Case Report: Polycythemia vera presenting as persistent unexplained low-grade fever

Abstract

Persistent fever as an initial manifestation of polycythemia vera (PV) is uncommon and may lead to diagnostic delay. We report a 72-year-old woman with recurrent low-grade fever for 1 month, with a maximum temperature not exceeding 38.0 °C. Although this presentation did not meet the classic fever-of-unknown-origin temperature threshold, it prompted an FUO-like diagnostic evaluation because routine infectious and autoimmune investigations were unrevealing and empirical antimicrobial therapy was ineffective. Laboratory evaluation revealed elevated hemoglobin and hematocrit levels, accompanied by leukocytosis and initially high-normal platelet counts that later progressed to thrombocytosis. Chest CT/PET-CT showed diffuse ground-glass/interstitial pulmonary changes; active bacterial pneumonia was considered unlikely based on the absence of respiratory symptoms, procalcitonin at the upper limit of the normal range, negative cultures and sputum smears, and absence of FDG-avid pulmonary consolidation, although a concomitant viral or noninfectious inflammatory pulmonary process could not be completely excluded. Bone marrow biopsy showed hypercellular marrow with panmyelosis and megakaryocytic proliferation, and molecular testing identified a JAK2 V617F mutation with a high allele burden. The diagnosis of PV was established based on the 5th edition of the World Health Organization (WHO) diagnostic criteria. The patient was treated with hydroxyurea and aspirin, resulting in gradual resolution of fever and improvement in hematological parameters. This case highlights that PV should be considered in the differential diagnosis of persistent unexplained low-grade fever when erythrocytosis and other myeloproliferative features are present, while alternative pulmonary causes should be assessed carefully.

Introduction

Fever of unknown origin (FUO) is classically defined as a body temperature exceeding 38.3 °C on several occasions for more than 3 weeks, with no established diagnosis despite appropriate evaluation (2). However, patients with prolonged unexplained low-grade fever may still undergo an FUO-like diagnostic work-up when symptoms persist and routine evaluation is unrevealing. Polycythemia vera (PV) is a chronic myeloproliferative neoplasm driven by JAK2 mutations and characterized by clonal proliferation of erythroid cells (1, 3).

Clinically, patients typically present with symptoms such as pruritus, headache, splenomegaly, and thromboembolic events, while some may also experience nonspecific systemic manifestations including fatigue and night sweats (4).

Here, we describe a 72-year-old woman presenting with recurrent low-grade fever for 1 month, without clear infectious symptoms and unresponsive to empirical antimicrobial therapy. The maximum documented temperature did not exceed 38.0 °C and therefore did not fulfill the classic FUO definition; nevertheless, the prolonged unexplained course prompted a broad FUO-like evaluation. Initial laboratory evaluation revealed elevated hemoglobin and hematocrit levels, accompanied by leukocytosis and high-normal platelet counts that subsequently developed into thrombocytosis, raising suspicion for an underlying hematologic disorder.

Although PV is well defined diagnostically, cases presenting primarily with persistent unexplained fever remain uncommon and may be easily misinterpreted as infectious or inflammatory diseases, leading to delayed recognition. Therefore, awareness of such atypical presentations is of clinical importance. This report aims to highlight PV as a potential hematologic diagnosis in patients with prolonged unexplained low-grade fever and to discuss the possible role of inflammation in its pathophysiology.

Case description

A 72-year-old woman was admitted for recurrent low-grade fever lasting 1 month, with a maximum temperature not exceeding 38.0 °C, accompanied by chills, headache, and generalized weakness. The patient had previously received empirical antibiotic therapy with cephalosporins and penicillin at another hospital, but with no significant clinical improvement, leading to her transfer to our hospital for further management. The patient denied weight loss, night sweats, cough, dyspnea, abdominal pain, or joint symptoms. No relevant history of hematologic disease, thrombosis, chronic inflammatory disease, or long-term immunosuppressive therapy was identified on clinical interview. No family history of erythrocytosis, thrombosis, or myeloproliferative neoplasms was reported; however, blood counts in first-degree relatives were not available.

Physical examination on admission revealed no significant abnormalities, and no palpable hepatosplenomegaly was detected. Admission laboratory tests showed hemoglobin 166 g/L, hematocrit 53.1%, white blood cells 11.53 × 10⁹/L, and platelets 393 × 10⁹/L. C-reactive protein was 38.7 mg/L, interleukin-6 was 39 pg/mL, procalcitonin was at the upper limit of the normal range (0.05 ng/mL; reference range, 0–0.05 ng/mL), and erythropoietin was 2.4 mIU/mL.

To further evaluate potential infectious and autoimmune etiologies, comprehensive investigations were performed. Multiple blood cultures, sputum smears, and a comprehensive panel of autoimmune-related antibodies yielded negative results. Chest CT performed before admission showed chronic bronchitis/emphysematous and interstitial changes, right middle-lobe segmental atelectasis, and multiple scattered small pulmonary nodules. The CT component of 18F-FDG PET/CT also showed diffuse ground-glass/interstitial pulmonary changes. There was no focal FDG-avid pulmonary consolidation, pleural effusion, or hypermetabolic lymphadenopathy. Together with the absence of cough or dyspnea, procalcitonin at the upper limit of the normal range, and lack of response to antibacterial therapy, active bacterial pneumonia was considered unlikely. However, because respiratory viral PCR testing was not performed, a concomitant viral infection or noninfectious inflammatory pulmonary process could not be fully excluded.

The same 18F-FDG PET/CT scan revealed mildly heterogeneous increased bone marrow metabolism throughout the body, accompanied by mild splenomegaly, with no clear signs of malignancy (Figure 1). These findings suggested the possibility of a myeloproliferative disorder.

Figure 1.

18F-FDG PET/CT and chest CT findings. The CT component showed diffuse ground-glass/interstitial pulmonary changes, but no focal FDG-avid pulmonary consolidation, pleural effusion, or hypermetabolic lymphadenopathy was identified. Diffuse and mildly heterogeneous FDG uptake was observed throughout the bone marrow, accompanied by mild splenomegaly. No focal lesions suggestive of malignancy were identified.

Based on the comprehensive clinical presentation and imaging findings, bone marrow aspiration, bone marrow biopsy, and relevant molecular tests were performed. The bone marrow biopsy specimen from the right posterior iliac crest showed hypercellular marrow (approximately 70%) with panmyelosis. Granulocytic and erythroid precursors were present at multiple maturation stages, with an approximately preserved myeloid-to-erythroid ratio. Megakaryocytes were readily identifiable, predominantly lobulated, with some enlarged hyperlobulated forms. Representative H&E-stained biopsy images are shown in Figure 2. Immunohistochemistry showed MPO-positive granulopoiesis, E-cadherin-positive erythropoiesis, and CD61-positive megakaryocytes, with only scattered/low CD34 and CD117 positivity. Reticulin staining was MF-0, and iron staining was negative. Testing for the JAK2 V617F mutation was positive, with a mutation burden of 88.25%; JAK2 exon 12 mutation testing was negative. Together, the bone marrow biopsy findings, erythrocytosis, and JAK2 V617F positivity supported the diagnosis of PV according to the 5th edition of the WHO diagnostic criteria (1).

Figure 2.

Bone marrow biopsy findings. Representative de-identified H&E-stained bone marrow biopsy images obtained from the right posterior iliac crest. (A) Low-power view showing hypercellular marrow with reduced adipose spaces and increased hematopoietic cells (H&E, 10 × 10). (B) Higher-power view showing trilineage hematopoietic proliferation, with readily identifiable lobulated/hyperlobulated megakaryocytes in the hematopoietic area (H&E, 10 × 20).

Following the definitive diagnosis, the patient received cytoreductive therapy and antiplatelet therapy. Aspirin 100 mg once daily was started during hospitalization, and hydroxyurea was initiated at 0.5 g once daily on hospital day 8 and subsequently adjusted to 0.5 g twice daily before discharge. The patient was discharged on September 6, 2025 (hospital day 12) to continue medication at home and undergo regular outpatient follow-up. Notably, the patient's temperature did not immediately return to normal at the start of treatment but gradually decreased during ongoing therapy. As treatment continued, hemoglobin and hematocrit levels gradually decreased, and the C-reactive protein level showed a downward trend (Table 1). On the last available follow-up, the platelet count had decreased to 80 × 10⁹/L, suggesting possible hydroxyurea-related myelosuppression; close hematological monitoring and dose reassessment were therefore recommended. No bleeding or thrombotic event was observed.

Table 1.

Changes in laboratory parameters during treatment and follow-up.

Parameter	Admission (Aug 26, 2025)	Pre-treatment peak (Aug 30, 2025)	Early treatment (Sep 3, 2025)	Follow-up (Sep 16, 2025)	Follow-up (Sep 23, 2025)	Follow-up (Oct 14, 2025)
Hemoglobin (g/L)	166	169	179	170	159	135
Hematocrit (%)	53.1	54.7	55.5	54.4	51.4	42.3
White blood cell count (× 109/L)	11.53	11.4	13.01	14.68	8.83	3.51
Platelet count (× 109/L)	393	446	593	499	275	80
C-reactive protein (mg/L)	38.7	—	26.1	—	—	—
Interleukin-6 (pg/mL)	39	—	—	—	—	—
Procalcitonin (ng/mL)	0.05	—	—	—	—	—
EPO (mIU/mL)	2.4	—	—	—	—	—

Data are presented as absolute values. Missing values are indicated by “—.”

Normal reference ranges: hemoglobin, 115–150 g/L; hematocrit, 35.0%−45.0%; white blood cells, 3.5–9.5 × 10⁹/L; platelets, 125–350 × 10⁹/L; C-reactive protein, <8.0 mg/L; interleukin-6, <7.0 pg/mL; procalcitonin, 0–0.05 ng/mL; erythropoietin, 0.59–18.5 mIU/mL.

Figure 3 summarizes the clinical course of body temperature and hemoglobin levels during hospitalization and follow-up. The parallel improvement in fever and hematological parameters suggests a temporal association with disease control, but this observation should not be interpreted as proof of a causal antipyretic effect of hydroxyurea. A concise clinical timeline is provided in Table 2.

Figure 3.

Clinical course of body temperature and hemoglobin levels during hospitalization and follow-up. The graph illustrates the clinical course from admission (Day 0). During the pre-treatment period (Days 1–7), persistent low-grade fever was observed despite empirical antimicrobial therapy. Following initiation of hydroxyurea on hospital day 8 (arrow; initially 0.5 g/day and later adjusted to 0.5 g twice daily), fever gradually resolved during cytoreductive therapy and follow-up, in parallel with improvement in hematological parameters. This temporal pattern does not establish causality.

Table 2.

Clinical timeline of the episode of care and follow-up.

Date/time point	Key findings or interventions	Clinical interpretation/outcome
Aug 24, 2025	Chest CT before admission showed chronic bronchitis/emphysematous and interstitial changes, right middle-lobe segmental atelectasis, scattered small pulmonary nodules, and diffuse ground-glass/interstitial changes.	Pulmonary findings were considered as a potential alternative explanation for fever. Active bacterial pneumonia was considered unlikely, but viral or noninfectious inflammatory pulmonary processes could not be fully excluded.
Aug 26, 2025 (admission)	Recurrent low-grade fever; Hb 166 g/L, Hct 53.1%, WBC 11.53 × 109/L, PLT 393 × 109/L; CRP 38.7 mg/L, IL-6 39 pg/mL, PCT 0.05 ng/mL (upper limit of normal), and non-elevated EPO despite erythrocytosis.	Infectious, autoimmune, malignant, and hematologic causes were evaluated.
Aug 30, 2025	18F-FDG PET/CT showed diffuse mildly heterogeneous bone marrow uptake and mild splenomegaly, without FDG-avid pulmonary consolidation, hypermetabolic lymphadenopathy, or focal malignancy.	Findings raised suspicion of an underlying myeloproliferative neoplasm.
Hospital day 8	Hydroxyurea was initiated at 0.5 g once daily; aspirin 100 mg once daily was continued.	Cytoreductive and antiplatelet treatment was started after PV diagnosis.
Sep 6, 2025 (discharge)	Hydroxyurea was adjusted to 0.5 g twice daily before discharge.	The patient continued treatment at home with outpatient hematology follow-up.
Sep 16–Sep 23, 2025	Hemoglobin and hematocrit decreased gradually; fever had resolved clinically.	Clinical and hematological improvement was observed.
Oct 14, 2025	Hb 135 g/L, Hct 42.3%, WBC 3.51 × 109/L, PLT 80 × 109/L.	Possible hydroxyurea-related myelosuppression was considered; close monitoring and dose reassessment were recommended. No bleeding or thrombotic event was observed.

Discussion

Polycythemia vera is primarily driven by sustained activation of the JAK2-STAT signaling pathway (3, 5), which not only promotes abnormal hematopoiesis but also induces a chronic inflammatory state. Recent studies have increasingly recognized that myeloproliferative neoplasms can be regarded as “inflammation-driven tumors,” with chronic inflammation not only contributing to disease onset and progression but also potentially shaping their clinical phenotype and symptom spectrum to some extent (6).

Previous studies have shown that levels of circulating inflammatory cytokines (such as IL-6, TNF-α, and IL-1β) are elevated in PV and other myeloproliferative neoplasms. These inflammatory mediators are implicated not only in disease pathogenesis but also in the development of clinical symptoms (7, 8). Among these, IL-6, as an important endogenous pyrogen, can induce a febrile response by acting on the hypothalamic thermoregulatory center (9, 10). Therefore, from a mechanistic perspective, cytokine-mediated immune activation may provide a biological basis for fever in selected PV patients.

Nevertheless, fever as a primary or initial manifestation of PV remains relatively rare. Previous studies have shown that systemic symptoms in patients with polycythemia vera are more commonly observed in advanced stages of the disease, often in association with splenomegaly, thrombotic events, or progression to myelofibrosis (3, 11), suggesting that fever is not a typical early manifestation of this disease.

In contrast to the classic PV phenotype dominated by prominent polycythemia, severe splenomegaly, and thrombotic events (3, 11), our patient primarily exhibited persistent unexplained low-grade fever. This suggests a possible atypical, inflammation-dominant clinical presentation. Furthermore, previous reports of PV cases with fever as the primary manifestation remain limited, making such atypical presentations more prone to being overlooked in clinical practice.

An important issue in this case is whether the abnormal chest CT findings could provide an alternative explanation for fever. The CT component of PET/CT showed diffuse ground-glass/interstitial pulmonary changes, and a viral or noninfectious inflammatory pulmonary process was considered in the differential diagnosis. Several findings argued against active bacterial pneumonia, including the absence of cough and dyspnea, procalcitonin at the upper limit of the normal range, negative cultures and sputum smears, lack of focal FDG-avid pulmonary consolidation or hypermetabolic lymphadenopathy, and absence of clinical response to empirical antibacterial therapy. Nevertheless, because respiratory viral PCR testing and follow-up chest CT were not available, a concomitant viral or noninfectious inflammatory pulmonary process could not be completely excluded. Accordingly, the association between PV and fever in this case should be interpreted as temporal and clinically plausible rather than definitive.

The diagnostic work-up of erythrocytosis should also distinguish PV from other myeloproliferative neoplasms and from familial erythrocytosis. In patients with elevated hemoglobin, hematocrit, and leukocytosis, concurrent molecular and cytogenetic assessment, including BCR::ABL1 transcript testing and conventional karyotyping, may help avoid overlooking chronic myeloid leukemia. Evaluation of blood counts in first-degree relatives may also be useful when familial erythrocytosis is suspected. In the present case, BCR::ABL1 transcript testing, conventional karyotyping, and first-degree-relative blood count evaluation were not performed. This represents a limitation of the diagnostic work-up. Nevertheless, the inappropriately non-elevated erythropoietin level despite erythrocytosis, together with the high-burden JAK2 V617F mutation, bone marrow panmyelosis, negative iron staining, and clinical response to cytoreductive therapy supported a diagnosis of PV.

Notably, the patient's temperature fluctuations demonstrated a treatment-associated temporal pattern. During the initial hospitalization period (Days 1–7), prior to cytoreductive therapy, low-grade fever persisted despite antimicrobial treatment. Following the initiation of hydroxyurea, fever gradually resolved during the period of cytoreductive therapy and follow-up, in parallel with declining hematocrit and hemoglobin levels. This temporal association is consistent with, but does not prove, a relationship between fever and PV-related clonal hematopoiesis with accompanying inflammatory activation. In the absence of serial cytokine measurements, respiratory viral testing, and direct mechanistic evidence, a causal relationship cannot be established. Further studies are required to validate this observation.

Currently, case reports of PV presenting primarily with fever remain limited, and the specific mechanisms have not been fully elucidated. This case provides further observational clinical evidence regarding the role of inflammation in the clinical presentation of PV and, to some extent, expands the clinical spectrum of this disease, indicating that inflammation-driven mechanisms may play an important role in certain atypical PV phenotypes.

The strengths of this report include detailed documentation of the fever course, serial hematological parameters, inflammatory markers, PET/CT findings, bone marrow morphology, molecular confirmation, treatment course, and follow-up outcome. The main limitations are the single-case design, the inability to establish causality between PV and fever, the absence of serial cytokine measurements, lack of respiratory viral PCR testing and follow-up chest CT, incomplete exclusion of concomitant pulmonary inflammatory processes, absence of BCR::ABL1 transcript testing and conventional karyotyping, and lack of first-degree-relative blood count evaluation. These limitations should be considered when interpreting this case.

Patient perspective

The patient reported that the prolonged recurrent fever and lack of improvement after empirical antibiotic therapy caused substantial concern. After the diagnosis of PV and the need for long-term monitoring were explained, she accepted cytoreductive therapy and antiplatelet treatment. During follow-up, she reported resolution of fever and improvement in fatigue, and she expressed willingness to continue regular hematology follow-up.

Conclusion

From a clinical perspective, PV and other myeloproliferative neoplasms should be considered in the differential diagnosis of prolonged unexplained low-grade fever, particularly when erythrocytosis, leukocytosis, thrombocytosis, an inappropriately non-elevated erythropoietin level, or abnormal bone marrow metabolism are present. Increased awareness of such atypical presentations may reduce unnecessary antimicrobial use and facilitate timely hematologic evaluation. However, alternative infectious or inflammatory causes, including pulmonary processes, should be carefully assessed before attributing fever to PV. Future studies incorporating longitudinal cytokine profiling may further clarify the mechanistic link between clonal hematopoiesis and fever in PV.

Funding Statement

The author(s) declared that financial support was not received for this work and/or its publication.

Data availability statement

The original contributions presented in the study are included in the article. Further inquiries can be directed to the corresponding author.

Ethics statement

This case report involving a human participant was reviewed and approved by the Ethics Committee of Linyi People's Hospital in accordance with the local legislation and institutional requirements. Written informed consent for the publication of this case report and any potentially identifiable images or data included in this article was obtained from the patient's legally authorized representative.

Author contributions

LH: Data curation, Formal analysis, Investigation, Writing – original draft, Writing – review & editing. JZ: Validation, Writing – review & editing. XL: Supervision, Writing – review & editing.

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Generative AI statement

The author(s) declared that Generative AI was not used in the creation of this manuscript.

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