Introduction

Kaposi‘s sarcoma (KS) is an acquired immunodeficiency syndrome (AIDS)-defining neoplasm associated with human herpesvirus-8 (HHV-8) [1]. Pulmonary manifestations can occur and include involvement of the tracheobronchial tree, parenchyma, and pleural space. The incidence of KS has dramatically decreased in recent years, which is attributable to the widespread use of highly active antiretroviral therapy (HAART). As a result, awareness of this disease among frontline clinicians is likely waning. We have recently encountered a series of patients with pulmonary KS at our institution who presented with not only the typical cutaneous and airway lesions but also with thoracic complications of KS such as chylothorax and chylopericardium, immune reconstitution inflammatory syndrome (IRIS), and diffuse alveolar hemorrhage (DAH). We present this series of patients to review both the usual and atypical manifestations of KS for clinicians who have had less exposure to this disease since the advent of HAART.

Case 1

A 48-year-old African-American man with a history of AIDS (CD4+ lymphocyte count 16 cells/µL; viral load 377 million copies/ml) was admitted with a complaint of nausea and vomiting in the setting of noncompliance with medications, including HAART. He had also noticed right ankle swelling starting 2 weeks prior.

Physical examination was remarkable for multiple verrucous lesions with yellow-colored discharge predominantly around his right ankle (Fig. 1a). Laboratory evaluation was notable for a white blood cell (WBC) count of 3000 cells/uL (normal range 4.5–11,000 cells/µL) and a hemoglobin level of 8.8 g/dL (normal range 13.5–17.5 g/dL). Computed tomography (CT) of the chest, abdomen, and pelvis showed a left peri-hilar infiltrate (Fig. 1b) as well as a rectal mass. Blood and sputum cultures for bacteria, mycobacteria, and fungi yielded no growth. Skin biopsy of one of the ankle lesions demonstrated KS. He then underwent bronchoscopy, which revealed multiple violaceous mucosal lesions consistent with KS (Fig. 1c). Bronchoalveolar lavage (BAL) fluid contained 6000 copies of HHV-8 DNA/ml (LOQ < 107 copies/ml). Endoscopic rectal biopsy was likewise positive for KS.

Fig. 1
figure 1

a Photographic image of the verrucous lesions with yellow exudation that were noted to surround the patient’s ankle. b CT scan of the chest showing a spear- or flame-like consolidation emanating from the left hilum toward the periphery, a typical finding in pulmonary KS. c Bronchoscopic image showing violaceous lesions on the tracheal mucosa consistent with KS

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Despite re-introduction of HAART and initiation of doxorubicin chemotherapy for KS, the patient eventually developed septic shock with respiratory failure and expired following a prolonged hospitalization.

Case 2

A 26-year-old Mexican man with AIDS and diabetes mellitus presented with abdominal pain of 4 days’ duration. He also complained of fever, dyspnea, and orthopnea. Additional past medical history included cutaneous KS confirmed by skin biopsy 1 year previously. At the time of presentation, he was receiving liposomal doxorubicin chemotherapy co-administered with dexamethasone as well as radiation therapy. He was taking no other medications. There was no recent travel, sick contacts, or reported substance abuse.

On admission, his vital signs were blood pressure 133/86 mmHg, pulse 95 beats/min, respirations 28 breaths/min, an oxygen saturation of 95 % on supplemental oxygen via nasal cannula at 2 liters/min, and a rectal temperature of 38.1 °C. Physical examination revealed a patient in moderate distress with decreased breath sounds over the right chest with dullness to percussion. Cardiac auscultation was normal. The abdomen was diffusely tender without peritoneal signs. There were multiple cutaneous lesions on the left lower extremity consistent with KS.

Initial laboratory evaluation was remarkable for a blood leukocyte count of 15,000 cells/µL, a serum glucose of 376 mg/dL (normal range 70–110 mg/dL), and positive serum ketones with a pH of 7.29. The CD4+ lymphocyte count was found to be 43 cells/µL with an HIV viral load (VL) of <400 copies/ml. His plain chest radiograph showed near-total opacification of the right hemithorax due to a large pleural effusion (Fig. 2). Antibiotics and an insulin infusion were started, and the patient was admitted to the medical intensive care unit for management of diabetic ketoacidosis (DKA) and presumed infection. Thoracentesis yielded approximately 800 ml of turbid yellow fluid, and laboratory characteristics of which are listed in Table 1. Bacterial culture ultimately grew Group B Streptococcus. Tachycardia and worsening oxygenation prompted urgent echocardiography, which revealed a large pericardial effusion with diastolic collapse of the right atrium and ventricle consistent with cardiac tamponade physiology. Subsequent pericardiocentesis yielded 450 ml of milky fluid whose features are listed in Table 1. The patient refused further pleural space intervention. His DKA eventually resolved, his dyspnea improved, and he was discharged on hospital day 18 following completion of a prolonged antibiotic course. Residual pericardial (small) and pleural (moderate) collections remained evident at time of discharge.

Fig. 2
figure 2

Chest radiograph showing a large right-sided opacity consistent with a pleural effusion

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Table 1 Summary of the pleural and pericardial fluid characteristics
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Case 3

A 48-year-old man with a history of intravenous drug use, AIDS, biopsy proven KS of the eyelid and lung, as well as a history of Pneumocystis jierovecii pneumonia (PJP), was admitted for progressive dyspnea, fever, and cough productive of yellow sputum with an admixture of blood. He had not been taking HAART. He was found to have a CD4+ lymphocyte count of 8 cells/µL with an HIV VL of 211,000 copies/ml. In the hospital, he received antibiotics for pneumonia, and his HAART regimen was restarted. He was discharged but then returned soon thereafter—approximately 2 weeks after re-initiation of HAART—with worsening shortness of breath, fever, fatigue, and diarrhea.

On physical examination, his oxygen saturation was 93 % on room air. He was wheezing bilaterally. He was noted to have cutaneous lesions on his lower extremities and eyelids consistent with KS. The HIV VL had decreased to 6961 copies/ml. Repeat CD4+ lymphocyte testing was not performed. The serum lactate dehydrogenase was 215 U/L (normal range 90–225 U/L).

Broad-spectrum antibiotics were started, including trimethoprim/sulfamethoxazole to cover PJP. Blood and sputum cultures returned negative for bacteria, mycobacteria, and fungi, yet serial chest radiographs showed worsening reticulonodular densities presumed to represent IRIS (Fig. 3). Despite high-dose corticosteroid treatment, his condition continued to deteriorate. He refused a bronchoscopy and expired 15 days after presentation.

Fig. 3
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a, b Chest radiographs obtained 1 week apart demonstrate worsening of reticulonodular densities, predominantly in the lower lobes

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Case 4

A 39-year-old man with AIDS who was noncompliant with HAART presented with a 25 lb (11 kg) weight loss, dyspnea, and blood-streaked sputum for 8 months. He had been evaluated at two different hospitals, where multiple sputum smears and cultures for acid-fast bacilli were negative. He had refused a bronchoscopy. Physical examination revealed an oxygen saturation of 84 % on room air, crackles and rhonchi at the lung bases, as well as hyperpigmented lesions consistent with cutaneous KS in the inguinal and perianal areas.

Laboratory values were significant for a WBC count of 15,000 cells/uL, hemoglobin level 9 g/dl, platelet count 33,000/µL (normal range 130–400,000/µL), CD4 + lymphocyte count 14 cells/µL, and an HIV viral load 400,000 copies/ml. Biopsy of the cutaneous lesions was positive for KS. CT of the chest showed bilateral lower lobe consolidation (Fig. 4) as well as areas of nodular and ground glass opacities.

Fig. 4
figure 4

CT of the chest showing bilateral airspace consolidation consistent with DAH, most pronounced in the lower lobes

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The patient was endotracheally intubated for progressive hypoxemic respiratory failure. He was admitted to the medical intensive care unit and treated with cefepime, vancomycin, dapsone, doxycycline, and paclitaxel. Bronchoscopy revealed diffuse cherry-red mucosal discoloration with patchy violaceous lesions in multiple lower airways. Blood welled up continuously from numerous segmental bronchi bilaterally. Serial aliquots of BAL fluid demonstrated non-resolving bleeding consistent with DAH. Right middle lobe endobronchial and right lower lobe transbronchial biopsies demonstrated KS of the bronchial mucosa and lung parenchyma, respectively (Fig. 5). Platelets were transfused to maintain counts greater than 50,000/µL. Subsequently his condition continued to deteriorate, so his family requested withdrawal of mechanical ventilation and transition to palliative care. The patient expired 1 week after presentation.

Fig. 5
figure 5

Transbronchial biopsy demonstrating spindle cell proliferation (arrows) characteristic of KS (Hematoxylin and eosin, original magnification ×400)

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Pulmonary KS

KS is an angiosarcomatous opportunistic neoplasm associated with HHV-8. It is believed to evolve from an angioproliferative response to this virus that eventually transforms into malignancy [1]. Prior to the AIDS epidemic, it was a rare tumor primarily seen in men of Mediterranean ancestry, in sub-Saharan Africa, and in transplant recipients. The prevalence of KS has again declined since the advent of HAART due to improving immune function and the antitumorigenic properties of antiretroviral medications, particularly protease inhibitors [2, 3]. The occurrence of KS in the AIDS population in the HAART era has been linked to psychosocial problems and the resultant gaps in HIV care [4]. All four of our patients were either noncompliant with HAART or not receiving treatment.

Thoracic manifestations are common in AIDS-related KS and are usually preceded or accompanied by mucocutaneous lesions [1]. Pulmonary involvement may affect the tracheobronchial tree, parenchyma, and pleural space. Hilar and mediastinal lymphadenopathy is seen less commonly and is usually non-bulky when present [5]. Patients could be asymptomatic or present with cough, dyspnea, and—less frequently—hemoptysis [6]. The characteristic finding on chest radiographs is bilateral infiltrates emanating from the hila with areas of both coalescence and discrete nodularity [7]. CT provides greater definition and demonstrates these opacities to be characteristically peribronchial and perivascular in distribution, a pattern that correlates well with findings on pathology [7]. CT also detects a higher rate of lymphadenopathy and is more sensitive for pleural effusions [5, 8].

Bronchoscopy is an important tool for the diagnosis of pulmonary KS and the exclusion of concomitant lung infection. In patients with known mucocutaneous disease, visualization of characteristic violaceous endobronchial lesions is sufficient to establish the diagnosis. If necessary, histologic confirmation with transbronchial or endobronchial biopsies can be pursued at the expense of an increased risk of bleeding [6]. Because of the patchy nature of involvement, the diagnostic yield of bronchoscopic biopsies is 26–60 %, and even open lung biopsy has a diagnostic yield of only about 50 % [6, 9, 10]. Histology demonstrates irregularly shaped vessels with erythrocyte extravasation and spindle cell proliferation. An alternative to biopsy is detection of HHV-8 DNA by polymerase chain reaction in BAL fluid, which has a sensitivity and specificity of 75 and 97 %, respectively, for pulmonary KS [11]. The appearance of HHV-8 DNA may even predate clinically apparent KS [12].

KS-associated pleural effusions are thought to be the most common cause of pleural effusions in AIDS patients and seldom occur without parenchymal involvement [13]. At the height of the AIDS epidemic, thoracic KS was noted to be complicated by pleural effusions in over 60 % of cases [14]. Typical KS pleural effusions are serosanguinous lymphocyte-predominant exudates, and although pleural fluid cytology in such cases is not expected to be diagnostic, thoracentesis is helpful to exclude infection and chylothorax. KS lesions implant on the visceral pleura and account for the bloody nature of these effusions [9]. Pericardial effusions are less common and likewise tend to be hemorrhagic [15].

Complications of Pulmonary KS

Reported complications of pulmonary KS include chylothorax, IRIS in treated patients, and DAH in untreated patients. The patient in Case 2 developed chylous pleural and pericardial effusions. Case 3 illustrates IRIS characterized by worsening clinical and radiographic findings despite treatment of infection and reduction in viral load after initiation of HAART. Unfortunately, a repeat CD4+ lymphocyte count was not obtained in that case. The patient in Case 4 had DAH as suggested by clinico-radiographic findings and confirmed by bronchoscopy.

Chylothorax and Chylopericardium

The literature contains rare cases of chylothorax attributable to KS [16–19]. Malignancy is the most common non-traumatic cause of chylothorax, which occurs due to obstruction of the thoracic duct by tumor or lymphadenopathy. The latter is believed to account for this phenomenon in KS [20]. Leakage of chyle into the pericardial space gives rise to the analogous but much rarer entity known as chylopericardium, which has not been previously described in association with KS. It is most commonly idiopathic; among known causes, surgery and malignancy are the most frequent [21]. In the largest published series of chylopericardium cases, 33 % of patients exhibited cardiac tamponade physiology [21]. Diagnostic criteria for chylopericardium are not well-defined, but, like in all chylous effusions, the typical fluid is turbid with a predominance of lymphocytes and a very high triglyceride level (i.e., >500 mg/dL). In the series by Dib et al., the highest reported triglyceride level was 2546 mg/dL, far lower than that seen in Case 2 [21]. In fact, Case 2 may represent the highest published pericardial fluid triglyceride concentration. Although a pericardial fluid triglyceride to cholesterol ratio could not be obtained due to the absence of a cholesterol level, the combination of milky pericardial fluid with a triglyceride level >500 mg/dL is sufficient for the confident diagnosis of chylopericardium, especially when chylothorax is concurrently present. The neutrophilic predominance seen in the pleural and pericardial samples of the patient in Case 2 can be attributed to bacterial superinfection, itself a rare event since chyle is known to have bacteriostatic properties [22–25].

Diffuse Alveolar Hemorrhage

DAH is a complication of untreated pulmonary KS. It is suggested by the clinical findings of dyspnea, cough, hypoxemia, and anemia accompanied by bilateral infiltrates on chest radiograph or CT scan. The diagnosis is confirmed by bronchoscopic inspection to exclude a focal source of bleeding and demonstrate progressively bloodier BAL return. Hemosiderin-laden macrophage percentage of >20 % in BAL fluid lends supporting evidence, though this finding has been reported in patients without DAH as well [26]. The pathogenesis of DAH in KS is potentially related to HHV-8’s propensity for angiogenesis and increased vascular permeability mediated through activation of a G-protein-coupled receptor [27]. Production of interleukin-1, interleukin-6, fibroblast growth factor, and vascular endothelial growth factor by the spindle cells may further propagate a vicious cycle of proliferation and permeability [28]. HIV itself can induce a capillaritis, although alveolar hemorrhage has not been associated with HIV without underlying pulmonary disease [29]. DAH rates as high as 75 % were reported in pulmonary KS patients in the pre-HAART era [9, 30]. The incidence of this complication has predictably decreased since the advent of HAART [31]. A study of alveolar hemorrhage in 232 HIV patients identified pulmonary KS as one of four risk factors independently associated with DAH in that sample (OR 5.3, p = 0.003) [29].

Immune Reconstitution Inflammatory Syndrome

KS-associated IRIS is characterized by paradoxical clinical deterioration following initiation of HAART despite HIV VL suppression and CD4+ lymphocyte increase [32]. This is thought to represent a non-specific inflammatory response by a recovering immune system. The majority of cases occur within 3 months of treatment initiation [33]. Manifestations of this complication of KS include progressive mucocutaneous lesions, lymphedema, airway compromise, mediastinal lymphadenopathy, pleural effusions, and worsening lung parenchymal opacities [34]. Predictors of the development of IRIS in KS patients are not well-defined. A prospective study of 69 African patients with AIDS and KS found four independent risk factors for IRIS: (1) clinical pretreatment of KS (HR 91.7), (2) detectable plasma HHV-8 DNA (HR 24.4), (3) hematocrit <30 % (HR 26.5), and (4) plasma HIV-1 RNA VL (HR 34.6 per log viral load increase) [35]. In a retrospectively studied cohort of 196 patients with AIDS-defining opportunistic infections acquired between 1995–2011, KS itself was found to be an independent risk factor for IRIS (OR 6.7, p < 0.05) [33]. These investigators also showed that morbidity and mortality was higher in IRIS with visceral KS when compared to cutaneous KS and to IRIS due to other infections.

Conclusions

The incidence of KS in the AIDS population has dramatically decreased in the HAART era. Unfortunately, due to psychosocial or financial difficulties, a subgroup of AIDS patients is not taking HAART and is thus susceptible to de novo KS or exacerbation of pre-existing disease. Because of its declining incidence, today’s clinicians are less likely to encounter KS, including its pulmonary manifestations. Familiarity with the typical pulmonary findings of KS, as well as its unusual thoracic complications, can lead to timely recognition and appropriate treatment.