Human Immunodeficiency Virus Lymphadenitis



Human Immunodeficiency Virus Lymphadenitis


Tariq Muzzafar, MBBS





Key Facts


Terminology



  • Human immunodeficiency virus (HIV)


  • Lymphadenitis caused by HIV infection


Clinical Issues



  • History of high-risk exposure should be sought


Microscopic Pathology



  • Histologic findings can be divided into stages


  • Florid follicular hyperplasia



    • Irregularly shaped follicles, attenuation of mantle zones, follicle lysis, hemorrhage


  • Mixed pattern



    • Transitional stage


  • Follicular involution



    • Small, hypocellular, hyalinized follicles


    • Expanded paracortical regions


    • Moderate lymphocyte depletion, plasmacytosis, vascular proliferation


  • Lymphocyte depletion



    • Predominantly medullary cords and sinusoids


    • Marked lymphocyte depletion with absence of follicles and paracortical areas


    • Predominance of histiocytes and plasma cells; subcapsular and sinusoidal fibrosis


  • Histologic changes partially reversed by HAART


Top Differential Diagnoses



  • Other causes of acute lymphadenitis



    • Infectious mononucleosis (EBV+)


  • Castleman disease, hyaline-vascular variant


  • AIDS-related lymphomas



    • Non-Hodgkin lymphoma


    • Hodgkin lymphoma







Thin section transmission electron micrograph of HIV. The viral core is the dark area in the center. (Courtesy A. Harrison, P. Feorino, CDC Public Health Image Library, #10860).






This 3D rendering of HIV demonstrates the viral membrane (blue), the density between the membrane and core (yellow), and the capsid (red). (Courtesy J. Briggs, PhD.)


TERMINOLOGY


Abbreviations



  • Human immunodeficiency virus (HIV)


Synonyms



  • Acquired immune deficiency syndrome (AIDS) lymphadenitis


  • HIV lymphadenopathy


Definitions



  • Lymphadenitis caused by HIV infection


ETIOLOGY/PATHOGENESIS


Infectious Agents



  • HIV-1 underwent single cross-species transmission from chimpanzees to humans 100 years ago



    • Virus diversified in humans into many genetic subtypes: A-D


  • Most sexually transmitted HIV infections are initiated by a single variant



    • Initial target cells are CD4(+) T cells


  • HIV, a retrovirus belonging to the lentivirus family has



    • 9 genes


    • 2 copies of single-stranded RNA in core


    • Reverse transcriptase generates double-stranded DNA copy that integrates into host genome



      • Covalently forms a provirus


    • Provirus can remain latent or be highly expressed, forming progeny viruses


  • Icosahedral structure with 72 external spikes composed of envelope proteins gp120 and gp41



    • Crucial for cell attachment and entry


  • HIV has tropism for CD4(+) T cells, monocytes, and follicular dendritic cells



    • gp120 binds with CD4 receptor and subsequently with chemokines CR5 and CXCR4



      • Leads to fusion of viral and cellular membranes and internalization of viral complex


  • 4 nucleocapsid proteins: p24, p17, p9, and p7


Pathogenesis of HIV Lymphadenopathy



  • High HIV antigen density, marked inflammation, and adhesion molecule expression by lymphocytes



    • Leads to lymphocyte sequestration


  • Exposure to increased cytokine levels results in lymphocyte death


  • Prolonged inflammation leads to fibrosis resulting in



    • Disrupted maturation of T cells


    • Decreased naive circulating CD4(+) T cells


  • Follicular dendritic cells in germinal centers entrap HIV


CLINICAL ISSUES


Epidemiology



  • Incidence



    • 2.7 million new HIV infections per year in 2007 globally


    • Prevalence is stable at 0.8%


    • 33.2 million people have HIV infection or AIDS


    • 2 million deaths per year related to AIDS


  • Age



    • Patients 15-24 years old represent 45% of new HIV infections globally


    • Estimated 370,000 children < 14 years old were infected in 2007


    • 2 million children with HIV


  • Gender



    • No sex preference; stable globally


  • Ethnicity



    • Sub-Saharan Africa accounts for 67% of total people and 90% of children living with HIV



      • Predominantly heterosexual transmission in general population


      • Accounts for 75% of AIDS-related deaths



    • Asia overall has shown a trend toward a decrease in new HIV infections and an increase in AIDS-related deaths



      • National trends vary considerably


      • Recreational drug use, commercial sex work, and male-male sex are major factors in transmission


    • Eastern Europe and Central Asia have shown a rising trend in number of people living with HIV infection



      • Number of new infections has been slowing


      • Recreational drug use and commercial sex work are major factors in transmission


    • Western and Central Europe show stable trends



      • Heterosexual transmission is major mode of transmission


    • Caribbean basin, South and North America show stable trends



      • Male-male sex is major mode of transmission, followed by heterosexual transmission


      • Number of persons living with HIV infection has increased as result of therapy


Presentation



  • Acute (primary) phase of HIV infection



    • Can present as flu-like or mononucleosis type of syndrome with nonspecific symptoms



      • Findings: Fever, lymphadenopathy, skin rash, myalgia, arthralgia, headache, diarrhea, oral ulcers


      • Clinical diagnosis of acute HIV infection can be challenging


    • Usually lasts several weeks


    • Opportunistic infections can occur during transient CD4 lymphopenia



      • Most common: Oral and esophageal candidiasis


  • Chronic phase of HIV infection is characterized by dysregulated or suppressed immunity



    • HIV infection can generally be latent for a number of years


    • Eventually patients develop symptoms and abnormalities related to low CD4(+) count



      • Polyclonal hypergammaglobulinemia


      • Altered levels of cytokines (e.g., IL-6, TNF-α) and activation markers (e.g., CD38 on T cells)


      • Opportunistic infections: Mycobacterium tuberculosis, Pneumocystis jiroveci (formerly known as P. carinii)


      • Neoplasms: Lymphomas, Kaposi sarcoma


  • ˜ 50% of HIV(+) patients with lymphadenopathy are asymptomatic



    • Usually, lymph node biopsy shows follicular hyperplasia


Laboratory Tests



  • Acute (primary) phase of HIV infection



    • Leukopenia, thrombocytopenia, elevated serum transaminase level


    • Viremia at high titers; CD4(+) T cells and monocytes infected


    • 3rd generation enzyme immunoassays used in clinical practice and in blood banks in USA do not detect HIV antibodies until 3-7 weeks after infection


  • Chronic phase of HIV infection



    • Drop in CD4(+) counts to < 200/mm3


    • Findings related to specific opportunistic infections


  • Diagnosis of acute infection is established by demonstrating



    • High viral load


    • p24 antigen in patient with typical clinical features and negative or indeterminate HIV serologic test


  • Serologic testing



    • Based on detection of IgG against HIV antigens in serum



      • p24, a nucleocapsid protein


      • gp120 and gp41, envelope proteins


    • Centers for Disease Control (CDC) criteria for positive serology include



      • Antibodies to gp120 plus antibodies to either gp41 or p24


    • Antibodies to gp41 and p24 antigens are 1st detectable serologic markers following HIV infection



      • IgG antibodies appear 6-12 weeks following infection in most patients (by 6 months in 95%)


      • Antibodies persist for life


    • Results are reported as positive, negative, or indeterminate



    • Criteria for a positive test: Repeatedly positive enzyme immunoassay test followed by a positive Western blot analysis



      • Positive test should be confirmed by repeat testing or corroborating laboratory data


    • Accuracy of HIV serologic testing is high



      • 99.3% sensitivity and 99.7% specificity according to CDC survey


    • Rapid tests can be done at point of care and read by provider



      • High diagnostic accuracy comparable to standard serological tests and much cheaper


      • Results can be available in minutes


Treatment



  • Drugs



    • Highly active antiretroviral therapy (HAART)



      • Increases disease-free survival by suppressing viral replication and improving immunologic function


    • Indications for HAART



      • History of AIDS-defining illness, CD4 count < 350 cells/mm3, pregnant women, and HIV-associated nephropathy


    • Syndrome resembling primary HIV infection occurs in patients 2-4 weeks after HAART is discontinued



      • Fever, lymphadenopathy, and rash; plasma viremia rises and CD4(+) counts fall


Prognosis



  • HIV infection can be indolent for years but will eventually become lethal without HAART


  • Lymph nodes in HIV(+) patients show histologic progression without therapy, from follicular hyperplasia to lymphocyte depletion


  • Lymph node biopsy findings in HIV(+) patients correlate, in part, with outcome



    • Patients with follicular hyperplasia or mixed pattern have



      • Longer survival


      • Lower incidence of opportunistic infections


    • Patients with lymphocyte depletion have very poor prognosis


  • HIV(+) patients have increased risk of non-Hodgkin and Hodgkin lymphoma



    • HAART has reduced risk of non-Hodgkin lymphoma but not Hodgkin lymphoma


MACROSCOPIC FEATURES


General Features



  • Enlarged lymph nodes in follicular hyperplasia


  • Small, shrunken lymph nodes in lymphocyte depletion



    • Often not biopsied but detected at autopsy


MICROSCOPIC PATHOLOGY


Histologic Features

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Jul 8, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Human Immunodeficiency Virus Lymphadenitis

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