Febrile #70 – Strep on the GAS!

April 3, 2023

Summary

Drs. Anastasia “Tash” Theodosiou and Chrissie Jones chat about the diagnosis and management of Group A streptococcal infections and the recent increase in GAS cases in the UK

Credits

Hosts: Tash Theodosiou, Sara Dong

Guest: Chrissie Jones

Writing: Tash Theodosiou, Chrissie Jones, Sara Dong

Producing/Editing/Cover Art/Infographics: Sara Dong

Our Guests

Dr. Anastasia “Tash” Theodosiou

Dr. Theodosiou is an adult infectious diseases and microbiology registrar at the University of Southampton. She is currently completing a PhD supervised by Dr. Chrissie Jones (see below!). Her research involves a commensal human challenge model in pregnancy to study the respiratory microbiome in mother-infant pairs. Check out her website – Hello Micro!

Dr. Chrissie Jones

Dr. Jones is an Associate Professor of Paediatric Infectious Diseases at the University of Southampton.

Culture

Tash shared her adventures exploring Scotland

Chrissie recommended The Christie Affair

Consult Notes

Case Summary

5 year old previously healthy child with GAS pharyngitis
3 year old sibling with GAS empyema

Key Points

Group A Streptococcus (GAS)!

Given the significant media attention to a recent large increase in GAS caseload in UK with more reported scarlet fever, invasive infection, and deaths, this episode was created as an opportunity to review the management of GAS!

Before we start, here are a few key resource for strep pharyngitis:

GAS pharyngitis introduction & epidemiology

The most common GAS infection is acute pharyngotonsillitis (pharyngitis), which presents often with features such as:
- - Sore throat with tonsillar inflammation
  - Tender anterior cervical lymphadenopathy
  - Palatal petechiae
  - Strawberry tongue
Purulent complications of pharyngitis include:
- - Peritonsillar or retropharyngeal abscess
  - Suppurative cervical adenitis
  - Rarely, sinusitis, otitis media, and others
Nonsuppurative complications include:
- - Acute rheumatic fever (RF)
    - - Sequela of GAS pharyngitis
      - Endemic in parts of Africa, Asia, and the Pacific (including Australian and New Zealand indigenous populations)
      - US, Canada, and most of Europe are considered low-risk RF populations although sporadic cases do occur
  - Acute poststreptococcal glomerulonephritis (GN)
GAS pharyngitis is most common among school-aged children with a peak at 7-8 years old
- - Acute strep pharyngitis is rare in children <3 years old: These children may present with rhinitis, protracted febrile illness, anorexia, irritability instead
Incubation 2-5 days
Up to 30% of pharyngitis is GAS in kids (vs only 5-15% in adults)
Pharyngitis usually results from contact with respiratory secretions of someone with GAS pharyngitis
- - Close contact in schools, child care centers, contact sports, boarding school, and military installations facilitates transmission
Strep pharyngitis is more common during late autumn, winter, spring in temperate climates and during close contact at school
Some resources:

GAS pharyngitis diagnosis

Children more likely to have GAS are those with acute onset of sore throat and clinical symptoms such as pharyngeal exudate, pain on swallowing, fever, enlarged tender anterior cervical lymph nodes
Testing is generally not recommended for children younger than 3 and children with pharyngitis with obvious viral symptoms (eg rhinorrhea, cough, hoarseness, oral ulcers)
There are some known scoring systems to use for evaluating pharyngitis in the primary care setting

Centor Score (Modified/McIsaac) includes:

Age:
- +1 if 3-14 years old
- 0 if 15-44 years old
- -1 if >=45 years old
Exudate or swelling of tonsils +1
Tender/swollen anterior cervical lymph nodes +1
Temp >38C +1
Cough absent +1

FeverPAIN Score includes:

Fever in past 24 hrs +1
Absence of cough or coryza +1
Symptom onset <=3 days +1
Purulent tonsils +1
Severe tonsil inflammation +1

Score ≥4, 51-53% probability of strep pharyngitis
Score 3, 28-35%
Score 2, 11-17%
Score 1, 5-10%
Score 0, 1-2.5%

Score of ≥4 is associated with 62-65% isolation of streptococcus
Score of 3 is associated with 39-48%
Score of 2 is associated with 30-35%
Score of 0-1 is associated with 13-18% (close to background carriage rates)

Derived from this original study: Centor RM, Witherspoon JM, Dalton HP, Brody CE, Link K. The diagnosis of strep throat in adults in the emergency room. Med Decis Making. 1981;1(3):239-246. doi:10.1177/0272989X8100100304

Modified later to include age: McIsaac WJ, White D, Tannenbaum D, Low DE. A clinical score to reduce unnecessary antibiotic use in patients with sore throat. CMAJ. 1998;158(1):75-83.

Derived from this study: Little P, Hobbs FD, Moore M, et al. Clinical score and rapid antigen detection test to guide antibiotic use for sore throats: randomised controlled trial of PRISM (primary care streptococcal management) [published correction appears in BMJ. 2018 Mar 5;360:k1068]. BMJ. 2013;347:f5806. Published 2013 Oct 10. doi:10.1136/bmj.f5806

Validated in children and adults: McIsaac WJ, Kellner JD, Aufricht P, Vanjaka A, Low DE. Empirical validation of guidelines for the management of pharyngitis in children and adults [published correction appears in JAMA. 2005 Dec 7;294(21):2700]. JAMA. 2004;291(13):1587-1595. doi:10.1001/jama.291.13.1587

Another validation: Fine AM, Nizet V, Mandl KD. Large-scale validation of the Centor and McIsaac scores to predict group A streptococcal pharyngitis. Arch Intern Med. 2012;172(11):847-852. doi:10.1001/archinternmed.2012.950

There is also a RCT looking at the FeverPAIN score here: Little P, Hobbs FD, Moore M, et al. PRImary care Streptococcal Management (PRISM) study: in vitro study, diagnostic cohorts and a pragmatic adaptive randomised controlled trial with nested qualitative study and cost-effectiveness study. Health Technol Assess. 2014;18(6):vii-101. doi:10.3310/hta18060

Another reference: Little P, Moore M, Hobbs FD, et al. PRImary care Streptococcal Management (PRISM) study: identifying clinical variables associated with Lancefield group A β-haemolytic streptococci and Lancefield non-Group A streptococcal throat infections from two cohorts of patients presenting with an acute sore throat. BMJ Open. 2013;3(10):e003943. Published 2013 Oct 25. doi:10.1136/bmjopen-2013-003943

Should we take a throat swab?
- UK = only if diagnostic uncertainty or concern regarding antibiotic resistance
  - feverPAIN 4 equivalent to swab in UK population, so score is used to decide whether to treat rather than whether to swab
    - Usually treat if 4 or above; temporarily reduced to 3 in the UK due to increased circulation in the community; but will be increased to 4 again soon
- US = score used to decide whether to swab = kids >3 yo with rapid antigen test (PLUS culture if RADT negative or not available)

What tests are available for GAS pharyngitis?

Specimens should be obtained by vigorously swabbing both tonsils and posterior pharynx
The diagnosis of GAS pharyngitis is supported by RADT, positive throat culture, or molecular assay

Several rapid antigen detection tests (RADT) are available
- - Specificity is high ≥95% (very few false positive results)
  - Sensitivity varies considerably, generally 80-85% (so false negatives occur)
The sensitivity of test are highly dependent on quality of throat swab specimen, experience of test performer, and rigor of culture method used for comparison
Given high specificity of rapid antigen-based tests,
- - a positive result does not require culture confirmation
  - but a negative result requires confirmatory test in children
These tests are available at point of care and are based on enzyme or acid extraction of antigen from throat swabs

Throat culture on blood agar can confirm GAS infection [reference standard]
- - High sensitivity (90-95%)
  - Latex agglutination helps with differentiating GAS from other beta-hemolytic strep
  - False negative cultures results occur in <10% of symptomatic patients when adequate swab is obtained
  - One advantage is that culture can identify other bacterial causes of pharyngitis (eg, group C or G Strep, Arcanobacterium haemolyticum) – although most labs don’t routinely identify these pathogens unless requested
  - Slower turn around time (24-48 hrs) and must be performed in a lab

Molecular assays are available as well (PCR, nucleic acid amplification test)
- - Standard molecular assays have high sensitivity ≥97% and are faster than throat culture (1-3 hrs)
    - - Not point of care and still must be performed in lab
      - Can be expensive
  - Rapid molecular assays have high sensitivity (≥95%) and specificity (>90%) with rapid turnaround time of under 25 minutes
  - Follow-up throat cultures are not necessary with negative molecular assay results

Recovery of GAS organisms from the pharynx, including the number of colonies on a culture plate, does not distinguish patients with true acute streptococcal infection from chronic streptococcal carriers with intercurrent viral pharyngitis
As a reminder, Tash discussed spectrum bias = performance of test depends on the pretest probability
- - i.e. PTP of GAS in kids with sore throat = up to 30% (higher during outbreaks); i.e. sensitivity 70% would miss many >> confirm negatives with culture
  - Vs. adult/<3 yo PTP 5-10%, so don’t confirm negative with culture
Some resources:

What is the rationale for treating GAS pharyngitis with antibiotics?

To decrease duration and severity of symptoms, but…
- - Symptoms will resolve in 3-5 days for most patients
  - Symptoms are only decreased by 16-24h if antibiotics given within 48 hrs
  - Spinks A, Glasziou PP, Del Mar CB. Antibiotics for sore throat. Cochrane Database Syst Rev. 2013;2013(11):CD000023. Published 2013 Nov 5. doi:10.1002/14651858.CD000023.pub4
To decrease transmission to close contacts (especially to elderly / vulnerable)
- - Rate of GAS transmission from index case to close contacts is estimated between 5-50%
To decrease acute suppurative complications (such as otitis media, abscess or invasive infection)
To prevent delayed sequelae, particularly acute rheumatic fever
- - Even if started up to 9 days after symptom onset
  - Antimicrobial therapy to prevent GN after pyoderma or pharyngitis is not effective

Chrissie touched on number needed to treat (NNT) in certain settings:
- - NNT >4000 to prevent 1 quinsy from sore throat or 1 mastoiditis from OM… But only 39 for pneumonia in elderly
    - - Petersen I, Johnson AM, Islam A, Duckworth G, Livermore DM, Hayward AC. Protective effect of antibiotics against serious complications of common respiratory tract infections: retrospective cohort study with the UK General Practice Research Database. BMJ. 2007;335(7627):982. doi:10.1136/bmj.39345.405243.BE
  - NNT to prevent a 2ary case = about 300, but 82 for elderly couples & 50 for mother-neonate pairs
    - - Mearkle R, Saavedra-Campos M, Lamagni T, et al. Household transmission of invasive group A Streptococcus infections in England: a population-based study, 2009, 2011 to 2013. Euro Surveill. 2017;22(19):30532. doi:10.2807/1560-7917.ES.2017.22.19.30532
  - NNT for ARF estimated around 50 in high incidence setting… But difficult to extrapolate to v low incidence Western setting, theoretically many orders of mag higher
    - - Robertson KA, Volmink JA, Mayosi BM. Antibiotics for the primary prevention of acute rheumatic fever: a meta-analysis. BMC Cardiovasc Disord. 2005;5(1):11. Published 2005 May 31. doi:10.1186/1471-2261-5-11

Treatment of GAS pharyngitis

As an overview: S pyogenes is uniformly susceptible to all beta-lactam antibiotics
- - Susceptibility testing is needed only for non-beta-lactam agents (such as macrolide or clindamycin) to which S pyogenes can be resistant
Conventional wisdom = 10-day course of penicillin V = drug of choice for GAS pharyngitis
In reality, a 10-day course of amoxicillin is often used
- - Just as effective, better taste, fewer doses
IM penicillin G benzathine is appropriate therapy but administration may be painful
If nonanaphylactic allergy to PCN:
- - 10-day course of first-gen oral cephalosporin (cephalexin)
If immediate anaphylactic or type I hypersensitivity to PCN:
- - 10-day course of clindamycin
  - 5-day course of azithromycin
  - These are not preferred and should only be used if other options cannot be used
Tetracyclines, sulfonamides, fluoroquinolones should not be used for treating GAS pharyngitis
Macrolide resistance is common or rising in some communities – 7% UK (2-32% Europe), up to 20% USA
Why is there no penicillin resistance despite 80yrs of use?! There has never been a report of a clinical isolate of GAS that is resistant to PCN
- - Not entirely clear; PBP mutations not observed in clinical isolates
  - GM GAS strains engineered to express low-affinity PBP had much lower survival & virulence in vitro
  - i.e. penicillin resistance = too big a cost to bug’s survival
Cochrane review comparing penicillin vs other antibiotics = low-certainty evidence of varying quality, not a clear significant difference: van Driel ML, De Sutter AIM, Thorning S, Christiaens T. Different antibiotic treatments for group A streptococcal pharyngitis. Cochrane Database of Systematic Reviews 2021, Issue 3. Art. No.: CD004406. DOI: 10.1002/14651858.CD004406.pub5. Accessed 01 April 2023.
- - 19 trials comparing PCN to other antibiotics
  - Conclusions: uncertain if any clinically relevant differences
  - These results do not demonstrate that cephalosporins / macrolides are more effective than PCN for treatment of GAS pharyngitis

Duration of therapy for strep pharyngitis - does it have to be 10 days?

Guidelines tell us that a course shorter than 10 days is less likely to achieve bacterial eradication and is associated with more recurrence of infection, but it’s worth taking a dive into the background here. We covered some of this in the episode. Another great resource was the IDWeek 2022 Mano-a-Mano debate on whether GAS pharyngitis requires 10 days of antibiotic treatment from Drs. Jeffrey Gerber & Nicole Poole!
To summarize generally, the rationale/arguments for using 10 days (which is recommended by IDSA/CDC/AAP):
- - Shorter course treatment, particularly with penicillin, is associated with inferior bacteriologic eradication rates
  - Data examining prevention of acute rheumatic fever suggests use of 10 days over shorter course
The first large controlled trial for GAS was published in 1946, but there was no specific duration of therapy. Most patients received 1-5 days
- - SPINK WW, RANTZ LA, et al. Sulfadiazine and penicillin for hemolytic streptococcus infections of the upper respiratory tract; an evaluation in tonsillitis, nasopharyngitis and scarlet fever. Arch Intern Med (Chic). 1946 Mar;77:260-94. doi: 10.1001/archinte.1946.00210380025003. PMID: 21025322.
The 10 day duration was first introduced in 1947
- - GOERNER JR, MASSELL BF, JONES TD. Use of penicillin in the treatment of carriers of beta-hemolytic streptococci among patients with rheumatic fever. N Engl J Med. 1947;237(16):576-580. doi:10.1056/NEJM194710162371602
    - - Descriptive case series of 18 chronic carriers of GAS and 2 cases of acute strep tonsillitis who were treated with 10 days of IM penicillin >> 17/20 had eradication
      - Authors concluded that IM PCN x 10 day can eradicate the Strep carrier state
  - No specific reason for 10 days
The same authors then examined oral penicillin vs IM for GAS eradication and 10 days was used
- - Eradication was noted in 94% of patients in IM group vs 78% in the oral penicillin group. These groups were not compared, but authors concluded that 10 days might be better than 5d
  - MASSELL BF, DOW JW, JONES TD. Orally administered penicillin in patients with rheumatic fever. J Am Med Assoc. 1948 Dec 4;138(14):1030-6. doi: 10.1001/jama.1948.02900140022005. PMID: 18890448.
  - MASSELL BF, STURGIS GP, KNOBLOCH JD, STREEPER RB, HALL TN, NORCROSS P. Prevention of rheumatic fever by prompt penicillin therapy of hemolytic streptococcic respiratory infections; progress report. J Am Med Assoc. 1951 Aug 18;146(16):1469-74. doi: 10.1001/jama.1951.03670160011004. PMID: 14850321.
Studies in the 1950s used IM penicillin as a single dose or multiple doses over 4 days and found a 3% risk of acute rheumatic fever was reduced to <1% – but no oral antimicrobials were noted
- - These were done at an Air Force base in Wyoming, and later a program of prophylaxis was done in 1951 where recruits were grouped as: oral PCN BID x 5 days, oral PCN BID x 10 days, or control
  - There weren’t really details on the choices of duration and no statistical analysis was done – it just showed that 10 day group had lower carriage rate – but authors concluded that “it is probably necessary for penicillin to be given for approximately 10 days to eliminate GAS from carriers”
  - WANNAMAKER LW, DENNY FW, PERRY WD, et al. The effect of penicillin prophylaxis on streptococcal disease rates and the carrier state. N Engl J Med. 1953;249(1):1-7. doi:10.1056/NEJM195307022490101
  - McFARLAND RB, COLVIN VG, SEAL JR. Mass prophylaxis of epidemic streptococcal infections with benzathine penicillin G. II. Experience at a naval training center during the winter of 1956-57. N Engl J Med. 1958;258(26):1277-1284. doi:10.1056/NEJM195806262582601
In the 1950s, this data was used to make a recommendation for injectable depot procaine PCN every third day for 3 doses or oral PCN x 10 days to prevent rheumatic fever (although studies hadn’t been conducted on oral penicillin to prevent RF)
- - STATEMENTS of American Heart Association Council on Rheumatic Fever and Congenital Heart Disease. J Am Med Assoc. 1953 Jan 10;151(2):141-3. PMID: 12999527.
Additional studies from the 1950s continued to look at treatment of GAS, often stating oral treatment needed to be 8-10 days (although without clear explanations)
And at this point, the 10 day duration was appearing in various ID textbooks
So the results of those earlier Air Force base studies (on military recruit with highly symptomatic exudative pharyngitis) were applied to the civilian population, but the risk of acute rheumatic fever is likely much lower in other settings
Treating for 10 days has been thought to enhance the rate of GAS eradication from oropharynx when compared to 5 or 7 days in more recent studies since the 1980s
- - Schwartz RH, Wientzen RL Jr, Pedreira F, Feroli EJ, Mella GW, Guandolo VL. Penicillin V for group A streptococcal pharyngotonsillitis. A randomized trial of seven vs ten days’ therapy. JAMA. 1981;246(16):1790-1795. doi:10.1001/jama.246.16.1790
    - - First large study of short-course penicillin treatment: 7-day group had 31% failure rate while 10-day group had 18% failure rate
  - Gerber MA, Randolph MF, Chanatry J, Wright LL, De Meo K, Kaplan EL. Five vs ten days of penicillin V therapy for streptococcal pharyngitis. Am J Dis Child. 1987;141(2):224-227. doi:10.1001/archpedi.1987.04460020114043
    - - Compared 5 vs 10 days. Failure rate in 5-day group was 18% vs 18-day group of 6%
  - Skoog Ståhlgren G, Tyrstrup M, Edlund C, et al. Penicillin V four times daily for five days versus three times daily for 10 days in patients with pharyngotonsillitis caused by group A streptococci: randomised controlled, open label, non-inferiority study. BMJ. 2019;367:l5337. Published 2019 Oct 4. doi:10.1136/bmj.l5337
    - - In this RCT comparing 5d course of PCN vs 10 day course, clinical cure rates were similar between groups (90% vs 94%), but wide confidence intervals suggested that treatment differences may be apparent with larger sample size (n=433 in this study)
      - Bacterial eradication rates were lower in 5d group (80% vs 91%)
Nonpenicillin oral antimicrobials have been examined as well, given for <10 days
- - Falagas ME, Vouloumanou EK, Matthaiou DK, Kapaskelis AM, Karageorgopoulos DE. Effectiveness and safety of short-course vs long-course antibiotic therapy for group a beta hemolytic streptococcal tonsillopharyngitis: a meta-analysis of randomized trials. Mayo Clin Proc. 2008;83(8):880-889.
    - - Meta-analysis of randomized trials
      - 11 RCTs, 5-7 days vs 10
      - Microbiological eradication inferior for short-course (8 RCTs, 1607 patients, OR 0.49, 95% CI 0.32-0.74)
        PCN (3 RCTs, 500 patients; OR 0.36, 95% CI 0.13-0.99)
        Cephalosporins (4 RCTs, 1018 patients; OR 0.62, 95% CI 0.38-1.03)
Here is recent Cochrane review and update, which concluded 3-6 days had comparable efficacy compared to standard duration (10-day) oral penicillin in acute GAS pharyngitis. No conclusion could be drawn regarding efficacy of acute rheumatic fever prevention
- - Altamimi S, Khalil A, Khalaiwi KA, Milner R, Pusic MV, Al Othman MA. Short versus standard duration antibiotic therapy for acute streptococcal pharyngitis in children. Cochrane Database Syst Rev. 2009 Jan 21;(1):CD004872. doi: 10.1002/14651858.CD004872.pub2. Update in: Cochrane Database Syst Rev. 2012;8:CD004872. PMID: 19160243.
  - Altamimi S, Khalil A, Khalaiwi KA, Milner RA, Pusic MV, Al Othman MA. Short-term late-generation antibiotics versus longer term penicillin for acute streptococcal pharyngitis in children. Cochrane Database Syst Rev. 2012 Aug 15;(8):CD004872. doi: 10.1002/14651858.CD004872.pub3. PMID: 22895944.
So difficult to know how clinically important the distinction is between 10 days and perhaps 5-7 days – and – whether benefits of longer courses definitely outweigh the potential harms in high income countries (where antibiotic use is high and rates of GAS suppurative and non-suppurative complications are very low)
Check out this article for a nice overview: Radetsky M. Hostage to History: The Duration of Antimicrobial Treatment for Acute Streptococcal Pharyngitis. Pediatr Infect Dis J. 2017 May;36(5):507-512. doi: 10.1097/INF.0000000000001480. PMID: 28030530.

Other management considerations?

Return to school guidance
- - Exclude from school until 12 hrs (USA) – 24 hrs (UK) after starting antibiotics and afebrile
  - No one else in household needs swab or antibiotics if asymptomatic
  - Child doesn’t need repeat swab at end of course
Patients with repeated pharyngitis episodes at short intervals in whom GAS is documented pose a challenge. True recurrent infection is unlikely – more likely chronic carriage and intercurrent viral infections; usually no need to give antibiotics
Population carriage is up to 25% in school-age kids
- - Many will be asymptomatic transient or chronic carriers
  - Asymptomatic & chronic carriers MUCH less likely to transmit & less likely to develop IGAS themselves => i.e. usually no need to treat
  - Can consider eradication if high risk of complications, or outbreaks assoc with more virulent subtype); standard 10d abx +/- consider rif (USA)
  - Some resources on the prevalence of strep carriage:

What are other Group A Streptococcal infection presentations?

Scarlet fever
- - Exotoxin-producing GAS
  - Febrile illness first (usually with pharyngitis, much less commonly after SSTI)
  - Confluent erythematous “sandpaper” rash develops 12-48 hrs later (starts centrally and spreads; may peel at fingers/toes/groin)
  - Other than rash, the epidemiologic features, symptoms, sequelae, and treatment of scarlet fever are the same as those of strep pharyngitis
  - Antibiotics: 10d PCN
  - Notifiable in UK but not in US
Skin is the second most common site of GAS infection:
- - Pyoderma or impetigo (indistinguishable from S.aureus clinically)
    - - Longer incubation (10 days) and younger (2-5 yo) (vs pharyngitis)
  - Cellulitis and erysipelas
  - Streptococcal skin infections can be followed by GN, occasionally in epidemics, but GAS skin infection has not been proven to lead to RF
Others: vaginitis, bacteremia, sepsis, pneumonia, endocarditis, pericarditis, septic arthritis, necrotizing fasciitis, purpura fulminans, osteomyelitis, myositis, surgical wound infection, omphalitis
Another association to note:
- - PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections) is a subset of PANS (pediatric acute-onset neuropsychiatric syndrome)
    - - Association between GAS infection and sudden onset of obsessive-compulsive behavior, tic disorders, or other unexplained neurologic changes
      - Data for this association, diagnosis, and management relies on small studies and expert evaluation

Invasive GAS infection and STSS

Invasive Grp A Strep infections often encompass bacteremia with or without a focus of infection
- - Can present as streptococcal toxic shock syndrome (STSS), overwhelming sepsis, necrotizing skin infection
  - Although portal of entry is unknown in most invasive GAS infections, it is presumably skin or mucous membranes
Streptococcal toxic shock syndrome (STSS)
- - Infection of normally sterile body site(s) such as blood, pleura, CSF, etc with a toxin-producing GAS strain
  - Severe acute illness with fever, generalized erythroderma, rapid-onset hypotension, and signs of multi-organ involvement
  - Local soft tissue infection associated with severe, rapidly increasing pain is common
  - But STSS can occur without an identifiable focus of infection!
  - Occurs at any age
  - Incubation period not known but has been noted as short as 14 hrs when associated with subcutaneous inoculation of organisms (such as penetrating trauma or puerperal sepsis)
  - Diagnosed based on clinical and lab findings with isolation of GAS organisms; >50% of patients with STSS have positive blood cultures
In suspected invasive GAS infections, cultures of blood and focal sites of possible infection should be obtained
- - Blood cultures + sterile site & collection cultures
  - Very high bioburden of disease, so not surprising if positive
  - However, the organisms are exquisitely sensitive, so cultures may be negative after antibiotics started
  - If negative, can do PCR
Isolates can be sent to reference labs for typing
- - There are >240 distinct serotypes or genotypes of GAS (Streptococcus pyogenes)
  - Identified based on M-protein serotype or M-protein gene sequence (emm types)
  - emm typing is more discriminating than M-protein serotyping
  - Epidemiologic studies indicate an association between certain emm types and disease, such as:
    - - Types 1, 3, 5, 6, 14, 18, 19, 24 ~~ rheumatic fever
      - Types 2, 49, 55, 57, 59, 60, 61 ~~ pyoderma and acute GN
      - Types 1, 6, 12 ~~ pharyngitis and acute GN
  - Although many M-types can cause STSS, most cases are caused by emm 1 and emm 3 strains producing at least 1 pyrogenic exotoxin, most commonly streptococcal pyrogenic exotoxin A (speA)
    - - These toxins are superantigens >> stimulating production of TNF and other inflammatory mediators >> capillary leak and other physiologic changes (hypotension, multiorgan damage)
      - In the UK, an increase in scarlet fever cases since 2016 has been associated with a new strain of emm1 (M1UK lineage)

Management of IGAS infection / STSS

Antimicrobial treatment of STSS or serious IGAS infection:

IV beta-lactam is preferred (PCN or cefazolin/ceftriaxone)
- - Clindamycin +/- vancomycin if anaphylaxis and/or concern for MRSA
Addition of clindamycin to penicillin is recommended for serious GAS infection
- - Intracellular (rather than cell wall) = 50S ribosomal subunit, disrupts protein synthesis = i.e. switch off toxin production
  - Not affected by inoculum size = Does not display Eagle Effect (paradoxical reduced efficacy of beta-lactam at concentration higher than optimal bactericidal concentration)
    - - Unclear mechanism, may be because of very high bioburden = bugs in stationary rather than log phase, so beta-lactam unable to act
      - Higher doses may antagonize/downregulate PBP or precipitate drug (in vitro)
  - Has long postantimicrobial effect
  - Inhibits bacterial protein synthesis, which results in suppression of synthesis of S pyogenes antiphagocytic M-protein and bacterial toxins
  - Should not be used alone!
Some may use linezolid instead of clindamycin as the adjunctive antibiotics in STSS or necrotizing infection. Read more about the debate of clindamycin vs linezolid in this article I highly recommend: Cortés-Penfield N, Ryder JH. Should Linezolid Replace Clindamycin as the Adjunctive Antimicrobial of Choice in Group A Streptococcal Necrotizing Soft Tissue Infection and Toxic Shock Syndrome? A Focused Debate. Clin Infect Dis. 2023;76(2):346-350. doi:10.1093/cid/ciac720
- - Total duration of therapy is based upon the clinical course and primary site of infection

Additional management notes:

Supportive care with fluid management is critical, particularly in those with multisystem organ failure
Another key = Aggressive source control depending on the site of infection
IVIG often used as adjunct therapy
- - Limited evidence but generally recommend if toxic shock
Infection control: isolate until 24 hrs after antibiotics start + report to HPA (UK) / CDC (USA)
Contact prophylaxis: consider only if high risk AND prolonged contact in 7d prior to symptoms
- - Guided by public health input
  - High risk is not strictly defined. US + UK guidance include examples: 37 wks gestation until 1 month post partum; neonates <1 month; elderly; active or recent chickenpox; HIV

The current IGAS UK outbreak

Post-COVID rise in co-circulating respiratory viruses may be driving rise in IGAS LRTI/empyema
More cases = more deaths (even though case fatality rate hasn’t increased = 8.4%)
Big public focus on kids, but 85% of IGAS cases in outbreak were actually in >65 yo
NOT due to change in circulating strains – still emm1 (about half of all cases), then emm12 (and then emm89, 108, 33)
Non-invasive GAS (including scarlet fever) is also up but unclear why
A few resources/readings:
- - WHO Disease Outbreak 2022-12-15: Increased incidence of scarlet fever and invasive Group A Streptococcus infection – multicountry
  - UK Health Security Agency, last updated 2023-03-30: Group A streptococcal infections: report on seasonal activity in England, 2022-2023

Big picture - Global burden of disease

Implicated in 500,000 deaths/year
Globally rheumatic fever is much bigger cause of M&M than acute infection
>33 million cases/year, >300,000 deaths/yr
Rare in high income countries because of availability of antibiotics and different circulating strains
Roth GA, Huffman MD, Moran AE, et al. Global and regional patterns in cardiovascular mortality from 1990 to 2013. Circulation. 2015;132(17):1667-1678. doi:10.1161/CIRCULATIONAHA.114.008720
Carapetis JR, Steer AC, Mulholland EK, Weber M. The global burden of group A streptococcal diseases. Lancet Infect Dis. 2005;5(11):685-694. doi:10.1016/S1473-3099(05)70267-X

Tash touched on why isn’t there a GAS vaccine?

1940s – whole killed GAS bacteria = very reactogenic, didn’t prevent disease
1960s – purified M proteins = ?inc RF in immunised kids. Unclear if was actually due to vaccine, but caused big controversy => USA FDA ban 1970s until early 2000s
… And not v profitable for vaccine companies, given burden of disease is mainly in LMIC!
Ongoing barriers – lack of good immune correlates of protection; lack of good animal models; concerns about autoimmune complications (given immune nature of non-suppurative GAS complications)…
- GAS human challenge models to help test early phase vaccines
Recent progress:
- WHO resolution 2018 = recognise RHD as a global health priority
- Wellcome Trust Strep A Vaccine Global Consortium (SAVAC)

Episode Art & Infographics

Infographics

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Goal

Listeners will be able to diagnose and manage Grp A Strep pharyngitis.

Learning Objectives

After listening to this episode, listeners will be able to:

Compare and contrast the use of Centor/McIsaac score and the FeverPAIN score for diagnosis of GAS pharyngitis
Discuss the rationale for treating GAS pharyngitis with antibiotics
Describe the key principles in management of streptococcal toxic shock syndrome

Disclosures

Our guests as well as Febrile podcast and hosts report no relevant financial disclosures

Citation

Jones, C., Theodosiou, A., Dong, S. “#70: Strep on the GAS!”. Febrile: A Cultured Podcast. https://player.captivate.fm/episode/89cd4c8b-5336-4683-9bea-19a5a217af50

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