Fever with lymphadenopathy

Fever with lymphadenopathy is a temperature of 38.0 C or over with enlarged lymph nodes, either localised to one region or generalised. Most are caused by infection.

Definitions. A node is abnormal when over 1 cm in diameter (epitrochlear over 0.5 cm, inguinal over 1.5 cm), or when it is hard, matted, fixed, rapidly growing, or in the supraclavicular fossa. Localised lymphadenopathy involves one region. Generalised lymphadenopathy involves 2 or more noncontiguous regions.

Mechanisms. Reactive hyperplasia, direct infection of the node (lymphadenitis), infiltration by tumour or histiocytes, and granulomatous inflammation.

Patterns by site

• Cervical: pharyngitis, dental infection, mononucleosis, cat scratch disease, tuberculosis (scrofula), lymphoma, nasopharyngeal carcinoma, Kikuchi disease, toxoplasmosis and rubella.
• Supraclavicular: always suspicious (lung, gastrointestinal and breast cancer, lymphoma, tuberculosis).
• Axillary: infection of the arm or breast, cat scratch disease, brucellosis, lymphoma and breast cancer.
• Inguinal: leg and genital infection, sexually transmitted infection (lymphogranuloma venereum, chancroid, syphilis, herpes), lymphatic filariasis and plague.
• Generalised: HIV, Epstein-Barr virus and cytomegalovirus infection, syphilis, tuberculosis, lymphoma, leukaemia, systemic lupus erythematosus, sarcoidosis, drug reaction, brucellosis and visceral leishmaniasis.

Key distinctions. Tender, warm nodes suggest acute infection. Painless, firm, rubbery nodes suggest lymphoma. Hard, fixed nodes suggest metastasis. Matted nodes with sinus formation suggest tuberculosis. A node with a draining lesion and fever after animal exposure suggests cat scratch disease, tularaemia or plague.

History

• Onset, tempo and duration of enlargement, pain, change in size, and which regions are involved.
• Fever pattern, night sweats, weight loss over 10% in 6 months, itch, alcohol induced node pain (Hodgkin lymphoma), fatigue, and bone pain.
• Preceding sore throat, dental problem, skin wound, insect bite, scratch, or genital ulcer.
• Exposures: cats and kittens, rabbits, ticks, rodents and fleas, livestock, unpasteurised milk, raw meat, soil and thorns, tuberculosis contacts, travel, mosquito bites and freshwater exposure.
• Sexual history, injecting drug use, HIV risk and blood transfusion.
• Drugs: phenytoin, carbamazepine, allopurinol, hydralazine, penicillins, sulphonamides, isoniazid, atenolol, captopril and others causing serum sickness or hypersensitivity.
• Joint pain, rash, mouth ulcers and eye symptoms.
• HIV status, immunosuppression, vaccination, family history of lymphoma, and prior cancers.
• Cough, breathlessness, abdominal pain and bowel symptoms.

Examination

• Vital signs, perfusion and general condition. Weight and body mass index.
• All node regions (occipital, preauricular, cervical, supraclavicular, axillary, epitrochlear, inguinal, popliteal): size, number, consistency, tenderness, fixation, matting, overlying skin changes, sinus or fluctuance. Measure and record in centimetres.
• Drainage area: scalp, ears, mouth, throat, teeth, skin of the head and neck, breast, arms, legs, genitalia and anus. Look for primary lesions (eschar, chancre, bite, ulcer).
• Oropharynx: exudate, tonsillar enlargement, palatal petechiae, oral candida, hairy leukoplakia, ulcers and gum swelling.
• Liver and spleen size, abdominal masses and ascites.
• Skin: rash, nodules, petechiae, purpura, vesicles and erythema nodosum.
• Chest and heart examination. Joint swelling. Testes. Fundoscopy.
• Lymphoedema and elephantiasis (filariasis), and the Winterbottom sign (posterior cervical nodes in trypanosomiasis).

Red flags

• Nodes over 2 cm, hard, fixed or matted, or rapidly enlarging over weeks.
• Supraclavicular, scalene or epitrochlear enlargement.
• Fever with weight loss, night sweats, pruritus and hepatosplenomegaly.
• Bleeding, bruising, pallor or abnormal blood count (leukaemia, haemophagocytic lymphohistiocytosis).
• Airway compression (stridor, dysphagia), superior vena cava obstruction signs, or spinal cord compression symptoms.
• Fever with generalised lymphadenopathy and organ dysfunction (haemophagocytic lymphohistiocytosis, hypersensitivity syndrome, sepsis).
• Painful swollen node with sepsis, bubo with fever and exposure to fleas, rodents or a plague outbreak.
• HIV with CD4 under 200 cells/microlitre and new lymphadenopathy.
• Nodes persisting over 4 weeks without a cause, or enlarging despite antibiotics.
• Immunosuppression, pregnancy and children with a neck mass.

Special groups

• Pregnancy: toxoplasmosis, cytomegalovirus infection, syphilis and lymphoma require early specialist input. Avoid doxycycline and fluoroquinolones.
• Children: reactive nodes are common and usually benign, with cat scratch disease, nontuberculous mycobacterial lymphadenitis, Kawasaki disease, tuberculosis and lymphoma as important causes.
• Older adults: metastasis, lymphoma, tuberculosis reactivation and drug related causes.
• Immunocompromised: atypical mycobacteria, histoplasmosis, penicilliosis, cryptococcosis, toxoplasmosis, Kaposi sarcoma, lymphoma and IRIS after antiretroviral therapy.
• Region specific: tuberculous lymphadenitis, lymphatic filariasis, trypanosomiasis, visceral leishmaniasis, plague, brucellosis, Burkitt lymphoma, endemic Kaposi sarcoma, histoplasmosis, penicilliosis and lymphogranuloma venereum.

Viral

• Infectious mononucleosis (Epstein-Barr virus): pharyngitis, posterior cervical nodes, splenomegaly, atypical lymphocytes.
• Cytomegalovirus infection.
• Acute HIV infection and persistent generalised lymphadenopathy.
• Rubella, measles and adenovirus infection.
• Herpes simplex (primary genital infection with inguinal nodes).
• Dengue and mpox (marked lymphadenopathy in mpox).
• Hepatitis B prodrome.

Bacterial and rickettsial

• Streptococcal pharyngitis and dental or skin infection with regional lymphadenitis.
• Staphylococcal lymphadenitis and abscess.
• Cat scratch disease (Bartonella henselae): tender regional node after a scratch or bite.
• Tuberculous lymphadenitis (scrofula): painless matted cervical nodes, may form sinuses.
• Nontuberculous mycobacterial lymphadenitis (children).
• Secondary syphilis (generalised painless nodes, rash) and primary syphilis (regional nodes with chancre).
• Lymphogranuloma venereum and chancroid (painful inguinal buboes).
• Brucellosis.
• Tularaemia (ulceroglandular).
• Plague (bubonic).
• Anthrax, cutaneous with regional nodes.
• Rickettsial disease (African tick bite fever with regional nodes and eschar, scrub typhus).
• Melioidosis and glanders.
• Typhoid fever with mesenteric adenitis.
• Leptospirosis, rat bite fever, Lyme disease and relapsing fever.
• Yersinia mesenteric adenitis.

Fungal and parasitic

• Histoplasmosis, penicilliosis and cryptococcosis.
• Toxoplasmosis.
• Visceral leishmaniasis.
• East and West African trypanosomiasis.
• Lymphatic filariasis (acute adenolymphangitis).
• Loiasis and onchocerciasis nodes.
• Acute schistosomiasis.
• Malaria with reactive adenopathy, rare.

Neoplastic and haematological

• Hodgkin lymphoma and non Hodgkin lymphoma, including Burkitt lymphoma.
• Acute and chronic leukaemia.
• Kaposi sarcoma and Castleman disease.
• Metastatic carcinoma (head and neck, breast, lung, gastrointestinal, genitourinary, melanoma).
• Haemophagocytic lymphohistiocytosis.
• Langerhans cell histiocytosis and Rosai-Dorfman disease.
• Angioimmunoblastic T cell lymphoma.

Inflammatory and drug related

• Systemic lupus erythematosus.
• Adult onset Still disease.
• Sarcoidosis.
• Kawasaki disease (unilateral cervical node over 1.5 cm).
• Kikuchi-Fujimoto disease (histiocytic necrotising lymphadenitis).
• Rheumatoid arthritis.
• Serum sickness and drug hypersensitivity (including DRESS).
• Immunoglobulin G4 related disease.
• Autoimmune lymphoproliferative disorders.

Step 1. Triage. Look for sepsis, airway compression, bleeding, tumour lysis risk, and features of haemophagocytic lymphohistiocytosis. Treat life threatening conditions first.

Step 2. Classify the pattern. Localised or generalised, acute or persistent, tender or painless, the drainage area, and associated exposure. Localised acute tender nodes with a clear source may be observed or treated for 2 to 4 weeks. Persistent nodes or any red flag need a tissue diagnosis.

Step 3. First line tests

• Full blood count with differential and film: atypical lymphocytes (Epstein-Barr virus, cytomegalovirus, toxoplasmosis, acute HIV), lymphocytosis, blasts, cytopenias, eosinophilia (drug reaction, helminth, lymphoma).
• ESR, CRP, LDH (raised in lymphoma and leukaemia), uric acid, urea, creatinine, electrolytes, calcium, liver tests, albumin, ferritin and urinalysis.
• Blood cultures, malaria rapid test and films, HIV test, syphilis serology, and hepatitis B and C serology.
• Throat swab or rapid test for group A streptococcus.
• Heterophile antibody (monospot) and Epstein-Barr virus viral capsid antigen IgM, cytomegalovirus IgM or PCR, and toxoplasma IgG and IgM. Heterophile tests can be negative in the first week and in young children.
• Interferon gamma release assay or tuberculin test (does not exclude active disease), chest radiograph, and sputum nucleic acid amplification test.
• Bartonella serology or PCR, Brucella culture and serology, tularaemia serology, rickettsial PCR and serology, and chlamydia serology or lymphogranuloma venereum PCR from a genital swab or bubo aspirate when indicated.
• Pregnancy test.
• ANA, anti dsDNA, complement and rheumatoid factor when autoimmune disease is suspected.

Step 4. Imaging

• Ultrasound of the node: reactive nodes are oval with long to short axis ratio of 2 or more and a preserved echogenic hilum with central vascularity. Round shape, loss of the hilum, cortical thickening, necrosis, calcification (tuberculosis) and chaotic peripheral vascularity suggest malignancy or tuberculosis.
• CT of neck, chest, abdomen and pelvis for generalised or persistent disease, mediastinal nodes and staging.
• PET CT for staging and for selecting the biopsy site in lymphoma.
• Abdominal ultrasound for hepatosplenomegaly and mesenteric nodes.

Step 5. Tissue diagnosis. Do this early for nodes over 2 cm, persisting over 4 weeks, enlarging, or with red flags, and before any corticosteroid.

• Excisional biopsy of the most abnormal node (not the largest) is preferred for suspected lymphoma, with the whole node sent fresh for histology, immunohistochemistry, flow cytometry, cytogenetics, and culture (bacterial, mycobacterial and fungal).
• Core needle biopsy when excision is not feasible. Fine needle aspiration is useful for tuberculosis (Gram, Ziehl-Neelsen stain, nucleic acid amplification and culture), metastatic carcinoma and abscess, but cannot reliably diagnose or classify lymphoma.
• In suspected tuberculous scrofula avoid incisional biopsy and drainage, which can cause chronic sinuses. Use aspiration.
• Bone marrow aspirate and trephine for cytopenias, blasts, suspected haemophagocytic lymphohistiocytosis, and staging.
• Biopsy of the primary lesion (chancre, ulcer, eschar) when present.
• Skin snips and Leishmania tests: splenic or bone marrow aspirate for visceral leishmaniasis, rK39 rapid test and PCR. Blood film, card agglutination test and lymph node aspirate for trypanosomiasis. Night blood film for lymphatic filariasis (samples taken between 22:00 and 02:00 for Wuchereria bancrofti), or antigen test.

Step 6. Interpretation. Histology can show granulomas (tuberculosis, sarcoidosis, cat scratch disease, fungal infection), stellate necrosis with neutrophils (cat scratch disease), histiocytic necrosis without neutrophils (Kikuchi disease), atypical lymphoid proliferation (lymphoma) and Reed-Sternberg cells (Hodgkin lymphoma). In HIV, interpret with CD4 count and viral load.

Limits. A node biopsy can be nonspecific (reactive hyperplasia), and repeat biopsy may be needed if nodes keep growing. Fine needle aspiration can miss lymphoma. Serology is often negative early. Tuberculin and interferon gamma release assays are often negative in HIV and malnutrition. Monospot tests are less reliable in the first week.

Immediate. Sepsis, airway compromise, superior vena cava obstruction, spinal cord compression and tumour lysis syndrome are treated as emergencies. For sepsis give oxygen, blood cultures, crystalloid boluses of 250 to 500 mL with reassessment, noradrenaline to keep mean arterial pressure at 65 mmHg or over, and antibiotics within 1 hour.

Suspected plague: isolate and give gentamicin 5 mg/kg intravenously once daily with doxycycline 100 mg twice daily, and notify public health. Do not give systemic corticosteroids for undiagnosed lymphadenopathy, because they can obscure lymphoma and tuberculosis and prevent diagnosis, unless airway obstruction or haemophagocytic lymphohistiocytosis requires it, and only after a biopsy where possible.

Symptomatic care. Paracetamol 1 g orally every 6 hours (maximum 4 g daily; 3 g daily in hepatic impairment, chronic alcohol use or weight under 50 kg). Ibuprofen 400 mg orally three times daily with food, maximum 1.2 g daily without specialist advice, avoided in kidney impairment, peptic ulcer, dengue and anticoagulation. Warm compresses for tender nodes. Rest and fluids.

Cause directed

• Acute bacterial lymphadenitis (streptococcal or staphylococcal): flucloxacillin 500 mg to 1 g orally four times daily for 7 to 10 days (clarithromycin 250 to 500 mg orally twice daily if penicillin allergic). Aspirate or drain fluctuant nodes. Streptococcal pharyngitis: phenoxymethylpenicillin 500 mg orally four times daily for 10 days.
• Infectious mononucleosis: supportive care, avoid amoxicillin and contact sport for 4 weeks. Corticosteroids (prednisolone 40 mg orally daily for 5 to 7 days) only for airway obstruction, severe thrombocytopenia or haemolysis, with evidence of benefit limited.
• Cytomegalovirus infection in immunocompetent patients: supportive care only.
• Acute HIV infection and persistent lymphadenopathy: start antiretroviral therapy and test partners.
• Cat scratch disease: azithromycin 500 mg orally once, then 250 mg once daily for 4 days (shortens node resolution in large nodes). Aspirate suppurative nodes. Immunocompromised patients and bacillary angiomatosis: doxycycline 100 mg orally twice daily or erythromycin 500 mg four times daily for 3 months.
• Tuberculous lymphadenitis: isoniazid 5 mg/kg (maximum 300 mg), rifampicin 10 mg/kg (maximum 600 mg), pyrazinamide 25 mg/kg (maximum 2 g) and ethambutol 15 to 20 mg/kg orally daily for 2 months, then isoniazid and rifampicin for 4 months, with pyridoxine 25 to 50 mg daily. Check liver tests at baseline and monthly at first. Expect paradoxical enlargement in 20 to 30% of patients, which does not mean failure. Aspirate fluctuant nodes. Start antiretroviral therapy within 2 to 8 weeks in HIV, in specialist care.
• Nontuberculous mycobacterial lymphadenitis in children: surgical excision is the usual treatment, with clarithromycin and rifabutin under specialist care when surgery is not possible.
• Syphilis (primary, secondary or early latent): benzathine benzylpenicillin 2.4 million units intramuscularly once. If penicillin allergic and not pregnant: doxycycline 100 mg orally twice daily for 14 days. Late latent disease: benzathine benzylpenicillin 2.4 million units intramuscularly weekly for 3 weeks. Warn about the Jarisch-Herxheimer reaction. Trace contacts.
• Lymphogranuloma venereum: doxycycline 100 mg orally twice daily for 21 days (azithromycin 1 g orally weekly for 3 weeks in pregnancy), with aspiration of fluctuant buboes through normal skin.
• Chancroid: azithromycin 1 g orally once, or ceftriaxone 250 mg intramuscularly once.
• Brucellosis: doxycycline 100 mg orally twice daily for 6 weeks plus gentamicin 5 mg/kg intravenously or intramuscularly once daily for 7 days, or rifampicin 600 to 900 mg daily (specialist). Avoid doxycycline in pregnancy.
• Tularaemia: gentamicin 5 mg/kg intravenously once daily for 7 to 14 days in severe disease, or doxycycline 100 mg orally twice daily for 14 to 21 days in mild disease.
• Plague: gentamicin 5 mg/kg intravenously once daily with doxycycline 100 mg twice daily, notification, isolation, and prophylaxis for contacts.
• African tick bite fever and other rickettsial disease: doxycycline 100 mg orally twice daily for 5 to 7 days and for at least 3 days after fever settles.
• Toxoplasmosis in immunocompetent patients: usually no drug treatment. In pregnancy, give spiramycin 1 g orally every 8 hours and refer for foetal medicine care. In immunocompromised patients, pyrimethamine 200 mg loading then 50 to 75 mg daily with sulphadiazine 1 to 1.5 g orally every 6 hours and folinic acid 10 to 25 mg daily, under specialist care.
• Lymphatic filariasis: doxycycline 200 mg orally daily for 4 to 6 weeks (not in pregnancy or under 8 years), with diethylcarbamazine 6 mg/kg orally daily for 12 days, or single dose diethylcarbamazine 6 mg/kg with albendazole 400 mg after excluding loiasis and onchocerciasis, under specialist direction. Limb hygiene, antibiotics for acute attacks (flucloxacillin 500 mg four times daily for 7 days), and compression for lymphoedema.
• Visceral leishmaniasis: liposomal amphotericin B (total dose 20 to 30 mg/kg given as 3 to 5 mg/kg intravenously on separate days), or in East Africa sodium stibogluconate 20 mg/kg intramuscularly daily with paromomycin 15 mg/kg intramuscularly daily for 17 days, under specialist direction with ECG, liver, pancreas and kidney monitoring.
• African trypanosomiasis: specialist treatment based on stage and species after lumbar puncture.
• Histoplasmosis, penicilliosis and cryptococcosis in HIV: liposomal amphotericin B 3 to 5 mg/kg intravenously daily for 2 weeks, then itraconazole 200 mg orally twice daily for 10 weeks and 200 mg daily as maintenance.
• Lymphoma and leukaemia: urgent haematology and oncology referral for staging and treatment. Tumour lysis prevention in high risk disease: hydration and allopurinol 300 mg orally daily (100 mg when creatinine clearance is under 30 mL/min), or rasburicase 0.2 mg/kg intravenously daily after G6PD testing.
• Haemophagocytic lymphohistiocytosis: urgent haematology referral, dexamethasone 10 mg/m2 daily, treatment of the trigger, and intensive care support.
• Kawasaki disease: intravenous immunoglobulin 2 g/kg as a single infusion over 10 to 12 hours, with aspirin as directed by the paediatric specialist.
• Kikuchi-Fujimoto disease: self limiting over 1 to 4 months, NSAIDs for symptoms (ibuprofen 400 mg three times daily), and prednisolone 0.5 to 1 mg/kg daily for 1 to 2 weeks with taper for severe or prolonged disease. Exclude lupus.
• Systemic lupus erythematosus, adult onset Still disease and sarcoidosis: rheumatology or specialist referral.
• Drug hypersensitivity: stop the culprit. DRESS needs prednisolone 0.5 to 1 mg/kg orally daily (maximum 80 mg), tapered over 6 to 12 weeks, with eosinophils, liver tests, creatinine and troponin monitoring.
• Metastasis: oncology referral and staging.
• Observation: for localised nodes under 2 cm with a clear benign cause and no red flags, review at 2 to 4 weeks. Biopsy any node that persists over 4 weeks, enlarges, or has red flags.

Monitoring. Measure and record node size at each visit with ultrasound where possible. Vital signs and temperature daily in hospital. Weekly blood count, liver tests and creatinine on tuberculosis therapy for the first month. Review at 2 to 4 weeks for observed nodes and at 4 to 6 weeks after treatment of infection.

Referral and escalation. Haematology or oncology within 2 weeks for suspected lymphoma, leukaemia or metastasis, and same day for haemophagocytic lymphohistiocytosis. Infectious diseases for tuberculosis, HIV, travel related disease, filariasis, leishmaniasis, brucellosis and unexplained fever. ENT or surgical review for a neck mass and biopsy. Rheumatology for autoimmune disease. Paediatrics for children with persistent nodes. Public health for tuberculosis, plague, tularaemia, syphilis, HIV, brucellosis and other notifiable disease.

Admission criteria. Sepsis, airway compromise, haemophagocytic lymphohistiocytosis, suspected plague, abscess requiring drainage, severe pancytopenia, inability to take oral therapy, immunocompromise with high fever, and organ dysfunction.

Discharge and follow up. Discharge when stable, tolerating oral intake, with a clear plan for biopsy results and review within 1 to 2 weeks. Tuberculosis treatment needs directly observed therapy and contact screening. Safety net advice: return for rapid node growth, new nodes, difficulty breathing or swallowing, bleeding, weight loss, night sweats, persistent fever, new rash, or swelling of the face or arms.