Pericardial effusion as a complication of chronic graft versus host disease

Abstract

A 24-year-old man with previous matched unrelated donor allogenic bone marrow transplant for aplastic anaemia and chronic graft versus host disease on steroid taper presented with progressively worsening anasarca. CT revealed large pericardial effusion, while echocardiogram was concerning for early tamponade physiology. He underwent emergent pericardiocentesis with pericardial drain placement. Extensive rheumatological and infectious work-up was unrevealing with patient’s presentation attributed to pericardial graft versus host disease. This highlights the need of physicians to be aware of pericardial serositis as a complication of graft versus host disease due to its life-threatening complications, which require immediate intervention.

Background

Pericardial effusion is a rare but potentially life-threatening consequence of allogeneic haematopoietic stem cell transplantation (HSCT) with a feared complication of cardiac tamponade.^{1 2} The causes of pericardial effusions are numerous, with the highest risk of tamponade in bacterial, fungal, HIV-associated, neoplastic or haemorrhagic effusions.² Graft versus host disease (GvHD) is a rare cause of pericardial serositis in stem cell transplant patients. Meanwhile, specific diagnostic criteria for multiple organ involvement in GvHD are well-defined; pericardial effusion secondary to GvHD remains to be a diagnosis of exclusion.³ Here, we present a case of a pericardial effusion in the setting of GvHD in order to raise awareness of healthcare professionals that, although rare, GvHD pericardial serositis is possible and can lead to tamponade requiring immediate pericardial drain or window.

Case presentation

A 24-year-old man with history of severe aplastic anaemia treated with a matched unrelated donor (MUD) allogenic bone marrow transplant presented as a direct admission from his oncologist for progressively worsening facial swelling and anasarca. Since his transplant, approximately 16 months prior, the patient has been treated for recurrent chronic graft versus host disease (cGvHD) with gastrointestinal involvement, requiring high-dose prednisone. In the previous 2 months, he developed eye swelling with progression to facial swelling, followed by upper extremity pitting oedema, and finally anasarca. During that time, his steroids for cGvHD were slowly tapered. In the 2 weeks preceding admission, he had developed recurrence of nausea, emesis and loose bowel movements.

Two weeks prior to admission, laboratory work-up was performed to evaluate for other potential causes including heart failure, nephrosis and cirrhosis—all of which were unremarkable. Due to persistent angioedema, he was evaluated in the allergy clinic given the continued concern for an allergic cause.

On admission, outpatient medications included prednisone, famotidine and benadryl. Patient reported no known allergies. His family history was negative for autoimmune disorders and angioedema. He denied smoking, alcohol or drug use.

Patient was afebrile. His blood pressure was 113/53 mm Hg with a heart rate of 101 beats/min. He was breathing at 20 breaths/min with normal oxygenation, speaking in full sentences on room air. Symmetric swelling of bilateral upper eyelids, with moderate to severe oedema of the lips and pitting oedema of all extremities. Cardiovascular examination showed tachycardia, the heart sounds were not perceptibly reduced. Pulsus paradoxus was not measured. Lungs were clear, while abdomen was soft, non-distended and non-tender.

Investigations

Complete blood count, comprehensive metabolic panel, thyroid-stimulating hormone and T4 were normal. Allergen panel and C1-esterase inhibitor were negative. C reactive protein 12.9 mg/L (0.00–3.00 mg/L), but erythrocyte sedimentation rate, rheumatoid factor, cyclic citrullinated peptide, antinuclear, antimicrosomal, double-stranded DNA, cardiolipin and lupus anticoagulant, anti-topoisomerase, centromere, anti-U1-ribonucleoprotein, Sjogren’s syndrome A and B antibodies were unremarkable. Infectious work-up included respiratory viral panel, Aspergillus, cytomegalovirus, Epstein-Barr virus, HIV, syphilis, coccidioidomycosis, coxsackie virus, which were negative. Bacterial and fungal cultures of blood did not show any organisms.

A chest radiograph demonstrated an enlarged cardiac silhouette with a small left pleural effusion. CT of the chest showed large pericardial effusion with moderate to large bilateral pleural effusions, and normal superior vena cava (figure 1). Transthoracic echocardiogram demonstrated a large pericardial effusion with diastolic collapse of the right ventricle with early tamponade (figure 2).

Figure 1.

CT chest revealing large pericardial effusion.

Figure 2.

Transthoracic echocardiogram confirming pericardial effusion.

Differential diagnosis

• Infectious aetiologies: Viral pericarditis (adenovirus, coxsackievirus, HIV), bacterial (Pneumococcus, Staphylococcus, Streptococcus), mycobacterial, fungal (coccidioidomycosis and histoplasmosis).²

• Rheumatological causes include connective tissue disease such as systemic lupus erythematosus, rheumatoid arthritis, scleroderma, as well as vasculitis like polyarteritis nodosa, temporal arteritis or Churg-Strauss disease.²

• Medication-induced pericardial effusions often occur in the setting of procainamide, hydralazine and isoniazid use.²

• Haemorrhagic effusions can occur as a result of trauma or cardiac manipulation procedures (cardiac surgery, percutaneous coronary intervention or pacemaker placement).²

Treatment

A diagnostic and therapeutic pericardiocentesis was performed with 500 mL of yellow fluid drained after initial placement of the pericardial drain, followed by additional output of 1 L in the next 12 hours. Cell count showed 226/mm³ total nucleated cells with a lymphocyte predominance at 82%. Gram stain, acid-fast bacilli stain (auramine O stain) and culture, bacterial, viral and fungal cultures were negative. Cytology revealed reactive mesothelial cells without evidence of malignancy. Following pericardiocentesis, patient required additional diuretics to improve his hypervolaemic state. As rheumatological and infectious work-up has been unrevealing, patient’s pericardial effusion was attributed to GvHD, supported by resurgence of gastrointestinal symptoms as steroids were tapered. Maintenance oral prednisone was changed to methylprednisolone 75 mg daily and addition of CellCept 1 g two times per day. Patient’s facial swelling resolved. Repeat echocardiogram showed trivial pericardial effusion. Pericardial drain was removed 7 days after placement once minimal output from the drain was achieved. Pericardial biopsy was not performed due to patient’s response to treatment and in order to avoid another invasive procedure. Patient was discharged on prednisone 80 mg orally daily, CellCept 1 g two times per day, with oncology and cardiology follow-up.

Outcome and follow-up

On discharge from the hospital, patient was seen by his outpatient haematologist. His facial swelling and upper extremity oedema did not recur. He was continued on prednisone 80 mg daily and CellCept 1000 mg two times per day, with consideration of adding Ruxolitinib as an outpatient due to continued cGvHD despite long-term steroids.

Discussion

Pericardial effusions can present with a multitude of symptoms, depending on the timing of the pericardial fluid expansion. In an acute accumulation, as little as 100 mL of fluid in the pericardial space can cause haemodynamic instability, whereas an indolent accumulation can lead to more than 1000 mL of fluid with relatively minimal symptoms.⁴ Regardless of aetiology, the evaluation and treatment is pericardial fluid analysis and drainage with either a percutaneous drain or pericardial window. Viral pericardial effusion is the most common in the developing world. But other aetiologies to consider are inflammatory (eg, lupus, rheumatoid arthritis or Sjogren’s syndrome), neoplastic, traumatic, cardiac (post-myocardial infarction or aortic dissection), nephrosis, cirrhosis, endocrinopathy or drug induced.⁵ In developing countries, tuberculosis (TB) accounts for 70% of pericarditis with 6-month mortality of 25% without HIV infection and 40% with HIV infection. Although, in developed world TB pericarditis accounts for less than 5% of cases, it should be suspected in immigrants from endemic areas and immunocompromised individuals.⁶

It is important to consider rheumatological and autoimmune processes, infectious aetiology and drug-induced serositis before entertaining the idea of GvHD as the cause of effusion. While uncommon, the event has been reported and studied in case reports and single-centre retrospective studies.^{1 7–11}

In a single-centre retrospective study, Liu and colleagues evaluated 601 patients (262 autologous, 189 related and 150 MUDs) who underwent stem cell transplant. Six patients developed large pericardial effusion (five sibling related and one MUD). Four of these six were late onset (>241 days), with all late-onset patients having manifestations of GvHD in other organ systems. No incidents of pericardial effusions was noted with the autologous transplant patients.¹⁰ In a similar study by Norkin et al, 858 patients were examined (512 autologous, 148 related, 198 MUD) in which 7 patients suffered from large pericardial effusion and tamponade; all 7 patients had received unrelated transplants with median diagnosis day at 229. In addition, six of seven patients had known cGvHD, while four of the six were amidst tapering off of immunosuppressive therapy when they developed this complication.¹¹

A more recent analysis by Liu et al showed similar conclusions, but had additional analysis regarding risk factors. In this study, 12 patients were noted to have large pericardial effusions after HSCT (391 patients studied, with 198 matched sibling donors, 183MUD, 2 umbilical cord blood and 8 related donor). Three patients had an unrelated donor and nine had that of sibling. In the late-onset group, 4 of 12 patients had chronic GvHD. Additionally, this study also investigated pre-transplant and post-transplant risk factors in the development of pericardial effusion. Pre-transplant risk consisted largely of age, while no statistical significance was noted with gender, underlying disease or conditioning regimens. Post-transplant risks were also examined, demonstrating that age, number of transplants and history of cGvHD placed patients at risk of developing an effusion (p=0.001).¹

Learning points.

• Physicians must also consider the idea that pericardial effusion and tamponade may also be a manifestation of graft versus host disease (GvHD).

• Viral, inflammatory, infectious and drug-induced cardiotoxicity need to be excluded prior to GvHD as this is a diagnosis of exclusion.

• Appropriate treatment should be pursued with pericardial drain or window.