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Chest radiology. European. Radiology. Review article. Computed tomography of the thorax in HIV disease. S. P. G. Padley, L. J. King. Department of Radiology ...
Eur. Radiol. 9, 1556±1569 (1999) Ó Springer-Verlag 1999

European Radiology

Chest radiology

Review article Computed tomography of the thorax in HIV disease S. P. G. Padley, L. J. King Department of Radiology, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK Received: 28 September 1998; Revision received: 28 December 1998; Accepted: 26 January 1999

Abstract. A wide variety of thoracic disorders can arise in patients infected with the human immunodeficiency virus (HIV), although recent developments in the therapeutic management of AIDS patients has resulted in a changing pattern of chest disease. The use of CT in the diagnosis and management of these thoracic manifestations is discussed along with the CT appearances of the various infectious and non-infectious complications of the acquired immune deficiency syndrome (AIDS) which are commonly encountered in clinical practice. Key words: HIV ± Computed tomography ± Thorax ± Chest radiography

Introduction Many different pathological processes occur in the thorax as a result of HIV disease, causing considerable morbidity and mortality. Any individual disease process may be manifest in numerous ways either alone or in combination. This propensity for radiological variation creates a considerable challenge to the expertise of the radiologist in the interpretation of chest radiographs and thoracic CT scans. There is much to be gained from efforts to gather background information in any individual case including the nature of HIV acquisition, CD4 count and current drug therapy. In addition, the acuteness of onset and severity of the illness are also important, as is a history of previous infectious or non-infectious complications. Furthermore, the results of important yet relatively simple tests, such as pulse oximetry, and sputum microscopy, will also narrow the differential diagnosis.

Correspondence to: S. P. G. Padley

The role of CT scanning Over the past decade there have been numerous studies describing the CT manifestations of common and less common thoracic manifestations of AIDS. Several authors have expounded the utility of CT scanning in the clinical management of AIDS patients with thoracic disease. Most studies, however, have looked retrospectively at a series of patients in whom the diagnoses had already been established, with analysis limited mainly to radiological description. There have been a few important exceptions to this trend, most notably those series by Hartman et al. [1] and Kang et al. [2]. Hartman and colleagues [1] assessed the accuracy of CTin the diagnosis of thoracic complications of AIDS by reviewing the CT scans of 122 patients (102 with and 20 without disease). They found that a confident diagnosis could be reached in 48 % of cases, and when a confident diagnosis was made, it was correct in 92 % of cases. Interestingly, some of the same authors found, in a subsequent publication by Kang et al. comparing the diagnostic yield of CT with the diagnostic yield of the chest radiograph, that the improvement in diagnostic accuracy provided by CT was modest [2]. They stated that ªin the majority of cases the chest radiograph provides adequate information and CT is not warrantedº. In our institution we attempt to define the likely contribution of a CT scan towards patient management in each particular case, rather than utilising CT as a regular step in the work-up of patients presenting with respiratory symptoms. However, CT does have an important role and there are numerous clear indications which include the following: 1. Suspected chest disease in the face of a normal or probably normal chest radiograph 2. Clarification of abnormalities present on the chest radiograph, including disease extent and pattern of parenchymal change 3. Evaluation of mediastinal contour abnormalities evident on the chest radiograph, particularly assessment of mediastinal lymph node enlargement

S. P. G. Padley and L. J. King: CT of the thorax in HIV disease

Fig. 1. Relationship between declining CD4 count and onset of HIV-associated pathologies. OHL oral hairy leucoplakia; PML progressive multifocal leucoencephalopathy; ADC AIDS dementia complex; MAC mycobacterium avium complex; CMV cytomegalovirus

4. Staging or re-staging of malignant disease 5. Biopsy planning, including identification of representative lesions, and choice of biopsy technique Radiographic pattern recognition Sider and co-workers have demonstrated the potential utility of pattern recognition in HIV disease [3]. The radiological manifestations of thoracic disease in this population, however, are non-specific, thus accentuating the importance of radiological interpretation being supported by clinical details. For example, Kaposi's sarcoma (KS) is unlikely to occur unless a patient has acquired AIDS through bisexual or homosexual contact, and is also unlikely with a CD4 count greater than 200 cells/ mm3. In the absence of these factors, and whatever the radiological appearances, a suggested diagnosis of KS is very unlikely to be correct. This principle holds true for numerous other AIDS-related chest diseases. Opportunistic chest infections, for example, do not generally occur prior to a fall in the CD4 count to less than 200 cells/mm3, and numerous other disease processes tend to only be encountered as the CD4 count falls below certain threshold levels (Fig. 1). Thus, the application of disease pattern-recognition guidelines must be combined with the current clinical situation to allow maximum yield from the CT findings. Changes in presentation and epidemiology of HIV disease in the thorax Since the start of the AIDS epidemic respiratory disease has been an important cause of morbidity and mortality, and the majority of HIV-infected patients will suffer from a pulmonary complication during the course of

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their illness. Numerous factors have recently influenced the epidemiology of AIDS. Changes in therapy, most notably the introduction of combination anti-viral therapy and the use of prophylactic antibiotics, have led to changes in the spectrum and frequency of numerous thoracic diseases. As effective prophylaxis and treatments are developed for the more traditional respiratory tract pathogens that cause disease in the AIDS population, less virulent organisms are becoming increasingly frequent causes of morbidity. There has been a documented reduction in Pneumocystis carinii pneumonia (PCP) as a result of pentamidine prophylaxis, an increase in the frequency of Mycobacterium avium complex (MAC) and cytomegalovirus (CMV), and a reduction in new presentations of KS [4]. There have also been changes in the population characteristics of patients with AIDS. A greater proportion of new cases are now being reported in women and children as a result of heterosexual contact or IV drug abuse, and there has been a relative reduction in the proportion of new cases arising from homosexual or bisexual acquisition. CT of pulmonary disease in AIDS Within the constraints given herein, CT has an important place in the management of patients with chest symptoms, both in disease process identification and diagnosis. The spectrum of pathologies will be covered under groups of similar diseases or individual disease processes, as appropriate, and in addition to CT appearances, trends in epidemiology and the clinical application of CT are discussed. Pneumocystis carinii pneumonia Pneumocystis carinii pneumonia (PCP) was previously the commonest respiratory tract infection to occur in the AIDS population, and was also the commonest AIDS-defining illness in a large early series [3]. The impact of prophylactic preventative therapy has been to reduce ninefold the likelihood of PCP in the 6 months following a fall of the CD4 count below 200. PCP prophylaxis has also been shown to increase life expectancy in this severely immunosuppressed group when combined with anti-viral therapy, compared with patients taking anti-viral therapy alone [5]. Bacterial pneumonia has now superseded PCP as the commonest chest infection overall, but PCP remains a significant problem which still occurs in the majority of patients at some time during their illness and is still the most common opportunistic chest infection. Pneumocystis carinii pneumonia is slightly commoner in homosexuals than in IV drug abusers, and is also more common in males and in the white population, whatever the method of HIV acquisition [5, 6]. Although PCP becomes increasingly common as the CD4 count falls below 200, it may still occur above this level. Patients with PCP are usually hypoxic, with a his-

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S. P. G. Padley and L. J. King: CT of the thorax in HIV disease

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Fig. 2. A 28-year-old male HIV patient with Pneumocystis carinii pneumonia (PCP) infection complicated by pneumomediastinum (white arrows) and subcutaneous emphysema (black arrows). Bilateral ground-glass shadowing is present and there is a small area of cystic change posteriorly within the left lung (arrowheads) Fig. 3. Chest CT of a 41-year-old male HIV patient with PCP showing typical bilateral ground-glass shadowing Fig. 4 a, b. Two cases of atypical PCP. a Multiple thick-walled cystic spaces, bronchial wall thickening and dilatation (arrows). These changes persisted following treatment of acute infection. b A 41year-old male with thick-walled cysts at both lung apices in association with surrounding ground-glass infiltrate Fig. 5 a, b. Computed tomography scans in two patients with bacterial lung infections. a A 35-year-old male AIDS patient with pulmonary consolidation (open arrows) due to a community acquired pneumonia, complicated by empyema formation (curved arrow). b Multiple cavitating nodules (arrows) due to staphylococcal lung abscesses in a 36-year-old female HIV-positive drug abuser. The CD4 count was high, and the patient had not yet converted to full-blown AIDS

tory of cough and fever developing over several days. Radiographically the chest X-ray is occasionally normal but most commonly demonstrates bilateral ground-glass or reticular infiltrates most marked in a peri-hilar distribution. The diagnosis of PCP is strongly suspected by the combination of a typical history and low CD4 count, coupled with hypoxia on room air, or early desaturation on exercise (reliable only if there has not been a previ-

ous episode of PCP). An induced sputum sample usually provides a definitive diagnosis. If sufficient diagnostic doubt persists to prevent institution of therapy, then bronchoscopy with bronchoalveolar lavage (BAL), and occasionally transbronchial biopsy, may be required. In our institution there is relatively little use of highresolution CT (HRCT) in suspected PCP, although there is a role for CT in the assessment of atypical cases and management of complications of PCP, especially pneumothorax and surgical emphysema (Fig. 2). Other workers have proposed that CT and especially HRCT has a role in prevention of other more invasive diagnostic procedures, since it has been shown to be reliable in detecting parenchymal change when the diagnosis is suspected but the chest radiograph is normal or equivocal [7]. Several other studies have supported the ability of HRCT to confidently diagnose PCP based on typical radiological features (Fig. 3) [1, 2]. During the first episode of PCP, the acute infection classically results in a peri-hilar ground-glass infiltrate, often in a geographical distribution, with areas of affected lung interspersed by normal lung parenchyma. In addition to the groundglass change, there is associated thickening of the interlobular septa, which is often the feature that is slowest to resolve radiologically. Pneumocystis carinii pneumonia is an example of a disease process in the HIV population that may demonstrate considerable variation in its radiological appearances, and a variety of less typical patterns have been described both on chest radiography

S. P. G. Padley and L. J. King: CT of the thorax in HIV disease

and CT. These less common appearances include the development of focal areas of consolidation, focal mass lesions, multiple lung nodules, pleural fluid, pneumothorax, focal cavitation and lymph node enlargement. Whereas cavitation in an area of ground-glass change (Fig. 4 b) or pneumothorax are both suggestive of PCP, the other changes have a wide variety of possible causes, most notably bacterial pneumonias including typical or atypical mycobacterial infection. Bacterial pneumonia The widespread use of anti-PCP prophylaxis, and the changing demographics of the HIV-positive population, have both contributed to the increased incidence of bacterial pneumonia. Overall, bacterial infections have now become the commonest infective thoracic complication of HIV disease [8, 9]. Whereas bronchitis and sinusitis are more common than bacterial pneumonia, individually they are now all more common than PCP. Thus recurrent pyogenic bacterial pneumonia is now the most common clinically apparent parenchymal lung infection in the HIV population, both before and after the onset of AIDS [8]. Bacterial pneumonias tend to occur throughout the course of HIV illness, becoming increasingly common with a falling CD4 count. Since they often occur at relatively high CD4 counts, bacterial infections tend to be the first pneumonic process to occur prior to the onset of full-blown AIDS. Recurrent bacterial pneumonia is now included in the Centre for Disease Control list of AIDS-defining illnesses. The incidence overall is approximately five times that in an otherwise similar HIV-negative population [8], and within an HIV cohort tends to be more common in IV drug abusers [10]. Furthermore, the incidence of pneumococcal disease, including pneumonia, is ten times greater, and the development of pneumococcal septicaemia 100 times greater, than in the general population [11]. The clinical presentation of pneumonia is generally the same as in the general population, and the disease usually follows a similar clinical course. The organisms encountered mirror those seen in the general population, although less common organisms are identified with relatively greater frequency. The majority of community acquired pneumonias are due to Streptococcus pneumoniae, Haemophilus influenzae, Pseudomonas aeruginosa and Streptococcus viridans [9, 10], although opportunistic bacterial infections are encountered in the later stages on immunosuppression, including Rhodococcus equi and Rochalimaea sp. Radiographically lobar and segmental consolidation are usual, but an increased frequency of interstitial infiltration has been reported [12, 13, 14]; thus, differentiation from opportunistic infection is often not possible from the chest radiograph. The tendency to cavitation, empyema and para-pneumonic effusion formation and rapid progression are greater than in the general population (Fig. 5). Differentiating bacterial infection from Mycobacterium tuberculosis (TB) and PCP is difficult

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when the appearances are atypical, as demonstrated in the studies by Boiselle et al. [13] and Magnenat et al. [14]. Computed tomography may be useful in patients with bacterial pneumonia, especially when the appearances are atypical and culture or serology has failed to identify the organism. Cavitation and pleural complications are also better delineated on CT than on plain radiographs, but in the majority of cases CT is not required. Bacterial chest infections in the HIV population are frequently not pneumonic in nature. In numerous recent studies the important morbidity associated with bronchitis, bronchiolitis and bronchiectasis have been highlighted [10, 15, 16, 17, 18]. Chest radiographs often reveal the impression of an interstitial infiltrate or multiple small nodules [19]. High-resolution CT in these cases allows the true bronchocentric nature of the disease to be appreciated. The HRCT technique may also demonstrate airway abnormalities despite a normal chest radiograph [10]. Typical changes are of small airways plugging, producing branching centrilobular nodules if affecting the respiratory and terminal bronchioles (ªtree-in-budº appearance), or larger branching opacities when subsegmental bronchial impaction is present (Fig. 6). The airway obstruction may also manifest itself as mosaic attenuation, especially on expiratory images which serve to differentiate airway disease from ground-glass change due to parenchymal infiltrate [10]. Bronchiectasis in the segmental and subsegmental airways is increasingly recognised and may give rise to chronic symptomatic lung disease, with acute exacerbations and chronic sputum production [20]. Mycobacterium tuberculosis Tuberculosis (TB) is relatively common in the AIDS population, and the incidence seems less related to the means of acquisition of HIV than to the prevalence of TB in the local community [21]. This would seem to fit with the relative increased incidence in the IV drug abuse population, who tend to be found in areas with high TB prevalence. Overall, the incidence of TB is several hundred times greater in the AIDS population than in the general population [21]. Although TB tends to become increasingly common towards the later stages of immunosuppression, it is, like bacterial pneumonia, an infective complication that may occur at relatively high CD4 counts. Since the inclusion of TB as an AIDS-defining illness in 1993, it has accounted for 7 % of AIDS-defining diagnoses [22]. The clinical and radiological presentation of TB is dependent on the level of immunosuppression. At higher CD4 counts the appearances resemble re-activation TB in the general population, but disease at lower CD4 counts is more akin to primary infection, with marked nodal enlargement, pleural disease and a tendency to haematological and bronchopulmonary dissemination. As patients become more immunosuppressed they may

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S. P. G. Padley and L. J. King: CT of the thorax in HIV disease Fig. 6. Airways abnormality in HIV disease. A 36-year-old male patient with recurrent bronchitis and an equivocal chest radiograph. Computed tomography demonstrates subsegmental bronchiectasis (curved arrows) associated with plugging of the peripheral small airways (straight arrows) Fig. 7. A 39-year-old AIDS patient with reactivation tuberculosis in the apical segment of the right lower lobe (arrows). The diagnosis was confirmed by percutaneous needle biopsy after the usual diagnostic tests had been negative

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8 Fig. 8. Cavitatory and bronchopneumonic tuberculosis in a 30year-old male HIV-positive patient. The right lung has been largely destroyed by tuberculosis, with extensive volume loss and cavitation. Bronchopneumonic spread is evident in the left lung where there are multiple branching centrilobular nodules. This was an AIDS-defining illness Fig. 9. Centrally necrotic mediastinal lymph node enlargement in an AIDS patient with tuberculosis. There is rim enhancement (white arrow) following intravenous contrast administration. A small right pleural effusion is present (black arrow)

become anergic to skin testing. The mainstay of diagnosis is expectorated or induced sputum examined by microscopy, culture or increasingly polymerase chain reaction testing. The importance of making a timely diagnosis has been recently accentuated in the series by Kramer et al. who reported increased mortality when a diagnosis of TB was delayed due to failure of the usual diagnostic tests [23]. Response to therapy is dependent on

9 sensitivity, with increasingly high rates of drug-resistant strains being reported. Radiological appearances, as mentioned herein, may be typical of reactivation TB (Fig. 7), but atypical patterns occur, and numerous series have highlighted the radiological differences in the appearances of TB between the HIV and general populations [24, 25]. These differences include lobar consolidation at unusual sites, florid lymph node enlargement, bronchopulmonary patterns and miliary spread (Fig. 8). Cavitation tends to become less common at lower CD4 counts. An important minority of patients may have normal chest radiographs despite active TB, and this is increasingly common at low CD4 counts [26]. As a result of the high number of normal or atypical appearances in their series, Greenberg et al. questioned the utility of the chest radiograph in the diagnostic work-up of chest disease in the HIV population [26]. Computed tomography scanning may demonstrate typical features, including cavitation, consolidation,

S. P. G. Padley and L. J. King: CT of the thorax in HIV disease

nodal enlargement with necrosis and centrilobular branching nodules. When nodal enlargement is present, CT scanning following IV contrast may show a typical pattern of peripheral nodal enhancement, and central low attenuation (Fig. 9), a finding that is believed to be sufficiently specific to allow empirical therapy to be commenced if the diagnosis of TB has not otherwise been established [10]. Lymphadenopathy and parenchymal lung disease may also become more pronounced following the introduction of anti-viral therapy due to a partial reversal of the previous immunological anergy. Unlike most radiological series that examined the differences in the chest radiograph between HIV and non-HIV populations, Leung et al. found no such difference in the CT appearances between these populations, at either high or low ( < 200 cells/mm3) CD4 counts [25]. Atypical mycobacteria Mycobacterium avium complex (MAC) within the chest may have appearances that are similar to TB, but the radiological spectrum is wide (Fig. 10) [27], and the diagnosis usually requires isolation of the organism from blood or bone marrow. The chest is rarely the sole site of disease, usually being involved as part of disseminated infection, typically being acquired enterally, and usually associated with very low CD4 counts. A normal chest radiograph is more common than in TB, pleural effusions are more common with MAC and miliary disease is particularly uncommon. Nodal disease is usually less florid than in TB at the same stage of immunosuppression. Bacillary angiomatosis Infection with the bacillus Bartonella henselae occurs almost exclusively in AIDS patients and results in localised areas of vascular proliferation at numerous anatomical sites including the airways and lung parenchyma. On CT the appearances vary from solitary to multiple pulmonary nodules of varying size ranging from 1 mm to several centimetres in diameter [28, 29]. Associated mediastinal lymphadenopathy is a common finding and intense enhancement of both the nodules and intrathoracic nodes is reported following intravenous contrast which probably reflects the marked vascularity of these lesions [28, 29]. Fungal chest infections Fungal infections are reasonably common in AIDS despite the fact that host defence mechanisms rely more on phagocytic cells than on T-cell-mediated mechanisms. The relative frequency of different varieties of fungal pathogens is largely dependent on the endemic rate in the local population.

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Cryptoccocal pneumonia Cryptococcus is the commonest pulmonary fungal pathogen in the AIDS population, accounting for up to 15 % of pneumonic episodes in some series [30]. Although cryptococcal meningitis is the commonest disease manifestation, the lung is the port of entry. Cryptococcal infection may be asymptomatic but causes a clinically apparent pneumonia in approximately 30 % of patients [31]. In common with other fungal infections, Cryptococcus tends to occur at low CD4 counts of less than 100 cells/mm3. The diagnosis may be established by the combination of a positive cryptococcal antigen test, together with isolation of the organism by microscopy or culture, from expectorated or induced sputum, or from bronchial washings, transbronchial biopsy, or occasionally percutaneous needle biopsy. There is some variety in the radiological series of cryptococcal pneumonia [30, 31, 32]. The commonest descriptions include reticular or reticulonodular interstitial infiltrates, alveolar consolidation, ground-glass change, miliary nodules, lymphadenopathy and small pleural effusions. The more classical appearances of focal nodule formation, with or without cavitation, are relatively rare in the HIV population. With this wide variation in appearance, cryptococcal pneumonia should be considered in the differential diagnosis of PCP, TB and pyogenic bacterial infections [32]. Computed tomography may be used to clarify the chest radiographic appearances, especially when a combination of pathologies is suspected. The diagnostic accuracy of CT for cryptococcal infection has not been specifically studied, although the ability of CT to correctly identify fungal pneumonia were assessed in the series by Hartman et al. [1]. They included 11 cases of fungal infection in there series of 122 patients and found that a diagnosis of fungal infection was correctly included in the top three choices in 86 %, and was the correct first choice diagnosis in 41 %. They used the CT findings in previously published series as a guide and made a diagnosis of fungal infection based on the presence of nodules and masses (that may be cavitating), mycetoma formation, miliary nodules, lymphadenopathy and effusions (Fig. 11). Aspergillus infection As patients with profound immunosuppression are surviving for longer in the latter stages of HIV infection, Aspergillus infection is becoming increasingly encountered. Numerous forms of infection have been described, usually in series based on chest radiographic appearances. The CT appearances are most commonly those of thick-walled cavities or lung abscess formation (Fig. 12), and Staples et al. [33] showed that, in keeping with findings in other groups of immunocompromised patients, these appearances were pathologically due to haemorrhagic infarction secondary to angioinvasion.

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Fig. 10. Multiple soft tissue density nodules (arrows) in the right upper lobe in a 47-year-old male. Mycobacterium avium complex was subsequently isolated from induced sputum samples. The CT appearances are similar to Mycobacterium tuberculosis Fig. 11. A 36-year-old male AIDS patient with mass like consolidation in the left upper lobe and surrounding ground-glass shadowing. Cryptococcus was isolated from the sputum and the lesion resolved on anti fungal therapy Fig. 12. Aspergillus chest infection resulting in lung abscess formation. There are two moderately thick-walled, irregular cavities in the posterior segment of the right upper lobe (white arrows). Associated pleural thickening is present (black arrow) Fig. 13. A 34-year-old male AIDS patient with aspergillus bronchopneumonia. Bilateral lower lobe consolidation is present on the chest CT scan. Irregular centrilobular branching nodules (arrows) are demonstrated on the right due to disease centred on the airways. Bilateral pleural effusions are also present

Three other patterns of disease due to Aspergillus infection have also been described in this population and two of these affect the airways. The first pattern is necrotising tracheobronchial aspergillosis [34], resulting in nodular thickening of the tracheal and bronchial walls due to plaque-like lesions of Aspergillus. The second pattern involves the more distal airways and causes bronchial obstruction due to plugs of endoluminal fungus, akin to allergic bronchopulmonary aspergillosis. These patients may be severely unwell, and radiographically may have bilateral lower lobe atelectasis and consolidation (Fig. 13) [35]. The final pattern of disease is mycetoma formation, and in keeping with the non-HIV population these most frequently occur in a pre-existing cavity, either due to PCP or more usually TB. Computed tomography may be useful in delineating the extent and severity of Aspergillus infection, and

S. P. G. Padley and L. J. King: CT of the thorax in HIV disease

when the appearances are typical, with focal pulmonary nodules surrounded by ground-glass changes, or mycetoma formation, then a confident diagnosis can be suggested. Although the diagnostic confidence level can be high, there are no pathognomonic appearances, and demonstration of the organism is usually required. Histoplasmosis Histoplasmosis is relatively uncommon in the AIDS population unless the patient comes from or lives in an endemic area. Pulmonary disease may occur alone or, more commonly, in association with disseminated disease, and usually at profound levels of immunosuppression. In a series of 18 patients born in endemic areas but living elsewhere, the pulmonary component of disseminated histoplasmosis infection included bilateral nodular or interstitial shadowing [36]. In this series, and also in the study by Conces et al. [37], the nodules were usually less than 3 mm. This study also included patients with patchy consolidation. Since the radiological appearances are non-specific, the diagnosis requires isolation of the organism from the lungs or elsewhere. Sputum analysis has been found to be unreliable and examination of bronchial aspirates is often necessary for diagnosis [38]. In keeping with other causes of opportunistic infections, CT is particularly useful in the patient who has symptoms but in whom the chest radiograph is normal. Nocardia Nocardiosis is well described in immunocompromised patients, particularly after organ transplantation, and has been documented in AIDS patients usually when the CD4 count is low [39]. A study by Kramer and Uttamchandani of 21 HIV-positive patients with pulmonary Nocardia found the radiological appearances to be variable [40]. Lobar or multilobar consolidation was the commonest appearance seen in 52 % of patients. Solitary pulmonary masses were identified in 24 % of cases, reticulonodular infiltrates in 33 % and pleural effusions in 33 % (Fig. 14). Cavitation was also a common feature which was identified within masses or areas of consolidation in 62 % of cases. The typical radiological appearances may raise the possibility of Nocardia, but the diagnosis depends on demonstration of the organism Nocardia asteroides on sputum culture, lavage or biopsy. Viral infections Numerous viruses are known to infect the lungs of AIDS patients. Cytomegalovirus (CMV) is the most common viral pathogen to cause morbidity and mortality in patients with AIDS [41, 42]. Although commonly recovered from the lungs of AIDS patients at autopsy and isolated from bronchial washings or biopsy samples,

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the presence of CMV does not necessarily indicate clinical infection. Proven cases of clinically relevant pneumonitis have been notably limited. Diagnosis of CMV pneumonitis requires identification of the typical CMV inclusion bodies, but these may be present in the absence of symptoms. When there are symptoms of respiratory infection and CMV inclusion bodies are detected in the absence of other pathogens, anti-CMV treatment can prove valuable for relief of symptoms and may even prove lifesaving. Waxman et al. [43] described a series of patients admitted with pneumonia who underwent thorough investigation, and in whom CMV was the only lung isolate. These patients had very low CD4 counts (averaging 29 cells/mm3) and presented with hypoxia, increased respiratory rates and interstitial infiltrates. In this series of nine patients, five were treated with anti-viral therapy and recovered. Three were untreated and died of respiratory failure, with CMV pneumonitis confirmed at post-mortem examination. Some recent studies report an increase in prevalence of CMV pneumonitis [42, 44] which appears to result from the increased use of steroid therapy in AIDS patients and longer survival of severely immunocompromised patients. Patients with pneumonitis are all severely immunocompromised having CD4 counts below 100, and in one series of 21 patients below 50 cells/mm3 [45]. In this series CMV pneumonitis was rarely found in isolation, frequently being in combination with extrathoracic CMV infection or Kaposi's sarcoma. Two thirds of the patients in this series were also on PCP prophylaxis. The radiological appearances of CMV pneumonitis are varied and non-specific. They include alveolar, interstitial and nodular infiltrates on chest radiographs, which are most typically peri-hilar and extend into the lower zones. Usually these appearances are attributed to PCP. The CT appearances of CMV pneumonitis have also been reported and include ground-glass attenuation, dense consolidation, bronchial wall thickening or bronchiectasis, interstitial reticulation without air-space disease and discrete pulmonary nodules or masses [45]. Herpes simplex virus (HSV) is rare as a cause of pneumonia in the HIV population, and when encountered is usually associated with profound immunosuppression. Pulmonary HSV infection is much less common than CMV and manifests as either a focal necrotising tracheo-bronchitis or a diffuse interstitial pneumonitis [46]. The few case reports of HSV pneumonia have been in association with other pathogens, especially Pneumocystis carinii [47, 48]. Respiratory syncytial virus and Varicella zoster are also occasional causes of pneumonitis [49]. Epstein-Barr virus has been implicated in the pathogenesis of lymphocytic interstitial pneumonia, and the human immunodeficiency virus itself may infect pulmonary macrophages [50]. Parasitic infections Strongyloides stercoralis is a rare infection in the HIV population and may occur many years after travel to an endemic area. There are scant case reports [51, 52] doc-

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umenting pulmonary infiltrates in patients with disseminated infection. Isolation of the organism from the lung has been reported, with rapid improvement in symptoms following institution of anti-helminthic drug therapy. The radiological appearances are non-specific. Toxoplasma gondii is an obligate intracellular parasite and is also a rare cause of lung disease in the HIV population. Pomeroy and Filice reported shortness of breath, cough, fever and rales in association with hepatosplenomegaly in immunocompromised patients [53]. Goodman and Schnapp reported nodular infiltrates or reticulonodular infiltrates similar to PCP in a series of patients with pulmonary toxoplasmosis [54]. The radiological features are therefore non-specific and the diagnosis is most frequently made from bronchial washings. Cryptosporidium and Microsporidium are both protozoans that most commonly affect the gastrointestinal tract in the HIV population, and only rarely cause lung disease [55, 56]. The appearances are non-specific with pulmonary infiltrates and pleural effusions both described, and the diagnosis being made from BAL fluid. Rhodococcus equi is an intracellular parasite that has been reported to cause cavitating pneumonia in a small number of HIV patients, usually with a history of exposure to horses or horse manure. Radiological appearances include pulmonary consolidation sometimes with cavitation. On CT six of nine patients had mediastinal adenopathy mimicking lymphoma and two also had multiple pulmonary nodules [57]. Diagnosis depends on culture results and biopsy. Neoplastic diseases Kaposi's sarcoma Kaposi's sarcoma and lymphoma are the commonest thoracic malignancies in HIV patients. Pulmonary KS affects 18±47 % of patients with known cutaneous KS [58, 59], and affects the lung parenchyma, pleura or tracheo-bronchial tree. A virus from the herpes family has been identified as the causal agent for Kaposi's sarcoma and is referred to as Kaposi's-sarcoma-associated herpes virus (KSHV) or human herpes virus 8 [60, 61, 62]. Almost all cases of KS have been documented in either homosexual or bisexual men and their partners. The commonest reported CT finding is of ill-defined parenchymal nodules which may be surrounded by a small area of ground-glass shadowing. Bilateral peri-hilar pulmonary infiltrates are seen in the majority of patients, which extend into the pulmonary parenchyma along the broncho-vascular bundles (Fig. 15). Associated findings include thickening of the interlobular septa and nodularity of the fissures. Pleural effusions, pericardial effusions and mediastinal lymphadenopathy are also described [63]. Wolfe et al. have reported chest wall disease involving the sternum, ribs, thoracic spine and subcutaneous tissues in 53 % of patients with KS [64].

S. P. G. Padley and L. J. King: CT of the thorax in HIV disease

Lymphoma Lymphoma occurs with increased frequency in patients with AIDS and is typically a high-grade, B-cell, nonHodgkin's lymphoma (NHL). Prognosis following a diagnosis of lymphoma is usually poor, although death is rarely directly attributable to the lymphoma [42]. The reported incidence of thoracic involvement in AIDS-related lymphoma (ARL) varies from 5±20 % in most clinical series [65, 66, 67, 68, 69] but may be more common. Eisner et al. have recently reported thoracic involvement at autopsy in 71 % of patients with ARL which compared to an incidence of only 5.8 % in their clinical series [70]. Although NHL is a frequent AIDSdefining illness, pulmonary involvement tends to occur in the advanced stages of immunosuppression [66, 70, 71]. Hodgkin's lymphoma is also reported in AIDS patients but is less common than NHL [71]. The most frequent imaging findings of thoracic ARL are multiple pleural (Fig. 16) or intrapulmonary masses which are usually peripheral and occasionally show cavitation, although ARL may occasionally appear as a solitary pulmonary nodule (Fig. 17) [72]. Pleural effusions or mediastinal lymphadenopathy are also recognised [69, 70] and a high incidence of thoracic lymphadenopathy is reported by some authors [70], although the disease is more typically extranodal (Fig. 18). These radiological findings overlap with the appearances of several other infectious and non-infectious processes in the Fig. 14. A CT scan of a 46-year-old male demonstrating a right up- V per lobe soft tissue mass surrounded by ground-glass shadowing due to Nocardia asteroides. The diagnosis was established by percutaneous needle biopsy Fig. 15. Pulmonary Kaposi's sarcoma in a 55-year-old male. The chest CT scan shows multiple lung nodules in a bronchocentric distribution adjacent to the left hilum Fig. 16. AIDS-related lymphoma. Isolated soft tissue density pleural mass (arrows) in a 32-year-old male, diagnosed on CT-guided percutaneous biopsy as high-grade, B-cell non-Hodgkin's lymphoma. A subsequent bone marrow aspirate also demonstrated lymphomatous infiltration Fig. 17. A CT scan of a 59-year-old male patient with a left lower lobe solitary pulmonary nodule due to AIDS-related high-grade non-Hodgkin's lymphoma. An air bronchogram (short arrow) and a small area of cavitation (long arrow) are noted centrally within the lesion. The diagnosis was established by percutaneous needle biopsy Fig. 18. Chest CT scan showing bilateral pulmonary infiltrates with air bronchograms (arrows) in a 41-year-old male HIV patient due to high-grade, B-cell non-Hodgkin's lymphoma Fig. 19 a, b. Lymphocytic interstitial pneumonitis in two adult female patients with heterosexual acquisition of HIV. a Typical changes of LIP with multiple, discrete, soft tissue density nodules distributed throughout the lung parenchyma on high-resolution CT. The diagnosis was established by exclusion of infective organisms and demonstration of typical features on transbronchial biopsy. b Atypical appearances of lymphocytic interstitial pneumonitis (LIP). There had been gradual progression of mid- and lower-zone pulmonary reticulo-nodular infiltrate over the previous 3 years. High-resolution CT demonstrates confluent consolidation in a strikingly peri-bronchovascular distribution. Transbronchial biopsy confirmed the diagnosis of LIP

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AIDS patient. The CT-guided biopsy technique has been shown to be effective in differentiating between lymphoma, non-lymphomatous malignant disease such as lung carcinoma and lesions which are infective in origin [69, 73]. Another rare form of AIDS-related B-cell lymphoma has been described in association with herpes virus 8 infection, which presents as pleural, pericardial or peritoneal effusions and has been referred to as bodycavity-based lymphoma [74] or primary effusion lymphoma. Computed tomography may demonstrate unilateral or bilateral pleural effusions and minor, diffuse thickening of the parietal pleura. Discrete pleural plaques or nodular pleural thickenings are not described and there are no associated parenchymal opacities or enlarged mediastinal lymph nodes [75]. Diagnosis of body cavity lymphoma distinct from other causes of a pleural effusion relies on demonstration of malignant cells in a pleural aspirate. Herpes virus 8 infection may also be demonstrated in these patients. Lung carcinoma There are several reported series of lung carcinoma occurring in patients with AIDS [73, 76, 77, 78, 79, 80]. It is not clear from these studies whether AIDS patients have an increased risk of developing primary malignant lung tumours. Braun et al. identified a 14-fold increase in the incidence of lung cancer in their population of 500 HIV sero-positive patients [79] compared with the overall risk for white male persons. However, Chan et al. did not identify an increased incidence of lung cancer in patients with AIDS compared with patients ªat riskº of AIDS in the pre-HIV era [81]. The published data does suggest that there are clinical differences between patients with lung cancer who are HIV infected and those who are not. The HIV infected patients are typically younger at the time of diagnosis [78, 79], have more advanced disease [77] and a shorter survival time than non-HIV-infected patients who present with lung cancer [77, 82]. There is also a striking male preponderance. The documented cell types are similar to those found in young sero-negative patients and are most commonly adenocarcinomas [76, 77, 78, 82]. Unlike KS and lymphoma, no associated mutagenic viral agent has been identified in relation to the development of lung cancer in AIDS patients. If there is a true increase in the prevalence of lung carcinoma, it may be secondary to deficiencies in immunoregulation [77] or to other risk factors such as smoking of cigarettes or marijuana [83]. The CD4 count does not appear to correlate with the development of lung carcinoma [78]. The radiological manifestations of lung carcinoma in HIV-infected individuals do not differ significantly from the appearances in non-infected patients with a central or peripheral mass associated with mediastinal adenopathy, obstructive consolidation or atelectasis, a pleural effusion or pleural mass. Pleural thickening may be identified which can be extensive, and in some cases is the only radiological abnormality [76, 78]. Fish-

S. P. G. Padley and L. J. King: CT of the thorax in HIV disease

man et al. reported a striking predisposition for peripheral tumours to occur in the upper lobes in their series of 30 patients and have postulated that post-inflammatory scarring may be relevant in HIV patients [76]. Once again the imaging features can be seen to overlap with other HIV-associated thoracic disease processes and the appearances may be complicated by the presence of superimposed infiltrates due to an intercurrent infective process [76, 82]. The non-specific radiological appearances may be partly responsible for the relatively late diagnosis of lung cancer in these patients. Lymphoproliferative disorders There is a spectrum of non-infectious lymphoproliferative disorders which affect the lungs of AIDS patients including lymphocytic interstitial pneumonitis (LIP), atypical lymphoproliferative disorder with reactive cells and pulmonary mucosa-associated lymphoid tissue lymphoma [84]. Lymphocytic interstitial pneumonitis is a reactive pulmonary lymphoid disorder occurring more commonly in immunocompromised patients including those with AIDS. In the paediatric population LIP is an AIDS-defining disease, but the association with AIDS in the adult population is controversial as LIP also occurs in non-HIV-infected adults. On CT the findings vary from diffuse bilateral areas of ground-glass shadowing to discrete 2- to 4-cm diameter nodules which may show a peri-bronchovascular distribution (Fig. 19) [84]. Bronchiolitis obliterans Bronchiolitis obliterans with organising pneumonia is a relatively common histopathological response to various conditions. It is usually diagnosed by open-lung biopsy and is potentially treatable with corticosteroids. Radiological appearances are similar in the AIDS and non-HIV-infected populations with increased reticular interstitial markings, scattered centrilobular nodules or areas of consolidation [85]. Non-specific interstitial pneumonitis Non-specific interstitial pneumonitis is a poorly defined condition that occurs in the immunosuppressed patient with or without AIDS in the absence of a detectable opportunistic infection or neoplasm. The cause of non-specific interstitial pneumonitis is unknown, but various aetiological agents have been suggested including HIV virus itself [86]. The reported incidence of non-specific interstitial pneumonitis in adult AIDS patients with pulmonary symptoms varies from 4.6 to 38 % [87, 88, 89, 90, 91, 92]. It appears to be more common in Africa where PCP is relatively rare [91], and may be more common in IV drug abusers than in homosexual men [93]. Symptoms in patients with histological confirmation of the diagnosis are variable, and along with physical find-

S. P. G. Padley and L. J. King: CT of the thorax in HIV disease

ings are similar to patients with PCP [88]. Reduction in the diffusion capacity of the lungs tends to be a more constant feature of non-specific interstitial pneumonitis, although the blood gas values are also similar in patients with PCP [88]. The chest radiographic appearances are non-specific. Appearances can be normal or there may be an alveolar or interstitial infiltrate. The differentiation from opportunistic infection depends on non-radiological investigations. Bronchiectasis has been noted in numerous patients [94]. Failure to respond to treatment for infective causes and a relatively indolent course should raise the possibility of this diagnosis in a susceptible patient. Conclusion There is a wide spectrum of chest diseases in the HIV population. Since the lungs have a limited variety of responses to infective and non-infective insults, there is considerable overlap in the radiological manifestations of different conditions. Computed tomography has an important role in the investigation and management of patients with HIV-associated lung disease, but should be employed prudently and after assessment of the overall clinical status of the patient. The chest radiograph in conjunction with the history and examination, sputum analysis, pulse oximetry and other simple tests is frequently sufficient for diagnosis and initiation of treatment. Computed tomography is reserved for those patients who present specific clinical problems that may benefit from the advantages of cross-sectional imaging. These include patients with chest symptoms but normal or nearly normal chest radiographs, atypical presentations, multiple concurrent pathologies, patients being considered for biopsy and tumour staging. References 1. Hartman TE, Primack SL, Muller NL, Staples CA (1994) Diagnosis of thoracic complications in AIDS: accuracy of CT. AJR 3: 547±553 2. Kang EY, Staples CA, McGuinness G, Primack SL, Muller NL (1996) Detection and differential diagnosis of pulmonary infections and tumors in patients with AIDS: value of chest radiography versus CT. AJR 166: 15±19 3. Sider L, Gabriel H, Curry DR, Pham MS (1993) Pattern recognition of the pulmonary manifestations of AIDS on CT scans. Radiographics 13: 771±784 4. Katz MH, Hessol NA, Buchbinder SP, Hirozawa A, O'Malley P, Holmberg SD (1994) Temporal trends of opportunistic infections and malignancies in homosexual men with AIDS. J Infect Dis 170: 198±202 5. Osmond D, Charlebois E, Lang W, Shiboski S, Moss A (1994) Changes in AIDS survival time in two San Francisco cohorts of homosexual men, 1983 to 1993. J Am Med Assoc 271: 1083±1087 6. Stansell JD, Osmond DH, Charlebois E, LaVange L, Wallace JM, Alexander BV, Glassroth J, Kvale PA, Rosen MJ, Reichman LB, Turner JR, Hopewell PC (1997) Predictors of Pneumocystis carinii pneumonia in HIV-infected persons. Pulmonary Complications of HIV Infection Study Group. Am J Respir Crit Care Med 155: 60±66

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1569 83. Tashkin DP, Coulson AH, Clark VA, Simmons M, Bourque LB, Duann S, Spivey GH, Gong H (1987) Respiratory symptoms and lung function in habitual heavy smokers of marijuana alone, smokers of marijuana and tobacco, smokers of tobacco alone, and nonsmokers. Am Rev Respir Dis 135: 209±216 84. McGuinness G, Scholes JV, Jagirdar JS, Lubat E, Leitman BS, Bhalla M, McCauley DI, Garay SM, Naidich DP (1995) Unusual lymphoproliferative disorders in nine adults with HIV or AIDS: CT and pathologic findings. Radiology 197: 59±65 85. Diaz F, Collazos J, Martinez E, Mayo J (1997) Bronchiolitis obliterans in a patient with HIV infection. Respir Med 91: 171±173 86. Travis WD, Fox CH, Devaney KO, Weiss LM, O'Leary TJ, Ognibene FP, Suffredini AF, Rosen MJ, Cohen MB, Shelhamer J (1992) Lymphoid pneumonitis in 50 adult patients infected with the human immunodeficiency virus: lymphocytic interstitial pneumonitis versus nonspecific interstitial pneumonitis. Hum Pathol 23: 529±541 87. Simmons JT, Suffredini AF, Lack EE, Brenner M, Ognibene FP, Shelhamer JH, Clifford Lane H, Fauci AS, Masur H (1987) Nonspecific interstitial pneumonitis in patients with AIDS: radiologic features. AJR 149: 265±268 88. Sattler F, Nichols L, Hirano L, Hiti A, Hofman F, Hughlett C, Zeng L, Boylen CT, Koss M (1997) Nonspecific interstitial pneumonitis mimicking Pneumocystis carinii pneumonia. Am J Respir Crit Care Med 156: 912±917 89. Weinberg A, Duarte MI (1993) Respiratory complications in Brazilian patients infected with human immunodeficiency virus. Rev Inst Med Trop Sao Paulo 35: 129±139 90. Speich R, Weber R, Vogt P, Kronauer CM, Luthy R, Russi EW (1998) Aspecific and lymphocytic interstitial pneumonia in HIV infection. Schweiz Med Wochenschr 119: 601±612 91. Batungwanayo J, Taelman H, Lucas S, Bogaerts J, Alard D, Kagame A, Blanche P, Clerinx J, van de Perre P, Allen S (1994) Pulmonary disease associated with the human immunodeficiency virus in Kigali, Rwanda. A fiberoptic bronchoscopic study of 111 cases of undetermined aetiology. Am J Respir Crit Care Med 149: 1591±1596 92. Suffredini AF, Ognibene FP, Lack EE, Simmons JT, Brenner M, Gill VJ, Clifford Lane H, Fauci AS, Parrillo JE, Masur H, Shelhamer JH (1987) Nonspecific interstitial pneumonitis: a common cause of pulmonary disease in the acquired immunodeficiency syndrome. Ann Intern Med 107: 7±13 93. Jimenez ML, Aspa J, Padilla B, Ancochea J, Gonzalez A, Fraga J, Santos I, Martinez R, Gomez Herruz P, Lopez Brea M (1991) Fiberoptic bronchoscopic diagnosis of pulmonary disease in 151 HIV infected patients with pneumonitis. Eur J Clin Microbiol Infect Dis 10: 491±496 94. McGuiness G, Naidich DP, Garay S, Leitman BS, McCauley DI (1993) AIDS associated bronchiectasis: CT features. J Comput Assist Tomogr 17: 260±266