Persistent generalized lymphadenopathy

Persistent generalized lymphadenopathy (PGL) is a clinical syndrome defined as the palpable enlargement of lymph nodes greater than 1 cm in diameter at two or more extrainguinal sites, persisting for more than three months without an identifiable cause other than underlying systemic conditions.^[1] This condition is most commonly associated with human immunodeficiency virus (HIV) infection, particularly during its early, asymptomatic stages, where it serves as an initial manifestation in a substantial proportion of infected individuals, historically up to 70% in the pre-antiretroviral therapy era.^[2] With modern antiretroviral therapy (ART), PGL is less prevalent and often regresses upon treatment initiation. In HIV-positive patients, PGL reflects an immune response to the virus, involving follicular hyperplasia and architectural changes in lymph nodes, and it may precede progression to acquired immunodeficiency syndrome (AIDS).^[3] While primarily linked to HIV, PGL can also arise from other opportunistic infections such as tuberculosis, cytomegalovirus, or toxoplasmosis in immunocompromised hosts, as well as less frequently from autoimmune disorders or malignancies.^[2]^[4]

Definition and Background

Definition

Persistent generalized lymphadenopathy (PGL) is defined as the enlargement of lymph nodes in two or more non-contiguous sites lasting for more than three months. This condition is most commonly observed in the context of human immunodeficiency virus (HIV) infection, where it represents an early manifestation of immune system involvement.^[5] Key diagnostic criteria for PGL include the involvement of lymph nodes in at least two non-contiguous regions, such as the cervical, axillary, or occipital areas (extrainguinal sites); nodes measuring greater than 1 cm in diameter; and the exclusion of alternative causes, including malignancies, acute infections, or other systemic diseases.^[5]^[6] These criteria ensure that the lymphadenopathy is deemed persistent and generalized rather than attributable to a reversible or localized process. PGL must be differentiated from localized lymphadenopathy, which is confined to a single contiguous anatomic region and often reflects a regional infection or inflammation, as well as from transient generalized lymphadenopathy, which typically resolves within weeks in response to self-limiting viral or bacterial illnesses.^[6]^[7] This distinction is crucial for appropriate clinical evaluation and management.^[8]

Historical Context

Persistent generalized lymphadenopathy (PGL) was first recognized as a distinct clinical entity in the early 1980s amid the emerging AIDS epidemic, initially observed among homosexual men presenting with unexplained lymph node enlargement without overt opportunistic infections. Reports to the Centers for Disease Control and Prevention (CDC) began in late 1981, highlighting cases of prolonged lymphadenopathy in this population, which was soon linked to the broader syndrome of acquired immunodeficiency. By May 1982, the CDC published a detailed epidemiologic investigation of 57 cases, defining PGL as palpable lymphadenopathy lasting at least three months in two or more extra-inguinal sites, excluding known causes such as infections, medications, or malignancies, with biopsies often revealing reactive hyperplasia.^[9] This recognition positioned PGL as an early marker in the spectrum of HIV-related illnesses, preceding full-blown AIDS. Key milestones in the 1980s further solidified PGL's association with HIV. The 1982 CDC surveillance efforts incorporated PGL into evolving case definitions for AIDS-related conditions, viewing it as a prodromal sign among at-risk groups. In 1984, histopathological studies confirmed characteristic follicular hyperplasia in lymph nodes from patients with PGL, AIDS, or AIDS-related complex (ARC), distinguishing it from other reactive processes through features like enlarged germinal centers, mantle zone attenuation, and follicle lysis, suggesting an immune dysregulation driven by the then-newly identified human immunodeficiency virus (HIV).^[10] These findings, based on examinations of over two dozen cases, underscored PGL's role in early HIV pathogenesis and raised concerns about its potential progression to lymphoproliferative disorders. Over time, understanding of PGL evolved from its classification within ARC—a term coined in the mid-1980s for symptomatic but non-AIDS HIV states including PGL, fever, weight loss, and fatigue—to its current view as a manifestation of untreated chronic HIV infection, often occurring in the asymptomatic or early symptomatic phase before CD4 cell depletion leads to AIDS. Longitudinal studies from the 1980s, such as a 4.5-year follow-up of homosexual men with PGL, demonstrated variable progression rates to AIDS, informing the shift toward recognizing PGL as a reversible indicator of immune activation in the ART era. Today, PGL is integrated into WHO staging as part of stage 1 HIV disease, emphasizing its historical significance in delineating the natural history of HIV.^[5]

Etiology

Primary Association with HIV

Persistent generalized lymphadenopathy (PGL) is predominantly caused by human immunodeficiency virus (HIV) infection, representing one of the most common early manifestations in untreated individuals. It occurs in 50% to 70% of patients during the initial phases of HIV, particularly in those who are otherwise asymptomatic.^[11] This condition arises as the virus establishes infection in lymphoid tissues, leading to widespread lymph node enlargement that persists for months or longer without significant symptoms.^[12] The underlying mechanism involves active HIV replication within lymphoid organs, where the virus primarily targets CD4+ T cells, inducing chronic immune activation and hyperplasia. This replication disrupts normal lymph node architecture, causing follicular enlargement and an influx of immune cells as the body mounts a sustained response to the infection.^[13] Concurrently, progressive CD4+ T-cell depletion exacerbates node swelling by impairing immune regulation and promoting ongoing inflammation, though the nodes remain non-tender and stable in size during this phase.^[5] PGL typically emerges during the chronic phase of HIV infection, corresponding to CDC clinical category A (asymptomatic infection or PGL) or WHO clinical stage 1, before advancing to more symptomatic stages or AIDS-defining conditions. In this period, which can last several years in untreated cases, PGL serves as a sentinel indicator of ongoing viral persistence and immune compromise, often preceding a decline in CD4 counts below 500 cells/μL.^[14]^[15]

Rare Non-HIV Causes

While human immunodeficiency virus (HIV) infection remains the primary etiology of persistent generalized lymphadenopathy (PGL), defined as enlargement of lymph nodes in two or more noncontiguous sites lasting more than three months, several rare non-HIV-related conditions can mimic this presentation and necessitate exclusion in the differential diagnosis.^[6] Autoimmune disorders, particularly systemic lupus erythematosus (SLE), can cause reactive lymphoid hyperplasia leading to PGL. In SLE, lymphadenopathy occurs in up to 50% of cases and may be the initial manifestation, involving multiple peripheral sites such as cervical, axillary, and inguinal nodes due to immune complex deposition and follicular hyperplasia.^[16] This feature correlates with active disease and higher autoantibody titers, though it is less common in modern cohorts with earlier diagnosis and treatment.^[17] Sarcoidosis, a granulomatous disorder, also frequently causes generalized lymphadenopathy, often involving hilar and peripheral nodes, mimicking lymphoma or infection.^[6] Other autoimmune conditions like rheumatoid arthritis or Sjögren's syndrome occasionally contribute, but SLE and sarcoidosis are among the most frequently implicated.^[18] Malignancies, including Hodgkin lymphoma, non-Hodgkin lymphoma (NHL), and chronic lymphocytic leukemia (CLL), often present with persistent, painless generalized lymphadenopathy that closely resembles PGL. Hodgkin lymphoma typically manifests with painless cervical or supraclavicular node enlargement that can become generalized, affecting over 80% of patients at diagnosis.^[19] NHL, particularly low-grade subtypes like follicular lymphoma, manifests in over two-thirds of patients with waxing-and-waning peripheral node enlargement across multiple sites, driven by neoplastic B-cell proliferation.^[20] Similarly, CLL typically involves diffuse lymphadenopathy in early stages, affecting cervical, axillary, and abdominal nodes, and can persist for months without systemic symptoms initially.^[21] These lymphoproliferative disorders require biopsy for distinction, as they account for a small but critical proportion of non-infectious PGL mimics.^[6] Infectious causes beyond HIV, such as tuberculosis (TB) and Epstein-Barr virus (EBV) in immunocompetent hosts, can rarely produce chronic generalized lymphadenopathy. Extrapulmonary TB, especially in endemic areas, leads to persistent necrotic lymphadenopathy in multiple sites, defined as nodes larger than 1 cm enduring over four weeks, often with constitutional symptoms like fever and weight loss.^[22] In immunocompetent individuals, EBV may trigger chronic active infection, resulting in prolonged lymphadenopathy resembling PGL, though this is exceptional and typically evolves into lymphoproliferative disorders if untreated.^[23] Other infections like cytomegalovirus or toxoplasmosis are even less common culprits.^[6] Drug reactions, exemplified by phenytoin, can induce pseudolymphoma syndrome mimicking PGL through hypersensitivity mechanisms. Phenytoin-associated lymphadenopathy presents as generalized, tender node enlargement often within weeks of initiation, categorized histologically as pseudolymphomatous with follicular hyperplasia and atypical lymphocytes, persisting until drug discontinuation.^[24] This reaction, part of drug reaction with eosinophilia and systemic symptoms (DRESS), affects multiple sites and resolves reversibly, distinguishing it from malignancy.^[25] Aromatic anticonvulsants like phenytoin are the most notorious, with rare progression to true lymphoma reported.^[26]

Pathophysiology

Lymph Node Histology

In early persistent generalized lymphadenopathy (PGL) associated with HIV infection, lymph node biopsies characteristically reveal follicular hyperplasia, marked by enlarged and irregular germinal centers surrounded by expanded mantle zones.^[27] This pattern reflects heightened B-cell proliferation and retention of antigens within the lymphoid architecture.^[13] As PGL progresses in advanced HIV disease, histological features shift toward follicular involution, with lymphoid depletion, hypocellularity, and progressive fibrosis replacing the initial hyperplastic changes.^[13] Electron microscopy of these nodes often demonstrates HIV viral particles, particularly trapped on the surface of follicular dendritic cells, confirming active viral persistence within the tissue.^[28] Immunohistochemical analysis highlights increased numbers of B-cells in the hyperplastic follicles, alongside follicular dendritic cells that prominently retain HIV antigens such as the p24 core protein.^[29] These markers underscore the role of B-cell zones in viral trapping and the overall immune activation in HIV.^[30]

Immune Mechanisms

Persistent generalized lymphadenopathy (PGL) in HIV infection arises from chronic immune stimulation driven by persistent viral replication and antigen presentation, which triggers widespread activation of the immune system. HIV virions and infected cells stimulate T lymphocytes, leading to the release of pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), which amplify immune responses and contribute to lymph node enlargement.^[31] This chronic activation results in polyclonal B-cell proliferation, characterized by non-specific expansion of B-cell clones and hypergammaglobulinemia, as HIV indirectly drives B-cell hyperactivity through T-cell dysregulation and direct effects on B cells via gp120 binding.^[32] Seminal studies have shown that this polyclonal activation is a hallmark of early HIV disease, correlating with elevated serum immunoglobulin levels and contributing to the sustained lymphadenopathy observed in PGL.^[33] A central mechanism perpetuating PGL involves follicular dendritic cells (FDCs) within germinal centers of lymph nodes, which efficiently trap and retain HIV virions on their surface via complement and Fc receptors. This trapping creates a persistent reservoir of infectious virus and antigens, prolonging immune stimulation and preventing clearance, even as circulating viral loads fluctuate.^[34] FDCs thus act as a nidus for ongoing B-cell and T-cell activation, sustaining follicular hyperplasia and the architectural changes that define PGL. High-impact research has demonstrated that this FDC-mediated viral persistence is evident across disease stages, underscoring its role in maintaining chronic inflammation.^[31] As HIV progresses, immune mechanisms evolve with declining CD4+ T-cell counts, leading to a gradual shift from the hyperplastic phase of PGL—marked by explosive lymphoid proliferation—to an involutional phase characterized by follicular atrophy and lymph node depletion. This transition typically occurs when CD4 counts fall below 200 cells/μL, reflecting exhaustion of the immune response due to profound T-cell loss and unresolved inflammation.^[35] Influential histopathological analyses have linked this shift to diminished cytokine-driven proliferation and increased fibrosis, highlighting the dynamic interplay between viral persistence and immune failure in advanced disease.

Clinical Features

Symptoms

Persistent generalized lymphadenopathy (PGL) is frequently asymptomatic, representing a common feature of early HIV infection without accompanying subjective complaints in most patients.^[5] However, in a subset of cases, individuals may experience mild, nonspecific symptoms such as fatigue, low-grade fever, or night sweats, often attributable to the underlying immune response or progression of HIV.^[6] These symptoms are typically subtle and do not dominate the clinical picture. Weight loss or generalized malaise can also occur, particularly as HIV advances beyond the initial stages, reflecting systemic effects rather than direct node involvement.^[5] Rarely, patients report localized discomfort from the enlarged lymph nodes, though this is uncommon and usually mild.^[6] The subjective symptoms of PGL, when present, tend to persist for months in parallel with the ongoing lymphadenopathy, lacking spontaneous resolution and mirroring the chronic nature of the condition in early HIV.^[12]

Physical Examination Findings

Persistent generalized lymphadenopathy (PGL) is characterized by symmetrical enlargement of lymph nodes in multiple noncontiguous extrainguinal sites, typically involving at least two or more regions such as the cervical (including posterior), axillary, and occipital areas, though inguinal nodes may also be affected.^[36] Nodes are generally palpable, measuring greater than 1 cm (typically 1 to 2 cm) in diameter, and exhibit a firm to rubbery consistency, remaining mobile and non-tender on palpation.^[6]^[11] Unlike acute infectious lymphadenopathies, PGL lacks overlying skin changes, such as erythema or warmth, and shows no evidence of suppuration or fluctuance, helping to differentiate it from suppurative processes.^[6]

Diagnosis

Initial Evaluation

The initial evaluation of a patient suspected of having persistent generalized lymphadenopathy (PGL) begins with a comprehensive medical history to identify the duration and context of lymph node enlargement. Clinicians should inquire about the onset and progression of node swelling, particularly if it has persisted for more than three months in at least two extrainguinal sites, as this duration distinguishes PGL from transient reactive lymphadenopathy.^[2] Key elements include assessing risk factors for HIV infection, such as unprotected sexual intercourse, intravenous drug use, recent blood transfusions, or occupational exposures, alongside recent infections, travel history, and current medications that might contribute to lymphadenopathy.^[6] Associated symptoms like fever, night sweats, unexplained weight loss, fatigue, or pruritus should also be documented, as they may indicate an underlying systemic process.^[37] A thorough physical examination follows to confirm generalized involvement and exclude acute conditions. Vital signs, including temperature, blood pressure, heart rate, and respiratory rate, are assessed to rule out signs of acute illness such as fever or hemodynamic instability.^[38] The examination focuses on palpating lymph node chains in multiple regions, such as cervical, axillary, and inguinal areas, to verify enlargement in non-contiguous sites; typical findings include rubbery, non-tender nodes measuring 1-2 cm, as detailed in the physical examination findings section.^[37] The skin overlying the nodes and adjacent areas should be inspected for rashes, lesions, or signs of infection, while a general survey evaluates for cachexia or other systemic clues.^[6] Risk stratification is essential during this phase to guide further management, with high suspicion for HIV warranted if lymphadenopathy persists beyond three months without an identifiable alternative cause, given PGL's strong association with early HIV infection.^[2] Patients with multiple HIV risk factors or constitutional symptoms are prioritized for expedited evaluation, emphasizing the need for a non-judgmental approach to elicit accurate history.^[38] This preliminary assessment helps differentiate PGL from localized or self-limiting causes, setting the stage for targeted diagnostic confirmation.^[37]

Confirmatory Tests

Confirmatory tests for persistent generalized lymphadenopathy (PGL) primarily aim to establish the underlying etiology, with a strong emphasis on HIV infection as the most common cause. The diagnostic approach begins with targeted HIV serologic testing, followed by additional evaluations such as lymph node biopsy, imaging, and supportive blood analyses if needed to rule out alternative diagnoses. HIV testing is the cornerstone of confirmation in suspected PGL cases, utilizing a sequential algorithm recommended by the Centers for Disease Control and Prevention (CDC). Initial screening involves a fourth-generation antigen/antibody immunoassay that detects HIV-1/HIV-2 antibodies and the HIV-1 p24 antigen in serum or plasma; reactive results are followed by an HIV-1/HIV-2 differentiation immunoassay to distinguish between HIV-1, HIV-2, or indeterminate infections. If the differentiation assay is indeterminate or negative in high-risk individuals, a nucleic acid test (NAT), such as HIV-1 RNA PCR, confirms acute or established infection by detecting viral RNA. Following HIV confirmation, a CD4 T-cell count is performed via flow cytometry to assess immune status and stage the disease, as PGL typically manifests in early HIV infection with CD4 counts often above 500 cells/μL. In HIV-negative patients or those with atypical features (e.g., rapid progression, focal involvement, or constitutional symptoms suggesting malignancy), excisional lymph node biopsy is indicated for definitive histopathological evaluation. Biopsy typically reveals characteristic follicular hyperplasia with enlarged germinal centers, mantle zone atrophy, and interfollicular vascular proliferation in HIV-related PGL, reflecting polyclonal B-cell activation and immune dysregulation.^[27] This finding helps differentiate PGL from lymphomas or other reactive processes, though fine-needle aspiration may be used initially for less invasive assessment if excision is not feasible.^[39] Imaging modalities, such as computed tomography (CT) or ultrasound, are employed to evaluate the extent of lymphadenopathy, measure node dimensions (typically >1 cm in PGL), and exclude malignancies or complications. Contrast-enhanced CT of the neck, chest, abdomen, and pelvis demonstrates generalized nodal enlargement in multiple noncontiguous sites, with nodes often showing homogeneous attenuation in benign HIV-related cases versus necrotic or enhancing features suggestive of lymphoma or infection.^[39] Ultrasound complements CT by providing real-time assessment of superficial nodes (e.g., cervical or axillary), identifying hypoechoic, rounded morphology, and guiding biopsies while avoiding radiation exposure.^[40] Ancillary blood tests support confirmation by excluding non-HIV causes. A complete blood count (CBC) with peripheral smear evaluates for anemia, leukopenia, or atypical lymphocytes indicative of systemic involvement, while elevated lactate dehydrogenase (LDH) levels (>250 U/L) may signal lymphoproliferative disorders or tissue turnover in persistent cases.^[40] These tests, combined with the above, ensure a comprehensive differential diagnosis without unnecessary invasiveness.

Management

Antiretroviral Therapy

Antiretroviral therapy (ART) serves as the primary treatment for persistent generalized lymphadenopathy (PGL) in the context of HIV infection, addressing the underlying viral replication that drives lymph node enlargement. By suppressing HIV replication, ART facilitates immune reconstitution, which typically leads to regression of lymphadenopathy.^[41] Both the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC) recommend initiating ART immediately upon HIV diagnosis for all patients, including those presenting with PGL, regardless of CD4 cell count or viral load, to optimize health outcomes and prevent disease progression.^[42]^[43] Current guidelines endorse integrase strand transfer inhibitor (INSTI)-based regimens as first-line therapy for most treatment-naïve patients due to their efficacy, tolerability, and high barrier to resistance. A preferred regimen is bictegravir combined with emtricitabine and tenofovir alafenamide (BIC/FTC/TAF), a single-tablet formulation that simplifies adherence and achieves rapid viral suppression.^[44] Alternative INSTI options, such as dolutegravir with two nucleoside reverse transcriptase inhibitors, are also recommended based on individual factors like comorbidities and drug interactions.^[44] Response to ART in patients with PGL is monitored through serial measurements of plasma HIV RNA (viral load) and CD4 cell counts, with virologic suppression to undetectable levels (<50 copies/mL) and CD4 recovery above 200 cells/μL serving as key indicators of treatment success and lymph node regression. Adherence counseling is integral, as suboptimal adherence increases the risk of virologic failure and persistent symptoms; strategies include patient education, reminder systems, and addressing barriers such as stigma or access issues.^[45]^[46] Effective ART generally improves long-term outcomes for PGL by preventing progression to more severe HIV stages.^[45]

Supportive Care

Supportive care for persistent generalized lymphadenopathy (PGL) in HIV patients emphasizes symptom relief, prevention of complications, and holistic management to improve quality of life. While antiretroviral therapy (ART) remains the cornerstone of treatment for underlying HIV infection, adjunctive measures address discomfort from enlarged lymph nodes and support overall well-being. Pain from tender lymph nodes can be managed with nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, which provide short-term relief for discomfort associated with swelling in HIV-related lymphadenopathy.^[47] These agents are recommended as first-line options for musculoskeletal pain in people with HIV, with monitoring for gastrointestinal or renal side effects, particularly in those with advanced disease.^[48] Routine monitoring for opportunistic infections is essential, as PGL may precede immune decline; prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMX) is indicated for Pneumocystis jirovecii pneumonia (PCP) prevention when CD4 counts fall below 200 cells/µL, reducing infection risk by over 90% in at-risk HIV patients.^[49] This approach, along with regular screening for other infections like toxoplasmosis, helps mitigate complications in those with persistent nodal enlargement. Nutritional support plays a key role in bolstering immune function and countering HIV-related weight loss or malnutrition, with recommendations for increased caloric intake through nutrient-dense foods rich in proteins, vitamins, and minerals to enhance treatment tolerance and maintain body weight.^[50] Counseling on HIV status disclosure is also integral, providing guidance to patients on sharing their diagnosis with partners, family, or healthcare providers to facilitate safer practices, access support, and reduce transmission risks, often through structured sessions emphasizing legal and emotional aspects.^[51] Follow-up examinations every 3-6 months are advised to assess clinical response, including physical evaluation of lymph nodes, viral load monitoring, and CD4 count to guide ongoing care and detect any progression.^[52] To minimize invasive procedures, unnecessary lymph node biopsies should be avoided once ART initiation leads to nodal regression, as generalized enlargement in PGL typically resolves without intervention, reserving biopsy for atypical, focal, or non-responsive cases to rule out malignancy or other pathologies.^[53]

Prognosis and Complications

Long-Term Outcomes

In patients with HIV who receive effective antiretroviral therapy (ART), persistent generalized lymphadenopathy (PGL) typically resolves completely within months to years, reflecting the restoration of immune function and reduction in viral replication.^[47] Adherence to ART substantially reduces the risk of progression to AIDS by achieving sustained viral suppression and maintaining CD4+ T-cell counts above critical thresholds, with AIDS events occurring in less than 1% per year in suppressed patients.^[45] Early initiation of ART further enhances these outcomes, minimizing lymphoid tissue damage and supporting long-term immune recovery.^[54] Without treatment, PGL signals an early stage of HIV infection where disease progression is common, with 50-70% of untreated individuals advancing to AIDS within 5-10 years due to progressive immune depletion and opportunistic infections.^[55] Even after viral suppression with ART, residual fibrosis in lymph nodes may persist in some patients, potentially contributing to incomplete immune reconstitution and increased risk of non-AIDS complications.^[56] Overall survival rates for individuals with PGL have improved dramatically with modern HIV management, approaching near-normal life expectancy when ART is initiated early and maintained consistently.^[57] For example, a 20-year-old starting ART with high CD4 counts can expect to live into their 70s or beyond, comparable to the general population in high-resource settings.^[54] While most data on PGL prognosis pertain to HIV-associated cases, outcomes for non-HIV PGL depend on the underlying cause; for example, resolution is common with treatment of infections like tuberculosis, whereas autoimmune or malignant causes may require specific therapies with variable prognoses.^[12]

Associated Risks

Persistent generalized lymphadenopathy (PGL) in HIV infection heightens the susceptibility to opportunistic infections due to progressive immune dysregulation, particularly the depletion of CD4+ T cells, which impairs the body's ability to combat pathogens. Common examples include oral candidiasis and tuberculosis, with the latter frequently presenting as extrapulmonary involvement in endemic regions, comprising up to 40-50% of TB cases among HIV patients in parts of Africa.^[58] Untreated or advanced PGL also elevates the risk of lymphoma development, as the chronic lymphoid hyperplasia can progress to malignant transformation, with HIV-infected individuals facing a 60- to 200-fold higher incidence of non-Hodgkin lymphoma compared to the general population. While node suppuration is rare in uncomplicated PGL, it can occur in advanced stages secondary to superimposed infections such as Mycobacterium avium complex or tuberculosis, potentially leading to abscess formation.^[3] Furthermore, the persistent immune activation and inflammation underlying PGL contribute to long-term cardiovascular and metabolic complications when HIV remains uncontrolled, including a 1.5- to 2-fold increased risk of atherosclerotic cardiovascular disease driven by elevated systemic inflammatory markers.^[59]

Epidemiology

Prevalence in HIV Populations

Persistent generalized lymphadenopathy (PGL) was a common manifestation in untreated individuals with HIV during the chronic phase of infection, particularly when CD4+ T-cell counts range from 200 to 500 cells/μL, affecting up to 70% of such patients in early studies.^[2] This prevalence reflected the immune system's response to ongoing viral replication, leading to lymphoid hyperplasia in multiple lymph node sites.^[3] In contrast, with the widespread availability and use of antiretroviral therapy (ART), the incidence of PGL has substantially decreased, as effective viral suppression promotes immune reconstitution and resolves lymphadenopathy. As of 2024, with 77% global ART coverage, PGL is now rare in treated patients.^[60]^[41] During acute HIV seroconversion, generalized lymphadenopathy occurs at higher rates, reported in up to 70% of symptomatic cases, often as part of the initial retroviral syndrome before transitioning to persistent features in the chronic stage.^[61] This early presentation typically involves symmetric enlargement of cervical, axillary, and inguinal nodes, driven by acute immune activation against the virus. As CD4 counts recover with ART initiation during or after this phase, PGL tends to regress, underscoring the therapy's role in mitigating long-term lymphoid involvement.^[62] In the early HIV epidemics of the 1980s, PGL was notably more prevalent among men who have sex with men (MSM) and injection drug users, the primary groups affected in initial outbreaks, with studies documenting it in over half of asymptomatic seropositive individuals in these cohorts.^[63] This demographic pattern highlighted PGL as an early clinical marker of HIV infection before the advent of ART.^[64]

Geographic Variations

Persistent generalized lymphadenopathy (PGL) exhibits notable geographic variations, primarily driven by disparities in HIV prevalence, timing of diagnosis, and antiretroviral therapy (ART) access. In sub-Saharan Africa, where HIV burdens the population most heavily and late diagnosis is common, PGL remains a frequent manifestation among untreated individuals. A study in Zambia from 1989–1990 found that among 727 lymph node biopsies, 52% were due to tuberculous lymphadenitis and 22% showed primary HIV lymphadenopathy, with 91% of tested adults positive for HIV, highlighting the high intersection of untreated HIV and lymphadenopathy in this region.^[65] In contrast, regions with advanced healthcare infrastructure, such as Western Europe and the United States, report low PGL incidence in HIV-positive populations, owing to widespread early screening and ART initiation that suppress viral loads and resolve early lymphoproliferative responses. For instance, ART coverage exceeds 90% in these areas as of 2024, minimizing progression to symptomatic stages like PGL.^[66] Co-infection patterns further influence PGL presentation regionally. In high-tuberculosis-burden areas like India and Southeast Asia, TB-associated lymphadenopathy is more prevalent among HIV patients, often mimicking or exacerbating PGL. In India, HIV-TB coinfection affects around 10-25% of HIV patients based on studies from the early 2020s, with TB frequently causing nodal involvement in untreated HIV.^[67]^[68] Global efforts, including the UNAIDS 90-90-90 targets launched in 2014, have contributed to declining PGL rates since 2010 by enhancing diagnosis, treatment, and viral suppression, particularly in low- and middle-income countries, thereby reducing the pool of untreated HIV cases prone to early manifestations like PGL.^[69]