The changing spectrum of pulmonary disease in patients with HIV infection on antiretroviral therapy

Introduction The pulmonary manifestations of HIV disease in 2005 can be divided into two sets of presentations. For patients who do not have access to care, and who are not taking antiretroviral or chemoprophylactic drugs, opportunistic infections and neoplasms continue to occur. Pulmonary disease caused by Streptococcus pneumoniae, Pneumocystis carinii (now known as Pneumocystis jiroveci pneumonia; PCP), Mycobacterium tuberculosis, lymphoma, and Kaposi's sarcoma present much as they did in the 1980s. Management has improved in terms of new diagnostic, therapeutic, and preventive strategies, as reviewed in guidelines issued jointly by the National Institutes of Health, Centers for Disease Control and Prevention, and Infectious Disease Society of America (available online at http://www.aidsinfo.nih.gov). Patients in the United States who are taking combination antiretroviral therapy (ART) and specific chemoprophylaxis demonstrate very different manifestations compared with patients in the 1980s who were receiving no ART or chemoprophylaxis. Some of these new manifestations are caused by the augmented immune response that occurs soon after ART is instituted, i.e. immune reconstitution syndromes. Other new manifestations are facilitated by prolonged patient survival at both high and low CD4 T-lymphocyte counts that result from ART. This prolonged survival has allowed other processes to occur after long periods of immunosuppression, e.g. neoplastic processes such as lymphoma and perhaps various solid tumors, and other entities such as pulmonary hypertension. This review will focus primarily on changing pulmonary manifestations in the populations in the United States and western Europe that have access to ART. Current causes of pulmonary morbidity and mortality in the USA: epidemiological trends The causes of mortality and morbidity in patients with HIV have drastically changed over the past few years as a result of the use of ART. Before the use of potent antiretroviral drugs, pulmonary disorders caused an enormous percentage of the overall mortality from HIV. In one autopsy study from 1982 to 1988, all 75 patients had one or more pulmonary processes at the time of death. Opportunistic infections were responsible for 76% of these pulmonary processes [1]. In a prospective multicenter trial investigating respiratory complications from 1988 to 1994, HIV-infected patients had higher rates of both upper and lower respiratory infections than HIV-uninfected controls [2]. Respiratory infections were more common at all CD4 T-cell strata than for HIV-uninfected controls. Over 98% of respiratory complications were infectious [2]. The most frequent respiratory complications were acute bronchitis, bacterial pneumonia and PCP [2]. Since the introduction of ART, the overall mortality of HIV-infected patients, and the mortality caused by pulmonary processes, has dropped dramatically (Fig. 1). An analysis of the Center for Disease Control and Prevention's HIV Outpatient Study (HOPS), in which over 7300 patients have been followed in over 180 000 visits since 1993, found reductions in overall pulmonary mortality and morbidity between 1994 and 2003 (Fig. 2, Fig. 3, Fig. 4).Fig. 1: Mortality and HAART use over time in HIV Outpatient Study (HOPS) cohort, fourth quarter, 2003 update. Deaths per 100 person-years;pulmonary deaths per 100 person-years;percentage of patients on HAART.Fig. 2: Pulmonary, cardiovascular, and hepatic hospitalizations as percentage of total hospitalizations of HIV Outpatient Study (HOPS) participants, fourth quarter, 2003 update. Total pulmonary diagnoses;total cardiovascular diagnoses;total hepatic diagnoses;total renal diagnoses.Fig. 3: Specific pulmonary processes as a percentage of total hospitalizations in the HIV Outpatient Study (HOPS) cohort, fourth quarter, 2003 update. All pulmonary conditions; Pneumocystis jiroveci pneumonia (PCP);non-PCP pneumonia;asthma, bronchitis, chronic obstructive pulmonary disease;tuberculosis;lung cancer.Fig. 4: Pneumocystis jiroveci pneumonia deaths, hospitalizations, and total cases per 100 person-years, HIV Outpatient Study (HOPS) cohort, fourth quarter, 2003 update. Total Pneumocystis jiroveci pneumonia (PCP) cases;PCP hospitalizations;PCP deaths.Data from the HOPS study also demonstrate that pulmonary disease has declined as a cause of hospitalization for HIV-infected patients compared with other causes (Fig. 2). The increasing percentage of hospitalizations for cardiac etiologies also highlights the need to recognize the potential for chest complaints to represent atherosclerotic disease. A large, prospective study demonstrated that cardiovascular events increase with each year of ART [3]. The rates and causes of hospitalizations associated with pulmonary disease from the HOPS cohort have also changed since the beginning of the HIV epidemic (Fig. 3). PCP is responsible for a declining fraction of the pulmonary processes requiring hospitalization compared with other types of pulmonary pathology (Fig. 3). In particular, total cases, hospitalizations and deaths from PCP have decreased since the beginning of the epidemic (Fig. 4, Fig. 5). Some non-infectious etiologies, in contrast, have not decreased as significantly since the widespread use of ART (Fig. 3). Other studies have corroborated these findings [4–8]. Practitioners are thus seeing a very different spectrum of disease presenting in HIV-infected patients.Fig. 5: Chest computed tomography of Pneumocystis jiroveci pneumonia at initial diagnosis and after 20 days of therapy.Antiretroviral therapy as a cause of respiratory disease There are four specific issues regarding ART that deserve special attention regarding respiratory manifestations. First, patients may present with unexplained tachypnea and dyspnea in the absence of pulmonary pathology. Clinicians must recognize that the tachypnea and dyspnea may be caused by nucleoside-induced lactic acidosis [9]. This lactic acidosis can be reversed by discontinuing the offending agents if the clinician recognizes the etiological link before end-organ damage is irreversible. Second, enfuvirtide, or T-20, has been associated with an increased incidence of bacterial pneumonias [10]. The biological basis of the observation has not been explained. There is little guidance available as to the need to stop enfuvirtide if a bacterial pneumonia occurs in patients taking this drug. Third, abacavir can produce a hypersensitivity reaction, with fever, rash, and myalgias. Patients can manifest dyspnea (13%), cough (27%), and pharyngitis (13%) [11]. In approximately 20% of patients, pulmonary infiltrates are seen [12]. If patients stop abacavir, and then restart it, distributive shock and death can occur [13–15]. Clinicians thus need to consider this syndrome in their differential diagnosis so that patients are not rechallenged with abacavir, leading to disastrous consequences. Fourth, antiretroviral agents can produce intense immunological reactions (immune reconstitution syndromes) that can be clinically important, or life threatening. Should antiretroviral therapy be initiated or continued when patients develop pulmonary disease? When patients present with acute pulmonary disease, healthcare practitioners must decide how to manage ART. Initiating ART could be beneficial for patients with acute pulmonary disease: improving immunological and inflammatory responses could hasten recovery. However, there are several reasons to consider withholding ART. First, as described below, intense inflammatory responses can exacerbate lung dysfunction. Second, antiretroviral agents are all associated with toxicities. When patients with acute pulmonary processes develop rash, liver function abnormalities, or cytopenias, for example, clinicians often have difficulty determining whether the toxicity is caused by HIV, the acute pathogenic process, the specific therapy for the pulmonary process, or the newly prescribed ART. Third, many antiretroviral agents cause drug interactions. The protease inhibitors and the non-nucleoside reverse transcriptase inhibitors have complex interactions with the cytochrome p-450 system, making serum concentrations of concurrent drugs unpredictable, and making their own pharmacokinetics difficult to anticipate. Withholding antiretroviral agents may thus be a safer option than initiating them in terms of avoiding undesirable drug–drug interactions. If such patients are administered ART and have unpredictable pharmacokinetics, irreversible HIV drug resistance may be promoted. Stopping drugs does not promote resistance, and may be a preferable strategy for patients who may not have predictable absorption or kinetics. Such a strategy also prevents drug toxicities and drug interactions from becoming problems superimposed on the issues being acutely managed. In addition, most antiretroviral agents (except zidovudine and enfuvirtide) are only available as oral agents. Therefore, if patients are seriously ill, e.g. with respiratory failure, they may not be able to absorb oral drugs adequately. There are thus many reasons to adopt a conservative strategy and withhold ART from patients with acute respiratory processes, and to initiate or continue ART only if there is clear and well thought out benefit, and if the drug pharmacokinetics are carefully considered. Immune reconstitution syndrome When ART is initiated, patients with HIV infection may demonstrate new clinical manifestations as a result of enhanced immune response, i.e. immune reconstitution syndrome. Much of the current information about this syndrome is based on small case series. The true incidence of immune reconstitution syndrome is not yet clear, although it will presumably differ in various populations depending on the pathogens the patient has been exposed to and the degree of immune deficit when ART was initiated. It appears that the patients most likely to develop this syndrome are patients with low CD4 T-cell counts (e.g. < 50 cells/μl) and high viral loads (> 100 000 copies/μl) who have had a good virological response to ART. At least one retrospective review found that 31.7% of patients with known underlying opportunistic infections who received ART developed immune reconstitution syndrome [16]. The syndrome may manifest in the first few days after the initiation of ART when the viral load has fallen but before the CD4 T-cell count has increased as a result of an improvement in qualitative T-cell function as CD4 T cells become less activated. This improved qualitative T-cell function leads to a more robust response against organisms or antigens [17]. The range and severity of manifestations is wide, as indicated in Table 1. Some patients have clinically apparent but trivial syndromes, such as the appearance of an asymptomatic pulmonary nodule or mediastinal lymph node, wheereas other patients develop extensive organ dysfunction (Fig. 6). Many of the listed syndromes are clearly related to recognized microbial pathogens. However, some are related to tumors or to syndromes of uncertain cause. As there is not a clear case definition for immune reconstitution syndrome, it is difficult to determine if all of the listed syndromes are true examples of immune reconstitution syndrome, or if some are unrelated coincidental occurrences.Table 1: Disease processes associated with immune reconstitution syndromes.Fig. 6: Chest computed tomography in a patient with fever and chest pain after initiation of antiretroviral therapy found to be cryptococcal infection.There is no consensus or specific laboratory marker regarding the optimal method for diagnosing these immune reconstitution syndromes. When patients starting ART develop new manifestations, they merit a methodical evaluation to determine whether the syndrome represents a new, active, infectious process, a new neoplastic process, or some other disease entity in need of specific intervention. The distinction between a new opportunistic infection and an immune reconstitution syndrome can be subtle. The histology of immune and inflammatory response does not distinguish the acute opportunistic infections from immune reconstitution syndromes: responses to either may be composed of lymphocytes and monocytes with or without granulomas and necrosis. Negative cultures can be useful, although there is inconsistency in the published literature, emphasizing the lack of consistency in defining this syndrome. In the absence of data to direct the optimal management clinicians are to a clinical about when to use how long to continue the and when to use agents or This be by the severity of the syndrome, the of the virological and CD4 T-cell response to ART, and the specific Pneumocystis jiroveci pneumonia Immune reconstitution syndromes can occur in patients with infectious processes such as PCP In one small case patients with PCP CD4 T-lymphocyte count of improved on and ART therapy days of PCP diagnosis All developed acute respiratory a of days findings of inflammatory with a few Pneumocystis were thought to be with an immune reconstitution syndrome often this occurs when ART is initiated soon after PCP is but there are such cases to over an immune reconstitution syndrome one to consider ART for many after PCP The optimal time to has not been i.e. time to the that an immune reconstitution syndrome will but not an of time such that other opportunistic processes are likely to occur. Mycobacterium Immune reconstitution syndrome is common in patients with tuberculosis, or patients with who have initiated therapy in the past few or In one prospective study of patients with with therapy of HIV-infected patients with ART of HIV-infected patients not taking ART developed clinical with immune reconstitution syndromes after the initiation of syndromes days after the initiation of ART. In retrospective study the first of ART in of patients who had received at least two initial of A from in of patients to be likely in patients who had a in HIV viral load in patients with immune reconstitution syndrome in without an and a increase in CD4 T-lymphocyte counts for with a clinical in without an apparent immune reconstitution The of ART initiation also the incidence of immune reconstitution In a retrospective study out of starting ART less than after starting therapy developed immunological only one out of developed such reactions when starting after a of more than For patient populations in which is the potential for immune reconstitution syndromes a It clearly be to ART to the response to therapy and to other opportunistic infections from studies are there are no regarding when to antiretroviral therapy in the of However, one be if a patient is with and HIV, the therapy be clinicians the initiation of ART for after the of therapy Patients with lower CD4 T-lymphocyte counts be for therapy with ART. Patients with higher CD4 T-lymphocyte counts with CD4 T-lymphocyte counts than can therapy is Immune reconstitution syndrome and reactions can also be associated with other such as pulmonary Mycobacterium complex infection (Fig. Immune reconstitution syndromes may occur in patients with i.e. who have had a clinically apparent syndrome as a result of In contrast, as it that immune reconstitution syndromes caused by Mycobacterium occur in who have had Chest computed tomography in a patient with from mediastinal after initiation of antiretroviral therapy found to be from Mycobacterium with from complications of HIV disease In the United States and western Kaposi's sarcoma has been a for HIV-infected the incidence has decreased with the use of ART In the HIV of ART had a much higher incidence of Kaposi's sarcoma than of ART The with over participants, demonstrated the incidence of Kaposi's sarcoma patients receiving ART decreased with the increasing time since the initiation of ART there was an < in the incidence of Kaposi's sarcoma between 1994 and 2003 in the In patients with pulmonary Kaposi's the CD4 T-lymphocyte count is although the range was In one only of patients with Kaposi's sarcoma had a CD4 T-lymphocyte count than emphasizing that most cases occur at low CD4 T-cell counts Patients with pulmonary Kaposi's sarcoma present with of and chest also of in the In a of pulmonary Kaposi's all patients with and with Chest pain was in patients in patients and fever in four patients (13%) patients have In one only of patients had lung without Chest are In one case patients had had a and had on the chest Chest computed tomography demonstrate or in a (Fig. Chest computed tomography of Kaposi's diagnosis of Kaposi's sarcoma is often of the or The or are and are not for other manifestations A is also is not for the is also not the can be with the cells of Kaposi's A diagnosis on or For patients with Kaposi's the survival in the was approximately although patients often of processes other than Kaposi's sarcoma ART and combination such as with or the response rates have improved ART therapy is also associated with a of death in patients with pulmonary Kaposi's sarcoma receiving There is thus a for in to patients with clinically Kaposi's sarcoma current Immune reconstitution syndromes have been in with Kaposi's sarcoma with ART lymphoma lymphoma has been the most common studies a in the incidence of in the past few years since the introduction of ART In the HIV the of compared with the was much higher for compared with patients on ART In one retrospective study the of decreased from per cases in 1988 to per cases in study from found a in the incidence of from to from to cases per Therefore, for the incidence appears to be However, the of patient the of lymphoma may not be declining as occurs in patients at all CD4 T-lymphocyte although the of is higher at lower CD4 T-lymphocyte counts The CD4 T-lymphocyte count has been to be lower in patients with pulmonary than in without such In a small of patients with pulmonary the CD4 T-lymphocyte count was patients with pulmonary present with cough and dyspnea The chest demonstrate or In a case of patients in and in of the and with have also been There are no in the to in patients with HIV compared with patients without a diagnosis of disease may be with a or are not The most in the ART has been the of the of for the patients were often with a conservative for HIV-infected patients has for of populations As has become more other of therapy for lymphoma are being is being in some There has been some as to whether to continue ART In one study of patients antiretroviral therapy patients with and was associated with high response with in of patients, but toxicities. 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The HIV Outpatient Study (HOPS) The HOPS the and and of Prevention, National Center for HIV, and Centers for Disease Control and and of of and and Infectious Disease and and of and of and and and of at This was by National Institutes of from the and from the Centers for Disease Control and The have no or other that a of The findings and in this are of the and do not represent the of the National Center for HIV, and Prevention, Centers for Disease Control and