Dr. John J. Treanor, Chapter 162, Influenza Virus

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Chapter 162 – Influenza Virus
JOHN J. TREANOR
Influenza is an acute, usually self-limited, febrile illness caused by infection with
influenza type A or B virus that occurs in outbreaks of varying severity almost
every winter. The attack rates during such outbreaks may be as high as 10% to
40% over a 5- to 6-week period. The most common clinical manifestations are
fever, malaise, and cough. The two most important features of influenza are the
epidemic nature of the disease and the mortality that results in part from its
pulmonary complications.
HISTORY
Influenza virus has been causing recurrent epidemics of febrile respiratory disease
every 1 to 3 years for at least the past 400 years.[1][2] Although the disease is not
associated with a characteristic manifestation such as rash, the high attack rate, the
explosive nature of the epidemic, and the frequency of cough allow the
identification of some past epidemics. For example, Sydenham’s account of an
epidemic that occurred in 1679 is a clear description of influenza.[3] Hirsch
tabulated 299 outbreaks occurring at an average interval of 2.4 years between 1173
and 1875.[1] As discussed later, severe epidemics of worldwide scope occur less
often and are referred to as pandemics. The first recorded pandemic that clearly fits
the description of influenza occurred in 1580, although others may have occurred
earlier. Since then, 31 pandemics have been described. The greatest pandemic in
recorded history occurred in 1918–1919 when, during three “waves” of influenza,
21 million deaths were recorded worldwide, among them 549,000 in the United
States.[4]
The modern understanding of influenza was ushered in by Smith and associates
when they isolated influenza A virus in ferrets in 1933.[5] Influenza B virus was
isolated by Francis in 1939[6] and influenza C virus by Taylor in 1950.[7] The
discovery by Burnet in 1936 that influenza virus could be grown in embryonated
hens’ eggs allowed extensive study of the properties of the virus and the
development of inactivated vaccines.[8] Animal cell culture systems for the growth
of influenza viruses were developed in the 1950s.[9] The phenomenon of
hemagglutination, which was discovered by Hirst in 1941, led to simple and
inexpensive methods for the measurement of virus and specific antibody.[10]
Evidence of the protective efficacy of inactivated vaccines was developed in the
1940s.[11][12] Vaccines have been in widespread use in various parts of the world
since, but usually for only selected segments of a population. The use of live
vaccines for influenza was first suggested shortly after the virus was discovered,[13]
but the first live vaccine was not licensed in the United States until 2003,
approximately 70 years later. Finally, four antiviral agents in two classes have been
approved for prevention and treatment of influenza. These include the so-called
M2 inhibitors, amantadine in the mid-1960s, rimantadine in 1993, and the
neuraminidase inhibitors zanamivir and oseltamivir in 2000. Although the M2
inhibitors are active against only influenza A, the neuraminidase inhibitors are
clinically active against both influenza A and B viruses.
THE VIRUSES
Classification
Influenza viruses belong to the family Orthomyxoviridae and are classified into
three distinct types, influenza A, influenza B, and influenza C virus, on the basis of
major antigenic differences. In addition, there are significant differences in genetic
organization, structure, host range, epidemiology, and clinical characteristics
between the three influenza virus types ( Table 162–1 ). However, all three viruses
share certain features that are fundamental to their biologic behavior, including the
presence of a host-cell derived envelope, envelope glycoproteins of critical
importance in virus entry and egress from cells, and a segmented genome of
negative sense (i.e., opposite of message sense), single-stranded RNA. The
standard nomenclature for influenza viruses includes the influenza type, place of
initial isolation, strain designation, and year of isolation. For example, the
influenza A virus isolated by Francis[14] from a patient in Puerto Rico in 1934 is
given the strain designation A/Puerto Rico/8/34, sometimes referred to as PR8
virus. Influenza A viruses are further divided into subtypes on the basis of their
hemagglutinin (H) and neuraminidase (N) activity (e.g., H1N1 or H3N2).
Table 162-1 -- Differences among Influenza A, B, and C Viruses
Influenza A
Influenza B
Influenza C
Genetics
8 gene segments
8 gene segments
7 gene segments
Structure
10 viral proteins
11 viral proteins
9 viral proteins
M2 unique
NB unique
HEF unique
Host range
Humans, swine, equine,
Humans only
avian, marine mammals
Humans
swine
and
Antigenic shift and Antigenic drift only. More Antigenic drift
Epidemiology drift. Drift is generally than one variant may only. Multiple
linear
cocirculate
variants
Clinical
features
May
cause
large
pandemics
with
significant mortality in
young persons
Severe disease generally
Mild
disease
confined to older adults or
without
persons at high risk;
seasonality
pandemics not seen
Morphologic Characteristics
The morphologic characteristics of all influenza virus types, subtypes, and strains
are similar. Electron microscopic studies estimate their size to be 80 to 120 nm in
diameter and show them to be enveloped viruses covered with surface projections
or spikes. They may exist as spherical or elongated filamentous particles as well (
Fig. 162–1 ). The latter predominate in newly isolated strains, whereas most
laboratory-adapted strains consist almost entirely of spherical particles. The
filamentous forms vary in length but may be up to 40 nm long. A schematic
diagram of an influenza A virus is shown in Figure 162–2 .
Figure 162-1 Electron micrograph of influenza A/USSR/77 H1N1 (×189,000).
Figure 162-2 Schematic model of an influenza A virus.
Eight structural proteins have been identified in influenza A viruses. The surface
spikes are glycoproteins that possess either hemagglutinin (HA) or neuraminidase
(NA) activity. Each rod-shaped HA spike measures approximately 4 nm in
diameter by 14 nm in length. They can be removed from the intact virion by
sodium dodecyl sulfate, by bromelain, or by chymotrypsin. Each spike is a trimer
composed of three HA polypeptides, each with a molecular weight of 75,000 to
80,000, resulting in a trimer with a molecular weight of approximately 224,640.[15]
The HA is synthesized as a monomer (HA0), which is cleaved by host-cell
proteases into HA1 and HA2 components that remain linked together. Antigenic
sites and sites for binding to cells are located in the globular head of the molecule.
The viral NA is an enzyme that catalyzes the removal of terminal sialic acids (Nacetyl neuraminic acid) from sialic acid–containing glycoproteins. The NA spike is
shaped like a mushroom rather than a rod and has a molecular weight of 240,000.
The intact NA consists of a tetramer of NA polypeptides, each with a molecular
weight of 58,000. As in HA, the antigenic sites and the enzyme active site are
located in the mushroom-shaped head.
At least 15 highly divergent, antigenically distinct HAs have been described in
influenza A viruses (H1 to H15), as well as at least nine distinct NAs (N1 to N9).
A third integral membrane protein, the M2 protein, is also present in small amounts
on the viral envelope.
Interior to the envelope is the matrix, or M1, protein.[16] This protein is believed to
provide stability to the virion. Within the envelope are eight physically discrete
nucleocapsid segments ( Table 162–2 ). Each nucleocapsid is composed of a single
segment of genomic RNA intimately associated with the viral nucleoprotein (NP),
with the three polymerase proteins PB1, PB2, and PA bound to one end. These socalled internal viral proteins are important targets for cross-reactive, viral-specific
cytotoxic T lymphocytes (CTL). Two nonstructural viral proteins, NS1 and NS2
(also referred to as the nuclear export protein, or NEP), are also found within
infected cells. Small amounts of NEP may be present within virions.
Table 162-2 -- Genes and Protein Products of Influenza A Virus
RNA
Segment
Number
Gene Product
Name of Protein
Description
1
PB1
Basic polymerase
RNA transcriptase
1
2
PB2
Basic polymerase Cap
binding,
2
cleavage
3
PA
Acidic polymerase Unknown
4
HA
Hemagglutinin
Viral attachment to cell membranes;
membrane fusion
5
NA
Neuraminidase
Cleaves sialic acid from cell surface;
released from membranes; prevents
aggregation
6
NP
Nucleoprotein
Encapsidates RNA; regulation
transcription/replication
M
Matrix
Surrounds viral core; controls nuclear
transport
M2
Matrix 2
Ion channel; required for uncoating
Nonstructural
Antagonizes type I interferons, may
be involved in regulation of mRNA
transport from nucleus
7
8
Proposed Functions
endonucleolytic
of
NS1
NEP (NS2)
Nuclear
export
Transport of newly assembled RNP
protein
from nucleus to cytoplasm
(?structural)
EPIDEMIOLOGY
Disease Impact
Influenza epidemics are regularly associated with excess morbidity and
mortality,[17] usually expressed in the form of excess rates of pneumonia and
influenza-associated hospitalizations and deaths during epidemics.[17][18]
Pneumonia and influenza deaths fluctuate annually in a predictable fashion with
peaks in the winter and troughs in the summer. Observed pneumonia- and
influenza-related death rates are compared with an expected baseline derived from
a time-series regression model,[19] which allows calculation of excess mortality due
to influenza epidemics. A tabulation of levels of excess pneumonia and influenza
deaths (i.e., deaths in which specific International Classification of Diseases [ICD]9 codes are recorded as the cause of death) attributable to influenza epidemics[20] is
shown in Table 162–3 , compared with the estimated percentage of isolates which
were typed as influenza A (H3N2), A (H1N1), or B in each year. Significant levels
of excess mortality are reported in most years. Generally, the level of excess
mortality is highest in years when influenza A (H3N2) viruses predominate, but
influenza B and to a lesser extent H1N1 viruses also can be associated with excess
mortality. Because not all influenza-related deaths are manifested as pneumonia,
the pneumonia and influenza mortality statistics probably underestimate the true
impact of influenza on the population. Table 162–3 also lists the all-cause excess
mortality, defined as deaths due to any cause, above a similarly derived baseline,
that occur during periods of influenza epidemic activity. Although less precise than
the pneumonia- and influenza-related deaths, all-cause mortality is probably a
more accurate reflection of the total burden of influenza. Recent studies suggest
that even higher levels of mortality might be attributable to influenza, potentially
as high as 51,000 deaths annually in the United States.[21]
Table 162-3 -- Estimated Excess Pneumonia- and Influenza-Related Deaths and
Excess Mortality of All Causes during Influenza Epidemics
Percent of Isolates That Were Pneumoniaand All-Cause
of the Following (Sub) Type Influenza-Related Excess Excess Deaths
Year
H3N2
H1N1
B
Deaths (Range)
(Range)
1972/73 90
0
10
7900 (5500–10,300)
18,300 (1200–
35,000)
1973/74 20
0
80
00
00
1974/75 100
0
0
6500 (4100–8900)
15,100
32,100)
1975/76 70
0
30
11,800 (9200–14,400)
24,600 (3400–
45,900)
1976/77 5
0
95
00
00
1977/78 60
26
14
8300 (6000–10,500)
46,200 (19,800–
72,700)
1978/79 0
98
2
00
00
1979/80 2
1
97
5100 (3500–6700)
17,300
34,100)
1980/81 77
23
0
11,700 (9100–14,200)
47,200 (27,800–
66,600)
1981/82 1
24
75
2100 (600–3700)
00
1982/83 79
10
11
4700 (2800–6700)
9600 (0–19,200)
1983/84 5
50
45
3500 (1600–5400)
8200 (0–17,600)
1984/85 97
0
3
8100 (6600–9600)
36,200 (17,700–
54,700)
1985/86 24
0
76
6700 (4900–8500)
34,000 (6800–
61,200)
1986/87 —
—
—
1800 (1100–2500)
16,800 (1900–
31,700)
1987/88 0
80
20
7400 (5600–9100)
33,400 (12,900–
53,800)
1988/89 45
45
10
5100 (3600–6600)
10,500
(0–
(600–
(800–
Year
Percent of Isolates That Were Pneumoniaof the Following (Sub) Type Influenza-Related
H3N2
H1N1
B
Deaths (Range)
and All-Cause
Excess Excess Deaths
(Range)
20,200)
1989/90 90
1
9
10,100 (8500–11,700)
43,600 (27,600–
59,600)
1990/91 4
3
93
4200 (2400–6100)
23,000
46,000)
1991/92 19
81
0
6600 (5600–7700)
41,700 (19,600–
63,700)
(0–
Data from Table 153–3 in Treaner JL. Influenza virus. In: Mandell GL, Bennett JE,
Dolin R, eds. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious
Diseases, ed. 5. Philadelphia: Saunders; 2000:1826; and Simonsen L, Clarke MJ,
Williamson DW, et al. The impact of influenza epidemics on mortality. Introducing a
severity index. Am J Public Health. 1947;87:1944–1950.
Mortality is only the most severe manifestation of influenza impact, and similar
techniques can be used to estimate excess morbidity due to influenza epidemics.[22]
Data from the Tecumseh Community Health Study have been used to estimate that
influenza is responsible for from 13.8 to 16.0 million excess respiratory illnesses
per year in the United States among individuals less than 20 years of age, and for
4.1 to 4.5 million excess illnesses in older individuals.[22]
Influenza is usually associated with a U-shaped epidemic curve. Attack rates are
generally highest in the young, whereas mortality is generally highest among older
adults ( Fig. 162–3 ).[17][23] Excess morbidity and mortality are particularly high in
those with certain high-risk medical conditions, including adults and children with
cardiovascular and pulmonary conditions such as asthma, or those requiring
regular medical care because of chronic metabolic disease, renal dysfunction,
hemoglobinopathies, or immunodeficiency.[24] Influenza-related death rates in
nursing home residents with comorbid conditions are as high as 2.8% per year.[25]
Figure 162-3 Typical epidemic curve in the interpandemic era, showing the rates of
medically attended illness (green line, rate per 100), hospitalizations for acute respiratory
disease (blue line, rate per 10,000), and pneumonia- and influenza-related mortality (red line,
rate per 100,000) by age for several seasons of influenza in Houston, Texas. Attack rates and
hospitalizations occur at both extremes of age, but mortality occurs largely in those older than
65 years. (Data from Glezen WP, Keitel WA, Taber LH, et al. Age distribution of patients with
medically attended illnesses caused by sequential variants of influenza A/H1N1: Comparison
to age-specific infection rates, 1978–1989. Am J Epidemiol. 1991;133:296–304.)
Influenza also results in more severe disease and significant mortality in
individuals with human immunodeficiency virus (HIV) infection,[26][27] in those
with iatrogenic immunosuppression,[28] and in women in the second or third
trimester of pregnancy.[29] Influenza is being increasingly recognized as an
important health problem in young children. Rates of influenza-related
hospitalizations are particularly high in healthy children under 2 years of age,
where rates approach those of older children with high-risk conditions.[30][31][32] In
addition, a high rate of secondary complications, particularly otitis media and
pneumonia, occur in children with influenza infection.[33] Disease impact is
particularly severe in both adults and children with chronic pulmonary diseases,
especially asthma.[34][35][36] It should be recognized that although complication rates
are higher in older adults and debilitated persons, the majority of individuals
hospitalized during influenza epidemics were ambulatory and leading productive
lives prior to their acute illness.[24]
Much of the impact of influenza is related to the malaise and consequent disability
that it produces, even in young, healthy individuals. It has been estimated that a
typical case of influenza, on average, is associated with 5 to 6 days of restricted
activity, 3 to 4 days of bed disability, and about 3 days lost from work or
school.[37][38] The average number of medical visits for cases in which medical
attention was sought was from 1.1 to 3.6, depending on year of the outbreak and
age of the patient. It is worth noting that direct medical costs of illness account for
only about 20% or the total expenses of a case of influenza, with a major
proportion (30% to 50%) of the economic impact due to loss of productivity. In
one study, influenza in schoolchildren resulted in 37 missed school days by
children and 20 days of missed work by parents, per 100 children.[39] Influenza is
also associated with decreased job performance in working adults[40][41] and
reduced levels of independent functioning in older adults.[42]
Epidemic Influenza
An epidemic is an outbreak of influenza confined to one location, such as a city,
town, or country. In a given community, epidemics of influenza A virus infection
have a characteristic pattern. A graphic description of an epidemic due to an
A/Victoria/75/H3N2-like virus that occurred in 1976 in Houston, Texas, is shown
in Figure 162–4 . Such localized epidemics begin rather abruptly, reach a sharp
peak in 2 to 3 weeks, and last 5 to 6 weeks.[43] Reports of increased numbers of
children with febrile respiratory illness are often the first indication of influenza,
although on occasion, an outbreak in a nursing home is the very first indication of
influenza in a community. Outbreaks in children are usually soon followed by the
occurrence of influenza-like illnesses among adults. The next event is increased
hospital admissions for patients with pneumonia, exacerbation of chronic
obstructive pulmonary disease, croup, and congestive heart failure. Increased
school and industrial absenteeism also occurs, but these events are insensitive and
late indicators of influenza in a community.[43] Although an increased number of
deaths due to pneumonia is a highly specific indicator of influenza, it invariably
lags behind the other indications because of two factors: the time from the onset of
illness to time of death and the delay involved in reporting deaths to public health
officials.[44] During epidemics, average overall attack rates are estimated to be 10%
to 20%, but in selected populations or age groups, attack rates of 40% to 50% are
not unusual.[45] The factors that lead to termination of an outbreak in any given
location are unclear, because usually the outbreak ceases before the supply of
susceptible individuals is exhausted.
Figure 162-4 Correlation of the nonvirologic indexes of epidemiologic influenza with the number of
isolates of A/Victoria virus according to week, Houston, 1976. (Industrial absenteeism is determined by
the percentage with respiratory complaints.) (From Glezen WP, Couch RB. Interpandemic influenza in
the Houston area, 1974–1976. N Engl J Med. 1978;298:587–593, with permission.)
In temperate climates in either hemisphere, epidemics occur almost exclusively in
the winter months (generally October to April in the Northern Hemisphere, and
May to September in the Southern Hemisphere), whereas influenza may be seen
year round in the tropics. The reasons for these seasonal changes are not entirely
clear. Modeling studies suggest that the effect can mostly be explained by
postulating seasonal effects on virus transmissibility.[46] Such effects could be the
result of more favorable environmental conditions for virus survival,[47] or of
behavioral changes that increase transmission, such as indoor crowding. In large
countries such as the United States or Australia, regional differences in the time
occurrence of influenza outbreaks are also apparent. It is not uncommon to have
major outbreaks occurring in some communities or regions while others are
experiencing modest activity or none whatsoever.
Usually, a single strain of influenza virus will prevail during an epidemic of
influenza, and other respiratory viruses decrease in frequency.[45][48] However, this
is not always the case, and occasionally two different strains within a single
subtype (e.g., A/Victoria/3/75/H3N2 and A/Texas/1/77/H3N2)[49] or two different
influenza A subtypes (H1N1 and H3N2) circulate simultaneously. Furthermore,
concomitant outbreaks of influenza A and B or simultaneous outbreaks of
influenza A and respiratory syncytial virus have been demonstrated.[50] In many
years, the end of the influenza epidemic season is characterized by a brief spike in
cases due to a new strain. These limited outbreaks, which have been referred to as
a “herald wave,” often predict the predominant strain in the next influenza
season.[51]
Pandemic Influenza
In contrast to the familiar pattern of epidemic influenza, pandemics are severe
outbreaks that rapidly progress to involve all parts of the world and are associated
with the emergence of a new virus to which the overall population possesses no
immunity. Characteristics of pandemics include extremely rapid transmission with
concurrent outbreaks throughout the globe; the occurrence of disease outside the
usual seasonality, including during the summer months; high attack rates in all age
groups, with high levels of mortality particularly in healthy young adults[52]; and
multiple waves of disease immediately before and after the main outbreak. The
interval between pandemics is quite variable and unpredictable, but it is likely that
pandemics of influenza will continue to occur in the future.
Antigenic Variation
One of the unique and most remarkable features of influenza virus is the frequency
with which changes in antigenicity occur; these changes are referred to as antigenic
variation. Alteration of the antigen structure of the virus leads to infection with
variants to which little or no resistance is present in the population at risk. The
phenomenon of antigenic variation helps explain why influenza continues to be a
major epidemic disease of humans.
Antigenic variation involves principally the two external glycoproteins of the virus,
HA and NA, and is referred to as antigenic drift or antigenic shift, depending on
whether the variation is small or great.
Antigenic Drift
Antigenic drift refers to relatively minor antigenic changes that occur frequently
(every year or every few years) within the HA and/or NA of the virus. It is
generally accepted that the mechanism of antigenic drift, which has been studied
more intensively for the HA, is one of gradual accumulation of amino acid changes
in one or more of the five identified major antigenic sites on the HA molecule.[53]
Because antibody generated by exposure to previous strains does not neutralize the
antigenic variant as effectively as it did the wild type, immunologic selection takes
place, and the variant supplants previous strains as the predominant virus in the
epidemic. Support for this thesis comes from experimental work demonstrating
that antigenic variants (generated by drift) can be produced in cell cultures in the
presence of limiting amounts of antibody, and these variants have similar single
amino acid sequences in the HA.[54][55][56][57]
Comparison of the HA gene sequences of influenza viruses isolated in successive
years reveals differences in the patterns of HA evolution between influenza A, B,
and C viruses. Generally, a single lineage, or relatively few lineages, of influenza
A virus circulate in humans, and the accumulation of point mutations in the HA is
linear, with each strain replacing the previously circulating one. This is particularly
true of H3 influenza A viruses.[53][58] In contrast, multiple lineages of influenza C
virus cocirculate, as shown by sequence comparisons of the HEF gene. The
evolution of influenza B viruses is somewhere between these two examples, with
relatively few lineages of the HA gene (but more than one) cocirculating.[59]
Relatively less information is available regarding the evolution of NA gene
sequences, but these appear to follow a similar pattern.[60]
Antigenic Shift
The major antigenic shifts that herald pandemic influenza presumably result from a
different mechanism. These viruses are “new” viruses to which the population has
no immunity. There is very little or no serologic relationship between the HA (or
NA) antigens of the “old” and “new” viruses; hence, in nomenclature, each
receives a different designation. The schema shown in Figure 162–5 ties together
the concepts of antigenic shift and antigenic drift in relation to population
immunity.[61] When a new virus, here called HxNx, to which antibody is lacking, is
introduced into a population, pandemic influenza results. After one or more waves
of pandemic influenza, the proportion of immune individuals in the population
increases. This situation favors the emergence of viruses with antigenic changes in
the HA and/or NA, whose spread through the partially immune population is thus
facilitated. This phenomenon is repeated with subsequent epidemics due to strains
of influenza A/HxNx that exhibit some antigenic drift. After 10 to 30 years of
circulation of variants with this given subtype, the level of immunity in the
population to all variants within the subtype is very high, and the conditions for the
spread of a new virus, HyNy, become favorable, with the emergence of a new
pandemic of influenza.
Figure 162-5 Schema of the occurrence of influenza pandemics and epidemics in relation
to the level of immunity in the population. A/HxNx and A/HyNy represent influenza viruses
with completely different hemagglutinins and neuraminidases. (Modified from Kilbourne ED.
The epidemiology of influenza. In: Kilbourne ED, ed. The Influenza Viruses and Influenza. New
York: Academic Press; 1975:483, with permission.)
The pattern of replacement of HA and NA subtypes during the most recent century
of pandemics is shown in Figure 162–6 and is based both on virus isolation and
serologic studies of individuals who lived through previous pandemics. Such
studies suggest that the pandemic of 1889 was associated with viruses of an H2N2
type, followed by a pandemic in 1901 caused by an H3N8-type virus.[62] Virologic
and polymerase chain reaction (PCR) studies have shown that the “Spanish”
pandemic of 1918 (mentioned previously) was caused by an H1N1 virus, which in
turn was supplanted in the “Asian” pandemic of 1957 by H2N2 viruses. In 1968,
the “Hong Kong” pandemic was caused by viruses of the H3N2 subtype. In 1977,
viruses of the H1N1 subtype were reintroduced through an unknown mechanism.
These viruses are genetically identical to the H1N1 viruses that were circulating in
1950. Since 1977, influenza A viruses of both the H1N1 and H3N2 subtypes have
cocirculated.
Figure 162-6 Recent pandemics of influenza. The duration of circulation of viruses of
various subtypes is shown by the boxes. Because the nature of influenza epidemics prior to
1918 is known only by serologic means, those boxes are shaded tan. Below the time line is
given the ages of individuals in 2004 who were alive during the various epidemic periods of
earlier influenza subtypes. For example, individuals currently living who are between the ages
of 47 and 86 probably experienced their first influenza A infection as an H1N1 virus.
Individuals who are 36 years of age or younger have never been infected with H2N2 viruses.
The degree of genetic difference between subtypes, 30% or greater, precludes their
arising by simple point mutation, and the origin of new pandemic strains has been
the subject of intense interest and study, for obvious reasons. The most plausible
explanation for their origin takes into account three features of this phenomenon:
that the virus has a segmented genome, that pandemics occur only with influenza
A viruses, and that influenza A viruses, but not other influenza viruses, maintain a
large reservoir of genetic diversity in animals.
Influenza A viruses infect a variety of species, including man, swine, horses,
marine mammals, and in particular, birds. In fact, no less than 15 unique HA
subtypes (H1 to H15)[63] and nine NA subtypes (N1 to N9)[64] have been identified
in avian influenza viruses. Fortunately, avian influenza A viruses themselves
appear to be relatively restricted in their ability to replicate in humans.[65] The
precise molecular mechanisms responsible for the host-range preferences of avian
influenza A viruses are not completely known, but several factors probably play a
role. The divergent evolution of the genes of these viruses in avian hosts could
have resulted in less efficient interactions between undefined viral and mammalian
host cell components. The relative attenuation of avian-human influenza
reassortants for man[66] supports a role for non-HA genes in this restriction. In
addition, the HAs of avian and mammalian influenza viruses display a different
host-cell receptor specificity, with avian viruses preferring receptors containing
sialic acid–galactose linkages of the α2➙3 variety, and mammalian viruses tending
toward α2➙6 linkages.
Extensive sequence analysis has suggested at least two mechanisms by which
avian viruses can circumvent these barriers to interspecies transmission. These
studies have shown significant sequence similarity between the HA, NA, and PB1
gene segments of the pandemic H2N2 virus and avian viruses,[67][68] and between
the H3 and PB1 gene segments of the pandemic H3N2 virus and avian
viruses,[67][69] suggesting that in some circumstances, new pandemic viruses arise
by reassortment between avian viruses, which provide novel surface glycoproteins,
and human viruses, which provide genes allowing efficient replication in humans.
Reassortment would be facilitated by the presence of a third species that is
susceptible to infection with both avian and human viruses, such as the pig. Avianto-swine transmission has been demonstrated previously in nature,[70][71] and
naturally occurring avian–human reassortant viruses have been recovered in
pigs.[72] However, there are likely to be constraints on what types of reassortants
are viable; in particular, it has been suggested that the hemagglutinins of recent
human influenza A viruses are not compatible with the matrix genes of current
avian viruses,[73] and phenomena of this type may limit the possibilities for
generation of pandemic viruses by reassortment.
A second mechanism would involve adaptation of avian viruses to the human host
by evolution in swine, and this is supported by sequence analysis showing that the
1918 pandemic was most likely the result of direct introduction of a swine
influenza A virus into humans.[74] Recently, it has been shown that avian H1N1
viruses introduced into swine populations are evolving in these animals and have
switched receptor specificity to a more mammalian type.[75] This type of evolution
is very likely facilitated by the presence of both types of receptors in pig tracheal
epithelia.[75]
Finally, avian viruses might also be directly introduced into human populations
without prior reassortment or adaptation in an intermediate host. Avian viruses of
three different hemagglutinin subtypes, H5, H7, and H9, have caused human
disease, and in the case of the H5 and H7 viruses, some illnesses have been severe
or even fatal.[76][77][78] In 1997, an outbreak of H5N1 infection occurred in Hong
Kong, in which 18 people were hospitalized and six died. A second outbreak in
February 2003 involved two cases and one fatality.[79] Additional human cases of
H5N1 were reported in early 2004, from Vietnam and Thailand.[80] A large
outbreak of H7N7 infection in The Netherlands in April of 2003 involved 87
human cases. Most of the individuals had illness restricted to conjunctivitis, but
one fatality associated with severe pulmonary involvement occurred.[81] Human
infection with avian H9N2 virus has also been reported.[82] Human infection
appears to take place in the context of intense exposure to infected bird droppings
in live bird markets or in agricultural settings. However, despite the presence of
virus in the respiratory tract of infected individuals, person-to-person transmission
appears to occur rarely, if ever.[83] The specific barrier to transmission is unclear,
but there is considerable concern that eventually these introductions will result in
generation of a transmission-competent virus.
PATHOGENESIS AND HOST RESPONSE
Cellular Pathogenesis
Influenza virus infection is acquired by a mechanism involving the transfer of
virus-containing respiratory secretions from an infected to a susceptible person.[84]
A number of lines of evidence indicate that small-particle aerosols (<10 μm mass
median diameter) are the predominant factor in such person-to-person
transmission. First, large amounts of virus are present in respiratory secretions of
infected persons at the time of illness and are thus available for dispersion in smallparticle aerosols created by sneezing, coughing, and talking.[84] Second, the
explosive nature and simultaneous onset in many persons suggest that a single
infected person can transmit virus to a large number of susceptible individuals.
Furthermore, influenza virus type A has been shown to be relatively stable in
small-particle aerosols at a variety of relative humidities and temperatures, but
survival appears to be favored by low relative humidity and low environmental
temperature.[85] In experimental influenza in volunteers, inoculation with smallparticle aerosols produces an illness that more closely mimics natural disease than
does inoculation with large drops into the nose.[86][87] Finally, in such experimental
infections, doses of 137 to 300 times the median tissue-culture infective dose
(TCID50) are required to infect by nasal drops, whereas 0.6 to 3.0 TCID50 (i.e., a
100-fold lower dose) is infectious by the aerosol route.[86][87]
Once virus is deposited on the respiratory tract epithelium, it can attach to and
penetrate columnar epithelial cells if not prevented from doing so by specific
secretory antibody (IgA), by nonspecific mucoproteins to which virus may attach,
or by the mechanical action of the mucociliary apparatus. After adsorption, virus
replication begins, leading to cell death through several mechanisms. There is a
dramatic shutoff of host-cell protein synthesis that occurs at several levels. Newly
synthesized cellular mRNAs are degraded (probably because cleavage by the virus
cap endonuclease renders these transcripts susceptible to hydrolysis by cellular
nuclease),[88] whereas translation of already-synthesized cytoplasmic mRNAs is
blocked at both initiation and elongation.[89] Finally, expression of the influenza
virus PA protein has been shown to induce generalized degradation of coexpressed
proteins through an unknown mechanism.[90] Ultimately, the loss of critical cellular
proteins very likely contributes to cell death.
In addition to effects leading to cell necrosis, infection of cells with influenza A
and B viruses causes cell death by apoptosis,[91][92] a form of cell death
characterized by fragmentation of nuclear DNA. Bronchiolar epithelial and
alveolar cells harvested from experimentally infected mice also exhibit apoptotic
changes, suggesting that this mechanism of cell death may be important in the
pathogenesis of influenza in vivo.[93] The specific mechanism by which influenza
virus induces apoptosis is unclear, but it may be related to induction of Fas antigen
by double-stranded RNA during virus replication.[94] An unusual viral protein of
influenza A viruses, encoded by a second open reading frame in the PB1 gene and
therefore referred to as PB1-F2, also plays a role in induction of apoptosis by
poisoning mitochondria.[95]
Virus release continues for several hours before cell death ensues. Released virus
then may initiate infection in adjacent and nearby cells, so within a few replication
cycles, a large number of cells in the respiratory tract are releasing virus and dying
as a result of the virus replication. The time between the incubation period and the
onset of illness and virus shedding varies from 18 to 72 hours depending in part on
the inoculum dose.[84][96]
Influenza virus infection of peripheral blood mononuclear cells, including
polymorphonuclear leukocytes (PMNs), lymphocytes, and monocytes, is
nonproductive, but it is associated with measurable defects in cellular function that
may be relevant to the pathogenesis of influenza-related infectious complications.
These include defects in PML chemotaxis and phagocytosis[97] as well as decreased
proliferation and costimulation by mononuclear cells.[98][99] The effects are
mediated by virus replication and possibly by a direct toxic effect of certain virus
proteins, including hemagglutinin, neuraminidase,[100][101] and nucleoprotein.[102] It
has been noted that the short portion of the sequence of the influenza A virus NP is
homologous to a naturally occurring peptide found in normal bronchoalveolar
lavage fluid that inhibits PMN chemotaxis and oxidative burst.[103]
Virus Shedding
Quantitation of virus in respiratory tract specimens reveals a characteristic pattern (
Fig. 162–7 ). Virus is first detected just before the onset of illness (within 24
hours), rapidly rises to a peak of 3.0 to 7.0 log10 TCID50/mL, remains elevated for
24 to 48 hours, and then rapidly decreases to low titers.[84][104] Usually, virus is no
longer detectable after 5 to 10 days of virus shedding. However, because of the
relative lack of immunity in the young, more prolonged shedding of higher titers of
virus is seen in children.[105]
Figure 162-7 Time course of virus shedding, symptoms, and cytokine responses of healthy
adults after experimental inoculation with wild-type A/Texas/36/91 virus by nasal drops. A,
Mean log10 virus titer (tissue-culture infective dose [TCID50]/mL nasal secretions), clinical
symptom scores, and nasal mucus weights (in grams). B, Nasal cytokine levels measured by
enzyme-linked immunosorbent assay (ELISA) (pg/mL lavage fluid, corrected for collection
efficiency). In both graphs, multiple measurements have been combined for illustration, so
that the y-axes are relative values only. Peak values reported in each assay are approximately
as follows: virus titer, 3.6 log10 TCID50/mL nasal secretions; symptom score, 7.0; nasal mucus
weight, 7.0 g; interleukin (IL)-6, 450 pg/mL; interferon (IFN)-α, 150 pg/mL; tumor necrosis
factor (TNF)-α, 270 pg/mL; IL-8, 9000 pg/mL. (Data from Hayden FG, Fritz R, Lobo MC, et
al. Local and systemic cytokine responses during experimental human influenza A virus
infection: Relation to symptom formation and host defense. J Clin Invest. 1998;101:643–649.)
The severity of illness correlates temporally with quantities of virus shed in
experimental influenza in volunteers, thus suggesting that a major mechanism in
the production of illness is cell death resulting from viral replication.[84] Although
the clinical manifestations of influenza are dominated by systemic symptoms, viral
replication is limited to the respiratory tract. Instead, systemic symptoms are
probably due to the release of potent cytokines, such as type I interferons, tumor
necrosis factor, and interleukins (ILs), by infected cells and responding
lymphocytes.[104]
Histopathology
Bronchoscopy of individuals with typical, uncomplicated acute influenza has
revealed diffuse inflammation of the larynx, trachea, and bronchi, with mucosal
injection and edema.[106][107] Biopsy in these cases has revealed a range of
histologic findings, from vacuolization of columnar cells with cell loss, to
extensive desquamation of the ciliated columnar epithelium down to the basal layer
of cells ( Fig. 162–8 ).[107][108] Individual cells show shrinkage, pyknotic nuclei, and
a loss of cilia. Viral antigen can be demonstrated in epithelial cells[109] but is not
seen in the basal cell layer.[110] Generally, the tissue response becomes more
prominent as one moves distally in the airway.[107] Epithelial damage is
accompanied by cellular infiltrates primarily composed of lymphocytes and
histiocytes.[107] Histologic findings on autopsy in more severe cases show extensive
necrotizing tracheobronchitis, with ulceration and sloughing of the bronchial
mucosa,[108][111] extensive hemorrhage, hyaline membrane formation, and a paucity
of PMN infiltration ( Fig. 162–9 ). Patients with secondary bacterial pneumonia
have the changes characteristic of bacterial pneumonia in addition to the
tracheobronchial findings of influenza ( Fig. 162–10 ). Recovery is associated with
rapid regeneration of the epithelial cell layer and with pseudometaplasia.
Figure 162-8 A small bronchus in acute influenza A infection shows ulceration and
attempted regeneration of epithelium (H&E, ×100). (Courtesy of I. D. Stuard, Reading, Pa.)
Figure 162-9 Lung parenchyma in primary influenza viral pneumonia shows extensive
hemorrhage, acellular hyaline membrane lining alveolar ducts and alveoli, and a paucity of
inflammatory cells within the alveoli (H&E, ×400). (Courtesy of I. D. Stuard, Reading, Pa.)
Figure 162-10 Lung parenchyma in secondary bacterial infection (Streptococcus
pneumoniae) complicating influenza A virus infection. Note the marked intra-alveolar
polymorphonuclear cell exudate (H&E, ×400). (Courtesy of I. D. Stuard, Reading, Pa.)
Pathophysiology
Abnormalities of pulmonary function are frequently demonstrated in otherwise
healthy, nonasthmatic young adults with uncomplicated (nonpneumonic) acute
influenza. Demonstrated defects include diminished forced flow rates, increased
total pulmonary resistance, and decreased density-dependent forced flow rates
consistent with generalized increased resistance in airways less than 2 mm in
diameter,[112][113] as well as increased responses to bronchoprovocation.[112] In
addition, abnormalities of carbon monoxide diffusing capacity[114] and increases in
the alveolar-arterial oxygen gradient[115] have been seen. Of note, pulmonary
function defects can persist for weeks after clinical recovery. Influenza in
asthmatics[116] or in patients with chronic obstructive disease[117] may result in
acute declines in forced expiratory vital capacity (FVC) or forced expiratory
volume in 1 second (FEV1). Individuals with acute influenza may be more
susceptible to bronchoconstriction from air pollutants such as nitrates.[118]
Primary viral pneumonia is an uncommon but frequently severe complication of
acute influenza. In this situation, virus infection reaches the lung either by
contiguous spread from the upper respiratory tract or by inhalation. The trachea
and bronchi contain bloody fluid, and the mucosa is hyperemic.[119] Tracheitis,
bronchitis, and bronchiolitis are seen, with loss of normal ciliated epithelial cells.
Submucosal hyperemia, focal hemorrhage, edema, and cellular infiltrate are
present. The alveolar spaces contain varying numbers of neutrophils and
mononuclear cells admixed with fibrin and edema fluid. The alveolar capillaries
may be markedly hyperemic with intra-alveolar hemorrhage. Acellular hyaline
membranes line many of the alveolar ducts and alveoli.[119] Pathologic findings
seen by biopsy of lung in nonfatal cases are similar to those described in fatal
cases.[120]
Bacterial superinfection is a well-recognized complication of viral pneumonia and
accounts for a large proportion of the morbidity and mortality of viral lower
respiratory tract disease, especially in adults. Consequently, the spectrum of
disease and pathophysiology of bacterial superinfection has been studied
intensively, and a number of factors have been identified in viral respiratory
disease that could play a role in increasing the risk of bacterial infection.[121]
Uncomplicated influenza is associated with significant abnormalities in ciliary
clearance mechanisms.[122][123] In addition, increased adherence of bacteria to virusinfected epithelial cells has been demonstrated.[124][125] The disruption of the
normal epithelial cell barrier to infection, and loss of mucociliary clearance
undoubtedly enhance bacterial pathogenesis.[107][126] In addition, influenza infection
may upregulate certain cell surface receptors involved in bacterial adherence.[127]
Alterations in PMNs and mononuclear cells, described earlier, may also contribute
to enhanced bacterial infection.[98][128][129]
Viral Factors That Influence Pathogenicity
Clinical characteristics of illness during the 1918 influenza pandemic differed from
those of subsequent pandemics, with higher mortality rates in young adults. The
viral factors, if any, that might have been responsible for this behavior remain
unknown. Extensive analysis of genetic sequences recovered from preserved
specimens of material from victims of the pandemic have not revealed obvious
differences between the 1918 influenza virus and more conventional influenza
viruses, but investigations are continuing. Since that time, there has been little
direct evidence for major inherent differences in viral strains as regards to
pathogenic potential in humans. Instead, the severity of epidemics is most likely
determined largely by the status of immunity in the population. However, in
certain situations, individual viral proteins have been demonstrated to have a
significant impact on pathogenicity. This is particularly true for the HA and NS1
proteins.
An essential feature of influenza A virus replication is that proteolytic cleavage of
the HA is required to generate infectious virus, and this plays a role in the most
clear-cut demonstration of the role of an individual influenza virus protein in
pathogenicity. Infection of fowl with avian influenza viruses can result in a
relatively avirulent, asymptomatic infection limited to the respiratory and
gastrointestinal mucosa, or in a virulent, rapidly progressive, fatal systemic
infection with involvement of the brain and other visceral organs. Comparison of
the HAs of virulent and avirulent strains of H5 subtype and H7 subtype influenza
A viruses has shown that the structure of the HA cleavage site is critical in
determining the virulence phenotype in this model. Proteases capable of cleaving
the HA of avirulent viruses, such as tryptase Clara,[130] are restricted in distribution
to cells of the respiratory and gastrointestinal mucosa, thereby limiting replication
to these areas. However, addition of several basic amino acids to the cleavage
site,[131] coupled with the absence of a nearby glycosylation site,[132] renders the
hemagglutinin capable of being cleaved by ubiquitous cellular furin-like
proteases[133] and allows these viruses to escape the confines of the mucosa and
replicate systemically in chickens.[134]
As described previously, human infections with H5 and H7 viruses can be fatal,
and as it turns out, these viruses also have the highly cleavable form of
hemagglutinin. Although some of these viruses also have a high level of lethality
in mice, to date there has been no evidence of replication of these viruses outside
the respiratory tract in man. Thus, the potential role of HA cleavability in
pathogenesis in humans is currently unknown. Interestingly, evaluation of the
nucleotide sequence of the HA from the 1918 pandemic virus did not reveal this
virus to have the highly cleavable type of HA.[74]
Both influenza A and influenza B viruses use the NS1 protein as a mechanism to
circumvent the host type-I interferon response. The NS gene antagonizes the action
of type-I interferons through an unknown mechanism, and absence of the NS1
protein renders the virus incapable of growth in interferon-competent systems. The
NS gene of the H5 avian viruses appears to be especially potent in this regard, and
this may provide a partial explanation for its enhanced virulence in mice. Recent
reports have suggested that H5 viruses associated with fatal cases in humans have
changes in nucleotide sequences in the N51 gene that result both in increased
resistance to the action of interferon and in the ability to induce proinflammatory
cytokines.[135] In contrast, when the NS gene of the 1918 pandemic human virus
was placed in the background of an avirulent influenza virus and administered to
mice, more attenuated disease, rather than enhanced disease, was the result,
suggesting the effect is host specific.
Multiple additional animal models have been described in which it is possible to
generate influenza viruses with altered levels of pathogenicity. A variety of classic
genetic and molecular biologic techniques have been used to evaluate the role of
specific viral genes or gene products in determining the virulence of influenza
viruses in these models. An exhaustive review of these studies is beyond the scope
of this chapter, but they have generally shown that virulence is a multigenic trait
whose specific basis varies with the virus strains and the models
used.[136][137][138][139]
Immunology
Epidemiologic and experimental observations in humans have shown that infection
with influenza virus results in long-lived resistance to reinfection with the
homologous virus.[140] In addition, variable degrees of cross-protection within a
subtype have been observed, but infection induces essentially no protection across
subtypes,[141] or between types A and B. Infection induces both systemic and local
antibody, as well as cytotoxic T-cell responses, each of which plays a role in
recovery from infection and resistance to reinfection.
Antibody Responses
Systemic Antibody Responses.
Infection with influenza virus results in the development of antibody to the
influenza virus envelope glycoproteins HA and NA, as well as to the structural M
and NP proteins. Some individuals may develop antibody to the M2 protein as
well.[142] As measured by enzyme-linked immunosorbent assay (ELISA), serum
IgM, IgA, and IgG antibody to the HA appear simultaneously within 2 weeks of
inoculation of virus.[143] The antibody response is more rapid after reinfection. The
development of anti-NA antibodies parallels that of hemagglutinin-inhibiting
(HAI) antibodies.[144] However, whereas responses to the HA develop after primary
infection, responses to the NA appear to require previous infection.[141] Peak
antibody responses are seen at 4 to 7 weeks after infection and decline slowly
thereafter; titers can still be detected years after infection even without reexposure.
Antibody to the HA can be measured by standard HAI tests or a variety of
ELISAs, and it neutralizes virus infectivity.[145] Because of the cost and
requirement for cell cultures for the neutralizing test, the HAI test is the primary
method of detecting antigenic relatedness among hemagglutinins of influenza
viruses. Antihemagglutinin antibody protects against both disease and infection
with the homologous virus.[146] Although there is no exact correlation, serum HAI
titers of 1:40 or greater, or serum neutralizing titers of 1:8 or greater, are associated
with protection against infection; HAI titers of 1:20 or 1:10 are associated with
lesser degrees of protection. Higher levels of antibody may be required for
complete protection in older adults.[147][148]
Protection in clinical studies has been shown to be primarily strain specific, but
some degree of protection is present against strains showing antigenic drift within
a subtype, depending on the degree of drift.[149][150] For example, Foy and
colleagues showed that influenza A vaccine (A/Hong Kong/68/H3N2) induced
protection against the drift variant A/England/72/H3N2 virus that persisted for 3
years.[149] Generally, antibody that is present in low quantity, or that is primarily
directed against a heterologous strain of influenza, may only modify the severity of
illness and not prevent infection.
Antibody to the NA can be measured by NA inhibition or ELISA. In contrast to
anti-HA antibody, anti-NA antibody does not neutralize virus infectivity but
instead reduces efficient release of virus from infected cells, resulting in decreased
plaque size in in vitro assays[151] and in reductions in the magnitude of virus
shedding in infected animals.[152][153] Observations on the relative protection of
those with anti-N2 antibody during the A/Hong Kong/68 (H3N2) pandemic,[144][154]
as well as experimental challenge studies in humans,[155] have shown that anti-NA
antibody can be protective against disease and results in decreased virus shedding
and severity of illness, but that it is infection permissive.[156] Passive transfer
studies in mice have also suggested that antibody to the M2 protein of influenza A
viruses may have a similar effect to that of anti-NA antibody.[157]
Antibody to internal viral proteins such as M or NP can be measured by the
complement fixation (CF) test. These antibodies are cross-reactive among type A
viruses, but they are non-neutralizing and do not appear to play a role in protective
immunity. They disappear much more rapidly (in weeks to months) than do
neutralizing, HAI, or anti-NA antibodies, primarily because they are
predominantly IgM rather than IgG, and thus they may be useful for diagnosis of
recent infection.
Mucosal Antibody Responses.
The majority of studies of mucosal responses to influenza in humans have
concentrated on measurement of HA responses by ELISA or by neutralization
tests, because nonspecific inhibitors of hemagglutination present in nasal mucus
interfere with the standard HAI test. These studies have demonstrated significant
mucosal responses to infection with wild-type virus or live-attenuated influenza
vaccines. Both IgA and IgG are found in nasal secretions. Nasal HA-specific IgG
is predominantly IgG1, and its levels correlate well with serum levels of HAspecific IgG1, suggesting that nasal IgG originates by passive diffusion from the
systemic compartment.[158] Nasal HA-specific IgA is predominantly polymeric and
IgA1, suggesting local synthesis. Serum HA-specific IgA is also mostly polymeric
IgA1. The origin of serum IgA after mucosal infection is unclear but may derive
from seeding of peripheral lymphoid tissue by memory cells derived from the
mucosa.[146]
Studies in mice and ferrets have emphasized the importance of local IgA antibody
in resistance to infection, particularly in protection of the upper respiratory tract.
Polymeric IgA was shown to be specifically transported into the nasal secretions of
mice and to protect against nasal challenge. Protection could be abrogated by
intranasal administration of antiserum against IgA but not IgM or IgG.[159] Local
antibody has also been shown to play a role in protection against antigenic variants
in mice.[160] Studies in humans have also suggested that the resistance to
reinfection induced by virus infection is mediated predominantly by local HAspecific IgA, whereas that induced by parenteral immunization with inactivated
virus depends also on systemic IgG.[155][161] Almost all persons with nasal
neutralizing antibody titers of 1:4 or greater are protected against influenza.[162][163]
Importantly, either mucosal or systemic antibody alone can be protective if present
in high enough concentrations, and optimal protection occurs when both serum and
nasal antibodies are present.[164]
Cellular Responses
Antibody responses to the HA are T-cell dependent[165][166][167] and class II
restricted. CD4+ cells provide help (Th) to B cells for production of antibody to the
HA and NA. Both CD4+ cells that recognize epitopes on the HA molecule, and
CD4+ cells that recognize epitopes on M, NP, or PB2 may provide help for HA
antibody production.[168] The epitopes on HA recognized by Th cells are distinct
from those recognized by neutralizing antibody,[169] and they may be cross-reactive
within a subtype. Influenza-specific Th cells also promote the generation of virusspecific CD8+ cytotoxic T lymphocytes.[170][171]
Recently, it has been recognized that Th responses can be further classified as type
1 (Th1) or type 2 (Th2) responses on the basis of the profile of cytokines produced
on in vitro challenge. Influenza virus infection of mice generates a strong Th1-type
response.[172] Th2-type cytokines (IL-4, IL-5, IL-6, IL-10) have been also described
in the lungs of mice infected with influenza virus.[173][174] Circumstantial evidence
suggests that protective immune responses to influenza are associated with Th1like responses. Adoptive transfer of anti-influenza T-cell clones secreting cytokines
of the Th2 type fails to promote viral clearance,[175] and administration of
interferon-γ delays viral clearance and development of CTL in influenza virus–
infected mice.[176] Of note, blockade of gamma interferon by interferon antibody
does not affect development of CTL responses but results in reduced migration of
PMNs to the lung in the murine model.[177] In addition, administration of IL-4 to
infected mice promotes Th2-type responses and results in markedly delayed viral
clearance.[178]
Influenza virus–infected cells can be lysed by antibody in the presence of
complement, by antibody-dependent cellular cytotoxicity,[179] or by the action of
cytotoxic T (Tc) lymphocytes. Generally, Tc lymphocytes express CD8+ and
recognize class I HLA. Such cells may recognize either HA or internal proteins
such as M, NP, or PB2.[180] Therefore, Tc lymphocytes may be subtype specific or,
in the case of those that recognize internal proteins, may be broadly cross-reactive,
lysing cells infected with influenza A but not influenza B virus.[181][182] In addition,
class II restricted cells may exhibit cytotoxic activity similar to that shown by class
I restricted cells.[182]
Extensive adoptive transfer experiments have shown that virus-specific Tc
lymphocytes
can
mediate
recovery
from
influenza
virus
[183][184][185][186][187][188]
infection,
including both HA-specific and cross-reactive Tc.
However, studies in mice lacking major histocompatibility complex (MHC) class I
have shown that Tc lymphocytes are not absolutely required for
recovery.[189][190][191]
Tc lymphocyte responses to influenza also develop in humans after influenza virus
infections, generally peaking on about day 14 after infection.[192] Although not
studied extensively, the presence of virusspecific prechallenge, class I–restricted
Tc lymphocytes has been shown to correlate with reductions in the duration and
level of virus replication in adults with low levels of serum HA and NA antibody
who were challenged with influenza A virus.[193] The role of Tc lymphocytes
directed against internal viral proteins in protection against severe disease in
humans is unclear, as the internal virus proteins were shared between viruses
causing the pandemics of 1957 and 1968 and the viruses in circulation immediately
prior to these pandemics.[68][194] Memory Tc-lymphocyte responses may play a role
in ameliorating the severity of disease and speeding recovery after infection, as
suggested by the finding of more severe influenza in individuals with severe
defects in cell-mediated immunity.[28]
CLINICAL FINDINGS
Uncomplicated Influenza
Typical uncomplicated influenza often begins with an abrupt onset of symptoms
after an incubation period of 1 to 2 days. Many patients can pinpoint the hour of
onset.[84][195][196][197] Initially, systemic symptoms predominate, including
feverishness, chilliness or frank shaking chills, headaches, myalgia, malaise, and
anorexia. In more severe cases, prostration is observed. Usually, myalgia or
headache is the most troublesome symptom, and the severity is related to the
height of the fever. Myalgia may involve the extremities or the long muscles of the
back. In children, calf muscle myalgia may be particularly prominent. Severe pain
in the eye muscles can be elicited by gazing laterally, and arthralgia but not frank
arthritis is commonly observed. Other ocular symptoms include tearing and
burning. The systemic symptoms usually persist for 3 days, the typical duration of
fever. Respiratory symptoms, particularly a dry cough, severe pharyngeal pain, and
nasal obstruction and discharge, are usually also present at the onset of illness but
are overshadowed by the systemic symptoms. The predominance of systemic
symptoms is a major feature distinguishing influenza from other viral upper
respiratory infections. Hoarseness and a dry or sore throat may also be present, but
these symptoms tend to appear as systemic symptoms diminish, and thus they
become more prominent as the disease progresses, persisting 3 to 4 days after the
fever subsides. Cough is the most frequent and troublesome of these symptoms and
may be accompanied by substernal discomfort or burning. Older adults may simply
present with high fever, lassitude, and confusion without the characteristic
respiratory complaints, which may not occur at all. In addition, there is a wide
range of symptomatology in healthy adults, ranging from classic influenza to mild
illness or asymptomatic infection.
Fever is the most important physical finding. The temperature usually rises rapidly
to a peak of 100° to 104° F, and occasionally to 106° F, within 12 hours of onset,
concurrent with the development of systemic symptoms. Fever is usually
continuous but may be intermittent, especially if antipyretics are administered. On
the second and third days of illness, the temperature elevation is usually 0.5° to
1.0° F lower than on the first day, and as the fever subsides, the systemic
symptoms diminish. Typically, the duration of fever is 3 days, but it may last 4 to 8
days. In a small number of cases, a second fever spike occurs on the third or fourth
day and results in a biphasic fever curve.
Early in the course of illness, the patient appears toxic, the face is flushed, and the
skin is hot and moist. The eyes are watery and reddened. A clear nasal discharge is
common, but nasal obstruction is uncommon. The mucous membranes of the nose
and throat are hyperemic, but exudate is not observed. Small, tender cervical
lymph nodes are often present. Transient scattered rhonchi or localized areas of
rales are found in less than 20% of cases. A convalescent period of 1, 2, or more
weeks to full recovery then ensues. Cough, lassitude, and malaise are the most
frequent symptoms during this period.
Available data suggest that illness associated with influenza B virus infection
closely resembles that described for influenza A, although some have suggested
that influenza B illness may be somewhat milder than influenza A illness.[198][199]
In contrast, influenza C infection, when it occurs, causes afebrile common colds
and rarely, if ever, produces the influenza syndrome.[200] It does not occur in
epidemics.
At the extremes of age, there are prominent differences in influenza. Influenza
attack rates are higher in children than in adults.[23][201] Maximal temperatures tend
to be higher among children, and cervical adenopathy is more frequent among
children than among adults.[96] Croup associated with influenza virus infection
occurs only among children.[202][203][204] Among older adults, fever remains a very
frequent finding, although the height of the febrile response may be lower than
among children and young adults. Pulmonary complications are far more frequent
in older adults than in any other age group.
Complications of Influenza
Pulmonary Complications
Two manifestations of pneumonia associated with influenza are well recognized:
primary influenza viral pneumonia and secondary bacterial infection. In addition,
less distinct and milder pulmonic syndromes often occur during an outbreak of
influenza that may represent tracheobronchitis, localized viral pneumonia, or
possibly mixed viral and bacterial pneumonia. Comparative features of these
clinical syndromes are shown in Table 162–4 . Studies to determine the interaction
between virus and bacteria have helped researchers understand the different
clinical patterns described here.[205]
Table 162-4 -- Comparative Features of Pulmonary Complications of Influenza
Secondary
Mixed Viral and Localized
Primary
Viral
Bacterial
Bacterial
Viral
Pneumonia
Pneumonia
Pneumonia
Pneumonia
Setting
Cardiovascular
disease;
Age
>65
yr; Any
associated
pregnancy;
?Normal
pulmonary disease with A or B
young
adult
(Hsw1N1)
Clinical
history
Relentless
progression from
classic
3-day
influenza
Improvement,
then
worsening
after
3-day
influenza
Features of both
Continuation
primary
and
of classic 3secondary
day syndrome
pneumonia
Bilateral
Physical
findings,
no Consolidation
examination
consolidation
Consolidation
Area of rales
Sputum
Pneumococcus,
Normal flora
Normal flora
Pneumococcus,
Secondary
Primary
Viral
Bacterial
Pneumonia
Pneumonia
bacteriology
Chest
radiography
Staphylococcus,
Haemophilus
influenzae
Bilateral findings Consolidation
Mixed Viral and Localized
Bacterial
Viral
Pneumonia
Pneumonia
Staphylococcus,
H. influenzae
Consolidation
Segmental
infiltrate
Leukocytosis
White blood
Leukocytosis with Leukocytosis with Usually
with a shift to the
cell count
a shift to the left a shift to the left normal
left
Isolation of
influenza
Yes
virus
No
Yes
Yes
Response to
No
antibiotics
Yes
Often
No
Mortality
Low
Variable
Very low
High
Primary Influenza Viral Pneumonia.
The syndrome of primary influenza viral pneumonia was first well documented in
the 1957–1958 outbreak.[106][119] However, it is clear that many deaths of young
healthy adults in the 1918–1919 outbreak were the result of this syndrome. In
outbreaks since 1918, primary influenza viral pneumonia has occurred
predominantly among persons with cardiovascular disease, especially rheumatic
heart disease with mitral stenosis, and to a lesser extent in others with chronic
cardiovascular and pulmonary disorders. The illness begins with a typical onset of
influenza, followed by a rapid progression of fever, cough, dyspnea, and cyanosis.
Physical examination and chest radiographs reveal bilateral findings consistent
with the adult respiratory disease syndrome but no consolidation. Blood gas studies
show marked hypoxia, Gram stain of the sputum fails to reveal significant bacteria,
and bacterial culture yields sparse growth of normal flora, whereas viral cultures
yield high titers of influenza A virus. Such patients do not respond to antibiotics
and mortality is high. At autopsy, findings consist of tracheitis, bronchitis, diffuse
hemorrhagic pneumonia, hyaline membranes lining alveolar ducts and alveoli, and
a paucity of inflammatory cells within the alveoli (see Figs. 162–9 and 162–10 ).
At the present time, late in the interpandemic era, severe primary influenza viral
pneumonia is rare.
Secondary Bacterial Pneumonia.
Secondary bacterial pneumonia often produces a syndrome that is clinically
indistinguishable from that occurring in the absence of influenza.[206][207] The
patients (most often older adults or those with chronic pulmonary, cardiac, and
metabolic or other disease) have a classic influenza illness followed by a period of
improvement lasting usually 4 to 14 days. Recrudescence of fever is associated
with symptoms and signs of bacterial pneumonia such as cough, sputum
production, and an area of consolidation detected on physical examination and a
chest radiograph. Gram staining and culture of sputum reveal a predominance of a
bacterial pathogen, most often Streptococcus pneumoniae or Haemophilus
influenzae, and, notably, an increased frequency of Staphylococcus aureus, which
is otherwise an uncommon cause of community-acquired pneumonia. Such
patients usually respond to specific antibiotic therapy. Analysis of different
radiographic patterns of pneumonia indicates that a variety of abnormalities can
occur in all ages.[208][209]
During an outbreak of influenza, many patients do not clearly fit into either of the
aforementioned categories.[210] The disease is not relentlessly progressive, and yet
the fever pattern may not be biphasic. These patients may have primary viral,
secondary bacterial, or mixed viral and bacterial infection of the lung. In more
recent epidemics, in which surveillance cultures of hospitalized patients have been
carried out, most patients with pneumonia and influenza presented early, while
they were still culture positive for influenza virus. Most responded to antibiotics
without the use of antivirals. In addition, milder forms of influenza viral
pneumonia involving only one lobe or segment have been described that do not
invariably lead to death, and that are more likely to be confused with pneumonia
caused by Mycoplasma pneumoniae than to pneumonia produced by bacterial
infection.
In children, pneumonia may occur, but it is less common than in adults. Bronchitis
may also occur as a result of influenza A or B virus infection, but respiratory
syncytial virus and parainfluenza virus type 3 are more important causes of
bronchiolitis.
Pulmonary Complications in Immunosuppressed Patients.
In patients with HIV infection, influenza has not been recognized as a major
clinical problem, although disease of greater severity has been noted in some
patients[211] and pneumonic complications of influenza have occurred. Additional
studies are required to better define the importance of influenza virus infection in
HIV-infected patients.
Influenza has been noted to cause severe disease with an increased incidence of
pneumonia in immunosuppressed children with cancer compared with agematched individuals without immunosuppression.[212] Severe disease associated
with pneumonia and death has been reported, particularly in bone marrow
transplant recipients and leukemic patients.[28][213][214] Relatively more
immunosuppressed individuals early after transplantation appear to be at greater
risk.[214] However, for reasons that are not completely clear, influenza has not
appeared to be quite the problem in this population that other respiratory viruses,
particularly paramyxoviruses, are. Influenza virus shedding can be quite prolonged
in immunosuppressed children,[215] particularly those with HIV and low CD4+
counts.[216] Because of the prolonged, unchecked replication of influenza viruses in
these individuals, resistance to antiviral drugs eventually occurs in many treated
patients.[215][217]
Other Pulmonary Complications.
In addition to pneumonia, other pulmonary complications of influenza have been
recognized.
Croup.
Significant numbers of cases of croup occur in influenza A and B
outbreaks.[202][203] Croup associated with influenza A virus appears to be more
severe but less frequent than that associated with parainfluenza virus types 1 or 3
or respiratory syncytial virus infections (see Chapters 153 and 155 ).
Exacerbation of Chronic Pulmonary Disease.
Acute exacerbation of chronic bronchitis, a phenomenon that is associated with
other respiratory disease–causing viruses and bacteria,[218][219][220] is common.
Studies by Monto and Ross have shown that such infections result in a permanent
loss of pulmonary function.[221] Another major illness that is exacerbated is asthma.
Often, stable asthmatics will worsen to status asthmaticus as a result of
influenza.[222][223] Another illness exacerbated by influenza is cystic fibrosis. In
children afflicted with this entity, influenza infections may lead to severe
complications.[224]
Frequency of Pulmonary Involvement.
The findings of persistent physiologic changes in the lower respiratory tract with
uncomplicated influenza discussed earlier suggest that viral invasion of the lower
respiratory tract is common in uncomplicated influenza and may help to explain
the relatively long convalescence. The frequency of overt involvement of the
respiratory tract has been answered in part by Fry.[208][209][225] In five successive
epidemics, he showed that the overall rate of chest complications
(tracheobronchitis or pneumonia) was 9.5% of cases. From the ages of 5 to 50, the
rate was low (4% to 8%), but it increased progressively after the age of 60,
reaching a level of 73% in those over 70 years of age. Foy et al. studied seven
successive epidemics of influenza A infection and showed that six of the seven
were associated with at least a doubling of pneumonia rates among adults.[226] Still
others have studied rates of admission to the hospital and have shown a lower
impact on hospitalization.[226][227][228]
Nonpulmonary Complications
Most of the complications of influenza have been evaluated in years when there
were sizable outbreaks.[119][229][230][231] However, as antigenic variation of a subtype
evolves and as the exposure of the population to vaccine and to virus occurs, the
full-blown influenza syndrome becomes a less frequent manifestation.
Nonetheless, infection rates may remain high, and consequences of infection in
severely compromised older adult patients remain significant.
Myositis.
Myositis and myoglobinuria with tender leg muscles and elevated serum creatine
phosphokinase (CPK) levels have been reported, mostly in children after influenza
A or B infection, most commonly after the latter,[232][233][234][235] but they can occur
in adults as well. Symptoms may be sufficiently severe to interfere with walking,
but neurologic changes are not evident.
Cardiac Complications.
Both myocarditis and pericarditis have been rarely associated with influenza A or
B virus infection.[236] Some investigators have associated influenza with
myocardial infarction. However, neither myocarditis nor pericarditis is commonly
observed at autopsy among those who died of primary influenza viral
pneumonia.[119] In patients with cardiac disease, the acquisition of influenza
provides a significant risk of death.[230][237][238]
Toxic Shock Syndrome.
In recent outbreaks of influenza A or B, a toxic shock–like syndrome has occurred
in previously healthy children or adults, presumably because viral infection
changed colonization and replication characteristics of the toxin-producing
staphylococcus.[239][240]
Central Nervous Complications.
Guillain-Barré syndrome has been reported to occur after influenza A infection, as
it has after numerous other infections, but no definite etiologic relationship has
been established. In addition, cases of transverse myelitis and encephalitis have
occurred rarely.[241][242] An etiologic association of these syndromes with influenza
virus infection has only infrequently been proven, and influenza infection accounts
at most for only a small proportion of cases of each of these symptoms. Early
reports of deaths associated with influenza A infection in children and young
adults during the 2003–2004 season, have implicated encephalitis as a prominent
feature.[243]
Reye’s Syndrome.
Reye’s syndrome is associated with many viral infections, prominently including
influenza and varicella in children. The classic manifestation is a change in mental
status occurring several days after a typical respiratory illness. Manifestations
range from lethargy to delirium, obtundation, seizures, and respiratory arrest.
Lumbar puncture reveals normal protein values and normal cell counts, confirming
the presence of encephalopathy rather than encephalitis or meningoencephalitis.
The most frequent laboratory abnormality is elevation of the blood ammonia value,
which occurs in almost all patients. Reye’s syndrome is almost exclusively seen in
children who have been given aspirin to treat febrile illnesses due to influenza and
other viruses, and it is important to use other antipyretics such as nonsteroidal antiinflammatory drugs in this situation. Children who require continuous aspirin
therapy are an important target group for influenza vaccination to reduce the risks
of Reye’s syndrome.
DIAGNOSIS
Virus Isolation
Virus isolation or detection of viral antigen in respiratory secretions is the
technique of greatest utility in the setting of acute illness. Virus can be isolated
readily from nasal swab specimens, throat swab specimens, nasal washes, or
combined nose and throat swab specimens. The general consensus is that throat
swab alone is probably less sensitive for detection than other samples. Virus can
also be isolated from sputum samples, if these are being produced.[244] Samples
should be placed into containers of viral transport medium and transported to the
laboratory as soon as possible, although the virus survives overnight if the
specimen is kept on ice. Specimens for influenza are inoculated onto rhesus
monkey kidney, cynomolgus monkey kidney, or Madin-Darby canine kidney cell
cultures, where virus is detected by cytopathic effect or hemadsorption. Less
commonly, embryonated eggs can be used for virus isolation. Over 90% of
positive cultures can be detected within 3 days of inoculation[245] and the remainder
by 5 to 7 days.
Rapid Diagnosis
A variety of techniques have been employed to speed the process. The most widely
used tests are based on immunologic detection of viral antigen in respiratory
secretions. For influenza, such tests include the Directigen Flu A+B (BectonDickenson), Flu OIA (BioStar), and QuickVue Influenza A+B test (Quidel
Corporation). In each of these tests, a sample of respiratory secretions is treated
with a mucolytic agent and then tested, either on a filter paper (Directigen), in an
optical device (Flu OIA), or with a dipstick (QuickVue) in which reaction with
specific antibody results in a color change. In a slight variation of this strategy, the
ZstatFlu (ZymeTx) test detects the presence of viral neuraminidase activity in the
sample using a chromogenic substrate; this test is based on the same chemistry
used to develop neuraminidase inhibitors. All of the tests are designed to detect
both influenza A and influenza B, are relatively simple to perform, and can provide
results within 30 minutes. Currently, both the QuickVue and Zstat tests are eligible
for Clinical Laboratory Improvement Amendment of 1998 (CLIA) waiver.
Additional tests are in development, and updated information is available at
http://www.cdc.gov/flu/professionals/labdiagnosis.htm .
The reported sensitivities of each test in comparison to cell culture have ranged
between 40% and 80%, and they are somewhat dependent on the nature of the
samples
tested
and
the
patients
from
whom
they
were
derived.[246][247][248][249][250][251] In general, sensitivities in adults and older adult
patients tend to be lower than those reported in young children, who shed much
larger quantities of virus in nasal secretions and therefore have much higher
concentrations of antigen in their samples.[252] Similarly, sensitivity is likely to be
higher early in the course of illness, when viral shedding is maximal. The
sensitivity of some tests for detection of influenza B viruses may be lower than that
for influenza A viruses.[247][251] Reported specificities have ranged from 85% to
100%. It is important to note in this regard that in each of these studies, a portion
of samples that are negative by culture and positive by rapid test are confirmed as
positive by PCR (see later).[245] Although all types of respiratory samples can be
used in such tests, the sensitivity appears to be better with nasopharyngeal swabs
and aspirates than with throat swabs or gargles.[246][253] As no published
comparative data are currently available that conclusively demonstrate superiority
of one test over another, decisions regarding a specific test are generally made on
the basis of convenience, cost, and the familiarity of the operator with the
technique. In most medical centers, the cost is approximately $20 per diagnostic
test.
A variety of approaches to direct detection of viral nucleic acids in clinical
specimens have also been explored for rapid diagnosis, including nucleic acid
hybridization and PCR amplification. PCR in particular has the advantage of being
potentially more sensitive than cell culture, and it may allow detection of virus in
samples in which the virions have lost viability. In addition, it is possible to devise
multiplex techniques so that a single test can detect a number of different
agents.[254] However, as PCR techniques are more labor intensive and technically
demanding, and they require specialized laboratory equipment, they generally have
not supplanted antigen detection for rapid diagnosis.
Serology
Serologic tests, such as complement fixation and hemagglutination inhibition, can
be used to retrospectively establish a diagnosis of influenza infection. Because
most individuals have been previously infected with influenza viruses, a single
serum is generally not adequate, and paired serum specimens, consisting of an
acute and a convalescent sera obtained 10 to 20 days later, should be submitted for
testing.
Epidemiologic Diagnosis
A diagnosis can also be made on epidemiologic grounds. That is, when the
presence of influenza virus is confirmed in a region or community, healthy adults
with acute influenza-like illness most commonly have influenza. In fact, several
studies have shown that the accuracy of a clinical diagnosis in healthy adults in the
setting of an influenza outbreak is as high as 80% to 90%.[255][256][257] In an analysis
of symptoms in young adults being assessed for entry into studies of influenza
virus treatment, the best multivariate predictors of laboratory-confirmed influenza
virus infection were cough and fever,[256] with an increasing predictive value with
increasing levels of fever. However, the predictive value of such a symptom
complex may be less in older adults[258] and in children.[259] In nursing homes, the
presence of cocirculating pathogens (such as respiratory syncytial virus) that can
result in identical symptoms can clearly complicate the ability to make a clinical
diagnosis of influenza specifically.[260][261]
Role of Rapid Diagnosis in Clinical Decision Making
The optimal use of rapid diagnostic tests in patient management is yet to be
defined. Such tests are most clearly useful in the rapid identification of outbreaks
within institutions or in the community, where the testing of multiple specimens
can compensate for the relative lack of sensitivity of the test for any single
specimen. The utility of rapid testing in other situations depends on a number of
factors beyond the specific performance of the test, including the extent of
influenza epidemic activity (i.e., the a priori likelihood of infection) and the
potential consequences of a positive or negative result.
TREATMENT
Uncomplicated Influenza
Four antiviral drugs are currently available for the prevention and treatment of
influenza. A comparison of the basic pharmacology and antiviral activity of these
agents is given in Table 162–5 , and they are described in detail later. Certain
general principles apply regardless of the specific form of therapy chosen. It is
important to recognize that individuals with an intact immune system who have
had previous influenza infections rapidly limit the replication of these viruses.
Therefore, the opportunity to impact viral replication with antiviral agents is
limited, and effective use of these agents requires early initiation of therapy. No
studies have ever demonstrated a benefit of antiviral therapy begun after 48 hours
or more of symptoms, and the greatest effect is typically seen when therapy is
started in the first 24 hours. The question of whether delayed therapy may be
useful in selected populations, such as immunosuppressed individuals, remains
unanswered.
Table 162-5 -- Antiviral Agents for Influenza
Amantadine
Rimantadine Zanamivir
Oseltamivir
Protein target
M2
M2
Neuraminidase
Neuraminidase
Activity
A only
A only
A and B
A and B
Side effects
CNS (13%)
GI (6%)
?Bronchospasm
GI (9%)
GI (3%)
GI (3%)
Metabolism
None
Multiple
(hepatic)
None
Hepatic
Excretion
Renal
Renal
others
Renal
Renal (tubular
secretion)
Drug interactions
Antihistamines,
None
anticholinergics
None
Probenecid
(increased levels
of oseltamivir)
None
CrCl
<
mL/min
Dose adjustments
≥65 yr old
needed
CrCl
<
mL/min
Contraindications
Acute-angle
glaucoma
+
≥65 yr old
50 CrCl < 10
mL/min
30
Severe
liver
dysfunction
Severe liver Underlying
dysfunction airways disease
FDA Approved Indications
Therapy
Prophylaxis
Adults
and
children ≥ year Adults only
of age
Yes
Yes
Adults
and Adults
and
children ≥ 7 children ≥ 1
years of age
year of age
No
Adults
and
children ≥ 13
years of age
CNS, central nervous system; CrCl, creatinine clearance; FDA, U.S. Food and Drug
Administration; GI, gastrointestinal.
M2 Inhibitors: Amantadine and Rimantadine
Mechanism of Action and Activity
The M2 inhibitors amantadine and rimantadine are related primary symmetrical
amines and are active against all strains of influenza A virus in a variety of cell
culture systems and animal models.[262] In cell culture, inhibitory levels for
influenza A virus range from 0.2 to 0.4 μg/mL for amantadine, and from 0.1 to 0.4
μg/mL for rimantadine.[263]
The antiviral activity of these drugs is the result of inhibition of the M2 ion channel
activity of susceptible viruses. The function of the M2 ion channel in viral
replication is to acidify the interior of the virion, disrupting the interaction between
the matrix and nucleoproteins, and allowing the ribonucleoproteins to be
transported to the nucleus, where replication occurs.[264] Thus, the antiviral effect is
primarily manifested in cell culture as inhibition of virus uncoating.[265][266] Similar
ion channels have been described for influenza B and C viruses; however, at
clinically achievable levels, these drugs are active against only influenza A.
Pharmacology and Side Effects
Although the mechanism of action and spectrum of activity for amantadine are
similar to those for rimantadine, there are important pharmacokinetic differences
between the two drugs.[267] Amantadine does not undergo metabolic change and is
excreted unchanged in the urine with a half-life of 12 to 18 hours. This leads to
rapid accumulation of amantadine in two settings: in patients with renal failure and
in older adults with reduced renal function because of age. In older adults, it is
recommended that the dosage of amantadine be reduced to no more than 100 mg
daily and perhaps even to 100 mg every other day after the first few days, although
extensive evidence of the efficacy for these lower doses is not available. By
contrast, rimantadine undergoes extensive metabolism. Less than 15% of the drug
is excreted in the urine unchanged, and the remainder is excreted as metabolic
products.[268] A dosage reduction to a maximum of 100 mg/day in older adults is
also recommended for rimantadine.
The most common side effects of amantadine are minor and reversible central
nervous system (CNS) side effects such as insomnia, dizziness, and difficulty in
concentrating.[269][270][271] These side effects may be more troublesome in older
adults, in whom confusion is noted in about 18% of recipients.[272] In addition,
amantadine use has been associated with seizures in individuals with prior seizure
disorder.[273] Minor gastrointestinal complaints have also been reported. The CNS
effects of amantadine are increased when these drugs are co-administered with
anticholinergics or antihistamines. In addition, trimethoprim-sulfamethoxazole
may inhibit tubular secretion of amantadine and increase the potential for CNS
toxicity.[274] There are no other known significant drug interactions with
amantadine. However, co-administration of amantadine with drugs known to have
CNS side effects may exacerbate those effects and thus should be avoided.
Rimantadine is associated with a considerably reduced rate of CNS side effects,
and in comparative studies of long-term administration, the rate of CNS side
effects was not significantly different from the rate with placebo.[271] There are no
known drug interactions that significantly affect the levels or metabolism of
rimantadine.
Efficacy
Both amantadine and rimantadine are effective in the therapy of experimentally
induced and naturally occurring influenza A. Amantadine treatment of H3N2
influenza A during the 1968 pandemic within the first 48 hours of illness was
associated with decreases in the duration of fever by about 24 hours[275] and with a
greater proportion of subjects considered to be “rapid resolvers.”[276][277] In
addition, treated individuals had more rapid decreases in individual symptoms of
cough, sore throat, and nasal obstruction.[278] Treatment with amantadine results in
significantly more rapid improvement in small airways dysfunction in healthy
adults with uncomplicated H3N2 influenza.[112][270]
Additional trials of amantadine therapy were performed when H1N1 viruses
reappeared in the late 1970s, with similar results. Early amantadine therapy of
influenza A/USSR/77 in otherwise healthy adults was shown to result in a more
rapid decrease in fever, and in a higher frequency of subjects reporting improved
symptoms at 48 hours compared with placebo.[269] In addition, treated subjects
were less likely to shed virus at 48 hours. In a second study conducted in young
adults infected with A/Brazil/78, amantadine therapy was associated with a more
rapid decrease in symptoms compared with aspirin therapy,[279] and with decreased
virus shedding.
Studies of rimantadine therapy of acute influenza in otherwise healthy adults with
uncomplicated influenza have shown levels of benefit essentially identical to those
seen with amantadine. Treatment of adults with H1N1[269] and H3N2[280] influenza
A resulted in improved symptoms, decreased fever, and reduced virus shedding
compared with placebo. When rimantadine and amantadine were directly
compared in a randomized trial,[269] the efficacies of the two drugs were essentially
identical.
Neither amantadine nor rimantadine has been subjected to extensive efficacy
evaluation in high-risk subjects. One placebo-controlled study carried out with
nursing home residents showed more rapid reduction in fever and in symptoms in
rimantadine recipients. Furthermore, physicians who were caring for these patients,
but who were blinded to study drug status, prescribed significantly fewer
antipyretics, antitussives, and antibiotics and obtained fewer chest radiographs for
the rimantadine recipients.[281]
Rimantadine has also been evaluated in the treatment of influenza A in children,
and shown to reduce the level of virus shedding early in infection when compared
with acetaminophen.[282][283] More variable effects on clinical symptom scores have
been seen, with one study showing a decrease in scores and fever compared with
acetaminophen,[282] and the other, in which illness was relatively mild, showing no
significant difference.[283] However, rimantadine is not currently licensed for
treatment of children in the United States.
Drug Resistance
Drug resistance has been a factor in limiting the more widespread use of these
antiviral agents.[284] Although resistant viruses are seen in less than 1% of
unexposed individuals,[285][286] they emerge fairly frequently in treated
individuals,[287][288] particularly children.[282] Resistance is the result of single point
mutations in the membrane-spanning region of the M2 protein, and it confers
complete cross-resistance between amantadine and rimantadine.[289] Resistant virus
can be transmitted to, and can cause disease in, susceptible contacts.[287][288][290]
Prolonged shedding of resistant viruses may occur in immunocompromised
patients, particularly children, and may continue even after therapy is
terminated,[291] consistent with the relative fitness of these resistant viruses.
Although vaccination combined with amantadine treatment can decrease the
generation and transmission of resistant viruses,[292][293] the problem of drug
resistance remains an important consideration and has limited enthusiasm for more
widespread use of these agents.
Neuraminidase Inhibitors: Zanamivir and Oseltamivir
Knowledge of the crystal structure of neuraminidase complexed with its substrate,
sialic acid,[294] has allowed the development of a series of sialic acid analogues
with neuraminidase-inhibiting activity.[295]
Mechanism of Action and Activity
The neuraminidase inhibitors act by inhibiting the functioning of the influenza
virus neuraminidase. This enzyme cleaves terminal sialic acid from sialic acid–
containing glycoproteins that serve as host cell receptors for attachment of
influenza viruses. As virus replication proceeds within the cell, neuraminidase is
synthesized and transported to the cell surface, where it removes the sialic acid
from these cell surface glycoproteins. Destruction of these receptors by
neuraminidase is critical in allowing newly formed viruses to subsequently egress
from the cell and spread to other cells. Studies with mutant, neuraminidasedeficient viruses have shown that in the absence of a functional neuraminidase,
virus remains attached to the host cell and to other virions.[296][297] In addition,
neuraminidase may be important in facilitating the penetration of virus through
secretions in the respiratory tract, which are rich in sialic acid–containing
macromolecules.[64]
Neuraminidase inhibitors are active against influenza viruses at millimolar
concentrations or less. Activity against clinical isolates assessed in plaque
inhibition tests ranges from concentrations of 0.01 to 16 μM. Influenza B viruses
are approximately 10-fold less sensitive than influenza A viruses, but they are still
sensitive well within clinically achievable concentrations. Among the influenza
viruses sensitive to neuraminidase inhibitors are avian viruses with all nine known
neuraminidase subtypes.
Pharmacology and Side Effects
Although zanamivir and oseltamivir have identical mechanisms of action and
similar profiles of antiviral activity, they have different pharmacologic properties.
Zanamivir (4-guanidino-Neu5Ac2en) is a polar molecule that is not orally
bioavailable. Therefore, effective use of this agent requires local administration.
The drug is currently supplied as a dry powder for oral inhalation, using the
Diskhaler device (GlaxoSmithKline) also used commonly for a variety of asthmarelated medications. Oseltamivir carboxylate is an orally bioavailable ethyl ester
prodrug of oseltamivir phosphate, a carbocyclic transition-state–based inhibitor of
the influenza virus neuraminidase.[298]
Oseltamivir is rapidly absorbed from the gastrointestinal tract and is converted in
the liver by hepatic esterases to the active metabolite, oseltamivir carboxylate. The
metabolite is excreted unchanged in the urine by tubular secretion, with a serum
half life of 6 to 10 hours. Administration of the drug with food may improve
tolerability without impacting drug levels. Zanamivir is not bioavailable by the oral
route and must be administered topically to be effective. The drug is supplied in
blister packs in which each blister contains 5 mg of zanamivir and 20 mg of lactose
carrier. The standard dose is therefore two inhalations twice a day. It is estimated
that approximately 4 mg of drug is actually delivered with each inhalation.
Intravenous dosing of zanamivir has also been studied, although this formulation is
not currently available for clinical use. In one small study, an intravenous dose of
600 mg twice daily was well tolerated and was effective in preventing
experimental infection of adults with influenza A (H1N1) virus.[299]
Both drugs have been well tolerated in clinical trials. The major adverse effects
reported for oseltamivir have been gastrointestinal upset, probably irritation due to
rapid release of the drug in the stomach. Rates of nausea can be substantially
reduced if the drug is taken with food. The most commonly reported adverse
effects in individuals treated with zanamivir have been diarrhea, nausea, and nasal
signs and symptoms, which have occurred at essentially the same rate as in placebo
recipients. In one study in which zanamivir was used in influenza-infected patients
with asthma or chronic obstructive pulmonary disease, the frequency of significant
changes in FEV1 or peak flow rates was higher in zanamivir than in placebo
recipients. For this reason, individuals with these pulmonary conditions should
have ready access to a rapidly acting bronchodilator when using zanamivir, in the
event that the drug precipitates bronchospasm.
The dose of oseltamivir should be reduced to 75 mg once daily in individuals with
renal impairment (i.e., with creatinine clearance of less than 30 mL/min). No data
are available regarding the use of the drug in individuals with more significant
levels of renal impairment. Likewise, no information is available regarding the use
of oseltamivir in individuals with hepatic impairment. Clinically significant drug
interactions have not been reported. Because oseltamivir is eliminated by tubular
secretion, probenecid increases serum levels of the active metabolite approximately
twofold. However, dosage adjustments are not necessary in individuals taking
probenecid. Co-administration of cimetidine, amoxicillin, or acetaminophen has no
effect on serum levels of oseltamivir or oseltamivir carboxylate.[300]
Although significant increases in the serum half-life of zanamivir are seen in the
presence of renal failure, the small amounts of the drug that are absorbed
systemically suggest that dosage adjustments would not be necessary. Studies of
the pharmacokinetics of the drug in the presence of impaired hepatic function have
not been reported.
Efficacy
Zanamivir and oseltamivir, the two available neuraminidase inhibitors, have shown
very similar results in clinical trials. Both drugs were initially evaluated in the
human experimental challenge model. Studies in which oseltamivir was
administered 28 hours after experimental infection showed reductions in viral
shedding, reduced symptom scores, and decreased frequencies of middle ear
abnormalities compared with placebo.[301] Zanamivir given by drops or spray as
late as 50 hours after infection also demonstrated reduced viral shedding, symptom
scores, nasal mucus weights, and middle ear abnormalities.[302][303] Similar effects
were seen with oseltamivir in adults experimentally infected with influenza B
virus.[304]
In studies of naturally occurring, uncomplicated influenza in healthy adults,
therapy with oseltamivir initiated within the first 36 hours of symptoms resulted in
30% to 40% reductions in the duration of symptoms and severity of illness and
reduced rates of prolonged coughing.[305][306] In addition, early therapy is
associated with a significantly earlier return to work or other normal activities.
Similarly, in healthy adults, early therapy of uncomplicated influenza A or B with
inhaled zanamivir has been shown to result in a reduction of approximately 0.8 to
1.5 days in the duration of influenza symptoms, and an earlier return to normal
activities.[307][308] Early treatment of healthy adults with zanamivir may also reduce
the frequency of complications, with reductions in the use of antibacterials and in
hospitalization.[309]
Both oseltamivir and zanamivir have been evaluated as therapy for children, but
only oseltamivir is currently licensed for pediatric use. Administration of
oseltamivir liquid at a dose of 2 mg/kg per dose twice daily for 5 days was well
tolerated and resulted in a 36-hour reduction in the duration of symptoms in
children with influenza A.[310] In addition, the use of oseltamivir was associated
with a 44% reduction in the frequency of otitis media complicating influenza, and
with reductions in antibiotic prescriptions in influenza-infected children. Similarly,
therapy of children 5 to 12 years old with symptomatic influenza A and B virus
infection who were treated within 36 hours with inhaled zanamivir (10 mg twice a
day) resulted in relief of symptoms 1.25 days earlier than did placebo recipients,
and a more rapid return to normal activities.[311]
Neuraminidase inhibitor therapy of influenza in adults with risk factors for
influenza complications has not been evaluated extensively. However, both drugs
have shown trends toward efficacy in such populations.[308][312] The results of metaanalyses of the pooled data from subsequent phase III studies have indicated that
early treatment with inhaled zanamivir is associated with a median reduction of
illness of 2.5 days in older adult and high-risk subjects, and a 3-day earlier return
to normal activities.[313] In these pooled analyses, early treatment of high-risk
adults and older adults resulted in a 43% reduction in the rates of complications
requiring antimicrobials.
Drug Resistance
Because the neuraminidase inhibitors interact with highly conserved residues
within the influenza virus neuraminidase, it has been hypothesized that antiviral
resistance will be a relatively limited problem. In fact, truly resistant viruses have
been infrequently isolated from immunologically intact individuals treated with
neuraminidase inhibitors in clinical trials to date.[314][315] Viruses with reduced
susceptibility to oseltamivir have been isolated from 1% of adult and 5.5% of
pediatric recipients.[316] Resistant viruses have been recovered more commonly
from immunosuppressed children.[217]
Viruses resistant to the in vitro antiviral activity of these agents have been isolated
after passage in cell culture. Analysis of these viruses has revealed two basic
mechanisms of resistance, and it illustrates the interactive roles of the viral HA and
NA in binding to and release from infected cells. Mutations within the catalytic
framework of the NA that abolish binding of the drugs have been described.[317][318]
Depending on the location of the mutation, these viruses may be specifically
resistant to only one inhibitor. Resistance mutations in the NA may be associated
with altered characteristics of the enzyme with significantly reduced
activity.[319][320]
A second type of mutation associated with cell cultured resistant viruses involves
mutations in the receptor binding region of the hemagglutinin. HA mutations
associated with resistance to neuraminidase inhibitors reduce the affinity of the HA
for its receptor, allowing cell-to-cell spread of virus in the absence of NA
activity.[317][321] It is even possible to generate inhibitor-dependent viruses, in
which the affinity for the receptor is apparently so low that NA activity must be
inhibited to allow the virus to bind at all. Resistant viruses with HA mutations
exhibit cross-resistance to these drugs in cell culture but may retain susceptibility
in animal models. Many of these viruses also exhibit reduced virulence in animals.
As expected, resistant viruses appear to have significantly reduced fitness, with
reduced levels of replication, attenuation in animals, and reduced ability to be
transmitted from animal to animal.[322][323][324] These characteristics probably
contribute to the relatively low frequency with which these viruses are detected
clinically.
Treatment of Complications
Supportive care, including fluid and electrolyte management, is important.
Supplemental oxygen, intubation, tracheotomy, assisted ventilation, and the use of
positive end-expiratory pressure may have a role depending on the severity of the
illness.[325] For patients with proven or suspected bacterial supra-infection,
appropriate antibiotics for the specific organism should be administered. Because
of the rapidly advancing nature of many cases of pneumonia occurring during an
influenza epidemic, therapy to cover the potential pathogens, including S.
pneumoniae and H. influenzae, and possibly S. aureus, is indicated if an etiologic
diagnosis cannot be made from a Gram stain of the sputum.
There have been no controlled studies of antiviral therapy for the treatment of
influenza viral pneumonia, so their use for this condition is based on extrapolation
from anecdotal case reports of benefit and on data indicating an effect of
amantadine on peripheral airways resistance in uncomplicated influenza.[112][270] In
a small controlled study, there was no difference in outcome between hospitalized
adults treated with the combination of rimantadine and zanamivir and those treated
with rimantadine alone, although both drugs were well tolerated.[326]
PREVENTION
Vaccines
Inactivated Influenza Vaccine
The most effective measure available for the control of influenza is the annual
administration of inactivated influenza vaccines. Chemically inactivated influenza
virus vaccines were first licensed in the United States in 1943. The original
vaccine, which consisted of formalin-inactivated whole virions grown in
embryonated chicken eggs, was demonstrated to have a protective efficacy of 70%
in healthy adults.[11] Since then, although there have been several important
advances in the techniques for producing vaccine, the basic vaccine strategy has
remained the same. The development of the zonal gradient centrifuge allowed
more efficient production and more highly purified vaccines from which
reactogenic contaminants had been removed.[327] Treatment of the whole virus with
solvents to create “split” vaccines, or with detergents to create “subunit” vaccines,
has resulted in a vaccine with fewer adverse reactions, particularly fever, than the
whole-cell vaccine.[328] The efficiency of vaccine production has also been
improved through the development of techniques to create so called high-yield
reassortant strains adapted to grow in high yield from hens’ eggs.[329] The current
vaccine is generally formulated as a trivalent preparation, containing one example
each of influenza A (H1N1) virus, A (H3N2) virus, and influenza B virus thought
to be most likely to cause disease in the upcoming season on the basis of
epidemiologic and antigenic analysis of currently circulating strains. Since the late
1970s, the vaccine has been standardized to contain at least 15 μg of each
hemagglutinin (HA) antigen as assessed by single radial immunodiffusion
(SRID).[330]
Safety.
Influenza vaccine is generally very well tolerated in adults. Rates of mild local
soreness after administration of inactivated influenza vaccine have been
documented to be in the range of 60% to 80% in multiple studies.[331][332][333][334]
Local side effects are slightly more common in women than in men.[331] Systemic
reactions, including malaise, flulike illnesses, and fever, are relatively uncommon.
Rates of transient, low-grade fever have varied from 2% to 10% of recipients in
these studies; these rates are only marginally increased above the rates in placebo
recipients.[331][335] Although whole-virus and split-product vaccines are similarly
reactogenic in adults,[336] whole-virus vaccines are associated with fever in
children[337] and are no longer available in the United States. Fever occurs in
approximately 8% to 11% of vaccinated children and may be associated with other
systemic symptoms such as myalgia, arthralgia, headache, and malaise.[338]
Severe, life-threatening, immediate hypersensitivity reactions to parenteral
inactivated vaccine have been rare. However, hypersensitivity to hens’ eggs, in
which the vaccine virus is grown, is a contraindication to vaccination. Generally, if
persons can eat eggs or egg-containing products, vaccination is safe. Although
vaccine is usually not administered to patients with a genuine anaphylactic
hypersensitivity to egg products, such individuals can be desensitized and safely
vaccinated if necessary.[339][340][341]
During the 1976 National Immunization Program against swine influenza, 45
million persons received influenza vaccine. In the first 4 to 6 weeks after
vaccination, the incidence of Guillain-Barré syndrome (GBS) among vaccinees
exceeded that among persons who did not receive the vaccine.[342] The estimated
risk of acquiring GBS during that vaccination program was 1 in 100,000
vaccinations; the mortality for those with GBS was 5% (i.e., 1 in 2,000,000
vaccinations), and another 5% to 10% had some residual neurologic
abnormality.[342] The relationship between inactivated influenza vaccines other
than the Swine/New Jersey/76 vaccine and GBS is less clear-cut. National
surveillance conducted since 1976 has generally not identified increased rates of
this syndrome after vaccination.[343] However, very slight increases in the risk of
GBS were seen after the 1992–1993 and 1993–1994 vaccines, representing an
excess of approximately one case per million persons vaccinated.[344]
Immune Response.
Increases in HAI antibody are seen in about 90% of healthy adult recipients of
vaccine.[336][345][346] Only a single dose of vaccine is required in individuals who
were previously vaccinated or who experienced prior infection with a related
subtype, but a two-dose schedule is required in unprimed individuals.[337][347]
Primed individuals generally respond with antibody that recognizes a broader
range of antigenic variants than do unprimed individuals.[348] Serum antibodies
peak between 2 and 4 months after vaccination but fall quickly, reaching near
baseline before the next influenza season.[349] Mucosal anti-influenza antibodies are
not generated efficiently by parenteral inactivated influenza vaccine.[350][351]
Cytotoxic T-lymphocyte or cellular immune responses have been reported after
administration of parenteral inactivated influenza vaccine to individuals primed by
previous infection.[352] It has recently been reported that human leukocyte antigen
(HLA) type is significantly associated with influenza vaccine responsiveness.[353]
Groups of adults with potentially decreased responses to inactivated influenza
vaccine include older adults,[354][355][356] individuals on immunosuppressive
therapy,[357]
those
with
renal
disease,[358]
and
some
transplant
[359][360][361][362]
recipients.
To be maximally effective, immunizations should be
given before transplantation, should avoid the nadir of white counts, and should
include vaccination of close contacts.[363] The responsiveness to influenza
vaccination in HIV-infected individuals is related to the degree of
immunosuppression.[364][365] Most patients with chronic lung disease respond
reasonably well to vaccination, and steroids at doses commonly used to treat
reactive airways disease do not appear to preclude vaccine responses.[366][367]
Efficacy and Effectiveness.
Inactivated influenza vaccine has been shown to be effective in the prevention of
influenza A in controlled studies conducted in young adults, with levels of
protection of 70% to 90% when there is a good antigenic match between the
vaccine and the epidemic virus.[150][368][369] In a recent randomized controlled
trial,[370] the efficacy of trivalent inactivated influenza vaccine (TIV) for preventing
culture-proven influenza A illness in adults was 76% (95% confidence interval
[CI], 58% to 87%) for H1N1 and 74% (95% CI, 52% to 86%) for H3N2. A
subanalysis of efficacy in children in this trial demonstrated efficacy of 91% and
77% in preventing symptomatic, culture-positive influenza A H1N1 and A H3N2
illness, respectively, compared with placebo.[371] Vaccination of working adults is
also associated with decreased absenteeism from work or school and is
significantly cost effective,[372] but these benefits do not extend to years when there
is not a good match between vaccine and circulating viruses.[373] In children, TIV
has reduced the rates of otitis media in some,[374][375] but not all,[376] studies.
Relatively few prospective trials of protective efficacy have been conducted in
high-risk populations. In one placebo-controlled prospective trial in an older adult
population, inactivated vaccine was approximately 58% effective in preventing
laboratory-documented influenza.[377] In addition, numerous retrospective casecontrol studies are available that have documented the effectiveness of inactivated
influenza vaccines in older adults.[24][378][379][380][381][382] Vaccine is protective
against influenza- and pneumonia-related hospitalization in older adults, and it is
accompanied by a decrease in all-cause mortality.[383] Vaccine has also been shown
to be protective in limited studies in other high-risk groups, including those with
HIV infection.[384] It has recently been shown that inactivated vaccine administered
to older adults and persons with coronary artery disease can reduce the rates of
coronary events or stroke during the influenza season.[385][386]
Live-Attenuated (Cold-Adapted) Influenza Vaccine
Recently, the first live-attenuated influenza vaccines for use in humans, the coldadapted influenza vaccine–trivalent (CAIV-T), was licensed for use in the United
States in the age group from 5 to 49 years. The use of live-attenuated viruses as
influenza vaccines offers several potential advantages over parenteral inactivated
vaccines, including induction of a mucosal immune response that closely mimics
the response induced by natural influenza virus infection.[387] In addition, the
potential superiority of such vaccines in protection of the upper respiratory tract[388]
might be useful in strategies using vaccine to limit transmission of influenza. In
practical terms, the use of the nasal, rather than the parenteral, route of
administration might be more acceptable to patients, particularly in certain age
groups.
Development of these vaccines takes advantage of the principle of reassortment to
generate rapidly attenuated vaccines for new antigenic variants ( Fig. 162–11
).[389][390] In this case, the master vaccine viruses are the cold-adapted influenza
A/Ann Arbor/6/60 (H2N2) and B/Ann Arbor/1/66 viruses, developed by Dr. John
Maassab at the University of Michigan in the 1960s.[391] The process of cold
adaptation is the repetitive passage of a virus at gradually decreasing temperature
until a virus is isolated that replicates efficiently at a low temperature at which the
replication of the original wild-type virus is significantly restricted.[392]
Figure 162-11 Genetic reassortment is used to generate new liveattenuated vaccine
viruses. The genetic basis of attenuation of the “master donor virus” is encoded in gene
segments other than the hemagglutinin (HA) or neuraminidase (NA). Using either mixed
infection in cell culture or reverse genetics techniques, the genes encoding the HA and NA of
new antigenic variants can be inserted into the background of the master donor virus to rapidly
create a new attenuated vaccine virus.
Genetic analysis of the cold-adapted A/Ann Arbor/6/60 virus has demonstrated
multiple mutations in all six of the so-called internal, or non-HA or NA, gene
segments, and analysis of single gene reassortants has shown that at least three of
these gene segments (PB1, PB2, and PA) participate in the attenuation of the virus
in animals and humans.[393][394] Recent studies have also implicated the NP gene in
this phenotype.[395] The basis of attenuation of the B/Ann Arbor/1/66 virus has
been worked out less completely. Mutations in five of the six internal gene
segments have been described,[396] and analysis of laboratory-derived revertant
viruses has implicated the PA gene segment as playing an important role in
attenuation.[397][398]
Safety.
CAIV-T or closely related formulations of CAIV have been well tolerated in
adults,[370][399][400][401][402][403] with rates of mild nasal symptoms (runny nose, nasal
congestion, or coryza) and sore throat occurring at rates slightly in excess of those
in placebo recipients. These vaccines have also been shown to be safe and well
tolerated in children,[371][404][405][406][407][408][409][410][411][412][413][414] although children
under 8 years have had slightly increased but variable rates of low-grade fever,
runny nose, and abdominal symptoms in the 7 days after vaccination compared
with placebo recipients. However, when considering all the pediatric studies in
aggregate, no consistent symptom was significantly more common in CAIV
recipients compared with placebo recipients. In older children, 11 to less than 16
years of age, sore throat was observed slightly more frequently in CAIV recipients
than in recipients of inactivated influenza.[371]
Safety has also been demonstrated in high-risk individuals who would not be able
to tolerate even minor lower respiratory tract inflammation. No significant vaccinerelated adverse events were seen in studies of children with cystic fibrosis[415][416]
or asthma,[417][418] and vaccinated children with asthma did not experience
significant changes in FEV1, use of beta-adrenergic rescue medications or asthma
symptom scores compared with placebo recipients.[418] CAIV has also been well
tolerated in adults with chronic obstructive airway disease.[419][420][421] Vaccine is
very well tolerated in older adults, although in one study vaccine recipients had a
13% excess of sore throats compared with those who received placebo.[399]
Young children with advanced HIV infection were reported to have difficulty
clearing wild-type influenza virus from the respiratory tract, and there have been
several reports of very prolonged virus shedding in highly immunosuppressed
individuals,[215] including children with acquired immunodeficiency syndrome
(AIDS). However, in small studies in adults[400] and children[408] with HIV who did
not have manifestations of AIDS, CAIV-T was well tolerated and not associated
with prolonged shedding.
Shedding of CAIV does occur in vaccinated adults and particularly in children.
Therefore, it is possible that live CAIV viruses could be transmitted to susceptible
contacts. However, this does not appear to happen frequently. No transmission of
CAIV from vaccine recipients to susceptible contacts was detected in studies of
young children involved in daycare-like settings where CAIV and placebo
recipients played together for up to 8 hours a day for 7 to 10 days after
vaccination.[390][422] In the largest study, 197 children between 8 and 36 months of
age in a daycare setting were randomized to receive trivalent CAIV or placebo, and
CAIV was detected in one placebo recipient; thus, the estimates of transmissibility
in this age group were 0.6% to 2.0%.[423] Importantly, samples of vaccine virus
recovered from vaccinated volunteer subjects have all retained the attenuated
phenotype and genotype.[423][424] Administration of CAIV to health care workers is
not recommended because of potential transmission of virus to patients. The high
cost of the vaccine has also restricted its use in institutional settings.
Immune Response.
Studies of the immunogenicity of cold-adapted reassortant vaccines have been
carried out in children, adults, and older adults. The results of these studies are
consistent with the hypothesis that the replication of cold-adapted vaccines in the
upper respiratory tract, and hence their immunogenicity, is influenced by the
susceptibility of the host at the time of vaccination. The frequency and magnitude
of immune responses to vaccination are therefore highest in young children,
intermediate in adults, and lowest in older adult subjects who have been repeatedly
infected with influenza viruses throughout their lifetime. In addition, the mucosally
administered CAIV is generally more effective than parenterally administered
inactivated influenza vaccine at inducing nasal HA-specific IgA, whereas
inactivated vaccine usually induces higher serum titers of HAI and HA-specific
IgG antibody.[425]
Most susceptible children demonstrate measurable serum and mucosal HA-specific
antibody responses.[306][307][409][410][412][414][416][426] Mucosal responses have been
demonstrated in up to 85% of young children after CAIV-T.[427] In contrast, adults
generally have a low rate of serum antibody response after CAIV,[370][402][403] and
relatively lower rates of mucosal responses.[428] Even in those prescreened to have
low prevaccination vaccine-specific influenza antibody, the rates of serum
antibody responses to intranasal CAIV in adults and older adults are low.[403][429]
However, the significance of these findings is unclear, as protection can be
demonstrated in some circumstances in the absence of detectable mucosal
responses,[430] and the specific levels of mucosal antibody required for protection
are unknown.
Although not studied extensively, limited data suggest that cold-adapted influenza
vaccines may induce antibody and cytotoxic T cells with more broadened
recognition within a subtype than seen after inactivated vaccine.[431][432] However,
these responses have been more difficult to measure in young children.[433]
Efficacy and Effectiveness.
CAIV-T was demonstrated to be efficacious in the prevention of influenza in a 2year, randomized, placebo-controlled trial conducted in 1314 children 15 to 74
months of age. Efficacy against culture-confirmed influenza illness in the first year
of this trial was 95% against influenza A/H3N2 and 91% against influenza B. In
the second year of the trial, the H3 component of the vaccine (A/Wuhan/93) was
not a close match with the predominant H3 virus that season, A/Sydney/95.
However, the efficacy of CAIV against this variant was 86% (95% CI, 75% to
92%),[405] suggesting that CAIV can induce protective immunity against drift
variants. The efficacy in children is also supported by smaller trials using bivalent
preparations of CAIV-T.[371][412]
Efficacy of CAIV-T against naturally acquired influenza in adults has not been
demonstrated directly. However, its efficacy was demonstrated in an experimental
infection study in which adults were given either trivalent live intranasal CAIV,
parenteral trivalent inactivated influenza vaccine, or placebo, and then
experimentally infected with wild-type influenza A/H1N1, A/H3N2, or B virus.[403]
The combined efficacy of CAIV-T in preventing laboratory-documented influenza
illness was 85%, consistent with observations from other experimental infection
studies conducted with monovalent CAIV.[161][388][434][435] In addition, in a large, 5year field trial in Nashville, Tennessee,[370] the efficacy of bivalent CAIV was 85%
(95% CI, 70% to 92%) against A/H1N1 illness and 58% (95% CI, 29%-75%)
against A/H3N2 illness. Use of CAIV-T in adults has also been shown to reduce
rates of severe febrile illness of any cause during the influenza season.[401]
No studies of the protective efficacy of CAIV alone have been conducted in older
adults because of the possibly reduced immunogenicity of the vaccine in this age
group. However, the combination of local live-attenuated influenza vaccine and
parenteral inactivated vaccine administered together was shown to result in an
approximately 60% decrease in cases of laboratory-confirmed influenza in an older
adult nursing home population, compared with inactivated vaccine alone.[436]
Recommendations for Vaccine Use
The main goal of the strategy for use of influenza vaccine is to reduce
complications by targeting vaccine to those individuals at highest risk of influenzarelated hospitalizations or death. Table 162–6 lists those groups for whom annual
influenza vaccination is currently recommended,[437] including older adults and
adults and children with chronic conditions known to increase the risk of influenza
complications. The age at which annual vaccination is recommended has been
lowered from 65 to 50. The rationale for this recommendation is to achieve higher
vaccination rates in adults with high-risk conditions, a large proportion of whom
are between 50 and 65 years old.
Table 162-6 -- Groups Targeted for Influenza Immunization
Persons at Increased Risk for Complications
• Persons aged ≥65 years
• Residents of nursing homes and other chronic-care facilities
• Adults and children with chronic pulmonary or cardiovascular diseases, including
asthma
• Adults and children with chronic metabolic diseases (including diabetes mellitus),
renal dysfunction, hemoglobinopathies, or immunosuppression (including HIV)
• Children and adolescents receiving long-term aspirin therapy
• Women who will be in the second or third trimester of pregnancy during the influenza
season
• Children aged 6 mo-23 mo
Persons Aged 50–64 Years
• Recommended for this entire age group to increase vaccination rates among persons in
this age group with high-risk conditions
Persons Who Can Transmit Influenza to Those at High Risk
• Physicians, nurses, and other personnel in both hospital and outpatient-care settings,
including medical emergency response workers
• Employees of nursing homes and assisted living and other chronic-care facilities who
have contact with patients or residents
• Persons who provide home care to persons in groups at high risk
• Household contacts (including children) of persons in groups at high risk
• Household contacts of children aged 0–23 months
Recommendations for annual vaccination of healthy children are also being
considered. The Advisory Committee on Immunization Practices (ACIP) has
recommended that practitioners vaccinate all children 6 to 23 months of age with
the influenza vaccine,[437] because of the high rates of influenza-related
hospitalizations and medically attended illness in this age group. An additional
benefit of widespread vaccination of young children could be reductions in rates of
influenza in other groups, because children play an important role in the
propagation of influenza epidemics in a community.[438] Relatively little direct
evidence supports the use of influenza vaccine to prevent transmission, but in one
study, mass vaccination of school-aged children resulted in reduced rates of
influenza in teachers and parents compared with a control community where
children were not vaccinated.[439] Vaccination of children in daycare has been
reported to reduce the rates of febrile respiratory illnesses in unvaccinated
household contacts.[440] In addition, it has been observed that influenza-related
mortality rates among older adults have increased in Japan, coincident with
discontinuation of that country’s policy of universal vaccination of school
children.[441] Such observations suggest that expanding the population of children
targeted for annual influenza immunization could be a reasonable approach to
reducing the impact of influenza in the whole community.
For similar reasons, vaccination of individuals who are in close contact with
persons with high-risk conditions is strongly recommended, including health care
workers. At a minimum, such a policy would reduce workplace absences and
prevent disruptions in care.[442] In addition, there is supportive evidence that
vaccination of health care workers reduces mortality in patients, at least among
residents of nursing homes, independently of the vaccination status of the patients
themselves.[443][444]
Except for the influenza pandemics of 1918–1919 and 1957–1958, influenza in
pregnancy has not been associated with increased mortality or fetal loss.[445]
However, the increased physiologic demands of pregnancy could be associated
with enhanced severity of influenza, and recent studies suggest that there is a
significant increase in hospitalizations for cardiorespiratory conditions among
women in the third trimester of pregnancy during influenza season.[29] There has
been a considerable experience with the use of influenza vaccine in pregnancy, and
it appears to be safe in this situation. Therefore, current recommendations are to
administer vaccine to women who will be in the second or third trimester (i.e., at
>14 weeks’ gestation) during influenza season.[446] A secondary benefit of this
strategy could be the provision of antibody to the infant, depending on the timing
of maternal immunization.[447] Because of the high rate of spontaneous fetal loss
during the first trimester, vaccination should generally be avoided during this
period, unless the pregnant woman has other high-risk medical conditions, in
which case vaccine should be administered regardless of the stage of pregnancy.
The duration of protective immunity appears to be limited, particularly in older
adults,[448] and in most years, one or more of the vaccine components are updated
to keep pace with antigenic drift in circulating viruses. Thus, current inactivated
vaccines must be administered yearly. In some situations, yearly administration has
been reported to result in decreased effectiveness.[449] Recent studies suggest that
prior immunization does not adversely affect immune responses to vaccination or
the protection afforded by inactivated vaccine, at least in healthy adults.[450]
Chemoprophylaxis
All four of the available antiviral agents are effective at preventing influenza
prophylaxis, provided drug is administered continuously throughout the period of
exposure. Several schemes for such prophylaxis have been evaluated, including
seasonal prophylaxis, where drug is administered throughout the influenza
epidemic season, generally 4 to 6 weeks; family prophylaxis, where drug is
administered to family members for a short period of time after recognition of an
index case in the family; and outbreak-initiated prophylaxis in institutions, which
could be considered to be a variation on the theme of family prophylaxis. In
addition, short-term antiviral prophylaxis can be considered for high-risk
individuals who are vaccinated during the influenza season.
Seasonal Prophylaxis
Seasonal prophylaxis with amantadine has been shown to result in protection rates
of 70%[451] to 90%[271] against H1N1 viruses, and 68% against H3N2 viruses.[452]
Seasonal prophylaxis with amantadine has also been effective in children, in whom
an approximately 90% reduction in laboratory-confirmed illness due to influenza A
H2N2 was reported.[453][454] Significantly fewer studies of prophylaxis with
rimantadine have been performed. However, when rimantadine and amantadine
were directly compared in seasonal prophylaxis in healthy adults, the levels of
protection were approximately equal.[271]
Both zanamivir and oseltamivir have also been shown to be protective in seasonal
prophylaxis. In healthy adults, inhaled zanamivir was shown to have about 67%
efficacy for prevention of confirmed influenza,[455] and in a similar study, the
efficacy of oral oseltamivir was 74%.[456] Both drugs were well tolerated on
prolonged use. However, only oseltamivir is approved for prophylaxis (for
individuals 2 and 3 years of age.)
Relatively less information is available about the use of any of the influenza
antivirals for prophylaxis in older adult or high-risk populations. In one study,
seasonal prophylaxis was highly effective in preventing laboratory-documented
influenza in older adult residents of retirement communities.[457] Importantly, 80%
of the subjects had previously been vaccinated, and prophylaxis resulted in a 91%
reduction in influenza in this group. Thus, vaccine and chemoprophylaxis had an
additive protective effect in older adults.
Family Prophylaxis
Results of outbreak prophylaxis in the family setting have yielded conflicting
results depending on whether the index case does or does not receive concurrent
therapy. When the index case was not treated with amantadine, protection of
family contacts was seen for both drugs.[458][459][460] However, if the index case was
treated with amantadine at the same time that contacts received prophylaxis, no
protection was seen,[287][461] presumably because of the generation and transmission
of resistant virus in this setting.[456] In contrast, use of oseltamivir[462] or
zanamivir[463] is associated with 80% protection without the development or
transmission of resistant virus. Generally, drug is administered to contacts for 5 to
7 days after recognition of the index case. It is important to realize that treated
individuals remain susceptible to infection from outside the family after such
prophylaxis is discontinued.
Outbreak Prophylaxis
Probably one of the most common uses of antiviral agents for influenza is to
terminate the transmission of influenza within institutions such as nursing homes
during outbreaks. Although this has not been subject to formal, placebo-controlled
study, many anecdotal reports support the efficacy of amantadine,[273][464][465]
zanamivir,[466] and oseltamivir[467][468] in this setting. When M2 inhibitors are used
for outbreak prophylaxis, individuals who are receiving treatment with amantadine
should be isolated from those who are receiving prophylaxis. Failure to adhere to
this practice is associated with the development and transmission of resistant
viruses within the institution.[290][469] One preliminary report has suggested that
prophylactic administration of zanamivir was successful in terminating an outbreak
of influenza in a nursing home in which cases continued to occur despite
amantadine prophylaxis.[470]
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