pathogenesis of dengue fever The haemorrhagic

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					 The pathogenesis of dengue
 haemorrhagic fever-
 A critical appraisal of current hypotheses


  The clinical manifestations encompassed by the term 'dengue            dominant role in the pathogenesis of severe dengue disease. 2,3
  haemorrhagic fever' are responsible for most of the admissions         More specifically, there is a difference of opinion whether or
  to hospital and deaths among people infected with dengue               not an acquired characteristic of the host, namely, an earlier
  viruses. Since there is wide variation in the incidence of these       dengue infection with a heterologous dengue serotype, consti-
  forms of the disease from one dengue outbreak or endemic              tutes a risk factor for the development of severe dengue
  area to another, a bener understanding of their pathogenesis          disease.
  could lead to strategies that might prevent severe disease and           One of the strongest arguments for an imponant role of
  death from dengue, even if infection itself cannot be prevented.      viral virulence in the pathogenesis of severe dengue is that
     In general, the more severe forms of dengue infection are          variation in the virulence of strains has been described for
  characterized by haemorrhage, hypovolaemic shock, or both.            most, if not all, viruses for which appropriate assay systems
  However, there is a difference of opinion whether it is appro-        are available. It would be surprising indeed if dengue strains
  priate or useful to characterize all dengue infections with hae-      and serotypes were an exception.
  morrhagic manifestations as 'dengue haemorrhagic fever'. For             Epidemiological evidence suggestive of differences in overall
  example, the latest edition of the guidelines on dengue hae-          virulence between dengue serotypes is the observation that
  morrhagic fever published by the World Health Organization l          dengue types 11 and III have been more co=only associated
  distinguishes between 'dengue haemorrhagic fever' on the one          with the dengue shock syndrome in south-east Asia over the
  hand and 'dengue fever with haemorrhagic manifestations' on           last 20 years than have dengue types I and IV. Evidence for
  the other. According to these guidelines, the former is charac-       variation in virulence among dengue strains of the same sero-
  terized by thrombocytopenia and haemoconcentration and can            type is more difficult to come by. There have been many
  be divided into four grades. The haemorrhagic aspect of the           instances of relatively avirulent epidemics caused by dengue
 first of these grades is limited to a positive tourniquet test.        types 11 and Ill, but alternative explanations cannot be ex-
 Thus, according to the WHO publication, a patient with a               cluded. Dengue strains potentially different in virulence have
 positive tourniquet test, :thrombocytopenia, and haemocon-             not as yet been analysed by appropriate molecular methods.
 centration would be considered to have 'dengue haemorrhagic            Another major obstacle in studies of dengue viral virulence is
 fever', whereas a patient with severe, or even fatal, gastro-          the lack of a laboratory animal or an in vilTo marker for viru-
 intestinal haemorrhage and thrombocytopenia but not haemo-            lence. At present, the only way to assay the virulence of dengue
 concentration, would have only 'dengue fever with haemor-             viruses is in man.
 rhagic manifestations'. Since thrombocytopenia is a common                While the concept of differences in dengue viral virulence is
 manifestation of all types of dengue infection and since chil-        almost certainly true, at least to some extent, certain epidemio-
 dren with fever, vomiting or diarrhoea from any cause can also        logical observations from the South Pacific are difficult to
 have haemoconcentration, one can imagine the difficulty that          explain, unless virulence is a rather labile characteristic. For
 at least some observers have in distinguishing the putative           example, when dengue type 11 swept through the South
 difference between 'dengue ha~morrhagic fever' and 'dengue            Pacific, beginning in 1971, it was almost certain that the same
 fever with haemorrhage'. I am not aware of any data, pub-             viral strain was carried from one island to another. Yet the
lished or unpublished, which justify the distinction made by           virus caused relatively severe disease on some islands such as
 the WHO guidelines on either pathogenetic or prognostic               Tahiti 4 and Niue s and very mild disease on others such as
grounds.                                                               Samoa and Tonga,6 The same phenomenon was observed with
    Everyone agrees that there is an entity known as the 'dengue       dengue type I beginning in 1975. However, in the type I
shock syndrome', a common form of life-threatening dengue,             epidemics, severe disease occurred in Tonga6 and on Niue,
which. is usually, but not always, accompanied by haemorrha-           and relatively mild disease on Tahiti? and Samoa. The dif-
gic manifestations. The remainder of this discussion concerns          ferences between the islands could not be explained by differ-
the pathogenesis of this syndrome, but this is not meant to            ences in previous experience with other dengue serotypes.
imply that its pathogenesis is necessarily the same as that of         Anecdotal evidence that dengue strains might change in viru-
the haemorrhagic manifestations of dengue. The laner are so            lence relatively easily, perhaps on the basis of rapid human-to-
common in both mild and severe dengue infections and, as               human passage, is the observation that a higher proportion of
noted above, their definition so controversial, that it is difficult   severe disease is often seen in the second half of an epidemic
to analyse data with respect to their pathogenesis.                    compared with the first half. This was noted, for example, in
    The outcome of any infection depends on the interaction            the large Greek epidemic in 1927 - 1928, 8 the Niue Island
between the infectious agent on one hand and host defences on          epidemic of 1972,5 and the Cuban epidemic of 1981 (G.P.
the other. In the case of dengue, there is a considerable diffe-       Kouri, M.G. Guzman and J. Bravo - unpublished observa-
rence of opinion whether the virus or the host plays the pre-          tions).
                                                                          Turning to characteristics of the host that may affect the
                                                                       outcome of dengue infection, I should like to comment on two
Arbovirus Program, Pacific Biomedical Research Center,                 innate factors - genetic background and age, and an acquired
University of Hawaii, Honolulu, Hawaii                                 factor, earlier dengue infection. It has been well documented
LEON ROSEN,      M.D., DRP.H.                                          in both laboratory animal models and observations on man
                                                                       that genetic factors can modulate the immune response of a
40                                                                                                  BYLAE TOT SAMT    11 OKTOBER 1986
host and hence the outcome of an infection. It would be sur-         cells, is known to be relatively insensitive. Of more impor-
prising if this were not true for dengue infections. At present      tance, the sensitivity of the system is known to vary from one
only anecdotal observations are available on this point for den-     test to another. I believe that viraemia levels could be legiti-
gue. One type of anecdotal observation is that it is not             mately compared in this system only if matched pairs of spe-
uncommon to observe multiple cases of severe dengue in the           cimens from primary and secondary infections of the same
same family during an outbreak - far more frequently than            serotype were assayed in parallel. Apparently, this was not
might be expected to occur by chance. For example, in the            done. The fact that viraemia was found to be higher in secon-
N iue Island outbreak of 1972,; there were 3 fatal cases among       dary infections with dengue type 11, but not with dengue
children in a single family out of a toral of 12 fatal cases in a    types I, III or IV, calls for an especially rigorous look at the
population of about 5 000 persons. Also, there have been seve-       data. Antibody enhancement of virus replication in cell cul-
ral examples of differences in anack rates for severe dengue         tures is not limited to dengue type 11, nor is the dengue shock
among different ethnic groups during the same epidemic -             syndrome caused exclusively by this serotype. As a maner of
for example, among Chinese in Malaysia. In most such in-             fact, dengue type III has been the predominant virus respon-
stances, environmental factors, such as differences in exposure      sible for the syndrome in several recent epidemics in south-
to vector mosquitoes cannot be excluded. However, the rela-          east Asia. 12
tive lack of severe disease among blacks during the 1981                The second experimental study cited in support of antibody
Cuban outbreak appears to be a real ethnic difference. 9             enhancement in the intact host consisted of comparing the
   It is well established that, in virgin soil epidemics of dengue   viraemias in two groups of five monkeys each. 11 Immediately
in which persons of all ages are infected, the common clinical       before being inoculated with dengue type 11 virus, one group
manifestations of dengue, such as fever, are more severe             of animals was infused intravenously with a human serum pool
among older children and adults compared with younger chil-          known to have an in vitro dengue virus replication enhance-
dren. This is similar to the experience with certain other infec-    ment titre of greater than 1:2000000. The other group of
tious diseases, such as rubella and poliomyelitis, in which cli-     animals received human serum without dengue antibody.
nical manifestations are more severe in infected adults than in      Three- to 50-fold higher peak viraemias were observed in the
infected children. No data are available on possible age diffe-      animals which had received antibody compared with those
rences in susceptibility to the dengue shock syndrome. In            which did not.
those epidemics in which a sufficiently large number of such             The problem with this experiment as evidence for antibody
cases have occurred, data are lacking on the number of indi-          enhancement in the intact host is that it may represent JUSt
viduals in the different age groups susceptible to infection          another in vitro experiment. Unfortunately, the sera tested for
with the responsible dengue serotype or serotypes.                    virus content were not assayed for in vitro antibody enhance-
   The most controversial aspect of the dengue pathogenesis           ment titre. Such tests were carried out on sera drawn from
question is whether or not an earlier heterologous dengue             monkeys shortly after they had been infused. The enhance-
infection constitutes a risk factor for development of the            ment titre in those animals which had received antibody was
dengue shock syndrome. Two types of data have been cited in           found to be about 1: 1 000000. Given this high titre, it is quite
support of this concept. One of the types is experimental. It is      likely that in vitro enhancing antibody was still present in the
said that lower primates experimentally infected with dengue          monkeys' sera at the time of their viraemia a few days later. If
type 11 virus develop higher levels of viraemia if they have          this were the case, the same data might have been obtained
actively or passively acquired heterologous dengue antibody           had the antibody not been given to the monkeys at all, but
than they do if they have no such antibody. The other type of         rather, just added to their sera after the laner were withdrawn
data cited in support of what can be called the sequential            for virus assay! Dengue plaque counts in LLC-MK2 cells can
infection hypothesis is epidemiological. Several studies are          be increased by small amounts of antibody. When such cells
said to show that the dengue shock syndrome occurs more fre-          are utilized for plaque reduction neutralization tests, a larger
quently during a second dengue infection than it does during a        number of plaques is often seen in wells with serum dilutions
first infection.                                                      just beyond the neutralization endpoint than in control wells
   It should also be noted that there is a voluminous literature      without antibody.
on antibody enhancement of the replication of dengue type 11             There are four other studies, involving man or lower pri-
virus in cell cultures. While it is clear that such enhancement       mates, in which flavivirus viraemia was compared in indi-
occurs with dengue viruses in vitro - just as it does with other      viduals with and without earlier flavivirus infection. In two of
flaviviruses and viruses of other taxonomic groups - the data         the studies, the second infecting virus was a vaccine strain of
are irrelevant to the sequential infection hypothesis unless          dengue type 11. In one,13 vaccine was given to men who pre-
enhancement also occurs in the intact host.                           viously either had been vaccinated with yellow fever virus, or
   The data on antibody enhancement of dengue virus replica-          had not. In the other,14 vaccine was given to monkeys which
tion in lower primates consist of two studies from the same           had previously been infected with dengue types I, III or IV,
laboratory.IO.I! In the first study, it was found that in monkeys     or had not been infected with any of the viruses. In the other
infected with dengue type 11 virus after a previous dengue            two of the four studies, the second infecting virus was yellow
type I, III or IV infection, mean peak viraemia was higher            fever. In onep yellow fever vaccine virus was given to indi-
than that of monkeys with primary infection with the same             viduals who previously had been infected naturally with Japa-
virus. IQ Mean peak viraemia for secondary type I, III and IV         nese encephalitis virus, or had not. In the orher,16 virulent yel-
infection either was the same or was lower than that for the          low fever virus was given to monkeys which previously had
corresponding primary infection.                                      been infected with dengue type 11 virus, or had not. In none
   I do not find the data on dengue type 11 viraemia convin-          of these studies was a higher viraemia observed in previously-
cing for the following reasons: First, the magnitude of peak          infected individuals than in those previously non-immune.
viraemia in the monkeys, as measured in this study, was                  It is, of course, impossible to prove a negative proposition.
extremely variable. For example, while the mean peak virae-           Thus, it is not possible to prove that antibody enhancement of
mia in secondary infections was said to be 13 times higher            dengue infection does not occur in the intact host. It can be
than that in primary infections, the variation in peak viraemia       argued that enhancement occurs only with certain dengue
from one individual animal to another in both primary and             serotypes or strains, or only under certain special conditions.
secondary infections was 1 000 times or more. Second, the             However, in view of the alternative interpretations suggested
viral assay system used, namely plaque assay in LLC-MK2               for the two studies which are cited in support of the antibody

SUPPLEMENT TO SAMJ      11 OCTOBER 1986                                                                                              41
  enhancement concept, I believe that the burden of proof             whether or not an earlier dengue infection constitutes a risk
  should still lie with those who believe the concept is valid.       factor for the development of the dengue shocJc syndrome.
  Confirmation of the experimental data by another laboratory,        Aside from the technical problems mentioned, there is also the
  with modifications to meet the criticisms expressed, would be       problem of the relatively low and unpredictable incidence of
  especially convincing.                                              the shock syndrome - even in highly endemic areas. The best
     In my opinion, there is also considerable question about the     chance of obtaining good data is to investigate thoroughly the
  three epidemiological studies,I7-19 all from Thailand, cited in     experiments that nature provides.
  support of the sequential infection hypothesis. In order to
  demonstrate that people who have had a previous heterologous        REFERENCES
  dengue infection are at greater risk of developing the dengue
                                                                       I. Technical Advisory Comminee on Dengue Haemorrhagic Fever for the
  shock syndrome than others, it is first necessary to be able to            South East Asian and Western Pacific Regions. Guide for Diagnosis, Treac-
  define the denominators, that is, the two populations at risk.             menc and Concrol of Dengue Haemorrhagic Fever. 2nd ed. Geneva: World
                                                                             Health Organization, 1980: 1-30.
  There are several problems in the published studies in this           2. Rosen L. 'The Emperor's New Oothes' revisited, or reflections on the parho-
  regard. First, there is the difficulty in assessing the earlier            genesis of dengue hemorrhagic fever. Am ] Trop Med Hyg 1977; 26:
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                                                                        3. Halstead S. The pathogenesis of dengue: molecular epidemiology in infec-
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                                                                            Tahiti associated with hemorrhagic manifestations. Am] Trap Med Hyg
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                                                                            primary dengue infection on a Pacific island. Am] Trop Med Hyg 1974; 23:
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 the question whether or not the risk of developing the shock          6. Gubler DJ, Reed D, Rosen L, Hitchcock JC jun. Epidemiologic, clinical,
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                                                                            Med Hyg 1978; 27: 581-589.
 sent. Finally, there is the question whether or not children of       7. Kaeuffer H, Pichon G, Merlin M ec al. Apropos d'une epidemie controlee
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 the shock syndrome.                                                   8. Copanaris P. L'epidemie de dengue en Grece au cours de !'ete 1928'. Office
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                                                                       9. Guzman MG, Kouri GP, Bravo J ec al. Dengue haemorrhagic fever in
 respect of the numerator in risk assessment, namely, the ap-               Cuba: 1. Serological confirmation of clinical diagnosis. Tram R Soc Trap
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 respect to earlier dengue infection. It is important that there      10. Halstead SB, Shotwell H, CasaJs J. Studies on the pathogenesis of dengue
                                                                            infection in monkeys: n. Oinicallaboratory responses to heterologous infec-
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                                                                           keys by passively transferred antibody.] Infecc Dis 1979; 140: 527-533.
 uncommon in the studies under consideration, any primary             12. Sumarmo, Wulur H, Jabja E, Gubler DJ, Sultaryono W, Sorensen K. Qi-
 infection that was fatal, or one with only a single serum sam-            nical observations on virologically confirmed fatal dengue infections in
 ple, or one with a second sample collected 7 days or less after           Jakarta, Indonesia. Bull WHO 1983; 61: 693-701.
                                                                      13. Bancroft WH, Scon RM, Eckels KH ec al. Dengue virus rype 2 vaccine:
 onset, would automatically be excluded - since there would                reactogeniciry and immunogeniciry in soldiers. ] Infecc Dis 1984; 149:
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                                                                      14: Kraiselburd E, Kessler MJ, Torres-Blasini G. Lack of viraemia and limited
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appearance of high-titred antibody. Then there is the impor-               with DEN-2IS-1 vaccine. Trans R Soc Trap Med Hyg 1984; 78: 445-448.
                                                                      15. Sweet BH, Wisseman CL jun, Kitaoka M, Tarniya T. Immunological stu-
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assumed, for example, that the serological responses of shock              administration of 17D yellow fever vaccine. Am] Trap Med Hyg 1962; 12:
syndrome patients with primary infections will be the same as         16. Theilet M, Anderson CR. The relative resistance of dengu.e-immune mon-
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                                                                      17. Halstead SB, Nimmannitya S, Cohen SN. Observations related to pathoge-
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                                                                      18. Russell PK, Yuill TM, Nisalak A, Udomsakdi S, Gould DJ, Winter PE. An
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42                                                                                                        BYLAE TOT SAMT        11 OKTOBER 1986

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