Two Important News Stories

[Harrison]

There were two interesting news stories in the past week. I found of them useful for different reasons, but the common link between the two highlights the criticality of a healthy immune system. The first one will blow your mind – especially if you ponder the implications of the findings. The second one is sad for obvious reasons -- 45 people died!

Fatal Yeast Infections Make A Clean Getaway By Catching The Blood Cell Bus
http://www.medicalnewstoday.com/articles/120826.php

Deaths of 45 Patients Linked To 4 Arthritis Drugs, FDA Issues Stronger Warnings
http://www.allheadlinenews.com/articles/7012182129
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Fatal Yeast Infections Make A Clean Getaway By Catching The Blood Cell Bus
09 Sep 2008

Yeast fungus cells that kill thousands of AIDS patients every year escape detection by our bodies' defences by hiding inside our own defence cells, and hitch a ride through our systems before attacking and spreading, scientists heard today (Tuesday 9 September 2008) at the Society for General Microbiology's Autumn meeting being held this week at Trinity College, Dublin.

Cells of the Cryptococcus yeast responsible for one of the three most life-threatening infections that commonly attack HIV infected patients, causing cryptococcal meningitis, are using a previously unknown way to avoid detection, according to scientists from the University of Birmingham, UK.

"We have shown that these airborne yeast cells can hide inside our bodies' own white blood cells, called macrophages, and then use them as vehicles to travel around inside our bodies, using them just like a bus," said Miss Hansong Ma of the University of Birmingham. "The yeast cells then escape from inside the macrophages when they arrive at the right destination - but importantly, they do this without killing the macrophage, which would trigger alarm bells."

When a host's cells are invaded by bacteria, fungi or viruses the invaders usually use the opportunity to multiply inside the cells and escape by bursting out, killing the host and releasing thousands of copies of the pathogen to attack other cells. The death of the host cell releases debris and by-products which usually triggers our bodies into mounting an immune response, causing inflammation.

"This new method of remaining inside the host cells means that the pathogen can spread more efficiently round our bodies and is protected from the natural defences in our bloodstream that would normally kill the yeast or other invader," said Hansong Ma. "Yeast cells avoid killing or damaging the macrophages. They leave by a method that we call 'vomocytosis'; the yeast cells are acting like spies rather than terrorists, and go unnoticed, giving them more time to establish an infection."

Although the use of antiretroviral drugs is cutting the number of AIDS patients with Cryptococcus infections there is still a major epidemic in Southeast Asia and Africa. Up to 30% of AIDS patients there are infected, and up to 44% will die from the disease within 8 weeks. Even in the USA or European countries like France where antiretroviral drug treatments are readily available, one in ten infected patients will die.

"We badly need to better understand the interaction between hosts, viruses and attacking pathogens like the yeast fungus to help us find new drug targets and so design new ways to treat these patients," said Hansong Ma.

"We used time-lapse microscope photography to identify this new escape mechanism, and watched the yeast cells escaping into the fluid surrounding cells or, remarkably, directly into other host cells through cell-to-cell transmission, continuing to avoid detection by using this extremely rapid vomocytosis," said Hansong Ma. "Worryingly, this enables the cryptococci to avoid antifungal drugs and other treatments as well as our normal immune system, and may allow the yeast to become latent, achieving a long-term infectious state which could then be spread even further, to other individuals, without anyone realising."

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Deaths of 45 Patients Linked To 4 Arthritis Drugs, FDA Issues Stronger Warnings

Source: Lucy Goodchild
Society for General Microbiology

Nidhi Sharma - AHN News Writer
Washington D.C. (AHN) - Four rheumatoid arthritis drugs have received stronger warnings from the U.S. Food and Drug Administration (FDA) after the drugs have been linked to deaths in 45 patients.

The FDA has received 240 reports of people taking the drugs Cimzia, Enbrel, Humira, and Remicade, which are called TNF blockers. All of then developed histoplasmosis, a fungal infection that starts as a respiratory infection and can spread throughout the body.

The 45 patients who died include at least 12 who hadn't been diagnosed with histoplasmosis right away, Web MD reports. More deaths were reported from other fungal infections, though the FDA wouldn't say how many. The histoplasmosis patients ranged in age from 8 to 86 years; none of the deaths involved children.
The new warnings, posted Thursday on the FDA's Web site, ordered the companies to strengthen existing cautions in a black box in the drugs' prescribing information, the agency's strictest form of caution.

The FDA wants patients and doctors to watch for signs and symptoms of histoplasmosis, including persistent fever, cough, shortness of breath, and fatigue. They also must educate doctors about the risk and symptoms of fungal infections.

This isn't the first safety warning from the FDA over the so-called TNF blockers as the federal agency said in June that it was investigating a possible link between the drugs and an increased risk of cancer in children and young adults. That review is still in progress. TNF blockers suppress the immune system and are used to treat conditions. The medicines are approved to treat a variety of conditions, including rheumatoid arthritis, juvenile idiopathic arthritis, psoriasis and Crohn's disease.

[Justin]

Rich,

These are great topics... I'm just not following your thought process.

There were two interesting news stories in the past week. I found of them useful for different reasons, but the common link between the two highlights the criticality of a healthy immune system. The first one will blow your mind – especially if you ponder the implications of the findings.

I think the first study “blew” my mind to avoid AIDS at all costs…just curious, what kind of implications are you pondering?

Crytococcus neoformans can lead to meningitis and pneumonia. This yeast is found in pigeon droppings. It is inhaled causing a local infection in the lung, subsequently resulting in most patients being asymptomatic; however some develop pneumonia.

The yeast may spread via blood, especially to the CNS leading to meningitis (an abscess forms). This is confirmed via lumbar puncture to obtain and analyze cerebral spinal fluid. The CSF has a characteristic “starry night” appearance: India ink stains the thick polysaccharide capsule of the budding yeast. Damage to the brain results from pressure and displacement of brain tissue, not inflammation.

Cryptococcal meningitis is prevalent among AIDS patients, and without lifelong treatment, these patients will relapse.

C. neoformans is an opportunistic pathogen in AIDS patients. This means that an HIV+ AIDS patient with T cell count between (200 and 50 CD4+ Th cells / mirco l) will be susceptible to C. neoformans, which leads to fungal meningitis.

At T cell counts less than 200 common opportunistic infections like C. neoformans / neoplasms ultimately cause death -- this is considered advanced disease or AIDS (200 begins the cut-off for AIDS).

In the grand scheme of things, AIDS patients have extremely low levels of helper T cells (which help keep your immune system in check). In other words this pathogen is not frequently encountered in the general population and if it is (usually amateur bird keepers or those exposed to bird droppings) it is easily treated with amphotericin B and flucytosine. However, fluconazole is used for life-time suppression in AIDS patients due to the T cell issues mentioned earlier.
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TNF-alpha blockers are extremely powerful drugs. They are so strong in fact that patients are susceptible to opportunistic pathogens—such as fungi. This is the only similarity between these two stories—that both patient populations have severely compromised immune systems, which makes them more susceptible to opportunistic pathogens. It is very sad to see patients dying due to these drugs. They are immunocompromised and susceptible to this pathogen that our immune system can readily take care of.

Histoplasma capsulatum is characteristically found in AIDS patients, for example, when their T cell levels drop below 50 and, once again, these AIDS patients will usually die from this opportunistic pathogen.

I am not sure how these two stories relate to one another—-except that they involve well known opportunistic fungi that the medical community usually sees in extremely sick patients such as those with AIDS.

-Justin

[Harrison]

Justin, just one comment for now -- many patients I've spoken with are on or have been on these drugs: Cimzia, Enbrel, Humira, and Remicade.

More (specifics) on this issue in the months and years ahead.

[Justin]

The drugs you have listed above have had a "black box" warning, which indicates possible life-threatening adverse effects, since coming on the market.

The FDA and physicians know about the well-documented increased risk of infection on these drugs including histoplasmosis. There have been serious side effects as a result of these medications in the past--these are incredibly powerful drugs.

What the FDA is now doing is adding this risk of histoplasmosis to the drugs black box warning.

-Justin