Cardiac tamponade, a critical medical emergency, mandates immediate intervention due to its life-threatening hemodynamic instability. While Coxsackie B virus infrequently leads to cardiac tamponade, documented cases are scarce. Moreover, the simultaneous occurrence of bilateral pleural effusion adds an unusual dimension to its clinical presentation. Serositis, a hallmark of connective tissue disorders like systemic lupus erythematosus (SLE), is encountered often. Yet its co-presentation with hemorrhagic viral pleural effusion and cardiac tamponade of this severity remains exceptionally rare.

A 77-year-old male with a medical history notable for SLE, relapsing polychondritis, and paroxysmal atrial fibrillation, presented with palpitations and dyspnea. Electrocardiography revealed atrial fibrillation with rapid ventricular response, necessitating immediate cardioversion in the emergency department due to hemodynamic instability. Subsequent chest computed tomography demonstrated moderate pericardial effusion alongside bilateral pleural effusions. Despite initial stabilization, recurrent episodes of hemodynamic instability ensued. Prompt transthoracic echocardiography confirmed tamponade physiology, prompting urgent pericardiocentesis and thoracentesis with drainage of serosanguinous fluid. Fluid analysis confirmed an exudative nature. Exacerbation of SLE was ruled out (by normal anti-dsDNA antibodies and complement levels (especially CH50, C3, C4)), while serological testing revealed elevated Coxsackie B1 virus titers (1:80).

Coxsackie B virus exhibits diverse clinical manifestations, ranging from benign viral prodrome to severe cardiac involvement. Maintaining a high clinical suspicion is crucial to avoid anchoring bias and for timely diagnosis, especially in distinguishing viral-induced pathology from more conventional causes like SLE. This case underscores the importance of recognizing rare viral etiologies in patients with similar presentations mimicking an exacerbation of underlying autoimmune disorders.