Toxoplasmosis: New findings and challenges

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There are coccidian stages in the cat intestine, where the toxoplasmosis parasite forms oocysts, (Image: David Ferguson, Oxford University)

Toxoplasma gondii, according to journalist Christie Wilcox writing in Scientific American, is arguably the most interesting parasite on the planet.”

This single-celled protozoan undergoes a sexual cycle in cats, where it produces a highly infectious form of the parasite called oocysts. These are excreted by the cats and find their way into water, soil, sandboxes, gardens, livestock animals, and humans. In a new host, the parasite settles as cysts in various tissues, including the host’s brain, where it remains for the remainder of its host’s life.

Teams led by Rima McLeod, MD, professor of ophthalmology, visual sciences, and pediatrics (infectious diseases) and Medical Director of the Toxoplasmosis Center at the University of Chicago, have been studying this parasite and the disease it causes for decades. On September 18th, 2015, they published two papers along with colleagues from Stanford University in Clinical Infectious Diseases, the leading clinical, peer reviewed, specialty journal of the Infectious Disease Society of America. These papers present recent findings from the National Collaborative Chicago-based Toxoplasmosis Longitudinal Study (NCCCTS) of families who have a child with congenital toxoplasmosis.

One of the new studies, a “brief report,” focused on how strains of this parasite, isolates with differing genetics, cause different patterns of hydrocephalus—excessive accumulation of fluid—in the human brain. The other study, a “major article,” documented the unexpectedly high prevalence of infection, and the surprisingly high incidence of active infections, with Toxoplasma gondii in the fathers of children born with the infection.

ScienceLife felt it was time to take another look at this parasite, which infects more than two billion people worldwide, more than any other disease-causing parasite, as well as the seriousness of the diseases it causes, how that occurs, how it is spread, current medicines that improve outcomes, and what is still needed and why.

Questions and Answers:

First, some background: What are Toxoplasma gondii and toxoplasmosis and who do they affect?

The parasite is called Toxoplasma gondii. An estimated 60 million people in the United States are chronically infected with the protozoan Toxoplasma gondii. Most people with a mature and functional immune system are able to keep the parasite in check, but when a woman gets infected for the first time during pregnancy and passes the parasite on to her unborn child, the consequences can be profound, include devastating harm to the brain and eyes without treatment. The disease caused is called congenital toxoplasmosis when it is acquired before birth. Disease also can occur in those with compromised immune systems, such as those who have had transplanted organs or those with cancer or its treatment or AIDS. Some persons develop active eye disease or other organ damage without known immune compromise. Active infection may recrudesce from dormant parasites.

ToxoFlow

Definitive stages of the life cycle where the exchange of genetic material takes place in the cat intestine (image by David Ferguson, Oxford Univeristy).

How do people acquire a Toxoplasma infection?

The parasite can infect most warm-blooded animals, including humans, but the primary host in which genetic exchange occurs is cats. An acutely infected cat typically excretes up to 500 million oocysts in two weeks. Even one oocyst is infectious. . Thus, garden greens can harbor oocysts. They can be picked up by children (or their parents) playing in an open sandbox. They can even be inhaled during cleanup chores in a barn with a population of “mousers.” The oocysts can persist in warm moist soil or water for up to a year. Colleagues at John’s Hopkins University have estimated that every square foot of soil in the United States contains from 1 to 400 oocysts. The infection also can be acquired from meat that contains the tissue cysts, when the meat has not been cooked sufficiently to kill the encysted organisms.

Tell me about your brief report: What is the link between the genetics of this parasite and hydrocephalus?

We found that discrete strains exist in the U.S., reflecting divergent genetic lineages, and these strains can damage the brains of infected babies in different ways. This explains, in part, why the strains cause various anatomical patterns of hydrocephalus. This is likely based on the strain-specific secretion of differing versions of proteins that interact differently with the human host’s brain cells. One strain causes obstruction of a narrow channel, the diameter of a pin, which serves as a conduit for the flow of fluid through the brain. Other strains change the resorption of fluid and the elasticity of the chamber through which the fluid flows. When the flow is obstructed, and fluid backs up, it presses on the brain, which can cause lasting damage if not corrected promptly.

Parasite Strain-Figure 1_Low QualityDoes it change how you manage such patients?

Oh yes, definitely. People used to think we couldn’t do anything about the fluid buildup with certain patterns of ventricular dilatation and thought this was just due to destruction of brain, but now we work with neurosurgeons to place a shunt, a small tube that diverts flow of the fluid so that it does not cause compression of adjacent brain tissue even for this pattern. Then patients get better. That you can shunt more than just the obstructive pattern of hydrocephalus was an important finding. We plan to submit a more detailed description of this work to a neurosurgical journal soon.

The other paper is about clusters within families. How contagious is this parasite, and why?

For a long time we have considered congenital toxoplasmosis in a family as a disease primarily of the mother and baby. But in this study, when we looked for it, we saw that sometimes the fathers also get the infection, apparently at about the same time. If it’s acquired from contaminated food or water, the dad may be exposed to the same source as the mother. We had seen this before, in an Amish family where all but one of the 9 children were acutely infected, probably from a sandbox or a henhouse where there were cats around. Others have described similar groups of cases in North America caused by either oocysts or contaminated meat. There are multiple substantial epidemics in Brazil right now, affecting hundreds of people with a high incidence of eye disease.

Previous studies showed that about 10 percent of all males aged 12 to 49 years old test positive for Toxoplasma infection. When we looked at our families, we found that 36 percent of the fathers of children with toxoplasmosis also have this parasite. This is a significantly larger number.

We can tell from blood tests how long ago people were infected. We found that six of the dads in the study had been infected within the previous year. One of them had eye disease. So it’s important to look at the whole family.

Are you sure this is spread through contaminated food?

No. It’s hard to be certain.

What does that mean to a clinician?

It means that if you see signs of toxoplasmosis in one person, you should look carefully at the whole family, especially if there is anyone who is either immunocompromised, or pregnant. You should look at the kids too.

The clusters paper mentions another potential means of transmission. You suggest that this disease could be transmitted sexually.

We don’t have direct evidence that Toxoplasma infection is transmitted sexually, but it is a possibility that deserves a careful study. We know that T. gondii tachyzoites are present in seminal fluid from infected rams, goats, dogs and humans. Female sheep and dogs have been infected through sexual contact or artificial insemination involving a donor infected male. This might be one factor in the high rates of paternal infection. Our co-authors at Stanford are planning to pursue addressing this question.

So, the studies don’t show this, but do you think it could move from female to male?

We just don’t know.

Your group’s work, with NIH and philanthropic support, has defined utility, safety and efficacy of pyrimethamine in the treatment of gestational and congenital toxoplasmosis in the U.S. over the past 35 years. You are considered one of the most knowledgeable physicians specializing in this disease in the US and a leading expert in caring for persons with toxoplasmosis, as well as performing innovative, cutting-edge basic and translational research. How do you feel about the sudden substantial price hike for a drug that is a fundamental component in the treatment of toxoplasmosis?

I’m a doctor and a scientist, not an economist or health policy expert, nor do I know about what are profits versus other uses of resources within the company that makes this medicine. Thus, I speak from the viewpoint of someone who has devoted her life to helping patients and families who have serious illnesses due to this parasite and what I have observed in a limited way first hand.

My primary concern is to make certain that all who need this medicine have immediate access to it and timely first-rate, effective clinical care, without any hardship from cost of medicines. I am not a paid consultant nor have I accepted any gifts or support from this company so what I am describing is simply my own first-hand experience as I work to obtain this essential medicine for my patients, or helped all other physicians who contacted me where the medicine was needed for their patients to do so.

In my limited experience, so far, those currently involved with organizing distribution of this vital medicine, pyrimethamine, have worked hard to make it available to all patients promptly, regardless of payer status, without creating financial hardship for either patients with costs or difficulties for physicians with paperwork. They worked expeditiously to improve distribution and logistics for obtaining the medicine. They have said that they provide medicine without charge to medically indigent patients, without increase to those with Medicare, charges rebated to the states in full for those with Medicaid or Medicaid HMOs. For those with indemnity insurance there is a maximum co-pay of $10 per month I was told. They have a charity that can assist with other costs. It does not seem that any patient should be afraid they cannot obtain medicines or that they will be hurt by high charges. Patients have called with those concerns but it seems that medicines are available to all in a timely manner, without high charges.

What I mean when I say this is workable is that there appears to be availability of medication for all patients I have directly cared for or been involved with, regardless of their ability to pay for this medicine and not incurring financial problems. The distribution system appears so far to be workable and I am told additional improvements, and lowering the cost, are in process. This reduction in cost will take place following a careful analysis of costs to the company versus payer mix and reimbursements from the first month of distribution take place.

Is this service available to all physicians in your specialty?

Yes, it appears to be. This was quickly translated into making certain that the American Academy of Pediatrics (AAP) and the HIV Medicine Association (HIVMA) provided information for their members on how to access this medicine for all patients, urgently and emergently. Timely initiation of treatment is of the essence for better outcomes. It is critical to assure those with this infection that medicine and care remain readily available for them. As you can well imagine, it is truly frightening to be told and think otherwise, and not to know that care and medicines really do remain available to all.

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The protozoan Toxoplasma gondii, tissue cyst in brain (D. Ferguson, Oxford University)

Does that solve the problem?

No. To my knowledge there has been no pharmaceutical company support for research on this disease or development of new medicines or vaccines for humans in the U.S. for many decades. Such support is needed to bring new medicines, vaccines and other advances to patients. And this is not the only problem. Governmental funding for research has been hampered by concerns over congressional shut-downs, sequesters, fights over budget priorities, and more limited resources.

My research group and collaborators perform innovative research to understand how the infection occurs, as well as addressing prevention, diagnosis, treatment, making improved treatments and creating effective vaccines. This work has taken place over decades and continues to the present. Some of this work is clinical and translational and some of this work is basic science. There are a number of other first-rate research groups in the U.S. performing innovative basic science work on this as well.

I hope the sudden unexpected glare of attention focused to this disease helps raise awareness and facilitates work that leads to definitive cures and prevention. This disease is profoundly understudied and underfunded relative to the gravity of illness and the frequency of lifelong infection. An estimated two billion people are infected with T. gondii, with unknown consequences. So, boosting resources that help with care and improve prevention, diagnosis and treatment of toxoplasmosis is worthwhile.

What do we need to move this field forward to the finish line of definitive prevention and cures?
We need new medicines with fewer side effects; medicines that can eliminate latent parasites which cause recurrent disease (pyrimethamine plus sulfadiazine or azithromycin do not); a vaccine to prevent infection; better point of care diagnostic tests that improve prenatal and newborn screening and at low cost. We and others are working in each of these areas with promising results, but there are other unanswered questions and still are medical problems facing those with this infection. For example, a few months ago we saw a patient with bilateral retinal detachments and significant visual impairment which developed when treated with second line treatment with Bactrim (trimethoprim sulfamethoxazole), which some physicians recommend but we do not use at the Toxoplasmosis Center as we have seen outcomes like this with this less active medicine combination (Grossman, Remington, 1979). Continued prompt use of pyrimethamine until such new measures are available is critical.

mcloudFor example, the child in the adjacent photograph is followed at the University of Chicago. At birth, she was expected to be paralyzed, but with treatment with pyrimethamine and other antimicrobials (treatments we and others in the National Collaborative Treatment Study developed) is making good progress. She was sitting, playing with a musical toy last week (adjacent photo, shown with permission), surpassing expectations all had for her at birth.

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