Atypical Measles in Adolescents and Young Adults DAVID B. MARTIN, M.D.; LEONARD B. WEINER, M.D.; PHILLIP I. NIEBURG, M.D.; and DONALD C. BLAIR, M.D.; Syracuse, New York Seven patients, aged 12 to 19 years, had atypical measles. Prodromal symptoms of fever, malaise, myalgia, headache, nausea, and vomiting were commonly followed by coryza, sore throat, conjunctivitis, photophobia, nonproductive cough, and pleuritic pain. The characteristic rash was erythematous, maculopapular, and progressed frequently to vesicular, petechial, or purpuric lesions. It initially involved palms and soles with subsequent spread to proximal extremities and the trunk, sparing the face. Six of six chest roentgenograms showed infiltrates. Findings not previously described in atypical measles included liver enzyme elevations, thrombocytopenia, disseminated intravascular coagulation, possible transmission among three siblings, and suspected cardiac involvement. Measles complement fixation titers compatible with recent infection were seen in all patients. All patients had previously received killed measles vaccine. A substantial number of persons who are older adolescents or young adults may be at risk of developing atypical measles.

T H E D E V E L O P M E N T of a vaccine protective against measles brought with it the chance to control a troublesome infectious illness and its tragic consequences. Shortly after the introduction of the first vaccines in 1963, however, a new illness characterized by fever, an unusual skin rash, and respiratory symptoms appeared in children who had earlier received inactivated measles vaccine. Since the first description of atypical measles by Rauh and Schmidt in 1965 (1), several reports primarily involving preadolescents have appeared (2-15). At the Upstate Medical Center, State University of New York, Syracuse, we have recently seen seven patients with atypical measles, some of whom had previously unreported findings. This syndrome is now occurring in older adolescents and young adults and is of increasing interest to internists. Clinical Presentations

Seven patients with atypical measles were seen by the Adult or Pediatric Infectious Disease Sections at the Upstate Medical Center between May 1975 and April 1977 (Table 1). All cases occurred in the spring. Three occurred during known community outbreaks of measles (16); exposure to measles could not be documented for the others. Five were boys; mean age was 15.4 years (range, 12 to 19 years). All patients had high spiking fevers, often to 40 °C. Malaise, myalgia, headache, nausea, and vomiting were prominent prodromal symptoms, lasting 2 to 9 days (mean, 4.4 days). Frequently, coryza (four cases), sore throat (three cases), conjunctivitis (six cases), and photophobia then appeared, followed shortly by nonproductive • From the Sections of Infectious Diseases, Departments of Medicine and Pediatrics, Upstate Medical Center; Syracuse, New York.

Annals of Internal Medicine 90:877-881, 1979

cough, sometimes with pleuritic pain. All patients had respiratory symptoms. A rash appeared in all patients, usually on the third or fourth day. The rash showed a characteristic pattern, always being seen initially on the distal extremities around the palms, wrists, soles, and ankles; it then spread to involve the proximal extremities, the trunk, and occasionally the face. Petechiae were seen on the conjunctiva and soft palate (one patient each). The rash was initially maculopapular and erythematous in all patients and commonly progressed to vesicles and petechial or purpuric lesions. Occasionally it was pruritic. One patient had periorbital edema, and another had arthralgia of the knees, fingers, and wrists. None had strawberry tongue or Koplik's spots. Six patients had abnormal chest roentgenogram findings—six with diffuse infiltrates, two with lobar infiltrates, and three with hilar adenopathy. One subject (Patient 1) had cardiomegaly at admission and may have had transient myocarditis or pericarditis. This patient is of interest because two of his brothers also had atypical measles. PATIENT 1

A previously healthy 18-year-old white boy was admitted to Upstate Medical Center for a 5-day illness characterized by fever, malaise, myalgia, nausea, vomiting, earache, and photophobia, followed by coryza and nonproductive cough. On the day before admission a rash erupted on his wrists and the dorsa of his feet. He had received a killed, killed, live measles vaccine sequence at monthly intervals when he was 5 years old. He was acutely ill with fever of 39 °C. His conjunctivae and posterior pharynx were erythematous but without exudate. Clear nasal discharge was present and shotty anterior and posterior cervical nodes palpable. He had rales and decreased breath sounds at the base of his right lung. His heart was enlarged to the left of the midclavicular line, with a regular rhythm and a grade II/VI systolic ejection murmur at the base; no gallops were heard. The rash remained most concentrated on his feet and wrists; a few scattered lesions later appeared on his trunk, palms, and soles but spared his face. The rash was maculopapular, erythematous, and nonpruritic; some of the lesions became hemorrhagic after 24 h (Figure 1). Admission laboratory data included hemoglobin concentration of 11.2 g/dL; leukocyte count 5000/mm3 with 63% neutrophils, 8% band forms, 11% lymphocytes, 1% atypical lymphocytes, 15% monocytes, and 2% eosinophils; platelet count 107 000/mm3; and lactic dehydrogenase (LDH) 242 IU/mL. Cold agglutinins, VDRL, heterophil, and proteus OX-19 titer were negative. A chest roentgenogram showed cardiomegaly and an infiltrate in the posterior segment of the right lower lobe (Figure 2). There were nonspecific S-T segment changes on an electrocardiogram. By the third hospital day he was afebrile. Echocardiographic findings at that time were normal, and the heart murmur could no longer be heard. A chest roentgenogram on the fourth day showed normal heart size and clearing of the infiltrate. The patient was discharged on the sixth hospital day after substantial clearing of his rash. Acute and convalescent measles ©1979 American College of Physicians

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Table 1. CI inical Prese ntations of S even Patients with At ypical Measle;5 Rash

Respiratory Symptoms

39.5

Maculopapular, hemorrhagic

Nonproductive cough

3/10/77 (4) 4/21/77 (3)

39.5 41.0

Maculopapular, vesicular Maculopapular, hemorrhagic

Nonproductive cough Nonproductive cough

14

5/16/75 (2)

39.5

Maculopapular, petechial, vesicular, pruritic

Dyspnea, pleuritic pain, respiratory distress

F

12

3/9/76 (3)

40.0

6

M

13

3/14/76(9)

39.0

Maculopapular, vesicular, pruritic Maculopapular, petechial, vesicular

Dyspnea, nonproductive cough Nonproductive cough

7

F

19

5/17/75 (6)

40.6

Maculopapular, petechial

Dyspnea, nonproductive cough, respiratory distress

Patient

Sex

Age

1

M

2 3

Date of Illness (Prodrome Duration, d)

Fever

18

4/1/77 (4)

M M

15 17

4

M

5

yr

°C

* LDH = lactic dehydrogenase (normal, 50 to 200 IU/mL). t Vaccine series: KKL = killed, killed, live, KK = killed, killed. % Measles complement fixation antibody titers. § ND = not done.

complement fixation titers were both 1:512. PATIENT 2

Ten days before onset of illness in Patient 1, his 15-year-old brother had had a febrile illness with a similar rash accompanied by a nonproductive cough. Medical treatment was not sought at the time of illness. At 2 years of age he also had received a killed, killed, live measles vaccine series. Measles complement fixation antibody titer 7 weeks after his illness was 1:16. PATIENT 3

Two weeks after Patient l's discharge from the hospital, his 17-year-old brother was admitted after fever, malaise, sore throat, anorexia, earache, headache, photophobia, and nonproductive cough of 7 days' duration. Two days before admission, he had developed a rash similar to those of his brothers, beginning on the ankles and wrists and spreading to the trunk and face. At age 4, he had received the same series of measles vaccinations as his brothers. His hospital course was similar to Patient 1 's. Measles complement fixation antibody titers were 1:16 (acute) and 1:512 (convalescent). F i v e other siblings in this family had had natural measles infections, had not been vaccinated, and did not bec o m e ill w h e n these brothers did. N o c o m m o n source of measles for the three brothers w a s ascertained. In all of our patients, anemia w a s either absent or mild. Peripheral leukocyte counts were in the normal range ( 4 9 0 0 to 10 6 0 0 / m m 3 ) with a mild to marked percentage of immature granulocytic forms. In four patients in w h o m later counts were obtained, eosinophilia in the range of 8 % to 1 1 % appeared after several days. Erythrocyte sedimentation rates were elevated in three patients. Renal function w a s normal in all, a l t h o u g h t w o patients had mild transient hematuria. Five of five patients tested had mild elevations o f serum L D H , and t w o of these also had elevated serum glutamic-oxalacetic and serum glutamic-pyruvic transaminases. Platelet counts 878

were in the low-normal range in five o f six patients in w h o m they were obtained. O n e of these patients had a prolonged bleeding time ( > 9 m i n ) with normal prothrombin and partial thromboplastin times. A n o t h e r patient's course (Patient 4) w a s highly suggestive of disseminated intravascular coagulation. PATIENT 4

A 14-year-old white boy was admitted to Upstate Medical Center with lethargy, anorexia, vomiting, nonproductive cough, and retrosternal pleuritic pain of 5 days' duration. Three days before admission, he noted a pruritic rash on his wrists and legs, which spread to his extremities and trunk. He had received a sequence of killed, killed, live measles vaccine at 4 years of age. At admission, he appeared acutely ill with fever of 39 °C and respiratory rate of 30/min. Bibasilar rales were present. An erythematous maculopapular rash was most concentrated over his distal extremities with several petechiae on his feet. Hemoglobin concentration was 12.7 g/dL; leukocyte count 10 300/mm 3 with 20% neutrophils, 69% band forms, 2% metamyelocytes, 3 % lymphocytes, and 6% monocytes; platelet count 195 000/mm 3 ; and prothrombin time 12.0/9.1 s. A chest roentgenogram showed mediastinal enlargement with hilar adenopathy and multiple poorly defined bilateral infiltrates (Figure 3). On the third hospital day, he had markedly increased numbers of petechiae. In addition, he developed increased respiratory distress with tachypnea (40 to 50/min), nasal flaring, intercostal retractions, pleural friction rub, and increased densities on chest roentgenogram. Arterial blood gases on 30% 0 2 by mask were pH 7.47; Po 2 80 mm Hg; Pco 2 35 mm Hg; and HC0 3 , 26 meq/L. Platelet count was 189 000/mm 3 ; prothrombin time 11.5/9.9 s; partial thromboplastin time 40.8/27.9 s; fibrinogen 1020 mg/dL; and fibrin split products 80 u-g/mL (normal < 10). By the fifth hospital day some of his skin lesions had become vesicular, but his fever had decreased and he felt better. Lowgrade consumption coagulopathy was suggested by the platelet count 145 000/mm 3 ; prothrombin time 12.8/9.7 s; partial thromboplastin time 49.2/29.1 s; thrombin time 34.0/21.6 s;

June 1979 • Annals of Internal Medicine • Volume 90 • Number 4

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Table 1. (Continued) Chest Roentgenogram

Platelet Count

Serum LDH*

Vaccinef (Age, yr)

Antibody Titer J: (Date) Acute

Right lower lobe infiltrate, cardiomegaly ND§ Left perihilar infiltrate, hilar enlargement Diffuse bilateral infiltrates, hilar enlargement Right upper lobe infiltrate Diffuse bilateral infiltrates, hilar enlargement Diffuse bilateral infiltrates

Patient

Convalescent

cells/mm*

IU/mL

107 000

242

KKL(5)

1:512 (4/3/77)

1:512(4/27/77)

1

ND 120 000

ND 394

KKL (2) KKL(4)

ND 1:16 (4/22/77)

1:16(4/27/77) 1:512 (6/2/77)

2 3

145 000

ND

KKL (4)

1:256 (6/25/75)

4

Low normal Normal

ND

KK (1.5)

1:128 (3/31/76)

5

306

KKL (4)

< 1:4 (3/16/76)

1:256 (3/29/76)

6

175 000

280

KKL (7)

ND

1:512 (6/18/75)

7

Ivy bleeding time 9.5 min; fibrinogen 515 mg/dL; fibrin split products 20 /ng/mL; and borderline low Factor V assay (52%). Bone marrow aspirate showed normal cellularity, normal erythrocytic/myelocytic ratio, increased numbers of plasma cells, and slightly increased numbers of megakaryocytes. His clinical improvement proceeded rapidly with defervescence, partial clearing of his rash, and decreased respiratory symptoms, although chest roentgenogram findings remained abnormal for 6 months. He was discharged on the seventh hospital day. Acute (Day 5 of illness) and convalescent (5 weeks later) measles complement fixation antibody titers were < 1:4 and 1:256, respectively. All of our patients had been vaccinated between the ages of 12 months and 5 years, that is, 10 to 13 years before the occurrence of atypical measles. One patient received only killed vaccine; six had received killed, killed, live series of measles vaccine. None had been revaccinated. Measles complement fixation antibody titers were measured by the New York State Department of Health Laboratories in Albany. Single titers > 1:64 or a fourfold rise between acute and convalescent titers (sera obtained 3 to 7 weeks apart) was considered diagnostic of recent infection. Titers of 1:16 indicated past infection at an undetermined time. In typical measles, titers begin to fall after 1 to 2 months; analogous data are not available for atypical measles. The dates of onset of illness in our patients and the interval between acute and convalescent serum specimens are shown in Table 1. Titers compatible with recent infection were seen in all of our patients.

< 1 : 4 (5/16/75) 1:32(3/15/76)

produced or distributed after 1967, in part because the immunity it induced was short-lived but also because of increasing awareness of atypical measles. Although the syndrome of atypical measles has interested pediatricians for years, it is increasingly within the province of the internist as the population at risk ages. More than 200 cases of atypical measles have now been described in the English literature (1-15). In many respects, our cases were similar to those previously reported: occurrence in the spring, high fever, atypical rash, respiratory symptoms, abnormal chest roentgenogram findings, and vaccination history. Among the previous cases for which information is available, 57 patients had received killed vaccine; 49 killed and live; three live; and five live plus immune serum globulin. Six of our seven patients had received killed, killed, live sequences; one

Discussion

Formalin-inactivated (killed) measles virus vaccine and attenuated live virus measles vaccine (Edmonston B strain) became available in 1963. A further attenuated variant of the latter vaccine (Attenuvax®; Merck Sharp & Dohme, West Point, Pennsylvania) was licensed in 1968 and is widely used today (17). Killed vaccine was not

Figure 1 . Atypical measles rash in an 18-year-old boy (Patient 1). Martin et al. • Atypical Measles

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Figure 2 . Chest roentgenogram of an 18-year-old boy (Patient 1) with atypical measles showing right lower lobe infiltrate and cardiomegaly.

had received two killed inoculations (Table 1). With the exception of one previously reported series (12), almost all prior cases occurred in patients younger than 10 years of age; all of ours were older, with a mean age of 15.4 years. In addition to the age difference, our patients had several previously unreported characteristics: possible transmission of atypical measles among three siblings, suspected cardiac involvement, liver enzyme elevations, mild thrombocytopenia, and laboratory manifestations of disseminated intravascular coagulation. Thrombocytopenia has not been previously reported in atypical measles. The low-normal platelet counts in some of our patients (Table 1) raise the possibility of inhibition of production or release of platelets by the bone marrow (as may occur with live vaccine administration [18]). Alternatively, as with Patient 4, some degree of disseminated intravascular coagulation may occur. This can be seen in other viral illnesses, and peripheral platelet destruction may occur in natural measles (19). Hematologic manifestations of this syndrome may be more severe in older age groups. Although viral cultures of our patients were not obtained, reported attempts to culture measles virus from patients with atypical measles have not been successful (2-4); atypical measles has generally not been considered contagious. Only one report has appeared suggesting measles transmission from a patient with atypical measles (20). However, our observation of three cases occurring at 2-week intervals in a single family further suggests the possibility of secondary transmission by these patients. The prominence of lung involvement in atypical measles deserves special emphasis, since this aspect of the disease is important in the differential diagnosis. More than three fourths of all patients reported (including our patients) have had abnormal chest roentgenogram find3 3 0

June 1979

ings: hilar adenopathy; patchy, diffuse, or lobar infiltrates; pleural effusions; or residual nodular lesions (6, 21). Skin manifestations of atypical measles are characterized by the centripetal spread of a maculopapular rash that often progresses to purpuric lesions and vesicles. Difficulty may arise in distinguishing this illness from other febrile illnesses with similar rashes; Rocky Mountain spotted fever is the disease most likely to be confused with atypical measles. Differentiation from atypical measles is aided by recollection of a tick bite, occurrence of the disease in mid-to-late summer, appropriate geographic location, rarity of pulmonary involvement, and definitive serologic findings. Also to be considered in the differential diagnosis of atypical measles are meningococcemia, enteroviral infection, drug reaction, scarlet fever, anaphylactoid purpura, infectious mononucleosis, gonococcemia with dermatitis, Mycoplasma pneumoniae infection, infective endocarditis, secondary syphilis, typhoid fever, typhus, coccidioidomycosis, and disseminated intravascular coagulation from any cause. Two major explanations have been suggested for the pathogenesis of atypical measles. One theory holds that humoral immunity, in the form of antigen-antibody complexes, is responsible for the atypical rash and other manifestations of the syndrome (22). Bellanti and colleagues (23) have found IgG, measles antigen, and complement within the site of skin lesions of atypical measles. A second theory is that of enhanced cell-mediated immunity. Although the humoral immunity imparted by killed measles vaccine is short-lived, the cellular immunity induced by that vaccine persists and may be responsible for the manifestations of atypical measles (24, 25). The demonstration of delayed cutaneous hypersensitivity to intradermal measles vaccine in previous killed-vaccine recipi-

Figure 3. Chest roentgenogram of a 14-year-old boy (Patient 4) with atypical measles showing mediastinal enlargement, hilar adenopathy, and poorly defined bilateral infiltrates.

• Annals of Internal Medicine • Volume 90 • Number 4

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ents and the absence of a similar response in previous live-vaccine recipients is taken as evidence for this theory (24). Recent investigations of antibody response and lymphocyte stimulation in previous killed-measles-vaccine recipients who were revaccinated with live measles vaccine lend credence to this latter theory (25). As many as 1 836 300 doses of killed vaccine may have been administered from 1963-1967 (26). Many of the recipients may still be at risk of developing atypical measles. We wish to remind physicians who care for adolescents and young adults of the need to carefully check measles vaccination histories in these age groups. Live measles vaccine should be given to those without documented history of natural measles or of live measles vaccination at or after 1 year of age (27). This recommendation specifically includes those who previously received a killed measles vaccine series or killed-live sequences where the killed-live vaccination interval was 3 months or less (27). In this latter setting, a 19% incidence of significant systemic or local reaction, or both, to revaccination with live vaccine has been reported (25). We re-emphasize that most persons at risk of developing atypical measles are now 12 years of age or older; many have reached adulthood. As this group ages, atypical measles may present an increasing problem for the internist.

6. Y O U N G LW, SMITH DI, G L A S G O W LA: Pneumonia of atypical measles. Residual nodular lesions. Am J Roentgenol Radium Ther Nucl Med 110:439-448, 1970 7. L I N N E M A N N CC J R , R O T T E TC, SCHIFF G M , Y O U T S E Y JL: A seroepi-

demiologic study of a measles epidemic in a highly immunized population. Am J Epidemiol 95:238-246, 1972 8. BRODSKY AL: Atypical measles. Severe illness in recipients of killed measles virus vaccine upon exposure to natural infection. JAMA 222:1415-1416, 1972 9. C H E R R Y J D , F E I G I N R D , LOBES LA J R , SHACKELFORD PG: Atypical

measles in children previously immunized with attenuated measles virus vaccine. Pediatrics 50:712-717, 1972 10. H O R W I T Z MS, G R O S E C, FISHER M: Atypical measles rash mimicking Rocky Mountain spotted fever (letter). N Engl J Med 289:1203-1204, 1973 11. S T G E M E JW JR, G E O R G E BL, BUSH BM: Exaggerated natural measles following attenuated virus immunization. Pediatrics 57:148-150, 1976 12. C E N T E R FOR D I S E A S E C O N T R O L : Atypical measles—California, 1974-

75. Morbid Mortal Weekly Rep 25:245-246, 1976 13. H A A S EJ, W E N D T VE: Atypical measles 14 years after immunization. JAMA 236:1050, 1976 14. W E L L I V E R RC, C H E R R Y J D , H O L T Z M A N AE: Typical, modified, and

atypical measles. An emerging problem in the adolescent and adult. Arch Intern Med 137:39-41, 1977 15. CHATTERJI M, M A N K A D V: Failure of attenuated viral vaccine in prevention of atypical measles. JAMA 238:2635, 1977 16. W E I N E R LB, C O R W I N R M , N I E B U R G PI, F E L D M A N HA: A measles

outbreak among adolescents. / Pediatr 90:17-20, 1977 17. K R U G M A N S: Present status of measles and rubella immunization in the United States: a medical progress report. J Pediatr 78:1-16, 1971 18. OSKI FA, N A I M A N JL: Effect of live measles vaccine on the platelet count. N Engl J Med 275:352-356, 1966 19. H U D S O N JB, W E I N S T E I N L, C H A N G T-W: Thrombocytopenic purpura

in measles. J Pediatr 48:48-56, 1956 20. M C C A R T H Y VP, C A R L I L E JR, C H O CT, D U D D I N G BA: A new chal-

lenge: measles and measles immunization. J Kans Med Soc 79:111-114, 1978

• Requests for reprints should be addressed to David B. Martin, M.D.; Infectious Disease Section, Munson Medical Center, Traverse City, MI 49684. Received 10 October 1978; revision accepted 8 March 1979.

21. LAPTOOK A, W I N D E, NUSSBAUM M, S H E N K E R IR: Pulmonary lesions

References

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1. R A U H LW, SCHMIDT R: Measles immunization with killed virus vaccine Am JDis Child 109:232-237, 1965 2. F U L G I N I T I VA, E L L E R JJ, D O W N I E AW, K E M P E CH: Altered reactivi-

ty to measles virus. Atypical measles in children previously immunized with inactivated measles virus vaccines. JAMA 202:1075-1080, 1967 3. N A D E R PR, H O R W I T Z MS, ROUSSEAU J: Atypical exanthem following exposure to natural measles, eleven cases in children previously inoculated with killed vaccine. J Pediatr 72:22-28, 1968 4. GOKIERT JG, BEAMISH WE: Altered reactivity to measles virus in previously vaccinated children. Can Med Assoc J 103:724-727, 1970 5. M C L E A N D M , K E T T Y L S G D M , H I N G S T O N J, M O O R E PS, P A R I S RP,

RIGG JM: Atypical measles following immunization with killed measles vaccine. Can Med Assoc J 103:743-744, 1970

in atypical measles. Pediatrics 62:42-46, 1978 22. E L L E R JJ: Inactivated myxovirus vaccines, atypical illness, and delayed hypersensitivity. J Pediatr 74:664-666, 1969 Antibody responses in serum and nasal secretions of children immunized with inactivated and attenuated measles-virus vaccines. N Engl J Med 280:628-633, 1969 24. FULGINITI VA, A R T H U R JH: Altered reactivity to measles virus. / Pediatr 75:609-616, 1969 25. K R A U S E PJ, C H E R R Y JD, N A I D I T C H MJ, D E S E D A - T O U S J, W A L B E R G H

EJ: Re vaccination of previous recipients of killed measles vaccine: clinical and immunologic studies. J Pediatr 93:565-571, 1978 26. CENTER FOR DISEASE CONTROL: Measles Surveillance Report No. 10, 1973-1976. Atlanta, July 1977 27. CENTER FOR DISEASE CONTROL: Measles prevention. Morbid Mortal Weekly Rep 27:427-430, 435-437, 1978

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Atypical measles in adolescents and young adults.

Atypical Measles in Adolescents and Young Adults DAVID B. MARTIN, M.D.; LEONARD B. WEINER, M.D.; PHILLIP I. NIEBURG, M.D.; and DONALD C. BLAIR, M.D.;...
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