COVID-19 and the mystery of CD68-negative cardiac histiocytoses

Medical News: Researchers from various leading Russian institutions have uncovered a link between extremely rare CD68-negative histiocytoses and COVID-19. This study focuses on four intriguing cases of cardiac involvement in patients with histiocytoses, a condition where abnormal histiocytes - immune cells originating from monocytes - accumulate in body tissues. These cases have raised significant questions regarding the connection between the viral infection and the development of these rare diseases. The study, conducted by researchers from Almazov National Medical Research Centre, Lomonosov Moscow State University, and St. Petersburg State University, presents a fascinating insight into this potential link.


COVID-19 and the mystery of CD68-negative cardiac histiocytoses

Understanding Histiocytoses and Their Rarity
Histiocytoses are known to be rare disorders that affect various organs by causing an accumulation of abnormal immune cells. These conditions, which are often difficult to diagnose, include subtypes such as Erdheim–Chester disease (ECD), Langerhans cell histiocytosis (LCH), and Rosai–Dorfman disease. The subtypes vary in their severity and the organs they affect, with some leading to self-resolving symptoms while others require aggressive treatments.
 
This Medical News report delves into the uncommon occurrence of CD68-negative histiocytoses, where the affected immune cells do not express the CD68 protein, typically used as a marker for histiocytes. Adding to the complexity, these cases show the expression of the SARS-CoV-2 spike protein in immune cells, raising questions about a possible connection between COVID-19 and histiocytosis development.
 
Four Cases of CD68-Negative Cardiac Histiocytoses
-Case 1: Erdheim–Chester Disease with Pericardial Involvement
The first case involved a 67-year-old man with a history of joint disease who presented with pericardial effusion and exophthalmos (bulging eyes). The patient had tested positive for mild COVID-19 twice, in 2021 and 2022. After further imaging studies, including PET scans, he was diagnosed with Erdheim–Chester disease, a rare form of histiocytosis that affects multiple organ systems.

Histological analysis of pericardial tissue revealed infiltration by large histiocytes expressing CD163 and the SARS-CoV-2 spike protein, but minimal CD68 expression. Genetic testing confirmed a mutation in the BRAF gene, commonly associated with Erdheim–Chester disease. The patient’s treatment involved the use of vemurafenib, a BRAF-kinase inhibitor, along with corticosteroids, which led to significant improvement, including the regression of exophthalmos and pericardial effusion.
 
-Case 2: Xanthogranulomatous Myopericarditis Post-COVID-19
A 63-year-old man with a history of COVID-19 was diagnosed with constrictive pericarditis and severe heart failure. A biopsy of his pericardium revealed xanthogranulomatous inflammation, characterized by the presence of macrophages and cholesterol crystals. CD163 and the SARS-CoV-2 spike protein were strongly expressed in the histiocytes, but CD68 was largely absent.

Tragically, the patient passed away from ventricular fibrillation a week later. His autopsy confirmed the diagnosis of xanthogranulomatous myopericarditis and highlighted the role of COVID-19 in potentially triggering this rare cardiac condition.
 
-Case 3: Xanthogranulomatosis in a Newborn
 In a rare pediatric case, a 1-month-old girl with congenital heart disease died from heart failure. Autopsy findings revealed extensive xanthogranulomatous lesions in her heart, with histiocytes expressing CD163 and the SARS-CoV-2 spike protein but not CD68. The findings led researchers to suspect that a prenatal COVID-19 infection in the mother could have contributed to the development of the disease in the infant.
 
-Case 4: Constrictive Pericarditis in a 57-Year-Old Man
The final case involved a 57-year-old man with constrictive pericarditis and heart failure. Similar to the previous cases, his pericardium was infiltrated by histiocytes that expressed CD163 and the SARS-CoV-2 spike protein but showed little CD68 expression. Despite receiving treatment, the patient continued to struggle with heart failure and required ongoing monitoring.
 
The Role of COVID-19 in Histiocytoses Development
These four cases share a common thread: each patient had either been infected with or exposed to SARS-CoV-2, the virus that causes COVID-19. In all cases, histiocytes expressed the spike protein of the virus, suggesting a possible association between COVID-19 and the onset of these rare histiocytic diseases.

COVID-19 is known to trigger a hyperinflammatory state, often referred to as a cytokine storm. This can lead to an overactive immune response, which may, in turn, cause abnormal accumulation of immune cells in various tissues. The persistence of the virus in immune cells, such as macrophages, could potentially explain why these patients developed histiocytosis.
 
Although histiocytoses are rare, their emergence in these patients raises concerns about whether COVID-19 might be a trigger for the disease. This article highlights the need for further research into this potential link, particularly with the ongoing prevalence of COVID-19.
 
Key Study Findings
-Rare CD68-Negative Histiocytes:
 All four cases involved histiocytes that did not express the CD68 protein, an unusual finding in histiocytoses. However, these cells did express CD163, another macrophage marker, as well as the SARS-CoV-2 spike protein.
 
-COVID-19 Connection:
Each patient had a history of COVID-19 or had been exposed to the virus. The presence of the virus's spike protein in the histiocytes suggests that SARS-CoV-2 may play a role in triggering or exacerbating histiocytoses.
 
-Genetic Mutations:
In one case, the BRAF V600E mutation was detected, a genetic marker associated with Erdheim–Chester disease. Genetic testing could help guide targeted therapies for similar patients.
 
-Positive Treatment Outcomes:
The patient with Erdheim–Chester disease responded well to vemurafenib, a targeted therapy for BRAF mutations. This underscores the importance of genetic testing in rare histiocytic diseases to determine the best course of treatment.
 
Conclusions
The findings in these four cases of CD68-negative cardiac histiocytoses suggest a potential link between COVID-19 and the development of these rare diseases. The fact that all patients showed the expression of the SARS-CoV-2 spike protein in their immune cells raises important questions about the role of the virus in triggering histiocytosis.
 
While these findings are preliminary, they underscore the need for further research to explore the relationship between viral infections like COVID-19 and the onset of histiocytoses. As the world continues to battle the ongoing COVID-19 pandemic, understanding its long-term impact on the immune system remains crucial.
 
Future studies should focus on larger patient samples and include extensive genetic testing to better understand the mechanisms behind these rare diseases. Only through continued research can we hope to uncover the full scope of COVID-19’s effects on the body.
 
The study findings were published in the peer-reviewed International Journal of Molecular Sciences.
https://www.mdpi.com/1422-0067/25/18/10086
 
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https://www.thailandmedical.news/news/breaking-covid-19-news-sars-cov-2-also-infects-and-impairs-hematopoietic-stem-cells