Malaria is caused by Plasmodium falciparum, P. vivax, P. ovale and P. malar- iae, as well as the predominantly simian parasite P. knowlesi. It is transmit- ted by the bite of female anopheline mosquitoes, and occurs throughout the tropics and subtropics at altitudes below 1500 m. The WHO estimates that 214 million cases occurred in 2015, 88% of these in Africa. P. fal- ciparum is now resistant to chloroquine and sulfadoxine- pyrimethamine in South- East Asia and throughout Africa. Reversal of the resurgence in malaria by improved vector and disease control is a major goal of the WHO.
Travellers are susceptible to malaria. Most cases are caused by P. fal- ciparum, usually from Africa, and of these 1% die because of late diagno- sis. Migrants from endemic countries resident in nonendemic countries are particularly at risk if they visit relatives in their country of origin. They have lost their partial immunity and frequently do not take malaria prophylaxis.
People living near airports in Europe occasionally acquire malaria from acci- dentally imported mosquitoes.
Life cycle
The female anopheline mosquito becomes infected by feeding on human blood containing malarial parasite gametocytes. Human infection starts when an infected mosquito inoculates saliva containing sporozoites into the skin during feeding; these disappear from human blood within half an hour and enter the liver. After some days merozoites leave the liver and invade red blood cells, where further multiplication takes place, producing schizonts (Fig. 5.10). Rupture of the schizont releases more merozoites into the blood and causes fever, the periodicity of which depends on the spe- cies of parasite (see below).
P. vivax and P. ovale may persist in liver cells as dormant forms, hypno- zoites, capable of developing into merozoites months or years later. Thus, the first attack of clinical malaria may occur long after the patient has left the endemic area, and the disease may relapse after treatment with drugs that only kill the erythrocytic stage of the parasite. P. falciparum, P. knowlesi and P. malariae have no persistent exo- erythrocytic phase, but recrudescence of fever may result from multiplication of parasites in red cells that have not been eliminated by treatment and immune processes.
Clinical features
The pathology in malaria is caused by haemolysis of infected red cells and adherence of infected red blood cells to capillaries.
Neurological Coma Hypoglycaemia Seizures Cranial nerve palsies Opisthotonus
Respiratory Pulmonary oedema Secondary bacterial pneumonia
Abdomen Jaundice
Tender liver edge with hepatitis Pain in left upper quadrant
with splenomegaly Fever
Cardiovascular Shock
Cardiac failure (‘algid malaria’) Dysrhythmias with quinine Renal
Acute renal failure Severe haemolysis resulting in haemoglobinuria (‘blackwater fever’) Optic fundi
Blood Parasitaemia Anaemia Thrombocytopenia Coagulopathy Disconjugate gaze due
to cranial nerve palsy
Malaria retinopathy with Roth’s spots
Ring form Ring form in RBCs
Trophozoite
Schizont P. vivax in RBCs
Blood film showing parasitaemia P. falciparum
Fig. 5.10 Features of Plasmodium falciparum infection.
P. falciparum infection: (Fig. 5.10) This is the most dangerous of the malar- ias. The onset is often insidious, with malaise, headache and vomiting. Cough and mild diarrhoea are also common. The fever has no particular pattern.
Jaundice is common as a result of haemolysis and hepatic dysfunction. The liver and spleen enlarge and become tender, and anaemia and thrombocyto- penia develop rapidly. Complications of falciparum malaria are summarised in Box 5.19. Previous splenectomy increases the risk of severe malaria.
P. vivax and P. ovale infection: In many cases the illness starts with several days of continued fever before the development of classical bouts of fever on alternate days. Fever starts with a rigor. The patient feels cold, and the temperature rises to around 40°C. After half an hour to an hour, the hot or flush phase begins. It lasts several hours and gives way to profuse perspiration and a gradual fall in temperature. The cycle is repeated 48 hours later. Gradually the spleen and liver enlarge and may become tender.
Anaemia develops slowly. Relapses are frequent in the first 2 years after leaving the malarious area.
P. malariae and P. knowlesi infection: This is usually associated with mild symptoms and bouts of fever every third day. Parasitaemia may persist for many years with the occasional recrudescence of fever, or without produc- ing any symptoms. P. malariae causes glomerulonephritis and the nephrotic syndrome in children. P knowlesi is usually mild but can deteriorate rapidly.
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Investigations
Giemsa- stained thick and thin blood films should be examined. In the thick film erythrocytes are lysed, releasing all blood stages of the para- site. This facilitates the diagnosis of low- level parasitaemias. A thin film is essential to confirm the diagnosis, species and, in P. falciparum infec- tions, to quantify the parasite load (by counting the percentage of infected erythrocytes).
Immunochromatographic ‘dipstick’ tests for P. falciparum antigens are now marketed and provide a useful nonmicroscopic means of diagnos- ing this infection. They should be used alongside blood film examination, and are especially useful when the microscopist is less experienced. PCR remains largely a research tool.
Management
Mild P. falciparum malaria: P. falciparum is now resistant to chloroquine and sulfadoxine- pyrimethamine almost worldwide, so an artemisinin- based treatment is recommended. Co- artemether (artemether and lumefantrine) is
5.19 Severe manifestations of P. falciparum malaria and their management
Cerebral malaria Coma Convulsions
Maintain airway, exclude other causes, ventilate if necessary
Diazepam or paraldehyde
Hyperpyrexia Tepid sponging, fan, paracetamol
Hypoglycaemia Monitor blood glucose, IV dextrose
infusion Severe anaemia (PCV <15%) Transfusion
Acute pulmonary oedema Nurse at 45°, venesect, limit IV fluids, diuretics, CPAP, haemofilter
Acute renal failure Exclude other causes, dialysis (peritoneal or haemodialysis)
Bleeding/coagulopathy Transfuse screened fresh blood, or FFP, cryoprecipitate
Metabolic acidosis Fluids, oxygen, treat sepsis and hypo- glycaemia
Shock (‘algid malaria’) Suspect Gram- negative septicaemia, IV antimicrobials, fluid resuscitation Aspiration pneumonia IV antimicrobials, oxygen, physiotherapy Hyperparasitaemia Partial or full exchange transfusion,
haemapheresis
(From WHO. Severe falciparum malaria. In: Severe and complicated malaria. 3rd ed.
Trans R Soc Trop Med Hyg 2000; 94 (suppl. 1): S1– 41.)
given at a dose of four tablets at 0, 8, 24, 36, 48 and 60 hours. Alternatives are quinine (600 mg quinine salt three times daily for 5–7 days), followed by doxycycline or clindamycin. Doxycycline should be avoided in pregnancy, and artemether in early pregnancy. The WHO recommends artemisinin- based combination therapy, but artemisinin resistance is appearing in South- East Asia.
Complicated P. falciparum malaria: Severe malaria (parasite count
>2% in any nonimmune patient) is a medical emergency. Immediate man- agement should include IV artesunate (2.4 mg/kg IV at 0, 12 and 24 hours, then daily for 7 days). When the patient has recovered sufficiently, oral arte- sunate 2 mg/kg once daily is given instead of infusions to a total cumulative dose of 17 to 18 mg/kg. IV quinine salt is an alternative, with ECG monitor- ing. Management of the complications of severe P. falciparum infection is summarised in Box 5.19.
Non- falciparum malaria: P. vivax, P. ovale, P. knowlesi and P. malariae infections should be treated with oral chloroquine (600 mg chloroquine base, followed at 6 hours by 300 mg, then 150 mg twice daily for two more days). Relapses can be prevented by taking one of the antimalarial drugs in suppressive doses. Radical cure is achieved in P. vivax and P. ovale using primaquine, which destroys the hypnozoite phase in the liver, after check- ing glucose- 6- phosphate dehydrogenase (G6PD) status. Haemolysis may develop in those who are G6PD- deficient. Cyanosis as a result of the forma- tion of methaemoglobin in the red cells is more common, but not dangerous.
Prevention
Clinical attacks of malaria may be preventable with chemoprophylaxis using chloroquine, atovaquone plus proguanil (Malarone), doxycycline or meflo- quine. The risk of malaria in the area to be visited and the degree of chlo- roquine resistance guide the recommendations for prophylaxis. Updated recommendations are summarised at www.fitfortravel.nhs.uk. Many agents must be taken in advance of travel and continued after return. Mefloquine is useful in areas of multiple drug resistance, but contraindications exist. Use of insecticide- treated bed nets, insect repellents and protective clothing are also important means of reducing infection. Research to produce a fully- protective malaria vaccine is ongoing.
Babesiosis
This is caused by a tickborne intra- erythrocytic protozoon parasite. Patients present with fever 1 to 4 weeks after a tick bite. Severe illness is seen in splenectomised patients. The diagnosis is made by blood film examination.
Treatment is with quinine and clindamycin.
African trypanosomiasis (sleeping sickness)
African sleeping sickness is caused by trypanosomes conveyed to humans by the bites of infected tsetse flies and is unique to sub- Saharan Africa. The disease has declined by 60% since 1990 because of improved control. Try- panosoma brucei gambiense has a wide distribution in West and Central Africa and accounts for 90% of cases. T. brucei rhodesiense is found in parts of East and Central Africa and, unlike gambiense, has a large reservoir in wild animals. Transmission is common at riversides and in wooded grasslands.
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Clinical features
A tsetse fly bite is painful and commonly becomes inflamed; if trypano- somes are introduced, the site may again become painful and swollen around 10 days later (‘trypanosomal chancre’), associated with regional lymphadenopathy. Within 2 to 3 weeks of infection the trypanosomes invade the blood stream. The early haematolymphatic stage gives way to a late encephalitic stage.
Rhodesiense infections: Acute and severe. Within days or a few weeks the patient is usually severely ill and may have developed pleural effusions and signs of myocarditis or hepatitis. There may be a pete- chial rash. The patient may die before there are signs of involvement of the CNS. If the illness is less acute, drowsiness, tremors and coma develop.
Gambiense infection: Slow course, with irregular bouts of fever and firm, discrete, rubbery and painless lymphadenopathy, particularly in the posterior triangle of the neck. The spleen and liver may become palpable.
After some months without treatment, the CNS is invaded. Patients develop headache, altered behaviour, cognitive impairment, insomnia by night and sleepiness by day, delirium and eventually tremors, pareses, wasting, coma and death.
Investigations
• Thick and thin malaria blood films will reveal trypanosomes. • Lymph node aspirate may be more sensitive in gambiense infection. • The card agglutination trypanosomiasis test allows simple serological screening for gambiense. • Lumbar puncture: with CNS involvement, CSF will reveal raised protein, WCC and IgM, and diminished glucose.
Management
Therapeutic options for African trypanosomiasis are limited, as most antitry- panosomal drugs are toxic and expensive. The prognosis is good if treat- ment is begun before CNS involvement. For early gambiense, pentamidine 4 mg/kg IM or IV is given for 7 days. Early rhodesiense is treated with intravenous suramin five injections of 20 mg/kg given weekly. For those with CNS disease, eflornithine and nifurtimox are used for gambiense, and melarsoprol for rhodesiense.
American trypanosomiasis (Chagas’ disease)
Chagas’ disease occurs widely in South and Central America. The cause is Trypanosoma cruzi, transmitted to humans from the faeces of a redu- viid (triatomine) bug, in which the trypanosomes develop before infecting humans. Infected faeces are rubbed in through the conjunctiva, mucosa of the mouth or nose or abrasions of the skin. Blood transfusions are respon- sible for up to 5% of infections, and congenital transmission may also occur.
Clinical features
Acute phase: The acute phase is seen in only 1% to 2% of infected individuals infected before the age of 15 years. Young children (1–5 years of age) are most commonly affected. The entrance of T. cruzi through an abra- sion produces a dusky- red firm swelling and regional lymphadenopathy.
A conjunctival lesion, although less common, is more characteristic; the unilateral firm reddish swelling of the lids may close the eye, and this con- stitutes ‘Romaña’s sign’. In a few patients, an acute generalised infection soon appears, with a transient morbilliform or urticarial rash, fever, lymph- adenopathy and enlargement of the spleen and liver. In a small minority of patients, acute myocarditis and heart failure or neurological features, including personality changes and signs of meningoencephalitis, may be seen. The acute infection may be fatal to infants.
Chronic phase: About 50% to 70% of infected patients become sero- positive and develop an indeterminate form when no parasitaemia is detect- able. They have a normal lifespan with no symptoms, but are a natural reservoir for the disease and maintain the life cycle of parasites. After a latent period of several years, 10% to 30% of chronic cases develop low- grade myocarditis and damage to conducting fibres causing a cardiomyopathy. In nearly 10% of patients, damage to Auerbach’s plexus results in dilatation of various parts of the alimentary canal, especially the colon and oesophagus, so- called ‘mega’ disease. Dilatation of the bile ducts and bronchi are also a recognised sequelae. Reactivation of Chagas’ disease can occur in patients with HIV if the CD4 count falls to less than 200 cells/mm3 (p. 178).
Investigations
• Blood film: T. cruzi is easily detectable in the acute illness. • Chronic disease: xenodiagnosis- infection- free, laboratory- bred reduviid bugs feed on the patient, and the bugs’ faeces are subsequently examined for parasites. • PCR: parasite DNA detection by PCR is highly sensitive in blood or in bug faeces in xenodiagnosis. • Antibody detection is also highly sensitive.
Management
Nifurtimox (10 mg/kg daily for 90 days) and benznidazole (5 mg/kg daily for 60 days), both given as divided daily doses, are parasiticidal drugs. Either can be used in the acute and early chronic phase. Adverse reactions are frequent (30%–55%), but cure rates of up to 80% result. Surgery may be required for ‘mega’ disease. Prevention involves destruction of the bugs with insecticides and screening of blood donors.
Toxoplasmosis
Toxoplasma gondii is an intracellular parasite. The sexual phase of its life cycle occurs in the small intestinal epithelium of the cat. Oöcysts shed in cat faeces survive in moist conditions for weeks or months and spread to intermediate hosts (pigs, sheep and also humans) through contaminated soil. Once ingested, the parasite transforms into rapidly dividing tachyzo- ites. Microscopic tissue cysts develop containing bradyzoites, which persist for the lifetime of the host. Cats become infected or reinfected by ingesting tissue cysts in prey.
Human infection occurs via oöcyst- contaminated soil, salads and veg- etables, or by eating under- cooked meat containing tissue cysts. Sheep, pigs and rabbits are the most common meat sources. Outbreaks have occurred after consumption of unfiltered water. In developed countries, toxoplasmosis is the most common protozoal infection; around 22% of adults in the UK are seropositive.
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A conjunctival lesion, although less common, is more characteristic; the unilateral firm reddish swelling of the lids may close the eye, and this con- stitutes ‘Romaña’s sign’. In a few patients, an acute generalised infection soon appears, with a transient morbilliform or urticarial rash, fever, lymph- adenopathy and enlargement of the spleen and liver. In a small minority of patients, acute myocarditis and heart failure or neurological features, including personality changes and signs of meningoencephalitis, may be seen. The acute infection may be fatal to infants.
Chronic phase: About 50% to 70% of infected patients become sero- positive and develop an indeterminate form when no parasitaemia is detect- able. They have a normal lifespan with no symptoms, but are a natural reservoir for the disease and maintain the life cycle of parasites. After a latent period of several years, 10% to 30% of chronic cases develop low- grade myocarditis and damage to conducting fibres causing a cardiomyopathy. In nearly 10% of patients, damage to Auerbach’s plexus results in dilatation of various parts of the alimentary canal, especially the colon and oesophagus, so- called ‘mega’ disease. Dilatation of the bile ducts and bronchi are also a recognised sequelae. Reactivation of Chagas’ disease can occur in patients with HIV if the CD4 count falls to less than 200 cells/mm3 (p. 178).
Investigations
• Blood film: T. cruzi is easily detectable in the acute illness. • Chronic disease: xenodiagnosis- infection- free, laboratory- bred reduviid bugs feed on the patient, and the bugs’ faeces are subsequently examined for parasites. • PCR: parasite DNA detection by PCR is highly sensitive in blood or in bug faeces in xenodiagnosis. • Antibody detection is also highly sensitive.
Management
Nifurtimox (10 mg/kg daily for 90 days) and benznidazole (5 mg/kg daily for 60 days), both given as divided daily doses, are parasiticidal drugs. Either can be used in the acute and early chronic phase. Adverse reactions are frequent (30%–55%), but cure rates of up to 80% result. Surgery may be required for ‘mega’ disease. Prevention involves destruction of the bugs with insecticides and screening of blood donors.
Toxoplasmosis
Toxoplasma gondii is an intracellular parasite. The sexual phase of its life cycle occurs in the small intestinal epithelium of the cat. Oöcysts shed in cat faeces survive in moist conditions for weeks or months and spread to intermediate hosts (pigs, sheep and also humans) through contaminated soil. Once ingested, the parasite transforms into rapidly dividing tachyzo- ites. Microscopic tissue cysts develop containing bradyzoites, which persist for the lifetime of the host. Cats become infected or reinfected by ingesting tissue cysts in prey.
Human infection occurs via oöcyst- contaminated soil, salads and veg- etables, or by eating under- cooked meat containing tissue cysts. Sheep, pigs and rabbits are the most common meat sources. Outbreaks have occurred after consumption of unfiltered water. In developed countries, toxoplasmosis is the most common protozoal infection; around 22% of adults in the UK are seropositive.
Clinical features
In most immunocompetent individuals, including children and pregnant women, the infection goes unnoticed. In around 10% of patients it causes a self- limiting illness, most common in adults aged 25 to 35 years. The presenting feature is usually painless lymphadenopathy. Systemic symp- toms, which are ‘flu- like’, are infrequent. Complete resolution usually occurs within a few months, although symptoms and lymphadenopathy tend to fluctuate unpredictably, and some patients do not recover com- pletely for a year or more. Encephalitis, myocarditis, polymyositis, pneu- monitis or hepatitis occasionally occur in immunocompetent patients, but are more common in the immunocompromised. Toxoplasmosis acquired in utero by vertical spread can also cause retinochoroiditis, hydrocephalus and microcephaly.
Investigations
The Sabin–Feldman indirect fluorescent antibody test is used in immuno- competent patients. A fourfold rise in IgG or the presence of IgM indicates acute infection. The presence of high- avidity IgG excludes infection in the past 3 to 4 months, which is important in pregnancy. In immunocompro- mised patients, Toxoplasma organisms can be detected histochemically in a lymph node biopsy or other tissue with T. gondii antiserum, or by using PCR to detect Toxoplasma- specific DNA.
Management
Because the disease is usually self- limiting, treatment is reserved for rare cases of severe or progressive disease, and for infection in immunocom- promised patients. T. gondii infection responds poorly to antimicrobial ther- apy, but pyrimethamine, sulfadiazine and folinic acid may be used.
Leishmaniasis
Leishmaniasis is caused by unicellular flagellate intracellular protozoa belonging to the genus Leishmania. It comprises three broad groups of disorder:
• Visceral leishmaniasis (VL, kala- azar). • Cutaneous leishmaniasis (CL).
• Mucosal leishmaniasis (ML).
Although most clinical syndromes are caused by zoonotic transmission of parasites from animals (chiefly canine and rodent reservoirs) to humans through phlebotomine sandfly vectors, humans are the only known res- ervoir (anthroponotic person- to- person transmission) in major VL foci in the Indian subcontinent and injection drug users. Leishmaniasis occurs in around 100 countries, with an estimated annual incidence of 0.9 to 1.3 mil- lion new cases (25% VL).
Life cycle
Flagellar promastigotes (10–20 μm) are introduced by the feeding female sandfly (Phlebotomus in the eastern hemisphere, Lutzomyia and Psy- chodopygus in the western hemisphere). The promastigotes are taken up by neutrophils, which undergo apoptosis and are engulfed by macrophages in which the parasites transform into amastigotes (2–4 μm, Leishman- Donovan bodies). These multiply, causing macrophage lysis and infection of other cells. Sandflies pick up amastigotes when feeding on infected