African Trypanosomiasis in a British Soldier

By Croft, Ashley M Kitson, Martin M; Jackson, Christopher J; Minton, Elizabeth J; Friend, Howard M

Background: Sleeping sickness (human African trypanosomiasis) is a parasitic infection transmitted by day-biting tsetse flies. The diagnostic standard is microscopy of blood, lymph node aspirates, or cerebrospinal fluid. The disease is invariably fatal if not treated. There are >300,000 new cases of sleeping sickness each year and ~100,000 deaths. Case Presentation: We describe a British soldier who acquired sleeping sickness in Malawi. He gave no history of a painful insect bite but presented with classic early signs of sleeping sickness (a primary chancre, regional lymphadenopathy, circinate erythema, and a cyclical fever pattern). His condition worsened in the next week, and trypanosomes were observed in a blood sample. The patient was aeromedically evacuated to Johannesburg, where stage 1 Trypanosoma brucei rhodesiense infection was confirmed; he also had renal and liver failure, pancytopenia, and heart block. He was treated with intravenously administered suramin, and he recovered fully over the next 5 months. Recommendations: Medical officers deploying to eastern and southeastern Africa must be familiar with the common presenting signs and symptoms of T. b. rhodesiense sleeping sickness and should have 24-hour access to a reliable, local, clinical microscopy service. Confirmed sleeping sickness requires immediate transfer to a tertiary diagnostic and treatment center, where suramin (for T. b. rhodesiense infection), pentamidine (for Trypanosoma brucei gambiense infection), and melarsoprol (for stage 2 disease) must be immediately available. Introduction

Epidemiology of Sleeping Sickness

Human African trypanosomiasis, or sleeping sickness, affects one- half of Africa’s continental land mass. The disease is considered to have had a greater negative impact on the economic development of central Africa than any other.1 There are >300,000 new cases of sleeping sickness each year and -100,000 deaths.2- 3 Since 1990, the rate of infection has risen tenfold.4

Sleeping sickness is confined to the equatorial region and occurs in a patchy distribution throughout central and southeastern Africa, including Malawi.5 During a 3-year period of national surveillance (November 1986 to September 1989), 33 cases of sleeping sickness were recorded from the Kasungu National Park.6 The greatest risk of acquiring sleeping sickness in Malawi is during the dry season, which in most years runs from May to October.5

Sleeping sickness is transmitted by tsetse flies of the genus Glossma and is caused by two different parasite subspecies, that is, Trypanosoma brucei rhodesiense, which causes acute sleeping sickness, and Trypanosoma brucei gambiense, which causes a more- chronic disease presentation.7 Key differences between the two forms of the disease are summarized in Table I. Game animals and cattle are the natural reservoirs of T. b. rhodesiense, and humans, domestic pigs, and some wild mammals are the natural reservoirs of T. b. gambiense.8

The survival of Trypanosoma brucei in mammalian hosts derives from its ability to very readily alter its antigenic profile.9 The bloodstream forms of T. brucei are covered with a dense coat of highly immunogenic glycoproteins, which stimulate the production of specific antibodies, mainly of the IgM subclass.10 Approximately 2% of each new T. brucei generation expresses a different surface glycoprotein, thus stimulating the production of a new IgM population; this process enables the parasite to elude the host immune response. ‘ ‘ Over time, trypanosomes are able to penetrate the central nervous system (CNS), probably through damage to and breakdown of the choroid plexus.” Death is most commonly attributable to neurological involvement, leading to neglect, malnutrition, infection, and eventual coma.7- 11

Clinical Presentation

The early symptoms of sleeping sickness can be nonspecific, and it is essential for medical officers in disease-endemic areas to consider trypanosomiasis in the differential diagnosis of any patient with a febrile illness.12 Tsetse bites can be quite painful, and they often leave a small, self-healing mark.13 Wien trypanosomal infection follows a tsetse bite, a more-pronounced, longerlasting, local reaction occurs, with injected trypanosomes multiplying at the bite site.

A small red papule develops after ~5 days, expanding over the next 7 to 10 days to a hard, painful, round, pruritic nodule, the “erythematous pseudo-furuncle” (up to 3 cm in diameter).13 At this stage, the lesion usually is warm, painful, and somewhat tender (although it is painless in some cases) and typically is surrounded by an intense erythematous tissue reaction, with local edema; the whole complex is called a primary chancre, or trypanosomal chancre.2 The chancre usually persists for ~3 weeks and then subsides spontaneously, to be replaced by a hyperpigmented, painless, nontender eschar (Fig. I).7 During this time, lymph nodes in the region of the bite may become enlarged as drainage from the bite site occurs.2

Ten days after the initial bite, trypanosomes enter and multiply in the bloodstream, causing a fever characterized by cyclical bouts of pyrexia.7 In pale-skinned patients, each bout often coincides with the appearance of large areas of transient circinate erythema, that is, a fleeting, blotchy, sharply circumscribed rash with roughly circular margins.7 The fever of sleepIng sickness Is often Intense and tends to be highest In the evening.12 It lasts a maximum of 1 week and may be accompanied by headache and general malaise.13 Egress of trypanosomes into Interstitial spaces, where multiplication also takes place, is thought to be facilitated by Increased vascular permeability.14

In T. b. rhodesiense infection, the disease may then progress rapidly to produce pleural effusion, splenomegaly, anemia, hepatitis, tlbial periostitis, iridocyclitis, myocarditis, and, in heavy infections, death resulting from acute meningoencephalitis.15 In hospital-based case series, one-third of treated patients were found to have abnormal electrocardiograms.16

In T. b. gambiense trypanosomiasis, the disease may first present as a mild cyclical fever, with lymphadenopathy and splenomegaly; the CNS becomes involved 6 to 12 months later, with headache, personality and mood changes, parkinsonism, sleep inversion, and finally global brain dysfunction and death.15

Diagnosis and Treatment

The diagnostic standard for trypanosomiasis is detection of trypanosomes in blood, lymph node aspirates, or cerebrospinal fluid (CSF).7- 15 In early presentations of T. b. rhodesiense, parasites are often easily seen in thin, thick, or wet blood films (Fig. II); microscopy-positive cases are classified as stage 1, or hemolymphatic trypanosomiasis.17 Lumbar puncture should always be offered in stage 1 sleeping sickness to determine whether the CNS has been invaded; if results are positive, then the disease is classified as stage 2 infection. When CNS invasion has occurred, the CSF reveals lymphocytic pleocytosis and an increased protein content; trypanosomes may be found in stained films of the centrifuge deposit.18

In T. b. gambiense infection, parasites may be scanty and not easily detected through microscopy. A presumptive diagnosis of T. b. gambiense disease can often be made in the field through the trypanosomiasis card agglutination test; however, this serological test is ineffective for diagnosing T. b. rhodesiense infection.19

T. b. rhodesiense and T. b. gambiense pathogens are morphologically identical, although it is usually possible to infer the infecting subspecies from the geographic history (Table I). When clinical doubt exists regarding the trypanosome subspecies, this can be resolved through a variety of laboratory techniques, including protein electrophoresis and immunoglobulin subclass determination, and through modern molecular methods such as polymerase chain reaction amplification.20- 21

Sleeping sickness is invariably fatal if not treated.15 Treatment of stage 1 disease is with intravenously administered suramin for T. b. rhodesiense and pentamidine for T. b. gombiense; stage 2 cases of both infecting subspecies are treated with melarsoprol.3 Eflornithine is effective against stage 2 T. b. gombiense infection but not against stage 2 T. b. rhodesiense disease.3 Because there is a risk for anaphylactic shock from suramin, current recommendations are to start treatment with a test dose, followed by five injections of 20 mg/kg (with a maximum of 1 g per injection), administered at intervals of 5 to 7 days.22 With adequate treatment, most extraneural disease is cured. In the presence of CNS infection, cure rates are >80%.” We present a case of sleeping sickness that occurred in a British soldier in Malawi, in late 2005.

Case Presentation

Disease Acquisition

A 26-year-old British enlisted soldier deployed to Malawi in the fall of 2005 as an instructor attached to a 6-week, overseas, training program run from the Infantry Battle School, Wales. He was of Scottish origin and was normally stationed at the Infantry Training College in Catterick, North Yorkshire. He was Caucasian and male, with no significant medical history. He was taking mefloquine (250 mg) weekly, as malaria chemoprophylaxis, but no other drugs. Immediately before deployment, he treated his uniform with permethrin (Peripel 10; Bayer Environmental Science, Hertsfordshire, United Kingdom), under collective arrangements at the Infantry Battle School. He had never previously visited Africa. A total of 273 British troops flew to Lilongwe, the capital of Malawi, to take part in the training exercise. From Lilongwe, they deployed by road to the exercise location in the Kasungu National Park, close to the Zambian border. The soldier arrived in the game park on September 28, 2005.

Once in the exercise area, which was a dry savanna location within the national park, the patient lived in a two-man canvas tent, which was shared with a colleague. The patient took his morning and evening meals at a central safari lodge, overlooking a small lake frequented by game animals. In keeping with British military policy, he used a mosquito net at night and applied Army- issue N,JV-diethyl-m-toluamide (slow-release, polymerbased, cream formulation with 32% active ingredient) as an insect repellent.23

Presenting Symptoms and Initial Findings

On November 14, 2005, the patient reported to the exercise medical officer. He gave a 24-hour history of insomnia, lethargy, and vomiting. On examination, he was found to have an inflamed lump on the upper medial aspect of his right thigh, a palpable lymph node in his right groin, and a blotchy rash over his right leg. He had pyrexia of 38.50C. A malaria reagent strip test (immunochromatograpnic test) proved negative.

The patient’s lump was diagnosed as an insect or arthropod bite with secondary bacterial infection, although the patient could not recall a specific bite at that site. The patient was prescribed a 1- week course of flucloxacillin (250 mg, four times per day) and was instructed to move his shared tent closer to the medical aid post, for observation.

Over the next 5 days, the patient’s condition worsened. He remained lucid but continued to vomit regularly. He had resting tachycardia of 96 beats per minute, and his temperature fluctuated between 38.O0C and 39.30C. He was treated conservatively with orally administered fluids, which he vomited up, and with analgesic agents (ibuprofen and cocodamol).

On November 19, 2005, the training program ended and the patient moved, with his instructor colleagues, to a beach hotel on Lake Malawi before flying back to the United Kingdom from Lilongwe the following day. The patient was profoundly ill by that time, and he collapsed in his hotel room, with a high fever and rigors. He was given emergency first aid (cooling in a bath) by a colleague and was then driven to the British High Commission clinic in Lilongwe, where he was seen immediately that day (a Sunday).

Investigations and Clinical Progress

On examination in Lilongwe, the patient was fully conscious and alert but looked ill, jaundiced, and dehydrated. His hemoglobin level was 14.7 g/dL, and he had a normal white blood cell count (11.3 x 10″ cells per L), with a lowplatelet count (35 x 109 cells per L). A malaria reagent strip test was again negative. Blood was drawn into a centrifugation tube containing acridine orange dye and was centrifuged for 5 minutes; actively moving parasites were then clearly visible in the supernatant, with lowpower microscopy. A wet blood film was prepared and stained with Field’s stain A and B, and the motile parasites were identified morphologically as trypanosomes.

The patient was diagnosed as having sleeping sickness. A normal saline infusion was started, and the patient was aeromedically evacuated that evening to a Johannesburg hospital. In Johannesburg, the patient was found to have renal failure, deranged liver function and pancytopenia, and profound thrombocytopenia (16 x 109 cells per L). Repeat blood film staining and examination confirmed the presence of trypanosomes. From the patient’s geographic and clinical history, it was inferred that these were A. b. rhodestense subspecies.

The patient was treated with a standard course of intravenously administered suramin on days 1 (test dose), 4,7,10, and 14. He did not undergo lumbar puncture at the time of hospitalization, because of his low platelet count, and he went on to develop cardiac complications, including second-degree heart block. All of these abnormalities resolved during his course of suramin treatment.

On day 8, the patient underwent lumbar puncture and CSF cell count and examination, which proved normal (total white blood cell count, 1 cell per juL; polymorphonuclear cell count, O cells per / tL; mononuclear cell count, 1 cell per fiL; red blood cell count, 1 cell per ie). There was no evidence of neurological involvement; therefore, the patient was treated as having stage 1 hemolymphatic trypanosomiasis.

The patient’s clinical condition improved rapidly, and he was repatriated by air to the United Kingdom on December 7, 2005. He received his final suramin injection as an outpatient in a British tertiary care center, and his repeat blood tests were all normal.

The patient remained fatigued for some weeks following his Illness and did not regain his former body weight until 2 months after his return to the United Kingdom. He underwent his last specialist review on April 4,2006, at which time he was entirely well. He declined follow-up lumbar puncture and was discharged from further treatment or investigations.

Discussion

This was the first case of African trypanosomiasls to occur in the British Army In living memory. There exists one previously published report of sleeping sickness (stage 2 disease) in French Army parachutists in Rwanda,24 and this Is the second published military report of which we are aware.

This case shows that tsetse files may not be repelled by pyrethroid Impregnation of clothing or by the application of polymerbased JV.N-diethyl-m-toluamide to exposed skin. Our patient was bitten through his uniform (Fig. 1), although it had been treated with permethrin just a few weeks previously. Although tsetse bites are described In the literature as being painful, our patient could not recall having ever received a painful insect bite at or near the site of his primary chancre.

There is no immediate prospect of vaccine control of sleeping sickness, because of the parasite’s ability to elude the host’s Immune system through antigenic variability.9 Chemoprophylaxis is not recommended because of the high human toxlcity of the drugs that are known to be active against African trypanosomes.14

There is a theoretical risk that patients with stage 2 trypanosomiasls who have undergone successful treatment may experience relapse at a later date. Consequently, 2- or 3-year follow-up monitoring of treated stage 2 cases is recommended, with lumbar puncture at 6-month intervals.11,25

In the case of our patient, the likelihood of relapse was considered to be negligible. There was adequate evidence, both clinically and from the lumbar puncture performed in Johannesburg, that the patient’s CNS had not been invaded at any time. The dosage of suramin was adequate and was fully delivered. The patient was advised that any symptoms of malaise or fever in the future should prompt him to seek full clinical and laboratory reassessment, including lumbar puncture.

Suramin is a drug for which the demand in nonordiseaseendemic areas is likely to remain low. It is manufactured by Bayer AG (Wuppertal, Germany) under the trade name Germanin and is available in vials containing 1 g of off-white powder.

There have been well-documented difficulties in procuring suramin for patients diagnosed in the United Kingdom as having stage 1 T. b. rhodesiense sleeping sickness.16 These difficulties need to be addressed before any planned military deployment to eastern or southeastern Africa (that is, through preemptive acquisition and stockpiling of adequate supplies of suramin) and not after cases of sleeping sickness have presented to medical personnel.

Conclusions

In most rural areas of eastern and southeastern Africa, T. b. rhodesiense presents a low-level, daytime, occupational health risk to soldiers engaged in military operations or training. cases are likely to occur sporadically and Infrequently. In Malawi, the period of greatest risk for T. b. rhodestense disease Is during the dry season.

T. b. gambtense has greater epidemic potential than T. b. rhodestense Infection and is a daytime disease threat to troops operating along river and lake margins in western and northcentral Africa. The threat can be mitigated by siting camps appropriately and avoiding endemic foci during daylight hours.

Medical personnel deploying to eastern and southeastern Africa in support of military operations or exercises must be familiar with the common presenting signs and symptoms of T. b. rhodestense sleeping sickness. In view of the lethality of the disease, deployed medical officers should be trained microscopists or have 24-hour access, 7 days per week, to a reliable local microscopy service. Confirmed sleeping sickness requires Immediate transfer to a tertiary diagnostic and treatment center. Suramln (for T. b. rhodesfense infection) or pentamidlne (for T. b. gombfense disease) must be Immediately available at that tertiary care center. Melarsoprol must also be Immediately available, for any presentation of stage 2 disease.

Acknowledgments

We thank the patient for giving us permission to publish details of this case, Prof. Malcolm Molyneux (University of Malawi, Blantyre) for helpful clinical advice, and Lance Nkana (U.S. Embassy Clinic, Lilongwe) for permission to use the clinical photograph reproduced In Figure 2.

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Guarantor; Lt Col Ashley M. Croft, RAMC

Contributors: Lt Col Ashley M. Croft, RAMC*; Martin M. Kitson, MDf; Col Christopher J. Jackson, RAMCf; Elizabeth J. Minton, PhDf; Howard M. Friend, MD[section]

*Headquarters Fifth Division, Shrewsbury, United Kingdom.

fVimy Barracks Medical Centre, Catterick, United Kingdom.

^Infectious Diseases Department, St. James’s University Hospital, Leeds, United Kingdom.

[section]British High Commission Clinic, Lilongwe, Malawi.

This manuscript was received for review in July 2006. The revised manuscript was accepted for publication In January 2007.

Reprint & Copyright (c) by Association of Military Surgeons of U.S., 2007.

Copyright Association of Military Surgeons of the United States Jul 2007

(c) 2007 Military Medicine. Provided by ProQuest Information and Learning. All rights Reserved.