Opinion | Group A Strep’s Most Sinister Sequelae

Arriving in Montana in the 1890s, his Norwegian-American forebears claimed rural homesteads and started to farm. By the mid-20th century, two of his grandparents had died of rheumatic heart disease, which — as we all learned in medical school — sometimes follows an untreated case of group A strep (GAS) pharyngitis. Around 1950, while in sixth grade, he himself suffered pharyngitis and scarlet fever. A few weeks later, his urine turned rusty-red.

It was not until the future physician spied his own darkened urine — which, in hindsight, strongly suggested post-streptococcal glomerulonephritis, a kidney disease that can develop following GAS pharyngitis or pyoderma — that Dennis Stevens finally saw a doctor. Back then, “antibiotics were not widely available to civilians,” Stevens, now an MD and PhD, recently told me. But Stevens was lucky. In his case, his doctor gave him sulfa pills that likely prevented long-term renal damage.

Is it any wonder that Stevens would later become a renowned clinician-scientist with a primary focus on GAS after completing two degrees in microbiology, attending medical school, training in infectious diseases, serving as a senior medical officer in the U.S. Army, and, eventually, as a professor of medicine at the University of Washington and chief of infectious diseases at the V.A. Hospital in Boise, Idaho?

I recently turned to Stevens for insight into the new pediatric surge of GAS infections in the U.S., U.K., and beyond.

Some Recent History

Scarlet fever and rheumatic fever complicating strep throat largely disappeared after World War II due to the increasing availability of penicillin. Nonetheless, major epidemics of scarlet fever — a classic illness, which nearly always follows strep throat — began in Hong Kong and China as early as 2011 to 2014 and have continued to present day. Although they remain sensitive to penicillin, it is worrying that the current Asian strains are 100% resistant to erythromycin and clindamycin.

This brings us to today. Although it is clear that a new pediatric surge in GAS scarlet fever and death is occurring in the U.S., U.K., Ireland, Holland, Sweden, and Australia, important questions remain.

For example: of the 4,622 cases of scarlet fever that occurred in Great Britain between September 2022 and January 15, 2023, did any of them present as streptococcal sepsis or a “flesh-eating” attack on tissue accompanied by streptococcal toxic shock syndrome? Further questions surround the current type of global strains and their production of toxins. According to Stevens, nearly 90% of GAS scarlet fever strains in the world today have similar M-protein “fingerprints,” but recent strains isolated from patients in Great Britain produce far greater amounts of a dangerous toxin called SpeA than ever before reported. SpeA can trigger scarlet fever and can also play a role in the pathogenesis of shock and organ failure in certain patients with invasive GAS infections.

An Illustrative Case

In a chapter called “Life-Threatening Skin and Soft-Tissue Infections” for the latest edition of Netter’s Infectious Diseases, Stevens shares a story guaranteed to terrify as much as to teach about one grievous GAS syndrome that can quickly fell not just children, but anyone, including a healthy young adult. Here’s a recap:

A 25-year-old weight lifter strained his trapezius muscle, suffered immediate pain, and took ibuprofen. A day later the patient had worsening pain and nausea. In the ED, he was tachycardic and mildly febrile, but there was no redness or swelling overlying his tender muscle. He received IV morphine. He was then discharged with instructions to continue taking oral narcotics and ibuprofen.

I8 hours later, the patient developed rigors, emesis, and dizziness and returned to the ED with massive swelling, erythema and purple bullae over his affected muscle. By now, his WBC count showed a dramatic left shift (30% bands, 9% metamyelocytes and myelocytes), and his platelet count was 70,000, his bicarb 15, and his creatinine 2.5. Within 2 hours, he was profoundly hypotensive. Despite receiving 10 L of intravenous fluids, multiple antibiotics, and rapid surgical debridement (emergent histopathology of his necrotic muscle showed almost no white cells but specimens later grew GAS), he expired the next day.

Group A Strep’s Toxic Mayhem

We must never forget that Streptococcus pyogenes, also known as GAS, is not just one gram-positive, B-hemolytic bacterium that forms pinpoint, hemolytic, and sometimes mucoid colonies on agar but a family of roughly 150 strains, each with its own somatic virulence factor. In some cases, these M-proteins allow GAS organisms to resist phagocytosis by white cells and rapidly multiply in blood. But certain strains can also make extracellular products that liquefy pus and facilitate spread, leading to dire invasions like necrotizing fasciitis or puerperal sepsis. They can also make toxins that act like super-antigens, rapidly triggering hypotension, organ failure, and death.

The tragedy that befell the GAS-infected weight-lifter is a classic example of streptococcal toxic shock syndrome (TSS) first described by Stevens and colleagues in a 1989 paper published in the New England Journal of Medicine. In this series, 20 patients with a median age of 36 from Montana, Utah, Idaho, and Nevada presented with various forms of severe GAS infection, especially necrotizing fasciitis and myositis. Their mortality rate: 30%.

Ironically, the term “toxic shock syndrome” — which was initially coined in 1980 to describe a dramatic illness in vaginal carriers of Staph aureus who used hyper-absorbent tampons and was later linked to Staph-colonized wounds, among other sources — preceded “strep TSS” by almost a decade. Nonetheless, the Staph-related syndrome is far less lethal.

Clinical Pearls and Imperatives

There are a few key takeaways pertaining to GAS, especially as we work to understand and address the current outbreak in kids. Point number one: just like many other pathogens, hyper-virulent strains of GAS can circulate for a time and induce herd immunity. Those strains virtually disappear only to be followed by the emergence and spread of new, sometimes even more dangerous strains. This may partly explain why invasive infections often occur in younger, healthy, non-immune adults. Point number two: serologic M-typing and genetic sequencing can pinpoint a new strain, but only if the bug is cultured. A rapid antigen test cannot yield the same information.

The need to assess antibiotic sensitivity is another reason why Stevens strongly favors culturing patients who are likely GAS-infected in any site in their body. Although “there’s never been a clinical isolate resistant to penicillin,” he acknowledged, resistance to erythromycin and especially clindamycin — drugs that actually halt M-protein synthesis and suppress the production of toxins — is an ongoing worry.

“In the heat of the battle on day one, empiric treatment of a life-threatening invasive infection is crucial and should involve penicillin plus clindamycin,” Stevens said. “But if a provider already knows that strains circulating in their community are resistant to clindamycin, that could justify using a newer agent like linezolid, tedizolid, or omadacycline, all of which also suppress toxin production.”

More cautionary advice for frontline providers? Think long and hard before using non-steroidal anti-inflammatory drugs (NSAIDs) in patients with local trauma who could have early signs of invasive GAS — for example, severe pain, low-grade fever, and tachycardia. “NSAIDs increase cytokine production,” Stevens warns. “They also mask fever and pain and interfere with neutrophil function.”

Back to Strep Pharyngitis

In comparison to ordinary GAS pharyngitis, which still affects an estimated 616 million children and adults every year, strep TSS and invasive infections are exceedingly rare. In addition, the latter infections most frequently stem from a cutaneous site such as a burn, laceration, penetrating injury, surgical incision, or even an insect bite. In a pregnant or post-partum woman, strep TSS can also develop after a toxin-bearing GAS bacterium silently ascends into the uterus or infects an episiotomy. Sadly, cases in which GAS invades tissue previously injured by blunt trauma or muscle strain rarely provide clinical clues leading to early diagnosis and treatment, which is why they are sometimes so deadly.

In some ways, what is equally poignant is the fact that people who suffer these worst-case infections are often asymptomatic carriers of GAS in their throat.

So, what lies ahead for this ubiquitous foe that is once again causing serious global harm? According to Stevens, at the very least, the next few months should bring further clues about the agent’s silent points of entry and its hidden arsenal of toxins leading to acute, life-threatening illness in children and adults.

Claire Panosian Dunavan, MD, is a professor of medicine and infectious diseases at the David Geffen School of Medicine at UCLA and a past-president of the American Society of Tropical Medicine and Hygiene. You can read more of her writing in the “Of Parasites and Plagues” column.