Pyrexia of Unknown Origin – Differential Diagnosis ?

A 68-year-old man presented with a 3-week history of pyrexia of unknown origin. He also suffered from malaise, night sweats, rigors and weight loss but had no localizing symptoms. Pyrexia of unknown origin has a wide array of differential diagnoses and it can be challenging to find the correct diagnosis promptly. Examination of the patient indicated pallor and features of long-standing aortic regurgitation, but was otherwise unremarkable. Due to his history of valvular disease and a recent dental extraction, his investigations were tailored towards infective endocarditis. Blood cultures and echocardiography confirmed this diagnosis by Dukes’ criteria. He promptly received antibiotics, made a full recovery and was discharged. Copyright Royal Medical Society. All rights reserved. The copyright is retained by the author and the Royal Medical Society, except where explicitly otherwise stated. Scans have been produced by the Digital Imaging Unit at Edinburgh University Library. Res Medica is supported by the University of Edinburgh’s Journal Hosting Service: http://journals.ed.ac.uk ISSN: 2051-7580 (Online) ISSN: 0482-3206 (Print) Res Medica is published by the Royal Medical Society, 5/5 Bristo Square, Edinburgh, EH8 9AL Res Medica, 2013, 21(1):56-60 doi: 10.2218/resmedica.v21i1.209 Oswald A. http://journals.ed.ac.uk/resmedica Volume 21, Issue 1 Res Medica Background Pyrexia of unknown origin is defined as a fever of 38.3°C or more lasting at least 3 weeks and for which no cause can be identified after 3 days of investigations in hospital or after 3 or more outpatient visits. There are few other clinical presentations that produce such a wide array of differential diagnoses, including infections, malignancy and connective tissue disorders. Due to the high mortality rate of many of these conditions, especially if diagnosis is delayed, a high degree of suspicion is imperative. Thorough clinical assessment is vital to provide diagnostic clues and tailor investigations. Here, we report a case of pyrexia of unknown origin, which was found to be due to infective endocarditis (IE) in a gentleman with Marfan syndrome. IE is a rare endocardial infection with an annual incidence of 3–10 cases per 100,000 per annum. It can be bacterial, viral or fungal, predominately affecting those over age 60 and twice as many men as women. Over 50% have underlying heart problems (e.g. valvular disease) and intravenous drug use is an important risk factor. Unfortunately, diagnosis is commonly delayed as symptoms are often non-specific. Diagnosis is by Dukes’ criteria. Treatment is frequently with antibiotics, but surgery is indicated in uncontrolled infection, heart failure or embolic event. Prompt diagnosis is vital as mortality rates of between 14–46% have been reported and complications include congestive heart failure and stroke. Marfan syndrome, an additional uncommon condition affecting this patient, is an autosomal dominant disorder affecting fibrillin-1 (an extracellular matrix protein), which causes weakening of connective tissue. Common features are lens dislocation, skeletal features (e.g. arachnodactyly, scoliosis) and dural ectasia. Cardiac features include valve incompetence, such as in this case, and aortic dissection, which often requires monitoring and medication. Here, we describe the difficulty in diagnosing IE due to its non-specific presentation. We also aim to highlight how considering a patient’s characteristics can aid in the diagnosis of a non-specific complaint such as pyrexia of unknown origin. Finally, we discuss the guidelines for the use of prophylactic antibiotics in high risk individuals.


Background
Pyrexia of unknown origin is defined as a fever of 38.3°C or more lasting at least 3 weeks and for which no cause can be identified after 3 days of investigations in hospital or after 3 or more outpatient visits. 1 There are few other clinical presentations that produce such a wide array of differential diagnoses, including infections, malignancy and connective tissue disorders. 2Due to the high mortality rate of many of these conditions, especially if diagnosis is delayed, a high degree of suspicion is imperative.Thorough clinical assessment is vital to provide diagnostic clues and tailor investigations. 2re, we report a case of pyrexia of unknown origin, which was found to be due to infective endocarditis (IE) in a gentleman with Marfan syndrome.IE is a rare endocardial infection with an annual incidence of 3-10 cases per 100,000 per annum. 3It can be bacterial, viral or fungal, predominately affecting those over age 60 and twice as many men as women. 4Over 50% have underlying heart problems (e.g.valvular disease) and intravenous drug use is an important risk factor. 3Unfortunately, diagnosis is commonly delayed as symptoms are often non-specific.Diagnosis is by Dukes' criteria. 4Treatment is frequently with antibiotics, but surgery is indicated in uncontrolled infection, heart failure or embolic event. 3,6Prompt diagnosis is vital as mortality rates of between 14-46% have been reported and complications include congestive heart failure and stroke. 7rfan syndrome, an additional uncommon condition affecting this patient, is an autosomal dominant disorder affecting fibrillin-1 (an extracellular matrix protein), which causes weakening of connective tissue.Common features are lens dislocation, skeletal features (e.g.arachnodactyly, scoliosis) and dural ectasia.Cardiac features include valve incompetence, such as in this case, and aortic dissection, which often requires monitoring and medication. 8re, we describe the difficulty in diagnosing IE due to its non-specific presentation.We also aim to highlight how considering a patient's characteristics can aid in the diagnosis of a non-specific complaint such as pyrexia of unknown origin.Finally, we discuss the guidelines for the use of prophylactic antibiotics in high risk individuals.

Case Report
A 68-year-old gentleman with Marfan syndrome presented with a 3-week history of malaise and fever, and a 2-week history of rigors and night sweats.His appetite was poor, he had lost 2 kg of weight and felt slightly nauseated, but denied vomiting.He had no rashes or skin lesions and denied any other symptoms on systemic enquiry.His past medical history included aortic regurgitation (moderate and asymptomatic), essential hypertension, hypercholesterolaemia and benign prostatic hyperplasia (BPH), but he had no history of malignancy or long-standing infections.He is a retired, married, non-smoker and is fully independent.He denied recent foreign travel or intravenous drug use but had a dental extraction the previous month.
On general inspection, conjunctival pallor was present but there was no jaundice, cyanosis or rashes.His temperature was 38.5°C but his other observations were all normal.On cardiovascular examination, he had no splinter haemorrhages, finger clubbing, Osler's nodes or Janeway lesions.He had a collapsing radial pulse and a visible carotid pulsation (Corrigan's sign).His dentition was good and his JVP was not elevated.He had no palpable heaves or thrills but his apex beat had a heaving character in the sixth intercostal space, displaced 2 cm laterally of the midclavicular line.Heart sounds I + II were present with an early diastolic murmur (intensity grade 3), suggestive of aortic regurgitation.Peripheral pulses were normal.Examination of other systems was unremarkable.

Differential Diagnosis
Factors

Management, Outcome & Follow up
The patient was promptly prescribed intravenous benzylpenicillin and gentamicin as per BSAC guidelines. 4He was also prescribed paracetamol and thromboembolism prophylaxis.His clinical response and observations were monitored closely.A repeat echocardiogram was arranged the following week to assess valve function, vegetation size and if surgical repair was required.The patient responded well to antibiotics and did not require surgery.He continued on benzylpenicillin for 4 weeks and gentamicin for 2 weeks and was discharged home.

Discussion
Pyrexia of unknown origin has a wide range of differential diagnoses and requires prompt and appropriate investigations.IE is an important differential diagnosis and, due to its often non-specific presentation, it requires a high degree of suspicion.It has been reported that around 25% of those with IE have clinical signs for over one month before admission to hospital. 9Delay can lead to devastating and even multiple complications, for example cases of multiple embolic events and renal failure or splenic rupture and fatal intra-abdominal haemorrhage have been reported. 10,11ompt blood cultures and transoesophageal echocardiography are necessary to confirm the diagnosis of IE.Clinical examination is essential for excluding other causes and aiding diagnosis.Signs on examination include cardiac murmurs (which are present in around 50%) and vasculitic rashes. 3owever, classical signs including Janeway lesions or subconjuctival haemorrhages are only present in a minority and, therefore, their absence does not exclude the diagnosis, as illustrated by this case. 9 this case, acknowledging the patient's risk factors aided the prognosis, which included his valvular heart disease related to Marfan syndrome and a recent dental extraction.This indicates the importance of taking a thorough history and having an awareness of risk factors.Between 1955 and 2008, prophylactic antibiotics were prescribed as a preventative measure to those undergoing interventional procedures who were deemed to have a high risk of IE (e.g.those with valvular diseases).However, new guidelines published by NICE in 2008 stated it was no longer recommended to offer antibiotic prophylaxis as the potential benefits are minimal. 12It is possible that prophylactic antibiotics in this case could have prevented the development of IE.A similar case in 2011 was reported, where a patient with a congenital heart defect developed IE after a dental procedure, and the authors speculated whether the new guidelines were wise. 13This was reiterated by another case describing a previously independent 69-year-old man with a prosthetic aortic valve and known poor dentition, who developed IE 10 days after a dental procedure. 14He unfortunately developed a cerebrovascular complication and died.The authors questioned whether strict adherence to the new guidelines is appropriate and suggested the decision should be made by case by case decisions. 14nterestingly, the American Heart Association and the European Society for Cardiology both recommend prophylaxis for high risk individuals. 15,16From these cases it is clear that clinicians should be aware that a history of a recent interventional procedure, especially in susceptible individuals, is an important risk factor in the context of IE.

Key Learning Points
 Pyrexia of unknown origin has a wide range of differential diagnoses including infections, malignancies and connective tissue disorders.
 Infective endocarditis is a rare infection which can present with non-specific complaints, such as pyrexia and malaise.
 It generally affects elderly patients and other risk factors include intravenous drug use, valvular disease, prosthetic valves and cyanotic congenital heart disease.
 Having a high degree of suspicion of endocarditis is necessary for prompt diagnosis and management as mortality is high.
 NICE guidelines state that prophylactic antibiotics are no longer recommended as a preventative measure in those who are deemed to have a high risk of infective endocarditis undergoing interventional procedures.