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BMJ Clinical Review: Infectious Diseases and Public Health
By Babita Jyoti, Ahmed Hamad
BPP Learning Media LtdCopyright © 2016 BPP Learning Media Ltd
All rights reserved.
Investigating and managing pyrexia of unknown origin in adults
George M Varghese, professor, Paul Trowbridge, resident, Tom Doherty, consultant physician
Few clinical problems generate such a wide differential diagnosis as pyrexia (fever) of unknown origin. The initial definition proposed by Petersdorf and Beeson in 1961, later revised, is "a fever of 38.3°C (101°F) or more lasting for at least three weeks for which no cause can be identified after three days of investigation in hospital or after three or more outpatient visits." Essentially the term refers to a prolonged febrile illness without an obvious cause despite reasonable evaluation and diagnostic testing. A fever that is not self limiting for which no cause can be found can become a source of frustration for both patient and doctor. There is little consensus on how such patients should be investigated, although recent prospective studies have evaluated diagnostic protocols to suggest approaches to investigation. We discuss evidence from epidemiological and diagnostic studies and suggest an approach to investigating and managing pyrexia of unknown origin.
Immunocompromised individuals, those with HIV infection, and patients admitted to hospital for other reasons with persistent or unexplained fever represent distinct subgroups in which the likely causes, diagnosis, and treatment of pyrexia usually differ from those in patients who are not immunocompromised. We do not discuss these subgroups in this review other than to provide definitions of pyrexia of unknown origin in different groups of patients (see box 1).
Sources and selection criteria
We searched for papers that were published between 1966 and August 2010 using appropriate MESH terms (pyrexia of unknown origin, fever of unknown origin) in the National Library of Medicine's computerised search service (PubMed and other related databases). We also consulted Cochrane database systematic reviews. We reviewed all relevant articles as well as the cited references to identify further articles.
How common is pyrexia of unknown origin?
The true incidence and prevalence of pyrexia of unknown origin are uncertain. A study of 153 patients reported the prevalence in hospitalised patients in the 1980s to be around 3%. However, in the past two decades technological advances in diagnosis, particularly sophisticated imaging and improved culture techniques, have reduced the proportion of cases where the cause is unknown.
What causes pyrexia of unknown origin?
Pyrexia of unknown origin has a wide differential diagnosis. The most frequently encountered underlying causes of the pyrexia are listed in box 2. Broadly speaking, the three most common causes are infection, neoplasia, and connective tissue disease. Many prospective and retrospective studies have shown that pyrexia of unknown origin is more often caused by an atypical presentation of a common disease than by something exotic. Although causes of pyrexia of unknown origin vary substantially across geographical areas, a recent well conducted prospective cohort study and another retrospective evaluation from Europe reported the following proportions — infection 15-30%, neoplasia 10-30%, connective tissue disease 33-40%, miscellaneous (such as drug fever, hyperthyroidism, and factitious fever) 5-14%, undiagnosed 20-30%.
Data from several large prospective studies suggest that infective causes are becoming less common, probably because advanced imaging techniques and improved culture methods have become more widely available. For similar reasons, the proportion of cases of pyrexia of unknown origin attributed to neoplasia has steadily decreased over recent years. These trends do not hold true in less developed societies where infection, often with mycobacteria, remains common and advanced diagnostic techniques are often unavailable. Worth noting is that miscellaneous disorders are fairly common (see above).
How is pyrexia of unknown origin investigated?
Taking a thorough history and physical examination may often lead to a diagnosis. Repeating the history several times may elicit previously overlooked clues. Consider all symptoms as relevant since most patients with pyrexia of unknown origin present with a common disease that is atypically manifested. Eliciting a history of comorbid conditions and previously treated diseases such as endocarditis, tuberculosis, rheumatic fever, and cancer may provide important diagnostic clues. A surgical history that provides information about the type of surgery performed, postoperative complications and any indwelling foreign material could also be relevant. Travel history is important because it may provide information about possible exposure to endemic diseases such as malaria, histoplasmosis, or other fungal infections.
Potentially important clues may be found in aspects of the history that are not routinely discussed with patients, such as the sexual history; asking about specifics of sexual practices such as anal penetration leading to rectal abscesses may point to a possible source of infection. Ask about social habits, such as drug use, exposure to animals or pets, specifics of the patient's employment and hobbies. Enquire about unusual dietary habits, such as consumption of unpasteurised dairy products or rare meats. Check for any recent changes in medication that could have contributed to unexplained fever. A full obstetric and gynaecological history in women may provide clues to the underlying condition; for example a history of multiple miscarriages may suggest a connective tissue disease or pelvic pain may suggest tubo-ovarian pathology.
A persistent fever needs to be accurately documented because the pattern of the fever and its relation with the pulse rate (particularly a temperature-pulse disparity) may point to an underlying cause. Accurate charting of the fever may require admission to hospital. Temperature-pulse disparity may have diagnostic relevance in infections with intracellular organisms such as typhoid, brucellosis, and legionellosis.
Careful physical examination
Fever could arise from pathology in any system, so a thorough physical examination is important. It should include a full neurological examination, musculoskeletal, ear-nose-throat, dermatological, lymphatic, and urogenital examinations, and fundoscopy. Box 3 lists some common symptoms and signs and the causes of pyrexia that may be associated with them. Some well known causes of pyrexia of unknown origin are associated with particular signs; for example, temporal artery tenderness in temporal arteritis, lymphadenopathy in lymphoma and disseminated tuberculosis, and a heart murmur in bacterial endocarditis. Some clinical findings, although rare, are virtually diagnostic, such as Roth's spots in infective endocarditis.
The approach to investigating any patient with pyrexia of unknown origin should ideally be focused according to the patient's presentation and clinical signs. Basic laboratory and imaging studies may help to guide further evaluation. No list of tests has been widely accepted as being the minimal obligatory investigations, but basic investigations that have been suggested and used by researchers and clinicians in several studies are listed in the first part of the diagnostic algorithm (fig 1). Additional testing for atypical presentations of diseases that are specific to certain regions, such as Lyme disease, malaria, or histoplasmosis, may also be indicated.
Clues gleaned from the history, physical examination, and first round of diagnostic evaluations should be the basis for subsequent investigations that are tailored to the individual patient as shown in the diagnostic algorithm (fig 1). However, in the absence of potential clues, there are some data directing what further studies are of utility. Recent prospective studies have highlighted the usefulness of early use of FDG-PET ([18F] fluoro-2-deoxy-D-glucose positron emission tomography), which may be useful in helping to pinpoint a source of fever. Fluoro-2-deoxy-D-glucose is preferentially taken up by cells such as tumour and inflammatory cells, in which glucose metabolism is high. In a systematic review of eight prospective and retrospective studies including 302 patients, FDG-PET localised pathology directing further tests that led to diagnosis in over a third of patients. The diagnostic yield may be increased further by simultaneously using FDG-PET with conventional computed tomography (CT). Several small retrospective studies have shown sensitivities from 56% to 100%, specificities from 75% to 81%, and negative predictive values of 100%, when a combination of CT and FDG-PET scanning is used. Notably, FDG-PET was of no diagnostic benefit unless patients had an elevated erythrocyte sedimentation rate or raised concentrations of C-reactive protein.
Nuclear scintigraphy, for example with 67Ga-citrate and In labelled leukocytes, is a much cheaper and more widely available imaging technique that may perform a similar role in localising pathology, though it is more time consuming and less sensitive and specific than FDG-PET. In a retrospective study evaluating the contribution of 67Ga scintigraphy in 145 cases of pyrexia of unknown origin in Belgium between 1980 and 1989, only 29% of the scans were considered helpful in diagnosis and 49% of the abnormal scans were considered noncontributory to the diagnosis. The limited specificity and the generally unfavourable characteristics of 67Ga scintigraphy makes it less attractive than FDG-PET. A recent retrospective study including 31 patients with pyrexia of unknown origin, 111In leukocyte scintigraphy was reported to be helpful in 19% of all cases. However, the probability of reaching a diagnosis was observed in 71% with a sensitivity of 75% and specificity 83%. Leukocyte scintigraphy may be helpful in diagnosing inflammatory and infectious conditions and rarely of use in neoplasm.
Several studies, including two large multicentre prospective analyses, have looked at the usefulness of other investigations in the absence of diagnostic clues. The evidence from these studies supported the use of chest CT and abdominal CT or ultrasound (if not already performed), looking specifically for: abscesses, lymph nodes, or splenomegaly; cryoglobulins (mixed cyroglobulinaemia was surprisingly common even in the absence of known risk factors); and temporal artery biopsy, particularly in patients older than 55. Although many previous studies supported temporal artery biopsy for patients older than 55 in the absence of clues indicating potential temporal arteritis, the authors thought this invasive procedure should be done later in the process of evaluation as temporal arteritis was a less prominent cause of pyrexia of unknown origin than previous studies had indicated.
Evidence from one small but well done and recent retrospective analysis showed that bone marrow aspirate with trephine biopsy was diagnostic in nearly a fifth of patients and "helpful" for diagnosis in nearly a quarter. This was particularly, though not exclusively, true in the presence of thrombocytopenia or anaemia (haemoglobin <110 g/l). Bone marrow culture is thought to have a lower yield in immunocompetent individuals than in those who are immunocompromised, although this is probably less true in non-industrialised societies. Echocardiography is a non-invasive test that may be useful even in people with negative blood culture and without an audible heart murmur. Transoesophageal echocardiography (which has a diagnostic sensitivity of 95-100%, and a specificity of 98% for endocardial vegetations) is preferable to transthoracic echocardiography (sensitivity 63%, specificity 98%). Epstein-Barr virus, cytomegalovirus, toxoplasmosis, brucellosis, and coxiellosis are infections that can all present in a very non-specific way and serological tests for these infections may be useful. More invasive tests, such as lymph node or liver biopsy, and lumbar puncture, may be considered when the cause of fever remains unidentified after two step evaluation as described above and when clinical suspicion shows that these tests are indicated — see the later part of the diagnostic algorithm (fig 1).
What is a reasonable approach to management of pyrexiaof unknown origin?
Once a diagnosis has been established specific treatment can be started. For patients in whom a cause for the fever is not found and who are not clinically unwell, watching and waiting is reasonable. During this time of observation re-assess the history and physical examination, stepping back to re-evaluate the data, and consider new avenues to pursue. One large prospective study found an attributable mortality of only 3.2% at five years in people with pyrexia of unknown origin where a specific diagnosis could not be reached. The same study showed that most instances of pyrexia of unknown origin in which no diagnosis could be made resolved spontaneously, all of which suggests a good prognosis for people who remain without a diagnosis.
In most cases where the individual is clinically stable experts consider empirical treatment to be unnecessary. Patients who are clinically unstable or neutropenic require prompt and appropriate antibiotic treatment. Empiric tuberculosis drugs may be considered where tuberculosis is prevalent and suspected but cannot be confirmed. Rifampicin may suppress fever even when not from an infectious cause. Empirical use of steroids is generally discouraged because it may mask symptoms and lead to delayed diagnosis of, for example, an underlying haematological malignancy. Several experts have recommended treatment with non-steroidal anti-inflammatory drugs for patients who have already had exhaustive investigations without finding an underlying cause. This treatment may be beneficial to patients in some situations, such as an underlying inflammatory condition. However, the theory that a patient's response to such drugs allows the doctor to differentiate neoplastic from other causes of pyrexia of unknown origin has been refuted.
When a diagnosis remains elusive, a second opinion from a colleague in another medical specialty such as rheumatology, haematology, oncology, or infectious disease may be helpful.
Excerpted from BMJ Clinical Review: Infectious Diseases and Public Health by Babita Jyoti, Ahmed Hamad. Copyright © 2016 BPP Learning Media Ltd. Excerpted by permission of BPP Learning Media Ltd.
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Table of Contents
ContentsAbout the publisher, iii,
About The BMJ, iii,
About the editors, vi,
Introduction to Infectious Diseases and Public Health, vii,
Investigating and managing pyrexia of unknown origin in adults George M Varghese, Paul Trowbridge, Tom Doherty, 1,
Outpatient parenteral antimicrobial therapy Ann L N Chapman, 6,
Meticillin resistant Staphylococcus aureus in the hospital Jan Kluytmans, Marc Struelens, 10,
Prevention and medical management of Clostridium difficile infection J Shannon-Lowe, N J Matheson, F J Cooke, S H Aliyu, 15,
Preparing young travellers for low resource destinations Caoimhe Nic Fhogartaigh, Christopher Sanford, Ron H Behrens, 21,
Investigation and treatment of imported malaria in non-endemic countries Christopher J M Whitty, Peter L Chiodini, David G Lalloo, 26,
Dengue fever Senanayake A M Kularatne, 31,
Diagnosis and management of cellulitis Gokulan Phoenix, Saroj Das, Meera Joshi, 38,
HIV testing and management of newly diagnosed HIV Michael Rayment, David Asboe, Ann K Sullivan, 43,
HIV infection, antiretroviral treatment, ageing, and non-AIDS related morbidity Steven G Deeks, Andrew N Phillips, 51,
Ebola virus disease Nicholas J Beeching, Manuel Fenech, Catherine F Houlihan, 55,
Infectious mononucleosis Paul Lennon, Michael Crotty, John E Fenton, 65,
Multidrug resistant tuberculosis James Millard, Cesar Ugarte-Gil, David A J Moore, 70,
Actinomycosis V K Wong, T D Turmezei, V C Weston, 75,
Cryptosporidiosis A P Davies, R M Chalmers, 81,
The prevention and management of rabies Natasha S Crowcroft, Nisha Thampi, 86,
Diagnosis and management of schistosomiasis Darren J Gray, Allen G Ross, Yue-Sheng Li, Donald P McManus, 92,
Diagnosis, treatment, and management of echinococcosis Donald P McManus, Darren J Gray, Wenbao Zhang, Yurong Yang, 100,
Management of chronic hepatitis B infection Vinay Sundaram, Kris Kowdley, 107,
The role of pathogen genomics in assessing disease transmission Vitali Sintchenko, Edward C Holmes, 119,
Manifestation, diagnosis, and management of foodborne trematodiasis Thomas Fürst, Somphou Sayasone, Peter Odermatt, Jennifer Keiser, Jürg Utzinger]TC1 TC1[130,
Strongyloides stercoralis infection Daniel Greaves, Sian Coggle, Christopher Pollard, Sani H Aliyu, Elinor M Moore, 137,
Management of adolescents and adults with febrile illness in resource limited areas John A Crump, Sandy Gove, Christopher M Parry, 142,
Tick bite prevention and tick removal Christina Due, Wendy Fox, Jolyon M Medlock, Maaike Pietzsch, James G Logan, 148,
Bed bug infestation Celine Bernardeschi, Laurence Le Cleach, Pascal Delaunay, Olivier Chosidow, 153,
Management of sharps injuries in the healthcare setting Anna Riddell, Ioana Kennedy, C Y William Tong, 158,
The risks of radiation exposure related to diagnostic imaging and how to minimise them H E Davies, C G Wathen, F V Gleeson, 163,
Facemasks for the prevention of infection in healthcare and community settings C Raina MacIntyre, Abrar Ahmad Chughtai, 167,
Communicating risk Haroon Ahmed, Gurudutt Naik, Hannah Willoughby, Adrian G K Edwards, 178,