Notifications
Clear all

Lymphocyte Abnormalities with Clinical Correlations


ug
Posts: 33
 ug
Admin
Topic starter
(@mr-right)
Reporter
Joined: 4 months ago

 

INTRODUCTION

  • 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

LYMPHOCYTOSIS

  • 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)

 Cytomegalovirus

 Hepatitis

 Varicella

 Mumps

 Adenovirus

 HIV

 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

 Brucellosis

 Secondary and congenital syphilis

 Cat scratch fever

 Typhoid fever

 Diphtheria

  • 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

 Splenectomy

 Dermatitis herpetiformis

 Hyperthyroidism

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

LYMPHOPAENIA

  • 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

 Hypogammaglobulinaemia

  • 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

 Pneumonia

 Septicaemia

 Malaria

 HIV

 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;

 Radiotherapy

 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

 Uraemia

  • Others are;

 Aplastic anaemia

 Systemic lupus erythomatosus

 Myasthaenia gravis

 Graft Versus Host Disease (GVHD)  Pancreatic necrosis

INFECTIOUS MONONUCLEOSIS

  • 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

Symptoms

  • 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

CLINICAL FEATURES

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

BLOOD PICTURES:

  • 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

SEROLOGICAL CHANGES:

  • 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

DIFFERENTIAL DIAGNOSIS OF IM

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

TREATMENT OF IM

  • 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

HIV/AIDS

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

Types

  • 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

Pathogenesis

  • 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

CLINICAL PRESENTATION

  • 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

 Neutropenia

 Thrombocytopenia

 Lymphopaenia

 Hypergammaglobulinaemia

 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:

 Cardiomyopathy

 Arrhythmias

  • SECONDARY INFECTIONS:

 Pneumocystic carini pneumonia

 Chronic cryptosporidiosis

 Disseminated toxoplasmosis

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

  • SECONDARY CANCERS:

 Kaposis sarcoma

 Primary lymphoma of brain

 High grade Non-Hodgkins lymphoma

TREATMENT

  • 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

ANTIRETROVIRAL AGENTS

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

HIV) is the key

  • Nucleoside Reverse Transcriptase Inhibitors (RTI) Zidovudine

 Didanosine

 Zalcitabine

 Lamuvidine

  • Non-nucleoside RTI Efavirenz

 Nevirapine

 Detavirdine

  • Protease inhibitors Saquinavir  Indinavir

 Ritonavir, etc.

  • Integrase inhibitors Elvitegravir

 Dolutegravir

  • 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