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Case of the Month

December 2015

What is the final diagnosis?
K Sinclaire, SASTM

A 36-year-old Dutch female presented with a rash on her left forearm of four days duration. She felt unwell. She and her husband managed a lodge in Nacala, northern Mozambique. Pruritus was a prominent feature of the rash which blistered and showed signs of healing.

There was no travel history. She was a smoker with a 5-10 pack year history, had no allergies or chronic medical conditions and was taking a herbal oral spray for malaria prophylaxis. Her husband mentioned that their pet squirrel had died two weeks previously. Her vaccination status was unknown. There was no history of a tick bite.

She was, at the onset of the rash, seen at a district hospital locally where two rapid malaria antigen tests were both negative. The diagnosis made was that of a bacterial infection; cefaclor and an antihistamine were prescribed.

The day after she went to the clinic she developed severe back and neck pain with headache and diarrhoea. She felt dizzy when standing and developed an arthralgia of her knees. She had episodes of fever for which she took paracetamol. The headache continued to worsen despite the paracetamol.

Question 1: What is the differential diagnosis for this patient with fever, rash, headache and myalgia in remote northern Mozambique?

Answer to Q1
Malaria
Gastroenteritis
Dengue
Chikungunya
Typhoid fever
Epstein-Barr virus
Rickettsiosis
HIV seroconversion
Other systemic illnesses e.g. lupus, leukaemia/ lymphoma

As the patient was working in northern Mozambique, malaria tops the list. There was no evidence of an eschar nor lymphadenopathy, which would make a rickettsial infection unlikely. HIV seroconversion is also unlikely but cannot be excluded entirely.

Question 2: What tests should be done to confirm the diagnosis?
Answer to Q2

Given the rural situation with extremely limited access to laboratory facilities, a malaria antigen rapid test should be the first consideration. This should be repeated after 24 hours if the first test is negative. Consideration needs to be given to the correct administration of the test and whether or not the test covers just P. falciparum.
A full blood count should be requested as this might assist in confirming a diagnosis of malaria if the platelet count is low and an ALT should also be requested if available.

Case continued

A South African doctor at a nearby camp reviewed her. Her vital signs were BP 120/75 mm Hg, heart rate 87 beats per minute, temperature 37.80C. Small red bite marks where noted on her left forearm. She was advised to start treatment with artemether/lumefantrine (Coartem ® ).

The next morning her condition had worsened. She still had a headache, was feeling very weak and had started vomiting. She complained of chest tightness with difficulty in breathing as well as generalised myalgia and arthralgia. She was pyrexial with a temperature of 37.90C. She and her husband decided to travel to Nampula, (approximately 2.5 hours drive) to seek care at a larger medical facility. At the same time, authorisation was received from their insurance company for an air ambulance evacuation to South Africa.

She was evacuated to Johannesburg and admitted to hospital under the care of a physician. On admission, vital signs were normal and physical examination was unremarkable. The rash on her left forearm consisted of two raised erythematous lesions with a flattened centre that was resolving.

Question 3: The patient’s rash initially appeared similar to the one below. Which infectious disease may present with this type of rash?
Answer to Q3
This is the typical erythema migrans rash of Lyme disease

The rash does not always appear as in the image above, and approximately 20 – 30% of patients with Lyme disease do not develop a rash.

Question 4: Now that she is at a facility with access to investigations, what investigations should be requested, and why?
Answer to Q4

Full blood count - This will provide information relating to the white cell count, anaemia and possible thrombocytopenia.

Plasmodium PCR
She is on Coartem and it could be difficult to demonstrate parasitaemia microscopically and confirm the diagnosis of malaria – the PCR under these conditions would be the best way to confirm the diagnosis

ALT, bilirubin
To ensure that, if she does have malaria, she does not have hepatitis

Hepatitis A IgM and IgG
To exclude hepatitis A

Blood cultures
To exclude Salmonella typhi infection

Case continued – the following investigations were performed

She was initially treated with doxycycline and telithromycin . The malaria smear was negative and, as the antigen test for Plasmodium falciparum was positive, the Coartem ® was continued.

Question 5 - What is the aetiology and epidemiology/geographical distribution of Lyme disease?

Answer to Q5

Aetiology
Lyme disease is an infection caused by spirochetes of the Borrelia genus (B. burgdorferi) and is also known as Lyme borreliosis. It is transmitted by the bite of an infected Ixodes tick (such as the black-legged tick, Ixodes scapularis) and is the most common tick-borne infection across the United States and Europe. Squirrels are common hosts of Ixodes ticks. It is more likely that the nymphs will transmit the disease as the tick has to be attached for at least 36 – 48 hours for the organism to penetrate the skin. The adult tick is usually discovered quite soon in view of its size – the nymph is usually about 2 mm length. Person-to-person transmission does not occur although there is some evidence that transplacental transmission can occur.

Geographical distribution
Lyme disease occurs in foci across forested areas of the United States, and Asia as well as north-western, central and eastern Europe and is more common in the summer months.

Lyme disease is not endemic in South Africa or Mozambique – the Ixodes spp. vector ticks are not present in southern Africa, and there is no scientifically credible evidence that Lyme disease is naturally transmitted in southern Africa.

Refer to the map below depicting the geographical distribution of the Lyme disease vectors.

Question 6 - What are the clinical manifestations of Lyme Disease?

Answer to Q6
Clinical manifestations of Lyme disease are generally divided into three stages: early localised infection, early disseminated infection and late or persistent disease.

Early localised infection
After an incubation period of 3-32 days (usually within 7-14 days), a characteristic rash, erythema migrans, appears at the site of the tick bite in 80% of patients with Lyme disease. This slowly expanding rash forms an erythematous annular lesion, which may have some central clearing giving a characteristic bull’s eye or target appearance. Multiple lesions may be present and are due to haematogenous dissemination of spirochetes.
Other non-specific signs and symptoms may accompany early infection such as fatigue, headache, myalgia, arthralgia and fever.

Early disseminated infection
Early disseminated disease usually occurs within weeks to months of initial infections. Non-specific systemic manifestations such as fever and malaise may occur with other symptoms, depending on the organ system involved, most commonly musculoskeletal and neurological with cardiac symptoms being less common.

Musculoskeletal symptoms may include intermittent arthralgia. Neurological involvement most commonly manifests as cranial neuropathy (especially of the facial nerve), meningitis, radiculopathy and less commonly encephalopathy. Cardiac symptoms usually present as atrioventricular blockade of varying degrees and myopericarditis is less common.
Other presentations such as cutaneous involvement (borrelial lymphocytoma) and ocular manifestations can occur but are much less common.

Late or persistent disease
Late Lyme disease occurs months to a few years following the initial infection and patients and may present without a history of early disease. The most common feature is arthritis in one or a few joints, with the large joints being most commonly affected. Neurologic symptoms may also occur such as subacute encephalopathy or polyneuropathy. A late cutaneous complication, acrodermatitis chronica atrophicans, occurs almost exclusively in infections acquired in Europe.

Question 7 - How is Lyme disease diagnosed?
Answer to Q7
In areas such as South Africa where Lyme disease is not endemic, it is essential to obtain a detailed travel history to ascertain if the patient has travelled to any areas where Lyme disease occurs endemically. In addition it is also essential to enquire about activities during travel such as camping, hiking etc which may have resulted in exposure to ticks.

In a patient with a history of travel to an endemic area presenting with a typical erythema migrans rash, the diagnosis of Lyme disease can be made clinically without the need for further laboratory testing. Serology will likely be negative in such patients with early disease as the skin lesions often appear prior to the immunological response.

In patients without a certain history of exposure and the typical erythema migrans presentation laboratory testing in the form of serology is required. Antibodies may persist for years after convalescence and for this reason serological testing may not be conclusive for active infection and should be used as an adjunct to history and clinical assessment.

The US CDC recommends a two-step approach (image below). An initial enzyme-linked immunosorbent assay (ELISA) test is performed; if negative no further testing is required. If positive, a western blot test is performed to confirm the diagnosis.

Culture of the organism isolated from biopsy of skin lesions or lumbar puncture or synovial tap is possible; it usually reserved for research purposes as is the polymerase chain reaction (PCR).

Question 8 - What is the treatment of Lyme Disease?

Answer to Q8
The treatment of Lyme disease may depend on the stage and clinical manifestations.

Patients with early uncomplicated disease such as erythema migrans, mild systemic symptoms, isolated facial nerve palsy, are generally treated with oral antibiotic therapy. Oral antibiotics include doxycycline as the drug of choice (where there are no contraindications such as children under eight years of age or pregnancy), with amoxicillin and cefuroxime being used as alternatives. Patients with organ involvement such as meningitis or carditis may require intravenous therapy in which case ceftriaxone is the preferred agent with alternates being cefotaxime and penicillin.

Duration of therapy is recommended for 14-21 days but may need to be extended to 28 days for patients presenting with more severe infection or signs of late disease such as arthritis.

When adequately treated, Lyme disease usually has a very good prognosis. Patients treated in the early stages with appropriate antibiotics usually recover rapidly and have no further complications. In a very small percentage of patients, usually those who present with late disease, some musculoskeletal or neurological symptoms may persist following completion of treatment. This is not due to persistent infection and ongoing complaints are usually treated symptomatically.

Reinfection with Lyme disease can occur and there is currently no vaccine commercially available.
OUTCOME OF THE CASE

She was discharged after six days and instructed to continue another 14 days of doxycycline to complete a total of three weeks. She had ongoing headaches that responded well to analgesia. She mentioned that she had had malaria multiple times in the past although this episode of illness did not feel the same.

What is the final diagnosis?

LESSONS LEARNED

The positive serology (IgM) for Lyme disease must be considered a false positive test. The patient had no history of travel to an endemic area and resides in Mozambique which is not an endemic area. However, no reference to a false positive test resulting from malaria could be sourced.

To confirm the diagnosis repeat serology with a positive IgG and confirmation by western blot to Lyme disease would be essential. This was not done in this case.

A Plasmodium spp. PCR to establish a firm diagnosis of malaria in travellers who have been on chemoprophylaxis or have been on treatment is available in some laboratories and would have been helpful in confirming the diagnosis of malaria.

Malaria remains the number diagnosis in the patient – the rash more than likely had no bearing on her illness.

Establishing a definitive diagnosis in a rural setting with limited access to resources is difficult.

The importance of early evacuation to a medical centre should the patient not improve and a diagnosis not confirmed, must be considered.

Typhoid serology (Widal) is not an accurate method to diagnose typhoid fever: blood cultures remain the investigation of choice.

Resources:
  • Barlam TF, Kasper DL. In Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, Loscalzo J, editors. Harrison’s Principles of Internal Medicine. 17th ed. McGraw-Hill; 2009.
  • Mead PS. Epidemiology of Lyme disease. Infect Dis Clin North Am. 2015 Jun;29(2):187-210. doi: 10.1016/j.idc.2015.02.010.-
  • Marques AR. Laboratory diagnosis of Lyme disease: advances and challenges. Infect Dis Clin North Am. 2015 Jun;29(2):295-307. doi: 10.1016/j.idc.2015.02.005.
  • Beard CB, Steere AC, Mitty J. Epidemiology of Lyme disease. http://www.uptodate.com 
  • Hu L. Clinical manifestations of Lyme disease in adults
    • http://www.uptodate.com 
  • Hu L, Steere AC, Mitty J. Diagnosis of Lyme disease. http://www.uptodate.com 
  • Hu L, Steere AC, Mitty J. Treatment of Lyme disease. http://www.uptodate.com
  • Mead PS. Lyme Disease in CDC Health Information for International Travel 2016:235
  • Cook GC. Lyme disease in Manson’s Tropical Diseases 21st edition, 1153-1154

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