Anaplastic large cell lymphoma (ALCL) is a CD30-positive mature T-cell lymphoma. ALK-negative systemic ALCL typically affects older adults, with aggressive clinical behavior. Predominant gastrointestinal involvement is rare and may present with nonspecific systemic symptoms, posing diagnostic challenges, particularly when manifesting as fever of unknown origin. We report a case of a patient with ALK-negative systemic ALCL and predominant gastrointestinal involvement. The patient had a history of indolent cutaneous extranodal marginal zone B-cell lymphoma. The patient presented with a prolonged, intermittent fever and constitutional symptoms. The initial evaluations, including computed tomography, 18F-fluorodeoxyglucose positron emission tomography/computed tomography, and bone marrow examination, were not diagnostic. The persistent fever, which was accompanied by newly developed gastrointestinal symptoms and progressive hypoalbuminemia, prompted an endoscopic evaluation that revealed multiple ulcerofungating gastric lesions. Histopathological examination demonstrated the diffuse proliferation of large atypical lymphoid cells with high CD30 expression, no ALK expression, a high Ki-67 proliferation index, and clonal T-cell receptor gene rearrangement. These findings were consistent with ALK-negative systemic ALCL. Staging then revealed multifocal gastrointestinal involvement. The patient was treated with brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone, following which the febrile episodes improved. This case illustrates an uncommon gastrointestinal-predominant presentation of ALK-negative systemic ALCL presenting as fever of unknown origin. This case underscores the importance of continued diagnostic reassessment and symptom-guided tissue acquisition when conventional staging studies are not initially diagnostic, particularly in patients with a history of indolent lymphoma.

Subacute thyroiditis is an inflammatory thyroid disorder that typically presents with anterior neck pain, thyroid tenderness and transient thyrotoxicosis. Presentation as pyrexia of unknown origin (PUO) without classical thyroid symptoms is uncommon and may lead to diagnostic delay.We report a case of a patient in their late 50s who presented with persistent evening febrile spikes, weight loss and markedly elevated inflammatory markers, fulfilling the criteria for PUO. Extensive evaluation for infectious, malignant and autoimmune causes was unrevealing. Careful repeat clinical examination revealed mild thyroid enlargement, prompting thyroid function testing, which demonstrated suppressed thyroid-stimulating hormone with elevated thyroid hormone levels. Technetium-99m thyroid scintigraphy showed markedly reduced uptake, consistent with subacute thyroiditis.The patient was treated with corticosteroids, resulting in rapid defervescence of fever within 48 hours. This case highlights that subacute thyroiditis, although uncommon, should be considered in patients presenting with persistent unexplained fever and elevated inflammatory markers, even in the absence of classical thyroid symptoms.

Aspergillus lentulus is a slow-growing and drug-resistant fungus, which has been primarily reported in adults, usually immunocompromised ones, suffering from invasive pulmonary aspergillosis (IPA). This condition is rare in children. Here, we report a case of invasive pulmonary aspergillosis due to Aspergillus lentulus in a boy with no history of recurrent infections who presented with a prolonged fever of unknown origin. Based on chest CT scan findings showing typical halo signs, a fungal infection was strongly suspected. Empirical antifungal therapy was initiated at early admission but failed to resolve the persistent fever in this case. The causative pathogen was confirmed by blood metagenomic next-generation sequencing (mNGS). Subsequent genetic analysis identified a pathogenic mutation in the X-linked CYBB gene, confirming chronic granulomatous disease (CGD). Eventually, following a combination therapy of voriconazole and micafungin, the boy became afebrile and was discharged, pending hematopoietic stem cell transplantation (HSCT). To our knowledge, no previous cases of Aspergillus lentulus infection in children with CGD have been reported in the literature. This case underscores the critical importance of identifying the causative microorganism. It also highlights the value of emerging detection methods, such as mNGS. At present, there is no consensus for the optimal antifungal regimen against pediatric Aspergillus lentulus infections. Clinical improvement was achieved in this patient following combination therapy with voriconazole and micafungin, offering a practical therapeutic reference for managing this refractory fungal infection.

Fever is a recognized manifestation of active ulcerative colitis (UC); however, isolated fever in the absence of GI symptoms or objective evidence of active colonic inflammation is exceedingly uncommon. The diagnostic challenge is amplified in immunocompromised patients receiving biologic therapy, in whom occult infection must be rigorously excluded. We present a 68-year-old woman with a history of well-controlled HIV infection and recently diagnosed UC who was initiated on vedolizumab, mesalamine, and a prednisone taper in the outpatient setting. She presented with persistent daily fevers and initial concern for an infectious etiology of pyrexia. Ulcerative colitis appeared to be well treated, with outpatient CT demonstrating resolution of colitis, and the patient denied diarrhea, abdominal pain, hematochezia, or other symptoms suggestive of active disease. An extensive infectious workup, including blood cultures, viral studies, fungal biomarkers, Lyme disease testing, tick-borne testing, and autoimmune serologies, was negative. During the laboratory evaluation, thrombocytopenia, markedly elevated inflammatory markers, and elevated D-dimer levels were noted. Despite a comprehensive multidisciplinary evaluation, no infectious, malignant, thrombotic, or rheumatologic etiology was identified. Throughout her hospital course, the patient developed sequelae of a severe inflammatory response, including atrial fibrillation. The patient's fevers were ultimately attributed to an atypical systemic inflammatory manifestation of UC. This case highlights a rare presentation of UC manifesting predominantly as fever of unknown origin (FUO) despite apparent clinical and radiographic remission. Clinicians should recognize that significant systemic inflammation may occur even in the absence of overt GI disease activity after exclusion of alternative causes.

A 4-year-old boy presented with prolonged fever of unknown origin and systemic inflammation without early neurological signs. MRI revealed multifocal demyelination, and MOG antibodies were positive. He was diagnosed with ADEM and treated with steroids and IVIg, but relapsed twice, consistent with multiphasic disseminated encephalomyelitis (MDEM).

The timely differentiation of pathogens causing Fever of Unknown Origin (FUO) relies heavily on multiplex diagnostics. However, scaling up these existing platforms is severely restricted by the spectral overlap of fluorescent probes and the finite number of optical channels. Here, we present a topology-encoded diagnostic strategy that shifts the multiplexing dimension from spectral space to structural space, enabling target discrimination through discrete electrophoretic mobility signatures rather than fluorophore combinations. This platform integrates primer-blocked asymmetric amplification (PBA-amp) with programmable DNA nanostructure sensors (DNA-NS), in which target-specific single-stranded amplicons induce distinct topological transformations of the sensor scaffold. These transformations generate resolvable mobility states corresponding to individual targets, allowing multiplex identification using gel-resolved readouts. We demonstrated the duplex detection of Coxiella burnetii and Orientia tsutsugamushi, two prominent pathogens that cause clinically indistinguishable FUO, achieving an analytical sensitivity of down to 9.76 aM with high specificity against mismatched sequences. In clinical validation using 121 plasma-derived DNA samples, the platform exhibits an overall positive percent agreement of 96.4% -with all discordant cases strictly restricted to low titer samples near the stochastic limit (Ct > 36)- and a negative percent agreement of 100% compared to reference real-time PCR. By decoupling multiplex encoding from spectral constraints, this work establishes a structurally encoded framework for nucleic acid diagnostics, offering a scalable alternative to fluorescence-limited multiplexing while enabling simplified readout without the need for multichannel detection systems.

Familial Mediterranean fever (FMF) is an autoinflammatory genetic disorder characterized by prolonged periods of fever and serosal inflammation such as peritonitis, pleuritis, and arthritis. FMF is due to a mutation of the MEFV gene encoding pyrin. Although this disorder typically presents in early childhood with recurrent episodes that are self-limiting, atypical and long-lasting febrile episodes may cause significant diagnostic challenges, especially in regions where genetic testing for FMF is not easily available. In this study, we report a case of a four-year-old Syrian girl who presented with persistent fever unresponsive to antipyretics lasting for one month. With the high clinical suspicion, colchicine therapy was initiated, resulting in clinical improvement. This case illustrates the importance of maintaining clinical suspicion of FMF in the pediatric population presenting with persistent fever of unknown origin, and sheds light on the role of colchicine as a therapeutic and diagnostic medication when genetic testing is unavailable.

Relapsing polychondritis (RP) is a rare autoimmune disease of cartilaginous structures, often diagnosed late due to nonspecific presentations. Both RP and granulomatosis with polyangiitis (GPA) can cause diffuse tracheobronchial wall thickening on computed tomography (CT) and may be seronegative for anti-neutrophil cytoplasmic antibody (ANCA), creating a diagnostic impasse. We report a 46-year-old man with two months of fever, productive cough, and sternal pain. A saddle nose deformity was the only cartilaginous sign; serum ANCA was repeatedly negative. Neck CT showed diffuse tracheal and bilateral main bronchial wall thickening; the report listed amyloidosis and GPA as differential diagnoses, omitting RP. Despite laboratory, microbiological, and imaging workup, the fever fulfilled criteria for fever of unknown origin (FUO), prompting 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT. PET/CT demonstrated intense FDG uptake in the cartilaginous wall of the tracheobronchial tree, forming the classic inverted-Y sign, with bilateral costal cartilage hypermetabolism (a site not involved in GPA) and no uptake in the kidneys, sinuses, or orbits, collectively establishing a diagnosis of RP. Corticosteroid therapy elicited prompt clinical and biochemical response. This case demonstrates that 18F-FDG PET/CT can differentiate RP from GPA when CT and serology are uninformative.

Fever of unknown origin (FUO) remains a persistent diagnostic challenge in clinical medicine despite significant advances in laboratory testing and imaging techniques. The definition of FUO has evolved since the original criteria proposed in 1961 and currently refers to persistent fever exceeding approximately 38.2-38.3 °C without a definitive diagnosis after an adequate diagnostic evaluation. Gastrointestinal diseases represent an important but often underrecognized group of conditions associated with FUO. The aim of this review is to synthesize current evidence on the gastroenterological causes of FUO, with particular emphasis on pathophysiological mechanisms, diagnostic strategies, and therapeutic management. The analysis highlights the role of inflammatory, infectious, and neoplastic gastrointestinal disorders in the etiology of prolonged fever. Key mechanisms involve systemic inflammatory responses mediated by cytokines such as interleukin-1, interleukin-6, and tumor necrosis factor, as well as immune processes associated with the gut-associated lymphoid tissue (GALT) and interactions between intestinal microbiota and host immunity. Among the most frequently reported gastroenterological causes of FUO are inflammatory bowel diseases, intra-abdominal infections and abscesses, hepatobiliary disorders, pancreatitis, and gastrointestinal malignancies. Diagnostic evaluation requires a stepwise approach integrating laboratory testing, microbiological studies, imaging modalities, and endoscopic procedures, with advanced techniques such as computed tomography and fluorodeoxyglucose positron emission tomography improving detection of occult inflammatory or neoplastic processes. Therapeutic management is primarily guided by the identification of the underlying cause, while empirical treatment should be carefully considered to avoid masking diagnostic clues. A better understanding of the gastrointestinal mechanisms underlying FUO and the development of more efficient diagnostic algorithms may improve clinical outcomes and reduce the number of undiagnosed cases.