2nd August 2023

Protozoal Infections

Malaria

Malaria is a protozoal infection caused by Plasmodium species. It is the most common parasitic infection worldwide, with the main burden of disease largely in Africa. It is transmitted through the bite of the female Anopheles mosquito and has four different types that cause infection in humans: P. falciparum, P. vivax, P. ovale and P. malariae. Certain haemoglobinopathies (sickle cell disease, G6PD deficiency and thalassaemias) are protective against malaria as the parasites are less able to infect erythrocytes, or the red blood cells are more likely to die from oxidative stress. It is believed that regions endemic to malaria have higher rates of these haemoglobinopathies as it confers a natural selection advantage.

The gold standard diagnosis is with microscopy of Giemsa-stained blood films. Three samples should be sent on three successive days and are often complemented with rapid diagnostic tests (RDTs) for early management and referral. RDTs are restricted by speciation and do not help with the quantification of parasitaemia (percentage of infected cells in the blood).

Prevention for travellers is aimed at mosquito avoidance measures (e.g. mosquito nets) in conjunction with prophylaxis therapy in high-risk areas. Atovaquone-proguanil, mefloquine, doxycycline and tafenoquine are all effective agents, with the first two having the best side effect profiles. In pregnancy, travel to malaria endemic areas should be avoided, but if necessary, mefloquine is the drug of choice for prophylaxis.

Falciparum malaria

P. falciparum is the most common and severest form of malaria. The incubation period is usually 12 to 14 days. After the initial bite, sporozoites infect hepatocytes, undergo mitosis and become merozoites. Merozoites enter the bloodstream and infect erythrocytes, where they replicate further and differentiate. The erythrocyte ruptures, releasing more merozoites into the bloodstream.

Features in uncomplicated, mild disease are usually non-specific: fever, malaise, fatigue, tachycardia, nausea, abdominal pain and arthralgias. Cyclical fevers, a late disease manifestation, are rarely seen now due to early recognition and treatment.

Severe malaria is defined as parasitaemia with one or more of the following complications:

• Metabolic acidosis
• Respiratory distress or ARDS
• Renal failure and haemoglobinuria (blackwater fever)
• Circulatory collapse
• DIC or severe anaemia or haemolysis
• Hypoglycaemia
• Cerebral malaria (altered consciousness, delirium, seizures)

Treatment in uncomplicated falciparum malaria is with artemisinin-based combination therapies (ACT) in both chloroquine resistant and sensitive areas unless ACT is not readily available. In severe malaria, IV artesunate is the treatment of choice. Exchange transfusion is considered when parasitaemia > 10% and there is evidence of end-organ damage. However, the benefits are indeterminate.

Non-falciparum malaria

The most common form of non-falciparum malaria is P. vivax, followed by P. ovale and P. malariae. Vivax is endemic to central America and the Indian subcontinent, whereas ovale and malariae are more commonly seen in Africa. As part of their replication cycle, vivax and ovale produce liver hypnozoites that remain dormant and predispose to relapse anywhere between weeks to years after the initial infection.

Features are generally non-specific, including high-grade pyrexia, diaphoresis, abdominal pain, nausea and vomiting, myalgia and arthralgia. Physical examination often reveals hepatosplenomegaly and jaundice. Features of severe malaria are consistent with all species.

Treatment is similar to uncomplicated falciparum malaria, with WHO advising the use of artemisinin-based combination therapies (ACT) in both chloroquine resistant and sensitive areas unless ACT is not readily available. In the case of ovale and vivax, primaquine should be added to eradicate any liver hypnozoites.

Trypanosomiasis

Two variants of this potentially fatal protozoal disease are important – African trypanosomiasis (also known as sleeping sickness) and American trypanosomiasis (Chagas disease).

African trypanosomiasis (sleeping sickness)

Two forms of African trypanosomiasis are significant – Trypanosoma gambiense (predominates in west and central Africa) and trypanosoma rhodesiense (predominates in east and south Africa), where the latter runs a more acute course, with systemic symptoms usually presenting within 3 weeks. They are both transmitted through the bite of the tsetse fly. Trypanosoma rhodesiense tends to be more acute, but both can present with:

• Chancre – painful, erythematous, inflammatory lesion at the site of the infective bite
• Fever
• Posterior cervical lymphadenopathy
• Neurological abnormalities (late stage) – sleep disorder, behavioural changes, headaches, meningoencephalitis
• Rare features – amenorrhoea, impotence, cardiomyopathy

Diagnosis is through blood and CSF serology and microscopy and first line treatment with IV pentamidine.

American trypanosomiasis (Chagas disease)

American trypanosomiasis is caused by Trypanosoma cruzi, which is predominantly endemic in Latin America. The main transmission route is vector-borne, through the triatomine bug, but it can also be transmitted through contaminated food, blood transfusions and vertically, from mother to baby. The acute phase is largely asymptomatic but can present with non-specific symptoms of malaise and fever. Rarely, the illness may present with a ‘chagoma’, an erythematous nodule at the site of infection, usually on the face or extremities. In very rare cases, acute infection can result in acute myocarditis.

Treatment, usually with benznidazole, in the acute phase is most effective in preventing chronic Chagas. Chronic Chagas is a major cause of morbidity in developing countries. It most commonly results in dilated cardiomyopathy, causing heart failure and arrhythmias, and rarely in megaoesophagus and megacolon, causing dysphagia and constipation, respectively.

Cryptosporidiosis

Cryptosporidiosis is the most common form of protozoal diarrhoea encountered in the UK. It is largely self-limiting but can be life-threatening in immunocompromised patients. It usually presents with watery diarrhoea, crampy abdominal pain, fever, nausea and vomiting, lasting over 1 to 2 weeks.

In immunocompromised patients, symptoms can progress to complications, including cholangitis and pancreatitis. Diagnosis is through stool microscopy revealing red cysts with modified Ziehl-Neelsen stains. Treatment is mainly supportive; however, nitazoxanide can be used in severe cases. In HIV patients, commencing antiretroviral therapy usually resolves symptoms.

Leishmaniasis

Leishmaniases are a group of diseases caused by the protozoa Leishmania and transmitted through sandflies. The disease can be classified into three forms: cutaneous (C), mucocutaneous (MC) and visceral (V).

Treatment is complex and often based on form (C/MC/V), region of infection (differences within the same species are found in different regions, which may predispose to transformation into other types of leishmaniasis) and patient factors.

Cutaneous

• Mainly caused by Leishmania tropica and Leishmania mexicana
• Incubation period of weeks to months
• Presents with pruritic papules at bite sites
• Progresses to a nodule, then a plaque, finally becoming a painless ulcer with an indurated border
  • Lesions can then crust over
• At risk of transformation to MC leishmaniasis years after initial infection
• Treatment is indicated if infection occurs in South or Central America and in the immunosuppressed

Mucocutaneous

• Mainly caused by Leishmania braziliensis
• Characterised by mucosal destruction mainly involving the nose and pharynx
• Treatment is with pentoxifylline

Visceral

• Also known as kala-azar due to the darkening of the skin seen with this disease
• Mainly caused by Leishmania donovani and Leishmania infantum
• Incubation period is usually 2 to 6 months but can be up to years
• Insidious onset over weeks of weight loss, fever and hepatosplenomegaly
• Replication occurs in the reticulo-endothelial system – resulting in dysfunction in the spleen, bone marrow and liver, leading to pancytopenia and liver disease
• Investigation of choice is bone marrow or splenic aspirate
• Liposomal amphotericin B is the first line treatment
• Post kala-azar dermal leishmaniasis, a chronic skin rash, is occasionally observed six months to two years following therapy for visceral leishmaniasis. Presents with red or hypopigmented macules similar to cutaneous manifestations of leprosy. Most cases are self-resolving.

Amoebiasis

The amoeboid protozoan Entamoeba histolytica causes mild diarrhoea, dysentery and colitis. It is mainly transmitted via the faecal-oral route and rarely, but increasingly through male-male sexual contact. It is an infection that occurs mainly in developing countries or returning travellers from low-income territories.

The majority of patients are asymptomatic or have self-limiting, mild diarrhoea. Severe amoebic dysentery and infectious colitis usually occur in immunocompromised individuals, extremes of age, and those with significant comorbidities. Severe infection presents after a long incubation period of up to 3 weeks with abdominal pain and severe, profuse bloody diarrhoea. Rarely it may present with life-threatening lower gastrointestinal bleeding.

Diagnosis is made through antigen testing or stool microscopy (the sample must be kept warm, termed as “hot stool”). Treatment is with metronidazole followed by paromomycin to prevent relapse. Asymptomatic patients are treated with paromomycin. Extraintestinal features mainly present as single or multiple liver abscesses and rarely as lung and brain abscesses.

Toxoplasmosis

Toxoplasmosis, caused by the protozoan Toxoplasma gondii, is transmitted through ingesting oocytes from contamination by cats’ faeces, through vertical transmission, and from an infected donor in organ transplants. Toxoplasmosis infections range in severity and presentation when seen in immunocompetent, immunocompromised and congenital patients.

• Immunocompetent patients are usually asymptomatic but can suffer from a self-limiting syndrome similar to infectious mononucleosis, consisting of fever, malaise and lymphadenopathy. Diagnosed with serology, and treatment is supportive
• In immunosuppressed patients, three forms of the infection are recognised: cerebral toxoplasmosis, pneumonitis and chorioretinitis. Cerebral toxoplasmosis is seen in nearly half of the cerebral lesions associated with HIV. It presents with headache, confusion, reduced GCS and focal neurology. Brain imaging using CT and MRI scans show single or multiple ring enhancing lesions (See image below). Treatment with pyrimethamine and sulfadiazine is required.
• Congenital toxoplasmosis occurs through transplacental transmission from an infected mother to the foetus. Common clinical features include:
  • Neurological abnormalities: chorioretinitis, intracranial calcification, hydrocephalus
  • Lymphoproliferative abnormalities: jaundice, thrombocytopenia, anaemia, hepatosplenomegaly and lymphadenopathy.
  • Retinopathy and microcephaly are less commonly seen.

Multiple ring enhancing lesions on MRI scan

Image Source: Wikimedia Commons (2021). BrainToxoplasmosis MRI 8 22, Licensed under a creative commons licence. Available for free at: https://commons.wikimedia.org/wiki/File:BrainToxoplasmosis_MRI_8_22.png (Accessed: 10 March 2022).

Giardiasis

Giardiasis is caused by the protozoan Giardia lamblia. It is responsible for many diarrhoeal illnesses seen in international travellers. It is prevalent in resource deprived settings and in areas with poor sanitary conditions. It is mainly transmitted via the faeco-oral route but can also be transmitted through contaminated, uncooked food, contaminated water and male-male sexual contact.

Clinically self-limiting, giardiasis presents after a long incubation period of one to two weeks, mainly with GI symptoms of diarrhoea, malaise, foul-smelling stool, steatorrhoea, bloating, crampy abdominal pain and weight loss. Patients may also be asymptomatic. Diagnosis with stool antigen detection assays has superseded stool microscopy due to higher sensitivity and faster processing time. Treatment is with metronidazole if required.