Infectious mononucleosis in older adults
Although infectious mononucleosis is readily diagnosed in adolescents and young adults, it frequently presents a diagnostic challenge when it occurs in older adults. This article presents a case of infectious mononucleosis involving a 70-year-old woman and reviews the clinical and laboratory features of infectious mononucleosis in adults over age 40. The spectrum of atypical presentations of the disease among older adults is also discussed.
A 70-year-old woman was admitted to the hospital with fever, pharyngitis, back pain and dehydration. She had been in good health until two and one-half weeks before admission, when she noted left-sided lower back pain while playing tennis. Shortly thereafter, she developed daily fever (to 38.3 [degrees] C [ 101 [degrees] F]), sore throat, diffuse myalgias, right frontal headache, mild right upper quadrant and epigastric pain, and nausea.
The patient denied exposure to animals, seafood or persons with tuberculosis, and she had received no blood transfusions. One month before admission, she had been exposed briefly to a relative with infectious mononucleosis. She had a history of childhood tonsillectomy, colonic polypectomy 30 years prior to admission, irritable bowel syndrome and osteoarthritis. Medications included conjugated estrogens (discontinued four weeks before the onset of symptoms), butalbital, aspirin and diazepam.
The initial physical examination revealed mild exudative pharyngitis and palpable 1- to 2-cm lymph nodes in the posterior cervical, submandibular, axillary and inguinal regions. The liver edge was palpable 2 cm below the right costal margin.
Laboratory tests at this time showed a white blood cell count of 3,200 per mm[.sup.3] (3.2 x 10[.sup.9] per L), with 35 percent (0.35) segmented neutrophils, 18 percent (0.18) band cells, 36 percent (0.36) lymphocytes, 4 percent (0.04) reactive lymphocytes, 5 percent (0.05) monocytes and 1 percent (0.01) eosinophils. The hemoglobin level was 13.9 g per dL (139 g per L); hematocrit was 42.1 percent (0.42), and platelet count was 139,000 per mm[.sup.3] (139 x 10[.sup.9] per L).
Other laboratory values included serum creatinine, 0.9 mg per dL (69 [mu]mol per L); bilirubin, 0.4 mg per dL (7 [mu]mol per L); lactate dehydrogenase, 416 U per L (416 U per L); aspartate aminotransferase (AST), 339 U per L (339 U per L); alanine aminotransferase ALT), 390 U per L (390 U per L); alkaline phosphatase, 524 U per L (524 U per L), and amylase, 113 U per L (113 U per L). Tests for hepatitis B surface antigen, hepatitis A IgM antibody and cytomegalovirus antibody gave negative results. A slide test for heterophil antibody was positive. IgM and IgG antibodies to the Epstein-Barr virus capsid were detected.
During the next two weeks, anorexia, fever, headache and fatigue persisted and back pain increased. The patient was then admitted to the hospital. Exudative pharyngitis had worsened, and there was evidence of dehydration. On admission, the white blood cell count was 11,500 per mm[.sup.3] (11.5 x 10[.sup.9] per L), with 15 percent (0.15) segmented neutrophils, 7 percent (0.07) band cells, 53 percent (0.53) lymphocytes, 10 percent (0.10) atypical lymphocytes, 11 percent (0.11) monocytes, 3 percent (0.03) basophils and 1 percent (0.01) eosinophils; the platelet count was 270,000 per mm[.sup.3] (270 x 10[.sup.9] per L). Lactate dehydrogenase had increased to 456 U per L (456 U per L), and alkaline phosphatase to 889 U per L (889 U per L). Urinalysis and chest radiograph were normal; lumbosacral spine radiographs showed osteoarthritis. A throat culture yielded many beta-hemolytic non-group A streptococci. Intravenous fluids and erythromycin were administered. The patient was discharged in improved condition after six days.
Because of the patient’s age and localized back pain, the minor degree of lymphocytosis and small number of atypical lymphocytes, and the significant elevation of liver enzymes, infectious mononucleosis was initially not considered as a diagnosis in this case. The diagnosis was established, however, before unnecessary antibiotics were given and diagnostic tests for “fever of unknown origin” were carried out. The significance of the patient’s exposure to a relative with infectious mononucleosis is unclear.
Age and Immune Response
From 80 to 90 percent of infectious mononucleosis cases are caused by the Epstein-Barrvirus. (1-3) Epstein-Barr virus is a member of the herpesvirus group that infects at least 95 percent of the world’s population. (4,5) Epstein-Barr virus causes an initial systemic (primary) infection and then becomes latent in the B lymphocytes and lymphoid tissue of the host. (6) Latent-infection persists for the lifetime of the host.
Most infected persons are asymptomatic at the time of primary infection and can be identified only by serologic testing. (6) However, the likelihood of symptomatic primary infectious mononucleosis has been found to depend on the age at which the primary infection occurs. In the United States and Great Britain, seroconversion occurs in about one-half of children before the age of five, (7,8) but symptomatic infectious mononucleosis is rare in this age group. Clinically apparent infectious mononucleosis is much more common among adolescents who seroconvert. (6) It seems likely that the difference in clinical expression of infection in these two age groups reflects a fundamental difference in the way their immune systems react to Epstein-Barr virus, but this remains to be clarified.
The ratio of apparent to inapparent primary infection in older adults is unknown. Serologic surveys have shown that between 3 and 10 percent of adults over age 60 lack Epstein-Barr virus antibodies and are presumably at risk for primary Epstein-Barr virus infection and infectious mononucleosis. (9) In a small prospective study, (10) Epstein-Barr virus seroconversion occurred in six patients in a home for the aged, but none of these patients were symptomatic. Larger studies have not been performed.
Older adults have a diminished ability to inhibit the activity of latent Epstein-Barr virus if they are chronically infected. In latent infection, Epstein-Barr virus replication and synthetic metabolism are normally inhibited by the host’s cellular immune system. (11,12) In situations in which host cellular immunity is decreased, viral replication and protein synthesis increase. The host responds by producing increased antibodies to Epstein-Barr virus proteins. This response has been demonstrated in patients with cellular immune deficiencies (e.g., malignancy, renal transplantation). (13,14)
Numerous studies (15-18) have shown that Epstein-Barr virus antibodies increase significantly with age, presumably reflecting a deteriorating ability of the cellular immune system to “handle” the virus. No convincing evidence shows that this putative loss of control over latent Epstein-Barr virus in the older adult has any significant clinical consequences. It is not clear whether the “atypical” manifestations of acute infectious mononucleosis in older adults are a reflection of altered immune responsiveness to Epstein-Barr virus in this age group.
Incidence in Older Adults
Infectious mononucleosis is an uncommon illness in persons over 40 years of age; it occurs most frequently in adolescence and early adulthood. Age-specific incidence rates of heterophil-positive infectious mononucleosis, derived from two studies of large urban populations, are shown in Table 1. (19,20) The incidence rate peaks between ages 15 and 19 (345 to 671 per 100,000 population per year) and then declines steadily. The incidence in persons over age 35 is only two to four per 100,000 per year. The peak incidence occurs at a slightly later age in males (18 to 23 years) than in females (15 to 16 years), but by age 35 no gender difference in incidence rates is seen.
Clinical and Laboratory Features
The clinical features of infectious mononucleosis in persons under age 35 and in those over age 40 are compared in Table 2 [omitted]. (9,21-40) These data may be biased, however, because of a tendency to include unusual cases in case reports and case series. The prevalence of fever and rash is similar in the two age groups. Fever is the most common symptom in both age groups, occurring in 89 percent of adolescents and in 95 percent of patients over age 40. However, in a direct comparison of adolescents and patients over age 40 at the same institution, one study (21) found the duration of fever to be significantly longer in the older patients (median duration: 13 versus seven days).
Older adults have lower rates of pharyngitis, lymphadenopathy and splenomegaly, signs and symptoms that are typical of infectious mononucleosis in the adolescent. In contrast, older adults have substantially higher rates of hepatomegaly and jaundice.
A difference between the prevalence of hyperbilirubinemia in persons over age 40 and that in adolescents is also seen. (22,23) As shown in Table 3 [omitted], (9,21,24-36) serum bilirubin levels were greater than 2.0 mg per dL (34 [mu]mol per L) in 30 percent of older adults, compared with 3 percent of adolescents. Although the proportion of patients with serum transaminase and alkaline phosphatase elevations appears to be similar in the two age groups, one study (24) found AST and [gamma]-glutamyl transferase (GGT) levels to be substantially higher in patients aged 40 to 72 than in teenagers.
It has been reported that a number of patients over age 40 with infectious mononucleosis consistently lack lymphocytosis and atypical lymphocytes. Among older patients for whom published information was available, eight of 35 (23 percent) had less than 50 percent lymphocytes in the peripheral smear, and five of 31 (16 percent) had less than 5 percent atypical lymphocytes. (9,25-36) The extent to which atypical blood smears are found in adolescents is unclear, because most studies of these patients have required abnormal smears for study entry. In addition, seven patients over age 40 in whom the conventional heterophil antibody test or the spot test (Monospot) was consistently negative had Epstein-Barr virus-associated infectious mononucleosis confirmed by the presence of IgM antibody to the Epstein-Barr virus capsid. study (1) found that the prevalence of heterophil-negative infectious mononucleosis among patients with Epstein-Barr virus-associated infectious mononucleosis increases with age.
It is thus understandable that the diagnosis of infectious mononucleosis is often missed or delayed among older adults. The disease is uncommon in persons over age 40. The typical symptoms of lymphadenopathy, pharyngitis and splenomegaly are often absent. Fever is usually prolonged, and the frequent occurrence of isolated hepatomegaly and jaundice suggests other diagnoses. The blood smear may be atypical (often normal), and the Monospot and heterophil antibody tests may be negative. Initial diagnoses in patients over age 40 with infectious mononucleosis may be incorrect because of atypical clinical and laboratory features.
Prominent lymphadenopathy, either generalized (24,26) or localized, (28,35,37,38) in older patients with infectious mononucleosis has prompted the presumptive diagnosis of lymphoma. In a series of 27 patients over age 40 with infectious mononucleosis, three were found to have prominent lymphadenopathy as the major clinical feature. (24) When localized, lymphadenopathy is usually cervical. (28,37,38) report (35) describes a patient who presented with isolated hilar lymphadenopathy; the presumptive diagnosis was lymphoma, but bronchoscopy with cytology was negative and the Monospot and heterophil antibody tests were positive. Chest radiographs became normal over several weeks.
Lymph node biopsies are commonly performed. Histology may be benign” (28) or may be interpreted initially as malignant. In one study, (38) four patients over age 55 with Epstein-Barr virus-associated infectious mononucleosis underwent bone marrow biopsies after lymphoma was suspected. Their bone marrow aspirates were normal, but the biopsies showed focal collections of lymphocytes and small non-caseating granulomas. In this group of patients, clues to the diagnosis of infectious mononucleosis were lymphocytosis in the white blood cell differential count and abnormalities in liver enzyme values.
The atypical lymphocytes found in infectious mononucleosis can sometimes suggest chronic lymphocytic leukemia. (25,28,36,38) One patient with infectious mononucleosis and simultaneous acute infection with Epstein-Barr virus and cytomegalovirus had bizarre, immature lymphocytes, suggesting acute leukemia. (25) Another patient had petechiae and a platelet count of 7, 000 per mm[.sup.3] (7 x 10[.sup.9] per L), suggesting advanced leukemia. (21)
Bone marrow biopsies are typically performed, and marrow infiltration with mature lymphocytes can be thought to substantiate the diagnosis of chronic lymphocytic leukemia. (36) The diagnosis of infectious mononucleosis may be suggested by a reexamination of the peripheral blood smear, abnormal liver enzyme values and cervical lymphadenopathy.
The clinical constellation of fever, jaundice, right upper quadrant abdominal pain and an elevated alkaline phosphatase level in an older patient with infectious mononucleosis can suggest extrahepatic biliary obstruction. (24,26-28,31) In one series, (24) seven of 27 patients had primary symptoms of fever, jaundice and/or right upper quadrant pain; three underwent detailed evaluation for biliary obstruction.
Among patients with this presentation, an erlarged, palpable liver has been a common finding. (27,28,31) Reported peak bilirubin levels have ranged from 2.0 to 11.2 mg per dL (34 to 192 [mu]mol per L), alkaline phosphatase levels have ranged from 360 to 750 U per L (360 to 750 [mu]mol per L), and AST levels have ranged from 35 to 301 U per L (35 to 301 U per L). In these patients, the diagnosis of infectious mononucleosis was eventually suggested by a shift in the blood smear to lymphocyte predominance and atypical lymphocytes or by pharyngitis or other signs of infectious mononucleosis.
NEUROLOGIC SIGNS AND SYMPTOMS
In several reported cases, (9,24,32,35,39) neurologic signs and symptoms have been the predominant or sole manifestations of infectious mononucleosis in older patients. Some of these patients had peripheral neuropathies. One had Bell’s palsy on the right side and fever and was treated with dexamethasone. (9) Bell’s palsy was recognized as a late complication in another patient, who had a more typical presentation of infectious mononucleosis. (28) One patient had fever and acute bilateral optic neuritis manifested by blurred vision. (39)
This patient eventually had 25 percent atypical lymphocytes, abnormal liver enzyme values and a positive Monospot test. His vision returned to normal two months after prednisone therapy. Another patient, 69 years old, presented with a primary complaint of distal limb paresthesias and also had abnormal results on nerve conduction studies. (35)
Central nervous system manifestations also can dominate the presentation of infectious mononucleosis. One patient presented with Guillain-Barre syndrome (24); in another patient, Guillain-Barre syndrome followed exudative pharyngitis and a typical lymphocytosis. (27) Another patient presented with intellectual impairment and confusion that had contributed to two automobile accidents. (32) His mental status returned to normal after resolution of infectious mononucleosis.
FEVER OF UNKNOWN ORIGIN
In some cases of infectious mononucleosis involving patients over age 40, the combination of prolonged fever, nonspecific signs and symptoms, and nonspecific laboratory abnormalities has led to an evaluation for fever of unknown origin (9,21,2,4,29 40) In one series, (24) Six of 27 patients were initially classified in this way. Almost all such patients received empiric antibiotic therapy. They often underwent extensive diagnostic testing, including routine blood, sputum and urine cultures; serum tests for viral hepatitis and multiple infectious agents; cutaneous and microbiologic tests for tuberculosis; screening for rheumatologic, endocrine and malignant diseases; multiple radiographs and computed tomographic scans, and biopsies of bone marrow, temporal artery and muscle. The delay in diagnosis of infectious mononucleosis frequently reflected the fact that the disease was initially overlooked as a diagnostic possibility because of the patient’s age and the absence of typical symptoms.
Acute symptomatic Epstein-Barr virus infection in adults over age 40 is uncommon and often lacks the typical features of infectious mononucleosis seen in adolescents. In a patient over age 40 with unexplained fever lasting more than a week, Epstein-Barr virus-associated infectious mononucleosis should be suspected if any of the following features are present: lymphocytosis or the presence of atypical lymphocytes; lymphadenopathy (especially cervical); pharyngitis; splenomegaly; hepatomegaly; elevations of liver enzymes, and unexplained peripheral neuropathy or Guillain-Barre syndrome.
Infectious mononucleosis should also be kept in mind in patients with the presumptive diagnosis of lymphoma, lymphocytic leukemia, cholestatic jaundice or fever of unknown origin. Both a screening test for heterophil antibodies (e.g., Monospot) and a test for specific Epstein-Barr virus antibodies should be obtained when pursuing this diagnosis.
ACKNOWLEDGMENT: The authors would like to thank Marilyn Selcovitz for secretarial assistance in the preparation of the manuscript.
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Age-Specific Incidence of Infectious Mononucleosis (19,20)
Cases per 100,000
Age (years) population per year
PETER AXELROD, M. D. is assistant professor of medicine in the section of infectious diseases at Temple University School of Medicine, Philadelphia. Dr. Axelrod is a graduate of Yale University School of Medicine, New Haven, Conn., and completed an internship and a residency at Temple University Hospital.
ALBERT J. FINESTONE, M. D. is professor of medicine and associate dean in the Office for Continuing Medical Education at Temple University School of Medicine, where he earned his medical degree. Dr. Finestone completed an internship and residency in internal medicine at Temple University Hospital and served a fellowship in pathology at Georgetown University School of Medicine, Washington, D.C.
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