Leucocytosis (including neutrophilia and lymphocytosis)

Overview & Assessment in Primary Care

Definition:  White cell count >10.5 x 10⁹/L.

Assessment in primary care: 

Is there a specific lineage of increased white cells. If not, no further assessment is required.

Leucocytosis is most commonly a normal response to systemic illness. In those without an overt reactive cause it may be important to exclude a primary (clonal) haematological diagnosis.

• Is there an obvious reactive cause (infection, inflammation or neoplasia)?
• Is it due to an increase in the lymphocytes, neutrophils, monocytes or a combination? (If lymphocytosis and neutrophilia reactive cause is more likely than a clonal haematological disorder)
• Is the leucocytosis persistent and stable or progressive (and time scale of the latter)?
• Is it isolated or associated with any other cytopenias?
• Smoking commonly causes a mild neutrophilia and/or lymphocytosis.
• Are there symptoms or signs associated with a myeloproliferative or lymphoproliferative condition (especially ask about sweats, fevers, weight loss, itching and examine for spleen and lymph nodes).
• A blood film and CRP are useful initial investigations.

Please see attached flowchart to aid with triage

Neutrophilia

A neutrophilia is a common occurrence and rarely secondary to a haematological disorder. Bacterial infection is the commonest cause (suspected by clinical context, high CRP, myeloid left shift with toxic granulation on the blood film)

Common causes:

• Infection
• Necrosis
• Inflammation
• Ischaemia
• Drugs (corticosteroids)
• Pregnancy
• Smoking
• Myeloproliferative neoplasms (MPN)

 Who to refer:

• New suspected chronic myeloid leukaemia (FBC, film comment) -refer via Haematology - USC (2WW) pathway.
• White cell count >100 x 10⁹/L or hyperviscosity symptoms (headache, breathless, visual loss, thrombosis) -  telephone on call Haematology SpR via swithboard.
• Leucocytosis with leucoerythroblastic blood film - action as advised on report (may be reported in a number of scenarios and the so report should be directive if referral is indicated (which could be urgent or 2ww). In other situations referral may not be indicated, i.e. when there is a cause of the features. 

Urgent referrals are triaged daily and may be upgraded to USC/2WW or booked in adhoc if needed.

Referral to haematology should be considered routinely via eRS for:

• Persistent unexplained white cell count >20 x 10⁹/L
• Persistent unexplained monocytosis >1 x 10⁹/L with cytopenia. Action as advised on report/blood film comment.  Monocytosis may be reactive to inflammation/infection and in that situation does not need referral, so monocytosis also needs to be sustained to consider referral.
• Unexplained neutrophilia >15 x 10⁹/L
• Eosinophilia. If > 1.5 x 10⁹/L sustained for more than 1 month then request A&G or referral.  If 0.5-1.5 sustained for > 2-3 months then request A and G unless clinical findings indicate more urgent assessment is needed (such as features of eosinophilic end-organ damage, no history of travel or residence in helminth-endemic areas, and no features suggesting a malignancy).
• Basophilia - not an isolated indication for referral so only refer if other indications. If uncertainty then use A and G.

Haematological referral is usually not appropriate for:

Evidence of acute or chronic reactive cause of neutrophilia or monocytosis (e.g. elevated CRP). Suggest treating the underlying cause and reassessing the FBC following resolution of the causal illness. In uncertain cases, request a blood film and consider requesting  Haematology Advice & Guidancevia eRS.

For patients not meeting the criteria for referral, consider repeating the FBC in 3 months to assess for progression (or sooner if clinical context changes).

Red  Flags - Associations that may need urgent action:

Neutrophilia with:

• Rapidly increasing WCC
• An unwell patient
• Splenomegaly
• Significant cytopenias (Hb <100, Platelet <100)
• Abnormal blood film

Lymphocytosis

Definition: Lymphocytosis is defined as a lymphocyte count > 4 x 10⁹/l.

Reactive lymphocytes seen on a blood film indicates that the most likely cause is infection, typically viral.

Important points:  A transient, reactive lymphocytosis is frequently seen in acute viral infection, particularly infectious mononucleosis. This may take several weeks to resolve therefore in the absence of other cytopenias or major symptoms the usual approach is to retest in 4-6 weeks.

Flow cytometry can confirm presence of clonal B-cells/chronic lymphocytic leukaemia. If immunophenotyping/ flow cytometry demonstrates a polyclonal lymphocytosis then this indicates a reactive cause.

Chronic lymphocytosis is characteristic of chronic lymphocytic leukaemia (CLL), the incidence of which peaks between 60 and 80 years of age. In its early stages this condition is frequently asymptomatic with treatment only being required on significant progression.

Monoclonal B cell lymphocytosis is a common benign condition with low level clonal B cells with the same phenotype as CLL. It rarely progresses to CLL (1.1% of patients per year) and requires monitoring.

Investigations in primary care for patients with lymphocyte count > 4 x 10⁹/l

• Blood film
• Glandular fever screen
• HIV screen
• Repeat FBC in 4-6 weeks – viral lymphocytoses are frequently transient
• The laboratory may perform flow cytometry if results suggestive of a clonal cause or may advise sending an additional EDTA sample for this purpose in the blood film comment

Management in primary care:

• Lifestyle modification – smoking is a well-recognised cause of reactive lymphocytosis (plus mild neutrophilia). 
• Lymphocyte count <10x10⁹/L and patient asymptomatic, has no lymphadenopathy and no other cytopenias:
  • Community observation with 6 monthly FBC
  • Only send flow cytometry sample if lymphocyte count persistently >10x10⁹/L.
• Lymphocyte count >10x10⁹ persistently over 3 months
  • Send additional EDTA sample for peripheral blood flow cytometry to establish a diagnosis, if not done already
  • If criteria for referral not met - for community monitoring following guidance on flow report comment. Lab will send a letter to GP with advice for vaccination, monitoring and re-referral if diagnosis of MBL or CLL made (see below)

 Who to refer:

• Suspected acute leukaemia - immediate telephone referral via on call Haematology team.
• Any patient with red flags (see below) - Haematology - USC (2WW)  referral
• Rapidly rising lymphocyte count (>20x10⁹/L and doubling in less than 6 months) - Urgent referral via eRS.
• Lymphocytosis in association with:
  • Anaemia (Hb <100), thrombocytopenia (platelet <100) or neutropenia (neutrophils < 1) -  Urgent referral via eRS
  • Significant splenomegaly or rapidly progressive or bulky lymphadenopathy (>5cm) - Haematology - USC (2WW)  referral
  • B symptoms (weight loss >10%, drenching night sweats, unexplained fever) - Haematology - USC (2WW)  referral
  • Autoimmune cytopenias - Urgent referral via eRS.
• Please send additional EDTA sample for peripheral blood flow cytometry, if not already performed, alongside sending urgent referral.

Urgent referrals are triaged daily and may be upgraded to USC/2WW or booked in adhoc if needed.

Referral for specialist opinion is an option for:

• New diagnosis of clonal B cells or CLL with mild anaemia, thrombocytopenia or widespread small lymphadenopathy - Routine referral via eRS.
• Elderly, frail patients -  consider requesting Advice & Guidance Service via eRS first as monitoring in the community may be the most appropriate option.
• Patients not meeting the above criteria, but who would like a more detailed discussion about a new diagnosis of CLL with a haematologist - Routine referral via eRS.

Red Flags

Lymphocytosis in association with:

• B symptoms (weight loss >10%, drenching sweats, unexplained fevers)
• Splenomegaly or progressive lymphadenopathy
• Anaemia, thrombocytopenia or neutropenia

Monoclonal B Lymphocytosis (MBL)

Definition:

Monoclonal B lymphocytosis (MBL) is a benign condition defined as a clonal B-cell population in the peripheral blood with a clonal B lymphocyte count less than 5 X 10⁹/L (not total lymphocyte count, result in flow cytometry report) and no other signs of a lymphoproliferative disorder. The majority of cases of MBL have the immunophenotype of chronic lymphocytic leukaemia (CLL).

The diagnosis is usually suggested when a full blood count sample shows a persistent mild lymphocytosis and flow cytometry is triggered to assess further.

Important points:

Studies indicate that when assessed with standard diagnostic tests the incidence of MBL rises with age from around 4% in the 5^th decade of life to as high as 10% of those over 60 years of age. The majority of individuals with MBL will not develop a haematological malignancy.

Clonal lymphocyte count <0.5x10⁹/L = Low-count MBL

• Very low risk of progression, has no clear clinical implications, and requires no specific clinical follow-up or monitoring bloods

Clonal lymphocyte count 0.5-5x10⁹/L = high-count MBL

• 1.1% per year risk of progression to CLL requiring treatment
• Should have an annual full blood count in community and periodic examination for lymph nodes and hepatosplenomegaly.

Who to refer:

Urgent outpatient assessment:

• Not indicated

Referral for specialist opinion is usually appropriate for:

• Presence of other features that suggest the diagnosis may not be MBL:
  • anaemia, thrombocytopenia or neutropenia
  • splenomegaly or progressive lymphadenopathy
  • B symptoms (weight loss >10%, drenching sweats, unexplained fever)

In a new MBL diagnosis, you will receive guidance in the flow cytometry report comment and receive a letter with instructions for monitoring and referral.

Chronic lymphocytic leukaemia (CLL)

Definition: Chronic lymphocytic leukaemia (CLL) is a lymphoproliferative malignancy with clonal B cells ≥5x10⁹/L. It is the most common leukaemia and the incidence increases with age. It can present with lymphocytosis, B symptoms, lymphadenopathy or cytopenias. Small lymphocytic lymphoma (SLL) is the same disease but with only lymphadenopathy and no peripheral blood lymphocytosis. Many patients never need treatment and can be monitored in the community.

Management in primary care:

• Patients with new diagnosis of CLL will be automatically discussed in the MDT meeting and a letter sent to the GP with advice on monitoring and vaccination.
• Those not meeting referral criteria should be monitored in the community:
  • FBC at 6 monthly intervals and clinically assess as appropriate
• Patients with CLL require further vaccinations due to their immunocompromised state. The following vaccinations are required:
  • Annual Influenza vaccine.
  • Prevenar-13 followed at least 2 months later by Pneumovax-23. Pneumovax-23 should be repeated every 5 years.
  • Additional primary dose of the SARS-CoV-2 vaccine as well as seasonal booster doses. Household members are also recommended to be vaccinated.
  • Shingrix (recombinant varicella zoster) vaccine is available for those between 70-79 years. This is administered as 2 doses given 2 months apart.
• Live vaccinations (such as OPV, MMR, BCG and Yellow Fever) are not recommended in patients with CLL. We recommend patients keep a personal vaccine log and that functional antibody status should be checked 6 weeks post vaccine in those with recurrent infections.
• For patient information and support, see links below

Who to refer?

 Referral for specialist opinion is usually appropriate for:

• Rapidly rising lymphocyte count (>20x10⁹/L and doubling in less than 6 months)
• Lymphocytosis in association with:
  • Anaemia (Hb <100), thrombocytopenia (platelet <100) or neutropenia (neutrophils < 1)
  • Significant splenomegaly or rapidly progressive or bulky lymphadenopathy (>5cm)
  • B symptoms (weight loss >10%, drenching night sweats, unexplained fever)
  • Autoimmune cytopenias 

Referral for specialist opinion is an option for:

• New diagnosis of clonal B cells or CLL with mild anaemia, thrombocytopenia or widespread small lymphadenopathy
• In elderly, frail patients consider discussion via Advice and Guidance first as monitoring in the community may be the most appropriate option
• Patients not meeting the above criteria who would like a more detailed discussion about a new diagnosis of CLL with a haematologist can be considered for referral

Referral

URGENT ADVICE: 9am to 5pm via hospital switchboard for haematology SpR. ONLY for emergency advice. Out of hours and weekends – emergency advice may be obtained from the on-call haematology clinician via hospital switchboard.

NON-URGENT ADVICE: use Haematology Advice and Guidance service 

REFERRAL: via e-RS or Haematology - USC (2WW) as indicated.

Minimal information: the referral letter should include abnormal clinical findings (location, size, any associated features) and any abnormal full blood count results or other relevant test results, particularly if these investigations were not done in laboratories of the hospital to which the referral is made.

Resources

• GP information/education:
  • GP-GUIDE-FINAL-AMEND-1.pdf (cllsupport.org.uk)
• Patient support/information:
  • About CLL/SLL/MBL - CLL Support Association
  • Chronic Lymphocytic Leukaemia (CLL) | Leukaemia Care

• SWAG guidance:
  • Lymphocytosis (swagcanceralliance.nhs.uk)

• Monoclonal B-cell lymphocytosis (MBL): biology, natural history and clinical management. T D Shanafelt , P Ghia, M C Lanasa, O Landgren & A C Rawstron. Leukemia volume 24, pages 512–520 (2010).
•  Monoclonal B-cell lymphocytosis and early-stage chronic lymphocytic leukemia: diagnosis, natural history, and risk stratification. Paolo Strati and Tait D. Shanafelt. Blood  2015  126:454-462.

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