Hematologic Manifestations of Systemic Diseases *

Epidemiology.

EBV infection is acquired at an early age in lower socioeconomic groups. In economically privileged children, infection is often delayed until adolescence and young adulthood. About 40% of American children are seropositive for EBV by 5 years of age. In a report from the U.S. Military Academy at West Point, 63.5% of entering cadets had EBV antibody, indicative of previous infection. During the college years, the infection rate among susceptible individuals is 12% to 15% per year.

The pattern of infection in different groups of susceptible persons is probably best explained by transmission of this virus in throat secretions. EBV is present in the saliva of most patients with infectious mononucleosis, in up to 20% of healthy persons with EBV antibodies, and in 50% or more of seropositive patients receiving immunosuppressive drugs. The ease with which EBV is recovered from the oral secretions of persons with primary or reactivated EBV infection suggests that a cell type that freely permits EBV replication exists in the oropharynx. The oropharyngeal epithelial cell may be the target cell type that is productively infected in infectious mononucleosis. Transmission requires intimate contact. Intrafamilial spread, however, does occur frequently, and, in this setting, an incubation period of 4 to 6 weeks has been demonstrated. Another possible route of transmission of EBV is transfusion through white blood cells.

Clinical Manifestations.

The classic clinical manifestations of infectious mononucleosis are generally seen only in adolescents and young adults. Younger children rarely exhibit the typical findings of this disease, and most generally have only a mild viral respiratory illness.

The onset of typical illness is usually a subtle prodrome consisting of fatigue, malaise, sweating, feverishness, and anorexia. Headache, nausea, and vomiting are seen frequently. The most common symptom during this period is a sore throat, which begins slowly and increases in intensity over a 1-week period. The usual findings of infectious mononucleosis then follow ( Table 37-1 ). The course of fever often follows a specific pattern, with no temperature elevation in the morning but daily afternoon or evening peaks of 38.3° C to 39.4° C (101° F to 103° F). Occasionally, higher temperatures are observed. The fever usually lasts about 2 weeks.

Lymphadenopathy is seen in all patients. Symmetric, moderately enlarged, discrete, slightly tender nodes, especially in the posterior cervical region, are most characteristic. Adenopathy is common in the axillary, epitrochlear, and inguinal areas. The nodes are not matted and do not show signs of heat, redness, or fluctuation. Rarely, enlargement of the mediastinal glands constitutes the only evidence of adenopathy and may be confused with a lymphomatous process.

Splenomegaly occurs in more than 50% of patients with infectious mononucleosis. The spleen is usually just barely palpable but on rare occasion may be quite large. It is smooth, soft to firm, and sometimes slightly tender. In some patients, splenomegaly persists for months, but the most common situation is resolution by 2 to 3 weeks after onset of the illness.

Hepatomegaly occurs in about 20% of patients, and clinical jaundice is seen in 10%. The jaundice is invariably mild. Despite the low rate of occurrence of apparent hepatic dysfunction, virtually all patients with infectious mononucleosis demonstrate abnormal liver enzyme levels. Except in rare patients with acute liver failure, the hepatitis associated with this illness is self-limited. There is no evidence that chronic liver disease or cirrhosis results from infectious mononucleosis.

Rashes occur occasionally, and their manifestation follows no particular pattern. The rash may be a diffuse, faint, erythematous or maculopapular eruption, or it may be urticarial, scarlatiniform, petechial, or herpetiform. In general, the rashes of infectious mononucleosis have no unique features and are of little or no help for diagnosis. Circulating immune complexes and complement sequence activation occur only when rashes are present. If ampicillin is administered to patients with infectious mononucleosis, a rash will develop in 69% to 100%. Other penicillins may cause this response but less often. This rash is not an allergic reaction, and these antibiotics may be administered subsequently without ill effect.

Only a few patients with infectious mononucleosis have no pharyngitis. Almost all demonstrate hyperplasia of the pharyngeal lymphoid follicles. The presence of an exudate is common, and membrane formation occurs frequently. The inflammation may be severe enough to cause respiratory obstruction. Peritonsillar abscesses may complicate the course of the illness. A palatal enanthema is seen in about a third of patients and consists of crops of sharply circumscribed petechiae, symmetrically distributed at the junction of the soft palate. Unfortunately, such petechiae are not specific for infectious mononucleosis and have been described in rubella and other viral disorders. In fact, the entire pharyngeal manifestation of infectious mononucleosis is clinically indistinguishable from that of streptococcal disease.

Periorbital edema is not rare and occasionally leads to the erroneous suspicion that renal disease or hypoproteinemia is present. The edema is self-limited and lasts only a few days.

Complications.

Much attention is paid to the complications associated with infectious mononucleosis, although their overall occurrence is low ( Table 37-2 ). Hematologic complications of infectious mononucleosis include disturbances resulting in anemia, granulocytopenia, thrombocytopenia, and occasional coagulation defects. The rate of occurrence of these hematologic abnormalities is shown in Table 37-3 .

AIHA can occur with EBV infection and developed in approximately 3% of West Point cadets with infectious mononucleosis. When hemolysis does occur, it usually begins 1 to 2 weeks into the course of the illness. The majority of occurrences terminate in less than 1 month, and chronic hemolysis is rare. Although usually mild, hemolysis occasionally occurs rapidly and can then result in severe anemia. Jenkins reported the first instance of hemolytic anemia in infectious mononucleosis that was mediated by the temporary induction of a high-thermal amplitude cold agglutinin of anti-i specificity. Since then, several series have verified the high incidence of anti-i antibody as the cause of immune-mediated hemolysis in infectious mononucleosis. It should be noted that although hemolysis is not common in infectious mononucleosis, the presence of anti-i is seen in as many as 50% of all patients. Not all instances of immune hemolysis in infectious mononucleosis are caused by anti-i antibodies. Anti-N antibodies have also been reported, and in some patients the nature of the antibody has not been identified.

Aplastic anemia has been reported to follow the onset of infectious mononucleosis. Aplastic anemia caused by EBV infection has also been reported after bone marrow transplantation. Localization of EBV in the bone marrow of some patients with aplastic anemia supports a causative role of the virus in these aplastic anemia patients.

Granulocytopenia is common during the acute phase of infectious mononucleosis. It is rarely severe but, on occasion, is associated with a secondary bacterial infection. Bone marrow myeloid hyperplasia with myeloid arrest is the most typical finding. Spontaneous resolution is the rule.

Immune thrombocytopenia occurs rarely in infectious mononucleosis. Most occurrences of thrombocytopenia are mild. The signs and symptoms of severe occurrences are similar to those of primary ITP. Severe hemorrhagic complications are rare. Treatment of the thrombocytopenia of infectious mononucleosis in children is guided by bleeding symptoms. Treatment approaches are similar to primary ITP with first-line therapies with corticosteroids and/or intravenous immune globulin.

The incidence of the neurologic complications reported varies from 0.37% to 7.3%, depending on the series. A rare occurrence in adolescence is the “Alice in Wonderland” phenomenon in which objects are visualized in a very distorted fashion, with exaggerations in size, being either too large or too small. A transverse myelopathy characterized by a sudden onset of profound weakness of the lower extremities and urinary retention may complicate the clinical course of infectious mononucleosis.

Cardiac complications are rare and occur in 1% to 6% of reported series. They usually consist of only nonspecific T-wave changes or minor conduction abnormalities. Myocarditis and pericarditis are rare. Liver function abnormalities are rarely severe, although enzyme changes are common. Primary EBV infection has been associated with a Reye syndrome–like illness. Severe liver dysfunction causing death is a common complication of EBV infection in the X-linked lymphoproliferative syndrome. Hepatic dysfunction is uniformly present with this disorder at the time of death and is the cause of death in about a third of such patients. An unusual manifestation of infectious mononucleosis is intense jaundice. It generally results from a combination of hemolysis and mild hepatitis. Spontaneous rupture of the spleen may occur.

Respiratory difficulties usually consist of upper airway obstruction. Transient interstitial infiltrations, some with effusions, have been recorded. Infectious mononucleosis should be considered in the differential diagnosis of any child with pleural effusions. Renal complications of infectious mononucleosis generally consist of hematuria associated with a mild nephritis. Not all occurrences have been clearly separated from poststreptococcal glomerulonephritis. Severe rhabdomyolysis can be associated on rare occasion with EBV infection. Eye findings in infectious mononucleosis are unusual but may be significant when they do occur. Severe retinochoroiditis is such an ocular complication. In some patients with infectious mononucleosis, lethargy, particularly daytime lethargy, is seen for prolonged periods, often longer than a year.

X-linked lymphoproliferative syndrome is associated with fatal or severe infectious mononucleosis, acquired hypogammaglobulinemia, and malignant lymphoma. Details about X-linked lymphoproliferative syndrome can be found in Chapter 24 .

A variety of malignancies have been linked to EBV, including clonal T-cell proliferations. In patients who undergo transplantation, a spectrum of lymphoproliferative diseases may occur as a result of activation of EBV. These diseases may vary from an infectious mononucleosis–like polyclonal B-cell proliferation to a monoclonal B-cell lymphoma. EBV infection can also result in a hemophagocytic syndrome. The total spectrum of the rare complications and unusual syndromes associated with EBV infection have been reviewed by Timár and colleagues.

Laboratory Diagnosis.

Atypical lymphocytosis is the hallmark of infectious mononucleosis ( Fig. 37-10 ). Several attempts have been made to classify these abnormal cells on morphologic grounds, the best known method being that of Downey and McKinlay. However, it is clear that atypical lymphocytes cannot be easily classified into separate categories and that a spectrum of cell types exists. In general, the atypical lymphocytes of infectious mononucleosis are large, but they vary in size considerably. Their outlines are irregular, and many cells show a characteristic tendency to flow around adjacent erythrocytes. Nuclei are large and usually eccentrically located and pleomorphic, with abundant coarse chromatin and occasional nucleoli. The cytoplasm is generally abundant and typically basophilic. Cytoplasmic vacuoles may be seen. These types of cells are not morphologically specific for infectious mononucleosis and can be seen in other viral infections and after administration of a number of medications.

The vast majority of atypical lymphocytes from patients with infectious mononucleosis are thymus derived. These atypical cells possess human T-lymphocyte–specific antigens, as well as sheep erythrocyte receptors. T lymphocytes appear to lack receptors for EBV, and it would appear that only B lymphocytes are infected by this virus. A possible unifying interpretation of the role of T lymphocytes is that these cells represent an immune reaction that protects against this potentially oncogenic virus. Increased numbers of B cells are found during the first week of illness and decline to normal levels in 3 weeks. T lymphocytes reach their peak later, usually 10 to 14 days after the onset of symptoms, and remain elevated for 5 weeks. There may be an early reversal of the ratio of T to B lymphocytes, with a subsequent increase in the percentage of T cells during the second through fifth weeks of illness. It is possible that both T and B cells may be “transformed” into atypical lymphocytes—B cells by infection with EBV and T cells by an immunologic response to viral antigen itself—or the B cells may respond to altered antigens on their surface. EBV-infected B lymphocytes account for only a minority of the atypical lymphocytes found in peripheral blood. In the very early stages of symptomatic illness, however, nearly 20% of all B cells in the circulation may be infected with the virus. The majority of atypical lymphocytes are T lymphocytes. Natural killer (NK) cell activity has been shown to be present during the acute phase of infectious mononucleosis. Interferons, which are inducers of NK cell activity, may have an inhibitory effect on the outgrowth of EBV-infected B lymphocytes in vitro. Significant anergy and diminished lymphocyte responsiveness in vitro to mitogens and antigens exist during the first week of illness. These lymphocyte changes are reflected in a great increase in uric acid turnover, with 55% of infected patients having serum uric acid levels of 8 mg/dL or higher.

Patients with infectious mononucleosis have lymph node pathologic findings that are easily confused with lymphoma. The nodal architecture is distorted by large, dark lymphoid cells, and the capsule may be infiltrated. Reed-Sternberg cells have been reported on several occasions. Pathologic changes are not confined to lymphoid tissue, however. Perivascular cuffing of the brain vasculature, inflammation of the liver, and inflammatory infiltration of the kidney and bone marrow have been repeatedly observed.

The heterophil antibody is so named because the antigen to which the antibody reacts is found in more than one species. The antibody, like anti-i, is an IgM macroglobulin. It agglutinates sheep red blood cells and can be removed completely from serum by preincubation with beef red blood cells but not with guinea pig kidney. Heterophil antibody titers usually increase after the third day of illness, peak at 2 weeks, and may remain positive for several months before ultimately becoming negative (unlike the antibody specific for EBV). This traditional Paul-Bunnell serologic agglutination method has been largely replaced for screening purposes by the spot test, in which finely ground guinea pig kidney or beef red blood cell stroma is added to serum on a slide, followed by a drop of horse cells. Results of the test are considered positive if agglutination occurs in the presence of guinea pig kidney (which absorbs out Forssman antibody but not heterophil antibody) but are negative with beef red blood cell stroma. The spot test requires only 2 minutes and is 96% to 99% accurate. Results of both the Paul-Bunnell test and the spot test are usually negative in preschool-aged children, in whom heterophil antibody production is limited. This age group does produce diagnostic levels of EBV-specific antibody.

EBV is a herpeslike DNA virus. It is a relatively complex virus, and a variety of virus-associated antigens have been described. Antibodies to viral capsid antigen (VCA) and early antigen (EA) are detected early after the onset of EBV-associated infectious mononucleosis. Levels of antibodies to VCA reach their peak at about 3 weeks after the onset of clinical illness. Their levels decline somewhat thereafter, but they remain for life. Antibodies to EA usually last 2 to 4 months. EA has two components that are differentiated by their immunofluorescent staining: “D” for diffuse and “R” for restricted staining. A technique for determining EBV-specific IgM has been described. EBV-specific IgM almost always occurs in the acute phase of infectious mononucleosis. It rarely persists more than 2 to 3 months. During this period, virus shedding from the oropharynx is easily demonstrable.

Figure 37-11 shows the characteristic antibody patterns observed in young adults with EBV-induced infectious mononucleosis. Before infection, no antibodies are present. During the acute phase of illness, high titers of IgM and IgG antibodies to VCA are seen. IgM antibodies are transient and disappear after 1 to 2 months. Antibodies appearing against EA disappear after a few weeks to months. Antibodies against Epstein-Barr nuclear antigen are the last to appear and are seen 1 to 2 months after the illness. In young infants, VCA IgM is found in only 60% of patients and EA antibody is identified in only 50%. The only persistent antibody response should be VCA IgG and antibodies to Epstein-Barr nuclear antigen.

Treatment.

There is no evidence that bed rest or rest in general shortens the clinical course of infectious mononucleosis. Patients will determine their own level of activity. The most significant risk during acute illness is splenic rupture, but its incidence is extremely low.

Corticosteroid therapy is often used for infectious mononucleosis. Although these agents may produce improvement of symptoms, enhancement of general well-being, and reduction of fever, their use for these purposes should be restricted. Less controversial is the use of corticosteroid therapy for patients with airway obstruction secondary to tonsillar hypertrophy, severe hemolytic anemia, or thrombocytopenia and bleeding.

Epidemiology.

In the early 1980s, a newly described constellation of symptoms that resulted from immune compromise and led to death from opportunistic infections and unusual malignancies was recognized. These early descriptions of what is now known as acquired immunodeficiency syndrome (AIDS) heralded the beginning of what has become one of the major medical, public health, and social issues of our time. Identification of the human immunodeficiency virus (HIV), a retrovirus, as the etiologic agent that transmits the disease has led to major advances in understanding the pathogenesis of AIDS. At least two types of HIV, HIV-1 and HIV-2, exist; both are considered lentiviruses based on similarities in genetic composition, mechanisms of replication, and interaction with their hosts. A characteristic of lentivirus infections is that they cause slowly progressive disease with an incubation period of months to years before clinical symptoms appear. The worldwide spread of AIDS has led to a plethora of information about the biology of the virus and its epidemiology and incidence projections in different countries, as well as a concerted search for effective means of prevention and treatment.

The first occurrences of AIDS in the pediatric population in the United States took place in children born to mothers infected with HIV or in children, especially neonates, who had received blood products contaminated with HIV. The AIDS pandemic in Africa and, in particular, southern Africa has reached catastrophic proportions. The incidence of the disease in eastern Europe, India, and Thailand and throughout most of the Third World poses many political, social, and medical challenges, a discussion of which that is beyond the scope of this chapter.

Transmitted primarily through contact with infected lymphocytes and monocytes, HIV may be found in blood, semen, and vaginal secretions. Isolation of the virus from 13- and 15-week abortuses, placenta, and cord blood provides strong support for intrauterine infection. Maternal-fetal transfusion at delivery is another possible route of infection. Postpartum transmission via breastmilk, although possible, is rare. Accordingly, in countries in which safe feeding substitutes are not readily available, breastfeeding should not be curtailed; however, in developed countries where alternatives exist, breastfeeding by HIV-infected women is discouraged.

The rate of transmission from an untreated mother to child is estimated to be about 25% based on several studies from the United States and Europe. Transmission from mother to child can be significantly reduced by the use of antiretroviral therapy during pregnancy, labor, and the neonatal period.

Major advances in screening and testing of the blood supply in the United States after 1985 led to a reduction in the risk of receiving a contaminated single transfusion in 1988 to 1 in 250,000. The first screening test is a questionnaire to exclude people who engage in high-risk activities. The next step is an enzyme-linked immunosorbent assay (ELISA) for detection of antibodies to HIV antigens. In rare individuals who are infected but seronegative, HIV can escape detection, but sensitive screening tests detect the viral genome by PCR assay. Tragically, individuals with bleeding disorders such as hemophilia A and B who received clotting factors from a large donor pool for a single infusion had an increased likelihood of acquiring AIDS before modern blood screening practice and factor preparation.

Clinical Manifestations.

Infection with HIV results in a spectrum of disease from an asymptomatic state to severe immunodeficiency involving multiple organ systems. The heterogeneity of symptoms is explained by the underlying pathophysiologic course in that (1) the incubation period may be weeks, months, or years; (2) the direct cytopathic effect on target cells, predominantly CD4+ lymphocytes, monocytes, and accessory cells, results in dysregulation of the immune system; and (3) the viral elimination phase that is accompanied by a host response to infection varies with the immune competence of the host. Because many children are infected congenitally, they show signs early in life and often have constitutional symptoms such as unexplained diarrhea, fever, night sweats, generalized lymphadenopathy, and hepatosplenomegaly. Failure to thrive and developmental delay are often prominent early manifestations of HIV infection in children. Susceptibility to recurrent infections by common bacterial and viral pathogens, as well as to opportunistic infections, increases the index of suspicion that the underlying disorder is AIDS. These and other manifestations of HIV infection are summarized in Box 37-1 .