†RR: Unadjusted risk ratio
‡aRR: Adjusted risk ratio; Adjusted for age, sex,
tobacco use, exercise level, hypertension, diabetes, high blood
cholesterol, heart failure, previous history of CHD and
BMI
§Includes both annual influenza seasons of 2017 and
2018
DISCUSSION:
To the best of our knowledge,
this is the first study in Bangladesh to investigate the prevalence of
recent CRI and laboratory confirmed influenza among patients with AMI.
The results of this study indicate that a significant proportion of the
participants had a history of CRI within a week of AMI onset and that
qRT-PCR-confirmed influenza was present, suggesting that recent acute
respiratory illness and influenza may potentially contribute to
triggering AMI. Notably, the self-reported CRI among AMI patients was
prevalent during both influenza and non-influenza seasons, indicating
that the circulation of non-influenza respiratory viral pathogens could
also potentially play a role in triggering the onset of AMI
(34-36). These findings highlight the
need for further investigation into the potential association between
recent respiratory illnesses and AMI, including the identification of
specific viral pathogens and mechanisms underlying this association.
About one third of the enrolled AMI patients during the 2017 influenza
season reported history of CRI which was much more frequent than that
reported during 2018 influenza season. This could be validated in the
context of report by the national hospital-based influenza surveillance
program in Bangladesh indicating a relatively more severe influenza
epidemic and upward surge in severe acute respiratory illness (SARI)
admissions occurred in the country during the 2017 compared to the 2018
influenza season (37) suggesting that
there could be a potential link between the intensity of the influenza
season and the number of AMI cases associated with influenza. The
current study did not find a statistically significant association
between recent CRI and the severity of myocardial damage, as defined by
STEMI or high blood troponin. However, in general, the proportion of
STEMI cases over NSTEMI was higher during the influenza season compared
to the non-influenza season, and this difference was statistically
significant in the unadjusted but not in adjusted regression analysis.
It is possible that unrecognized recent influenza infection may play a
role in triggering STEMI, however, further research is needed to
establish a definitive relationship. Although our findings imply a
potential link between recent acute respiratory illnesses and influenza
with the occurrence of AMI, it is crucial to acknowledge that our
study’s cross-sectional design does not allow us to establish a
definitive association between the exposures and the outcome and hence
recommend further validation. Further studies, including case-control
studies or prospective cohort studies, are needed to confirm an
association and elucidate the mechanisms underlying this association.
However, these results do highlight the importance of considering the
potential impact of respiratory illness, including seasonal influenza,
on cardiovascular health among population in Bangladesh. Importance of
further research and analysis of the potential benefits of robust
infection control measures and influenza vaccination programs for AMI
prevention cannot be overstated.
Previous studies have reported a wide range of frequencies of recent
respiratory illness among AMI cases, ranging from 2.8% to 60.3%
(16). The overall frequency of recent CRI
in this study (11.3%) is comparable to previous reports
(16), from London (14.3%) and Finland
(12.2%), and the frequency of CRI during the 2017 influenza season in
this study (36%) is comparable to reports (16), from Sydney, Australia
(31.1%), Massachusetts (28%), London (24.3%), Finland (28%) and
lastly from Karachi, Pakistan (37) (36.2%). However, it is possible
that the differences in reported frequency of acute respiratory illness
among AMI cases across studies may be attributed to various factors,
such as demographic variations among participants and discrepancies in
the criteria used to define recent acute respiratory illness. Most of
the previous studies were conducted in high-income countries where the
average age of recruited AMI patients was over 60 years old, which was
significantly older than the average age of participants in our study
(52 years). While Warren et al. (38)
defined recent acute respiratory illness for AMI cases as having both
respiratory and systemic symptoms with an onset of illness within the
past month, our criteria for CRI did not include systemic symptoms. This
difference in criteria may be an important limiting factor in
appropriately classifying cases with recent acute respiratory illness,
as including systemic symptoms in the criteria for recent acute
respiratory illness may be crucial in accurately identifying cases that
have truly had a recent acute respiratory infection. Our study’s
definition for CRI (32,
33) only included respiratory symptoms
that developed within a week of AMI in order to minimize recall bias. We
believe that major cardiovascular events following an acute respiratory
infection are more clinically plausible during this timeframe than a
longer period of time after the infection. Despite the lack of systemic
symptoms in our case definition, we still believe that our definition
for recent respiratory illness in the current study is clinically
sensitive enough to increase the likelihood of capturing cases with
recent respiratory infection preceding onset of AMI. However, we
acknowledge that our definition may have lower specificity, potentially
leading to the inclusion of false positive cases for CRI. Another
potential contributing factor to the differing frequencies across
previous studies is that some were restricted to only influenza seasons
while others were conducted during both influenza
(30, 38)
and non-influenza seasons (39).
Due to cross-sectional study design, we were unable to show a direct
association between recent CRI and AMI. However, several previous
case-control studies showed an association of recent respiratory illness
with AMI. A case-control study based on large general practice database
in Europe showed risk of AMI incidence twofold within 7 days after
respiratory infection (39,
40). Another longitudinal
population-based cohort study performed in United States indicated risk
of acute cardiovascular events including AMI, stroke and death highest
during the first month of hospitalization for pneumonia
(39, 40).
In general AMI cases could be as much as twice more likely than controls
to report history of recent respiratory illness occurring within 7 days
of AMI onset and the strength of this association is lesser for
respiratory illness occurring >7 days of onset of AMI and
fell over time (30,
38, 39).
There is high double burden of both acute respiratory infections as well
as acute cardiovascular events (26) in
Bangladesh and despite evidence in other countries there is no data for
Bangladesh about prevalence of recent respiratory illness preceding
onset of AMI.
We reported a low frequency of influenza positivity in AMI cases. In the
previous studies, the frequency of influenza detection by real-time PCR,
paired serum influenza antibodies and single baseline influenza antibody
titer among AMI patients ranged from 14% to
86.3%(16). The detection rates may
considerably vary due to study specific laboratory methods applied,
pattern as well as intensity of influenza strains during study period,
and study conducted during both or either influenza and/or non-influenza
seasons. The most confirmatory standard test method to diagnose
influenza is RT-PCR test of respiratory swabs as recommended by WHO.
Most of the previous studies identified low numbers of influenza by PCR
alone (30,
38, 41).
Nevertheless, investigators considered using baseline serology
(41) and analysis of paired serums
(30) for IgG or baseline serology for IgA
(38) to report additional influenza with
or without PCR. The WHO recommends swabbing patients within 10 days of
onset of respiratory symptoms to increase the likelihood of detecting
influenza RNA by PCR before diminution of viral shedding
(42). There is still limited clarity on
the exact timeline of onset of AMI after influenza infection, hence PCR
test will likely have lower sensitivity if viral shedding diminishes
before swabbing AMI patients. However, to maximize sensitivity to detect
viral shedding, all participants in our study were swabbed within 72
hours of the onset of AMI. Serological analysis of convalescent serum in
addition to PCR could have enhanced the sensitivity to detect more
influenza positive AMI patients which is limitation of the current
study. Moreover, due to administrative delays, we enrolled and tested
only a minimal number of AMI cases during the peak influenza months
May-September in 2017 influenza season when sequentially A(H1N1)pdm09,
A/H3, and influenza B were the predominant strains circulating
nationally (37).
During the current study, all cases of rRT-PCR confirmed influenza among
AMI patients were identified only within the influenza seasons. The
influenza subtypes that were identified fully corresponded to the
month-specific circulating influenza strains identified through the
national influenza surveillance scheme in the country
(37) signifying typical influenza strains
were also circulating among AMI patients in Bangladesh during the 2017
and 2018 influenza seasons. Interestingly, our study found a higher
frequency of real-time PCR confirmed influenza in AMI patients compared
to similar studies conducted in high income countries, where only 0/70
and 1/275 AMI cases tested positive for influenza nucleic acid
(30, 38).
It is possible that the population in Bangladesh has a higher
susceptibility to influenza-associated AMI due to factors such as low
vaccination rates, or high prevalence of cardiovascular co-morbidities.
Nevertheless, our study design was cross-sectional and did not have a
control group, therefore not specifically designed to investigate the
association between laboratory confirmed influenza and AMI. However,
very few previous case-control studies were able to reveal a direct
association between laboratory confirmed influenza and AMI
(41), perhaps due to the fact that
influenza may be less common in the particular age group where AMI
usually occurs. Conversely, more case-control studies have reported
significant effectiveness of influenza vaccine against AMI
(16, 30)
which could be an indirect evidence of influenza’s association with AMI.
Analyses in the current study to assess association of recent CRI with
severity of myocardial damage, when restricted to only influenza
seasons, showed frequencies of recent CRI generally higher among STEMI
than NSTEMI which was statistically not significant. Besides, it is
noteworthy that although not statistically significant, we observed a
strong positive trend in the association between CRI and high-troponin
among AMI patients, and in some cases likelihood of development of AMI
with high-troponin level was up to 80% higher among patients with CRI
compared to those without, for example during 2018 influenza season.
Furthermore, all of the identified influenza strains were exclusive to
STEMI cases, emphasizing the need to consider these findings in patient
evaluations. Both STEMI and high troponin level are related to severe
myocardial damage. We assume that the analyses restricted to only
influenza seasons were underpowered to find statistically significant
results due to the small sample size within the subgroups related to
myocardial damage. Nevertheless, there is previous evidence that
influenza infection may increase the risk while the influenza vaccine is
effective against large size infarcts, high troponin or CK-MB levels in
patients with AMI (43). An upward trend
of association between CRI and STEMI or high-troponin observed in the
current study should be interpreted with caution as this may indicate a
possible link between seasonality of acute respiratory infections
including influenza and AMI events of greater myocardial damage among
high risk unvaccinated individuals, which could be further explored
through robust analytical studies conducted across multiple seasons. We
believe, the magnitude and direction of such associations would depend
considerably on the intensity and pattern of circulating seasonal
influenza strains embedded within climatic factors
(35, 44)
and perhaps additionally and importantly, on clinically unrecognized
respiratory viral infections (11,
13, 34).
For example, five out of seven influenza positive cases in the current
study did not report recent CRI which may imply that link between
influenza and AMI may be more complex than our current understanding.
This may also suggest that there may be other mechanisms by which
influenza increases the risk of AMI, even in the absence of an acute
respiratory illness. For example, influenza may cause changes in the
immune system, blood clotting, or cardiac function increasing the risk
of AMI. Alternatively, it may be that the individuals in the study who
tested positive for influenza but did not report recent acute
respiratory illness had underlying conditions predisposing them to AMI,
and the influenza infection simply acted as a trigger
(45). Accordingly, further analysis in
the current study showed higher prevalence of STEMI among participants
during influenza season than during non-influenza season. The univariate
analysis showed there was a significant 9% increase in the risk of
STEMI during influenza than during non-influenza season suggesting that
acute respiratory illnesses may increase the risk of STEMI during
influenza season.
The underlying pathophysiology of STEMI is complete blockage of the
coronary artery by atherothrombosis causing transmural cardiac
myonecrosis. This is primarily driven by an acute end stage of a chronic
inflammatory atherosclerotic lesion characterized by abrupt rupturing of
the de-stabilized atherosclerotic plaque due to short term exposure of
certain triggering factors that may differ from the number of known
cardiovascular risk factors (46). Such
triggers of plaque rupture can include respiratory viral infections
including influenza along with smoking, excessive alcohol, hypertension,
heavy physical exertion or any kind of stressful events
(47, 48).
One study showed respiratory viral infections can precipitate both STEMI
and NSTEMI and was positively associated with risk of mortality among
NSTEMI, but not among STEMI (49).
Nevertheless, patients after STEMI have a higher in-hospital mortality
rate and worse short-term outcome while NSTEMI patients have poorer
long-term prognosis (50). Blood troponin
level are well correlated to the extent of infarction in both STEMI and
NSTEMI but more impressive in STEMI (51,
52). In the current study, age at onset
of STEMI was significantly lower than NSTEMI, suggesting that these
different subtypes of AMI may have different risk factors and underlying
mechanisms. Further research is needed to explore the relationship
between influenza and different subtypes of AMI, as well as any factors
influencing the association between influenza and STEMI. Preventing
early onset STEMI is crucial in Bangladesh, where the age of onset for
AMI is much earlier than in high-income countries. A simple yet
effective measure to combat this issue could be the administration of
the influenza vaccine. This could not only help curb the early onset of
STEMI, but also significantly lower in-hospital mortality among young
individuals in Bangladesh.
The immune system plays a critical role in both the pathophysiology of
AMI and the physiological mechanisms behind the protection offered by
the influenza vaccine against AMI. This interplay between the immune
system and AMI highlights the vital importance of understanding the
intricacies of this relationship in order to effectively prevent and
treat AMI. Dominant pro-inflammatory over the anti-inflammatory
component of the immune system may favor sudden atherosclerosis
progression leading to acute cardiovascular events like AMI
(53). Influenza virus can induce
significant acute changes in pro-inflammatory cytokine levels in blood
and pro-inflammatory as well as prothrombotic effects in atherosclerotic
plaques which can trigger AMI onset through plaque
destabilization(54). However, there are
inter-individual differences in the intensity of an rapid
pro-inflammatory response which may explain the difference in the level
of risk of AMI among individuals in response to an acute stimulus such
as influenza (55). Investigations
continue globally to understand the relationship between influenza and
AMI, with the goal of using influenza vaccination to prevent AMI in
high-risk individuals. Several observational studies
(16, 30,
56), small scale
(57, 58)
and large scale (22) randomized clinical
trials reported protective efficacy of influenza vaccine against adverse
cardiovascular events including hospitalization or death due to AMI.
Animal study showed influenza vaccine stabilized atherosclerotic plaque
through promoting anti-inflammatory atheroprotective immune response
(59) implying possibly a greater
protection against underlying pathophysiology of onset of STEMI than
NSTEMI. Influenza vaccine has been shown to blunt pro-inflammatory and
enhance anti-inflammatory mediators after coronary artery bypass surgery
(60).