Granulomatous lesions in the bone marrow in infectious mononucleosis; a comparison of the changes in the bone marrow in infectious mononucleosis with those in brucellosis,tuberculosis, sarcoidosis and lymphatic leukemia

1. The findings in the blood and in aspirated bone marrow in 23 cases of infectious mononucleosis have been described.

2. Unequivocal evidence of involvement of the bone marrow has been found in70 per cent of the cases.

3. Evidence of granulomatous inflammation of the marrow was found in 48 percent of the cases.

4. Epithelioid cells were found in the films of bone marrow in 48 per cent of thecases. These cells appear morphologically identical with those seen in imprints oflymph nodes from infectious mononucleosis and sarcoidosis and with the epithelioid cells seen in films of the marrow in brucellosis, sarcoidosis and tuberculosis.

5. The granulomatous lesions of infectious mononucleosis seem most similar tothose of brucellosis, but they also resemble the small granulomatous lesions ofsarcoidosis and tuberculosis.

6. Lymphocytosis of the marrow as well as of the blood was demonstrated in allcases. Evidence of formation of lymphocytes in the marrow was presented, and thealtered lymphocytes of infectious mononucleosis were found in films of the marrow.The degree of lymphocytosis of the marrow in infectious mononucleosis was shownto be less than that in lymphatic leukemia. Lymphocytosis of the marrow was notfound in brucellosis, sarcoidosis or tuberculosis. The lymphocytic reaction demonstrable in the marrow in infectious mononucleosis is believed to be of value in differential diagnosis.

Note: ACKNOWLEDGMENTSWe wish to acknowledge the generous cooperation of Dr. Ruth E. Boynton and the Staff of theStudent’s Health Service of the University of Minnesota throughout the course of this year long studyof infectious mononucleosis. We are indebted to Dr. T. Edward Bell and Dr. James Cardy for performingthe sternal aspirations. The photomicrographs were made by Mr. Henry Morris.

     

Primary infection with Epstein-Barr virus in infants in the United States: clinical and serologic observations.

Previous studies in Ghana had shown that primary infections with Epstein-Barr virus in infants under the age of two years remain silent and evoke antibody responses different from those seen in infectious mononucleosis. In order to determine whether or not these observations were limited to Africa, 80 American infants presenting with minor infectious complaints were studied serologically; 14 (17.5%) showed evidence of recent or current primary infections with Epstein-Barr virus. The clinical features of these 14 infants were similar to those of the other 66 and did not suggest a diagnosis of infectious mononucleosis, nor were there histories of a recent infectious mononucleosis-like illness. Ten (72%) had antibodies to the early antigen complex induced by Epstein-Barr virus; however, these antibodies were directed, as in the Ghanaian infants, against the restricted rather than the diffuse components, in contrast to the pattern generally observed in infectious mononucleosis. Possible reasons for the differences between the responses of infants and those of older individuals to primary infection with Epstein-Barr virus and to the early antigen complex are discussed.     

Diagnostic evaluation of mononucleosis-like illnesses

Clinicians face a diagnostic challenge when a patient with the classic fever, pharyngitis, and lymphadenopathy triad of infectious mononucleosis has a negative “spot” heterophile antibody test. This screening test, although commonly considered sensitive for the presence of Epstein-Barr virus (EBV) infection, may be negative early after infection. A growing number of pathogens have been reported to cause heterophile-negative mononucleosis-like illnesses, including cytomegalovirus (CMV), human herpesvirus 6 (HHV-6), human immunodeficiency virus (HIV), adenovirus, herpes simplex virus (HSV), Streptococcus pyogenes, and Toxoplasma gondii. Other infectious and noninfectious disorders also may present in ways that mimic mononucleosis, but fail to generate EBV’s archetypal triad of clinical findings. A systematic approach to the diagnosis of mononucleosis-like illnesses ensures that conditions warranting specific therapy are distinguished from others requiring only supportive care.     

Epstein-Barr virus and the elderly host

The ability of the Epstein-Barr virus (EBV) to cause latent lifelong infection in the host and its capabilities of transformation may have important implications for the elderly host. Reports in the literature and hospital records were reviewed to determine the activity of EBV in the elderly. Seroepidemiologic surveys demonstrated that 90%-97% of adults more than 60 years old were seropositive for EBV. Geometric mean antibody titers and the percentage of individuals with high antibody titers to EBV increased with age--changes that were not associated with clinical illness. Only 29 cases of infectious mononucleosis have been reported in adults more than 60 years old. The elderly with infectious mononucleosis had significantly fewer occurrences of pharyngitis, lymphadenopathy, and splenomegaly when compared with young adults. The cases of two patients with illnesses that did not meet full criteria for infectious mononucleosis but may still have represented clinical manifestations of EBV infection are presented. Other EBV-associated diseases reported in the elderly include nasopharyngeal carcinoma and possibly B cell lymphoproliferative disease but not a chronic mononucleosis-like syndrome.     

Atypical sarcoidosis: a case report and literature review

An African American man was admitted with multiple systemic symptoms. The work-up revealed a unilateral cavitary lung mass with hilar adenopathy, sub-centimeter abdominal mesenteric lymph nodes, and a natural killer cell lymphocytosis in the bone marrow. Transbronchial biopsy revealed areas of noncaseating granulomas suspicious for sarcoidosis. Additional studies for infectious and malignant agents were negative.     

Characteristic bone marrow findings in patients with UBA1 somatic mutations and VEXAS syndrome

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is a newly characterized syndrome with underlying somatic UBA1 mutations in myeloid cells linking hematologic disease with autoinflammatory rheumatologic disorders. Hematologic abnormalities, particularly peripheral blood cytopenia(s) may prompt bone marrow evaluation in patients with known or unrecognized VEXAS syndrome. This review highlights key findings and diagnostic considerations encountered during bone marrow examination in patients with this disorder. Frequently reported hematologic changes include macrocytic anemia, cytoplasmic vacuoles in myeloid and erythroid precursors, marrow hypercellularity, and varying degrees of dysplasia. Myelodysplastic syndrome and plasma cell neoplasms have been diagnosed in patients with VEXAS syndrome. Macrophage activation syndrome and/or hemophagocytic lymphohistiocytosis and monoclonal B-cell lymphocytosis have also been reported. The bone marrow is a target organ in VEXAS syndrome. Heightened awareness of the bone marrow features and hematologic complications may aid in identifying individuals with VEXAS who may benefit from increased disease surveillance or alternative therapeutic strategies.     

Acute granulomatous disease of the liver

Summary Although the medical literature stresses the chronic nature of hepatic granulomas, we encountered, during a time span of several months, 2 patients with an acute febrile illness and hepatic involvement. Liver biopsy in both revealed epithelioid and mononuclear cell granulomas throughout the liver. Both patients had lymphocytosis and atypical forms in the peripheral blood. Heterophile antibody titers, performed multiple times in the course of their illnesses, were normal. Both patients recovered, 1 after 3 weeks and 1 after 6 weeks.Prior to our experience with these patients, we encountered 2 other patients who had similar clinical and laboratory findings. Because we were not sufficiently aware of the diagnostic possibilities, and because they were getting better, liver biopsy was not performed. Only after the third case was encountered were our suspicions aroused.There is one similar report in the literature. The clinical and laboratory features in their patients and in ours suggest an infectious mononucleosis-like illness. Similar biopsy findings are occasionally encountered in heterophile antibody-positive infectious mononucleosis. Our cases may be a new disease entity or a variant of one previously described.     

Epstein-Barr virus in the bone marrow of patients with aplastic anemia

STUDY OBJECTIVE: To determine whether Epstein-Barr virus is present in the bone marrow of patients with aplastic anemia. DESIGN: Assay of fresh and fixed bone marrow specimens for Epstein-Barr virus using immunofluorescence for nuclear antigen, Southern analysis with an Epstein-Barr virus specific probe, and in-situ hybridization. SETTING: Governmental medical referral center. PATIENTS: Five patients were studied prospectively: three who previously had infectious mononucleosis, one with a recent viral pneumonitis, and one who was asymptomatic. Stored DNA samples from other patients with aplastic anemia were also screened. MEASUREMENTS AND MAIN RESULTS: Epstein-Barr virus DNA and protein were detected in the bone marrow of 5 patients studied prospectively and in 1 of 40 patients studied retrospectively. As estimated by in-situ hybridization, about 3% to 5% of marrow cells were infected with virus in those patients who had not received acyclovir. In contrast, Epstein-Barr virus DNA was not detected in peripheral blood DNA of these patients, nor were Epstein-Barr virus proteins or DNA found in the bone marrow of normal donors, patients with other hematologic diseases, or in 1 patient with acute infectious mononucleosis. Analysis of DNA fragments by hybridization with Epstein-Barr virus probes showed a pattern dissimilar to the type of Epstein-Barr virus usually associated with infectious mononucleosis. CONCLUSIONS: Aplastic anemia may be associated with Epstein-Barr virus more commonly than suspected by history. Localization of the virus in the bone marrow supports a causative role for Epstein-Barr virus in bone marrow failure.     

Unexplained bone marrow granulomas: Is amiodarone the culprit? A report of 2 cases

Granulomas in the bone marrow are usually caused by infectious or hematological diseases, and drugs are only rarely implicated as causative agents. Recent reports have drawn attention to the role of amiodarone in the etiology of bone marrow granulomas. We report two cases of amiodarone-induced bone marrow granulomas in patients being investigated for refractory anemia and pancytopenia, respectively. Since both patients had life-threatening arrhythmias, discontinuation of the drug followed by rechallenge was not possible. Both patients did well in spite of continued amiodarone therapy, indicating that the underlying hematological illnesses were unrelated to the granulomas. Amiodarone should be considered as a possible cause of bone marrow granulomas after the exclusion of other causes. Continued use of amiodarone after granuloma formation must be dictated by the underlying cardiac condition.     

Drug-induced mononucleosis-like hepatic injury in a patient with systemic lupus erythematosus

A case of systemic lupus erythematosus (SLE) with mononucleosis-like hepatic injury was described. An emergent cesarean section was performed in a 25 yr-old house wife at 34 weeks gestation, followed by administration of several antibiotics. After the surgery she complained of high fever, hepatomegaly and dull right hypochondralgia, and mild liver dysfunction was also found. The liver biopsy showed prominent mononuclear cell infiltration in the sinusoids with minimum hepatocellular necrosis and mild triaditis, resembling hepatic lesion in infectious mononucleosis (mononucleosis-like injury). There were no clinical and serological features suggestive of infectious mononucleosis. This hepatic lesion was thought to be a manifestation of allergic reaction to drugs to which the lymphocyte stimulation test was found to be positive. Immunological abnormalities inherent in SLE might be related to occurrence of such allergic drug reaction.     

Drug-induced mononucleosis-like hepatic injury in a patient with systemic lupus erythematosus

A case of systemic lupus erythematosus (SLE) with mononucleosis-like hepatic injury was described. An emergent cesarean section was performed in a 25 yr-old house wife at 34 weeks gestation, followed by administration of several antibiotics. After the surgery she complained of high fever, hepatomegaly and dull right hypochondralgia, and mild liver dysfunction was also found. The liver biopsy showed prominent mononuclear cell infiltration in the sinusoids with minimum hepatocellular necrosis and mild triaditis, resembling hepatic lesion in infectious mononucleosis (mononucleosis-like injury). There were no clinical and serological features suggestive of infectious mononucleosis. This hepatic lesion was thought to be a manifestation of allergic reaction to drugs to which the lymphocyte stimulation test was found to be positive. Immunological abnormalities inherent in SLE might be related to occurrence of such allergic drug reaction.     

Cold agglutinins in infectious mononucleosis and heterophil-antibody-negative mononucleosis-like syndromes.

Cold agglutinins (CA) were evaluated prospectively in patients with various mononucleosis syndromes and in a large control group. Cold agglutinins with anti-i specificity were seen mainly in heterophil-positive or -negative Epstein-Barr virus (EBV)-induced infectious mononucleosis (31.8% of cases). Unclassified CA with equal reactivity against cord and adult erythrocytes were seen in 56 of 150 (37.3%) cases of heterophil-antibody-positive infectious mononucleosis (IM), in 1 of 7 (14.3%) cases of heterophil-negative EBV-induced IM, and in 12 of 31 (38.7%) cases of the heterophil-negative mononucleosis-like syndrome due to cytomegalovirus or other unspecified agents. One patient with heterophil-positive IM had a persistent, partially papain sensitive CA with anti-Pr-like activity. Anti-i CA were seen in less than 1.0% of healthy young adults (500) or patients without mononucleosis (500) submitted for heterophil studies. Unclassified CA were noted in 3.2% of the latter 1000 samples.     

Mononucleosis syndrome and acute monocytic leukemia

The association of infectious mononucleosis and an immunocompromised host such as occurs in acute leukemia is reported. The most common cause of infectious mononucleosis is Epstein-Barr virus (EBV) and cytomegalovirus (CMV). Patients with mononucleosis syndrome caused by other agents are rare. We report a case of acute monocytic leukemia (AMoL) who developed varicella zoster virus (VZV) mononucleosis syndrome in the bone marrow recovery phase after myelosuppression due to high-dose cytarabine. Mononuclear leukocytes appearing during the mononucleosis syndrome were very similar to the initial leukemic cells. Varicella zoster virus mononucleosis syndrome was confirmed by delayed herpes zoster rash with dermatomal distribution.     

Postsplenectomy Cytomegalovirus Mononucleosis is a Distinct Clinicopathologic Syndrome

Lymphocytosis in response to viral infection, such as infectious mononucleosis, rarely exceeds 20 × 10⁹/L in the adult population. Transfusion-acquired cytomegalovirus (CMV) mononucleosis after trauma-related splenectomy may cause prominent lymphocytosis, but the history and timing usually hint at the diagnosis. We describe a case of severe CMV mononucleosis that was acquired naturally decades after splenectomy. Together with the 2 similar cases that we reported recently, these cases all presented as initial diagnostic challenge because of a remote history of splenectomy, a prolonged febrile illness (~ 4 weeks), marked lymphocytosis (peak 27.9 × 10⁹/L), and undetectable or weakened anti-CMV IgM antibody response. The diagnosis was eventually established through detection of circulating CMV antigen or DNA and a year or longer follow-up with serial determination of IgM and IgG antibodies. Two similar cases were also identified in the literature and reviewed. Although the impaired IgM response may confuse the diagnosis, it correlates well with recent studies showing that human blood IgM memory B cells are circulating splenic marginal zone B cells; asplenic or splenectomized individuals, irrespective of the underlying cause, have undetectable IgM memory B cells. Together, these findings suggest that distant or recent postsplenectomy CMV mononucleosis represents a distinct clinicopathologic syndrome resulting from poor control of early viremia because of the lack of both splenic filtration and the typical brisk IgM response. For the practicing clinician, recognizing these features may aid timely diagnosis and treatment.     

Primary human immunodeficiency virus infection. Clinical and serologic aspects

The identification of characteristic clinical, serologic, and immunologic responses to primary HIV infection has contributed greatly to our understanding of the natural history of HIV infection. Subjects usually present with a mononucleosis-like illness and during the period of primary infection there is a characteristic four-phase T cell response. Early serologic findings of infection include IgM antibody and free HIV p24 antigen. Tests for mononucleosis yield negative results, but atypical lymphocytosis may be present. We believe there are three primary goals for future research into primary HIV infection: to further define the features of this phase of infection, to develop early intervention strategies effective against HIV, and to further develop and foster education strategies that will prevent primary HIV infection.     

Hematologic differences in heterophile-positive and heterophile-negative infectious mononucleosis

Infectious mononucleosis (IM) due to all causes is characterized by atypical lymphocytosis. We sought to compare hematologic parameters of infectious mononucleosis due to Epstein-Barr virus (EBV) infection (heterophile antibody (HA) positive) with mononucleosis due to other causes. Mono-Latex Slide Agglutination Test results and complete blood counts (CBC) of 147 patients with mononucleosis were retrospectively analyzed. Leukocyte count, absolute lymphocyte count, and presence of atypical lymphocytes in EBV-positive and EBV-negative groups were statistically compared. We analyzed 68 EBV-positive and 79 EBV-negative cases. EBV-positive patients were significantly younger than EBV-negative patients were. Mean total WBC count and mean absolute lymphocyte count were significantly higher in EBV-positive patients. Absolute lymphocytosis, absolute leukocytosis, and atypical lymphocytosis were also significantly more frequent in EBV-positive patients. Leukopenia was more frequently seen in EBV-negative patients.     

Use of cloned probes to detect Epstein-Barr viral DNA in tissues of patients with neoplastic and lymphoproliferative diseases

Cloned fragments of the Epstein-Barr virus (EBV) genome were used to examine tissues from 145 patients for the presence of EBV DNA by two techniques: (1) nucleic acid hybridization of cell spots from which the DNA had been extracted in situ and (2) hybridization of DNA that had been transferred to nitrocellulose by Southern blotting. EBV DNA was found in tissues from four adults and five children with American Burkitt's lymphoma, infectious mononucleosis, lymphoma following bone marrow transplant, central nervous system lymphoma, nasopharyngeal carcinoma, and fatal polyclonal B-cell lymphoma following mononucleosis; two patients also had chronic pneumonitis, failure to thrive, and abnormal immune function. Six of the nine patients whose tissues contained EBV DNA had a demonstrable or presumed associated immunologic disorder. EBV DNA was not found in normal tissues or in a variety of hematologic neoplasms and other disorders. Nucleic acid hybridization methods can be used for the routine examination of the association of EBV with lymphomas and other lymphoproliferative syndromes occurring in immunodeficient individuals.     

Paroxysmal nocturnal hemoglobinuria associated with infectious mononucleosis.

A previously healthy 16-yr-old girl was found to have pancytopenia, low reticulocyte count, a cellular bone marrow, and a negative Coombs test, all coincident with clinical and laboratory evidence of infectious mononucleosis. Symptoms and signs of infectious mononucleosis subsided, but pancytopenia and hemolytic anemia persisted. Sucrose hemolysis and acid hemolysis tests supported a diagnosis of paroxysmal nocturnal hemoglobinuria (PNH). After 18 mo, the platelet count is normal, but leukopenia and hemolytic anemia continue. The development of PNH in this patient suggests it may have resulted from an effect of infectious mononucleosis.     

The relationship between atypical lymphocytosis and serological tests in infectious mononucleosis

The relationship between serological tests for infectious mononucleosis was compared with atypical lymphocytosis in one hundred cases with clinical features of the disease. All blood samples showed atypical lymphocytosis greater than 20 per cent of the total leucocyte count. Positive serological tests were obtained in 69 of these patients, whereas in patients with more than 40 per cent atypical lymphocytosis all had positive serology. Of the 31 patients with negative serological tests for infectious mononucleosis, significant antibody titres to Toxoplasma gondii were obtained in five and to cytomegalovirus in two. Twenty-four patients remained undiagnosed. The Paul-Bunnell-Davidsohn positive patients had a significantly higher white cell count, lymphocyte count and atypical lymphocyte count than the toxoplasmosis group or the undiagnosed group.     

Atypical infectious mononucleosis in a patient receiving tumor necrosis factor alpha inhibitory treatment

The objective is to report a case of atypical acute infectious mononucleosis in a juvenile ankylosing spondylitis patient who was treated with infliximab. A 20-year-old man was hospitalized for the evaluation of lymphadenopathy and systemic symptoms. His symptoms developed at the eighth week of the infliximab treatment and he required hospitalization. Lymph node biopsy was performed and he was diagnosed as atypical infectious mononucleosis (absence of fever, pharyngitis, lymphocytosis and negative atypical lymphocytosis on blood smear). Infections have become major concerns in patients treated with TNF-blocking agents. In theoretical base, it is not surprising as TNF-α has a crucial role in the body’s defense against both bacterial and viral invasion. Blocking the action of TNF may also change the course of the disease and could lead to a delay in the diagnosis. TNF-α-blocking treatment may mask the typical symptoms of infectious mononucleosis and atypical cases should be included in the differential diagnosis of lymphadenopathy in patients receiving anti-TNF-α agents.