From the Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
Received for publication March 17, 2003; accepted for publication May 30, 2003.
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ABSTRACT |
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communicable diseases; disease outbreaks
Abbreviations: Abbreviation: AIDS, acquired immunodeficiency syndrome.
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INTRODUCTION |
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THE COURSE OF A SINGLE INFECTION |
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Not all infections necessarily lead to clinical disease. The proportion clinical among infections varies greatly, from below 1 percent for polio to over 90 percent for measles and smallpox. Insofar as subclinical infections may still be infectious, the ability to identify chains of transmission from clinical cases is strongly influenced by this factor and will be very difficult if an appreciable proportion of infections are not recognized (as for polio). Whether or not transmission occurs in the absence of clinical manifestations, the interval between successive infections is analogous, but not identical, to the serial interval between clinical onsets of successive cases and is called here the "transmission interval."
Time from infection to infectiousness
Some authors have described this as the "latent period," although this may not be ideal given that the terms "latency" and "latent period" itself are used in a variety of other microbiologic and epidemiologic contexts (1). The interval is difficult to measure, as we rarely observe infection transmission events, except by inference from detailed contact histories. The start of infectiousness may in theory also be inferred from data on the shedding of infectious agents, as in respiratory secretions or in stools, or the appearance of infectious stages in the blood (e.g., Plasmodium gametocytes). Such data are not easily or often collected, however, and thus there are fewer data on this interval than for the incubation period, for example. We do know that, for some infections, individuals may become infectious appreciably before onset of disease (human immunodeficiency virus/acquired immunodeficiency syndrome (AIDS) and hepatitis A being examples), and for others the opposite occurs (e.g., the infectious gametocytes of falciparum malaria appear several days after onset of illness) (2).
Duration of infectiousness
This period is also difficult to measure, requiring the accumulation of detailed contact histories of linked cases or else data on shedding of the infectious agent. Beyond this difficulty, the level of infectiousness can vary considerably during the course of the infectious period for several reasons. This will reflect the time course of the concentration of agents shed into the environment, as well as of the clinical manifestations of a disease (e.g., coughing), and their implications for individual and social behavior (including restricted activity or hospitalization) and hence for contact. The actual numbers of transmissions of infection from individual cases and their distribution over time, which will ultimately be manifested in the pattern of subsequent disease in the community, will reflect all of these factors.
Incubation period
Although the basic definition of an incubation period (time from infection to clinical onset) is widely accepted, its measurement also has difficulties. In addition to the timing of the infection event, the timing of disease onset may be difficult (it may be insidious, or people may just not remember precisely), and data are sometimes presented with reference to the onset or maximum of some clearly defined symptom, such as a rash. Some descriptions fail to clarify just how the onset was defined, making interpretation difficult. Despite such difficulties, incubation period estimates, typically expressed as ranges, are available for most infectious diseases (2).
An important paper by Sartwell (3) demonstrated that frequency distributions of incubation periods are typically "right skew" or "log normal," meaning that they have a long right-hand tail but look symmetric if the time axis is plotted on a logarithmic scale. For this reason, some authors have preferred to summarize incubation periods with a median or geometric mean, rather than an arithmetic mean (the geometric mean is the antilog of the arithmetic mean of the logarithms). The actual distributions reflect variations in infectious dose, in replication times of the pathogen, and in levels of susceptibility among members of the host population. There is good evidence for an inverse relation between incubation period and infectious dose (higher dose, shorter incubation) for some infections (typhoid is a classic example) but not others (2). Most of the literature on incubation periods relates to diseases with relatively short periods, with comparatively little discussion on the more difficult problem of defining incubation periods when disease occurs many years after initial infection, as with tuberculosis (4). The important exception to this generalization is AIDS, the incubation period of which has attracted much attention because of its importance in predictions of future disease burden (5).
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THE INTERVAL BETWEEN SUCCESSIVE INFECTIONS (TRANSMISSION INTERVAL) |
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THE INTERVAL BETWEEN SUCCESSIVE CLINICAL CASES (CLINICAL ONSET SERIAL INTERVAL) |
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The maximum clinical onset interval (called here Sx) will occur if transmission occurs as late as possible relative to person As clinical onset (thus, TA is a large positive number) and with a maximum incubation period for person B. The range can be very great for infections with extended periods of infectiousness, certainly many decades and perhaps as long as a century. Consider a child (person A) who contracts varicella virus infection and associated chickenpox in the first year or two of life and then many decades later has an episode of zoster, thereby infecting his or her great-grandchild (person B), who then has chickenpox as a result. No doubt this has occurred! Other herpesvirus diseases, mycobacterial diseases such as leprosy and tuberculosis, and perhaps also prion diseases also have this potential, because of the propensity for their infections to be lifelong.
The actual clinical onset serial intervals for any disease will follow a frequency distribution between these minimum and maximum extremes. The cleanest observed data on such distributions are seen in records of outbreaks with a single primary case and associated secondary cases (with the proviso that the single source case may not be typical or representative). Figure 2 shows examples of such data on measles and smallpox, showing clear separation of secondary cases from single primaries, as well as also subsequent 3° and 4° cases. (Although the definition of primary, secondary, tertiary [1°, 2°, 3°, ...] cases has little ambiguity, some authors speak of secondaries as the "first generation." There is disagreement on this latter terminology within and between disciplines, with different applications in the context of epidemiology, genetics, migrant studies, and microbiology [e.g., relating to the serial passage of infectious agents in laboratories], the confusion arising because some workers number as generations the successive groups of individuals or cases or organisms, whereas others number the successive transmissions between them. Because of this we will avoid numbering "generations" here.) In many data sets of various diseases, the 3° and 4° case groups overlap in time.
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The observed intervals between clinical onsets may also be affected by control measures. If infected individuals are recognized early, their infectious periods may be curtailed by treatment or isolation, in which circumstance we would expect case-to-case intervals to shorten on average over time, during the course of an epidemic. For this reason, one might expect transmission from the primary to secondary cases in outbreaks to provide the fullest distribution of potential clinical onset intervals for the infection concerned.
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HOUSEHOLD DATA |
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EPIDEMIOLOGIC TRACING |
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ANALYSIS |
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Measles
According to a widely used reference, the incubation period of measles is "About 10 days, but may be 7 to 18 days from exposure to onset of fever, usually 14 days until rash appears; rarely as long as 1921 days" (2, p. 331), the "rash appears on the third to the seventh day" after the onset of prodromal fever, and the infectious period is "from 1 day before the beginning of the prodromal period (usually about 4 days before rash onset) to 4 days after appearance of the rash; minimal after the second day of rash" (2, p. 330). On the basis of this description, we would expect the rash-to-rash serial interval to fall between a minimum of 6 days (i.e., TA = 4; IB = 7 + 3) and a maximum of 25 days (TA = 4; IB = 21). (An extreme interpretation of the text could suggest minimal TA = 8 if a case were infectious 1 day prior to prodrome and if there were 7 days from prodrome to rash, thus giving a minimum rash-to-rash interval of 2 days (TA = 8; IB = 7 + 3). Similarly, the text might be interpreted as saying that IB could be as long as 18 days to prodrome plus 7 more days to rash, thus making a maximum rash-to-rash interval of 29 days (TA = 4; IB = 18 + 7)). The implied range between onsets of prodromes is from 6 (TA = 1; IB = 7) to 29 days (TA = 7 + 4; IB = 18).
The two community measles outbreaks illustrated in figure 2 show very similar temporal patterns. The larger outbreak, which might on account of its size be less influenced by chance than the other smaller example, suggests a range of serial intervals from 9 to 17 days, and all the data in both outbreaks are consistent with this. In contrast, the household data sets illustrated in figure 3 show patterns that are similar between themselves, despite coming from very different settings, but that differ from the community outbreaks. The serial intervals appear to be shorter (minimum, 6 days; mode, 11 days) in the household context than in the community, consistent with transmissions occurring earlier and perhaps implying a higher dose and a shorter incubation period in the household context.
Smallpox
According to the same reference, the incubation period of smallpox is "From 719 days; commonly 1014 days to onset of illness and 24 more days to onset of rash"; and cases are infectious "From the time of development of the earliest lesions to disappearance of all scabs; about 3 weeks. The patient is most contagious during the pre-eruptive period by aerosol droplets from oropharyngeal lesions" (2, p. 457). Interpreting this to mean that cases can be infectious from 4 days prior to 21 days after rash onset, the full range of rash-to-rash intervals would extend from 5 days minimum (TA = 4; IB = 7 + 2) to 44 days maximum (TA = 21; IB = 19 + 4). The interval between illness onsets should be from 3 (TA = 4; IB = 7) to 44 (TA = 4 + 21; IB = 19) days.
The two smallpox outbreaks illustrated here show similar distributions for the successive generations. The Kosovo outbreak (figure 2, part C) was sufficiently large to provide a reasonable distribution, with intervals from primary to secondary cases ranging from 14 to 20 days. This is considerably shorter than the theoretical range, probably reflecting that transmission occurred during a narrow time window around the time of clinical onset of the primary case. Interestingly, the earliest and latest tertiary cases occur at exactly double the times to the earliest and latest secondary cases, as predicted, implying narrow transmission periods from the secondary cases as well. The quaternary case generation is right truncated, indicating that control (vaccination and quarantine) was successful in breaking transmission entirely from the later tertiary cases. The Meschede outbreak (figure 2, part D) took place in a hospital setting, the secondary cases being attributable to aerosol transmission, prior to the primary cases being moved to another hospital.
Chickenpox
The incubation period is "from 2 to 3 weeks; commonly 1416 days; may be prolonged after passive immunization ... and in the immunodeficient" (2, p. 93). The period of communicability starts "as long as 5 but usually 1 to 2 days before onset of rash, and continuing until all lesions are crusted (usually about 5 days) ..." (2, p. 94). Assuming that the incubation period is measured to rash onset (the rash occurs early in chickenpox) implies that the interval between case (rash) onsets should range between 9 (TA = 5; IB = 14) and 26 (TA = 5; IB = 21) days. The intervals observed in the Shetland outbreak (range, 919 days; mean, 14 days) (figure 4, part A) fall within this range. The fact that the intervals following the zoster and varicella cases were similar was emphasized in the original paper as evidence supporting the identity of the agents (13). The primary zoster case was the father of the two secondary cases and, thus, the interval backwards to his source case may have been several decades.
Tuberculosis
For some infections, the definitions become even less clear. For example, "Incubation periodfrom infection to demonstrable primary lesion or significant tuberculin reaction (note: this is not a clinical endpoint), about 210 weeks. While the subsequent risk of progressive pulmonary or extrapulmonary TB [tuberculosis] is greatest within the first year or two after infection, latent infection may persist for a lifetime," and "Period of communicabilityTheoretically as long as viable tubercle bacilli are being discharged in the sputum" (2, p. 524). Data such as those in figure 4, part B, are limited to a relatively narrow (for tuberculosis) time window, in this case excluding intervals greater than 2.5 years, many of which must occur as a consequence of the reactivation of long-term latent infections (14). Inferences about the full distribution of case-to-case intervals of tuberculosis are complicated by uncertainties over the proportion of cases among older individuals that represent recent primary or reinfections versus reactivations of old infection. Any attempt to describe the full distribution must thus be based upon assumptions concerning pathogenesis, and it will also be influenced by time trends in infection risk and by the demography of the host population, insofar as the frequency of long incubation and serial intervals will be related to life expectancy (4).
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DISCUSSION |
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Panum (15), in his classic description of measles on the Faroe Islands in 1846, noted that one can infer when patients are infectious by relating data on incubation periods to the case-to-case interval (these intervals are similar in measles, indicating that patients are most infectious at the time of clinical onset). Hope Simpson (16), some of whose data are illustrated in figure 3, part A, and figure 4, part A, used similar reasoning in discussing infectious periods.
Case onset serial intervals are functions of several variables: of times to infectiousness, duration of infectiousness, and time to disease (incubation period). They are also influenced by the pattern of numbers of contacts over time (itself influenced by individual behavioral and social factors), by control interventions, and by stochastic effects. They may be complicated further by dependence between these variables; that is, the time to onset and the duration of infectiousness are unlikely to be independent of each other, let alone independent of the incubation period or of the implementation of control interventions. Examples such as presented here are illustrative, and they will have been influenced by all these factors. Although the range of possible serial intervals can be estimated from descriptions of infectious and incubation ranges, as shown above, the more severe the condition, the more likely it is that actual serial intervals will fall in the shorter part of the range, given that illness, isolation, and control measures will tend to curtail transmission. Serial intervals in households or other close contact settings will tend to be shorter than in community settings, as illustrated in figure 3, given that close contact predisposes to early infection and also that there may be an inverse association between dose and incubation period.
The parameter definitions quoted in this paper are from a reference that is widely used in infectious disease control (2), but it should be noted that such definitions differ between texts. For example, with reference to measles, one may also read the following: "The incubation period (to onset of fever) is 813 days, usually about 10 days. The period of communicability starts just before the onset of the prodrome and lasts until four days after the rash appears" (17, p. 140), or "The first symptoms ... occur after a 1012 day incubation period.... The prodromal stage ... lasts 2 to 4 days ... generally considered to be infectious 2 to 4 days before to 4 days after rash onset" (18, p. 223). Each of these (and several other published) definitions differs slightly from the one used above. None of these references cites the data upon which the estimates are based. None of the published definitions is written in a manner that is easily translated into serial intervals.
In the context of an infectious disease outbreak, a public health officer may be presented with one or more (index) cases of a disease, and among the first questions are those concerning the source (if the source was a clinical case, then it had onset within the range of one serial interval before the index cases) and the extent of propagation (if index cases are secondary to a single source case, then they should appear over an interval of time equal to (Sx Sn)). Questions of this sort would be of particular importance in the response to a new or emerging infection or to a bioterrorist incident.
The average clinical onset serial interval will be the same as the average infection transmission interval (the former being far easier to observe than the latter) only if the distribution of infectiousness periods, relative to time of infection onset, is independent of whether or not individuals manifest signs of clinical disease. This is probably not true for many infections. Even if the average clinical onset and transmission intervals are similar, the frequency distributions of these two statistics will generally be different. This is because the variation in incubation period affects only the former, the interval between clinical onsets, and has no direct influence upon the transmission interval. Although a source case must by definition become infected prior to its secondary, it is possible, as noted above and in figure 1, part B, for a secondary case to have clinical onset prior to that of its source.
In the estimation of time trends of infection, a key statistic is the reproduction number (defined as the average number of transmissions per case) and whether this is greater or less than unityimplying that each case is responsible, on average, for more or less than one successful transmission (19). The statistic is then the factor of increase or decrease in infection incidence over a period equal to the mean transmission interval.
Another context in which the serial interval is important is that of calculating secondary attack rates, themselves the traditional measure of infectiousness or transmissibility. Calculation of such statistics requires a denominator of the number of individuals exposed to a primary case and a numerator of the number of cases attributable to that exposure, which should be defined as those arising within one case onset serial interval (distribution) from the primary case (20).
A particularly long interval between clinical cases may reflect either a long infectious period of the source or a long incubation period of the recipient case. Alternatively, it may reflect that transmission is not by direct contagion, but was indirect, with the agent sequestered in the environment within a vector or in a zoonotic cycle. In other circumstances, a long interval between identified cases may reflect that transmission went unobserved through subclinically infected individuals. The latter is an especially important issue in the context of the current global polio eradication program, whose success requires the eradication of infection but whose surveillance is dependent largely upon identifying clinical cases, although less than 1 percent of infections are associated with clinical disease.
The very long transmission interval for some infections, such as herpesvirus and mycobacterial infections, has important implications for the ability of such agents to persist in small human populations. It was recognized by Black et al. (21) that antibodies for herpesviruses were found consistently in small and isolated populations, indicating that these infections have a small "critical population size" (minimum total human population size necessary for persistence of the infection). This reflects the ability of these agents to persist for long periods within individuals, ultimately to cause infections in new generations of susceptible individuals that have appeared in the interim.
Yet another problem complicates the measurement of long incubation and serial intervals, as occur with mycobacterial and prion diseases. Insofar as an older individual cannot experience a very long subsequent incubation period if s/he becomes infected, but clinical onset in such an individual could reflect a very long prior incubation period, it is clear that these intervals will be a function of age and whether they are examined prospectively from a primary case or retrospectively from secondary cases. This issue has been recognized in some analyses of incubation periods of prion diseases (22) and has been examined explicitly in the context of describing the full serial interval distribution of tuberculosis (4).
The propensity for persistent infections and/or long incubation periods, and, hence, long serial intervals, poses a particular problem in the context of eradication or elimination programs, as exemplified by the current World Health Organization efforts with regard to polio and leprosy. It is now known that certain classes of immunodeficient individuals can continue to pass vaccine-derived polioviruses in their feces for several years (23), and, despite the very best control efforts, it is certain that new and infectious cases of leprosy will arise many decades from now, after very long incubation periods. The circumstances surrounding these individuals will influence the long-term trends of these diseases and must be considered in the planning of control strategies.
In addition to data on incubation periods and duration of infectiousness, the accumulation of observations on transmission and clinical onset serial intervals, with explicit stipulation of the onset criterion employed, and their inclusion in standard texts and control manuals, would be a useful contribution to guide public health interpretation and action.
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ACKNOWLEDGMENTS |
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NOTES |
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REFERENCES |
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