Sandbox:mani karimzade
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# Special consideration when adding information from observational studies

# Overview
Monocytosis is a common nonspecific finding usually representing the reactive innate immunity. Circulating Monocytes ( with 1-3 day half life for classical monocytes ) are precursors of Macrophages and myeloid dendritic cells which can also act as an antigen presenting cells to other lymphocytes. Monocytosis can also occur Among morbid pathological conditions like inflammatory diseases or neoplasms, so it could be clinically challenging for physicians to evaluate Monocytosis. underlying Protozoa infections were known to be the main cause of Monocytosis. Since Leukocytes traffic are mainly controlled by different ChemoKine's; Understanding this versatile and dynamic  interaction of ChemoKine's with Monocytes may help to have a more complete picture of monocytosis. Angiotensin-II/AGTR1A-signaling pathway helps the monocytes to move into the blood circulation. Inflammation can also stimulate the bone marrow to signal the monocytes to enter the circulation; persistent stimulation of bone marrow may alter the receptor distribution on monocytes surface which can lead to a sudden egress of monocytes into circulation.
There are three major Monocytes ( Classical, Intermediate, and nonclassical ) including other subtypes. Today Singel-cell RNA sequencing (scRNA-seq ) is used for monocytes transcriptomic analysis but The high plasticity of monocytes subpopulations makes it difficult to distinct them. pathway analyzing is another promising method to understand monocytes and monocytosis.
Clinicians should always look for other causes of monocytosis after excluding reactive monocytosis. for example to differentiate CMML (Chronic myelomonocytic leukemia) with reactive monocytosis clinicians used Classical monocytes ( CD14++/CD16) count as a biomarker which today is not correlated with CMML diagnosis.  Although for diagnosis of CMML  we can use this biomarker ( with help of OKM5 monoclonal antibody which binds to monocyte membrane protein and platelet membrane protein ) for flow Cytometry but these monocyte-like cells lack nonspecific Esterase.  So it is also important to consider whether the Monocytosis is persistent or not. Monocyte count is not correlated with survival in CMML transformation to Acute Leukemia which is a rare and aggressive form classified as acute myeloid leukemia with myelo-dysplasia-related changes  ( but increased marrow blasts count is correlated with decreased survival ( confirmed with CD34 )).
Not only evaluating the Monocytes population with flow cytometry is necessary in the case of myeloid neoplasm speculation; but also it is important to evaluate the Monocytes population morphology, due to various atypical expressions of its CD markers ( Cluster of Differentiation ).
Monocytosis is correlated with an increased risk of DVT ( Deep vein thrombosis ) and Cerebral infarcts and Subarachnoid hemorrhage, which emphasizes their role in coagulation cascade. 

# Historical Perspective
 was first discovered by , a , in /during/following . Monocytes name was suggested by one of the most Epic and enigmatic pathologist " James Homer Wright ".  
The association between  and  was made in/during .
In ,  was the first to discover the association between  and the development of .
In ,  mutations were first implicated in the pathogenesis of .
There have been several outbreaks of , including -----.
In ,  was developed by  to treat/diagnose .

# Classification
Based on CMML diagnostic Criteria; PB monocytosis 1  109/L, with monocytes accounting for 10% of the WBC count is considered as Monocytosis. 
After Discovery of flow cytometry and monoclonal antibodies in 1989 scientists start to classify Monocytes subpopulations, Then a panel of experts finally categorized these subpopulations to 3 groups ( classical, intermediate, non-classical ). The newer approach to classify Monocytes population is to also consider the expression of "slan" which is a carbohydrate modification of p-selectin glycoprotein ligand 1 ( PSGL-1 ). It is believed "slan" plays an important role in monocytes migration and is a good marker in the expanding list of markers to evaluate monocytes subpopulations.
There is no established system for the classification of .
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 may be classified according to  into  subtypes/groups: , , , and .
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 may be classified into  subtypes based on , , and .
 may be classified into several subtypes based on , , and .
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Based on the duration of symptoms,  may be classified as either acute or chronic.
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If the staging system involves specific and characteristic findings and features:
According to the , there are  stages of  based on the , , and . Each stage is assigned a  and a  that designate the  and .
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The staging of  is based on the .
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There is no established system for the staging of .

# Pathophysiology
Monocytosis arises from monocytes which have diverse roles. Monocytes ( with 12-20 m diameter ) are similar with Neutrophils in terms of tissue penetration; their bi-lobed kidney shaped nucleus helps them to have more chromatin flexibility and deformation and they constitue 5% of nucleated circulating blood cell population. Monocytes as a part of innate immunity; could respond to PAMP ( pathogen-associated molecular patterns ) and DAMP ( danger-associated molecular patterns ) with PRR ( pattern-recognition receptors ) and can activate inflammasome ( through TLR's and MYD88 which results in secretion of interferon- and the consequent pro-inflammatory mediators like IL-1 ).  Inflammasome can activate pyroptosis in different cell populations.
There are 3 major types of monocytes: classical ( CD14++CD16 ), intermediate ( CD14++CD16+ ) and nonclassical ( CD14+CD16++). Classical type usually consist 85-90 percent of the monocyte population in the body. The Classical monocytes is released from bone marrow and then it could be transformed to the intermediate monocyte first and then it could transform to the non-classical monocyte sub-population. Non-classical monocytes are known as protector of vasculature ( with 7.4 day circulation duration in the blood ).  During inflammation non-classical monocytes count increases rapidly and contributes to ROS production and phagocytosis.Classical Monocytes are known to react in bacterial infection and inflammation through NLRP3 inflammasome signaling pathways.  It was believed that Monocytes sub-populations mainly react to the tissue responses to mobilize and control the further local mono-nuclear phagocytic population in the tissues, but today it is known that Monocytes give rise to dendritic cells and Macrophages are replenished in the tissue by their own ( in artery wall ). 
The exact pathogenesis of Monocytosis is not fully understood. Rapid early migration of monocytes to the tissue is dependent on MCP-1. The trans-endothelial migration of Monocytes starts with monocytes tethering to the endothelium and then through contact of Selectin's and Integrin's  with VCAM-1 and ICAM-1, ICAM-2 and then finally with PECAM during Diapedesis.
The more Monocytes circulate in the blood, the more Monocytes interact with the artery wall. For example, in animal models, it was shown that cholesterol can induce Monocytosis from bone marrow and lead to a pro-inflammatory state ( not inflammatory state ) in arteries and disrupt the usual macrophage balance in the artery wall. The imbalance of monocytes and macrophages which are not completely understood will result in more lipo-toxic events in macrophages resides in the artery wall due to macrophage reduced mobility; thus more Necrotic lesions are formed in atherosclerotic situations.
It is known that intermediate monocytes can produce a lot of IL-6, TNF-, and IL-1 in response to LPS ( which can interact with CD14 ) but our understanding of each subpopulation in Human models is limited and needs further investigations. For example, it is hard to distinguish the role of non-classical subpopulation vs intermediate subpopulation in cytokine production. Monocytes expressing CD16+ could increase CD8+ T cells responses. Thus maybe in COVID-19 patients when there is a shift toward the non-classical population and the T cell exhaustion; this transformation of intermediate to non-classical is happening catastrophically and limits the intermediate type to balance the CD8+ T cell population. It seems that the more mature monocytes become, The more shift toward an inflammatory state could be expected.
One of the major pathways activated during the inflammatory state in monocytes is the NFKB pathway, which is directly correlated with TNF- production in their environment and results in more inflammatory cytokine production.

# Causes
The most common cause of Monocytosis is nonspecific, and its usually reactive to a secondary cause ( reactive Monocytosis ).
some causes of peripheral Monocytosis are : chronic stress, chronic infections ( sub-acute bacterial endocarditis, malaria, congenital syphilis, pertussis infection ) , Immune disorders and inflammatory disorders, post-splenectomy, Neutropenia and Bone marrow recovery, hemolytic anemia's  and iatrogenic causes (eg, radiation therapy), Solid tumors, Myocardial infarction, Myeloid or lymphoid or plasma cell malignancies and Cutaneous myeloid dendritic cell dyscrasia and atherosclerosis . 
After excluding all possible secondary causes a physician should look for Neoplastic causes. The most important one is CMML ( chronic myelomonocytic leukemia ) a type of myelodysplastic/myeloproliferative neoplasm (MDS/MPN). The main neoplastic entities with Monocytosis are :
1. Myelodysplastic/Myeloproliferative neoplasms ( represent with monocytopenia which is correlated with more adverse outcome ) 
2. Acute myeloid leukemia with Monocytic differentiation
3. Myeloproliferative neoplasms
4. Myeloid/lymphoid neoplasms with PDGFRA, PDGFRB, or FGFR1 rearrangement or PCM1-JAK2 fusion

# Differentiating ((Page name)) from other Diseases
 must be differentiated from other diseases that cause , , and , such as , , and .
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 must be differentiated from , , and .

# Epidemiology and Demographics
The incidence/prevalence of  is approximately  per 100,000 individuals worldwide.
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In , the incidence/prevalence of  was estimated to be  cases per 100,000 individuals worldwide.
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In , the incidence of  is approximately  per 100,000 individuals with a case-fatality rate of %.
Patients of all age groups may develop .
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The incidence of  increases with age; the median age at diagnosis is  years.
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 commonly affects individuals younger than/older than  years of age.
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 is usually first diagnosed among .
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 commonly affects .
There is no racial predilection to .
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 usually affects individuals of the  race.  individuals are less likely to develop .
 affects men and women equally.
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 are more commonly affected by  than . The  to  ratio is approximately  to 1.
The majority of  cases are reported in .
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 is a common/rare disease that tends to affect  and .

# Risk Factors
There are no established risk factors for .
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The most potent risk factor in the development of  is . Other risk factors include , , and .
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Common risk factors in the development of  include , , , and .
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Common risk factors in the development of  may be occupational, environmental, genetic, and viral.

# Screening
There is insufficient evidence to recommend routine screening for .
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According to the , screening for  is not recommended.
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According to the , screening for  by  is recommended every  among patients with , , and .

# Natural History, Complications, and Prognosis
If left untreated, % of patients with  may progress to develop , , and .
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Common complications of  include , , and .
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Prognosis is generally excellent/good/poor, and the 1/5/10-year mortality/survival rate of patients with  is approximately %.

# Diagnosis

## Diagnostic Study of Choice
The diagnosis of  is made when at least  of the following  diagnostic criteria are met: , , , and .
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The diagnosis of  is based on the  criteria, which include , , and .
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The diagnosis of  is based on the  definition, which includes , , and .
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There are no established criteria for the diagnosis of .

## History and Symptoms
The majority of patients with  are asymptomatic.
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The hallmark of  is . A positive history of  and  is suggestive of . The most common symptoms of  include , , and . Common symptoms of  include , , and . Less common symptoms of  include , , and .

## Physical Examination
Patients with  usually appear . Physical examination of patients with  is usually remarkable for , , and .
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Common physical examination findings of  include , , and .
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The presence of  on physical examination is diagnostic of .
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The presence of  on physical examination is highly suggestive of .

## Laboratory Findings
An elevated/reduced concentration of serum/blood/urinary/CSF/other  is diagnostic of .
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Laboratory findings consistent with the diagnosis of  include , , and .
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 is usually normal among patients with .
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Some patients with  may have elevated/reduced concentration of , which is usually suggestive of .
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There are no diagnostic laboratory findings associated with .

## Electrocardiogram
There are no ECG findings associated with .
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An ECG may be helpful in the diagnosis of . Findings on an ECG suggestive of/diagnostic of  include , , and .

## X-ray
There are no x-ray findings associated with .
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An x-ray may be helpful in the diagnosis of . Findings on an x-ray suggestive of/diagnostic of  include , , and .
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There are no x-ray findings associated with . However, an x-ray may be helpful in the diagnosis of complications of , which include , , and .

## Echocardiography or Ultrasound
There are no echocardiography/ultrasound  findings associated with .
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Echocardiography/ultrasound  may be helpful in the diagnosis of . Findings on an echocardiography/ultrasound suggestive of/diagnostic of  include , , and .
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There are no echocardiography/ultrasound  findings associated with . However, an echocardiography/ultrasound  may be helpful in the diagnosis of complications of , which include , , and .

## CT scan
There are no CT scan findings associated with .
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 CT scan may be helpful in the diagnosis of . Findings on CT scan suggestive of/diagnostic of  include , , and .
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There are no CT scan findings associated with . However, a CT scan may be helpful in the diagnosis of complications of , which include , , and .

## MRI
There are no MRI findings associated with .
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 MRI may be helpful in the diagnosis of . Findings on MRI suggestive of/diagnostic of  include , , and .
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There are no MRI findings associated with . However, a MRI may be helpful in the diagnosis of complications of , which include , , and .

## Other Imaging Findings
There are no other imaging findings associated with .
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 may be helpful in the diagnosis of . Findings on an  suggestive of/diagnostic of  include , , and .

## Other Diagnostic Studies
There are no other diagnostic studies associated with .
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 may be helpful in the diagnosis of . Findings suggestive of/diagnostic of  include , , and .
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Other diagnostic studies for  include , which demonstrates , , and , and , which demonstrates , , and .

# Treatment

## Medical Therapy
There is no treatment for ; the mainstay of therapy is supportive care.
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Supportive therapy for  includes , , and .
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The majority of cases of  are self-limited and require only supportive care.
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 is a medical emergency and requires prompt treatment.
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The mainstay of treatment for  is .
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The optimal therapy for  depends on the stage at diagnosis.
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 is recommended among all patients who develop .
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Pharmacologic medical therapy is recommended among patients with , , and .
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Pharmacologic medical therapies for  include (either) , , and/or .
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Empiric therapy for  depends on  and .
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Patients with  are treated with , whereas patients with  are treated with .

## Surgery
Surgical intervention is not recommended for the management of .
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Surgery is not the first-line treatment option for patients with . Surgery is usually reserved for patients with either , , and 
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The mainstay of treatment for  is medical therapy. Surgery is usually reserved for patients with either , , and/or .
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The feasibility of surgery depends on the stage of  at diagnosis.
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Surgery is the mainstay of treatment for .

## Primary Prevention
There are no established measures for the primary prevention of .
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There are no available vaccines against .
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Effective measures for the primary prevention of  include , , and .
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 vaccine is recommended for  to prevent . Other primary prevention strategies include , , and .

## Secondary Prevention
There are no established measures for the secondary prevention of .
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Effective measures for the secondary prevention of  include , , and .