7.1
Bacterial Infection
Bacterial Infections
Salivary gland infections are in general not a common condition. The incidence, complications, and mortality rates of salivary gland infections have decreased largely due to improved oral hygiene and advances in health care. There remains a risk of mortality. Bacterial infection of the salivary glands is believed to be due to retrograde spread through the papillae of the ducts, salivary stasis, and/or obstruction of salivary flow.
Retrograde spread can arise from dental infections or tonsillitis. Nosocomial organisms can enter the oral cavity after oral instrumentation. Neonates can develop salivary gland infections secondary to transitory bacteremia. Salivary stasis may occur as a result of dehydration or reduced salivary production. Hospitalization, the post-operative state, medically prescribed reduced fluid intake, advanced age, radiation therapy, medications (anticholinergics, diuretics, antidepressants), Sjögren syndrome, depression, and anorexia all contribute as risk factors to stasis. The most common cause of obstruction to saliva flow is a calculus within the salivary gland or duct ( Fig. 7.1.1 ).
The parotid gland is most often involved in bacterial infections. Parotid gland saliva contains fewer lysozymes, and lower concentrations of secretory immunoglobulin A (IgA), and sialic acids which inhibit bacterial adherence by causing agglutination of bacteria and glycoproteins. Infrequently, seeding of bacteria into the gland during fine needle aspiration cytology (FNAC) of a pre-existing lesion such as Warthin tumor may result in local inflammation.
Microbiology
Staphylococcus aureus is by far the most predominant organism cultured, followed by anaerobic organisms such as Peptostreptococcus spp., Prevotella spp. and Fusobacterium spp. Other aerobic and facultative pathogens sometimes implicated include Streptococcus spp. (including S. pneumoniae and S. pyogenes ) and Haemophilus influenzae . There is roughly an equal proportion of aerobic and facultative bacteria compared with anaerobic bacteria, with a mean of 1.6 isolates per specimen. Klebsiella pneumoniae and Escherichia coli are common in hospital-acquired parotitis. Adherence of Gram-negative organisms at the duct papillae can occur in immunocompromised or debilitated patients from a deficiency of fibronectin, a glycoprotein in the extracellular matrix. Children in Southeast Asia may develop parotitis secondary to Burkholderia pseudomallei , an aerobic organism found in soil and surface water. Lastly, methicillin-resistant Staphylococcus aureus (MRSA) parotitis can occur in neonates.
Signs and Symptoms
Bacterial parotitis is predominantly unilateral. Patients present with a diffuse painful swelling in the cheek or angle of jaw that is tender and warm. The thick fascial layer around the parotid often contains the infection within the gland, hence it is uncommon for parotid abscesses to erupt through the skin. Intraorally, the papilla may appear inflamed. Pus can sometimes be milked out of or be seen from the duct. The floor of the mouth may be elevated and tense in submandibular gland infections. An abscess involving the deep parotid lobe and deep neck spaces may manifest as trismus, neck swelling and medialization of the oropharyngeal wall or tonsil ( Fig. 7.1.2 ). Rare cases of facial nerve dysfunction are caused by nerve compression or neurotoxins causing neuritis. Neoplasm, however, needs to be excluded.
Imaging is often not necessary at the initial presentation for most infections. Ultrasound, although operator dependent, can be performed initially. Computed tomography (CT) or magnetic resonance imaging (MRI) of the salivary glands offer much greater detail and can detect an underlying calculus, abscess or neoplasm. Confirming the size of the abscess, sepsis, and failure to improve are indications for imaging.
Complications
An infection may develop into a frank abscess. Inflammation may spread to the surrounding muscles such as the temporalis and pterygoids, resulting in trismus. Involvement of the deep neck spaces may lead to sepsis, carotid artery aneurysm, jugular vein thrombosis, airway compromise, and even mediastinitis. Elderly patients are more susceptible to sepsis from a poorly controlled salivary gland infection.
Treatment
Conservative measures include adequate hydration, warm packs, massage, and sialogogues. Antibiotic choice is often empirical. Amoxicillin/clavulanic acid targets Gram-positive and anaerobic flora. Clindamycin can be selected if the patient is allergic to penicillin. If hospital-acquired, Gram-negative organisms should be covered. Intravenous antibiotics can be initiated if there is no improvement after 24–48 hours.
Surgery may be necessary if the gland contains a sizable abscess. A linear incision in the form of the superior limb of a modified Blair incision and a skin crease incision should be employed for parotid and submandibular gland abscesses, respectively ( Fig. 7.1.3 ). A skin flap should be raised to expose the gland. Needle aspiration prior to making an incision into the gland may be helpful. Incision into the parotid gland should be made parallel to the direction of the facial nerve fibers. The facial nerve is not dissected or exposed deliberately. Blunt dissection is used to explore the pocket, followed by irrigation and placement of a passive drain. The drain can guide insertion of a cannula to facilitate saline flushing. Serial aspiration with ultrasound is a method of managing a discrete abscess in patients who refuse or are unfit for surgery under general anesthesia.
Chronic Bacterial Parotitis
Chronic bacterial parotitis, 10 times more common in children (see Chapter 8.4 ), can manifest as either intermittent parotid swelling or a continuous discomfort within the gland. MRI sialography reveals salivary duct strictures and dilatations that have a “sausage-like appearance”.
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The parotid gland is the most commonly infected salivary gland, followed by the submandibular gland.
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Bacterial infection of the salivary glands is due to retrograde spread through the papillae of the ducts, salivary stasis, and/or obstruction of salivary flow.
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Staphylococcus aureus is the most common organism cultured in acute bacterial infections, followed by anaerobic organisms.
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Conservative management including antibiotics is usually adequate for acute salivary gland infections, failing which surgery can be performed.
7.2
Autoimmune
7.2.1
Sjögren Syndrome
Introduction
Sjögren syndrome (SS) is a chronic autoimmune disease characterized by hypofunction of salivary and lacrimal glands, and possible systemic multiorgan manifestations. The hallmark of the disease is dry eyes, dry mouth, fatigue, and joint pain. The clinical features of SS can be divided into two broad categories of exocrine glandular features and extraglandular features. SS is defined as primary when it presents alone and secondary when it is in the presence of another autoimmune disease. The autoimmune diseases associated with SS include rheumatoid arthritis, systemic lupus erythematosus, etc. SS is most common in women in their 50s but can affect men, adolescents, and young adults. The female to male ratio is 9 : 1, with a prevalence of 0.03–0.1% in the adult population.
Diagnosis and Evaluation
Although there are defined classification criteria for SS, practical challenges remain for the clinician in making an accurate diagnosis because there is no single gold standard test for diagnosing SS. The investigators from the Sjögren’s International Collaborative Clinical Alliance (SICCA) and the European League Against Rheumatism (EULAR) Sjögren’s Task Force formed the International Sjögren’s Syndrome Criteria Working Group. In 2016, this working group endorsed the American College of Rheumatology/European League Against Rheumatism classification criteria for primary SS ( Table 7.2.1.1 ). The classification of primary SS applies to any individual who meets the inclusion criteria, does not have any of the conditions listed as exclusion criteria, and has a score of ≥4 when the weights from the five criteria items are summed. The inclusion criteria are applicable to any patient with at least one symptom of ocular or oral dryness, defined as a positive response to at least one of the following questions: (1) Have you had daily, persistent, troublesome dry eyes for more than 3 months? (2) Do you have a recurrent sensation of sand or gravel in the eyes? (3) Do you use tear substitutes more than three times a day? (4) Have you had a daily feeling of dry mouth for more than 3 months? (5) Do you frequently drink liquids to aid swallowing dry food? The exclusion criteria that are also considered as the differential diagnosis of SS include: (a) history of head and neck radiation treatment; (b) active hepatitis C infection (with confirmation by polymerase chain reaction [PCR]); (c) AIDS; (d) sarcoidosis; (e) amyloidosis; (f) graft-versus-host disease; (g) IgG4-related disease. Focal lymphocytic sialadenitis with a focus score of at least 1 focus/4 mm 2 of tissue and anti-SSA/Ro antibody positivity have the highest weight in the criteria set, each scoring 3 points.
| Item | Weight/Score |
|---|---|
| Labial salivary gland with focal lymphocytic sialadenitis and focus score of ≥1 foci/4 mm 2 . a | 3 |
| Anti-SSA/Ro-positive. | 3 |
| Ocular staining score ≥5 (or van Bijsterveld score ≥4) in at least one eye. b,c | 1 |
| Schirmer test ≤5 mm/5 min in at least one eye. b | 1 |
| Unstimulated whole saliva flow rate ≤0.1 mL/min. b,d | 1 |
a The histopathologic examination should be performed by a pathologist with expertise in the diagnosis of focal lymphocytic sialadenitis and focus score count, using the protocol described by Daniels et al.
b Patients who are normally taking anticholinergic drugs should be evaluated for objective signs of salivary hypofunction and ocular dryness after a sufficient interval without these medications in order for these components to be a valid measure of oral and ocular dryness.
c Ocular staining score described by Whitcher et al. ; van Bijsterveld score described by van Bijsterveld.
d Unstimulated whole saliva flow rate measurement described by Navazesh and Kumar.
Patients suspected of SS should undergo a thorough medical history and physical examination with attention to the characteristic features of SS and other systemic manifestations of rheumatic diseases, e.g., rheumatic arthritis, systemic lupus erythematosus, and conditions that may resemble SS.
Diagnostic Testing
Evaluation on Dry Mouth
Salivary hypofunction can be tested by sialometry and scintigraphy, but these two tests are often not available in routine clinical setting. Minor salivary gland biopsy with focal lymphocytic sialadenitis and a focus score of ≥1 foci/4 mm 2 provides a histologic ground for the diagnosis. The focus score is defined as the number of lymphocytic foci adjacent to normal-appearing mucous acini and containing >50 lymphocytes/4 mm 2 of glandular tissue. However, many patients are reluctant to undergo this procedure since it carries a certain risk of complications.
There are a growing number of studies supporting the use of salivary gland imaging for the diagnosis of SS. The two most often used imaging modalities are magnetic resonance imaging (MRI) and ultrasonography. MRI of the parotid glands in SS is characterized by inhomogeneity of the parenchyma on both T1 and T2 weighted sequences. There is typically a nodular pattern, characterized by multiple hypo- and hyperintense areas of varying size. This “honeycomb” or “salt-and-pepper” pattern is thought to arise from fatty infiltration, fibrosis, ductal dilation, and lymphoid infiltration of parotid lobules. MRI results correlate well with those of salivary gland biopsy.
In recent years, there has been rapid advancement in the ultrasonography of the salivary gland. The ultrasonographic images are characterized by multiple hypoechoic areas with convex borders. Hyperechoic linear bands, cysts, and calcifications may be evident in more advanced disease. In contrast to MRI, ultrasound is more accessible and can be readily used. Recent data have shown a good to excellent diagnostic accuracy of B-mode ultrasound. However, it should also be kept in mind that ultrasound is operator-dependent. Further studies are required to validate and standardize the ultrasound definition, diagnostic procedures, and scoring system of salivary gland in SS.
Evaluation on Dry Eye
All patients should be evaluated by an ophthalmologist for the presence of dry eye on a formal examination. The examinations include the Schirmer test, a slit-lamp examination for assessment of tear break-up time, and ocular surface staining.
Serological Testing
Patients with primary SS often possess antibodies to the Ro/SSA (anti-Ro/anti-SSA) or La/SSB antigens (anti-La/anti-SSB), and many patients possess both. The frequency of anti-Ro/SSA and/or anti-La/SSB antibodies has varied between studies, but generally 60–80% of patients with primary SS exhibit one or both of these autoantibodies.
Anti-Ro/SSA antibody reactivity is directed at two distinct polypeptide antigens with molecular weights of 60 kDa and 52 kDa that are encoded by different genes. Patients with SS may express activity against both the 60 kDa and the 52 kDa proteins or against either protein alone. The majority show reactivity against both antigens. The presence of anti-Ro52 antibodies has been associated with more severe disease.
In considering the diagnosis of SS, it is important to bear in mind that anti-Ro/SSA is not a specific antibody to SS. Other conditions such as systemic lupus erythematosus, systemic sclerosis, inflammatory myopathies, autoimmune liver diseases, etc., could also be characterized by the presence of anti-Ro/SSA.
Systemic Manifestations
Systemic manifestations occur in 30–40% of the patients with primary SS. Lymphocytic infiltration of the epithelial tissues of parenchymal organs beyond the exocrine glands may affect lung, kidney, and liver, causing obstructive bronchiolitis, interstitial nephritis, and primary biliary cirrhosis. Immune complex microvascular deposition as a result of the ongoing B-cell hyperreactivity can result in extraepithelial manifestations, such as palpable purpura, cryoglobulinemia-associated glomerulonephritis, interstitial pneumonitis, and peripheral neuropathy.
Risk of Lymphoma
The most severe complication of SS is the development of non-Hodgkin lymphoma (NHL). The risk of lymphoma is about 15–20 times as high among patients with primary SS as in the general population (lifetime risk, 5–10%). SS-associated NHL are largely B cell in origin. They frequently involve the mucosa-associated lymphoid tissue (MALT) near the marginal zone. Extranodal sites are often involved and include the salivary glands, gastrointestinal tract, lung, skin, thymus, and thyroid gland. Clinicians should be aware of signs suggestive of lymphoproliferation, including a significant increase in the size of the salivary glands, especially when accompanied by dominant masses, lymphadenopathy, splenomegaly, and pulmonary infiltrates. Risk factors for the development of lymphoma in patients with primary SS include recurrent swelling of parotid glands, splenomegaly, lymphadenopathy, purpura, rheumatoid factor, cryoglobulinemia, low C4 level, and a focus score of >3 in the labial salivary gland biopsy.
Treatment
The goals of treatment for patients with SS include: (1) to relieve dryness symptoms; (2) to prevent complications of mucosal dryness, e.g., dental decay, corneal ulceration; (3) to detect and manage systemic manifestations and lymphoma early. Each patient should be offered holistic evaluation and management by a multidisciplinary team, which includes a rheumatologist, an ophthalmologist, and a dentist. The management approach is generally the same for primary or secondary SS. All patients should receive comprehensive education on the importance of meticulous self-care and preventive intervention.
Dry Mouth
The mainstay of symptomatic treatment is water. The importance of adequate hydration of the oral cavity cannot be overemphasized. Water should be taken with small sips frequently. Water is not only able to relieve the immediate sense of dryness and to hydrate the oral mucosa, it also helps with chewing and swallowing. Medications that may worsen oral dryness, especially those with anticholinergic side effects, should be avoided. Patients should be counseled on general environmental measures designed to enhance moisture, such as the use of humidifier and the avoidance of hot-air heating systems and excessive air-conditioning.
Due to the loss of antimicrobial, remineralizing, and cleansing properties of saliva, there is a marked increase in dental caries. Fungal infections of candida species are frequent and may be resistant to treatment. Meticulous oral hygiene should include toothbrushing after each meal and the use of dental floss and dental appliances such as interdental brushes for cleaning between teeth. Regular and frequent dental checks are needed. Sugar intake should be minimized. When sugary foods are consumed, the teeth should be brushed, or at least rinsed immediately. Regular use of acidic beverages, like soft drinks, should be avoided. A fluoride-containing toothpaste should be used, since fluoride helps to repair early demineralization of the tooth and strengthens the tooth surface.
Saliva can be stimulated by any oral activity. Patients may use sugar-free gums, lozenges, candies, or mints for symptomatic relief of xerostomia. The use of sugar-free and low-acid products must be stressed. Xylitol is an acceptable sweetener that has been shown to reduce dental caries.
In patients who do not respond adequately to the basic measures mentioned above, and who continue to find the symptoms distressing, further measures of muscarinic agonists, including pilocarpine and cevimeline could be considered. The benefits of pilocarpine and cevimeline have been shown in several randomized trials of each drug. These include increased salivary flow and improvement in symptoms of dry mouth when compared with placebo.
Dry Eye
The initial management should focus on symptomatic relief and the prevention of ocular damage. The treatment is determined by the severity of the dryness and the severity of symptoms. Patients should be educated on the strategies for tear conservation and the effective use of artificial tears.
Systemic Manifestations
While some treatments may improve symptoms and prevent complications of SS, currently there is no cure. There are both gaps and challenges in treatments involving both local and systemic manifestations of SS and, to date, no immunomodulatory drug has proved to be efficacious in primary SS. The decision to adopt systemic treatment and the choice of the specific treatment in primary SS is often driven by the organ involved and the severity of the disease activity. The few randomized controlled trials evaluating the use of conventional disease-modifying antirheumatic drugs and biologics in patients with SS did not provide conclusive evidence supporting their efficacy. Treatment strategies are often based on personal experience acquired in other autoimmune rheumatic diseases such as rheumatoid arthritis and systemic lupus erythematosus, rather than on strong scientific evidence. Despite a better understanding of the pathogenesis of SS, together with the advances in molecular biology and engineering, the development of targeted therapies to interfere with or to block the various pathologic pathways in SS remains a great challenge for both the scientists and researchers. More studies are needed to combat this complex autoimmune disease, with an ultimate aim to improve the quality of life for all the SS patients.
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Minor salivary gland biopsy with focal lymphocytic sialadenitis and a focus score of ≥1 foci/4 mm 2 provides a histological ground for the diagnosis.
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The frequency of anti-Ro/SSA and/or anti-La/SSB antibodies has varied between studies, but generally 60–80% of patients with primary SS exhibit one or both of these autoantibodies.
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The risk of lymphoma is about 15–20 times as high among patients with primary SS as in the general population.
7.2.2
IgG4-Related Disease
IgG4-related disease (IgG4-RD) is a systemic, chronic, immune-mediated systemic disease described in Japan in the first years of the 21st century. The key histopathologic feature of the disease is the infiltration of IgG4-bearing plasma cells. Many diseases previously considered “idiopathic” are now included in the clinical IgG4-RD spectrum (Mikulicz disease, Küttner tumor, Riedel thyroiditis, Ormond disease). Although the disease has been described in nearly all racial and ethnic groups, more than two-thirds of cases have been reported from Asian countries ( Fig. 7.2.2.1 ). A review of nearly 3500 reported patients found a mean age at diagnosis of 61 years with a clear male predominance (73% of patients). In 2012, an international multidisciplinary study group suggested the name “IgG4-RD”.
Clinical Presentation
IgG4-RD has now been reported in nearly every organ of the human body ( Fig. 7.2.2.2 ). The pancreas is the organ most frequently involved in >40% of reported cases presenting as a systemic disease, but IgG4-RD also affects a large number of other organs and systems, including the lungs, pleura, mediastinum, kidneys, retroperitoneum, mesentery, urinary tract, meninges, thyroid, hypophysis, joints and bones, peripheral nerves, prostate, breasts, testes, and the gut. Therefore, the presenting features of the disease vary substantially according to which specialty evaluates the patient first, but the physicians most frequently involved are gastroenterologists, ophthalmologists, otolaryngologists, nephrologists, urologists, dermatologists, neurologists, and rheumatologists/internists. The key for clinical suspicion of IgG4-RD is a patient presenting with tumefactive lesions in one or more organs (40% of patients have single-organ involvement), lesions that may be diagnosed incidentally through radiologic findings or unexpectedly in pathologic specimens. The enlarged organs may be visible on the physical examination (salivary or lacrimal gland swelling, lymphadenopathy, thyroid enlargement) or in imaging diagnostic tests (enlargement of the pancreas, liver, spleen, or kidneys). Signs and symptoms at presentation are diverse and may be divided into general and organ-specific.
Head and Neck Involvement
The major salivary glands are the second most frequently involved organ in IgG4-RD, including patients with Mikulicz disease (bilateral swelling of at least two major salivary or lacrimal glands) and those with Küttner disease (chronic sclerosing sialadenitis that affects the submandibular glands). IgG4-related glandular involvement has been specifically studied in 10 studies, including 158 patients with Mikulicz disease and 42 with Küttner disease. Glandular swelling, often subacute, was the key sign on examination: submandibular glands were affected in 94% of patients, parotid glands 29%, and sublingual glands only in eight cases. Bilateral involvement was more frequent in systemic than in localized IgG4-RD. A recent study has reported that all affected glands showed well-defined borders, with two types of sonographic appearance (localized tumor-forming and diffuse focal involvement). In patients with IgG4-related glandular disease, sicca symptoms have been reported in 62% of patients. Two studies have analyzed nasal involvement specifically. The main nasal symptoms reported were crusting, rhinorrhea, postnasal drip and polyposis. Rhinitis (often in an allergic/atopic context) and sinusitis are prevalent. Nasal biopsy has been suggested as a safe and useful diagnostic tool. Allergic processes or an atopic background have been reported in ~20% of systemic patients. The two main types of cutaneous lesions are erythematous plaques and subcutaneous nodules. The main locations of cutaneous lesions are often related to the main head and neck involvements (salivary and lacrimal glands), including the periauricular, eyelid, cheek, temporal, and mandible regions. Adenopathies are often associated with local or regional IgG4-related extranodal involvement: the most frequent location is cervical in patients with salivary gland involvement. Involvement of cranial nerves is often related to adjacent tumoral masses. The best examples are the involvement of the optic nerves and trigeminal branches (supra/infraorbital nerves) by ocular masses. Other infrequent upper airway involvements included hearing loss, mastoiditis, otitis media, larynx involvement, and destructive bone involvement affecting the bones of the orbit, or the temporal, maxillary, or mastoid bones.
Diagnostic Approach
The diagnosis of IgG4-RD relies on the coexistence of various clinical, laboratory, and histopathologic findings, although none are pathognomonic alone. IgG4-RD should be suspected in patients presenting with unexplained enlargement or swelling of one or more organs. Four laboratory abnormalities may lead to suspicion of IgG4-RD: eosinophilia, hypergammaglobulinemia, elevated serum immunoglobulin(Ig)E levels, and hypocomplementemia. Raised IgG4 levels were the key feature in identifying the first cases of IgG4-RD (autoimmune pancreatitis, Mikulicz disease), and were subsequently considered a key diagnostic feature. However, IgG4 levels are raised in a wide range of diseases, and recent studies have reported some significant limitations of serum IgG4 measurement and their role in making the diagnosis should be de-emphasized. Histopathologic studies and IgG4 tissue immunostaining are the most reliable diagnostic tools at this time, although they are not pathognomonic and may show significant variations according to the organ biopsied, the time of disease evolution, or the therapies administered ( Fig. 7.2.2.3 ). Flow cytometry measuring circulating plasmablasts is likely to play an increasingly important role in the diagnosis and longitudinal management of IgG4-RD in the future. The great majority of reported studies based the diagnosis of IgG4-RD on a compatible clinical picture, together with elevated serum IgG4 levels and a highly suggestive histopathologic scenario. International multidisciplinary collaboration is near to publish the new set of ACR/EULAR classification criteria.
Treatment
The optimum therapeutic management of IgG4-RD has not yet been established. Glucocorticoids (GC) remain the main therapeutic approach, although no controlled studies have specifically evaluated their use in unselected IgG4-RD series. Therapeutic guidelines recommend the use of GC as first-line therapeutic agents, with 94% of agreement between experts on the use of prednisolone (0.6 mg/kg per day) for 4 weeks as induction therapy. After the first 4 weeks of induction therapy, the GC dose can be tapered gradually during a 3–6-month period to a maintenance dose of 2.5–5.0 mg/day for up to 3 years. The selection of a “steroid-sparing” agent is challenged by the paucity of data on the efficacy of conventional agents for IgG4-RD, since the use of immunosuppressive agents in IgG4-RD is based on the same level of evidence as that for GC (uncontrolled studies). The emergence of biologic therapies has increased the therapeutic armamentarium available for treating the most refractory/severe cases of IgG4-RD, but their use is limited by the lack of licensing. Rituximab (RTX) was first reported to be useful in 2010 and is the biologic option typically used as the first option following GC ; it was used less frequently as induction therapy (only eight cases with an efficacy of 75%), and more frequently as rescue therapy in patients who failed to achieve or sustain disease remission with GC treatment. Finally, the lack of any therapeutic intervention has been reported in 13% of patients. In some specific organ involvements, this percentage was higher, reaching 71% in IgG4-related lymphadenopathy, 35% in IgG4-related salivary involvement, or 40% in IgG4-related skin involvement. Wait-and-see management may be appropriate in asymptomatic patients with lymphadenopathy, cutaneous features, or mild salivary gland enlargement.
