virus infection: Epidemiology, pathogenesis, presentation, diagnosis, and prevention PhD, Z]/[aoc £ Robinson, MD, and Ursula Kuhnle, ~rD
Dengue virus infection is now the most com- mon arthropod-borne disease worldwide with an increasing incidence in the tropical regions of Asia, Africa, and Central and South America. It presents a spectrum of disease, ranging from a harmless flulike ill- ness to a severe hemorrhagic fever with high morbidity and mortality, the latter almost entirely in children. The virus is transmitted by mosquitoes, AedeJ aegypti and Aedea albopic-
taJ. Cold-resistant strains of Aedes vectors have been identified that may pose a threat to children living in temperate zones. 1-4
It is estimated that 100 million cases of infection occur worldwide per year. Between 1986 and 1990 1.5 million cases of dengue hemorrhagic fever or dengue shock syndrome with 15,940 deaths were reported to the World Health Organi- zation. Deaths occurred primarily in chil- dren between the ages of 5 and 15 years. It is clear that dengue virus infection is the most important arthropod-borne viral dis- ease in human beings both in terms of mor- bidity and mortality rates, s' 6
GLOBAL DISTRIBUTION
Dengue occurs in endemic and epidem- ic forms. Recorded epidemics of a
denguelike disease date to 1779, when outbreaks were reported in Batavia (pre- sent-day Jakarta) and Cairo. Since then epidemics have been reported in Phila- delphia (1780), Zanzibar (1825 and 1870), Calcutta (1824, 1853, 1871, and 1905), the West Indies (1827), Hong Kong (1901), Greece (1927-1928), Australia (1925-1926; 1942), the United States (1922), and Japan (1942-1945). 7-9
See related article, p. 525.
The earlier outbreaks were uncompli- cated cases of dengue fever characterized by high-grade fever and severe bone and back pains. Hemorrhagic complications have been increasingly documented in outbreaks since 1944. Between 1956 and 1989 more than 2.5 million cases of D H F were reported to the World Health Organization with 42,751 deaths. 5 Southeast Asia, part icularly Thailand, /V[yanmar, and Vietnam, are the most af- fected areas, where large D H F epidemics occur each 3 to 4 years. 10-13 For example,
between 1982 and 1987 Thailand record- ed more than 403,000 cases of D H F with approximately 2400 fatalities. Dengue he- morrhagic fever is among the 10 leading causes of illness and death in hospitalized children in these areas. 11
In recent years several countries with long-standing dengue virus activity report- ed epidemics of D H F for the first time (Fig. 1). China experienced its first epi- demic of D H F on Hainan Island in 1985-1986 with a morbidity of 1915 per 100,000 residents. 14 India (where D F has been endemic and with numerous epi- demics reported in the past 200 years) ex-
perienced the first outbreak of DHF/DSS in New Delhi in 1988, with 24 patients hospitalized within 2 mouths and a case fa- tality rate of 33%. 15 In 1989 D H F / D S S was reported for the first time in Tahiti and New Caledonia. 16'17 In 1990 Sri Lanka re- ported 935 cases with 54 deaths. 18
In the Americas there is an increasing incidence of D F and DHF. The first large epidemic of D H F occurred in Cuba in 1981 with 24,000 cases of D H F and 10,000 cases of DSS reported with 158 deaths during a 3-month period. 19'20 In
1986 and 1987 massive outbreaks of D F were reported in Brazil. 21'22 Subsequent
serologic investigations estimated almost 4 million cases of D F compared with the clinically estimated 1 million. 21 In 1988 an outbreak of D F was reported at 1700 m above sea level in Guerrero State, Mexico. 23 In 1990 almost one fourth of
the 300,000 people living in Iquitos, Peru, contracted D F 24 and in the same year 3108 cases of D H F with 78 deaths were reported in Venezuela. 25
The increasingly widespread distribu- tion and the rising incidence of dengue virus infections is related to increased dis- tribution ofA. aegypti and to the increase in urban population in the "mega-cities" of Southeast Asia. Lack of effective pro- grams to contain the vector, development, and deterioration of the urban environ- ment are responsible. However, the rea- son for the change from simple D F epi- demics to a severe hemorrhagic disease,
THE JOURNAL OF PEDIATRICS Volume 13 I, N u m b e r 4
KAUTNER, ROBINSON,AND KUHNLE
often associated with shock, DHF/DSS, . . . . . is not well understood. , a ~ ~ t~ 3~ ~
Furthermore, increased air travel and c=,,, hence the spread ofthe mosquito vector al- t3o ~ t " .
most certainly facilitates the spread of ~ ~ ~ ' f f e : ~ ~ ~ ' ~ DF'26 A linlited number °f "imP°fred" a~, ~ ~ ~ ( f l cases of DF and DHF have been reported from New Zealand, 27 the Netherlands, 28 ~, 4 . . 1.4 England, 29 Germany, and Switzerland. a°'al ' ~" ,.,, 1.2 " ~ ' ~ , ) ~ Inthe United States 22 of24 confirmed ~ ~ ~ a ~ J ~r t ~BL . a f "
The known natural hosts for dengue viruses are man, lower primates, and mos- quitoes. The arthropod vectors are mem- bers of the genus Aedea that thrive both in urban and rural areas. 3a-as The predomi- nant species implicated in disease trans- mission are A. aegypti and A. albopictu~. 56-a8
Aedea aegypt£ considered the most effi- cient vector, originated in the forests of Africa and has now spread throughout most of the world and is found between 50 degrees north latitude and 20 degrees south latitutde. 3942 The female mosquito feeds during the daytime, with peak activ- ity in the morning and late afternoon. 43'44 After feeding on a viremic individual, the mosquito may transmit the virus directly by change of host, or after 8 to 10 days during the time the virus multiplies in the salivary glands. 45 The infected mosquito then remains capable of transmission for its entire life. 43 Transovarian transmission of dengue viruses has been document- ed, 35'46'47 anclA, aeyyptf eggs are highly re- sistant to desiccation and can survive for extended periods. 48 These facts may ex- plain the occurrence of spontaneous out- breaks of DF.
Aedes a/bapictua is indigenous to Southeast Asia, feeds during the day, and has been shown to have a higher biting frequency than A. azgypH. 49 Recently it has been introduced into Nigeria, Europe, and the United States, apparently by shipments of used automobile tires. In the United States, A. albopicl~ has spread as far north as Chicago. 50"52 With the spread of the adaptable, cold-resistant strains of A. albopict~o to Europe, it has been sug- gested that conditions might arise, which
F ~ . 1. World map demonstrating the,global distribution of the various clinical forms of dengue virus in- fections and of the various subtypes of dengue viruses, Adapted from Halstead SB.The XXth century pan- demic: need for surveillance and research.World Health Stat Q 1992;45:292-8. Reprinted with permission.
are suitable for a major European out- break of dengue virus infection .4
T H E V IRUSES
Dengue viruses are members of the family Flaviviridae, which include human pathogens, such as the Japanese en- cephalitis virus and yellow fever virus. 53 Four dengue virus serotypes and various "biotypes" can be differentiated.
All members of the family Flaviviridae share common morphologie characteris- tics, genome structure, and replication and translation strategies. 2Vrtature dengue virus particles consist of a single-stranded ribonucleic acid genome surrounded by an approximately icosahedral nucleocap- sid with a diameter of 30 nm. The nucleo- capsid is covered by a lipid envelope of 10 nm thickness derived from host cell mem- branes and contains the envelope and membrane proteins. 53
The viral genome of approximately 11 kb is infectious, has a messenger-like pos- itive polarity, and can be translated in vitro. The 5" end of the RNA has a type I cap structure but lacks a poly A tail at the 5" end. 54-56 It contains a si@e open read- ing frame of about 10,000 nucleotides en- coding three structural and seven non- structural proteins. The gene order is 5"- C-prM(M)-E-NS 1-NSYA-NSYB-
NS5-NS4A-NSdB-NS5. The proteins are synthesized as a polyprotein of about 5000 aminoacids that is processed co- translationally and posttranslationally by viral and host proteases. 57-66
The structural proteins include a capsid protein rich in arginine and lysine residues and a nonglycosylated prYi protein pro- duced from a glycosylated precursor in a late step of virus maturation. 54'55,67'68 The major structural envelope protein is in- volved in the main biologic functions of the virus particle such as cell tropism, acid- catalyzed membrane fusion, and the in- duction of hemagglutination-inhibiting, neutralizing, and protective antibodies. 69
The first nonstructural protein is NS1, a glycoprotein with a function in the virus life cycle that is unknown. 7° NS1 proteins are detected in high titers in patients with secondary dengue infections, but are rarely found in primary infectlons. 71 The NS2 region codes for two proteins (NSYA and NSYB) that are thought to be implicated in polyprotein processing; whereas NS5 is probably the viral pro- teinase that functions in the cytosol. 65'66'72 The NS4 region codes for two small hy- drophobic proteins that seem to be in- volved in the establishment of the mem- branebound RNA replication complex. The protein encoded by the NS5 gene has a molecular weight of 105,000 and is the most conserved flavivirus protein. On the
517
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F~. 2. Typical bright red rash of a dengue virus infection with clear areas scattered in between, the so- called "islands of white in a sea of red."
basis of the amino acid sequence, this pro- tein is believed to be the virus-encoded RNA-dependent RNA polymerase. 7a
CLINICAL AND LABORATORY MANIFESTATIONS
The clinical features of dengue virus in- fection vary from an asymptomatic infec- tion to a febrile "flulike" infection (DF) to the more severe DHF, which can lead to DSS. 74'76 This clinical variability is poor- ly understood and seems to be related to the age and sex of the individual but also to the immunologic and nutritional status. Dengue hemorrhagic fever is most likely to develop in immune-competent, well- nourished girls between the ages of 7 and 12 years. 76 Dengue viruses tend to cause a mild illness in the yew young infant, but DHF/DSS can develop in infants born to immune mothers as a result of waning passive maternal antibodies. 77 Dengue hemorrhagic fever is rare after the age of lb years.
The incubation period of DF after the mosquito bite (as well as the febrile peri- od) averages 4 days. Dengue fever may manifest with fever and a discrete macular or maculopapular rash. In this situation
the clinical differentiation from other viral illnesses may not be possible, recovery is rapid, and need for supportive treatment is minimal) In more severe DF, the tem- perature rises rapidly (frequendy reach- ing a9 ° c or higher) and persists for 5 to 6 days. Fever is characteristically biphasic and returns to almost normal in the mid- die of the febrile period giving rise to the saddleback temperature chart. It reaches its highest level during the last 24 hours before abatement. The patient is general- ly ill. Symptoms include headache and retroorbital pain, particularly when pres- sure is applied to the eyes ("Fire is coming out of my eyes"). Arthralgia, myalgia, and a macular or maculopapular rash may ap- pear at the onset. Some patients report se- vere backache (back-break fever), sore throat, or abdominal pain, which can be severe enough to be confused with appen- dicitis. The febrile period usually lasts up to 6 days during which time the rash may become diffusely erythematous with clear areas scattered in between, the so-called "islands of white in a sea of red" (Fig. 2). These patients are lethargic with accom- panying anorexia and nausea. Hepato- megaly can be present, although spleno- megaly is uncommon. Laboratory parameters are generally normal but platelets can be decreased and serum he- patic enzyme levels (alanine aminotrans-
ferase in particular) may be moderately elevated (rarely exceeding 100 IU/L). Differentiation from viral, certain bacteri- al infections, and Kawasaki disease can be difficult. Recovery from DF is usually complete in 7 to 10 days.
The incubation period for DHF is un- known but is probably similar to that of DE Dengue hemorrhagic fever com- mences acutely with high fever and many of the symptoms of DE However, drowsi- ness and lethargy tend to be more marked. In addition, there is increased vascular permeability and abnormal he- mostasis that can lead to hypovolemia and hypotension, and in severe cases, result in hypovolemic shock often complicated by severe internal bleeding.
The hemorrhagic manifestations appear usually by the third day and consist of scattered petechiae over the trunk, limbs, and axillae. These petechiae are associat- ed with, or may be preceded by a positive tourniquet test result. Bleeding at veni- puncture sites is the rule, and there may be hemorrhage from the gastrointestinal tract, nose, and gums. After 2 to 7 days, and as the fever begins to subside, signs of circulatory insufficiency can appear; the patient becomes restless and sweaty with cold extremities. Pleural effusion, charac- teristically on the right side, and abdomi- nal ascites may be noted. These features are almost diagnostic of DHF. With ap- propriate treatment this phase usually re- solves within 24 to 48 hours. 78'79
Dengue shock syndrome results from leakage of plasma into the extravascular compartment. Rapid and poor volume pulse, hypotension, cold extremities, and restlessness occur. In addition to the plas- ma leakage, which is the result of general- ized vasculitis, disseminated intravascular coagulation is present. Dengue shock syn- drome is usually a progression of D H E but there are patients who have circulato- ry insufficiency when first seen after a febrile illness of only short duration. 80
Increasingly neurologic manifestations are recognized as a separate entity and not as sequelae of hemorrhage, acidosis, or shock. Direct isolation of virus in the cerebrospinal fluid and brain tissue ap- pears to indicate infectious encephalitis. However, further clinical, pathologic, and
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autopsy studies are necessary to deter- mine the clinical relevance. 81-83
Laboratory investigations in D H F con- sistently reveal thrombocytopenia that may reach levels of 20,000 platelets/mm a or less. Depending on the hemoconcen- tration and severity of shock the hemat- ocrit can be increased by 20% or more. Commonly hypoalbuminemia, hypo- volemia, and moderately elevated serum aminotransferase and blood urea nitrogen levels can be documented. Partial throm- boplastin time and the thrombin time may be prolonged. 79 Hypofibrinogenemia and complement depletion correlate with the severity of the disease.
The pathologic findings in D H F are vasculifis of small vessels in soft tissues and viscera. Lymph gland hyperplasia and areas of necrosis in spleen, liver, and bone marrow are also noted as is maturation ar- rest of megakaryocytes./Vlacroscopically there are petechial hemorrhages, ecchy- moses, and effusions into pleural cavities and into the peritoneal cavity. 84
PATHOGENESIS
The pathogenesis of D H F is not clear; D H F is rare in early infancy and uncom- mon in adulthood. Infection with one dengue serotype provides lifelong homol- ogous immunity gut limited heterologous immunity. Almost aH patients with D H F have had previous experience with at least one of the four seroWpes of dengue virus- es, leading to the hypothesis that het- erotypic antibodies from a previous dengue virus infection promote increased viral replication within mononuclear leukocytes--the phenomenon of anti- body-dependent enhancement. 85 Further- more, immunologic processes aimed at eliminating dengue virusMnfected cells can result in the release of cytokines with vasoactive or procoagulant properties, the release of interferon-7, and the activation of complement. 86-88
Other hypotheses suggest that D H F re- sults from infection by a more virulent biotype of the virus or even from unfavor- able host factors such as concomitant bac- terial infection. Thus during the last Vene- zuelan hemorrhagic epidemic a dengue 2
subtype could be genetically identified as a Southeast Asian biotype, a9
Whether certain ethnic groups are more susceptible or resistant to the hemorrhag- ic manifestations of dengue is suggested from epidemiologic studies. As shown in Fig. 1, severe hemorrhagic disease is more common in Southeast Asia compared with Africa and America. In the 1981 dengue outbreak in Cuba it was observed that black individuals are relatively resis- tant to DHF/DSS and a "resistance gene" present in the African population has been speculated. 89
Regardless of the inciting cause, in- creased vascular permeability results in hemoconcentration, reduced blood vol- ume, poor tissue perfusion, tissue hypox- ia, and shock. The cause of bleeding in D H F appears to be complex and may in- volve one or more of the following: throm- bocytopenia, microvascular inju W, platelet dysfunction, and disseminated in- travascular coagulation. The mortality rate for D H F ranges from 1% to 30% de- pending on availability of supportive care.
DIAGNOSIS
The diagnosis of dengue relies in most cases on clinical judgment because only a few major centers have the facilities and means to perform and verify the clinical impression. Diagnostic criteria for DHS based on clinical observations have been proposed by the World Health Organ- izafion and should be used to avoid over- diagnosis. 90
The c[&ical cr#eria for diagnosis are as follows: (1) fever; (2) hemorrhagic mani- festations, including at least a positive tourniquet test result and a major or minor bleeding phenomenon; (3) hepatic enlargement; (4) shock (high pulse rate and narrowing of the pulse pressure to 20 mm Hg or less, or hypotension). The/ab- oratory criteria include (5) thrombocytope- nia (_<100,000/mm3), and (6) hemoeon- centration (hematocrit increase ->20%). Thrombocytopenia with concurrent high hematocrit levels differentiates D H F from classic DE
CurrenCy routine laborato W diagnosis of dengue infections depends on virus iso-
lation or the detection of dengue virus-specific antibodies. The isolation of viruses from clinical specimens can be carried out in cultured mosquito cells, such as AP-61 or C6/56 cell cultures. 91-94 When dengue virus serotype-specifie monoclonal antibodies are used, virus identification by indirect immunofluores- cence can be achieved within 2 weeks. 95'% The development of mosquito inoculation techniques has not only improved the sen- sitivity but also reduced the time required for virus isolation and identification. Parenteral inoculation of adult A. albapic- tua yields results in 7 days. 97"98 Virus iso- lation by intracerebral inoculation of Toxorbyncbitis spZendens mosquito or its fourth instar larvae can even be achieved within 2 to 5 days. 99'1°°
The serologic identification of the vari- ous types of dengue virus infection is com- plicated by the occurrence of cross-reac- tive antibodies to antigenic determinants shared by all four dengue viruses and other members of the flavivirus family. 1°1 The commonly used serologic test is the hemagglutination inhibition test) °2 In a prima W infection dengue hemagglutina- tion inhibition antibody titer is generally less than 1:20 in a sample collected within the first 4 days after the onset of symp- toms. In the convalescent phase sample (collected 1 to 4 weeks after the onset of symptoms) a fourfold or greater rise in antibody fiter is detected, with antibody titer _<1:1280.103
A seconda W dengue infection is charac- terized by the rapid appearance of broad- ly cross-reactive antibodies. Hemag- glutinafion inhibition fiters of 1:20 in the acute-phase sample rise to _>1:2560 in the convalescent phase sample. An antibody fiter of >1:1280 in the acute-phase sample without a fourfold or greater increase in the second sample also is considered pre- sumptive of recent infection. An improved and less time-consuming method is a cap- ture enzyme-linked immunosorbent assay that can detect specific anti-dengue IgM in a single acute-phase sample. 104
Recently commercial kits for the detec- tion of specific IgG as well as IgM anti- bodies have become available. They are based on a dot enzyme assay or a nitro- cellulose membrane-based capture for-
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mat, respectively, and should be suitable for field research. 105-107
An alternative to virus isolation is the detection of viral RNA by reverse tran- scription polymerase chain reaction. There are various protocols available using different primers and template iso- lation. 67'108113 Reverse transcription
polymerase chain reaction coupled with hybridization with labeled serotype-spe- cific probes can detect as few as 4 plaque-forming units per 100 btl serum and gives the best results early in the acute phase of the disease when dengue antibodies are still low. 112 Less than 1 ~tl of serum can be sufficient for the detec- tion of viral RNA. 114 Reverse transcrip- tion polymerase chain reaction is a high- ly sensitive technique of particular value in the early diagnosis of dengue infec- tion, but at present is only available in re- search settings.
THERAPY AND MANAGEMENT
The management of DF is supportive with bed rest, adequate fluid intake, and control of fever and pain with antipyretics and analgesics (e.g., paracetamol). Use of aspirin is contraindicated because of the increased bleeding tendency. Patients can be treated as outpatients if close monitor- hag is possible.
Differentiation between DF and D H F is difficult in the early stages and frequent measurements of the platelet count and hematocrit are necessary. A fall in the platelet count and a rising hemotocrit level indicate development of the shock syndrome. Narrowing of the pulse pres- sure and hypotension indicate shock, which must be treated as a medical emer- gency. The major problem in DHF/DSS is fluid loss rather than blood loss, and management must be directed toward maintenance of blood volume and blood pressure. Mild cases respond after 1 or 2 days of plasma expansion with isotonic or half isotonic saline solution.
Decreased levels of coagulation factors indicate disseminated intravascular coag- ulation; infusion of heparin and replace- ment of c o @ a t i o n factors may be re-
quired. Severe hemorrhage may require blood transfusion, preferably with fresh whole blood; concentrated platelet infu- sions may be required. Regular clinical and laboratory monitoring is mandatory. Re- versal of plasma leakage can be expected within 12 to 24 hours; intravenous infu- sion must be reduced because hypervo- lemia can lead to acute heart failure, 115-118
In some centers corticosteroids (methyl- prednisoloue) or carbazochrome sodium sulfonate (acona [AC-17]) are used to sta- bilize capillary permeability and reduce plasma leakage. A relatively large, placebo- controlled; double-blind study has not shown a positive effect from steroids in DSS, whereas a somewhat smaller and less stringent study claimed a beneficial ef- fect of AC-17 in D H E Whether this dif- ference is a direct drug effect or reflection of the different patient populations studied cannot be decided with the available data. Further studies that take into account the varying degrees of severity of D H F and DSS are indicated before a fmal conclu- sion can be drawn. 119'120
PREVENTION Mosquito control measures
As long as there is no vaccine available, the spread of DF and D H F can only be curtailed by controlling vector popula- tions. This approach was successfully started in the Americas at the beginning of this century, and eradication programs were started in 1947. The mosquitoes reemerged when specific programs aimed at their eradication were given lower pri- ority. In addition, insecticide resistance has been a problem in some areas. I21
In addition to insecticide application to control adult mosquito populations, breeding sites of Aedes mosquitoes should be reduced vigorously. Stagnant water and water containers should be avoided. Education programs must be implement- ed and legislation providing fines for those allowing Aedes breeding sites might be helpful. 122'1% Insect repellents are use- ful to prevent mosquito bites. However, it must not be forgotten that programs to eradicate mosquito vectors impose a great financial burden on developing countries and are ineffective in situations of open
conflict, lawlessness, and large-scale refugee migrations.
Vaccine Development Currently no vaccine is available to pro-
tect against dengue infections. The major concern in the development of a dengue vaccine is an immunologic response in the vaccinee that could lead to antlbody-de- pendent enhancement of infection and thus produce DHF/DSS. Candidate vac- cines based on live attenuated viruses should therefore contain all four serotypes to give comprehensive protection without adverse side effects.
In 1944 a serially attenuated, dengue 1 virus candidate vaccine prepared in mouse brain was tested in human volun- teers, but abandoned because the sub- strate was thought to be unsafe. 124-127 Recently live attenuated vaccines have been developed by multiple passages in primary clog kidney cells by researchers at the Mahidol University in Bangkok and candidate monovalent, bivalent, trivalent, and tetravalent vaccines are currently being tested in phase I and II trials with favorable results in Thailand. 128"131
Efforts to create a subunit vaccine by use of recombinant D N A technology have been initiated because of the concern of possible reversion of a live attenuated vaccine to a virulent strain. Recombinant proteins have beerl expressed in Escbericbia col~ as well as vaccinia viruses and insect cells (Spodo#era frugiperda) using engineered baculoviruses. 132-I43 Both the structural and the NS1 proteins have been shown to elicit protective im- munity in monkeys and mice and thus the development of safe vaccines appears to be feasible. 133-135'157'159'141
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50 Years Ago in The Journal of Pediatrics RHEUMATIC FEVER RECURRENCE IN CHILDREN WITHOUT SULFONAMIDE PROPHYLAXIS: AN EVALUATION OF ENVIRONMENTAL FACTORS
Jackson RL, Kelly HG, Ro/~ret CH, Duane JM. J Pediatr 1947,'31:390-402
Fifty years ago in rural Iowa, just as in urban American settings, rheumatic fever (RF) was a threat for indivt~- ual patients and a major public health problem for schoolchildren. Hospitals were fdled with patients with RF and rheumatic heart disease, and there were numerous reports describing the high incidence of RF and prevalence of rheumatic heart disease. In contrast, half a century later, the reduction in RF incidence in industrialized countries is striking. Yet in most of the developing world, the disease remains at a level comparable to that alluded to by Jackson and colleagues. The perceptive article by Jackson et al. described the relationship between recurrences of RF and suboptimal social, economic, and nutritional status. The decline in incidence of RF in industrialized countries began before the clinical introduction of antibiotics; this reduction has historically been associated with improving social and economic factors. Yet during the past decade, a "resurgence" of RF has been described in North American middle class suburban children with ready access to medical care and in military recruits. These
published observations suggest that factors other than social and economic status are equally important. "Rheumatogenic" potential and the virulence of specific strains of group A streptococci cannot be ignored. It was not possible to study such variables in the laboratory 50 years ago. Thus the relationship between social, econom- ic, and nutritional status and microbiologic and immunologic factors could not be compared at the time when the disease was so common. Maybe the fact that the pathogenesis of this unique disease remains incompletely defined
is a consequence. Antibiotics and better living conditions are clearly not the complete solution to controlling group A streptococ-
cal infections and their complications. One attractive theoretical approach to conquering this major cardiovascu- lar disease would be development of a cost-effective vaccine. Perhaps this can be realized in the not too distant fu- ture. Then it is possible that the incidence of RF and the prevalence of rheumatic heart disease, sometimes referred to as the most preventable of all cardiovascular diseases, could be significantly reduced. Despite a need to improve social and economic status of at-risk pediatric populations for many health-related reasons, time-tested techniques of accurate diagnosis and appropriate antibiotic therapy for the preceding streptococcal infection will continue to be the most practical and effective methods of control.
Ed,~ard L. Kaplan, ~ID, and James H. Ztloller, ~/ID Department of Pediatrics University of Minnesota
