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Ovid: Oxford Handbook of Genitourinary Medicine, HIV, and Aids

Editors: Pattman, Richard; Snow, Michael; Handy, Pauline; Sankar, K. Nathan; Elawad, Babiker Title: Oxford Handbook of Genitourinary Medicine, HIV, and Aids, 1st Edition Copyright ©2005 Oxford University Press > Table of Contents > HIV/AIDS > Chapter 46 – HIV: pyrexia of unknown origin Chapter 46 HIV: pyrexia of unknown origin P.456
Introduction Pyrexia of unknown origin (PUO) was defined by Petersdorf and Beeson (1961) as a temperature of >38.3°C on multiple occasions over a period of >3 weeks with failure to reach a diagnosis after 1 week of investigation. HIV-related diseases are an important cause of prolonged fever and must be considered in patients with PUO. In patients with known HIV infection PUO may arise during follow-up. Durack and Street (1991) produced a definition of HIV associated PUO, including temperatures >38.3°C on multiple occasions over a period of >4 weeks for out-patients or 3 days for inpatients, with negative microbiological results after at least 2 days incubation. PUO occurs predominantly in the late stages of infection with CD4 counts <100cells/µL and is less common in patients on effective HAART. In the general population, infections account for only 33% of PUO. However, in HIV positive patients, infectious diseases are the predominant aetiology accounting for 80–90% with neoplasia and drug reactions accounting for most of the others. A cause can be found in 80%. In those with undetermined diagnoses fever may settle spontaneously. In the general population a single pathology is almost universal but two or more simultaneous pathologies may be found in about 20% of HIV-related cases. Even if patients are taking standard prophylaxis against agents, such as Pneumocystis jiroveci (carinii) or Mycobacterium avium complex (MAC), these cannot be excluded without appropriate investigation. There are important geographical differences e.g. tuberculosis and leishmaniasis are much more common in Europe compared with USA. It is also important to consider non-HIV-related causes and other infections, e.g. gonorrhoea, whose presentation may be modified by immunodeficiency. Strenuous diagnostic efforts are important in PUO as it may enable the diagnosis and treatment of infections before the onset of specific organ dysfunction, e.g. a Pneumocystis jiroveci infection. A careful history including sexual, travel, and drugs (prescribed and non-prescribed) is mandatory. HIV-related aetiology (data from Europe and USA)

  • Mycobacterial infection
    • Mycobacterium tuberculosis: 7% (USA)–37% (Europe). CD4 count may be normal
    • Mycobacterium avium complex: 12–31% (CD4 count <100cells/µL)
    • Others (e.g. M. kansasii, M. genavense): 1–5%.
  • Pneumocystis jiroveci: 5–13% (CD4 count <200cells/µL)
  • Viral
    • Cytomegalovirus: 5–9% (CD4 count <50cells/µL)
    • HIV itself, herpes simplex virus, varicella zoster virus, parvovirus B19, adenovirus, hepatitis virus B and C: 2–7%.
  • P.457

  • Bacterial: 5–7%.
  • Fungal (cryptococcosis, candidaemia, disseminated histoplasmosis, aspergillosis, Penicillium marneffei: 2–8% (CD4 count <200cells/µL)
  • Parasitic
    • Leishmaniasis: ~0% (USA)—12% (Europe)
    • Toxoplasmosis: 1–3%
    • Others (isosporiasis, cryptosporidiosis): <1%.
  • Neoplasia
    • Lymphoma: 5–10% (CD4 count may be normal)
    • Kaposi sarcoma: isolated reports.
  • Drugs: <1%.
  • Other unusual causes include Reiter’s syndrome, non-specific hepatitis, Castleman’s disease, angiofollicular hyperplasia.

Diagnosis Careful history taking followed by examination especially for lymphadeno-pathy, hepatosplenomegaly, and retinal abnormalities (through dilated pupils). All patients should have 1st level (non-invasive) investigation proceeding to 2nd level (invasive) if diagnosis is not established. 1st level includes

  • Full blood count/differential white count, liver function tests, C-reactive protein, urinalysis
  • Pulse oximetry
  • Chest X-ray
  • Repeated cultures of blood, sputum, urine, and faeces as indicated for bacteria, mycobacteria, and fungi
  • Blood film examination
  • Serum cryptococcal antigen
  • Other specific serologies indicated by travel or exposure history

2nd level includes

  • Abdominal and thoracic computerized tomography (CT)
  • Exercise oximetry
  • Gallium scan
  • Bronchoscopy with broncho-alveolar lavage
  • Biopsy (histology and microbiology)—bone marrow, liver, lymph node (including mediastinoscopic), skin, intestinal/oesophageal mucosa
  • Lumbar puncture
  • PCR for CMV

Causes of PUO unrelated to HIV must not be forgotten and may require other investigations e.g. auto-antibody screen. Management This depends on the underlying cause. Cases where no underlying additional pathology is found may respond to HAART. As in any fever, general measures such as good hydration, antipyretics, and reassurance are important. In patients with late stage HIV disease and limited treatment options, palliation with steroids may be necessary. MAC infections and, less commonly, leishmaniasis often present with unexplained pyrexia without focal organ involvement. Other causes of HIV-related PUO that may present with clinical features specific to their 1° infection site are described elsewhere in this book. P.459
Non-HIV-related causes of PUO Infection Bacterial

  • Site specific
    • abscesses, urinary tract infection, endocarditis, hepatobiliary infection, osteomyelitis.
  • General
    • syphilis, relapsing fever, Lyme disease, gonorrhoea, lymphogranuloma venereum, psittacosis, salmonellosis, Q fever.


  • CMV, Epstein–Barr virus, hepatitis viruses.

Fungi (usually only if immunosuppressed)

  • Candidiasis.


  • malaria, toxoplasmosis.

Connective tissue/autoimmune diseases

  • Rheumatoid arthritis, Still’s disease, systemic lupus erythematosis.


  • Giant cell arteritis, polymyalgia rheumatica, polyarteritis nodosa.

Granulomatous diseases

  • Sarcoidosis, regional enteritis, granulomatous hepatitis.


  • Lymphomas, Hodgkin’s disease, leukaemias, solid tumours especially renal cell carcinoma, malignant histiocytosis.

Inherited diseases

  • Familial Mediterranean fever.


  • Antibiotic reactions.


  • Hyperthyroidism.

Factitious P.460
Mycobacterium avium complex Ubiquitous and frequently isolated from soil, food, and water. Infection usually affects those with CD4 counts <100cells/µL (median 1° 10cells/µL). Any organ can be affected, most commonly lymph nodes, spleen, gastrointestinal tract, lungs, and bone marrow but most patients develop disseminated infection without prior localization. Symptoms may be severe. Clinical features Most common is pyrexia (in ~90%) with night sweats, diarrhoea/abdominal pain/nausea and vomiting/weight loss, lymphadenopathy, and hepato-splenomegaly. Investigations and diagnosis

  • FBC—anaemia (common and often severe).
  • LFTs—↑ alkaline phosphatase (common).
  • Blood cultures.
  • Culture of material from bone marrow, lymph nodes, and liver.
  • Staining of material from bone marrow, lymph nodes (Plate 23), liver for mycobacteria (marrow provides rapid diagnosis in ~30%).
  • PCR testing of potentially infected material (if available).
  • X-rays may show internal lymphadenopathy with a typical abscess pattern on CT.

Management 3–4 drug regimens are recommended as multiresistance is usual. A macrolide (clarithromycin 500mg daily twice or azithromycin500mg daily) plus ethambutol 15mg/kg daily plus a rifamycin (rifabutin 450–600mg/day or rifampicin 450–600mg/day) and/or a quinolone (e.g. ciprofloxacin 500mg daily twice). Data is lacking to advise on the duration of treatment. HAART should also be commenced taking into account potential drug interactions. Steroids may be required to ameliorate severe fever. 1° prophylaxis is now rarely required because of the effectiveness of HAART, but may be considered for those with a CD4 count <50cells/µL. Effective drugs include azithromycin (1.2g weekly), clarithromycin 500mg daily twice and rifabutin (less effective). Visceral leishmaniasis Caused by Leishmania spp., protozoa transmitted by sandflies from rodents, small carnivores, dogs, foxes, and humans. Typically presents with fever, malaise, weight loss, hepatosplenomegaly, and lymphadenopathy. Diagnosed by identifying organism in tissue by microscopy (Leishman–Donovan bodies in macrophages), culture, or PCR. Fine-needle aspiration of spleen is most sensitive (about 98%) but bone marrow aspiration safer with 54–86% sensitivity. Serology (immunofluorescent antibody test and direct agglutination test) insensitive (up to 76%) unless high protozoal load. Treated with sodium stibogluconate 20mg/kg/day IV/IM for 28 days or liposomal amphotericin B.

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