association group coxsackieviruses pericarditis, …produce pericarditis or myocarditis in man,...

INFECriON AND IMMUNITY, Sept. 1973, p. 341-348Copyright 0 1973 American Society for Microbiology

Vol. 8, No. 3Printed in U.S.A.

Association of Group B Coxsackieviruses withCases of Pericarditis, Myocarditis, or

Pleurodynia by Demonstration ofImmunoglobulin M Antibody

NATHALIE J. SCHMIDT, ROBERT L. MAGOFFIN, AND EDWIN H. LENNETTE

Viral and Rickettsial Disease Laboratory, California State Department of Public Health,Berkeley, California 94704

Received for publication 8 May 1973

Tests for immunoglobulin M (IgM) antibody to group B coxsackieviruses wereperformed on sera from 259 patients with a clinical diagnosis of pericarditis,myocarditis, or pleurodynia on whom there were no definitive serological or virusisolation findings to establish a viral etiology, and on 259 "control" patients withclinical diagnoses of viral or mycoplasmal pneumonia or pneumonitis. IgMantibodies to coxsackievirus types Bi, B3, B4, B5, and B6 were detected by amicro-immunodiffusion technique, and antibodies to virus type B2 were detectedby reduction of neutralizing antibodies with ethanethiol. Of the patients withpericarditis, myocarditis, or pleurodynia, 27% (70) had IgM antibody to group Bcoxsackieviruses, as compared with 8% in the control group. On retrospectivereview of the clinical diagnosis, some of the patients in the control group withIgM antibody were found to have had additional clinical findings which could beattributed to a coxsackievirus infection. Coxsackievirus IgM antibody wasdemonstrable in 30% of 113 patients in the study group for whom virus isolationhad been attempted with negative results. The presence of coxsackievirus IgM isdiscussed in relation to the time of serum collection, age of the patients, andmonth of onset of illness.

The ability of group B coxsackieviruses toproduce pericarditis or myocarditis in man,particularly in infants, is well recognized, (1, 3,8, 9, 17, 18, 28). However, a clear-cut laboratorydiagnosis of group B coxsackievirus infection,based upon virus isolation or demonstration of asignificant rise in antibody titer during thecourse of illness, can be established only infre-quently in sporadic cases of pericarditis ormyocarditis (2, 10, 11, 27). In cases of pleuro-dynia, recovery of coxsackievirus or significantrises in antibody titer, or both, are more fre-quently demonstrable, but there is still a fairlyhigh proportion of sporadic cases in which thereare no positive laboratory findings. For exam-ple, in 1970, the period covered by this report,specimens were submitted to this laboratory onmore than 250 patients with a clinical diagnosisof pericarditis, myocarditis, or pleurodynia; agroup B coxsackievirus was isolated from twopatients with chest pain compatible with aclinical diagnosis of pleurodynia, and one pa-tient with a clinical diagnosis of pericarditis

showed fourfold or greater rises in neutralizingantibody titer to three types of group B coxsack-ievirus.

It has been speculated that pericarditis, myo-carditis, or pleurodynia may occur relativelylate in the course of coxsackievirus infections, ata time when antibody levels are already ele-vated and virus is no longer being shed or iscombined with antibody.

Previous studies from this laboratory haveshown that immunoglobulin (Ig) M antibody togroup B coxsackievirus types 1, 3, 4, 5, and 6and group A, type 9 can be demonstrated byimmunodiffusion tests (24-26). IgM antibodyreacts type-specifically with the intact virion ofcoxsackieviruses and forms an immunoprecipi-tate distinct from that produced by IgG anti-body and empty capsids. It has also been shownthat the initial antibody response to group Bcoxsackievirus infections consists of the produc-tion of IgM antibody, which is gradually re-placed in 4 to 6 weeks by IgG (26). Thepossibility was considered that detection of IgM

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SCHMIDT, MAGOFFIN, AND LENNETTE

antibody might be used to demonstrate currentor recent group B coxsackievirus infections inpatients with a clinical diagnosis of pericarditis,myocarditis, or pleurodynia who had no otherlaboratory findings to implicate coxsack-ieviruses or other viruses as the etiologicalagent. This report describes the occurrence ofIgM antibodies to group B coxsackieviruses insera submitted to this laboratory from patientswith a clinical diagnosis of pericarditis, myocar-ditis, or pleurodynia, and in a control group ofpatients with clinical diagnoses of viral ormycoplasmal pneumonia.

MATERIALS AND METHODSSera examined. Tests were performed on sera

routinely submitted to this laboratory for diagnosis ofviral infection. Paired or single sera were tested from259 patients with clinical diagnoses of pericarditis(148 cases), myocarditis (92 cases) or pleurodynia (19cases) and on 259 patients with a clinical diagnosis ofviral or mycoplasmal pneumonia. The sera wereselected on the basis of a computer printout whichlisted all patients with these diagnoses (based onclinical findings given on the laboratory request form)and with an onset of illness during 1970. The studygroup included all myocarditis, pericarditis, or pleu-rodynia patients from whom sera were available in1970 and the control group was selected to include anequal number of paired and single serum specimensfrom pneumonia patients during the same period,matching by sex. In each group 121 patients hadpaired serum specimens and 138 had only a singlespecimen. There were 145 males and 114 females ineach group. Equal numbers of specimens from thestudy group and the control group were tested for IgMantibody in each run, and the individuals performingthe tests were unaware of the group to which thepatient belonged.

Immunodiffusion tests. Antigens for group B cox-sackievirus types 1, 3, 4, 5, and 6 were prepared frominfected HeLa cell culture fluids concentrated 300-fold by high-speed centrifugation. Satisfactory anti-gens for demonstration of IgM antibody requiredstarting material with an infectivity titer of at least1056 mean tissue culture dose per ml. Tests wereconducted by a micro-method previously described(24). The gel consisted of 0.8% agarose in 0.01 Mtris(hydroxymethyl)aminomethane buffer, 0.1 MNaCl, 0.001 M ethylenediaminetetraacetic acid and0.05% sodium azide; it had a pH of 7.6. Sera wereexamined undiluted and unheated for the presence ofprecipitating antibodies.

Demonstration of IgM antibody to coxsackie-virus type B2. Because it has not been possible todifferentiate between IgM and IgG antibodies tocoxsackievirus type B2 in immunodiffusion reactions(24, 25), treatment of sera with the sulfhydryl reduc-ing agent ethanethiol (15) was used to demonstrateIgM antibodies to this virus type. A 1:4 dilution oftest serum was mixed with an equal volume of 0.06 Methanethiol, incubated at room temperature for 3 hand then heated at 56 C for 30 min to inactivate the

serum and vaporize the sulfhydryl reagent. Thetreated serum was tested in a micro-metabolic-inhibi-tion system (21) in parallel with untreated serum(inactivated at 56 C for 30 min), and a fourfold orgreater reduction in neutralizing antibody titer of theethanethiol-treated portion was considered to suggestthe presence of IgM antibody. Reproducibility of asignificant titer decrease in another run was regardedas a valid demonstration of IgM antibody to coxsack-ievirus type B2.

Virus isolation attempts. Attempts to isolatecoxsackieviruses from clinical specimens were madeby inoculation of test material into primary or second-ary rhesus monkey kidney cell cultures and humanfetal diploid cell cultures by procedures describedelsewhere (21).

RESULTSOccurrence of IgM antibody to group B

coxsackieviruses. Of the patients in the peri-carditis, myocarditis, and pleurodynia group,27% had IgM antibody to group B coxsack-ieviruses as compared with 8% in the controlgroup (Table 1). There was little differencebetween males and females in the percentageshowing IgM antibody in either group. Table 2shows the occurrence of IgM antibody by clini-cal syndrome. A higher proportion of patients inthe pleurodynia group had IgM antibody thanin the pericarditis or myocarditis groups, butthere was a total of only 19 pleurodynia pa-tients.

After testing was completed, it was foundthat when specimen submission slips on thecontrol patients with coxsackievirus IgM anti-body were reexamined in detail, six of thepatients in the pneumonia group had clinicalevidence of cardiac or central nervous systeminvolvement suggestive of a coxsackievirus in-fection. The additional findings in these pa-tients included clinical signs of heart failure,pericarditis, and encephalitis.Type specificity of group B coxsackievirus

IgM antibody. In 1970 there were no recognizedoutbreaks of group B coxsackievirus infectionsin California, and virus isolations were madeonly from sporadic cases, usually with clinicalsigns of aseptic meningitis, scattered through-out the state. The virus types most frequentlyrecovered were Bi, B2, and B4. The typespecificity of the IgM antibody to group Bcoxsackieviruses demonstrated in the study andcontrol groups is shown in Table 3. As previ-ously noted (25, 26), some individuals werefound to have IgM antibody to more than onegroup B coxsackievirus type. In both groups thegreatest number of patients showed IgM anti-body for coxsackievirus type B4, followed bytypes B1 and B2.

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COXSACKIEVIRUS IgM ANTIBODY

TABLE 1. Occurrence of IgM antibody to group Bcoxsackieviruses in patients with pericarditis,

myocarditis, or pleurodynia and in patients in thecontrol group

IgM antibody to

No. group BGroup tested coxsackievirus

No. %

Pericarditis, myocarditis, 259 70 27pleurodynia

Males 145 41 28Females 114 29 25

Controla 259 21 8Males 145 11 8Females 114 10 9

a Patients with a clinical diagnosis of viral ormycoplasmal pneumonia.

TABLE 2. Occurrence of IgM antibody to group Bcoxsackieviruses in various clinical syndromes

IgM antibody to

No.of groupBClinical diagnosis patients coxsackieviruses

No. %

Study groupPericarditis 148 40 27Myocarditis 92 23 25Pleurodynia 19 7 37Totals 259 70 27

Control group (pneu- 259 21 8monia)

Relationship between time of specimen col-lection and presence of IgM antibody togroup B coxsackieviruses in patients withpericarditis, myocarditis, or pleurodynia.Table 4 shows the occurrence of IgM antibodyto group B coxsackieviruses by time intervalafter onset for patients in both the study andcontrol groups. In neither group was IgM dem-onstrated in specimens collected later than 42days after onset. Table 5 compares the numberof patients in the study group with paired serumspecimens and with single specimens whoshowed IgM antibody to group B coxsack-ieviruses, and it relates the presence of IgMantibody to the time of specimen collection. Alarger proportion of patients with paired serum

specimens showed IgM antibody than did thosewith a single specimen. Five of the patientsshowed IgM antibody only in the convalescent-phase serum, and these were all patients fromwhom the acute-phase serum was collectedwithin the first 3 days after onset of illness.Seven of the patients had IgM antibody only in

the acute-phase specimen, and there was widevariation in the collection times of the convales-cent-phase sera from these patients in whichIgM antibody was no longer demonstrable.None of the three convalescent-phase sera col-lected later than 42 days after onset had demon-strable IgM antibody, and all of the singleserum specimens which contained IgM anti-body were collected less than 36 days after onsetof illness.Virus isolation attempts on pericarditis,

myocarditis, or pleurodynia patients. Effortsto recover a coxsackievirus from patients in thestudy group are summarized in Table 6. It isseen that virus isolation attempts were per-formed in 113 of the cases, none of which yieldeda virus. Approximately equal numbers of pa-tients without isolation attempts and with neg-ative results had IgM antibody to group Bcoxsackieviruses. For the patients with negativeresults, most of the specimens tested were fecalspecimens, and approximately one-half of theisolation attempts were made on specimenscollected within the first week after onset ofillness. Thus, negative virus isolation resultswere obtained despite the fact that appropriatespecimens collected at suitable times were ex-amined. This is in marked contrast to theexperience in this laboratory with cases ofaseptic meningitis due to coxsackieviruses inwhich the virus is readily recovered from stoolsand spinal fluid in a high proportion of cases.However, 30% of the pericarditis, myocarditis,or pleurodynia patients with negative isolationresults possessed IgM antibody for group Bcoxsackieviruses.Place of residence and months of onset for

patients in study and control groups. Approx-imately 70% of the patients in both the studygroup and the control group were from eightcounties in the San Francisco Bay area. Theremainder of the patients in each group weredistributed throughout 16 other counties inCalifornia. Of the patients who had IgM anti-body to group B coxsackieviruses, 42 of 70 in thestudy group and 10 of 21 in the control groupwere from the San Francisco Bay area.

Table 7 shows the month of onset of illness forpatients in the study group and the controlgroup and the occurrence of IgM antibody bymonth of onset. The number of pericarditis,myocarditis, or pleurodynia patients was highin January, decreased during the spring andsummer months, and increased in the autumnand early winter months. For the most part, theoccurrence of IgM in the study group followedthis same pattern. The demonstration of IgMantibody in the control group was also more

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TABLE 3. Type specificity of group B coxsackievirus IgM antibody detected in patients with pericarditis,myocarditis, or pleurodynia and in control group

No. of patients with coxsackievirus IgM antibody to

Group No. positive/ Virusno. tested type 1 type 2 types 3 types 4 types 5 types

only

Pericarditis, myocarditis, pleuro- 70/259 56 11 1 1 1dynia Bi 8 7 1 1

B2 6 5B3 3 1 1 1B4 36 8 1 1B5 1 1 1 1 1136 2 1 1 1

Control (pneumonia) 21/259la 3131 3132 2B3 1B4 14 2B5 1B6 1

TABLE 4. Occurrence ofIgM antibody to group B coxsackieviruses by time interval after onset in patients withpericarditis, myocarditis, or pleurodynia and in control group of patients with pneumonia

Pericarditis, myocarditis, Pneumonia patientsDays after pleurodynia patients

onset ~No. of sera gM±- No. of sera 1M+ M-onset |tested Ig' + IgM _ tested IgM +

| l

1-3 86 26 60 65 4 614-7 80 17 63 80 7 738-14 49 10 39 84 7 7715-21 72 21 51 84 9 7522-28 36 12 24 36 3 3329-35 27 12 15 15 0 1536-42 5 1 4 7 0 743-49 6 0 6 6 0 650> 19 0 19 3 0 3Total sera 380 99 281 380 30 350Total patients 259 70 189 259 21 238

TABLE 5. Time of specimen collection for patients with pericarditis, myocarditis, or pleurodynia showing IgMantibody to group B coxsackieviruses

Serum No. of No. of Days after onsetspecimens patients patientsexamined positive 1-3 4-7 8-14 15-21 22-28 29-35 36-42 >43

Paired 121 41 (34%)First serumIgM + 17 8 6 3 2IgM - 5

Second serum1gM + 3 14 9 7 11gM - 2 1 1 3

Single 138 29 (21%)IgM + 9 9 1 4 1 5

Totals 259 70IgM + 26 17 10 21 12 12 1 0IgM - 5 0 0 2 1 0 1 3



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TABLE 6. Results of virus isolation attempts onpericarditis, myocarditis, or pleurodynia patients

sAll patients |Patients with IgMIsolation results Allpatent antibody to group B

coxsackieviruses (70)

Not done 146 36Negative 113 34Specimen tested

Fecal 108 32Pericardial

fluid 4 2Autopsy tissue 1 0

Days after onsetspecimencollected

1-3 18 74-6 35 117-10 40 10>10 20 6

frequent in cases occurring during the months ofAugust to November. Over the past years therecovery of coxsackieviruses from clinical mate-rials in this laboratory has also shown a seasonalpattern, with the greatest number of virusisolations being made in late summer and theautumn months.Relationship between age and occurrence

of IgM antibody to group B coxsackieviruses.Table 8 shows the ages of patients in the studyand control groups and the occurrence of IgMcoxsackievirus antibody in each age group.There was a greater number of control patientsthan study patients in children through 10 yearsof age, but only one of 30 control patientsshowed IgM antibody as compared with threeof 12 in the study group. In the age group from11 through 20 years there were roughly compar-able numbers of patients in each group, andsimilar numbers showed IgM antibody to groupB coxsackieviruses. Of particular interest is thegreater number of pericarditis, myocarditis, or

pleurodynia patients in the 21- through 60-yearage groups showing IgM antibody to group Bcoxsackieviruses as compared with control pa-tients in the same age groups.

DISCUSSION

The detection of IgM antibody to group Bcoxsackieviruses provided evidence of a currentor recent infection in just over one-fourth (27%)of a group of 259 patients with clinical diagnosesof pericarditis, myocarditis, or pleurodynia forwhom there were no other laboratory findings toconfirm a viral infection. This would appear tooffer a promising approach for further investiga-tions on the possible role of coxsackieviruses in

other clinical syndromes suspected to be of viraletiology.

It is noteworthy that, although group B cox-sackieviruses are the principal agents suspectedin virtually all of the cases of pericarditis ormyocarditis on whom clinical specimens aresubmitted to our laboratory for virological stud-ies, nearly three-fourths of the cases in thepresent study failed to show evidence of acurrent or recent coxsackievirus infection. Itshould be emphasized, however, that clinicaldiagnoses in this study were taken from labora-tory request forms and accompanying corre-spondence and were not further substantiated.IgM antibody for coxsackievirus types Bi, B3,

B4, B5, and B6 can be demonstrated relativelysimply by micro-immunodiffusion techniqueswhich lend themselves to large-scale studies.However, antigens used for detection of IgMantibody must be prepared from infected tissueculture fluids with high infectivity titers, sinceit is the intact virion with which the IgMantibody reacts (22, 26). Demonstration of IgMantibody for coxsackievirus type B2 is morecomplex, since it is based upon dissociating theIgM antibody with a sulfhydryl reducing agentand then assaying for neutralizing antibodies.However, the use of a micro-colorimetric neu-tralization test (21) greatly facilitates this pro-cedure.The fact that IgM antibody to group B

coxsackieviruses was found in a relatively highproportion of patients from whom it was im-possible to recover virus would be in keepingwith the view that pericarditis and myocarditisare likely to be late events in the course of cox-sackievirus infections, at a time when virusexcretion has ceased or virus is masked by anti-body. The possibility also exists that coxsackie-virus infections complicated by pericarditis,myocarditis, or pleurodynia may result in a pro-longed production of IgM antibody. Prolongedrubella IgM antibody production has been notedin rubella infections complicated by thrombo-cytopenic purpura or carpal-tunnel compres-sion (7), and prolonged persistence of IgM anti-body to measles virus has been found in somepatients with subacute sclerosing panencepha-litis (5) and multiple sclerosis (14).

Several other investigations have suggestedthe association of group B coxsackieviruses witha high proportion of sporadic pericarditis ormyocarditis cases (2, 11, 20, 27), but in each ofthese studies there were very few cases in whichvirus was isolated or significant increases inantibody titer could be demonstrated. Instead,the possible association of coxsackieviruses wasbased, in most cases, upon the presence of

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TABLE 7. Month of onset of illness for patients with pericarditis, myocarditis, or pleurodynia and of controlgroup

Patient group

Month of onset Pericarditis, myocarditis, pleurodynia Pneumonia, pneumonitis, mycoplasma(1970) Patients with IgM Patients with IgM

All patients antibody to group B All patients antibody to group Bcoxsackieviruses coxsackieviruses

January 38 11 17 1February 14 3 14 0March 16 0 10 0April 12 4 8 1May 13 1 5 2June 13 4 6 0July 17 6 26 1August 13 8 32 4September 30 10 40 2October 34 8 34 7November 33 10 37 3December 26 5 30 0Totals 259 70 259 21

TABLE 8. Age of pericarditis, myocarditis, or pleurodynia patients and of control group

Patient group

Age range Pericarditis, myocarditis, pleurodynia Pneumonia, pneumonitis, myocoplasma(years) Patients with IgM Patients with IgM

All patients antibody to group B All patients antibody to group Bcoxsackieviruses coxsackieviruses

<1 6 0 9 01-10 12 3 34 1

11-.20 23 10 25 921-30 59 15 45 531-40 52 24 47 141-50 39 6 37 151-60 45 7 36 161-70 16 4 18 3>70 7 1 8 0

Totals 259 70 259 21

moderate to high levels of neutralizing antibodyto a coxsackievirus type or upon the demonstra-tion of a fourfold or greater decline in antibodytiter over a period of time following illness, bothof which are of speculative value for establish-ing a temporal relationship between infectionand illness. Moderate to high levels of neutraliz-ing antibody to one or more group B coxsack-ievirus types from past, frequently subclinical,infections are often encountered in the normalpopulation and in individuals with other ill-nesses unrelated to a coxsackievirus infection(13, 19). Further, the decay of neutralizingantibodies to enteroviruses occurs at such varia-ble rates (4, 12, 23) that the demonstration of adeclining titer may be coincidental, the anti-body having been elicited by a long-past infec-

tion not associated with the patient's presentillness. Thus the diagnostic significance of sta-tionary or declining levels of neutralizing anti-body to coxsackieviruses in patients with car-diac disease is highly equivocal, especially inthe absence of comparative data on antibodylevels in a control group.

In the present study on IgM antibody tocoxsackieviruses, the spectrum of patientsavailable for study did not permit an exactmatching with respect to age and dates of onsetin the study and control groups; however, thetwo groups were not greatly disparate and thelikelihood of finding coxsackievirus IgM anti-body would appear to have been weighted infavor of the control group, since it contained agreater number of patients in childhood age



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groups in which enterovirus infections mostfrequently occur and a greater number of pa-tients with onsets in months in which coxsack-ievirus infections are most prevalent. However,there were over three times as many patients inthe study group showing coxsackievirus IgMantibody as were seen in the control group.

The finding of IgM antibody to group Bcoxsackieviruses in 21 patients (8%) in thecontrol group may in part represent a back-ground level of unrelated recent coxsackievirusinfections occurring in patients with respiratorydisease, but in six of these patients (included inthe controls on the basis of a clinical diagnosis ofpneumonia) additional clinical findings of car-

diac or central nervous system signs might beconsidered equally suggestive of a coxsackie-virus infection. Although a control group ofpneumonia patients was the best available tous and was used on the basis that coxsackie-viruses have not been frequently implicated as

etiological agents of lower respiratory tract dis-ease, such an association may occasionally oc-

cur (6, 16). Also, overlapping symptoms suchas cough and chest pain may occur in pleuro-dynia or pneumonia, and in the absence of moreprecise clinical records and X-ray findings al-lowance should be made in our findings forpossible inaccuracies in the clinical diagnosis.

ACKNOWLEDGMENTS

The authors are indebted to Juanita Dennis for assistancein these studies.

This study was supported by Public Health Service grantAI-01475 from the National Institute of Allergy and InfectiousDiseases.

LITERATURE CITED

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3. Berkovich, S., R. Rodrigues-Torres, and J.-S. Lin. 1968.Virologic studies in children with acute myocarditis.Amer. J. Dis. Child. 115:207-212.

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7. Haire, M., and D. S. M. Hadden. 1970. Immunoglobulinresponses in rubella and its complications. Brit. Med.J. 3:130-132.

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9. Javett, S. N., S. Heymann, B. Mundel, W. J. Pepler, H.I. Lurie, J. Gear, V. Measroch, and Z. Kirsch. 1956.Myocarditis in the newbom infant. A study of an

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15. Murray, E. S., J. M. O'Connor, and J. A. Gaon. 1965.Differentiation of 19S and 7S complement fixing anti-bodies in primary versus recrudescent typhus by eitherethanethiol or heat. Proc. Soc. Exp. Biol. Med.119:291-297.

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17. Null, F. C., and C. H. Castle. 1959. Adult pericarditis andmyocarditis due to Coxsackievirus group B, type 5. N.Engl. J. Med. 261:937-942.

18. Plager, H., R. Beebe, and J. K. Miller. 1962. CoxsackieB-5 pericarditis in pregnancy. Arch. Int. Med.110:735-738.

19. Ray, C. G., G. W. Sciple, P. Holden, and T. D. Y. Chin.1967. Acute febrile CNS illness in an endemic area ofTexas. Pub. Health Rep. 82:785-793.

20. Sainani, G. S., E. Krompotic, and S. J. Slodki. 1968.Adult heart disease due to the Coxsackie virus Binfection. Medicine 47:133-147.

21. Schmidt, N. J. 1969. Tissue culture technics for diagnos-tic virology, p. 79-178. In E. H. Lennette and N. J.Schmidt (ed.), Diagnostic procedures for viral andrickettsial infections, 4th ed. American Public HealthAssoc., Inc., New York.

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sium chloride density gradients. J. Immunol.90:654-662.

23. Schmidt, N. J., J. Dennis, E. H. Lennette, H. H. Ho, andT. T. Shinomoto. 1965. Antibody responses of rhesus(Macaca mulatta) monkeys experimentally infectedwith coxsackieviruses of group B and group A, type 9. I.Antibody responses within the coxsackievirus group. J.Immunol. 95:54-69.

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Coxsackieviruses. II. Serologic diagnosis of Coxsackievirus infections by the gel double diffusion technique.J. Immunol. 89:96-105.

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28. Walker, S, J., G. A. McNaughton, and D. M. McLean.1959. Coxsackie B5 virus infections in children: To-ronto, 1958. Can. J. Pub. Health 50:461-467.

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association group coxsackieviruses pericarditis, …produce pericarditis or myocarditis in man,...

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