Allopurinol‐Induced Lymphadenopathy: A Case Report

Lymphadenopathy can occur in response to a variety of conditions, including infections, malignancies, autoimmune diseases, and drug reactions.1 Although lymphadenopathy is a common clinical finding, isolated generalized lymphadenopathy is often a challenging condition to diagnose because it can be caused by multiple underlying etiologies. In particular, drug-induced lymphadenopathy is a common cause, yet it is often overlooked in the differential diagnosis. Although allopurinol is widely prescribed for the management of gout, its association with isolated lymphadenopathy in the absence of other systemic diseases remains unestablished. This presentation may mimic other systemic conditions, potentially complicating the diagnostic process.2 We present a case of a 56-year-old Caucasian male patient with a history of non-crystal-proven gout, who had been initiated on 300 mg allopurinol daily since 2021. The last episode of gout he had was two years since initial diagnosis, with approximately two flares per year. He reported new-onset left flank pain, prompting a computed tomography (CT) scan that demonstrated scattered, mildly enlarged mesenteric and bilateral pelvic lymph nodes, stable compared to imaging from one year prior (Figure 1). The pain was likely attributable to lymphadenopathy. Approximately one month later, he developed fatigue, malaise, and persistent productive cough for which he sought medical attention and was prescribed prednisone and doxycycline. This regimen appeared to be effective for a short period, before his symptoms resurfaced approximately two weeks thereafter with additional symptoms of increased shortness of breath, facial swelling, bilateral lower extremity petechiae, pruritic and diffuse maculopapular rash, and oral ulcerations. A CT scan conducted at that time revealed mild diffuse bronchial wall thickening indicative of bronchitis, scattered areas of air trapping, and multiple enlarged lymph nodes—bilateral axillary, hilar, mediastinal, and upper abdominal lymph nodes. Complete blood count revealed new-onset leukocytosis accompanied by an eosinophil count of 1,500 cells/μL. Notably, the patient's eosinophil count before symptom onset was 100 cells/μL. Based on clinical presentation and laboratory findings, the patient's Registry of Severe Cutaneous Adverse Reaction score was calculated to be 5, supporting a probable diagnosis of drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome. The presumed inciting medication, doxycycline, was discontinued, and the patient was initiated on 100 mg prednisone daily for four to six weeks. Laboratory workup during admission included a CT scan (Supplementary Figure 1A) with multiple enlarged hilar, paratracheal, bilateral axillary, mesenteric, and retroperitoneal lymph nodes, the largest of which within the mediastinum. Mild mesenteric stranding was seen in the right upper quadrant. After the scan, patient was initiated on glucocorticoid therapy, with a subsequent positron emission tomography (PET) scan (Supplementary Figure 1B) that showed mildly hypermetabolic lymphadenopathy involving the chest, abdomen, and pelvis with decreased sizes of the lymph nodes compared to prior scans, particularly in the right axillary, paratracheal, subcarinal, left distal periaortic, portocaval, right external iliac, and right inguinal lymph nodes. Serum Epstein–Barr virus (EBV) DNA was elevated at 29,476 copies/mL. Coxsackie B virus IgG (type 4) was positive; however, infectious disease consultants deemed this unlikely to represent active infection given steroid-responsive rash and absence of meningeal or pericardial signs. Extensive autoimmune and infectious workup was negative, including antinuclear antibody, rheumatoid factor, antineutrophil cytoplasmic antibody, respiratory viral panel (COVID-19, respiratory syncytial virus, influenza), blood cultures, hepatitis panel, HIV-1/2, human herpesvirus–6/8, cytomegalovirus (CMV), syphilis, rickettsial and tick-borne pathogens (Lyme, Anaplasma, Ehrlichia), Brucella, Coxiella, and fungal antigens/antibodies (Coccidioides, Histoplasma, Blastomyces, Aspergillus). Markers of inflammation were mildly elevated (C-reactive protein 10.76 mg/L, erythrocyte sedimentation rate 26 mm/hr). Beta-2 microglobulin was 2.8 mg/L. Free light chains were elevated (kappa 13.37 mg/dL, lambda 12.21 mg/dL; ratio 1.10), with normal immunoglobulin levels (IgG 2,212 mg/dL, IgA 437 mg/dL, IgM 130 mg/dL). Serum protein electrophoresis showed no monoclonal proteins. Posthospitalization, left axillary core lymph node, right inguinal lymph node, skin, and bone marrow biopsies revealed no evidence of malignancy, granulomas, necrosis, infection, EBV, or CMV. Repeat PET scan six months thereafter showed persistent hypermetabolic lymph nodes above/below diaphragm with increased activity compared to the prior PET imaging, as well as new uptake diffusely throughout the spleen (Supplementary Figure 1C). The differential diagnosis for isolated generalized lymphadenopathy includes a wide range of etiologies, such as hematologic malignancies (eg, lymphoma, leukemia), infectious processes (including EBV, CMV, and tuberculosis), IgG4-related disease, sarcoidosis, and HIV infection.1 To investigate these possibilities, multiple lymph node biopsies were performed. Histopathological examination revealed no evidence of malignancy, lymphoproliferative disorders, granulomatous inflammation, or infectious organisms. It is noteworthy that systemic glucocorticoids had been administered before the initial biopsies, which may have modified histopathological features and potentially confounded diagnostic interpretation. This is particularly relevant for the three biopsies obtained within one to three months of glucocorticoid exposure. Notably, however, a subsequent biopsy performed eight months later demonstrated findings consistent with those of the earlier specimens. After ruling out the above differentials, allopurinol was discontinued six months after the last PET scan. A follow-up CT three months after the discontinuation of the medication demonstrated complete resolution of previously noted axillary, mediastinal, and pelvic lymphadenopathy, as well as resolution of prior splenic uptake (Supplementary Figure 1D). Allopurinol, a xanthine oxidase inhibitor commonly used to treat gout, is the most frequently implicated agent in DRESS syndrome.2-4 DRESS syndrome is characterized by cutaneous eruption, fever, peripheral eosinophilia, and multiorgan involvement.3 Although doxycycline is not among the most common causative agents—such as allopurinol, anticonvulsants, or sulfonamides—it has been reported in the literature.5 The present case identifies doxycycline as the likely offending agent. Clinicians may not immediately suspect DRESS syndrome following a short course of doxycycline (eg, 5–10 days for bronchitis), particularly when symptoms emerge after the medication has been discontinued; however, this delayed onset is characteristic of DRESS syndrome, which typically manifests two to eight weeks after initiation of the triggering agent, and doxycycline-induced cases with similar latency have been documented in the literature.5 Lymphadenopathy associated with DRESS syndrome typically resolves within weeks to a few months following withdrawal of the offending agent and initiation of appropriate therapy. Therefore, persistent lymphadenopathy beyond this expected timeframe should prompt consideration of alternative or additional diagnoses. In the present case, although the patient fulfilled clinical criteria for DRESS syndrome—complicating the diagnostic evaluation—the prolonged and generalized lymphadenopathy was ultimately attributed to allopurinol, particularly given that the lymphadenopathy predated the onset of DRESS syndrome–related systemic symptoms by several months. This temporal dissociation suggests that the lymphadenopathy may have represented a distinct immunologic process, possibly related to long-term allopurinol exposure, rather than being solely attributable to the acute DRESS syndrome episode. There are currently no documented reports in the literature describing isolated allopurinol-induced lymphadenopathy in the absence of the broader DRESS syndrome. This case highlights a potentially underrecognized clinical presentation and underscores the need for further case reports and investigative studies to better characterize this association. Both authors contributed to at least one of the following manuscript preparation roles: conceptualization AND/OR methodology, investigation, formal analysis, data curation, visualization, and validation AND drafting or reviewing/editing the final draft. As corresponding author, Dr Harata confirms that all authors have provided the final approval of the version to be published and takes responsibility for the affirmations regarding article submission (eg, not under consideration by another journal), the integrity of the data presented, and the statements regarding compliance with institutional review board/Declaration of Helsinki requirements. Disclosure Form: Supplemental Figure 1A Axial CT images at Month 1.25, showing multiple enlarged hilar, paratracheal, bilateral axillary, mesenteric, and retroperitoneal lymph nodes, the largest of which within the mediastinum measures 1.5 × 2.8 × 2.3 cm. Mild mesenteric stranding seen in the right upper quadrant. Supplemental Figure 1B: Axial PET images showed several enlarged and mildly hypermetabolic axillary, mediastinal, hilar, and pelvic lymph nodes, decreased in size compared to CT depicted on supplemental figure 1A. L axillary lymph node max SUV 3.8, paratracheal lymph node max SUV 3.7 and 8mm, previously 12mm. Subcarinal node max SUV 3.5 and 9mm, previously 13mm. Portal node with max SUV 6.8 and 11mm, previously 19mm. Right external iliac lymph node with max SUV 4.8 and 10mm, previously 15mm. Left common femoral lymph node with max SUV 2.3 and 8mm, previously 15mm. Hepatomegaly present. Supplemental Figure 1C: Axial PET images at Month 7, of the chest, abdomen, and pelvis with FDG avid left greater than right axillary (max SUB 4.1, previously 3.3), right lower paratracheal (max SUV 6.7, previously 3.7), subcarinal station 7 (max SUV 4.3, previously 3.5), portacaval (max SUV 8.8, previously 6.8), distal left periaortic (Max SUV 5.7, previously 3.4), right external iliac (max SUV 11.0, previously 4.5), and right inguinal (max SUV 6.9, previously 2.4) lymph nodes with diffuse FDG uptake involving the splenic parenchyma (max SUV 6.3, previously 4.1, which is now greater than liver background (max SUV 5.5). Persistent, slightly increased metabolic activity of lymph nodes above/below the diaphragm with the development of FDG uptake diffusely throughout the splenic parenchyma, which is greater than liver background. Supplemental Figure 1D: Axial PET images at Month 16, of the chest, abdomen, and pelvis with an index right external iliac node is currently measuring 1.2 × 0.9cm, previously 2.2 × 1.3. Max SUV is significantly decreased below that of liver 3.0, previously 11.0. Mediastinal and hilar lymph nodes show decrease in metabolic activity, and are now subcentimer in size. An index right paratracheal lymph node with max SUV 2.7, previously 4.2. Overall decrease in metabolic activity of axillary lymph nodes, with max SUV 1.2, previously 3.6. Left axillary lymph node shows a max SUV of 2.0, previously 4.1. No FDG avid lesion in the spleen, indicating complete resolution. Complete resolution of previously noted axillary, mediastinal, and pelvic lymphadenopathy, as well as resolution of prior splenic uptake. The right inguinal external iliac and right obturator lymph nodes, and the left inguinal lymph nodes show decreased size and metabolic activity. 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