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Case of the Month

May 2018

Dr Evan Shoul, Prof Lucille Blumberg, Prof John Frean

Case presentation
A 52 year old man was flown to a Johannesburg hospital from Zambia on 10 January 2018. He had been on holiday in the South Luangwa National Park, having arrived there 2 weeks prior to his transfer to South Africa.

Presenting history:
6 January 2018:
He developed frontal headaches and reduced appetite in the evening.

7 January
By the next morning, his headaches had worsened. He now complained of fever, rigors and backache. He had lost his appetite but had no nausea, vomiting or diarrhoea.

8 January
He developed diarrhoea which was watery with no blood. His right foot became swollen and purple. A local doctor assessed this as cellulitis and prescribed flucloxacillin. A rapid malaria test was negative according to the patient.

9 January
He now noted jaundice with dark urine. The doctor was again consulted, tested his urine and noted ‘bilirubin in the urine’. The patient had generalised myalgia, worsening headaches and further episodes of diarrhoea. A repeat rapid malaria test was negative.

10 January
His headaches continued to worsen along with persistent fever. Myalgias worsened, especially involving his lower back. He also noted bilateral knee pain. He was then transferred via medical evacuation to South Africa.

Systemic enquiry:
Central nervous system – headaches, no neck-stiffness, paraesthesiae over right knee and photophobia noted on day of transfer

Eyes – vision normal, no conjunctivitis noted.

Ear, nose, throat – recent sore throat one week before. No cervical nodes noted. No other ENT issues.

Chest – no cough, mild shortness of breath on moderate exertion. No chest pain.

Abdomen – no nausea/vomiting. No abdominal pain/cramps. Diarrhoea as noted. Appetite reduced since onset of symptoms.

Genito-urinary – no dysuria/no haematuria. Dark urine for 3–4 days despite adequate oral fluid intake.

Musculo-skeletal - bilateral knee and right foot pain 3 days prior to presentation.

Skin - macular rash noted over abdomen over preceding few days.

Background history:
Allergies: nil
Surgical history: nil
Medical history: hypercholesterolaemia – on atorvastatin 20mg daily x 25 years
Also, on sertraline 100mg daily.
No diabetes mellitus/hypertension/epilepsy/asthma.
Social: lives with his wife and 4 children in Melbourne, Australia. Works as managing director of a safety equipment company. Smokes <5 cigarettes a day and drinks at least 4 units of alcohol per day.

Travel history: current trip – family holiday in Zambia, visiting national parks. Staying in upmarket lodges, drinking bottled water, eating prepared food. Reports being bitten by many mosquitoes, flies, “other bugs”. He also travels annually to rural China for business.

Clinical examination:
On admission, awake and alert but acutely ill, uncomfortable and agitated.
Vital signs: heart rate – 120 beats/min, BP 100/60mmHg, Temp 39.5°C, oxygen saturation 94% on nasal prong oxygen at 2L/min. Weight 100kg.

On general examination, he was markedly jaundiced. No nodes, oedema, pallor, cyanosis or clubbing. He was not clinically dehydrated. He had a fine macular rash over his abdomen. He also had numerous small raised erythematous reactions likely secondary to insect bites – mostly over his back, trunk, legs. Chest exam: no distress, resonant, clear
Cardiac exam: pulse regular, good volume. Normal cardiac auscultation.
Abdomen: no distension, soft, non-tender. No organomegaly.
Neuro: GCS 15/15, no focal deficit.

Figure 1: Lesions from bites noted on lower limbs.

Preliminary investigations:
Admission: 10 January 2018

White cell count 3.28 x 109 cells/L
Haemoglobin 12.9 g/dL
Platelets 78 x 109/L

Malaria thick and thin smear – negative
Malaria common antigen – negative
Malaria falciparum antigen – negative

Sodium 132 mmol/L
Potassium 3.0 mmol/L
Urea 7.6 mmol/L
Creatinine 201 µmol/L

Bilirubin (total) 138 µmol/L
Bilirubin (conjugated) 97 µmol/L
Alkaline phosphatase 355 U/L
Gamma GT 436 U/L
ALT 270 U/L
AST 457 U/L
C-reactive protein 376 mg/dL
International normalised ratio 1.3

Question 1: What is the differential diagnosis of fever and thrombocytopenia in a returning traveller?

Answer to Q1

Infectious:
Viral:EBV, CMV, HIV
Bacterial:Ehrlichiosis; anaplasmosis; Babesiosis; miliary TB, brucellosis, relapsing fever, leptospirosis, rickettsial infections, Salmonella spp.
Parasitic:malaria, visceral leishmaniasis, trypanosomiasis
Fungal:histoplasmosis

Non-infectious:
Malignant:haematological – lymphoma/leukemia, multiple myeloma - myeloproliferative disorders
Miscellaneous:drugs, cirrhosis
Rheumatic/inflammatory:Haemophagocytic lymphohistiocytosis, Gaucher disease

Clinical course
The patient underwent further testing. This included: viral hepatitis A/B/C screen, blood cultures, urine mc&s, urine protein/creatinine ratio, leptospira serology, rickettsial serology, peripheral blood smear.

A diagnostic result was received:

Figure 2: Thick smear of peripheral blood

Figure 3: Thin smear of peripheral blood

Question 2: What is the diagnosis?

Answer to Q2
A: East African trypanosomiasis

There are 2 forms of trypanosomiasis: a slow, progressive form endemic to western and central Africa caused by Trypanosoma brucei gambiense (West African trypanosomiasis, WAT) and a more rapidly progressive form caused by Trypanosoma brucei rhodesiense found in eastern and southern Africa (East African trypanosomiasis, EAT).

This patient’s clinical picture, particularly the characteristic chancre, his geographical exposure, together with the findings on peripheral smear, are consistent with East African trypanosomiasis.

Question 3: How is this infection transmitted?

Answer to Q3

The vector for transmission is the tsetse fly.

The lifecycle of T.brucei starts with the tsetse fly biting an infected animal – eg. cattle in EAT or humans in WAT. The bloodmeal includes trypanosomes. The parasites undergo structural and physiological changes as they traverse the fly’s midgut. Consequently, highly infective forms of the parasite reach the salivary glands. Once the tsetse fly bites the human host, the parasite enters and spreads throughout the blood stream leading to systemic disease.

Tsetse flies have a few characteristic features. Their wings lie scissor-like across the back when in the resting position. They also extend past the abdomen. Wings have a disctinctive hatchet-shaped discal cell. Tsetse flies are found in a variety of environments in Africa – including savannah, riverine and forest habitats.

Tsetse flies are day-biters. They are attracted to dark colours such as black or blue and are known to chase moving targets.

Question 4: What are the clinical features and the different clinical stages of trypanosomiasis?

Answer to Q4

The presentation of EAT is usually acute with progression to the second stage of the infection within a few weeks. WAT has a more chronic course with an estimated mean duration of 3 years. Travellers present following an incubation period of <3 weeks for EAT and <1 month for WAT.

Chancre At the site of the tsetse fly bite, a dermal reaction develops, usually a few centimetres in diameter. This is known as a chancre. It occurs within 2-3 days of the bite in up to a quarter of patients. It mostly occurs in EAT and is only rarely noted in cases of WAT.

Clinical Stages The infection typically goes through 2 stages. Firstly, a haemolymphatic stage followed by a meningo-encephalitic stage as trypanosomes penetrate the CNS via the blood-brain barrier.

The first stage of WAT presents with episodes of fever, separated by periods of days or months. Other symptoms include headaches and lymphadenopathy which is most commonly in the posterior triangle though can be generalised. Hepatosplenomegaly may also be noted clinically. Liver involvement with jaundice is more frequently seen in EAT. Cardiac involvement may manifest as a perimyocarditis. A non-pruritic, erythematous macular rash is seen in a third of patients with EAT. Gastro-intestinal symptoms are more common in EAT. Severe complications such as multi-organ failure, disseminated intravascular coagulopathy, renal failure and coma may also occur, particularly with EAT.

Second-stage disease is characterised by neuropsychiatric complaints accompanying first-stage clinical findings. Fever is less common in this stage. Sleep disorders including inverted sleep cycles with daytime somnolence and nocturnal insomnia are characteristic. A variety of neurological manifestations may also be noted, including tremors, focal movement disorders, motor weakness, speech disorders and ataxia. Psychiatric issues are frequently noted. These include emotional lability, confusion, apathy, aggressive behaviour and mania.

Question 5: How is the infection diagnosed?

Answer to Q5

Trypanosomiasis is diagnosed by identifying the parasite with microscopic examination of thick or thin smears of peripheral blood. In EAT, the level of parasitemia is usually high. In WAT, parasitemia is cyclical in nature and therefore more uncommon. Parasites may be identified in peripheral blood or on lymph node aspirate. In some cases, concentration methods may be required to identify trypanosomes.

Assessment of second stage disease warrants a lumbar puncture and examination of cerebrospinal fluid (CSF). More than 5 white blood cells/μL or the detection of trypanosomes is considered second stage disease. Characteristic white blood cells, called morula cells, may be noted on CSF.

Serology-based testing is only available for T.brucei gambiense and relies on detecting specific antibodies. It is known as the card agglutination for trypanosomiasis (CATT) and has been used mainly in the screening of at-risk populations for mass control of WAT. Rapid diagnostic tests are available for WAT in endemic areas and have been used for passive screening and surveillance. Serological tests are however very unreliable with a positive predictive value less than 5%.

Polymerase chain reaction (PCR) on blood has a sensitivity and specificity of >97% though this diagnostic modality is not easily available in the field and remains a reference tool.

Imaging modalities such as magnetic resonance imaging (MRI) show characteristic findings such as cerebral white matter changes, hyperintensities in the basal ganglia, internal and external capsules and enlarged ventricles.

Question 6: How is trypanosomiasis treated?

Answer to Q6

Treatment options are based on the causative organism and the clinical stage. Drugs used to treat first-stage disease do not treat second-stage disease. Second-stage therapies should not be used for first-stage infections as they cross the blood-brain barrier and hence have greater toxicity and are more difficult to administer

First stage treatment
Pentamidine: this is the first line option for WAT and maintains more than 95% efficacy despite decades of use. It may be administered intra-muscularly for 7 days or as an intravenous infusion. Adverse effects include hypotension, nephrotoxicity and electrolyte disturbances.

Suramin: this agent is used for first-stage EAT. It is given as a slow infusion in a complex regimen spaced over a month. A test dose is required due to the risk of hypersensitivity reactions. Side effects occur frequently and are mostly reversible. Most often, these include nephrotoxicity, peripheral neuropathy and thrombocytopenia.

Second stage treatment
Nifurtimox-eflornithine combination therapy (NECT) is indicated for second-stage WAT. It has higher cure rates (>95%), lower rate of mortality (<1%) and easier administration with fewer side effects than melarsoprol and eflornithine monotherapy. Gastrointestinal side effects with NECT are very common. Neuropsychiatric effects, such as sleep disturbances, irritability and mood changes along with myelosuppression may also be noted.
Melarsoprol is the only therapeutic option for second-stage EAT but may be used as a salvage regimen for WAT. It has significant toxicity, the most important being an encephalopathic syndrome occurring in around 10% of cases and is associated with a high mortality rate. Co-administration of steroids may prevent or alleviate the encephalopathy. Headache, fever and gastrointestinal complications may also be encountered.

Out come of the Case

Patients require regular follow-up for up to 24 months. This includes clinical assessment and laboratory testing of peripheral smears and CSF as parasites may remain viable for prolonged periods and lead to relapses.

Clinical course

The patient received a test dose of suramin which he tolerated well. He then received suramin on day 1, 3, 5, 11, 17, 23 and 30 according to dosing schedules documented in the South African Medicines Formulary. He initially developed a diffuse macular rash and worsening thrombocytopenia which was thought to be from the therapy. Peripheral blood was cleared of parasites after 2 doses of suramin and his CSF examination was clear. His renal and hepatic dysfunction gradually improved and he was discharged to complete the last 2 doses of suramin in Australia.
Melarsoprol is the only therapeutic option for second-stage EAT but may be used as a salvage regimen for WAT. It has significant toxicity, the most important being an encephalopathic syndrome occurring in around 10% of cases and is associated with a high mortality rate. Co-administration of steroids may prevent or alleviate the encephalopathy. Headache, fever and gastrointestinal complications may also be encountered.

References

  • Cunha BA, Lortholary O, Cunha CB. Fever of unknown origin: A clinical approach. Am J Med 2015;128:1138.e1-1138.e15
  • Kennedy PGE. Clinical features, diagnosis, and treatment of human African trypanosomiasis (sleeping sickness). Lancet Neurol 2013;12:186-94.
  • Handbook of Medical Entomology and Vector-borne Diseases. Coetzee M ed. National Institute of Communicable Diseases, Johannesburg, South Africa.
  • Buscher P, Cecchi G, Jamonneau V, Priotto G. Human African trypanosomiasis. Lancet 2017;390:2397-409.
  • Sanford Guide to Antimicrobial Therapy, electronic version of 12 April 2018 (accessed 15 April 2018)

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