Introduction

Sarcoidosis is a multisystem autoimmune disease that can impact any part of the body and any part of an organ system. This autoimmune disease has an unknown etiology regarding the development of non-necrotizing granulomas. It is induced as a result of an overreactive inflammatory response to foreign antigens, such as external particulates that are able to spread systemically within the body. Sarcoidosis primarily begins at the ages of 30 and 50 years of age, where it normally manifests in the lungs and the lymph nodes - intrathoracic involvement.¹ Most sarcoidosis cases are intrathoracic (90%) with an asymptomatic phenotype and involve the accumulation of granulomas that can be self-remitting within 12 to 36 months - the time-limited disease pathway.¹

On the other hand, a more severe chronic course of disease progression occurs in around 10-30% of patients with sarcoidosis, whereby these patients require prolonged treatment strategies to control specific life-threatening disease manifestations such as portal hypertension, cardiac sarcoidosis, and advanced hepatic sarcoidosis in the form of liver cirrhosis.¹ Granuloma formation is widely misunderstood based on the heterogeneity in systemic localization. However, the histological profile of granulomas within different organs is similar, consisting of tightly organized groups of multinucleated giant cells and macrophage-derived epithelioid cells that are immersed within fibroblasts and lymphocytes.²

Monocytes are essential to the mononuclear phagocyte system, which involves the identification and engulfment of foreign bodies like antigens induce an inflammatory response.³ These cells also play a crucial role in the regulation of lymphocytes by differentiating into dendritic cells that can act as antigen-presenting cells, thus controlling the immune response. In normal physiological conditions, the monocyte count in adult humans, male or female, sits around 0.2 to 0.8 x 10⁹/L, but upon pro-inflammatory responses, monocyte levels increase dramatically, and according to the World Health Organization, if these levels remain above 1 x 10⁹/L for more than three months then this is clinically defined as monocytosis.³

Interestingly, monocytosis is  linked to chronic autoinflammatory disorders where there is a dysregulation in the immune response due to overactive T cells. One of these disorders encompasses granulomatous disorders like sarcoidosis and inflammatory bowel disease (ulcerative colitis).³

Monocytes have a clearly defined role in the pathogenesis of sarcoidosis as they result in the production of monocyte-derived macrophages, which combine to form giant multinucleated cells - a core component to all sarcoid granulomas.⁴

Pathophysiology of Sarcoidosis

Granuloma formation begins with an initial triggering of the immune system via the presence of a foreign antigen. Once the antigen is detected by the human leukocyte antigen (HLA), it is present in the T lymphocytes (Th1) by binding to the Th1 surface receptors. This complementary binding initiates the release of inflammatory cytokines such as tumor necrosis factor (TNF-ɑ), interleukin-1 (required for proper development and function of T effector cells), and IL-6.² The release of these pro-inflammatory cytokines stimulates an inflammatory cascade that further promotes the secretion of interferon-Ɣ(IFN-Ɣ), IL-2, and IL-12 cytokines that recruit monocytes and macrophages for the engulfment of these foreign antigens.² The aggregation of monocytes and CD4+ T cells forms giant multinucleated cells, otherwise known as granulomas.⁴

Monocytosis in the Context of Sarcoidosis

Causes of monocytosis 

A high monocyte count can have many underlying causes with the most common being infectious diseases like mononucleosis or autoimmune diseases like lupus. It is important to know that clinical signs of monocytosis do not correlate to one specific disease and require further investigation to determine the root cause for monocyte increase. For example, activities that induce some stress on the body, like harsh exercise regimens, increase monocyte concentrations. Also, chronic stress and pregnancy can create monocytosis conditions as a result of the increased stress upon the body. The symptomatology of monocytosis is unclear as monocytosis is the result of the disease manifestation occurring, which produces a set of corresponding symptoms that are either non-specific or unique to the disease.  

Monocytes are essential within the mononuclear phagocyte system (MPS), which also consists of macrophages and monocyte-derived dendritic cells, with a core responsibility of phagocytosing foreign antigens, releasing pro-inflammatory cytokines, and presenting antigens to Th1 cells via pattern recognition receptors (PRRs), for example the toll-like receptor (TLR).⁵ Activation of TH1 cells causes further recruitment of monocytes and macrophages through the release of inflammatory cytokines, which allows macrophages to join together, forming multinucleated giant cells - a component of granulomas.^4,5

Diagnostic Significance

Monocytosis is clearly defined as elevated monocyte counts above 1 x 10⁹/L for more than three months, indicating systemic inflammation. One of the first methods of evaluating a patient with suspected monocytosis is screening their infectious disease exposure history and physical examinations.³ It is essential to understand the travel history and risk of specific diseases that may also cause increased counts of monocytes, like tuberculosis - a pulmonary disease that induces fibrosis of the lungs.

Diagnostic procedures for monocytosis  

• When monocytosis is suspected, a clinician may recommend a complete blood count (CBC) to measure the amount of red blood cells (RBCs) and white blood cells (WBCs). 
• A peripheral blood smear can be used to assess the phenotypic characteristics of blood cells under a microscope to further delineate between monocytosis and other similar conditions.
• An absolute monocyte count is used to test the number of monocytes within your blood, which can give the clinician an idea of whether a person is currently experiencing an inflammatory response and if further testing is needed. 
• Morphology of monocytes should be investigated on a peripheral smear for dysplasia. 
• For persistent monocytosis, a monocyte compartment flow cytometry assessment can be used to distinguish between rheumatological or infectious diseases.³

Diagnostic procedures for sarcoidosis 

• CT and MRI scans are normally considered for sarcoidosis that is thought to be intrathoracic - accounting for up to 90% of sarcoidosis patients.¹
• For extrathoracic sarcoidosis conditions like hepatic sarcoidosis, liver function tests will be used to assess the involvement of the liver in granulomatous disease. Firstly, the angiotensin-converting enzyme (ACE) is one of the best biomarkers for sarcoidosis since this is always elevated.⁶
• Liver function tests will also be carried out to assess the levels of bilirubin, alkaline phosphatase, and transaminases alongside ultrasound to identify morphological abnormalities such as granuloma formation within hepatic architecture.  

Clinical Implications

Monocyte levels have been shown to be increased in sarcoidosis with increasing amounts of pro-inflammatory cytokines such as TNF-ɑ and IL-2. Since monocytes give rise to activated macrophages that fuse to form multinucleated giant cells, higher levels of monocytes upon initial diagnosis are linked to poorer outcomes.  

Management and Treatment

In order to treat monocytosis, it is essential to treat the underlying condition that is causing the increase and aggregation of monocytes, like sarcoidosis. 

There are many treatments for suppressing the inflammatory response, such as the application of steroids like corticosteroids and immunosuppressants.

With the absence of dysplasia from peripheral blood smear tests and isolated monocytes, then a repeated CBC test is considered in three months. If monocytosis is persistent, a monocyte compartment flow is used to identify reactive causes. In the absence of reactive causes and normal monocyte phenotypes (CD14++/CD16-), a bone marrow evaluation is needed. On the other hand, if the monocyte phenotype is CD16+ or the reactive causes are of non-neoplastic etiology more tests for autoimmune diseases are considered.³

Prognosis and Outcomes

Increased monocyte counts are a sign of an underlying condition driving inflammation, which can be an exhaustive list of conditions. It is key to use specific testing methods to distinguish between these suspected diseases and connect them to monocytosis. Once a disease has been identified, a prognosis and tailored treatment plan can be put into action. 

In the case of sarcoidosis, around two-thirds of patients follow the self-remitting disease pathway, where the majority will recover from the disease within 12 to 36 months from diagnosis.¹ On the other hand, 10 to 30% of patients with sarcoidosis will follow the chronic disease pathway, which can lead to system granuloma formation and to the development of life-threatening disease manifestations like portal hypertension, liver cirrhosis, and cardiac sarcoidosis.¹ It is known that patients with chronic sarcoidosis have a poorer prognosis than those with acute onset disease. Those patients with elevated blood intermediate monocytes were less likely to achieve granuloma remission after two years whilst larger amounts of TNF-producing monocytes within blood plasma concur with a more severe chronic form of sarcoidosis.⁷

FAQ

Can I prevent monocytosis? 

Monocytosis is a result of an underlying condition that is driving an inflammatory response. As monocytosis is linked to dysfunctional immune systems and autoimmunity, the best way to avoid this is to maintain a strong immune system. Other suggestions include: 

• Maintaining a well-balanced diet 
• Regular exercise 
• Stop smoking 
• Reduce chronic stress 
• Maintain a healthy sleep pattern  

Summary 

Sarcoidosis is a multisystemic autoimmune disease characterized by the random localization of non-necrotizing granulomas, primarily affecting the lungs, skin, and lymph nodes. The etiology of granuloma formation is unknown but heavily linked to dysregulation in the inflammatory response and usually accompanied by monocytosis. Monocytosis is defined as elevated monocyte counts above 1 x 10^9/L for longer than three months. Monocytes are crucial in the mononuclear phagocyte system, which acts to identify foreign antigens and particulates. During overactive inflammation, excessive monocyte activation drives the compounding of activated macrophages, which form multinucleated giant cells for granuloma formation. Diagnosing monocytosis involves a series of blood tests, peripheral blood smears, and flow cytometry, while sarcoidosis requires imaging, ultrasound, and liver function tests. Elevated monocyte levels help monitor sarcoidosis progression and treatment plans, which typically involve the application of corticosteroids and immunosuppressants. Prognosis varies between ethnic groups, with African Americans are prone to chronic systemic disease compared to Caucasians who are prone to gradual onset sarcoidosis.