Fever of unknown origin
BMJ 2025; 388 doi: https://doi.org/10.1136/bmj-2024-080847 (Published 06 January 2025) Cite this as: BMJ 2025;388:e080847
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Dear Editor,
We read with interest the clinical update on ‘Fever of unknown origin’ provided by Wright et al., in the January edition of the BMJ (1). We were disappointed to see the suggestion in table 4 that testing for human immunodeficiency virus (HIV) should be considered in ‘patients with fever, chills, night sweats, fatigue, myalgia, lymphadenopathy, headache, sore throat, diarrhoea and opportunistic infections plus a history of high risk sexual activity or/and substance use disorders’.
Fever or pyrexia of unknown origin (FUO/PUO) is an HIV clinical indicator condition, and testing should be offered regardless of the presence or absence of any additional epidemiological factor (2). This symptom-based testing approach is supported by the inclusion of HIV serology as a minimal standard investigation for FUO in the Delphi-generated consensus-based recommendations referred to in the body of the article (3). It is surprising that the authors then revert to recommending a conditional testing approach in table 4.
It is well recognised that relying on a clinician’s perception of ‘risk’ is a major barrier to the provision of HIV testing when appropriate (4). Individuals may not feel comfortable or able to share information around sexual activity or substance use in all settings, and indeed it may not be relevant due to changing epidemiological patterns. Furthermore, the terminology ‘high risk’ is stigmatising and alienating, and perpetuates the historic exceptionalism of HIV testing.
Both NHS Scotland and NHS England are endeavouring to eliminate HIV transmission by 2030. Normalising the routine offer of an HIV test by all clinicians in all relevant clinical settings is essential to this. We hope that the reference to additional risk-based testing for HIV in individuals with FUO is an oversight by the authors, and we would appreciate a formal correction.
Yours faithfully,
Dr Naomi Bulteel*, Consultant Physician in Infectious Diseases & GIM and Clinical Lead for HIV, NHS Lothian
Dr James Taylor*, Consultant Physician in Infectious Diseases & GIM and Clinical Lead for HIV, NHS Borders
Dr Daniela Brawley*, Consultant in Sexual Health & HIV, Sexual Health & HIV Lead for NHS Grampian and co-chair of SHPN HIV Clinical Leads
Dr Kirsty Abu-Rajab, Consultant in HIV & GU Medicine, Lead Clinician for Sexual Health & HIV, NHS Forth Valley
Dr Sam Allen, Consultant Physician in Infectious Diseases, NHS Ayrshire & Arran
Dr Indranil Banerjee, Consultant Physician in GU & HIV Medicine, NHS Fife
Dr Bridie Howe, HIV Clinical Lead, NHS Highland
Dr Gwyneth Jones, Consultant Physician and BBV Clinical Lead and Secondary Care Interface Lead, NHS Dumfries & Galloway
Dr Nicholas Kennedy, Consultant Physician in Infectious Diseases & General Medicine and Lead Clinician for Lanarkshire BBV Prevention & Care Network, NHS Lanarkshire
Dr Rona MacDonald, Consultant Physician in GUM, NHS Greater Glasgow & Clyde and Ayrshire & Arran, and Chair BASHH Clinical Governance Committee
Dr Rebecca Metcalfe, Consultant Physician in Sexual Health & HIV, NHS Greater Glasgow & Clyde and Co-Chair of HIV-TEDI Testing Subgroup
Dr Jocelyn Skaaning, Specialty Doctor in Sexual Health and Clinical Lead for Primary Care BBV, NHS Ayrshire & Arran
Dr Kate Templeton, Consultant Clinical Scientist, NHS Lothian and Specialty Advisor to the Chief Medical Officer for Virology in Scotland
*Joint first authors
References:
1. Wright W F, Durso S C, Forry C, Rovers C P. Fever of unknown origin. BMJ 2025; 388: e080847 doi:10.1136/bmj-2024-080847
2. Palfreeman A, Sullivan A, Rayment M et al. British HIV Association/British Association for Sexual Health and HIV/British Infection Association adult HIV testing guidelines 2020. HIV Med 2020; 21 Suppl 6: 1-26.
3. Wright WF, Stelmash L, Betrains A, Mulders-Manders CM, Rovers CP, Vanderschueren S, Auwaerter PG; International Fever and Inflammation of Unknown Origin Research Working Group. Recommendations for Updating Fever and Inflammation of Unknown Origin From a Modified Delphi Consensus Panel. Open Forum Infect Dis. 2024 Jun 10;11(7)
4. Bulteel N, Henderson N, Parris V, Capstick R, Premchand N, Hunter E, Perry M. HIV testing in secondary care: a multicentre longitudinal mixed methods electronic survey of non-HIV specialist hospital physicians in South-East Scotland and Northern England. J R Coll Physicians Edinb. 2021 Sep;51(3):230-236. doi: 10.4997/JRCPE.2021.305. PMID: 34528609.
Competing interests: No competing interests
Dear Editor
Wright WF and colleagues provide a comprehensive and in-depth clinical update on fever of unknown origin (FUO), offering valuable insights for both clinical practice and research [1]. However, there are still certain aspects that warrant further exploration and supplementation.
A critical consideration is that some cases of FUO are caused by rare genetic diseases, which can sometimes lead to severe complications such as haemophagocytic lymphohistiocytosis (HLH) [2-4]. These conditions often present with complex and non-specific clinical features, making them difficult to diagnose using traditional methods. As technology advances and the cost of genetic testing decreases, methods like targeted sequencing and whole-exome sequencing (WES) are becoming more accessible. These technologies, particularly WES and whole-genome sequencing (WGS), allow for a deeper investigation into pathogenic gene mutations, providing essential support in diagnosing rare diseases. Identifying the genetic cause not only facilitates a precise diagnosis and targeted treatment but also provides critical insights for genetic counseling and family disease prevention, enabling at-risk family members to take appropriate preventive measures.
Furthermore, genetic testing plays a crucial role in diagnosing certain adult-onset autoinflammatory diseases, such as Vacuoles, E1 Enzyme, X-linked, Autoinflammatory Syndrome (VEXAS) [5,6]. VEXAS syndrome is a rare condition with diverse and often non-specific clinical manifestations, making it difficult to diagnose with conventional methods. Genetic testing enables the precise identification of pathogenic mutations, such as those in the UBA1 gene, facilitating early diagnosis and tailored treatment, which significantly improves patient prognosis.
Therefore, future research and clinical practice regarding FUO should include genetic testing technologies alongside other diagnostic tools, particularly for rare genetic diseases and specific autoinflammatory conditions. This will enhance diagnostic accuracy, improve patient outcomes, and contribute to more personalized care.
Yours sincerely,
Huihui Chi
Physician, Department of Rheumatology and Immunology,
Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Ningqi Dai
MD, Department of Rheumatology and Immunology,
Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Chengde Yang
Professor, Department of Rheumatology and Immunology,
Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
1. Wright WF, Durso SC, Forry C, Rovers CP. Fever of unknown origin. BMJ (Clinical research ed). 2025;388:e080847.
2. Shinar Y, Obici L, Aksentijevich I, et al. Guidelines for the genetic diagnosis of hereditary recurrent fevers. Annals of the rheumatic diseases. 2012;71(10):1599-1605.
3. Rood JE, Behrens EM. Inherited Autoinflammatory Syndromes. Annual review of pathology. 2022;17:227-249.
4. Henter JI, Horne A, Aricó M, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatric blood & cancer. 2007;48(2):124-131.
5. Beck DB, Ferrada MA, Sikora KA, et al. Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease. 2020;383(27):2628-2638.
6. Torreggiani S, Castellan FS, Aksentijevich I, Beck DB. Somatic mutations in autoinflammatory and autoimmune disease. Nature reviews Rheumatology. 2024;20(11):683-698.
Competing interests: No competing interests
Dear Editor
Wright and colleagues' otherwise helpful clinical update on fever of unknown origin (1) misses an opportunity to remind clinicians to consider malignant catatonia as a potential cause of the phenomenon.
Catatonia is a severe syndrome that can affect speech, movement and complex behaviour, ranging from akinetic stupor to severe motoric excitement (2). Traditionally falling within the realm of psychiatry (3), it readily occurs in general medical conditions in the absence of mental illness (4). It can be caused by myriad diseases such as autoimmune encephalitis, systemic lupus erythematosus, multiple sclerosis, neural injury, structural brain pathology including neoplasm, epilepsy and endocrine or metabolic disturbances, as well as by therapeutic and recreational drug use (4). Additionally, it has been recognised in up to 20% of individuals with autism and linked to multiple genetic syndromes with distinct somatic and neuropsychiatric phenotypes (5).
First identified by Stauder in 1934, the "malignant" form presents with additional autonomic instability, manifesting as labile blood pressure, heart rate, respiratory rate and, crucially, temperature (2,3,4); one variant is the drug-induced malignant neuroleptic syndrome (2). Malignant catatonia carries a mortality of 10% (4) and requires prompt electroconvulsive therapy alongside high-dose benzodiazepines to save life (2). Such management should be immediate and adjunctive to ongoing investigations and concurrent treatment of the underlying pathology (6).
Yet the condition is under-recognised across the lifespan in general hospitals (7). Anecdotally, core signs of catatonia are overlooked by emergency and general physicians, intensivists, neurologists and even neuropsychiatrists as features of delirium or atypical manifestations of the underlying disease and may be masked by induced sedation. It seems common for spiking temperatures and other manifestations of dysautonomia to be addressed in isolation, without recognition or management of the wider syndrome. The erroneous historical belief that all catatonia is equated with schizophrenia may also lead to life-threatening diagnostic delay (3).
Malignant catatonia should be considered as a differential diagnosis whenever fluctuating fever of unknown origin is observed alongside other features of dysautonomia. If the presence of supporting motor, vocal or behavioural signs is even suspected, it is imperative that a psychiatrist with experience of recognising and treating catatonia is involved early in the patient's care, even in the absence of "psychiatric" symptoms.
Yours faithfully
Richard Braithwaite MRCPsych
Consultant Psychiatrist in Neuromodulation
Sussex Partnership NHS Foundation Trust, UK
Lee E Wachtel MD
Professor of Psychiatry
Johns Hopkins School of Medicine, USA
1. Wright WF, Durso SC, Forry C, Rovers CP. Fever of unknown origin. BMJ. 2025 Jan 6;388:e080847. doi: 10.1136/bmj-2024-080847. PMID: 39761983.
2. Connell J, Oldham M, Pandharipande P, Dittus RS, Wilson A, Mart M, Heckers S, Ely EW, Wilson JE. Malignant Catatonia: A Review for the Intensivist. J Intensive Care Med. 2023 Feb;38(2):137-150. doi: 10.1177/08850666221114303. Epub 2022 Jul 21. PMID: 35861966.
3. Csihi L, Ungvari GS, Caroff SN, Gazdag G. First 150 years of catatonia: Looking back at its complicated history and forward to the road ahead. World J Psychiatry. 2024 May 19;14(5):600-606. doi: 10.5498/wjp.v14.i5.600. PMID: 38808080; PMCID: PMC11129151.
4. Rogers JP, Oldham MA, Fricchione G, Northoff G, Ellen Wilson J, Mann SC, Francis A, Wieck A, Elizabeth Wachtel L, Lewis G, Grover S, Hirjak D, Ahuja N, Zandi MS, Young AH, Fone K, Andrews S, Kessler D, Saifee T, Gee S, Baldwin DS, David AS. Evidence-based consensus guidelines for the management of catatonia: Recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2023 Apr;37(4):327-369. doi: 10.1177/02698811231158232. Epub 2023 Apr 11. PMID: 37039129; PMCID: PMC10101189.
5. Wachtel L, Luccarelli J, Falligant JM, Smith JR. Electroconvulsive therapy in autism spectrum disorders: an update to the literature. Curr Opin Psychiatry. 2024 Dec 23. doi: 10.1097/YCO.0000000000000985. Epub ahead of print. PMID: 39804212.
6. Kraiter FG, May DT, Slauer RD, Abburi N, Eckstein C, Shah S, Komisar JR, Feigal JP. Catatonia in anti-NMDA receptor encephalitis: a case series and approach to improve outcomes with electroconvulsive therapy. BMJ Neurol Open. 2024 Nov 12;6(2):e000812. doi: 10.1136/bmjno-2024-000812. PMID: 39564516; PMCID: PMC11575251.
7. Llesuy JR, Medina M, Jacobson KC, Cooper JJ. Catatonia Under-Diagnosis in the General Hospital. J Neuropsychiatry Clin Neurosci. 2018 Spring;30(2):145-151. doi: 10.1176/appi.neuropsych.17060123. Epub 2018 Jan 12. PMID: 29325478.
Competing interests: No competing interests
Dear Editor,
Wright WF et al. gave a comprehensive update on the causes and diagnosis of fever of unknown origin (FUO) [1]. We understand and agree with the rationale for withholding therapy wherever possible until the underlying cause of the fever has been determined to prevent diagnosis obfuscation, however, we would advise haemophagocytic lymphohistiocytosis (HLH) be added to their list of exceptional situations in which empirical therapy should not be withheld.
HLH is a hyperinflammatory syndrome that may present as FUO and/or complicate many of the underlying causes of FUO. HLH is characterised by unremitting fever, falling blood counts and hyperferritaemia (3Fs) caused by persistently activated cytotoxic lymphocytes and macrophages, resulting in excessive proinflammatory cytokine production [2,3]. In adults, HLH typically arises as a secondary condition (sHLH) that can be triggered by infections, malignancies, autoimmune/autoinflammatory diseases and medications. Importantly, HLH may be a superadded issue in FUO and the clinical question in a person with FUO ‘is there evidence of hyperinflammation?’ and use of the 3Fs to address this is key. Overall mortality is high, with data suggesting a 1-year survival of 56%, incidence has increased dramatically in the UK between 2001-2016, likely due to increased clinician awareness but it is probable that this condition remains underrecognised and underdiagnosed [4].
There is evidence that the prompt initiation of immunosuppressive therapy including with corticosteroids and anakinra (recombinant IL-1 receptor blocker) can improve patient outcomes and reduce mortality[5]. This, in conjunction with identification of the underlying trigger and multi-disciplinary team (MDT) working has also been shown to reduce patient mortality [3].
We would therefore urge clinicians managing a patient with FUO to always consider HLH, as prompt initiation of immunosuppressive therapy in parallel to diagnosing the underlying cause may have a profound positive impact on patient outcomes.
References
1. Wright W F, Durso S C, Forry C, Rovers C P. Fever of unknown origin BMJ 2025; 388 :e080847 doi:10.1136/bmj-2024-080847
2. Cox MF, Mackenzie S, Low R, et al. Diagnosis and investigation of suspected haemophagocytic lymphohistiocytosis in adults: 2023 Hyperinflammation and HLH Across Speciality Collaboration (HiHASC) consensus guideline. Lancet Rheumatol. 2024;6(1):e51-e62. doi:10.1016/S2665-9913(23)00273-
3. Getting It Right First Time (GIRFT). Haemophagocytic lymphohistiocytosis (HLH). Guidance on the diagnosis, treatment, management and governance. 2024. Available from: https://gettingitrightfirsttime.co.uk/wp-content/uploads/2024/07/HLH-Gui...
4. West J, Stilwell P, Liu H, et al. 1-year survival in haemophagocytic lymphohistiocytosis: a nationwide cohort study from England 2003-2018. J Hematol Oncol. 2023;16(1):56. Published 2023 May 26. doi:10.1186/s13045-023-01434-
5. Baldo F, Erkens RGA, Mizuta M, et al. Current treatment in macrophage activation syndrome worldwide: a systematic literature review to inform the METAPHOR project. Rheumatology (Oxford). 2025;64(1):32-44. doi:10.1093/rheumatology/keae391
Competing interests: No competing interests
Dear Editor
Wright WF, et al. gave a vivid description of recent definitions and approaches to fever of unknown origin (FUO) [1]. Despite the advancement of diagnostic tools, FUO remains a subjective diagnosis of prolonged fever in most cases.
The zoonotic infections that cause fever of unknown origin account for about half of all human infections [2]. Common examples of both common and unusual zoonoses include leptospirosis (fever with icterus), rickettsiosis (fever with rash), babesiosis (fever with chills), and brucellosis (undulant fever). Similarly, the neglected tropical diseases—leprosy and lymphatic filariasis—are the forgotten causes of FUO in the tropics [3, 4].
Although hormonal hyperthermia is an infrequent cause of fever of unknown origin, a patient suffering from fever rising up to 101°F of prolonged duration was ultimately found to be in a state of thyrotoxicosis [5].
References-
1. Wright W F, Durso S C, Forry C, Rovers C P. Fever of unknown origin BMJ 2025; 388 :e080847 doi:10.1136/bmj-2024-080847
2. Cleri DJ, Ricketti AJ, Vernaleo JR. Fever of unknown origin due to zoonoses. Infect Dis Clin North Am. 2007 Dec;21(4):963-96, viii-ix. doi: 10.1016/j.idc.2007.08.009.
3. Singh RK. Lucio's phenomenon. J Assoc Physicians India. 2003 May;51:529. PMID: 12974445.
4. Hakeem S C, V A1, Srivasta N, et al. An Unusual Presentation of Filariasis as Pyrexia of Unknown Origin: Case Report. Amrita Journal of Medicine 2022;18(3):100-101.| DOI: 10.4103/AMJM.AMJM_27_22
5. Singh RK. Forgotten Cause of Fever. BMJ-SA ed 2004;20:790.
Competing interests: No competing interests
Reply to “Clinical Updates Fever of Unknown Origin” by Wright et al.
TO THE EDITOR,
We appreciate Bulteel and colleagues’ interest in our review[1] and their questions that allow us to clarify some key points as well as bring to our attention the multicenter survey by Bulteel et al.[2] and guidelines by Palfreeman et al.[3] These references are represented as evidence-based data that would contradict our recommendations for the conditional use of human immunodeficiency virus (HIV) serology (i.e., only in those who disclose risk factors) to the current minimal investigations defining a patient as classic fever of unknown origin (FUO).[3,4] We concur with Bulteel et al.[2] that the timely diagnosis of HIV is a public health priority and that screening and testing for HIV in individuals with epidemiological risk factors for acquisition and indicator conditions, regardless of any demographic or behavioral risk assessment, is important to the goal of eliminating HIV transmission by 2030. We also agree with Palfreeman et al.[3] that the cost-effectiveness threshold of 0.1% undiagnosed HIV prevalence should not be seen as restrictive where there is an identified need for testing; such as for evaluating patients with prolonged unexplained fevers. However, we would consider this as hypothesis-generating and opinion-based recommendations for classic FUO patients (i.e., given the guidelines list a grade 1 strength of recommendation but evidence rating D).
Among those tested, FUO-associated HIV has been reported to range from 1.4-5.3% in some studies.[5,6] However, the prevalence of individuals living with undiagnosed HIV in this population has not been fully established. Given the overall estimated FUO prevalence of 1.9-2.0%, we surmise the prevalence of undiagnosed HIV in this population of patients to be lower than the cost-effectiveness threshold.[1,4,5] While both publications report HIV testing should be offered to patients with unexplained fevers, we agree that the threshold for HIV testing should be low but question the authors conclusions that universal screening in all geographic locations, and healthcare systems is both effective and cost-effective for FUO.[5]
We are also unaware of any study directly comparing the components of the current minimal investigations defining a patient as classic FUO. Therefore, our Delphi consensus[4] did not advocate using HIV serology as part of the inclusionary criteria per se and the question of which tests should be used in this role remains unanswered. We support further research into the optimal tests that could define these patients but maintain that there remains little compelling evidence of what role HIV serology should play in the defining criteria. The lack of multicenter, high-quality studies, and the extensive differential diagnosis of FUO also means that clinical judgment remains an essential component of care. Referring these patients to expert physicians to evaluate for potential diagnostic clues (PDCs) from the history and physical examination prior to the use of specialized testing or rendering a FUO diagnosis, is consistent with the goals of diagnostic stewardship.
We also valued the input concerning Table 4. Recognizing specialized testing for suspected FUO-associated diseases is important for primary care physicians, we included HIV testing in these examples. We appreciate the confusion this might have caused with our readers but maintain the comments regarding HIV testing were not intended to serve as formal recommendations but rather only were intended to serve as examples of specialized testing. For formal HIV testing recommendations, we refer the authors and readers to the most recent published guidelines.[3,7]
Regarding the authors suggested stigmatization involved our use of the terminology “high-risk”, we assure readers that the language of our review was not intended to perpetuate ignorance, bias, or stigma.[1] While we agree language matters, appropriate or acceptable terminology can vary geographically, culturally, and over time. By using this terminology of “high-risk”, we sought to be consistent with the same terminology used in the United States, and British guidelines.[3,7] Although our review is not primarily focused on HIV, we embrace the reality that HIV language is constantly evolving and it is up to us to evolve with it from a place of respect, dignity, and humility.[8] Our FUO review emphasizes the need for further investigations into diagnostic testing strategies, including HIV testing, to meet geographical variations in diseases across heterogeneous populations and the ecology of medical care.
References:
1. Wright WF, Durso SC, Forry C, Rovers CP. Fever of unknown origin. BMJ. 2025 Jan 6;388:e080847. doi: 10.1136/bmj-2024-080847.
2. Bulteel N, Henderson N, Parris V, Capstick R, Premchand N, Hunter E, Perry M. HIV testing in secondary care: a multicentre longitudinal mixed methods electronic survey of non-HIV specialist hospital physicians in South-East Scotland and Northern England. J R Coll Physicians Edinb. 2021 Sep;51(3):230-236. doi: 10.4997/JRCPE.2021.305.
3. Palfreeman A, Sullivan A, Rayment M, et al. British HIV Association/British Association for Sexual Health and HIV/British Infection Association adult HIV testing guidelines 2020. HIV Med. 2020 Dec;21 Suppl 6:1-26. doi: 10.1111/hiv.13015.
4. Wright WF, Stelmash L, Betrains A, et al.; International Fever and Inflammation of Unknown Origin Research Working Group. Recommendations for Updating Fever and Inflammation of Unknown Origin From a Modified Delphi Consensus Panel. Open Forum Infect Dis. 2024 Jun 10;11(7):ofae298. doi: 10.1093/ofid/ofae298.
5. Wright WF, Yenokyan G, Simner PJ, Carroll KC, Auwaerter PG. Geographic Variation of Infectious Disease Diagnoses Among Patients With Fever of Unknown Origin: A Systematic Review and Meta-analysis. Open Forum Infect Dis. 2022 Apr 9;9(5):ofac151. doi: 10.1093/ofid/ofac151.
6. Siikamäki HM, Kivelä PS, Sipilä PN, et al. Fever in travelers returning from malaria-endemic areas: don't look for malaria only. J Travel Med. 2011 Jul-Aug;18(4):239-44. doi: 10.1111/j.1708-8305.2011.00532.x.
7. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV. Department of Health and Human Services. 2024. Available at https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv. Accessed (March 19, 2025)
8. United Nations Programme on HIV/AIDS (UNAIDS). UNAIDS TERMINOLOGY GUIDELINES. 2024. Available at https://www.unaids.org/en/resources/documents/2024/terminology_guidelines Accessed (April 1, 2025) [pages 4-11, and 14]
Competing interests: No competing interests