LEUKOCYTE DISORDERS

Leukocytes are primarily involved in immunological defence mechanisms of body and leukocytic disorders may be qualitative or quantitative.

Qualitative leukocytic disorders, i.e.

Quantitative leukocytic disorders are generally acquired as a consequence of—(a) immune activity, e.g. infection, inflammation or allergy, or (b) bone­marrow defects, e.g. aplastic anemia or leukemia. These abnormalities may be generalized or limited to one or more components of leukocyte cadre, i.e. granulocytes (neutrophils, eosinophils and monocytes) or lymphocytes.

Total and differential leukocyte counts (TLC/DLC) vary with age in early childhood, being highest at birth with predominance of polymorphs. While TLC drops gradually to adult level by 7 years, polymorph percentage drops during first 6 months, before rising again to reach adult levels by 4-6 years (Table 19.2). Some common and important quantitative leukocyte abnormalities are as follows:

Leukemoid reactions: A TLC gt;50,000#8725;mm³ is termed as leukemoid reaction, which is usually neutrophilic and

associated with transient appearance of immature cells in circulation, e.g. metamyelocyte and melocytes.

Leukemoid reactions may be seen in—(a) fulminant bacterial infections and septicemia, (b) acute hemorrhage,

(c) acute hemolytic reactions, and (d) infections in children with leukocyte adhesion deficiency.

Neutrophils are circulatory phagocytes which mainly act against pyogenic bacteria and are involved in-(a) nonspecific immunity to engulf and digest foreign antigens, and (b) processing of these antigens for further immune reactions. While neutrophils have a short circulatory half-life of ~6-2 hours, large number of partially differentiated cells are present in bone marrow and vascular endothelium (marginating pool), which may be readily mobilized and rapidly differentiated into neutrophils during infections.

Neutropenia is the most important leukocytic abnor­mality, generally defined as absolute neutrophil counts (ANC) lt;1500#8725;mm³ and stratified as mild (lt;1500-1000/ mm³), moderate (lt;1000-500/mm³) and severe (lt;500/ mm³).

Etiology: Neutropenia may be transient or persistent. Acute transient neutropenia usually indicates excessive use of these immunological cells in acute infections, while persistent neutropenia may be due to: (a) acquired marrow disorders, e.g. aplastic anemia or leukemia, (b) intrinsic marrow disorders, e.g. cyclic neutropenia, or (c) peripheral destruction in chronic infections or immunological disorders (Table 19.16).

Clinical presentation of neutropenia is directly related to its severity, characterized by increased risk of infections. Mild to moderate neutropenia is generally well tolerated, while localized skin/mucosal infections are more common at ANC lt;500#8725;mm³. Very severe neutropenia (ANC lt;200) is associated with generalized and poten­tially fatal infections, e.g. septicemia, pneumonia, etc.

Disproportionately less signs of inflammation with mini­mal pus formation is an important feature of sepsis in

TABLE 19.16: Causes of neutropenia

• Infections: Viral infections, sepsis, HIV

• Drugs

Immunological: Penicillin, phenytoin, phenobarbitone Idiosyncratic: Chloramphenicol

Cytotoxic: Anti-malignancy drugs, radiation

• Immune neutropenia

Autoimmune neutropenia (Isolated/syndromic*)

Autoimmune neutropenia of infancy

Neonatal alloimmune neutropenia

• Bone marrow defects

Inherited: Cyclic neutropenia, Kostmann syndrome

Acqd: Malignancy, myelodysplasia, aplastic anemia

• Peripheral sequestration: Hypersplenism

• Others: PEM, megaloblastic anemia

*with other autoimmune disorders, e.g. SLE neutropenic cases. Staphylococci and gram-negative bacteria are dominant pathogens in neutropenic children. Neutropenic children are not excessively prone to viral, fungal or parasitic infections as well as bacterial meningitis, if not associated with other immunological defects.

Diagnosis rests on serial ANC counts to confirm transient, cyclic or persistent nature of neutropenia, along with bone marrow studies in chronic neutropenia or pancytopenia. Other relevant investigations, e.g. antineutrophil antibodies are indicated in select cases.

Treatment includes early diagnosis and treatment of infections (see febrile neutropenia, Ch 10.1.5), along with management of primary cause.

Severe or chronic symptomatic neutropenia may benefit from recombinant G-CSF therapy (SC 3.4-11.5 #956;g#8725;kg#8725;day), while bone marrow transplant must be considered in severe congenital neutropnia.

Some important causes of neutropenia are as follows:

• Viral infections causes of transient neutropenia due to redistribution of neutrophils from circulatory to tissue (marginating) pool. Although neutrophilia is more common in bacterial infections, moderate/ severe neutropenia in bacterial infections indicates severe sepsis with poor prognosis.

• Drug-induced neutropenia is more common in adults due to several mechanisms, e.g. toxic (chemotherapy/ radiotherapy), idiosyncratic (chloramphenicol) immunological (penicillin) or hypersensitivity (phenytoin, phenobarb) reactions. While cytotoxic neutropenia is dose-related and appears after 7-10 days of chemo/ radiotherapy, others are usually not dose-related.

• Immune neutropenia is characterized by presence of anti-neutrophil antibodies in circulation with excessive destruction of neutrophils. Important variants include:

- Neonatal alloimmune neutropenia, like Rh- hemolytic disease, denotes transplacental transfer of maternal alloantibodies (IgG) after prior sensitization. These cases are asymptomatic or present with delayed separation of umbilical cord and mild/moderate neonatal infections by usual organisms, which respond well to antibiotics. Neutrophil counts normalize by the end of first week. Transient neutropenia is also common in babies born to mothers with autoimmune disorders, lasting longer for few weeks or months.

- Autoimmune neutropenia, analogous to autoimmune hemolytic anemia or thrombocytopenia, may be an isolated feature or a part of generalized connective tissue disorders.

Autoimmune neutropenia of infancy is a relatively benign disorder that generally presents at 5-15 months of age with recurrent minor or superficial infections in next 6 months-2 years, before

spontaneous recovery. Diagnosis rests on presence of antineutrophil antibodies in serum and treatment includes recombinant human G-CSF therapy, only in cases with severe infection or before surgery.

• Inherited neutropenia is rare and indicates intrinsic defects in proliferation and/ or maturation of myeloid stem cells, including two important causes:

- Cyclic neutropenia is an autosomal dominant defect in proliferation and maturation of myeloid stem cells, characterized by periodic oscillations in ANCs from normal to neutropenia, with an average cycle of 21 days. During neutropenic phase, child may suffer from fever, oral ulcers, sore throat or occasionally, serious infections. Cycles become less prominent with advancing age, reducing severity of symptoms and neutropenia.

- Kostmann syndrome (severe congenital neutro­penia) is an autosomal recessive disease, characte­rized by an arrest in myeloid maturation at promyelocytic stage. These cases have severe neutropenia (lt;200/mm3) with marked monocytosis and present with recurrent, severe pyogenic infections since infancy. Unless treated with regular G-CSF therapy, most cases die before adolescence due to severe infections.

Neutrophilia, i.e. elevated ANC in peripheral blood, is an indicator of bacterial infection or tissue inflammation, due to-(a) increased mobilization of these cells from bone marrow or marginating pool, as well as (b) actual increase in marrow production.

Normally, up to 5% neutrophils in peripheral blood are in immature forms, i.e. Band cells. Presence of gt;5% neutrophils in band form or as precursor cells, e.g.

Acute neutrophilia is seen in—(a) acute bacterial infection or inflammation, (b) massive tissue injury, e.g. burns, trauma or surgery, (c) chronic hemolytic anemia, (d) drug therapy with adrenaline, steroids and hematopoietic colony stimulating factors. Adrenaline releases neutrophils from marginating pool while steroids accentuate their mobilization from bone marrow.

Chronic neutrophilia is uncommon, seen in—(a) chronic infection/blood loss, (b) vasculitis states, (c) malignancies, e.g. chronic myeloid leukemia, (d) post­splenectomy, and (e) prolonged steroid therapy.

Life-long neutrophilia generally indicate—(a) congenital asplenia, or (b) leukocyte adhesion defects; though also seen in Down syndrome or familial myeloproliferative disorders.

Monocytes, i.e. granulocytes with large horse-shoe shaped nucleus, are circulatory precursors of macro­phages (tissue phagocytes). After circulatory half-life of 2-5 days, these cells migrate into tissues and transform

TABLE 19.17: Causes of eosinophilia

• Allergic: Asthma, allergic rhinitis

• Infections: Worm infestations, filaria

• Systemic diseases:

- Lungs: Tropical pulmonary eosinophilia, Loffier syndrome

- GIT: Chronic inflammatory bowel diseases

- Marrow: T-cell lymphoma, histiocytosis

• Immunological: Job syndrome*, Wiskott-Aldrich syndrome

• Idiopathic hypereosinophilic syndrome

*Hyper IgE Syndrome

into macrophages with tissue-specific characters, e.g. Kupffer cells in liver and alveolar macrophages in lungs. Monocytosis: Transient monocytosis is common in many bacterial, viral protozoal or rickettsial infections, while sustained monocytosis is seen in chronic neutropenia, post-splenectomy, and malignant disorders.

Eosinophils are primarily involved in allergic disorders and cytotoxic action against helminths. Through various proteins contained in their granules, e.g.

Eosinophilia is the hallmark of allergic disorders, though absolute eosinophil count (AEC) does not necessarily correlates with severity of allergy (Table 19.17). AEC is more elevated in acute rather than chronic allergic disorders, sometimes exceeding 20,000/mm3 (Eosinophilic leukemoid reaction).

Helminthic infestations are another important cause of mild/moderate eosinophilia that parallels with degree of tissue invasion by parasite. Eosinophilia is unlikely in non-invasive parasitic infestations, e.g. giardia or pinworm infestations.

Idiopathic hypereosinophilic syndrome is a leuko- proliferative disorder characterized by—(a) persistently elevated AEC gt;1500 for at least 6 months, (b) absence of other cause, and (c) evidence of systemic organ involvement. Endomyocardial thrombosis and fibrosis are important complication of sustained eosinophilia, though other organs may also be involved. Therapy aims to suppress eosinophilia with corticosteroids. Hydroxyurea may be used in steroid-resistant cases. Most cases with organ involvement or steroid resistance die within 3 years of diagnosis.

Eosinopenia is relatively uncommon, may be seen in some cases with—(a) corticosteroid therapy, and (b) active bacterial/viral infections.

Lymphocytes have a central role in antigen-specific immune response, though also participate in non-antigen specific immunity.

Circulating lymphocytes may be classified according to the morphology (large vs small lymphocytes) or site of development (T vs B cells). T-cells are primarily involved

in cellular immunity and further sub-classified according to functions (helper, suppressor or natural killer cells) and CD markers (mainly CD₄ and CD8) About 65% of T-lymphocytes carry CD₄ marker with normal CD₄: CD₈ ratio of 1.8:2.0. B lymphocytes are involved in synthesis of immunoglobulins (Ch 8.1).

Lymphocytopenia generally indicates excessive cell destruction in—(a) infections, e.g. HIV, typhoid, (b) drugs, e.g. cytotoxic agents, radiation, steroids, (c) autoimmune disorders, and (d) inherited immunodeficiency disorders, e.g. Wiskott-Aldrich syndrome; though also seen in (e) disorders with ineffective erythropoiesis, e.g. aplastic anemia.

Lymphocytosis is the usual response to—(a) viral infections sp. Infectious mononucleosis, while other important causes include — (b) pertussis, (c) tuberculosis,

(d) brucellosis, (e) acute lymphocytic leukemia, and (f) endocrinal disorders, e.g. thyrotoxicosis and Addison disease.

19.9