Lymphadenopathy reflects disease involving the reticuloendothelial system, secondary to an increase in normal lymphocytes and macrophages in response to an antigen. Most lymphadenopathy in children is due to benign, self-limited disease such as viral infections. Other, less common etiologies responsible for adenopathy include nodal accumulation of inflammatory cells in response to an infection in the node (lymphadenitis), neoplastic lymphocytes or macrophages (lymphoma), or metabolite-laden macrophages in storage diseases (Gaucher disease).
Lymph nodes, in conjunction with the spleen, tonsils, adenoids, and Peyer patches, are highly organized centers of immune cells that filter antigen from the extracellular fluid. Directly interior to a lymph node's fibrous capsule is the subcapsular sinus. This allows lymph, an ultrafiltrate of blood, to traverse from the afferent lymph vessels, through the sinuses, and out the efferent vessels. The sinuses are studded with macrophages, which remove 99% of all delivered antigens.
Interior to the subcapsular sinus is the cortex, which contains primary follicles, secondary follicles, and the interfollicular zone. Follicles within the cortex are major sites of B-cell proliferation, whereas the interfollicular zone is the site of antigen-dependent T-cell differentiation and proliferation. The deepest structure within the lymph node is the medulla, consisting of cords of plasma cells and small B lymphocytes that facilitate immunoglobulin secretion into the exiting lymph.
The lymph node, with its high concentration of lymphocytes and antigen-presenting cells, is an ideal organ for receiving antigens that gain access through the skin or gastrointestinal tract. Nodes have considerable capacity for growth and change. Lymph node size depends on the person's age, the location of the lymph node in the body, and antecedent immunological events. In neonates, lymph nodes are barely perceptible, but a progressive increase in total lymph node mass is observed until later childhood. Lymph node atrophy begins during adolescence and continues through later life.
The laboratory evaluation of lymphadenopathy must be directed by the history and physical examination and is based on the size and other characteristics of the nodes and the overall clinical assessment of the patient. When a laboratory evaluation is indicated, it must be driven by the clinical evaluation.[1]
The following studies should be considered for chronic lymphadenopathy (>3 wk):
Chest radiography may be helpful in elucidating mediastinal adenopathy and underlying diseases affecting the lungs, including tuberculosis, coccidioidomycosis, lymphomas, neuroblastoma, histiocytoses, and Gaucher disease.[2]
Supraclavicular adenopathy, with its high associated rate of serious underlying disease, may be an indication for computed tomography (CT) scan of the chest, abdomen, or both.
If the size, location, or character of the lymphadenopathy suggests malignancy, the need for laboratory studies and biopsy is more urgent than it would otherwise be. If laboratory testing is inconclusive, a lymph node biopsy is immediately indicated.
Treatment is determined by the specific underlying etiology of lymphadenopathy. Most clinicians treat children with cervical lymphadenopathy conservatively. Antibiotics should be given only if a bacterial infection is suspected.
Management of superior vena cava syndrome requires emergency care, including chemotherapy and possibly radiation therapy.
Surgical care usually involves a biopsy. If lymphadenitis is present, aspirate may be needed for culture, and removal of the affected node may be indicated.
Lymphadenopathy reflects disease involving the reticuloendothelial system, secondary to an increase in normal lymphocytes and macrophages in response to an antigen. Most lymphadenopathy in children is due to benign, self-limited disease such as viral infections. Other, less common etiologies responsible for adenopathy include nodal accumulation of inflammatory cells in response to an infection in the node (lymphadenitis), neoplastic lymphocytes or macrophages (lymphoma), or metabolite-laden macrophages in storage diseases (Gaucher disease).
United States
The precise incidence of lymphadenopathy is not known, but estimates of palpable adenopathy in childhood vary from 38-45%,[3] and lymphadenopathy is one of the most common clinical problems encountered in pediatrics.[4] Determining whether adenopathy is simply a normal response to frequent viral infections within an age group or if it is significant enough to consider more serious underlying disease is often difficult.
In the United States, common viral and bacterial infections are overwhelmingly the most common cause of adenopathy. Infectious mononucleosis and cytomegalovirus (CMV) are important etiologies, but adenopathy is usually caused by common viral upper respiratory tract infections. Localized lymphadenitis is most often caused by staphylococci and beta-hemolytic streptococci.
Other infections, such as human immunodeficiency virus (HIV), malignancies, and autoimmune diseases, are less common causes of adenopathy.
International
Infections that are rarely observed in the United States, such as tuberculosis, typhoid fever, leishmaniasis, trypanosomiasis, schistosomiasis, filariasis, and fungal infections, are common causes of lymphadenopathy in developing nations.[5] HIV infections must be strongly considered in areas of high incidence.
In the United States, mortality and serious morbidity caused by adenopathy are unusual given the common infectious etiologies.
Race is not a factor in most lymphadenopathy. Rare causes may be associated with particular ethnic groups (eg, sarcoidosis in Africans, Kikuchi-Fujimoto disease in Asians).
Sex does not influence childhood lymphadenopathy.
Adenopathy is most common in young children whose immune systems are responding to newly encountered infections. Adenopathy may be seen in one third of neonates and infants, usually in nodes that drain areas with mild skin irritation. Generalized adenopathy is rare in the neonate and suggests congenital infections, such as CMV. Adenopathy related to malignancy is rare at all ages. If diagnosed, it is often secondary to leukemia or neuroblastoma in younger children, and to Hodgkin lymphoma in adolescents.[7]
The differential diagnosis of acute lymphadenopathy is broad. A patient's medical history and review of systems is important in narrowing this differential. Upon examination, recognizing the pattern of lymph drainage aids in seeking an infectious focus.[8]
Although the underlying etiology is often self-limited infection, more serious underlying etiologies must be quickly recognized. Serious infections and malignancies are important considerations, as discussed in Outline - Etiologies of Lymphadenopathy.
In adolescents, screening for intravenous drug use and sexual activity is important.
Assess the size, location, and character of the adenopathy, along with any associated physical findings. Erythema, tenderness, warmth, and fluctuance suggests lymphadenitis, and nodes that are fixed (nonmoveable), matted together, firm, and nontender suggest malignancy, although this distinction is not invariable.
A retrospective study by Lin et al indicated that clinicians should suspect the presence of Kikuchi-Fujimoto disease in children with febrile cervical lymphadenopathy, particularly when leukopenia and monocytosis occur concomitantly with it.[12]
Generalized lymphadenopathy is defined as enlargement of more than 2 noncontiguous lymph node groups. A thorough history and physical examination are critical in establishing a diagnosis. Causes of generalized lymphadenopathy include infections, autoimmune diseases, malignancies, histiocytoses, storage diseases, benign hyperplasia, and drug reactions.
Infections
Generalized lymphadenopathy is most often associated with systemic viral infections.
Infectious mononucleosis results in widespread adenopathy.
Roseola infantum (caused by human herpes virus 6), cytomegalovirus (CMV), varicella, and adenovirus all cause generalized lymphadenopathy.
Human immunodeficiency virus (HIV) is often associated with generalized adenopathy, which may be the presenting sign. Children with HIV are at increased risk for tuberculosis, as well.[13]
Although usually associated with localized node enlargement, some bacterial infections present with generalized adenopathy. Examples include typhoid fever caused by Salmonella typhi, syphilis, plague, and tuberculosis. Less common bacteremias, including those caused by endocarditis, result in generalized lymphadenopathies.
In an ultrasonographic study, Bélard et al found that 46 of 102 pediatric patients (45%) with microbiologically confirmed or clinically diagnosed pulmonary tuberculosis had abdominal lymphadenopathy suggestive of abdominal tuberculosis. This indicated that in children, abdominal tuberculosis is a frequent complication of pulmonary tuberculosis.[14]
Malignant etiologies
Concern about malignant etiologies often drives further diagnostic testing in children with adenopathy. Malignancy is often associated with constitutional signs, such as fever, anorexia, nonspecific aches and pains, weight loss, and night sweats. The acute leukemias and lymphomas often present with these nonspecific findings.
Generalized lymphadenopathy is present at diagnosis in two thirds of children with acute lymphoblastic leukemia (ALL) and in one third of children with acute myeloblastic leukemia (AML). Abnormalities of peripheral blood counts usually lead to the correct diagnosis. The lymphomas more often present with regional lymphadenopathy, but generalized lymphadenopathy occurs.
Constitutional signs and symptoms observed in the leukemias are less reliable findings in the lymphomas. Only one third of children with Hodgkin disease and 10% with non-Hodgkin lymphoma display them. Malignancies usually present with nodes that tend to be firmer and less mobile or matted; however, this finding can be misleading. Benign reactive lymph nodes may be associated with fibrotic reactions that make them firm.
Storage diseases
Generalized lymphadenopathy is an important manifestation of the lipid storage diseases. In Niemann-Pick disease, sphingomyelin and other lipids accumulate in the spleen, liver, lymph nodes, and CNS. In Gaucher disease, the accumulation of the glucosylceramide leads to the engorgement of the spleen, lymph nodes, and the bone marrow. Although widespread lymphadenopathy is common, additional findings, such as hepatosplenomegaly and developmental delay in Niemann-Pick disease and blood dyscrasias in Gaucher disease, are usually present. These diagnoses are established by leukocyte assay.
Drug reactions
Adverse drug reactions can cause generalized lymphadenopathy. Within a couple of weeks of initiating phenytoin, some patients experience a syndrome of regional or generalized lymph node enlargement, followed by a severe maculopapular rash, fever, hepatosplenomegaly, jaundice, and anemia. These symptoms abate 2-3 months after discontinuation of the drug. Several other drugs are implicated in similar symptomatology, including mephenytoin, pyrimethamine, phenylbutazone, allopurinol, and isoniazid.
Other nonneoplastic etiologies
Rare nonneoplastic causes of generalized lymphadenopathy include Langerhans cell histiocytosis and Epstein-Barr virus (EBV)-associated lymphoproliferative disease. Autoimmune etiologies include juvenile rheumatoid arthritis, which often presents with adenopathy, especially during the acute phases of the disease. Sarcoidosis and graft versus host disease also merit consideration.
Regional lymphadenopathy involves enlargement of a single node or multiple contiguous nodal regions. Lymph nodes are clustered in groups throughout the body and are concentrated in the head and neck, axillae, mediastinum, abdomen, and along the vascular trunks of the extremities. Each group drains lymph from a particular region of the body. Knowledge of the pattern of lymph drainage aids in determining the etiology.
Cervical lymphadenopathy
Cervical lymphadenopathy is a common problem in children.[15] Cervical nodes drain the tongue, external ear, parotid gland, and deeper structures of the neck, including the larynx, thyroid, and trachea. Inflammation or direct infection of these areas causes subsequent engorgement and hyperplasia of their respective node groups. Adenopathy is most common in cervical nodes in children and is usually related to infectious etiologies. Lymphadenopathy posterior to the sternocleidomastoid is typically a more ominous finding, with a higher risk of serious underlying disease.
Infectious etiologies include the following:
Noninfectious etiologies include the following:
A literature review by Deosthali et al found nonspecific, benign etiology to be the most common diagnosis (67.8%) for pediatric cervical lymphadenopathy. The next most common etiologies were Epstein-Barr virus (8.86%), malignancy (4.69%), and granulomatous disease (4.06%), with non-Hodgkin lymphoma being the most common malignant condition (46.0%), and tuberculosis, the most common granulomatous disease (73.4%).[17]
Submaxillary and submental lymphadenopathy
These nodes drain the teeth, tongue, gums, and buccal mucosa. Their enlargement is usually the result of localized infection, such as pharyngitis, herpetic gingivostomatitis, and dental abscess.
Occipital lymphadenopathy
Occipital nodes drain the posterior scalp. These nodes are palpable in 5% of healthy children. Common etiologies of occipital lymphadenopathy include tinea capitis, seborrheic dermatitis, insect bites, orbital cellulitis, and pediculosis. Viral etiologies include rubella and roseola infantum. Rarely, occipital lymphadenopathy may be noted after enucleation of the eye for retinoblastoma.
Preauricular lymphadenopathy
Preauricular nodes drain the conjunctivae, skin of the cheek, eyelids, and temporal region of the scalp and rarely are palpable in healthy children. The oculoglandular syndrome consists of severe conjunctivitis, corneal ulceration, eyelid edema, and ipsilateral preauricular lymphadenopathy. Chlamydia trachomatis and adenovirus can cause this syndrome.
Mediastinal lymphadenopathy
Mediastinal nodes drain the thoracic viscera, including the lungs, heart, thymus, and thoracic esophagus. Because these nodes are not directly demonstrable upon physical examination, their enlargement must be indirectly assessed. Supraclavicular adenopathy is often associated with mediastinal adenopathy. Mediastinal nodes may cause cough, wheezing, dysphagia, airway erosion with hemoptysis, atelectasis, and the obstruction of the great vessels, which constitutes superior vena cava syndrome. Airway compromise may be life threatening.
Mediastinal lymphadenopathy is usually a sign of serious underlying disease. More than 95% of mediastinal masses are caused by tumors or cysts. Lymphomas and acute lymphoblastic leukemia are the most common etiologies and usually involve the anterior mediastinum. These malignancies are associated with a high risk of superior vena cava syndrome and are associated with several potentially life-threatening complications, as follows:
Unlike most other adenopathies, mediastinal lymphadenopathy is less frequently a result of infection. Infections frequently involve the hilar region and include histoplasmosis, coccidioidomycosis, and tuberculosis.
Nonlymphoid mediastinal tumors may be confused with adenopathy. These include neurogenic tumors (usually found in the posterior mediastinum), germ cell tumors, and teratomas.
Nonneoplastic conditions may also be confused with mediastinal adenopathy. These include the typically large thymus of a child, substernal thyroid glands, bronchogenic cysts, and abnormalities of the great vessels.
Supraclavicular lymphadenopathy
Supraclavicular nodes drain the head, neck, arms, superficial thorax, lungs, mediastinum, and abdomen. Left supraclavicular nodes also reflect intra-abdominal drainage and enlarge in response to malignancies in that region. This is particularly true when adenopathy in this region occurs in the absence of other cervical adenopathy.
Right supraclavicular nodes drain the lung and mediastinum and are typically enlarged with intrathoracic lesions.
Serious underlying disease is frequent in children with supraclavicular adenopathy and always merits further evaluation. The potential for malignancy necessitates peripheral blood counts, skin testing for tuberculosis, and chemical studies, including uric acid, lactate dehydrogenase, calcium (Ca), phosphorus (P), and renal and hepatic function studies. Chest radiography and possibly CT scanning are indicated.
Several important infections may occur with supraclavicular adenopathy, including tuberculosis, histoplasmosis, and coccidioidomycosis.
Early lymph node biopsy should be considered in children with supraclavicular adenopathy.
Axillary lymphadenopathy
Axillary nodes drain the hand, arm, lateral chest, abdominal walls, and the lateral portion of the breast.
A common cause of axillary lymphadenopathy is catscratch disease. Local axillary skin infection and irritation commonly are associated with local adenopathy. Other etiologies include recent immunizations in the arm (particularly with bacille Calmette-Guerin vaccine), brucellosis, juvenile rheumatoid arthritis, and non-Hodgkin lymphoma.
Hidradenitis suppurativa is a condition of enlarged tender lymph nodes that typically affects children with obesity and is caused by recurrent abscesses of lymph nodes in the axillary chain. The etiology is unknown, and treatment may include antibiotics. Many patients require incision and drainage.
Abdominal lymphadenopathy
Abdominal nodes drain the lower extremities, pelvis, and abdominal organs. Although abdominal adenopathy is not usually demonstrable upon physical examination, abdominal pain, backache, increased urinary frequency, constipation, and intestinal obstruction secondary to intussusception are possible presentations.
Mesenteric adenitis is thought to be viral in etiology and is characterized by right lower quadrant abdominal pain caused by nodal enlargement near the ileocecal valve. Differentiating mesenteric adenitis from appendicitis may be difficult.
Mesenteric adenopathy may be caused by non-Hodgkin lymphoma or Hodgkin disease.
Typhoid fever and ulcerative colitis are other etiologies of mesenteric adenopathy.
Iliac and inguinal lymphadenopathy
The lower extremities, perineum, buttocks, genitalia, and lower abdominal wall drain to these nodes. They are typically palpable in healthy children, although they are usually no larger than 1-1.5 cm in diameter. Regional lymphadenopathy is typically caused by infection; however, insect bites and diaper dermatitis are also frequent. Nonlymphoid masses that may be confused with adenopathy include hernias, ectopic testes, and lipomas.
I. Generalized lymphadenopathy
II. Regional lymphadenopathy
The laboratory evaluation of lymphadenopathy must be directed by the history and physical examination and is based on the size and other characteristics of the nodes and the overall clinical assessment of the patient. When a laboratory evaluation is indicated, it must be driven by the clinical evaluation.[1]
The following studies should be considered for chronic lymphadenopathy (>3 wk):
Evaluation of hepatic and renal function and a urine analysis are useful in identifying underlying systemic disorders that may be associated with lymphadenopathy. When evaluating specific regional adenopathy, lymph node aspirate for culture may be important if lymphadenitis is clinically suspected.
Titers for specific microorganisms may be indicated, particularly if generalized adenopathy is present. These may include Epstein-Barr virus, cytomegalovirus (CMV), Toxoplasma species, and human immunodeficiency virus (HIV).
Chest radiography may be helpful in elucidating mediastinal adenopathy and underlying diseases affecting the lungs, including tuberculosis, coccidioidomycosis, lymphomas, neuroblastoma, histiocytoses, and Gaucher disease.[2]
Supraclavicular adenopathy, with its high associated rate of serious underlying disease, may be an indication for computed tomography (CT) scan of the chest, abdomen, or both.
A retrospective study by Razek et al indicated that diffusion-weighted magnetic resonance imaging (MRI) can be used to differentiate malignant from benign mediastinal lymphadenopathy in children. In the study, which included 29 children with mediastinal lymphadenopathy, patients were assessed with single-shot echo planar diffusion-weighted MRI, with the mean apparent diffusion coefficient (ADC) for the malignant condition being significantly below that for benign mediastinal lymphadenopathy.[18] However, although this study may represent an important advance in the imaging of mediastinal/hilar lymphadenopathy, the results must be confirmed before the routine use of this technique can be recommended.
Positron-emission tomography (PET) scanning is not helpful as a screening tool as benign and malignant conditions may cause intense uptake.[19] However, PET scanning is helpful in the staging of lymphomas once a diagnosis is made.[20]
Ultrasonography may be helpful in documenting the extent of lymph node involvement and any changes in the lymph nodes.[21] In children with inguinal adenopathy or abdominal complaints, ultrasonography of the abdomen, CT scan of the abdomen, or both may be indicated.[22] Ultrasonography is rarely of diagnostic value for lymphadenopathy in childhood, even with advanced techniques.[23]
A study by Ying et al indicated that evaluation of the intranodal vascularity index is an effective means of diagnosing metastatic and tuberculous lymph nodes in patients with cervical lymphadenopathy. Using ultrasonographic images from 347 patients with palpable cervical lymph nodes, a customized computer program was used to quantify the intranodal vascularity index. With regard to distinguishing metastatic and tuberculous lymph nodes, the index was found to have a sensitivity and specificity of 80% and 73%, respectively; positive and negative predictive values of 91% and 51%, respectively; and an overall accuracy of 68%, when the cutoff vascularity index was 22%.[24]
A study by Tan et al indicated that shear-wave elastography (SWE) is an effective imaging modality for distinguishing benign from malignant superficial lymphadenopathy when the distinction cannot be made using conventional ultrasonography. The investigators found that in malignant lesions, the maximum and mean elastic modulus, as well as the standard deviation of the elastic modulus, were significantly higher than for benign lesions.[25]
The critical question is often whether or not to perform a lymph node biopsy; this requires an overall assessment of the history and physical examination as described above.
Images taken during and after a lymph node biopsy are shown below.
View Image | A lymph node biopsy is performed. Note that a marking pen has been used to outline the node before removal and that a silk suture has been used to pro.... |
View Image | A lymph node after removal by means of biopsy, which was performed completely under a local anesthetic technique. |
View Image | A gross image of a node following excision. The cut surface of the node shows the typical fish-flesh appearance seen with lymphoma. |
Treatment with antibiotics covering bacterial pathogens frequently implicated in lymphadenitis, followed by reevaluation in 2-4 weeks is reasonable, if clinical findings suggest lymphadenitis. Benign reactive adenopathy may be safely observed for months.[8]
If the size, location, or character of the lymphadenopathy suggests malignancy, the need for laboratory studies and biopsy is more urgent. If laboratory testing is inconclusive, a lymph node biopsy is immediately indicated.
Fine needle aspiration and core needle biopsy yield small samples with limited ability to perform flow cytometry and chromosomal analysis; most pediatric hematologists and pathologists prefer excisional biopsy. (However, a retrospective study by Sher-Locketz et al reported that fine-needle aspiration biopsy, as performed through an efficient laboratory-managed service, proved to be an acceptable replacement for surgical biopsy in the triage of pediatric lymphadenopathy.[26] )
Excisional biopsy also has limitations and may yield a definitive diagnosis in only 40-60% of patients because of inadequate specimen size, improper handling, or node-sampling error (eg, Hodgkin lymphoma); sampling more accessible nodes may miss the underlying malignancy.
The surgeon should therefore biopsy larger, firmer, and most recently enlarging nodes, even if it is technically difficult, with appropriate handling of the specimen. If an excisional biopsy does not reveal the diagnosis, a second biopsy may be indicated.
Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a widespread technique for tissue sampling from hilar and mediastinal lymph nodes; however, the predominant finding in routine care is a nondiagnostic cytology in more than 70% of patients.[27]
A multicenter study by Dhooria et al indicated that, as in adults, EBUS-TBNA and endoscopic ultrasonography with an echobronchoscope-guided fine-needle aspiration (EUS-B-FNA) can be safely and effectively used in children with mediastinal lymphadenopathy, providing a good diagnostic yield.[28]
A retrospective study by Wilczynski et al suggested that ultrasonographically guided full-core needle biopsy (UFCNB) is an effective alternative to whole surgical lymph node excision in the diagnosis of lymphadenopathy of unknown origin. The investigators found UFCNB to have a sensitivity of 94.4%, a specificity of 97.8%, and a diagnostic accuracy of 95.0%, with regard to the condition.[29]
Histiologic findings depend on the underlying etiology of the lymphadenopathy. Nonspecific changes consistent with reactive adenopathy are often the only findings. This is helpful in ruling out malignancy, histiocytoses, granulomatous disorders, and storage diseases. Specific infections can be diagnosed if tissues are appropriately stained.
When examining the tissue, histiologic findings are often inadequate. Flow cytometric and chromosomal analysis may provide critical information to permit a diagnosis to be established.
Staging is relevant only when a specific malignancy is diagnosed as the etiology of lymphadenopathy.
Treatment is determined by the specific underlying etiology of lymphadenopathy.
Surgical care usually involves a biopsy. If lymphadenitis is present, aspirate may be needed for culture, and removal of the affected node may be indicated.
Consultation with a pediatric hematologist, pediatric oncologist, or both is often useful, especially if the adenopathy seems to be more than reactive. Often, the most important decision for these children is whether further evaluation is necessary at all; experience in evaluating these children is frequently very helpful. The ability to provide a careful assessment of the peripheral blood smear may be particularly important.
Surgical consultation is usually helpful for lymph node biopsy, needle aspiration for culture, and for incision and drainage of obviously infected fluctuant nodes.
Diet plays little role in the pathophysiology of lymphadenopathy.
Internationally, many of the infectious etiologies may be associated with a higher risk of malnutrition.
Limitations on activity usually involve associated acute-onset splenomegaly. Any patient with an acutely enlarged spleen may need to be restricted from contact sports.
In infectious mononucleosis, rupture of the spleen can occur with relatively little trauma and can be fatal.
No specific medical therapy for lymphadenopathy is acknowledged.
Therapy is directed at the specific diagnosis, once established, and when appropriate.
Further outpatient treatment depends on establishing a diagnosis and determining management of that diagnosis.
Additional inpatient treatment depends on establishing the diagnosis and determining management based on that diagnosis.
Inpatient and ambulatory medications depend on the specific underlying etiology of the lymphadenopathy.
Transfer of the patient usually depends on the specific diagnosis. Patients who develop superior vena cava syndrome with either respiratory symptoms or obstruction to blood flow require emergency medical care and may require transfer to a tertiary care center.
Complications are usually related to the specific underlying disorder causing the lymphadenopathy; however, the lymphadenopathy itself can cause potentially serious complications.
The prognosis of lymphadenopathy almost entirely depends on the underlying etiology. Patients with specific complications, such as superior vena cava syndrome, are at risk unless this specific complication is managed. Their prognosis is dependent on the management of the neoplastic process resulting in superior vena cava syndrome.
Patient and family education depends on the specific etiology of the lymphadenopathy.