2384 SECTION XVII Viral InfectionsTABLE <strong>189</strong>–1 ■ CLINICAL FINDINGS IN 61 AND 43 ATLANTA, GEORGIA, CHILDREN* WHOSEROCONVERTED † TO HCV-229E AND HCV-OC43, RESPECTIVELY, 1960 TO 1968Virus (%) Virus (%)Initial Complaints 229E OC43 Physical Findings 229E OC43Sore throat 66 30 Pharyngeal injection 82 72Coryza 52 19 Coryza 64 49Cough 43 30 Fever, 37.6°C (99.6°F) <strong>and</strong> higher 34 40Fever 21 9Headache 15 NR Fever, 39°C (102.2°F) <strong>and</strong> higher 8 21Cervical adenitis 30 35Pulmonary rales (or dullness) NR 5Rash NR 2*A changing population of 120 to 175 white children 5 to 19 years of age (median, 9 to 11 years of age) in a churchsponsoredhome, 1960 to 1968. The children were housed in cottages of 8 to 12 persons, assigned on the basis of age <strong>and</strong>gender.† Paired acute <strong>and</strong> convalescent sera (2 to 3 weeks) showing fourfold or greater antibody rises by indirect hemagglutination(HCV-229E) or hemagglutination inhibition (HCV-OC43).NR, not reported.Adapted from Kaye, H.S., Marsh, H.B., <strong>and</strong> Dowdle, W.R.: Seroepidemiologic survey of coronavirus (strain OC43) relatedinfections in a children’s population. Am. J. Epidemiol. 94:43–49, 1971; <strong>and</strong> Kaye, H.S., <strong>and</strong> Dowdie, W.R.: Seroepidemiologicsurvey of coronavirus (strain 229E) infections in a population of children. Am. J. Epidemiol. 101:238–244, 1975.LOWER RESPIRATORY TRACT DISEASEAsthma <strong>and</strong> Recurrent WheezingSubstantial evidence indicates that HCoVs can precipitateasthma attacks. 35, 37, 65, 69, 79, 86 In a 2-year surveillance (1967to 1969) of 32 mostly atopic children 1 to 5 years of age hospitalizedin Denver for severe, recurrent bouts of wheezing,19 HCoV infections were diagnosed, 16 of them in a typicalsharp HCoV epidemic. 65 Six children were infected simultaneouslywith either parainfluenza virus or respiratorysyncytial virus. Of the remaining 13 patients, all were symptomatic:3 had mild wheezing, <strong>and</strong> 7 had acute asthmaattacks, 2 of which required intravenous therapy. Threepatients had pneumonia accompanied by radiographicchanges, <strong>and</strong> four were febrile (>38° C). HCoVs were not aslikely to cause wheezing as respiratory syncytial virus was<strong>and</strong> were more likely to cause only cold-like illnesses <strong>and</strong>fewer fevers. These findings have been confirmed in severalother studies. 69Pneumonia <strong>and</strong> Other <strong>Severe</strong> Lower RespiratoryTract InfectionsEvidence of the etiologic involvement of HCoVs in childrenhospitalized for lower respiratory tract disease has beenmore difficult to obtain. For example, among pediatricpatients with lower respiratory tract disease at Children’sHospital, Washington, D.C., the incidence of HCoV in illchildren, 3.5 percent, was actually lower than that in controlpatients with nonrespiratory disease, 8.2 percent. 67 In amore recent study of hospitalized patients with acute respiratorydisease, HCoV infection was found in only 2 of 83infants younger than 5 years of age in whom paired serawere available. 23 Better evidence of causation was found in astudy of infants hospitalized for lower respiratory tract diseaseduring 1967 to 1970. 63 Infections with both HCoV-229E<strong>and</strong> HCoV-OC43 were noted, <strong>and</strong> HCoV was the third mostfrequently occurring virus (behind respiratory syncytialvirus <strong>and</strong> parainfluenza virus 3), both in incidence <strong>and</strong> inspecific association with pneumonia <strong>and</strong> bronchiolitis (Table<strong>189</strong>–2). Many of these infants required oxygen. HCoV-229Ewas cultivated from oropharyngeal swabs from two of theinfants with pneumonia. In newborns, apnea <strong>and</strong> bradycardia94, 95have been described during coronavirus infection.HCoV-associated lower respiratory tract disease has beendetected in adults. A sharp outbreak of acute respiratory diseasesufficient to cause hospitalization of U.S. Marinerecruits was attributed at least partially to HCoV-OC43. 111The clearest association is seen in the elderly with cardiac orchronic obstructive pulmonary disease, in whom infectioncommonly is associated with lower respiratory tract symptoms,although they rarely lead to hospitalization or11, 25, 29, 96, 107death.TABLE <strong>189</strong>–2 ■ RELATIVE INCIDENCE OF VARIOUSRESPIRATORY VIRUS INFECTIONS IN INFANTSWITH PNEUMONIA OR BRONCHIOLITIS,COOK COUNTY HOSPITAL, CHICAGO,ILLINOIS, 1967 TO 1970Number of Infants with IndicatedCondition Who Were Positive for Virus (%)Virus Pneumonia Bronchiolitis TotalRespiratory syncytial 58 (25.1) 48 (32.2) 106 (27.9)Parainfluenza 3 54 (23.4) 28 (18.8) 82 (21.6)Coronavirus* 20 (8.7) 10 (6.7) 30 (7.9)Adenovirus 11 (4.8) 15 (10.1) 26 (6.8)Parainfluenza 1 11 (4.8) 9 (6.0) 20 (5.3)Influenza A 10 (4.3) 5 (3.4) 15 (4.0)Rhinovirus 6 (2.6) 2 (1.3) 8 (2.1)Parainfluenza 2 3 (1.3) 3 (2.0) 6 (1.6)Total 126 (55.0) 83 (55.7) 209Note: Infants were considered positive if virus was recovered or if theyhad serologic evidence of infection; 231 infants with pneumonia <strong>and</strong> 149infants with bronchiolitis were tested. Some infants were positive for morethan one virus.*Both HCV-229E <strong>and</strong> HCV-OC43.From McIntosh, K., Chao, R.K., Krause, H.E., et al.: Coronavirus infection inacute lower respiratory tract disease of infants. J. Infect. Dis. 130:502–507,1974.
CHAPTER <strong>189</strong> <strong>Coronaviruses</strong> <strong>and</strong> <strong>Toroviruses</strong>, <strong>Including</strong> <strong>Severe</strong> <strong>Acute</strong> Respiratory Syndrome (SARS) 2385Enteric Human Coronavirus <strong>and</strong>Torovirus InfectionsCORONAVIRUSESFrom the earliest descriptions of HCoVs, because of theprominence of coronaviruses as a cause of diarrhea in youngcalves <strong>and</strong> pigs, attempts have been made to find coronavirusesin the stool <strong>and</strong> associate them with enteric disease.The particles that have been seen, often called coronaviruslikeparticles (CVLPs), have appeared as frequently in stoolsfrom well subjects as in those with diarrhea in many studies,<strong>and</strong> at times they have been difficult to distinguish from cellularmembrane fragments. Indeed, their authenticity as21, 55, 72, 81viruses has been called into doubt on occasion.This situation has been confused further by the morerecent separation of toroviruses from enteric coronaviruses,although this separation probably will lead ultimately to clarificationof this murky field. Many of the specimens that wereconsidered to contain CVLPs in earlier papers may very wellhave contained toroviruses. At present, electron microscopiststhink that these virus genera can be distinguished in mostinstances on the basis of morphology alone, 22 <strong>and</strong> in manycases the presence of human toroviruses can be confirmedby serologic testing for stool antigens with bovine antisera4, 44, 47containing bovine torovirus (Breda virus) antibody.The first reports of HCoV as a possible cause of humangastroenteritis appeared in 1975; CVLPs were found by electronmicroscopy in the stools of English adults in threesharp outbreaks of nonbacterial gastroenteritis. 14, 16 In thesame year, CVLPs were reported in the stools of healthyadults in India. 60 These rather contrasting publications fromEngl<strong>and</strong> <strong>and</strong> India heralded the beginning of a continuingcontroversy on the etiologic importance of these agents as55, 72enteric pathogens.The firmest link of CVLPs to human enteric disease iswith gastroenteritis in the very young, especially neonatalnecrotizing enterocolitis (NEC). A controlled epidemiologicinvestigation of NEC was conducted in two hospitals inFrance, one with <strong>and</strong> one without an NEC outbreak. 18Within each hospital, newborns with “no pathologic occurrence”were used as controls. In the NEC-free hospital, noCVLPs were found in the stools of 21 controls, but 2 patientswith mild diarrhea had CVLPs. In the NEC hospital, 23 ofthe 32 (72%) NEC patients had fecal CVLPs, whereas only 3of 26 (11.5%) controls were positive (p < .02). Similarly,CVLPs were observed in infants who were part of a NECoutbreak in a special care nursery in Texas. 88 This outbreakyielded a virus that subsequently has been adapted togrowth in tissue culture <strong>and</strong> to some extent characterized. 53In September 1979, an episode of acute, severe (bloodystools, bilious gastric aspirates, abdominal distention) gastroenteritisoccurred in a neonatal intensive care unit inArizona, <strong>and</strong> several clinical signs were associated significantlywith CVLPs in patients’ stools. 106 Two children diedin this outbreak, <strong>and</strong> another infant death, with carefulelectron-microscopic description of coronavirus infection inthe distal end of the small bowel, occurred in Oklahoma. 89In Italy, a case-control study of infants <strong>and</strong> young childrenwith enteritis found a significant difference in fecal CVLPpresence between the ill <strong>and</strong> control groups: 16.3 percent inill children <strong>and</strong> 1.6 percent in controls (p
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