Generalised Lymphadenopathy

Generalised lymphadenopathy can be defined as enlargement of more than two noncontiguous lymph node groups.
Lymph nodes are part of the immune system that serves to defend the body against antigens entering lymph fluid via the skin, respiratory and gastrointestinal tract. Each lymph node consists of a fibrous capsule, enclosing a sinus stuffed with macrophages. The macrophages remove 99% of antigens delivered in this way.
Most generalised lymphadenopathy is due to benign self-limited disease, such as viral or bacterial infection, but it can be caused by a wide range of conditions (see Differential diagnosis, below).

The precise incidence of generalised lymphadenopathy is not known, and there are few studies relating to primary care, where most cases are seen.¹ Studies in the US estimate the incidence of palpable adenopathy in childhood to be between 37-54%.² Lymphadenopathy is one of the most common clinical problems encountered in paediatrics.
One Dutch study in primary care revealed a 0.6% annual unexplained incidence of lymphadenopathy in the general population. In Europe, the increased prevalence of tuberculosis and HIV³ is leading to a growing number of patients presenting with generalised lymphadenopathy from these causes.⁴

History

All GPs will be familiar with the patient, who is often a child or adolescent, presenting with generalised lymph node enlargement. Most of these cases will be due to self-limiting infection, but serious underlying causes must be quickly identified. A history should include the duration of the lymphadenopathy, whether any other household members are acutely ill, and whether there are any accompanying symptoms. Persistent fever, night sweats ,general malaise or weight loss may be pointers to significant disease. Bearing in mind the extensive list of differential diagnoses, it is important to keep the patient under review if spontaneous recovery does not occur. Presenting symptoms of more indolent diseases (e.g. tuberculosis, malignancy) may occur some time after the development of the initial lymphadenopathy.
In adolescents, a sexual history and history of intravenous drug use should be elicited.²

Examination

Most children have palpable lymph nodes whose relative size could qualify for lymphadenopathy in an adult. These are most prominent in the anterior cervical, inguinal and axillary regions and continue to increase in size until the age of 8-12, after which atrophy occurs. For proper assessment of generalised lymphadenopathy it is necessary to familiarise oneself with what is normal at a particular age. Bilateral anterior cervical lymph nodes up to 2 cm in diameter often are found in older healthy children or in those experiencing or recently recovering from an upper respiratory tract infection. Axillary nodes up to 1 cm and inguinal nodes up to 1.5 cm in diameter are also usually normal. A 1.5cm inguinal or a 2cm anterior cervical node, for example, would be considered normal in a 7 year old child, but would warrant further investigation in a 2 month old infant.²
Supraclavicular nodes of any size at any age warrant further investigation as they can be associated with malignancy in the chest and abdomen.⁵ Epitrochlear nodes (just above the elbow crease) can signify Hodgkin's Disease.⁶
Erythema, warmth, tenderness and fluctuance of a node suggests lymphadenitis of infective origin. Nodes that are firm, non-tender and matted together increase the possibility of malignancy.²
Measure the temperature to exclude pyrexia, and check for any local sources of infection including scalp, skin, ears, nose, pharynx and chest. Perform a systematic examination to exclude signs of obvious malignancy, and especially the abdomen to exclude hepatomegaly or splenomegaly.⁷

Generalised lymphadenopathy may be caused by a wide range of conditions, as follows:²
Viral

• Common upper respiratory infections
• Infectious mononucleosis, CMV
• Rubella, varicella, measles
• HIV
• Hepatitis A and B
• Roseola infantum (HHV6)
• Dengue fever
• Adenovirus

• Septicemia
• Typhoid fever
• Tuberculosis
• Syphilis
• Plague
• Lyme Disease
• Tularemia
• Brucellosis

• Toxoplasmosis, Leishmaniasis, Chagas' disease
• African Trypanosomiasis (Sleeping Sickness)

• e.g. Coccidioidomycosis

• Juvenile rheumatoid arthritis
• Systemic lupus erythematosus
• Drug reactions (eg, phenytoin, allopurinol, primidone)
• Serum sickness

• Gaucher disease
• Niemann-Pick disease

• Acute leukemias
• Lymphomas (Hodgkin, non-Hodgkin)
• Neuroblastoma
• Histiocytoses

In the vast majority of cases, once the history and physical examination are completed the clinician will be able to determine that the condition is self-limiting and requires no further investigation. However, in the event of a worrying history or suspicious findings, the following investigations may be indicated:

Laboratory investigations

• Full blood count and white cell differential. An erythrocyte sedimentation rate is nonspecific but may be of help
• Liver and renal function tests
• Urine analysis

If systemic infection is suspected, titres for CMV, Epstein-Barr virus, Toxoplasma, B.henselae (Cat scratch disease) and HIV, and skin testing for tuberculosis may be indicated, depending on prevalence.
If malignancy is suspected, lactate dehydrogenase (if high suggests increase turnover of cells in leukaemia or lymphoma⁸), uric acid,⁹ calcium, and phosphate, may be indicated.

Imaging²

• Chest X-ray may detect mediastinal adenopathy or pulmonary disease such as tuberculosis, lymphomas, coccidioidomycosis, neuroblastoma, histiocytoses, and Gaucher disease.
• Computerised tomography or chest and abdomen may be indicated, particularly if supraclavicular adenopathy is present.¹⁰
• Ultrasonography may be helpful in evaluating the extent of lymph node involvement in patients with lymphadenopathy and may be more sensitive than CT scanning in some instances.^2,10
• Newer imaging modalities such as 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) and magnetic resonance lymphography¹¹ are increasingly being used in the diagnosis and monitoring of lymphomas and other conditions involving generalised lymphadenopathies.¹²

Other tests

The decision to proceeding to more invasive tests should not be taken lightly, particularly where a child is involved, and should only be considered at first presentation if supraclavicular nodes are present, the nodes are large and generalised, or the history or examination are strongly suggestive of malignancy. Indications for further investigation include systemic symptoms despite normal laboratory findings and imaging, documented increase in lymph node size, and failure to respond to treatment for presumed infection.² Such investigations might include:

• Fine Needle Aspiration (FNA) - this can be performed in the outpatient department, has low morbidity, is cost effective, produces minimal scarring and does not require a general anaesthetic. It has been extensively used in adults, and is now being use in children.¹³ The sensitivity and specificity of FNA biopsy in determining the aetiology of lymphadenopathy is more than 90%.¹³
• Core Needle Biopsy - this uses a wider needle and can obtain more tissue. Guidance with ultrasound or CT is sometimes used as a refinement.¹⁴
• Excision biopsy - this has the advantage over needle biopsy in that sufficient tissue is obtained for oncology studies where malignancy is suspected.¹⁵ Inadequate specimen size, improper handling or preparation, and a poor choice of node sampling can affect results. Inguinal nodes should not be sampled in this way because their architecture frequently is distorted by chronic inflammatory changes.²

The most important aspect of management is the recognition and exclusion of serious disease, which can often mimic trivial self-limiting conditions in the early stages. Patients and parents should be advised to seek further advice if lymph node enlargement does not resolve, new enlargements develop, old symptoms persist or new ones appear.
Treatment depends on the causative agent and may include the following:

• Expectant management - e.g. viral infections, most cases of cat-scratch disease.
• Antimicrobial therapy - In the case of bacterial infection, the most likely culprits include Staphylococcus and Streptococcus species; therefore, a beta-lactamase resistant antibiotic is chosen.¹⁵ In patients with tuberculosis,follow local guidelines.
• Chemotherapy
• Radiotherapy
• Surgical Care: Apart from the diagnostic procedures outlines above, lymphadenitis may require aspiration or incision and drainage of large suppurative nodes to relieve discomfort, as well as obtaining aspirate for culture.
• Depending on the suspected underlying condition, referral to a paediatric infectious disease specialist, a surgeon, a haematologist or an oncologist may be required.

Complications depend to a large extent on the underlying aetiology. Two complications which may develop independent of the individual pathology are:
Superior vena cava syndrome - insidious compression of the superior vena cava (SVC) from mediastinal lymphadenopathy, presenting with cough, wheezing and respiratory tract obstruction.
Abdominal lymphadenopathy presenting with abdominal or back pain, urinary frequency and constipation. Intussusception can lead to intestinal obstruction and can be life threatening.²

This depends almost entirely on the underlying aetiology. However, the onset of complications such as abdominal lymphadenopathy or superior vena cava syndrome can alter the prognosis independent of the primary disease process.¹⁶