Pulmonary Complications in Human Immunodeficiency Virus Infection

What every physician needs to know:

As of 2015, 38.8 million individuals around the globe were living with human immunodeficiency virus (HIV). For many of these patients, the advent of effective combination antiretroviral therapy (cART) has proved lifesaving, helping to close the survival gap between people living with HIV (PLWH) and the general population. These medications, through immune reconstitution, have also fundamentally altered the natural history of this disease. The proportion of deaths amongst PLWH from acquired immune deficiency syndrome (AIDS)-defining infections and illnesses has decreased in favor of non-AIDS-defining cancers and cardiovascular disease. In much the same way, the burden of pulmonary disease in HIV has shifted away from infectious complications such as bacterial and Pneumocystis jirovecii pneumonia (PJP) towards chronic age-related lung conditions like lung cancer and chronic obstructive pulmonary disease (COPD). Greater awareness and recognition of these chronic lung diseases is now imperative in an aging HIV population. In this chapter, we review the most prevalent infectious and non-infectious pulmonary complications of HIV.

Classification:

• Infectious complications

  Bacterial pneumonia: Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus

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  Tuberculosis (TB)

  Pneumocystis jirovecii pneumonia (PJP)

  Other: Cryptococcus neoformans, Histoplasma capsulatum, Coccidioides immitis, and Blastomyces dermtitidis, Toxoplasmosa gondii

• Immune reconstitution inflammatory syndrome (IRIS)

• AIDS-related malignancy: Kaposi sarcoma (KS), non-Hodgkin lymphoma (NHL)

• Chronic obstructive pulmonary disease (COPD)

• Pulmonary hypertension

• Lung cancer

Are you sure your patient has pulmonary complications of HIV? What should you expect to find?

Infectious complications

Pulmonary infectious complications, in general, will mimic the clinical presentations of these infections in immunocompetent hosts. Typical symptoms include fever, cough, sputum production, and malaise. Symptoms can also be more occult, since PLWH can often not mount the inflammatory response necessary to generate the typical infectious symptoms. While PLWH often contract community-acquired pneumonia, they are also at risk of developing opportunistic pulmonary infections. Notable features of these infections are presented here, but refer to their respective chapters for extensive details regarding clinical presentation.

Bacterial pneumonia

Community acquired pneumonias are the most frequently encountered pulmonary infection in PLWH living in the western world. Certain aspects of HIV-associated bacterial pneumonia are similar to the general population in that the etiologic organisms are usually Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus. The clinical presentation, radiographic findings, and treatment approach similarly mirror that of the general population.

Tuberculosis

Tuberculosis (TB) remains amongst the most common opportunistic infection. However, clinical presentations can vary. In one South African study, almost half of PLWH with a positive TB sputum culture did not report a cough. TB also tends to disseminate more frequently in PLWH, and it often has extra-pulmonary manifestations as well as miliary pulmonary disease in these immunocompromised hosts.

Pneumocystis jirovecii pneumonia

In a patient with a low CD4 T-cell count, the gradual onset of dyspnea, cough, and fever should alert clinicians to the possibility of Pneumocystis jirovecii pneumonia (PJP). Since PJP is the most common pulmonary opportunist infection in PLWH, it should always be ruled out in a patient who presents with respiratory symptoms and a low CD4 count.

Other infections

Infections with Cryptococcus neoformans can present as pneumonia with or without meningeal involvement. Severe presentations with acute respiratory failure have been known to occur in HIV.

PLWH are also prone to developing more severe infections with endemic mycoses such as Histoplasma capsulatum, Cocidioides immitis, and Blastomyces dermtitidis. Histoplasmosis can behave as a mild pulmonary illness in those with immune recovery, but those with low CD4 T-cell counts may develop disseminated infection. Pulmonary involvement includes diffuse infiltrates, pleural effusions, adenopathy, cavitary lung lesions, and calcified granulomas. Severe disease with multiorgan failure and acute respiratory distress syndrome can also occur. Similarly, coccidioidomycosis may be a mild pulmonary illness in those with high CD4 T-cell counts, but disseminated disease in those with low CD4 T-cells counts (<250 cells/mm³) with infection of the lungs, meninges, and skin. Blastomycosis can also present as a severe disseminated disease and progressive pulmonary infection in patients with AIDS, carrying a high mortality rate.

Pulmonary infections with Aspergillus can range from allergic bronchopulmonary aspergillosis, aspergilloma, chronic necrotizing aspergillosis, invasive pulmonary aspergillosis (IPA), and aspergillus tracheobronchitis. For PLWH, IPA is by far the most significant of these manifestations. Clinical symptoms may include dyspnea, cough, fever, chest pain, and hemoptysis.

Toxoplasmosa gondii, a parasite whose oocytes transfer from cat feces, and can be ingested by humans, can cause both pneumonia and encephalitis in PLWH with CD4 T-cell counts <100 cells/mm³.

Immune reconstitution inflammatory syndrome

With the initiation of cART, the reconstitution of the immune system can result in a robust inflammatory response against pulmonary infections such as TB and PJP. Immune reconstitution inflammatory syndrome (IRIS) can manifest in two ways:

• A paradoxical response to treatment of infections in which the infectious symptoms appear to worsen as cART therapy is initiated.

• An unmasking of a previously unknown pulmonary infection when cART is initiated.

Approximately 16-18% of TB patients starting cART will develop IRIS with symptoms including fever, weight loss, cough, dyspnea, lymph node enlargement, and worsening infiltrates on chest imaging (often occurring within two to four weeks from the initiation of cART). Presentations may be severe enough to lead to acute respiratory distress syndrome and even death, with a reported mortality rate of 3%. On the other hand, IRIS associated with PJP, which affects 8%, carries a far less dire prognosis and rarely results in death. Nonetheless, patients may experience worsening hypoxia and dyspnea and for these reasons, severe PJP is often treated in conjunction with corticosteroids.

Kaposi Sarcoma

Kaposi sarcoma (KS) is a human herpes virus-8 (HHV-8)-associated malignancy thatcan present in the lung as nodules, endobronchial macules or papules, pleural effusions, and lymphadenopathy, often in conjunction with mucocutaneous involvement. Pulmonary symptoms are often occult, picked up as incidental findings on imaging. Pulmonary KS is also associated with hemoptysis and constitutional symptoms.

Non-Hodgkin lymphoma

Within the lung, Non-Hodgkin lymphoma (NHL) may manifest as nodules, masses, opacities, lymphadenopathy, endobronchial lesions, and pleural disease including effusions, plaques, or nodules. Presenting symptoms tend to be constitutional symptoms. However, occasionally the pulmonary nodules or masses create enough mass effect to cause cough or hemoptysis.

Chronic Obstructive Pulmonary Disease

Chronic Obstructive Pulmonary Disease (COPD) is a progressive disease of small airways obstruction, often marked by dyspnea, cough, sputum production, and periodic exacerbations. COPD in PLWH is clinically similar to COPD in the general population.

Pulmonary hypertension

HIV-associated pulmonary hypertension (PH) behaves very much like pulmonary arterial hypertension (PAH) and is classified as Group 1 PH under the World Health Organization guidelines. Patients may present with dyspnea, decreased exercise tolerance, chest pain, syncope, and signs of right heart failure with peripheral edema and ascites.

Lung cancer

Clinical presentation mimics that of the general population. Early disease is asymptomatic, with later disease notable for hemoptysis, cough, and constitutional symptoms. Mass effect of the tumors in the lungs or mediastinum can cause other symptoms and disease, such as post-obstructive pneumonia, SVC syndrome, and Horner’s syndrome.

Beware: there are other diseases that can mimic pulmonary complications in HIV

None

How and/or why did the patient develop pulmonary complications of HIV?

Infectious complications

When the CD4 count drops below 200 cells/mm³, PLWH are at greater risk for developing the aforementioned infectious diseases, particularly the opportunistic infections. The loss of the T-cell mediated immune response allows for propagation of otherwise pathogens.

Immune reconstitution inflammatory syndrome

IRIS develops due to the robust immune response that is elicited as the HIV infection is treated. Rising CD4 count and falling HIV viral levels allow the immune system to fight opportunistic infections, resulting in a paradoxical worsening of symptoms upon initiation of cART.

Kaposi Sarcoma

Kaposi sarcoma (KS) is a human herpes virus-8 (HHV-8)-associated malignancy that occurs exclusively in the setting of low CD4 count. Immune reconstitution with cART, which allows for the suppression of HHV-8, most often treats the malignancy as well.

Non-Hodgkin lymphoma

The pathogenesis of NHL is poorly understood. Similar to KS, it is postulated that immunosuppression allows for propagation of viruses like Epstein-Barr which then increase risk of NHL.

Chronic obstructive pulmonary disease (COPD)

The reason for increased risk of COPD in PLWH is not entirely understood.

Pulmonary hypertension

Pathologically, the PH observed in HIV is virtually identical to other forms of PAH in which plexiform lesions, medial hypertrophy, and concentric laminar intimal fibrosis are the predominant patterns. Proposed mechanisms include endothelial damage from HIV proteins such as gp120, Tat, and Nef, and human herpes virus 8 (HHV-8), which in Kaposi’s sarcoma causes similar plexiform vascular lesions.

Lung cancer

While the reasons for the increased risk of lung cancer among PLWH have yet to be completely elucidated, theories have pointed to a direct oncogenic effect of the HIV virus itself, chronic immunosuppression, and chronic inflammation.

Which individuals are at greatest risk of developing pulmonary complications of HIV?

Infectious complications

In general, risk for developing infectious complications of HIV increases dramatically when the CD4 count drops below 200 cells/mm³. Other risk factors specific to each pathogen are listed below.

Bacterial pneumonia

Compared to HIV-uninfected individuals, PLWH carry anywhere from a 10 to 35-fold risk of developing bacterial pneumonia with the likelihood of contracting an infection increasing with lower CD4 T-cell counts. Fortunately, the spread of cART has markedly attenuated the incidence rate.

Pneumocystis jirovecii pneumonia

PJP is the most common opportunistic infection in PLWH, and it almost exclusively occurs in HIV patients who have CD4 count less than 200 cells/mm³. Higher serum viral loads also increase risk for PJP. It should be noted that PJP can also develop in other patients who are iatrogenically immunosuppressed, including those taking prednisone for at least a month with an average of dose of 20 mg or more per day.

Tuberculosis

The spread of HIV around the globe has provided fertile ground for the concurrent spread of TB. In 2014, 12% of the world’s 9.6 million new TB diagnoses occurred in PLWH, the vast majority of whom resided in Africa.

Other infections

Histoplasmosis occurs predominantly in the Mississippi and Ohio River valleys as well as in part of Mexico, the Caribbean, and Central and South America. Coccidioidomycosis is found primarily in southwest United States, and Blastomycosis is found in the Ohio and Mississippi river valleys. Aspergillus infection tends to occur in patients with structurally abnormal lungs, although invasive pulmonary aspergillosis can also occur in a patient with normal lungs but low CD4 T-cell count.

Immune reconstitution inflammatory syndrome (IRIS)

Risk factors for developing IRIS include a lower CD4 T-cell count and higher viremia at the time cART is started, a more rapid fall in HIV viremia with treatment, and a shorter time interval between treatment of infection and initiation of cART.

Kaposi Sarcoma

Onset of KS is tightly linked with the degree of immunosuppression and the severity of HHV-8 viral load. Fortunately with cART, the cumulative incidence of disease decreased approximately 4% per year between 1996 and 2009.

Non-Hodgkin lymphoma

NHL is closely associated with advanced immunosuppression, but with the advent of cART, the risk of developing of NHL in PLWH has fallen significantly.

Chronic obstructive pulmonary disease (COPD)

Numerous epidemiologic studies have now demonstrated that PLWH face a disproportionate burden of COPD when compared to age- and sex-matched HIV-uninfected controls, a burden that persists even after accounting for cigarette smoking habits. In fact, it is not unusual to encounter moderate to severe COPD in PLWH as young 40-50 years of age. Multiple cohorts from around the world have now shown that despite mean ages in the fifth decade, up to a quarter of PLWH will meet criteria for airflow obstruction.

Pulmonary hypertension

PH afflicts an estimated 0.5% of PLWH living in developed countries. While still rare, this prevalence rate represents a significant increase over that in the general population, where PH is found in roughly 15 to 52 per million. New estimates out of Africa suggest that the prevalence of PH there may be even higher, with up to 14% of all PLWH meeting criteria for PH on either echocardiography or right heart catheterization. The exact reasons behind this phenomenon are unclear, but the steady decrease in incidence in the cART era (from 0.24% in 1993 to 0.02% in 2001 in the Swiss HIV Cohort Study) suggests that immune reconstitution and viral suppression may provide some degree of protection. Intravenous drug use also appears to be a risk factor for developing PH.

Lung cancer

PLWH appear to develop lung cancer far earlier (four years younger on average) and at rates far higher than the general population. Recent comparisons of cancer incidence between PLWH and the general population in the United States suggest just over 50% excess burden of lung cancer amongst PLWH. Like COPD, smoking alone has not been able to entirely explain this phenomenon. Epidemiologic studies have identified low CD4 T-cell counts, higher zenith HIV RNA levels, and any history of AIDS or AIDS-related lung infections as risk factors for developing lung cancer, in addition to the usual risk factors of age, smoking, and male sex.

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

All HIV patients presenting with new symptoms should have a CD4 count and HIV viral load measured, as low CD4 count and/or elevated viral load increase the risk of many pulmonary complications of HIV. Many of the other specific diagnostic studies, laboratory or otherwise, that apply to the general population are also diagnostic in PLWH. Notable considerations are mentioned here.

Bacterial pneumonia

Culturing of sputum, blood, and pleural fluid if necessary may be useful in identifying a culprit pathogen. 60% of PLWH with pneumococcal pneumonia will have positive blood cultures. There is also a serum antigen for Streptococcus pneumonia that can be tested in PLWH suspected of having pneumonia.

Tuberculosis

Diagnosis may be delayed by the high rate of smear-negative but culture-positive sputum samples in PLWH, particularly in those patients who have recently been exposed to fluoroquinolones. Induced sputum can improve the diagnostic yield with 72% of those with initially negative expectorated sputum cultures demonstrating culture positivity. Recently, the Xpert MTB/RIF automated nucleic acid amplification test, which can rapidly detect TB within two hours, has been recommended by the World Health Organization (WHO) as the initial diagnostic test in resource-limited settings given the almost 50% improvement in sensitivity compared to smear microscopy.

Pneumocystis jirovecii pneumonia

Diagnosis of PJP requires the direct microscopic visualization of the organism in respiratory samples. Induced sputum has a variable success rate with a sensitivity between 55 and 90%, heavily reliant on operator experience as well as laboratory expertise. A low burden of organisms in a patient on PJP prophylaxis may result in false negative tests; in this scenario, adjunctive tools such as PJP polymerase chain reaction (PCR) may be helpful in establishing the diagnosis. Of note, a positive PJP PCR can be found with colonization rather than active disease. Lactate dehydrogenase is elevated in at least 90% of patients with PJP, but this is a very non-specific finding. 1-3-beta-d-glucan levels may also be elevated, but caution that it can be elevated in other fungal infections as well. Arterial blood gas should also be drawn, as the alveolar-arterial gradient has application in determining appropriate treatment (see below).

Other infections

There is a serum antigen for Cryptococcus neoformans, urine antigen for Histoplasma capsulatum, and a serum antibody available for Coccidioides immitis. Direct visualization of the coccidiodes fungus in sputum or bronchoscopy specimens may be required as serologic tests can be falsely negative in PLWH even with disseminated disease. Serum galactomannan and 1,3-beta-d-glucan to diagnose Aspergillus have not been widely tested in PLWH, and case reports have documented cross-reactivity with other fungal infections in HIV.

Immune reconstitution inflammatory syndrome (IRIS)

There are no laboratory studies that can confirm the diagnosis of IRIS, and IRIS is a diagnosis of exclusion. However, basic blood work and infectious studies are warranted to rule out another infectious process.

Kaposi sarcoma

No lab studies are useful in making the diagnosis of KS.

Non-Hodgkin lymphoma

No lab studies are useful in making the diagnosis of NHL.

Chronic obstructive pulmonary disease (COPD)

No lab studies are useful in making the diagnosis of COPD.

Pulmonary hypertension

No lab studies are useful in making the diagnosis of PH.

Lung cancer

No lab studies are useful in making the diagnosis of lung cancer. There are paraneoplastic conditions that may cause lab abnormalities, and these tests may support the diagnosis. See chapter, “Paraneoplastic Syndromes Associated with Lung Cancer”.

What imaging studies will be helpful in making or excluding the diagnosis of pulmonary complications of HIV?

Bacterial pneumonia

Chest x-rays or CT chest can show pulmonary infiltrate. For more details see Community-Acquired Pneumonia chapter.

Tuberculosis

Screening for and diagnosing TB in this population continues to pose significant challenges for the public health community. Radiographic manifestations may be misleading; while PLWH with CD4 T-cell counts >200 cells/mm³ might display the typical reactivation pattern with upper-lobe cavitary lesions, those with more severe immunosuppression (CD4 T-cell counts <50 cells/mm³) may have completely normal chest x-rays. Other patterns include adenopathy, pleural effusions, ground glass opacities, miliary spread, and consolidations.

Pneumocystis jirovecii pneumonia

While the most common radiographic presentation is symmetric perihilar ground glass opacities, manifestations may be protean: ranging from a normal CXR to consolidation, cysts, nodules, pneumothoraces, enlarged lymph nodes, and pleural effusions.

Other infections

The endemic mycoses can present with pulmonary infiltrates and often have associated mediastinal lymphadenopathy. Imaging characteristics of IPA include nodules, cavitary lesions, and infiltrates.

Immune reconstitution inflammatory syndrome (IRIS)

There are no imaging studies that can confirm the diagnosis of IRIS, but the imaging findings of the associated infection may become more prominent.

Kaposi sarcoma

Chest radiograph classically can show pulmonary nodules, infrahilar thickening, and in advanced disease consolidative opacities representing a confluence of nodules. CT chest classically reveals peribronchial flame- or plume-shaped parenchymal opacities.

Non-Hodgkin lymphoma

CT chest will often show multiple areas of consolidation, in nodular or mass form. Mediastinal and hilar lymphadenopathy can be present in more disseminated disease.

Chronic obstructive pulmonary disease (COPD)

Chest imaging is not diagnostic of COPD. However, chest radiograph may show hyperinflation or flattening of the diaphragms. CT chest may show emphysema, particularly in a paraseptal distribution, or air trapping.

Pulmonary hypertension

Transthoracic echocardiography can be used to assess for right heart function and estimate the pulmonary artery systolic pressure (PASP). While not diagnostic, a PASP greater than 40 mmHg is suggestive of PH and should prompt further work up.

Lung cancer

Chest radiograph and CT chest can show pulmonary nodules or masses as well as hilar and mediastinal lymphadenopathy. These findings should prompt biopsy to confirm the diagnosis, particularly in patients who have added risk for lung cancer.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of pulmonary complications of HIV?

Chronic obstructive pulmonary disease (COPD)

Spirometry alone may inadequately identify all PLWH with airways disease and it may also fail to capture the degree of disease severity in HIV. St. George’s Respiratory Questionnaire scores performed in this population suggest that even PLWH with normal spirometry suffer from an inordinate burden of respiratory symptoms impacting their respiratory-related quality of life. Indeed, chest CT imaging of PLWH suggests that up to 50% may harbor evidence of COPD including small airways disease and emphysema, implying that spirometry alone may underestimate the incidence of disease. PLWH tend to display a paraseptal distribution of emphysema, and this finding might account for the disconnect between CT and spirometry findings. High clinical suspicion for COPD in a patient with normal or minimally abnormal spirometry should prompt further investigation with imaging.

What diagnostic procedures will be helpful in making or excluding the diagnosis of pulmonary complications of HIV?

Infectious complications

Screening tests for tuberculosis, both purified protein derivative (PPD) and interferon releases assays, are available. However, these should not be used to test for active disease. If sputum cultures are negative for TB but the disease is still suspected, addition of bronchoscopy with bronchoalveolar lavage can improve the diagnostic yield to a sensitivity of 84%. In the case of PJP, bronchoalveolar lavage has a sensitivity of 90-100% in PLWH.

Lumbar punctures should be performed in patients with apparently pulmonary-limited cryptococcal disease, as up to 90% will have concurrent meningitis.

Bronchoscopy cultures positive for Aspergillus in addition to histopathologic evidence of tissue invasion provide evidence for IPA. Bronchoalveolar lavage galactomannan has not been widely tested in PLWH.

For toxoplasmosis, diagnosis is often achieved via bronchoscopy and bronchoalveolar lavage through visualization of the tachyzoite form of T. gondii.

Kaposi sarcoma

Pulmonary Kaposi sarcoma can be diagnosed on bronchoscopy by visualizing classic red/purple endobronchial lesions and excluding other infectious etiologies. Bronchial biopsies have been associated with hemorrhage in up to 30% of cases, and therefore are not recommended.

Non-Hodgkin lymphoma

Endobronchial ultrasound with transbronchial needle aspiration can be used to make the diagnosis if there is mediastinal lymphadenopathy. Other invasive methods of obtaining tissue, such as percutaneous needle biopsy by radiology, open lung biopsy, or mediastinoscopy, can also be performed. For details see the chapter, “Malignant Lympholiferative Disorders of the Lung”.

Pulmonary hypertension

Echocardiography is a useful screening tool to identify elevated pulmonary artery systolic pressures (as noted above), but confirmation with right heart catheterization is necessary for formal diagnosis. Other causes of PH, including underlying lung disease, heart disease, chronic thromboembolic disease, and connective tissue disease, should be ruled out before implicating HIV as the putative cause.

Lung cancer

Tissue biopsy is necessary for diagnosis. Several modalities for obtaining tissue exist, and selection of the sampling technique is based on imaging studies. For details see the chapter, “Lung Cancer: General Considerations” and “Staging of Non-Small-Cell Lung Cancer”.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of pulmonary complications of HIV?

Kaposi sarcoma

Biopsy is not recommended due to risk of hemorrhage.

Non-Hodgkin lymphoma

Diagnosis is made on tissue biopsy. Cytologic analysis of bronchoalveolar lavage fluid or pleural fluid can also be helpful in establishing the diagnosis. For details see the chapter, “Malignant Lympholiferative Disorders of the Lung”.

Lung cancer

Diagnosis is made on tissue biopsy. Cytologic analysis of bronchoalveolar lavage fluid or pleural fluid can also be helpful in establishing the diagnosis. For details see the chapter, “Lung Cancer: General Considerations” and “Staging of Non-Small-Cell Lung Cancer”.

If you decide that the patient has pulmonary complications of HIV, how should the patient be managed?

Bacterial pneumonia

Even in the absence of a known pathogen, an empiric treatment regimen should be chosen according to local microbiologic patterns, comorbidities, and previous antibiotic history similar to the approach used for non-HIV patients.

Tuberculosis

Treatment of TB in PLWH generally follows the same principles as in the HIV-uninfected population: isoniazid, a rifamycin compound, pyrazinamide, and ethambutol for two months followed by isoniazid and a rifamycin compound for four months to complete a total six month course. Rifamycin compounds (particularly rifampin), however, are cytochrome P450 enzyme inducers and as such, can decrease drug levels of protease inhibitors, nonnucleoside transcriptase inhibitors, integrase inhibitors, and CCR5 antagonists. cART regimens or the choice of a rifamycin compound must therefore be tailored accordingly. Those on rifampin-containing therapy should be on efavirenz-based cART and protease inhibitors, elvitegravir, and cobicistat should be avoided altogether. Rifabutin has fewer interactions with antiretroviral medications. However, dose adjustments are necessary when used in conjunction with efavirenz and protease inhibitors.

While corticosteroids have been demonstrated to improve mortality in tuberculous meningitis, they do not have a role in the initial treatment of HIV-associated TB, unless considered for moderate-severe cases of IRIS.

Since the diagnosis can be more difficult to make, particularly in underserved communities, high index of suspicion for TB in an HIV-infected individual should prompt the initiation of empiric treatment while culture results are pending.

Pneumocystis jirovecii pneumonia

Trimethoprim-sulfamethoxazole (TMP-SMX) is first-line therapy, while pentamidine, clindamycin-primaquine, or atovaquone can be used for those who cannot take or are intolerant of TMP-SMX. The addition of corticosteroids is recommended for those with severe hypoxia (PaO₂ < 70 mmHg on room air or an alveolar-arterial oxygen gradient of ≥ 35 mmHg). A standard corticosteroid regimen is prednisone 40 mg twice daily for five days, followed by 40 mg daily for five days, then 20 mg daily for 11 days. Given the diagnostic difficulty and need to initiate treatment quickly, empiric treatment should be initiated in patients with high pre-test probability in the absence of definitive proof of infection.

Other infections

Treatment of mild to moderate pulmonary-limited cryptococcosis requires fluconazole for 6 to 12 months. Severe cases with extrapulmonary involvement requires induction therapy with amphotericin and flucytosine for at least 2 weeks, followed by fluconazole consolidation therapy for 8 weeks, then fluconazole maintenance therapy for a total year long treatment duration. For severe cases of the other endemic mycoses in PLWH, treatment with amphotericin B is warranted.

Voriconazole is the first line therapy for IPA, however, interactions with protease inhibitors, non-nucleoside reverse transcriptase inhibitors, and elvitegravir/cobicistat are well-known. Voriconazole levels may be required to adequately monitor therapy, given that levels can decrease with these cART agents.

Treatment for T. gondii should include pyrimethamine and sulfadiazine for a minimum of 3 weeks.

Immune reconstitution inflammatory syndrome (IRIS)

Anti-inflammatory therapy may be indicated in certain cases of IRIS, particularly if associated with PJP (see above). Given the excess morbidity and mortality associated with untreated HIV, though, it is not recommended to stop cART in the event of IRIS. Whether anti-inflammatory therapy is effective in treating TB-IRIS has not been well-studied. Non-steroidal anti-inflammatory medications for mild cases and corticosteroids for severe cases can be considered based on improvements observed in case reports.

Kaposi sarcoma

Treatment is primarily based on the initiation of cART with lesions regressing as the immune system reconstitutes. For those with disease progression on cART or severe disease, the addition of systemic chemotherapy with anthracyclines is recommended.

Non-Hodgkin lymphoma

In addition to initiating cART, treatment includes systemic chemotherapy.

Chronic obstructive pulmonary disease (COPD)

Given that there are no clinical trials focusing specifically on treatments of COPD in PLWH, the management of COPD in this population is largely extrapolated from recommendations made for COPD patients in the general community. Smoking cessation, influenza and pneumococcal vaccinations, bronchodilation, pulmonary rehabilitation, and oxygen therapy when necessary are therefore mainstays of treatment. Importantly, though, the introduction of inhaled corticosteroids (ICS) must be carefully considered in PLWH. ICS are absolutely contraindicated in patients also on ritonavir- or cobicistat-containing cART regimens. As strong inhibitors of cytochrome P450 3A4, both ritonavir and cobicistat can cause severe adrenal suppression and Cushing’s syndrome when used in conjunction with ICS-containing inhalers. While this is particularly true of the more potent ICS formulations, the use of even lower potency steroids such as beclomethasone must be approached with caution. Secondly, the increased risk of pneumonia associated with ICS such as fluticasone must also be considered in an immunocompromised patient population at high risk for pulmonary infections. As a result, muscarinic antagonists and beta agonists should be first line agents for PLWH with COPD requiring long-acting inhaler control.

In the general COPD population, lung transplantation has afforded extended survival in the appropriate patient. HIV infection, however, has long remained an absolute contraindication to lung transplantation given the reservations regarding the high degree of immunosuppression required to prevent allograft rejection and drug interactions between immunosuppressive agents and cART regimens. Recently, though, case reports of successful lung transplantation in HIV recipients for conditions such as pulmonary hypertension and pulmonary fibrosis raise hope that this may be a selective therapeutic option in the future.

Pulmonary hypertension

Experience with advanced PH therapies in PLWH is limited and confined to small observational trials. Bosentan, an oral endothelin receptor antagonist, appears to improve hemodynamics, 6 minute walk distance, NYHA functional class, and quality of life in PLWH. Case reports on the use of sildenafil, a phosphodiesterase-5 inhibitor, also suggest a beneficial effect on dyspnea and pulmonary artery pressures. However, drug interactions between sildenafil and protease inhibitors, whereby the half-life and AUC of sildenafil can double, may require close clinical monitoring. Epoprostenol infusions in a study of 6 PLWH improved hemodynamics and NYHA functional class and in one retrospective review were associated with improved survival.

Lung cancer

Treatment of lung cancer in HIV parallels that in the general population. See chapters, “Lung Cancer: General Considerations” and “Staging of Non-Small-Cell Lung Cancer”.

What is the prognosis for patients managed in the recommended ways?

Bacterial pneumonia

For a comparable age range and illness severity, PLWH carry a higher mortality rate (approximately a 7% 30-day mortality rate) for bacterial pneumonia, particularly those with CD4 T-cell counts <100 cells/mm³. S. pneumoniae confers additional risk, as PLWH are 40-60 times more likely to develop invasive pneumococcal disease, including bacteremia and empyema.

Tuberculosis

While greater access to cART has managed to decrease the number of deaths related to TB by 32% between 2004 and 2014, PLWH still accounted for a third of the 1.5 million deaths around the world due to TB in 2015.

Pneumocystis jirovecii pneumonia

PJP has been linked with HIV since the initial days of the epidemic when outbreaks in San Francisco and New York City triggered the investigation of a new immunosuppressive disorder. Often the first presentation of an HIV, PJP was routinely a severe infection with mortality rates as high as 40%. Fortunately, with the spread of cART and the use of PJP prophylaxis for those with CD4 T-cell counts <200 cells/mm³, the prevalence of PJP has fallen precipitously as has the mortality rate to now less than 20%.

Other infections

Invasive pulmonary aspergillosis previously carried a median survival of two months in the early 1990s. Since then, in the cART era, the incidence of IPA has decreased from 19 to 2.2 cases per 10,000 person-years, while the median survival has also improved to 29 months.

Immune reconstitution inflammatory syndrome (IRIS)

Most often, IRIS is a self-limited course. However, some studies site up to a 5% mortality rate of IRIS in general. Tuberculosis-associated IRIS has been shown to have a mortality rate of 2%, and although much less common, IRIS and cryptococcal meningitis had a mortality rate of up to 20%. PJP associated IRIS tends to carry the best prognosis.

Non-Hodgkin lymphoma

Prognosis has improved for PLWH with NHL in the cART era, with around 50% year survival.

Pulmonary hypertension

HIV-associated PH is felt to carry a poor prognosis: 1-year mortality rates have been reported at approximately 25%. While data from the Swiss HIV Cohort Study suggests a trend towards improved survival in the cART era compared to the pre-cART era, inconsistencies in treatment regimens, both from an HIV and PH perspective, cloud overall mortality assessments. Further prospective analyses of PLWH with PH on both cART and advanced therapies will better define current survival.

Lung cancer

Unfortunately, the diagnosis of lung cancer in PLWH carries a poor prognosis with just under 60% dead by one year. These dismal survival rates also compare unfavorably to those in HIV-uninfected lung cancer patients, even after stage of diagnosis is considered. The excess mortality amongst PLWH is furthermore not simply the consequence of HIV/AIDS or infectious complications, but appears to be directly related to cancer-specific mortality itself. While tumor biology may certainly be altered in the setting of HIV, PLWH with lung cancer often do not receive stage-appropriate treatment for their condition. Why this disparity persists is unknown, whether the product of a decision to refuse treatment made by PLWH themselves or whether PLWH are simply not offered treatments.

What other considerations exist for patients with pulmonary complications of HIV?

Infectious complications

Prevention and prophylaxis are extremely important in this vulnerable patient population to prevent complications of HIV/AIDS.

Bacterial pneumonia

All PLWH should be given pneumococcal vaccinations with both the polysaccharide (PPSV23) and conjugate (PVC13) vaccines. Cigarette smoking, which increases the risk of bacterial pneumonia by 5-fold, should also be addressed with cessation programs offered.

Tuberculosis

PLWH also face a higher likelihood of reactivating latent TB. Rates of 10% per year in endemic areas compared with the 5-15% lifetime risk that HIV-uninfected patients face have been reported. All PLWH should be screened for latent TB infection (LTBI) through either the tuberculin skin test (TST) or interferon-gamma release assays (IGRA), both appearing to demonstrate equivalent performance. While IGRA offers the advantage of a single patient visit, its higher cost may be prohibitive for resource-limited settings. WHO recommendations therefore state that either a TST or IGRA may be used in high-income countries whereas a TST is preferable in low-income countries. A TST is considered positive in PLWH at ≥5 mm. Importantly, PLWH with CD4 T-cell counts <200 cells/mm³ may have false negative tests and repeat testing should be performed once immune reconstitution has been achieved. Once active TB has been ruled out in those with either a positive TST or IGRA, treatment for latent TB should be initiated with isoniazid daily, isoniazid twice weekly for nine months, or rifampin or rifabutin daily for four months. Treatment or LTBI has been shown to significantly reduce the rates of reactivation, although all-cause mortality is unchanged.

Pneumocystis jirovecii pneumonia

Patients with CD4 counts < 200 cells/mm³ should initiate PJP prophylaxis. TMP-SMX is the preferred agent, although oral dapsone, oral atovaquone, or inhaled pentamidine are alternatives. Prophylaxis can be discontinued once the CD4 count is maintained > 200 cell/mm³ for 3 consecutive months.

Other infections

When the CD4 count becomes < 250 cell/mm³, coccidiomycosis should be screened for with serum IgG and IgM in PLWH who live in endemic areas. If a patient seroconverts, fluconazole should be initiated and continued until the CD4 count is > 250 cell/mm³ for 6 consecutive months. If the patient has a CD4 T-cell count is less than 100 cells/mm³ and a positive T. gondii IgG, primary prophylaxis with TMP/SMX should be given. In those intolerant to TMP-SMX, dapsone plus pyrimethamine/leucovorin is used as an alternative. Lastly, once the CD4 count is < 50 cells/mm³ prophylaxis against Mycobacterium avium complex (MAC) should be initiated with azithromycin.

Lung cancer

Given the poor prognosis associated with lung cancer in HIV, attention has recently been paid to the benefits of lung cancer screening to identify cancers at earlier and curable stages. The National Lung Screening Trial (NLST) did not specifically focus on PLWH. Extrapolation of its screening criteria (current smokers or former smokers who had quit in the past 15 years, aged 55-74 with ≥30 pack-year smoking history) to PLWH who are known to develop lung cancer earlier than the general population may not necessarily be appropriate.

In addition, a higher rate of pulmonary infections in PLWH could translate into a higher rate of false positive scans. Indeed, a retrospective review applying NLST guidelines to CT scans from PLWH found that those with CD4 T-cell counts <200 cells/mm³ were three times more likely to have false positive nodules. Suggested criteria tailored specifically for the HIV population in one recent prospective trial included the following: asymptomatic HIV infection, age ≥40 years, active smoker within the past 3 years with ≥20 pack-year smoking history, a nadir CD4 T-cell count <350 cells/mm³, and a current CD4 T-cell count of >100 cells/mm³. Using these parameters, 10 cases of lung cancer were identified out of a cohort of 442 PLWH screened, with 6 discovered at early stages. While this trial was not designed to evaluate the mortality benefits of lung cancer screening in PLWH, it did demonstrate the feasibility of using these modified criteria to guide screening in HIV.

Figure 1.

Figure 2.

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