Chemokine receptors of T cells and of B cells in lymphatic filarial infection: a role for CCR9 in pathogenesis

We examined the expression of chemokine receptors on the surfaces of T cells and B cells from 27 individuals either with lymphatic filarial disease (lymphedema), with the asymptomatic or subclinical form of filarial infection, or without filarial infection. Individuals with lymphedema exhibited increased percentages of CCR9-expressing T cells and CCR9-expressing B cells and decreased percentages of both CXCR1-and-CXCR3-expressing T cells and CXCR1-and-CXCR3-expressing B cells, compared with asymptomatic or uninfected individuals. A significant correlation was found between the grade of lymphedema and the percentage of CCR9-expressing T cells and CCR9-expressing B cells. The percentages of CCR9-expressing T cells and CCR9-expressing B cells from patients with lymphedema was significantly up-regulated in response to live, infective-stage larvae of Brugia malayi but not to microfilariae of this parasite. Finally, individuals with lymphedema had significantly higher concentrations of interleukin-8, macrophage inflammatory protein (MIP)-1alpha , MIP-1beta , monocyte chemotactic protein 1, thymus-and-activation-regulated chemokine, and interferon-inducible protein 10 in their serum than did uninfected individuals. These results suggest that chemokine receptors (particularly CCR9) are involved in the pathogenesis of lymphatic filarial disease and that trafficking of particular cellular subsets may influence clinical outcome.     

The relationship between the drainage function of inguinal lymph nodes and unilateral pelvic cancer-related lymphedema: A retrospective analysis

The aim of this study was to investigate the relationship between iliolumbar lymph nodes (LNs), inguinal LNs, and unilateral pelvic cancer-related lymphedema by retrospective analysis of lymphoscintigraphy data.Ninety-six patients (3 men and 93 women; mean age, 53.3 ± 11.3 years) with pelvic cancer-related lymphedema were enrolled in this retrospective study. Lymphoscintigraphy was performed at 1 hour and 4 to 6 hours after injection. The visualization of inguinal LNs and iliolumbar LNs were recorded.According to statistical analysis, the display of inguinal LNs in lymphoscintigraphy has a significant negative correlation with ipsilateral lower limb lymphedema (P < .01, r = –0.561). However, there is no correlation between the show of iliolumbar LNs and ipsilateral lower extremity lymphedema (P = .056, r = –0.138). When lymphoscintigraphy was performed at 1 hour after injection, there were 13 out of 96 patients without inguinal LNs revealed on imaging, but at 4 to 6 hours after injection, inguinal LNs were seen in lymphoscintigraphy.The drainage function of inguinal LNs has a significant negative correlation with ipsilateral pelvic cancer-related lymphedema. Treatment dedicated to restoring the drainage function of LNs in the inguinal region may effectively relieve lymphedema. The image acquisition at 4 to 6 hours after injection is necessary for significant additional information.     

Preliminary evaluation of a new,more simplified physiotherapy technique for lymphatic drainage

The aim of the present study was to evaluate a new, more simplified physiotherapy technique for management of peripheral lymphedema. Fifteen patients (11 female, 4 male) with ages varying from 22 to 63 years (average 54 years) were included in this study. All presented with stage I or II lower limb lymphedema confirmed by lymphoscintigraphy. Each patient underwent a newly designed modified manual lymph drainage technique regularly performed five times a week, one hour per session after one month. The new technique consisted of utilizing sticks, rollers or other cylindrical, flexible, and malleable material which served as a lymph promoting drainage device. All patients demonstrated a highly significant uniform reduction in girth of the leg affected by lymphedema (circumference reduction 2 to 4 cm; average 2.4 cm). After treatment, repeat lymphoscintigraphy suggested a generalized improvement in the scintiscans compared with the initial patterns. This new manual lymph drainage technique efficiently reduces peripheral lymphedema and is less cumbersome and time consuming than standard combined ("decongestive") physiotherapy methods.     

Lymphedema in China--experiences and prospects

The history of prevention and treatment of lymphedema in China is long. Filarial lymphedema was the most common type of the disease in the past with 5 million patients countrywide in the 1950's. Great efforts have gone into controlling filariasis during the past 50 years, and China now has essentially eliminated filariasis. In contrast to the reduction in filarial lymphedema, there has been a trend of increase in secondary lymphedema cases after malignant tumor surgery. Although there are no precise figures on the incidence of lymphedema nationwide, physicians and therapists are in great clinical demand. Traditional Chinese medicine has shown effectiveness for prevention and treatment of inflammation and alleviating swelling. The combination with Western medicine may offer improved methods for lymphedema treatment.     

Limb lymphedema as a first manifestation of primary intestinal lymphangiectasia (Waldmann's disease)

Primary intestinal lymphangiectasia (Waldmann's disease) is characterized by protein-losing enteropathy occurring more frequently in childhood. Chronic diarrhea and diffuse edema are the main clinical manifestations. Peripheral lymphedema may also be associated. Lymphedema is usually present at the time of diagnosis or appears later in the course of the disease. We report the observation of a 31-year-old man suffering from an upper, lower limb and genital lymphedema many years before diagnosis of primary intestinal lymphangiectasia was established. Lower limb lymphoscintigraphy confirmed lymphedema and duodenal biopsies lymphangiectasia. Hypoproteinemia, lymphopenia and hypogammaglobulinemia were also noted. Treatment of lymphedema included low stretch bandaging and elastic stocking. No dietary management with a low-fat diet was added. Search for primary intestinal lymphangiectasia with biological parameters would be useful when primary lymphedema is present. Especially since primary intestinal lymphangiectasia may be complicated by occurrence of B cell lymphoma.     

Reactivity to bacterial,fungal, and parasite antigens in patients with lymphedema and elephantiasis

Both secondary infections and antifilarial immunity are thought to play roles in the development and progression of lymphedema. To investigate this issue, immune responses to a panel of bacterial, fungal, and parasite antigens were examined for women with lymphedema and elephantiasis (n = 28) and for women with no clinical evidence of lymphatic dysfunction who were either microfilaremic (Mf+, n = 23) or microfilaria- and filarial antigen-negative (Ag-, n = 24). The prevalence and intensity of delayed-type hypersensitivity (DTH) responses was similar for most recall antigens; for individual antigens, lymphedema patients were significantly more likely to be reactive only to Proteus. Lymphedema patients with a history of three or more attacks of adenolymphangitis in the last 18 months showed increased DTH reactivity to Trichophyton. Proliferative responses to fungal and bacterial antigens were similar for all three groups; however, antigen-negative women, independent of disease status, mounted greater responses to filarial antigen. In contrast, lymphedema patients had higher levels of antifilarial specific IgG1, IgG2, and IgG3 and higher IgG responses to streptolysin O than either Ag- or Mf+ women. In persons with lymphatic filariasis, immune reactivity is influenced by disease status as well as infection status.     

Contribution of lymphoscintigraphy in the exploration of lymphedema in children

OBJECTIVES: The objectives of this work were a) to assess the feasibility of lymphoscintigraphy in very young children, and b) to assess its usefulness in understanding the underlying pathophysiology. PATIENTS AND METHODS: Forty-one children (age range 3 months-16 years) with primary lymphedema of the lower and/or upper limbs underwent lymphosinctigraphy using 99mTC-labeled colloid (Nanocis or Nanocol) injected subcutaneous at the foot and/or hand level. Recording time, which depended on the child's age, included at least static images during the thirty minutes following injection and four hours later. RESULTS: Abnormal activity of the lymph collectors, nodes, and interstitial space were analyzed according to age (> or < 2 years). Abnormal findings were classed as simple hypoplasia (n=18) or other type of lymph disease: diffuse lymphatic dysplasia (n=6), mixed vascular dysmorphism (n=5), amniotic bride disease (n=1), and hypoplasia revealed by occurrence of a minor factor (n=11). These observations demonstrate the role of lymphoscintigraphy in the diagnosis and prognostic evaluation of lymphedema in children. CONCLUSION: Lymphoscintigraphy is a useful technique for very young children with lymphedema providing further information contributing to overall exploration.     

Health workers' agreement in clinical description of filarial lymphedema

Severity of lymphedema and presence of entry lesions are risk factors for acute bacterial dermatolym-phangioadenitis (ADLA) in those with filarial lymphedema. Recurrent ADLA causes acute morbidity and progression of lymphedema severity; however, there is little work assessing the ability of health workers to reliably stage disease severity and identify risk entry lesions. This knowledge is important in initiation of management and assessing interventions. We evaluated inter-rater reliability with two independent health workers rating both legs of 17 patients using a questionnaire and the Dreyer classification of lymphedema. The health workers could reliably stage lymphedema with high agreement (RMAC weighted kappa of 0.89) and identify nail, interdigital, and other skin lesions. However, there was less consistency in identifying the clinical nature of skin lesions. This indicates that the Dreyer classification can be a replicable way to stage lymphedema and a questionnaire can deliver high observer agreement on the presence of risk lesions.     

Detection of serum IgG antibodies specific for Wolbachia surface protein in rhesus monkeys infected with Brugia malayi.

The mechanism of lymphedema development in individuals with lymphatic filariasis is presently poorly understood. To investigate whether Wolbachia, symbiotic bacteria living within filarial nematodes, may be involved in disease progression, Wolbachia-specific immune responses were assayed in a group of Brugia malayi-infected rhesus monkeys. Serum IgG antibodies specific for a major Wolbachia surface protein (WSP) were detected in 2 of 12 infected monkeys. It is interesting that both of these monkeys developed lymphedema after becoming amicrofilaremic. WSP-specific antibody responses were temporally associated with increases in antifilarial IgG1 antibodies as well as lymphedema development. These findings suggest that Wolbachia may be important in understanding disease caused by filarial worms.     

High resolution unenhanced computed tomography in patients with swollen legs

PURPOSE: To evaluate the accuracy of computed tomography (CT) scan imaging in distinguishing lymphedema from deep venous thrombosis (DVT) and lipodystrophy (lipedema) in patients with swollen legs. MATERIAL AND METHODS: CT scans of the lower limbs were performed in 55 patients with 76 swollen legs (44 lymphedemas, 12 DVT and 20 lipedemas). Thirty-four normal contralateral legs were also similarly evaluated. Primary lymphedema was verified by lymphography or lymphoscintigraphy, whereas secondary lymphedema was documented by a typical clinical history. DVT was established by ultrasound Doppler imaging. The diagnosis of lipedema was made with bilateral swollen legs where lymphoscintigraphy and Doppler examination were both unremarkable. Qualitative CT analysis was based on skin thickening, subcutaneous edema accumulation with a honeycombed pattern, and muscle compartment enlargement. RESULTS: Sensitivity and specificity of CT scan for the diagnosis of lymphedema was 93 and 100%, respectively; for lipedema it was 95 and 100%, respectively; andfor DVT it was 91 and 99%, respectively. Skin thickening was found in 42 lymphedemas (95%), in 9 DVT (75%), and in 2 lipedemas (16%). Subcutaneous edema accumulation was demonstrated in 42 legs (95%) with lymphedema and in 5 (42%) with DVT but in none with lipedema. A honeycombed pattern was present only in lymphedema (18 legs or 41%); muscle enlargement was present in all patients with DVT, in no patient with lipedema, and in 4 (9%) with lymphedema. CONCLUSION: Edema accumulation is readily demonstrated with plain CT scan and is not present in lipedema. Specific CT features of the subcutaneous fat and muscle compartments allow accurate differentiation between lymphedema and DVT.     

Transient lower extremity lymphedema following COVID-19 vaccination: A case report

Rationale:Complications from COVID-19 vaccines have yet to be sufficiently analyzed because they are rapidly approved without long-term data. In particular, there are no case reports of lymphedema in a healthy patient following vaccination. Herein, we report a patient who underwent transient lymphedema after vaccination with BNT16b2.Patient concerns:A 79-year-old woman with pitting edema in both lower legs after administration of a second dose of Pfizer vaccine was referred to our clinic. In the absence of clinical evidence of swelling during the laboratory evaluation, we suspected deep vein thrombosis. However, ultrasonographic findings revealed no evidence of venous thrombosis or varicose veins.Diagnosis:On the basis of lymphoscintigraphy, the patient was diagnosed with transient lymphedema with decreased lymphatic transport in both lower extremities.Intervention:The patient received intensive physiotherapy, including complex decongestive physiotherapy and pneumatic pump compression, to improve the lymphatic circulation. Furthermore, the patient was trained to apply a multilayer compressive bandage to the lower extremities.Outcomes:At 2 months follow-up after rehabilitative treatment, the patient''s symptoms improved without recurring lymphedema.Lessons:In the absence of clinical evidence of swelling during laboratory evaluation or ultrasonographic investigations suggesting deep vein thrombosis, we should consider the possibility of lymphatic disorders.     

Les lymphœdèmes : du diagnostic au traitement

Lymphedema results from impaired lymphatic transport with increased limb volume. Lymphedema are divided in primary and secondary forms. Upper-limb lymphedema secondary to breast cancer treatment is the most frequent in France. Primary lymphedema is sporadic, rarely familial or associated with complex malformative or genetic disorders. Diagnosis of lymphedema is mainly clinical and lymphoscintigraphy is useful in primary form to assess precisely the lymphatic function of the two limbs. Erysipelas (cellulitis) is the main complication, but psychological or functional discomfort may occur throughout the course of lymphedema. Lipedema is the main differential diagnosis, defined as an abnormal accumulation of fat from hip to ankle. Lymphedema management is based on complete decongestive physiotherapy (multilayer low-stretch bandage, manual lymph drainage, skin care, exercises). The first phase of treatment leads to a reduction of lymphedema volume and the second phase stabilizes the volume. Multilayer low-stretch bandage and elastic compression is the cornerstone of the complete decongestive physiotherapy. Patient-education programs, including self-management, aim to improve patient autonomy.     

A family study of lymphedema of the leg in a lymphatic filariasis-endemic area

The risk of filarial lymphedema may not be equivalent for all members of filaria-exposed populations. While evidence for a genetic factor that influences acquisition of infection has been growing, very little work has addressed whether there is a genetic basis to the development of disease due to lymphatic filariasis. We designed a family study of lymphedema in a rural community in Haiti to assess disease aggregation. Three hundred sixty-eight female patients sixteen years of age or older were enrolled at a lymphedema treatment clinic between June 1995 and December 1999. After applying additional eligibility criteria, 172 probands were enrolled into the family study for detailed pedigree collection between September 1998 and December 1999. Fifty-three lymphedema cases were identified among the probands' parents, full-siblings, children, half-siblings, and mating partners of the parents. Twelve of the 53 cases were among males. The proportion of cases occurring in a biologic parent of the proband was higher than in unrelated individuals married into the proband's family (P = 0.0010). This is the first large family study based on pedigrees to assess the familial aggregation of lymphedema due to filariasis. This family study will be useful to investigate the role of genes and environment in the development of filarial-related lymphedema.     

Comparative analysis of lymphoscintigraphy between lipedema and lower limb lymphedema

Lipedema is characterized by bilateral enlargement of the legs due to abnormal deposition of fat tissue from pelvis to ankles. It is seen most frequently in obese women. Lipedema appears to be a distinct clinical entity but may be confounded with lymphedema. AIM OF THE STUDY: To analyze and to compare between lipedema and lymphedema the qualitative and quantitative aspects of lymphoscintigraphy. METHODS: Fifteen women with lipedema were recruited. Mean age of onset of lipedema was 31.5 +/- 15 years. Body mass index was 35.1 +/- 7.9 kg/m2, 13 women were obese. Lipedema was compared to 15 cases of primary lymphedema (women: 13, men: 2) of the lower limbs (unilateral: 13, bilateral: 2), with a mean age at onset of 28.7 +/- 12.6 years. Lymphoscintigraphy of the lower limbs with morphologic (visualization of inguinal lymph nodes) and kinetic (half-life, lymphatic speed of the colloid) studies was performed in all cases. RESULTS: Absence of visualization of inguinal lymph nodes was observed in 14/15 cases of lymphedema and in 1/15 cases of lipedema (p<0.001). In the 13 cases of unilateral lymphedema, colloid half-life was higher in the pathologic limb than in the controlateral limb (230 +/- 92 vs 121 +/- 36 minutes, p<0.01) and lymphatic speed of the colloid was slower (6.91 +/- 0.86 vs 8.16 +/- 1.02 cm/min, p<0.001). The two patients with bilateral lymphedema had an increased half-life and decreased lymphatic speed of the colloid. Colloid half-life was significantly higher in lipedema than in controlateral limbs of lymphedema (154 +/- 23 vs 121 +/- 36 minutes, p<0.01) with no difference in lymphatic speed of the colloid. Colloid half-life was significantly higher in lymphedema than in lipedema (230 +/- 92 vs 154 +/- 23 minutes, p<0.01) and the lymphatic speed of the colloid was slower (6.91 +/- 0.86 vs 8.10 +/- 0.45 cm/min, p<0.001). CONCLUSION: Lower limb lymphoscintigraphy showed lymphatic insufficiency in lipedema without morphologic abnormality as seen in lymphedema. Lymphoscintigraphy is not indispensable but is a useful tool when diagnosis is doubtful. Treatment is difficult and may include weight loss and possible surgery.     

Lymphedema in a 7-year-old boy infected with Wuchereria bancrofti in Sierra Leone: A case report

We present a case of congenital lymphedema in a 7-year-old boy in Sierra Leone with active filarial infection and penile edema. The genital edema with onset at 6 months of age may have been due to a congenital abnormality in lymphatic drainage. Other possible causes of childhood lymphedema, including Milroy's disease, are discussed.     

The lymphovenous microsurgical shunts for treatment of lymphedema of lower limbs: indications in 2011

The microsurgical lympho-venous shunts have become one of the generally accepted modalities in treatment of limb lymphedema. This review highlight the indications for this procedure after over 40 years. This study was based on the personal experience of one surgeon and on the review of the literature. Patients with postinflammatory, postsurgical, idiopathic and hyperplastic lymphedema of lower limbs were included in the study. Basing on the review of results of the last 40 years the contemporary indications are: 1) lymphedema with local segmental obstruction but still partly patent distal lymphatics seen on functional lymphoscintigraphy (standard walking or pneumatic compression) and without an active inflammatory process in the skin, subcutaneous tissue and lymph vessels (DLA-dermatolymphangioadenitis); 2) classified according the etiology of lymphedema, this operation can bring about satisfactory results in cases of hyperplastic, postsurgical and postinflammatory types of lymphedema, whereas primary idiopathic lymphedema of non-genetic type should be treated with conservative means, although in a small number of cases an improvement was observed after lympho-venous shunting as long as 10 years. Microsurgical lymph node or lymphatic vessel to vein shunts have their established position among the therapy modalities for lymphedema of lower limbs in a strictly defined group of patients using lymphoscintigraphic imaging.     

Lymphatic Filariasis: Perspectives on Lymphatic Remodeling and Contractile Dysfunction in Filarial Disease Pathogenesis

Lymphatic filariasis, one of the most debilitating diseases associated with the lymphatic system, affects over a hundred million people worldwide and manifests itself in a variety of severe clinical pathologies. The filarial parasites specifically target the lymphatics and impair lymph flow, which is critical for the normal functions of the lymphatic system in maintenance of body fluid balance and physiological interstitial fluid transport. The resultant contractile dysfunction of the lymphatics causes fluid accumulation and lymphedema, one of the major pathologies associated with filarial infection. In this review, we take a closer look at the contractile mechanisms of the lymphatics, its altered functions, and remodeling during an inflammatory state and how it relates to the severe pathogenesis underlying a filarial infection. We further elaborate on the complex host–parasite interactions, and molecular mechanisms contributing to the disease pathogenesis. The overall emphasis is on elucidating some of the emerging concepts and new directions that aim to harness the process of lymphangiogenesis or enhance contractility in a dysfunctional lymphatics, thereby restoring the fluid imbalance and mitigating the pathological conditions of lymphatic filariasis.     

Relationship between lymphoscintigraphy and clinical findings in lower limb lymphedema (LO): toward a comprehensive staging

Although radionuclide lymphoscintigraphy (RNL) is widely used diagnostically for patients with lymphedema (LE), it has not been utilized for LE staging, which is still based upon clinical findings. The aim of this work is to establish whether the results of both conventional RNL and fusion imaging obtained from hybrid detectors may be used for a comprehensive clinicoimaging staging in LE. Radiolabeled nanocolloids (0.2 ml) were subcutaneously injected in 4,328 patients (23-78 years) with clinical lower limb LE and without venous disease. Patients were classified according to the ISL classification and had a minimal follow-up of 2 years. Images were taken 60 minutes after the injection as a whole body scanning and fusion images of functional SPET and anatomical CT. Clinical and RNL results were not in accordance, and a specific RNL staging was established. The association of clinical and functional staging yields a new method to grade LE patients, and this staging correlated with treatment efficacy. RNL is an important tool in lymphology, and its association with the clinical evaluation offers a new grading system which may be able to delineate patients with good prognosis, patients at risk for a complex decongestive physiotherapy (CDP) failure, and patients who may benefit from other therapeutic protocols.     

Treatment of end-stage lymphedema following radiotherapy for lymphoma: A case report

Rationale: Despite significant advances in microsurgical techniques, simultaneous vascularized lymph node transfer (VLNT) and lymphovenous anastomosis (LVA) surgeries may be effective for treatment of end-stage lymphedema. This case report describes the successful treatment of end-stage lymphedema with VLNT and LVA.Patient Concerns:A 72-year-old patient with bilateral lower extremity lymphedema was referred to our lymphedema clinic. This patient had a history of lymphoma and treated with radiotherapy on right inguinal area 26 years ago. Interestingly, the patient developed lymphedema on both the right and left lower extremities although she had radiotherapy on her right inguinal area.Diagnosis:According to the indocyanine green lymphography, lymphoscintigraphy, and magnetic resonance lymphangiography, the patient was diagnosed with end-stage lymphedema (International Society of Lymphology stage 3).Intervention:The patient underwent simultaneous VLNT and LVA for treatment of end-stage lymphedema.Outcomes:Significant reduction in circumference and volume of lower extremity was achieved following simultaneous VLNT and LVALessons:Simultaneous VLNT and LVA surgeries may be effective in patients with end-stage lymphedema.     

Syndromic classification of hereditary lymphedema

Since the late 1800's, the familial occurrence of peripheral lymphedema has been well-documented in Milroy and Meige syndromes. However, the presence of lymphedema in many other hereditary dysmorphic syndromes has not been fully appreciated. In order to establish more standardized and detailed clinical phenotypic criteria as the basis for rational classification and for greater precision in screening and genetic linkage studies, we conducted a comprehensive literature search and review of OMIM-identified and non-identified hereditary syndromes in which lymphedema was reported as a feature. Modes of inheritance, associated clinical features and images, and specific organ involvement were inventoried and suggested pathophysiologic mechanisms noted. The findings support the recommendation that when peripheral lymphedema of undetermined etiology is found, further careful, comprehensive clinical, including detailed dysmorphic, evaluation along with lymphatic imaging with subsequent syndromic classification is warranted. This information can provide clues to underlying pathogenesis and form the basis for genetic counseling and prognostication as well as offer guidance to the clinical investigator translating research at the molecular level into new approaches for evaluation and therapy.