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Lymphocyte Abnormalities with Clinical Correlations

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  • Lymphocyte abnormalities are as common as that of other cellular components of the blood
  • Abnormalities could be;
    • Quantitative
    • Qualitative
  • It could also be; ü Benign
    • Malignant

Quantitative Abnormalities

  • Most common
  • Defined as reduced or raised total lymphocytes count
  • It is lymphocytosis when the count is raised and lymphopaenia when the count is reduced
  • Lymphocytes constitute about 20-40% of the total WBC count of 4-11 × 109/L (whites) or 2.5-10 × 109/L (blacks)
  • Absolute lymphocyte count is 1.5-3.5 × 109/L Qualitative Abnormalities
  • Very rare
  • Defined as morphological disorders that affect the functions of lymphocytes  Commonly present as primary lymphopaenia


  • Defined as count above 3.5 × 109/L
  • Often occurs in infant and young children in response to infections that produce neutrophil reactions in adults
  • Causes could be broadly divided into 2;
    • Non malignant
    • Malignant

Non Malignant Causes

  • Usually result in mild (3.5-10 × 109/L) to moderate (10-50 × 109/L) lymphocytosis
    • Viral infections

 Infectious mononucleosis (IM)







 Others are chicken pox, Herpes simplex, etc.

  • Bacteria

 Pertussis (Whooping cough) – lymphocytosis is seen in the 2nd to 3rd = week of infections in children over the age of 6 months

 Healing TB


 Secondary and congenital syphilis

 Cat scratch fever

 Typhoid fever


  • Protozoal infections Toxoplasmosis

 Malaria (occasionally)

  • Others are;

 Serum sickness – a type III or immune complexes mediated hypersensitivity reaction where immune system reacts to medicine that

contains proteins used to treat immune conditions

 Allergic drug reactions


 Dermatitis herpetiformis


Malignant Causes

  • These result into moderate (10-50 × 109/L) to severe (>50 × 109/L) lymphocytosis

 Acute lymphoblastic leukaemia

 Chronic lymphocytic leukaemia

 Hodgkin’s lymphoma

 Non-Hodgkin’s lymphoma

 Multiple myeloma

 Hairy cell leukaemia

 Metastatic melanoma


  • Defined as absolute lymphocyte count below 1.5 × 109/L
  • Could also be mild, moderate or severe ü MILD:0-1.5 × 109/L
    • MODERATE:5-1.0 × 109/L
    • SEVERE: <0.5 × 109/L
  • Causes could be primary or secondary

Primary Lymphopaenia

  • Most of the primary causes are qualitative (inherited) abnormalities
  • They almost always present with reduced counts
  • They are primary immunodeficiencies including; ü B cells (antibody deficiency); X-linked agammaglobulinaemia

 Congenital hypogammaglobulinaemia

 Acquired common variable

 Selective IgA or IgG subclass deficiency


  • T cells

 Thymic aplasia (DiGeorge syndrome)

 Purine Nucleoside Phosphorylase (PNP) deficiency

 Lymphocyte-function-associated antigen deficiency

  • Mixed B and T cells

 Severe combined immunodeficiency

 Bloom’s syndrome

 Ataxia telangiectasia

 Wiskott-Aldrich syndrome

Secondary Lymphopaenia

  • More common than primary ones. Causes are;
    • Infections; Influenza





 Colorado thick fever and

 Viruses (occasionally)

  • Loss of lymphocytes as in; Intestinal lymphagiectasia

 Whipple’s disease

 Severe right sided heart failure

 Lymphatic fistula

  • Therapeutic procedures like;


 Use of anti-lymphocyte globulin

 Use of corticosteroids

 Use of cytotoxic drugs

  • Neoplasms;

 Metastatic cancers to bone marrow, e.g. breast cancer, prostate cancer

 Advanced Hodgkin’s lymphoma (lymphocyte depleted)

  • Nutritional/Metabolic;

 Vitamin B12 and folate deficiency

 Zinc deficiency


  • Others are;

 Aplastic anaemia

 Systemic lupus erythomatosus

 Myasthaenia gravis

 Graft Versus Host Disease (GVHD)  Pancreatic necrosis


  • Benign lymphocytosis Aetiology
  • Caused by Epstein-Barr virus (EBV)
  • EBV infects B lymphocytes
  • It enters B lymphocytes through a receptor called CD21
  • Infections in children usually results in immunity without developing clinical manifestations of the diseases
  • Infection with EBV is associated with clinical manifestations usually only after the age of 10 years
  • The diseases has its highest prevalence in young adults between 10-30 years of age
  • Very rare after the age of 40 years


  • It has an incubation period of about 7-10 weeks
  • Symptoms usually start abruptly with;
    • Fatigue
    • Malaise[1]
    • Feverishness
    • Sore throat; and
    • Anorexia
  • These symptoms usually last for about 3 weeks


Range from:

  • Bilateral non-inflammatory cervical lymphadenopathy in 75% of patients
  • Splenomegaly in 50% of patients
  • Sore throat in 50% of patients
  • Secondary lymphoid organs enlargement
  • Hepatomegaly in 10% of patients
  • Jaundice
  • Morbilliform rash
  • Severe headache
  • Eye signs (photophobia, conjunctivitis)
  • Peripheral neuropathy
  • Severe anaemia from autoimmune haemolysis


  • Leukocytosis above 10-20 × 109/L occurs in the 2nd and 3rd week
    • This is due to absolute increase in the total numbers of small B lymphocytes and of activated T cells
    • Most of the activated T-cells are CD8+ Cytotoxic T cells and occasionally CD4+ and NK cells
  • Eosinophilia and thrombocytopenia can also occur


  • 3 types of antibodies are produced in IM;
    • Virus specific
    • Heterophile
    • Auto

Virus Specific Antibodies

  • IgM anti-viral capsid antigens (VCA) antibodies are developed during the incubation period
  • IgG anti-VCA antibodies developed in the 2nd week
  • Anti-Nuclear Antibodies (ANA)–antibodies to EBV nuclear antigens–also develop

Heterophile Antibodies

  • Heterophile means reacting with cells of another species
  • Agglutinins directed against sheep red cells are produced
  • However, agglutinins produced in IM exclusively agglutinate horse red cells
  • This forms the bases for Paul Bunnel Monospot Test for IM
  • Serum titre of anti-horse red cell agglutinins of 1 in 112 (1:112) is highly suggestive of the disease
  • Heterophile antibodies provide a routine serological test for IM but are commonly negative especially in children and patients above 25 years Auto Antibodies
  • There is a raised total serum immunoglobulins
  • These autoantibodies include;
    • Cold reactive anti-I antibodies
    • Donath-Landsteiner cold haemolysins
    • Rheumatoid factors ü Anti-nuclear antibodies


  • They are other non-malignant causes of lymphocytosis
  • Here, heterophile antibodies are usually negative


  • No specific treatment
  • Treatment is symptomatic
  • Steroids are used to treat the associated haemolytic anaemia, thrombocytopaenia and neurological complications
  • Patients characteristically develop an erythematous rash if given ampicillin therapy
  • Most patients recover fully 4-6 weeks after initial symptoms


  • Human Immunodeficiency Virus (HIV) infection is one of the common causes of secondary lymphopaenia


  • There are 2 types of HIV
    • HIV I (commonest and the more extensively studied) ü HIV II
  • Both belong to the family called Retroviridae and sub-family Lentivirinae HIV I Genes
  • HIV I contains 3 major genes;
    • Gag – codes for the core proteins
    • Pol – codes for reverse transcriptase, integrase and protease (Mnemonic – RIP) ü Env – codes for envelop proteins
  • These are proteins needed to assemble and reassemble a complete viral particle


  • HIV binds to CD4 antigen on CD4+ T lymphocytes through its gp120 receptor
  • CD4+ T lymphocytes are the primary targets of HIV
  • Interactions between CD4 and HIV envelop proteins mediate syncytia formation
  • These are multinucleate collections of fused infected and uninfected cells
  • Other cells can also harbor HIV, e.g. monocytes/macrophages and platelets, but mechanism of entry is poorly understood
  • HIV genome gets incorporated into the host cell genome and codes for 3 different proteins that helps the virus for further morphogenesis and maturation;
    • Reverse transcriptase
    • Integrase, and
    • Protease

[Mnemonic – RIP]

  • At the early stage of infection, body immune system tries to eradicate the virally infected cells by recruiting other cells of immune system;
    • B cells
    • CD8+ Cytotoxic T cells
    • NK cells
  • At this stage, there is lymphocytosis
  • But because of persistence of infection as a result of continuous morphogenesis and maturation of the virus, the immune system is overwhelmed and there is mild, moderate and eventually, severe lymphopaenia
  • At this stage, secondary infections, viral, bacterial, protozoan, both common and opportunistic, set in


  • HIV infection results in a spectrum of diseases ranging from asymptomatic to severe immunodeficiencies
  • Window period[2] and incubation period[3] varies widely, ranging from weeks, months or years
  • Constitutional symptoms predominate early after the incubation period:
    • Unexplained diarrhea
    • Fever
    • Night sweat
    • Weight loss
    • Generalized lymphadenopathy
    • Hepatosplenomegally
    • Failure to thrive and developmental delay in children  Almost all systems in the body are affected: ü Haematology: Anaemia





 Decrease in CD4:CD8 ratio (normal is 0.9-3.7 in adults)

  • CNS:

 Impaired brain growth

 Progressive systemic motor defects (paresis, abnormal tone, ataxia, gait imbalance)

  • CVS:




 Pneumocystic carini pneumonia

 Chronic cryptosporidiosis

 Disseminated toxoplasmosis

 Herpes Zoster (Shingles), a reactivation of previous infection with Herpes varicella-zoster virus


 Kaposis sarcoma

 Primary lymphoma of brain

 High grade Non-Hodgkins lymphoma


  • Broadly divided into:
    • Use of antiretroviral agents (ART)
    • Prophylaxis/treatment of opportunistic infections
    • Treatment of other pathologies e.g. surgical removal/cytotoxic chemotherapy for malignancies


  • Pharmacological attack on HIV reverse transcriptase (the dominant unique feature of

HIV) is the key

  • Nucleoside Reverse Transcriptase Inhibitors (RTI) Zidovudine




  • Non-nucleoside RTI Efavirenz



  • Protease inhibitors Saquinavir  Indinavir

 Ritonavir, etc.

  • Integrase inhibitors Elvitegravir


  • Chemokine receptor antagonists Meraviroc
  • Fusion inhibitors – Cloned CD4 molecules to compete with CD4 receptors on T cells and thereby inactivate viral particles Enfuvirtide (Fuzeon)
  • Treatment now involves the use of these drugs in combinations


[1] Malaise – a vague feeling of  being unwell

[2] The time elapsed between exposure to a pathogenic organism and the appearance of antibodies

[3] The time elapsed between exposure to a pathogenic organism and the appearance of signs and symptoms