Background
Sepsis and the more severe form, septic shock, are devastating conditions with high mortality and morbidity caused by a systemic infection leading to organ dysfunction [
1,
2]. A recent extensive systemic review of observational studies from North America and Europe showed that 10% of patients admitted to intensive care units (ICUs) were diagnosed with septic shock, with an ICU mortality of 38% [
3]. Gram-negative bacteria are the most common group of sepsis-causing organism (62%), but the incidence of gram-positive bacteria has increased in frequency over time [
4].
One important gram-positive bacterium that causes sepsis is group A streptococcus (GAS), and it is remarkable how this very common bacterium, usually causing mild diseases such as pharyngitis and impetigo, can cause invasive infections that include necrotising fasciitis and streptococcal toxic shock syndrome (STSS). From a global perspective, GAS ranks among the top 10 infectious causes of human mortality [
5]. GAS strains are classified based on serological typing of the T antigen, or genetic differences in the cell surface M protein, encoded by the
emm gene. More than 220 different
emm-types have been described [
6,
7]. M proteins are virulence factors that contribute to the massive inflammatory effect seen in sepsis via stimulation of immune cells leading to extensive cytokine release [
8].
Incidences of invasive group A streptococcus (iGAS) have usually been reported to be around 6 cases per 100,000 people per year [
9,
10], with a dominance of
emm1 in around 30%. In a prospective epidemiological study of a cohort of 142 adults and children from Greece [
11], it was demonstrated that
emm1 was associated with more severe infections such as STSS and higher ICU admission rates compared to other iGAS. Another major epidemiological study from North America included 9557 cases of iGAS retrospectively (3.8 cases per 100,000 people per year), with a mortality of 11.7%, and presented the most common
emm-type to be
emm1 (22%) [
12]. Only 13–15% of patients with iGAS have been described to develop STSS, but the mortality in this group is usually high, with a range between 23 and 44% [
13].
There are many valuable studies on iGAS infections where general patients are mixed with critically ill patients [
14‐
18]. To the best of our knowledge, there is a paucity of studies where critically ill patients with iGAS are studied as a separate cohort and compared to other critically ill patients. Therefore, we performed this observational registry study on patients with iGAS infection who had been admitted to the ICU, with the primary aim to describe these patients in detail and with the secondary aim to evaluate mortality and morbidity in this cohort as compared to other patients with severe sepsis or septic shock admitted to the ICU without iGAS infection. Our hypothesis was that patients with iGAS infection fare worse concerning both morbidity and mortality than other patients with severe sepsis or septic shock admitted to the ICU.
Discussion
In this single-centre retrospective registry study on critically ill patients with severe sepsis or septic shock, we identified 53 unique patients with iGAS over a 12-year period. Patients with iGAS had a lower median age than the non-iGAS patients, presented a lower median SAPS 3 score at admission and had a higher incidence of cardiovascular cause for admission. After correction for severity of illness and age, iGAS infection was associated with lower mortality risk. Morbidity analyses, also corrected for severity of illness and age, demonstrated that patients with iGAS infection were more likely to develop renal failure measured with AKIN-crea.
Our hypothesis that patients with iGAS infection would fare worse concerning both morbidity and mortality compared to controls was proven wrong with regard to mortality and proven right in one aspect with regard to morbidity, i.e. renal failure. These are unexpected findings because patients with iGAS infection in general, and those presenting the
emm1/T1 antigen in particular, have previously been described as having worse survival rates [
18,
27,
28]. However, it should be noted that these studies were performed in cohorts of general patients and not only in critically ill patients, as in the present study. Furthermore, the control group in the present study included only patients with severe sepsis and septic shock, i.e. a control group with severely ill patients. Beyond that, we suggest at least two explanations for our findings. Firstly, iGAS infections are widely recognised as aggressive acute conditions where surgical treatment must be initiated without delay. This surgical treatment is normally very effective as source control and is also complemented with necessary pharmacological treatment with antibiotics and sometimes IVIG. In contrast, patients in the control group were very heterogeneous and source control is rarely as straightforward and effective as with iGAS. Regression analyses were not corrected for the fast and effective treatment in the iGAS group, which may represent a bias in the analyses. Secondly, SAPS 3 may not be sensitive enough to describe the true difference of severity of illness between the groups. As an example, it can be mentioned that comorbidity must be very severe to affect the SAPS 3 score. Considering the higher median age of patients in the control group, it is possible that patients in the control group were more severely ill than SAPS 3 will reflect. In summary, the fast and effective source control in the iGAS group, together with possible underestimated severity of illness in the control group, may contribute to the unexpected results in the corrected regression analyses.
It can be argued that the comparison between only culture-positive patients in the iGAS group with a mixture of culture-positive and culture-negative patients in the control group is unfair. The sensitivity analyses that were performed to test if this imbalance affected the main results demonstrated that it did not which indicates that this imbalance between groups did not explain the results (Additional file
1).
Although studies on critically ill patients with iGAS in the ICU are scarce, studies on all patients admitted to a hospital with iGAS are more common. Mortality in all patients with GAS infection has previously been reported to be 8–23% in the first 7 days [
7,
29]. Two studies have reported mortality rates of 38–40% in patients with iGAS admitted to the ICU [
30,
31]. However, in Stockmann and colleagues’ large epidemiological study on ICU patients with iGAS infection in Utah, including an impressive 1514 patients over 8 years (2002–2010), they found a mortality rate of 6% in iGAS patients > 18 years old admitted to the ICU [
9]. This is in agreement with the present study where ICU mortality was 5.7% for iGAS patients (Table
5). Based on aggregated reports from the Public Health Agency in the region in which we performed our study, and given the catchment of 335,000 inhabitants for the University Hospital in Lund, the incidence of iGAS in our material was estimated at 6.0 per 100,000 inhabitants, which is in agreement with the study from Utah where the incidence was 6.3 per 100,000 inhabitants. Furthermore, in the study from Utah, the proportion of patients with iGAS infection admitted to ICU was 19%, compared to an estimated 18% (53 per 295) in the present study.
In the present study, the incidence of renal failure during the ICU stay was high in the iGAS group. The reasons for acute kidney injury (AKI) in septic patients are multifactorial. Disturbed microcirculation is considered to play an important role, since AKI in sepsis can develop in the presence of normal renal blood flow [
32]. Overproduction of reactive oxygen, nitrogen species and cytokines that lead to downregulation of cell function to minimise energy demand, and thereby improving cell survival of tubular cells, are other mechanisms [
32,
33]. M1 protein, situated on the surface of GAS, is a known virulence factor that leads to extensive cytokine release from monocytes and endothelial cells [
8]. A rare form of acute interstitial nephritis (AIN) has also been described, where the virulence factor streptococcal pyrogenic exotoxin B (SPE B) seems to induce tubule-interstitial damage via T cell proliferation and cytokine production [
34]. All this indicates that the renal failure in iGAS infection may be due to the bacteria and the immunological response induced, rather than diminished blood flow as a consequence of the hypotension in sepsis/septic shock. This may, at least in part, explain why patients in the iGAS group developed a higher degree of renal failure measured with AKIN-crea and were still more likely to survive.
A notable finding in our study is that only 50% of patients in the non-iGAS group, and 60% in the iGAS group, were diagnosed with septic shock according to the Sepsis 3 definition. In a study from 2017, Sterling and colleagues reported that in a cohort of 470 patients diagnosed with septic shock using older definitions, only 43% had septic shock according to Sepsis 3. As expected, the mortality in the two different groups differed (29% in the group meeting Sepsis 3 criteria compared to 14% using the older definition) [
35]. In a large review and meta-analysis performed by Vincent and colleagues, the overall pooled frequency of septic shock diagnosed at ICU admission was 10% according to Sepsis 2 but decreased to 6.5% using Sepsis 3 criteria [
3]. Taken together, this points out that Sepsis 2 overestimates the incidence of septic shock compared to Sepsis 3, which is also confirmed in our data.
Fifty patients with iGAS were typed regarding
emm/T-type. Of these, 50% were typed as
emm1 or T1. This is in agreement with the distribution of
emm1 during the years with peak incidences reported from the Public Health Agency of Sweden. In 2017–2018, the incidence of iGAS in Sweden was 7.9 per 100,000 people, with a 30-day mortality of 12%. The most frequent types were
emm1 (48%), 3, 4, 12, 28 and 89 [
10]. In 2012–2013, there was also a peak in the incidence of iGAS (7.8 per 100,000) with
emm1 (42%) dominating. The years between 2013 and 2017 reported an incidence of 5.8–6.6 per 100,000 and an
emm1 frequency between 20 and 32% [
10]. This indicates that there is a variation over time of the
emm-types and that
emm1 is responsible for the peak in incidences.
In our material, the majority of patients with necrotising fasciitis were found in the emm1/T1 group (72% vs 44% in the non-emm1/T1, p = 0.08). The severity of the infections in the emm1/T1 group was also underlined by a lower DAF vasopressor and higher AKIN-crea in relation to non-emm1/T1. There was, however, no difference in mortality regarding emm/T-type. This might be explained by the possibility of achieving easier source control by interventions in the operating room regarding the soft tissue infections more common in the emm1/T1 group, in addition to correct antibiotics and in some cases IVIG.
We recognise the limitations of the present study due to its retrospective nature. It should be noted that as in every study based on results from cultures from sterile sites, there is a risk of false-negative cultures, for example, due to cultures taken after the first dose of antibiotics. Another aspect that should be taken into consideration is that in the multivariable logistic regression analysis, higher age seemed to be associated with lower risk of respiratory failure. This result is not in agreement with the other findings in this study and the reason remains unexplained but may represent a statistical type I error. Furthermore, the number of iGAS patients is rather limited and collected from a single centre, which may not give the study sufficient power for risk prediction of all outcomes and may also question the external validity of the results.
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