DEVELOPMENT, DIAGNOSIS AND TREATMENT OF INFECTIONS
The incidence of infections of the lymphatic vessels and lymph nodes (lymphangio-adenitis) varies depending on predisposing conditions. Risk factors, in particular for the lower extremities, are: skin barrier dysfunctions (ulcers, wounds, bedsores, dermatosis, which may be complicated by infections of lymphatic-lymph nodes in 23.8% of cases); Athlete’s foot (tinea pedis) in 61%; lymphedema, which is the most important risk factor (71.2%); venous insufficiency with peripheral edemas, in 2.9%; and obesity, in 2% of cases, while no correlation has been observed with diabetes, alcoholism, and cigarette smoking. Among specific chronic diseases, tubercular lymphadenitis is the most common extra-pulmonary picture of tuberculosis. While its incidence has significantly decreased in the ’70s, its frequency has recently increased again. In 90% of cases, it has a cervical involvement, mostly affecting cervical (80-95% of cases) and submandibular lymph nodes, followed by supraclavicular and nuchal regions. Multiple and bilateral lymph node involvement is common. Children and teenagers are the most frequently affected age group, but also adults and older people may be affected.
The most common aetiological agents of acute lymphangitis are streptococci (in particular, erysipelas, group A beta-hemolytic streptococcus), staphylococci, coli, and pneumococci. Skin wounds, surface or deep infection foci (e.g. pimples, thrombophlebitis), nail and periungual mycoses, athlete’s foot, external genitalia, and perianal mycoses may provide easy access for germs. The same pathogens can also trigger clinical pictures with chronic evolution (for example in the lower limbs, when associated with chronic venous insufficiency, due to trophic skin lesions). Deep chronic lymphangitis, which are often spread by the superficial lymphatic network, affect lymphatic drainage and worsen peripheral edema.
Lymphadenitis may either follow a direct pathogen settlement in the lymph node, or result out of a distant action of the same pathogen, that has settled in a tributary territory of the lymph node. More commonly, lymphangitis seen by surgeons are expressions of primary cutaneous or mucous infection foci, which, through the passage of the lymph fluid, reach the lymph nodes. Therefore, lymphangitis is almost always associated with lymphadenitis but, also frequently, lymphadenitis may be present without lymphangitis. Haematogenous lymphadenitis, mostly observed during generalized septicaemic infections, are less common. In this case, lymph node involvement is generalized, as a septicaemic process expression. Bacterial agents and toxins of various natures cause lymph node reactions, all of which, while lacking any specific clinical and pathologic anatomy features, show generic signs of inflammation. No matter how the inflammation stimulus reaches the lymph node, the latter may react either in a very intense way (even causing lymph node necrosis), or with reaction processes that are difficult to distinguish from standard or slightly altered functional activity.
These different degrees of pathogenetic mechanisms and defense reactions can be seen in acute lymphadeniteis, which, at times, are characterized only by transient lymph node swelling, but may also rapidly evolve into both abscesses and chronic lymphadenitis.
Pathologic anatomy classification and staging
Lymphangitis (inflammation of lymphatic pathways) is classified into acute and chronic.
Acute lymphangitis includes diffuse (reticular or erysipeloid) and troncular (involving a superficial lymphatic collector) forms. Further, lymphangitis can be grouped into surface and deep lymphangitis, depending on whether the supra or sub-fascial lymphatics are involved. Erysipelas is an acute bacterial infection of the derma and hypoderma associated with clinical signs of inflammation. Most commonly, it affects the lower extremities, but it may also involve the face and the upper extremities. It is generally associated with lymphadenitis in the satellite lymph nodes. Truncular lymphangitis involves a less severe erythematous form, but, especially in immunodepressed patients, it may evolve into more severe – suppurative and gangrenous – forms, with development of a lymphangitic and perilymphangitic plaques, due to infiltration and diffusion of the suppurative phlegmon into the surrounding tissue, as well as development of phlyctena and scabs, that may also become quite deep. In these cases, considering a differential diagnosis with necrotizing fascitis is recommended. Deep lymphangitis is rare and it also features different stages of severity, from the erythematous to the phlegmonous an asexual form, which may well be the starting point of septicaemia. Also in these cases, the lymph nodes proximal to the infection, starting from deep lymph nodes, are involved.
Chronic lymphangitis is classified into aspecific and specific. In chronic aspecific lymphangitis, the lymphatic vessel wall becomes thicker, due to hyperplasia of myoepithelial cells and progressive deposition of collagen and fibroblasts between smooth-muscle cells, until complete obliteration of the lymphatic collector and subsequent peripheral lymphedema. In the initial lymphatics and pre-collectors, endothelial proliferation can be observed, which also leads to vessel occlusion. Chronic specific lymphangitis include tubercular, luetic, leprous lymphangitis, and those related to fungi and parasites (such as filaria). In particular, for tubercular forms, lymphatic vessels play a key role. Vessel walls are thicker and disseminated with tubercles, while caseous material may be found inside the vessel lumen. Bulky bacillar loads may be disseminated in the lumen of the thoracic duct, with likely subsequent generalized miliary tuberculosis. Filaria infestation is found in tropical countries (India, Brazil, China). It is most commonly caused by Wuchereria bancrofti and Brugia malati. Lymphatic vessels and lymph nodes are damaged when the parasite dies and accumulates in lymphatic collectors, thus destroying the valves and damaging the vessel walls.
Lymphadenitis are classified into acute and chronic and, in the majority of cases, they make up a satellite picture of the inflammation-infection process in the primary site. Acute lymphadenitis comprises hyperemic-edematous (or hyperplastic), and purulent forms. In hyperplastic lymphadenitis, lymph nodes are swollen and soft due to edema and hyperemia, with numerous macrophages engaged in phagocytic activity inside dilated marginal sinuses and serous fluid-containing lymphocytes, erythrocytes, and granulocytes. Other common features of lymph nodes under inflammative conditions are sinus histiocytosis and lymphatic follicle hyperplasia (follicular lymphadenitis). Purulent lymphadenitis features suppurative or suppurative-necrotic foci. Later on, suppurative, initially punctiform foci, are likely to pool together, resulting in abscesses that may involve the entire lymph node and even the capsule (periadenitis), and surrounding tissues (periglandular phlegmon or adenophlegmon). Also, fistulas can develop in the skin or in more internal organs (bronchi, esophagus, peritoneum).
Chronic aspecific lymphadenitis feature proliferative and sclerotic processes. Lymph nodes increase in volume and thickness. In addition to sinus histiocytosis, hypertrophy of follicle germinative centers, and proliferation of pulp reticular cells, the capsule, trabeculae, and the reticular mesh become thicker, with subsequent reduction in the number of lymphocytes. In the most advanced stages, the lymph node structure is replaced through progressive scleroialinosis. Specific chronic lymphangitis include a tubercular form, which is grouped into an epithelioid nodular (lymph nodes are covered with small grayish nodules – so called tubercles -, mostly made of epithelioid Langhans-type giant cells) and a caseous form, where the mass is caseous, and the lymph nodes, increased in both volume and thickness, are often clustered together in big packages, with a white-yellowish surface, and a soft texture like cooked potatoes. Most lesions evolve into total or partial calcification of the caseous masses, which become encapsulated by capsular and pericapsular connective tissue. Conversely, if the caseous matter is softened through a process of caseous periadenitis, it may drain out, either forming a serous cavity, or leak into a bronchus, the esophagus, etc., depending on the glandular district involved (tubercular fistulas).
Other forms of specific chronic lymphadenitis are sarcoidosic, luetic, toxoplasmosic, mononucleosic, and AIDS lymphadenopathy. Epithelioid granulomas (sarcoid nodules) in several sites are a typical histological feature of sarcoidosis. The most frequently affected organs are lymph nodes (benign lymphogranuloma or Besnier-Boeck-Schaumann disease), lungs, skin, eyes, and bones. In luetic lymphadenitis, lymph nodes may be involved by the syphilitic infection in all three stages of the disease: conspicuous hyperplasia of lymphatic follicles, inflammative impairment of parenchymal, hilar, and capsular vessels, periadenitis with increased reticular fibers (pulp) and collagen (trabeculae and capsule). In toxoplasmosis, lymph nodes (mostly cervical-nuchal) increase in volume and thickness, while maintaining the lymph node architecture with numerous micronodules of epithelioid histiocytes in the pulp and in secondary follicles, hyperplasia of lymphatic follicles, immature sinus histiocytosis, and plasmocytic hyperplasia. Mononucleosic lymphadenitis is characterized by moderately larger lymph nodes, pulp hyperplasia, with a peculiar cell pattern and heterogeneity of cell population (lymphocytes, reticular cells, plasmacells, immunoblasts, etc.). In AIDS, 4 four different evolution stages of lymphadenopathy can be observed:
- Follicular hyperplasia,
- Vascular and follicular hyperplasia,
- Areas of initial lymphocytic depletion, associated with marked follicular degeneration,
- Total disruption of lymph node architecture, with marked and diffuse follicular depletion, until total disappearance of follicles and parenchyma, consisting of stromal cells and vessels only.
Physiopathology and clinical aspects
Acute lymphangitis include a reticular or diffuse (erysipeloid) a troncular form, depending on whether dermal network vessels or lymphatic collectors directly are involved. Further, lymphangitis can by grouped into superficial (dermato-lymphangitis) and deeplymphangitis, involving sub-fascial lymphatics. The erysipeloid reticular form presents with sudden pain and an erythematous, edematous area, hyperaesthesia, and tenderness. This area extends progressively, with well-defined margins. It is generally associated with hyperpyrexia and, sometimes, with satellite lymphangio-adenitis (dermato-lymphangio-adenitis, DLA). In those areas with a particularly loose connective tissue – such as eyelids, foreskin, and labia majora – a very conspicuous edema may be observed. Troncular lymphangitis is most commonly observed in the extremities, and it is particularly frequent in the arm and forearm. It features one or more reddish, hyperaemic striae that are tender and painful, straight, parallel to the course of veins and yet discreet, running from the infection access point (for example, a skin wound) to proximal lymph nodes (DLA) of the affected limb (axillary or inguinal). No hard cord typical of superficial thrombophlebitis along the affected vein can be observed: lymphangitis is visible, while phlebitis is palpable. Sometimes, severe, soft and peripheral edema can be associated with it. In both the reticular and the truncular forms, general symptoms of infectious disease are also present. Fever may be very high and intermittent, with even suppurative complications (adenophlegmona, abscesses along the lymphangitis pathway) and septicemia (septic shock). Deep lymphangitis, although more uncommon than the previous ones as a primary clinical disease, is commonly observed in association with septic thrombophlebitis, especially of the lower extremities. The clinical picture features pain, edema, local signs of inflammation, as well as general signs of infection. This clinical picture may evolve into bursitis, arthrosynovitis, and distant metastatic abscesses. In some cases, a concurrent superficial lymphangitis (double lymphangitis) can be observed. Lymph nodes are always affected AND the deep lymph nodes are initially involved. Also, in deep lymphangitis, the development of phlegmona and abscesses can be the starting point of a septicemic process.
Chronic aspecific lymphangitis is characterized by the progressive onset of peripheral, hard edema, with progressive deposition of a fibrosclerotic tissue component (until development of so called elephantiasis), caused by a gradual obliteration of the lumen of lymphatic collectors attacked by chronic inflammation processes. Among the forms of specific chronic lymphangitis, the tubercular form is characterized by the development of palpable nodules along lymphatic vessel pathways and by the leak of caseous matter from ulcerated areas and the sites of fistulas.
With regard to acute lymphadenitis, the clinical picture features pain, increased volume of one or more lymph nodes, tenderness, and fever. The skin above the affected site can be normal (in hyperaemic-edematous forms) or hyperaemic, hot, edematous, adherent to underlying lymph node structures, sometimes with fluctuation (which is a sign of abscess development), until it becomes ulcerated, leaking purulent matter (in suppurative forms, such as adeno-phlegmon or abscess), and with septic fever. Muscles too are often contracted due to an irritative processes, with lockjaw in sub-maxillary adeno-phlegmon, and psoas contracture when the disease involves the iliac region.
Aspecific chronic lymphadenitis is characterized by increased volume and thickness of one or more lymph nodes, which are not tender, with normal skin above (mobile swelling along surface and deep planes). Lymph node mobility is a particularly useful clinical sign for differential diagnosis from chronic specific forms (especially tubercular ones), and primary and metastatic tumors. The onset of aspecific lymphadenitis draws the attention to the presence of a primary infection focus in the lymph node tributary area or in the affected lymph nodes (pyoderma, eczema, tooth granuloma, gingivitis, infection of the pharynx, anus, genitalia, etc.). In a lymph node, which is already the site of chronic infection, and is hard and swollen, episodes of inflammation recrudescence may occur, hence symptoms become acute or subacute, and sometimes abscesses can develop. Among chronic specific lymphadenitis, the tubercular form is the most interesting from a surgical point of view. A more or less extensive involvement of the lymph nodes is a typical feature, in the presence of a primary and recent focus of infection, with anatomic correspondence between the area where the Koch’s bacillus has penetrated (either the skin or the mucosae) and satellite lymphatic stations. Tuberculosis may affect lymph nodes even when no other signs of tuberculosis are present in any other organs or systems. Cervical lymph nodes are a typical site. In this disease – which, in the past, was called “scrofula” – lymph nodes are initially swollen, mobile, but not tender. When periadenitis develops, caused by inflammation extending beyond the capsule, lymph nodes become attached to each other and to the surrounding tissues, thus causing the typical look of a flushed skin, mostly cyanotic and particularly thin, in some points, until fistula formation and leak of caseous matter.
The clinical features of acute reticular or troncular lymphangitis are generally sufficient to make an accurate diagnosis. However, it is important to properly evaluate the clinical parameters of infection severity, namely: local signs and symptoms (pain, vesicles, purpura, cutaneous necrosis, infection extent, involvement of the face), general signs and symptoms (fever, general conditions, haze, shock), age, associated diseases (diabetes, obesity, cardiovascular diseases, alcoholism), required therapyadministration (oral drugs, i.m., or intravenous). It is also necessary to make a differential diagnosis with other bacterial infections with specific cutaneous manifestation (staphylococcus, pasteurella, haemofilus influenzae), contact dermatitis, phlebitis, superficial thrombophlebitis, diffusive cellulite or phlegmona, necrotizing fascitis, foreign body rejection, and compartment syndrome. In addition to the clinical picture already described in the relevant paragraph (see above), color-Doppler ultrasound is particularly useful to rule out any superficial thrombophlebitis or deep venous thrombosis. Ultrasounds or CT scan provide information on the extent and depth of infection and on the actual involvement of the various affected tissues and organs, in particular in case of deep lymphangitis, for which differential diagnosis from phlegmona, osteomyelitis, etc. is quite difficult. With regard to chronic lymphangitis, a more or less severe picture of lymphedema could be caused by the progressive obliteration of the lymphatic vessel lumen, in particular when it is evolving into elephantiasis: in this case, the diagnosis is mainly clinical, since we can observe a hard edema, negative pitting, positive Stemmer sign (thickened skin fold at the base of the second toe which cannot be lifted). However, lymphoscintigraphy can help confirm the lymphostatic nature of the edema: with this imaging technique, superficial and deep lymphatic drainage of the affected limb/s can be investigated in a non-invasive way. In tubercular forms, in case of diagnostic doubts, either a skin biopsy at the level of a nodule along the hard lymphatic cord palpable through the skin, or a cultural test of the leak from a fistula or a skin ulcer are recommended.
Diagnosis of acute lymphadenitis is also mostly based on the clinical picture of the disease (see). When it is located in the inguinal-crural region, a differential diagnosis with complicated (non reducible, incarcerated, or strangulated) crural hernia might be necessary, which is easily performed with ultrasound. Also, chronic lymphadenitis is to be diagnosed based on information about the patient’s medical history, objective examination, and lab tests. Ultrasound examinationof superficial lymph nodes offers great advantages. Modern ultrasound equipment, with high frequency probes, offers a high spatial – 0.7 to 1.00 mm – resolution, allowing the visualization of healthy superficial lymph nodes, distinguishing them from sick ones, and differentiating between the various diseases (according to their shape, structure, margins, diameter, and vascularization), also thanks to the use of contrast ultrasound techniques (stabilized microbubbles administered by i.v. injection). Superficial or deep whole body lymphoscintigraphygives useful information about lymph node sites affected by lymphoadenitis and the degree of subsequent peripheral lymph stasis. However, most often, biopsy alone – with a needle-biopsy or surgical lymph node resection – can clear any diagnostic doubts. Therefore, percutaneous biopsy is still an important technique to study superficial lymph nodes. However, since small metastases in normal volume lymph nodes cannot be detected with US, CT and MR imaging techniques, a high number of biopsies are often necessary. Surgical biopsies, in particular, if performed in “critical” sites such as armpits and groins, may lead to early (lymphangitis, lymphorrhoea, suture dehiscence) or late (lymphedema) complications, unless they are performed to meet the criteria of minimal invasiveness and based on a careful clinical evaluation of the lymphatic circulation of the affected limb/s, in order to detect any signs of a natural predisposition to developing lymphatic circulation dysfunctions. In these cases, before any lymph node biopsy, a lymphoscintigraphy is recommended, and some specific therapeutic strategies to prevent lymphedema should be adopted – see Lymphedema Prevention.
To treat acute erysipeloid lymphangitis, an antibiotic therapy is recommended, initially with broad-spectrum antibiotics, and later with targeted antibiograms. A combination of Amoxicillin and Clavulanic Acid, Macrolides, and Cephalosporins are the most commonly employed drugs. For prophylaxis of recurrent lymphangitis, slow-release penicillin is used (Benzatinic Benzylpenicillin), 1,200,000 UI dosage, every 15-21 days, also for 1-2 years, depending on the case.
Anticoagulants are recommended for patients with a high risk of thrombosis and thromboembolic events (namely patients with varices, previous history of phlebitis, etc.).
Cortisone is also useful during the acute phase; conversely, NSAIDs are not recommended, because they could trigger a Steven-Johnson syndrome (acute hypersensitivity syndrome, characterized by erythema multiforme or erythema polymorphous), or Lyell’s syndrome (toxic epidermal necrolysis).
Further, modestly compressive, multilayer, functional bandaging medicated with antibiotic (in particular Gentamicin) ointment, in combination with, or not, cortisone and zinc oxide (either ointment or bandages) is also a good adjuvant therapy.
Finally, a proper treatment of infection accesses is key, through careful hygiene, disinfection, accurate medication and, if necessary, local and general antimycotic drugs.
Therapy of non-suppurative lymphadenitis is also based on the administration of antibiotics during both the acute phase and for prophylaxis. In asexual forms (adenophleghmon), any suppurative collection must be surgically removed, followed by appropriate medication with hydrogen peroxide and iodated solutions.
A specific treatment is required for specific lymphangitis and lymphadenitis (tubercular, luetic, etc.), according to the classic protocols of antibiotic chemotherapy, aimed at the underlying disease. In tubercular forms, in order to prevent spontaneous fistula formation, the cold abscess must be surgically drained, followed by specific antibiotic lavages (with streptomycin, riphampycin). Should a surgical resection be necessary (in case of very bulky lymph nodes), it must be carefully performed to avoid any leak of caseous fluid into the surrounding tissues, thus promoting a quick healing, while preventing likely complications (lymphorrhoea, lymphangitis, suture dehiscence).