Update on Toxic Shock Syndrome

THE PUBLIC FIRST learned of toxic shock syndrome (TSS) not from the healthcare community but from television news anchors. In 1978, public health officials traced an outbreak of fatal staphylococcal infections in women and teen girls to a new line of super-absorbent tampons. James K. Todd, MD, a Denver pediatrician, had coined the phrase “toxic shock syndrome” earlier that year after another outbreak of staph infections led to blood poisoning from toxins produced by the bacteria. As news reports of women contracting the disease after using the new tampons spread across the country, TSS entered the public consciousness.

Although no longer the feared infection it was in the late 1970s and early 1980s, it remains a dangerous condition that strikes unexpectedly and affects otherwise healthy patients. Today, about half of all TSS cases remain associated with tampon use, with the remaining cases the result of other staph infections caused by burns, cuts, insect bites and intravaginal birth control devices.

TSS is a fairly rare condition with estimates ranging from three cases per 100,000 people to even lower. The TSS Information Service (a program funded by personal hygiene companies in Great Britain) says there are approximately 40 cases per year in the United Kingdom, two to three of which are fatal.¹ Even in cases not involving menstruation, women are three times more likely than men to contract TSS for reasons not entirely understood.²

What Is TSS?

Similar to scarlet fever, TSS is a secondary condition caused by a bacterial infection. Symptoms of TSS and the damage it causes to the body are a result of toxic poisons secreted by bacteria during an infection.

While the underlying cause of TSS is generally a staph infection, it can also be caused by a Streptococcus pyogenes (or group A Streptococcus) infection. This is often referred to as streptococcal toxic shock-like syndrome, or STSS.³ An even rarer form of TSS, but one that is much more virulent, is caused by toxins secreted by the bacteria Clostridium sordellii or Clostridium perfringens.⁴

Both Staphylococcus aureus and Streptococcus pyogenes are normal denizens in human bodies that live on the skin, in the nasal passages and in the vaginal canal. About one-third of people have the staph bacteria living on them, causing no symptoms or health problems. And, while the strep bacteria is less common, it is still found on a significant swath of the population without incident. It is not entirely clear what causes these organisms to experience sudden, explosive growth, but when they do, the amount of toxins they normally produce as part of their life cycle similarly spike, leading to the rare case of TSS if those toxins end up in the bloodstream.

Both clostridium species are also part of the human microbial flora. Up to 10 percent of females harbor Clostridium sordellii with no ill effects, generally in the vaginal canal.⁵ And, Clostridium perfringens is a normal part of the human intestines’ microbial biome.

During an infection, TSS or its related syndromes can develop only if the toxins enter the bloodstream. Once the toxins spread through the body, they cause hypotensive shock. As blood pressure drops, the brain, heart, lungs, kidneys and other organs don’t get enough oxygen to function normally, so the body begins to shut down, just as it does when it experiences any other kind of shock.⁶

Causes of TSS

As mentioned earlier, TSS was first seen during an outbreak of staph infections among women using a new type of highly absorbent tampon in 1978. But it has since been found to also occur following staph infections in wounds, cuts and burns, pneumonia and even bone infections.³

With the new tampons, the bacteria was able to grow exceptionally well in the menses collected in the tampon. Leaving one in for more than eight hours seems to be a highly correlative risk factor.⁷ Also, the process of inserting and removing tampons creates microabrasions on the vaginal wall, allowing the toxins to enter the bloodstream. In the case of burns and cuts, the bacteria that normally live on the surface of the skin can begin to grow more rapidly once they are able to penetrate the body’s normal protective coating via the wound, where they also have access to the circulatory system.

STSS is most often associated with chickenpox or a skin infection, or in patients with compromised immune systems.⁴

While both Staphylococcus aureus and Streptococcal pyogenes produce a variety of toxins that can cause illness if they enter the bloodstream (such as enterotoxin, which causes most cases of food poisoning), the main culprit in TSS is TSS toxin.⁸ This is a superantigen that causes the body to react by releasing massive amounts of cytokines (regulatory proteins that trigger the production of T helper cells), which then leads to systemic shock as blood pressure drops.

With Streptococcal pyogenes, the main culprits are pyrogenic exotoxin A and pyrogenic exotoxin B.⁹ These have a very similar reaction to the body’s defense system to the TSS toxin, with the overproduction of T cells causing the body to go into shock. A study in 2004 found some rare cases of STSS caused by group B streptococcus (Streptococcus agalactiae).¹⁰

TSS cases caused by Clostridium sordellii are quite rare, but generally prove fatal. Clostridium sordellii produces a hemorrhagic toxin and a lethal toxin, both of which are very difficult to counteract.¹¹ These infections have been documented to have led to the death of women shortly after childbirth, following elective abortion and after miscarriage. In addition, newborns have had the infection enter via their umbilical cord stump.¹² Researchers are not sure why postabortion women are three times more likely for the clostridium bacteria to colonize in their vaginal canal compared to other nonpregnant women.¹³

Although all three types of TSS (TSS, STSS and clostridium) are caused by bacterial infection, it is not considered an infectious disease since it cannot spread from patient to patient.

Symptoms and Progression of TSS

The Mayo Clinic lists the following as typical symptoms of TSS:¹⁴

• High fever
• Sudden drop in blood pressure
• Vomiting or diarrhea
• Rash that looks like sunburn and often appears on the soles or palms
• Muscle aches
• Seizures
• Headaches
• Red eyes, mouth or throat
• Redness around the vaginal opening
• Confusion

Symptoms generally manifest within about two days of the underlying infection’s beginning.⁴ It is recommended that anyone exhibiting any of these symptoms who has an open wound, a skin infection or is using a tampon or intravaginal birth control method (a diaphragm, cervical cap, sponge) seek emergency treatment immediately.¹⁴

The range of symptoms of STSS are similar, but not identical:⁴

• Severe pain at the site of the infection
• Difficulty breathing
• Bruising
• Low blood pressure
• Unusual bleeding

Anyone exhibiting these symptoms following chickenpox or a skin infection, or suffering from a compromised immune system, should likewise seek immediate emergency care.

If left untreated, low blood pressure associated with TSS and STSS may result in additional symptoms as the condition progresses: Skin may begin to slough off from the palms and soles, urine output may decline and the individual may feel listless and lack energy. Both TSS and STSS can progress rapidly, and death may occur within hours if not promptly treated.

Clostridium sordellii nearly always starts with an infection in the uterus, and the toxins spread to the bloodstream from the uterine walls. These infections generally do not cause a fever. Instead, symptoms may include:⁴

• Abdomen tender to the touch
• Abdominal swelling
• High red and white blood cell counts
• Influenza-like symptoms
• Elevated heart rate

Similar to TSS and STSS, this form of toxic shock can advance rapidly, with progression measured in hours or days.

Diagnosing and Treating TSS

Diagnosing any of the three variants of TSS is based on recent health history and a blood or swab culture from an obvious or suspected site of infection.¹⁵ If diagnosis is made in a nonacute setting, transfer to a hospital should be arranged immediately due to the rapid progression of the syndrome.

In cases in which a tampon or intravaginal contraceptive is being used, it should be removed immediately if the patient has not already done so. If TSS is likely the result of a burn or wound, the affected areas should be cleaned and disinfected.

Once a blood or swab test has confirmed the presence of one of the bacteria that can lead to TSS, an antibiotic can be prescribed to help reduce the source of infection. Additional tests may then be ordered to determine how far the toxins have advanced in the body. These tests may include a chest X-ray, CT scan or lumbar puncture to determine how well the patient’s organs are functioning.¹⁶

Depending on the progression of the poisoning from the toxins, medication to raise blood pressure may be indicated. If the kidneys are struggling due to shock, dialysis may be necessary. Oxygen assistance can help with breathing difficulties, and a blood transfusion can help lower toxin levels. Intravenous immune globulin (IVIG) may also be prescribed to help the individual’s immune system fight the infection.¹⁷ In extreme cases, surgery may be necessary to remove dead tissue and prevent gangrene.

Today, despite advances in detection, diagnosis and treatment, the mortality rate for TSS is still between 5 percent and 15 percent.⁴

^Preventing TSS

Using low-absorbency tampons and changing tampons regularly will greatly reduce the chance of contracting TSS. Using menstrual pads instead of tampons can lower it even more. Britain’s National Health Service also provides these additional tips:¹⁸

• Seek medical care whenever a burn or wound shows signs of infection.
• Avoid inserting bandages or packing material to treat a nosebleed.
• Always wash hands before and after inserting or removing a tampon.
• Never use more than one tampon at a time.
• Women who have previously had TSS should avoid using tampons and intravaginal contraceptives in the future.
• Carefully follow instructions on how long to leave in intravaginal contraceptive devices.

TSS and STSS caused by Clostridium sordellii and Clostridium perfringens are not easily prevented since the triggers that cause these infections to bloom are not well understood. Recurrent infections are an issue for anyone who has had TSS or STSS, with some studies indicating up to 30 percent of individuals will have a second bout of TSS.⁷

Ongoing Research

Given the rarity of TSS and its two related variants, it is perhaps not surprising there are very few ongoing studies evaluating the disease. In fact, fewer than a half-dozen are listed on ClinicalTrials.gov. The most promising study was conducted in 2016 at the Medical University of Vienna in Austria. The double-blind trial tested the efficacy of a TSS toxin variant in stimulating an immune response in 46 study subjects. No participants developed TSS in the study, and all of those given the toxin developed immunity. The study’s authors felt these results warranted further investigation to see if a vaccine could be developed.¹⁹ The Hospices Civils de Lyon in France is preparing a study to test how effective IVIG treatment is in preventing organ damage during TSS in children. This study is still listed as active, but is not yet ready to recruit participants.²⁰

Research into the underlying infections that lead to TSS is far more extensive, particularly for Staphylococcus aureus, with several hundred recent or ongoing studies. Among the more interesting are:

• Using RNA blood markers to identify Staphylococcus aureus infections in patients (France)
• Mother-to-infant transmission of Staphylococcus aureus (Israel)
• Nasal carriage of Staphylococcus aureus in healthcare settings (France)
• Potential methods of decolonizing patients of Staphylococcus aureus before surgery (France)
• Reducing transmission of Staphylococcus aureus in surgical settings (University of Iowa)

There are also several potential vaccines being investigated, and dozens of studies are looking at treating a Staphylococcus aureus infection with a variety of antibiotics, all of which could, if proven effective, find their way into emergency room protocols for treating TSS.

Among the other causes of TSS variants, Streptococcal pyogenes has six recent or ongoing trials listed. The Centre for Clinical Studies in Victoria, Australia, is presently recruiting for a study on a potential vaccination. The Butantan Institute in Brazil is also recruiting for a study into a possible vaccination based on a synthetic polypeptide. Another study is looking into the effectiveness of various antibiotic treatments.

Clostridium sordellii and Clostridium perfringens have been the subject of only one recent study conducted six years ago, which sought to determine a baseline for what percentage of women carry the bacteria in their vagina or rectum.²¹

Looking Ahead

Since the initial outbreak of TSS in the late 1970s, manufacturers of tampons have changed their design and construction, which has greatly reduced the incidence of TSS caused by Staphylococcal aureus. However, the condition still arises occasionally, requiring patients to seek emergency care immediately.

STSS and the clostridium variants remain rare, but they also occur in otherwise healthy patients and are thus impossible to predict and simply have to be dealt with like any other medical emergency.

While research may eventually bring about a vaccine for TSS and even STSS, for the foreseeable future, physicians will continue to emphasize hygienic best practices with tampons and intravaginal devices, as well as how to care for burns and other open wounds. And, patients with compromised immune systems should be attentive to all possible symptoms so infections can be addressed swiftly to avoid potentially fatal reactions to bacterial toxins.