Tuberculosis

Tuberculosis! Not an eradicated disease. In fact, it's making a large comeback, due to the combined factors of the HIV epidemic and consequences of people thinking they'd eradicated it. People thought it was a dying disease, stopped funding research and public health efforts against it, and suddenly the numbers were rising rapidly. Also, as Kaitlyn pointed out, TB has many animal reservoirs (including elephants!), and so it is very hard to eradicate completely.

Tuberculosis is transmitted primarily through tiny airborne droplets (called droplet nuclei!). These can remain in  the air for several hours after someone sneezes or coughs them out. Typically you need about 8 hours with an actively infected person to become infected yourself. An open case of TB will infect 12-15 people per year.

TB lives mainly in the lungs. The primary infection will form a necrosing granuloma, which is frequently described as "cheesy" in appearance.

TB evades the immune system by forcing the cells that would normally kill it to increase their pH's. This allows the TB to keep living inside the body. Once infected, a person will stay infected for years, sometimes even for life. 90% of people will never show symptoms. The only evidence is a positive test.

Risk of TB is 10% for a normal healthy person over their lifetime. However, if a person has HIV, this risk increases to 10% per year!

Without treatment, after 5 years, 50% of people with TB will die, 25% will be self cured, and 25% will remain ill with chronic, infectious TB.

The most common symptoms of TB are coughs that persist for over 3 weeks, sputum production, and unexplained weight less. It will show up on x-rays as a blob in the lung called the Ghon focus, or in apical scarring.

Photo Credit: wikipedia.org

Skin tests are the most common way to test for TB. Since the bacterium grows so slowly, several days are required to allow the arm to swell to its full extent. A generation of TB will grow in 12-24 hours - typically bacteria have a generation of 20 minutes! A full culture in the lab takes about 6 weeks. Healthy people need to swell over 15mm to be considered positive, Children over 10mm, and people with HIV only 5mm.

TB is also having a problem because it's becoming drug resistant. For this reason, treatment must be given every day for a very long period of time. If any time is skipped, the risk of the bacterium mutating more and becoming more drug resistant is high. For this reason, many people are needed to help monitor TB drug administration.

There are about 9 million new cases of TB a year, and 1.8 million fail to get treatment of any sort. 50-70% of people with untreated TB will die from the disease. 98% of deaths are in low and mid income countries. TB is the leading cause of death amongst people with HIV.

People are trying to prevent TB spread through the use of directly observed therapy, to make sure that people take all of their drugs on time every day. What really needs to happen is people need to train in HIV treatment AND TB treatment, as both diseases often happen simultaneously.

River Blindness

River blindness is a disease described by it's most devastating side effect, though not everyone who encounters the parasite will become blind. It's caused by the Onchocerca volvulus worm, and it's estimated to infect 18 million people worldwide, of which 800,000 are visually impaired, and 270,000 are completely blind.

Onchocerca is found widely in Central Africa and Central and South America, though the Americas have shown great progress in eradication. It's transmitted by riverine blackflies, which, surprise, hang out by rivers! Typically fast flowing ones, exactly the type people would live to build their settlements by. The adults live in nodules in the human skin, which are typically raised. Interestingly, these nodules favor the lower regions of the body in Africa and the upper regions of the body in the Americas. The microfilaria of this species migrate through the skin, which causes a very intense itching effect, to the extent that people frequently get permanently disfigured skin from the intensity of their scratching. Because they migrate through the skin, blood samples won't tell you anything. Instead, skin samples must be taken and processed to see if there's any microfilaria hanging out there. Fun!

Photo Credit: Emedicine.com

The most serious manifestation of Onchocerca volvulus is ocular lesions that lead to blindness. The microfilaria enter the eye, which causes irritation, which makes a tiny patch of scar tissue in the eye. Too many of these can lead to progressive blindness. These in the eye are diagnosed in an interesting manner - the patient is made to wait for a while with their eyes parallel with the floor. They then quickly raise their head up, and a doctor shines a light in their eyes and looks for falling particles.

Photo Credit: eyewiki.org

Mass Drug Administration has reduced the disease in many areas to the point that it can't be sustained anymore. Go public health!

Filaria!

Filaria (which causes Human Filariasis) are a group of parasites that are found in pretty different areas of the world, all of which cause different symptoms. However, they're grouped together because most of them look very similar in diagnostics. The three big ones are Wucheria bancrofti, Brugia malayi, and Onchocerca volvulus. Wucheria bancrofti and Brugia malayi produce pretty similar symptoms, while Onchocerca volvulus creates a syndrome known as River Blindness, which I'll go over in the next post.

The filariasis causing worms are unique in that they create microfilaria instead of the traditional eggs. These are basically motile eggs - they aren't yet larva, but they do move around. They can be sheathed or unsheathed, and they can display periodicity which corresponds to the preferred intermediate host. (Pretty cool!) They tend to be circulating in the blood during these periods, but can be completely undetectable when they're not in this period.

Wucheria bancrofti live in the tropical and sub-tropical regions of the world. Humans are the only known definitive host, which means if we get rid of it in humans it won't come back! However, this is kind of hard, because not everyone who has this infestation shows symptoms, or the microfilaria might not be present when a blood sample is taken.

The adult forms of Wucheria bancrofti lives in the lymph nodes. They tend to like those closest to the groin, which will become important in a minute. The microfilaria migrate into the blood, where they display a nocturnal periodicity. It is hypothesized that they go to the lungs when they're not in the blood.

Most often Wucheria bancrofti is transmitted by Culex quinqefasciatus mosquitoes, though several other species can transmit it. The mosquito takes a blood meal, ingesting the microfilaria. These mature to infective larva inside the mosquito. When the mosquito takes a meal from a human, these wiggle their way down the proboscis of the mosquito, infecting the human. They migrate to the human lymph nodes, where they mature.

The adults can live up to 5 years in the body. The microfilaria can live 1-2, during which time the person is actively infectious.

The most common pathology is asymptomatic microfilaremia. This means that the microfilaria are just chilling out and circulating in the blood. They'll show up on a slide, but won't really cause any problems. People can develop lymphangitis. However, in cases of long infections or large infections, people can develop chronic lymphadema and eventual elephantiasis (the most well known characteristic of Filariasis). Wucheria bancrofti in particular can cause hydrocele and scrotal elephantiasis, which I'm not going to put a picture of, but if you're interested I suggest looking up.

What tends to happen is adults living in the lymphatic channels cause dilation and chronic edema due to gravity. As the worms die, collagen builds around them, forcing the lymph nodes open even farther. This causes the lymph to not drain properly, which makes it collect in the extremities. Unfortunately, even if the worms are taken care of (with DEC), this process is irreversible, as extensive damage has been done to the lymph nodes.

Diagnosis is done through looking at the blood in a lab (which must be done over several hours, as the microfilaria could show up at different times), or through using an ultrasound to examine the lymph nodes. They create a characteristic "Filaria Dance Sign", which can be seen in this video: http://www.youtube.com/watch?v=d3KWh6xqQm0

Brugia malayi is very similar to Wucheria bancrofti, but its geographic distribution is limited to Southeast Asia. Differentiation is done based on the microfilaria, as the adults look quite similar. It has reservoir hosts in macaques and  leaf monkeys. It creates similar pathology, except that hydrocele is not seen. It's also primarily transmitted by Mansonia species of mosquitoes.

Photo Credit: Stanford.edu

On the left: Wucheria bancrofti microfilaria

On the right: Brugia malayi microfilaria

These are nicely stained so they look really different. They usually don't. 

HIV History

HIV was discovered in 1981, though retrospective studies have discovered cases in Africa as early at the 1930s. In 1981, 26 cases of Kaposi's sarcoma were found in male patients in the US, all of whom identified as homosexual. These cases were centered around San Francisco and New York. Previously, Kaposi's sarcoma had only infected elderly men of Jewish or Mediterranean ancestry. In addition, this new version was much more aggressive than had previously been seen, leading doctors to seek a link between these new cases.

Photo Credit: http://www.meddean.luc.edu/

Above is a normal case of Kaposi's sarcoma. Below is an advanced case in a HIV positive patient.

Photo Credit: wikipedia.com

Within the same population that were getting these infections, other diseases that were normally only associated with immunocompromised patients were occurring, most notable non-Hodgkins lymphoma Pneumocystis pneumonia, which do not normally infect healthy people. Since the doctors did not know what to look for, or how to look for it, they did not know what was causing these infections.

The virus was isolated in 1983 and 1984 by two people, both using the same strain of virus. No other infectious agent has been isolated in such a short time. Luc Montagnier and Robert Gallo, a French scientist and an American scientist respectively, were the two discoverers of the virus.

Never before had an infection been found that so completely destroyed the hosts immune system. The hidden nature of the virus, as well as its rapid evolution time, are both key factors working against the discovery of a cure.

HIV Prevalence and Transmission

Okay, not a parasite. But it is probably the most well known microbial infection of our time. Human Immunodeficiency Virus infects an estimated 35 million people worldwide. There are two main types, HIV-1 and HIV-2, both of which can have sub-types. Subtype B is most common in the Americas and Europe, while Subtype C is the most common in Africa and Asia. HIV-1 is found worldwide, while HIV-2 is endemic to West Africa. They are retroviruses, which are a family of enveloped viruses that replicate in the host cell through a process of reverse transcriptase.

HIV is of zoonotic origin. HIV-1 probably came from Chimpanzees, while HIV-2 came from Sooty mangabeys (another primate). What likely occurred was that a hunter was butchering the primate, which was infected, and their blood entered the hunter, transmitting the disease. Phylogenic evidence indicates that viruses have been transmitted to humans this way on at least 8 occasions.

 As most know, HIV is transmitted through sexual contact. Interestingly, heterosexual sex is the most common transmitter worldwide, while homosexual sex is the most common transmitter in the US. However, being the receptive partner in either act can have as high as a 30% risk of transmission. HIV can also be transmitted through IV drug use, from mother to child, from blood transfusion, and from transplanted tissue. Being pricked with a needle that had previously been in contact with HIV positive blood, such as a nurse being accidentally stuck, is only 0.3%. Having other STIs greatly increases the risk of infection.

When the virus first enters the body, the innate immune system does what it would do for any unknown pathogen - it binds the virus to dendritic cells, which then carry it to the lymph nodes. Once here, the virus infects the helper T cells, which were supposed to be recruiting the antibodies to fight it. Because of host immune responses against the cells, after the initial infection the infected person may go into a period of latency, in which they have no symptoms, for as long as 15 years.

When a person is first infected, this viral load is very high. Initial infections often produce flu-like symptoms. This continues for approximately a year after initial infection, but then drops and remains extremely low until a time at which both T cells and anti-HIV antibodies become low in the body. T cells decrease fairly regularly over time in an untreated person, while anti-HIV antibodies remain at a fairly high level until the T-cell count drops too low, at which point they plummet.

When the T-cell count goes down too far, other symptoms begin occurring. This includes unexplained weight loss (over 10% of body weight), recurrent respiratory tract infections, Angular cheilitis, oral ulcerations, fungal infection of nails, and pruritic eruptions on the skin.

Once the host becomes immunocompromised, which means that they no longer have enough T cells to fight off any sort of infection, opportunistic infections start. This means that things which would not normally be able to grow in a healthy person can grow in them, such as Oral Hairy Leukoplaikia, a condition in which the tongue takes on a hairy appearance. Tuberculosis rates are also much higher in patients with HIV.

HIV testing is now much better than it initially was, but it can still take up to 2 weeks for antibodies to appear in the blood at such an extent that a test would show positive, making it very necessary for those doing the test to ask when the most recent day in which a person could have become infected was. Before the new rapid tests were invented, which can give results in under an hour, it is estimated that 90% of people with HIV did not know their status. In one South Africa study done in the 80s, only 17% of people who came to be tested came back for their results. Even now that we have the rapid tests, it is estimated that as many as 50% of people living with HIV do not know their status.


If you'd like to see a visual of HIV infecting host cells, this video is pretty cool: http://www.youtube.com/watch?v=RO8MP3wMvqg

Trichuris trichuria

Trichuris trichuria is the last of the intestinal nematodes for now! It's also known as whipworm. It's also the first one in a few posts where humans are the definitive hosts. It's found worldwide, especially in tropics and subtropics. Co-infections with ascaris are quite common.

Adult Trichuris trichuria live in the colon, caecum, and appendix. Their anterior end is buried in the mucosal epithelium, allowing their posterior ends to move freely in the intestine. Adults can live for several years inside the body.

Photo Credit: medicine.cmu.ac.edu

The female whipworm produces a ton of eggs. These are passed out of the body unembryonated, then develop for 3 weeks in the soil. Again, these are easily preventable if feces are not allowed to sit around in places for weeks where people can come by and touch them again! The eggs are barrel-shaped, with a thick smooth shell, and bi-polar plugs. Once they're swallowed, they hatch in the upper small intestine, undergo further development, and make their way down to where they really want to live, where they embed themselves.

Photo Source: wikipedia.com

The adults have an interesting feature called the stichosome,which is a collection of secretory cells that line the esophagus and produce proteins. It's been theorized that these aid in the ingestion of nutrients from the intestinal mucosa, since the Trichuris mouths are embedded.

Signs only occur when a person is highly infected. It may cause abdominal pain, diarrhea, weight loss, and tenesmus, which basically means a feeling of having to go to the bathroom all the time. There may be Charcot-Leyden crystals in the stool, which are little pink crystals caused by allergic reactions. Anemia is much less common than with hookworm infections. They can cause prolapse of the rectum, especially in children, as they weaken the rectum at the same time as they create an urge to push.

They may also produce long term deficits in development and cognitive functions.

Diagnosis can be made though seeing the eggs in feces, or the adult worms may be seen during sigmoidoscopy. Treatment is done with albendazole and mebendazole, and is done a lot with school children.

Metastrongyles - Lung Worms!

Two versions of these lovely worms. The first is Angiostrongylus cantonensis, adults of which live in, you guessed it, the lungs! Typically rat lungs though, not human lungs. They lay their eggs in the lungs, and when the larva hatch, they break into the respiratory tract and migrate up the trachea, where they are then swallowed and pass out of the rat body. They are then ingested by snails or slugs. In these hosts, the larva progress from L1 stage to L3 stage, at which point they are infective again. New rats then either eat the snails, or eat food that the snails have passed over, which deposits it on the new food source. Once they are eaten, the larva migrate to the central nervous system, where they can develop in the brain. They then migrate back to the lung.

Humans are infected either when they eat the infected snail or slug, or when they eat something such as lettuce that the slug has passed over. When the larva tries to migrate to the brain, it causes eosiniphilic meningitis and meningoencephilitics. Most larva die in the brain, which can cause an even worse inflammatory reaction. The only real treatment for this one is corticosteriods, as apart from surgery there is no real way to get the larva out of the brain.

Photo Credit: ajtmh.org

The other kind is Angiostrongylus costaricensis. These are also typically found in rats, though they live in the mesenteric arteries. The female Angiostrongylus costaricensis deposits eggs in the rat intesten, which are passed with the feces. Again, slugs/snails are the intermediate hosts, and once they are ingested again by rats, they migrate via the lymph system and blood to the mesenteries. This one presents pretty differently, typically as acute abdominal pain, low-grade fever for 2-4 weeks, a tumor like painful mass, and high eosiniphilia. Surgery is possible, as are anti-helminthic treatments.

Both adult worms look pretty similar. They are slender with a reduced or rudimentary buccal capsule. 3-5 cm in length. The females have a spiral shape down their length, caused by uterine branches.

Photo Credit: Wikipedia.com