Objectives
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Myeloid cells in the bone marrow can be divided into:
The initial neutrophilia of bacterial infection is due to mobilization of neutrophils from the bone marrow storage pool into the circulation. The marrow storage or reserve pool consists principally of neutrophils and band forms. Metamyelocytes are not released to the blood except under extreme circumstances. For patients with underlying bone marrow disorders associated with a reduction of storage pool size, the capacity to develop neutrophilia is impaired.
Most patients with Gram positive bacterial infections have neutrophilia. Increased levels of activated complement products, G-CSF, and pro-inflammatory cytokines TNF-a, IL-1 and IL-6 may cause this response. Bacterial infections that have an insidious onset and cause splenomegaly, such as typhoid fever and brucellosis, characteristically do not show neutrophilia except in initial or disseminated phases. Miliary TB is an important cause of leukaemoid reaction. In chronic infections, neutrophilia is maintained through increased myeloid cell proliferation and hence an expanded post-mitotic pool.
Infections caused by Gram negative bacteria, particularly those resulting in septic shock, may cause extreme neutrophilia on the one hand but neutropenia on the other. The latter results from mature cells being mobilized from the marrow faster than the proliferation rate. The neutropenia in these instances is associated with a bone marrow picture of extreme left-shift or maturation arrest. It is usually associated with thrombocytopenia and deranged clotting profile. With adequate control of severe sepsis, there is a return of neutrophil and platelet count to normal, and may even overshoot for some time before settling. The first sign of improvement is often an improvement of thrombocytopenia. The haematologcial changes ultimately depend on the stage of sepsis, rate of peripheral consumption and bone marrow reserve.
Neutropenia
Neutropenia may result from acute or chronic bacterial, viral, parasitic or rickettsial diseases. Possible mechanisms for neutropenia include:
Lymphocytosis
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Any patient with fever and lymphocytosis should have a throughout peripheral film review to distinguish between reactive and neoplastic causes of increased lymphocyte count.
Reactive lymphocytosis is seen in the mononucleosis syndromes (EBV, CMV, toxoplasmosis, viral hepatitis, HIV). A marked increase in morphologically normal lymphocytes occurs in Bordetella pertussis infection. Absolute lymphocytosis may reach 50 X 109/L but usually are in the range of 15 ¡V 25 X 109/L. These are T-helper cells that show a delay in exit from blood into lymphoid tissue.
Lymphocytopenia
Lymphocytopenia is typically seen in many inherited immunodeficiency disorders. It is also encountered in acquired immunodeficiency states in particular HIV infection, and following administration of drugs such as steroid and anti-thymocyte globulin or anti-lymphocyte globulin.
In acute sepsis, mild to moderate reduction of lymphocyte count is common and may be related to the release of glucocorticoids. Lymphocytopenia is also encountered in chronic infections especially TB.
Influenza and other acute viral infections may cause lymphocytopenia through direct destruction, trapping in the spleen or lymph nodes, or migration into the respiratory tract.
Monocytosis
Infectious diseases are common causes of monocytosis, especially chronic infections such as TB, typhoid and brucellosis. However, during acute bacterial infections, blood monocyte count may also be increased as part of leucocytosis, and therefore monocytosis is more significant when the total white cell count is not increased. A monocytosis may also be seen in the resolution phase of acute infection.
Monocytosis is found in 15 - 20% of patients with subacute bacterial endocarditis, and certain viruses especially CMV may induce an increase in blood monocyte count.
Eosinophilia
The mechanism underlying reactive eosinophilia in most situations is related to an accelerated bone marrow proliferation induced by factors originating from T lymphocytes. Eosinophil proliferation is mainly driven by cytokines IL-3 and IL-5, which is produced in a Th2 (and to a lesser extent Th1) response.
Infectious diseases associated with eosinophilia typically include parasitic (both protozoan and metazoan infestations) and fungal diseases. In TB and cryptococcal infection, an increased blood eosinophil count often signifies a Th2 response and is often associated with poorly controlled infection.
Thrombocytopenia and thrombocytosis
In bacterial infection, thrombocytopenia is usually due to peripheral causes, notably consumptive coagulopathy and peripheral sequestration in splenomegaly. On the other hand, thrombocytosis that is reactive to the chronic inflammatory process may be encountered in tuberculosis.
Thrombocytopenia in viral infections appears in two main settings, first as an almost universal feature of disseminated infection in the neonate or immunosuppressed patient and second as a rare complication of acute transient infection in previously healthy subjects. There are probably two main mechanisms of thrombocytopenia: either immune mediated platelet destruction with or without immune mediated megakaryocyte damage, or alternatively direct toxicity to megakaryocytes resulting from viral infection of these cells.
The majority of acute childhood immune thrombocytopenic purpura (ITP) is preceded by a viral illness. ITP is defined as isolated thrombocytopenia with no clinically apparent associated conditions or other causes of thrombocytopenia (e.g. systemic lupus erythematosus) and that the diagnosis of ITP is primarily one of exclusion. Having said that, few investigations are considered "necessary" in children in whom the history, physical examination, initial blood count and peripheral smear are compatible with a diagnosis of acute ITP, according to a recent guideline issued by the American Society of Hematology.
The need for careful examination of a blood smear cannot be over-emphasized. Features consistent with a diagnosis of ITP are thrombocytopenia with platelets being normal in size or may appear larger than normal, but uniformly giant platelets (approaching the size of red cells) should be absent. The morphology of red blood cells and white blood cells should be normal. Features that are inconsistent with a diagnosis of ITP should prompt further investigations.
The need for initial bone marrow aspiration (BMA) in children with acute ITP is controversial. There is a consensus that a BMA is not necessary if initial management is either observation alone or high dose intravenous immunoglobulin (IVIg). The issue that remains unsettled is whether a BMA needs to be performed in all children with acute ITP before starting corticosteroid therapy to exclude aplastic anaemia and leukaemia. Although these two conditions are extremely unlikely when the child's age, history, physical examination, complete blood count and peripheral smear are typical of acute ITP, most paediatricians continue to recommend that a BMA be performed in a child with presumed acute ITP before starting corticosteroid therapy.
Anaemia of infection
Anaemia is commonly observed in the patients with infections, particularly those in which the clinical course lasts longer than a month. Infections traditionally associated with anaemia include TB, empyema and lung abscess, osteomyelitis, subacute bacterial endocarditis, and chronic fungal infections. Anaemia of infection should be considered a subset of anaemia of chronic disorder (ACD), which is presumed to be the most frequent cause of anaemia other than blood loss and iron deficiency. ACD is certainly the commonest cause of anaemia in hospital patients.
Distinguishing ACD from iron deficiency anaemia (IDA)
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Although serum ferritin is the best biochemical indicator of reticuloendothelial iron status, it suffers from limited sensitivity in concurrent inflammatory disorders, and is frequently elevated out of proportion to iron stores.
The determination of serum soluble transferrin receptor concentration may distinguish ACD from IDA, but is not available in routine laboratories. It is elevated in IDA due to enhanced expression by erythroblasts and erythroid hyperplasia, but not in ACD.
Pathogenetic mechanism in ACD
ACD is principally mediated by cytokines TNFa and IL-1. The processes involved in its pathogenesis are:
Other causes of anaemia in infection
Disseminated intravascular coagulation (DIC) and sepsis
The minimal acceptable criteria for defining DIC are a systemic thrombohaemorrhagic disorder seen in association with well-defined clinical situations, together with laboratory evidence of:
Septicaemia is often associated with DIC, in particular infection by gram negative bacteria such as meningococcus. The triggering mechanisms consists of the initation of coagulation by endotoxin / bacterial lipopolysaccharide. Endotoxin activates factor XII to XIIa, induces a platelet release reaction, cause endothelial sloughing with later activation of XII-XIIa or XI-XIa, and release granulocyte procoagulant materials. Many Gram-positive bacteria are also noted to cause DIC through similar mechanisms. Viraemias, including HIV, are associated with DIC, the most common being varicella, hepatitis and CMV infection.
The laboratory tests that are most frequently abnormal in DIC are:
Blood film typically shows a microangiopathic picture with the presence of red cell fragments (schistocytes), polychromasia, occasional spherocytes and thrombocytopenia. However, one should bear in mind that TTP / HUS, which may also be triggered by infective agents, shows a similar morphology. In TTP / HUS, the coagulation profile is usually normal.
Parvovirus induced pure red cell aplasia
Parvovirus B19 is a member of the erythrovirus genus and so named because of their tropism and selective replication in erythroid progenitor cells. The erythroid tropism of B19 is due to tissue specific expression of its cellular receptor, the blood group P antigen. Patients that do not have the P antigen on their erythrocytes cannot be infected with the parvovirus B19. A previous prevalence study by the HKRCBTS shows that in Hong Kong Chinese, the population prevalence of P1 and P2 antigens are 28% and 72% respectively, and the prevalence of p phenotype is 0%. In Caucasians, the frequency of p phenotype is estimated to be 1:200,000.
The P antigen is found on erythroid progenitors, erythroblasts, megakaryoblasts and megakaryocytes. It is also present on endothelial cells (probably relates to pathogenesis of transplacental transmission, and vasculitis and rash of fifth disease), and on fetal myocardial cells.
Haematological consequences of B19 infection arise due to a direct cytotoxic effect on erythroid progenitors in bone marrow and interruption of erythrocyte production. In addition, the physiology of host haemopoiesis and competence of the immune response each determines the clinical manifestations of B19 infection.
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erythropoiesis |
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immunocompromised patients |
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Parvovirus B19 should be considered as differential diagnosis in any patient with anaemia associated with low or absent reticulocytes, especially in those who have underlying immunodeficiency or who are immunosuppressed. The diagnosis cannot be excluded when there is no known underlying disease because immune dysfunction may be clinically subtle. Bone marrow should be examined if feasible. In haematological disease due to B19 infection (transient aplastic crisis, pure red cell aplasia), there is generally a decrease or absence of erythroid precursors, with sparing of other lineages. Giant pronormoblasts may be visualized. B19 infection, nevertheless, should be considered in all cases of pure red cell aplasia diagnosed on bone marrow morphology.
Cold agglutinins and infection
Following infection with mycoplasma pneumoniae around 50% of patients show a rise in the titre of anti-I, a cold antibody normal present in low titre. This is an IgM antibody that reacts with adult red cells in the cold. Neonatal erythrocytes do not express I antigen and are not agglutinated. Following infectious mononucleosis, a similar cold-reacting antibody, anti-i, is frequently produced which in rare instances may affect adult I red cells and cause a similar picture. These antibodies associated with infections are polyclonal, in contrast to cold antibodies secondary to lymphoma that is monoclonal in nature.
The low thermal amplitude of the antibody results in red cell agglutination in the extremities and consequent complement fixation. IgM elutes from the cells on warming but intravascular haemolysis occurs if sufficient complement is bound.
The haemolysis associated with mycoplasma infection generally occurs 2 ¡V3 weeks after the acute illness with rapid onset of anaemia. The patient may notice red urine due to haemoglobinuria. In cold weather there may be acrocynaosis (painful blue discoloration of the extremities).
It is imperative that blood samples for investigation be kept at 37oC to avoid agglutination and haemolysis. Direct Coombs' test shows complement coating only. The anti-I titre is raised. Blood film shows red cell auto-agglutination.
HCV infection and cryoglobulinaemia
Cryoglobulins are cold-precipitable proteins found in serum. These components may be idiopathic in origin, occurring as a benign paraproteinaemia, or occur in the setting of myeloma, lymphoma or Waldenstrom's macroglobulinaemia. Mixed cryoglobulins have rheumatoid factor like activity and are usually composed of IgG molecules complexed with IgM molecules with anti-IgG reactivity.
Hepatitis C virus (HCV) infection is found in 80% to 90% of patients with essential mixed cryoglobulinemia(EMC) type II. EMC type II is characterized by the presence of polyclonal IgG and monoclonal IgM-k. Monoclonal IgM-k is secreted by clonal B cells, and this may suggest that low-grade non-Hodgkin lymphoma (NHL) is the underlying disorder of EMC.
The association between EMC, HCV, and NHL raises the possibility that HCV may be involved in the pathogenesis of lymphoma. Several epidemiological studies conducted in Italy, Japan, and North America showed that the prevalence of HCV seropositivity or viraemia (RNA) is significantly increased in patients with B-NHL (but not in patients with Hodgkin disease or T-cell lymphoma) relative to the general population.
More recently, t(14;18) rearrangement as seen in low grade follicular lymphoma is found to be significantly increased in EMC associated with HCV than those not associated with HCV. The mechanism of HCV-induced lymphoproliferation is still debated. HCVhas been reported to induce clonal B-cell expansions in the peripheral blood of infected patients. HCVsequenceswere also detected in pathologic lymph node biopsies in 13 of 34 patients with NHL, and HCV-associated proteins are detected within lymphoma cells. However, HCV RNA sequences cannot be integrated into the host genome, and the mechanism of inducing clonality remains unresolved. A different mechanism may involve chronic antigenic stimulation induced by HCV infection leading to B cell proliferation and later to the emergence of a clone that has a proliferative advantage and, after additional genetic hits, transforms to NHL. Thus it remains to be elucidated whether HCVactivates its oncogenic potential by indirect mechanisms or uses anti-apoptotic pathways directly.
Cytopenia is frequently encountered in HIV infected individuals. Possible pathogenic mechanisms inlcude the followings:
Haematological malignancies with viral etiology
EBV is etiologically linked to Burkitt's lymphoma, high grade B-cell lymphoma in immunosuppressed host, Hodgkin's lymphoma, and nasal and non-nasal NK/T cell lymphoma (predilection for Orientals), while HTLV-1 is associated with adult T cell leukaemia / lymphoma (ATLL).
KSHV (HHV 8) is first discovered in primary effusion lymphoma and subsequently is found to be associated with multicentric Castleman's disease, especially in HIV infected individuals. More recently, this virus is detected in dendritic cells in bone marrow of multiple myeloma patients. However, the evidence for an etiological link between HHV 8 and multiple myeloma is still controversial, as the finding cannot be reproduced by several groups of investigators.
Infection associated haemophagocytic syndrome
Haemophagocytic syndromes (HS) are the clinical manifestations of an increased
macrophage activity with haemophagocytosis. Pathophysiology is related to a
dysregulation of T lymphocytes and excessive production of cytokines. The main
clinical features are fever, hepatosplenomegaly, adenopathies, skin rash, cytopenia,
liver derangement, increased triglyceride and ferritin, and coagulopathy. While
inherited HS in the form of familial haemophagocytic lymphohistiocytosis exists,
most of the HS encountered in clinical practice is reactive to infection or
lymphoma (reactive haemophagocytic syndrome, RHS).
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The general agreed diagnostic criteria of HS are summarized below. A diagnosis of HS requires all criteria to be fulfilled. A thorough search for family history, initiating infections and malignancies should be undertaken.
Infection has been found to be associated with HS in half of all reported cases, and incriminated organisms include viruses (majority), bacteria, fungi and parasites.
EBV is considered to be the cause of most cases of virus associated haemophagocytic syndrome (VAHS). Overt HS may be observed in primary EBV infection or reactivation, most often in children. It is now apparent that certain subjects show EBV susceptibility, which may be clearly defined such as immunodeficiency secondary to immunosuppressive treatment or inherited defects like Chediak Higashi disease. X-linked lymphoproliferative syndrome (XLP) is associated with fatal EBV infection characterized by severe HS and hepatic dysfunction. However, in some individuals, the selective susceptibility to EBV infection remains elusive. Interestingly, the histiocytic proliferation has been found to be clonal in rare instances.
HS is also associated with various kinds of disseminated bacterial infection. However, pancytopenia and coagulopathy is common at terminal stages of septicaemia, and determining whether it is a cause or effect of macrophage activation is very difficult.
Rare cases of HS associated with fungal (histoplasma, candida, cryptococcus) or parasitic (leishmania, babesia, toxoplasma, pneumocystis) infections are described.
A care search for and treatment of infectious disease is basic in HS. Immunomodulation (IVIg, cyclosporine A, VP-16) may have to be considered. In clinical practice, if the search for infections is not forthcoming, an underlying lymphoma should be considered and diligently excluded.
References