endocrine organ, it seeks self preservation. If it begins to disappear through diet or exercise, it can suppress the release leptin (which tells the hypothalamus to instruct us to stop eating), tricking us into believing we are still hungry.

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Brown fat is found on the upper back of healthy human infants and adults. Brown fat (also known as the good fat) releases stored energy as heat when we are cold. However, it also produces some inflammatory chemicals. As you can see, all fat is the same, and there can be many reasons why people are overweight or obese, including some medical conditions that make it very difficult, if not impossible, to reduce the amount of fat we have, or to alter the balance of white fat to brown fat.

Medical conditions that are well known to cause or to complicate overweight or obesity include some genetic syndromes and endocrine disorders (remember, white fat is an endocrine organ). The most prevalent of these include Prader-Willi Syndrome, a genetic disorder caused by the loss of function of specific genes. Prader-Willi Syndrome causes weak muscles, poor feeding, and slow development in infants, yet causes young children to be constantly hungry, often leading to obesity and type 2 diabetes. Because the endocrine system produces hormones that are critical in maintaining the balance of energy in the body, endocrine disorders can cause overweight and obesity.

Hypothyroidism. People with this condition have low levels of thyroid hormones. Thyroid hormones, in particular, triiodothyronine (T3) and its prohormone, thyroxine (T4). T3 and T4 affect nearly every physiological process in the body, including metabolism, body temperature, and heart rate. These tyrosine-based hormones are produced by the thyroid gland, and underproduction (hypothyroidism) significantly slows metabolism. For people with hypothyroidism, even drastic reductions in caloric intake are insufficient to normalize weight. People with hypothyroidism also have difficulty producing body heat, and as a result, have a lower body temperature, and are unable to use stored fat efficiently as energy.

Cushing’s Syndrome. People suffering from Cushing’s have high levels of glucocorticoids, including cortisol, in their blood. Abnormally high cortisol levels trick the body into thinking it is under constant stress. As a result, people have an increase in appetite and the body will store more fat. The symptoms of Cushing’s can include high blood pressure, abdominal obesity (Apple shape) but with thin arms and legs, often with a round face. Cushing’s can develop after taking some medicines, or if the body manufactures too much cortisol.

Type-2 Diabetes. In healthy individuals, insulin released from the pancreas activates glucose uptake in peripheral organs. Insulin is activated by the rise in postprandial (after eating) rise in blood glucose. Insulin promotes increased glycolysis and respiration and enables the storage of glucose and lipids through the stimulation of glycogenesis (glucose is added to glycogen), lipogenesis (acetyl-CoA is converted to fatty acids), and protein synthesis (generating new proteins). Insulin also reduces degradation and recirculation of carbohydrates and lipids by inhibiting gluconeogenesis (forming glucose from non-sugars) and lipolysis (breakdown of lipids). The causes associated with Type-2 diabetes are complicated and include a number of preconditions including genetics, life style, diet, and family history.

Tumors. There are some tumors, such as craniopharyngioma (a type of brain tumor derived from pituitary gland embryonic tissue), that occurs most commonly in children, can also cause severe obesity, because the tumor grows near or invades the part of the brain that helps regulate hunger.

Medicines. There is a host of medications that can cause weight gain, and may lead to obesity. Medicines such as antipsychotics, antidepressants, antiepileptics (used to treat epilepsy), and antihyperglycemics (used to lower blood glucose) can cause weight gain, which can lead to weight gain and obesity.

Abnormal Microbiome. As previously discussed, obesity has been characterized as an imbalance between energy intake and energy expenditure and involves a complex process that involves genetic, biological, and environmental factors. One area that has attracted renewed interest is the Microbiome, or as it is commonly called, the “Gut Biome.” The human digestive track contains over 100 trillion microbial cells. These calls have the essential role of digesting food, processing and extracting energy from digesting material, and regulating metabolism. When this microenvironment is altered, through poor diet, medications, or the introduction of chemicals (pesticides, herbicides, improper foods) the microbial ecosystem fails to function properly. Scientists have researched how the introductions of unhealthy feed, residue from pesticides or herbicides, have been associated with increased metabolic and immune disorders in animals. In humans, the molecular interactions linking this microbiome with host energy metabolism, fat accumulation, and disruptions to immune response have been identified.

When you see someone who is overweight or obese, before you conclude they overeat and have a poor diet, remember, things are seldom as simple as they first appear.

 

 

 

 

Cyclospora Infection: What it is, where it came from, and why you want to avoid it.

Cyclospora_cayetanensisRecently, the Centers for Disease Control and Prevention (CDC) issued warnings concerning infection by a parasitic protozoan named Cyclospora cayetanensis. This pathogen was first identified in the late 1970s, making it a relative newcomer in the realm of human misery. The protozoan was first identified as a form of blue-green algae, and later as a form of Cryptosporidium (the cause of cryptosporidiosis), before being properly identified and cataloged as a pathological protozoan. The Food and Drug Administration of the United States (FDA) recently (2017) banned some cilantro for Mexico due to the use of infected human waste used to fertilize some fields.

Since its first discovery, Cyclospora has been identified as the cause of some cases of where patients complained of severe diarrhea, abdominal cramping, nausea, and weight loss. In cases of early diagnosis, treatment is relatively straightforward and often consists of antibiotics, (Sulfamethoxazole/trimethoprim), or in cases of allergy to sulfa drugs, Ciprofloxacin (a non-sulfa antibiotic) can be used. Cyclospora can only be positively identified through Laboratory test of stool, and identification they require samples over the course of several days. Likely symptoms include frequent watery diarrhea, loss of appetite and weight loss, bloating and flatulence, stomach cramps, fever, and bouts of constipation. Some people will experience muscle aches and fever as well as a general fatigue. In developing countries, diarrheal diseases can be a significant threat to health, however safe drinking water may not always be available. To assess dehydration watch for dry mouth and tongue, reduced tear production, decreased urine output it, and in severe cases, sunken eyes. Dehydration is a serious symptom and may require hospitalization for intravenous fluids for some patients due to high risk of desiccation, including people suffering from serious illnesses, aged adults, and especially infants and small children.

Epidemiology. Cyclospora infection has only one known path, ingesting the protozoans in contaminated food or water. For this reason, outbreaks are reported following the consumption of contaminated fruits and vegetables. Because the protozoan is most common in tropical and subtropical regions, recent cases in the United States have been linked to imported produce coming from Central America and included cilantro, basil, lettuce, snow peas, and even raspberries. Investigators discovered that some farmers were using human excrement to fertilize fields, thus spreading the disease. When an Oocyst (an encapsulated egg-shell-like structure that allows the Cyclospora zygote a protective environment to transfer to a new host) is ingested, either suspended in water or on food, it enters the small intestine where it attaches to the mucosa (intestine wall) where it incubates for a week or so. The Oocyst emerges in the gastrointestinal tract, freeing the sporozoites that invade the epithelial cells of the small intestine. Inside the cells they undergo asexual multiplication and sexual development to mature into Oocyst, which will be shed in waste before emerging as adult protozoa. There has never been a better time to start your kitchen garden.

Pathology. In cases where Cyclospora infection is not identified and treated, chronic complications can occur such as Guillain-Barre Syndrome, acalculous cholecystopathy (a form of inflammation of the gallbladder), biliary disease (a form of biliary cirrhosis damaging the liver), and Reiter’s Syndrome (a form of reactive arthritis that develops as the immune system attempts to rid the body of the infection). Cyclospora infection is a nationally notifiable disease in the United States. The National Notifiable Diseases Surveillance System is a nationwide collaboration that enables all levels of public health, from local to international, to monitor, control, and prevent the occurrence and spread of infectious and noninfectious diseases. The CDC urges healthcare providers to watch for cases where patients have prolonged or reoccurring symptoms including watery diarrhea, particularly if they have recently traveled to tropical and subtropical regions. If such cases occur, health care providers should consider ordering a test for Cyclospora infection, however, most laboratories in the United States do not routinely test for Cyclospora, even when a stool sample has been tested for parasites in general. Therefore health  providers must request this test specifically.

New Cases in the U.S. Since May 1 of 2017, over 200 new cases of cyclospora infection have occurred. This is more than double the total new cases for the same period in 2016 according to the CDC.  The CDC reported that cases were reported in nearly 30 states. Of the 200 cases, nearly 20 patients were hospitalized.

Prevention. As the CDC points out, prevention is limited to avoiding food or water that may be contaminated, and to observe safe food handling procedures including thoroughly washing all fruits and vegetables will help, but may not remove all of the organisms. Cyclospora is often not killed by currently used disinfectants, and its ability to transmit as an Oocyst makes it a difficult protozoan to prevent. Primary risk factors include traveling in developing countries, as Cyclospora infection can be found worldwide, and anyone consuming food or water contaminated with this protozoan can be infected.

 

For more information, or to learn about other protozoans and parasites, go to the CDC website at https://www.cdc.gov/parasites/about.html

On Inference, Causation, Correlation, and Association: How Scientists Assign Outcomes of Research, and why it is Important.

Thanks to my friend and associate Michael Lo for his input on this.

chi-eq1Recently, the media seems intent on furthering the scientific ignorance that seems to be rampant in American culture. From Alternative facts to inconvenient truths, science is taking a beating at the hands of pseudoscientists, politicians, and others who have no business making scientific pronouncements. A pet peeve of mine is when those who don’t understand statistics start quoting statistics, particularly cause-and-effect. The most recent example of this is the statement that marijuana causes depression. But before we get into these ridiculous ideas, it is necessary to outline the terms of scientific research, as the media doesn’t seem to think this is important.

Without delving too far into multivariate analysis or regression, and in keeping with the brevity of this article, I shall keep short, limiting the discussion to the relationship between two variables. In the case given above, the use of marijuana causes in 100% of the cases depression. No one has ever used marijuana that did not suffer depression, and that that depression could be proved directly from the use of marijuana. You can easily see how ridiculous and unscientific such statements are.

This is because when we state there is a causal relationship between two variables, we are stating that one causes the other. Every time, even after adjusting for any other variable or modifier, we are stating empirically that in 100% of the cases, correcting for any bias, one variable creates or directly affects the other variable always. As you might imagine, cause is a term that scientists very rarely, if ever use. So what terms should you look for instead?

Correlation. When we say there is a correlation between two variables, this does not mean that they are somehow connected. A prime example is an increase in global mean temperature that corresponds with the reduction of the number of pirates. One need not be a scientist to say that, although there is a correlation between these variables, they are not likely related in any way. Few research scientists use the term correlation. Politicians use it frequently as it infers a connection between two variables however it truly says nothing. Clearly, there is a correlation between global mean temperature and the total number of pirates; however, to suggest that these two variables are somehow associated (one affecting the other) would be naïve at best, and deceptive at worst.

2000px-PiratesVsTemp(en).svgAssociation. Now we’re starting to talk the scientific lingo. When we examine two or more variables, and we find that one influences the other to a greater degree (based on a percentage or confidence interval to denote how certain we want to be about the relationship). In my dissertation, I examine the relationship between variables related to child abuse and chronic disease, among them type-2 diabetes, hypertension, and dyslipidemia. Because I wanted to be as certain as reasonably possible, I used a confidence interval of 95%. A confidence interval of 95% will give you a P-value <0.05. What this means is that there is a less than 5% chance that the results of your statistical test are merely chance.

While this is the standard in medical research, you may decide that you want to be as certain as possible that the relationship among your variables is really present. You would then use a 99% confidence interval, and you would expect a P-value of <.01. With a confidence interval (CI) of 99%, you are essentially saying that the outcome you found is as near to 100% as possible. In fact, even if you were to use a CI of 99.99999999999%, and the resulting P-value was <.0000000001 (with statistical software this is very easy to do), this would still not prove cause. You see how difficult it is for a scientist to say that one thing causes another? So you can imagine how ridiculous it sounds to scientists when politicians claim it.

Even if we find an association (we like to use the term statistically significant association) there maybe other variables that can account for or affect our outcome. For example, in my own research, where I studied the association between child abuse and chronic disease, I had to control for other variables, for example socioeconomics, family history of disease, behavioral variables (tobacco use, alcohol use, physical activity, physical fitness level, vocation, income, and several others) that may modify (affect in some way) my results.

To measure association, we use a few simple tests, among them the Chi-square test. Chi-square tests of association generally assess whether the observed association has less than a 5% (or less than 1%) chance of occurring due to NO effect of the other variable. To be certain our sample size is sufficient, we run a G*Power Analysis which will give us our minimum sample size. For example, if I wanted to test for association between two variables with a CI of 95%, we would need at least 34 subjects. Now, if we wish to be really, really certain, we wanted a CI of 99%, this would require just under 11,000 (10,881) subjects! If we have too small a sample group we can use a different association test called the Fisher’s Exact Test.

In the case of the article claiming that use of marijuana causes depression, I was unable to find any corresponding data to support the conclusions. Had the data been available (as a medical research scientist I have access to most studies conducted in the United States), locating the corresponding data to this study proved impossible. Had I been able to locate the data and review it, ensuring that the researcher did indeed control for other variables, I could conclude that they had performed their due diligence to ensure that the association between marijuana use and depression is supported. However, this is not the case.

One quick method of ascertaining whether or not a study has been conducted using the scientific method is to look for the data tables. If there are no data tables, then most likely there was no data. Another way is to look for the verbiage. Watch for terms such as causation, causes, or anything that seems inflammatory.

In a culture of alternative facts and scientific ignorance, the reader should be cognizant of what they’re reading and how to tell if it’s science or something else that begins with S.

How Targeted Drugs Fight Disease, and why Funding Research is Critical

Antibody_diagramRecently our family has been once again forced to deal with a diagnosis of cancer. I have avoided writing on this subject in the past but have decided to write a brief article on the advances in cancer treatments. I enlisted the help of my good friend and research molecular biologist, Vera Chang from Oregon State University.

Anyone who has been diagnosed with cancer, or has a family member afflicted with this disease, knows all too well how difficult it can be to treat. Beyond the disease itself, there is the stigma and gloom that accompanies it. Despite the promises of new treatments, it is still a horrifying and gut wrenching illness.

Diagnosed early, cancer is often curable, and the survivability of many forms of cancer has risen steadily as new research and new treatments have been discovered. If the diagnosis is not made early, prospects for a full recovery are remote.

Most of the various forms of cancer are not caused by pathogens for which we can develop a vaccine. It is a particular degeneration of our cells that multiply and changes into entirely new cell-forms that become a tumor. The tumor then sends out cells and spreads in processes known as invasion and metastasis.

Traditional methods of treating cancer are surgical removal of the tumor and adjacent tissues followed by chemotherapy and radiotherapy. The problem with these treatments is their lack of specificity. Chemotherapies and radiotherapies target both cancer cells and healthy cells. Today, researchers are developing new ways to battle this disease by targeting the mechanisms that allow cancer cells to form, grow and spread.

All cells in our bodies require oxygen and nutrients (and the removal of waste products) to survive. Cancer cells are no different. As a cluster of cancer cells grows larger, those cells at the center get further away from the blood vessels that bring the necessary oxygen and nutrients to the body’s cells.

Cancer cells are still OUR cells, and like all cells, they cannot survive without oxygen and nutrient. When the cancer cells begin to grow rapidly, they become starved for oxygen and nutrients. These cells release chemicals called angiogenic factors (FGF-1 and VEGF) that stimulate proliferation of nearby endothelial cells to form new blood vessels to bring oxygen and nutrients to the cancer cells. Without angiogenesis, the cancer cells cannot grow or spread.

Once new blood vessels form, cancer cells have access to other tissues and organ systems; as the tumor grows, it takes up all the resources that the blood vessels provide causing pressure on surrounding tissues. Because cancer cells grow much faster than normal tissue, they can spread through the lymphatic system, part of our immune system, invade nearby tissues, and travel through the blood stream.

Cancer researchers have identified three ways tumors can invade surrounding tissue. First, tumors can grow too large and force themselves mechanically into nearby soft tissue. Second, tumors can break down cell tissues using enzymes. These same enzymes are found in normal cells and are used to break down invading bacteria or viruses or to repair damage to the cell structure. They are a critical part of the healing process. Unfortunately, some cancer cells contain significant amounts of these enzymes, far more than normal cells. The third way tumors invade by is by producing cells that move around far more efficiently than normal cells. Researchers have discovered a substance produced by cancer cells that enable them to move, although they are not yet certain how this material plays a part in the spreading of cancer.

cancer cell pushing outwardAs resources become scarce at the origin of tumor growth, some cancer cells travel a long distance in the body. This process is called metastasis. Some cancer cells change their shape or digest the wall of the blood vessels or lymphatic vessels to get into the blood stream. Once in the blood stream, these cells can travel to other organ systems (for example, breast cancer cells metastasize to the lungs for the unlimited supply of oxygen, while colon cancer cells metastasize to the liver for an endless source of nutrition).

Targeted Therapies

Scientists are developing custom-made treatments, called targeted therapies, to block the growth and spread of cancer directly without harming healthy cells. One of the targeted therapies uses our immune system as the weapon.

Our immune system is a complex arrangement of different cell types and more than 100 different chemicals whose mission is to protect us from foreign organisms like bacteria and viruses. These cells are imbued with the ability to recognize any substance as either belonging to the body or foreign (invader). Once the immune system recognizes a material as an invader, various cells and hundreds of different chemicals come together to coordinate an attack and remove the invader. Our immune system has evolved over millions of years to protect us from the continual onslaught by invading organisms. However, cancer cells are not invaders. They are an enemy from within that has developed ways to mask themselves from our immune system.

The primary purpose of targeted drugs is to help our immune system recognized these cancer cells by targeting unusual substances found in cancer cells like the proteins cancer cells require for growing and moving. Once cancerous proteins are found, our immune system will start attacking either the proteins themselves or the cell producing them. Targeting these proteins, and aiding the immune system to attack cancer is exciting research because these drugs can prevent or reduce cancer cells ability to grow, move and spread, and eventually lead to their isolation and destruction. One area of research that is showing great promise is called Monoclonal antibodies.

Monoclonal antibodies first entered research in the early 1980s to treat non-Hodgkin’s lymphoma. Since that time, researchers have made great strides using these targeted therapies in cancer treatment. These treatments began by identifying which therapies may prove useful. This process, known as biomarker identification, is the identification of antigens that uniquely present on the surface of cancer cells. One of the promising monoclonal antibodies in fighting breast cancer functions by recognizing a human epidermal growth factor receptor 2 (HER2) protein. HER2 is an oncogene that can transform a cell into a tumor cell and is amplified in 20-30% of early stage breast cancers. Thus, breast cancer patients treated with HER2- targeted antibodies can improve disease-free survival rates.

Unfortunately, no one treatment is effective for every cancer, or every person. Therefore, research in targeted therapies is critical and life-saving.