INFECTIONS

INFECTIONS

EPIDEMIOLOGY

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 limbs, are represented by: alterations of the skin barrier (ulcers, wounds, bedsores, dermatoses), which are complicated by infectious episodes in the lymphatic-lymphatic pathways in 23.8% of cases; interdigital cracks and maceration (athlete’s foot) in 61%; lymphedema, which is the most important risk factor (71.2%); venous insufficiency with peripheral edema, in 2.9%; and obesity, in 2% of cases.  No correlation with diabetes, alcoholism and smoking was observed.Among the specific chronic forms, tuberculous lymphadenitis is the most frequent extra-pulmonary manifestation of tuberculosis. Despite a significant decrease in incidence up to the 1970s, it has begun to increase in frequency in recent years. In 90% of cases, it has a cervical site, mostly in the cervical lymph nodes (80-95% of cases) and in the submandibular lymph nodes, followed by the supraclavicular and the nuchal nodes. Often the lymph node involvement is multiple and bilateral. The most affected ages are childhood and adolescence, but adult and advanced age is not excluded.

PATHOGENESIS

The most common etiologic agents of acute lymphangitis are streptococci (in particular for erysipelas, beta-hemolytic streptococcus group A), staphylococci, colibacilli, and pneumococci. Entranceways for these bacteria are represented by cutaneous wounds, superficial or deep infectious foci (e.g., boils, thrombophlebitis), by nail and peri-ungual fungal infections, interdigital or macerating lesions (athlete’s foot type), fungal infections of the external genitalia, and perianal fungal infections. The same pathogens can also cause chronically evolving clinical pictures (e.g., in the lower limbs when a chronic venous insufficiency is present, due to the presence of cutaneous trophic lesions). Deep chronic lymphangitis, often propagated from the superficial lymphatic network, aggravates lymphatic drainage and causes a worsening of peripheral edema. Lymphadenitis can result in the direct establishment of the pathogen in the lymph node, or it can be the effect of a distant action of the same agent located in a territory to which the lymph node is tributary. More frequently, lymphadenitis coming to the surgeon’s observation is an expression of primary foci of cutaneous or mucosal infection which, through the lymph, reach the lymph nodes. Therefore, lymphangitis is almost always associated with lymphadenitis but, not infrequently, lymphadenitis is present without lymphangitis. Hematogenous lymphadenitis is less common, most of which are seen in general, sepsis-related, infectious diseases. In this case, the lymph node involvement is widespread as an expression and manifestation of the septicemic process. Bacterial agents and toxins of various kinds give rise to lymph node reactions which, although lacking specific clinical and anatomo-pathological characteristics, are united by the general signs of inflammation. In whatever way that the inflammatory stimulus reaches the lymph node, it can respond very strongly (until nodal necrosis), or with reactive phenomena that are difficult to distinguish from those of normal or just enhanced functional activity.This marked variety in degree of the pathogenic mechanisms, and in the defense reaction, are observed both in an acute course of lymphadenitis, sometimes marked only by fleeting lymph node swelling, but sometimes rapidly evolving at an increasing rate, and also in chronic lymphadenitis.

 

ANATOMO-PATHOLOGICAL AND STAGING CLASSIFICATION

Lymphangitis (inflammation of the lymphatic pathways) is divided into acute and chronic forms.

Acute lymphangitis includes diffuse (reticular or erysipeloid) and truncular (involving a superficial lymphatic collector) forms. Form of lymphangitis are also sub-dividable into superficial and deep, depending on the involvement of the lymphatics above or below the fascia. Erysipelas is an acute bacterial infection of the dermis and hypodermis, associated with clinical signs of inflammation. Most often it affects the lower limbs and, in particular, the leg, but it can also affect the face and the upper limbs. Erysipelas is generally associated with lymphadenitis in correspondence with the lymphoglandular satellite stations. Truncular lymphangitis includes an erythematous type, which is a less severe form, but it can also evolve, especially in immunodepressed subjects, into more severe, suppurative and gangrenous forms, with the formation of real lymphangitic and peri-lymphangitic plaques that lead to infiltration and diffusion of phlegm and suppuration to the surrounding tissues, up to the formation of eschars. These forms can also move from the superficial to deep tissues (having a differential diagnosis with necrotizing fasciitis). Deep lymphangitis is rarer and also includes stages of severity, such as phlegmonous and asexual forms, which may represent the starting point of septicemia. Even in these cases, frequently, proximal lymph node inflammation is associated with the site of infection, then it affects the deep lymph node stations.

 

Chronic lymphangitis is divided into non-specific and specific forms. Nonspecific chronic lymphangitis is characterized by a thickening of the lymphatic wall, caused by hyperplasia of myoepithelial cells and by the progressive deposition of collagen and fibroblasts between the smooth muscle cells until the complete obliteration of the lymphatic collector and consequent development of peripheral lymphedema. In the initial lymphatics and in the pre-collectors, endothelial proliferation is observed, leading to the same result of vasal occlusion. Specific chronic lymphangitis includes tuberculous, syphilis, leprosy, fungal, and parasitic forms (filaria type). In particular for the tuberculous forms, the lymphatic vessels play an important role. The vessel walls are thickened and disseminated with tubercles and the lumen may also contain caseous material. Large numbers of bacilli can be disseminated in the lumen of the thoracic duct, leading to generalized miliary tuberculosis. Heartworm disease infestation is found in tropical climates (India, Brazil, China) and is most commonly caused by Wuchereria Bancrofti and Brugia Malayi. Lymphatic and lymph node damage occurs when the parasite dies and gets stuck in the lymphatic collectors, causing destruction of the valves and lesions to the vessel wall. Lymphadenitis can also be divided into acute and chronic forms and, in most cases, represents a satellite manifestation of the inflammatory-infectious process of the native site. Acute lymphadenitis includes the hyperemic-edematous (or hyperplastic) form and the purulent form. In hyperplastic lymphadenitis, the lymph nodes are swollen and have a soft consistency due to edema and hyperaemia, with the presence of enlarged macrophages in phagocytic activity and serous fluid containing lymphocytes, blood cells and granulocytes. Other frequent features in inflammatory states of the lymph nodes are histiocytosis of the sinuses and hyperplasia of the lymphatic follicles (follicular lymphadenitis). Purulent lymphadenitis is characterized by suppurative or suppurative-necrotic foci. Suppurative outbreaks, at first punctiform, can then flow together giving rise to abscesses that can involve the whole lymph node and also the capsule (periadenitis) and the surrounding tissues (phlegmonic, peri-glandular or adeno-phlegmonic). It can also form cutaneous fistulas or fistulas towards internal organs (bronchi, esophagus, peritoneum).

Nonspecific chronic lymphadenitis is characterized by proliferative and sclerotic phenomena. The lymph nodes are increased in volume and consistency and, in addition to histiocytosis of the sinuses, hypertrophy of the germinal centers of the follicles and proliferation of the reticular cells of the pulp, there is a thickening of the capsule, trabeculae and reticular mesh, with consequent reduction in the lymphocyte number. The lymphoglandular structure in advanced stages is subverted by a process of progressive sclerohyalinosis. Among the specific forms of chronic lymphadenitis, the tuberculosis form is further distinguished into a nodular epithelioid form (the lymph node appears sprinkled with grayish nodules, the typical tubercles, consisting mainly of giant epithelioid cells like Langhan cells) and in a caseous form (when the caseosis is massive, the lymph nodes, increased in volume and consistency, often appear grouped in large packs and have a white-yellowish and friable surface, seeming like cooked potato). The evolution of the lesions is represented mainly by the total or partial calcification of the caseous masses, which remain encapsulated by a capsular and pericapsular connective reaction. On the contrary, if the caseous substance undergoes a softening phenomena, associated with a process of caseous peri-adenitis, it is possible for it to be emptied outwards, or in a serous cavity in a bronchus, in the esophagus, etc., according to the glandular region concerned (tuberculous fistulae).

 

Other forms of specific chronic lymphadenitis include sarcoidosis, syphilis, toxoplasmosis, mononucleosis and lymphadenopathy associated to HIV. Sarcoidosis is characterized histologically by the presence of characteristic epithelioid granulomas (sarcoid nodules) in several locations. The most frequently affected organs are the lymph nodes (benign lymphogranuloma or Besnier-Boeck-Schaumann disease), lung, skin, eyes and bones. In syphilitic lymphadenitis, the lymph nodes may be affected by syphilitic infection in all three stages of the disease: conspicuous hyperplasia of lymphatic follicles, inflammatory changes of the parenchymal, hilar and capsular vessels, periadenitis and an increase in reticular fibers (pulp) and collagen (trabeculae and capsule). In toxoplasmosis, the lymph nodes (mostly cervico-nuchal) have increased volume and consistency, with conservation of the lymph node architecture and the presence of numerous micronodules of epithelioid histiocytes in the pulp and secondary follicles, hyperplasia of lymphatic follicles, immature histiocytosis of the sinuses, and plasmocytic hyperplasia. Mononucleosic lymphadenitis is characterized by moderately increased lymph node volume, with pulp hyperplasia, which is characteristized by heterogeneity of the cell population (lymphocytes, reticular cells, plasma cells, immunoblasts, etc.). In HIV, there are 4 evolutionary degrees of lymphadenopathy:

  1. Follicular hyperplasia,
  2. Vascular and follicular hyperplasia,
  3. Initial areas of lymphocyte depletion associated with marked follicular degeneration,
  4. Complete lymph node architectural subversion, with marked and diffuse follicular depletion, up to the total absence of follicles with the parenchyma consisting only of stromal cells and vessels.

 PHYSIOPATHOLOGY AND CLINICAL SIGNS

We recognize two forms of acute lymphangitis: the reticular or diffused (erysipeloid) and the truncular, depending on whether the vessels of the dermal network are involved or the lymphatic collectors are directly involved. The superficial lymphangitis (dermato-lymphangitis) is also distinguished from the deep form by the involvement of the subfascial lymphatic structures.

The erysipeloid reticular form manifests itself through the sudden appearance of pain and an erythematous, oedematous, hyperesthestic area, which is painful to compression and in progressive extension, with well-defined margins, generally associated with hyperpyrexia and, sometimes, with satellite lympatic adenitis (dermato-lymphangio-adenitis, DLA). In areas where the connective tissue is particularly loose, such as the eyelids, the foreskin, the labia majora, the edema can be very conspicuous.

Truncular lymphangitis is most commonly seen in the limbs, with high frequency in the forearm and arm. It is characterized by the appearance of one or more hyperemic reddish streaks, painful, rectilinear, parallel to the course of the veins but independent of them, radiating from the site of the infection (eg a cutaneous wound) to the proximal lymph nodes ( DLA) of the affected limb (axillary or inguinal). The typical hard cord of the superficial thrombophlebitis is not appreciable: that corresponds to an affected vein (lymphangitis is seen; phlebitis, instead, is palpated) and it can be associated to soft, peripheral edema, sometimes quite marked. General symptoms of infectious disease often coexist, both in the reticular and truncular form. Fever can be very high and take on an intermittent character, up to complications of a suppurative nature (adeno-phlegmon, abscesses along the course of the lymphangitis) and septicemia (septic shock).

 

Deep lymphangitis is the rarest of the aforementioned clinically primitive manifestations; it is a common association of septic thrombophlebitis, especially in the lower limbs. The clinical picture is characterized by pain, edema, local signs of inflammation, and general signs of infection. The evolution of the clinical picture can lead to the formation of bursitis, arthosinovitis and distant metastatic abscesses. In some cases, it may be associated with a consensual superficial lymphangitis (double lymphangitis). The lymph nodes are always affected and the stations involved initially are the deep ones.

Chronic aspecific lymphangitis is characterized by the progressive appearance of hard type of peripheral edema with the deposition, over a period of time, of a marked fibrosclerotic tissue component (up to so-called elephantiasis), due to the gradual obliteration of the lymphatic collector lumen due to chronic inflammatory phenomena. Among the forms of specific chronic lymphangitis, the tubercular one is characterized by the appearance of palpable nodules along the course of the lymphatic vessels and for the discharge of caseous material from ulcerated areas and sites of fistulization.

 

Regarding acute lymphadenitis, the clinical picture is characterized by pain, increased volume of one or more lymph nodes; pain when compressed, with the appearance of fever. The overlying skin may be normal (in hyperemic-edematous forms) or be hyperemic, warm, oedematous, and adherent to the underlying lymph node structures, sometimes with the appearance of fluctuation (sign of abscess formation), up to ulceration, resulting in purulent material (in the suppurative forms, like adenophlegmon or abscess), with associated septic fever. The muscles are often contracted due to irritation-type phenomena, with trismus occurring in the sub-maxillary adenophlegmons and psoas contracture in the iliac locations.

 

Nonspecific chronic lymphadenitis is characterized by an increase in the volume and in the consistency of one or more non-painful lymph nodes, with normal overlying skin (a mobile swelling on the superficial and deep surfaces). The clinical sign of lymph node mobility is particularly useful for the differential diagnosis with specific chronic forms (especially tuberculous) and primitive or metastatic neoplasms. The appearance of nonspecific lymphadenitis is a sign of the presence of a primary source of infection in the tributary area of ​​the affected lymph node(s) (pyoderma, eczema, dental granuloma, gingivitis, infection of the pharynx, anus, genitals, etc. ).

In a lymph node that is already affected by chronic infection, with swelling and hardening, episodes of inflammatory recurrence may occur, so the symptoms take an acute or subacute pattern, sometimes arriving at an abscess. Among the specific chronic lymphadenitis, tuberculosis is a reason of greater surgical interest. A more or less extensive grouping of lymph nodes is characteristic in the presence of a primitive and recent outbreak of infection, with precise anatomical correspondence between the penetration area of ​​Koch’s bacillus (skin or mucous membranes) and satellite lymphatic stations involved.

Tuberculosis can be a disease of the lymph nodes even in the absence of any other signs of tuberculosis in other organs and systems. One of the typical sites is represented by cervical lymph nodes (previously known as “scrofula” disease), which initially appear swollen, mobile and non-painful. When a process of periadenitis is established, by extension of the inflammation beyond the capsule, the lymph nodes become fixed to each other and to the surrounding tissues, determining the characteristic appearance of reddened skin, tendentially cyanotic, and particularly thin in some points: the final step is fistulization with leakage of caseous material.

 DIAGNOSIS

The clinical features of acute reticular or truncular lymphangitis are mostly sufficient to make accurate diagnosis. It is important, however, to evaluate the clinical parameters of severity of the infectious picture, which are represented by: local signs and symptoms (pain, vesicles, purpura, skin necrosis, extent of infection, face involvement), general signs and symptoms (fever, general conditions, confusional state, shock condition), age, associated diseases (diabetes, obesity, cardiovascular disease, alcoholism), and modality required for a therapy (oral medication, IM or need for IV therapy). It is also necessary to make a differential diagnosis with other pathologies such as bacterial infections with specific skin manifestations (staphylococcus, pasteurella, haemofilus influenzae), contact dermatitis, phlebitis and superficial thrombophlebitis, diffuse cellulitis or phlegmon, necrotizing fasciitis, rejection of prosthetic material, and compartment syndrome. In addition to the clinical features already described in the specific paragraph, eco-color-Doppler is particularly useful for excluding the presence or absence of superficial thrombophlebitis or deep vein thrombosis. Ultrasonography and CT scans provide information on the extent and depth of the infectious process and on the degree of involvement of the various tissues and organs affected; particularly in the case of deep lymphangitis, which presents considerable difficulties in differential diagnosis with phlegmon, osteomyelitis, etc.

 

Regarding chronic lymphangitis, lymphedema is determined by the progressive obliteration of the lymphatic vessel lumen, especially if it shows an evolution to elefantiasic type; in this case the diagnosis is mainly clinical, being a hard edema, scarcely pitting (negative fovea sign), with a positive Stemmer sign (inability to pinch the skin at the base of the 2nd toe). However, confirmation of the lymphatic nature of edema can be provided by lymphoscintigraphy, which allows a non-invasive analysis of the superficial and deep lymphatic drainage of the affected limb or limbs. In case of diagnostic doubts of tuberculous forms, it can be useful to perform a cutaneous biopsy examination in correspondence to a nodule along the course of the lymphatic hard cord, appreciable on the skin, or culture examination of the material that emerges from a fistula or from an ulcerated skin area.

 

In case of acute lymphadenitis, diagnosis is based mainly on the clinical features of the disease (v.). In the case of an inguinal-crural localization, differential diagnosis may be necessary, such as with a complicated crural hernia (non-reducible, incarcerated or strangulated), which is easily done by ultrasound examination. Even in cases of chronic lymphadenitis, the diagnosis is based on medical history, physical examination, and laboratory investigations. Significant advantages are provided by an ultrasound examination of the superficial lymph nodes. Modern ultrasound equipment, with high frequency probes, has a high spatial resolution in the order of 0.7 – 1.00 mm, allowing visualization of the normal superficial lymph nodes, to distinguish them from pathological ones, and to differentiate the different pathologies (on the basis of the form, structure, margins, diameters and vascularization of the nodes), also thanks to the use of ultrasound contrast agents (IV stabilized microbubbles injections). The superficial and deep whole body lymphoscintigraphy provides useful information on the lymph glandular sites affected by the lymphadenitis process and of any consequent peripheral lymph stasis.

 

In many cases, only a biopsy examination can resolve the diagnostic doubts, through needle biopsy or surgical exeresis of the lymph node. Percutaneous biopsy remains, therefore, an important technique for the study of superficial lymph nodes; however, the inability of US, CT and MRI to recognize small metastases in lymph nodes of normal volume requires a high number of biopsy samples. Surgical biopsy, especially if performed in “critical” sites such as the armpit or the groin, can lead to the appearance of precocious (lymphangitis, lymphorrhoea, suture dehiscence) or late (lymphedema) complications if not conducted according to minimally invasive criteria and on the basis of a careful prior clinical evaluation of the lymphatic circulation status of the affected limb or limbs. The goal of this examination is the detection of any signs of constitutional predisposition to manifest alterations in lymphatic circulation (in which case, it is advisable to perform a lymphoscintigraphy before the lymph node biopsy and to adopt specific preventive therapeutic strategies).

 

 THERAPY

The treatment of an acute picture of erysipeloid lymphangitis involves the use of an initial broad-spectrum antibiotic therapy and subsequently a targeted therapy based on an antibiogram. The most frequently used drugs are the combination of amoxicillin and clavulanic acid, macrolides, and cephalosporins. Prophylaxis of recurrent lymphangitis attacks is carried out with long-acting penicillin (benzylpenicillina benzatinica), dosage: 1,200,000 IU, every 15-21 days, up to 1-2 years, depending on the case.

Anticoagulants drugs are indicated in patients at risk for thrombotic and thromboembolic episodes (presence of varices, previous episodes of phlebitis, etc.).

The use of cortisones is useful in the acute phase, while the use of NSAIDs is not recommended, as it could cause the appearance of Steven-Johnson syndrome (acute hypersensitivity syndrome, characterized by erythema multiforme or polymorphic erythema) or Lyell’s syndrome (toxic epidermal necrolysis).

A valid therapeutic aid is a moderately compressive multi-layer medicated therapeutic bandage with antibiotic ointments (in particular gentamycin), plus or minus cortisone and zinc oxide (in paste or bandages).

Finally, it is important to treat the entrance sites of the infection through adequate hygiene, disinfection, accurate dressings and, if necessary, local and general antifungal applications, particularly between the toes of the feet.

The therapy of non-suppurative lymphadenitis is also based on the use of antibiotics both for the acute phase and for the prophylaxis. In forms with abscess (adenophlegmon) it is opportune to surgically drain the suppurative collection and to prepare a suitable medical lavage by washing the site with hydrogen peroxide and iodate solutions.

The specific forms of lymphangitis and lymphadenitis (tuberculosis, syphilis, etc.) require specific treatment according to the classical schemes of antibiotic chemotherapy, aimed at the treatment of the underlying pathology. In tuberculous forms, in order to prevent spontaneous fistulization, it is advisable to surgically drain the cold abscess and to wash with specific antibiotics (streptomycin, rifampicin). In the event that it is necessary (presence of very large lymph node packages), surgical removal must be carried out, paying particular attention to not spread the caseous material to the surrounding tissues, in order to promote, together with adequate antibiotic therapy, rapid healing and to prevent possible complications (lymphorrhea, lymphangitis, suture dehiscence).

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