Head and Neck Manifestations in the Immunocompromised Host

Biology and Immunology

HIV infects and debilitates lymphocytes and macrophages, leading to progressive immune compromise. Acquired immunodeficiency syndrome (AIDS) is diagnosed when CD4 count drops below 200 cells/mm or patients develop OI not normally seen in immunocompetent patients. Anecdotal reports 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 entire world population. World Health Organization figures show that in 2017, 1.8 million people were newly infected with HIV. While 940,000 million people died of AIDS-related deaths, this represented a more than 50% decrease from the peak rates in 2004. Worldwide there are an estimated 36.9 million people living with HIV, with the African region continuing to be the most severely impacted. In the United States, approximately 1.1 million people were living with HIV as of 2015, with more than 39,000 new cases diagnosed in 2016 alone. Most new cases tend to be concentrated in urban areas, with highest regional rates occurring in the Northeast, followed by the South, West, and Midwest (although the South has the highest overall number of people living with HIV).

Transmission of HIV occurs through contaminated body fluids and tissues. The virus from an infected patient may inoculate the bloodstream of another individual through a breach in the skin or mucosa or via intravenous (IV) infusion. Modes of transmission include sexual intercourse, the sharing of needles by IV drug users, vertical transmission from mother to child, and rarely by transfusion of contaminated blood products or by accidental exposure in health care workers. Gay and bisexual men are more severely affected by HIV and AIDS than any other group, and despite decreased diagnoses among women, heterosexuals, and people who inject drugs (PWID) during the 2010 to 2015 period, these populations also continue to be impacted.

HIV is a retrovirus of 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, CD4 T cells and macrophages are affected, 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 T-helper subset of T lymphocytes that is also expressed on macrophages. Fusion of the viral and cell membranes allows entry of the viral core into the cell. Reverse transcriptase, an enzyme carried by the virus, allows transcription of RNA into DNA (a reversal of normal transcription) and 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 mismatching, combined with the amount of replication that occurs, establishes a vast pool of genetic diversity that gives the virus an advantage in the acquisition of drug resistance and provides a critical barrier to vaccine development.

Diagnosis and Classification

Both the WHO and CDC surveillance case definitions require laboratory confirmation of HIV infection ( Table 10.2 ). HIV infection in adults has traditionally been diagnosed based upon positive HIV antibody testing by enzyme immunoassay followed by a confirmatory HIV antibody test or positive virologic test for HIV and its components (HIV-RNA, HIV-DNA, or HIV p24 antigen). More recently, CDC guidelines have allowed for antibody immunoassays and nucleic acid tests (NATs) to be incorporated into a multitest algorithm that combines the adult and pediatric criteria of HIV infection diagnosis. Clinical staging is used after a patient has been confirmed to have HIV infection, and staging is useful for baseline assessment and for follow-up during treatment ( Box 10.2 ). The clinical stages correlate with progression of disease and prognosis for untreated disease.

The WHO clinical stages include HIV infection (stages 1 and 2), advanced HIV disease (stage 3), and AIDS (stage 4). The revised CDC case definition allows classification into one of five stages. Stage 0 includes early infection with negative test within 6 months of HIV diagnosis. Stage 3 classification is AIDS. The fifth stage includes Unknown status. Recognizing that immunologic testing (CD4 T-lymphocyte count) is not universally available, the WHO recommends using clinical and immunologic criteria for staging. In contrast to WHO staging, the CDC recommends using only immunologic criteria for staging except for stage 3 (AIDS), which can be defined by a CD4 count below 200 cells/µL, CD4 percentage below 14, or the presence of an AIDS-defining condition ( Box 10.3 ).

Highly Active Antiretroviral Therapy

When left untreated, HIV infection causes gradual debilitation of the immune system over a period of years, resulting in profound immunocompromise and AIDS. Advances in understanding of HIV biology have allowed for the development of antiretroviral therapy (ART) agents that target various steps critical to the viral life cycle. Current drugs do not eradicate the virus; thus the major goals of treatment are the prevention of virus entry into CD4 cells, inhibition of viral replication, reduction in HIV-associated morbidity, and prevention of vertical transmission. Antiretroviral agents from five classes of drugs are currently available to treat HIV infection. These include nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors, fusion inhibitors, CCR5 antagonists, and integrase strand transfer inhibitors (INSTIs). The use of multiagent combination drugs to target different stages of the viral life cycle allows for more effective suppression of viral replication and delayed emergence of drug resistance, forming the basis of highly active antiretroviral therapy (HAART). Typical HAART regimens combine three or more different kinds of drugs, such as two NRTIs with a PI or two NRTIs with an NNRTI.

Since the introduction of HAART in the mid-1990s, life expectancy of patients infected with HIV has increased significantly. The use of HAART was credited for a greater than 45% decline in AIDS-related mortality during the late 1990s. The proportion of deaths caused by AIDS compared with non–AIDS-related causes of death has decreased dramatically, from 94% in the pre-HAART era to 47% in the HAART era, and median age at death has increased from 49 to 66 years.

The CDC recommends initiation of ART in all patients infected with HIV, regardless of CD4 lymphocyte count, to reduce the risk of disease progression and to prevent transmission of HIV. Drug-resistance testing is recommended for all patients diagnosed with HIV, regardless of whether treatment will be initiated. Initial treatment generally consists of two NRTIs in combination with one of the following: an INSTI, and NNRTI, or a PI with a pharmacokinetic enhancer. The choice of regimen is determined by pretreatment HIV viral load and CD4 count, patient comorbidities such as liver and cardiovascular disease, potential drug interactions, results of genotypic drug-resistance testing, and adherence potential.

Recent Advances

Immune Reconstitution Inflammatory Syndrome

Although the use of HAART has led to a decline in HIV-associated morbidity and mortality, some patients who receive therapy demonstrate unexpected clinical deterioration despite improved CD4 count and decreased viral load. The most widely accepted term for this phenomenon is immune reconstitution inflammatory syndrome (IRIS). Two subtypes have been described—paradoxic and unmasking IRIS. Patients with paradoxic IRIS exhibit worsening symptoms or a new manifestation of a known infection. In unmasking IRIS , diseases that were not previously suspected become apparent shortly after initiation of HAART. In both types of IRIS, the inflammatory response to the underlying condition is more severe than would be expected in a patient presenting with a new opportunistic infection. The incidence of IRIS is variably reported, from less than 10% to more than 50%. A large meta-analysis found overall incidence to be 13%, with an exponential increase seen in patients with a pretreatment CD4 count below 50 cells/µL. Most cases occur within 60 to 90 days of initiation of HAART. Consensus is lacking on the definition and diagnostic criteria for IRIS, but most proposed definitions include confirmed diagnosis of HIV, temporal association between the development of IRIS and initiation of HAART, demonstration of immune reconstitution in response to HAART (e.g., increased CD4 count and decreased viral load), clinical deterioration marked by an inflammatory process, and exclusion of other etiologies that may account for the clinical worsening. The most common pathogens associated with IRIS are Mycobacterium (tuberculous and nontuberculous), Cryptococcus , herpesviruses, hepatitis B and C viruses, and human papillomavirus (HPV). In a small prospective study in which 19% of patients developed IRIS, 13% had involvement of the head and neck; the most common manifestations were Kaposi sarcoma (KS) and tuberculosis (TB). Timing of ART initiation in patients with active OI presents a challenge, but evidence suggests that early initiation leads to lower rates of AIDS-associated mortality, albeit at the cost of increased incidence of IRIS. In general, patients who present with suspected of presenting with IRIS-related symptoms should continue on ART while the OI are treated. A possible exception to this includes cases of known cryptococcal meningitis, in which case studies have shown increased mortality and no increased CSF clearance with immediate ART initiation.

IRIS has also been described in patients with non-HIV immune deficiency, including solid-organ and stem cell transplant recipients (TRs). Patients who come to medical attention with unmasking of cryptococcosis, TB, cytomegalovirus (CMV) disease, and leprosy have been described in, and may lead to, transplant organ rejection. In both HIV-positive and HIV-negative patients with IRIS, corticosteroids are often used to counteract the inflammatory host response, but management of these patients remains a challenge.

Occupational Exposure to Human Immunodeficiency Virus Infection

With more than nearly 1 million HIV-positive children and adults in the United States, and given the high prevalence of head and neck complaints among these patients, most otolaryngologists will encounter HIV-positive patients in their practice. An understanding of the risks of occupational transmission, as well as precautions that may minimize such transmission, is essential. The CDC conducted 150 investigations from 1985 to 2013 of health care personnel with documented HIV seroconversion that was potentially acquired occupationally. Of these, 58 cases were confirmed to be occupationally acquired, the most recent occurring in 1999. Because of the voluntary nature of the reporting system, underreporting of cases is possible. Exposures that carry a risk for HIV transmission are percutaneous injuries (e.g., needlesticks or cuts with a sharp object) or contact of mucous membranes or nonintact skin with blood, tissue, or other body fluids that are potentially infectious. The risk of transmission from fluid other than blood or of transmission through intact skin is too low to be estimated in prospective studies. Although cerebrospinal fluid (CSF) carries a risk of infection, nasal secretions, sputum, sweat, tears, urine, and vomitus are not considered infectious, unless they are visibly bloody. Although injury from suture needles has been suggested as a possible source of occupational exposure to HIV, it has not been confirmed as a source of transmission in prospective studies. A lower viral load (<1500 RNA copies/mL) or one that is below the limits of detection probably reduces but 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. The CDC recommends that standard precautions, formerly known as universal precautions, be used in the care of all patients, regardless of presumed infection status. These include hand hygiene, use of personal protective equipment (gloves, gown, mask, eye protection, and/or face shield), safe handling of sharps, and proper cough etiquette (symptomatic individuals must cover the mouth and nose when sneezing or coughing). Despite such precautions, needlesticks and mucosal exposures will occur. After exposure to blood or other infectious fluids, the following actions should be taken immediately: wash needlesticks and cuts with soap and water; flush nose, mouth, or skin with water; and irrigate eyes with clean water, saline, or sterile irrigants. In order to minimize the risk of disease transmission, postexposure prophylaxis (PEP) should be initiated within hours of exposure and should continue for 4 weeks. Since 2013, guidelines have recommended at least three prophylactic ART medications (to the degree tolerated) for any occupational HIV exposure ( Table 10.3 ). 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. If newer fourth-generation testing is available, guidelines allow cessation of testing after 4 months. Follow-up after potential occupational exposure should otherwise include counseling, early reevaluation, and repeat testing. Prevention of HIV transmission following PEP is not complete. There have been at least 20 cases of seroconversion despite the use of PEP, some of whom received multiple drug regimens. Thus careful adherence to standard precautions and avoidance of exposure remain the most prudent ways to prevent infection.

Manifestations of Immunodeficiency in the Head and Neck

The upper aerodigestive tract is a portal of entry for microorganisms, and a functioning immune system is necessary to prevent infections in the head and neck and to prevent the entry of pathogens into the lower respiratory and gastrointestinal (GI) tracts. In some cases, subtle findings such as lymphoid hypertrophy evidenced by adenoid enlargement or inflammation may be the initial clinical presentation of HIV, emphasizing the need for appropriate clinical awareness. Many infections that affect immunodeficient patients are the same processes that involve the head and neck in immune-competent individuals, but they have a greater impact on immunodeficient patients. Infectious diseases commonly encountered in immunodeficient patients involve the oral cavity, ears, temporal bone, paranasal sinuses, and cervical lymph nodes. In addition, other immune-modulated diseases, such as inflammatory disorders and malignancies, occur at higher rates in immunodeficient patients. Box 10.4 summarizes the manifestations of immunodeficiency most likely to be encountered in the head and neck.

Kaposi Sarcoma

Presentation and Diagnosis

Compared with the classic and endemic forms of KS, IT-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. AIDS-KS is associated with a shortened life expectancy, although most patients die from opportunistic infection or lymphoma and not from KS per se. Many patients develop multiple lesions and 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, whereas IT-KS tends to occur in the lower extremities. Oral KS occurs in roughly one-third of AIDS-KS patients, whereas in IT-KS cutaneous lesions are most common. Among cases of non–AIDS-KS in the head and neck, the most common sites of presentation are the palate and oropharynx. Cutaneous disease occurs as multicentric macular and papular lesions that are nontender and nonblanching. These frequently coalesce and progress to violaceous, nodular lesions ( Fig. 10.1 ). They are usually asymptomatic but may become pruritic and aesthetically displeasing. Mucosal KS commonly occurs in the oral cavity, and oral KS may be a first sign of HIV infection. Mucosal KS is associated with lower CD4 counts than is cutaneous disease. Oral KS may resemble cyclosporine-associated gingival hyperplasia in TRs, but cyclosporine usually causes generalized fibrotic gingival hyperplasia, whereas oral KS produces a more localized red-purple enlargement. The most frequently affected sites in oral KS are the hard palate, gingiva, and tongue. Mucosal KS is more likely to be symptomatic than is cutaneous disease. Lesions may cause loose teeth and are associated with pain, ulceration, and bleeding.

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. These most commonly involve the GI tract, liver, spleen, and lungs. GI disease is often asymptomatic. Median survival in pulmonary KS without treatment is only a few months. 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 KS and may identify lymphatic or extrapulmonary involvement.

Otolaryngologists may encounter patients with KS of the larynx associated with symptoms that range from chronic cough or hoarseness to acute upper airway obstruction. Most patients with laryngeal KS have concomitant cutaneous lesions. If diagnosis and treatment proceed appropriately, acute airway obstruction may be avoided. Treatment—local with isolated disease or systemic with multicentric disease—is recommended to avoid progression to airway compromise.

Once the diagnosis of KS is suspected, biopsy is obtained for pathologic confirmation. The histopathology of the different epidemiologic types of KS is nearly identical, with minor differences seen between AIDS-KS and non–AIDS-KS specimens. KS is characterized by angioproliferation, spindle cells, inflammatory infiltrate, and edema. Lesions occur in several different morphologic types, the most common of which are patches, plaques, and nodules. Nodular lesions are more common in IT-KS and AIDS-KS and are marked by proliferation of slitlike vascular channels, extravasated erythrocytes, and spindle-cell proliferation ( Fig. 10.2 ). 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. The identification of HHV8 DNA may help distinguish KS from other vascular lesions. If KS is identified in a patient without a known history of HIV infection, an HIV test is warranted.

At the initial evaluation of a KS patient, a complete skin examination and head and neck examination should be performed. A normal examination in these areas does not ensure the absence of KS, because clinically significant visceral lesions may occur 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. Constitutional symptoms—such as fevers, night sweats, and weight loss—should be recorded along with the patient's immunologic status, including CD4 count and viral load.