Dear Editor
Thank you for offering an insight into the current spike of TB in the UK. Whilst I agree with the authors that if the UK is serious about the elimination of TB, it must expand testing and treatment of latent infection, however, I am particularly concerned that preventing TB is mentioned nowhere in your article. I wonder if ignoring the importance of vaccination was genuinely missed by the authors, or if it was left behind purposely, albeit without explaining why.
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