The problem of HIV-related lymphadenopathy Lymphadenopathy is a common condition in patients with HIV infection. WILANDI JACOBS, MB ChB, MMed (Surg) Surgeon in private practice, Northern Cape Province Wilandi Jacobs obtained the MB ChB and MMed (Surg) degrees at the University of the Free State. She was then employed by the SAMS for a number of years. She now runs a successful private practice in the Northern Cape Province.

Correspondence to: W Jacobs ([email protected])

As the prevalence of the human immunodeficiency virus (HIV) • nodes adherent to surrounding tissues increases worldwide, the number of patients presenting to GPs • nodes accompanied by other systemic symptoms. and health care personnel with associated disease is increasing. Lymphadenopathy is a common presenting condition, with many Lymphadenopathy is a common potential interventions and pitfalls. presentation with many potential The concerns/problems with lymph nodes are essentially the interventions and pitfalls. following: • It is a common presentation in HIV-positive patients early in the Definition seroconversion phase through to end-stage disease. Lymphadenopathy is normally classified as generalised (occurring in • It is imperative not to miss a treatable or potentially treatable cause multiple nodal basins throughout the body) or localised (occurring in for the lymphadenopathy. a single nodal basin) and is characterised by lymph nodes greater than • If one were to perform a lymph node biopsy on every patient it 1 cm in diameter. would be impractical and costly and submit many patients to an unnecessary procedure. Persistent generalised lymphadenopathy (PGL) has one major cause, i.e. persistent follicular hyperplasia from chronic HIV infection. PGL However, the ‘gold standard’ for diagnosing the cause of the lymph requires no treatment if the lymph nodes remain stable in number, nodes and excluding serious pathology still remains open biopsy. It location and size. is against this background that all other investigations in the HIV- positive population must be measured. The definition of PGL must include the following:2 • lymph nodes remain stable in number, location and size There are approximately 600 lymph nodes in the normal human body. • appropriate investigations reveal no cause Lymph nodes, including the spleen, adenoids, Peyer’s patches and • lymph nodes are less than 2 cm in size tonsils, are highly organised collections of immune cells that filter • two or more non-contiguous sites antigens from the extracellular fluid. The sinuses have a large number • persists for more than 3 months. of macrophages, which remove approximately 99% of all antigens that cross lymph nodes. In normal individuals without pathological disease axillary, inguinal and submandibular glands may be palpated. Epidemiology of lymphadenopathy Race History3 Race is not a factor in lymphadenopathy, but rare causes may be In a patient presenting with lymphadenopathy the following points associated with particular racial groups, e.g. sarcoidosis in blacks and should be noted in the patient’s file: Kikuchi fugimora in Asians. • whether the lymph nodes are new • whether they are progressing, i.e. enlarging Gender • whether they are persistent Gender does not influence lymphadenopathy. • presence of constitutional symptoms, e.g. fever, sweats, fatigue and weight loss Age • presence of localised pathology, e.g. axillary nodes in a patient with Lymphadenopathy is more common in young children as they are a breast mass exposed to new infections/antigens. One-third of neonates and • full systemic history infants may have lymphadenopathy. Generalised lymphadenopathy • review of previous results, e.g. HIV serostatus, CD4 count, viral is rare in the neonate and would suggest a congenital infection, e.g. load cytomegalovirus. • medications – current or previous (see Annexure 1) • history of trauma Which nodes to investigate • history of TB contact/exposure This question is fundamental in the management of HIV • history of sexual behaviour lymphadenopathy. • history of risk-taking behaviours • exposure to household pets. In the following cases nodes need to be further investigated or treated:1 Examination • rapid enlargement of a previously stable node • Vital signs should be recorded. • group of enlarged nodes, i.e. not generalised • Complete examination of all lymph node basins should be done. • nodes with abnormal consistency • Documentation should include: • tender nodes • Location – may be helpful in narrowing the differential diagnosis, • fluctuant nodes e.g. cat scratch disease typically causes cervical or axillary • asymmetrical nodes lymphadenopathy.

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• Size – generally, nodes less than 1 Occipital lymph nodes Iliac and inguinal lymph nodes cm are considered normal. However, • Occipital nodes drain the posterior scalp. • These nodes drain the lower limbs, epitrochlear nodes larger than 0.5 cm • They may be palpable in 5% of healthy perineum, buttocks, genitalia and lower or inguinal nodes larger than 1.5 cm children. abdominal wall. should be considered abnormal. The • Common causes are tinea capitis, • They are considered pathological if greater size of the node has no bearing on the seborrhoeic dermatitis, insect bites and than 1.5 cm in diameter. specific diagnosis. An abnormal chest orbital cellulitis. • These nodes are typically caused by radiograph and lymph nodes greater • Viral causes include rubella and roseola infections. than 2 cm in children are predictive infantum. • A full genital and anal examination is of granulomatous disease or cancer warranted. (predominantly lymphomas). Peri-auricular lymph nodes • Consistency – very hard nodes are typical • These nodes drain the conjunctiva, Persistent generalised of malignancy, while firm, rubbery eyelids, temporal region of the scalp and nodes suggest lymphoma. Softer nodes skin of the cheek. lymphadenopathy (PGL) are usually caused by infective or • Thorough examination of the eye to has one major cause, inflammatory conditions. Shotty nodes exclude conjunctivitis, corneal ulceration typically have a viral aetiology and and eyelid infections should be done. i.e. persistent follicular suppurant nodes may be fluctuant. hyperplasia from • Mobility – nodes that seem attached Mediastinal lymph nodes and move as a unit are usually referred • These nodes drain the thoracic viscera. chronic HIV infection. to as matted and can be benign or • They are not detected on physical malignant. examination, but by radiological Investigations5 • Presence/absence of tenderness – when investigations. All investigations should be tailored to the capsule of a node stretches, it results • Mediastinal nodes may cause cough, the patient’s presenting complaints and to in pain. This stretching is usually caused wheezing, dysphagia, haemoptysis, what was found on systemic examination, by inflammation, with suppuration or atelectasis and superior vena cava including any of the following not directly haemorrhage into a necrotic centre of a syndrome – an indication for urgent related to the lymph node: malignant node. Pain is not an accurate referral to a specialist. • CD4 count determinant of a benign or malignant • HIV viral load condition. Supraclavicular lymph nodes • full blood count • If a node is localised, the area/areas • These nodes drain the head, neck, arms, • liver function test drained by that node should be carefully superficial thorax, lungs, mediastinum • chest radiograph examined, e.g. cervicoaxillary – examine and abdomen. • sputum for TB/acid-fast bacilli the breast and head and neck area. • Left supraclavicular nodes (Virchow- • test for sexually transmitted disease, e.g. • A full systemic examination should be Trosier's nodes) reflect intra-abdominal rapid plasma reagin test done, focusing on hepatomegaly and the drainage, especially when there are • blood cultures respiratory and genitourinary systems. no other lymph nodes in the cervical • evaluation of renal function and region. urinalysis One-third of neonates • Right-sided supraclavicular nodes • ultrasonography. and infants may have typically enlarge in the case of intra- thoracic lesions. Biopsy lymphadenopathy. Before a biopsy is done, treatment with Axillary lymph nodes antibiotics (covering bacterial pathogens Areas of particular interest4 • These nodes drain the hand, arm, lateral frequently implicated in lymphadenitis) and Cervical lymph nodes chest, abdominal wall and breast. re-evaluation in 2 - 4 weeks is a reasonable • Cervical lymphadenopathy is common in • In patients with a high risk of breast managment option. The major question in children. carcinoma, mammography may be HIV lymphadenopathy remains, i.e. which • Cervical nodes drain the tongue, external warranted. patients should be observed, which patients ear, parotid gland and deep structures of • These nodes may occur after should undergo fine needle aspiration the neck. immunisation. (FNA),6 and in which patients an open biopsy • Lymph nodes posterior to the • Hydradenitis suppurativa may be a cause should be done. As already stated, histology sternocleidomastoid (posterior triangle) of axillary lymph nodes. (as opposed to cytology) remains the gold are more ominous and carry a high standard in diagnosing the aetiology of risk of serious underlying disease, e.g. Abdominal lymph nodes lymphadenopathy. However, obtaining tissue malignancy. • These nodes drain the pelvis, lower for histology either by core needle biopsy • Cervical lymphadenopathy may be caused extremities and abdominal organs. (CNB) or entire lymph node excision carries by infection. • They are not readily discernible on associated risks. The risks associated with clinical examination. CNB are possible injuriy to neurovascular Submental and submandibular lymph • They may present with abdominal pain, bundles and pain. The quantity of the tissue nodes backache, increased urinary frequency, obtained is limited and sampling error may • These nodes drain the teeth, tongue and constipation or bowel obstruction occur. buccal mucosa. secondary to intussusception. • They require thorough examination of the • Mesenteric adenitis may have a viral If a biopsy is considered, the largest and most oral cavity. aetiology, but may also be confused with abnormal node (not necessarily the most • They may require referral to a dentist. appendicitis. easily accessible node) should be excised. • Submental and submandibular lymph- • Mesenteric adenopathy may also be Inguinal and axillary nodes are not suitable adenopathy is usually caused by localised caused by neoplasms, typically Hodgkin’s for biopsy as they often show reactive infections such as pharyngitis, gingivitis disease and non-Hodgkin’s lymphoma. hyperplasia. In the setting of generalised and dental abscesses.

AUGUST 2010 Vol.28 No.8 CME 365 HIV-related lymphadenopathy lymphadenopathy lymph node biopsy should Annexure 1. Causes of generalised lymphadenopathy be avoided, as it is most likely of viral origin 7 and can lead the pathologist to making the Medications that may cause lymphadenopathy: Allopurinol erroneous diagnosis of malignancy. Atenolol Captopril FNA often does not lead to a diagnosis Carbamazepine because of non-representative samples, Cephalosporins inability to evaluate the architecture of the Gold entire node and the small amount of tissue/ Hydralazine cells obtained. In addition, there is a small Penicillin but discernible risk of sinus tract formation Phenytoin depending on the underlying pathology. Primidone Pyrimethamine Any tissue obtained is a golden opportunity Quinidine for management of these patients, and Sulfonamides therefore tissue should be sent for: Sulindac • histopathology (submitted in formalin) Causes of infection • bacterial cultures (submitted in saline) HIV infection, including persistent generalised lympadenopathy • mycobacterial cultures Mononucleosis, Epstein-Barr virus • fungal cultures. Mycobacterium avium complex Tuberculosis (TB) In one study, excisional biopsies yielded Cytomegalovirus a definitive diagnosis in only 40 - 60% of Secondary syphilis patients for 4 main reasons: Toxoplasmosis • inadequate specimen size Histoplasmosis and other fungal infections • improper handling Bartonella infection (bacillary angiomatosis) • node sampling error Hepatitis B • tissue sent for incorrect test. Lyme disease Chlamydia (lymphogranuloma venereum) Inguinal nodes typically show architectural Widespread skin infections Immune reconstitution inflammatory syndrome (IRIS) distortion owing to chronic infections. Follicular hyperplasia Pain is not an accurate Localised lymphadenopathy Any of the above determinant of a benign Infectious causes or malignant condition. Oropharyngeal and dental infections Cellulitis or abscesses Causes of generalised Chancroid lymphadenopathy TB (scrofula) In a Dutch study it was noted that of the Neoplastic causes 2 556 patients seen in a general practice, only Lymphoma 256 (approximately 10%) were referred to a Acute and chronic lymphocytic leukaemias specialist. Of these, only 82 (3.2%) required Other malignancies and metastatic cancers a biopsy and only 1.1% were diagnosed with Kaposi’s sarcoma malignancy. The conclusion remains that Other causes the vast majority of lymphadenopathies are Reactive process – benign due to a benign infective cause. However, Sarcoidosis it should also be noted that these patients Hypersensitivity reactions to medication still require treatment for infective/non- Serum illness neoplastic causes. Rheumatoid arthritis Castleman’s disease HIV-positive patients represent a distinct group for various reasons: • Is the generalised lymphadenopathy due to HIV? • Is the lymphadenopathy due to an HIV- In a nutshell related disease? • Lymphadenopathy is a common presenting symptom of HIV infection. • Is the lymphadenopathy unrelated to the • The fundamental goal is to exclude malignancy or serious treatable causes. HIV? • Lymphadenopathy in HIV-positive patients requires a full history, an examination and a deter- mination of the cause. Annexure 1 lists the causes of • Special investigations should be tailored to what is suspected on history and examination. lymphadenopathy. This list is by no means • It is of fundamental importance to determine which patients need further investigation. complete but represents the most common • Location, size, consistency, mobility and presence or absence of tenderness are important. causes of lymphadenopathy in the HIV/ • Knowledge of the lymph node drainage area and the causes is essential. AIDS population.

References available at www.cmej.org.za

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