Lymphocytopenia

Introduction

Lymphocytopenia (also known as lymphopenia) refers to a low absolute lymphocyte count (ALC).¹
Lymphocytopenia can occur in normal physiological conditions or be associated with abnormal pathogenic status such as autoimmune diseases.
Lymphocytopenia occurs as part of the stress response, and is therefore:
- Common in acutely ill patients.
- Reversible once the acute illness resolves.
Lymphocytopenia is a relatively common finding in everyday practice. Its causes and significance, however, are poorly understood.

Definitions

Normal values for absolute lymphocyte count (ALC) 1-4 x 10⁹/L (1,000 – 4,000/microL), but may vary in different laboratories.²
Lymphocytopenia:
- Refers to a decrease of peripheral blood lymphocytes, which generally corresponds to an ALC < 1.0 x 10⁹/L (<1000/microL) in adults.
- Reflects primarily a reduction in T cell counts (usually CD4+ cells).

Epidemiology

Lymphocytopenia reported prevalence 1.5-3% of complete blood count samples from both community and hospitalized patients.³
Transient CD4 lymphocytopenia estimated to occur in healthy HIV-negative individuals within a 95% confidence interval from 0.4–4.1% at any given time.⁴
Lymphocytopenia (ALC < 1.0 x 10⁹/L) reported in 61% of 753 patients admitted to ICU for at least 3 days with a shock or persistent low blood pressure.⁵

Pathogenesis

Lymphocytes are white blood cells involved in the immune response.
Most of the peripheral lymphocytes are T lymphocytes (60%-80%); remainder are B lymphocytes (8%-15%) and natural killer cells.
Absolute numbers and proportions of lymphocytes are relatively stable in normal conditions.
Most lymphocytopenias result from a reduction in T cell numbers.
Lymphocytopenia may result from:
- Reduced lymphocyte production, for example secondary to:
  - Malnutrition
  - Primary immunodeficiencies
- Increased lymphocyte destruction, for example secondary to:
  - HIV
  - Autoimmune disease such as systemic lupus erythematosus and dermatomyositis
  - Radiation therapy
- Increased lymphocyte apoptosis, e.g., secondary to sepsis
- Altered distribution of lymphocytes between the blood and different lymphoid tissues, for example secondary to:
  - Glucocorticoids
  - Tuberculosis
  - Influenza
  - Sarcoidosis

Causes

- Since the reference interval for the lymphocyte count covers the central 95% of values in a healthy population, 2.5% of normal individuals will have values below the reference interval.
- Primary:
  - Uncommon monogenic disorders, including a wide range of primary immunodeficiency diseases, such as:
    - Severe combined immunodeficiency
    - Common variable immune deficiency
    - Omenn syndrome (OS)
    - Wiskott–Aldrich syndrome (WAS)
    - DiGeorge syndrome
  - Characterized by recurrent, severe or unusual infections, failure to thrive in children, and sometimes autoimmune and inflammatory complications.
- Secondary:
  - Lymphocytopenia is a common finding during the systemic inflammatory response:
    - In a cohort of 1042 hospital patients with ALC <0.6×10⁹/L:
      - Causes included:
        
        Bacterial or fungal sepsis (24%)
        
        Recent surgery (22%)
        
        Malignancy (17%)
        
        Corticosteroid treatment (15%)
      - A low count persisted beyond six months in only 6% of subsequent analyses.
    - In a cohort of 21,331 consecutive adult emergency admissions to general medical or infectious disease wards
      - Neutrophilia and Lymphocytopenia were both associated with bacteremia.
      - Lymphocytopenia was the better predictor in this cohort.
      - Both neutrophilia and Lymphocytopenia were more predictive of bacteremia than the total white blood cell count.
  - Infection:
    - Lymphocytopenia mostly transient and therefore probably ‘physiologic’ responses to an alteration of the cytokine and inflammatory environment.
    - Viral illnesses:
      - HIV
      - Influenza
        
        68% of adult patients and 92% of pediatric patients had reduced lymphocyte counts during the 2009 influenza A pandemic.⁶
      - Coronaviruses (eg, SARS, SARS-CoV-2)⁷
        
        Significant Lymphocytopenia more common in severe cases.
        
        Association reported between lymphocytopenia and:
        
        Acute respiratory distress syndrome
        
        Need of ICU care
        
        Lymphocytopenia may be caused by:
        
        Direct infection of cells, leading to their lysis
        
        Cytokine induced lymphocyte apoptosis
        
        Suppressed lymphocyte proliferation
      - Hepatitis
      - Measles
      - Epstein–Barr virus
      - Cytomegalovirus
    - Bacterial (including tuberculosis)
    - Parasitic (including malaria)
    - Fungal (including histoplasmosis)
  - Medication: ⁸
    - Lymphocytopenia is a common adverse event in patients receiving drugs used to treat malignancies and autoimmune diseases.
    - Most cytotoxic drugs affect all lymphocytes; but percentage of CD4 T cell reduction is usually greater and relative increase in CD8 T cells is often observed.
    - Monoclonal antibodies that target specific cell-type-specific markers induce removal of target lymphocytes from circulation.
    - Agents that cause lymphocytopenia include:
      - Immunosuppressive agents such as:
        
        Corticosteroids
        
        Methotrexate
        
        Azathioprine
        
        Cyclophosphamide
      - Monoclonal antibody therapies such as:
        
        Rituximab
        
        CAMPATH-1H
        
        Muromonab
      - Purine nucleoside analogs such as:
        
        Fludarabine
        
        Cladribine
      - Other medications:
        
        Paclitaxel
        
        Cimetidine
        
        Opioids
        
        Carbamazepine
        
        Bisphosphonates
        
        Imidazole
        
        Calcitonin
        
        Ipriflavone
        
        Linomide
  - Systemic disorders:⁹
    - Autoimmune diseases ¹⁰
      - Systemic lupus erythematosus (SLE):
        
        Lymphocytopenia is part of the ACR and SLICC criteria for SLE.¹¹
        
        Lymphocytopenia is the most common WBC abnormality among patients with SLE.
        
        Lymphocytopenia (lymphocyte count < 1.5 × 10⁹/L on ≥ 2 occasions) in 15%-82% of patients with SLE in systematic review of 9 studies.¹²
        
        Lymphocyte count <0.5×109 /L observed in 10% of patients
        
        Lymphocytopenia occurs independently of neutropenia but may also contribute to the leukopenia seen in these patients.
        
        Lymphocytopenia observed frequently in patients with active or severe disease.
        
        Lymphocyte levels may fluctuate during the clinical course, irrespective of treatment; development of lymphocytopenia during the course of disease is frequently associated with disease relapse and is a predictors of flares.
        
        Glucocorticoids and immunosuppressive drugs may contribute to the Lymphocytopenia in severe disease.
        
        Both T and B lymphocyte subpopulations may be affected, though T cell numbers are affected more than B cells. The null lymphocyte subpopulation is frequently spared.
        
        In particular, the CD4+ subset of T cells is more profoundly affected, although the CD4/CD8 ratio is usually unchanged.
        
        Pathogenesis of lymphocytopenia is still unclear; may include:
        
        Antilymphocyte antibodies
        
        Apoptosis may also play a role
        
        Complement activation
        
        Presence of lymphocytopenia may be clinically silent or be associated with increased risk of infections and/or active SLE.
        
        Lymphocytopenia has also been demonstrated in patients with SLE who developed P. jiroveci when compared with age-matched systemic lupus erythematosus controls.¹³
        
        Use of prophylaxis against P. jiroveci should be considered in patients with lymphocyte counts ≤0.35×10⁹/L.
      - Rheumatoid arthritis (RA)
        
        Lymphocytopenia is a common finding during follow-up of patients with RA and is generally ascribed to the medications used to treat the disease (glucocorticoids, disease-modifying antirheumatic drugs [DMARDs], and biotherapies).
        
        In a British cohort, among 66 RA patients:
        
        10 (15%) had persistent lymphocytopenia after 1 year in the absence of Felty’s
        syndrome or drugs known to decrease lymphocyte counts
        
        Lymphocytopenia was associated with rheumatoid factor (RF) positivity and
        emerged as a possible marker for severe disease
      - Sjogren’s syndrome
        
        A study of 214 patients with primary Sjogren’s syndrome detected CD4 lymphocytopenia below 0.3×10⁹/L in eight patients (3.7%).¹⁴
        
        Serious opportunistic infections are rare in patients with Sjogren’s syndrome and CD4 lymphocytopenia.
      - In a ESPOIR cohort of recent-onset arthritis of 813 patients:
        
        The baseline prevalence of lymphocytopenia (<1.0×10⁹/L) was 6.2%.
        
        The diagnoses considered most likely by the rheumatologists after 3 years in the 50 patients with baseline lymphocytopenia were:
        
        RA in 54.0%
        
        Unclassified arthritis in 30.0%
        
        SLE 6.0%
        
        Spondyloarthritis in 4.0%
        
        Sjögren’s syndrome in 2.0%
    - Inflammatory bowel disease (IBD):
      - Many medications used in treating IBD, especially steroids, cause lymphocytopenia.
      - 30% of patients with Crohn’s disease admitted for intestinal resections have severe peripheral lymphocytopenia (lymphocyte counts <1.0×10⁹/L), which may be related to disease activity and duration as well as treatment side effects.¹⁷
      - lymphocytopenia and CD4, CD8, and CD19 lymphocyte subsets have been proposed as
        markers of more severe sarcoidosis, and patients with lymphocytopenia with sarcoidosis may be particularly responsive to anti–TNF-a treatment ¹⁸
    - Malignancy:
      - Previously published studies have shown that lymphocytopenia is frequently observed in patients with advanced cancers and is a powerful predictor of chemotherapy-induced toxicity.
      - Lymphocytopenia is an independent prognostic factor for overall and progression-free survival in several cancers.¹⁹
      - Lymphocytopenia may occur in:
        
        Lymphoproliferative disorders:
        
        Non-Hodgkin’s lymphoma
        
        Large cell lymphoma
        
        Mucosa associated lymphatic tissue (MALT)
        
        Burkitt’s lymphoma
        
        Mycosis fungoides
        
        Solid organ malignancies, including:²⁰
        
        Sarcomas
        
        Breast cancer
        
        Pancreatic cancer
  - Other conditions:
    - Severe malnutrition protein-energy undernutrition
    - Alcohol abuse
    - Radiotherapy
    - Recent surgery
- Idiopathic lymphocytopenia:²¹
  - Initially described in 1992.
  - Was originally portrayed as “AIDS without HIV” on the basis of the presence of similar presenting opportunistic infections and a low CD4+ T-cell count but a negative HIV test.
  - Mainly caused by CD4+ lymphocyte deficiency, possibly from diminished generation of T cell precursors.
  - Defined as a CD4 count of less than 0.3 x 10⁹/L measured at least twice 6 weeks apart in the absence of any disease or therapy that may be associated with lymphocytopenia.
  - The most important differential diagnosis of low CD4 lymphocytopenia is HIV infection.
  - Associated with increased susceptibility to viral, encapsulated fungal, and mycobacterial diseases, as well as with a reduced response to novel antigens and an increased risk of cancer.²²

Clinical Presentation

Lymphocytopenia usually found incidentally in an otherwise healthy individual during routine blood count.
May occur in the context of an acutely ill patient in the hospital or in an outpatient with an underlying disease or medication associated with lymphocytopenia.
Questions to ask on history:
- Does the patient have a history of a recent (within the past six months) infection, especially viral?
- Is the patient taking any medication that may cause lymphocytopenia (such as immunosuppressive agents, chemotherapy)?
- Does the patient have symptoms or history of underlying systemic disorder associated with lymphocytopenia, including autoimmune/connective tissue disease, malignancy, renal or cardiac failure, or sarcoidosis?
- Is the patient malnourished or a heavy drinker?
- Is there a history of failure to thrive or infections that may suggest underlying immune deficiency (such as pneumocystis, severe warts, long history of recurrent infections)?
- What is the severity and duration of lymphocytopenia?

Diagnosis

Repeat complete blood count (CBC) and WBC differential to confirm lymphocytopenia.
Examine peripheral blood smear.
Renal function tests
Liver function tests
HIV test in patients with high risk activities or those with chronic severe unexplained lymphocytopenia.
Antinuclear antibody screen and rheumatoid factor test in patients with possible connective tissue disorder.
Serum immunoglobulin assessment – in patients with primary immunodeficiency, global decrease in immunoglobulins (hypogammaglobulinemia) or reduction in specific immunoglobulin isotypes (for example, IgG, IgA, and IgM) may be observed.
According to UpToDate: “When the underlying diagnosis is not obvious from the initial evaluation and review of medications, we assess HIV status and measure lymphocyte subpopulations (eg, CD4 count) and immunoglobulin levels.”
Additional testing for suspected primary immunodeficiency:
- Immunoglobulin levels and leukocyte and lymphocyte subpopulations.
- Screening tests for humoral immunity dysfunction include:
  - serum immunoglobulin measurements
  - serum specific antibody titers
  - antibody response to booster immunization
  - total B cell count
- Screening tests for cellular immunity dysfunction include:
  - T cell receptor excision circle (TREC) assay
  - CD8 and CD4 T cell and natural killer cell counts
  - cutaneous delayed hypersensitivity
  - spontaneous natural killer cytotoxicity

Treatment

Treat the underlying condition.
If the patient has an immunodeficiency syndrome associated with hypogammaglobulinemia, immunoglobulin replacement therapy may be administered.
According to UpToDate: “we generally do not intervene for patients with asymptomatic lymphocytopenia without an associated illness.”

Prognosis

Most cases of lymphocytopenia in acutely ill patient (e.g., associated with acute illness, notably sepsis and trauma) are transient/reversible.
While association between neutropenia and increase in risk of infection is well established, it is unclear if incidental lymphocytopenia results in increased risk of infection in the general population:
- One study found a 2.4-fold increased risk of urinary tract infection and lower respiratory tract infection among 156 long-term facility care residents with lymphocytopenia.²³
- 2 studies with 167 and 91 participants found that lymphocytopenia in patients with systemic autoimmune diseases was associated with a 5.2- and 4.7-fold increased risk of infection, respectively.²⁴
- A study examining of 753 patients in intensive care units found that lymphocytopenia:²⁵
  - At admittance was
    - Associated with a 1.6-fold increased risk of infection
    - Not associated with 28-day mortality. However
  - That persisted at day 3 was associated with:
    - 1.4-fold increased risk of infection
    - 1.7-fold increased risk of 28-day mortality.
- Cohort of 98,344 individuals from the from the general population (Copenhagen General Population Study):
  - Lymphocytopenia was defined as a lymphocyte count below the 2.5th percentile of the population distribution (<1.1 × 10⁹/l).
  - Median of 6 years of follow-up.
  - Lymphocytopenia present in 2,352 of the 98,344 (2.4%).
  - Lymphocytopenia was associated with increased risk of hospitalization due to any infection, pneumonia, skin infection, urinary tract infection, sepsis, diarrheal disease, endocarditis, and other infections after adjusting for potential explanatory factors including blood neutrophil count.
  - Multivariable-adjusted hazard ratios of 1.41 for any infection.
  - Lymphocytopenia was also associated with a 1.7-fold increased risk of infection-related death.
  - Study did not address questions of causality.
It is generally believed that chronic severe lymphocytopenia (lymphocyte count < 0.5 × 10⁹/L), especially those with CD4 T-lymphocytopenia, regardless of the etiology, may itself increase risk of opportunistic infections such as pneumocystis pneumonia, esophageal candidiasis, herpes zoster, and systemic cytomegalovirus.
The clinical consequences of CD8+ lymphocytopenia are less well documented.

Cases

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