Influenza
Introduction
Influenza viruses belong to the Orthomyxovirus family. They are classified into influenza
A, B, and C based on their core proteins. The envelope of the influenza A virus contains
two major surface glycoproteins: hemagglutinin (HA) and neuraminidase (NA). HA is
responsible for cell attachment and membrane fusion, and NA enables the release of
new virions from the cell through its cleaving of the bonds between HA and sialic
acid. It also has a role in viral ingress by cleaving sialylated mucins to allow virus
penetration through the mucous layer.[1]
Influenza A viruses are subclassified based on the HA and NA glycoproteins. World
Health Organization (WHO) nomenclature for the classification of influenza virus consists
of the following two parts.[2]
There are currently 18 subtypes of HA (H 1–18) and 11 subtypes of NA (N 1–11). These
mostly circulate in wild birds. There are three combinations that are known to have
circulated widely in humans: A/H1N1, A/H2N2, and A/H3N2.[3] The influenza B virus was first isolated in 1940. It circulates solely in humans
and has no animal reservoir.[3]
Minor changes in the protein structure of the influenza A virus are known as antigenic
drift. These mutations allow the virus to evade the immune system and cause further
outbreaks of influenza. Antigenic drifts occur in influenza A, B, and C viruses. The
segmented genome of influenza A virus genome allows for the exchange of entire gene
segments in the event that two different influenza A viruses simultaneously infect
and replicate in the same host cell.[4] Antigenic shift is caused by reassortment of two different subtypes of influenza
virus (such as between an animal and a human subtype), which causes a phenotypic change.
Antigenic shift only occurs in influenza A virus as it infects more than just humans.
Antigenic shifts can result in epidemics and pandemics. Both the pandemic strains
in 1957 and 1968 were derived by genetic reassortment between human and avian viruses.[5]
Epidemics and Pandemics
Epidemics occur annually and, according to the WHO, result in an estimated 3 to 5
million cases of serious illness and in approximately 290,000 to 650,000 deaths per
year. There were three influenza virus pandemics in the 20th century (1918, 1957,
and 1968), and one pandemic in the 21st century (2009).[6] The influenza pandemic of 1918 to 1919 was the most catastrophic in recorded history.
An estimated one-third of the world's population (∼500 million people) were infected
with the virus.[7] Total deaths were estimated at around 50 million,[8]
[9]; however, it is acknowledged that the death toll may have been significantly higher
than this and may, in fact, have reached 100 million.[9]
Origin of Human Pandemic Strains
Influenza viruses in humans originate from birds and swine.[3] The first human influenza A virus was isolated in 1933 and was designated H1N1.
This circulated until 1957 when it was replaced by the H2N2 subtype (Asian influenza).
In 1968, the Hong Kong (H3N2) virus appeared, after which the H2N2 Asian strains were
no longer detectable in humans. Then, in 1977, the H1N1 virus reappeared (likely having
escaped from a laboratory).[5] The H1N1 and H3N2 viruses, along with influenza B viruses, have continued to cocirculate
in the human population, undergoing considerable evolution through antigenic drift.[3]
Influenza: Pathophysiology
Influenza virions recognize potential host cells by detecting sialic acid and binding
to it using the HA viral glycoprotein.[10] Sialic (N-acetylneuraminic) acid is found on nearly all animal cells. It forms either
an α-2,3 or α-2,6 linkage, and it is this configuration that is recognized by the
HA protein.[10] The α-2,3 linkage is the major sialic acid found in the gastrointestinal tract of
the duck. In contrast, the major sialic acid found in upper respiratory epithelial
cells in humans contains the α-2,6 linkage. It is for this reason that not all avian
strains can easily infect humans. For example, in order for avian influenza (H5N1)
to infect humans, it must penetrate deep into the alveoli where there are more α-2,3
receptors.[11] Once the virus attaches to the host cell, it enters the cell through receptor-mediated
endocytosis. The envelope fuses with the host cell, and M2 proteins (a target for
amantadine) form ion channels, allowing entry of ribonucleoproteins necessary for
viral uncoating and replication.[10] Initial response to infection is characterized by proinflammatory state. Th1 cells
are activated and release proinflammatory cytokines such as tumor necrosis factor-α
(TNF-α), interferon-γ (IFN-γ), and interleukin (IL)-2.[12]
[13] The secondary phase of infection is characterized by the anti-inflammatory state.
It is in this state that activated Th2 cells secrete cytokines such as IL-4 and IL-10.[12]
[14] It is this state of depressed immune activation that leads to secondary infections
such as bacterial coinfections and CMV reactivation.[15]
The influenza virus has developed its own host of mechanisms to counteract the activity
of major antiviral cytokines such as INF- γ. Influenza proteins such as NS-1, which
antagonize and inhibit the actions of IFN, PBF-F2 proteins that inhibit IFN induction,
viral polymerase that inhibits IFN function, and M2 protein prevents TLR induction.[16]
Viral infections can trigger the dysregulation of the immune system by inducing a
massive cytokine response. This cytokine storm can cause endothelial damage and dysfunction,
deregulation of coagulation, and, consequently, alteration of microvascular permeability,
tissue edema, and shock.[17] In severe influenza, this vascular hyperpermeability can lead to acute lung injury,
multiorgan failure, and encephalopathy.[16] Different strains of influenza elicit different immune responses. It has been suggested
that H5N1 may cause a higher viral load and hypercytokinemia.[18]
[19] It has also been shown that H5N1 viral replication is not confined to the respiratory
tract but also occurs in the intestine.[20]
Clinical Features
Influenza is an acute respiratory disease characterized in its full form by the sudden
onset of respiratory and systemic symptoms, with high fever as a characteristic feature.[21] While influenza A and B are the most common causes of this influenzalike illness
(ILI), other pathogens such as influenza C, parainfluenza, respiratory syncytial virus
(RSV), and Mycoplasma pneumoniae can also cause it.[21]
Different strains have been found to elicit different clinical features. Influenza
A H3N2 infection has been found to be more severe than H1N1 or B in terms of fever,
leukopenia, or C-reactive protein, whereas gastrointestinal symptoms seem to be more
common in influenza B.[22] However, another study found similar clinical manifestations and outcomes among
adults with influenza A and those with influenza B.[23] Wie et al described that leukopenia or thrombocytopenia was found to occur more
often in patients with influenza B; however, the rate of hospitalization and hospital
length of stay (LOS) were found to be higher in those with influenza A (H3N2). In
addition, the proportion of males to females and of elderly population were significantly
higher for patients with influenza A compared with those with influenza B.[24]
Viral Pneumonia
Viral pneumonia is the most common complication of influenza infection. A study in
2015 looked at risk factors for developing pneumonia from influenza infection. Among
4,765 adults hospitalized with influenza, 1,392 (29%) had pneumonia. In multivariable
analysis, factors associated with pneumonia were age ≥ 75 years, Caucasian race, nursing
home residence, chronic lung disease, immunosuppression, and asthma. Patients with
pneumonia were significantly more likely to require ICU admission (27 vs. 10%), require
invasive mechanical ventilation (MV; 18 vs. 5%), and have an increased risk of death
(9 vs. 2%).[25] Influenza-associated pneumonia may be either primary viral influenza pneumonia,
secondary bacterial pneumonia, or influenza–bacterial coinfection. Patients with pneumonia
are significantly more likely to have a hospital LOS greater than 1 week, require
ICU admission, require MV, and have an increased risk of death.[25]
Among patients with viral pneumonia, factors independently associated with a poor
outcome (defined as ICU admission, the need for MV, or death) included nursing home
residence, chronic lung disease, cardiovascular disease, renal disease, and immunosuppression.
Of note, older age was found as a protective factor among patients hospitalized with
pneumonia.[25]
Risk Factors for Severe Influenza Infection
Coleman et al examined the risk factors for serious outcomes associated with influenza
illness in high-income countries (HICs) versus low- and middle-income countries (LMICs).
They found that patients more likely to suffer severe outcomes (ICU admission, and/or
death) were more vulnerable populations such as those affected with comorbidities
(malignancies, immune-suppressing conditions, and renal, cardiac, and lung diseases
including tuberculosis).[26] Another important risk factor is pregnancy. Pregnant women in LMICs were at 66 percent
increased risk of severe outcome compared with other patients with influenza; however,
there was no increased risk for pregnant women in HICs. Similarly, patients with HIV
were not at an increased risk of severe outcome in HICs; however, they were at an
increased risk of LMICs.[26]
Coinfection
While treatment of CAP has traditionally focused on bacterial etiology, more recent
research has indicated that viruses may be involved in 15 to 30% of CAP.[27]
[28]
[29] Rapid diagnostic testing is thus of vital importance in identifying the offending
pathogen, initiating targeted treatment, and preventing the inappropriate use of antibiotics.
Systematic reviews and meta-analyses found that respiratory viruses are detected in
approximately 22% of CAP patients.[30]
[31] Influenza is consistently the most common viral pathogen identified. There was a
trend toward lower identification of viral pathogens in studies published from 2001
to 2009 as opposed to studies published after 2010.[30] In this study, the viruses most commonly identified in European adult patients with
CAP from more to less frequent were influenza (A & B), rhinovirus, coronavirus, parainfluenza,
human metapneumovirus, RSV, and adenovirus.
Bacterial Coinfection
The frequency of bacterial coinfection in patients with influenza was reported as
being between 11 and 35%. Streptococcus pneumoniae and S. aureus were the most common pathogens accounting for 35 and 28% of identified coinfecting
bacteria, respectively. Influenza infection has been associated with 11 to 14% of
pneumococcal pneumonia during influenza season and 5 to 6% overall.[32] In addition, Grabowska et al found that 6 to 10% of cases of invasive pneumococcal
disease were associated with influenza per year or 12 to 20% per influenza season.[33] Several other pathogens such as nonfermenting gram-negative bacilli have also been
identified as causing coinfections.[34] There are several reasons for propensity to bacterial coinfection that are complex
and not yet fully explained ([Fig. 1]). There appear to be organism-specific interactions with S. aureus and S. pneumoniae that cause a higher rate of infection with these bacteria.[16] A recent multicenter study by Martin-Loeches et al, which included almost 3,000
critically ill patients, has shown that coinfections are occurring more frequently
since 2009. Coinfection was more likely to occur in older and immunosuppressed patients.
In addition, coinfection was an independent risk factor for ICU mortality, 28-day
mortality, and hospital mortality.[35]
Fig. 1 Complication of influenza infection in patients admitted to hospital settings.
Another recent multicenter study analyzing immunosuppressed patients found that the
category of infectious etiology of respiratory failure (influenza, noninfluenza, influenza
plus coinfection, and noninfectious) was associated with ICU but not hospital mortality.[36]
Invasive Pulmonary Aspergillosis
A Spanish group in 2011 reported the first cases of invasive aspergillosis (IA) when
patients were admitted to the ICU due to influenza infections.[37] A retrospective multicenter cohort study by Schauwvlieghe et al examined the incidence
of IA in patients admitted to the ICU with severe influenza. They found that IA was
present in 32% (38/117) of immunocompromised patients and 14% (45/315) immunocompetent
patients.[38] The incidence of IA was almost equal in patients with influenza A and those with
influenza B. In addition, they compared 315 nonimmunocompromised influenza-positive
patients with an equal number of nonimmunocompromised influenza-negative patients
with severe CAP. They found that influenza was “independently associated with invasive
pulmonary aspergillosis.”[38]
Treatment
Data on the use of NA inhibitors (NAI) in intensive care patients are limited. A meta-analysis
by Muthuri et al showed that early initiation (≤2 days after symptom onset) of NAI
treatment versus late initiation (treatment commenced >2 days after symptom onset)
reduced mortality and requirement of ventilatory support but did not reduce the incidence
of influenza-related pneumonia in patients with influenza A(H1N1)pdm09. They found
that among the critically ill patient population, NAI use was associated with a reduction
in mortality compared with no therapy (odds ratio [OR]: 0.72; 95% confidence interval
[CI]: 0.56–0.94) and that early use of NAIs was associated with a reduction in mortality
compared with late initiation of treatment (OR: 0.62; 95% CI: 0.49–0.77).[39]
The impact of early (≤2 days of symptom onset) versus late (>2 days after symptom
onset) administration of oseltamivir was also examined by Rodrigo et al. This was
a prospective observational study of adult patients admitted to ICU with microbiologically
confirmed influenza A during the 2009 influenza season in Spain. The study included
657 patients. In the entire patient population, there was a nonsignificant difference
in ICU mortality in patients who received early treatment (EL) versus late treatment
(LT) (OR: 1.45; 95% CI: 0.96–2.21).[40]
A further subgroup analysis looked at the 404 patients who required MV. Of these,
385 patients received effective antiviral therapy. ET was initiated in 20.5% of patients
(n = 79), whereas LT was initiated in 79.5% of patients (n = 306). LT compared with ET was associated with increased ICU LOS (22.7 ± 16.7 vs.
18.4 ± 14.2 days; p = 0.03), hospital LOS (34.0 ± 20.3 vs. 27.2 ± 18.2 days; p = 0.001), and MV days (17.4 ± 15.2 vs. 14.0 ± 12.4; p = 0.04). ICU mortality was also higher with LT (34.3%) than with ET (21.5%; OR: 1.9;
95% CI: 1.06–3.41). These findings suggest that early oseltamivir administration was
associated with improved outcomes in ventilated patients during the 2009 H1N1 pandemic.[40] A study by Lytras et al examined the effect of early oseltamivir treatment on mortality
in critically ill patients infected with influenza A/H1N1, A/H2N3, and influenza B
over eight seasons from 2010 to 2011 and from 2017 to 2018. This was a cohort study
including 1,330 patients, of whom 622 (46.8%) died in the ICU. Among patients with
influenza A/H3N2, there was a reduction in mortality observed in the ET group compared
with the LT group (33.7 vs. 48.4% respectively; p = 0.029). Median LOS in the ICU was also shorter in the ET group (12 vs. 15 days;
p = 0.003). In this study, no significant effect of early versus late oseltamivir was
observed for influenza A/H1N1 or influenza B.[41]
Concerns regarding the absorption of oseltamivir in critically ill patients have led
to several studies of the use of high-dose oseltamivir. The standard dose of 75 mg
twice daily was found to achieve similar plasma levels in critically ill patients
compared with ambulatory patients. These concentrations were far in excess of concentrations
required to maximally inhibit NA activity of the virus.[42] High-dose oseltamivir has also been shown to achieve similar effects to standard
dose oseltamivir in terms of mortality and viral RNA.[43] While 5 days of oseltamivir has been the standard duration of therapy in ambulatory
patients, it has been suggested that therapy should be continued in patients who remain
in a critical state after 5 days of treatment.[44]
[45] The intravenous NAI, peramivir, has been shown to be as effective as oral oseltamivir
in terms of mortality and length ICU stay.[46] It could thus be considered as an alternative in those unable to take oral oseltamivir.
Other potential treatments have been investigated. A systematic review and meta-analysis
by Mair-Jenkins et al examined studies on convalescent plasma for the treatment of
severe acute respiratory infections of viral etiology. It included a post hoc meta-analysis
of pooled data from eight comparative studies: two studies on SARS-CoV (severe acute
respiratory syndrome-coronavirus) infection, two on influenza A(H1N1)pdm09 infection,
one on avian influenza A(H5N1) infection, and three on Spanish influenza A(H1N1) infection.
The results from this meta-analysis suggest that convalescent plasma may have an impact
on reducing mortality and viral load in patients with severe acute respiratory infections
of viral etiology.[44] There have been case reports of a rapid reduction in detectable viral load in patients
with influenza A (H5N1) treated with convalescent plasma without significant serious
events.[47]
[48]
[49]
A prospective cohort study conducted during the H1N1 2009 pandemic included 93 patients
with severe infection requiring intensive care. Twenty patients (21.5%) received convalescent
plasma. Mortality in the treatment group was significantly lower (20.0 vs. 54.8%;
p = 0.01). Respiratory tract viral load, IL-6, Il-10, and TNF-α were also significantly
lower in the treatment group.[50]
Different studies have tried to analyze the association of the role of adjuvant immunomodulatory
agents for the treatment of severe influenza, including corticosteroids, statins,
macrolides, nonimmune intravenous immunoglobulin, N-acetylcysteine, pamidronate, nitazoxanide,
chloroquine, antiC5a antibody, IFNs, human mesenchymal stromal cells, mycophenolic
acid, peroxisome proliferator-activated receptors agonists, nonsteroidal anti-inflammatory
agents, and mesalazine, with the role of plasmapheresis and hemoperfusion as a rescue
therapy.[51] While none of these immunomodulatory therapies have shown any benefit, we have to
acknowledge that the evidence is unclear due to limited published database on randomized
controlled trials (RCTs). In critically ill patients, two of these coadjuvant treatments
have gathered most of the attention: macrolides and corticosteroids. The use of macrolides
was analyzed in a large cohort of patients with the use of a propensity score analysis,
and their use was not associated with any benefit in critically ill patients.[52]
A Cochrane review (originally published in 2016 followed by updated review in 2019)
included 30 studies with 99,224 participants and found that corticosteroid therapy
was associated with increased mortality. A similar increase in risk of mortality was
seen in a stratified analysis of studies reporting adjusted estimates. An association
between corticosteroid therapy and increased mortality was also seen in a pooled analysis
of six studies that reported adjusted hazard ratios (HRs) (HR: 1.49; 95% CI: 1.09–2.02;
I
2 = 69%). Increased odds of hospital-acquired infection related to corticosteroid therapy
were found in a pooled analysis of seven studies (pooled OR: 2.74; 95% CI: 1.51–4.95;
I
2 = 90%); all were unadjusted estimates, and the data was graded as of very low certainty.
Limitations of the review included inconsistent reporting of variables and low quality
of data specific to mortality.[53]
Corticosteroids have been shown in several meta-analyses to be associated with increased
mortality.[54]
[55]
[56] As a caveat, it has been suggested that corticosteroids may have been given to the
sicker patients in the studies included in these meta-analyses, patients in whom the
mortality was going to be higher anyway. The authors of these meta-analyses also concluded
that there is a lack of sufficiently powered randomized trials examining the issue.
Regarding extracorporeal life support, the 2009 pandemic saw an increase in frequency
of the use of venovenous extracorporeal membrane oxygenation (ECMO) as a rescue therapy
in patients with severe acute respiratory distress syndrome (ARDS). A systematic review
by Sukhal et al examined the use of ECMO in severe influenza infection. While there
is a lack of randomized trials in the study, their results do suggest a benefit from
the initiation of ECMO in severe respiratory failure secondary to H1N1 influenza.[57]
Nonrespiratory Complications
Cardiovascular Complications
The incidence of myocarditis in patients with influenza may be as high as 10%.[58] It commonly occurs between days 4 and 7 after the onset of influenza symptoms.[59] Myocarditis is diagnosed based on a combination of symptoms, elevated cardiac enzymes,
and echocardiographic findings. Myocarditis is not limited to those with severe respiratory
manifestations of influenza. Symptoms related to myocarditis, such as chest pain,
dyspnea, and syncope, may have been the cause of presentation to hospital in the first
instance.[59] The clinical manifestations range from subclinical myocarditis to sudden death,
new-onset atrial or ventricular arrhythmias, complete heart block, heart failure,
pericardial effusion, cardiac tamponade, and acute myocardial infection (AMI)-like
syndromes.[58]
[60] The most common complication is congestive heart failure diagnosed by global hypokinesis
on echo/MRI (magnetic resonance imaging), which has been reported in 84% (37/44) of
patients with influenza-associated myocarditis. The majority (70%; 26/37) of those
who had myocarditis-related reduced ejection fraction (ranging from 8 to 50%) experienced
resolution of their systolic function, typically within 20 days of the onset of dysfunction.[60]
Many patients who develop influenza-related myocarditis require advanced cardiac support
therapies such as intra-aortic balloon pumps and ECMO. Early diagnosis is paramount,
and mortality has been reported as approximately 23%.[60] It is important to note that reduced ejection fraction in the absence of myocarditis
has been reported in influenza infection. Right ventricular dysfunction appears to
be more common than left ventricular dysfunction and is over and above what would
normally be expected in patients with ARDS.[61]
A meta-analysis of case–control studies by Barnes et al found that recent influenza
infection, ILI, or respiratory tract infection was significantly more likely in AMI
cases (pooled OR: 2.01; 95% CI: 1.47–2.76). In addition, influenza vaccination was
negatively associated with AMI (pooled OR: 0.71; 95% CI: 0.56–0.91).[49] These findings are in keeping with other studies on the association between influenza
and AMI,[62]
[63] and influenza vaccination and AMI.[64]
[65] The pathogenesis may be due to several mechanisms, including increased coronary
and systemic inflammatory activity that drives procoagulant processes, dominant prothrombotic
conditions, increased biomechanical stress on coronary arteries, variations in the
coronary arterial tone, disturbed hemodynamic hemostasis, and altered metabolic balance.[66]
Other less common cardiovascular complications are dysrhythmias and pericarditis.
The most commonly reported cardiac arrhythmias associated with influenza are atrioventricular
conduction block and ventricular fibrillation. These are usually due to underlying
fulminant myocarditis.[58] Although pericarditis is a recognized complication of influenza infection, it is
often mild and uncomplicated.[58]
Neurologic Complications
Influenza-associated encephalitis or encephalopathy is a syndrome characterized by
an impaired level of consciousness occurring within a few days of influenza infection.
The most common neurologic symptoms are confusion and seizures. MRI and computed tomography
(CT) commonly produce abnormal findings, with lesions being located throughout the
brain with no characteristic patterns or areas of focus.[67]
While the most common associated agents in Guillain–Barre's syndrome (GBS) are Campylobacter jejuni, M. pneumoniae, and EBV, 60 to 70% of cases of GBS do not have a clear etiology identified.[60] Influenza virus has been proposed as an important and underrecognized cause of GBS.
Numerous studies have found a significantly increased risk of GBS in the months following
influenza infection.[68]
[69]
In addition to neurologic complications, elevation in creatine kinase (CK) has been
suggested as a biomarker of the severity of influenza infection. In a study by Borgatta
et al of cases of influenza A pH1N1 infection in 2009, CK ≥ 500 UI/L was associated
with greater renal dysfunction and requirement of renal replacement therapy. Increase
of CK ≥ 1,000 UI/L was associated with greater intubation risk, longer duration of
MV, and 5 extra days of ICU and hospital LOS.[70] Rhabdomyolysis, although rare, has been reported in association with influenza infection.[60]
Mortality
The hospitalization fatality risk, defined as the probability of death among H1N1pdm09
patients who required hospitalization for medical reasons, was examined in a systematic
review and meta-analysis by Wong et al. Crude estimates of the HFR ranged from 0 to
52%. There was, however, substantial heterogeneity of studies. Higher estimates came
from tertiary-care referral hospitals in countries with lower gross domestic products
(GDPs). Countries with lower GDPs were hypothesized to have had higher thresholds
for hospital admission and ICU treatment. The hospitalized cases may have been more
severe than in countries with higher GDPs. The risk of death would thus have been
higher. In wealthy countries, the estimate was 1 to 3% in all settings.[71] A systematic review by Khandaker et al found a confirmed case fatality rate of 1.1%
in HICs and 4.6% in upper- and lower-middle income countries during the pandemic of
2009.[72] The mortality rate for critically ill patients with severe influenza requiring admission
to the ICU during the 2009 to 2010 pandemic was approximately 26% in HICs, 37% in
upper-middle income countries, and 58% in lower-middle income countries.[73]
Other Severe Nosocomial Viral Infection in Immunocompromised Patients
Immunoparalysis following the initial proinflammatory response to physiological insult
(sepsis, trauma, etc.) is frequent in nonimmunocompromised ICU patients.[74] One of the consequences of this immunoparalysis is the reactivation of latent viruses,
with herpesviridae (mostly HSV, CMV, and EBV) being the most frequent.
Herpes Simplex Virus
Numerous studies have evaluated HSV reactivation in ICU patients[75]
[76]
[77]
[78]
[79] ([Table 1]). To summarize these studies, HSV reactivation starts in the oropharyngeal tract
in 20 to 50% of ICU patients, 3 to 5 days after ICU admission, followed by a descending
lower respiratory tract colonization in 20 to 65% of mechanically ventilated patients,
after a median of 7 days of MV and with a peak of virus load 12 days after MV start.[80] In some patients, a true lung infection (HSV bronchopneumonitis) can occur after
a median of 14 days of MV; in a study evaluating 201 patients with prolonged (>4 days)
MV, Luyt et al found that 20% of them had HSV bronchopneumonitis with cytological
and/or histological signs of deep lung infection.[76] Distinguishing HSV lung reactivation from infection may be difficult; indeed, lung
infection is defined by clinical signs, presence of HSV, and cytological/histological
criteria, that is, HSV-specific nuclear inclusions on cells collected during bronchoalveolar
lavage (BAL).[76] However, this technique is difficult to implement and may be subjective. Virus load
in BAL fluid, with a cutoff set at 105 copies/mL, may be a good alternative.[76]
[78]
[81]
Table 1
Main studies having evaluated HSV, CMV, and EBV reactivation in ICU patients
|
Study
|
Population
|
Virus reactivation frequency, N (%)
|
Method of detection
|
|
HSV reactivation
|
|
Bruynseels et al, 2003[75]
|
764 patients, 361 of them receiving MV
|
169 /764 (22%) in the throat
58/361 (19%) in distal airways
|
Viral culture
|
|
Ong et al, 2004[77]
|
393 receiving MV
|
106 (27%)
|
PCR
|
|
Luyt et al, 2007[76]
|
201 patients ventilated for >4 d, suspected of having developed VAP
|
109 (54%) in the throat
129 (64%) in distal airways
|
PCR, viral culture
|
|
Linssen et al, 2008[78]
|
260 patients suspected of having developed VAP
|
99 (32%) in distal airways
|
PCR
|
|
Costa et al, 2012[79]
|
127 patients suspected of having developed VAP
|
38 (31%) in distal airways
|
PCR
|
|
CMV blood reactivation
|
|
Jaber et al, 2005[85]
|
237 patients with fever
|
40 (17%)
|
pp65 antigen
|
|
Limaye et al, 2008[86]
|
120 CMV-seropositive patients
|
39 (33%)
|
PCR
|
|
Chiche et al, 2009[87]
|
242 mechanically ventilated patients
|
33 (14%)
|
pp65 antigen
|
|
Limaye et al, 2017[88]
|
72 CMV-seropositive patients included in the placebo arm
|
28 (39%)
|
PCR
|
|
CMV lung disease
|
|
Papazian et al, 1996[89]
|
86 patients with acute respiratory failure or VAP
|
25 (29%)
|
Histology (autopsy or biopsy)
|
|
Papazian et al, 2007[90]
|
100 patients with unexplained ARDS
|
30 (30%)
|
Histology (biopsy)
|
|
Chiche et al, 2009[87]
|
242 mechanically ventilated patients
|
11 (5%)
|
Viral culture
|
|
EBV reactivation
|
|
Tachikawa et al, 2014[93]
|
87 patients with unexplained ARDS
|
16 (18%) in BAL fluid
|
PCR in BAL fluid
|
|
Libert et al, 2015[94]
|
86 EBV-seropositive patients with ICU LOS ≥5 days
|
61 (71%) EBV detection in the blood
|
PCR in blood
|
|
Ong et al, 2017[95]
|
329 immunocompetent patients with septic shock
|
157 (48%) EBV detection in the blood
|
PCR in blood
|
Abbreviations: ARDS, acute respiratory distress syndrome; BAL, bronchoalveolar lavage;
CMV, cytomegalovirus; EBV, Epstein-Barr virus; HSV, herpes simplex virus; ICU, intensive
care unit; LOS, length of stay; MV, mechanical ventilation; PCR, polymerase chain
reaction; VAP, ventilator-associated pneumonia.
HSV reactivation is associated with a poor outcome; a meta-analysis showed that HSV
reactivation was associated with mortality (OR: 1.8; 95% CI: 1.2–2.6)[82]; however, the exact significance of HSV reactivation (i.e., bystander or true pathogen
with its own morbidity/mortality) remains to be determined. To date, only one small
randomized controlled study using prophylactic acyclovir failed to demonstrate any
clinical beneficial effect of antiviral treatment.[83] One retrospective study found an improvement in mortality in HSV carriers having
received acyclovir,[84] and one prospective study failed to show any beneficial effect of acyclovir in patients
with HSV bronchopneumonitis.[76]
Cytomegalovirus
Blood and/or lung CMV reactivation may occur in ICU patients[85]
[86]
[87]
[88]
[89]
[90] ([Table 1]). Blood CMV reactivation occurs in one-third of CMV-seropositive ICU patients after
a median of 4 to 12 days after admission. Lung CMV reactivation/infection is less
frequent, occurring in 5% of mechanically ventilated patients[87]; but the frequency can reach 30% in patients with acute lung injury without an obvious
cause.[89]
[90] A recent meta-analysis showed that 27% of ICU may experience CMV reactivation, whatever
be the site (blood or lung) of reactivation.[91] Although CMV blood reactivation is associated with poor prognosis,[82]
[91] no study has evaluated the relationship between CMV blood reactivation and CMV disease
(i.e., organ involvement). CMV lung disease has been almost exclusively diagnosed
using histology on lung biopsies or autopsies,[89]
[90] whereas the use of cytology on BAL-collected cells (looking for CMV-specific inclusions)
or quantitative polymerase chain reaction (PCR) has never been investigated.
Like HSV, CMV reactivation is associated with a poor outcome; a recent meta-analysis
showed that CMV reactivation in nonimmunocompromised patients was associated with
mortality (OR: 1.72; 95% CI: 1.04–2.85).[91] Moreover, Limaye et al found that CMV virus load was associated with mortality:
the higher the virus load, the higher the mortality.[86] However, again, the exact significance of CMV reactivation is not known; it could
be a marker of severity (bystander) or a pathogen with true morbidity and/or mortality.
Two randomized controlled trials evaluating the effectiveness of prophylactic anti-CMV
treatment in CMV-positive ICU patients were recently published.[88]
[92] The first one evaluated prophylactic valganciclovir or valacyclovir, as compared
with a placebo, to decrease CMV reactivation. While inclusions in the valacyclovir
arm were prematurely stopped due to unexplained increased mortality, patients treated
with valganciclovir had less CMV reactivation than, but similar outcomes to, placebo-treated
patients.[92] In the second one, a double-blind, placebo-controlled trial, the authors evaluated
prophylactic ganciclovir to reduce IL-6 level (measured 14 days after randomization).
Although ganciclovir failed to reduce IL-6 level at day 14, as compared with placebo,
there was a trend toward increased ventilator-free days at day 28 in patients having
received ganciclovir, but with similar mortality.[88]
Epstein-Barr Virus
Recently, some authors investigated the frequency of EBV DNA detection in BAL fluid[93] or in the blood[94]
[95] using PCR ([Table 1]). They found that EBV DNA detection is frequent in ICU patients and seems to be
associated with mortality.[94]
[95] Again, the exact significance of EBV detection in ICU patients has to be determined,
and thus to consider a specific treatment against EBV in ICU patients with EBV DNA
detection is to date premature.
In summary, herpesviridae reactivations are frequent in ICU patients and associated
with mortality. However, the exact significance of herpesviridae reactivation is poorly
understood. In some cases, it is associated with a true disease; but in some cases,
the relationship between viral reactivation and viral disease is not established.
In these latter cases, whereas a specific antiviral treatment may improve outcome
remains to be determined. To date, neither prophylactic acyclovir to prevent HSV reactivation
nor prophylactic ganciclovir to prevent CMV reactivation can be recommended; preemptive
treatment with acyclovir in patients with oropharyngeal HSV reactivation or ganciclovir
in patients with CMV blood reactivation is under investigation (PTH [Preemptive Treatment
for Herpesviridae] study, Clinical Trials n° NCT02152358). Curative treatment of HSV
bronchopneumonitis or CMV lung disease is based on expert opinions in patients with
either cytological/histological proofs of lung involvement, high viral load, or specific
clinical and biological patterns suggestive of CMV.[96]
[97]
