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Severe community-acquired pneumonia due to Streptococcus pyogenes in the Newcastle area

Background
An apparent increase in the incidence of severe community-acquired pneumonia (CAP) caused by Streptococcus pyogenes (group A Streptococcus - GAS) was observed during 2017 in the Newcastle area. The study was undertaken to establish whether there was a true increase in severe S. pyogenes pneumonia and to explore its epidemiology and clinical features.


Methods
The study was a retrospective descriptive study of S. pyogenes pneumonia set in two tertiary referral hospitals in Newcastle, a large regional city, during the period 2007 to 2018. Subjects were adults identified as having S. pyogenes pneumonia by searching a database of severe CAP (defined as requiring intensive care unit [ICU] admission) for the period 2007-2018. Laboratory records were also searched for sterile site isolates of S. pyogenes to identify patients not requiring ICU admission.


Results
There were 13 cases of S. pyogenes CAP identified during the study period, of whom 12 (92%) required ICU admission. S. pyogenes accounted for 12/728 (1.6%) cases of severe CAP during the study period. The severity of S. pyogenes pneumonia was high despite a mean patient age of 48 years and 7/13 (54%) having no significant past medical history. The mortality rate was 2/13 (15%). Viral co-infection was found in 6/12 (50%) of patients tested. Overall 7/12 (58%) of the patients with severe S. pyogenes CAP during the study period presented in the winter or spring of 2017.


Conclusions
Streptococcus pyogenes is a rare cause of severe CAP in the Newcastle area, but there was a marked increase in frequency observed during the 2017 influenza season. Further study of the epidemiology of invasive GAS (iGAS) disease in Newcastle is warranted to identify emerging trends in this severe infection.


Methods
The study was a retrospective descriptive study of S. pyogenes pneumonia set in two tertiary referral hospitals in Newcastle, a large regional city, during the period 2007 to 2018. Subjects were adults identified as having S. pyogenes pneumonia by searching a database of severe CAP (defined as requiring intensive care unit [ICU] admission) for the period 2007-2018. Laboratory records were also searched for sterile site isolates of S. pyogenes to identify patients not requiring ICU admission.

Results
There were 13 cases of S. pyogenes CAP identified during the study period, of whom 12 (92%) required ICU admission. S. pyogenes accounted for 12/728 (1.6%) cases of severe CAP during the study period. The severity of S. pyogenes pneumonia was high despite a mean patient age of 48 years and 7/13 (54%) having no significant past medical history. The mortality rate was 2/13 (15%). Viral co-infection was found in 6/12 (50%) of patients tested. Overall 7/12 (58%) of the patients with severe S. pyogenes CAP during the study period presented in the winter or spring of 2017.

Conclusions
Streptococcus pyogenes is a rare cause of severe CAP in the Newcastle area, but there was a marked increase in frequency observed during the 2017 influenza season. Further study of the epidemiology of invasive GAS (iGAS) disease in Newcastle is warranted to identify emerging trends in this severe infection.

Introduction
Streptococcus pyogenes commonly causes localised illness such as pharyngitis and skin/soft tissue infections (e.g. impetigo, cellulitis); it sometimes causes asymptomatic colonisation. S. pyogenes also causes invasive diseases which include bacteraemia, pneumonia, necrotising fasciitis and streptococcal toxic shock syndrome. During the early 20th century, prior to the introduction of antibiotics, S. pyogenes caused about 2-5% of bacterial pneumonia. 1 Large outbreaks of S. pyogenes pneumonia were sometimes seen as complications of respiratory virus infections such as influenza and measles. 1 S. pyogenes pneumonia has since become a relatively rare disease, with recent publications largely limited to case reports, small case series, reviews of recent literature and larger series of invasive S. pyogenes infections of all types ( Table 1). The latter include studies from Victoria and Western Sydney as well as tropical Australia (Northern Territory, north Queensland) [2][3][4][5][6][7] (Table 2).
During the winter and early spring of 2017, it was noticed that there were a number of patients presenting to public hospitals in Newcastle, New South Wales, with severe community-acquired pneumonia due to Streptococcus pyogenes. The current study was performed in order to assess whether there was a true increase in the local incidence of S. pyogenes pneumonia, and to describe its clinical features in a local population. A secondary aim was to determine the frequency of viral co-infection in these patients.

Setting, data collection
A database was maintained of episodes of severe community-acquired pneumonia, as defined by the requirement for intensive care unit (ICU) admission, at each of two tertiary referral centres in Newcastle (John Hunter Hospital and Calvary Mater Newcastle) during the period 1 January 2007 to 31 December 2018. The data were collected using a combination of prospective and retrospective methods. Information recorded in a spreadsheet included demographic details such as age, sex, comorbidities; clinical characteristics including requirement for inotropic support or mechanical ventilation, presence of acute kidney injury, length of hospital stay; and diagnostic information such as chest x-ray findings, inflammatory markers (C-reactive protein, procalcitonin) and tests for etiology of pneumonia (blood and sputum cultures, urinary Legionella and pneumococcal antigens, multiplex respiratory virus nucleic acid amplification tests [NAAT], pleural fluid culture and NAAT). The multiplex respiratory virus NAAT (Ausdiagnostics, Mascot, Australia) was available from 2012 and tested for influenza, parainfluenza, respiratory syncytial virus (RSV), adenovirus, picornavirus and human metapneumovirus. Prior to 2012, influenza was tested by NAAT and the other viruses by direct fluorescent antibody testing (DFA). The investigation of pneumonia etiology and the choice of diagnostic tests was directed by the treating team. A search was made for further patients with S. pyogenes pneumonia who were not admitted to ICU by searching the NSW Health Pathology database for positive blood cultures for S. pyogenes, which were cross-checked with admission chest x-ray reports. The study included only adult patients (aged ≥ 18 years). S. pyogenes was identified using Gram stain followed by serologic antigen testing and MALDI-TOF mass spectrometry (VITEK MS, bioMerieux).

Definitions
The diagnosis of community-acquired pneumonia was confirmed by the following: a chest x-ray report of a new pulmonary infiltrate documented within 24 hours of hospital admission; a clinical diagnosis of community-acquired pneumonia by the treating team; and clinical and/or laboratory findings consistent with infection. The following criteria were used to define S. pyogenes as the cause of community acquired pneumonia: positive blood or pleural fluid culture, or pleural fluid NAAT.

Patient characteristics
For the 12-year period from 1 January 2007 to 31 December 2018, a total of 213 adult patients with positive blood cultures for S. pyogenes were identified by searching the NSW Health Pathology database. There were 13 identified cases of community-acquired pneumonia due to S. pyogenes in adults, of whom all except one had severe CAP requiring ICU admission. The mean age was 48 years (range 18-77) and median 46 years; seven patients were male and 6 female. There was a striking increase in the number of cases diagnosed in 2017, with 7 of 13 cases (54%) occurring that year, which coincided with a severe influenza season (Tables 3,  4). Two of the patients presenting in 2017 lived less than 10 kilometres apart and presented to

Clinical course
S. pyogenes pneumonia was typically severe, with 12 of 13 (92%) patients admitted to ICU and the mortality rate 17% (2 of 12) when the outcome was known (one patient was transferred to a hospital outside the area without follow-up data). The two fatal cases died within 24 hours of presentation. Mechanical ventilation was required for 67% of patients (8 of 12), inotropic support for 67% (8 of 12) and haemodialysis for 33% (4 of 12). Surgery was undertaken in three patients, thoracotomy and decortication of empyema in two and below knee amputation in one. The mean length of stay for survivors was 28.2 days (range 5-116 days).

Microbiology
The streptococcal etiology for the S. pyogenes CAP was defined by positive blood cultures in 85% (11 of 13) of patients. Of the 2 patients with negative blood cultures, one had a positive pleural fluid culture for S. pyogenes and the other had Gram positive cocci seen on pleural fluid Gram stain with negative culture but positive 16S rRNA for S. pyogenes (Table 6).

Radiology
The chest x-ray for most patients showed extensive consolidation which was multilobar in 3 of 13 (23%) and bilateral in 3 of 13 (23%); rapid progression of consolidation was frequent.

Non-severe S. pyogenes CAP
In addition to the 12 patients with severe S. pyogenes pneumonia requiring ICU admission, only one other patient was identified over the study period of 2007-2018 who was admitted to hospital with S. pyogenes pneumonia of lesser severity (i.e. not requiring ICU admission).

S. pyogenes and severe CAP frequency
There was an increase in the total number of iGAS episodes during 2017, with 49 episodes in that year compared to 29 episodes in 2016 and 12 to 25 cases per year in the other years of the study.
The yearly number of cases of severe CAP (defined by ICU admission) ranged from 42 to 77 during the study period. In 2017 there were 73 episodes, which was the third-highest yearly total recorded during 2007-2018.
S. pyogenes accounted for 1.6% (12/728) cases of severe CAP over the course of the study. In 2017, 9.6% (7/73) of the patients with severe CAP had S. pyogenes infection; rates for other years studied were between zero and 2% with the exception of 2010 (3.5%, 2/57).

Discussion
There have been a number of publications describing rates of invasive S. pyogenes infection (iGAS) in different geographical areas, including data on the proportion of cases due to pneumonia as well as other types of infection ( Table 1). The Australian studies were mostly performed in tropical regions with large Aboriginal and Torres Strait Islander populations. A study of iGAS epidemiology was reported from western Sydney although the patient numbers were relatively small. 7 Pneumonia has accounted for between 6.6% 4 and 10.8% 3 of iGAS infections in published studies from different areas of Australia. The overall mortality from iGAS infection has ranged from 7% 2 to 13.8% 4 in Australian series, with the incidence between 2.1 per 100,000 per year in Victoria 6 and 82.5 per 100,000 per year in Aboriginal and Torres Strait Islander people in North Queensland. 2 Large series from western Europe and North America have reported the incidence of iGAS infections to range between 1.5 per 100,000 per year 8 and 6.3 per 100,000 per year, 9 comparable to that reported from Victoria. A consistent finding in larger surveys is that the mortality in GAS pneumonia is about twice that of iGAS infection as a whole. 9 There have been several case series of S. pyogenes pneumonia reported in the literature, as well as a literature review which included 16 cases from the past 3 decades. In the current study, the key features (Table 6) include high mortality and about half of the infections occurring in patients without pre-existing medical problems. A further 4 patients with severe S. pyogenes pneumonia have been reported in detail since the above literature review. [10][11][12] Other recent case series described 6 patients requiring ICU treatment for severe S. pyogenes pneumonia over the period 1999-2016 13 and 3 patients who rapidly died from severe S. pyogenes pneumonia with pulmonary haemorrhage. 14 The current study found a lower mortality rate (15%) than did the literature review for S. pyogenes pneumonia (38%) 15 or the two largest case series of GAS pneumonia (20%, 47%). 16,17 Previous studies showed relatively high proportions of otherwise healthy patients (32 to 63%), 15,16 similar to our findings that 6 of 12 (50%) patients with severe S. pyogenes pneumonia lacked significant comorbidities. We found that 50% of patients (6/12) had viral coinfection, which was particularly common during the 2017 upsurge in incidence of S. pyogenes pneumonia (5 of 7 patients tested) and included human metapneumovirus and RSV as well as influenza; the former two viruses have not been described before in association with S. pyogenes pneumo-nia to our knowledge. The 2017 influenza season reported unprecedented high incidences in New South Wales (Table 3).
We found that S. pyogenes was an uncommon cause of severe CAP, accounting for just 1.6% of 728 episodes over the period 2007-2018, but 9.6% of 73 episodes occurring in 2017. S. pyogenes pneumonia was usually severe, as shown by the requirement for ICU admission in 12 of 13 patients (92%) admitted to hospital. The rate of preceding influenza infection (4/13; 31%) in this study is noteworthy and warrants further investigation from other locations in Australia.
The exact pathogenesis of influenza virus predisposing to S. pyogenes pneumonia is not clear but believed to be due to several factors including increased production of fibronectin during influenza infection; increased accessibility of S. pyogenes to bind to fibronectin, facilitated by removal of sialic acid residues from the surfaces of host cells;, and activation of TGF-β by the neuraminidase enzyme. The latter process results in a signalling cascade causing increased fibronectin expression and hence bacterial adherence. 18 The protective effect of influenza vaccine on bacterial superinfection and severe bacterial pneumonia is uncertain. Another study showed that influenza vaccine led to enhanced clearance of microorganisms in the superinfected mice and hence suppressed mortality. 19 This study is one of the largest case series of adult S. pyogenes pneumonia reported in the literature. We employed a search strategy that maximised the identification of cases of S. pyogenes pneumonia by using multiple sources of data (ICU database for patient identification, pathology database for blood or pleural fluid cultures) and cross-checking with chest x-ray reports and electronic medical records. The ICU database search terms were intentionally broad (e.g. pneumonia, sepsis, respiratory infection) to avoid missing cases. It is possible that some cases of S. pyogenes pneumonia were missed if positive cultures were performed by other pathology services, although the number was expected to be very small. Patients treated in a private hospital may also have been missed.
Potential weaknesses of the study included a subjective definition of severe CAP (though used in numerous past studies), the geographically limited study population, not having detailed local data on overall iGAS incidence and the lack of emm-typing of the S. pyogenes isolates.
Likely reasons for the increased incidence of S. pyogenes pneumonia during 2017 may include the increased circulation and infection rates for influenza (Table 3) and other respiratory viruses, changes in circulating strains of S. pyogenes with more virulent strains predominating, and declining community and individual patient antibody titres against the prevalent strains of S. pyogenes. Further molecular analysis of the S. pyogenes isolates was not possible for reasons of funding, but emm-typing may have been helpful to further characterise the local epidemiology of invasive S. pyogenes infection. Specifically, the emergence of a new emm type or increased circulation of an existing emm type with particular tropism for causing pneumonia would have relevance to the community. Results of molecular analysis may also strengthen the case for mandatory public health notification of iGAS episodes, and may contribute toward the potential development of a GAS polyvalent vaccine in the future. To this end, a study which aims to study the local epidemiology of iGAS infection in more detail, with the addition of typing, is underway.

Conclusion
In the Newcastle area, Streptococcus pyogenes was an uncommon cause of severe communityacquired pneumonia during 2007 to 2018, but a dramatic increase in cases occurred during the severe influenza season in 2017. Viral coinfection occurred in half of the patients with severe S. pyogenes pneumonia, including RSV and human metapneumovirus as well as influenza A and B. Streptococcus pyogenes pneumonia was typically a severe bacteraemic illness with most patients requiring ICU admission and prolonged hospital admission, despite a relatively low age range with many being previously healthy. Further study of the S. pyogenes isolates, including emm typing and more data on S. pyogenes CAP and overall iGAS incidence in NSW, may help our understanding of the local epidemiology of this severe infection.