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    Approach to Fever of Unknown Origin in Patients with HIV/AIDS

    Cardinal Presentations / Presenting Problems, Infections

    Last Reviewed on Feb 08, 2023
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    By James Reid,Andrew Au


    • Fever of unknown origin represents a clinical challenge in patients with HIV given the population’s increased risk for disseminated opportunistic infection.
    • The relative frequency of opportunistic infections is dictated by CD4 count, and local prevalence of infectious agents.
    • Fever of unknown origin (FUO) in adults is defined as a temperature greater than 38.3°C (100.9°F) lasting for more than 3 weeks with no obvious source, despite appropriate investigation.

    Diagnostic Process


    • New site-specific symptoms.
    • Last CD4+ lymphocyte count.
    • Current treatment and adherence (e.g., HAART).
    • Recent history of drug intake, travel, or unprotected sexual contact.
    • Recent antibiotic treatment.
    • Surgical history.
    • Underlying comorbid conditions.
    • Past microbiology records – history of antibiotic resistant organisms or bacteremia.



    • Skin lesions and lymph nodes.
    • Oropharynx and sinuses.
    • Full ophthalmic examination.
    • Chest and lungs.
    • Abdomen.
    • Genital and perianal/rectal area.*
      * DRE should be avoided in immunocompromised patients.
    • Central nervous system.




    • CBC with differential.
    • Creatinine, electrolytes.
    • Liver function tests, coagulation screen, LDH.
    • Blood cultures: two sets – one peripheral and one from CVC.
    • Microbiologic testing from suspected sites of infection:
      • Urinalysis and culture.
      • Sputum microscopy and culture.
      • Stool microscopy and culture.
      • Skin lesion (aspirate, biopsy, swab, culture).
      • Chest radiograph.
      • Lumbar puncture.


    HIV-Specific Testing

    • Syphilis and toxoplasma serology.
    • HIV serology.
    • CD4 cell count and percentage.
    • HIV RNA viral load.
    • Viral hepatitis A, B, C.

    Imaging and Further Tests

    • CT abdomen/pelvis.
    • CT chest.
    • PET scan.
    • Echocardiography.
    • Bronchoalveolar lavage.
    • Bone marrow aspiration/biopsy.
    • Lymph node biopsy.

    Testing by Infection

    • STIs: Syphilis EIA, Gonorrhea and Chlamydia NAAT, Trichomonas NAAT.
    • Candida spp: culture from oral swab.
    • CMV: PCR of saliva.
    • Cryptococcus: serum and CSF for cryptococcal antigen.
    • Toxoplasma: anti-toxoplasma antibodies.
    • Mycobacterium tuberculosis: AFB stain and culture, NAAT, or mycobacterial culture from an isolate (sputum, bronchial fluid, gastric fluid, CSF, pleural fluid, peritoneal fluid, etc.)
    • Mycobacterium avium complex: AFB stain and culture.







    Pneumocystis pneumonia (PCP) (Pneumocystis jiroveci)

    1. Outpatient: indicated for mild to moderate PCP.
    • Trimethoprim-sulfamethoxazole (TMP-SMX) 2 double strength (DS) tablets (TMP 160 mg/SMX 800 mg per DS tablet) q8hr for 21 days.
    1. Intravenous: indicated for moderate to severe PCP.
    • Trimethoprim (15-20 mg/kg/day) – sulfamethoxazole (75-100 mg/kg/day) divided q6-8hr.
    • Adjunctive prednisone 40 mg PO BID for 5 days, then 50 mg PO OD for 5 days, then 20 mg PO OD for 11 days.


    1. Cryptococcal meningitis OR severe pulmonary disease OR disseminated infection.
    • Liposomal amphotericin B 3-4 mg/kg/day IV plus 5-flucytosine 25 mg/kg PO QID, or
    • Amphotericin B deoxycholate 7-1.0 mg/kg/day IV plus 5-flucytosine 25 mg/kg/day PO QID.
    1. Cryptococcosis without CNS involvement.
    • Fluconazole 400 mg (6 mg/kg) PO OD for 6-12 months.


    1. Oropharyngeal Candidiasis
    2. Systemic therapy
    • Fluconazole 100 mg PO OD for 7-14 days.
    1. Topical therapy
    • Nystatin suspension 200,000-500,000 units swish and swallow, QID, or
    • Gentian violet 5 mL (0.00165%) swish and gargle for 2 minutes and then expectorate, BID.
    1. Esophageal Candidiasis
    • Fluconazole 200-500 mg PO OD.
    1. Vulvovaginal Candidiasis
    2. Uncomplicated vulvovaginitis
    • Fluconazole 150 mg PO single dose, or
    • Clotrimazole 2% cream 5g intravaginally OD for 3 days.
    1. Severe vulvovaginitis
    • Fluconazole 150 mg PO, followed by 1-2 repeat doses at 3-day intervals, or
    • Clotrimazole 2% cream 5g intravaginally OD for 7-14 days.



    Indication: Patients in whom MAC is recovered from tissue biopsy (e.g., bone marrow) or normally sterile body fluid (e.g., blood).

    • Clarithromycin 500 mg BID or 1000 mg XL once daily PLUS

    Ethambutol 15 mg/kg OD PLUS

    Rifabutin 300 mg OD (dose adjusted as needed for drug interactions).


    Indication: Confirmed or presumed mycobacterial infection.

    • Isoniazid 300 mg OD PLUS

    Rifampin 10 mg/kg OD (maximum 600 mg/day) PLUS

    Pyrazinamide 20-30 mg/kg OD PLUS

    Ethambutol 15-25 mg/kg/ OD PLUS

    Pyridoxine 25-50 mg OD



    Community-acquired pneumonia

    Hospital-acquired pneumonia



    1. Primary, secondary, and early (< 1 yr) latent syphilis
    • Benzathine penicillin G (Bicillin) 2.4 million units (1.2 m.u. in each buttock) once.
    1. Tertiary and late (> 1 yr) latent syphilis
    • Benzathine penicillin G (Bicillin) 2.4 million units (1.2 m.u. in each buttock) IM weekly x 3 doses.
    1. Neurosyphilis
    • Aqueous crystalline penicillin G 3-4 million units IV q4h x 10-14 days.



    1. Cellulitis (no abscess, wound, or penetrating trauma)
    • Mild Infection: Cephalexin 500 mg PO QID x 5-10 days.
    • Moderate to severe infection: Cefazolin 1-2 g IV q8h.
    1. Cellulitis (with associated abscess, wound, or penetrating trauma (including IVDU)
    • Mild infection
      • I+D PLUS

    TMP-SMX 1-2 DS tablets BID PLUS

    Cephalexin 500 mg PO QID x 5-10 days

    • Severe infection
      • I+D PLUS

    Vancomycin 15 mg/kg IV q12h or linezolid 600 mg PO/IV q12h


    CMV Retinitis, Esophagitis, or Colitis

    1. Oral
    • Induction: Valganciclovir 900 mg PO BID x 14-21 days.
    • Maintenance: valganciclovir 900 mg PO daily.
    1. Intravenous
    • Induction: ganciclovir 5 mg/kg IV BID x 14-21 days.
    • Maintenance: ganciclovir 5 mg/kg IV daily.

    Note: CMV retinitis should be managed by a qualified specialist in conjunction with an experienced ophthalmologist.



    1. Mild to moderate mucocutaneous infection (e.g. orolabial or genital)

    Treat until lesions have healed, usually for 7-14 days.

    • Acyclovir 400 mg PO 3-5 times a day, or
    • Famciclovir 500 mg PO BID, or
    • Valacyclovir 1000 mg PO BID
    1. Severe mucocutaneous infection
    • Acyclovir 5 mg/kg IV q8h



    1. Primary varicella infection (chickenpox)
    • Acyclovir 10 mg/kg q8h x 7-10 days
    1. Dermatomal herpes zoster
    • Famciclovir 500 mg PO TID x 7-10 days, or
    • Valacyclovir 1 g PO TID x 7-10 days

    Quality Of Evidence?



    Related Information

    Reference List

    1. Benson, C. A., Brooks, J. T., Holmes, K. K., Kaplan, J. E., Masur, H., & Pau, A. (2009). Guidelines for prevention and treatment opportunistic infections in adults and adolescents with HIV from the CDC, the National Institutes of Health, and the HIV Medicine Association/Infectious Diseases Society of America. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf.

    2. Bissuel, F., Leport, C., Perronne, C., Longuet, P., & VILDE, J. L. (1994). Fever of unknown origin in HIV‐infected patients: a critical analysis of a retrospective series of 57 cases. Journal of internal medicine, 236(5), 529-535.

    3. Florence, E., Bottieau, E., Lynen, L., & Colebunders, R. (2002). Patients with HIV infection and fever: a diagnostic approach. Acta Clinica Belgica, 57(4), 184-190.

    4. Hot, Arnaud, Laura Schmulewitz, Jean-Paul Viard, and Olivier Lortholary. Fever of unknown origin in HIV/AIDS patients. Infectious disease clinics of North America 21, 4(2007), 1013-1032.

    5. Nguyen, T. K., Nguyen, Y. H., Nguyen, H. T., Khong, Q. M., & Tran, N. K. (2022). Etiologies of fever of unknown origin in HIV/AIDS patients, Hanoi, Vietnam. BMC Infectious Diseases, 22(1), 1-8.

    6. Therapeutic guidelines for opportunistic infections. (2022). BC Centre for Excellence in HIV/AIDS. Available at https://bccfe.ca/sites/default/files/uploads/Guidelines/BC-CfE_Therapeutic_Guidelines_for_Opportunistic_Infections-%5bOCT2022%5d.pdf.


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