Differentials
Sepsis
SIGNS / SYMPTOMS
Preceding symptoms and signs of localized infection may be more obvious.
Infectious endocarditis
SIGNS / SYMPTOMS
New heart murmur may be detected. Peripheral signs including splinter hemorrhages, Janeway lesions, Osler nodes, and Roth spots may be present.
INVESTIGATIONS
Echocardiogram may reveal valvular, mobile vegetations.
Hematuria may be detected on urine dipstick and urine microscopy.
Biliary infection
SIGNS / SYMPTOMS
Preceding symptoms and signs of localized biliary infection such as abdominal pain and tenderness in the right upper quadrant. A positive Murphy sign is often present.
INVESTIGATIONS
Abdominal ultrasound shows signs of acute cholecystitis including pericholecystic fluid, distended gallbladder, thickened gallbladder wall. Gallstones may be visualized.
CT scan may show signs of cholecystitis including irregular thickening of the gallbladder wall, poor contract-enhancement of the gallbladder wall, increased density of fatty tissue around the gallbladder, gas in the gallbladder lumen or wall, membranous structures in the lumen, perigallbladder abscess.Targeted cultures: may be positive for a specific infective organism.[6]
Urinary tract infection
SIGNS / SYMPTOMS
Preceding symptoms and signs of upper or lower urinary tract infection such as dysuria, urinary frequency, cloudy-looking urine.
INVESTIGATIONS
Dipstick urine analysis is positive for leukocyte esterase and/or nitrite.
Urine microscopy shows leukocytes and/or bacteria.
Urine culture is positive for one or more infective organisms.
Ultrasound scan of renal tract may demonstrate signs of obstruction associated with urinary infection.
CT scan of the renal tract may demonstrate signs of acute pyelonephritis, or signs of obstruction associated with urinary infection.
Tuberculosis (TB)
SIGNS / SYMPTOMS
Risk factors for TB may be present such as residence in/travel from TB-endemic region, silicosis, HIV, or immunosuppression. Cough may be present with pulmonary TB.
INVESTIGATIONS
Chest x-ray may show fibronodular opacities in upper lobes with or without cavitation, may show other atypical signs, or may be normal.
Specimen from the site of infection may be positive for Mycobacterium tuberculosis in sputum testing; for example, acid-fast bacilli smear, sputum culture, nucleic acid amplification testing (NAAT).
There may be a positive result from a tuberculin skin test (TST) or an interferon-gamma release assay (IGRAs) for M tuberculosis, although a negative result does not exclude TB.[69]
CT scan chest may show the same patterns of disease as seen with the chest x-ray.
Viral infection (e.g., HIV, viral hepatitis, parvovirus B19, measles, rubella)
SIGNS / SYMPTOMS
Specific features of each infection can help differentiate clinically.
INVESTIGATIONS
Serology, PCR: positive for the specific infection.[47]
Parasitological (e.g., toxoplasmosis, abscessed parasitosis)
SIGNS / SYMPTOMS
Specific features of each infection can help differentiate clinically
INVESTIGATIONS
Serology, PCR: positive for the specific infection.[47]
Drug-related hypersensitivity
SIGNS / SYMPTOMS
This may include a wide array of mucosal and skin manifestations typically 1-3 weeks after exposure to a new drug. Medication review may suggest a possible association between a new drug starting and the development of clinical signs.
Generalized macular or papular rash.
Drug rash with eosinophilia and systemic systems (DRESS) involves a rash that is more widespread than that in AOSD.
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) involves mucosal lesions and erythematous cutaneous macules progressing to blisters following a fever and sore throat.[70]
INVESTIGATIONS
A blood (whole blood, plasma, or serum) concentration of the suspect drug above the usual target range. Skin testing (via skin prick tests, intradermal tests, or patch tests) may help to identify a causative drug. If DRESS is present there may be liver function test abnormalities associated with hepatitis and eosinophilia detected on CBC.
Hodgkin lymphoma
SIGNS / SYMPTOMS
Dyspnea; cough; generalized pruritus; nonsymmetric, fixed and indurated lymph node enlargement; superior vena cava syndrome.
INVESTIGATIONS
Lymph node biopsy shows typical histologic features.
Non-Hodgkin lymphoma
SIGNS / SYMPTOMS
May be asymptomatic in low-grade presentations.More aggressive lymphoma may present with peripheral lymph node enlargement; splenomegaly; weight loss; fever; dyspnea; cough.
INVESTIGATIONS
Lymph node biopsy shows typical histologic features and is the preferred diagnostic test for most patients. Rarely, bone marrow aspirate and biopsy is the only available site to make the diagnosis.
Myeloproliferative disorders (e.g., chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, primary myelofibrosis)
SIGNS / SYMPTOMS
Erythromelalgia, arterial and venous thrombosis, evidence of bleeding, livedo reticularis.
INVESTIGATIONS
Bone marrow biopsy showing abnormal cells according to the type of myeloproliferative disorder.
In chronic myeloid leukemia, peripheral blood smear shows most white blood cells are neutrophils with a left shift (mature or maturing myeloid cells).
Abnormal hematocrit in polycythemia vera.
Solid cancers (e.g., of the kidney, colon, lung)
SIGNS / SYMPTOMS
Symptoms and signs predominantly associated with the affected organ (e.g., cough with lung cancer).
INVESTIGATIONS
Imaging (e.g., CT scan, PET/CT scan) showing one or more masses consistent with tumor.
Biopsies from the site, which may be obtained endoscopically, confirming malignancy.
Rheumatoid arthritis
SIGNS / SYMPTOMS
No differentiating symptoms/signs in early presentations.
Systemic lupus erythematosus (SLE)
SIGNS / SYMPTOMS
Malar (butterfly) rash, photosensitive skin, discoid skin rash.
Raynaud phenomenon.
There may be evidence of venous or arterial thrombosis.
INVESTIGATIONS
Antinuclear autoantibodies typically positive, but may also be positive in other connective tissue diseases. Anti-dsDNA and anti-Smith antibodies are highly specific for SLE.
Idiopathic inflammatory myopathies/dermatomyositis
SIGNS / SYMPTOMS
Muscle weakness and atrophy.
Heliotrope rash (violaceous to dusky-red rash) with eyelid edema - highly suggestive of dermatomyositis.
Gottron papules (violaceous to dusty-red flat-topped papules and plaques over the dorsal surface of knuckles and more rarely the wrists, elbows, knees, and malleoli) with dermatomyositis.
INVESTIGATIONS
Muscle MRI may show increased edema with dermatomyositis and polymyositis.
Muscle biopsy may show perivascular or interfascicular inflammation, endothelial hyperplasia in the intramuscular blood vessels, perifascicular atrophy with dermatomyositis; endomysial inflammatory infiltrates, muscle necrosis, atrophy, muscle fiber regeneration with polymyositis.
Skin biopsy may show vacuolar alteration of the basal layer of the epidermis, necrotic keratinocytes, vascular dilation, perivascular lymphocytic infiltrate with dermatomyositis.
Polyarteritis nodosa or other vasculitis
SIGNS / SYMPTOMS
Signs of mononeuritis multiplex, paresthesia, diastolic blood pressure >90 mmHg.
INVESTIGATIONS
Antineutrophil cytoplasmic antibodies (ANCA): positive in ANCA-associated vasculitis but negative in polyarteritis nodosa.
Arteriography shows evidence of vasculitis, such as beading, aneurysm, or smooth tapering vessel stenosis. May test positive for hepatitis B virus infection.
Biopsy of affected tissue, if feasible, can help establish the diagnosis.
In polyarteritis nodosa, renal angiogram may show the classical feature of aneurysms.
Post-streptococcal arthritis
SIGNS / SYMPTOMS
No obvious differentiating symptoms or signs
INVESTIGATIONS
Antistreptolysin O: titers showing recent streptococcal infection.
Reactive arthritis
SIGNS / SYMPTOMS
Conjunctivitis, symptoms of urethritis, and arthritis occurring after an infection.
INVESTIGATIONS
HLA-B27 may be positive (although a negative test does not exclude reactive arthritis).
MRI of affected joints: sacroiliitis or enthesopathy/enthesitis
Sarcoidosis
SIGNS / SYMPTOMS
Cough, dyspnea, wheeze, signs of uveitis.
INVESTIGATIONS
Chest x-ray: bilateral hilar adenopathy
Serum angiotensin converting enzyme (ACE) elevated in about half of patients.
Biopsy of lesion - histology showing noncaseating granulomatosis.
Familial Mediterranean fever
SIGNS / SYMPTOMS
Positive family history.
More likely to have Italian, Greek, Turkish, Armenian, Sephardi Jewish, or Japanese ethnicity.
Erysipeloid erythema may be present (7% to 40% of patients).[71]
Peritonitis may be present.
INVESTIGATIONS
Mediterranean fever (MEFV) gene analysis: mutation present
Mevalonate kinase deficiency
SIGNS / SYMPTOMS
May be triggered by vaccination, although a provoking trigger is not always present.
INVESTIGATIONS
Elevated serum IgD >100 mg/dL.
Urinary mevalonic acid elevated during an attack.
Mevalonate kinase analysis showing deficiency in enzyme activity
NLRP3 autoinflammatory disease (NLRP3-AID) (formerly known as cryopyrin-associated periodic syndrome or CAPS)
SIGNS / SYMPTOMS
Positive family history.
Urticaria-like neutrophilic rash (neutrophilic urticarial dermatosis).
Sensorineural hearing loss.
Conjunctivitis/uveitis
INVESTIGATIONS
NLRP3 (formerly CIAS1) gene analysis: pathogenic variant identified.
Schnitzler syndrome
SIGNS / SYMPTOMS
Urticarial-like neutrophilic rash (neutrophilic urticarial dermatosis).
Deep bone pain.
INVESTIGATIONS
Serum electrophoresis/immune fixation shows monoclonal gammopathy of undetermined significance (MGUS): monoclonal IgM gammopathy present in majority of patients (IgG in a minority)
VEXAS syndrome
SIGNS / SYMPTOMS
Generally has onset at an older age.
May be associated with a myelodysplastic syndrome and, in rare cases, can present as such.
Periorbital edema.
History of relapsing polychondritis and thrombotic events.
INVESTIGATIONS
CBC: cytopenia.
UBA1 gene analysis: pathogenic variant identified.
Febrile neutrophilic dermatosis (Sweet syndrome)
SIGNS / SYMPTOMS
Characteristic tender eruptions.
INVESTIGATIONS
Biopsy of skin lesion: infiltrate of neutrophils in the dermis.
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