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Fever of Unknown Origin: History, Assessment, and Differential

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Overview

Fever (pyrexia) of unknown origin is defined as a temperature >38.3°C for >3 weeks with no obvious source despite evaluation for at least 1 week in hospital. There is a vast range of differential diagnoses for fever, therefore, when taking a history, start broad and ask screening questions, then narrow down questions based on what is found.

In some cases, a fever of unknown origin may be idiopathic.

Introduction

Introduce using WIPE:

  • Wash hands
  • Introduce yourself self and your role
  • Patient name, date of birth, and how they would like to be called
  • Explain, gain consent, offer a chaperone, and ask about pain

Identify the reasons for the consultation:

  • Ask an open question – what’s brought them in today?
  • Check for anything else – is there anything else they’d like to talk about?
  • Confirm what the consultation will entail – is this what they would like to talk about?

History

Background

Explore the background and timeline. Some general questions to ask about all symptoms include:

  • What were the events leading up to this?
  • Ask about onset:
    • When did it start?
    • What were they doing when it started?
    • Was it sudden or gradual?
  • Ask about the timeline:
    • Is it continuous or intermittent?
    • Is it getting better, worse, or staying the same?
    • Does anything trigger it?
    • Has this ever happened before?

Fever

Questions relating to fever include:

  • Clarification – what do they mean by fever?
  • Onset and timeline – as discussed above, particularly its pattern, any peaks or troughs?
  • General related symptoms – these may help point towards a possible cause:

Screening questions

Ask quick screening questions to narrow down the likely cause:

  • Malignancy:
    • Constitutional symptoms – unexplained weight loss, night sweats, malaise, anorexia
    • Haematological disturbance – fatigue, dyspnoea, easy bleeding/bruising, recurrent infection
  • Infections:
    • Neurological – headaches, neck stiffness, non-blanching rash, photophobia, confusion, drowsiness
    • Cardiorespiratory – chest pain, dyspnoea, cough +/- sputum, haemoptysis
    • Genitourinary – dysuria, haematuria, urinary frequency
    • Gastrointestinal – vomiting, diarrhoea, nausea, abdominal pain
    • Genitourinary – abnormal vaginal/penile discharge, recent unprotected sex with a new partner
    • Rheumatological/dermatological – joint pain, stiffness, swelling, rashes, ulcers, dry eyes, dry mouth
    • Ear, nose, and throat – sore throat, ear pain, nasal discharge/congestion, facial pain
    • Dental – mouth/tooth pain
    • Deep vein thrombosis – calf swelling, calf pain
  • Any recent foreign travel? – further questions are discussed below

Foreign travel questions

Ask about where they went and stayed:

  • What countries?
  • When did they arrive and return home?
  • Did they stay in an urban or rural environment?
  • What type of accommodation did they stay in?

Ask about possible risks – normalise this question (e.g. “these are questions we ask all patients with these symptoms if you don’t mind”):

  • Food and drink:
    • Any high-risk foods? (e.g. street food)
    • Any high-risk drinking? (e.g. unsterilised water)
  • Animals and insects:
    • Any animal/insect bites?
    • Any close contact with animals?
  • Contacts:
    • Any unwell close contacts? – do they know what the other person has?
  • Sexual intercourse:
  • Swimming:
    • Any swimming in lakes/rivers?
    • Any other water activities? (e.g. rafting)
  • Procedures:
    • Any hospital admission?
    • Any piercings?
    • Any tattoos?
    • Any intravenous drug use?

Summarise

Summarise and clarify:

  • Summarise the story so far and what you have heard
  • Ask the patient and clarify if this is correct

Ideas, concerns, expectations, and impact

Ask about:

  • Ideas – can they think of any reasons as to why this is happening?
  • Concerns – is there anything they are specifically worried about?
  • Expectations – what would they like to get out of the consultation?
  • Impact – how has this affected their day-to-day life?

Past medical history

Questions include:

  • Do they have any other medical conditions?
    • Specifically ask about HIV, cancer, and any previous infections
  • Have they ever had any previous surgery?
  • Do they take any regular medications?
    • Specifically ask about immunosuppressive, antiviral, antimalarial, and chemotherapy drugs
  • Do they take any over-the-counter medications, herbal remedies, or supplements?

Allergy history

Are they allergic to anything?

  • What happens during the allergic reaction?

Family history

Is there any family history of anything similar?

  • Specifically ask about HIV, tuberculosis, malaria, cancer, and autoimmune disease

Social history

Do they smoke?

  • If so, how much and how long?
  • If appropriate, would they like any support for this?

Do they drink alcohol?

  • If so, how much and how long?
  • If appropriate, would they like any support for this?

Do they use any illicit drugs?

  • If so, how much and how long?
  • If appropriate, would they like any support for this?

Ask about occupation and support:

  • What is their occupation?
  • Who’s at home? – ask further questions for contact tracing:
    • How many people?
    • Any shared rooms?
    • Any dependents?
  • What support do they have?

Physical Examinations

Overview

Physical examinations will need to focus on potential systems highlighted in the history. Some features may include:

  • General features:
    • Tachycardia, tachypnoea, and hypotension can suggest severe infection
    • Skin rashes, lymphadenopathy, and abdominal masses may be present
    • Wounds or infected medical equipment (e.g. cannulas) may be present
  • Cardiorespiratory – crackles, reduced air entry, bronchial breathing – pneumonia
  • Abdominal – tenderness, peritonism, bloating, masses
  • Neurological – reduced Glasgow coma score, focal neurological deficits, headache, photophobia, Kernig’s sign, Brudzinski’s sign – central nervous system infections
  • Ear, nose, and throat – ear canal erythema, bulging tympanic membrane, sore throat, tonsillar exudates
  • Musculoskeletal:
    • Calf tenderness and swelling – deep vein thrombosis
    • Joint pain, swelling, erythema, reduced range of motion – septic arthritis, osteomyelitis

Investigations

Overview

When suggesting investigations in an OSCE, the BOXES (Blood tests, Orifice tests, X-rays/imaging, ECGs, Special tests) mnemonic is useful for deciding the order of investigations:

  • Blood tests:
    • Full blood count (FBC) and differential – for infection, malignancy, immunocompromised state
    • C-reactive protein or erythrocyte sedimentation rate (ESR) – may be elevated in inflammation and infection
    • Liver function tests (LFTs) – as a baseline and for liver infection
    • Urea and electrolytes (U&Es) – as a baseline and for acute kidney injury
    • Blood cultures – if febrile and sepsis is suspected
    • Blood film – may identify abnormal cells, protozoa
    • Autoantibodies – such as anti-nuclear antibodies and rheumatoid factor for rheumatological diseases
    • HIV testing – if HIV is suspected
    • Interferon-gamma release assay – if tuberculosis is suspected
  • Orifice tests:
    • Urine microscopy, culture, and sensitivity – may identify pathogen
    • Swabs of discharge (e.g. wounds, penile, vaginal, throat) – may identify pathogen
  • X-rays/imaging:
    • Chest X-ray – for pulmonary infection
    • Abdominal ultrasound – for any abdominal masses/suspected abdominal organ infection
  • Special tests:
    • CT/MRI – may be necessary

Differential Diagnoses: Infective

Tuberculosis (TB)

History:

  • Risk factors – living in an endemic country, exposure to infected contact, HIV, immunosuppression, poverty and deprivation, intravenous drug use
  • Constitutional symptoms – fevers, weight loss, night sweats
  • Respiratory symptoms – cough, sputum, dyspnoea, haemoptysis (late sign)
  • Extrapulmonary symptoms – rash, lymphadenopathy, bone/joint pain, headache, dysuria 

Physical examination:

  • Respiratory findings – crackles, decreased breath sounds, dullness to percussion
  • Extrapulmonary features – lymphadenopathy, bone pain, joint swelling, abdominal pain, nerve palsy
  • Erythema nodosum

Investigations:

  • Sputum smear – can identify acid-fast bacilli, non-specific as all Mycobacteria species stain
  • Nucleic acid amplification tests (NAAT) – take ~48 hours, less sensitive than culture
  • Sputum culture – gold-standard and identifies drug sensitivities (takes ~1-3 weeks)
  • HIV test – offer to all people with TB as immunosuppression can reactivate it and cause presentation
  • Chest X-ray – hilar lymphadenopathy, upper lobe cavitation (can suggest reactivation), pleural effusion

HIV

History:

  • Risk factors – high-risk sexual activity (e.g. unprotected sexual intercourse, multiple sexual partners), intravenous drug use, needlestick injuries
  • Non-specific seroconversion symptoms – fever, weight loss, myalgia, lymphadenopathy, diarrhoea, sore throat 
  • Severe, prolonged, unusual, and/or recurrent infections
  • AIDS-defining illnesses – pneumocystis pneumonia, tuberculosis, toxoplasmosis, cerebral lymphoma, cytomegalovirus infection, Kaposi’s sarcoma, candidiasis etc.

Physical examination:

  • Lymphadenopathy
  • Features of an AIDS-defining illness

Investigations:

  • Combined HIV antibody and p24 antigen test – positive

Pneumonia (in general)

History:

  • Risk factors – advancing age, contact with an infected person, immunosuppression, HIV
  • Systemic upset – fever, malaise 
  • Respiratory symptoms – cough, sputum production, dyspnoea, chest pain

Physical examination:

  • Respiratory findings – crackles, decreased breath sounds, dullness to percussion

Investigations:

  • FBC – may show leukocytosis
  • CRP – may be elevated
  • Chest X-ray – shows opacification +/- infiltrates
  • Sputum culture, microscopy, and sensitivities – identifies organism

Mycoplasma pneumonia

History:

  • Risk factors – younger people (usually <30 years old), overcrowding, exposure to a person with infection, smoking
  • Prodrome of flu-like symptoms – fever, chills, malaise, myalgia, headaches
  • Followed by cough and shortness of breath – children may have wheezing

Physical examination:

  • Respiratory findings – crackles, decreased breath sounds, dullness to percussion
  • Erythema multiforme and erythema nodosum
  • Neurological disorders – including Guillain-Barré syndrome and meningoencephalitis:
  • Bullous myringitis – characterised by intensely painful bullae/vesicles on the tympanic membrane.

Investigations:

  • Full blood count (FBC) – may show haemolytic anaemia
  • Cold agglutinins test – may be positive
  • Liver function tests (LFTs) – may show elevated transaminases
  • Chest X-ray – may show bilateral consolidation
  • Antibody serology – used for diagnosis, but retrospectively:
    • Antibodies can take 2-4 weeks to develop, therefore Mycoplasma pneumoniae is often diagnosed retrospectively.
    • Cultures are difficult and relatively insensitive.

Legionella pneumonia

History:

  • Risk factors – poorly maintained/stagnant water systems (e.g. air conditioners, recent plumbing)
  • Acute flu-like symptoms (e.g. malaise, myalgia, headaches) and fever (~95%)
  • Dry cough

Physical examination:

  • Relative bradycardia
  • Respiratory findings – crackles, decreased breath sounds, dullness to percussion

Investigations:

  • Full blood count (FBC): may show lymphopenia
  • Urea and electrolytes (U&Es): may show hyponatraemia
  • Liver function tests (LFTs): may show elevated transaminases
  • Urinary antigen is the diagnostic test of choice
  • Chest X-ray: may show mid-lower zone consolidation and pleural effusions in 1/3 of people

Osteomyelitis

History:

  • Risk factors – immunocompromised state, bacteraemia (e.g. infective endocarditis), intravenous drug use, sickle-cell disease (particularly Salmonella species), diabetes mellitus, peripheral arterial disease, ulcers, skin lesions
  • Tenderness, reduced range of motion, inability to weight bear
  • Systemic upset – fever, malaise 

Physical examination:

  • Tenderness, erythema, and swelling over the affected area

Investigations:

  • FBC: may show leukocytosis
  • CRP or ESR: may be elevated
  • Blood cultures: should be taken before antibiotics, but do not delay them, identifies organism
  • MRI: diagnostic test of choice

Urinary tract infection (UTI) and pyelonephritis

History:

Physical examination:

  • Suprapubic tenderness
  • Flank pain, costovertebral tenderness in pyelonephritis

Investigations:

  • FBC – may show leukocytosis
  • Urine dipstick – shows nitrites, may have leukocytes +/- blood
  • Urine culture, microscopy, and sensitivity – identifies organism 

Sinusitis

History:

  • Risk factors – viral upper respiratory tract infection, allergic rhinitis, smoking, anatomical variation, deviated septum, polyps
  • Sinus problems – nasal congestion, discharge, throat irritation, post-nasal drip, halitosis, facial pain

Physical examination:

  • Facial pain over the affected sinus

Investigations – clinical diagnosis, rhinoscopy may assist diagnosis

Viral hepatitis

History:

  • Risk factors for B and C – high-risk sexual activity, intravenous drug use, breastfeeding, close contact, tattoos, piercings
  • Risk factors for A and E – eating/drinking high-risk food and drink, poor sanitation, close contact with an infected person
  • Flu-like symptoms – fever, malaise, anorexia, nausea, vomiting
  • Hepatic symptoms – jaundice, abdominal pain, dark urine, pale stools

Physical examination:

  • Jaundice
  • Hepatomegaly – may be tender

Investigations:

Infectious mononucleosis due to Epstein-Barr virus infection

History:

  • Risk factors – sharing utensils, kissing (‘kissing disease’), immunosuppression
  • Triad of fever, sore throat and lymphadenopathy
  • A maculopapular, pruritic rash if amoxicillin is taken during infection in nearly all patients

Physical examination:

  • Lymphadenopathy – often cervical, but can be generalised
  • Tonsillar erythema and exudates
  • Palatal petechiae may be seen
  • Splenomegaly 
  • Hepatomegaly

Investigations:

  • FBC and blood film – shows lymphocytosis and may show atypical lymphocytes
  • Heterophile antibodies (Monospot test) – ideally should be done in the 2nd week
  • LFTs – may show transiently elevated transaminases

Rheumatic fever

History:

  • Risk factors – poverty, younger age, overcrowding, family history
  • Migratory arthritis, chest pain, palpitations, dyspnoea, Sydenham’s chorea

Physical examination:

Investigations:

  • FBC – may show leukocytosis
  • ESR or CRP – usually raised
  • Blood cultures – to rule out sepsis or infective endocarditis
  • Anti-streptococcal serology – anti-streptolysin – may be positive
  • Throat swab and culture/polymerase chain reaction/rapid antigen test – may show evidence of Streptococcus pyogenes infection
  • ECG – may show PR prolongation
  • Chest x-ray – may show cardiomegaly and congestive cardiac failure
  • Echocardiogram – may show valvular dysfunction e.g. mitral regurgitation

Lyme disease

History:

  • Risk factors – tick exposure and tick bites (e.g. hiking)
  • Erythema migrans at tick bite location
  • Non-specific flu-like features – fever, headache, lethargy, joint pain, nausea
  • Later features – neurological problems (e.g. facial nerve palsy, meningitis, encephalitis), cardiovascular problems (e.g. heart block, myocarditis) 

Physical examination:

  • Erythema migrans rash

Investigations:

  • Diagnosed clinically if erythema migrans is present
  • Enzyme-linked immunosorbent assay (ELISA) for Borrelia burgdorferi antibodies:
    • If positive or equivocal, arrange an immunoblot test
    • If negative but clinical suspicion is high, retest ELISA 4-6 weeks later:
      • If still negative but suspected in someone with symptoms >12 weeks, arrange immunoblot testing

Malaria

History:

  • Risk factors – travel to an endemic area, mosquito bites, exposure to water where mosquitos mate
  • Non-specific features – high, spiking fevers, lethargy, headaches, myalgia, nausea, vomiting, jaundice, abdominal pain
  • Cyclical fever may be present – every 48 hours for Plasmodium vivax and Plasmodium ovale, every 72 hours for Plasmodium malariae

Physical examination:

  • Jaundice may be seen
  • Splenomegaly may be seen

Investigations:

  • FBC – may show anaemia and thrombocytopenia
  • U&Es – severe infection can cause renal dysfunction
  • LFTs – unconjugated bilirubin due to haemolysis
  • Serum blood glucose – shows hypoglycaemia in severe disease
  • Arterial/venous blood gas – shows metabolic acidosis in severe disease
  • Thick and thin blood films are the gold standard diagnostic test – identifies parasites

Enteric fever (typhoid)

History:

  • Risk factors – travel to an endemic area, unsanitary conditions, contaminated food/water
  • Initially systemic upset – fever, headaches, malaise, nausea 
  • Gastrointestinal features – constipation and pain

Physical examination:

  • Relative bradycardia
  • Rose spots – small red macules on the skin of the trunk

Investigations:

  • Full blood count: may show leukopenia and thrombocytopenia
  • Liver function tests (LFTs): may show elevated transaminases
  • Blood, urine, or stool cultures: may be positive

Q fever

History:

  • Risk factors – exposure to dust from infected animals
  • Sudden high fever, malaise, myalgia, headaches
  • Atypical pneumonia may develop – dry cough

Physical examination:

  • Features of pneumonia

Investigations:

  • Liver function tests (LFTs): may show elevated transaminases and alkaline phosphatase
  • Serology or polymerase chain reaction (PCR): confirms diagnosis

Dengue fever

History:

  • Risk factors – travel to an endemic area, mosquito bites
  • Non-specific features – fever, retro-orbital headache, myalgia, arthralgia, maculopapular rash
  • Thrombocytopenia, haemorrhage, disseminated intravascular coagulopathy, shock – bruising, bleeding, petechiae, purpura

Physical examination:

  • Petechiae, purpura, ecchymoses
  • Maculopapular rash

Abscess (in general)

History:

  • Recent infection/surgery in affected area (e.g. meningitis, or abdominal surgery)
  • Spiking/swinging fever

Physical examination:

  • Fluctuant, erythematous, tender mass
  • Abdominal tenderness, features of peritonism
  • Pus somewhere, pus nowhere, pus under the diaphragm – subphrenic abscess can be difficult to identify

Investigations:

  • CT: identifies and characterises abscess

Infective endocarditis (IE)

History:

  • Risk factors – intravenous drug use, valvular heart disease, congenital heart disease, valve replacement, invasive procedures (e.g. haemodialysis), dental procedure
  • Non-specific – fever, night sweats, malaise, fatigue, anorexia, weight loss
  • Cardiorespiratory – dyspnoea 

Physical examination:

  • New murmur
  • Petechiae in the conjunctiva, on the chest or abdominal wall, dorsum of the hands and feet, or in the oral mucosa and soft palate
  • Splinter haemorrhages
  • Osler’s nodes
  • Clubbing – usually if long-standing
  • Roth’s spots – retinal haemorrhages with pale centres
  • Janeway’s lesions – usually with Staphylococcus aureus IE

Investigations:

  • Blood cultures – do not delay giving empirical antibiotics
  • FBC – may show leukocytosis
  • CRP – may be elevated
  • Urinalysis – may show haematuria, RBC casts, white cell casts, proteinuria, and pyuria, suggesting distal IE spread
  • ECG – may cause PR prolongation or AV node blocks
  • Echocardiography – may show valvular, mobile vegetations

Differential Diagnoses: Malignancy

Malignancy (in general)

History:

  • Constitutional symptoms – fever, weight loss, night sweats, anorexia, malaise
  • Brain metastases – headaches, mental state changes, focal neurological deficits
  • Lung metastases – dyspnoea, cough
  • Bone metastases – intractable bone pain

Investigations – depend on the suspected site

Leukaemia (in general)

History:

  • Fatigue, dyspnoea, bruising, recurrent infections
  • Constitutional symptoms – weight loss, night sweats 

Physical examination:

  • Pallor
  • Hepatosplenomegaly

Investigations:

  • FBC – deranged cell counts
  • Blood films – may identify abnormal morphology
  • Bone marrow biopsy – diagnostic

Lymphoma (in general)

History:

  • Lymphadenopathy – non-tender
  • B-symptoms – fever, weight loss, night sweats
  • General features – fatigue, pruritus, dyspnoea

Physical examination:

  • Lymphadenopathy
  • Hepatosplenomegaly

Investigations:

  • FBC – bone marrow involvement may lead to pancytopenia, some subtypes can cause lymphocytosis
  • Blood film – may reveal abnormal cells
  • Lymph node biopsy – diagnostic test

Differential Diagnoses: Autoimmune and Inflammatory

Rheumatoid arthritis

History:

  • More common in women
  • Joint pain and swelling
  • Morning stiffness >30 minutes – 1 hour
  • Pain and stiffness improve on exertion
  • Systemic upset – fever, malaise

Physical examination:

  • Swan neck deformity
  • Boutonnière’s deformity
  • Bilateral distal polyarthropathy
  • Joints affected include MCPs and PIPs, but any can be affected

Investigations:

  • FBC – may show anaemia
  • CRP or ESR – may be elevated
  • Rheumatoid factor – positive
  • Anti-citrullinated peptide antibody (anti-CCP) – positive
  • X-ray of the hands and feet – loss of joint space, juxta-articular osteoporosis, soft tissue swelling, periarticular erosions, or subluxation

Systemic lupus erythematosus

History:

  • Risk factors – female sex, African-Caribbean, family history, smoking
  • General symptoms – fever, fatigue, lymphadenopathy, mouth ulcers 
  • Skin and hair – malar (butterfly) rash over the cheeks and bridge of the nose, sparing the nasolabial folds, photosensitive rash
  • Musculoskeletal symptoms – joint and muscle pains, often with early morning stiffness
  • Other – pulmonary (pleurisy), cardiovascular (pericarditis), neuropsychiatric (anxiety, depression, psychosis, seizures)

Physical examination:

  • Malar (butterfly) rash over the cheeks and bridge of the nose, sparing the nasolabial folds
  • Photosensitive rash
  • Discoid skin rashes
  • Alopecia
  • Lymphadenopathy

Investigations:

  • FBC – anaemia/leukopenia/thrombocytopenia
  • ESR – monitoring disease activity
  • CRP – often normal during active disease, elevation can suggest underlying infection
  • Anti-nuclear antibodies (ANA) – present in 95% of patients with SLE
  • Anti-double-stranded DNA (anti-dsDNA) – high specificity (>99%) but less sensitive
  • Other autoantibodies – anti-Smith, anti-Ro (SS-A), and anti-La (SS-B)
  • Activated partial thromboplastin time (APTT) – prolonged if antiphospholipid syndrome present
  • U&Es and urinalysis – identifies renal manifestations (haematuria, casts, proteinuria)
  • Complement levels – C3 and C4 may be low in active disease

Polymyalgia rheumatica (PMR)

History:

  • Risk factors – >50 years old, giant cell arteritis, female sex
  • Symptoms usually emerge subacutely (<1 month) – aching morning stiffness in proximal limb muscles, morning stiffness/pain in the shoulder girdle/pelvic girdle for >1 hour
  • Other non-specific symptoms – low-grade fever, anorexia, weight loss, malaise

Physical examination:

  • No true limb weakness – patients may report weakness but this is due to the pain and stiffness
  • Rapidly responds to corticosteroids

Investigations:

  • ESR or CRP – elevated
  • Creatine kinase (CK) – normal, not elevated in PMR

Giant cell arteritis

History:

  • Female sex, polymyalgia rheumatica history, >50 years old
  • Symptoms arise subacutely (generally <1 month) – headache, scalp pain/tenderness, jaw pain/claudication
  • Visual disturbances – diplopia, painless loss of vision, changes to colour vision
  • Non-specific systemic symptoms – low-grade fever, muscle aches, anorexia, night sweats, lethargy

Physical examination:

  • Fundoscopy shows a pale, swollen optic disc with blurred margins (due to anterior ischaemic optic neuropathy)
  • Temporal arteries may be palpable, tender, enlarged, ‘beady’, may have an absent pulse

Investigations:

  • ESR or CRP – ideally before starting high-dose corticosteroid, elevated and fall with corticosteroid use
  • Vascular ultrasonography of the temporal artery – wall thickening which may be non-compressible (halo sign), stenosis, or occlusion
  • Temporal artery biopsy – do not perform a biopsy if this delays treatment and shows skip lesions

Vasculitis (in general)

History:

  • Constitutional features (e.g. malaise, headaches, low-grade fever, and weight loss)
  • Purpuric/petechial rash over the extensor surfaces of the arms, legs and buttocks
  • Arthralgia, abdominal pain
  • Some types – sinusitis, haemoptysis, haematuria

Investigations:

  • Antineutrophil cytoplasmic antibodies (ANCA) – often positive

Sarcoidosis

History:

  • Risk factors – African ethnicity, <50 years old, female, family history
  • Dry cough, dyspnoea, lymphadenopathy, skin rash (erythema nodosum) 

Physical examination:

  • Erythema nodosum
  • Lymphadenopathy – usually axillary, cervical, inguinal, and submandibular
  • Symptoms of uveitis – red, painful eye, blurred vision, photophobia
  • Lupus pernio – hardened, raised, purple lesions on the nose, cheeks, lips, and ears

Investigations:

  • Chest x-ray – may show bilateral hilar lymphadenopathy
  • Serum calcium – hypercalcaemia is often present due to the cells in the granulomas producing calcitriol
  • Serum ACE – usually elevated
  • U&Es – may be deranged
  • Tuberculin skin test (Mantoux) – negative
  • ESR – usually raised
  • Tissue biopsy – shows non-caseating granulomas

Crohn’s disease

History:

  • Risk factors – family history, smoking, NSAID use
  • Non-specific features – fatigue, weight loss, malaise, fever
  • Chronic and unexplained diarrhoea (for more than 4-6 weeks), may be bloody
  • Abdominal pain

Physical examination:

  • Finger clubbing
  • Mouth ulcers
  • Pallor:
  • Signs of malnutrition and malabsorption – in children, there may be a failure to thrive or delayed puberty
  • Abdominal tenderness or a mass – often in the lower right quadrant suggesting terminal ileal inflammation
  • Signs of perianal disease – perianal pain or tenderness, skin tags, fissures, fistulas, abscesses

Investigations:

  • FBC – may show anaemia, increased white cells suggest acute or chronic inflammation, increased platelets suggest active inflammation
  • Iron studies – may show iron deficiency
  • Haematinics – may show B12 and folate deficiency
  • CRP or ESR – elevated in inflammation and correlates with disease activity
  • Stool testing – to rule out an infection such as Clostridioides difficile
  • Faecal calprotectin – a non-specific marker released from neutrophils in gastrointestinal tract inflammation
  • Colonoscopy with biopsies – diagnostic test, may show skip lesions, transmural inflammation, goblet cells, and granulomas suggest CD
  • Barium fluoroscopy, CT, or MRI – may be used to assess the bowels in regions inaccessible by endoscopy

Ulcerative colitis

History:

  • Risk factors – family history, NSAID use, infection
  • Bloody diarrhoea, rectal bleeding, faecal urgency, faecal incontinence, tenesmus
  • Abdominal pain – generally in the lower left quadrant
  • Non-specific symptoms – fatigue, malaise, anorexia, fever

Investigations:

  • FBC – may show anaemia, increased white cells, increased platelets
  • Iron studies – for iron deficiency
  • Haematinics – for serum B12 and folate deficiency
  • LFTs – may show/be used in monitoring for primary sclerosing cholangitis (PSC)
  • CRP or ESR – elevated in inflammation and correlates with disease activity
  • Stool testing – to rule out an infection such as Clostridium difficile
  • Faecal calprotectin – non-specific marker released from neutrophils in gastrointestinal tract inflammation
  • Colonoscopy with biopsies – the diagnostic test

Differential Diagnoses: Other

Deep vein thrombosis

History:

  • Risk factors – cancer, recent surgery/hospitalisation/trauma, chemotherapy, bedbound/prolonged immobility/travel, oestrogen-containing contraception or hormone replacement therapy, pregnancy/post-partum period, dehydration
  • Unilateral calf swelling – measured 10 cm below the tibial tuberosity
  • Localised tenderness to palpation along the deep vein system of the affected area
  • Erythema, asymmetric oedema, prominent superficial veins

Investigations – see deep vein thrombosis

Hyperthyroidism

History:

  • Risk factors – smoking, family history, female sex, iodine deficiency, head and neck irradiation, pregnancy (post-partum thyroiditis), amiodarone, exogenous thyroid hormone use
  • Weight loss despite increased appetite, restlessness, heat intolerance, palpitations, diarrhoea, sweating, tremors, psychiatric problems (anxiety, psychosis), oligomenorrhoea/amenorrhoea

Physical examination:

  • Hands – sweaty and warm palms, palmar erythema, fine tremor, thyroid acropachy
  • Tachycardia, atrial fibrillation
  • Hair thinning/loss
  • Brisk reflexes
  • Goitre
  • Proximal myopathy
  • Lid lag 
  • Graves’ disease – exophthalmos, ophthalmoplegia, pretibial myxoedema

Investigations:

  • TFTs – TSH low, T3 raised, T4 raised
  • TSH receptor antibodies (TRAb) – positive in Graves’ disease
  • Thyroid peroxidase antibodies (TPOAb) – positive in Hashimoto’s thyroiditis
  • Thyroid ultrasound – considered if a goitre is detected
  • Radioactive iodine uptake testing (thyroid scintigraphy) – helps distinguish between different causes of goitre

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