Epidemiology, Risk Factors, and Pathogenesis

In the general population, Kaposi sarcoma is a rare benign skin tumor that develops in the skin of the lower extremities in elderly men from the Mediterranean area. The disease, originally described in 1872 by the Hungarian physician Moricz Kaposi, is 100 to 1000 times more frequent in persons with HIV-1 infection than in the general population and is associated with an aggressive course. The incidence of AIDS-associated Kaposi sarcoma has, however, declined substantially over the past 2 decades. Before the advent of cART, incidence rates ranged from 25 to 50 cases per 1000 person-years of follow-up (PYFU) but have steadily declined, so that the incidence in a cART-treated population is less than 5 per 1000 PYFU. Approximately 5% to 10% of all diagnosed cases of AIDS are based on a finding of Kaposi sarcoma. HIV-1–infected men who have sex with men have a 20 times higher risk for development of this tumor than in persons in other transmission groups. Frequency increases with lower CD4⁺ T cell counts, but the disease can occur at all levels of immunodeficiency. Thus, when Kaposi sarcoma is the AIDS-defining illness, it may occur at a relatively higher CD4⁺ T cell count than other such illnesses.

Kaposi sarcoma is an angioproliferative inflammatory condition that is associated with infection with human herpesvirus type 8 (HHV-8). Gene expression profiling shows that the lesions consist of aberrant endothelial and inflammatory cells of lymphatic origin. HHV-8, a γ-2 herpesvirus of the Rhadinovirus genus, has been demonstrated in all forms of Kaposi sarcoma, and in situ hybridization has demonstrated the presence of HHV-8 RNA and DNA in spindle, endothelial, and mononuclear cells of the tumor. HHV-8 DNA is detectable in peripheral blood before the development of the tumor, and increased viral replication is evident before onset of symptoms. More than 80% of patients with AIDS-associated Kaposi sarcoma have antibodies to HHV-8. HHV-8 may exert its oncogenic potential in several ways. The HHV-8 genome contains several genes that are homologues to human genes. Among these is a latent nuclear antigen that binds to p53 and associates viral DNA to human DNA during mitosis; a viral cyclin that activates cyclin-dependent kinases to prevent human cells from remaining in a G₁ phase; a constitutively expressed receptor (viral interleukin-8 receptor) that may be involved in angiogenesis; a Bcl-2 like protein that prevents apoptosis; and viral homologues to cytokines (viral macrophage inflammatory protein [MIP] and viral interleukin-6) that may be responsible for some of the constitutive symptoms associated with Kaposi sarcoma. Cytokines are required for HHV-8–infected endothelial cells to acquire their phenotype and for continued growth of the tumor. The HIV-1 Tat protein upregulates cytokines and metalloproteinases that further promotes the oncogenic potential of Kaposi sarcoma cells.

Genetics

Genetic polymorphisms of the Fc-γ receptor IIIA, the interleukin-6 and interleukin-8 promoter regions have been associated with an increased risk for development of Kaposi sarcoma. Some human leukocyte antigen (HLA) types also have been associated with this disease.

Clinical Features

Cutaneous and mucocutaneous manifestations of AIDS-associated Kaposi sarcoma are the more common and usually precede visceral disease by months to years. Skin and visceral lesions appear as red or violet macules, papules, or nodules that may coalesce to form plaque-like lesions. Lesions may affect any area of the skin and involve any organ system. Lymphadenopathy is frequent.

Pulmonary Kaposi sarcoma may cause nonproductive cough, hemoptysis, shortness of breath, chest pain, and fever. In rare instances, involvement of the larynx or trachea may cause airway obstruction. Extrapulmonary involvement is frequent, but 15% of cases of Kaposi sarcoma occur without skin lesions. CD4⁺ cell counts are low (0 to 100/µL) at the time of diagnosis. Examination of the lungs usually shows no abnormalities. Chest radiograph may be normal in appearance but commonly shows singular or multiple peribronchovascular nodules (Figure 30-1, A and B). Diffuse infiltration and air space consolidation also may be present. Pleural effusion is common. Hilar and mediastinal lymphadenopathy may be visible on chest films but are better visualized with computed tomography (CT) scanning. With pulmonary disease, CT scans typically reveal peribronchovascular nodules that are larger than 1 cm in diameter. The role of magnetic resonance imaging (MRI) or positron emission tomography (PET) in the diagnosis and management of pulmonary Kaposi sarcoma is not clear.

Figure 30-1 Pulmonary Kaposi sarcoma. A and B, Chest radiographs showing multiple peribronchovascular nodules. C, Typical violet-red endobronchial nodule visualized through a fiberbronchoscope. D, Transbronchial biopsy specimen of pulmonary Kaposi sarcoma lesion.

(C, Courtesy Dr. L. Huang. D, Courtesy Dr. J. Junge.)

Diagnosis

Pulmonary Kaposi sarcoma is highly likely in a HIV-1–infected person with a CD4⁺ cell count of less than 100/µL, the characteristic cutaneous or mucocutaneous lesions, and pulmonary symptoms. Bronchoscopy is useful to visualize typical endobronchial lesions (see Figure 30-1, C). These are flat or slightly raised and occur throughout the tracheobronchial tree but are seen most frequently at airway bifurcations. Pleural effusions usually are exudative and may be serous or serosanguineous. Serum lactate dehydrogenase may be elevated. Histologic verification is usually not required for a diagnosis of Kaposi sarcoma. Endobronchial biopsy may confer a substantial risk of severe bleeding, but biopsy may be necessary in cases in which bronchial involvement is lacking. In such cases, transbronchial or percutaneous needle biopsy is useful. In cases of pleural Kaposi sarcoma, video-assisted thoracoscopy can be used to visualize pleural lesions and to perform biopsy. Open lung biopsy in this setting is obsolete because of the associated complications. Lung biopsy specimens show typical features of Kaposi sarcoma, which include a tumor-like infiltrate with a peribronchovascular distribution of spindle cells. Slitlike spaces without endothelium contain extravasated erythrocytes (see Figure 30-1, D). In situ hybridization and immunostaining usually are positive for HHV-8. HHV-8 DNA is detectable in bronchoalveolar lavage fluid (BAL) cells.

Treatment

All patients with Kaposi sarcoma should be treated with cART, but immune reconstitution may induce an inflammatory reaction and flare of the disease within 2 to 8 weeks of initiation of this therapy. Cutaneous and mucocutaneous lesions of AIDS-associated Kaposi sarcoma usually regress with cART without chemotherapy but may require additional local radiotherapy. Visceral Kaposi sarcoma, however, will necessitate chemotherapy. Concomitant use of cART increases the response rate to chemotherapy. All patients should be offered P. jirovecii prophylaxis regardless of their CD4⁺ cell count. Pegylated liposomal doxorubicin or liposomal daunorubicin are used for first-line treatment of Kaposi sarcoma, in addition to cART. In randomized multicenter trials, response rates and adverse effect profiles to both agents given as monotherapy proved to be superior to conventional chemotherapy.

Liposomal anthracyclines are well tolerated overall. Myelosuppression is the most important dose-limiting toxicity. The risk of drug-drug interactions with antiretroviral agents is low for anthracyclines. The taxane paclitaxel, in combination with granulocyte colony-stimulating factor (G-CSF), is approved for second-line treatment of Kaposi sarcoma. Experience with paclitaxel and pulmonary Kaposi sarcoma is limited, and the use of paclitaxel is associated with more severe adverse effects than those reported with anthracyclines. Paclitaxel has potential serious drug-drug interactions with antiretroviral drugs.

Due to the high cost of anthracyclines and taxanes their use may be limited in resource-poor settings. Alternatively, the most widely used regimen for the treatment of pulmonary Kaposi sarcoma, a combination regimen of doxorubicin (Adriamycin), bleomycin, and vincristine (ABV) may be used. Vincristine may be replaced with vinblastine in patients with polyneuropathy. The combination is given every 2 weeks. Response is evaluated after four to six series of chemotherapy. Response rates are 30% to 50%. Adverse side effects include anemia, neutropenia, thrombopenia, neuropathy, mucositis and alopecia. There are potential drug-drug interactions between vincristine or vinblastine and antiretroviral agents.

Investigational agents include thalidomide, imatinib, mTOR inhibitors, IL-12, and fumagilin.

Clinical Course and Prevention

Untreated pulmonary Kaposi sarcoma is associated with a median survival of less than 6 months. Combination ART improves survival in HIV-1–infected patients with pulmonary Kaposi sarcoma receiving chemotherapy to 50% and above. Severe immunodeficiency (CD4⁺ cell count below 100/µL), pleural effusion and/or hypoxia are associated with a particularly rapid course of this disease. Prevention is best accomplished through treatment of the underlying HIV-1–related immunodeficiency with cART.

Epidemiology, Risk Factors, and Pathogenesis

Castleman disease is a rare lymphoproliferative disease characterized by angiofollicular proliferation. Three histologic variants—hyaline vascular, plasma cell, and mixed—and two clinical types, localized and multicentric, have been described. The incidence of Castleman disease is increased in patients with HIV-1 infection. Multicentric Castleman disease (MCD) is associated with concomitant AIDS-associated Kaposi sarcoma. One study found HHV-8 DNA in 14 of 14 cases of HIV-1–associated MCD but in only 7 of 17 non–HIV-1–infected cases. HHV-8 DNA was detected in only 1 of 34 lymph node biopsy specimens from HIV-1–uninfected patients with localized disease. MCD frequently transforms to the non-Hodgkin form of lymphoma. Pulmonary involvement in Castleman in HIV-1 infection is exceedingly rare but probably also is underdiagnosed.

Clinical Features

The localized form of Castleman disease usually manifests as mediastinal lymph node hyperplasia without systemic symptoms. Signs and symptoms of multicentric disease include fever, generalized lymphadenopathy, fatigue, hepatosplenomegaly, and pancytopenia. Symptoms are thought to be related in part to cytokine disarray by viral homologues of IL-6 and IL-10 encoded by the HHV-8 genome. Symptoms and signs of pulmonary involvement include shortness of breath, cough, and bilateral crackles. Worsening of symptoms often is preceded by HHV-8 viremia. CD4⁺ cell counts vary, ranging from normal to extremely low, indicating severe immunodeficiency. Chest radiographs and CT scans may show noduloreticular interstitial infiltration, mediastinal lymphadenopathy, or pleural effusions.

Diagnosis

Bronchoscopy findings usually are normal. Analysis of BAL fluid cells may show hypercellularity and lymphocytosis. A lung biopsy is required to confirm the diagnosis. HHV-8 DNA usually is detected in biopsy specimens by immunostaining or in situ hybridization techniques.

Treatment

Localized disease is cured by surgical resection. Treatment of MCD is difficult and may include corticosteroids, chemotherapy, immune therapy, and/or radiation therapy. Specific antiherpesvirus therapy with ganciclovir or foscarnet to reduce the HHV-8 replication has been shown to be of some use. Treatment with rituximab (anti-CD20 monoclonal antibody) for HIV-associated MCD is now considered the “gold standard.” The most significant adverse effect may be progression of concomitant Kaposi sarcoma. Mild to moderate infections may occur.

Clinical Course and Prevention

Survival rates are poor but have improved in the era of cART, with a 5-year overall survival of approximately 50%. Patients with multicentric Castleman disease often develop non-Hodgkin lymphoma, discussed next.

Epidemiology, Risk Factors, and Pathogenesis

In the pre-cART era, non-Hodgkin lymphoma (NHL) represented the second most common HIV-1–associated cancer after Kaposi sarcoma. With the introduction of cART, rates of NHL have declined by 40% to 70% for most histologic subtypes. Despite the decline in incidence, NHL is now one of the most common initial AIDS-defining illnesses: The risk of low-grade lymphoma (although not AIDS-defining) is increased 4-fold, the risk of high-grade lymphoma is increased 600-fold, and the risk of primary brain lymphoma is increased 3600-fold with HIV-1 infection over corresponding risks in the absence of infection. Recognized risk factors for development of NHL include concomitant infection with Epstein-Barr virus (EBV) and/or HHV-8, as well as male gender, increased age, and immunodeficiency. A diagnosis of AIDS usually precedes primary pulmonary lymphoma.

Most AIDS-related NHLs belong to one of three categories of high-grade B cell lymphomas: Burkitt lymphoma, centroblastic lymphoma, and immunoblastic lymphoma. Burkitt and Burkitt-like lymphomas tend to occur in patients with relatively high CD4⁺ cell counts, as compared with centroblastic large cell and immunoblastic lymphomas, which occur at low CD4⁺ cell counts. The incidence of Burkitt lymphoma is unchanged in the era of cART. Pulmonary NHL can manifest either as primary or secondary involvement. Dissemination is common for NHL, but primary pulmonary lymphoma is a rare condition, accounting for less than 0.5% of HIV-1–related lymphomas.

The pathogenesis of NHL is complex and involves immune dysfunction together with dysregulation of cytokine responses, chronic antigen stimulation, and co-infection with EBV and HHV-8.

Genetics

Somatic mutations of immunoglobulin, c-Myc, Bcl-6, and p53 genes are associated with transformation into lymphoma. Overexpression of Bcl-2 is associated with resistance to chemotherapy and a poor prognosis. Persons heterozygous for the CCR-5 chemokine Δ32 mutation may be at reduced risk for NHL, whereas the stromal cell–derived factor 1 (SDF1)-3′A chemokine variant may be associated with an increased risk for NHL.

Clinical Features

Patients may present with nodal or extranodal disease and may have systemic symptoms. Clinical signs of advanced NHL with pulmonary involvement include fever, night sweats, and weight loss (B symptoms). Manifestations of primary pulmonary involvement include shortness of breath, cough, and chest pain. Primary pulmonary lymphoma is associated with CD4⁺ cell counts less than 50/µL. Anemia, thrombocytopenia, and leukopenia are frequent findings. Serum lactate dehydrogenase often is elevated with secondary but not primary pulmonary involvement. Chest radiographs and CT scans commonly show isolated or multiple central or peripheral nodules (Figure 30-2, A). Mediastinal lymphadenopathy and pleural effusion are less common.

Figure 30-2 Primary pulmonary non-Hodgkin lymphoma. A, Chest radiograph showing a single, large central nodule (arrow). B, Transbronchial biopsy specimen of non-Hodgkin lymphoma (N). The patient also had Pneumocystis jirovecii pneumonia (P).

(Courtesy Dr. J. Junge.)

Diagnosis

Fiberoptic bronchoscopy usually is normal. Cytologic examination of BAL fluid may reveal lymphoma cells, but biopsy is required to establish a histologic diagnosis. Transbronchial biopsy has reasonable diagnostic yield for secondary but not primary pulmonary lymphoma. Percutaneous thoracic needle biopsy is the most commonly used method to obtain tissue for diagnosis. In rare cases, video-assisted thoracoscopic or open lung biopsy may be necessary. Histologically, the lymphoma invades the alveolar septa and vascular walls (see Figure 30-2, B). Necrosis is frequent. Most tumors are high-grade centroblastic or immunoblastic large B cell lymphomas that are EBV-positive and overexpress Bcl-2.

Treatment

There is no evidence to indicate that primary or secondary pulmonary NHL should be treated differently from NHL in general. Chemotherapy regimens that include cyclophosphamide, doxorubicin, vincristine (Oncovin), and prednisone (CHOP), or CHOP-rituximab (CHOP-R), or etoposide, prednisone, vincristine (Oncovin), cyclophosphamide, and doxorubicin (EPOCH) are used in conjunction with cART. CHOP-R may be beneficial in primary pulmonary lymphoma because these often overexpress bcl-2. No significant drug-drug interactions occur between commonly used cART regimens and CHOP. Use of cART is associated with less anemia, thrombocytopenia, and other adverse effects of chemotherapy.

Clinical Course and Prevention

The median survival from primary pulmonary lymphoma is less than 4 months with chemotherapy alone. Survival from lymphoma has improved in the cART era.

Epidemiology, Risk Factors, and Pathogenesis

Primary effusion lymphoma (PEL), or body cavity–associated lymphoma, is a rare type of non-Hodgkin lymphoma that occurs almost exclusively with HIV-1 infection. PELs grow mainly in the body cavities (pleural, pericardial, and peritoneal) as lymphomatous effusions without an identifiable contiguous tumor mass. PEL occurs predominantly in men who have sex with men and are seropositive for HHV-8. In contrast with NHL, PEL lacks c-myc gene rearrangements. PEL is positive for HHV-8 and Epstein-Barr virus, expresses CD45, exhibits clonal immunoglobulin gene rearrangements, and lacks bcl2, bcl6, ras, and TP53 gene alterations.

Clinical Features

PEL is associated with progressive immunodeficiency and consequently low CD4⁺ cell counts. Patients usually have a previous diagnosis of Kaposi sarcoma. Clinical manifestations include fever, generalized lymphadenopathy, and fatigue. Symptoms and signs of pleural involvement include shortness of breath and cough. Chest radiographs show unilateral or bilateral effusion. CT scans are useful to rule out localized masses representing NHL, Kaposi sarcoma, or other neoplastic disease. PEL usually remains localized to the body cavity of origin.

Diagnosis

The diagnosis is based on the demonstration of morphologic, immunophenotypic, immunogenotypic, viral and molecular characteristics of pleural fluid. Demonstration of HHV-8 often is necessary.

Treatment

Treatment follows guidelines for treatment of NHL and should include chemotherapy together with cART.

Clinical Course and Prevention

PEL has an aggressive clinical course and is associated with a high mortality rate. The 1-year overall survival rate is 40%.

Epidemiology, Risk Factors, and Pathogenesis

The risk for development of small cell carcinoma, non–small cell carcinoma, and bronchoalveolar carcinoma is two to five times greater among persons with HIV-1 infection than in the general population, and such cancers appear at a younger age. Adenocarcinoma accounts for a majority of cases. Men are affected more often than women. The risk is increased with a CD4⁺ cell count less than 500/µL. From 60% to 80% of HIV-1–infected persons are smokers, and this factor contributes significantly to the excess risk. Epidemiologic modeling, however, shows that smoking alone cannot account for the excess risk, suggesting that other cofactors are at play. It is possible that smoking may additively or synergistically together with HIV-1 infection affect the lung more severely than in non–HIV-1–infected persons. HIV-1 may enhance lung damage, leading to increased oxidative stress.

Clinical Features

Clinical features do not differ from those of lung cancer in general, but HIV-1–infected patients tend to be younger at presentation. Symptoms and signs of localized disease may be subtle but may include persistent cough, shortness of breath, chest pain, and weight loss as the disease develops. Chest radiographs and CT scans may show nodular or diffuse infiltrates, hilar or mediastinal lymphadenopathy, or pleural effusion.

Diagnosis

Fiberoptic bronchoscopy may reveal bronchial invasion. Biopsy is required to establish a histologic diagnosis, and specimens can be obtained by transbronchial, percutaneous thoracic, open lung, or video-assisted thoracoscopic techniques.

Treatment

Treatment of HIV-1–associated lung cancer follows current guidelines for treatment of non–HIV-1–associated lung cancer, as described in Chapter 67.

Clinical Course and Prevention

Patients with HIV-1 infection tend to present with more advanced disease. Studies indicate that overall survival is shortened for persons with HIV-1 infection and lung cancer compared with the general population.

Epidemiology, Risk Factors, and Pathogenesis

Nonspecific interstitial pneumonitis (NIP), also known as chronic interstitial pneumonitis, is a common cause of pulmonary disease in adults with advanced, untreated HIV-1 infection. Half of HIV-1–infected adults without pulmonary symptoms and with CD4⁺ T lymphocyte counts below 200 cells/µl show histopathologic changes characteristic of NIP. The incidence of NIP at different CD4⁺ strata is unknown. NIP is rare in children.

The etiology of NIP is unknown. There is evidence of HIV-1 RNA expression in pulmonary CD4⁺ T lymphocytes and macrophages. Cytotoxic CD8⁺ T cells are the predominant lymphocyte type, and it is speculated that these cells induce pulmonary inflammation. Other mechanisms of lung damage include increased levels of inflammatory mediators (e.g., cytokines and leukotrienes) and release of superoxide anion from activated alveolar macrophages.

Clinical Features

The signs and symptoms of NIP are unspecific and resemble many clinical manifestations of HIV-1 infection such as cough, shortness of breath, and fever. Extrapulmonary involvement is rare. Examination of the lungs usually yields normal findings. There may be subtle hypoxia that further increases on exercise. Chest radiographs and CT scans may be normal in appearance or show diffuse alveolar, nodular, or interstitial infiltrates that are indistinguishable from those typically seen in other common HIV-1–associated infections (Figure 30-3, A). Pleural effusion is less common.

Figure 30-3 Nonspecific interstitial pneumonitis. A, Chest radiograph showing noninfectious bilateral diffuse infiltration before start of combination antiretroviral therapy. B, Transbronchial biopsy specimen.

(Courtesy Dr. J. Junge.)

Diagnosis

Suspicion of NIP should arise when standard histocytologic studies, microbiologic staining and culture, and molecular techniques do not yield a pathogen. Thus, NIP is a diagnosis of exclusion. Tissue specimens are required to establish the diagnosis and may be obtained by bronchoscopy, fine needle aspiration, or open lung biopsy procedures. Transbronchial biopsy specimens characteristically show various degrees of perivascular, peribronchial, and pleural lymphocyte and plasma cell infiltration. Edema, fibrin deposition, pneumocyte hyperplasia, and thickening of alveolar septa are common; alveolar septal infiltration is uncommon (see Figure 30-3, B). Lymphoid aggregates are frequently seen. BAL fluid analysis shows lymphocytosis and a decrease in relative and absolute numbers of alveolar macrophages. Because of the risks involved with biopsy procedures, some clinicians make a presumptive diagnosis after ruling out an infectious cause for the patient’s pulmonary symptoms.

Treatment

Symptoms may resolve without therapy. In view of the association of NIP with severe immunodeficiency, however, initiation of cART is almost always indicated. Data from several case series indicate that cART leads to resolution of symptoms and the pathologic changes.

Clinical Course and Prevention

The natural course of NIP without cART is chronic and rarely leads to respiratory failure. Some individuals may be asymptomatic. NIP is best prevented by initiating cART before the development of moderate to severe immunodeficiency.

Epidemiology, Risk Factors, and Pathogenesis

Lymphocytic interstitial pneumonitis (LIP) is a disease of unknown etiology associated with HIV-1 infection and autoimmune disease. LIP occurs predominantly and not infrequently among untreated infants and children, in whom LIP is an AIDS-defining illness. LIP is rare among adults. An association has been observed between LIP and advanced HIV-1 disease. As with NIP, HIV-1 RNA expression in pulmonary CD4⁺ T lymphocytes and macrophages has been reported.

Clinical Features

As with NIP, the symptoms of LIP are unspecific and include non-productive cough, shortness of breath, and fever. Extrapulmonary involvement of lymph nodes is common and generalized lymphadenopathy is frequent. Peripheral CD8⁺ T lymphocytosis is characteristic. Clubbing has been reported among children. Chest radiographs may be normal but commonly show diffuse alveolar, nodular, or interstitial infiltration. Pleural effusion is common. CT scans may reveal peribronchial nodules or a diffuse ground glass appearance.

Diagnosis

Similar to NIP, LIP is an exclusion diagnosis that requires tissue samples to establish the diagnosis. Transbronchial biopsy is characterized by peribronchial, perivascular, and pleural infiltration of lymphocytic and plasma cells. These findings are also characteristic of NIP. However, septal infiltration differentiates LIP from NIP. Lymphoid aggregates are common.

Treatment

Treatment of LIP is directed at the underlying immunodeficiency caused by HIV-1. Initiation of cART is associated with resolution of pulmonary symptoms.

Clinical Course and Prevention

The natural course of LIP is variable and ranges from spontaneous remission to respiratory failure. LIP is best prevented by initiating cART before the development of moderate to severe immunodeficiency.

Epidemiology, Risk Factors, and Pathogenesis

HIV-1–infected smokers are 10% to 25% more likely than smokers without infection to have chronic obstructive pulmonary disease (COPD). Several factors that increase the risk for development of COPD are frequent among HIV-1–infected patients, including a high prevalence of tobacco smoking, intravenous drug use, and recurrent bacterial and opportunistic infections. COPD develops at younger age and is more prevalent among African Americans. Currently, it is unknown whether HIV-1 infection per se or the increased life expectancy associated with cART, or a combination of the two factors, accounts for the increased prevalence of COPD. Evidence appears to support all three possibilities. Ongoing viral replication and activation of pulmonary cytotoxic T lymphocytes may lead to parenchymal destruction by mechanisms similar to the effects of tobacco smoking. Advanced HIV-1 disease is associated with impairment of lung function. Some studies suggest a synergistic effect of HIV-1 and smoking, which may explain why HIV-1–infected patients may develop COPD at a younger age. HIV-1–infected intravenous drug users have reduced FEV₁, FVC, and diffusing capacity of carbon monoxide (DLCO) compared with persons in other transmission categories. This respiratory impairment may be explained in part by the fact that these patients more frequently are heavy smokers and suffer from recurrent lower respiratory infections. Pulmonary bacterial and opportunistic infections (e.g., P. jirovecii pneumonia) are associated with permanent reductions in FEV₁, FVC, FEV₁/FVC, and DLCO after recovery from the infection.

Chapter 41 deals with COPD in detail.

Genetics

Mutations in the α₁-antitrypsin gene predispose affected persons to the development of emphysema.

Clinical Features

Signs and symptoms of COPD do not differ between persons with and those without HIV-1 infection and include cough, sputum production, shortness of breath, wheezing, and chest tightness. HIV-1–infected patients may be younger.

Diagnosis

Spirometry is central to the diagnosis. Reductions in FEV₁, FVC, and FEV₁/FVC will confirm the diagnosis and establish the severity of the condition. A radiograph is useful to distinguish between COPD or emphysema and other lung and heart conditions manifesting with similar symptoms. Arterial blood gas analysis is performed to confirm hypercapnia or to establish the need for oxygen treatment.

Treatment

Treatment does not differ from COPD treatment in general. Therapy includes bronchodilators, inhaled glucocorticosteroids, and pulmonary rehabilitation. Influenza and pneumococcal vaccination is recommended and does not confer any increased risk for HIV-1 disease progression. Oxygen treatment follows general guidelines.

No important drug interactions between antiretrovirals and bronchodilators have been noted, except between some protease inhibitors and theophylline. There is the potential of drug interactions between protease inhibitors and inhaled glucocorticosteroids, but not with nucleoside and non-nucleoside analogues. Nicotine can be used to treat tobacco dependency together with antiretrovirals. There is a potential drug interaction with bupropion and protease inhibitors and non-nucleoside analogues. Similar interactions may occur with vareniclin.

Clinical Course and Prevention

The clinical course usually is not any different from that for COPD in the general population. Smoking cessation is central to successful prevention of further disease progression. Care also should be taken to avoid secondary smoke exposure. Avoidance of lung irritants is important. COPD is not believed to affect HIV-1 disease progression. Antiretroviral management of HIV-1 infection should follow national and international guidelines and should not be delayed.

Epidemiology, Risk Factors, and Pathogenesis

Pulmonary hypertension is an infrequent cause of pulmonary disease among HIV-1–infected patients. However, the incidence (approximately 0.5%) is higher than for non–HIV-1–infected persons (about 0.02%), and the risk increases with age. A careful examination is required to distinguish between primary and secondary forms of pulmonary hypertension. HIV-1 infection per se is assumed to induce vascular changes associated with primary pulmonary hypertension, whereas drug use (with associated foreign particle microembolism), COPD, interstitial pulmonary disease, essential hypertension, ischemic heart disease, chronic thromboembolism, and valvular heart disease contribute to secondary pulmonary hypertension. Some reports have implicated concurrent infection with HHV-8 in the pathogenesis of pulmonary hypertension.

The pathogenesis remains unclear. Remodeling of the media and adventitia of the arterial pulmonary tree, the extracellular matrix and plexiform lesion characterize HIV-1–related and non–HIV-1–related sporadic forms. The increase in pulmonary vascular resistance may be caused by vascular growth factors, mechanical obstruction of the pulmonary arteries, hypoxia, or other stimuli. Chronic changes may remain even after the initiating insult or factor is removed. Pulmonary vascular resistance increases right ventricular systolic pressure, with consequent dilatation and dysfunction, ultimately leading to right ventricular failure.

Genetics

Familial primary pulmonary hypertension is characterized by autosomal dominant inheritance and incomplete penetrance. A mutation in the type II bone morphogenetic protein receptor (BMPR II) has been associated with this disorder.

Clinical Features

The predominant symptom is dyspnea, particularly exertional dyspnea. This symptom is nonspecific, so the diagnosis often is made late in the clinical course. Other common symptoms and signs may include other nonspecific complaints and findings such as fatigue, angina, syncope or near syncope, and peripheral edema. Pulmonary hypertension may occur at any CD4⁺ cell count.

Diagnosis

A full diagnostic evaluation is crucial to rule out non–HIV-1–related causes, because they may necessitate other specific therapy. The chest radiograph shows cardiomegaly and enlarged central pulmonary arteries, or signs of emphysema suggestive of chronic obstructive pulmonary disease, or interstitial infiltration suggestive of parenchymal disease. Echocardiogram usually confirms right axis deviation and right ventricular hypertrophy (P pulmonale). Echocardiography provides imaging of right atrial and ventricle enlargement, tricuspidal regurgitation and reduced left ventricular size. Arterial blood gases commonly demonstrate hypoxia. Pulmonary function test is helpful to distinguish between obstructive or restrictive underlying pulmonary causes. Perfusion lung scans or CT performed with use of intravenous contrast can rule out central and peripherally located thrombi. Additionally, the lung parenchymal CT images may establish alternative diagnoses. Magnetic resonance pulmonary angiography is promising because it also provides assessment of right ventricular function. Eventually, cardiac catheterization will be necessary to measure pulmonary artery pressure, cardiac output, and left ventricular filling pressure.

Treatment

HIV-1–associated pulmonary hypertension has been treated with epoprostenol, inhaled prostacyclin, inhaled iloprost, bosentan (an endothelin receptor antagonist), and sildenafil. The effect of each agent is variable, but these drugs generally improve dyspnea and exercise tolerance. The effect is temporary, however, and concerns have emerged regarding adverse effects. Combination ART is associated with improved hemodynamics and survival. Use of anticoagulation is not supported by available evidence.

Clinical Course and Prevention

Pulmonary hypertension progresses to heart failure over 1 to 2 years despite therapy and is associated with a poor survival rate. Higher CD4⁺ cell counts have been associated with better survival.