Practice Essentials
Since approximately 2000, there has been a steady increase in opioid use disorder infective endocarditis (OUD-IE). The COVID-19 pandemic has significantly accelerated the rise in both OUD and IE. This article will examine the significant effect of concurrent COVID-19 infection upon the epidemiology, pathogenesis, clinical presentation, diagnosis, treatment, and outcomes of OUD-IE.
Background
This case demonstrates the overlap between IE and COVID-19, which makes accurate clinical diagnosis difficult and results in delayed treatment.
The patient is a 28 year-old woman with a history of opiate use disorder (OUD) on methadone who has recently relapsed. She suffers from untreated chronic hepatitis C virus (HCV) infection and polycystic ovary syndrome (PCOS) and is on oral contraception. The patient presented to the emergency department 12 days after the onset of symptoms including low grade fever and fatigue. In the emergency department, she tested positive for COVID-19. Within 3 days after admission to the hospital, and despite high dose dexamethasone, baricitinib therapy, and broad spectrum antibiotics, she progressed to severe acute respiratory distress syndrome (ARDS) that required intubation. She remained febrile. A D-dimer level was 100K ng/mL. The computed tomography pulmonary embolus (CT-PE) examination demonstrated bilateral subsegmental pulmonary emboli. No vegetations were identified on transthoracic echocardiogram (TTE). That night, a venous ultrasound of the right leg showed findings consistent with a new deep venous thrombosis (DVT). Testing was unable to determine whether the source was subsegmental pulmonary emboli, DVT, COVID-19 infection, OUD-IE, or was associated with OCPs. A heparin drip was started, cultures of blood and sputum were negative, and a transesophageal echocardiogram (TEE) was ordered. The patient continued to be febrile, and septic emboli on the pulps of her fingers were identified. Empiric antibiotics were restarted. Repeat blood cultures remained negative. Should there be further work-up?
The challenge with patients with OUD-IE with concurrent COVID-19 infection is the significant overlap between symptoms, physical findings, laboratory, and imaging findings between both these conditions. The purpose of this article is to provide a time-based approach to recognize the predominant pathologic process at any one given time.
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Pathophysiology
The development of OUD-IE in normal heart valves may be related to the scarring effect of various materials that are contained within the injected drug. A more likely explanation is the ability of Staphylococcus aureus (S aureus) to directly invade and damage endothelial cells of the valve.
COVID-19 infection may produce a systemic inflammatory state that may scar the endothelium with resultant loss of anticoagulation properties. This pro-thrombotic state of COVID-19 allows for the formation of thrombi on valvular surfaces, enabling S aureus or other infectious pathogens to adhere to valvular surfaces, intravascular devices, and extravascular devices.
The pro-thrombotic property of COVID-19 infection is hypothesized to be the major factor for the development of IE among otherwise healthy individuals, those with a history of OUD, or an immunocompromised state for up to several months after being infected with COVID-19. [1, 2, 3] Before the COVID-19 pandemic, 70% of OUD-IE was right-sided and usually involved the tricuspid valve. More than one valve may be involved during the COVID-19 era. There are cases that recognize infection by multiple organisms. [4, 5, 6] COVID-19 coinfection may predispose to multiple valve involvement in all types of IE. [4]
There appear to be three major pathological mechanisms of COVID-19 infection: thrombosis, inflammation, and coinfection. The inflammatory response to COVID-19 is produced by excessive production of various cytokines particularly in the pattern of interleukin 1 (IL-1) and IL-6 pathways (see Table 1). Immunologic studies have shown that elevated C-reactive protein (CRP) reflects IL-6-mediated pro-inflammatory pathways, whereas elevated ferritin reveals immune dysregulation in IL-1 and interferon-gamma (IFN-γ). [7, 8, 9] The thrombotic pattern is defined as a CRP less than 10 μg/dL, ferritin less than 3,000 mg/mL, and a D-dimer greater than 5,000 mg/mL, which would require evaluation for pulmonary emboli (PEs) and DVTs before determining the need for anticoagulation. There is evidence that COVID-19 infection may lead to persistent microthrombi that put patients at increased risk for further endothelial damage, myocarditis, and DVT formation even after resolution of clinical symptoms.
It appears that the involvement of the endothelium leads to activation of platelets. This is brought about by the interaction of the virus' spike proteins with endothelial associated angiotensin converting enzyme 2-receptor (ACE2-R). The end result is recurrent cycles of intravascular coagulation and inflammation of the cardiac endothelium, both of which can lead to the development of OUD-IE. [10]
Table 1: Clinical Complication Patterns of COVID-19 Infection (Open Table in a new window)
Major Pathological Mechanisms |
Definitions |
Targeted Pathogenic Pathway |
Onset of Symptoms (Days) |
Coinfection |
Bacterial, fungal, viral co-infection |
Interaction of viral specific proteins with host receptors leading to endothelial activation and dysfunction [7] | 6-12 |
Inflammatory |
Endothelitis due to platelet activation [7] | ||
|
↑ CRP ↓ ferritin |
IL-6 |
8-13 |
|
↑ CRP ↑ ferritin |
IL-1, IL-6 |
10-13 |
|
↓ CRP ↑ ferritin |
IL- 1 |
11-16 |
Thrombotic |
DVT, PE |
Hypercoagulable state induced by COVID-19 infection [7] | 10-18 |
Adapted from Garcia-Vidal et al [7]
Garcia-Vidal et al applied these classifications to individual patients in a systematic effort to deliver personalized care. They demonstrated that doing so resulted in a statistically significant improvement in clinical status (see below for further discussion). [7]
Epidemiology
The incidence of OUD-IE cases has risen locally and internationally, with a twofold increase internationally between 2000 and 2018. [11] Historically, OUD-IE affects older populations due to comorbidities, cardiac hardware, and immunocompromised states, but more recent data documents that OUD-IE is involving younger marginalized populations with low socioeconomic status, injection drug users, the uninsured, and individuals with comorbidities including HIV or HCV infection. [12] Infectious complications among people with OUD-IE have been localized to urban centers; however, between 2016 and 2019, rates increased by 85.8% in urban centers compared with 81.7% in rural locations. [12]
Tables
Major Pathological Mechanisms |
Definitions |
Targeted Pathogenic Pathway |
Onset of Symptoms (Days) |
Coinfection |
Bacterial, fungal, viral co-infection |
Interaction of viral specific proteins with host receptors leading to endothelial activation and dysfunction [7] | 6-12 |
Inflammatory |
Endothelitis due to platelet activation [7] | ||
|
↑ CRP ↓ ferritin |
IL-6 |
8-13 |
|
↑ CRP ↑ ferritin |
IL-1, IL-6 |
10-13 |
|
↓ CRP ↑ ferritin |
IL- 1 |
11-16 |
Thrombotic |
DVT, PE |
Hypercoagulable state induced by COVID-19 infection [7] | 10-18 |
Differential Diagnoses of OUD-IE during the COVID-19 Pandemic |
|
