Intractable pleural effusion in Kaposi sarcoma following antiretroviral therapy in a Caucasian female infected with HIV

Abstract

We report the case of a 57-year-old Caucasian woman with AIDS-related disseminated Kaposi sarcoma (KS) characterised by the combination of several unusual features. The chylous nature of the pleural effusions, the documented parietal pleural involvement at thoracoscopy and the marked clinical worsening through an immune reconstitution syndrome following antiretroviral therapy initiation represent several rare situations that occurred in the same female patient. In addition, the use of indwelling pleural catheters for dyspnoea palliation also represents a rare therapeutic intervention. This case is a reminder of the possibility of AIDS-related pleural KS, now uncommon in the era of antiretroviral therapy.

Background

Kaposi sarcoma (KS) is a vascular tumour associated with human herpes virus 8 (HHV-8) and most often also with HIV. Such tumour is an AIDS defining illness according to WHO and Center for Disease Control and Prevention, and may present with pleural effusion in HIV/AIDS patients.^1–4

The incidence of KS has significantly declined since the introduction of potent antiretroviral therapy (ART).⁵ We herein report the case of a middle-aged Caucasian woman with AIDS-associated disseminated KS characterised by the unusual combination of a chylous effusion with KS parietal pleural involvement that markedly worsened during an immune-reconstitution syndrome, and was managed using an indwelling pleural catheter (IPC) to control her dyspnoea.

Case presentation

A 57-year-old heterosexual Caucasian woman presented in June 2018 with dyspnoea and a moderate left pleural effusion. Her medical history included stage IV follicular lymphoma with bone marrow involvement diagnosed in December 2016. She had a partial response after six cycles of rituximab and bendamustine up to June 2017. Her post-treatment course was complicated by persistent pancytopenia and multiple opportunistic infections. She was eventually diagnosed with HIV in April 2018 with a CD4 cell count of 2 cells/µL (1%) and a log₁₀ HIV plasma viral load of 4.93 copies/mL. She was immediately started on ART consisting of emtricitabine, tenofovir and raltegravir.

At the time of HIV diagnosis, she only had a minimal left pleural effusion that remained asymptomatic, and hypermetabolic pleural lesions were present on positron emission tomography (PET) scan. Two months after ART initiation, the patient developed progressive shortness of breath, dry cough and fatigue. Chest CT showed new faint ground glass areas in the right upper lobe, a tiny right effusion, a moderate left pleural effusion with stable mediastinal adenopathies. Multiple diagnostic and therapeutic left thoracenteses were performed within a month due to rapid recurrence of cloudy serosanguinous pleural fluid. Analyses of the pleural fluid demonstrated a sterile exudate (pleural/serum protein ratio 0.62, lactate dehydrogenase (LDH) ratio 0.59) with a mononuclear cell predominance. Cytology showed reactive mesothelial cells without lymphocytes evocating primary effusion lymphoma. Flow cytometry showed reduced B-cell population with expansion of Natural Killer (NK) cell proportion comprising 84% of lymphocytes. Pleural fluid triglycerides were 6.43 mmol/L, compatible with a chylothorax. Her circulating CD4 T cell count was 17 cells/µL (10%), with a log₁₀ HIV plasma viral load decreased to 3.06 copies/mL following ART initiation.

A left-sided medical thoracoscopy was performed in July 2018. Multiple violaceous nodules with diffuse hypervascular patches were found on the parietal and diaphragmatic pleural surfaces (figure 1). A left IPC was inserted at the end of the procedure. Mycobacterial and fungal cultures of biopsy samples were negative. The histology of the parietal pleural lesions showed vascular proliferation with spindle cells exhibiting positive immunohistochemistry (IHC) for HHV-8, compatible with KS (figure 2). HHV-8 PCR in blood was also positive. No findings compatible with Castleman or primary effusion lymphoma were present.

Figure 1.

Thoracoscopic view showed multiple violaceous nodules and hypervascular patches on the left parietal pleural surface.

Figure 2.

(A) The left inguinal node core biopsy and pleura both showed atypical spindle cells forming short disorganised fascicles with small vascular channels compatible with Kaposi sarcoma. (B) Immunohistochemistry for human herpes virus (HHV-8) latent nuclear antigen (LNA-1; clone 13B10 cell Marque, Rocklin, California) showed strong nuclear brown staining, confirming HHV-8-related infection of Kaposi sarcoma. Images taken at 200× magnification with Aperio ImageScope (version 12.1) after scanning with the Aperio XT platform.

The patient was diagnosed with disseminated KS on the basis of distribution of multifocal hypermetabolic lesions on PET scan (figure 3) and a left inguinal lymph node biopsy. She had no skin lesions. An IPC was inserted on the right side in early August 2018 to palliate a recurrent effusion. The right pleural fluid had biochemical characteristics similar to the left effusion, and cytology was also negative for malignant cells.

Figure 3.

PET-CT images displayed multiple areas of hypermetabolic activity on bilateral pleura, pleural effusion, pericardial effusion, ascites, bilateral lungs, extensive diffuse adenopathies and hypermetabolic lesion on the left adrenal gland.

Systemic chemotherapy with liposomal doxorubicin (Caelyx) (20 mg/m² every 21 days) was started in mid-August 2018 and continued for 6 months. Then, to reduce cytotoxicity of chemotherapy, a tyrosine kinase inhibitor imatinib 400 mg po daily was orally given for 3 months for her disseminated KS with visceral involvement. ART was continued throughout. HHV-8 PCR in blood became undetectable after initiation of chemotherapy.

Her treatment was complicated early on by febrile neutropenia and a right IPC-related Pseudomonas aeruginosa empyema, treated successfully with piperacillin–tazobactam and daily IPC drainages until the latter was removed 1 week later.

Outcome and follow-up

The left pleural effusion slowly decreased over 6 months, and the left IPC was removed in March 2019. The last PET scan in April 2019 demonstrated marked improvement of all previous hypermetabolic sites. Her CD4 cell count has remained low, at 125 cells/µL. Her functional status and blood parameters progressively improved (table 1), and the pleural effusions have not recurred thus far.

Table 1.

Blood parameters’ improvement overtime

Parameters	Apr 2018	Jun 2018	Sep 2019	Dec 2018	Mar 2019	Jun 2019	Aug 2019
Haemoglobin (g/L)	81	98	93	85	129	132	134
CD4 count (cells/μL)	2	17	14	34	36	125	127
Log10 HIV viral load (copies/mL)	4.93	3.06	2.70	2.77	2.02	2.04	1.84

Discussion

The incidence of KS continuously declined overtime after the introduction of ART.⁶ KS typically occurs in patients with CD4 cell count below 200.^{7 8} The most common manifestation in KS is cutaneous lesions, and in absence of ART it may spread to various organs including lymph nodes and mucosal tissues such as lungs and the gastrointestinal tract. Pulmonary KS can be intraparenchymal, endobronchial, pleural, and can involve lymph nodes. The bronchoscopic image with violaceous or red, flat or raised endobronchial patches or plaques is sufficient for a presumptive diagnosis of pulmonary KS without biopsy in the presence of mucocutaneous lesions.^{9 10} Histological features include angiogenesis and inflammation along with spindle cell proliferation. With disease progression, lesions transform from patches to plaques and then to nodules.¹¹ Detection of HHV-8 infection using PCR amplification or IHC staining on biopsy specimens helps confirm the diagnosis of KS.¹²

The first line treatment of advanced KS is ART and systemic chemotherapy with liposomal anthracycline (doxorubicin, daunorubicin). Other agents such as taxanes, vinorelbine, etoposide and interferon-alfa can be used as subsequent line of therapy.¹³ Imatinib, which inhibits platelet-derived growth factor and c-kit receptors, also demonstrated efficacy and tolerability in some patients for the treatment of AIDS-related KS in a multicenter phase II trial; however, patients with symptomatic visceral disease requiring chemotherapy were excluded from the study.^{14 15} There is no controlled evidence showing that chemotherapy can reduce KS-associated chylothorax drainage. Its impact is hard to differentiate from the effects of therapeutic interventions such as pleurodesis, tube drainage and dietary modifications, which are not supported by robust data either. Although pulmonary KS patients were included in trials documenting the efficacy of chemotherapy, those trials offer no information on the subgroup of patients with a pleural effusion or chylothorax.¹⁶ We nevertheless postulate that the reduction of pleural drainage overtime in this patient was at least in part related to chemotherapy-induced reduction of the pleural and lymphatic burden of disease.

Pleural effusions in HIV/AIDS patients have a wide differential diagnosis, and a pleural biopsy is often required to exclude an opportunistic infection or malignant conditions including lung cancer, non-Hodgkin's lymphoma, primary effusion lymphoma, KS and multicentric Castleman’s disease. Pleural involvement in KS can be isolated or in combination with parenchymal and endobronchial lesions, and most often coexists with cutaneous lesions. Thoracic involvement in AIDS-related KS occurs in about 20% of cases, of which up to 60% develop the typical bloody or serosanguinous effusion.¹⁷ Pleural lesions in KS are thought to occur predominantly on the visceral pleural surface.^{9 17}

The co-occurrence of multiple atypical features makes this case unusual. First, the occurrence of KS-associated pleural effusions is now rarely encountered in practice, whereas it used to be the most common cause of pleural effusion in HIV patients. This case thus serves as a reminder to include KS as a diagnostic consideration, even when cutaneous lesions are absent. Second, it occurred in a Caucasian heterosexual woman, whose husband (also diagnosed with HIV infection around the same time) was also reportedly strictly heterosexual. AIDS-associated KS is much more common in black and Hispanic homosexual or bisexual men.¹⁸

Although chylothorax has been reported with KS, it remains a rare occurrence.^19–23 Two hypotheses have been postulated for the development of chylothorax in KS: thoracic duct obstruction or infiltration secondary to metastases, and in-situ KS of the lymphatic system.²⁴ Our patient had only mild mediastinal adenopathy, thus we suspect that microscopic lymphatics obstruction was the cause in this case.

The parietal pleural involvement is also atypical and rarely reported, as most reports described visceral pleural involvement.¹⁹ Thoracoscopy was not done systematically in all patients with pleural KS in the published series, so the exactitude of and the reason for the reported predominance of visceral pleura involvement are undetermined. Although an immune reconstitution syndrome is possible in patients with KS with CD4 below 100 cells/mm³, it is less common than with other infections, occurring at a rate of 6.4% based on a systematic review and meta-analysis of published series.²⁵ Pulmonary KS-associated immune reconstitution inflammatory syndrome (IRIS) has been described. Volkow et al demonstrated that the median time from starting ART to pulmonary KS-associated IRIS was around 10 weeks.²⁶ A recent retrospective series suggested that starting ART containing integrase inhibitors (particularly raltegravir) in patients with low CD4 count was independently associated with an increased risk of IRIS, but this remains controversial.²⁷ Consistent with these findings, our patient developed rapidly progressive disseminated KS with pleural involvement 8 weeks after ART initiation which included raltegravir. The patient had a rapidly reducing HIV viral load, but her CD4 remained below 100 cells/mm³.

Lastly, the use of IPC to deal with KS-associated chylous effusions has not been reported before. IPC have a proven efficacy and safety in the palliation of malignant pleural effusions, but previous clinical trials excluded patients with impaired immunity and/or chylothorax.^28–30 The use of IPCs has not been shown to increase the risk of infection while patients receive chemotherapy.³¹ Although the use of IPC for chylothorax remains a controversial issue, it has been used safely to palliate both malignant and benign chylous effusions in a small number of patients.^{32 33} However, no report has specifically addressed the safety of IPCs in HIV/AIDS patients. Although the use of IPCs in our patient controlled her dyspnoea, she developed an IPC-related empyema few weeks after insertion of the right-sided catheter. Hence, caution should be exercised when contemplating the use of IPC in patients with multiple risk factors for infection.

In conclusion, this case illustrates that the classic finding of KS-associated pleural effusion in AIDS patients should still be considered as a diagnostic possibility, even in Caucasian women. The KS effusion can be chylous, and direct parietal pleural involvement can be observed by thoracoscopy. Although useful for controlling dyspnoea, the use of IPCs in severely immunosuppressed patients should be considered with caution due to the risk to develop infections.

Learning points.

• Pulmonary Kaposi sarcoma (KS)-associated immune reconstitution inflammatory syndrome should be remembered as a possible cause of pleural effusion following antiretroviral therapy initiation for AIDS.

• The typical violaceous plaques/patches of KS lesion can be detected not only on visceral pleura but also on the parietal pleural surface.

• Chylous effusion in AIDS-related KS can be found, even though there is no obvious thoracic duct obstruction.

• Indwelling pleural catheters can be used for symptom control of intractable pleural effusions in severely immunocompromised patients, but with caution given the risks of infection.