Atypical Measles in Adolescents: Evaluation of Clinical and Pulmonary Function WILLIAM J. HALL, M.D.; and CAROLINE BREESE HALL, M.D.; Rochester, New York
During a community outbreak of measles, 10 patients aged 11 through 19 were hospitalized with prominent pulmonary infiltrates and clinical manifestations of high fever and rash. Diagnoses of atypical measles were confirmed by hemagglutination-inhibition and complement-fixation antibody studies. Patients were followed with pulmonary function studies for 12 weeks. The most common admitting diagnoses were varicella, scarlet fever, meningococcemia, and Rocky Mountain spotted fever, due largely to the protean cutaneous manifestations. Roentgenographic studies showed diffuse, segmental, and nodular chest lesions. Hypoxemia (mean arterial Po2, 5 8 mm Hg) and markedly reduced lung volumes were noted. Gradual resolution of physiologic abnormalities was noted during 12 weeks, but two children had persistent nodular densities seen on chest roentgenograms. Atypical measles in the older child and young adult has a wide spectrum of pulmonary manifestations ranging from acute respiratory failure to isolated nodular lesions. Proper recognition of this syndrome will prevent unnecessary invasive diagnostic procedures. T H E O C C U R R E N C E of a new clinical syndrome after exposure to wild measles virus in persons who had previously received inactivated measles vaccine was initially reported in 1965 (1). Since then a number of reports in the pediatric literature have delineated the varied clinical picture of "atypical measles" with its prominent pulmonary involvement (2-4). Although many of these patients are now being seen by internists, this syndrome is not well described in the adult medical literature and may be confused with a number of unusual diseases requiring extensive diagnostic procedures. T h e pathologic process that causes atypical measles is not completely understood, but an abnormal immune reaction in a previously sensitized host has been suggested (5). Ascertaining the physiologic alterations associated with the pulmonary involvement may further our understanding of the pathophysiology of this curious disease. Therefore, when an outbreak of rubeola occurred in Rochester, New York, the study described here was undertaken in an attempt to delineate the physiologic alterations in the lungs of patients hospitalized with atypical measles. Second, we describe the clinical manifestations of these patients, because the syndrome of atypical measles seems to have widened since the initial descriptions more than a decade ago. Not only are these children now becoming young adults under the care of internists, but their clinical presentation is varied, mimicking a number of unusual diseases. • From the Departments of Medicine and Pediatrics, University of Rochester School of Medicine; Rochester, N e w York. 8 8 2
Annals of Internal Medicine 9 0 : 8 8 2 8 8 6 , 1 9 7 9
Patients and Methods As part of an infectious disease surveillance program, the monthly prevalence of measles cases is closely monitored in our community (6). During January and February 1976, there was an abrupt rise in the number of reported cases of measles, which gradually tapered off during the next 4 months. This outbreak was characterized by large numbers of cases reported from area high schools. During the first 5 months of 1976, 32 patients were referred to us for evaluation of illnesses that were subsequently diagnosed as atypical measles. Ten of these patients, all with prominent pulmonary findings, were hospitalized and form the group studied. These patients were evaluated clinically and with pulmonary function studies at the time of admission and at 2, 4, and 12 weeks subsequently. Laboratory evaluation included complete blood counts, chest roentgenograms, electrolytes, urinalysis, throat and sputum cultures for bacteria, and nasal wash or nose-plus-throat specimens for viral isolation. Paired sera were obtained for examination of measles complement-fixation and hemagglutination-inhibition antibody content. In three patients, already in the convalescent phase of their illness at the time of admission, only one serum was obtained. Both the complementfixation and hemagglutination-inhibition tests were done in microtiter plates using standard methods (7, 8). Arterial blood samples were obtained by percutaneous radial artery puncture and analyzed on an IL Model 313 blood gas analyzer (Instrument Laboratories, Lexington, Massachusetts). Samples were obtained while patients were breathing ambient air. Follow-up samples were obtained at 2, 4, and in some cases, 12 weeks, until arterial Po 2 values had reverted to normal levels. Pulmonary function studies were done in all 10 subjects during their acute hospitalization and at 4 and 12 weeks thereafter. Each subject did at least three maximal forced expiratory maneuvers into a 13.5-L Stead-Wells spirometer (Warren E. Collins, Braintree, Massachusetts). Vital capacity and forced expiratory volume in 1 s were calculated by methods described by Kory and associates (9). Values were expressed as percent of predicted normal values published by Morris, Koski, and Johnson (10) and Polgar and Promadkat (11). Functional residual capacity was measured in a body plethysmograph (12), and was used in deriving total lung capacity. Single-breath carbon monoxide diffusing capacity was determined by the methods of Olgilvie (13). Statistical significance of changes in pulmonary function data over time was evaluated by paired t testing (14). Results Table 1 summarizes some of the pertinent clinical and laboratory features of this illness. T h e disease predominantly affected teenagers and males ( 8 0 % ) . All patients had been immunized between 1963 and 1965 with two or three doses of killed measles virus vaccine. Five had one dose of live virus vaccine in addition. In all patients the illness started abruptly with fever and rash. T h e fever was generally high and prolonged, lasting an average of 16 d (Table 1). Coryza and conjunctivitis were notably absent, but a nonproductive cough with dyspnea was present in eight of the 10 patients at © 1 9 7 9 American College of Physicians
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Table 1. CIlinica 1 and Lciboratory Data on 10 Subjects wil:h Atypical Measles Patient
Sex
Age
yr 1 2 3 4 5 6 7 8 9 10 Mean SD
M F M M F M M M M M
13 14 17 15 11 16 15 12 19 14 14 2.4
Temperature Maximum
>38°C
°C 40.6 39.5 39.1 40.0 38.3 40.0 40.1 39.5 38.4 39.0 39.4 0.74
d 8 13 16 21 22 15 14 17 11 20 16 4
Initial Diagnosis*
V SF SF V M, RMSF V RMSF M,RMSF V SF
Leukocytes Total
Bands
10/mm*
%
5.0 7.4 6.5 5.4 9.0 5.2 5.8 5.9 4.3 4.2 5.9 1.5
17 20 19 14 20 8 19 9 18 24 16.9 5
Chest Roentgenogram*
D S S S S,N S
s s sS,N
Pulmonary Function Testsf VC
FEVj/FVC
% pred
%
40 56 52 65 66 45 50 80 51 48 55 12
42 81 87 80 85 80 87 85 78 79 78 13
DL
Arterial Po 2
% pred mm Hg 41 48 49 52 60 45 62 71 65 60 55 10
42 52 60 56 59 65 60 55 61 71 58 8
* V = varicella; SF = scarlet fever; M = meningococcemia; RMSF = Rocky Mountain spotted fever; D = diffuse; S = segmental; N = nodular, t VC = vital capacity; FEVi = forced expiratory volume in 1 s; FVC = forced vital capacity; DL = single-breath diffusing capacity; % pred = percent of normal values drawn from published data (see text).
the time of admission. Almost all had headache, myalgias, general malaise, and anorexia. But despite these constitutional symptoms and the high fever, the patients did not seem markedly toxic or septic. The exanthem was striking and varied, but generally could be categorized into one of three appearances. The first was a predominantly vesicular rash that elicited the initial diagnosis of chickenpox with pneumonia. The vesicles appeared singly or in crops, mainly over the trunk, occasionally with a hemorrhagic base (Figure 1, upper left). The second type of rash was predominantly petechial with some purpura and elicited the initial diagnosis of meningococcemia or Rocky Mountain spotted fever. The petechial rash, generally mixed with small maculopapular lesions, was predominantly on the trunk and extremities with relative sparing of the face (Figure 1, upper right). A few of the lesions progressed to purpura. The third form of the rash was a predominantly erythematous, maculopapular rash that most commonly elicited the diagnosis of scarlet fever. The lesions tended to be small and bright red and to coalesce, with particular prominence on the trunk, in the skin folds under the axilla, and in the groin. The exanthem also involved the arms and particularly the legs, including the palms and soles. Although the maculopapular lesions tended to be slightly larger than those classically associated with scarlet fever, the overall appearance in two patients was strikingly similar, with a "boiled lobster" erythema (Figure 1, lower left) and even a strawberry tongue (Figure 1, lower right). Various combinations of these three types of rashes were seen in individual patients. Four of the patients had the first type of rash, predominantly vesicular with an appearance most like chickenpox. In three of these patients vesicles were the sole cutaneous manifestations, and in one they were combined with maculopapules. Three patients had the "scarlet fever" type of rash, which was predominantly erythematous and maculopapular. Petechiae were also present in these patients, and in two
of them there was an occasional vesicular lesion. The remaining three patients had an exanthem that was predominantly petechial and purpuric, but, in two, some vesicles or hemorrhagic vesicles were also present. A consistent finding was a low-to-normal leukocyte count with a left shift (Table 1). The leukocyte count on admission ranged from 4200 to 9000 cells per cubic millimetre. Seven of the patients had more than 16% band forms (range, 8% to 24%) of the total differential count. Examination and culture of the sputum for bacteria were not helpful, and all specimens for viral isolation were negative for measles and other viruses. Serologic testing showed that all seven patients who had an initial serum obtained within 6 days from the onset of their illness had a fourfold rise in complement fixation or in hemagglutination-inhibition antibody titers. Two patients were not admitted until the second week of illness and one not until 2 months later for persistent pulmonary problems; all had significantly high titers found on the initial blood specimen. Characteristic of these patients with atypical measles was the very abrupt and high rise in the antibody titers within a few days. In several patients initial specimens had undetectable levels of complement-fixation or hemagglutination-inhibition antibody and within 4 to 8 days showed a marked rise in titer, in the range of 1:512 or 1:1024. Abnormalities of the admitting chest roentgenogram were seen in all 10 subjects. The most common abnormality, found in nine of 10 subjects, was a segmental infiltrate (Figure 2, left). These infiltrates cleared completely during the 12-week follow-up in seven subjects. In two patients, however, the segmental infiltrate improved, but a residual faint nodule persisted throughout the 12 weeks of follow-up (Figure 2, right). One patient (Patient 1) presented with diffuse alveolar infiltrates and acute respiratory failure with clinical, physiologic, and roentgenographic findings similar to those of the adult respiratory distress syndrome. The arterial blood gas measurements and standard pulHall and Hall • Atypical Measles in Adolescents
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Figure 1 Upper Left. The vesicular rash of atypical measles. Individual vesicles often had a hemorrhagic base, mimicking varicella. Upper Right. Petechial rash with areas of purpura similar to the exanthem seen in Rocky Mountain spotted fever. Lower Left. Erythematous "scarlet fever" exanthem associated with atypical measles. Lower Right. "Strawberry tongue" exanthem seen in association with the erythematous maculopapular exanthem of atypical measles.
monary function tests done on these patients showed that abnormalities persisted for weeks to months, despite clinical improvement. Table 1 shows arterial Po 2 values with patients breathing room air at the time of admission. A mean value of 58 mm Hg was seen initially. The lowest value, 42 mm Hg, was seen in Patient 1, with the patient presenting with acute respiratory failure. Two weeks later, four of 10 still had residual hypoxemia (defined in our laboratories as arterial Po 2 less than 88 mm Hg), and 4 weeks later two still had arterial Po 2 values below normal. At 12 weeks, all subjects had reverted to normal levels. Pulmonary function studies included lung volumes, forced flow rates, and diffusing capacity obtained serially in all patients (Table 1). Mean values for these tests at the time of initial evaluation were indicative of appreciable restrictive pulmonary disease. Diminution in maximal expiratory flow rates was not a pronounced finding. Four weeks after illness, lung volumes and diffusing capacity had improved. However, at this time four of the 10 patients still had abnormal chest roentgenograms. By Week 12, values for pulmonary function studies had returned to within normal limits. Mean values as percent predicted were: vital capacity, 93%; total lung capacity, 98%; dif004
fusing capacity, 97%. This improvement was statistically significant (P < 0.01). Eight patients had normal chest roentgenograms. Two patients still showed faint residual nodules (Figure 2). Discussion
Although atypical measles has been described in pediatric literature as early as 1965, internists may not be familiar with this syndrome that can present as a diagnostic conundrum. Yet that atypical measles is becoming a disease of teenagers and young adults and will be seen with increasing frequency in the adult population in years to come is apparent. The patients in a series from our community published in 1970 had a mean age of 7, contrasting with the mean age of 14 in our patients. Recent case reports have described this syndrome in 19-to-24-yearold patients (15, 16). The target population will continue to be primarily the recipients of killed virus vaccine. An estimated 600 000 to 900 000 persons were immunized with this agent between 1963 and 1967 (17). Most recipients were approximately 1 year of age, and therefore are now teenagers. Of perhaps even greater importance have been reports of atypical measles occurring in patients who had received only live attenuated measles vaccine.
June 1979 • Annals of Internal Medicine • Volume 90 • Number 6
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These observations suggest that the population at risk may encompass most young adults (18, 19). During the years since the original description of atypical measles, the clinical spectrum seems to have widened. In general, patients described earlier were more severely ill with purpuric skin nodules, peripheral edema, pleural effusions, muscle weakness, and sometimes abdominal pain with vomiting, albuminuria, and even oliguria (2, 4, 5). Our patients were not as critically ill, and of the entire 32 cases diagnosed only 10 were admitted to the hospital. This could result from a greater awareness of the entity of atypical measles in more recent years that allows diagnosis of milder cases or could be because the disease actually has become milder. With an increasing span of years since inoculation of the killed antigen, the intensity of the immune response may have diminished. Similarly, the roentgenographic patterns seen in our patients differ from those previously reported in younger patients. Young, Smith, and Glasgow (3) evaluated 10 children hospitalized with atypical measles and found hilar adenopathy and pneumonia in all cases and pleural fluid in seven of 10. They emphasized the frequent progression to residual nodular lesions. In the present series a greater spectrum of pulmonary infiltrates was found, ranging from isolated, segmental consolidation to generalized alveolar and interstitial infiltrates characteristic of acute respiratory failure. The more varied infiltrates seen in our patients may simply represent the wide variety of presenting roentgenographic patterns of atypical measles or may represent the more typical patterns of the disease in the older patient. The pathogenesis of the atypical measles syndrome is unclear. An immunologic or hypersensitivity reaction seems most likely, considering the specificity of the atypical measles response. Several theories have been suggested that hypothesize an "immunologic imbalance" elicited by the killed measles antigen between persisting cell-me-
diated immunity and the once-present humoral antibody or absent secretory antibody response (5, 20). Alternatively, an immune complex, or generalized Arthus reaction (21), has been suggested. The striking and prolonged alterations in gas exchange and pulmonary mechanics noted in these patients may provide some insight into the pathogenesis of the pulmonary lesion in atypical measles. All patients presented with hypoxemia and severe restrictive lung disease. Despite these initial findings, complete physiologic resolution was seen in all cases during the 12-week duration of the study. Because all cases were culture-negative for measles virus, that persistent viral replication, as has been reported in giant cell pneumonitis (22), was responsible for the prolonged physiologic changes observed is unlikely. Although other respiratory viral infections such as influenza virus, respiratory syncytial virus, and rhinovirus have been associated with comparably prolonged abnormalities of pulmonary function, the alterations noted in these illness are almost exclusively of an obstructive nature (23-25). That in those cases viral infection is associated with acute airway epithelial damage and inflammatory exudate and bronchial hyperreactivity has been postulated (24, 26). This physiologic pattern was not found in these cases of atypical measles. The transient hypoxemia and restrictive pattern are similar to the physiologic changes noted in hypersensitivity pneumonitis (27). Immune complex and delayed hypersensitivity immunologic reactions have been suggested as mechanisms of tissue injury in both hypersensitivity pneumonitis (28) and atypical measles (5). The physiologic abnormalities seen in these patients are consistent with the known effects on pulmonary function of these immunologic reactions. Perhaps the most important aspect of atypical measles, which is largely a self-limited illness, is the propensity for
Figure 2 Left. Right upper lobe segmental infiltrate in a patient with atypical measles (Patient 5). This roentgenographic pattern was seen in nine of 1 0 subjects of this report. Right. Residual right upper lobe nodule seen on examination 12 weeks after initial evaluations in same case. Hall and Hall • Atypical Measles in Adolescents
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885
this symptom complex to be mistaken for more serious illness. Our data suggest that physiologic resolution, although lagging behind clinical improvement, is to be expected. Awareness of the characteristic features of this illness should enhance the probability of prompt recognition. Atypical measles has two major clinical presentations. It may present, as in this series, as a dramatic clinical syndrome of abrupt high fever, a rash that is usually initially peripheral in distribution, and near simultaneously pulmonary involvement. The alternative mode of presentation will be in the patient found to have a solitary or multiple pulmonary nodularity on chest roentgenogram (3). In most instances, history will indicate an antecedent clinical syndrome. Laboratory data will usually confirm the diagnosis. Patients will characteristically present with leukopenia and a left-shifted differential count. Bacterial and viral cultures will be mainly useful in excluding other pathogens. In contrast to conventional measles infection, measles virus in atypical measles has not been isolated. Specific serologic diagnosis in the form of hemagglutination-inhibition and complement-fixation antibody tests are available at most hospitals and state laboratories. Characteristically high titers are seen very early in the course of this disease (4). Most importantly, invasive procedures, such as lung biopsy (15), should not be required in diagnosing this disease if the appropriate level of clinical recognition exists. A C K N O W L E D G M E N T S : Grant support: in part by Contract No. N O l A1-22503 from the Infectious Disease Branch, National Institute of Allergy and Infectious Disease, National Institutes of Health; Bethesda, Maryland. Dr. William J. Hall is supported by National Heart and Lung Institute Pulmonary Academic Award No. HL70822. • Requests for reprints should be addressed to William J. Hall, M.D.; Box 692, Pulmonary Disease Unit, University of Rochester School of Medicine; 601 Elmwood Avenue; Rochester, NY 14642.
test reactivity and antibody response to measles virus antigens in recipients of killed measles virus vaccine. J Pediatr 75:604-616, 1969 6. H A L L CB, DOUGLAS R G JR: Respiratory syncytial virus and influenza: practical community surveillance. Am J Dis Child 130:615-620, 1976 7. ENDERS JF: Measles virus (rubeola), in Diagnostic Procedures of Viral and Ricketsial Diseases, 3rd ed., edited by L E N E T T E EH, SCHMIDT NJ. New York, American Public Health Association, 1964, pp. 528-552 8. HIERHOLZER JC, SUGGS MT, H A L L EC: Standardized viral hemagglutination-inhibition tests. II. Description and statistical evaluation. Appl Microbiol 18:824, 1969 9. K O R Y R C , C A L L A H A N R, B O R E N H G , S Y N E R JC: The Veterans Ad-
ministration Army cooperative study of pulmonary function. I. Clinical spirometry in normal men. Am J Med 30:243-258, 1961 10. MORRIS JF, KOSKI A, JOHNSON LC: Spirometric standards for healthy nonsmoking adults. Am Rev Respir Dis 103:57-67, 1971 11. POLGAR G, PROMADKAT V: Pulmonary Function Testing in Children: Techniques and Standards. Philadelphia, W. B. Saunders Co., 1971, p. 88 12. D U B O I S AB, B O T E L H O SY, B E D E L L G N , M A R S H A L L R, C O M R O E J H
JR: A rapid plethysmography method for measuring thoracic gas volume: a comparison with a nitrogen washout method for measuring functional residual capacity in normal subjects. / Clin Invest 35:322-326, 1956 13. O L G I L V I E CM, F O R S T E R R G , B L A K E M O R E WS, M O R T O N JW: A stan-
dardized breath holding technique for the clinical measurement of the diffusing capacity of the lung for carbon monoxide. / Clin Invest 36:117, 1957 14. DIXON WJ, MASSEY FM JR: Introduction to Statistical Analysis, 3rd ed. New York, McGraw Hill Book Company, 1969, p. 5 15. C H U N P K C : Multiple pulmonary nodules in a young man. Chest 73:527-528, 1978 16. 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-
1975. Morbid Mortal Weekly Rep 25:245-246, 1976 17. HALSEY NA: Current status of measles in the United States 1973-77. / Infect Dis 137:847-853, 1978 18. C H E R R Y J D , F E I G I N R D , L O B E S LA J R , S H A C K E L F O R D P G : Atypical
measles in children previously immunized with attenuated measles virus vaccine. Pediatrics 50:712-717, 1972 19. 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 20.
B E L L A N T I JA, SANGA R L , K L U T I N I S B, B R A N D T B, A R T E N S T E I N MS:
Antibody response in serum and nasal secretions of children immunized with inactivated and attenuated measles-virus vaccines. N Engl J Med 280:628-633, 1969 21. BELLANTI J A: Biologic significance of the secretory yA immunoglobins. Pediatrics 48:715-729, 1971 22.
M C C A R T H Y K, M I T U S A, C H E A T H A M W, P E E B L E S T C : Isolation of
virus of measles from three fatal cases of giant cell pneumonia. Am J Dis Child 96:500-501, 1958
Received 14 September 1978; revision accepted 12 March 1979.
23.
References
DM: Pulmonary mechanics after uncomplicated influenza A infection. Am Rev Respir Dis 113:141-147, 1976 24. H A L L WJ, H A L L CB, SPEERS DM: Respiratory syncytial virus infection in adults. Clinical, virologic, and serial pulmonary function studies. Ann Intern Med 88:203-205, 1978
1. R A U H LW, SCHMIDT R: Measles immunization with killed virus vaccine. Am JDis Child 109:232-237, 1965 2. N A D E R PR, H O R O 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 3. 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 4. 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 CM: Altered reactivi-
ty to measles virus: atypical measles in children previously immunized with inactivated measles virus vaccines. JAMA 202:1075-1080, 1967 5. FULGINITI VA, A R T H U R JM: Altered reactivity to measles virus: skin
g36
25.
H A L L WJ, D O U G L A S R G , H Y D E RW, R O T H F K , CROSS AS, SPEERS
F R I D Y W W J R , I N G R A M R H , H I E R H O L Z E R JC, C O L E M A N M T : Air-
ways function during mild viral respiratory illness. Ann Intern Med 80:150-155, 1974 26.
E M P E Y DW, L A I T I N E N LA, JACOBS L, G O L D WM, N A D E L J A: Mecha-
nisms of bronchial hyperreactivity in normal subjects after upper respiratory tract infection. Am Rev Respir Dis 113:131-139, 1976 27. SCHLUETER DP: Response of the lung to inhaled antigens. Am J Med 57:476-492, 1974 28. ROBERTS R C , M O O R E UL: Immunopathogenesis of hypersensitivity pneumonitis. Am Rev Respir Dis 116:1075-1090, 1977
June 1979 • Annals of Internal Medicine • Volume 90 • Number 6
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During a community outbreak of measles, 10 patients aged 11 through 19 were hospitalized with prominent pulmonary infiltrates and clinical manifestations of high fever and rash. Diagnoses of atypical measles were confirmed by hemagglutination-inhibition and complement-fixation antibody studies. Patients were followed with pulmonary function studies for 12 weeks. The most common admitting diagnoses were varicella, scarlet fever, meningococcemia, and Rocky Mountain spotted fever, due largely to the protean cutaneous manifestations. Roentgenographic studies showed diffuse, segmental, and nodular chest lesions. Hypoxemia (mean arterial Po2, 5 8 mm Hg) and markedly reduced lung volumes were noted. Gradual resolution of physiologic abnormalities was noted during 12 weeks, but two children had persistent nodular densities seen on chest roentgenograms. Atypical measles in the older child and young adult has a wide spectrum of pulmonary manifestations ranging from acute respiratory failure to isolated nodular lesions. Proper recognition of this syndrome will prevent unnecessary invasive diagnostic procedures. T H E O C C U R R E N C E of a new clinical syndrome after exposure to wild measles virus in persons who had previously received inactivated measles vaccine was initially reported in 1965 (1). Since then a number of reports in the pediatric literature have delineated the varied clinical picture of "atypical measles" with its prominent pulmonary involvement (2-4). Although many of these patients are now being seen by internists, this syndrome is not well described in the adult medical literature and may be confused with a number of unusual diseases requiring extensive diagnostic procedures. T h e pathologic process that causes atypical measles is not completely understood, but an abnormal immune reaction in a previously sensitized host has been suggested (5). Ascertaining the physiologic alterations associated with the pulmonary involvement may further our understanding of the pathophysiology of this curious disease. Therefore, when an outbreak of rubeola occurred in Rochester, New York, the study described here was undertaken in an attempt to delineate the physiologic alterations in the lungs of patients hospitalized with atypical measles. Second, we describe the clinical manifestations of these patients, because the syndrome of atypical measles seems to have widened since the initial descriptions more than a decade ago. Not only are these children now becoming young adults under the care of internists, but their clinical presentation is varied, mimicking a number of unusual diseases. • From the Departments of Medicine and Pediatrics, University of Rochester School of Medicine; Rochester, N e w York. 8 8 2
Annals of Internal Medicine 9 0 : 8 8 2 8 8 6 , 1 9 7 9
Patients and Methods As part of an infectious disease surveillance program, the monthly prevalence of measles cases is closely monitored in our community (6). During January and February 1976, there was an abrupt rise in the number of reported cases of measles, which gradually tapered off during the next 4 months. This outbreak was characterized by large numbers of cases reported from area high schools. During the first 5 months of 1976, 32 patients were referred to us for evaluation of illnesses that were subsequently diagnosed as atypical measles. Ten of these patients, all with prominent pulmonary findings, were hospitalized and form the group studied. These patients were evaluated clinically and with pulmonary function studies at the time of admission and at 2, 4, and 12 weeks subsequently. Laboratory evaluation included complete blood counts, chest roentgenograms, electrolytes, urinalysis, throat and sputum cultures for bacteria, and nasal wash or nose-plus-throat specimens for viral isolation. Paired sera were obtained for examination of measles complement-fixation and hemagglutination-inhibition antibody content. In three patients, already in the convalescent phase of their illness at the time of admission, only one serum was obtained. Both the complementfixation and hemagglutination-inhibition tests were done in microtiter plates using standard methods (7, 8). Arterial blood samples were obtained by percutaneous radial artery puncture and analyzed on an IL Model 313 blood gas analyzer (Instrument Laboratories, Lexington, Massachusetts). Samples were obtained while patients were breathing ambient air. Follow-up samples were obtained at 2, 4, and in some cases, 12 weeks, until arterial Po 2 values had reverted to normal levels. Pulmonary function studies were done in all 10 subjects during their acute hospitalization and at 4 and 12 weeks thereafter. Each subject did at least three maximal forced expiratory maneuvers into a 13.5-L Stead-Wells spirometer (Warren E. Collins, Braintree, Massachusetts). Vital capacity and forced expiratory volume in 1 s were calculated by methods described by Kory and associates (9). Values were expressed as percent of predicted normal values published by Morris, Koski, and Johnson (10) and Polgar and Promadkat (11). Functional residual capacity was measured in a body plethysmograph (12), and was used in deriving total lung capacity. Single-breath carbon monoxide diffusing capacity was determined by the methods of Olgilvie (13). Statistical significance of changes in pulmonary function data over time was evaluated by paired t testing (14). Results Table 1 summarizes some of the pertinent clinical and laboratory features of this illness. T h e disease predominantly affected teenagers and males ( 8 0 % ) . All patients had been immunized between 1963 and 1965 with two or three doses of killed measles virus vaccine. Five had one dose of live virus vaccine in addition. In all patients the illness started abruptly with fever and rash. T h e fever was generally high and prolonged, lasting an average of 16 d (Table 1). Coryza and conjunctivitis were notably absent, but a nonproductive cough with dyspnea was present in eight of the 10 patients at © 1 9 7 9 American College of Physicians
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Table 1. CIlinica 1 and Lciboratory Data on 10 Subjects wil:h Atypical Measles Patient
Sex
Age
yr 1 2 3 4 5 6 7 8 9 10 Mean SD
M F M M F M M M M M
13 14 17 15 11 16 15 12 19 14 14 2.4
Temperature Maximum
>38°C
°C 40.6 39.5 39.1 40.0 38.3 40.0 40.1 39.5 38.4 39.0 39.4 0.74
d 8 13 16 21 22 15 14 17 11 20 16 4
Initial Diagnosis*
V SF SF V M, RMSF V RMSF M,RMSF V SF
Leukocytes Total
Bands
10/mm*
%
5.0 7.4 6.5 5.4 9.0 5.2 5.8 5.9 4.3 4.2 5.9 1.5
17 20 19 14 20 8 19 9 18 24 16.9 5
Chest Roentgenogram*
D S S S S,N S
s s sS,N
Pulmonary Function Testsf VC
FEVj/FVC
% pred
%
40 56 52 65 66 45 50 80 51 48 55 12
42 81 87 80 85 80 87 85 78 79 78 13
DL
Arterial Po 2
% pred mm Hg 41 48 49 52 60 45 62 71 65 60 55 10
42 52 60 56 59 65 60 55 61 71 58 8
* V = varicella; SF = scarlet fever; M = meningococcemia; RMSF = Rocky Mountain spotted fever; D = diffuse; S = segmental; N = nodular, t VC = vital capacity; FEVi = forced expiratory volume in 1 s; FVC = forced vital capacity; DL = single-breath diffusing capacity; % pred = percent of normal values drawn from published data (see text).
the time of admission. Almost all had headache, myalgias, general malaise, and anorexia. But despite these constitutional symptoms and the high fever, the patients did not seem markedly toxic or septic. The exanthem was striking and varied, but generally could be categorized into one of three appearances. The first was a predominantly vesicular rash that elicited the initial diagnosis of chickenpox with pneumonia. The vesicles appeared singly or in crops, mainly over the trunk, occasionally with a hemorrhagic base (Figure 1, upper left). The second type of rash was predominantly petechial with some purpura and elicited the initial diagnosis of meningococcemia or Rocky Mountain spotted fever. The petechial rash, generally mixed with small maculopapular lesions, was predominantly on the trunk and extremities with relative sparing of the face (Figure 1, upper right). A few of the lesions progressed to purpura. The third form of the rash was a predominantly erythematous, maculopapular rash that most commonly elicited the diagnosis of scarlet fever. The lesions tended to be small and bright red and to coalesce, with particular prominence on the trunk, in the skin folds under the axilla, and in the groin. The exanthem also involved the arms and particularly the legs, including the palms and soles. Although the maculopapular lesions tended to be slightly larger than those classically associated with scarlet fever, the overall appearance in two patients was strikingly similar, with a "boiled lobster" erythema (Figure 1, lower left) and even a strawberry tongue (Figure 1, lower right). Various combinations of these three types of rashes were seen in individual patients. Four of the patients had the first type of rash, predominantly vesicular with an appearance most like chickenpox. In three of these patients vesicles were the sole cutaneous manifestations, and in one they were combined with maculopapules. Three patients had the "scarlet fever" type of rash, which was predominantly erythematous and maculopapular. Petechiae were also present in these patients, and in two
of them there was an occasional vesicular lesion. The remaining three patients had an exanthem that was predominantly petechial and purpuric, but, in two, some vesicles or hemorrhagic vesicles were also present. A consistent finding was a low-to-normal leukocyte count with a left shift (Table 1). The leukocyte count on admission ranged from 4200 to 9000 cells per cubic millimetre. Seven of the patients had more than 16% band forms (range, 8% to 24%) of the total differential count. Examination and culture of the sputum for bacteria were not helpful, and all specimens for viral isolation were negative for measles and other viruses. Serologic testing showed that all seven patients who had an initial serum obtained within 6 days from the onset of their illness had a fourfold rise in complement fixation or in hemagglutination-inhibition antibody titers. Two patients were not admitted until the second week of illness and one not until 2 months later for persistent pulmonary problems; all had significantly high titers found on the initial blood specimen. Characteristic of these patients with atypical measles was the very abrupt and high rise in the antibody titers within a few days. In several patients initial specimens had undetectable levels of complement-fixation or hemagglutination-inhibition antibody and within 4 to 8 days showed a marked rise in titer, in the range of 1:512 or 1:1024. Abnormalities of the admitting chest roentgenogram were seen in all 10 subjects. The most common abnormality, found in nine of 10 subjects, was a segmental infiltrate (Figure 2, left). These infiltrates cleared completely during the 12-week follow-up in seven subjects. In two patients, however, the segmental infiltrate improved, but a residual faint nodule persisted throughout the 12 weeks of follow-up (Figure 2, right). One patient (Patient 1) presented with diffuse alveolar infiltrates and acute respiratory failure with clinical, physiologic, and roentgenographic findings similar to those of the adult respiratory distress syndrome. The arterial blood gas measurements and standard pulHall and Hall • Atypical Measles in Adolescents
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Figure 1 Upper Left. The vesicular rash of atypical measles. Individual vesicles often had a hemorrhagic base, mimicking varicella. Upper Right. Petechial rash with areas of purpura similar to the exanthem seen in Rocky Mountain spotted fever. Lower Left. Erythematous "scarlet fever" exanthem associated with atypical measles. Lower Right. "Strawberry tongue" exanthem seen in association with the erythematous maculopapular exanthem of atypical measles.
monary function tests done on these patients showed that abnormalities persisted for weeks to months, despite clinical improvement. Table 1 shows arterial Po 2 values with patients breathing room air at the time of admission. A mean value of 58 mm Hg was seen initially. The lowest value, 42 mm Hg, was seen in Patient 1, with the patient presenting with acute respiratory failure. Two weeks later, four of 10 still had residual hypoxemia (defined in our laboratories as arterial Po 2 less than 88 mm Hg), and 4 weeks later two still had arterial Po 2 values below normal. At 12 weeks, all subjects had reverted to normal levels. Pulmonary function studies included lung volumes, forced flow rates, and diffusing capacity obtained serially in all patients (Table 1). Mean values for these tests at the time of initial evaluation were indicative of appreciable restrictive pulmonary disease. Diminution in maximal expiratory flow rates was not a pronounced finding. Four weeks after illness, lung volumes and diffusing capacity had improved. However, at this time four of the 10 patients still had abnormal chest roentgenograms. By Week 12, values for pulmonary function studies had returned to within normal limits. Mean values as percent predicted were: vital capacity, 93%; total lung capacity, 98%; dif004
fusing capacity, 97%. This improvement was statistically significant (P < 0.01). Eight patients had normal chest roentgenograms. Two patients still showed faint residual nodules (Figure 2). Discussion
Although atypical measles has been described in pediatric literature as early as 1965, internists may not be familiar with this syndrome that can present as a diagnostic conundrum. Yet that atypical measles is becoming a disease of teenagers and young adults and will be seen with increasing frequency in the adult population in years to come is apparent. The patients in a series from our community published in 1970 had a mean age of 7, contrasting with the mean age of 14 in our patients. Recent case reports have described this syndrome in 19-to-24-yearold patients (15, 16). The target population will continue to be primarily the recipients of killed virus vaccine. An estimated 600 000 to 900 000 persons were immunized with this agent between 1963 and 1967 (17). Most recipients were approximately 1 year of age, and therefore are now teenagers. Of perhaps even greater importance have been reports of atypical measles occurring in patients who had received only live attenuated measles vaccine.
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These observations suggest that the population at risk may encompass most young adults (18, 19). During the years since the original description of atypical measles, the clinical spectrum seems to have widened. In general, patients described earlier were more severely ill with purpuric skin nodules, peripheral edema, pleural effusions, muscle weakness, and sometimes abdominal pain with vomiting, albuminuria, and even oliguria (2, 4, 5). Our patients were not as critically ill, and of the entire 32 cases diagnosed only 10 were admitted to the hospital. This could result from a greater awareness of the entity of atypical measles in more recent years that allows diagnosis of milder cases or could be because the disease actually has become milder. With an increasing span of years since inoculation of the killed antigen, the intensity of the immune response may have diminished. Similarly, the roentgenographic patterns seen in our patients differ from those previously reported in younger patients. Young, Smith, and Glasgow (3) evaluated 10 children hospitalized with atypical measles and found hilar adenopathy and pneumonia in all cases and pleural fluid in seven of 10. They emphasized the frequent progression to residual nodular lesions. In the present series a greater spectrum of pulmonary infiltrates was found, ranging from isolated, segmental consolidation to generalized alveolar and interstitial infiltrates characteristic of acute respiratory failure. The more varied infiltrates seen in our patients may simply represent the wide variety of presenting roentgenographic patterns of atypical measles or may represent the more typical patterns of the disease in the older patient. The pathogenesis of the atypical measles syndrome is unclear. An immunologic or hypersensitivity reaction seems most likely, considering the specificity of the atypical measles response. Several theories have been suggested that hypothesize an "immunologic imbalance" elicited by the killed measles antigen between persisting cell-me-
diated immunity and the once-present humoral antibody or absent secretory antibody response (5, 20). Alternatively, an immune complex, or generalized Arthus reaction (21), has been suggested. The striking and prolonged alterations in gas exchange and pulmonary mechanics noted in these patients may provide some insight into the pathogenesis of the pulmonary lesion in atypical measles. All patients presented with hypoxemia and severe restrictive lung disease. Despite these initial findings, complete physiologic resolution was seen in all cases during the 12-week duration of the study. Because all cases were culture-negative for measles virus, that persistent viral replication, as has been reported in giant cell pneumonitis (22), was responsible for the prolonged physiologic changes observed is unlikely. Although other respiratory viral infections such as influenza virus, respiratory syncytial virus, and rhinovirus have been associated with comparably prolonged abnormalities of pulmonary function, the alterations noted in these illness are almost exclusively of an obstructive nature (23-25). That in those cases viral infection is associated with acute airway epithelial damage and inflammatory exudate and bronchial hyperreactivity has been postulated (24, 26). This physiologic pattern was not found in these cases of atypical measles. The transient hypoxemia and restrictive pattern are similar to the physiologic changes noted in hypersensitivity pneumonitis (27). Immune complex and delayed hypersensitivity immunologic reactions have been suggested as mechanisms of tissue injury in both hypersensitivity pneumonitis (28) and atypical measles (5). The physiologic abnormalities seen in these patients are consistent with the known effects on pulmonary function of these immunologic reactions. Perhaps the most important aspect of atypical measles, which is largely a self-limited illness, is the propensity for
Figure 2 Left. Right upper lobe segmental infiltrate in a patient with atypical measles (Patient 5). This roentgenographic pattern was seen in nine of 1 0 subjects of this report. Right. Residual right upper lobe nodule seen on examination 12 weeks after initial evaluations in same case. Hall and Hall • Atypical Measles in Adolescents
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this symptom complex to be mistaken for more serious illness. Our data suggest that physiologic resolution, although lagging behind clinical improvement, is to be expected. Awareness of the characteristic features of this illness should enhance the probability of prompt recognition. Atypical measles has two major clinical presentations. It may present, as in this series, as a dramatic clinical syndrome of abrupt high fever, a rash that is usually initially peripheral in distribution, and near simultaneously pulmonary involvement. The alternative mode of presentation will be in the patient found to have a solitary or multiple pulmonary nodularity on chest roentgenogram (3). In most instances, history will indicate an antecedent clinical syndrome. Laboratory data will usually confirm the diagnosis. Patients will characteristically present with leukopenia and a left-shifted differential count. Bacterial and viral cultures will be mainly useful in excluding other pathogens. In contrast to conventional measles infection, measles virus in atypical measles has not been isolated. Specific serologic diagnosis in the form of hemagglutination-inhibition and complement-fixation antibody tests are available at most hospitals and state laboratories. Characteristically high titers are seen very early in the course of this disease (4). Most importantly, invasive procedures, such as lung biopsy (15), should not be required in diagnosing this disease if the appropriate level of clinical recognition exists. A C K N O W L E D G M E N T S : Grant support: in part by Contract No. N O l A1-22503 from the Infectious Disease Branch, National Institute of Allergy and Infectious Disease, National Institutes of Health; Bethesda, Maryland. Dr. William J. Hall is supported by National Heart and Lung Institute Pulmonary Academic Award No. HL70822. • Requests for reprints should be addressed to William J. Hall, M.D.; Box 692, Pulmonary Disease Unit, University of Rochester School of Medicine; 601 Elmwood Avenue; Rochester, NY 14642.
test reactivity and antibody response to measles virus antigens in recipients of killed measles virus vaccine. J Pediatr 75:604-616, 1969 6. H A L L CB, DOUGLAS R G JR: Respiratory syncytial virus and influenza: practical community surveillance. Am J Dis Child 130:615-620, 1976 7. ENDERS JF: Measles virus (rubeola), in Diagnostic Procedures of Viral and Ricketsial Diseases, 3rd ed., edited by L E N E T T E EH, SCHMIDT NJ. New York, American Public Health Association, 1964, pp. 528-552 8. HIERHOLZER JC, SUGGS MT, H A L L EC: Standardized viral hemagglutination-inhibition tests. II. Description and statistical evaluation. Appl Microbiol 18:824, 1969 9. K O R Y R C , C A L L A H A N R, B O R E N H G , S Y N E R JC: The Veterans Ad-
ministration Army cooperative study of pulmonary function. I. Clinical spirometry in normal men. Am J Med 30:243-258, 1961 10. MORRIS JF, KOSKI A, JOHNSON LC: Spirometric standards for healthy nonsmoking adults. Am Rev Respir Dis 103:57-67, 1971 11. POLGAR G, PROMADKAT V: Pulmonary Function Testing in Children: Techniques and Standards. Philadelphia, W. B. Saunders Co., 1971, p. 88 12. D U B O I S AB, B O T E L H O SY, B E D E L L G N , M A R S H A L L R, C O M R O E J H
JR: A rapid plethysmography method for measuring thoracic gas volume: a comparison with a nitrogen washout method for measuring functional residual capacity in normal subjects. / Clin Invest 35:322-326, 1956 13. O L G I L V I E CM, F O R S T E R R G , B L A K E M O R E WS, M O R T O N JW: A stan-
dardized breath holding technique for the clinical measurement of the diffusing capacity of the lung for carbon monoxide. / Clin Invest 36:117, 1957 14. DIXON WJ, MASSEY FM JR: Introduction to Statistical Analysis, 3rd ed. New York, McGraw Hill Book Company, 1969, p. 5 15. C H U N P K C : Multiple pulmonary nodules in a young man. Chest 73:527-528, 1978 16. 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-
1975. Morbid Mortal Weekly Rep 25:245-246, 1976 17. HALSEY NA: Current status of measles in the United States 1973-77. / Infect Dis 137:847-853, 1978 18. C H E R R Y J D , F E I G I N R D , L O B E S LA J R , S H A C K E L F O R D P G : Atypical
measles in children previously immunized with attenuated measles virus vaccine. Pediatrics 50:712-717, 1972 19. 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 20.
B E L L A N T I JA, SANGA R L , K L U T I N I S B, B R A N D T B, A R T E N S T E I N MS:
Antibody response in serum and nasal secretions of children immunized with inactivated and attenuated measles-virus vaccines. N Engl J Med 280:628-633, 1969 21. BELLANTI J A: Biologic significance of the secretory yA immunoglobins. Pediatrics 48:715-729, 1971 22.
M C C A R T H Y K, M I T U S A, C H E A T H A M W, P E E B L E S T C : Isolation of
virus of measles from three fatal cases of giant cell pneumonia. Am J Dis Child 96:500-501, 1958
Received 14 September 1978; revision accepted 12 March 1979.
23.
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