Key learning points:
– Pregnant people should avoid infection with Toxoplasma
– A very high number of people are infected with Toxoplasma in the UK, but only a small percentage of people develop toxoplasmosis
– There is no vaccine to prevent Toxoplasma infection in humans but it can be diagnosed, and where toxoplasmosis develops it can be treated
The term toxoplasmosis can be used to describe a variety of diseases caused by the protozoan parasite Toxoplasma gondii (abbreviated to Toxoplasma). This is distinct from merely being infected with Toxoplasma, which for the vast majority of people causes no apparent symptoms. However, toxoplasmosis can be a serious and even life-threatening disease for people who are immunocompromised such as those developing acquired immune deficiency syndrome (AIDS) those undergoing immunosuppressive treatment post organ transplant. Pregnant women are at risk of abortion and their fetuses are at risk of contracting congenital disease in utero.1
Toxoplasma infection types
In the UK, depending on region, 23-33% of people are infected with Toxoplasma.2,3 However, as in the rest of Europe, North America and most parts of the world that have been extensively studied, only a relatively small percentage of those infected are considered to have toxoplasmosis as defined by having a disease with pathological consequences.1 This is because infection with Toxoplasma is asymptomatic in most people. Although, some experience febrile illness that can easily be mistaken for a viral illness such as influenza. If this is diagnosed it is sometimes referred to as ‘acute toxoplasmosis’. As most people rapidly control the parasite and febrile symptoms are not diagnostic, they are never diagnosed and therefore, are unaware of what caused their illness. Once past this initial febrile period most people have no symptoms, but still harbour living parasites in their brain, muscles and eyes. These people are sometimes considered to have a chronic Toxoplasma infection.1 It was long thought that only a relatively small number of apparently healthy adults infected with Toxoplasma develop ocular toxoplasmosis, which is true for many geographical areas including Europe and North America. However, in relatively recent years, geographical differences in toxoplasmosis disease frequency patterns have emerged.4,5,6 Notably, in South America strains of Toxoplasma exist, which are associated with increased disease severity including ocular toxoplasmosis.4,5,6 Consequently, travellers to South America are logically at risk of infection with virulent strains of Toxoplasma, which needs to be considered in the diagnosis of people with ocular disease returning to the UK.
Recent research has suggested the possibility that people with chronic Toxoplasma infection might have an increased likelihood of developing certain other conditions including schizophrenia.7,8 This is a contentious area of research that needs more work to establish cause and effect.7
Toxoplasmosis in immunocompromised
People who are immunocompromised such as those developing AIDS are at risk of toxoplasmic encephalitis (TE), less frequently ocular toxoplasmosis (OT) and sometimes disseminated disease. Disease can be due to reactivation of the cyst stages present in the brains of people with a chronic Toxoplasma infection or due to a new infection. Disease can be fatal if not treated.1
The consequences of toxoplasmosis in pregnant women
Infection during pregnancy can result in abortion or congenital infection. The vast majority of people with chronic Toxoplasma infections are generally protected from these effects due to their existing immunity. Only rare cases of congenital infection have occurred in women with a chronic Toxoplasma infection. In contrast, women who are infected for the first time during pregnancy are at risk of abortion and their fetuses are at risk of contracting congenital disease. The risk of abortion is high if maternal infection is acquired during the first trimester, intermediate in the second trimester and low in the third trimester. Conversely, the risk of congenital infection increases when maternal infection occurs in the third trimester, but is intermediate in the second trimester and relatively low in the first. Importantly, infection in the first trimester has severe consequences for the fetus including life-threatening hydrocephalus, physical and mental impairments and ocular disease including blindness. Infection in the final trimester is often asymptomatic or causes relatively mild symptoms in the child at birth. However, those born with mild or asymptomatic congenital disease will suffer recurrent disease throughout their lives, which normally manifests as progressive ocular disease. This is sometimes not apparent until teenage years. As the Toxoplasma damages the retina when it is active and this cannot be repaired, each episode results in permanent accumulative damage to sight. This requires careful management with repeated treatments during ‘flare-ups’ to prevent blindness.8
What causes toxoplasmosis?
Humans become infected with Toxoplasma from eating undercooked meat from infected animals or ingesting infectious stages spread in the environment in cat feaces.
The Toxoplasma parasite is capable of infecting mammals, birds and even some fish. These animals act as intermediate hosts where the parasite multiplies rapidly as tachyzoites that are quickly controlled with the immune response before transforming into bradyzoites that form cysts in the brain and muscle where they resist the immune response. Cysts in meat are a source of infection for humans. However, if these cysts stages are eaten by cats, they undergo a sexual process in the intestine of the cat that results in the production of an additional infectious stage, termed the oocyst, which is released in cat feaces. Cats are therefore referred to as the definitive host. The oocyst stages are highly environmentally resistant and infectious not only to humans, but also other intermediate hosts. Consequently, to prevent infection humans should avoid raw or undercooked meat that might harbor cysts and avoid contact with oocysts in cat feaces in the environment and food or water that might be contaminated with cat feaces. This in practice involves cooking meat to well-done, washing fruit and vegetables before eating and washing hands after gardening. People at high risk of serious disease or severe consequences following infection especially immune compromised and pregnant people should be especially vigilant.9
Signs and symptoms
The most common symptom of acute disease in an otherwise healthy individual with acute toxoplasmosis is lymphadenopathy. These enlarged lymph nodes may be mistaken for lymphoma in otherwise asymptomatic patients. Sometimes lymphadenopathy is accompanied with fever, malaise, stiff neck, myalgia, arthralgia, headache, sore throat, maculopapular rash (sparing palms and soles), urticarial, hepatoslenomegaly or hepatitis.
Toxoplasma infection can cause ocular lesions in the form of chorioretinitis even in cases of acute acquired toxoplasmosis, but also due to congenital infection. Chorioretinitis may cause blurred vision, scotomata, pain, photophobia or epiphora. Acute active lesions are recognisable through ophthalmoscopy examination by their hypopigmented diffuse appearance, while non-active healed scars are recognised from their hyperpigmented distinct borders.
Toxoplasmic encephalitis, which is most common in immune compromised people, can manifest as headaches, seizures, high temperatures or blurred vision.1 Studies before effective anti-retroviral therapy was developed demonstrated that around 50% of people seropositive for Toxoplasma with HIV would develop toxoplasmic encephalitis.1
Around 20% of women acquiring Toxoplasma during pregnancy develop symptoms. Consequently, some countries have national screening programmes in place that involve testing for serological evidence of infection early during pregnancy and then at various times throughout pregnancy (e.g. monthly in France). However, at the moment universal screening during pregnancy is not recommended in the UK. In France treatment of infected women during pregnancy has been demonstrated to reduce the incidence of congenital transmission.1 Studies in the USA and France demonstrate that treatment of infected fetuses in utero and infants post-natally reduces the severity of disease.1 Disease symptoms at birth in congenitally infected infants range from asymptomatic to severe including hydrocephalus, blindness, epilepsy and cerebral palsy. Many and arguably all people asymptomatic at birth go on to develop the disease, mainly retinitis later in life.1
Dealing with patients with suspected toxoplasmosis
Suspected cases of toxoplasmosis can be investigated through serological testing and/or polymerase chain reaction (PCR) at the Toxoplasma reference laboratories (Swansea for England, Wales and Inverness, Raigmore for Scotland). In England and Wales from 2008-2012 an annual average of 365 cases of toxoplasmosis were reported. An average of 222 cases were reported in immune competent individuals mainly presenting with lymphadenopathy. Approximately 73 cases per year were diagnosed in immunosuppressed people who had central nervous system and systemic symptoms. Over the five year period 190 pregnant women were diagnosed, 28 of which lost their fetus due to still birth. There were 33 congenital cases of toxoplasmosis. All of these figures are an underestimate of the true numbers.10 The cause of stillbirths are not generally investigated and many cases of congenital toxoplasmosis are asymptomatic at birth. High levels of Toxoplasma specific immunoglobulin (IgG) levels are suggestive of chronic infection, but the presence of immunoglobulin M (IgM) and rising IgG levels indicate a recently acquired infection. The presence of Toxoplasma can be confirmed in tissue biopsies or amniotic fluid by PCR.1 Current treatment options are detailed below and available in the British National Formulary.
The majority of people are never treated as they are asymptomatic and/or not diagnosed. However, where disease is diagnosed it is normally due to it being serious or life-threatening and warrants treatment. Current treatments only limit multiplication of tachyzoite stages and do not eliminate cysts stages. Consequently, people often require long-term or repeated treatments.1
Children with congenital toxoplasmosis, people with ocular disease and immunocompromised people with toxoplasmosis are treated with a combination of sulphadiazine and pyrimethamine that target parasite folate synthesis. Pyrimethamine can affect hematopoiesis resulting in neutropenia. To some extent this can be overcome through co-administration of folinic acid, which humans can use, but the parasite is incapable of using. Importantly folic acid supplementation is not an alternative to folinic acid as this can be used by the parasite and ablates the therapeutic benefit of pyrimethamine. Blood counts should also be performed weekly. Allergy to sulphadiazine, which manifests as a rash can necessitate its discontinuation, Azithromycin, clarithromycin and clindamycin have also been used in combination with pyrimethamine.1
Pregnant women with acute disease can be treated with spiromycin, which reduces the likelihood of congenital transmission while not crossing the placenta. After the first trimester, pyrimethamine and sulphadiazine with folinic acid are given where there is evidence of placental or fetal infection. Newborns whose mothers are known to have acquired Toxoplasma infection during pregnancy are given spiromycin while waiting for their infectious status to be determined. Congenital toxoplasmosis in neonates is treated with pyrimethamine and sulphadiazine with folinic acid for 12 months.1
The policy of relying on primary prevention rather than universal screening for Toxoplasma infection during pregnancy could change as there is growing evidence from France and the USA that screening can identify mothers at risk and treatment during pregnancy reduces the chances of fetal infection.1 In the meantime educating risk groups and especially pregnant people on how to avoid Toxoplasma infection is the primary means to reduce the incidence of this devastating disease.
1. Mcleod R, Tubbergenn, CV, Montoyoa JG, Petersen E. Human Toxoplasma infection Weiss LM, Kim K (eds) Toxoplasma gondii; The model Apicomplexan; Perspectives and Methods, 2nd ed. Amsterdam: Elsevier.
2. Pappas G, Roussos N, Falagas ME. Toxoplasmosis snapshots: global status of Toxoplasma gondii seroprevalence and implications for pregnancy and congenital toxoplasmosis. International Journal of Parasitology 2009;39: 1385-94.
3. Joynson DH. Epidemiology of toxoplasmosis in the UK. Scandinavian Journal of Infectious Diseases Supplement 1992;84:65-9.
4. Kijlstra A, Petersen E. Epidemiology, pathophysiology, and the future of ocular toxoplasmosis. Ocular Immunology and Inflammation 2014;22(2):138-47.
5. Vasconcelos-Santos DV. Ocular manifestations of systemic disease: toxoplasmosis. Current Opinions in Ophthalmology 2012; 23(6):543-50.
6. Dubey JP, Lago EG, Gennari SM, Su C, Jones JL. Toxoplasmosis in humans and animals in Brazil: high prevalence, high burden of disease, and epidemiology. Parasitology 2012;139(11):1375-424.
7. Henriquez SA, Brett R, Alexander J, Pratt J, Roberts CW. Neuropsychiatric disease and Toxoplasma gondii infection. Neuroimmunomodulation 2009;16(2):122-33.
8. Su E, Honda A, Latkany, P. Human Toxoplasma infection Weiss LM, Kim K (eds) Toxoplasma gondii; The model Apicomplexan; Perspectives and Methods, 2nd ed. Amsterdam: Elsevier.
9: Dubey JP. History of the discovery of the life cycle of Toxoplasma gondii. International Journal for Parasitology 2009;39(8):877-82.
10. Halsby K, Guy E, Said B, Francis J, O'Connor C, Kirkbride H, Morgan D. Enhanced surveillance for toxoplasmosis in England and Wales, 2008-2012. Epidemiology and Infection 2014;142(8):1653-60.
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