, HIV VL decrease >1 log), and no new infection found or adverse drug reaction.Pyrexia of unknown origin (PUO) was defined by R. G. Petersdorf and P. B. Beeson (Medicine 40, 1–30, 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. D. T. Durack and A. C. Street (Curr Clin Top Infect Dis 11, 35–51, 1991) produced a definition of HIV-associated PUO, including temperatures >38.3°C on multiple occasions over a period of >4 weeks for outpatients 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 <100 cells/µL and is less common in patients on effective ART. In the general population, infections account for only 33% of PUO. However, infectious diseases are the predominant cause in PLWH, accounting for 80–90% with neoplasia (lymphoma commonest) 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 or MAC, these cannot be excluded without appropriate investigation.
There are important geographical differences, e.g. tuberculosis and leishmaniasis are much more common in Europe than in the USA. It is also important to consider non-HIV-related causes and other infections, 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 PCP). A careful history, including sexual, lifetime history of travel, immunization, consumption and source of dairy products, family history, animal contact, and drugs (prescribed and non-prescribed) is mandatory.
• Mycobacterium tuberculosis—7% (USA) to 37% (Europe). CD4 count may be normal
• MAC—12–31% (CD4 count <100 cells/µL).
• Others (e.g. M. kansasii, M. genavense)—1–5%.
• PCP—5–13% (CD4 count <200 cells/µL).
• CMV—5–9% (CD4 count <50 cells/µL)
• HIV itself, HSV, VZV, parvovirus B19, adenovirus, HBV, and HCV—2–7%.
• Fungal (cryptococcosis, candidaemia, disseminated histoplasmosis, aspergillosis, Penicillium marneffei): 2–8% (CD4 count <200 cells/µL).
• Leishmaniasis—0% (USA) to 12% (Europe)
• Others (isosporiasis, cryptosporidiosis)—<1%.
• Lymphoma—5–10% (CD4 count may be normal)
• Other unusual causes include Reiter’s syndrome, non-specific hepatitis, Castleman’s disease, and angiofollicular hyperplasia.
Careful history-taking, including length of symptoms, systemic enquiry, sexual, lifetime history of travel, immunization, consumption and source of dairy products, family history, occupational history, personality change, animal contact, contact with ticks and insect bites, past medical history, and drugs (prescribed and non-prescribed) is mandatory.
Examination especially for lymphadenopathy, abdominal (hepatosplenomegaly), skin rash, full cardiology (looking for murmurs, splinter haemorrhages) respiratory (listening for crackles, effusions), neurological (full neurological examination essential, and should include tests of memory and collateral for change in personality), and retinal abnormalities (through dilated pupils). Examination should be repeated over time.
All patients should have first level (non-invasive) investigation proceeding to second level (invasive) if diagnosis is not established.
• FBC/differential WCC, LFTs, CRP, ESR, ferritin, urinalysis, CD4 count, and HIV VL.
• Repeated cultures of blood, sputum, urine, and faeces as indicated for bacteria, mycobacteria (requires specific mycobacteria culture bottles), and fungi. STI screen.
• Serum cryptococcal antigen (if CD4<200 cells/µl).
• Serology for syphilis and other specific serologies indicated by travel or exposure history.
Further investigation is dictated by level of immunosuppression, results of 1st level investigation, and clinical examination/history.
Include:
• bronchoscopy with broncho-alveolar lavage
• fluorodeoxyglucose positron emission tomography (PET) is helpful to guide biopsy and highlight areas of abnormality not picked up on routine imaging.
• Biopsy (histology and microbiology—must include fungal and mycobacterial culture): bone marrow (useful if significant immunosuppression, anaemia, or cytopaenia), liver (particularly if enlarged or raised alkaline phosphatase—mycobacterial infection), lymph node (including mediastinoscopic or endoscopic ultrasound), skin rash, intestinal (if loose stool), oesophageal mucosa (if dysphagia/odynophagia).
• CMV PCR (CD4 <200 cells/µl), EBV PCR (may be raised in lymphoma).
Causes of PUO unrelated to HIV must not be forgotten (Box 48.1) and may require other investigations, e.g. auto-antibody screen and isotope-labelled white cell scan.
Consider serology depending on history, country of origin/travel, and examination for: CMV, EBV, toxoplasma, parvovirus, coxiella, mycoplasma, Chlamydia pneumoniae, syphilis, bartonella, brucella, rickettsia, leptospirosis, borrelia, histoplasma, coccididioidomycosis, and cryptococcus.
Consider serum PCR for CMV (rising or high CMV PCR correlates with development of end-organ disease, but not diagnostic), parvovirus (particularly if anaemic), EBV (may be positive in lymphoma), and HHV-8 (associated with KS and Castleman’s disease).
Consider drugs, including antiretrovirals and antituberculous medication. These should be considered, particularly in the setting of eosinophilia or significant liver injury following initiation of therapy.
Consider IRIS particularly in patients with a diagnosis of TB/MAC/other deep-seated infection who have had response to treatment (CD4 , HIV VL decrease >1 log), and no new infection found or adverse drug reaction.
Box 48.1 Non-HIV-related causes of PUO
• Site-specific: abscesses, urinary tract infection, prostatitis, pelvic inflammatory disease, endocarditis, hepatobiliary infection, osteomyelitis.
• General: syphilis, relapsing fever, Lyme disease, gonorrhoea, lymphogranuloma venereum, psittacosis, salmonellosis, Q-fever.
CMV, EBV, hepatitis viruses.
Candidiasis.
Malaria, toxoplasmosis.
Rheumatoid arthritis, Still’s disease, systemic lupus erythematosus.
Giant cell arteritis, polymyalgia rheumatica, polyarteritis nodosa.
Sarcoidosis, regional enteritis, granulomatous hepatitis.
Lymphomas, Hodgkin’s disease, leukaemias, solid tumours (especially renal cell carcinoma), malignant histiocytosis.
Familial Mediterranean fever.
Antibiotic reactions.
Factitious
Management depends on the underlying cause. Cases where no underlying additional pathology is found may respond to ART, if not already treated. 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. IRIS may require steroids if severe systemic symptoms or danger of focal damage, e.g. neurological.
Other causes of HIV-related PUO, which may present with clinical features specific to their infection site are described elsewhere in this book.
Ubiquitous and frequently isolated from soil, food, and water. Infection usually affects those with CD4 counts <100 cells/µL (median 10 cells/µL). Any organ can be affected; most commonly lymph nodes, spleen, GI tract, lungs, and bone marrow, but often patients develop disseminated infection without prior localization.
Most common is pyrexia (in ~9%) with night sweats, fatigue, diarrhoea/abdominal pain/nausea and vomiting/weight loss, lymph-adenopathy, and hepato-splenomegaly.
• FBC: anaemia (common and often severe).
• LFTs: alkaline phosphatase (common).
• Blood cultures (>95% sensitivity for disseminated MAC).
• Culture of material from bone marrow, lymph nodes, and liver.
• Staining of material from bone marrow, lymph nodes (Plate 6), and liver for mycobacteria (marrow provides rapid diagnosis in ~3%).
• X-rays may show internal lymphadenopathy with a typical abscess pattern on CT.
Plate 6 Ziehl– Nielsen stain Mycobacteria (48).
Three or four drug regimens are recommended as multi-resistance is usual, macrolide use associated with better outcome.
A macrolide (clarithromycin 500 mg bd or azithromycin 500 mg daily) plus ethambutol 15 mg/kg daily +/– rifamycin (rifabutin 300 mg/day or rifampicin 450–600 mg/day), particularly if severe disease or a quinolone (e.g. moxifloxacin 400 mg daily) or if unable to use any one first-line drug. Data to advise on the duration of treatment are lacking, but it should be a minimum of 12 months or until virological and clinical response and CD4 >100 cells/µL for at least 3 months. ART 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 ART, but may be considered for those with a CD4 count <50 cells/µL. Azithromycin recommended (1250 mg weekly). Combination with rifabutin does not increase survival and leads to drug interactions, and is not recommended. Prophylaxis can be stopped once CD4 is >50 cells/L for >3–6 months on ART.
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. Pancytopenia may occur.
Consider if PUO, hepatosplenomegaly, or bone marrow dysfunction. 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 is safer with 54–86% sensitivity. Serology (immunofluorescent antibody test and direct agglutination test) is insensitive unless high protozoal load.
Treat with sodium stibogluconate 20 mg/kg/day IV/IM for 28 days or liposomal amphotericin B. 2° prophylaxis with amphotericin or sodium stibogluconate every 2–4 weeks is essential to prevent recurrence (occurs in 60–90% without prophylaxis). Daily itraconazole may be effective prophylaxis.