Lymphadenopathy

SECTION 2 Syndromes by Body System: The Lymphatic System

15 

Lymphadenopathy ETHAN RUBINSTEIN†  |  YOAV KEYNAN

KEY CONCEPTS • An enlarged lymph node should lead to a detailed history and physical examination of all palpable lymph node stations. • Localized lymphadenopathy should trigger a search for etiology in the catchment area of the affected node. • The location of an enlarged node may provide diagnostic clues as to the etiology. • Generalized adenopathy (involving three or more lymph node groups) should always be investigated with imaging, to assess lymph nodes that are not within reach, and with further specific tests. • Localized lymphadenopathy, persisting for more than a month, in the presence of constitutional symptoms should be considered for biopsy. • Localized or generalized lymphadenopathy of unknown cause requires HIV testing as part of the diagnostic investigations.

• the paracortical region, underneath the cortex, which is composed mainly of T lymphocytes and dendritic cells; and • the medulla, the innermost region, containing fewer lympho-

cytes than the other two regions but more plasma cells that secrete immunoglobulins. Afferent lymphatic vessels empty the lymph drained from the tissues into the subcapsular sinus; from there the lymph flows through the cortex, paracortex and medulla, allowing phagocytic and dendritic cells to trap any foreign material. The efferent lymphatic vessels carry lymph rich in lymphocytes and antibodies into the circulatory system. The lymph node has two functions: • it acts as a defensive barrier; and • it serves as a factory for lymphocyte maturation and differentiation and as an antibody production site during antigenic challenge.

LYMPHADENITIS Lymphadenitis is an inflammation of the lymph node. The initial phase of an acute inflammation consists of swelling and hyperplasia

The human lymphatic system

Introduction The body has approximately 600 lymph nodes, but only those in the cervical, submandibular, axillary or inguinal regions are normally palpable in healthy people. Lymphadenopathy is a change in the size and/ or consistency of a lymph node or lymph node group (regional lymphadenopathy), or may be generalized involving multiple sites and multiple lymph node groups. The lymph node system is the major component of the body’s surveillance system against foreign invaders and functions as the hub where antigen-presenting cells interact with lymphoid cells to generate an adaptive immune response against myriad foreign antigens including microbial pathogens, tumor cells, immune complexes and foreign material. The lymphoid system grows rapidly during childhood and achieves twice the adult size in early adolescence. Thereafter it starts regressing, reaching adult maturity at about the age of 20–25 years. Lymphadenopathy, particularly peripheral, is thus a common finding in childhood, adolescence and young adulthood.1 Lymphadenopathy may be divided into acute and chronic lymphadenitis, i.e. inflammatory lymphadenopathy, lymphadenopathy that accompanies lymphoproliferative disease, infiltrative lymphadenopathy secondary to malignant disease and reactive lymphadenopathy that may be infectious or noninfectious. Table 15-1 summarizes the differential diagnosis of lymphadenopathy.

Preauricular Postauricular Suboccipital

Submental Submandibular

Supraclavicular

Cervical

Axillary nodes

Mesenteric Lumbar nodes

Pathogenesis and Pathology THE NORMAL LYMPH NODE Lymph nodes are widely distributed throughout the human body, particularly at potential portals (Figure 15-1). The normal lymph node is an oval, encapsulated, soft structure, 1–2 cm in diameter with an average weight of approximately 1 g. Histologically the lymph node can be divided into three regions (Figure 15-2):2 • the cortex, the outermost layer, which is composed mainly of B lymphocytes and macrophages arranged in primary follicles; †

Deceased

136

Rectosacral nodes

Inguinal nodes

Figure 15-1  The human lymphatic system.



Chapter 15  Lymphadenopathy

TABLE 15-1 

137

Differential Diagnosis of Lymphadenopathy

Etiology

Regional

Generalized

Suppurative/Caseating

INFECTIOUS LYMPHADENOPATHY Bacterial (Acute) Streptococcal

+

+

Scarlet fever

+

Staphylococcal

+

Diphtheria

+

Ludwig’s angina

+

Tuberculosis

+

+

Syphilis

+

+

Chancroid

+

+ +

+

Plague

+

+

Tularemia

+

+

Rat-bite fever

+*

Anthrax

+ +

Melioidosis Glanders

+

Cat-scratch disease

+

+ +

+

+

Typhoid fever Rickettsial Boutonneuse fever

+*

Scrub typhus

+

Rickettsial pox

+

Chlamydial Lymphogranuloma venereum

+

+

Viral Measles

+

Rubella

+

Infectious mononucleosis

+

HIV/AIDS

+

Cytomegalovirus infection

+

Dengue

+

West Nile fever

+

Lassa fever

+

Genital herpes

+

Epidemic keratoconjunctivitis (adenovirus)

+

Pharyngoconjuctival fever (adenovirus)

+

+ +

Mycotic +

Histoplasmosis Coccidioidomycosis

+

Paracoccidioidomycosis

+

Cryptococcosis

+

+

+

Protozoan +

Visceral leishmaniasis Leishmaniasis

+

+

Continued on following page

138 TABLE 15-1 

SECTION 2  Syndromes by Body System: The Lymphatic System

Differential Diagnosis of Lymphadenopathy (Continued)

Etiology African trypanosomiasis

Regional

Generalized

+

+

Suppurative/Caseating

+

Chagas disease +

Toxoplasmosis

+

Helminthic Loa loa

+

Onchocerciasis

+

+ (Bubo) + (Bubo) +

Filariasis NONINFECTIOUS LYMPHADENOPATHY Sarcoidosis

+

Connective tissue disorders

+

Kawasaki disease

+

+

Rosai–Dorfman disease

+

+

Kikuchi’s disease

+

+

Castleman’s disease

+

+ +

Drug hypersensitivity +

Silicone breast implant Infiltrative Malignant Metastatic carcinoma

+

Metastatic melanoma

+

+

+

Leukemia Infiltrative nonmalignant Lipid storage disease

+

Amyloid

+

Primary Lymphoproliferative +

Lymphoma

+

Angioimmunoblastic lymphadenopathy

+

Lymphomatoid granulomatosis

+

Malignant histiocytosis

+

Drug Induced Allopurinol, atenolol, captopril, carbamazepine, cephalosporins, gold hydralazine, penicillin, phenytoin, primidone, pyrimethamine, quinidine, sulfonamides, sulindac

+

*Ulceroglandular

of the sinusoidal lining cells and infiltration by leukocytes and edema. This leads to distention of the node’s capsule which causes local pain. The process may progress to abscess formation causing the node to become fluctuant depending on the causative micro-organism and the host response. The node may break into the skin and produce a draining sinus. Following the infection the node resumes its normal architecture or, if severely damaged, may obliterate completely. Acutely inflamed lymph nodes are most commonly caused by entrapped microbes. Chronic lymphadenitis is typically a proliferative process with either follicular hyperplasia or paracortical lymphoid hyperplasia depending on the cause of the inflammation; such nodes are nontender.

Epidemiology In children the cause of lymphadenopathy is apparent in most cases. In approximately 80% of the cases it is benign, mainly reactive–

infectious in origin. In contrast, lymphadenopathy in adults more often reflects serious disease. One study revealed a 0.6% annual incidence of unexplained lymphadenopathy in the general population. Of 2556 patients with unexplained lymphadenopathy, 3.2% required a biopsy but only 1.1% had a malignancy. The probability of a neoplasm affecting enlarged peripheral lymph nodes increases steadily with age; in those older than 50 years who are referred for biopsy because of longstanding enlarged lymph nodes, more than 60% of cases of lymphadenopathy are due to a malignancy.2,3 In contrast, in primary care settings, patients 40 years of age and older with unexplained lymphadenopathy have about a 4% risk of cancer versus a 0.4% risk in patients younger than age 40.4 In tropical and subtropical regions leading causes may include parasitic diseases as well as infections. Lymphadenopathy is defined as generalized whenever three or more anatomically discrete groups of lymph nodes are involved. The different infectious etiologies of generalized lymphadenopathy are shown in Table 15-1. Occasionally lymph nodes that are not palpable



Chapter 15  Lymphadenopathy

may be involved, as is the case with lymph node involvement in anthrax or typhoid (abdominal), sarcoidosis and tuberculosis (mediastinal). Viral diseases are the major cause of generalized lymphadenopathy. The bacterial diseases that may cause generalized lymphadenopathy include tuberculosis, typhoid fever, brucellosis, syphilis and leptospirosis. In the differential diagnosis of generalized lymphadenopathy important parameters are the age of the patient, epidemiologic factors, relevant traveling, contact with sick individuals, accompanying signs and symptoms (rash, splenomegaly), and laboratory findings.

Clinical Features REGIONAL LYMPHADENOPATHY AND LYMPHADENITIS Acute Suppurative Lymphadenitis Acute suppurative lymphadenitis is commonly caused by pyogenic infections, arising from draining of the organisms causing the initial focus of infection (especially Staphylococcus aureus or group A streptococci). The most commonly involved sites are the submandibular, cervical, inguinal and axillary lymph node groups. The affected lymph node is extremely tender and firm, although it may be fluctuant, and the overlying skin may be red and warm. There are usually systemic manifestations. Acute cervical lymphadenitis due to a pyogenic infection is more common in children than adults. In both children and adults it is commonly due to staphylococcal infec-

139

tions of the face or neck and, uncommonly, it may be a complication of streptococcal pharyngitis.5 In adults, anaerobic bacteria, of which the predominant species are Prevotella spp., Peptostreptococcus spp., Propionibacterium acnes and Fusobacterium spp., are recovered in 30% of cervical lymphadenitis cases, 13% are anaerobes alone and 17% are mixed anaerobic–aerobic bacteria.6 Acute pyogenic cervical lymphadenitis is unilateral. In contrast, acute bilateral cervical lymphadenitis is commonly due to viral upper respiratory infection, infectious mononucleosis, streptococcal pharyngitis or localized periodontal infections. Acute suppurative axillary lymphadenitis is a severe infection with prominent systemic manifestations and axillary pain that radiates to the shoulder and down to the arm. The axilla, arm, shoulder and supraclavicular and pectoral areas are markedly edematous, but there are no signs of skin infection or lymphangitis. The portal of entry of the infecting bacteria (group A streptococci or Staph. aureus) is often a traumatic lesion of the arm.7 Rapidly enlarging lymph nodes may be accompanied by systemic manifestations, including toxic shock syndrome, without obvious genital or skin lesions.8,9 Patients who have chronic granulomatous disease experience recurrent pyogenic infections, of which the most common manifestations are lower respiratory tract infections, suppurative lymphadenitis, subcutaneous abscesses and hepatic abscesses.10 The infecting pathogens are catalase-positive organisms such as Staph. aureus, Serratia marcescens, Burkholderia (Pseudomonas) cepacia and Aspergillus spp. The histologic appearance of the lymph node is one of inflammation with granuloma formation and necrosis.10,11

Cat-Scratch Disease The lymph node Afferent lymphatic vessels Germinal center

Postcapillary venule

Primary lymphoid follicle Cortex Cross-section of a post-capillary venule

Paracortex Medulla

Capsule

Mantle of cells Lymphatic artery Lymphatic vein

Efferent lymphatic vessel

Figure 15-2  The lymph node.

TABLE 15-2 

Cat-scratch disease typically manifests after a cat scratch or bite as regional lymphadenopathy distal to the involved lymph node. The mode of transmission is presumably direct contact with the causative agent, primarily Bartonella henselae. The disease occurs worldwide, with healthy children and adolescents being most frequently affected.12 A history of a trivial cat scratch or a bite by a kitten can be elicited in most cases.13 Occasionally, typical cat-scratch disease cases can be caused by other pathogenic Bartonella sp. (i.e. Bartonella clarridgeiae).14 Tender lymphadenopathy develops within 1–3 weeks after inoculation. Commonly, an erythematous papule at the site of inoculation precedes the development of lymphadenopathy and may last for several weeks. Regional lymph node enlargement is the sole manifestation in one-half of the patients. Most commonly the cervical, axillary or epitrochlear lymph nodes are involved, but any peripheral nodes at multiple sites may be enlarged. In one-third of the patients, low-grade fever is present, and about 15% have systemic manifestations such as malaise, headache, splenomegaly and sore throat. Unusual clinical manifestations occur in 10% of patients; the most frequent of these is the oculoglandular syndrome of Parinaud,13,15 which is conjunctivitis with ipsilateral preauricular lymphadenitis (Table 15-2). The adenopathy subsides spontaneously within several months. Occasionally, aspiration of a suppurative lymph node is needed to relieve pain. The diagnosis is based on epidemiologic exposure and can be confirmed by detection of serum antibody to B. henselae.13 Occasional

Oculoglandular Syndromes

Disease

Infecting Organism

Features

Cat-scratch disease

Bartonella henselae

Parinaud’s sign in 3%, conjunctivitis in 6%

Tularemia

Francisella tularensis

Parinaud’s sign in 5%

Lymphogranuloma venereum

Chlamydia trachomatis

Parinaud’s sign in <1%

Pharyngoconjunctival fever

Adenovirus 3,7

Common in children

Epidemic keratoconjunctivitis

Adenovirus 8, 19, 37

Occasionally seen in adults

Chagas disease

Trypanosoma cruzi

Romaña’s sign

140

SECTION 2  Syndromes by Body System: The Lymphatic System

Figure 15-3  Tuberculous lymphadenitis of the axilla.

cat-scratch disease cases caused by other pathogenic Bartonella may, however, be serologically negative.14 In atypical presentations or whenever a neoplastic or mycobacterial process is suspected, a lymph node biopsy or aspirate may be needed.

Mycobacterial Lymphadenitis This is the most common form of extrapulmonary tuberculosis in the Western world.16 Tuberculous cervical lymphadenitis is caused by spread of Mycobacterium tuberculosis from a lung infection. Scrofula often presents as a one-sided red, painless mass, located along the upper border of the sternocleidomastoid muscle or in the supraclavicular area or axilla. In areas in which both tuberculosis and HIV are prevalent, tuberculous lymphadenitis may be the presenting sign in 50% of young children and is often associated with intrathoracic disease17 (Figure 15-3). Currently most tuberculous lymphadenitis is caused by M. tuberculosis and atypical mycobacteria, particularly M. scrofulosum and M. avium complex (MAC).18 The process is indolent and slowly progressive and is not accompanied by systemic symptoms. If systemic signs appear, or the process is outside the cervical lesion, miliary tuberculosis should be suspected. With M. bovis infection the primary focus is usually the tonsil or the pharynx. The diagnosis of mycobacterial lymphadenitis is confirmed microbiologically and with histology of the afflicted lymph node. Fine needle aspiration frequently reveals the presence of granuloma but only rarely yields smears that are positive or material that is culture positive.18 Microbiologic and histologic examinations are complementary as M. tuberculosis has been isolated from lymph nodes not showing granuloma, and granulomata have occasionally grown atypical mycobacteria. Acid-fast bacilli are only rarely seen in smears except in HIV co-infected patients. New diagnostic techniques such as DNA hybridization, polymerase chain reaction (PCR) and blotting techniques hold promise for more accurate and rapid diagnosis19 (see Chapter 185). Lymphadenopathy may occur after initiation of antiretroviral therapy, as a result of immune reconstitution.

Plague and Tularemia Both these infections are zoonoses that produce rather similar manifestations, mostly fever and regional lymphadenitis.20 Plague and tularemia may be used as bioterrorism agents as they are highly infectious when dispersed by the airborne route.21,22 Plague is caused by Yersinia pestis (see Chapter 126). Most human cases are in the bubonic form transmitted by the bite of infected fleas. After an incubation period of 2–8 days patients develop sudden fever, chills, malaise and headache. Usually by the same time or within a few hours, a painfully swollen regional lymph node appears in the draining region of the inoculation site, commonly in the axilla, neck or groin. The primary lesion is occasionally found at the bite site and may develop into an area of cellulitis or an abscess. Over the next few days,

Figure 15-4  Bubonic plague, axillary bubo and accompanying edema.

TABLE 15-3 

Differential Diagnosis of Infectious Inguinal Lymphadenopathy

Sexually Transmitted Diseases

Other Diseases

Syphilis

Pyogenic infections

Lymphogranuloma venereum

Cellulitis

Chancroid

Plague

Genital herpes

Filariasis

Granuloma inguinale

Onchocerciasis

the discrete lymph nodes become matted together to form the characteristic bubo with extensive surrounding edema (Figure 15-4). The matted lymph nodes are exquisitely tender. Isolation of Y. pestis from an aspirated bubo, blood, bone marrow and multiple organs is possible but bacterial growth is slow; rapid identification can be accomplished by a characteristic Gram or Wayson stain. Such patients should be immediately isolated, reported and treated.22 Tularemia (see Chapter 127) occurs only in the northern hemisphere. Over 80% of infections are acquired by handling infected animals or by tick or deer fly bites. In the Western world most cases are sporadic, whereas in other parts of the world large water-borne, arthropod-borne and airborne outbreaks have been reported. Infection commonly manifests as an ulceroglandular or oculoglandular syndrome.21 The most common portals of entry are the skin and the conjunctiva, with an ulcer or a pustule, or in the case of the conjunctiva or eyelid, conjunctivitis, a papule or an ulcer, developing 1–10 days after exposure. Regional lymphadenopathy follows and the enlarged lymph nodes may suppurate. Systemic manifestations are common but systemic toxicity and prostration is absent. Presumptive diagnosis is made on epidemiologic grounds and confirmed by specific serologic tests.23

INGUINAL LYMPHADENOPATHY Sexually transmitted diseases (STDs) and metastatic genital neoplastic disease are the most common causes of inguinal lymphadenopathy. The differential diagnosis of infectious inguinal lymphadenopathy is shown in Table 15-3.

Chancroid Chancroid is caused by Haemophilus ducreyi and in some parts of the world (e.g. Thailand) it is one of the most common causes of genital ulcer with inguinal lymphadenopathy (see Chapter 64). The chancroid ulcer is a painful, nonindurated lesion that appears 1 day to several weeks after inoculation. Inguinal lymphadenitis occurs in between



Chapter 15  Lymphadenopathy

141

patient only one chancre appears but in the immunocompromised patient, especially in patients who have AIDS, multiple chancres may be seen. In women and homosexual men, the chancre may be located in the perianal region or in the anal canal. Regional painless lymphadenopathy is characteristic at this stage of disease. The chancre usually heals and disappears after 3–6 weeks, but the lymphadenopathy may persist for longer. The symptoms of secondary syphilis appear 2–8 weeks after the chancre has healed, with generalized lymphadenopathy and various skin lesions in the majority of patients. Chancre and secondary syphilis manifestations may coexist in HIV-infected individuals. Epitrochlear lymphadenopathy suggests the diagnosis.26

Genital Herpes The typical vesicles associated with inguinal lymphadenopathy usually suggest the correct diagnosis. Rarely, lymph node enlargement may appear before the rash develops.27 The lymphadenopathy associated with primary herpes is either unilateral or bilateral; in severe cases generalized lymphadenopathy may also occur. Genital lesions and lymphadenopathy are common in genital herpes in the immunocompetent host; however, massive lymphadenitis is frequently seen in the immunocompromised patient. The diagnosis is based on isolation of herpes simplex virus from a skin lesion, preferably from a vesicle28 (see also Chapter 62). Figure 15-5  Groove sign of lymphogranuloma venereum. There is cleavage of extensive lymphadenopathy by the inguinal ligament.

one-third and one-half of untreated cases. The lymph nodes are enlarged, painful and tender. The process is most commonly unilateral and, without treatment, can progress to suppuration with periadenitis and involvement of the overlying skin (bubo). Culture provides the definitive diagnosis; however, H. ducreyi is a fastidious organism and immediate direct inoculation into specific culture media is required for bacterial growth and isolation. Chemotherapy is sufficient in most uncomplicated cases but abscesses that are more than 5 cm in diameter may need surgical drainage24 (see also Chapter 64).

Lymphogranuloma Venereum Lymphogranuloma venereum is a rare STD caused by C. trachomatis serovars L1, L2 and L3. The typical vesicular lesions appear 1–2 weeks after inoculation but the incubation period varies between 5 and 20 days. The lesions often go unnoticed by the patient. Inguinal lymphadenopathy appears 1–6 weeks after the vesicles disappear. The lymphadenopathy is most commonly unilateral but is bilateral in 30–40% of patients. The nodes are painful and the groove sign (cleavage of the enlarged nodes by the inguinal ligament) is seen in 25% of patients (Figure 15-5). The involved lymph nodes frequently coalesce to form a bubo. If untreated, the nodes may rupture and a nonhealing fistula is formed. The anorectal syndrome, which occurs mainly in women and homosexual men, results from involvement of the pelvic lymph nodes. In the male, abscess formation may occur in the dorsal lymphatic of the penis and cause tissue destruction and elephantiasis of the penis. Chlamydia trachomatis can be isolated from both blood and aspirates of lymph nodes in approximately 30% of cases. Incision of the bubo is not warranted for diagnosis and positive serologic tests or nucleic acid amplification based assays in the appropriate clinical setting are highly sensitive and specific for the diagnosis25 (see Chapter 64).

Syphilis The lymphadenopathy of primary syphilis is easily differentiated from chancroid and lymphogranuloma venereum because nodes involved in syphilis are firm, only moderately enlarged, nonsuppurative and painless. The classic primary chancre appears 14–30 days after inoculation and is a nonexudative, painless ulcer. In the immunocompetent

Granuloma Inguinale Granuloma inguinale (donovanosis) is caused by Calymmatobacterium granulomatis. The disease is rare in the Western world but is a major cause of genital ulcer in south-east India, Brazil and some parts of Africa. The penile papules of granuloma inguinale appear within days of inoculation and rapidly ulcerate to form a red, granulomatous, painless ulcer with a characteristic surface that bleeds easily on contact. Subcutaneous spread into the inguinal region results in swellings (pseudobuboes) that are not a true adenitis. Lymphedema and elephantiasis occasionally result from scarring and blockage of the lymphatics. Granuloma inguinale should be differentiated from other genital ulcerative lesions with inguinal lymphadenopathy. The diagnosis is established through the demonstration of the typical intracellular Donovan bodies in stained smears obtained from the lesions29 (see Chapter 64).

PARASITIC LYMPHADENOPATHY Toxoplasmosis Lymphadenopathy is an important clinical sign of acquired primary toxoplasmosis in the immunocompetent and occurs in up to 84% (mean 64%) of cases in different studies. Lymphadenopathy is typically found in the neck, most commonly in the posterior and anterior cervical regions, followed by the suboccipital region, the axillae and then the groins. It is usually found at single sites in adults (in 90%), but multiple sites are more common in children. Retroperitoneal or mesenteric lymphadenopathy occur occasionally and cause abdominal pain. Toxoplasmic lymphadenopathy has been described in unusual sites such as the lung hilus, the mammary gland, parotid gland and chest wall.30 Lymphadenopathy may be the only symptom of toxoplasmosis but generally there are additional symptoms – often fever and rarely splenomegaly and/or hepatomegaly. In approximately 15% of cases, Toxoplasma lymphadenopathy is associated with fever, headache, myalgia and sore throat that may mimic infectious mononucleosis. On palpation, the lymph nodes are usually discrete, of varying firmness, and may or may not be tender; they rarely suppurate or ulcerate. A chronic lymphadenopathy fluctuating in size over several months has also been described.30 The histologic appearance should be differentiated from lymphoma, cat-scratch disease and Kikuchi’s lymphadenitis. Enlarged glands will usually resolve within 1–2 months in 60% of patients. However, 25% of patients take 2–4 months to return to normal, 8% take 4–6 months and in 6% the enlarged lymph nodes do not return to normal until much later.

142

SECTION 2  Syndromes by Body System: The Lymphatic System

The diagnosis of toxoplasmosis cannot be made solely on clinical grounds. Histologic features in lymph node biopsies are suggestive of toxoplasmosis but are not diagnostic.30 Antibodies to Toxoplasma gondii are usually detectable within 2 weeks of infection and reach a peak within 2 months. Toxoplasma lymphadenopathy in immunocompetent patients normally resolves without treatment. Acute infection by Toxoplasma gondii is common worldwide. The prevalence of seropositivity by the fourth decade of life in North America is 30–50% and higher than 90% in certain European countries.31 Toxoplasmosis has been estimated to cause between 3% and 7% of clinically significant lymphadenopathy. The differential diagnosis of Toxoplasma from lymphoma may, on occasion, save unnecessary invasive diagnostic workup.

Leishmaniasis (see Chapter 123) Enlarged lymph nodes occur in the majority (77%) of people with confirmed cutaneous leishmaniasis in South America and in patients who have Leishmania major and L. tropica acquired in equatorial Africa and the Middle East.32,33 Lymphadenopathy may precede the cutaneous lesion by some 2 weeks in two-thirds of the cases. Cultures of the lymph nodes obtained by aspiration or biopsy are more frequently positive (86%) than cultures obtained from the skin lesions. In Brazil lymphadenopathy (whether localized or generalized) may often be the first, and sometimes the only, symptom of cutaneous leishmaniasis.34,35 Lymph node histology may show necrotizing or suppurative granulomas, sometimes with discharging sinuses. Patients who have leishmanial lymphadenopathy often have fever, hepatomegaly, splenomegaly, intense skin reaction and lymphocyte proliferation when exposed to suitable antigenic stimulation. In an endemic area, therefore, an unexplained lymphadenopathy should prompt an investigation for leishmaniasis.

African Trypanosomiasis (see Chapter 110) Human African trypanosomiasis, or sleeping sickness, is an illness endemic to sub-Saharan Africa, caused by the flagellate protozoan, Trypanosoma brucei, which exists in two morphologically identical subspecies: Trypanosoma brucei rhodesiense (East African or Rhodesian African trypanosomiasis) and Trypanosoma brucei gambiense (West African or Gambian African trypanosomiasis). Both of these parasites are transmitted to human hosts by bites of infected tsetse flies (Glossina species), which are found only in Africa. Humans are infected following a fly bite, which occasionally causes a skin chancre at the site. These injected trypomastigotes further mature and divide in the blood and lymphatic system, causing symptoms of malaise, intermittent fever, rash and wasting. Eventually, the parasitic invasion reaches the central nervous system (CNS), causing behavioral and neurologic changes, such as encephalitis and coma. In the first stage of the disease the major findings are painless skin chancre that appears about 5–15 days after the bite, intermittent fever (refractory to antimalarials), general malaise, myalgia, and headache usually 3 weeks after the tsetse fly bite, accompanied by generalized lymphadenopathy, pruritus, urticaria and facial edema (minority of patients). Axillary and inguinal lymphadenopathy is noted more often in patients with the East African form; cervical lymphadenopathy is more commonly observed in patients with the West African form. The classic Winterbottom’s sign is clearly visible (i.e. enlarged, nontender, mobile posterior cervical lymph node) (Figure 15-6). Fevers, tachycardia, irregular rash, edema and weight loss ensue. Lymphadenopathy has to be differentiated from tuberculosis lymphadenitis, HIV and cancer. A definitive diagnosis of infection requires detection of trypanosomes in blood, lymph nodes, cerebrospinal fluid, skin chancre aspirates or bone marrow. The standard serologic assay to diagnose West African trypanosomiasis is the card agglutination test for trypanosomiasis (CATT), results of which are available in only 10 minutes. It is highly sensitive (96%) but less specific because of cross-reactivity with animal trypano-

Figure 15-6  Winterbottom’s sign: lymph node enlargement in the posterior neck, a sign of African trypanosomiasis.

somes. Commercial antibody tests for East African trypanosomiasis are not available. For early- and late-stage disease, treatment usually results in resolution of symptoms and rapid clearance of parasitemia on repeat blood smears. Most patients experience full recovery following treatment.36,37

American Trypanosomiasis (Chagas Disease)38 (see Chapter 124) Lymphadenopathy appears in around two out of three patients with the acute disease; additional signs and symptoms also occur. An enlarged liver and spleen are mainly observed in children, whereas generalized lymphadenopathy is observed in 60% of all patients. Subcutaneous edema, either generalized or localized to the face and/or lower extremities, is observed in 30–50% of cases.

Filariasis39 (see Chapter 121) The most common symptoms of filarial lymphatic disease include fever, inguinal or axillary lymphadenopathy, distinctive lymphangitis spreading retrogradely from the lymph node where the filaria reside to the periphery, testicular and/or inguinal pain, skin exfoliation, and limb or genital swelling. Such attacks last for 3–7 days and recur between 6 and 12 times per year. Attacks subside spontaneously without specific therapy. Affected lymph nodes are enlarged and painful, and the surrounding lymph vessels also appear inflamed and indurated. With the continuation of lymphangitis and lymphadenitis, pitting edema of the skin appears; this is transformed into brawny edema of the involved area causing thickening of the subcutaneous tissue and hyperkeratosis. Coarsening of the skin ensues with deep fissuring and nodular and papillomatous hyperplastic skin changes. Occasionally local lymphedema appears causing penile, testicular, labial or limb enlargement. In some patients passage of cloudy milklike urine may denote chyluria. Occasionally local thrombophlebitis may complicate the clinical picture. Infection by Brugia malayi may result in an abscess of the local lymphatic apparatus leaving characteristic scars.

Onchocerciasis40 The major manifestations of the disease are dermatitis, onchocercoma, lymphadenitis and visual impairment or blindness. Mild to moderate lymphadenopathy is common, particularly in the inguinal and femoral areas. Involved nodes are characteristically firm and nontender; at times they may reach gigantic proportion and be associated with lymphedema causing elephantiasis (hanging groins). Itching skin and chronic papular onchodermatitis with depigmentation are



Chapter 15  Lymphadenopathy

bothersome, sometimes accompanied by lymphadenopathy in conjunction with secondarily infected skin lesions.

Wuchereria bancrofti Infection41 Lymphadenopathy is the striking feature of infection with Wuchereria bancrofti. Filaria are frequently found in the enlarged lymph node. While the peripheral blood smear and involved organs are characterized by intense eosinophilia, the histology of the lymph node may not reveal eosinophilic infiltration. At times, the genitalia may be involved with funiculitis, epididymitis, scrotal pain and skin changes and disfiguration of the penis. Scrotal lymphedema, hydrocele and elephantiasis may be present. In addition, characteristic gigantic swelling of the leg below the knee and of the arm below the elbow, described as elephantiasis, may develop as a result of lymphatic involvement. Occasionally obstruction of the retroperitoneal lymphatics occurs, leading to rupture of lymphatic vessels into the kidney and appearance of chyluria.

VIRAL LYMPHADENOPATHY HIV Lymphadenopathy is very common in HIV-infected individuals and may occur at any stage of HIV infection. Generalized lymphadenopathy was one of the characteristic manifestations of the AIDS epidemic, even before its etiology was recognized.42 In the San Francisco Men’s Health Cohort Study marked lymphadenopathy was present in 29% of seropositive men43 and 29.2% among 1616 HIV-positive persons in India.44 Acute retroviral syndrome is often associated with generalized lymph node enlargement (see Chapter 93). In the majority of cases it usually appears during the second week of the illness. The lymphadenopathy commonly involves the cervical, axillary and inguinal regions.45 In the early stage of the infection the lymph nodes are characterized histopathologically by pronounced follicular hyperplasia that, with progression of the disease, evolves into a pattern of follicular involution.46 Lymph node enlargement in patients with HIV, especially with immunosuppression, may indicate a serious local or systemic condition, and should be evaluated carefully. Rapid enlargement of a previously stable lymph node or a group of nodes requires evaluation to identify the cause and to determine whether treatment is needed. Similarly, nodes that are abnormal in consistency, tender to palpation, fluctuant, asymmetrical, adherent to surrounding tissues or accompanied by other symptoms should be evaluated promptly. A multitude of opportunistic infections and malignancies can cause lymphadenopathy in patients with HIV (see Chapter 94). The likely causes of lymphadenopathy, and thus the diagnostic workup, will depend in part on the patient’s degree of immunosuppression (Table 15-4). Sudden enlargement, pain or tenderness of a lymph node warrants further diagnostic procedures. In the evaluation of patients with HIV with lymph node enlargement, the history should include accompanying symptoms,

TABLE 15-4 

143

particularly constitutional symptoms such as fever, sweats, fatigue and unintentional weight loss. In addition, the patient should be asked about travel history, country of origin, disease exposures (e.g. tuberculosis) and risk behaviors (e.g. sexual activity). A comprehensive physical examination should be done with emphasis on lymph node distribution, size, mobility and consistency. The size and consistency of the spleen and liver should also be examined. In patients with a CD4 cell count >200 cells/µL, a tuberculin skin test should be done. Laboratory studies should include complete blood count, including a careful evaluation of the peripheral blood smear. CD4 cell count should be done as early as possible since the whole differential diagnosis will depend on this number. Evaluation of hepatic biochemistry, renal function and urine analysis are useful to identify underlying systemic disorders that may be associated with lymphadenopathy. Additional studies, such as lactate dehydrogenase (LDH), uric acid, calcium and phosphate, may be indicated if malignancy is suspected. Tests for specific organisms (e.g. Bartonella henselae) should be done according to clinical assessment. Imaging studies should include chest X-ray and, when appropriate, tomography. Mediastinal or hilar lymphadenopathy is not a part of the persistent generalized lymphadenopathy (PGL) syndrome and whenever isolated intrathoracic lymphadenopathy is detected, a thorough investigation for mycobacterial disease is recommended. In such cases tuberculosis is found in more than half of the patients.47 Fine needle aspiration biopsy (FNA-B) is a worthwhile procedure and may allow a rapid diagnosis, obviating the need for surgery and enabling swift treatment to be undertaken in both adults and children.48,49 If FNA-B is nondiagnostic (false-negative results are relatively common), an open biopsy for definitive evaluation should be done. Biopsy specimens should be sent for (myco)bacterial and fungal cultures, acid-fast staining for mycobacteria and cytologic examination. Most patients with PGL will not require any treatment. In most patients highly active antiretroviral therapy (HAART) will reduce viral load and lymphadenopathy will subside. When a specific diagnosis is made, specific therapy should be instituted.

Human T-lymphocyte Leukemia Virus 1 (HTLV 1)50 Generalized lymph node enlargement is the most common manifestation of HTLV-1 infection. Additional characteristic findings include skin lesions, hepatosplenomegaly, hypercalcemia, lymphocytosis with abnormal circulating lymphocytes and hyperimmunoglobulinemia. Geographic-dependent findings are tropical spastic paraparesis and myelopathy in some tropical areas. Untreated, the disease undergoes rapid clinical deterioration.

Infectious Mononucleosis Infectious mononucleosis is a disease of teenagers and young adults. It is classically characterized by fever, tonsillopharyngitis, lymphadenopathy, splenomegaly and atypical lymphocytes on peripheral blood smear. Epstein–Barr virus (EBV) is the cause in 80–90% of cases, followed by cytomegalovirus (CMV; 8–16%) and toxoplasmosis (1–2%).51

Causes of Lymphadenopathy in HIV-positive Patients

Generalized Lymphadenopathy

Localized Lymphadenopathy

HIV (acute or persistent generalized lymphadenopathy)

Local infection

Viral diseases (Epstein-Barr virus, cytomegalovirus, hepatitis B virus, hepatitis C virus)

Tuberculosis

Tuberculosis

Fungal disease (histoplasmosis, coccidioidomycosis, etc.)

Syphilis (secondary)

Lymphogranuloma venereum, chancroid

Bartonella henselae

Lymphoma or other malignancy

IRIS (immune reconstitution syndrome)

Castleman’s disease

Drugs (e.g. abacavir)

Kaposi’s sarcoma

Multicentric Castleman’s disease

144

SECTION 2  Syndromes by Body System: The Lymphatic System

It is usually a benign and self-limiting process. Patients exhibit generalized lymphadenopathy and localized lymph node enlargement with or without systemic manifestations. Lymphadenopathy is observed in the vast majority of children and young adults with infectious mononucleosis but only in approximately 45% of patients older than 40 years.52 Lymph nodes are usually moderately enlarged and not very tender; they can be found at the posterior cervical, axillary, epitrochlear, submandibular, submental and groin regions. Lymph node histology demonstrates paracortical immunoblastic proliferation as seen in many viral infections.53 Serious complications of infectious mononucleosis include meningoencephalitis with seizures, myelitis, peripheral neuropathy, splenic rupture, upper airway obstruction, interstitial pneumonitis and severe hepatitis with liver failure. Death is rather rare.

Management

Lymphadenopathy of long duration (>1 month) mandates a thorough investigation. While lymphadenopathy caused by the agent of catscratch disease, Bartonella henselae, and by Toxoplasma gondii can persist for several months, the presumed etiology may be in doubt if the enlarged lymph nodes persist for more than 6 months; in such cases a biopsy of the lymph node is indicated. Fine needle aspiration has replaced the previously often used open surgical biopsy, and is suitable for most diagnostic purposes (except for the diagnosis of lymphoma). The average rate of diagnosis of a biopsied lymph node is 50–60%. Among patients in whom a diagnosis cannot be established through a lymph node biopsy, 25% will develop a lymphoma within 1 year. Therefore patients who undergo a nondiagnostic lymph node biopsy need to be followed up.

THE ROLE OF AGE

Lymphadenopathy may be the presenting sign in many diseases. The physical examination of a patient needs to include a description of the most important lymph node groups (cervical, clavicular, axillary, inguinal) and a search for lymph node enlargement of unconventional sites (suboccipital, scalenal, epitrochlear, popliteal, etc.) when indicated. In adults, small lymph nodes, the size of a small olive, can be normally palpated in the inguinal region and in children in the suboccipital and submental regions. Enlarged and certainly persistent supraclavicular, scalenal, axillary and epitrochlear lymph nodes will usually require investigation, including aspiration or a biopsy of the node.

MODE OF PRESENTATION In acutely ill patients who have a tender enlarged lymph node, bacterial etiology is most likely, frequently but not always caused by grampositive cocci. A thorough ear, nose and throat examination is mandatory in lymphadenitis or lymphadenopathy of the cervical, submental and head regions. In endemic regions, plague, anthrax and tularemia should be suspected. An acutely ill patient found to have generalized lymphadenopathy (more than three sites) should be evaluated for systemic infections including infectious mononucleosis, typhoid fever, rickettsiosis, leptospirosis, miliary tuberculosis and tularemia, as well as disseminated streptococcal and staphylococcal infections. In mildly symptomatic younger individuals and in symptomatic transplant patients with generalized lymphadenopathy the most likely etiologies will be EBV, CMV and HIV; all of these require special laboratory investigations.54

TABLE 15-5 

DISEASE PROGRESSION

Lymphadenopathy is exceedingly common in the pediatric age group and represents a benign process in approximately 80% of cases. As such, a trial of antibiotics is justified prior to an extensive workup. In adults, particularly if over 50 years of age, lymphadenopathy (regional or generalized) that persists for several weeks requires a thorough evaluation and consideration for biopsy.

PHYSICAL CHARACTERISTICS OF THE ENLARGED LYMPH NODE The size, consistency and relation to surrounding and underlying tissues are important clues to the diagnosis of enlarged lymph nodes. Lymph nodes involved by an infective process tend to be large, soft and tender. Signs of local inflammation may be present and draining sinuses may be seen in tuberculous cervical lymphadenitis; inguinal draining sinuses are occasionally seen in lymphogranuloma venereum and chancroid. Nodes involved by lymphoma are characterized as rubbery, matted together and usually nontender. Metastatic lymph nodes due to carcinoma are usually firm, nontender and fixed to the surrounding tissues.

LOCATION Specific locations of enlarged lymph nodes are frequently associated with specific etiologies (Table 15-5). As intrathoracic and intraabdominal lymph nodes are usually not palpable, appropriate imaging studies are necessary (ultrasound, CT).

Location of Enlarged Lymph Node and Associated Disease

Site of Enlarged Lymph Node

Associated Disease or Condition

Occipital

Scalp infections, insect bites, head lice, allergy to hair shampoo

Posterior auricular

Rubella, infected ear piercing, otitis externa, HIV infection

Anterior auricular

Eye and conjunctival infection, tularemia

Posterior cervical

Toxoplasmosis

Submental

Dental and oral cavity infections

Anterior cervical and submandibular

Oral cavity infections, infectious mononucleosis, cytomegalovirus, HIV, tuberculosis

Supraclavicular

Neoplasia

Mediastinal

Sarcoidosis, tuberculosis, histoplasmosis, blastomycosis, anthrax, neoplasia (lymphoma, metastasis)

Axillary

Cat-scratch disease, pyogenic infections of the arm, neoplasia

Epitrochlear

Viral diseases, cat-scratch disease, tularemia, hand infections, secondary syphilis

Abdominal/retroperitoneal

Tuberculosis, yersiniosis, neoplasia

Inguinal

Genital herpes, syphilis, lymphogranuloma venereum, granuloma inguinale, filariasis, pediculosis pubis, neoplasia



Chapter 15  Lymphadenopathy

Head and Neck Lymphadenopathy The oropharyngeal cavity (including the teeth) is the most common cause for head and neck lymphadenopathy, followed by the nasal cavity and the skin covering the head and neck. In children and young adults enlarged lymph nodes must be differentiated from epidermoid cysts, thyroglossal cysts, branchial cysts and parotid and submental enlarged glands. Symmetric lymph node enlargement is usually benign and of viral etiology in most instances; unilateral lymph node enlargement raises a wider differential diagnosis list including viral etiology. The most common causes of unilateral enlargement include inflammation of a draining lymph node as a consequence of a local (bacterial) infection, cat-scratch disease, toxoplasmosis and neoplasia. If asymmetrical cervical lymph node enlargement persists beyond a few weeks and serologic tests for toxoplasmosis and cat-scratch disease are negative, a biopsy, usually with a fine needle, is indicated. An abnormal chest radiograph with associated unilateral cervical lymph node enlargement is highly suspicious (in 80% of patients) of neoplastic etiology or granulomatous disease, and in such instances a lymph node surgical biopsy may be more accurate than fine needle aspiration. Supraclavicular adenopathy, particularly in adults, is most likely to be neoplastic, frequently secondary to gastric cancer. Rare situations that may cause cervical lymphadenopathy include Kimura disease (eosinophilic hyperplastic lymphogranuloma) and Gianotti–Crosti syndrome (hepatitis B-associated lymphadenopathy in children) (see Chapter 9).

Axillary Lymphadenopathy Infections causing unilateral axillary lymphadenopathy include local infectious processes of the arm and hand, hidradenitis suppurativa, cat-scratch disease, HIV, toxoplasmosis and tularemia, streptococcal and staphylococcal lymphadenitis and sleeping sickness. Postvaccinational lymphadenopathy was regularly seen following smallpox vaccination and occurs occasionally following anthrax vaccination. It is also seen post measles vaccination where characteristic Warthin– Finkeldey multinucleated giant cells are seen on biopsy. Bacille Calmette–Guérin (BCG) vaccination is also occasionally accompanied by an enlarged local lymph node from which M. bovis may be isolated. Asymptomatic unilateral axillary lymph node enlargement is suspicious of being of neoplastic etiology. Bilateral axillary lymph node enlargement can be practically caused by all etiologies: viral, bacterial, protozoal, neoplastic, allergic and noninfectious inflammatory diseases.

Thoracic Lymphadenopathy Major etiologies causing thoracic lymphadenopathy include neoplasia, tuberculosis, sarcoidosis, endemic mycosis and anthrax. In children, mediastinal lymphadenopathy, uni- or bilateral with or without visible lung X-ray findings, is characteristic for primary tuberculosis; malignant lymphoma, however, may also present in this manner. The

145

tuberculin test is usually positive in tuberculosis; however, if negative, it should be repeated in 14 days. If still negative a lymph node biopsy is indicated. Occasionally disseminated atypical mycobacterial infection (e.g. M. cheloni, M. avium complex) may also manifest as thoracic or generalized lymphadenopathy. In adults, unilateral mediastinal and hilar lymphadenopathy without any other symptoms or signs suggests a neoplastic etiology and a biopsy to confirm the diagnosis is required. An exception may be the patient with HIV, or a person who arrives from an area endemic for tuberculosis or endemic fungal infection (such as histoplasmosis and coccidioidomycosis). Bilateral hilar lymphadenopathy in the asymptomatic young adult is commonly caused by sarcoidosis. In patients who have parenchymal involvement in addition to the hilar lymphadenopathy, a search for tuberculosis needs to be undertaken with sputum investigations (smear and culture) and, if necessary, bronchoscopy. Bronchoscopy increases the yield for M. tuberculosis in sputum-negative patients by 50–75%. The presence of an ulcerating granuloma on bronchoscopy will augment the positive rate even further.

Abdominal Lymphadenopathy Infectious etiologies of abdominal lymphadenopathy are few and include mesenteric and intestinal tuberculosis, Yersinia enterocolitica infection, Whipple’s disease and intestinal anthrax; occasionally Crohn’s disease will be accompanied by enlarged mesenteric lymph nodes. More commonly enlarged abdominal lymph nodes are of neoplastic etiology. Occasionally abdominal lymph node enlargement can be seen during attacks of familial Mediterranean fever (FMF) and similar disorders, such as Muckle–Wells syndrome, chronic infantile neurologic cutaneous articular syndrome (CINCA/NOMID), tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) and hyperimmunoglobulinemia D with periodic fever syndrome (HIDS).55

Inguinal Lymphadenopathy Inguinal lymph node enlargement is very common in a variety of STDs, namely syphilis, chancroid, lymphogranuloma venereum, granuloma inguinale, genital herpes, pediculosis pubis and HIV. In Women unguinal node enlargement can be secondary to inflammation of the Bartholin or Skene glands of the labia. Other causes include cat-scratch disease, purulent infections of the upper and lower leg (streptococcal and staphylococcal), Kikuchi’s disease and toxoplasmosis. In endemic areas or in travelers or immigrants returning from endemic areas the differential diagnosis should include filariasis, Bancroftian filariasis, onchocerciasis and human plague. References available online at expertconsult.com.

KEY REFERENCES Brook I., Frazier E.H.: Microbiology of cervical lymphadenitis in adults. Acta Otolaryngol 1998; 118:443-446. Craven R.B., Barnes A.M.: Plague and tularemia. Infect Dis Clin North Am 1991; 5:165-175. Ellison E., Lapuerta P., Martin S.E.: Fine needle aspiration (FNA) in HIV+ patients: results from a series of 655 aspirates. Cytopathology 1998; 9:222-229. Jackson L.A., Perkins B.A., Wenger J.D.: Cat-scratch disease in the United States. Am J Public Health 1993; 83:17071711. Lederman M.M., Margolis L.: The lymph node in HIV pathogenesis. Semin Immunol 2008; 20:187-195. Melrose W.D.: Lymphatic filariasis: new insights into an old disease. Int J Parasitol 2002; 32:947-960.

Michelow P., Meyers T., Dubb M., et al.: The utility of fine needle aspiration in HIV positive children. Cytopathology 2008; 19:86-93. Montoya J.G., Liesenfeld O.: Toxoplasmosis. Lancet 2004; 363:1965-1976. Perine P.L., Osoba A.O.: Lymphogranuloma venereum. In: Holmes K.K., Mardth P.A., Sparling P.F., et al., eds. Sexually transmitted diseases, 2nd ed. New York: McGraw-Hill; 1990:195-204. Segal G.H., Perkins S.L., Kjeldsberg C.R.: Benign lymphadenopathies in children and adolescents. Semin Diagn Pathol 1995; 12:288-302. Sinclair S., Beckman E., Ellman L.: Biopsy of enlarged, superficial lymph nodes. JAMA 1974; 228:602-603.

Slap G.B., Brooks J.S., Schwartz J.S.: When to perform biopsies of enlarged peripheral lymph nodes in young patients. JAMA 1984; 252:1321-1326. Sousa Ade Q., Parise M.E., Pompeu M.M., et al.: Bubonic leishmaniasis: a common manifestation of Leishmania (Viannia) braziliensis infection in Ceara, Brazil. Am J Trop Med Hyg 1995; 53:380-385. Wolinsky E.: Mycobacterial lymphadenitis in children: a prospective study of 105 nontuberculous cases with longterm follow-up. Clin Infect Dis 1995; 20:954-963.

Chapter 15  Lymphadenopathy 145.e1

REFERENCES 1. Slap G.B., Brooks J.S., Schwartz J.S.: When to perform biopsies of enlarged peripheral lymph nodes in young patients. JAMA 1984; 252:1321-1326. 2. Sinclair S., Beckman E., Ellman L.: Biopsy of enlarged, superficial lymph nodes. JAMA 1974; 228:602-603. 3. Buchino J.J., Jones V.F.: Fine needle aspiration in the evaluation of children with lymphadenopathy. Arch Pediatr Adolesc Med 1994; 148:1327-1330. 4. Fijten G.H., Blijham G.H.: Unexplained lymphadenopathy in family practice. An evaluation of the probability of malignant causes and the effectiveness of physicians’ workup. J Fam Pract 1988; 27:373-376. 5. Yamauchi T., Ferrieri P., Anthony B.F.: The etiology of acute cervical adenitis in children. Serological and bacteriologic studies. J Med Microbiol 1980; 13:37-43. 6. Brook I., Frazier E.H.: Microbiology of cervical lymphadenitis in adults. Acta Otolaryngol 1998; 118:443-446. 7. Boyce J.M.: Severe streptococcal axillary lymphadenitis. N Engl J Med 1990; 323:655-658. 8. Janssen F., Zelinky-Gurung A., Caumes E., et al.: Group A streptococcal cellulitis–adenitis in a patient with AIDS. J Am Acad Dermatol 1991; 24:363-365. 9. Ho D.D., Murata G.H.: Streptococcal lymphadenitis in homosexual men with chronic lymphadenopathy. Am J Med 1984; 77:151-153. 10. Liese J.G., Jendrossek V., Jansson A., et al.: Chronic granulomatous disease in adults. Lancet 1996; 347:220223. 11. Mouy R., Fischer A., Vilmer E., et al.: Incidence, severity and prevention of infections in chronic granulomatous disease. J Pediatr 1989; 114:550-560. 12. Jackson L.A., Perkins B.A., Wenger J.D.: Cat-scratch disease in the United States. Am J Public Health 1993; 83:1707-1711. 13. Zangwill K.M., Hamilton D.H., Perkins B.A., et al.: Catscratch disease in Connecticut. Epidemiology, risk factors, and evaluation of a new diagnostic test. N Engl J Med 1993; 329:8-13. 14. Kordick D.L., Halyard E.J., Hadfield T.L., et al.: Bartonella clarridgeiae, a newly recognized zoonotic pathogen causing inoculation papules, fever and lymphadenopathy (cat scratch disease). J Clin Microbiol 1997; 35:18131818. 15. Wear D.J., Malatry R.H., Zimmerman L.E., et al.: Catscratch bacilli in the conjunctiva of patients with Parinaud’s oculoglandular syndrome. Ophthalmology 1985; 92:1282-1287. 16. Summers G.D., McNichol M.W.: Tuberculosis of superficial lymph nodes. Br J Dis Chest 1980; 74:369-373. 17. Bem C., Patil P.S., Bharucha H., et al.: Importance of human immunodeficiency virus-associated lymphadenopathy and tuberculous lymphadenitis in patients undergoing lymph node biopsy in Zambia. Br J Surg 1996; 83:75-78. 18. Wolinsky E.: Mycobacterial lymphadenitis in children: a prospective study of 105 nontuberculous cases with long-term follow-up. Clin Infect Dis 1995; 20:954-963.

19. Pai M., O’Brien R.: New diagnostics for latent and active tuberculosis: state of the art and future prospects. Semin Respir Crit Care Med 2008; 29:560-568. 20. Craven R.B., Barnes A.M.: Plague and tularemia. Infect Dis Clin North Am 1991; 5:165-175. 21. Dennis D.T., Inglesby T.V., Henderson D.A., et al.: Tularemia as a biological weapon: medical and public health management. JAMA 2001; 285:2763-2773. 22. Inglesby T.V., Dennis D.T., Henderson D.A., et al.: Plague as a biological weapon: medical and public health management. Working Group on Civilian Biodefense. JAMA 2000; 283:2281-2290. 23. Nigrovic L.E., Wingerter S.L.: Tularemia. Infect Dis Clin North Am 2008; 22:489-504. 24. Hammond G.W., Slutchuk M., Scatiff J., et al.: Epidemiologic, clinical, laboratory and therapeutic features of an urban outbreak of chancroid in North America. Rev Infect Dis 1980; 2:867-879. 25. Perine P.L., Osoba A.O.: Lymphogranuloma venereum. In: Holmes K.K., Mardth P.A., Sparling P.F., et al., eds. Sexually transmitted diseases, 2nd ed. New York: McGraw-Hill; 1990:195-204. 26. Chapel T.A.: The signs and symptoms of secondary syphilis. Sex Transm Dis 1980; 7:161. 27. Miliauskas J.R., Leong A.S.: Localized herpes simplex lymphadenitis. Report of three cases and review of the literature. Histopathology 1991; 19:355-360. 28. Mertz G.J.: Genital herpes simplex virus infection. Med Clin North Am 1990; 74:1433-1454. 29. Sehgal V.N., Shyam Prasad A.L.: Donovanosis. Current concepts. Int J Dermatol 1986; 25:8-16. 30. Montoya J.G., Liesenfeld O.: Toxoplasmosis. Lancet 2004; 363:1965-1976. 31. Montoya J.G., Remington J.S.: Studies on the serodiagnosis of toxoplasmic lymphadenitis. Clin Infect Dis 1995; 20:781-789. 32. Sousa Ade Q., Parise M.E., Pompeu M.M., et al.: Bubonic leishmaniasis: a common manifestation of Leishmania (Viannia) braziliensis infection in Ceara, Brazil. Am J Trop Med Hyg 1995; 53:380-385. 33. Gaafar A., Ismail A., el Kadaro A.Y., et al.: Necrotizing and suppurative lymphadenitis in Leishmania major infections. Trop Med Int Health 1996; 1:243-250. 34. Harms G., Fraga F., Batroff B., et al.: Cutaneous leishmaniasis associated with extensive lymphadenopathy during an epidemic in Ceará State, northeast Brazil. Acta Trop 2005; 93:303-310. 35. Barral A., Guerreiro J., Bomfim G., et al.: Lymphadenopathy as the first sign of human cutaneous infection by Leishmania braziliensis. Am J Trop Med Hyg 1995; 53:256-259. 36. Courtin F., Jamonneau V., Duvallet G., et al.: Sleeping sickness in West Africa (1906–2006): changes in spatial repartition and lessons from the past. Trop Med Int Health 2008; 13:334-344. 37. Maudlin I.: African trypanosomiasis. Ann Trop Med Parasitol 2006; 100:679-701.

38. Bonney K.M., Engman D.M.: Chagas heart disease pathogenesis: one mechanism or many? Curr Mol Med 2008; 8:510-518. 39. Molyneux D.H.: Control of human parasitic diseases: context and overview. Adv Parasitol 2006; 61:1-45. 40. Udall D.N.: Recent updates on onchocerciasis: diagnosis and treatment. Clin Infect Dis 2007; 44:53-60. 41. Melrose W.D.: Lymphatic filariasis: new insights into an old disease. Int J Parasitol 2002; 32:947-960. 42. Metroka C.E., Cunningham-Rundles S., Pollack M.S., et al.: Generalized lymphadenopathy in homosexual men. Ann Intern Med 1983; 99:585-591. 43. Lang W., Anderson R.E., Perkins H., et al.: Clinical, immunologic, and serologic findings in men at risk for acquired immunodeficiency syndrome. The San Francisco Men’s Health Study. JAMA 1987; 257:326-330. 44. Shobhana A., Guha S.K., Mitra K., et al.: People living with HIV infection/AIDS – a study on lymph node FNAC and CD4 count. Indian J Med Microbiol 2002; 20:99-101. 45. Apoola A., Sammena A., Radcliffe K.: Primary HIV infection. Int J STD AIDS 2002; 13:71-78. 46. Lederman M.M., Margolis L.: The lymph node in HIV pathogenesis. Semin Immunol 2008; 20:187-195. 47. Said J.W.: AIDS related lymphadenopathies. Semin Diagn Pathol 1988; 5:365-375. 48. Ellison E., Lapuerta P., Martin S.E.: Fine needle aspiration (FNA) in HIV+ patients: results from a series of 655 aspirates. Cytopathology 1998; 9:222-229. 49. Michelow P., Meyers T., Dubb M., et al.: The utility of fine needle aspiration in HIV positive children. Cytopathology 2008; 19:86-93. 50. Verdonck K., González E., Van Dooren S., et al.: Human T-lymphotropic virus 1: recent knowledge about an ancient infection. Lancet Infect Dis 2007; 7:266-281. 51. Lajo A., Borque C., Del Castillo F., et al.: Mononucleosis caused by Epstein–Barr virus and cytomegalovirus in children: a comparative study of 124 cases. Pediatr Infect Dis J 1994; 13:56-60. 52. Ebell M.H.: Epstein–Barr virus infectious mononucleosis. Am Fam Physician 2004; 70:1279-1287. 53. Segal G.H., Perkins S.L., Kjeldsberg C.R.: Benign lymphadenopathies in children and adolescents. Semin Diagn Pathol 1995; 12:288-302. 54. Perkins S.L., Segal G.H., Kjeldsberg C.R.: Work-up of lymphadenopathy in children. Semin Diagn Pathol 1995; 12:284-287. 55. Simon A., van der Meer J.W.: Pathogenesis of familial periodic fever syndromes or hereditary autoinflammatory syndromes. Am J Physiol Regul Integr Comp Physiol 2007; 292:R86-R98.