Biology and Immunology

HIV infects and debilitates lymphocytes and macrophages leading to progressive immune compromise. Progressive decline in immune function in later stages of infection culminates in the acquired immunodeficiency syndrome (AIDS). Anecdotal reports³ of unusual infections and idiopathic immune deficiency, primarily in homosexual men, began in the early 1980s and rapidly grew into the HIV/AIDS epidemic that has affected the world population. Every day, more than 6800 people become infected with HIV and 5700 people die of AIDS.⁴ Worldwide, approximately 33.2 million people are living with HIV infection, with sub-Saharan Africa being the most severely affected region, where AIDS is the leading cause of death. After many years of increase, the global prevalence of HIV has stabilized and in some countries has even decreased.⁴ With wider availability of effective treatment, rates of death have also recently begun to decline.

Transmission of HIV occurs through body fluids and tissues. Virus from an infected patient may inoculate the bloodstream of another individual through a breach in skin or mucosa, or via intravenous infusion. Modes of transmission include sexual intercourse, the sharing of needles by intravenous drug users, vertical transmission from mother to child, and, rarely, transfusion of contaminated blood products or accidental exposure in health care workers. More than 50% of new HIV infections in the United States occur in men who have sex with men; infection after heterosexual intercourse and injection drug use lead to 32% and 18% of new infections, respectively.⁴

HIV is a retrovirus in the Lentivirus subfamily, named for the slow progression of disease in affected individuals. These viruses establish chronic infections with a long incubation time and slow progression of disease. Viruses in the Lentivirus family typically infect cells involved in immune modulation; in the case of HIV, that is primarily CD4 T cells and macrophages, resulting in defects in both humoral and cell-mediated immunity. The virus life cycle begins when the virus binds to the CD4 receptor, a surface protein on the helper T subset of T lymphocytes, which is also expressed on macrophages. Fusion of the viral and cell membranes allows entry of the viral core into the cell. The reverse transcriptase enzyme, a protein carried by the virus, allows transcription of RNA into DNA (a reversal of normal transcription), then mediates transcription of the viral RNA genome into viral DNA. Viral integrase, another viral protein, then facilitates incorporation of the viral DNA into the host genome. The viral DNA is transcribed into multiple RNA copies by the host cell. This newly created RNA may be spliced and translated into viral proteins or it may remain intact as a future viral genome. Translation of some viral RNA sequences results in protein precursors or multiple proteins bound together. These precursors undergo proteolytic processing by a viral protease that liberates the functional viral proteins. These proteases are required for viral infectivity. Following replication of the viral genome and proteins, the new viruses bud from the infected cell and proceed to infect new cells. The viral DNA polymerase is error-prone, incorporating one mismatched nucleotide per genome per round of transcription. This, combined with the amount of replication that occurs, establishes a vast pool of genetic diversity.^5,6 The development of vast genetic diversity also gives the virus an advantage in the development of drug resistance and provides a critical barrier to vaccine development.

Diagnosis and Classification

HIV infection is diagnosed when anti-HIV antibodies are detected in the serum by screening enzyme-linked immunosorbent assay (ELISA) and is confirmed with specific antibody detection with Western blot. Persistent antibodies against HIV typically occur within 3 months of infection. The CDC classification system for HIV, last updated in 1993, is based on the clinical manifestations of disease and the patient’s CD4 count (Table 15-2).⁷ These classifications assist in assessing the level of immune compromise and the corresponding risk for development of opportunistic infection or neoplasm. Three clinical categories have been identified: (A) asymptomatic HIV infection, persistent generalized lymphadenopathy, or acute HIV infection (a mononucleosis-type syndrome); (B) symptomatic conditions such as oral thrush, oral hairy leukoplakia, and fungal sinusitis that are attributed to HIV infection but do not fall into category A or C; (C) AIDS-defining conditions (Table 15-3). Patients may be further stratified according to their CD4 counts: (1) >500 cells/µL; (2) 200 to 499 cells/µL; (3) <200 cells/µL. The lowest accurate CD4 count, not the most recent, is used for classification purposes. AIDS is diagnosed for any patient who develops an AIDS-defining illness (category C) or CD4 less than 200 cells/µL (category 3). The World Health Organization (WHO) classification for HIV infection includes four clinical stages⁸:

Table 15-3 AIDS-Defining Illnesses

Adapted from CDC 1993 revised classification system for HIV infection and expanded surveillance case definition for AIDS among adolescents and adults. MMWR Morb Mortal Wkly Rep. 1993;41(RR-17):1.

Occupational Exposure to Human Immunodeficiency Virus Infection

With more than 1.3 million HIV-positive children and adults in the United States⁴ and with the high prevalence of otolaryngologic complaints among these patients, most otolaryngologists will treat HIV-positive patients. An understanding of the risks of occupational transmission as well as precautions that may minimize such transmission is essential. There have been 57 documented cases of HIV seroconversion among U.S. health care personnel following occupational exposure, the most recent occurring in 2000.¹⁹ Because of the voluntary nature of the reporting system, there may be underreporting of cases. Exposures that carry a risk for HIV transmission are percutaneous injuries (e.g., needlestick or cut with a sharp object) or contact of mucous membrane or nonintact skin with blood, tissue, or body fluids that are potentially infectious. The risk of transmission from fluid other than blood or transmission through nonintact skin is too low to be estimated in prospective studies. Even though cerebrospinal fluid carries a risk of transmission, nasal secretions, saliva, sputum, sweat, tears, urine, and vomitus are not considered infectious unless they are visibly bloody.²⁰ Pooled prospective data suggest an average risk of HIV transmission of 0.3% for needlesticks and 0.09% following mucous membrane exposure.²¹ Whereas injury from suture needles has been suggested as a possible source of occupational exposure to HIV, such an injury has not been implicated as a source of transmission in prospective studies. Although a lower viral load (<1500 RNA copies/mL) or one that is below the limits of detection probably indicates a lower titer exposure, it does not rule out the possibility of transmission.

Prevention of blood exposure through the use of safe practices, barrier precautions, safe needle devices, and other innovations is the best way to prevent infection with HIV and other blood-borne pathogens.²² Simple strategies such as using double gloves, eye protection, impermeable gowns, and special techniques for passing sharp objects have all been suggested to minimize exposure risk. Despite such precautions, needlesticks and mucosal exposures will continue. After exposure to blood or other infectious fluids, the following actions should be taken immediately²²: Wash needlestick areas and cuts with soap and water; flush nose, mouth, or skin with water; irrigate eyes with clean water, saline, or sterile irrigants. To minimize the risk of disease transmission, postexposure prophylaxis (PEP) should be initiated within hours of exposure and should continue for 4 weeks.²⁰ The number of agents used depends on the type of exposure and risk profile of the source patient (Table 15-4). Treatment may be discontinued if the source patient subsequently tests negative for HIV infection and does not demonstrate any evidence of acute HIV infection. Exposed individuals should be tested for HIV at the time of exposure with follow-up testing at 6 weeks, 12 weeks, and 6 months after exposure.²⁰ Prevention of HIV transmission following PEP is not complete. There have been at least 20 cases of seroconversion despite the use of PEP,²¹ with some of the patients having received multiple drug regimens. Thus careful adherence to universal precautions with avoidance of exposure remains the most prudent way to prevent infection.

Kaposi’s Sarcoma

Presentation and Diagnosis

Compared with the classic and endemic forms of KS, immunosuppression-related KS and AIDS-KS are more aggressive. The clinical course of AIDS-KS ranges from an indolent, slowly progressive disease to a rapidly progressive and fatal course.²⁸ AIDS-KS is associated with a shortened life expectancy, although most patients die of opportunistic infection or lymphoma and not KS per se.⁵⁹ Multiple lesions develop in many patients, who more commonly have lymph node or visceral organ involvement. Frequently involved sites include the skin, oral mucosa, and lymph nodes. AIDS-KS occurs in the head and neck in as many as 70% of cases,^60,61 whereas immunosuppression-related KS tends to occur in the lower extremities.³⁰ Oral KS occurs in roughly one third of AIDS-KS,⁶² whereas in immunosuppression-related KS cutaneous lesions are most common.⁶³ Cutaneous disease presents as multicentric macular and papular lesions that are nontender and nonblanching. These frequently coalesce and progress to violaceous, nodular lesions (Fig. 15-1). They are usually asymptomatic but may become pruritic and aesthetically displeasing. Mucosal KS commonly occurs in the oral cavity, and oral KS, which is associated with lower CD4 counts than cutaneous disease,⁶⁶ may be a first sign of HIV infection.^64,65 Oral KS may resemble cyclosporine-associated gingival hyperplasia in organ transplant recipients but cyclosporine usually causes generalized fibrotic gingival hyperplasia whereas oral KS produces a more localized red-purple enlargement.⁶⁷ The most frequently affected sites in oral KS are the hard palate, gingiva, and tongue.⁶⁴ Mucosal KS is more likely to be symptomatic than cutaneous disease. Lesions may cause loose teeth and are associated with pain, ulceration, and bleeding.

Figure 15-1. Nodular Kaposi’s sarcoma of the gingiva and palate. Given the ulcerated and fungating appearance, the differential diagnosis includes non-Hodgkin’s lymphoma and squamous cell carcinoma.

(Courtesy of Dr. Russel Corio.)

Depending on its location, visceral KS may be asymptomatic or rapidly fatal. Postmortem studies suggest that more than 25% of AIDS-KS patients have visceral lesions.³⁰ These most commonly involve the gastrointestinal (GI) tract, liver, spleen, and lungs. GI disease is often asymptomatic, whereas median survival in pulmonary KS without treatment is only a few months.⁶⁸ The most common presenting symptoms of pulmonary KS are dyspnea and cough, usually without fever unless concomitant infection is present. It may be difficult to distinguish pulmonary KS from other neoplastic and infectious diseases clinically, thus radiologic studies play an important role in its diagnosis. Computed tomography (CT) of the chest is often sufficient to diagnose pulmonary KS⁶⁹ and may identify lymphatic or extrapulmonary involvement.⁶⁸

Otolaryngologists may encounter patients with KS of the larynx associated with symptoms ranging from chronic cough or hoarseness to acute upper airway obstruction.^70–73 If diagnosis and treatment proceed appropriately, acute airway obstruction may be avoided. Local treatment in isolated disease or systemic treatment in multicentric disease is recommended to avoid progression to airway compromise.⁷¹

Once the diagnosis of KS is suspected, biopsy may be performed for pathologic confirmation. The histopathology of KS is characterized by abnormal proliferation of lymphatics. Lesions may occur in three forms: patch, plaque, and nodule.⁷⁴ Nodular lesions are more common in immunosuppression-related and AIDS-KS, and are marked by proliferation of slitlike vascular channels, extravasated erythrocytes, and spindle-cell proliferation (Fig. 15-2). KS lesions may be mimicked by bacillary angiomatosis, which also causes vascular proliferative lesions. The presence of pleomorphic bacilli on Warthin-Starry silver stain helps distinguish bacillary angiomatosis.^75,76 The identification of HHV8 DNA may help distinguish KS from other vascular lesions.⁷⁷ If KS is identified in a patient without a known history of HIV infection, an HIV test is warranted.

Figure 15-2. Mucosal Kaposi’s sarcoma. A, Photomicrograph of submucosal Kaposi’s sarcoma showing slit-like vascular channels and scattered extravasation of erythrocytes (×100). B, Higher-power photomicrograph of the same lesion showing characteristic spindle cell proliferation (×200).

At the initial evaluation of a KS patient, a complete skin examination and oral cavity examination should be performed. A normal examination in these areas does not ensure the absence of KS because clinically significant visceral lesions may present in the absence of mucocutaneous disease. If unexplained GI or pulmonary symptoms are present, radiologic imaging of the chest and abdomen and GI endoscopy should be performed. The classic appearance of small, submucosal vascular nodules establishes the diagnosis of visceral KS. Endobronchial biopsy may result in significant hemorrhage and is discouraged. The constitutional symptoms of fevers, night sweats, and weight loss should be recorded as well as the immunologic status, including CD4 count and viral load.

Cutaneous Neoplasms

Immunosuppressed organ transplant recipients and HIV-positive patients have a higher risk of developing skin cancer compared to immunocompetent individuals. Risk factors for the development of skin cancer in immunosuppressed patients are the same as those in the general population, with fair skin, sun exposure, and family history of skin cancer being the principal factors.^91–94 Even though the rate of nonmelanoma skin cancer (NMSC) is increased in both groups, organ transplant recipients have a markedly higher risk than people with HIV/AIDS.²³ The incidence of NMSC in OTR can be as high as 34%.^95,96 In the general population, basal cell carcinoma (BCC) is more common than cutaneous squamous cell carcinoma (SCC), whereas organ transplant recipients develop SCC twice as frequently as BCC.⁹⁷ The risk of developing NMSC increases dramatically with longer posttransplant times.^97,98 At 10 years after transplantation, the prevalence of NMSC is 32%.⁹⁹ Within the HIV-positive population, BCC is second behind KS as the most common cutaneous malignancy, with a prevalence of 1.8%.⁹³ CD4 count does not correlate with the incidence or severity of NMSC.^100,101 Both groups have increased rates of lip SCC.^23,24 The evidence linking immunosuppression to increased risk of melanoma is less clear than for NMSC, in that increased rates of detection may reflect greater surveillance in immunosuppressed patients.^92,101

Compared to NMSC in the general population, NMSC in these patients, particularly SCC, is more often invasive and aggressive, with higher rates of metastasis and recurrence.^92,100–102 Melanoma also has more aggressive features in the setting of immune depression, and shorter disease-free intervals and overall survival have been demonstrated in HIV-positive patients.¹⁰³

Treatment outcomes vary with the type of skin cancer. Although more aggressive types of BCC in HIV-positive patients have been reported,^104–106 standard excisional techniques result in cure rates similar to those in the general population.^100,101 In contrast, cutaneous SCC is associated with higher mortality in immunosuppressed patients, with mortality around 3% in organ transplant recipients¹⁰⁷ and up to 50% in HIV patients who have metastatic SCC.¹⁰⁸ As in the management of Kaposi’s sarcoma, reduction of immunosuppression in organ transplant recipients is associated with reduced incidence and improved outcomes for skin cancer.¹⁰² There are no clear guidelines for the management of cutaneous SCC or melanoma in HIV patients, but local excision with early consideration for systemic therapy is generally recommended.¹⁰¹ Because of the aggressive nature of skin cancers in immunosuppressed patients, early detection with a low threshold for biopsy of suspicious lesions is recommended.

Squamous Cell Carcinoma

Data regarding the incidence of noncutaneous SCC in immunosuppressed patients are controversial. Several studies have reported increased incidence of noncutaneous SCC in organ transplant recipients, with one large series reporting a 0.5% incidence, which was a 20-fold increase over the control population.^109,110 In particular, patients undergoing liver transplantation had an even greater risk.^111,112 There have also been reports of increased head and neck SCC in HIV-positive patients.^24,113 Confounding factors of pretransplantation tobacco and alcohol use, however, may contribute to the increased incidence seen in both groups.^{109,112–114} High levels of immunosuppression in organ transplant recipients¹⁰⁹ and lower CD4 count in HIV-positive patients¹¹⁵ may confer an increased risk. Immunosuppressed patients, however, do appear to experience a more virulent clinical course than the general population. Organ transplant recipients and HIV-positive patients tend to present at an earlier age and with more advanced disease than their immunocompetent counterparts.^109,110,115 As in immunocompetent individuals, the larynx is the most common site of involvement, followed by the oral cavity and oropharynx.^114,116 Tobacco cessation and alcohol abuse counseling, as well as early detection through biopsies of suspicious lesions, are warranted.

Higher susceptibility to infection with HPV in organ transplant recipients and HIV-positive patients may play an important role in the development of noncutaneous head and neck SCC.^24,116 HPV infection has been associated with head and neck SCC, particularly of the tonsil.¹¹⁷ Organ transplant recipients and patients with HIV/AIDS also have increased incidence of other HPV-related cancers, such as cervical and anogenital cancer.²³ It is thought that immune compromise could lead to increased infection rates and failure to resolve the infections.¹¹⁸ As more insight is gained into the pathophysiology and clinical behavior of HPV-related cancers, management strategies and the role of prophylactic HPV vaccination in immunosuppressed patients may be better defined.

Treatment of organ transplant recipients and HIV-positive patients with head and neck SCC should follow established guidelines. Even though surgical intervention remains an important option, patients often require combined therapy for advanced disease. The use of chemotherapy in these patients may put them at significant risk for opportunistic infection. Little data exist regarding the tolerance and efficacy of radiation therapy; however, patients with HIV have been shown to tolerate radiation therapy to the head and neck.¹¹⁹

Lymphoma

HIV-positive patients and organ transplant recipients are at higher risk for developing non-Hodgkin’s lymphoma (NHL) and Hodgkin’s lymphoma (HL) than immunocompetent individuals. EBV-associated NHL is the most common type of lymphoma to develop in both groups. NHL comprises a heterogeneous group of tumors, but the overwhelming majority (>95%) are B-cell derived.⁷⁸ Lymphomas occurring in immunosuppressed organ transplant recipients are categorized within a disease entity known as posttransplantation lymphoproliferative disorder (PTLD). The WHO classification system divides PTLD into four categories^120,121:

The WHO classification for AIDS-related NHL includes three groups¹²²:

Most AIDS-related NHL are EBV-associated B-cell lymphomas such as Burkitt’s lymphoma, diffuse large B-cell lymphoma, and plasmablastic lymphoma (PBL).^{78,85,123,124}

EBV, along with HHV8, is a member of the gammaherpesvirus family. It is estimated that more than 90% of the world adult population is infected.¹²⁵ It is found in up to 50% of AIDS-related NHL¹²⁶ and nearly 90% of PTLD.¹²⁷ EBV alters tumor suppressor p53 gene expression and protein regulation, which is thought to play a role in oncogenesis,^44,85 but given the nearly ubiquitous presence of EBV infection, it may be that the intensity of immune suppression determines the risk of developing NHL.¹²⁶ However, immunosuppressed patients have not been found to have increased rates of EBV-associated nasopharyngeal cancer,¹²⁸ and a large proportion of AIDS-related NHL have not demonstrated EBV. Thus the role of EBV in NHL oncogenesis remains unclear and is an area of ongoing investigation.

AIDS-Related Non-Hodgkin’s Lymphoma

Posttransplantation Lymphoproliferative Disorder

PTLD is a complication of solid organ and hematopoietic transplantation marked by EBV-driven abnormal lymphoproliferation. The overall incidence in adults is approximately 2% to 3%,¹²⁷ while in children the incidence is close to 8%.¹⁶⁷ It is the second most common malignancy to develop in organ transplant recipients, after cutaneous malignancy.¹¹⁴ Nearly 40% of patients with PTLD present with findings in the head and neck, especially in Waldeyer’s ring and cervical lymph nodes.¹⁶⁸ PTLD involving the head and neck usually presents with mononucleosis-like symptoms and adenotonsillar hypertrophy, and may be associated with upper airway obstruction.^114,168,169 There are also reports of PTLD involving the nasal cavity and paranasal sinuses,^170,171 as well as facial cutaneous manifestations.¹⁴⁰

Most PTLDs are NHLs of the B-cell type.¹¹⁴ Incidence varies significantly with the type of organ transplanted, with the highest rates in multiorgan or intestinal transplants and lowest rates in renal transplants.¹²⁷ PTLD develops in the setting of severe immunosuppression, which impairs the formation of a cytotoxic T lymphocyte immune response to EBV. The risk of developing PTLD is highest in EBV-naive patients, which may account for the higher incidence in children. It occurs in a bimodal temporal distribution, with most cases occurring within the first 2 years after transplantation and a smaller peak occurring later than 2 years after transplantation.¹²⁷

Treatment should be directed first toward decreasing immunosuppression regimens to allow an adequate T-cell response. Up to 50% of patients respond to immunosuppression reduction.^172,173 Patients who fail to respond to immunosuppression reduction may require systemic therapy such as combination chemotherapy, cytokine therapy, or anti-CD20 therapy (rituximab).^114,127 Surgery is reserved for management of local symptoms, and acute upper airway obstruction caused by tonsillar hypertrophy may require tonsillectomy.¹⁷⁴

Hodgkin’s Lymphoma

Hodgkin’s lymphoma can be seen in transplant recipients and patients with HIV. In transplant patients, it is a much less common manifestation of PTLD than NHL, comprising only 1.8% to 3.5% of all PTLDs,¹⁷⁵ but its incidence is still 15-fold greater than that in the general population.¹⁷⁶ Risk factors for the development of HL in transplant recipients include bone marrow transplantation and a history of graft-versus-host disease (GVHD).^175,177 HL-like PTLD is clinically similar to classic HL occurring in the posttransplant setting but is distinguished by its pathologic features such as cell markers and background proliferation.^175,177 HL occurring in the setting of PTLD has a better prognosis than other PTLD lymphomas¹⁷⁶ and should be managed like other PTLD lymphomas with a focus on reduction of immunosuppression and appropriate chemotherapy.¹⁷⁵

Parotid Lesions in Human Immunodeficiency Virus

Parotid lesions are common in HIV-positive patients, especially children in whom up to 18% may present with parotid masses.^186–188 These lesions may result from AIDS-related malignancies such as NHL^143,144 or KS^189,190 or from diffuse infiltrative lymphocytosis syndrome (DILS), but the majority of parotid enlargement in HIV-positive patients is the result of a benign process known as benign lymphoepithelial cyst (BLEC). BLEC of the parotid produces persistent, nontender parotid enlargement associated with cervical lymphadenopathy in up to 90% of patients.¹⁹¹ Inspissated secretions can lead to duct obstruction with resulting sialadenitis and pain.¹⁹² These lesions have varying proportions of cystic and solid components,¹⁹³ and even though only unilateral clinical disease may be evident, radiologic evaluation nearly always reveals bilateral changes.^194,195 Histologically, BLEC has cyst walls lined by hyperplastic and metaplastic squamous epithelium, and contains aggregates of lymphoid proliferation.¹⁹¹ The differential diagnosis of cystic parotid lesions includes Sjögren’s syndrome, cystic Warthin’s tumor, and branchial cleft cysts. Bilateral cystic Warthin’s tumors may be differentiated radiologically from BLEC based on the presence of focal nodularity in Warthin’s tumors and the associated lymphadenopathy of BLEC.¹⁹⁵

Evaluation of HIV-positive patients who present with a parotid mass should begin with thorough history focusing on the time of onset and rate of growth of the mass as well as any symptoms associated with the mass such as pain. Constitutional symptoms such as weight loss, fever, and night sweats should be investigated and if present should alert the physician to the possibility of lymphoma or tuberculosis. Physical examination should focus on the common features of BLEC—the contralateral parotid should be examined for bilateral masses and the neck should be examined for lymphadenopathy. The examiner should look for evidence of malignancy such as induration, pain, fixation, and facial nerve dysfunction.

FNA can be useful in the diagnosis of parotid masses. Unilateral masses, or masses suspicious for malignancy, should undergo FNA. A study of 99 parotid FNAs in HIV-positive patients found 75% to be consistent with BLEC, 14% were infectious/inflammatory, and 6% were neoplastic. Of the neoplastic lesions, all were malignant, with three NHLs, one multiple myeloma, one metastatic adenocarcinoma from the lung, and one direct extension from a cutaneous BCC. In 6% of patients, the FNA was nondiagnostic.¹⁹⁶ FNA of BLEC reveals a heterogeneous lymphoid population, scattered foamy macrophages, and anucleated squamous cells in a proteinaceous background.¹⁹¹ Germinal centers, myoepithelial islands representing metaplasia of ductal epithelium, and cystic ductal dilatation (Fig. 15-3) differentiate BLEC from lymphoma.¹⁹⁷ Aspiration may also be useful for the relief of symptoms in larger cysts, although the lesions may recur. Initial aspirates should be sent for cytologic and microbiologic evaluation.

Figure 15-3. Benign lymphoepithelial cyst. Photomicrograph demonstrating squamous metaplasia of the ductal epithelium in human immunodeficiency virus–related cystic lymphoepithelial disease of the parotid gland (×200).

A variety of treatment options exist for patients with BLEC. Patients not already receiving HAART should be referred for treatment initiation because these lesions may regress with antiviral therapy.^198,199 For minimally symptomatic patients without significant cosmetic deformity, observation alone represents the best option. Low-dose radiation treatment results in a greater than 50% reduction in the size of the lesion. This improvement, however, typically lasts less than 10 months.²⁰⁰ Some patients are treated with repeated needle aspirations although the repetitive nature of this treatment is suboptimal. Needle aspiration combined with doxycycline or tetracycline sclerotherapy may result in significant size decrease.^201–203 A 1 mg/mL doxycycline solution has been used, injecting 1 to 2 mL through an intravenous catheter following cyst aspiration. Most patients are left with smaller residual fibrotic masses but long-term results of this treatment are unknown.^201,202

HIV-associated BLEC typically does not require parotidectomy. Parotidectomy may be considered in those rare cases of BLEC that undergo rapid size change, are disfiguring, or have significant pressure symptoms. Other indications for parotidectomy include FNA cytology suggestive of neoplasm or unilateral masses with a significant solid component or features worrisome for malignancy. There have been no reports of malignant transformation of BLEC.¹⁹¹

Diffuse Infiltrative Lymphocytosis Syndrome

Parotid gland enlargement associated with sicca symptoms was recognized in HIV-positive patients in the 1980s, and Itescu and colleagues first categorized DILS as a discrete entity in 1990.²⁰⁴ DILS occurs in the setting of HIV and is marked by salivary gland enlargement with circulating and visceral CD8 lymphocytosis. It is often associated with cervical lymphadenopathy, and up to 60% of patients also report sicca symptoms such as xerostomia and xerophthalmia.^192,205,206 In the pre-HAART era, DILS occurred in approximately 3% to 4% of HIV-positive patients, but in the HAART era its incidence has dropped significantly to less than 1%.²⁰⁵ It occurs twice as frequently in black patients as in whites.^207,208 Diagnosis is confirmed with minor salivary gland biopsy demonstrating lymphocytic infiltration or with positive gallium Ga67 scintigraphy when biopsy is not possible.¹⁹²

DILS is phenotypically similar to Sjögren’s syndrome in terms of salivary gland enlargement, sicca symptoms, and salivary gland histology. However, whereas parotid swelling is universal in DILS, it occurs in less than one third of patients with Sjögren’s syndrome.¹⁹² In addition, DILS is characterized by more frequent occurrence of extraglandular lymphocytic infiltration, predominance of CD8 cells in lymphoid aggregates (as opposed to CD4 in Sjögren’s syndrome), and the infrequent presence of serum autoantibodies.^192,205 Extraglandular disease in DILS may include lymphocytic interstitial pneumonitis in up to half of patients,²⁰⁹ but this complication is becoming less common in the HAART era.²⁰⁵

Xerostomia in Human Immunodeficiency Virus and Transplant Recipients

HIV-positive patients as well as patients who suffer from chronic graft-versus-host disease (GVHD) are significantly affected by xerostomia. The prevalence of xerostomia is reported to be 2% to 10% in HIV-positive patients.²¹⁰ Chronic GVHD may develop in up to 40% to 70% of patients receiving transplants from matched, unrelated donors,²¹¹ and 80% of patients with extensive GVHD complain of xerostomia.²¹² In the setting of HIV, some cases are iatrogenically induced by the use of HAART, antidepressants, and other drugs, whereas other cases are caused by chronic mouth breathing secondary to sinonasal disease or adenoidal hypertrophy. Still others are related to DILS as noted earlier. Salivary flow rates are diminished in the setting of HIV infection or GVHD,^210,213,214 which leads to increased incidence of dental caries and impaired deglutition. Salivary substitutes, frequent saline rinses, and sialogogues help alleviate these problems. Dental caries can be prevented with fluoride.

Cervical Adenopathy in Human Immunodeficiency Virus

Data regarding the incidence of cervical adenopathy are sparse, but one series demonstrated that of all HIV-positive patients presenting for FNA of an enlarged lymph node, 54% had cervical involvement.²²⁴ Approximately 40% of HIV-positive patients with adenopathy have benign reactive lymphadenopathy.^225–227 and 20% to 30% have tubercular etiology.²²⁶ In this background of hyperplastic adenopathy, however, cases of infectious and neoplastic etiology exist, including Mycobacterium tuberculosis, fungal infection, Pneumocystis jiroveci (formerly Pneumocystis carinii), lymphoma, KS, and other processes that also occur in the general population (Table 15-6).^224,225,227 Malignancy may be present in up to 10% of cases. Differentiating among these processes remains challenging, yet critical to the appropriate management of lymphadenopathy in the setting of immunosuppression. The tendencies for multiple pathologic processes to coexist in this population and the poor sensitivity of many clinical findings and tests often make it necessary to perform microbiologic and histologic evaluations of lymph node tissue.

Table 15-6 Differential Diagnosis of Lymphadenopathy in Immunosuppressed Patients

Extrapulmonary tuberculosis is the second most common cause of cervical lymphadenopathy in HIV-positive patients.^224,225,227 Tuberculosis is the leading cause of death in HIV-positive patients and effective treatments are available, thus prompt diagnosis and initiation of therapy are essential. The most common site of extrapulmonary tuberculosis involvement in HIV-positive patients is the lymph nodes,²²⁴ but other head and neck sites that may be involved include the larynx,^220,228,229 oral cavity and lip,^230,231 or the parotid gland.²³²

The patient’s immune status, as indicated by the history of opportunistic infection, CD4 count, and viral load, may help narrow the differential diagnosis of cervical adenopathy. Whereas NHL and mycobacterial infection are more likely to be present in the setting of advanced immunosuppression, the CD4 count alone is not sufficient to exclude malignancy or infection.^134,135,179 The purified protein derivative (PPD) or tuberculin skin test may facilitate the diagnosis of mycobacterial lymphadenitis. In the setting of advanced HIV infection and immune compromise, however, the patient may become anergic, resulting in a low sensitivity of the PPD test. The criterion for a positive result in an HIV-infected patient is a skin reaction greater than 5 mm in diameter rather than 10 mm as in the general population.

FNA biopsy should be the initial method of tissue sampling in most cases of suspicious cervical lymphadenopathy in the HIV-infected patient. If possible, a cell block should be created from the sample and the sample should be sent for cytology, flow cytometry, and culture and stains for aerobic and anaerobic bacteria, mycobacteria, and fungi. In the largest series among HIV-positive patients, FNA provided a definitive diagnosis in more than half of patients and directed further clinical investigation in another 30%, while 20% of the initial samples were inadequate for pathologic evaluation.²²⁷ A subsequent study in children corroborated these results, with only 8% of samples being inadequate for diagnosis.²²⁵

An FNA diagnosis of follicular hyperplasia should be correlated with the clinical picture and should not, by itself, absolve the clinician’s suspicion of lymphoma. The decision to perform a diagnostic open biopsy should be driven by a suspicion of malignancy or infection in the setting of a negative or inconclusive FNA.^217,233 Conditions that would favor proceeding with an open biopsy in the setting of an inconclusive finding include nodes greater than 2 cm and growing; onset associated with a low CD4 count; asymmetric, unilateral, or localized lymphadenopathy; constitutional symptoms of unknown origin; mediastinal adenopathy; or hepatosplenomegaly. Open biopsy of suspected metastatic carcinoma should be avoided and, if possible, the diagnosis should made by FNA. When metastatic carcinoma is diagnosed, a thorough examination of the upper aerodigestive tract should be performed under general anesthesia in search of a primary tumor.

Presentation and Pathogenesis

As in the general population, sinonasal complaints are common among immunosuppressed patients. Reports of prevalence among HIV-positive patients range from 10% to 68%, depending on the criteria used.^234–237 Nearly 50% of patients undergoing allogeneic stem cell transplantation (STC) complain of rhinosinusitis, and 12% of solid organ transplant recipients develop acute sinusitis.^238,239 Chronic graft-versus-host disease is a risk factor for sinusitis in hematopoietic transplant recipients.^238,240 The maxillary and ethmoid sinuses are most frequently involved,^234,241,242 and symptoms of acute or chronic sinusitis are similar to those of the general population. These include fever, facial pain or pressure, nasal congestion, and mucopurulent nasal discharge and postnasal drainage. Patients with chronic sinusitis are often relatively asymptomatic, reporting only congestion and nasal discharge. Some patients present initially with pulmonary complaints such as bronchospasm or infection, resulting from postnasal drainage.

Several pathogenic mechanisms have been proposed to account for the high incidence of sinusitis in immunocompromised patients. First, impaired systemic and local immunity due to HIV infection or immunosuppressive therapy leaves the host susceptible to infection.²³⁷ Second, decreased mucociliary clearance times in patients with HIV infection^243,244 and ciliary abnormalities in the nasal mucosa of bone marrow transplant recipients²⁴⁵ have been noted. Impaired mucociliary function may result in stasis of secretions and increased susceptibility to sinonasal infection, or may reflect damage to the nasal microenvironment from repeated infection resulting in reduced mucociliary clearance. Finally, some data suggest that polyclonal B-cell activation with increased production of immunoglobulin E leads to increased atopy in HIV-positive patients, manifesting as new or increased allergic symptoms (allergic rhinitis, drug allergies, and asthma).²⁴⁶ However, attempts to directly correlate sinusitis with atopic disease in HIV-positive patients have been unsuccessful,²³⁵ and a recent study in HIV-positive children did not find increased prevalence of atopy.²⁴⁷

The spectrum of bacteria implicated in immunosuppression-associated sinusitis is similar to that seen in the general population. The most common pathogens include Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in acute sinusitis and Staphylococcus, Pseudomonas, and anaerobes in chronic sinusitis.^248,249 Other unusual nonfungal pathogens cultured from immunocompromised patients include Legionella pneumophila,²⁵⁰ Acanthamoeba,^251–253 Mycobacterium kansasii, Pasteurella multocida,²⁵⁴ and cytomegalovirus.²⁵⁵

The clinical and radiologic characteristics of sinusitis are closely linked to the degree of immunosuppression. Patients with relatively normal immune function (CD4 ≥ 200 cells/µL) should be treated with standard regimens for acute and chronic sinusitis.^248,256 As immune function deteriorates, patients are more susceptible to extensive disease and chronic sinusitis is more likely to develop,²⁵⁷ thus antibiotic coverage should include Staphylococcus, Pseudomonas, and anaerobes.²⁴⁸ One report found that patients with a diagnosis of AIDS had significantly worse CT findings by the Lund Mackay classification system²⁵⁸ than did patients with HIV.²³⁴ Patients in more advanced stages of immunosuppression as reflected by CD4 less than 200 cells/µL or absolute neutrophil count (ANC) less than 600 cells/µL are at risk for infection with more aggressive disease such as pseudomonal or invasive fungal sinusitis.^259,260

Fungi such as Aspergillus and the Mucorales order (especially Rhizopus and Mucor) are particularly important pathogens in immunosuppression-related sinusitis because these organisms have the potential to cause invasive and oftentimes fatal disease.

The incidence of invasive fungal sinusitis (IFS) is 1.7% after hematopoietic transplantation,²³⁸ with the highest risk occurring in the immediate posttransplant period.^261,262 It is much more common in hematologic malignancy such as acute myelogenous leukemia (14% incidence) or acute lymphoblastic leukemia (4% incidence) than in HIV/AIDS or solid organ transplantation.^263,264 This difference in susceptibility may be explained by the fact that neutrophils are essential in the immune response to fungal infections.^265,266 Solid organ transplant recipients and patients with HIV/AIDS generally retain neutrophil function, but patients in the later stages of HIV can become neutropenic and typically are at risk for IFS when CD4 counts fall below 50 cells/µL.²⁶⁷ Regardless of the cause of immunosuppression, the major determinant of risk is the presence and duration of neutropenia (ANC < 600 cells/µL).^263,265 Prophylactic antifungal therapy in patients with hematologic malignancies and hematopoietic and solid organ transplant recipients has not been shown to be effective for the prevention of IFS.²⁶² Aspergillus fumigatus is the most common fungal pathogen in invasive and noninvasive sinusitis for both immunosuppressed and immunocompromised patients.²⁶⁰ Other fungi that have been isolated include Candida albicans,²⁶⁸ Rhizopus arrhizus,²⁶⁹ Cryptococcus neoformans,²⁷⁰ Exserohilum,²⁷¹ and Valsa sordida,²⁷² among others.²⁶³

Invasive fungal sinusitis is a life-threatening condition and early diagnosis and treatment are paramount. Histopathology combined with culture and stains is the most effective diagnostic approach for fungal sinusitis. Unilateral symptoms (facial paresthesias, swelling, pain, or rhinorrhea) with or without fever in a patient with ANC less than 600 cells/µL or CD4 less than 50 cells/µL should alert the clinician to the possibility of IFS. Proptosis along with cranial nerve findings, such as decreased extraocular motions or vision, suggests orbital involvement. Meningismus and mental status changes are late-stage symptoms suggestive of intracranial spread.

Diagnosis

The initial evaluation of an immunosuppressed patient with symptoms of sinusitis should include a thorough head and neck examination as well as nasal endoscopy in order to identify any mucosal or structural abnormalities. Endoscopy-guided cultures should be obtained if discharge from the middle meatus or sphenoethmoid recess is identified. The diagnosis of IFS can pose a challenge, because physical examination findings may be very subtle. The endoscopic findings range from pale, ischemic mucosa to well-circumscribed necrotic plaques. Perforations of the nasal septum and hard palate may be present. Fungal infection may be accompanied by suppuration, causing confusion with bacterial sinusitis.²⁶⁰

Radiologic studies often play a key role in diagnosis. Unilateral edema of the sinonasal mucosa with or without bony erosion on seen CT scan (Fig. 15-4) should lead to suspicion of fungal sinusitis or a neoplasm. But even though CT imaging is the study of choice to identify bony erosion, MRI is superior in delineating the intracranial or orbital extent of disease.²⁶¹ Changes seen on T1 images are isointense in bacterial and fungal infections, but the T2 images demonstrate low signal intensity for fungal disease and high intensity for bacterial disease. A low threshold for imaging patients with low neutrophil or CD4 counts is advised.

Figure 15-4. Computed tomography and magnetic resonance imaging of Aspergillus sinusitis. A, Coronal computed tomography of the paranasal sinuses shows left maxillary sinusitis with erosion of the superior lateral bony wall. B, T2-weighted axial magnetic resonance imaging of the same case shows thickened left maxillary sinus mucosa with a hyperintense signal consistent with inflammation and a transmural process of the lateral wall with a hypointense signal corresponding to the region of bone destruction in A. Differential diagnosis includes invasive fungal disease, lymphoma, and squamous cell carcinoma.

Invasive fungal sinusitis represents a diagnostic and therapeutic emergency and any suspicion should be addressed as soon as possible. Consideration may be made for inferior and/or middle turbinate biopsy^263,273 or diagnostic antral lavage²²⁶ with biopsy and histologic examination. Frozen section of biopsy specimen is often used to accelerate initiation of treatment with antifungal agents. Drainage from the middle meatus and biopsy tissue should be collected and sent for bacterial and fungal culture. There are as yet no uniform guidelines for the diagnosis of IFS, although any suspicious lesions should undergo biopsy with silver staining, histopathology, and culture.

Fungal sinusitis can extend via thrombophlebitic or hematologic spread and thus may enter into the orbit or intracranially without histologic evidence of mucosal invasion.²⁷⁴ The angiocentric invasion pattern of Aspergillus may allow extension of disease into the orbit or intracranially without evidence of bony destruction on imaging study. Thus, in the clinical scenario consistent with fungal sinusitis and fungal elements identified on silver stain or culture, treatment of fungal sinusitis should begin regardless of the histologic confirmation of invasion.

Treatment

The goals of management of sinusitis in immunocompromised patients include swift treatment of bacterial sinusitis and early identification of fungal sinusitis or neoplasm. Initial medical management of acute bacterial sinusitis consists of broad-spectrum antibiotics, decongestants, and saline irrigation. Antibiotics should have good coverage of Streptococcus, Staphylococcus, and H. influenzae; amoxicillin/clavulanate or cefuroxime represent good first-line choices. Antibiotic coverage should also include Pseudomonas and anaerobes in patients with moderate immunosuppression or those who do not respond to initial antibiotic treatment.²⁴⁸ Topical decongestants may enhance sinus drainage and provide symptomatic improvement.²⁷⁵ Patients should be followed closely, and if fever or local symptoms persist after 10 days of therapy, surgical drainage should be considered. Patients with a rapidly progressive course or toxic presentation should undergo early imaging and aggressive treatment, including parenteral antibiotics and possible surgical intervention. As culture and biopsy results become available, the antibiotic coverage may be narrowed. A total of 4 to 6 weeks of antibiotics should be administered.²⁵⁶

Fungal sinusitis should be suspected when fever or other symptoms persist despite aggressive medical treatment. Histopathology combined with culture and stains is the most effective diagnostic approach for fungal sinusitis. Sinusotomy and debridement should be pursued to establish drainage and obtain mucosa and sinus contents for histopathologic and microbiologic evaluation. Surgical intervention is particularly important for patients with a low neutrophil or CD4 count. Endoscopic or external approaches may be used depending on the surgeon’s preference. Fresh frozen section should be performed on suspicious mucosal lesions to allow rapid diagnosis and timely intervention.

Invasive fungal sinusitis requires immediate, aggressive treatment. Without treatment, mortality is reported to be 50% to 80% due to intracranial and orbital involvement.²⁶¹ Ideal treatment involves three components: systemic antifungal therapy, surgical debridement of infected tissue, and restoration of immune function. In particular, immunosuppression should be reversed because restoration of neutrophil count is required to prolong survival.^263,264 Granulocyte colony-stimulating factor has not been substantiated to be helpful in the treatment of invasive fungal sinusitis. Initiation of HAART should be considered in an attempt to improve the underlying immune status of HIV-positive patients. High-dose, broad-spectrum antifungal medication such as amphotericin B should be administered intravenously in all cases with a clinical picture compatible with IFS, regardless of whether invasion has been demonstrated histologically. Liposomal amphotericin B,^261,276 echinocandins such as caspofungin^277,278 or micafungin,²⁷⁹ and broad-spectrum triazoles such as posaconazole²⁸⁰ are alternative medical therapies for patients with poor renal function.

Surgical debridement of involved tissue is important to minimize fungal load, in that medical therapy alone is typically insufficient. The severity of infection and level of immune impairment should be considered when planning surgical intervention. Sinusotomy alone is insufficient; as much as possible, involved tissue should be debrided to bleeding margins.²⁶¹ Intraoperative frozen sections may assist in defining the extent of resection by determining the boundaries of invasion.²⁸¹ Transfacial approaches may be required in the setting of extensive disease, which may require maxillectomy, orbital exenteration, or craniofacial resection for optimal disease control; however, the chances of survival with intracranial extension are dismal.²⁸² Aggressive surgery must be considered in the context of the patient’s overall condition and prognosis. Postoperative management should continue intravenous antifungals with consideration for antifungal-containing saline irrigation.²⁸⁰ Careful follow-up and a low threshold for repeated surgical exploration is required. Patients in whom fungal disease appears clinically to have resolved may develop persistent chronic bacterial sinusitis, thus continued follow-up is necessary.²⁸³

Although more commonly involving the paranasal sinuses, invasive fungal infections of the pharynx and larynx have been described in HIV-positive^284–286 and other immunosuppressed patients.^287–290 Diagnosis and treatment of these invasive infections requires a high degree of suspicion and prompt initiation of medical therapy. In one case, a total laryngectomy was required for disease control.²⁹¹

Immunosuppressed patients with chronic sinusitis are also candidates for surgical intervention. Friedman and colleagues found that endoscopic sinus surgery in HIV-positive patients with chronic sinusitis resulted in symptomatic improvement in 75% of patients, comparable to their results in the general population. This effect was found to be independent of CD4 count and has led the authors to suggest the same treatment algorithm for chronic sinusitis in patients regardless of HIV status.²⁹² These findings were bolstered by Murphy and colleagues who showed a significant decrease in the symptoms of sinusitis and increased quality of life in HIV-positive patients with chronic sinusitis following endoscopic sinus surgery.²⁹³ Follow-up time in these studies was limited. Because of the devastating nature of invasive fungal sinusitis and the susceptibility of posttransplant patients to opportunistic infections, some authors advocate pretransplant endoscopic sinus surgery in patients who demonstrate evidence of sinusitis.^239,294

External and Middle Ear

Middle Ear

Eustachian tube obstruction caused by adenoidal hypertrophy or sinonasal disease is common in HIV-infected children and adults. It is therefore not surprising that otitis media (OM) commonly occurs in the HIV-infected population. Although there is no clear link between immunosuppression and increased incidence of OM,²²⁶ limited data suggest that HIV-positive patients may be more prone to systemic complications related to acute otitis media (AOM).^300,301 Serous otitis media (SOM) and conductive hearing loss (CHL) are more prevalent in adults and older children, whereas AOM more frequently occurs in young children.^300–302 The bacteriology of AOM parallels that in HIV-negative patients, with S. pneumoniae, H. influenzae, group A Streptococcus, and M. catarrhalis predominating.^301,303 Therefore initial therapy for acute OM is the same as that for the HIV-negative patient. In the severely immunocompromised child, antibiotic coverage should be expanded to include S. aureus, because there may be an increased incidence of this pathogenic organism in HIV-positive children.³⁰⁴ If OM persists, tympanocentesis should be considered to guide therapy by culture and sensitivity results.

The role of tympanostomy tube placement and adenoidectomy in the management of recurrent OM and persistent SOM is poorly established in HIV-infected patients. As with immunocompetent patients, placement of tympanostomy tubes may result in chronic otorrhea or persistent tympanic membrane perforation. It has not been established that these adverse scenarios are seen more frequently in HIV-positive patients. The severity of hearing loss and morbidity associated with OM should be taken into account when deciding whether to place tympanostomy tubes.

HIV-positive patients who progress to develop chronic otitis media, cholesteatoma, or persistent tympanic membrane perforations should be evaluated for surgical intervention. Advances in the treatment of HIV infection have resulted in HIV-positive patients living longer with relatively less immune compromise. The improved overall prognosis of HIV-positive patients may lead to an increase in chronic ear disease, and HIV patients undergoing elective otologic surgery have not been shown to have adverse events related to their immunosuppression.³⁰⁵

Systemic complications of AOM are uncommon in immunocompetent children, and some data suggest that these complications are more likely to occur in the setting of advanced immunocompromise.^301,306 Patients with suppurative OM refractory to antibiotics should undergo early tympanocentesis for culture and special stains, and granulation tissue, polyps, and other masses should be carefully biopsied to rule out neoplasms and atypical infections.

Hearing Loss

Early in the HIV epidemic, several small studies suggested higher levels of idiopathic sensorineural hearing loss (SNHL), primarily affecting the high frequencies in patients with HIV. However, more recent data have not demonstrated an increased incidence of idiopathic hearing loss in the HIV-positive population.^226,328 Antiretroviral treatment does not appear to cause increased rates of hearing loss.³²⁹ Although patients with HIV may not have clinical evidence of auditory dysfunction, many studies have demonstrated delayed wave latencies on auditory brainstem evoked response (ABR) testing.^330–333 These ABR abnormalities occur in patients with symptomatic or asymptomatic HIV infection. The central auditory pathway in the upper brainstem is dysfunctional in earlier stages of HIV infection as indicated by prolonged I-V and III-V intervals, whereas the lower brainstem is affected in advanced HIV infection as indicated by a prolonged I-III interval.³³⁴ These findings were attributed to the central nervous effects of HIV infection.

The labyrinth is not as common a site of HIV-related pathology as is the central auditory system. Few abnormal findings are present on temporal bone histopathology, even on specimens from which viruses have been cultured.³³⁵ However, a recent study demonstrated that patients with HIV had abnormal posturography results compared to normal individuals and that vestibular dysfunction worsens with advanced immunosuppresssion.³³⁶ These findings may reflect the CNS effects of HIV infection.

Opportunistic diseases including CNS toxoplasmosis, tuberculosis meningitis, cryptococcal meningitis, and NHL may also cause SNHL in the AIDS patient. Sudden deafness and vestibular hypofunction in association with acute HIV infection and aseptic meningitis has been demonstrated, possibly as a result of a viral labyrinthitis or cochleovestibular neuropathy.³³⁷

Oral Candidiasis

Candidal infection is the most common oral manifestation of HIV infection. In the era of HAART, the incidence of oral candidiasis has decreased by nearly 50%.³⁷⁵ Reports of prevalence of oral candidiasis are 10% to 24% for patients not on HAART, and 2% to 10% for those on HAART.^376,377 With CD4 counts less than 200 cells/µL, the prevalence increases to 39% for patients not receiving HAART.³⁷⁶ It also occurs in up to 20% of organ transplant recipients.^378,379 The most common organism responsible is Candida albicans, and up to 80% of all HIV-positive patients have oral colonization with C. albicans.³⁸⁰ Oral candidiasis is strongly related to lower CD4 counts and higher viral loads, and possibly with smoking.^381,382 The development of OC in patients on HAART is predictive for immune and virologic failure.^374,383

Candidal infection of the oral mucosa can take four forms³⁸⁴:

Figure 15-5. Pseudomembranous candidiasis and angular cheilitis. A, Pseudomembranous candidiasis of the lateral surface of the tongue. These smooth white plaques are easily scraped from the mucosa, leaving an erythematous and bleeding base. B, Angular cheilitis characterized by tender ulcers and fissures of the oral commissure as a result of candidal infection.

(Courtesy of Dr. Steven Ashman.)

The differential diagnosis of this lesion includes leukoplakia, carcinoma in situ, and oral hairy leukoplakia. Candidal infection can be diagnosed based on the resolution of these lesions with empiric anticandidal therapy. More definitive diagnosis can be made by a potassium hydroxide preparation or Gram stain of a scraping or by periodic acid–Schiff stain of a biopsy specimen. Candida species have also been reported to cause necrotizing lesions of the epiglottis in immunocompromised patients.^385,386

Oral candidiasis in patients with CD4 greater than 200 cells/µL is successfully managed with topical antifungals—nystatin suspension 5 mL four times per day, or clotrimazole troches 10 mg five times per day.³⁸⁷ For patients with CD4 counts less than 200 cells/µL, oral fluconazole or itraconazole is recommended, with ketoconazole as an alternative.³⁸⁸ Posaconazole has been demonstrated to be effective for oral candidiasis refractory to azoles.^389,390 The use of fluconazole prophylaxis for the prevention of oral candidiasis is not recommended due to the risk of side effects and lack of survival benefit.³⁹¹

Oral Hairy Leukoplakia

Oral hairy leukoplakia is a white lesion with a corrugated and shaggy surface; it most frequently occurs on the lateral surface of the tongue. Oral hairy leukoplakia affects 3% to 10% of HIV-positive patients,^392,393 and may also occur in immunosuppressed transplant recipients.^378,394 It is rare in children, occurring in only 3% to 4% of HIV-positive children.¹⁸⁶ Oral hairy leukoplakia is caused by EBV,³⁸⁷ and its presence in an otherwise asymptomatic patient is a strong indicator of a diagnosis of HIV infection with moderate to severe immunosuppression. Risk factors for the development of oral hairy leukoplakia include low CD4 count, high viral load, and the presence of oral candidiasis.^393,395,396 The presence of oral hairy leukoplakia is not as strongly predictive for immune and virologic failure as oral candidiasis.³⁸³

When an oral lesion persists despite a short course of anticandidal therapy, a biopsy is indicated to rule out a malignant or premalignant lesion. The differential diagnosis of oral hairy leukoplakia includes leukoplakia, carcinoma in situ, hypertrophic candidiasis, and lichen planus. Oral hairy leukoplakia is diagnosed on biopsy by the presence of hyperkeratosis, acanthosis, clear or “balloon” cells in the upper spinous cell layer with minimal inflammation, and the presence of EBV in the basal epithelial cells (Fig. 15-6).³⁸⁴ Once the diagnosis is made, further management is rarely needed because OHL is often asymptomatic and does not undergo malignant transformation. There are insufficient data to support evidence-based recommendations for treatment. Topical treatments such as podophyllin or retinoin have been investigated, but recurrence is common. One small study found that the addition of acyclovir with podophyllin cream resulted in complete remission at 12 months.³⁹⁷ The use of systemic antivirals (desciclovir, valacyclovir, acyclovir, ganciclovir, foscarnet, and famciclovir) has been reported, but the body of evidence is too small to determine their efficacy.³⁸⁷

Figure 15-6. Oral hairy leukoplakia. Characteristic hyperparakeratosis is present, as is a layer of “balloon cells” in the upper spinous cell layer.

(Courtesy of Dr. Russel Corio.)

Herpes Simplex Virus

Infections of the oral cavity by herpes simplex virus increase in all stages of HIV infection. Seropositivity for HSV approaches 95% in the HIV-positive community, compared to 80% in the general population.³⁹⁸ The prevalence of HSV lesions has decreased in the HAART era, and recent prevalence is reported at 2% to 3%.^186,399 Herpetic lesions are particularly persistent when the CD4 count is less than 100 cells/µL. Herpes labialis is the most common manifestation of herpes simplex infection of the oral cavity. When this manifestation occurs in the HIV-infected patient, these “fever blisters” are generally larger, more numerous, persist longer, and recur more frequently than in the general population. Intraoral infection by herpes simplex usually affects the keratinized and attached mucosa of the hard palate and gingiva and the dorsum of the tongue. The characteristic appearance is that of small round ulcers without an erythematous halo. Multiple ulcers can produce significant discomfort with mastication and swallowing, threatening nutrition. Herpes simplex virus (HSV) infection in the HIV-infected patient is likely to be prolonged and less localized than in the general population.

Herpes simplex infection is usually diagnosed empirically by the characteristic appearance of lesions and is treated with oral famciclovir, valacyclovir, or acyclovir for 7 days, although severe lesions may require intravenous acyclovir.³⁹⁸ For lesions that persist after adequate treatment, cell scrapings from the base of the lesion should be cultured for sensitivity testing. The treatment of choice for acyclovir-resistant HSV is intravenous foscarnet. Daily suppressive therapy with oral acyclovir, famciclovir, or valacyclovir should be considered for patients who have frequent or severe recurrences.

Oral Histoplasmosis

Histoplasmosis is a granulomatous fungal disease caused by Histoplasma capsulatum and is an AIDS-defining illness.⁴⁰⁰ H. capsulatum is endemic in areas of North, Central, and South America, Asia, and Africa, but it can be found throughout the world.⁴⁰¹ Nearly 50% to 80% of adults in endemic areas may be infected, with most being asymptomatic.⁴⁰² Although immunocompetent patients can develop oral lesions, oral histoplasmosis is strongly associated with HIV infection. In endemic areas, the prevalence of oral histoplasmosis is 3% in HIV-infected patients and less than 0.1% in non–HIV-infected patients,^400,403 thus any patient who presents with oral histoplasmosis should undergo HIV testing. Symptomatic histoplasmosis infection presents as acute pulmonary, chronic pulmonary, or disseminated disease.⁴⁰³ Mucocutaneous involvement most often occurs in the setting of disseminated histoplasmosis but can occur in isolation.⁴⁰⁰ Histoplasmosis affecting the nasal cavity⁴⁰⁴ and parotid gland⁴⁰⁵ of HIV-positive patients has been reported, and oral histoplasmosis may also occur in immunosuppressed organ transplant recipients.⁴⁰⁶ The presence of oral histoplasmosis is associated with CD4 counts less than 50 cells/µL and higher mortality at 6 months than for patients with disseminated histoplasmosis without oral involvement.^407,408

Patients with oral histoplasmosis present with painful, erythematous patches that progress to raised, granulomatous lesions that may be covered with an adherent pseudomembrane.⁴⁰⁰ Associated cervical adenopathy may be present.⁴⁰⁹ Diagnosis is established by antigen testing in body fluids and by biopsy of lesions with histology and culture for H. capsulatum.⁴⁰² For oral histoplasmosis occurring in the setting of disseminated disease, treatment depends upon the severity of disease.⁴⁰¹ For moderately severe or severe disease, systemic amphotericin B (3 mg/kg/day) for 1 to 2 weeks followed by oral itraconazole (200 mg three times daily for 3 days then 200 mg twice daily for 12 months) is recommended. For mild to moderate disease, oral itraconazole alone may be sufficient. Patients with CD4 counts less than 150 cells/µL or other immunosuppressed patients with recurrent disease should be placed on daily itraconazole prophylaxis.

Gingivitis and Periodontal Disease

Periodontal disease associated with HIV infection is classified into three categories⁴¹⁰:

With the use of HAART, the prevalence of periodontal disease has dropped from less than 10% to as low as less than 1% in one study.⁴¹⁰ The presence of necrotizing periodontal disease in a patient not known to have HIV infection should prompt serologic testing, because this disease is strongly associated with HIV. Patients with CD4 less than 200 cells/µL are much more likely to develop necrotizing periodontal disease than those with CD4 greater than 200 cells/µL.

The differential diagnosis of a destructive process that involves the soft tissue and bone of the alveolar crests includes lymphoma, SCC, KS, bacillary angiomatosis, fungal infection, and mycobacterial infection. The presence of bone destruction out of proportion with the soft tissue changes is more likely to be caused by bacillary angiomatosis than necrotizing ulcerative periodontitis.⁷⁶ Tissue should be sent for histopathologic and microbiologic testing. Periodontal consultation should be requested for appropriate and expeditious management of periodontal disease.

The mainstay of therapy for HIV-related gingivitis and periodontitis includes dental plaque removal and oral rinses with 10% povidone-iodine, with 0.1% to 0.2% chlorhexidine gluconate.³⁸⁴ Because periodontal disease in HIV-positive patients is closely associated with candidiasis, topical or systemic antifungal treatment should also be employed.⁴¹⁰ If present, necrotic tissue should be debrided and the teeth scaled. If patients fail to respond to initial management, parenteral antibiotic therapy with clindamycin or metronidazole should be instituted.

Aphthous Ulcers

Aphthous ulcers are of three types, all of which affect unattached oral mucosa. Herpetiform ulcers are smaller than 0.2 mm in diameter and are self-limited. Minor aphthous ulcers are well-circumscribed, painful ulcers less than 6 mm in diameter with an erythematous halo. In the HIV-infected patient, ulcers frequently coalesce to form larger lesions lasting about 2 weeks. Major aphthous ulcers (Sutton’s disease) are larger than 6 mm in diameter (Fig. 15-7). They are painful, persist for weeks, and threaten nutritional intake. They are difficult to grossly differentiate from malignancy. In the HAART era, the incidence of aphthous ulcers ranges from 1% to 8% in HIV-positive patients.^375,399,411

Figure 15-7. Major aphthous ulcer (Sutton’s disease) of the lower lip. This lesion is indistinguishable from lymphoma or squamous cell carcinoma and should undergo biopsy.

(Courtesy of Dr. Steven Ashman.)

Management should focus on ruling out malignancy, providing symptomatic relief, and monitoring nutritional status. The edge of the ulcer should be biopsied and submitted for histopathologic study to rule out lymphoma and SCC. The size, chronicity, and exquisite tenderness of major aphthous ulcers mandate close monitoring of body weight and the provision of liquid nutritional supplements. Initial treatment for minor ulcers with over-the-counter topical protective and analgesic medications is recommended.⁴¹² For major or nonhealing minor lesions, thalidomide (200 mg/day) has been shown to be effective for treatment, but ineffective for prevention of recurrence.³⁸⁷ Intralesional or systemic steroids have also been found to be effective.⁴¹²

Human Papillomavirus

Human papillomavirus (HPV) may cause oral or genital warts, which, like other HIV-associated oral lesions, occur with lower CD4 counts.⁴¹³ The incidence of oral warts in HIV-positive patients is 1.6%, and interestingly, the incidence of oral warts increases with lower viral loads.⁴¹⁴ Whether this phenomenon is explained by a mechanism similar to immune reconstitution syndrome is unclear. Oral HPV infection rates have not decreased in the HAART era, and in fact may have increased in white men infected with HIV.³⁸⁷ Few studies have investigated optimal management of these lesions in the HIV population, but surgery is the most common therapy for symptomatic lesions. Alternative therapies include cidofovir, bleomycin, cimetidine, podophyllin, or intralesional interferon.

Miscellaneous

Although more commonly involving the paranasal sinuses, invasive fungal infections of the pharynx and larynx have been described in HIV-positive^284–286 and other immunosuppressed patients.^287–290 Diagnosis and treatment of these invasive infections requires a high degree of suspicion and prompt initiation of medical therapy. In one case, a total laryngectomy was required for disease control.²⁹¹