STJDDEN NATI]RAL DEATII IN INFANCY & EARLY CHILDHOOD CHAPTER 4 INFE,CTIOUS CONDITIONS 't 204 ì:r INTRODUCTION ;T Sudden death is a well recognized sequel to infect¡ons with a wide variety of agents. The outcome of a particular infection depends on the age of the ¡nfant or child, the v¡rulence of the organism and the immunological status of the host. For example, certain bacteria, such as Neisseria meningidítis, are capable of producing a fulminant sept¡caemia in previously healthy children with death within hours, whereas Aspergillus sp. is generally only of concern in children who are immunodeficient. ln spite of the possibility of a lethal outcome from many 'rare' organisms in immunocompromised hosts, this chapter tends to concentrate on more usual clinical syndromes, with only occasional reference to more obscure entities. The format reflects the sequence followed in other chapters with a discussion of infections based on part¡cular organ systems or mechanisms rather than on specific classes of infectious agents. ln a review performed by the author of autopsy cases from the Adelaide Children's Hospital over the past 30 years the most common causes of rapid death were bacterial pneumonias, airway infections (including acute epiglottitis), meningitis, septicaemias, viral myocardilis and gastroenter¡t¡s. Table 4-1 lists possible microbiological causes of sudden death in childhood and Appendix l, Chapter 1 1, summarizes the types of mícrobiological specimens that can be taken in the workup of a septic case at'autopsy. 205 TABLE 4.1: TYPES OF INFECTIOUS ILLNESSES ASSOCIATED WITH SUDDEN PAEDIATR¡C DEATH 1 Cardiovascular 4. Haematological myocarditis malaria rheumatic fever 5. Gastrointestinal endocarditis gastroenteritis aort¡tis botulism arteritis primary peritonitis 2 Respiratory hydatid disease retropharyngeal abscess 6 Genitourinary poster¡or lingual abscess pyelonephritis acute epiglottitis 7 Generalized acute laryngotracheobronchitis septicaem¡a bacterial trache¡t¡s viraemia diphtheria endotoxaemia acute bacterial pneumonia ¡nterst¡t¡al pneumonitis bronchiolitis CARDIOVASCULAR CONDITIONS MYOCARDITIS Myocarditis is a well known cause of sudden and unexpected death in children of all ages and may be found in infants who present with 5¡p941,12a. Clinical Features t Although some infants and children may have symptoms and signs of heart failure4o, a significant number of cases will have nonspecific clinical features giving no indication of a primary cardiac problem pr¡or to autopsy lvide infral56. ln children a history of exercise_related collapse may suggest myocardial disease and a clinical diagnosis of acute myocardial infarction may have been considered6o. 206 STUDY #4-1 DEMONSTRATION OF THE ASSOCIATION BETWEEN MYOCARDITIS AND SUDDEN UNEXPECTED DEATH ¡N INFANCY AND CHILDHOOD INTRODUCTION Myocarditis is characterised histologically by an inflammatory infiltrate of the myocardium with necrosis and/or degeneration of adjacent myocytes, not typical of the ischaemic changes associated with coronary artery diseases. Clinically there may be great variability in symptomatology. To characterise further the clinicopatholog¡cal features of myocarditis found at autopsy in childhood, the following study was undertaken. MATERIALS AND METHODS The autopsy files of the Adelaide Children's Hospital from January 1954 to July 199O were reviewed. Data relating to age, sex, clinical presentation, macroscopic description and virological or bacteriological stud¡es were extracted. Histological slides were reviewed and only those cases which fulfilled accepted criteria were retaineds. Between one and 13 blocks (mean:3.6) were examined per case. Cases where the histological findings were more in keeping with ischaemic damage were excluded. Such findings included confluent areas of coagulative necrosis with a peripheral neutrophil infiltrate, and lesions where the subendocardial myocytes were preserveds. RESULTS Thirty-two cases of myocarditis were found out of a total of 4969 autopsies (0.64%). Eight cases which had been called myocarditis originally were discarded as no convincing myocyte necrosis could be demonstrated. The 32 cases were separated into two groups: Group A, 1161321, where myocarditis was an isolated significant finding, and Group B, .16132t', where myocarditis was incidental to other conditions to which death was ascribed. The sex rat¡o ¡n each group approached unity. No difference in age range was seen, although B/16 of Group A were aged one year or less compared to only 3/16 in Group B (Table 4-2). The duration of symptoms was similar in each group, from 12 hours to three weeks in Group A and from one 207 day to one month in Group B. ln each group there were five cases of sudden death (defined as death occurring within 24 hours of the onset of symptoms!. TABLE 4-2: CLINICAL FEATURES OF 32 PATIENTS WITH HIsToLoGIcAL EVIDENCE oF MYOCARDITIS AT AUTOPSY Group A Group B Total 16 16 M:F 9:7 7:9 Age Range I days-9 years 11 days-15years < 12 months 8 3 > 12 months 8 13 Duration of symptoms 12 hours-3 weeks 1 day-1 month Sudden death 5 5 Symptoms observed in Group B related to the ultimate cause of death which was bronchopneumonia in 1O (three cases with negative cultures, two cases cultures grew coliforms, lwo staphylococc.rs, one Pseudomonas sp, one Aspergittus teffeus, and one streptococcusl, meningitis in two lboth Acanthamoebal, subdural haematoma, encephalitis (culture negativel, (motor trauma vehicle accidentl and asphyxia (due to inhalation of foreign body) in one case each, ln Group A, where myocarditis alone was diagnosed, non specific symptoms such as anorexia, vomiting, tachypnoea and pyrexia were recorded. There were three cases where signs suggestive of heart failure were observed and three where no symptoms were noted prior to death. ln Group A 3/16 hearts and in Group B 5/16 hearts were grossly unremarkable, or showed only minor changes. Combinations of pallor, dilatation, hypertrophy (wt. >g5th percentile)36, endocardial fibrosis, petechial haemorrhage and pericardial effusion characterised the remainder (Table 4-3). No mural thrombi were present in any case. 208 TABLE 4-3: MACROSCOPIC APPEARANCE OF HEARTS w¡TH HISTOLOGICAL EVIDENCE OF MYOCARDITIS Group A Group B Normal or minor changes 3 5 Dilatation only 2 3 Dilatation & Pallor 6 1 Dilatation & Hypertrophy 5 1 Pallor in any chamber 6 2 Wt > 95 percentile 7 5 Petechial haemorrhages 4 2 Endocardial fibrosis in any chamber, with hypertrophy 4 0 Pericardial effusion with dilatation 2 0 Pericardial effusion 2 2 (Please note that these groups are not mutually exclusivel. Histologically, neutrophils were present in 8/16 Group B, compared to 4116 Group A hearts (Table 4-41. Conversely, 15/16 Group A and 9/16 Group B infiltrates included lymphocytes. Plasma cells and eosinophils were seen more frequently ¡n Group A. The only statist¡cally significant difference between the two groups was the presence of lymphocytes (two ta¡led test¡ng, : 0.05, 5% level of significance). 209 TABLE 44: HISTOLOGICAL FEATURES OF ISOI.ATED (GROUP A} AND "INCIDENTAL. (GRoUP B) MYOCARD¡TIS GroupA GroupB pValue Test Significance Applied Myoc¡e necrosis 16 16 Neutrophils 4 I o.27 + NS Lymphocytes 15 I 0.04 t* + Plasma cells 7 4 0.46 + NS Eosinophils 3 2 1.00 +* NS Key: + Yates corrected Chi-square ++ Fisher exact test (2 tailedl + Signifícant at the 5% level ( : 0.0b, 2 tailed testl NS Not signif¡cant. Virological studies were conducted in 10/16 Group A and 6/16 Group B cases. Antibody to coxsackie 84 virus was detected in one case from Group A, and in one case from Group B (that associated with inhalation of a foreign body). Antibody to varicella was detected in one case from Group A. Coxsackie 85 and 83 were cultured from brain and CSF respeclively in one case each from Group A. There were five cases in each group where sudden death was the mode of presentation (Table 4-5)' ln Group A, three of these patients were less than one year of age, three of the pat¡ents had macroscopically normal hearts, one heart had dilated chambers and weighed in excess of the 9Sth percentile, and the remaining heart had dilated chambers only. ln Group B sudden death occurred in one infant less than one year old. Only one heart in the five cases of sudden death in Group B was macroscopically unremarkable. Two hearts weighed >gsth percentile, one of which showed chamber dilatation, and the remaining two of which also showed dilated chambers. Microscopic examination showed a predominantly lymphocytíc infiltrate in all cases in both groups excepting one case in Group B where eosinophils predominated: other findings in this case included long standing bronchiectasis and colonizing 210 asperg¡llosis in lung sections. A second patient in Group B died suddenly from an inhaled foreign body, and in the remaining three significant bronchopneumonia was found. TABLE 4-5: CASES OF SUDDEN DEATH ASSOCIATED WITH |SO|-ATED (GROUP Al AND INCIDENTAL (GROUP BI MYOCARDITIS Group A fì :5 Group B n:5 Heart grossly normal 3 1 Heart dilated 2 3 Heart weight > 95th %ile 1 2 Age < 12 months 3 1 Drscuss¡oN ln the early part of the 20th Century the term "myocarditis" was used to signify any chronic myocardial disease3l. W¡th increased use of virological techniques it became apparent that an association existed between infection with certain viruses and myocarditis. These viruses include Coxsackie A and B, ECHO, polio, cytomegalo, rubella, mumps, Epstein Barr, influenza A and B, herpes, adeno and hepatitis virusesso. It is only recently that histologic criteria have been set out which specify that diagnosis requires myocyte necrosis, i.e. the finding of inflammatory cells alone is insufficient for the diagnosis since the presence of a normal myocardial lymphocyte population has been demonstrats6l15,119. For example, studies have demonstrated'myocarditis'(in the form of a lymphocytic infiltrate) of the conduction tracts in apparently well children who suffered sudden accidental death that was unrelated to any form of cardiac diseases4.