Toxoplasmosis – Symptoms, Diagnosis & Treatment
Toxoplasmosis is caused by the protozoan parasite Toxoplasma gondii. T. gondii currently infects approximately one-third of the global population. After infection, T. gondii forms cysts in tissues, including the brain, which can persist in the human body for life.1
Toxoplasmosis is most concerning during pregnancy and in immunocompromised patients. In immunocompetent individuals, toxoplasmosis is primarily considered a benign condition. However, acute toxoplasmosis in individuals with healthy immune systems can cause severe sequelae, including myocarditis, pericarditis, heart failure, pneumonia, respiratory failure, encephalitis, meningitis, Guillain-Barré syndrome, and death.2,3 Furthermore, the latest research suggests that even latent or subclinical toxoplasmosis can cause significant chronic health concerns in otherwise healthy and immunocompetent patients.4,5
What is Toxoplasmosis?
Toxoplasmosis is a Toxoplasma gondii infection. There are several clinically distinct forms of toxoplasmosis, including:
- Acute toxoplasmosis6
- Cerebral toxoplasmosis7
- Ocular toxoplasmosis8
- Pulmonary toxoplasmosis9
- Chronic toxoplasmosis5
- Congenital toxoplasmosis10,11
- Latent (subclinical) toxoplasmosis5,12
Congenital toxoplasmosis is characterized by the vertical transmission of T. gondii from mother to fetus.10 Acute toxoplasmosis in immunocompetent individuals presents as a flu-like illness characterized by nonspecific constitutional symptoms. Since T. gondii is neurotropic and oculotropic, it can also cause acute cerebral toxoplasmosis and ocular toxoplasmosis.10
Pulmonary toxoplasmosis occurs when T. gondii infects the lungs. Pulmonary toxoplasmosis can be challenging to diagnose because it is rare and has a variable clinical presentation. A review published in 2007 discovered only nine cases of pulmonary toxoplasmosis in the medical literature. Of note, most patients were young men, with a median age of 34 years, who had consumed raw or undercooked meat.13
Chronic toxoplasmosis is a long-term infection with persistent or recurrent clinical symptoms that may require medical treatment. Latent toxoplasmosis is a clinically mild, long-term (often lifelong) “asymptomatic” infection that may present with subtle, nonspecific symptoms or behavioral changes, some of which may worsen over time.5 Latent toxoplasmosis may progress to a chronic form, and chronic toxoplasmosis may revert to a latent subclinical state. Latent toxoplasmosis can reactivate into an acute infection with immunocompromise. Environmental factors, including stress, other infections, and certain medications, may also trigger reactivation.5
The Life Cycle of Toxoplasma gondii – Toxoplasmosis in Cats and Humans
Toxoplasma gondii only sexually reproduces in cats (domestic and wild); therefore, cats are the definitive host and ultimate source of all infections. Despite not sexually reproducing in humans, T. gondii does infect humans, leading to toxoplasmosis.14 Therefore, humans serve as intermediate hosts. Many other animals, including mice and birds (eaten by cats), also serve as intermediate hosts.15
There are four forms of Toxoplasma gondii:
- Oocysts, which are shed in the feces of the definitive feline host.
- Oocysts contain sporozoites and become infectious after sporulation.
- Tachyzoites – rapidly multiplying organisms found in the tissues.
- Bradyzoites – slowly multiplying organisms found in the tissues.
- Tissue cysts – walled structures that contain bradyzoites and are resistant to the immune system.15
Infected cats excrete between 2 and 20 million oocysts per day in their feces.16 After excretion, the oocysts sporulate in the environment until they produce eight haploid sporozoites encased within the oocyst wall. Sporulation occurs in 1 to 5 days under ideal conditions, but could take several weeks.15,16 The oocysts are not infectious until after sporulation; therefore, changing cat litter daily can help prevent transmission.17
Most cats excrete oocysts for 1-2 weeks; however, some cats can continue shedding for up to 3-4 weeks after infection. T. gondii oocysts are stable for over a year under a variety of environmental conditions.15,16
When T. gondii is ingested by an intermediate host, such as a human, the tissue cyst or oocyst wall is dissolved during digestion, which releases the bradyzoites or sporozoites into the gut lumen. The bradyzoites or sporozoites then enter the lamina propria of the small intestine and begin to multiply as tachyzoites. The tachyzoites disseminate to extraintestinal tissues within a few hours of infection via lymphatic and blood circulation.15
Tachyzoites can enter nearly any cell and multiply until the host cell ruptures. The released tachyzoites from the ruptured cell then enter surrounding cells. As the immune system begins to respond, the tachyzoites will disappear and form bradyzoites within tissue cysts to escape the immune response.1,15
Tissue cysts can form in many organs, but are most commonly found in the skeletal muscles, myocardium, and the central nervous system (CNS) in humans. Unfortunately, the tissue cysts with bradyzoites generally do not cause a host reaction and can persist for many years, possibly for life.15
Toxoplasma gondii is transmitted to humans via four routes:
- Ingestion of infectious oocysts from the environment, via contaminated water, hands, soil, fruits, or vegetables.
- Ingestion of undercooked meat that contains tissue cysts.
- Transmission from an infected mother to the fetus.
- Transplantation of an infected organ from an infected donor.15
Some research suggests that T. gondii can be transmitted sexually from male to female, which could increase the risk of congenital toxoplasmosis. The potential for the sexual transmission of Toxoplasma requires further study.12,18,19 Research also indicates that ticks could be a reservoir for the transmission of Toxoplasma; however, more investigation is needed.15,20-22
Toxoplasmosis – Signs and Symptoms
The severity of toxoplasmosis ranges from benign and asymptomatic to life-threatening with severe multi-organ involvement.1
The most common signs and symptoms of acute toxoplasmosis in immunocompetent individuals include:
- Chills10
- Elevated Toxoplasma gondii-specific antibody levels9
- Fever23
- Fatigue24
- Headaches10
- Hepatosplenomegaly24
- Lymphadenopathy10,24
- Myalgias10
- Pharyngitis24
- Rash10
Acute toxoplasmosis can be mistaken for the flu or an infection with the pathogens that cause mononucleosis, such as EBV or CMV. 24,25 In immunocompetent individuals, infection with Toxoplasma gondii is considered self-limited.26 However, the latest research shows that acute and latent toxoplasmosis in individuals with healthy immune systems can cause severe repercussions.2,10
Other signs, symptoms, sequelae, and health concerns associated with toxoplasmosis include:
Research suggests that Toxoplasma gondii may alter neurotransmitter levels and genetic expression, leading to many of the health concerns listed above.28,84,85 During its life cycle, research shows that T. gondii interacts with approximately 3000 host genes or proteins.28 T. gondii also influences the specific brain regions for cognition, mood, and emotion processing, neuroinflammation, and neuroendocrine changes to contribute to seemingly unrelated health concerns.49
While the bradyzoites in tissue cysts have traditionally been viewed as latent or “resting,” new research suggests that they continue to replicate. Therefore, tissue cysts can occasionally rupture and release parasites, which are readily controlled by the immune response in immunocompetent individuals. However, they can multiply and quickly disseminate if the host is immunocompromised.15
Acute toxoplasmosis is exceptionally severe in immunocompromised patients. Cases of disseminated toxoplasmosis after a stem cell transplant can reach a mortality rate of 80% with a median survival time of only 10 days post-diagnosis.51
Testing for Toxoplasmosis
Ideally, patients with any of the health concerns noted above will be tested for toxoplasmosis.10 Also, consider screening for asymptomatic latent or subclinical toxoplasmosis in those who are at increased risk of exposure to Toxoplasma gondii, including your patients who work in veterinary medicine.86
Diagnosing toxoplasmosis can be challenging in immunocompetent and immunocompromised patients. The diagnosis is easily missed in immunocompetent patients due to a lack of clinical suspicion. Toxoplasmosis often presents with nonspecific symptoms that mimic mononucleosis or the flu in this patient population.10 In immunocompetent individuals, serological testing for IgM and IgG antibodies in the blood is the diagnostic standard.10,24
Research suggests that IgM antibodies are detectable 5 days after infection and reach maximum levels in 1 to 2 months. IgG antibodies are detectable 1 to 2 weeks after infection and reach the highest levels in 3 to 6 months. Since they mediate long-term immunity, IgG antibodies are present in a significant percentage of the general population and often remain detectable for life in those with latent toxoplasmosis. A lack of IgM antibodies coupled with a high IgG level contributes to the diagnostic challenge.10
Assessing the secretory IgA (sIgA) antibody level in saliva can be ordered as a screening test or a valuable addition to the standard diagnostic work-up. Some evidence suggests that elevated IgA (including secretory IgA) levels may correlate well with an acute infection. Researchers, however, have also found elevated sIgA levels during latent toxoplasmosis. All positive findings, including an elevated T. gondii-specific salivary sIgA antibody level, must be interpreted in the context of the complete clinical picture and may require further assessment.87-95
In immunosuppressed patients, serologic testing is often not clinically useful due to an insufficient immune response and a lack of antibodies. Imaging, such as computed tomography (CT), positron emission tomography (PET), or magnetic resonance imaging (MRI), can support the diagnosis of toxoplasmosis in this patient population.10
While a standardized PCR test for toxoplasmosis is not available, PCR testing can diagnose toxoplasmosis in all patient populations. T. gondii DNA can be detected in blood and other bodily fluids, including cerebrospinal fluid and the aqueous humor of the eye. The detection of Toxoplasma DNA provides a definitive diagnosis.10,24,96
Muscle, lymph node, or organ biopsy also provides a definitive diagnosis based on the presence of tissue cysts, but it is a highly invasive procedure. A biopsy is rarely performed and often only ordered for patients who fail to show clinical or radiological improvement of symptoms within 14 days of treatment initiation.10,14 Amniocentesis and ultrasound can be ordered to diagnose toxoplasmosis during pregnancy.24 Additional tests that diagnose pulmonary toxoplasmosis include bronchoalveolar lavage and sputum analysis.68
Toxoplasmosis Prevention
Since the diagnosis of toxoplasmosis can be challenging and an infection with Toxoplasma gondii may result in lifelong or life-threatening health concerns, the prevention of T. gondii transmission is crucial.
Reduce the risk of a Toxoplasma gondii infection with the following guidelines:
- Avoid adopting stray cats and kittens. Younger outdoor cats are more likely to release Toxoplasma oocysts in their feces.17
- Avoid eating raw oysters, clams, and mussels.24,45
- Avoid unpasteurized milk, including goat milk.10,24
- Wear gloves when touching cat litter boxes, gardening, or handling any sand or soil that may have been in contact with cat feces. Also, perform appropriate hand hygiene afterward.10,24,45
- Change cat litter boxes daily, unless pregnant or immunocompromised, in which case someone else must change the litter box daily.17
- Cook all foods to safe temperatures.10,45
- Do not feed cats undercooked or raw meat and keep them indoors.24
- Drink only treated, boiled, or well-filtered water.24,45
- Freeze all meats for several days at sub-zero temperatures before cooking.10
- Wash or peel all fruits and vegetables.10,24,45
- Wash all surfaces, including utensils, dishes, cutting boards, and counters, that have come in contact with raw meat, poultry, seafood, and unwashed fruits or vegetables.10,17,24
- Cover outdoor children’s sandboxes to prevent cats from using them as a litter box.97
Naturopathic Toxoplasmosis Treatment & Management
According to the Mayo Clinic, toxoplasmosis is often benign and does not require treatment in immunocompetent patients.98 However, as explained above, even latent toxoplasmosis might cause long-term sequelae. All currently available therapeutic pharmaceutical regimens are only effective against the tachyzoites and cannot eliminate the long-term tissue cysts. Fortunately, early evidence suggests that some naturopathic treatment options may reduce the risk of infection and interfere with cyst development.49
Myristica fragrans (Nutmeg)
Myristica fragrans (nutmeg) is a spice used in foods and folk medicine. The bioactive constituent myrislignan perturbs the tachyzoite’s mitochondrial function, and pre-clinical research suggests that M. fragrans is also effective against the bradyzoite stage. In an animal study, M. fragrans offered minor protection against brain cyst development.49
Nigella sativa (Black Cumin)
Nigella sativa (black cumin) has a long history of use in traditional medicine. Modern clinical trials demonstrate that N. sativa is safe and effective for the treatment of autoimmune, inflammatory, and metabolic disorders. Animal studies show that the volatile oil component of N. sativa acts synergistically with the pharmaceutical pyrimethamine to reduce T. gondii load and damage to the liver and spleen during an acute infection. Preclinical evidence demonstrates that N. sativa seed oil may offer prophylactic and therapeutic effects during a chronic infection. N. sativa seed oil administered to animal models before infection or a few days after infection significantly reduced mortality and brain cyst load. The treated groups also exhibited an enhanced level of inducible nitric oxide synthase (iNOS) and fewer histopathological alterations compared with the untreated group.49
Thymus spp. (Thyme) Essential Oil
Administering Thymus spp. (thyme) essential oil at the time of or shortly after infection prevents the formation of brain cysts, according to an animal study. Administration of thyme extract to chronically infected animal models also lowers the brain cyst load and ameliorates the inflammatory brain lesions.49
Curcuma longa (Turmeric)
Curcuma longa (turmeric) is safe and effective for treating many diseases, based on the results of extensive clinical trials. One of the bioactive constituents in turmeric is curcumin, a pleiotropic compound that targets multiple signaling pathways. The FDA designates curcumin as a Generally Recognized as Safe (GRAS) dietary compound. Research shows that curcumin blocks parasite growth by inhibiting T. gondii glyoxalase 1 (GLO1) activity and targets the T. gondii detoxification pathway. However, the clinical bioactivity of curcumin is often limited by its low oral bioavailability, which is why researchers have developed nanocurcumin. Nanocurcumin encapsulates curcumin in nanomaterials to improve the solubility and therapeutic applications of curcumin, including as antiparasitic agents.49
In an animal model of acute toxoplasmosis, curcumin and nanocurcumin improved survival and reduced peritoneal tachyzoite load in infected animals. Moreover, when curcumin and the nanocurcumin were administered shortly after infection, significant reductions in the size and number of brain cysts in chronically infected animal models were noted. When administered separately, the nanocurcumin was superior to regular curcumin in alleviating the brain cyst burden.49
Resveratrol
Like curcumin, resveratrol is a polyphenol that also targets multiple cellular signaling pathways. Numerous clinical trials have demonstrated the efficacy, safety, pharmacokinetics, and promising therapeutic effects of resveratrol against cardiovascular, neurological, and metabolic diseases. To enhance the bioavailability and bioactivity, nanotechnology formulations of resveratrol have been developed.49
Research shows that pairing resveratrol nanoparticles with the pharmaceutical sulfamethoxazole-trimethoprim (ST) alleviates brain cyst burden, decreases the levels of serum pro-inflammatory cytokines, and increases the level of interleukin-10. The combined resveratrol & ST regimen also mitigates the cognitive and behavioral impairments normally observed during a chronic infection in the central nervous system (CNS). Unfortunately, the administration of free resveratrol, the nanoparticles, or ST alone showed no effect on the neurological sequelae; the benefits are truly synergistic.49 Outside of the CNS, evidence from pre-clinical studies suggests that resveratrol may modulate or inhibit damage in some organs, including the liver and lungs.99-102
Ellagitannins & Urolithin-A (UA) from Pomegranate
Pomegranate is a rich source of the polyphenols known as ellagitannins. Ellagitannins are metabolized to urolithins by the human gut microbiome. Urolithin-A (UA) is a powerful neuroprotectant against neurodegeneration, ischemic neuronal injury, and brain aging. Furthermore, in a human clinical trial, UA demonstrated a favorable safety profile and improved muscle health in elderly individuals. Pomegranate and UA also exhibit anti-T. gondii activity. UA interferes with intracellular tachyzoite growth and cyst formation in infected neural cells. In an animal study, the daily injection of UA shortly after infection reduced the severity of a chronic CNS infection compared to untreated animals.49
Rosmarinus officinalis (Rosemary)
Rosmarinus officinalis (Rosemary) extracts perturb cyst wall integrity. The administration of alcoholic and oil extracts 1 week before infection or 2 weeks following infection with T. gondii significantly reduced the brain cyst burden, cyst viability, and histopathological insults compared with the untreated group in an animal study. The surfaces of the cysts were marked with multiple depressions, protrusions, and irregularities in the brains of the treated animals upon ultrastructural analysis of the cysts via scanning electron microscopy. Furthermore, the isolation and inoculation of the damaged cysts into a healthy animal did not produce an infection, highlighting a loss in cyst viability after the administration of Rosemary in animal models.49
Artemisinin and Derivatives from Artemisia annua
Artemisinin (ART) is the bioactive constituent of Artemisia annua. ART and its derivatives, including artesunate, artemether, artemiside, and artemisone, have been reported to exhibit activity against tachyzoite growth in vitro that could control acute infection and prevent reactivated toxoplasmosis. ART appears to control tachyzoite growth by interfering with the parasite’s calcium homeostasis and mitochondrial physiology. In an animal study, the co-administration of artesunate and dihydroartemisinin interfered with the progression of chronic toxoplasmosis by perturbing cyst wall integrity. However, the cysts remained viable and produced secondary infections in healthy animals.49
Essential Omega-3 Polyunsaturated Fatty Acids
Abundant omega-3 polyunsaturated fatty acids could be protective against toxoplasmosis. One animal study showed that fish oil supplementation prevented toxoplasmosis. Researchers suspect that the fish oil disturbs fatty acid metabolism and availability for T. gondii growth. In another animal study, chronically infected animals with elevated levels of omega-3 polyunsaturated fatty acids exhibited lower brain cyst burdens compared to the animals with normal fatty acid levels.49
The Flavonoid Quercetin
Quercetin is a ubiquitous flavonoid present in many fruits and vegetables. Evidence suggests that quercetin may suppress tachyzoite differentiation into bradyzoites by inhibiting T. gondii Heat Shock Protein 70 (HSP70) and HSP90 synthesis. Since quercetin can cross the blood-brain barrier, it is plausible that quercetin could influence brain cyst burden and offer potential therapeutic value against chronic toxoplasmosis in the brain.49
Melatonin & Zinc for Immune Support
The results of one animal study suggest that supplementation with melatonin and zinc could be considered as an adjunctive therapy to the classic treatment of Toxoplasma retinochoroiditis if the beneficial outcomes can be confirmed in a clinical setting. Neither melatonin nor zinc alone demonstrated benefit. The combination of zinc and melatonin increased the infiltration of lymphocytes, CD3+, CD4+, and CD8+ cells as part of the immune response against T. gondii.103
Another study analyzed the effects of melatonin in monkey kidney cell epithelial cells after infection with T. gondii. Melatonin treatment reduced parasite proliferation in the kidney cells. After treatment with melatonin, T. gondii appeared to experience an apoptotic-like cell death. The results suggest that the use of melatonin or melatonin derivatives could be considered as an alternative or adjunctive treatment for toxoplasmosis in the future after further investigation.104
Lentinula edodes (Shiitake Mushroom)
Finally, the results of one animal study suggest that the bioactive constituent lentinan from Lentinula edodes (Shiitake mushroom) may protect against toxoplasmosis. While lentinan did not directly inhibit parasite growth in the study, lentinan prevented T. gondii-induced cognitive deficits and decreased the cyst burden, which correlated with behavioral performance. Lentinan also altered the transcriptome profile of genes related to neuroinflammation, microglial activation, synaptic function, neural development, and cognitive behavior in the hippocampus of infected animals. Moreover, lentinan reduced the infection-induced accumulation of microglia, ameliorated the neurite and synaptic ultrastructural damage, and downregulated the mRNA expression of proinflammatory cytokines.105
Further clinical research is required to confirm the protective effects of curcumin, quercetin, artesunate, resveratrol, melatonin, lentinan, and other naturopathic treatments for toxoplasmosis in humans. Unfortunately, the absence of clinically appropriate biomarkers for measuring brain cyst burden is a significant impediment to assessing the effectiveness of treatment options in humans. Neuroimaging techniques, such as MRI and CT, can assess the severity of toxoplasmic encephalitis. However, they cannot quantify the brain cyst burden. The lack of non-invasive techniques to monitor bradyzoite and cyst development in the brain makes clinical research difficult, especially when monitoring disease progression in immunocompetent patients with subclinical, latent, or chronic toxoplasmosis.49
Additional naturopathic and pharmaceutical treatment options are offered in your Provider Portal in the document: Toxoplasmosis Treatment Protocols (PDF)
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