General review definition divides PUO as classical, nosocomial, HIV-related and immunosuppression-related . For HIV infection, pyrexia of unknown origin (PUO) identifies a pattern of fever with temperature higher than 38.3 °C on several occasions over more than 4 weeks for outpatients, or more than 3 days duration in hospital, in which the diagnosis remains uncertain after an initial diagnostic work-up, including at least 2 days of incubation of microbiological cultures . It is a common clinical manifestation in HIV-seropositive patients with severe immunosuppression and probability of an infection-related aetiology for PUO in HIV infection increases with CD4 decline, i.e. greater risk if CD4 count <50 cells/μL than <100 cells/μL than >200 cells/μL .
- •Fever is rarely the result of the effects of HIV itself and investigation of a specific cause should be actively pursued  (level of evidence IV).
Causes of PUO in cohorts of HIV-seropositive patients vary between published studies and are influenced by diagnostic criteria used, degree of immunosuppression, risk category for HIV infection and geographical location of cohort. Comparison of causes of PUO in HIV-seropositive to seronegative patients shows that infection is the most frequent cause of PUO in patients with HIV infection whilst collagen diseases are more common in patients without HIV infection .
Many studies were performed before the widespread availability of antiretroviral therapy where the majority of patients had a very low CD4 cell count. The main causes of PUO in patients with severe immunodeficiency are infections and lymphoma [4,6]. Furthermore, these patients often have multiple diagnoses [6,7].
- •Multiple diagnoses are common, and should be considered in all persons with severe immunosuppression (level of evidence III).
A careful travel history is paramount. The commonest cause of PUO in a study from USA was disseminated Mycobacterium avium infection (DMAC)  whereas reports from southern Europe and Brazil have described disproportionately more cases of leishmania species or Mycobacterium tuberculosis [8,9]. Febrile illnesses are well described presentations in both disseminated histoplasmosis  and Penicillium marneffei [7,11] in persons who have travelled to or originated from an endemic area.
- •Take a careful history, including a lifetime travel history, as new and reactivation of tropical infections are not uncommon (level of evidence IV).
In the era of HAART, tuberculosis and lymphoma continue to be significant causes of PUO. However, as the HIV-seropositive population ages due to the success of HAART, multisystem diseases (encompassing rheumatic diseases, connective tissue disorders, vasculitis including temporal arteritis, polymyalgia rheumatica, and sarcoidosis) should be considered in the differential diagnosis .
PUO may present as a manifestation of antiretroviral therapy with the development of an immune reconstitution syndrome to an underlying pathogen such as DMAC, Mycobacterium tuberculosis or cryptococcus.
Fever persisting for a prolonged time may be the first presenting symptom of patients with systemic infections such as PCP , cryptococcal disease , HSV , syphilis and infective endocarditis. Fever and personality change have been reported for cryptococcal meningitis, HSV and VZV encephalitis.
Another cause of chronic fever in HIV-seropositive individuals, not addressed elsewhere in these guidelines, is Bartonellosis, an infection caused by Bartonella henselae or Bartonella quintana . It is associated with profound immunosuppression, usually with a CD4 count <50 cells/μL , so is less common in the post-HAART era. Individuals can present with non-specific features such as fever, lymphadenopathy, hepatosplenomegaly, abdominal pain, anaemia or elevated alkaline phosphatase . More specific features include bacillary angiomatosis in which cutaneous lesions that can be friable, red, vascular and exophytic proliferative lesions, non-descript papules or subcutaneous nodules may be observed . These can be difficult to distinguish from the lesions of Kaposi's sarcoma. Other presentations include osteolytic bone lesions and bacillary peliosis (usually caused by B. henselae) where patients can present with fever, abdominal pain, raised alkaline phosphatase and hypodense lesions on computed tomography of the liver and occasionally the spleen . Rarer presentations include nodular or ulcerated lesions of the gastrointestinal tract, which can present with haemorrhage, respiratory tract lesions or neurological manifestations including aseptic meningitis. Neuropsychiatric presentations have been described . Focal necrotising lymphadenopathy is more commonly associated with higher CD4 T-cell counts. Diagnosis involves culture and PCR of blood or biopsy specimens and serology . Treatment is with erythromycin 500 mg qid orally or doxycycline 100 mg bd for at least 3 months, though other macrolides may also be effective .
Other, less common causes of prolonged fever include drug-induced fever and thromboembolic disease.