|A variety of systemic illnesses including |
acute and chronic infections, neoplastic diseases, connective tissue disorders, and storage diseases are associated with hematologic manifestations. The hematologic manifestations are the result of following mechanisms:
- Bone marrow dysfunction
- Anemia or polycythemia
- Leukopenia or leukocytosis
Alterations in hemostasis
- Acquired inhibitors to coagulation factors
- Acquired Von Willebrand's disease
- Acquired platelet dysfunction
Alterations in leukocyte function
- Chronic infection is associated with the anemia of chronic illness
- Acute infection, particularly viral infection, can produce transient bone
marrow aplasia or selective transient erythrocytopenia.
- Parvovirus B-19 infection in people with an underlying haemolytic
disorder (such as sickle cell disease, hereditary spherocytosis) can
produce a rapid fall in hemoglobin and an erythroblastopenic crisis
marked by anemia and reticulocytopenia. There may be an associated neutropenia
- Many viral and bacterial illnesses may be associated with hemolysis.
White Cell Alterations
- Viral and bacterial infections can produce leukopenia and neutropenia.
- Neutrophilia with an increased band count and left shift frequently results from bacterial infection.
- Neonates, particularly premature infants, may not develop an increase in white cell count in response to infection.
- Eosinophilia may develop in response to parasitic infections.
- Severe infections, for example, gram-negative sepsis, can produce
disseminated intravascular coagulation (DIC).
Infection can produce thrombocytopenia through:
- Decreased marrow production
- Immune destruction
General Hematologic Signs of Infection
RED BLOOD CELL DISTURBANCES
The pathophysiologic finding of the anemia of chronic infection are similar to those of anemia of chromic disorders. Although some infections, particularly viral infections, cause transient bone marrow aplasia or selective erythroid aplasia, anemia from this cause is rare because of the long life span of the red blood cell. In contrast, patients with haemolytic anemia may experience a rapid decrease in hemoglobin concentration during viral and some bacterial infections. This is especially common in association with infectious episodes caused by parvovirus. Such infection should be considered in any child with a congenital haemolytic anemia who experiences an "aplastic" crisis.
Even common childhood infections, especially those associated with inflammation, will cause a decline in hemoglobin concentration. During active inflammation, the hemoglobin concentration declines about 13%, usually within 1 week, followed by an increase of nearly 25% during the resolution of active inflammation.
Severe haemolytic anemia may be observed in certain types of infection. Clostridial infections may result in a high titer of hemolysins and cause severe anemia with hemoglobinemia and cause severe anemia with hemoglobinemia and hemoglobinuria. A similar severe anemia may result from sepsis related to other bacterial organism, including staphylococci, streptococci, pneumococci, and Hemophilus influenzae. Immune haemolytic anemia mediated by a cold agglutinin may be observed with Listeria and Mycoplasma infections and occasionally with infections due to other organisms such as the Epstein-Barr virus (EBV).
Many viral illnesses may be associated with what appears to be a mild haemolytic anemia for which no pathologic mechanism has been defined. The most common morphologic finding under these circumstances is poikilocytosis. Certain viruses, such as most strains of influenza virus, contain neuraminidase activity, which is, at least theoretically, capable of affecting the sialic acid content of the red cell membrane. Whether this plays any significant role in the hemolysis associated with some viral diseases is not known. Many congenital infections, including cytomegalovirus, herpes simplex, rubella, toxoplasmosis, and syphilis, produce profound haemolytic anemia in the newborn period, even though these same agents may not significantly alter red cell survival at other times of life. The explanation for this also is unclear. Finally, anemia may result from blood loss associated with intestinal parasitic infestation.
WHITE BLOOD CELL DISTURBANCES
The white blood cell count may be normal, low, or high with infection. Viral illnesses may be associated with leukocyte counts less than 5000 cells/mm3, although bacterial diseases of certain types of overwhelming sepsis of any type may also cause leukopenia. The most common viral illnesses associated with leukopenia are infectious hepatitis, infectious mononucleosis, rubella, measles, and occasionally influenza. Of the bacterial infections, shigellosis may produce leukopenia with a marked increase in band cell forms. Sepsis caused by meningococci, pneumococci, staphylococci, and a few other bacterial pathogens may also cause leukopenia.
Neutrophilia, with or without an increase in band cell count, is a common result of bacterial infection. White blood cell counts do not differ between white and black children with bacteremia, and total white blood cell count and neutrophil counts may be interpreted without regard to race. Occasionally, viral illness will also initially present as a neutrophilia. A variety of morphologic changes may appear in the neutrophils of patients with infection. Dohle bodies, pale blue cyst like inclusion bodies usually located in the periphery of the cytoplasm of neutrophils, may appear in bacterial infections. They are occasionally associated with viral illness but are also commonly seen in patients with burns, massive trauma, and cancer as well as in pregnancy and after the use of cyclophosphamide. Dohle bodies are also seen in the May Hegglin anomaly. Increased size of neutrophil granules (toxic granulation) may be seen in both bacterial and viral illnesses as well as in many of the other disorders associated with the presence of Dohle bodies. Vacuolization of the cytoplasm of neutrophils is the next most common morphologic abnormality of neutrophils in patients with significant bacteremia, Zipursky and associates found toxic granulation, Dohle bodies, and vacuolization in 75, 29 and 24%, respectively, of the patients studied.
Increased neutrophil alkaline phosphatase activity and nitroblue tetrazolium dye reduction also may occur, but neither of these characteristics is specific for bacterial infection. Infections may be associated with the development of the Pelger-Huet anomaly, in which the granulocytes and eosinophils have one or two lobes per nucleus and assume a round, dumbbell, or peanut shape. This is most commonly observed with tuberculosis. The Pelger-Huet anomaly is seen in 1 in 6000 people as an autosomal disorder and is also observed occasionally in patients with preleukemia, leukemia, and other cancers and in those taking colchicines and sulfonamide mediations.
In newborns, especially those born prematurely, an increase in total white cell or mature neutrophil counts in the presence of infection may not be seen. In fact, a decrease in the neutrophil count often occurs. The most helpful signs of septicaemia in this age-group are an increase in the bank cell count and the presence of toxic granulations and Dohle bodies.
Leukocytosis may result from lymphocytosis. The most common infections producing the greatest increases in lymphocyte counts are infectious mononucleosis, cat scratch disease, "acute infectious lymphocytosis of childhood", and pertussis. Many other viral illnesses such as cytomegalovirus, rubella, mumps, and hepatitis may also cause an increase in the lymphocyte count. T lymphopenia is a common finding after measles infection. This is predominantly due to suppression of OKT4 + lymphocytes.
Eosinophilia may reflect the presence of parasitic infections. In the United States, the most common cause of marked elevations of eosinophil counts is Toxocara infestation, which is often accompanied by high titers of isohemagglutinins. Other parasites commonly causing eosinophilia include organisms belonging to Trichinella, Echinococcus, Filaria, Strongyloides, Schistosoma, Enterobius, and Ancylostoma and tapeworms other than Echinococcus. Allergic sensitization to mites may cause eosinophilia as well as fungal infections, especially aspergillosis. Eosinophilia is, of course, not specific for infestation. Marked degrees of eosinophilia may occur in association with prematurity. An absolute eosinophilia may be expected in about 75% of low-birth-weight infants. In some, the eosinophilia is marked (more than 3000 cells/mm3), and the maximal increase seems to occur at about the time birth weight is regained, although this is not true in all infants.
Monocytosis is occasionally seen with specific infections, especially tuberculosis, syphilis, and subacute bacterial endocarditis. Monocytosis is often noted early in the course of many infections and again on recovery, especially if it is associated with granulocytopenia. Basophilia is rarely seen in infection but has been reported with tuberculosis, influenza, and hookworm infestation.
CLOTTING ABNORMALITIES AND THROMBOCYTOPENIA
DIC may be triggered by infectious processes, of the infectious causes, gram-negative septicemias are probably most common. Meningococcus, Escherichia coli, Proteus, Pseudomonas, Aerobacter, and Klebsiella are among the most common etiologic agents recovered from the blood stream. Gram-positive septicaemia can cause a similar picture. The most common offender is Diplococcus pneumoniae, especially in asplenic individuals. Other gram-positive agents causing DIC include Staphylococcus aureus, Streptococcus, and Clostridium. A wide range of viral infections may cause a consumptive coagulopathy, often leading to purpura fulminans. Among the most common agents are those that cause infectious hepatitis, measles, rubella, varicella, and infectious mononucleosis. Less common causes of DIC are severe mycoplasmal, rickettsial, and malarial infections.
Thrombocytopenia occurring separately from a true disseminated consumptive process us quite common in many infectious processes, especially in association with infectious mononucleosis, cytomegalovirus infection, rubella, measles, gram-negative bacteria, and rickettsial diseases. Congenital viral infections and congenital syphilis and toxoplasmosis, if clinically apparent, almost invariably are associated with increased platelet turnover with or without thrombocytopenia. Thrombocytopenia may occur after immunization with live viral vaccines, especially measles vaccines. Corrigan found that thrombocytopenia without consumptive coagulopathy is an extremely common finding in infants and children with septicemias. In contrast, thrombocytosis is often present during the active phases of infectious processes. The platelet distribution width and mean platelet volume may be helpful in predicting whether thrombocytopenia is due to infection. In the late neonatal period, thrombocytopenia associated with an infection dramatically increase the mean platelet volume and platelet distribution width as determined by electronic counting equipment.
Immune complex-mediated thrombocytopenia is commonly associated with a variety of infectious agents.
Hematologic Aspects of Selected Specific Infections
Certain infectious processes are associated with specific or unique hematologic findings distinct from those described in the preceding section. These infections include Bordetella pertussis (pertussis or whooping cough), Salmonella typhus (typhoid fever), Mycobacterium tuberculosis (tuberculosis), Plasmodium falciparum (malaria), Clostridium perfringens, and bartonella bacilliformis (Bartonellosis or Carrion's disease).
Typhoid fever produces remarkable leukopenia and neutropenia early in the course of the illness. The number of bone marrow precursor cells is increased. A high white blood cell count in this disease usually suggests a secondary bacterial infection. The leukopenia of typhoid fever is often associated with thrombocytopenia. Shigellosis may also be associated with leukopenia. The hallmark of Shigella infection, however, is a sharp increase in the band cell count.
In the pediatric age group, C. perfringens infections are most common among adolescent females who have undergone septic abortions. This organism has a potent exotoxin, a lecithinase that disrupts cell membranes, liberating haemolytic materials such as lysolecithins. This disruption may result in fatal intravascular haemolytic anemia with spherocytosis.
Pertussis may cause a marked increase in the white blood cell count, with elevations to 40,000 cells/mm 3 or more, most of which is due to an increase in the lymphocyte count.
Tuberculosis produces a variety of hematologic abnormalities. Leukemoid reactions mimicking myeloproliferative disorders are common. Bone marrow involvement in military tuberculosis may result in a leukoerythroblastic pattern with teardrop-shaped red cells, nucleated red cells, and myeloblasts apparent in the peripheral blood smear. In this respect, the presentation of tuberculosis is similar to some occurrences of sarcoidosis. A bone marrow biopsy may show evidence of granulomas. Monocytosis is common, and thrombocytopenia and pancytopenia have been reported.
Bartonellosis is a disease transmitted by the sandfly and is associated with potentially severe haemolytic anemia. It was first recognized in 1885 when a medical student inoculated himself with the Bartonella organism. The student, Daniel Carrion, died of severe haemolytic anemia. For this reason, human bartonellosis, caused by B. bacilliformis, is still called Carrion disease. This organism will infect red blood cells, coating them and causing them to be rapidly removed from the circulation. Unlike material organisms, Bartonella organisms do not invade the red blood cell.
Hemolysis is common in malaria, especially with infection caused by P. falciparum. This disease, transmitted by Anopheles mosquitoes, results in parasitization with organisms at the merozoite stage within the red cell. The parasitization causes altered permeability and increased osmotic fragility. The presence of the organism within the cell is also reflected in a defect of red cell membrane shape. Hemolysis in malaria has been attributed to direct damage to the red cell by the parasite, to autoimmune destruction, to hypersplenism, to splenic pitting with formation of microspherocytes, and to loss of the cell surface negative change resulting from alteration of the cells metabolic functions by the parasite. In addition to destroying infected cells, the spleen may merely remove the offending organisms, leaving membrane pits or cavities that may be seen on scanning electron microscopic examination. A particularly severe form of hemolysis called backwater fever may occur with P. Falciparum infection. The basis of the massive hemolysis is unknown. Babesial and babesial-like infections produce intraerythrocytic merozoite forms similar to those seen in malaria. These infections may also cause a haemolytic anemia and DICs.
CHANGES IN CBC IN VIRAL ILLNESSES
Viral infections are among the most common illnesses in childhood and rapid advance has taken place in the diagnosis of viral illnesses with the availability of specific serological tests and virus isolation and culture techniques. For a practicing pediatrician these are seldom available in office practice and thus he may have to depend largely on the hematological manifestations of viral illnesses, though imprecise, serve as important clinical guidelines.
Some of the viral infections manifest with specific hematological syndromes which are readily recognizable like infectious mononucleosis caused by EBV, CMV viruses, PRCA (pure red cell aplasia) caused by HPV B19; bone marrow failure caused by hepatitis viruses and; malignancy T cell ALL caused by HTLV 1 virus, VAHS (virus associated hemophagocytic syndrome) is another syndrome more readily recognized due to refinement of its diagnostic criteria and enhanced awareness.
There is today a better understanding of immunological aspects of viral infections and their correlation with hematological changes. There is a better understanding of EBV related complications like bone marrow failure syndrome, lymphoproliferative disorders and VAHS. Viral infections very often results in changes in VBC count, platelet count, hemoglobin concentration; they also can result in coagulopathy like DIC; TEC (transient erythroblastopenia of childhood); VAHS, PRCA, bone marrow failure syndromes; immunodeficiency and lymphoproliferative disorders.
Changes in Leukocyte Count
Classically viral infections results in leucopenia but more commonly they cause mild leukocytosis with increase in both the granulocytes and lymphocytes. The pattern of leukocyte response was studies in normal volunteers and it was observed that lymphopenia was common early in the courses of illness; there was modest granulocytosis early in the course of illness followed by granulocytopenia late in the syndrome.(1) There was direct correlation between the clinical severity and the degree of hematological changes. Naturally infected children with various viral syndromes had increased total lymphocyte counts with stable granulocyte counts.(2)
Viruses commonly associated with neutropenia are: influenza,(1) hepatitis(3) rubella,(4) adenovirus,(1) coxsackie A,(5) dengue,(6) mumps, HIV and rarely EBV and CMV. The level of neutropenia is rarely severe enough to result in secondary bacterial infections. Bacterial infections complicating viral illnesses usually result from an alteration in mucosal barrier and due to depression of cellular immunity. There is transient reversal of CD4/CD8 ratio in severe viral illnesses. Certain viruses (influenza), in particular, cause in severe lymphopenia during acute illness which recovers during convalescence.(7) Measles infection result in severe lymphopenia due to selective suppression of CD4 helper lymphocytes. (6) Lymphocytosis is seen in rubella, mumps and hepatitis viral infections.
The underlying mechanism of WBC changes is not well established. A few of the postulated mechanisms include:
- Viral infection of circulating cells, e.g., direct lymphocytotoxicity: rubella, rubeola, CMV,(8) HBV, EBV
- Bone marrow progenitor cell infection and interruption of normal granulocyte production, e.g., rubeola, rubella, CMV
- Cytokine excess-interferon gamma inhibits hemopoietic cell proliferation(9)
Thrombocytopenia is very common during viral illness and its true frequency may be under stimulated. The increased awareness regarding thrombocytopenia may be due to the availability of accurate platelet count and automated cell counters. The fall in platelet count is dramatic. Yet the count may remain within the normal range. Bleeding is seldom manifest. Purpura observed in viral infections is, thus, due to local changes of vascular integrity and abnormal platelet function.
Thrombocytopenia rarely be a manifestation of severe coagulopathy or associated VAHS. Decreased platelet production as a cause of thrombocytopenia has been reported with mumps, varicella, EBV, rubella, dengue, CMV and HPV B19 infections.(10) In a classic study 38/44 children receiving live attenuated measles vaccine developed thrombocytopenia with maximum depression noted at one week and recovery by three weeks. Bone marrow studies showed that there was associated decrease in megakaryocytes with evidence of cytopathic changes with vacuolation of cytoplasm and nucleus.(11)
Mechanism of Thrombocytopenia in Viral Illness
- Decreased production: (10) Evidence-cytopathic changes of megakaryocytes e.g., dengue, measles
vaccination, CMV, rubella, varicella
- Decreased survival: Viral adsorption of platelets; e.g., rubella, (12) influenza,(13) varicella
- Immunological destruction: Evidence-preceding viral illness in childhood ITP and late occurrence of
thrombocytopenia in certain viral illness (14).
Antiplatelet antibodies directed to platelet antigen as part of the large immune response to virus are seen in EBV(15) while, immune complexes are noticed in mumps infection.(16) Antigen dependent antibody binding to platelets occurs in rubella.(7)
Some viral infection could alter platelet function variably. Thrombocytopenia may be rarely severe enough to warrant treatment. Recovery occurs with the recovery of illness.
Reticulocytopenia is common in those viral infections which cause leukopenia suggesting a mild suppression of erythropoiesis.(17) The effect on hemoglobin level is not marked due to a relative long half-life of erythrocytes compared to platelets or granulocytes. Transient decrease in RBC production is common. There is a mild decrease in RBC survival; the exact cause of which is not understood. It is believed that neuraminidase activity of some of the viruses may be responsible for the mild hemolysis (18) seen in viral infections.
Many viruses are associated with an AIHA (autoimmune haemolytic anemia). Both Coomb's positive and Coomb's negative haemolytic anemias are reported. Coomb's negative AIHA is due to cold agglutinins such as anti I antibodies produces in EBV infection.(19) Mechanism of immune destruction of platelets. Many causes of childhood AIHA have a preceding history of viral illness and commonly occur during convalescence phase of illness implicating and immune mechanism.(19) Anemia could also result because of transient erythrocytopenia (TEC) and pure red cell aplasia (PRCA),
Coagulation abnormalities in Viral Illness
Severe viral infection often have associated DIC. The inciting factors are multifactorial with platelet activation, reticuloendothelial cell damage, hemolysis, antigen-antibody complex formation, production of antiplatelet antibodies resulting in uncontrolled activation of coagulation pathways with excess thrombin generation and DIC.(20) Purpura fulminans is also preceded viral illness suggesting a possible etiological role for viruses. Viruses associated with DIC include varicella, vaccinia, variola, rubella, rubeola, dengue, arboviridae hemorrhagic fever viruses.(20)
Dengue hemorrhagic fever is well described in India and periodic epidemics are recognized with the last epidemic in the year 1998-99. The treatment of DIC in viral infection is similar to that of any other etiology. VAHS, hemophagocytic syndromes secondary to viral infection also have an associated coagulopathy due to excess of cytokine TNF alpha.
HEMATOLOGICAL SYNDROMES ASSOCIATED WITH VIRAL INFECTION:
Three hematological syndromes due to viral infections merit further discussion:
- HPV B19 infection and transient aplastic crisis
- Hematological changes in EBV infection
- Virus associated hemophagocytic syndrome (VAHS)
HPV B19 and Transient Aplastic Crisis:
Parvovirus was first discovered to be a human pathogen in 1975 and later proved to be related to the transient aplastic crisis in sickle cell disease.(21) Parvovirus is a DNA virus and a common pathogen in animals. In humans it is known to cause erythema infectiosum or fifth disease. It occurs sporadically as well as in epidemic form. In epidemic form it has been documented to result in a large numbers of cases of transient aplastic crisis (TAC) among patients with sickle cell disease and congenital spherocytosis.(22) HPV B19 is highly contagious with more than half of adult population having antibody to HPV B19. Transmission of HPV B19 through contaminated blood and blood products.
HPV B19 is cytotoxic to erythroid progenitor cells and profoundly inhibits erythroid colony formation (CFU-E) in culture; but is has little effect on other cell lines. The presence of HPV B19 in erythroid progenitor cells has been demonstrated by election microscopy and immunofluorescence.
Aplastic crisis due to HPV B19 in patients of chronic haemolytic anemia begins with non-specific manifestations of infectious disease. One fourth of these cases have a faint maculopapular rash. Reticulocytopenia develops followed by a drop in Hb concentration by 2 to 6 gm/dl.(23) In most cases, WBC and platelet counts are unaffected; but thrombocytopenia and neutropenia can occur and can rarely be severe.(24)
Bone marrow is cellular with severe erythroid hypoplasia with reversal of M:E ratio. Giant pronormoblasts with vacuolation and cytopathic changes are the morphological markers which provide to the presence of HPV B19 infection.
Crisis recovery starts by 6 to 8 days with reticulocytosis and this coincides with the development of IgM and IgG neutralizing antibodies which help clear the infection.(25) Children with chronic haemolytic anemia and TAC would require transfusion support to overcome the crisis. HPV B19 also causes suppression of erythropoiesis in normal children with a drop of Hb levels by not more than 1 to 2 gm/dl. In adults, HPV B19 also causes arthralgia and non-specific symptoms. A single infection confers life long immunity.
In an immunocompromised host, it causes protracted infection with persistent HPV antigenemia;(26) severe anemia necessitating transfusion support, severe neutropenia and thrombocytopenia. In HIV related immunosuppression HPV B19 is increasingly recognized as a cause for severe refractory anemia.
Infectious mononucleosis is caused by viruses such as EBV infection, CMV, HSV, hepatitis, HIV, protozoa like Toxoplasma gondii.
Infectious mononucleosis can be defined as any blood lymphocytosis induced in response to an infectious agent. More than 50% of circulating WBCs are lymphocytes with more than 20% of lymphocytes with plasmacytoid; monocytoid; lymphoplasmacytoid morphology. Reactive lymphocytes are of T cell origin and cellular equivalent of convalescent antibodies. Thus, reactive lymphocytosis is a late manifestation of infection and may not be detectable early in the courses of illness.
There are three clinically distinct mononucleosis syndromes:
- Pharyngeal form-it presents with fever sore throat pharyngitis malaise and is exclusively due to EBV infection.
- Glandular form-it presents primarily with lymph node involvement and is caused by EBV and Toxoplasma gondii.
- Typhoidal form-its presentation is with lethargy, vomiting, diarrhea, anorexia and fever but not with pharyngitis and is due to CMV virus. Since reactive lymphocytes take some time to appear after the onset of clinical symptoms; if the suspicion for the diagnosis of infectious mononucleosis is strong repeated testing along with clinical monitoring may be necessary.
Epstein Barr Virus (EBV)
Most cases of infectious mononucleosis are caused by EBV and the hematological effect of EBV are of special interest. This virus is ubiquitous and has specific effect on blood cell morphology, number and is associated in some cases with specific malignancies. BM failure and VAHS (virus associated hemophagocytic syndrome); immune deficiency and X-linked lymphoproliferative disorders. It has also been associated with Burkitt's lymphoma and nasopharyngeal carcinoma. In immunocompromised patients the EBV virus has been responsible for a spectrum of lymphoproliferative disorders and it is also associated with an increased incidence of development of smooth muscle tumor.
In underdeveloped countries, a majority of children EBV infection by the age of 3 to 5 years and majority of these infections are asymptomatic or present as non-specific febrile illness.(27) Later in life in the adolescent age-group EBV infection results in the classical pharyngeal form of infectious mononucleosis with fever, pharyngitis, lymphadenopathy, hepatosplenomegaly, rash, malaise body aches, arthralgias and myalgias. Some children develop and illness which has been termed variably as chronic infectious mononucleosis or chronic active EBV infection or persistent EBV infection.(28)
EBV gains entry into epithelial cells of oropharynx or B lymphocytes of Waldeyer's ring and induces polyclonal B cell proliferation with its ability to immortalize an infected B cell. A neoantigen expressed on EBV infected B cell results in an intense polyclonal T cell immune response. This causes destruction of EBV infected B cell resulting in pharyngitis. EBV infection B cells are polyclonally activated and secrete immunoglobulins with a wide range of specificities with autoantibodies directed against RBC's, WBCs, platelets resulting in AIHA (autoimmune haemolytic anemia), immune thrombocytopenia, and neutropenia. If the T cell response is inappropriate and since the infected B cell are immortalized; uncontrolled proliferation of these cells leads to lymphoproliferative disorders and lymphoma especially in immunocompromised cases.(29) Sometimes immunocompetent patients develop severe hypogammaglobulinemia which improve with time.
Atypical lymphocytosis is the hallmark of infectious mononucleosis with more than 20% atypical cells. Categorization of these cells based on morphology is of little help. Vast majority of these cells are of T cell origin and they protect against EBV infection. The number of B cells increased in the first week of illness and it declines by the 3 rd week. T lymphocyte counts peak by 10 th to 14 th day from onset of symptoms and remain elevated for 5 weeks. Heterophile antibody is so named because the antigen of which this antibody respond is found in more than one species. It agglutinates sheep RBCs and can be completely removed from serum by pre incubation with beef RBCs but only by Guinea pig kidney. The titer of these antibodies rises by third day, peaks at 2 weeks and remains positive for several months. The tests for these antibodies have been replaced by monospot test which is 96 to 99% accurate.
Since EBV is a complex DNA virus, a variety of antibodies to the virus associated antigen has been described. In acute infection there is a rise in antibodies to EA (early antigen) and VCA (viral capsid antigen) early in the course. Antibodies to EA last for 2 to 4 months while antibodies to VCA remain for life. Antibodies to EBNA (Epstein barr nuclear antigen) are the last to appear at 1 to 2 month after the illness. An acute infections thus suggested by the presence of anti EA, IgM, VCA antibodies and a past infection suggested by the presence of IgG anti-VCA and anti-EBNA antibodies. BM and lymph node changes can sometimes lead to a mistaken diagnosis of acute leukemia or non-Hodgkin's lymphoma. Other laboratory abnormalities are listed in the Table (1)
Hematological abnormalities in EBV infection(26)
Increased cold agglutinins
Chronic active EBV Virus Infection
This entity was recognized in early 1980 due to abnormal pattern of anti EBV antibodies pattern. Rickinson proposed the diagnostic criteria(30) for its identification:
- Chronic or recurrent infectious mononucleosis life symptoms lasting for a period of at least a year or longer.
An unusual pattern of EBV antibodies with raised anti EA and/or absent anti EBNA titers, and
No evidence of any prior immunological abnormality or any other recent infection.
The median age of presentation is 6 years with range from 2 months to 12 years with both sexes equally affected. Most of the patients presented with fever, hepatomegaly, splenomegaly and in the course of time, more than half developed anemia, lymphadenopathy, rash, jaundice and diarrhea. Cardiovascular disease and lymphoreticular malignancies are two major complications resulting in mortality. Lymphoreticular disorders seen include VAHS, large granular lymphocytic disorder, B cell lymphoma, monoclonal T cell lymphoproliferation. Autoimmune phenomenon like AIHA, hepatitis, thrombocytopenia are also seen. The outcome of CAEBV infection is extremely guarded with mortality of almost 60 to 90%. This is a distinct syndrome and can provide an important insight into the mechanism of disease with EBV infection.(31)
X-linked lymphoproliferative Disorder
The X-linked lymphoproliferative disorder was first described in 1975 in three families whose male members developed fatal infectious mononucleosis. There are three major phenotypes in X-linked lymphoproliferative syndrome fatal or severe infectious mononucleosis; acquired hypogammaglobulinemia, and malignant lymphoma. Of the males who become affected 70% die due to fatal infectious mononucleosis of those who survive 40% develop lymphoproliferative disorder and all survivors are immunocompromised. Eighty percent have absent or abnormal humoral response. Prior to contracting EBV infection all have normal humoral antibody response to infection. The serology shows a reactivation pattern with high anti-VCA, anti-EA and low anti-EBNA antibodies. BM shows VAHS with cytopenia and hypoplasia. A non X-linked susceptibility to EBV antibodies has been described. The prognosis is guarded and BM transplantation has been shown to cure the illness.(32)
Virus Associated Hemophagocytic Syndrome (VAHS)
Virus associated hemophagocytic syndrome is a distinct clinicopathological entity characterized by systemic proliferation of benign hemophagocytic histiocytes, fever, cytopenias, deranged liver functions, coagulopathy and organomegaly. This entity was for first properly characterized by Risdall et al in 1979 distinguishing this syndrome from malignant histiocytosis.(33) Since then a multitude a diseases other than viral infections have been recognized to be associated with hemophagocytic syndrome. Hence, it has been variably termed as infection associated hemophagocytic syndrome (IAHS) or histiocytic hyperplasia with hemophagocytosis (HHH) or reactive hemophagocytosis (RHS). It is a disorder of cytokine dysregulation with majority of symptoms explained by excess of TNF alpha and interferon gamma. The diagnostic criteria for VAHS are variably defined but should at least include cytopenia involving two cell lines and a readily identifiable hemophagocytic histiocytosis of more than 2% cells in the bone marrow.
The virus commonly associated with VAHS include-EBV, CMV, HSV, adenoviruses, HIV, varicella virus and parvovirus B19 (34) initially Risdall et al described it in immunocompromised patients but has since been observed in patients with normal immunity too.(33) This syndrome has nevertheless been most frequently observed in individuals with underlying immunosuppression allograft recipients, such as those who have been not suffering from leukemias, NHL, Hodgkin's disease and patients with collagen vascular disorder on high doses of steroids.(35) The incidence of VAHS is increasing probably because of the increased awareness of the condition and aggressive use of immunosuppressive agents. The clinical presentation is very often with fever, malaise, myalgia, generalized lymphadenopathy, hepatomegaly, and splenomegaly. The condition should be suspected if there is rapidly developing cytopenias, liver function abnormalities or associated coagulopathy. Bone marrow is cellular with increased mature histiocytes with benign cytologic characteristics with hemophagocytosis of RBCs, WBCs, platelet nucleated RBCs and WBC precursor cells. Since VAHS has been known to occur in a setting of underlying immunosuppression, a search for immunosuppression and lymphoma should be undertaken.(35) Lymph node and liver biopsy also reveal histiocytic hyperplasia with hemophagocytosis. VAHS must be differentiated from malignant histiocytosis as it is a potentially a reversible condition. In VAHS the morphology of histiocytes is benign, hemophagocytosis is prominent, there is lymphoid sinusoidal involvement without destructive effacement of lymph node architecture and skin involvement is not seen.(27) (35) The mortality in VAHS is high and there is at present no specific treatment. In immunosuppressed individuals withdrawal of immunosuppressive agents would help. Specific antiviral therapy has been tried and Immunomodulations with cyclosporine may be tried. Those individuals without underlying immunodeficiency have the best prognosis.(35)
Human immunodeficiency Virus
The main pathophysiology of human immunodeficiency virus (HIV) infection is a constant decline in CD4+ lymphocytes, leading to immune collapse and death. The other bone marrow cell lines also decline in concert with CD4+ cell numbers as HIV disease (acquired immunodeficiency syndrome (AIDS) progresses.
Thrombocytopenia occurs in about 40% of patients with AIDS. Initially, the clinical findings resemble those of immune thrombocytopenic purpura (ITP). Some degree of splenomegaly is common and the platelet-associated antibodies are often in the form of immune complexes that may contain antibodies with anti-HIV specificity. Megakaryocytes are normal or increased and production of platelets is reduced in the bone marrow.
Thrombotic thrombocytopenic purpura (TTP) is also associated with HIV disease. This occurs in advanced AIDS.
Anemia and neutropenia
HIV-infected individuals develop progressive cytopenia as immunosuppression advances. Anemia occurs in approximately 70-80% of patients and neutropenia in 50%. Cytopenias in advanced HIV disease are often of complex etiology and include the following:
A production defect appears to be most common.
Antibody and immune complexes associated with red and white cell surfaces may contribute. Up to 40% have erythrocyte-associated antibodies. Specific antibodies against I and U antigens have occasionally been noted. About 70% of patients with AIDS have neutrophil-associated antibodies.
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