Comprehensive, up-to-date information on HIV/AIDS treatment, prevention, and policy from the University of California San Francisco

The most common malignancy associated with HIV disease is KS, an idiopathic multiple sarcoma of the skin. KS occurs in 43% of homosexual or bisexual men with advanced HIV disease, only 4% of injection drug users, and essentially no hemophiliacs.(1) Although considered an opportunistic neoplasm, KS can manifest early in the patient's course with HIV infection, and may be the first clinical manifestation of their immunodeficiency. The typical HIV-associated KS lesion is pink or purple, not tender, and macular or slightly raised or nodular, and can occur on both cutaneous and mucosal surfaces. This process is frequently multicentric; thus, individuals with mucosal lesions often present with easily visible cutaneous lesions as well. Clinical history and characteristic appearance often allow clinical diagnosis, which a biopsy can confirm.

The clinical course of KS lesions is unpredictable. Many will slowly progress, others will remain static, and, in a few cases, the KS may regress.(2) Aggressive KS can cause pain, disfigurement, and functional problems, but death from pulmonary KS or KS-associated upper airway obstruction is unusual. Methods of treatment include local or systemic chemotherapy and radiation therapy. Cure is not a realistic goal; therefore, extensive surgical procedures, such as maxillectomy or lymphadenectomy, are not indicated given the systemic nature of this malignancy. The goals of therapy are to relieve symptoms and in some cases improve cosmetic problems. The clinician should be sure that the expected benefits outweigh the risks of treatment of the KS lesions. Another chapter in this volume describes therapy for KS in more detail.

NHL is the second most common malignancy associated with HIV disease. Most patients have fever, night sweats, and significant weight loss.(3) NHL appears late in the course of HIV disease, often after KS and opportunistic infections. Fine-needle aspiration biopsy (FNAB) can lead to the diagnosis of lymphoma, but evaluation of cell architecture and immunohistochemical analysis often require open biopsy. NHL frequently can present in the background of benign follicular hyperplasia, as seen in HIV lymphadenopathy; thus, diagnosis may require multiple FNABs. The histopathologic findings are variable, but the majority of these lymphomas are high grade.(3)

Treatment consists of aggressive systemic chemotherapy. HIV-infected patients with advanced disease have little tolerance for radiation therapy and often develop severe refractory mucositis even following small radiation doses to the upper aerodigestive tract.

The generalized proliferation of lymphoid tissue commonly associated with HIV disease often affects Waldeyer's ring (adenoids, lingual tonsils, and faucial tonsils). This association is so striking that adenoidal hypertrophy in a nonpediatric setting, even in an otherwise asymptomatic patient, should alert the clinician to a possible underlying HIV infection. The lymphoid hyperplasia found in the nasopharynx in these patients is apparently a manifestation of the HIV-associated lymphoid hyperplasia, seen in the peripheral lymph nodes as persistent generalized lymphadenopathy, and has a similar appearance on histopathologic examination.(4) This lymphoid hypertrophy usually involves the entire Waldeyer's ring, and is generally asymptomatic. Hypertrophic adenoidal tissue is common in this population and can cause recalcitrant nasal obstruction.(5,6) One report described airway obstruction by marked adenotonsillar lymphoid hypertrophy.(7)

Although nasal obstruction is the most common presenting symptom, acute or serous otitis media is also common. Systemic antibiotics, topical steroid sprays, or both treatments often relieve symptoms somewhat; however, when medical therapy fails, one should consider adenoidectomy and tympanotomy with tube placement if eustachian tube dysfunction is present. Stern et al.(4) recommend adenoidectomy to rule out lymphoma in all HIV-infected patients with massive adenoidal hypertrophy. In their series of seven HIV-infected patients undergoing adenoidectomy, benign lymphoid hyperplasia was found in every patient. We recommend magnetic resonance imaging (MRI) of the nasopharynx to rule out an erosive skull base process or asymmetric adenoid hypertrophy, which would suggest a lymphoma. We perform adenoidectomy for patients with a worrisome radiographic findings or for symptomatic relief of nasal obstruction in HIV-infected patients with massive adenoidal hypertrophy. Office biopsy or FNAB can be helpful to establish a diagnosis if positive, but does not definitively rule out lymphoma because of potential sampling error.

The terms "persistent generalized lymphadenopathy" and "HIV lymphadenopathy" describe the syndrome of unexplained diffuse lymphadenopathy involving two or more extrainguinal sites for longer than 3 months. Up to 70% of patients infected with HIV will develop this syndrome within the first few months after seroconversion, long before any other symptoms of HIV infection appear.(8)

The lymph nodes in HIV lymphadenopathy are soft and symmetrically distributed and can range from 1 to 5 cm.(9) Such findings are common in the head and neck locations, especially the posterior triangle.(10) On histopathologic examination, the lymph nodes have florid, reactive follicular hyperplasia, usually with some effacement of the follicular mantle by small lymphocytes and the presence of multinucleated giant cells. These findings are not specific for HIV infection or persistent generalized lymphadenopathy, and resemble the histopathologic picture of viral lymphadenitis found with CMV, varicella-zoster virus (VZV), and infectious mononucleosis.(9,11,12)

Follicular involution is another pattern noted in patients with HIV lymphadenopathy. The follicles are small, hypocellular, and hyalinized, but the paracortical regions are paradoxically hyperplastic. In contrast, lymph nodes in patients with symptomatic, late-stage HIV disease usually have a histopathologic picture labeled the lymphocyte depletion pattern. These lymph nodes have a washed-out appearance with few or no follicles and lack small lymphocytes. This pattern is associated with rapid progression of HIV disease and has a poor overall prognosis.

Clinicians should perform a biopsy of lymph nodes by fine-needle aspiration in the following situations:

1. Marked constitutional symptoms with otherwise negative findings on evaluation;

2. Adenopathy that is clearly asymmetric or nongeneralized;

3. A single disproportionately enlarging node in a patient with generalized adenopathy;

4. Peripheral cytopenia with otherwise negative findings on evaluation;

5. Other reasons for suspicion of a treatable pathologic process.

In one study of HIV-infected patients with bilateral lymphadenopathy, 50% of patients with prominent lymph nodes of 2 to 3 cm and 100% of those individuals with prominent lymph nodes larger than 3 cm demonstrated positive FNAB findings for other significant pathologic processes, such as neoplasms or infections.(12) In addition, all patients with unilateral lymphadenopathy, regardless of the size of the nodes, had positive biopsy findings for HIV-related neoplasm or infection.

Herpes zoster can often be a sign of decreasing cellular immunity associated with progression of HIV disease. Herpes zoster results from reactivation of the latent VZV and produces symptoms of burning pain, dysesthesia, and vesicular eruptions along the distribution of the affected nerve. In a prospective study of 48 high-risk patients with VZV infection of the thoracic region, Friedman-Kien et al.(13) found that 73% (35 of 48) were seropositive for HIV, and 17% (8 of 35) developed Centers for Disease Control (CDC)-defined AIDS during the 10- to 24-month follow-up, suggesting that VZV reactivation may be an early indication of progression of HIV disease. The diagnosis is usually based on the clinical appearance and confirmed with a Tzanck smear or viral culture.

Medical therapy includes acyclovir and analgesics. Oral acyclovir should be initiated with doses higher than those for herpes simplex (e.g., 800 mg 5 times daily). If oral therapy fails or if the clinical presentation is primary varicella zoster infection, intravenous acyclovir should be used (10 to 12 mg/kg infused over 1 hour every 8 hours for 7 to 14 days). Acyclovir often shortens the course of the infection, accelerates the resolution of infection-related pain, and in the case of VZV, may help prevent postherpetic neuralgia.(14) Foscarnet (e.g., 40 mg/kg intravenously over 24 hours via infusion pump) may be effective for acyclovir-resistant strains of VZV.

Non-HIV-infected patients, especially those with facial nerve involvement, benefit significantly from systemic steroids. Although steroid use remains controversial in these immune-suppressed patients, in difficult cases involving complete facial palsy or severe pain, the use of steroids should be considered.(15) The presence of other opportunistic infections or neoplasms are strong contraindications for systemic steroid use.

Postherpetic neuropathy characterized by severe pain and pruritus is often a bothersome lingering feature.(16) Herpes zoster lesions in patients with advanced HIV disease may persist for up to 10 months despite aggressive medical therapy. Disseminated disease can occur in the form of primary chickenpox.

As HIV disease progresses, up to 83% of patients develop extensive seborrheic dermatitis, often involving the face, scalp, and, less commonly, the periauricular region. Patients with seborrheic dermatitis of the external ear may present with recurrent superinfections of the involved skin, in some cases including the external ear.(17) Treatment of the involved skin with a commercially available dandruff shampoo as directed and the use of a topical steroid (cortisone cream 0.5% 3 times a day) usually control these lesions. Despite these measures, recurrences are common.

KS can arise either on the pinna or in the EAC. More severe symptoms, including conductive hearing loss, may arise if the tumor extends onto the tympanic membrane (TM) or into the middle ear. The carbon dioxide laser can excise canalicular KS. With TM involvement, however, the argon laser may spare more of the normal tissue, making a TM perforation less likely.(18)

Infections with either Pneumocystis or Mycobacterium tuberculosis separately can result in a tumor-like lesion in the EAC. With the increasing use of prophylactic treatment of patients for pulmonary Pneumocystis, the incidence of extrapulmonary infections has dramatically increased.(19) Subcutaneous cysts due to Pneumocystis carinii can occur in the EAC and can enlarge to occlude the entire canal.(15) Tuberculous infections of the middle ear can cause an aural polyp extending into the EAC. Such patients frequently have conductive hearing loss and sparse, clear otorrhea. Definitive diagnosis for these infections usually requires a biopsy, which usually reveals tuberculous organisms. While performing a biopsy, clinicians should take precaution to avoid injury to the structures deep to the TM. Clinicians should evaluate HIV-infected patients with tuberculous or pneumocystic infections of the ear for concurrent pulmonary infections with these organisms. Appropriate medical therapy for M. tuberculosis or Pneumocystis usually results in a rapid clinical resolution for both of these infections.(15)

External ear infections, including pinna cellulitis and otitis externa, occur in the HIV-infected patient. The pathophysiology, the organisms involved, and the incidence of these infections in the HIV-infected patient appear to be the same as in the immunocompetent patient.(18) Staphylococcus aureus is the most common organism isolated for pinna cellulitis, whereas Pseudomonas aeruginosa is frequently isolated from patients with otitis externa.

Most cases of pinna cellulitis respond to oral antibiotics (dicloxicillin, 500 mg orally 4 times a day for 10 days), but severe cases may necessitate the use of intravenous therapy. Management of otitis externa should include local ear drops with both antibiotics and steroids, such as Cortisporin, 4 drops in each ear affected 3 to 4 times a day, and the frequent removal of debris from the ear canal. This regimen usually leads to rapid resolution of the infection.(20,21) With more extensive soft tissue involvement, a systemic antibiotic, such as ciprofloxacin (500 to 750 mg orally 2 times a day) or levofloxcin (500 mg PO 1 times a day) for 14 days, may be beneficial.

In the immunocompromised or diabetic patient who does not respond to standard antibiotic regimens, the clinician should suspect skull base osteomyelitis, also known as malignant otitis externa. This diagnosis can be made using computed tomography (CT) images of the temporal bone. The most common pathogen involved is Pseudomonas, although in rare cases, fungal organisms such as Aspergillus may be responsible.(22) Treatment should include ceftazidime, 2 g intravenously every 12 hours for 1 to 2 weeks, and then oral ciprofloxacin until serial gallium scans show that the infection has resolved. One report described two cases of skull base osteomyelitis due to Aspergillus fumigatus in adult patients with advanced HIV disease.(23) Both responded to amphotericin B followed by oral itraconazole, 200 mg orally 2 times a day, although one patient also required surgical debridement.(23) It remains unclear whether the incidence of skull base osteomyelitis in HIV-infected patients is higher than in the general population.

Sensorineural hearing loss, both unilateral and bilateral, occurs in 21 to 49% of HIV-infected patients.(26,27) The majority of such patients have had a sensorineural hearing loss that steadily worsens with increasing frequencies, becoming moderate at high frequencies, but speech discrimination is usually near normal. A possible etiology is a primary infection by HIV of either the central nervous system (CNS) or peripheral auditory nerve. Increased latencies on auditory brain stem testing suggest central demyelination consistent with a viral infection. A recent study suggested that the abnormality is in the upper brain stem.(28) One report also described sudden sensorineural hearing loss with no clear cause in HIV-infected patients.(29) The incidence of sudden hearing loss does not seem to be increased in HIV-infected patients when compared to non-HIV-infected patients. Clinicians should consider other causes of the sensorineural hearing loss in HIV-infected patients, such as CNS infections, neoplasms, and past medications, particularly ototoxic agents. The diagnostic work-up should include a complete audiogram with impedance audiometry and auditory brain stem response testing, and a routine laboratory evaluation with serologic testing for syphilis. A thorough neurologic examination is mandatory for patients with a suspected CNS process, and clinicians should perform a lumbar puncture with associated chemistries, cytology, and cultures, and obtain CT or MRI scans of the brain. Aural rehabilitation with hearing aids should be considered for HIV-infected patients with no identified cause for hearing loss.(16) Use of any ototoxic medications such as furosemide and aminoglycosides should be avoided in patients with sensorineural hearing loss.

Vertigo can occur in the HIV-infected patient. When present, it is usually concurrent with a multitude of other neurologic symptoms. Vertigo is frequently a symptom of subacute encephalitis or HIV disease dementia complex.(18) HIV may directly affect the vestibular and auditory systems; however, verification requires further study.

Facial nerve paralysis is more common in the HIV-infected patient than in the immunocompetent patient. According to one report, up to 7.2% of patients with HIV disease will have either unilateral or bilateral facial paralysis.(18) In the majority of these patients, CNS processes are the cause of the facial paralysis; CNS toxoplasmosis is the most common identifiable cause, followed by HIV encephalitis and CNS lymphoma.

Idiopathic facial nerve palsy, or Bell's palsy, is the single most common diagnosis given for HIV-infected patients with seventh nerve paralysis. The leading theory for the cause of Bell's palsy is an infection of the facial nerve by herpes simplex virus (HSV). Researchers believe that the immunocompromise caused by the HIV infection allows greater incidence of viral infection and associated facial paralysis. The outcome in this patient group, like that in the general population, is excellent. The nerve usually recovers completely in 3 weeks to 3 months.(30,31) Standard therapy consists of corticosteroids such as prednisone, 60 mg PO orally every day for 4 days and then tapered over 10 days, and acyclovir, 200 mg orally 5 times a day, for all patients with Bell's palsy, if seen during the first 2 weeks of presentation. In the immunocompromised patient, however, concurrent opportunistic infections contraindicate the use of systemic steroids.

Herpes zoster infection, or the Ramsey Hunt syndrome, occurs more commonly in HIV-infected than in non-HIV-infected patients. Acyclovir therapy, 800 mg orally 5 times a day for 10 days, along with high-dose steroids, tapered as described for Bell's palsy, should be initiated as soon as possible.(32) This syndrome results from a chronic herpetic infection of the geniculate ganglion, which acutely results in painful herpetic vesicles in the distribution of the sensory component of the facial nerve along with facial palsy, which occasionally is permanent. Symptoms tend to be more severe in the HIV-infected than in the non-HIV-infected patient, and response to medical therapy is less predictable.

Cutaneous lesions of the nose or face are common presenting symptoms of HIV infection. KS, herpetic infection, and seborrhea-like dermatitis are three such conditions. While these are often primarily cosmetic problems, KS in particular can become symptomatic or widely disseminated.

Seborrheic Dermatitis

Facial seborrheic dermatitis also occurs in HIV-infected patients. Initially observed in 22% of the population with advanced HIV disease,(33) this rash can occur anywhere in the head and neck, but seems to have a predilection for the postauricular, nasal, and malar regions. The malar rash can resemble the butterfly pattern of systemic lupus erythematosus. Symptoms are predominantly cosmetic and a biopsy is rarely indicated.(34) Although we recommend treatment with topical corticosteroids, some cases are refractory.

Herpes Infections

Either herpes simplex or herpes zoster may cause the giant herpetic nasal ulcer.(27) Although characteristically originating in the nasal vestibule, they often extend onto the facial skin, sometimes reaching diameters of up to several centimeters.

Nasal stuffiness, a common symptom during HIV infection, has a wide-ranging differential diagnosis that includes adenoidal hypertrophy, allergic rhinitis, chronic sinusitis, and neoplasms of the nose, paranasal sinuses, or nasopharynx. History and physical examination, including indirect laryngoscopy, usually suffice for evaluation of obstructive symptoms; however, we recommend MRI or CT scanning followed by a biopsy for mass lesions or asymmetrically enlarged nasopharyngeal lymphoid tissue.

Curiously, although depressed cellular immunity results in decreased total lymphocyte and helper T-lymphocyte counts (CD4 counts), polyclonal B-cell activation produces increased circulating immune complexes with increased production of IgA, IgG, and IgE. This excessive IgE production is associated with increased IgE-mediated allergic symptoms, including allergic rhinitis. Sample et al.(40) reported a twofold increase in the incidence of allergic symptoms in HIV-infected men, noting a 41% incidence before HIV infection, compared with 87% after infection. Other investigators confirmed these increased IgE levels.(41,42) The presentation can include perennial profuse thick rhinorrhea and nasal congestion. It is important to rule out chronic bacterial sinusitis in this population through nasal endoscopy or CT imaging.

Treatment of IgE-mediated symptoms parallels that for other allergic patients. If possible, clinicians should identify specific environmental allergens and avoid them. Topical nasal steroid sprays can safely provide symptomatic relief in HIV-infected patients. There have been no reports of nasal infections with Candida or other opportunistic organisms resulting from the use of these sprays. Systemic antihistamines can also be effective. We recommend newer, second-generation antihistamines (e.g., loratidine, cetirizine, or fexfenadine) in HIV-infected patients because the pronounced anticholinergic activity inherent in older-generation antihistamines increases the viscosity and surface adhesiveness of already thick and tenacious nasal secretions. A recent initial report suggests certain patients benefit from the use of a topical anticholinergic spray, ipratroprium bromide (Atrovent), in the control of the volume of nasal discharge produced.(43) Because patients appear to vary in their response to these various medications, some trial and error is needed to best manage each individual patient's symptoms.

Presenting symptoms of sinonasal KS include nasal obstruction, intermittent epistaxis, and rhinorrhea. Although skin lesions can occur on the nose and face, sinus and intranasal lesions are less common.

The presenting symptoms of NHL include bleeding, nasal obstruction, rhinorrhea, or mass effect on the face, orbit, or other surrounding structures. Needle aspiration or tissue biopsy can confirm the diagnosis.

Rhinosinusitis is common in HIV-infected patients, with a reported prevalence of between 20 and 68%.(37) The reason these patients are so prone to infection is not entirely clear, but changes in the mucociliary clearance, a primary local defense mechanism for the sinuses, has been reported.(44) The entire spectrum of sinonasal inflammatory disease may be present and includes acute sinusitis, recurrent acute sinusitis, chronic sinusitis with mucosal thickening, or chronic rhinitis, indicated by nasal congestion and thick, mucopurulent postnasal drainage.

The bacteriology of acute sinusitis in this population includes the same organisms normally considered in the immunocompetent patient, namely Streptococcus pneumoniae, Moraxella catarrhalis, and H. influenzae. HIV-infected patients do seem to have a higher incidence of S. aureus and P aerginosa cultured from patients with acute and chronic sinusitis, often in association with anaerobic bacteria.(16,27,45,46) P. aeruginosa, which is an unusual pathogen in immunocompetent patients, accounts for up to 17% of acute sinusitis and 20% of cases of chronic sinusitis in the HIV-infected population.(45,47,48)

When patients are in the late stages of HIV infection, atypical opportunistic infections can occur in the nose or paranasal sinuses. Reports have described fungal sinusitis with Alternaria alternata, Aspergillus, Pseudallescheria boydii, Cryptococcus, and Candida albicans.(27,49-52) Although the incidence of rhinocerebral mucormycosis does not seem to be increased in the HIV-infected population,(53) increasing numbers of cases of invasive Aspergillus sinusitis have been reported.(54,55) These invasive fungal infections appear in a subacute fashion, distinct from the fulminant Aspergillus infections associated with bone marrow transplant patients.(55) Another report described rhinosinusitis secondary to primary CMV infection,(56,57) not surprising given the almost ubiquitous nature of CMV in this population. Other interesting case reports described sinusitis caused by the protozoans Acanthamoeba castellani,(58) Microsporidian, and Legionella pneumophila.(59) Clearly, clinicians must take an aggressive approach to the diagnosis and treatment for all patients who fail initial empiric antibiotic therapy. Antral lavage and culture is an important next step if symptoms persist following initial medical therapy.

The diagnosis and treatment of sinusitis in this population is similar to that for non-HIV-infected patients. Signs and symptoms can include fever, headache, localizing symptoms, and mucopurulent nasal drainage. In many patients, often initial findings relate primarily to the pulmonary system with recurrent bacterial pneumonias and bronchospasm. Although chronic, thick mucopurulent postnasal drainage is often the only symptom referable to the paranasal sinuses in these cases, radiographic studies usually reveal extensive paranasal sinus disease. Although plain sinus radiographs can be useful, CT scanning more clearly defines the extent of these persistent infections.(60) Nasal endoscopic examination is a valuable tool for diagnosis and for the evaluation of therapeutic response.

Standard outpatient medical therapy is often effective in this patient population. Clinicians must rigorously employ a dual approach, which includes an antibiotic as well as a decongestant. Amoxicillin (500 mg 3 times a day) or sulfamethoxazole-trimethoprim (400 mg/80 mg 2 times a day) may be used for primary treatment; however, amoxicillin with clavulanate (Augmentin) (875 mg 2 times a day) or an oral cephalosporin, such as cefuroxime axetil (Ceftin) (250 mg 2 times a day), is often more effective. Oral antibiotic therapy should continue for a minimum of 3 weeks. In patients resistant to therapy or with evidence of actual or impending extrasinus complications, hospital admission for intravenous antibiotics, surgical drainage, or both is imperative.(61)

Decongestant therapy is as important as antibiotic management. Systemic decongestants (usually pseudoephedrine, 120 mg every 12 hours) should be continued throughout the 3 weeks of therapy. We also recommend topical decongestant sprays; however, their use must be limited to the first 4 or 5 days of treatment to avoid rebound nasal congestion. Because guaifenesin (Humibid L.A., 1200 mg every 12 hours for the 3 weeks of antibiotic therapy) significantly thins nasal secretions and decreases nasal congestion, it is a valuable adjunct to treating sinusitis in HIV-infected patients.(62)

As the CD4 count decreases and immune function diminishes, sinusitis usually becomes chronic. At CD4 counts of less than 200 mm³, sinusitis becomes particularly resistant to standard therapy. In these patients, antibiotic coverage often must be broadened to include S. aureus, anaerobic bacteria, and P. aeruginosa. While empiric therapy may be continued in this situation, culture-directed antibiotic coverage is more effective. Amoxicillin with clavulanate (875 mg 2 times daily) usually is a good choice for chronic sinusitis, but provides poor coverage for P. aeruginosa. Furthermore, while this regimen theoretically provides good anaerobic coverage, the addition of metronidazole (250 mg 2 times daily; Flagyl) or clindamycin (Cleocin; 300 mg 3 times daily) often improves the clinical response. Levofloxacin (Levaquin; 500 mg once daily), plus clindamycin or Flagyl, is an excellent combination especially for P. aeruginosa and Staphylococcus. Treatment for chronic sinusitis should be continued for 5 or 6 weeks to optimize success.

The decongestant treatment for chronic sinusitis includes systemic decongestants; however, topical decongestant sprays do not work. We recommend treatment with the expectorant guaifenesin, and continue it chronically even after the infection has been successfully treated. Because of the chronic inflammation and resultant mucosal edema that accompanies chronic sinusitis, topical nasal steroids are routinely employed and continued chronically.

If the patient does not respond to medical therapy, sinus culture should be performed to rule out any unusual organisms. Maxillary puncture remains the gold standard for sinus culture, although endoscope-guided culture of the middle meatus will identify the pathogenic organisms in up to 90% of cases in the general population. Neither method will be able to identify viral infection or invasive fungal sinusitis, which requires histopathologic demonstration of the organism invading the tissue. In HIV-infected patients, multiple organisms such as CMV or Aspergillus may be cultured from the nasal passages or sinuses on routine culture.

Data detailing the incidence of extrasinus complications are not readily available. When complications of sinusitis occur, the clinical course is often fulminant and the response to therapy unpredictable. Traditional surgical and medical therapeutic options are usually effective only after a complex and prolonged clinical course.

In patients with a CD4 count of less than 50 cells/mm³ who have persistent sinus symptoms, in particular severe facial or headache pain that cannot be explained by any concurrent problems, the possibility of invasive fungal infection must be considered. On examination of the hard palate, nasal mucosa or skin overlying the sinuses, any ischemic or dark necrotic changes or extensive crusting is strongly suggestive of this type of fungal infection. In these immunocompromised patients, a CT scan of the sinuses may show minimal mucosal changes. The only way to make a definitive diagnosis is to obtain tissue for histopathologic studies and for culture.

When clinicians have exhausted all medical options, surgery can be performed to enhance drainage as well as obtain cultures and biopsy specimens to rule out unusual opportunistic infections. Endoscopic sinus surgery (ESS) is particularly effective. ESS is an outpatient procedure with minimal morbidity and has dramatically changed our threshold for performing sinus surgery for biopsy or to improve sinus drainage. Experience at San Francisco General Hospital and at the University of California San Francisco indicates that ESS results in symptomatic improvement in most HIV-infected patients. Surgical expectations and patient prognosis must be tempered by an understanding of the stage and progressive nature of the underlying HIV disease. An algorithm for the management of sinusitis in the HIV-infected patient is shown in Figure 1.

Oral candidiasis (thrush) is by far the most common oral condition in this population. Even for patients with CD4 counts from 200 to 500 mm³, thrush often is a recurring problem. This infection typically presents as tender, white, pseudomembranous or plaque-like lesions with underlying erosive erythematous mucosal surfaces; however, the less typical atrophic or chronic hypertrophic form is also often encountered. Another common form of oral candidiasis is angular cheilitis, which typically presents as a clinically obvious, nonhealing fissure at the oral commissure (the corners of the mouth). In atypical cases, a potassium hydroxide preparation of scrapings from these lesions is usually diagnostic.(68,69)

Although topical therapy with nystatin (Mycostatin) can be effective, repeated courses of other topical medications, such as oral troches of clotrimazole, can also be used and are sometimes more effective. Systemic therapy with ketoconazole (200 to 400 mg daily) often dramatically improves thrush that is unresponsive to topical regimens. This agent depends on gastric acidity for effective absorption. Serum levels are not adequate in patients taking H2 blockers or when ketoconazole is taken with antacids. Alternatively, fluconazole (200 mg/day) has better absorption in a nonacidic environment and fewer side effects, but it is substantially more expensive.(70,71) Severe cases unresponsive to all other therapeutic options may require intravenous amphotericin B therapy. When immunocompromise becomes severe in the late stages of HIV infection, suppression of oral Candida may require prophylactic antifungal agents, especially when patients take broad-spectrum antibiotics.

Oral herpes simplex is frequently associated with HIV disease. While HSV-1 is the usual strain, HSV-2 has also occurred orally, and herpes labialis is the most common presentation. Crops of "fever blisters" occur on the palate, gingiva, or other oral mucosal surfaces. Although similar to infection in non-HIV-infected patients, these lesions tend to be larger and more numerous, recur more frequently, and often persist longer. They can also extend onto adjacent skin and coalesce to form giant herpetic lesions.(16,72)

Treatment may not be necessary if the lesions are small, relatively asymptomatic, and beginning to heal. Otherwise, treatment consists of oral acyclovir (200 to 800 mg 5 times a day) for large or symptomatic lesions. Usually, however, these larger lesions require high-dose systemic antiviral agents, such as acyclovir (up to 4 g per day). Fortunately, acyclovir has minimal toxicity, making it useful for prophylaxis in patients with frequent recurrences. A commonly used dose for chronic suppression is 400 mg 2 times a day.

Varicella zoster also occurs in the oral cavity of HIV-infected patients, along the dermatomal distribution of the fifth cranial nerve, the trigeminal nerve, and as crops of vesicular lesions on the hard or soft palate, lips, and gingiva. While usually confined to the specific nerve distribution, viral dissemination occasionally occurs in severely immunocompromised patients. Lesions in the ophthalmic branch of the trigeminal nerve, especially vesicles at the tip of the nose, often herald infection of the cornea (zoster ophthalmicus). Zoster in this dermatome is an indication for aggressive management, usually including intravenous acyclovir, to prevent ophthalmic complications.

Hairy leukoplakia is a white, vertically corrugated lesion that appears along the anterior lateral border of the tongue, occurs almost exclusively in HIV-infected patients, and is associated with more rapid progression to the advanced stage of HIV disease (AIDS). In one study, the probability of developing CDC-defined AIDS was 50% at 16 months and up to 80% at 30 months in patients with hairy leukoplakia. Epstein-Barr virus (EBV) is associated with these lesions and is the probable cause. Hairy leukoplakia is primarily an asymptomatic condition requiring little more than recognition and observation. Often confused with oral candidiasis or hyperkeratotic leukoplakia, hairy leukoplakia is not a harbinger of more deeply seated infections or neoplasia. Treatment is generally unnecessary.(73-75)

One of the most painful and troublesome conditions of the oral cavity is recurrent aphthous ulcerations.(76) Whereas many non-HIV-infected persons have minor (< 6 mm in diameter) aphthous lesions, HIV-infected patients frequently present with giant (several centimeters in diameter) aphthous ulcerations. These lesions are usually the result of smaller lesions coalescing into large ulcers that can present anywhere in the oral cavity or pharynx. They can cause tremendous morbidity. In many instances, the severe odynophagia associated with giant aphthous stomatitis can produce anorexia and dehydration, and thus contribute to AIDS wasting and weight loss. Secondary infection further adds to the severe pain and constitutional symptoms accompanying this condition.(65) Details of treatment of aphthous ulcers are provided in the chapter concerning the oral manifestations of HIV disease.

Although the precise etiology of xerostomia is unclear, histopathologic changes in both the minor as well as the major salivary glands suggest a chronic inflammatory process in many ways similar to Sjögren's syndrome. More than just a bothersome condition, severe xerostomia can interfere with deglutition, thereby contributing to nutritional deficiencies. Furthermore, without meticulous attention to dental and oral hygiene, xerostomia will accelerate dental decay and the development of caries and periodontal disease. Frequent oral irrigations and saline rinses every 2 to 3 hours and the use of salivary substitutes often provide some relief. Sialagogues, such as sugarless gum or bethanechol, can also relieve some of the dry mouth symptoms. Clinicians should recommend a dental consultant for topical fluoride therapy to help prevent or arrest dental decay.(65,67,77,78)

By far, KS is the most common oral malignancy in HIV disease. Although these tumors can occur anywhere in the oral cavity, nearly 95% are found on the palate. Gingival surfaces as well as the oropharynx are other frequent sites. At first, these lesions are usually flat and asymptomatic, but they often become exophytic and ulcerated. Secondary infection often occurs, producing severe, increasing pain, difficulty with mastication and swallowing, and increasing difficulty maintaining good oral hygiene.(79,80)

When these lesions become symptomatic, clinicians can consider several treatment options. Low-dose radiation therapy (1,500 cGy) is usually very effective, although HIV-infected patients have reduced tissue tolerance to radiation and frequently develop severe mucositis after even low doses.(81) An alternative therapy that has been successful in some cases of oral and epiglottic KS is intralesional injection of vinblastine (0.01 to 0.04 mg every 2 to 4 weeks).(79,82,83)

NHL is a malignancy occurring with increased frequency in patients with HIV disease that often is found in the oral cavity. These lymphomas can occur anywhere in the mouth; frequent sites include the gingiva and the palate, with extension onto or from Waldeyer's ring, especially the tonsils. Usually not the initial manifestation of late-stage HIV disease, NHL generally is a grim prognostic sign. NHL is usually an exophytic tumor; however, it can present as a large ulcerative area in the mouth or pharynx. NHL can occasionally be confused with nonhealing giant aphthous lesions. To exclude NHL, clinicians should perform a biopsy on any nonhealing oral or pharyngeal ulceration that persists after aggressive medical management.(84,85)

In one study, squamous cell carcinoma of the oral cavity was reported to be more common in young homosexual men with advanced HIV disease when compared to the general population.(86) Although no clear causal relationship was established, an association was suggested. The extent and staging of the disease guide treatment. The increased morbidity associated with radiation therapy in HIV-infected patients, however, favors an approach heavily weighted toward surgical excision.

Aggressive gingivitis and periodontal disease are common in patients with HIV disease. In those individuals with more advanced HIV disease, these conditions can progress rapidly from mild gingivitis to a necrotizing process with severe pain, soft tissue loss and gingival recession, and bone exposure and sequestration. Oral antibiotics that aggressively target anaerobic organisms (e.g., clindamycin, 300 mg 4 times a day; metronidazole, 250 mg 4 times a day) may control the acute infection. Although diligent oral hygiene with frequent antibacterial mouth rinse can slow the progression and prevent periodontal complications in some patients, necrotizing ulcerative gingivitis often continues despite aggressive antibiotic measures. Topical irrigation with povidone-iodine (Betadine) and chlorhexidine gluconate (Peridex) is somewhat effective.(16,67,87)

Candidal infection can occur in the oropharynx, hypopharynx, and larynx, and usually results in severe odynophagia that often interferes with deglutition. When the larynx is affected, hoarseness is a prominent feature. Some degree of aspiration also occasionally results due to interference with normal laryngeal function. When the hypopharynx and larynx are affected, the clinician must entertain the possibility of esophageal candidiasis, and obtain appropriate diagnostic studies (barium swallow or esophagoscopy). Treatment in these cases usually requires systemic antifungal agents and response to therapy is less predictable. In general, candidiasis of the pharynx, larynx, and esophagus is associated with advanced HIV disease and CD4 counts less than 200.(88)

Herpes simplex lesions can occur in the pharynx and larynx. CMV infection has also been observed with increasing frequency. The clinical findings are often nonspecific; however, biopsy with histopathologic examination and viral culture will usually confirm the diagnosis. Systemic antiviral agents (ganciclovir or foscarnet) can produce symptomatic improvement for these patients. This diagnosis should be considered when empiric therapy for other infectious and inflammatory conditions is ineffective and malignant conditions have been excluded.(89)

As in the oral cavity, recurrent aphthous ulcerations also occur in the pharynx, manifesting as giant aphthous ulcers (> 2 cm) in the oropharyngeal region, especially the tonsillar pillars, tonsils, and base of the tongue. We have also encountered large aphthous lesions in the hypopharynx and nasopharynx. Treatment parallels that in the oral cavity. Severe symptoms associated with lesions in the pharynx and larynx, however, usually necessitate aggressive medical therapy and early nutritional support.

Acute adult epiglottitis has been observed in HIV-infected patients. As in the non-HIV-infected population, this condition is serious and potentially life-threatening. Symptoms usually consist of severe sore throat, odynophagia, laryngeal tenderness, fever, and malaise. Drooling, stridor, and airway obstruction are usually late symptoms in adults. Simple examination of the oral cavity and oropharynx is often unimpressive; however, the lack of clinically apparent disease in the setting of such severe symptoms should raise the suspicion of this potentially grave diagnosis. Tenderness to palpation and movement of the larynx is almost universal. Examination of the hypopharynx and larynx, either indirectly with a laryngeal mirror or using a fiberoptic nasopharyngoscope, will immediately reveal the diagnosis.(90)

The medical management of epiglottitis includes hospitalization, close airway observation or intubation (depending on the degree of airway compromise at presentation), intravenous antibiotics with broad-spectrum coverage (e.g., cefuroxime 1.5 g every 8 hours plus clindamycin 900 mg every 8 hours), and hydration. Failure to show improvement after 48 to 72 hours of aggressive therapy should raise the possibility of an infection with an unusual opportunistic organism or an underlying malignant process, and necessitates direct laryngoscopy for biopsy. Because of the severe secondary edema associated with biopsy in this setting, prolonged intubation or tracheotomy is often necessary for airway management.

Benign lymphoid adenotonsillar hyperplasia in Waldeyer's ring can often result in nasal airway obstruction, eustachian tube obstruction, and occasionally, oropharyngeal airway compromise. Even the lingual tonsillar tissue at the base of the tongue can become tremendously enlarged, resulting in dysphagia and obstructive apnea, especially when the patient is recumbent. Although antibiotic therapy occasionally relieves these symptoms, acute or chronic bacterial infection rarely underlies this problem. Surgery is the best alternative when this condition becomes symptomatic.(6,7) Clinicians must also carefully evaluate the nasopharynx in all such patients for neoplastic processes, especially KS and NHL, which can also produce eustachian tube dysfunction. Endoscopic examination or an imaging study of the nasopharynx (either CT or MRI) can allow identification of obstructing tumors. Specific diagnosis of tumor type often requires biopsy. Lymphoid hyperplasia is symmetric in appearance, in contrast to the neoplastic processes.

KS and NHL can occur in the pharynx and larynx. The ever-present risk of airway obstruction and interference with deglutition makes early aggressive therapy vital. Despite the mucositis that often accompanies radiation therapy, this treatment is the primary therapeutic tool for malignancies in this region. For tumors encroaching on the airway, prophylactic tracheotomy is worth considering because the acute inflammatory response accompanying radiation will often result in total airway obstruction before the tumor begins to regress. A nasal feeding tube is also helpful to ensure nutrition.(91-93)

Bacterial lymphadenitis and deep neck infections can present as an enlarging tender mass in the neck of HIV-infected patients, but the incidence compared to the immunocompetent population remains unclear. The majority of pathogens isolated from deep neck infections in HIV-infected patients are similar to those in the general population. Although enteric pathogens and unusual organisms have been found, they are quite rare.(105) In addition, there is a higher incidence of complications and more frequent recurrences in this patient population. Management should be surgical and aggressive, with cultures for mycotic, mycobacterial, and bacterial organisms from all involved tissue or any inflammatory exudate. If the patient does not respond to standard empiric intravenous antibiotic therapy, such as ampicillin with sulbactam (Unasyn) or cefuroxime (1.5 g every 8 hours) combined with Flagyl (500 mg every 6 hours) postoperatively, the clinician should have a low threshold for broadening antibiotic coverage.(105)

The incidence of M. tuberculosis (TB) infections is rising among HIV-infected patients, and an increasing proportion of such infections involve extrapulmonary disease.(106) Trends suggest that the incidence of active tuberculosis reported in patients with advanced HIV disease will grow well beyond the 4% reported in 1991.(107,108) In patients with advanced HIV disease, 50 to 67% of tuberculous infections will be extrapulmonary, most commonly involving the cervical nodes and the bone marrow.(109) The majority of patients with tuberculous lymphadenitis have no symptoms other than an enlarging neck mass.(109,110) Tuberculous lymph nodes are usually firm and not tender, but up to 10% of these masses can be inflamed and painful to palpation.(109)

A skin test (PPD) is useful in routine screening of asymptomatic persons at risk for TB, but it is not useful in the diagnosis of active disease. A positive PPD may be suggestive, but a PPD is commonly negative in the setting of active TB, even in non-HIV-infected individuals, and many persons with inactive TB -- especially immigrants to the United States -- will have a positive PPD without active disease. Thus, a PPD is not useful in ruling in, or ruling out, or characterizing mycobacterial disease. Anergy testing is not helpful in this setting and is no longer recommended because it is not standardized and gives variable results. A recent conversion from a negative to a positive PPD skin response is highly suspicious of a mycobacterial infection, and should prompt further evaluation with tissue or culture confirmation.

Diagnosis of mycobacterial disease must be based on culture and stains from tissue. In the majority of patients, FNAB can confirm diagnosis.(109,111) In the rare cases that require open biopsy, the classic caseating granulomas on histopathologic examination may be poorly formed or absent. Because nontuberculous mycobacteria cannot be differentiated from tuberculous strains on acid-fast staining, definitive diagnosis relies on culture of the organism. As a general rule, in M. tuberculosis infections, histopathologic examination reveals a few organisms per high-power field, in contrast to the multitude of organisms per high-power field in tissue infected by atypical mycobacterial infections. Most clinicians initiate empiric therapy for TB because cultures may require 6 weeks of growth before definitive typing of the organism is possible. Clinicians should also diligently examine any patient with cervical tuberculous lymphadenitis for pulmonary or systemic involvement to fully realize the extent of infection. Treatment of TB in HIV-infected patients is covered in detail in another chapter in this volume.

Before the HIV epidemic, the majority of patients presenting with nontuberculous mycobacterial infections were children. Immunocompetent adults with cervical mycobacteria were almost always infected by M. tuberculosis. In the HIV-infected population, however, Mycobacterium avium complex (MAC) infection is the most common mycobacterial infection. MAC infection appears to originate from the lungs, but it can be isolated from lymph nodes, as well as multiple other sites in up to 50% of affected patients.(111,112) Histopathologic analysis of the involved tissue usually reveals poorly formed granulomas or no granulomas at all. In the majority of cases, this Mycobacteria presents in end-stage HIV disease as a disseminated infection. It is unclear what effect this type of infection has on the overall survival of HIV-infected patients, because the majority of patients have concomitant life-threatening infections or neoplasms. If this Mycobacteria is isolated, further diagnostic measures are essential to detect disseminated MAC infection, as well as other opportunistic organisms. Unlike M. tuberculosis, the response of atypical mycobacterial infections to traditional antimycobacterial drugs is often poor.(111,112) Newer regimens including azithromycin or clarithromycin are effective. Treatment of MAC infections is described in another chapter in this volume.

Pneumocystis carinii

Pneumocystis carinii pneumonia (PCP) is the index for diagnosis in more than 60% of patients with the CDC-defined late stage of HIV disease called AIDS. Extrapulmonary Pneumocystis was previously associated only with overwhelming, often fatal, disseminated infection. With the use of prophylactic treatment for pulmonary Pneumocystis, the incidence of extrapulmonary disease has risen.(19) More recently, reports have described cervical infections without systemic or pulmonary involvement including an enlarging cervical mass from Pneumocystis infection of lymph nodes or the thyroid gland.(113,114) Thyroid involvement produces a diffuse goiter-like swelling and the patient can be clinically hypothyroid. Characteristic histopathologic findings include a flocculent (foamy) amorphous material in the dilated sinuses of the lymph nodes. The Gomori methenamine-silver stain can demonstrate the cystic form of Pneumocystis organisms in fine-needle aspiration specimens. The diagnosis of extrapulmonary Pneumocystis should prompt a careful search for both pulmonary and systemic disease. These cervical infections usually respond rapidly to medical therapy as used for pulmonary infections. Treatment of PCP is covered in another chapter in this volume.

Toxoplasmosis

Toxoplasmosis is an opportunistic organism frequently problematic in the HIV-infected population and is the most frequent cause of focal intracerebral lesions.(115) Latent infection with Toxoplasma is a frequent occurrence in the general population, but the incidence varies greatly with geographic and dietary factors.(116) In the non-HIV-infected population, localized cervical lymphadenopathy with minimal symptomatology is the most common clinical manifestation of toxoplasmosis.(117) In patients with HIV disease, toxoplasmosis results from the reactivation of latent infection, with subsequent development of toxoplasmic encephalitis. The incidence of localized lymph node disease in HIV-infected patients is unclear. One report described the isolation of Toxoplasma from lymph nodes of HIV-infected patients, usually with disseminated disease.(116) The diagnosis and management of toxoplasmosis is reviewed more extensively in another section.

Fungal Infections

Fungal infections, including cryptococcosis, histoplasmosis, and coccidioidomycosis, can manifest as a cervical mass in the HIV-infected patient. The incidence of each depends on the regional prevalence of these ubiquitous organisms. Cryptococcus neoformans is the most prevalent cause of deep-seated fungal infections in the HIV-infected population, occurring in 5 to 10% of these patients. Pulmonary cryptococcosis is the most frequent manifestation of infection, although cryptococcal meningitis is a more common presentation in the HIV-infected patient.(118) Pulmonary and disseminated forms of histoplasmosis and coccidioidomycosis are becoming more widespread in patients with advanced HIV disease as the incidence of HIV infections increases in areas in which Histoplasma or Coccidioides immitis is endemic.(119-121) There are apparently no reports of isolated lymph node disease caused by these pathogens in patients with HIV disease; thus, the isolation of these mycotic organisms from lymph nodes strongly suggests disseminated infection.(118,120) Serum and cerebrospinal fluid antigen titers correlate well with active cryptococcal disease. Serologic studies are not helpful, however, for histoplasmosis and coccidioidomycosis. On histopathologic examination, the typical granulomatous lesions of fungal infections may be absent. Clinicians should employ specific stains, such as Gomori methenamine-silver or mucicarmine, to identify fungal elements, and should send specimens from all neck mass biopsies for mycotic cultures. One report of non-HIV-related immunosuppressed patients described disseminated candidiasis presenting as an enlarging neck mass caused by either lymphadenopathy or myositis.(122) Isolation of any fungal organism from the cervical lymph nodes of HIV-infected patients requires further evaluation for systemic involvement. Therapy with amphotericin B is moderately effective. Diagnosis and therapy for these organisms are described elsewhere in this volume.

Both KS and NHL can initially present as an enlarging cervical mass. In one report, investigators described cervical lymph node presentation of KS in four of a series of 13 patients with advanced HIV disease with KS.(93) KS has also been found in intraparotid lymph nodes.(123) An FNAB of lymph nodes can diagnose KS, but its differentiation from bacillary epithelioid angiomatosis (cat-scratch disease) may require an open biopsy. The histopathology, natural history, and management are well described in other sections. NHL is the second most common HIV-associated malignancy. NHL commonly presents as a nontender, rapidly enlarging neck mass.

Other malignancies can also present as a progressively enlarging, painless neck mass. In this differential diagnosis are Hodgkin's disease and squamous cell carcinoma. The precise relationship between Hodgkin's disease and HIV disease has not been defined, but the natural history of Hodgkin's disease appears to be different in HIV-infected than in non-HIV-infected patients. In the HIV-infected patient, Hodgkin's disease is more aggressive and less responsive to treatment.(3) FNAB can frequently identify this malignancy, but the more detailed histologic analysis needed for treatment planning often requires excisional biopsy. Squamous cell carcinoma, the most common malignancy in the immunocompetent patient, has also occurred in patients with advanced HIV disease,(124) although there have been very limited numbers of cases, and the association of HIV with this carcinoma remains unclear. The work-up is the same as for the general population. The treatment is generally surgical, because HIV-infected patients tolerate radiotherapy very poorly.

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