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Leucopenia

Principles

  • The majority of white blood cells are either neutrophils (band cells and polymorphonuclear neutrophilic granulocytes, 35-70%) or lymphocytes (20-45%). The share of other white blood cells, eosinophils and basophils (granulocytes) and monocytes, is clearly lower.
  • Leucopenia is almost always caused by a reduced number of neutrophils.
  • Lymphocytopenia is only seldom associated with a specific disease. It may be seen in acute or chronic infections caused by a variety of microbes as well as both in congenital and acquired immune deficiency states.

Reference values

  • Leucopenia: white blood cells < 3.4 × 109 /l
  • Lymphocytopenia: blood lymphocytes < 1.2 × 109 /l
  • Neutropenia: blood neutrophils < 1.5-2.0 × 109 /l
  • Degree of neutropenia:
    • mild: neutrophils 1.0-1.5 × 109 /l
    • moderate: neutrophils 0.5-1.0 × 109 /l
    • severe: neutrophils < 0.5 × 109 /l
  • Agranulocytosis: a syndrome characterised by an unexpected, drug-induced severe neutropenia (< 0.2 × 109 /l) and associated infection. The term is not usually used as a synonym for severe neutropenia.
  • In some ethnic groups, such as those of African descent, neutropenia classified as mild to moderate occurs as a normal variant in healthy individuals.

Leucocytopenia and susceptibility to infections Colony Stimulating Factors for Chemotherapy Induced Febrile Neutropenia, Imipenem-Cilastatin for Febrile Neutropenic Patients, Antibiotic Prophylaxis for Neutropenic Patients, Oral Versus Intravenous Antibiotic Treatment for Febrile Neutropenia in Cancer Patients

  • A decreased number of B-lymphocytes predisposes the patient to bacterial infections whereas a decreased number of T-lymphocytes predisposes the patient to infections caused by viruses, certain bacteria, (mycobacteria, salmonella, listeria), fungi (candida, aspergillus) and parasites (toxoplasma). In HIV infection, the helper T cells count (CD4) is monitored and used as an indicator of the patient's susceptibility to infections.
  • Neutropenia predisposes the patient to bacterial infections. The susceptibility to infections is dependent on, for example,
    • the degree of neutropenia
      • neutrophils 1.0-1.5 × 109 /l: slightly increased risk of infection
      • neutrophils < 0.5 × 109 /l: significant risk of infection
    • whether the patient has co-existing conditions that increase the risk of infection, such as
      • immunosuppressive illness and/or medication
      • poorly functioning bone marrow
      • skin and/or mucous membrane ulcers.
  • The bacterial infections in a neutropenic patient may vary from mild oral (ulceration) and upper respiratory tract infections to life-threatening septic infections.
  • No purulent discharge will form in the absence of neutrophils. The diagnosis and localisation of an infection may therefore prove difficult in a neutropenic patient. In neutropenia, an infection will spread quickly throughout the body.
  • Bacterial infections associated with severe neutropenia should be treated with broad spectrum antimicrobial drugs, which must be started without delay as soon as blood cultures, and any other bacterial culture samples, have been collected. The use of granulocyte stimulating factors may be indicated.
  • See also article Infections in immunosuppressed and cancer patients Infections in Immunosuppressed and Cancer Patients.

Aetiology of leucocytopenia

Lymphocytopenia

  • In acute viral, bacterial and fungal infections, both lymphocytosis and lymphocytopenia can occur in a varying manner.
  • Lymphocytopenia may also be present in autoimmune diseases, allergies, chronic infections (tuberculosis, histoplasmosis, brucellosis), protein malnutrition, in association with malignancies as well as in congenital immune deficiency states.
  • Lymphocytopenia may also be associated with some medications, e.g.
    • glucocorticoids
    • antirheumatic drugs (TNF drugs, azathioprine, methotrexate).
    • many cancer drugs.

Drug-induced neutropenia

  • In adults, drugs are the most common cause of acute onset neutropenia which is usually mild and does not cause symptoms.
  • Cancer drugs and some immunosuppressive drugs will consistently cause neutropenia in all users.
  • Some drugs will cause neutropenia only occasionally in a small proportion of users (idiosyncratic neutropenia).
  • Agranulocytosis is a life-threatening drug-induced complication, and its relative risk is high during the use of clozapine Clozapine Therapy, antithyroid drugs, metamizole and sulfasalazine (may also be associated with other drugs). This is why some medicines may require blood count monitoring, and in the case of severe or moderate neutropenia, these medicines must be immediately discontinued.
  • A patient must never be administered a drug that has caused him/her agranulocytosis or severe idiosyncratic neutropenia in the past.
  • If a patient is taking several medicines, it can be difficult to know which, if any, of the medicines is causing neutropenia. If the patient is asymptomatic and only mild neutropenia is seen as a blood count abnormality, monitoring blood counts can be a valid option.

Neutropenia associated with infections

  • In addition to drugs, infections are one of the most common causes of acute neutropenia.
  • Many viruses are able to attenuate the production of neutrophils. In some cases, neutropenia continues for several weeks after the patient has recovered from the viral infection itself.
  • Bacterial infections usually cause neutrophilia rather than depress the cell production in the bone marrow. E.g. tularaemia and mycobacterial infections form an exception as the infection may involve the bone marrow itself. In severe infections, the neutrophil consumption by the tissues is usually not sufficient to cause neutropenia because a healthy bone marrow is able to increase its neutrophil production manifold. If the bone marrow functioning is impaired (e.g. blood disease, after cytotoxic treatment, alcoholism), neutropenia will occur much more readily during infections.
  • Some chronic infections (tuberculosis, typhoid fever, brucellosis, malaria) cause splenomegaly, and consequent hypersplenism may cause neutropenia.

Immunologic neutropenia

  • Alloimmune neonatal neutropenia is caused by antibodies, produced by the mother, passing through the placenta.
  • In autoimmune neutropenia, neutrophils are destroyed because the body inappropriately develops antibodies to its own neutrophils and also possibly to their precursor cells. Even at its worst, the neutropenia will only be moderate. If there is no other immune system disorder and the bone marrow function is good, the susceptibility to infections is usually relatively low in relation to the degree of neutropenia.
  • In certain autoimmune diseases, e.g. in systemic lupus erythematosus and rheumatoid arthritis, neutropenia is fairly common.

Neutropenia as a feature in haematological diseases

Abnormal distribution of neutrophils in the circulatory system

  • Half of the neutrophils in the blood are loosely bound to the blood vessel walls (margination), and they are quickly released to the circulating neutrophil pool during stressful situations. In some healthy individuals, the proportion of the marginated neutrophil pool is significantly higher than normal, leading to nominal neutropenia, i.e. pseudoneutropenia, where the risk of infection is not increased.
  • Splenomegaly of any aetiology may cause hypersplenism and associated anaemia, thrombocytopenia and/or neutropenia. In systemic lupus erythematosus, even a normal sized spleen may be overactive.

Chronic idiopathic neutropenia

  • Acquired, significant neutropenia without any obvious demonstrable cause is sometimes encountered in healthy individuals (exclusion diagnosis). The condition is not associated with an increased risk of infection and does not signify the onset of any other disease process.

Congenital and hereditary neutropenia

  • Congenital neutropenias are a group of rare diseases caused by bone marrow dysfunction, usually diagnosed due to infections in early childhood and their possible syndromic features.
  • The clinical picture of cyclic neutropenia can be so mild in single patients that the diagnosis may sometimes be made only in adulthood, as the disease is not associated with disorders of other organ systems.In it, symptomatic neutropenia (i.e. infections, oral mucosal ulcers) occurs at regular intervals, usually about every three weeks, lasting a few days at a time.

Investigations in neutropenia

  • The urgency of the investigations is dependent on the patient's symptoms, the degree of neutropenia, and whether there are, based on the blood count, possibly grounds to suspect a malignant blood disease.
  • A neutropenic patient's fever is always interpreted as a sign of infection until proven otherwise. In moderate and severe neutropenia, a febrile patient should be admitted to hospital, where an emergency assessment is initiated and broad-spectrum empirical antimicrobial therapy is started.
  • If the patient presents with severe neutropenia with an acute onset, the patient is admitted to hospital investigations as an emergency case. The aetiology may include drug-induced agranulocytosis or an undiagnosed blood disease.
    • Blast cells seen in the differential white blood cell count suggest acute leukaemia.The total leucocyte count may be low, normal or high, and the patient usually has anaemia and thrombocytopenia.
  • If the neutropenia is mild or moderate, the differential white blood cell count is normal and the patient has no anaemia and/or thrombocytopenia, the situation can usually be investigated and followed up in primary health care. If the condition becomes protracted, it can be assessed in specialized care on a non-urgent schedule.
    • In most cases, the neutropenia is caused by a medicine taken by the patient or a viral infection.
    • Neutropenia may also be associated with an underlying disease, e.g. systemic lupus erythematosus or rheumatoid arthritis, or an enlargedoveractive spleen.
  • It is important to establish whether neutropenia is a new, acquired finding or whether it has been present for a long time. It is important to check old laboratory reports and take a careful history.
    • A true, clinically significant neutropenia will cause recurrent infections and, in some patients, ulceration in the buccal mucosa.
    • In some ethnic populations and individual families, the neutrophil counts of completely healthy individuals may be lower than normal.

    References

    • Curtis BR. Non-chemotherapy drug-induced neutropenia: key points to manage the challenges. Hematology Am Soc Hematol Educ Program 2017;2017(1):187-193 [PubMed]
    • Gazitt T, Loughran TP Jr. Chronic neutropenia in LGL leukemia and rheumatoid arthritis. Hematology Am Soc Hematol Educ Program 2017;2017(1):181-186 [PubMed]
    • Newburger PE. Autoimmune and other acquired neutropenias. Hematology Am Soc Hematol Educ Program 2016;2016(1):38-42 [PubMed]
    • Gea-Banacloche J. Evidence-based approach to treatment of febrile neutropenia in hematologic malignancies. Hematology Am Soc Hematol Educ Program 2013;2013():414-22[PubMed]
    • Boxer LA. How to approach neutropenia. Hematology Am Soc Hematol Educ Program 2012;2012:174-82 [PubMed]