Fever Of Unknown Origin

Question 1

What is Lyme disease?

Answer 1

• Lyme disease is caused by the bacterium Borrelia burgdorferi, which is a spirochaete.
• Recent studies have shown that there are several genospecies and the group as a whole is referred to as B. burgdorferi sensu lato.
• Humans may contract it when they are bitten by ticks of the Ixodes species which are infected by B. burgdorferi.
• The disease is caused by the infection and the body’s immune response to infection.
• Different strains of Borrelia spp. cause different clinical manifestations of Lyme disease and this explains differences between the disease in Europe and the disease in the USA.

Question 2

What is the pathophysiology of Lyme disease?

Answer 2

The spirochaete responsible:
o Is transmitted by the tick. The tick must have fed on a host significantly infected with spirochaete to pass on the infection to man.
o Once it infects the tick, it has to go through a particular cycle of multiplication and dissemination to salivary glands within the tick before it can be passed on to the animal victim.
o A tick must be attached for some time to a person before infection can be passed on.

Once the spirochaete infects the host there may be one of several consequences:
o The infection is cleared by host defences. This means the person will have had no clinical manifestations, be asymptomatic but seropositive.
o The organism spreads by direct invasion. This is believed to be a feature in early disease.
o For example, erythema migrans is thought to result from the inflammatory response to direct invasion of the organism in the skin.
o The organism excites an immune response in the host, which causes a variety of clinical manifestations around the body. In such cases there is no evidence of direct bacterial invasion.
o The manifestations of Lyme disease are related to the particular Borrelia spp. strain involved.

Question 3

What is the presentation of early Lyme disease?

Answer 3

• Some of those infected will have no symptoms. Patients with Lyme disease may not remember being bitten by the often innocuous tick. The presentation depends on the stage of disease.

• Early Lyme disease (stage 1, or localised disease)
• The characteristic manifestation is erythema migrans:
o A circular rash at the site of the infectious tick attachment that radiates from the bite, within 3-36 days.
o In Europe this has been found to be the presenting sign in up to 90% of cases and may be the only manifestation.
o The rash is round or oval, and pink, red or purple. There is often central erythema with sparing around it, giving a target-like appearance; the diameter is usually larger than 5 cm. The target-like appearance is common in European-acquired infection.

Question 4

What is the presentation of disseminated Lyme disease?

Answer 4

• Disseminated Lyme disease (stage 2 disease)
• This disseminated stage is still considered to be early infection and occurs days to months later, with:
o Flu-like illness: symptoms include joint and muscle pains, headache, fever, tiredness, nausea or vomiting. This is more common in the USA.

o Neurological disorders or neuroborreliosis (10% of untreated cases):

• In Europe this is the second most common presentation after erythema migrans.
• Unilateral or bilateral facial nerve palsies are the most common neurological manifestations in Europe and the USA. Rarely, other cranial nerves may be involved.

o Meningism and meningitis may occur alone or with other neurological manifestations. It is usually at the mild end of the spectrum but can be more severe.

o Mild encephalitis producing malaise and fatigue.

o Peripheral mononeuritis

o Lymphocytic meningoradiculitis (Bannwarth’s syndrome), which is more common in Europe than in the USA.

o Cardiovascular problems: myopericarditis may occur but is rare in the UK. This presents with syncope, chest pain or breathlessness. ECG shows atrioventricular or first-degree heart block.

o Lymphocytomas: these are bluish-red nodular lesions infiltrated with lymphocytes. They typically appear on the earlobe or nipple. They occur occasionally in Europe and are very rare in the USA.

Question 5

What is the presentation of late manifestations of Lyme disease?

Answer 5

• Late manifestations of Lyme disease (stage 3 disease)
• Arthritis: It often presents as a large knee effusion, or a Baker’s cyst. There is occasional progression to a chronic arthritic condition.
• Acrodermatitis chronica atrophicans: this is a rare skin condition that can occur years after the infection. Extensor surfaces of the limbs develop blue-red discolouration and swelling. There can be associated peripheral neuropathy.
• Late neurological disorders: these include polyneuropathy, chronic encephalomyelitis, vertigo and psychosis.
• Chronic Lyme disease (persistent symptoms despite adequate therapy) and ‘post-Lyme syndrome’ (described as similar to chronic fatigue syndrome or fibromyalgia).

Question 6

What are the differentials of Lyme disease?

Answer 6

• Erythema migrans: 
o	Ringworm 
o	Cellulitis 
o	Urticaria 
o	Erythema nodosum 
o	Erythema multiforme
o	Contact dermatitis 
o	Erythema annulare centrifugum

• Chronic lyme disease: 
o	West nile virus 
o	Parvovirus B19
o	Relapsing fever 
o	Syphillis 
o	Leptospirosis 
o	Mycoplasma 
o	Infective endocarditis

Question 7

What is the investigations for Lyme disease?

Answer 7

• Patients with erythema migrans should be diagnosed with and treated for Lyme disease based on clinical assessment, without laboratory testing.
• Patients without erythema migrans who are suspected to have Lyme disease and who have an negative ELISA test within four weeks of developing symptoms, should have the test repeated 4-6 weeks later. The rationale is that testing before four weeks may result in a false negative test.
• Initial treatment for Lyme disease should be with antibiotics, with dose, duration and type determined by symptoms.

Question 8

What is the management of Lyme disease?

Answer 8

• If the tick is still attached, remove it. Grip the tick with fine-tipped or precision tweezers and pull upwards without twisting.
• Clean the skin afterwards with soap and water or an antiseptic preparation.
• The tick may be disposed of in normal household rubbish.
• Do NOT use petroleum jelly, alcohol, or nail varnish remover, or burn the tick off.
• Blood tests are NOT necessary; the diagnosis can be made clinically.
• Treat with an oral antibiotic for 2-3 weeks
• Seek advice from an ID specialist or a dermatologist about the need for testing and antibiotics if there is possible erythema migrans but no history or likely exposure to tick bites.
• Refer for immediate specialised assessment if there are signs of other systemic manifestations.
• Lyme disease is rarely fatal. Prognosis is usually good, even in untreated cases. Antibiotic treatment for early Lyme disease is highly effective.

Question 9

Which antibiotics can be used for the treatment of Lyme disease?

Answer 9

o Doxycycline 100 mg bd or amoxicillin 500 mg tds.
o Cefuroxime 500 mg bd if both are contra-indicated and there is no history of anaphylaxis with penicillins.
o For children aged under 12, use amoxicillin in age-dependent doses as per the British National Formulary (BNF) or cefuroxime 5 mg/kg twice per day (maximum 500 mg per dose and assuming there is no history of anaphylaxis with penicillins).
o For breast-feeding women, use amoxicillin or cefuroxime.
o For pregnant women, use amoxicillin or cefuroxime and inform an obstetrician. Lyme disease carries little direct risk to the pregnancy; however, there is a possible risk of uterine contraction following a reaction to treatment. (Jarisch-Herxheimer reaction - a reaction which may occur with any antibiotic treatment for Lyme disease in 15% of people in the first 24 hours and which may be mistaken for an allergic reaction.)

Question 10

What is malaria?

Answer 10

Malaria is a parasitic disease caused by infection by species of the genus Plasmodium.

Question 11

When should you consider malaria in a febrile patient?

Answer 11

Consider malaria in every febrile patient returning from a malaria-endemic area within the last year, especially in the previous three months, regardless of whether they have taken chemoprophylaxis, as prompt recognition and appropriate treatment will improve prognosis and prevent deaths.

Question 12

What is the classification of malaria.

Answer 12

Malaria is classified based on the species of the genus plasmodium.

Plasmodium falciparum:
o Responsible for severe disease and malaria-related deaths.
o Incubation 7-14 days (up to one year if semi-immune); most travellers present within eight weeks.
o Classical tertian and subtertian periodicity (paroxysms at 48- and 36-hour intervals) are rare; daily (quotidian) or irregular are more common.
o Most common cause of malaria.

Plasmodium vivax:
o Causes benign tertian malaria - fever every third day.
Incubation period of 12-17 days.
o Relapse due to dormant parasites in the liver.

Plasmodium ovale:
o Relapsing course as with p.vivax
o Incubation period of 15-18 days.

Plasmodium malariae:
o Causes benign quartan malaria - fever every fourth day - but this is frequently not observed, particularly in early infection.
Long incubation period (18-40 days).

Parasites can remain dormant in the blood. 5-10% present over a year after infection. With chronic infection, can cause nephrotic syndrome.

Question 13

What is the aetiology of malaria?

Answer 13

Humans acquire malaria after being bitten by an infected mosquito. The sporozoites in the saliva of the mosquito then travel via the bloodstream to the liver where they mature or, in certain species, may lie dormant (when they are known as hypnozoites).

The mature organisms then rupture to release further organisms (merozoites) into the blood, where they invade red blood cells and undergo asexual reproduction.

Feeding mosquitoes ingest these in a blood meal and in the mosquito gut they undergo sexual reproduction to produce thousands of infective sporozoites, and the cycle continues.

Malaria occurs almost exclusively in the tropics and subtropics. About 3.2 billion people - nearly half of the world’s population - are at risk of malaria.

Question 14

What are the risk factors for malaria?

Answer 14

• The poor (60% of deaths from malaria worldwide occur in the poorest 20% of the population, due to lack of access to effective treatment).
• Young children and infants.
• Pregnant women (especially primigravidae).
• Elderly people.
• Non-immune people (e.g., travellers, foreign workers).
• The risk of contracting malaria in travellers is proportional to the number of potentially infectious mosquito bites they receive.

Question 15

What are the risk factors for malaria in travellers?

Answer 15

o Travel to areas of high humidity and ambient temperature between 20-30°C (there is no malarial transmission <16°C or at altitudes >2000 m above sea level).

o Travel at times of high seasonal rainfall.

o Visits to rural locations (the risk of contracting malaria in African villages is eight times that in its urban areas).

o Staying in cheap backpacker accommodation.

o Being outdoors between dusk and dawn.

o Longer durations of travel.

Question 16

What is the treatment for resistant P.falciparum malaria?

Answer 16

• There are currently no effective alternatives to artemisinins for the treatment of resistant P. falciparum malaria.
• Artemisinin-based combination therapies (ACTs) are life-saving in areas of high resistance.
• In order to preserve the efficacy of artemisinins, the World Health Organization (WHO) has called for a ban on the use of oral artemisinin monotherapies.

Question 17

What is the presentation of malaria?

Answer 17

• In view of the life cycle of the malaria parasite, symptoms may occur from six days of naturally acquired infection to many months later. Most patients with P. falciparum infection present in the first month or within the first six months of infection. P. vivax or P. ovale infections commonly present later than six months after exposure and sometimes after years.
• There are no specific symptoms of malaria - so it is critical to consider the possibility of the diagnosis.
• Most missed malarial infections are wrongly diagnosed as nonspecific viral infections, influenza, gastroenteritis or hepatitis.
• Children, in particular, are more likely to present with nonspecific symptoms (fever, lethargy, malaise, somnolence) and to have gastrointestinal symptoms.

• Where malaria is a possibility:
o Take a careful exposure history (countries and areas of travel including stopovers and date of return, etc).
o Determine what prophylaxis has been taken - drug(s), dose and adherence, date of cessation.
o Pursue diagnostic tests urgently.

Question 18

Symptoms and signs of malaria

Answer 18

Symptoms
o	Fever, often recurring
o	Chills
o	Rigors
o	Headache
o	Cough
o	Myalgia
o	Gastrointestinal upset

Signs
o	Fever
o	Splenomegaly
o	Hepatomegaly
o	Jaundice
o	+/- abdominal tenderness

Signs of severe disease (usually P. falciparum)
o	Impaired consciousness.
o	Shortness of breath.
o	Bleeding.
o	Fits.
o	Hypovolaemia.
o	Hypoglycaemia.
o	Acute kidney injury.
o	Nephrotic syndrome.
o	Acute respiratory distress syndrome (during treatment).

Question 19

What are the differentials for malaria?

Answer 19

• Typhoid
• Hepatitis
• Dengue fever
• Influenza
• HIV
• Meningitis
• Viral haemorrhagic fevers

Question 20

What are the investigations for malaria?

Answer 20

• Thick and thin blood smears stained with Giemsa stain remain the ‘gold standard’.
o Advantages include low cost and high sensitivity and specificity when used by well-trained staff. Where there is suspicion of malaria, a venous blood specimen in an EDTA tube should be sent to the laboratory in under an hour. If there is potential for delay, refer the patient to hospital for testing.
o Where the blood film is negative, at least two further films should be obtained over the subsequent 48 hours, before excluding the diagnosis. Be aware that an individual can have malaria despite a negative film.
o This is particularly the case in pregnancy where parasite biomass can be sequestered in the placenta - seek expert help early if concerned.

Rapid diagnostic tests (RDTs) which detect parasite antigens are available and, being dipstick-based investigations, are easier to use for staff without microscopy training.

FBC - typically reveals thrombocytopenia and anaemia. Leukocytosis is rarely seen but is an indicator of a poor prognosis when present.

G6PD activity - prior to giving primaquine

LFTs- often abnormal

U&Es may show hyponatraemia and increased creatinine

Ill patients may also require:
•	Blood gases
•	Blood cultures 
•	CXR 
•	Lumbar puncture
•	Urine and stool culture 
•	Clotting studies

Question 21

What is the management of malaria?

Answer 21

The management of malaria depends not only on the severity of the disease but also the strain of Plasmodium involved and the degree of resistance that it exhibits. All cases should be discussed with infectious disease specialists - the local infectious diseases unit will be able to give advice and initiate appropriate treatment in line with the current UK guidelines.

Admission is usual for:
o	Severely unwell patients.
o	Patients with P. falciparum malaria.
o	Patients with mixed infections.
o	Patients in whom the strain cannot be identified.

Question 22

What is the treatment for non-falciparum malaria?

Answer 22

o G6PD activity should be measured in P. vivax or P. ovale infections, as the primaquine (which is necessary to eliminate the dormant hypnozoites and prevent recurrence) can cause haemolysis in those with G6PD deficiency.

o Current UK guidelines recommend:

• Chloroquine as the drug of choice for the treatment of all non-falciparum malaria - it is highly effective against P. malariae and P. ovale and most strains of P. vivax.
• Where chloroquine fails, resistant P. vivax malaria can be treated with quinine, artemether with lumefantrine or atovaquone-proguanil as for uncomplicated falciparum malaria.
• Prevention of relapse - primaquine is used to destroy liver stage parasites (unlicensed use):
• For treatment of P. ovale 15 mg primaquine/day for 14 days.

Question 23

What is the treatment for falciparum malaria?

Answer 23

o Current UK guidelines suggest as possible alternative regimens for adults:

• Oral quinine sulfate 600 mg/8 hours for 5-7 days plus doxycycline 200 mg daily (or clindamycin 450 mg/8 hours for pregnant women) for seven days.
• Atovaquone-proguanil (Malarone®): four standard tablets daily for three days.
• Artemether with lumefantrine (Riamet®): if weight >35 kg, four tablets stat and then a further four tablets at 8, 24, 36, 48 and 60 hours.

WHO revised their treatment guidelines in 2010 and maintain these as current guidance. These recommend that artemisinin-based combination therapies should be used first-line in preference to quinine. However, to date the UK has not yet changed its approach.

Question 24

What is the treatment for severe or complicated falciparum malaria?

Answer 24

IV quinine dihydrochloride is the first-line antimalarial drug. A loading dose of 20 mg/kg (to a maximum of 1.4 g) over four hours, followed by 10 mg/kg (to a maximum of 700 mg) every eight hours for the first 48 hours or until the patient can swallow is usual to reach high therapeutic blood levels quickly, although alternative regimens exist. ECG monitoring is required.

Oral quinine sulfate 600 mg tds should be substituted once the patient is well enough to complete a 5- to 7-day course in total.

Artesunate regimen - for named adult patient use only, on expert advice. This is usually given as an IV injection, repeated at 12 and 24 hours and daily thereafter. Rectal formulations also exist but tend to be used in resource-poor settings where IV therapy is not possible. IV artesunate has not been licensed in the UK but there is accumulating evidence that it offers a significant benefit over quinine where patients have very severe malaria or high parasite counts.

A second drug should always accompany these regimes. Current recommendations are for doxycycline 200 mg od (or clindamycin 450 mg tds for pregnant women) for a total of seven days from when the patient can swallow.

Question 25

What are the complications of malaria?

Answer 25

• Impaired consciousness or seizures (cerebral malaria).
• Renal impairment.
• Acidosis.
• Hypoglycaemia
• Pulmonary oedema or ARDS
• Anaemia
• Splenic rupture
• DIC
• Shock secondary to complicating bacteraemia
• Haemoglobinuria
• Multiple organ failure
• Death

Question 26

How can you prevent contracting malaria?

Answer 26

Use of effective chemoprophylaxis and insecticide-treated nets (ITNs) prevents about 90% of malaria.

Other behavioural modifications, such as avoiding outdoor activity after sunset, wearing long-sleeved shirts and trousers, using ITNs and insect repellant, must also be recognised as important.

Start weekly drug regimes one week before entering a malarious area (exceptions: 1-2 days for doxycycline or atovaquone with proguanil (Malarone®), two to three weeks for mefloquine) to become used to side-effects before travelling. Take after meals.

Continue until four weeks after return, to deal with infection contracted towards the end of the stay (except Malarone® which should be stopped one week after leaving). Discuss possible side-effects, and recommend seeking advice if there is any concern or medication has to be stopped.