• 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.

HISTORY

• 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.

PHYSICAL EXAMINATION

• 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.

INVESTIGATIONS

General

• 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.

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.

FUNGAL INFECTIONS

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.

2. 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.

Cryptococcosis

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.

2. Cryptococcosis without CNS involvement.

• Fluconazole 400 mg (6 mg/kg) PO OD for 6-12 months.

Candidiasis

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.

2. Esophageal Candidiasis

• Fluconazole 200-500 mg PO OD.

3. Vulvovaginal Candidiasis
4. 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.

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).

TUBERCULOSIS

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

PNEUMONIA

Community-acquired pneumonia

• Refer to Community Acquired Pneumonia (Adult) – Treatment

Hospital-acquired pneumonia

• Refer to Hospital Acquired Pneumonia (Adult) – Treatment

SYPHILIS

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.

2. 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.

3. Neurosyphilis

• Aqueous crystalline penicillin G 3-4 million units IV q4h x 10-14 days.

SKIN AND SOFT TISSUE INFECTIONS

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.

2. 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

CYTOMEGALOVIRUS

CMV Retinitis, Esophagitis, or Colitis

1. Oral

• Induction: Valganciclovir 900 mg PO BID x 14-21 days.
• Maintenance: valganciclovir 900 mg PO daily.

2. 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.

HERPES SIMPLEX VIRUS

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

2. Severe mucocutaneous infection

• Acyclovir 5 mg/kg IV q8h

VARICELLA ZOSTER VIRUS

1. Primary varicella infection (chickenpox)

• Acyclovir 10 mg/kg q8h x 7-10 days

2. Dermatomal herpes zoster

• Famciclovir 500 mg PO TID x 7-10 days, or
• Valacyclovir 1 g PO TID x 7-10 days

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.