Clinical REVIEW

Cutaneous in lymphoedema

Rose Cooper, Richard White

The typical diagnosis of in patients with lymphoedema includes and , but the true picture is more complex with the possibility of secondary complications such as lymphadenitis (adeno- ) and lymphangitis. The recent description of acute inflammatory episodes (or AIEs) has gone some way to explaining how a patient may be prone to rapid-onset febrile illness (Mortimer, 2000). This review summarises the current understanding of cutaneous infections and inflammatory presentations that are observed in lymphoedema and discusses associated immunological compromises.

major component of the lymphatic Secondary lymphoedema has diverse Key words system (especially in the axilla or groin) origins and develops in individuals who becomes obstructed and the drainage previously had a ‘normal’ lymphatic Lymphoedema of lymph is interrupted so that the system. Lymphatic filariasis (also known as Cellulitis fluid accumulates in tissue. There are elephantiasis) is an infection of the lymph Erysipelas multiple causes of obstruction such as nodes which is caused by nematode Acute inflammatory episodes tumour masses (either within lymphatic worms (most commonly Wuchereria vessels and tissue or in neighbouring bancrofti). It is transmitted to man when tissue), excess adipose tissue, surgical filarial larvae are introduced, mainly into removal of lymph nodes and associated lower limbs, by the bite of an infected vessels, the presence of fibrous scar mosquito and the infection becomes n 1999 the worldwide incidence of tissue (a result of chronic apparent about a year later. Some lymphoedema was estimated at 140 or radiation therapy), and infection with patients demonstrate more extensive Imillion per annum, with the perception parasitic worms. Prolonged lymphatic sequelae than others, ranging from few that it was a rare condition in Europe obstruction leads to continued dilation clinical signs to extensive inflammatory (Boccardo et al, 1999). It has since of lymphatic vessels and may result in responses. , rashes, eosinophilia, become clear that these estimates were increased deposition of fibrotic material lymphangitis and lymphadenitis can far too low and that lymphoedema and because lymph characteristically has a occur and repeated episodes can lead veno-lymphatic dysfunction are far more high protein content which is thought to to extensive fibrosis and blockage of common than expected (Moffatt et al, stimulate fibrogenesis. Hence, the patient lymphatic ducts, which results in gross 2003). Problems in accurately mapping presents with swollen limbs or trunk enlargement of limbs (Partano, 1987; Pani the epidemiology of this disease arise containing either excessive fluid and/or and Srividya, 1995). Usually the lower from difficulties in formulating a concise fibrotic material. limbs are most seriously affected. This definition, the varied nature of published type of lymphoedema is endemic in some epidemiological studies and the ambiguity Lymphoedema develops by tropical and subtropical areas. of the terminology that has been utilised several routes. It can be a congenital (Franks et al, 2006). condition that normally affects a Many forms of lymphoedema are single limb, although more extensive secondary to malignancies, particularly Lymphoedema is essentially a involvement is possible (Connell et following surgical removal of lymphatic condition in which tissue is distended al, 2008). This is commonly known as tissue and after radiotherapy. Between by the presence of lymph or interstitial primary lymphoedema and may not 25 and 33% patients who undergo fluid. It is a chronic and progressive be manifest immediately at birth. Either surgery for breast cancer are expected disease that usually develops when a a malformation or hypoplasia of the to develop lymphoedema in the arm can give rise to primary or trunk and the risk factors have been Rose Cooper is Professor of Microbiology, Cardiff School lymphoedema. It is a relatively uncommon identified (Franks et al, 2003). of Health Sciences, University of Wales Institute Cardiff disease, with prevalence in people under (UWIC); Richard White is Professor of Tissue Viability, 20 of age reported to be 1.15/100,000 Another causative factor in the University of Worcester (Smeltzer et al, 1985). development of lymphoedema is

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morbid obesity (Ryan, 2002). In occur (Figure 2). Lymphatic involvement is enlarged limbs with redundant skin usual, with lymphangitis and lymphadenitis folds and excess adipose tissue, possible. Often the patient is febrile components of the lymphatic system and may also exhibit malaise and . can become obstructed and this can In the past, erysipelas was known as St initiate lymphoedema or exacerbate Anthony’s fire. Treatment with existing secondary lymphoedema (intravenous for a severe infection, (Fife et al, 2008). Furthermore, the otherwise intramuscular or oral penicillin) inability of the morbidly obese to cope usually results in rapid resolution of with compression garments and their symptoms. Swelling may persist after the increasing immobility contributes to infection has resolved. increasing limb size and weight, with knock-on effects on lymphoedema and Cellulitis is an acute, diffuse, venous insufficiency (Fife et al, 2008). spreading, oedematous, suppurative Whether obesity and lymphoedema infection of deeper subcutaneous are genetically linked is not known. tissues and . It may sometimes involve muscle and be associated with Infections associated with lymphoedema formation. Cellulitis develops The skin is a natural barrier to infection more slowly than erysipelas, blistering that is known as the first line of defence. rarely occurs and the border of the Infections associated with the cutaneous affected area is not well defined. Again, Figure 1. Lymphoedema and acute cellulitis. layers are caused either by ingress of the patient may appear unwell and Reproduced by kind permission of Christine Moffatt. infectious agents through breaches describe an acute febrile episode in this mechanical barrier, or else before the development of the lesion The lymphatic system provides a delivered systemically in blood vessels. on the skin. Causative agents largely means of draining fluids, cells and foreign The human immune response depends responsible are pyogenes material from interstitial spaces. Hence on the two integrated protective and aureus, but other inflammatory cells and infectious agents mechanisms to the presence of agents , such as Gram negative , will be transported to regional lymph capable of causing infection: innate and can be implicated. Cellulitis often follows nodes from foci of infection associated acquired immunity. When these defence loss of skin integrity, with streptococcal with the skin. When infection involves mechanisms are overcome or evaded, infection associated with small breaks the lymphatic system, two outcomes are infection results. On the basis of their and with more possible. Lymphangitis is the inflammation location and presentation, infections and extensive skin damage (Grey, 1998). of lymphatic vessels where the channels inflammation in lymphoedema patients Treatment with penicillin is indicated, become dilated and distended by fluid, can be distinguished as erysipelas, unless S. aureus is confirmed, but a cellular debris and infective agents cellulitis (Figure 1), lymphangitis slower recovery will be seen compared moving away from an infected area. and lymphadenitis. The term ‘acute to erysipelas. Hospital admission for Lymphadenitis is the inflammation of inflammatory episode’ or AIE has been treatment is not unusual. Lymphoedema lymph nodes which become enlarged coined to describe a secondary acute patients are susceptible to repeated skin and painful with increasing numbers of inflammation which can be distinguished infections, yet the impact of these events infective agents. The progressive extension from chronic inflammation. The AIE is often underestimated. of painful red lines away from an infected has been considered separately from overt infection; however, a recent consensus document suggested that it was synonymous with cellulitis (British Lymphology Society [BLS], 2008).

Erysipelas is a well known infection of the superficial layers of the dermis that is caused by (a member of the beta haemolytic group A streptococci). It usually develops rapidly within 24 to 48 hours of bacterial invasion and it is mainly characterised by a peripherally spreading, hot, bright red, oedematous, infiltrated and sharply circumscribed plaque that has a raised border. Blistering of the affected area may Figure 2. Blistering as a result of erysipelas. Reproduced by kind permission of Val Robson.

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lesion towards enlarged and painful lymph entry (Dupuy et al, 1999). It was a multi- months after the onset of an episode of nodes characterises acute infection. Most centred study in which 167 patients that erysipelas in one leg and, of 33 patients virulent pathogens can cause this effect, were hospitalised for erysipelas of the leg with impaired lymphatic function in the but the beta haemolytic streptococci were compared to 294 controls. Using previously infected leg, 26 had impaired are commonly involved. Diagnosis multivariate analysis associations between lymphatic function in their uninfected always warrants immediate and vigorous local risk factors (history of leg surgery, leg. Therefore, it seems appropriate that intervention. radiotherapy, neurological disorders, leg patients presenting with a first episode , leg ulcers, pressure of erysipelas investigation for pre- Acute inflammatory episodes ulcers, leg oedema, lymphoedema, leg existing lymphatic dysfunction of both Recurrent febrile episodes were noted dermatosis, toe-web intertrigo, varicose legs be prioritised because the infection in lymphoedema patients in 1963 or varicosities) and general risk may signal the presence of underlying (Edwards, 1963). factors ( mellitus, obesity, smoking, lymphoedema (Damstra et al, 2008). sedentary occupation or alcohol misuse) These authors recommended that, More recently, AIEs have been were investigated. Seated position at work, ‘treatment of erysipelas should focus not recognised as attacks of apparent infection diabetes mellitus, alcohol misuse and only on the infection, but also on the that affect lymphoedema patients smoking were not found to be associated lymphological aspects, and long-standing (Mortimer, 2000). AIEs have also been with erysipelas of the leg. Lymphoedema treatment for lymphoedema is essential in called cellulitis, lymphangitis, episodic was shown to be the most prominent order to prevent recurrence of erysipelas dermatolymphangioadenitis, erysipelas and risk factor (present in 18% of patients), and aggravation of the pre-existing pseudo-erysipelas. They are characterised and the presence of an entry site (mainly lymphatic impairment’. by extremely rapid onset, so that within 30 fungal infections of toe webs) another minutes of the onset of flu-like symptoms important factor (Dupuy et al, 1999). A similar study in which patients the patient may be markedly unwell hospitalised with lower limb cellulitis were and be exhibiting a fever, and A prospective case-controlled investigated for lymphatic abnormalities delirium, together with a painful, swollen, study of risk factors for acute cellulitis by lymphoscintigraphy found a strong erythematous . These events identified strong risk factors to be association between abnormalities in develop so quickly in lymphoedema previous history of cellulitis, leg ulcer lymph drainage and lower limb cellulites patients that many carry with or saphenectomy, and the presence (Soo et al, 2008). Although this was a them at all times so that they can self- of possible sites of entry (dry skin, leg small study with only 30 patients, none medicate immediately. Unfortunately, AIEs lesions or intertrigo) (Björnsdóttir et had a prior diagnosis of lymphoedema, are not consistent in their characteristics. al, 2005). One hundred hospitalised yet 13/15 had abnormal scans and seven Sometimes pain without overt cellulitis cases were compared to 200 had clinical lymphoedema. inflammation can occur and in other cases control patients. Culture of toe web a low grade ‘grumbling’ condition continues specimens showed that the presence of Whether infected patients had for more lengthy periods until it is resolved dermatophyte infections was found to be previously unrecognised lymphatic by antibiotics. Typically, AIEs are recurrent more common in cellulitis patients, and abnormalities that increased their and length between episodes varies from a that S. aureus, ß-haemolytic streptococci susceptibility to erysipelas and cellulitis few weeks to more than a year (Mortimer, and Gram negative bacilli were isolated may be difficult to determine, because 2000). In lymphoedema, AIEs can be from toe webs. This suggests a likely the infections may cause lymphatic distinguished from classical erysipelas or entry point for the causative agents of damage that precipitates secondary cellulitis by the absence of a spreading, cellulitis, since dermatophyte infections lymphoedema (Keeley, 2008). Either way, erythematous margin. tend to cause cracks and fissures that early diagnosis provides the opportunity disrupt the integrity of skin between toes to prevent recurring infections that Predisposing factors for erysipelas, cellulitis (Björnsdóttir et al, 2005). aggravate lymphatic damage. The use of and AIEs compression garments after an episode Risk factors for episodes of recurring A recent study investigated the of erysipelas has been advocated infection in lymphoedema patients are link between erysipelas and lymphatic (Damstra et al, 2008), and larger studies numerous. Minor skin injuries, nematode impairment by examining patients are indicated (Soo et al, 2008). infection and skin diseases, such as fungal with erysipelas of unknown origin for infections have been implicated. Venous pre-existing lymphatic insufficiency Management of erysipelas, cellulitis and AIEs insufficiency, obesity, diabetes, immuno- in their unaffected limb (Damstra et The diagnosis and treatment of cellulitis suppression, respiratory infections and al, 2008). None of the 40 subjects have been outlined in guidelines such have also been identified as included in this prospective study had as those of CREST (Clinical Resource important risk factors. clinical signs of lymphoedema or any of Efficiency Support Team) in 2005 the predisposing comorbidities listed (available online at: www.gain-ni.org/ The first case-controlled study of above as risk factors for erysipelas or Guidelines/Management_Cellulitis_Adults. risk factors for erysipelas of the leg cellulitis. Both legs of each patient were asp). Recently, the British Lymphology emphasised lymphoedema and site of examined by lymphoscintigraphy four society (BLS) has also issued guidelines

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for assessment and management of by obstruction is likely to have a knock- cellulitis (available online at: www.thebls. on effect to immune competency. For com/concensus.php?bls_user=d7be61a7e example, an investigation into cutaneous

9bef06638316907afd02364). cell-mediated immunity in 35 women Key points with post-mastectomy lymphoedema The speed and severity of skin confirmed this assumption (Mallon et al, 8 Infections such as cellulitis and infections in lymphoedema patients 1997). Thirty-five patients were randomly erysipelas can develop very demand rapid antibiotic intervention, divided into two groups to test their quickly in lymphoedema. often on an empirical basis. The long- afferent sensitisation, and the function of term use of prophylactic strategies to the efferent loop of the allergic contact 8 The acute inflammatory reduce the number and severity of response using exposure episode is a frequent infections in lymphoedema patients was to dinitrochlorobenzene (DNCB). characteristic in lymphoedema: recommended for patients suffering Abnormal responses to the sensitising clinicians and patients should more than two episodes of cellulites agent demonstrated that suppressed be informed and alert to it and within 12 months (BLS, 2007). A review immune competence was found in the prepared to treat immediately. of the clinical evidence for the efficacy of lymphoedematous limb compared to antibiotics and anti-inflammatory agents the unaffected limb (Mallon et al, 1997). 8 In the presence of demonstrated inadequacies (Badger The likely mechanism is the impaired lymphoedema, antigen et al, 2009). Only four randomised migration of dendritic (Langerhans) presentation, particularly of controlled studies were included: two cells to the draining lymph nodes via pathogens, is abnormal. studied the effects of physical treatment lymphatic vessels, and the resultant sub- and selenium or a placebo in preventing optimal encounter with naive T-cells AIEs and two concerned ivermectin and (Randolph et al, 2005; Swartz et al, 2008). inflammation to lymphatic deterioration diethylcarbamazine (anti-parasite drugs) However, the underlying mechanisms for are beginning to be understood. The and penicillin to prevent lymphadenitis. the loss of immunocompetency are not need to prevent and manage these No treatments were shown to give fully understood and further research is events effectively is evident but not statistically significant reductions in AIEs in needed. universally realised. JL the limbs of lymphoedema patients and the need of further clinical evidence was Both chronic and acute skin identified (Badger et al, 2009). The skin inflammation have been linked closely References hygiene of patients with enlarged limbs is with lymphatic function (Jurisic Alitalo K, Tammela T, Petrova T (2005). an area of concern in preventing infection. and Detmar, 2009). The role of Lymphangiogenesis in development and Foot care was found to be important in lymphangiogenesis in inflammation seen human disease. Nature 438(7070): 946–53 preventing recurrent infections, especially in lymphoedema is not clear. Chemokines Badger C, Seers K, Preston N, Mortimer P if combined with penicillin and this finding such as nuclear factor kappa B (NF- (2009) Antibiotics/anti-inflammatories for was suggested to have relevance to the κB) and tumour factor alpha reducing acute inflammatory episodes in care of arms in breast cancer patients (TNF-α) may be important contributors lymphoedema of the limbs. Cochrane Database (Badger et al, 2009). (Ji, 2007). This may be an important Syst Rev 2009: (1): CD003143 factor in the development of AIEs where Björnsdóttir S, Gottfredsson M, Thórisdóttir A, The role of the lymphatic system in vascular endothelial growth factor (VEGF) et al (2005) Risk factors for acute cellulitis of the lower limb: a prospective case-controlled defence mechanisms receptor tyrosine kinase inhibitor has study. CID 41: 1416–22 The lymphatic system is actively involved been found to be an effective treatment in many physiological and pathological (Halin et al, 2008). Using an animal model Boccardo F, Michekini S, Zili A, Campisi C (1999) Epidemiology of . processes, including cancer metastasis of lymphoedema, Tabibiazar et al (2006) Phlebolymphology 26: 25–9 and inflammation (Alitalo et al, 2005). It have demonstrated that impaired mobility British Lymphology Society (2007) Consensus plays an important role in removing fluid of immunocompetent cells leads to Document on the Management of Cellulitis that contains complex macromolecules intense inflammatory changes. However, in Lymphoedema. Available online at: www. from the spaces between cells in tissues these results need to be translated into lymphoedema.org/lsn/consensus_on_ (tissue homeostasis) and in delivering the situation in humans. cellulitis_dec_06.pdf (last accessed on 31 July, vital components of the immune 2008) response to allergenic substances; in Conclusion Connell F, Brice G, Mortimer P (2008) particular, the mediation of the afferent This review illustrates the difficulties Phenotypic characterization of primary immune response via recruitment associated with the management of lymphoedema. Ann N Y Acad Sci 1131: 140–6 of antigen-presenting cells (typically cutaneous infections in lymphoedema, Damstra RJ, van Steensel MAM, Boomsma JHB, Langerhans cells) towards the lymph and, in our understanding of AIEs. Our Nelemans P, Veraart JCJM (2008) Erysipelas as a sin of subclinical primary lymphoedema: a nodes (Halin and Detmar, 2006; Jurisic knowledge of the complex risk factors prospective quantitative scintigraphic study of and Detmar, 2009). Interruption of is increasing, and the contribution of 40 patients with universal erysipelas of the leg. normal function or dysfunction caused the repeated infections and acute Br J Dermatol 158: 1210–15

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PROMOTING PROFESSIONAL LYMPHOEDEMA SERVICES BLS Lymphoedema Awareness Week 20 April 2009 signals the start of the British Lymphology Society’s Lymphoedema Awareness Week – the week in the year which will draw attention to the 120,000 men women and children in the UK and Ireland who suffer from Lymphoedema. Lymphoedema causes swelling of the limbs and body and remains an underestimated and largely misunderstood health problem – many health care practitioners have problems with its diagnosis and treatment. BLS are publishing the “5 Guides”; one for GPs and one for patients, which have been drawn up in consultation with partners in the Lymphoedema Support Network and Macmillan. The Guides will each flag the five key things the target audience need to know about Lymphoedema and will be backed by a dedicated website – www.blsawarenessweek.co.uk The Guides will be launched at the prestigious International Lymphoedema Conference being hosted by WoundsUK at Ascot Racecourse on 21/22/23 April. For further information contact [email protected]

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