Approach to Fever of Unknown Origin in Patients with HIV/AIDS
Cardinal Presentations / Presenting Problems, Infections
- 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.
- 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.
- 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.
- 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.
- 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.
OPPORTUNISTIC INFECTIONS BY CD4 COUNT
- Antibiotics are recommended in cases with clinical evidence of focus of infection. The threshold to administer antibiotics should be lower for patients with lower CD4 counts.
- Antibiotic choice is dictated by suspected or confirmed causative bacteria.
- See below for management by causative organism.
- Refer to BC Centre for Excellence in HIV/AIDS Therapeutic Guidelines for Opportunistic Infections for full details.
Pneumocystis pneumonia (PCP) (Pneumocystis jiroveci)
- 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.
- 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.
- 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.
- Cryptococcosis without CNS involvement.
- Fluconazole 400 mg (6 mg/kg) PO OD for 6-12 months.
- Oropharyngeal Candidiasis
- Systemic therapy
- Fluconazole 100 mg PO OD for 7-14 days.
- 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.
- Esophageal Candidiasis
- Fluconazole 200-500 mg PO OD.
- Vulvovaginal Candidiasis
- Uncomplicated vulvovaginitis
- Fluconazole 150 mg PO single dose, or
- Clotrimazole 2% cream 5g intravaginally OD for 3 days.
- 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.
MYCOBACTERIUM AVIUM COMPLEX (MAC)
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
- Primary, secondary, and early (< 1 yr) latent syphilis
- Benzathine penicillin G (Bicillin) 2.4 million units (1.2 m.u. in each buttock) once.
- 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.
- Aqueous crystalline penicillin G 3-4 million units IV q4h x 10-14 days.
SKIN AND SOFT TISSUE INFECTIONS
- 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.
- 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
- Induction: Valganciclovir 900 mg PO BID x 14-21 days.
- Maintenance: valganciclovir 900 mg PO daily.
- 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.
HERPES SIMPLEX VIRUS
- 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
- Severe mucocutaneous infection
- Acyclovir 5 mg/kg IV q8h
VARICELLA ZOSTER VIRUS
- Primary varicella infection (chickenpox)
- Acyclovir 10 mg/kg q8h x 7-10 days
- 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?
We are highly confident that the true effect lies close to that of the estimate of the effect. There is a wide range of studies included in the analyses with no major limitations, there is little variation between studies, and the summary estimate has a narrow confidence interval.
We consider that the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. There are only a few studies and some have limitations but not major flaws, there are some variations between studies, or the confidence interval of the summary estimate is wide.
When the true effect may be substantially different from the estimate of the effect. The studies have major flaws, there is important variations between studies, of the confidence interval of the summary estimate is very wide.
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.
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.
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.
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.
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.
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.
The purpose of this document is to provide health care professionals with key facts and recommendations for the diagnosis and treatment of patients in the emergency department. This summary was produced by Emergency Care BC (formerly the BC Emergency Medicine Network) and uses the best available knowledge at the time of publication. However, healthcare professionals should continue to use their own judgment and take into consideration context, resources and other relevant factors. Emergency Care BC is not liable for any damages, claims, liabilities, costs or obligations arising from the use of this document including loss or damages arising from any claims made by a third party. Emergency Care BC also assumes no responsibility or liability for changes made to this document without its consent.
Last Updated Feb 08, 2023
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