Plastic bronchitis in a man living with advanced HIV and disseminated Kaposi sarcoma: case report and discussion

Abstract

A 33-year-old man living with advanced HIV with a histologically confirmed diagnosis of Kaposi sarcoma presented during a SARS-CoV-2 outbreak with worsening shortness of breath. He was treated for confirmed SARS CoV-2 infection with minimal symptomatic response, and whilst undergoing KS treatment on the ward developed the rare complication of plastic bronchitis. He had a prolonged hospital admission undergoing treatment for his Kaposi sarcoma and plastic bronchitis whilst being evaluated for concurrent opportunistic infections.

Background

Introduction to Kaposi sarcoma and Kaposi sarcoma herpes virus-related disease

Human herpes virus 8 (HHV8) or Kaposi sarcoma herpes virus (KSHV) is the etiological agent for a manifold group of disorders including Kaposi sarcoma, primary effusion lymphoma (PEL) and multicentric Castleman’s disease (MCD).^1,2 Kaposi sarcoma inflammatory cytokine syndrome (KICS) and Kaposi sarcoma inflammatory reconstitution inflammatory syndrome (KS-IRIS) are also part of the spectrum of disease. ² KICS is a recently recognised syndrome, first described in 2010, that has many similarities with MCD. ¹ KS is a cytokine-mediated angio-proliferative disease causing a low-grade malignancy that typically affects the skin and oral mucosa, although disease can involve almost any organ. ¹ Visceral involvement is described in approximately 25% of cases with the gastrointestinal tract and respiratory system being most commonly affected.^1,3 Usually pulmonary involvement confers a worse prognosis. ¹ In HIV and KSHV co-infected patients, it is hypothesised that the HIV machinery directly promotes KSHV replication, while decreased CD4 counts and cytokine secretion indirectly contribute to the KSHV replication. In combination, these processes result in malignant transformation.^1,3 The cutaneous lesions of KS described as patches, plaques, nodules of varying sizes, may be infiltrative or involve the mucous membranes and internal visceral organs when disseminated. ⁴ Another manifestation or complication of KS is marked lymphedema. This typically occurs on the lower limbs. ⁴ The pathogenesis of the lymphedema is thought to be due to multicentric endothelial proliferation that can result in occlusion of the lymphatic vascular lumen and lymph node hypertrophy. ⁴ Extrinsic compression of the lymphatic channels can also result directly from the lesions themselves. ⁴ Typically, the skin becomes hyperpigmented and hyperkeratotic leading to the ‘woody hard’, non-pitting edema associated with KS. ³ The typical histology described in KS lesions shows spindle cell proliferation, slit-like vascular spaces and extravasated blood cells. ¹

Introduction to plastic bronchitis

Plastic bronchitis is a rare and serious disease with mortality rates varying from 6% to 60% depending on the underlying aetiology.^5,6 It is characterised by the expectoration or bronchoscopic removal of airway casts of two different types. Type 1 plastic bronchitis casts are described as being rich in inflammatory cells, fibrin and Charcot–Leyden crystals which are commonly associated with inflammatory conditions. ⁵ Type 2 plastic bronchitis casts are devoid of inflammation, scarcely cellular and mainly mucinous. They are associated with congenital heart disease and lymphatic abnormalities, with abnormal pulmonary lymphatic vessels and impaired drainage being key underlying factors. ⁵ The underlying aetiology of plastic bronchitis in children can be attributed to cardiovascular surgical procedures, some infections or inflammatory processes. ⁷ In contrast, the cause in adults is usually idiopathic. ⁷ Sometimes cardiopulmonary procedures or anatomic variations in lymphatic flow have been identified. ⁷ Other causes described in literature include infections such as influenza, HIV and SARS CoV-2, ⁸ Streptococcal spp. and Haemophilus spp., mycobacterial infections, and as a result of sickle cell-related acute chest syndrome, KS (rarely), ⁹ endobronchial renal cell metastases as well as some of the allergic respiratory conditions such as asthma, eosinophilic pneumonia and allergic bronchopulmonary aspergillosis. ⁶

Case presentation

This case report was conducted and reported in accordance with the CARE statement (Supplemental Material). ¹⁰

A 33-year-old man living with advanced HIV on antiretroviral therapy (tenofovir disoproxil fumarate/lamivudine/dolutegravir (TDF/3TC/DTG)) with an unknown HIV viral load and a histologically confirmed diagnosis of disseminated pulmonary and cutaneous KS presented to the KS clinic in May 2021 with a 2-month history of cough and progressively worsening shortness of breath over the preceding 2 weeks. The cough was productive of moderate amounts of mucoid, blood-stained sputum. He had bilateral pleuritic chest pain in the lower zones and complained of weight loss and fever, but denied night sweats. He was due to receive his third cycle of paclitaxel-based chemotherapy for KS; this was deferred since he was unwell. As a part of his admission workup, he had a positive SARS CoV-2 antigen test and was subsequently admitted to the “Red/Covid” zone for treatment. He received intravenous dexamethasone and oxygen supplementation. After 2 weeks, his SARS CoV-2 PCR test was negative, but he remained oxygen-dependent and severely dyspneic. During this 2-week period, his cough, dyspnea and chest pain persisted, and he complained of worsening warm, purplish lesions on both thighs. He had been diagnosed HIV positive in August 2020 (9 months prior to presentation) and had been taking TDF/3TC/DTG and cotrimoxazole since then, and fluconazole prophylaxis, having previously been treated for cryptococcal meningitis in December 2020. He had never received radiotherapy or bleomycin. He had no history of being treated for pulmonary TB or any other opportunistic lung infections prior to his diagnosis of KS. He had received two cycles of paclitaxel, the most recent being 3 weeks prior to his presentation to the KS clinic. On examination he was hypoxic with SpO₂ of 85% on RA, he had signs consistent with a right-sided pleural effusion and had scanty left mid/lower zones crackles. He had active KS lesions and lymphedema on both thighs. He had no palatal KS lesions. He had ascites and a smooth, non-tender hepatomegaly (17 cm liver span). CXR on admission is displayed as Figure 1.

Figure 1.

Chest radiograph taken on admission.

By June 2021, he had a CD4 count of 51 cells/µL. Viral load results were unavailable. His haemoglobin on admission was 7.7 g/dL, white cell count 15.5 × 10⁹/L and platelet 166 × 10⁹/L. Serum albumin was 24 g/L and liver function tests and urea and electrolytes were normal. His sputum GeneXpert and urine lipoarabinomannan were negative, and sputum fungal stains were negative. The pleural fluid was blood stained: pleural fluid Gram stain showed no organisms, Leishman stain showed mononuclear cells and no growth was obtained on culture.

He was admitted to a general medical ward for ongoing treatment and oxygen supplementation. However, after 3 months on the ward, he suddenly deteriorated with worsening dyspnea and hypoxia. His chest examination now revealed absent breath sounds on the left side. Unfortunately, an immediate CXR or ABG was not available. However, over several hours, the patient coughed up a large white tree-like cast and immediately felt better (Figures 2 and 3).

Figure 2.

Plastic cast expectorated by the patient the first time.

Figure 3.

Plastic cast expectorated by the patient a few days later.

Diagnostic assessment

The working diagnosis following the expectoration of the cast was plastic bronchitis and disseminated KS. Other differentials considered were underlying tuberculosis, possible disseminated fungal infections or SARS CoV-2 complications all of which were considered likely possibilities.

Therapeutic intervention

The patient received four chemotherapy cycles given after 3-week intervals while he had evidence of active KS disease and had no contraindications to the chemotherapy administration. He received blood transfusions prior to chemotherapy administration when required. He remained severely dyspneic and oxygen-dependent throughout his hospital stay. He was nebulised with sodium bicarbonate and N-acetyl cysteine which helped symptomatically. The histology of the plastic cast was reported as ‘fibrin cast with leukocytic infiltrates’.

Case progression

He continued to remain oxygen-dependent, and his KS remained active. He also continued to expectorate plastic casts periodically. Due to severe resource constraints, he was unable to have a CT of his chest done at any stage of his admission. Dynamic contrast magnetic resonance lymphangiography is not locally available. Bronchoscopy was never attempted due to the concerns with his hypoxia. He was later started on a trial of anti-TB medications mid-August given his risk factors and his delayed recovery, despite not having any definitive evidence of TB. This was a difficult decision to make, but HIV-associated TB is extremely difficult to diagnose and results in high mortality.^11,12 In a locally conducted study comparing the performance characteristic of the urine LAM against the sputum smear microscopy, the findings showed that the sensitivity of urine LAM was 49.2% versus 29.4% for sputum smear microscopy. ¹³ Other studies looking at the sensitivity of gene Xpert found rates of 85.6% sensitivity for sputum samples. ¹⁴ However, during another locally conducted study looking at the diagnostic performance of gene Xpert in patients with KS found a 9.9% prevalence estimate of pulmonary TB in patients with confirmed KS with a sensitivity for the gene Xpert of 23.5%. ¹⁵ Another meta-analysis looked at the prevalence of TB in post-mortem studies and showed that 43% of HIV-positive adults had evidence of TB at autopsy with 45.8% of confirmed TB cases being undiagnosed at the time of death. ¹² As a result of these studies, the concern for missing a TB diagnosis in spite of negative tests remains high in our setting. He subsequently deteriorated and died in October 2021 after a very prolonged 24-week hospital stay. No post-mortem examination was done.

Patient perspective

During this patient’s prolonged admission, he repeatedly asked the treating team if he was going to get better and could we do anything else to help him. These questions were difficult to answer at the time.

Discussion

Plastic bronchitis among adult patients is rare. Much of the published literature is based on small case studies, case reports and mainly pediatric populations.^16,17 It is hypothesized that aberrations to the lymphatic drainage perhaps due to infections, inflammation or trauma ¹⁶ is the most likely etiological factor. During the SARS CoV-2 era, it was noted that some severely ill, intubated and mechanically ventilated patients had thick, viscous material comprising mucin and cellular debris adherent to the endotracheal tube. ¹⁶ However, it is unclear whether there is any relationship between SARS CoV-2 infection and plastic bronchitis, although one case is described of an elderly lady who developed plastic bronchitis after SARS CoV-2 infection. ⁸ There is scarce information regarding plastic bronchitis in KS. One case report described a young man with very low CD4 count who presented with disseminated KS and plastic bronchitis. ¹⁸

A small study involving dynamic contrast-enhanced magnetic resonance lymphangiography and intranodal lymphangiography in adult patients with plastic bronchitis confirmed abnormal lymphatic flow either due to lymphatic reflux or due to communication of abnormal lymphatic vessels with the airways. ¹⁹ The majority of lymph is produced in the lower extremities, liver and intestines. Lymph from these sources converges and are then directed into the thoracic duct and discharged into the subclavian vein. Lymphocytes, antigen-presenting cells and other leukocytes enter the lymphatics through junctions in the walls of small vessels within tissues, travelling between lymph nodes throughout the lymphatic tree. ¹⁹ Chylomicrons are incorporated into the lymphatic fluid by lacteals in the intestine, contributing to the characteristic high fat content and milky appearance of chylous fluids. ¹⁹ The lung lymphatics also form a one-way vascular network, originating in the lobules at the lung periphery and progressing towards the hilum, draining into the axial lymphatics within the mediastinum. However, in cases of elevated pressures or obstruction within the thoracic duct, lymph from the system can flow retrogradely into the lung lymphatic channels, infiltrating the airways and distending the lung parenchyma. ¹⁹

KS is known to cause lymphoedema. It has also been associated with chylous effusions and ascites in recent case reports ²⁰ as well as older case reports such as one case with progressive pleural effusions thought to be chylous resulting in respiratory failure. ²¹ Given the links between chylous effusions and the abnormal lymphatics seen in KS, it seems reasonable to conclude that KS was the most likely agent leading to plastic bronchitis in our patient. However, given how frequently we see disseminated KS in our setting, the complication of plastic bronchitis seems extremely rare. We entertained the question of whether the interaction with SARS CoV-2 and KS compounded each other causing altered lymphatic flow and the development of the plastic casts, or whether another underlying infection was responsible.

Treatment recommendations depend on the underlying cause of the plastic bronchitis. ¹⁶ Treatment options can include percutaneous transabdominal catheterisation and embolization of aberrant lymphatics. ¹⁹ Airway clearance and thoracic duct ligation are possible treatments with some evidence. ²² Whilst other anecdotal evidence suggests hyperosmolar saline, low-dose oral macrolides and oral or inhaled corticosteroids might be useful for some kinds of casts. ²² The evidence supporting the use of expectorants and mucolytics is contentious and varied.^16,22 In this case, bronchoscopic removal of casts, extra-corporeal membrane oxygenation and magnetic resonance lymphangiography with subsequent embolization of aberrant lymphatics were not possible in our setting.

Summary

Plastic bronchitis is incredibly rare in our setting of relatively high prevalence of KS. This highly unusual case left many unanswered questions such as the possible Covid-19 and KS interaction and whether any other underlying fungal infections or tuberculosis may have exacerbated the situation. The case highlighted how difficult the management of KS complications can be in our severely resource-constrained setting. Tuberculosis was a major concern in our patient and confirming the diagnosis of TB is incredibly difficult due to the low sensitivity and availability of tests at the time. The management of this case was difficult given the limitations with access to cross-sectional imaging, lack of supporting laboratory investigations and advanced imaging such as magnetic resonance lymphangiography in our low-resource setting.