REVIEW
Management of pyrexia of unknown origin in HIV-positive
patients
C Babu MRCP DipGUM, O McQuillan MRCP DipGUM
Manchester Centre for Sexual Health, The Hathersage Centre, 280 Upper Brook Street, Manchester M13 OFH, UK
Summary: Recently, we managed the case of a young HIV-positive man with a pyrexial illness and severe constitutional symptoms,
the cause of which was elusive for several weeks. Here we review the causes of pyrexia of unknown origin in HIV-positive individuals,
review appropriate investigations and discuss possible empirical treatment when this is required.
Keywords: HIV, diagnosis
INTRODUCTION
We were inspired to conduct a review of the literature around
pyrexia of unknown origin (PUO) in HIV-positive individuals
following a case at our unit that we all found difcult and
at times frustrating to manage. Here we present those ndings
and also discuss strategies for managing such patients.
A 33-year-old gentleman was admitted to our hospital with
pyrexia and constitutional symptoms of several days duration.
Apart from pyrexia and some cardiovascular compromise,
there were no positive ndings on examination. He was
known to be HIV positive and had previously been managed
at a different unit, having only recently moved to our area.
His CD4 count was 240 cells  106/L and he was nave to anti-
retrovirals. Over subsequent weeks numerous investigations
were performed, which did not reveal the cause of his illness;
his PUO persisted and his clinical state deteriorated.
DEFINITIONS OF PUO
Petersdorf and Beeson1 classically dened PUO in 1961 as a
temperature of greater than 38.38C on multiple occasions over
a period of more than three weeks, with failure to reach a diag-
nosis after one week of inpatient investigations. Although
HIV-related conditions are an important cause of prolonged
fever and HIV testing should be performed at an early stage
in all cases of PUO where HIV status is unknown, patients
with known HIV can also present with a PUO during
follow-up. Despite the availability of new and sophisticated
diagnostic tools, PUO still poses a challenge in clinical
practice. In 1991, Durak and Street2 re-devised a denition for
HIV-related PUO as a pyrexia greater than 38.38C occurring
on multiple occasions over a period of more than four weeks
for outpatients or three days for inpatients, with negative micro-
biological results after at least two days incubation.
Correspondence to: Dr M Kingston
Email: margaret.kingston@cmft.nhs.uk
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and M Kingston MRCP DipGUM
CAUSES OF PUO
Within the general population studies have indicated that infec-
tions account for approximately 30% of causes of PUO (neo-
plasms 18%, collagen vascular diseases 12%, miscellaneous
causes 14% and undiagnosed 26%),3 whereas in HIV-positive
individuals PUO is usually caused by a disseminated opportu-
nistic infection (OI) accounting for over 70% of such presenta-
tions; with the single most frequently identiable cause being
mycobacterial infection. Furthermore, while a single pathology
is the norm in the general population with PUO, two or more
simultaneous causes can be identied in approximately one-
fth of HIV-related cases. Factors that inuence the nature of
infections include the patients CD4 count, use of prophylactic
agents and geographical setting (including country of resi-
dence, country of origin and travel history).4 12 Occult malig-
nancies, although much less common than infections, are an
important, consistent and at times coexistent cause of PUO in
reported case series: most frequently lymphoma (Hodgkins
or non-Hodgkins lymphoma), which may be complicated by
haemophagocytic syndrome.13,14 As in HIV-negative patients,
bacterial infections including occult collections, dental sepsis
and syphilis15 should be considered as well as drug reactions,16
autoimmune conditions such as thyrioditis17 or collagen vas-
cular diseases.18 Case reports of less frequently occurring infec-
tions, for example Babesiosis, demonstrate the importance of a
through travel history.19 Table 1 summarizes the commonly
identied causes of PUO in HIV-positive individuals
(adapted from the references given above). Given that in the
vast majority of cases an underlying cause for the PUO is
found, it is important not to attribute the pyrexia to the HIV
virus itself until other pathologies are ruled out.
REACHING A DIAGNOSIS
Establishing the cause(s) of a PUO can be a difcult and pro-
longed process and one that does not always result in a clear
answer. Before commencing a long list of investigations, a
careful and detailed history should be taken followed by a
DOI: 10.1258/ijsa.2008.008444. International Journal of STD & AIDS 2009; 20: 369 372
370 International Journal of STD & AIDS Volume 20 June 2009
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Table 1 Possible causes of PUO in HIV-positive individuals;

investigations should then be undertaken guided by the
most frequently occurring conditions given first history, examination and any consistent abnormalities of the
baseline investigations. It is crucial to maintain a measured and
Comments
logical approach to investigating a PUO and to regularly
Most frequently occurring conditions
re-visit the patients history and examination as relevant details
Mycobacterial infections The commonest cause of PUO in all case
series may be recalled by the patient or family and clinical signs may
MAC; disseminated infection found usually evolve. Despite this approach some PUOs may be difcult to
when CD4 count ,100 diagnose, or may be ongoing despite a positive diagnosis and
Mycobacterium tuberculosis; occurs at any appropriate treatment, which may indicate multiple pathologies
CD4 count
Bacterial infections Abscesses and occult collections,
and the need for further or repeated investigations. It is important
endocarditis, syphilis, dental sepsis, to remember that even in patients taking antimicrobial prophy-
systemic infections from enteric bacteria laxis against certain pathogens (usually for Pneumocystits jirovecii
Visceral leishmaniasis Geographical location and travel history pneumonia [PJP] or Mycobacterium avium complex), these causes
important
cannot be excluded without appropriate investigations.
PJP
Disseminated fungal Most importantly cryptococcosis, also The clinical utility of bone marrow (BM) biopsy for PUO in
infections histoplasmosis and penicillinosis HIV-positive patients is controversial. Kilby et al. 21 compared
(geographical location and travel history the utility of BM biopsy with that of blood cultures for myco-
important for these two) bacterial and fungal infections and found no difference in
Disseminated viral CMV; particularly when CD4 count ,100,
infections herpes simplex, varicella zoster,
turnaround time between the two, and concluded that the com-
parvovirus bined use of BM biopsy and culture as well as blood cultures
Lymphoma and other Hodgkins lymphoma, NHL, Kaposis provided the highest diagnostic yield. In a retrospective study
malignancies sarcoma of 72 HIV patients with PUO, BM examination was found to
Examples of less frequently occurring conditions
be a useful diagnostic procedure when an infectious process
Connective tissue Systemic lupus erythematosis, rheumatoid
diseases arthritis, Stills disease, polyarteritis was suspected, but it was not useful to establish the diagnosis
nodosa, giant cell arteritis of lymphoma.22 The low utility of a BM biopsy in diagnosing
Endocrine problems Thyroid disorders lymphoma, presenting as PUO, can be explained by the fact
Neoplasia Solid tumours (renal cell, colonic), that most HIV-positive patients have intermediate/high-grade
leukaemias, malignant histiocytosis
Parasitic infections Malaria, amoebic liver abscess
lymphomas, with a BM involvement of only 30%. In another
(geographical location and travel history study from Spain, 182 episodes of PUO in 160 HIV patients
important for these two), cryptosporidium, were retrospectively studied.23 Fifty-four of these episodes
babesiosis were diagnosed by a BM examination, and in 36 of these this
Miscellaneous Castlemans disease, haemophagocytic
was the only diagnostic tool. In this study, the presence of
lymphohistiocytosis, sarcoidosis,
factitious fever thrombocytopenia and an elevated serum aspartate amino-
transferase level were the factors associated with a high prob-
PUO pyrexia of unknown origin; MACMycobacterium avium complex; ability of obtaining the diagnosis through a BM study.
PJPPneumocystits jirovecii pneumonia; CMVcytomegalovirus;
A percutaneous liver biopsy (PLB) may also be useful for the
NHLnon-Hodgkins lymphoma
diagnosis of PUO in HIV-positive patients and has a diagnostic
yield of 45%.24 In a study of 58 HIV patients who underwent a
liver biopsy for the evaluation of PUO, PLB was diagnostic in 25
thorough clinical examination that should be regularly revisited cases, helpful in 13 and normal or non-specic in the remaining
and will often provide important clues to the underlying diag- 20.25 The presence of hepatomegaly or splenomegaly was
noses. The history should include a careful documentation of the most useful factor in predicting the usefulness of the PLB.
all symptoms, with particular attention to any localizing symp- Although liver and BM biopsies may frequently provide a
toms, sweats, weight loss, rashes, lumps or itching. Other import- method of diagnosis especially in the case of mycobacterial infec-
ant specic points to cover include documentation of any travel, tion,26 they are invasive and have associated risks; therefore, before
all concomitant and previous medications including recreational commencing such invasive investigations, the history, examin-
and herbal drug use, a detailed sexual history, immunization ation and results from other less invasive tests should be reviewed.
history, questions about any trauma, bites or injuries sustained,
past surgical and medical history, and contact with animals.
Clinical examination should include a full general and systemic
examination, especially looking for any lymphadenopathy, hepa- EMPIRICAL TREATMENT: WHAT AND
tosplenomegaly, abnormal nail and skin lesions or rashes, ear, WHEN TO CONSIDER, AND THE PROBLEM
nose and throat examination, dental examination, thyroid palpa- OF IMMUNE RECONSTITUTION
tion, genital (including rectal) examination, and any subtle INFLAMMATORY SYNDROME
neurological or eye signs (including dilated fundoscopy).3 The most effective treatment of a PUO is obviously the identi-
cation of and then the treatment for the causative condition(s);
however, as discussed earlier, making a denitive diagnosis
may be a lengthy and challenging process and a diagnosis
INVESTIGATIONS may prove elusive in up to 40% of patients.5,10 As many inves-
Investigations suggested are summarized in Table 2. There are tigations as possible should be conducted prior to initiation of
baseline investigations suggested for all HIV-positive patients, any treatment and whether to then initiate empirical antimicro-
many of which will already be performed in most pyrexial bial treatment depends on the clinical picture, which may
patients before the criteria for PUO are met. Targeted deteriorate and necessitate treatment prior to investigation

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Table 2 Appropriate investigations to consider in HIV-positive patients with PUO
Baseline investigations
Haematology: full blood count, ESR, blood film examination
Biochemistry: renal and liver function tests, CRP and LDH
Pulse oximetry at rest and on exertion; ABG if abnormal
Chest X-ray
Repeated blood cultures (3 sets) prior to antimicrobial therapy; standard bottles
plus those for fungal/mycobacterial culture
Urinalysis, microscopy and culture (consider also urine testing for
pneumococcal and legionella antigen)
Sputum examination microscopy and culture, plus TB examination and
P. jirovecii PCR
Mycobacterial stains, culture and PCR on any clinical samples obtained
Stool microscopy and culture plus examination for ova, cysts and parasites,
and for Clostridium difficile toxin
Serological tests for syphilis, respiratory pathogens, CMV, EBV, toxoplasma,
hepatitis A, B and C (consider E if travel history appropriate)
Cryptococcal antigen (CRAG)
Autoimmune screen including ANA, anti-DNA, rheumatoid factor, ENA, ANCA,
anti-Sm and anti-mitochondrial antibodies
CMV PCR
Sexually transmitted infection screen
Targeted and further investigations
Repeated blood cultures (standard bottles plus those for fungal/mycobacterial
culture)
Malaria antigen and blood film examination for malarial parasites
Serological/antigen/PCR tests for leishmaniasis and histoplasma
Bronchoscopy with BAL and trans-bronchial biopsies if appropriate
P. jirovecii PCR on blood, sputum, naso-pharyngeal or BAL specimens
Radiological investigations: ultrasound, CT, MRI scans. Other types of
radiological investigations including PET scanning20 may be helpful and
could be discussed with local radiologists
Serology/PCR tests for HHV8, Bartonella sp.
Lymph node biopsy (excision biopsy usually preferable) if any enlarged nodes
are identified
Liver biopsy (discussed further in the text)
Bone marrow aspirate and trephine (discussed further in the text)
Lumbar puncture if indicated by clinical history or examination
Hepatitis B and C, HSV, VZV, EBV, PCRs
Angiotensin-converting enzyme
ESR erythrocyte sedimentation rate; CRP C reactive protein; LDH lactate dehydrogenase; ABG arterial blood gas; PCR polymerase chain reaction;
CMV cytomegalovirus; EBV Epstein Barr virus; BAL bronchoalveloar lavage; CT computed tomography; MRI magnetic resonance imaging; PET positron
emission tomography; HSV herpes simplex virus; VZV varicella zoster virus
results being available or tests being conducted. Specic fea-
tures in the history or examination may point to a likely diag-
nosis, and HIV parameters such as CD4 count may also
guide the choice of empirical therapy.
Although mycobacterial infection is most common, infection
with other bacteria may account for up to 15% of cases of
PUO.4 Hence, broad-spectrum empirical antibacterial therapy
may be indicated. In this case an agent such as piperacillin/tazo-
bactam may be appropriate, although local epidemiology and
sensitivity patterns should be considered when choosing an
empirical agent. Antibiotics with antimycobacterial activity such
as ciprooxacin, clarithromycin and rifampicin should be used
with caution as they can hinder mycobacterial culture or generate
resistance, making subsequent therapy problematic. Empirical
antifungal therapy with an agent such as liposomal amphotericin
may also be indicated, in particular if there is a history of travel to
a region where endemic mycoses may be encountered.
As discussed earlier, mycobacterial infection is the common-
est cause of PUO in HIV, with non-tuberculous mycobacteria
more often seen in those with CD4 counts below 100.
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Babu et al. PUO in HIV 371
Comments
If expectorating
Clinical sampling informed by history, examination and investigations
Crucial if there are any localizing gastrointestinal symptoms, appropriate
travel history or recent antibiotic exposure
From blood or CSF (if examined)
Particularly during interruptions in any empirical or targeted therapy
As indicated by travel history/geographical location
As indicated by travel history/geographical location
As indicated by CXR (or other chest imaging), chest examination, ABG and
pulse oximetry on exertion
May be of targeted areas; for example the abdomen if hepatosplenomegaly
is present or the brain if there is localizing neurology, or may be part or
whole body scans in the absence of localizing symptoms, signs or other
abnormal investigations
Informed by skin examination
Samples sent for microbiological and histological examination
Samples sent for microbiological and histological examination
Samples sent for microbiological and histological examination
Opening and closing pressures recorded in recumbent position,
biochemistry, cell count, stains and culture for bacteria, mycobacteria
and fungi, viral and mycobacterial PCRs, CRAG, syphilis serology
Mycobacterial infection in the context of HIV can be more dif-
cult to conrm due to atypical presentations and fewer posi-
tive sputum smears, cultures and granulomas seen on biopsy
specimens.27 In an HIV-negative cohort of patients with
pulmonary disease treated empirically for tuberculosis (TB),
84.4% had subsequent clinical and radiological improvement.28
Treatment should be initiated with reference to the British HIV
Association Guidelines for TB and HIV co-infection.29
Further complicating the picture is the possibility of immune
reconstitution inammatory syndrome (IRIS), which, although
documented with many OIs after the initiation of highly
active antiretroviral treatment (HAART), is most frequently a
problem during mycobacterial treatment, when it has been
found to occur more often in those with HIV infection (28%)
than in those without (10%),30 and in HIV-positive patients is
more frequent in those receiving HAART.31 This can produce
a further diagnostic dilemma if a patient with a PUO is
started empirically on TB treatment and consequently develops
fever with clinical and/or radiological deterioration, and it is
unclear whether co-pathologies or IRIS is the culprit. Steroids
372 International Journal of STD & AIDS Volume 20 June 2009
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are the usual treatment for IRIS but this may also have the dis-
advantage of producing a clinical response masking in part or
full the underlying cause of the PUO, which may remain
undiagnosed only to relapse at a later date.
A recently presented study has suggested that antiretroviral
treatment started earlier (a median of 12 days) after initiation
of treatment of an OI reduced the risk of death or progression
to AIDS.32 Although this study included OIs that may cause
a PUO such as PJP and cyptococcal infections, it excluded TB,
thus making the signicance of this in mycobacterial infection
uncertain. Early initiation of HAART has also been shown to
improve survival in those with lymphoma.33
CONCLUSIONS
PUO in HIV-positive individuals remains a condition that can
present a diagnostic dilemma for clinicians and patients.
Compared to PUO occurring in HIV-negative patients, infec-
tious aetiologies and concurrent multiple pathologies occur
much more frequently, with the commonest being mycobacter-
ial infections. The likelihood of other infections is dependent on
geographical location and travel history, and underlying malig-
nancies are important to consider. As an underlying pathology
in addition to the HIV diagnosis is usually found, it is import-
ant not to attribute PUO to HIV infection itself until all appro-
priate diagnostic strategies have been employed.
In the case of our patient who prompted this review, he had a
nine-week hospital stay during which almost all of the diag-
nostic procedures discussed were employed and his PUO con-
tinued. His condition deteriorated and a number of empirical
treatments were tried and antiretroviral therapy commenced.
This proved to be a difcult time for the patient, his family
and the health-care workers involved, and we found that an
open, honest and regular dialogue between the medical and
nursing teams and the patient and his family were crucial.
An initial BM biopsy, which had been unhelpful, was repeated
and reported as demonstrating haemophagocytic syndrome,
and he died very shortly afterwards in the intensive care unit.
The nal reviewed report of the repeated BM examination
taken a few days prior to death revealed Hodgkins lymphoma.
ACKNOWLEDGEMENTS
We are grateful to Dr Andrew Dodgson, Consultant Microbiologist
at Manchester Royal Inrmary, for his review of the text and
contribution towards the section on empirical therapy.
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