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Febrile #70 – Strep on the GAS!

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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

Table of Contents

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!

Twitter

Dr. Chrissie Jones

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

Twitter

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

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

What is the rationale for treating GAS pharyngitis with antibiotics?

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?

Other management considerations?

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

Big picture - Global burden of disease

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

Find all the Febrile infographics here!

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

Transcript

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