Meningococcal meningitis is a potentially fatal bacterial infection of the brain and surrounding tissues that has been responsible for significant morbidity and mortality for hundreds of years. Today, sporadic and deadly outbreaks still occur, despite effective therapeutics and available vaccines. What is the story of meningococcal meningitis, and how has the disease continued to prevail despite technological advancements?
Meningococcal Disease Presentation
Meningococcal meningitis is caused by the organism Neisseria meningiditis, a gram-negative coccobacillus that exclusively infects humans. Approximately 10% of the population will be carrying the organism in their oropharynx (middle part of the throat) at any given time, and colonization of the oropharynx always precedes infection-a factor that likely contributed to outbreaks during the 19th century, when people were often living in close quarters or regular close contact with one another.
The 2 most common types of meningococcal disease are meningitis, an infection of the lining of the brain and spinal cord, and bloodstream infection (also known as meningococcemia), which often leads to sepsis, the body's extreme response to infection. Both types of infection can ultimately lead to death; meningococcal disease has a relatively high fatality rate (10-15%), even with appropriate antibiotic treatment.
Although meningococcal disease can affect anyone, some populations are more at risk, including babies younger than 12 months old, adolescents and young adults. Typical symptoms of meningitis include headache, stiff neck, fever, confusion, light sensitivity and nausea/vomiting. However, people with bloodstream or severe joint infections may not show typical signs of infection. Thus, health care providers and the public (family, friends and others) should be aware of other symptoms, including flu-like symptoms.
History of Meningococcal Meningitis Treatment and Prevention
While it is possible that meningococcal meningitis has been affecting people for thousands of years, the disease was not formally described until 1805 by Gaspard Vieusseaux, a Swiss general practitioner. After that, the disease was called many things, including non-contagious malignant cerebral fever, Diplococcus pneumoniae, Diplococcus intracellularis meningiditis and, finally, meningococcal meningitis. In the 19th century, the prognosis of meningococcal disease was so poor that it was rivaled only by the plague and cholera.
The high fatality of N. meningiditis in the 19th century led to medical acts of desperation, including various bizarre and potentially dangerous "treatments." Methods included, bloodletting; alcohol and opium consumption; the use of mercury, either topically or orally; sulphuric ether compresses; cerebrospinal fluid (CSF) drainage and puncturing the subarachnoid space, which surrounds the brain and spinal cord and contains spinal fluid.
Intrathecal Serum Therapy
Although diagnostic methods for meningococcal meningitis (e.g., Gram stain and culture) remained largely the same until very recently, therapeutic approaches evolved significantly between the 1890s and 1980s. The path to serum therapy was paved by researchers in the 1890s who were demonstrating its effectiveness against Clostridium tetani, Corynebacterium diphtheriae and Streptococcus pneumoniae. German physiologist Emil von Behring won a Nobel Prize in 1901 for demonstrating that infectious diseases (specifically diphtheria) could be cured by injecting humans with serum from recovered patients, and while he did not understand the concept of antigens or antibodies yet, he knew something in the blood was helping cure sick patients. This observation, along with the discovery that immunizing horses against a disease of interest, and then harvesting their serum, resulted in increased production of protective antibodies that could be used as an effective therapy against the disease of interest, paved the way for meningitis therapeutics.
In 1906, German researchers in Berlin, Wilhelm Kolle and August von Wassermann, described protection from meningococcal disease in guinea pigs using horse serum. Later, a polish clinician named Georg Jochmann took these findings even further and used serum therapy, delivered to humans via the fluid-filled space between the thin layers of tissue that cover the brain and spinal cord (intrathecal), with similar success. Around the same time, Simon Flexner was studying anti-meningococcal serum therapy at the Rockefeller institute in the U.S. Flexner further demonstrated the success of intrathecal serum therapy in primates and began immunizing horses to produce serum that could be used to treat humans. These groundbreaking findings in the early 1900s inspired many other researchers to study serum therapy, immunize and bleed horses.
For years, intrathecal serum therapy was considered the gold standard therapy for meningococcal disease, but the process was painful and labor intensive. The process started by draining at least 30 mL of CSF from the patient, and then replacing it with serum by way of numerous injections into the spinal column, or the use of a gravity infusion system. The patient would then be put into the Trendelenburg position (the pelvis suspended above the head; patient is positioned upside down). This procedure would be repeated until the patient's fever resolved, or gram-negative diplococci were no longer observed in the CSF. Despite hypersensitivity reactions in approximately 75% of patients, this methodology demonstrated good outcomes and was recommended until the 1940s.
Antibiotic Therapy for Bacterial Meningitis
In the early 1930s, studies by Gladwin Buttle and team, as well as Perrin Long and Eleanor Bliss, demonstrated that antibiotic treatment, specifically with sulphonamides, was more effective than serum therapy. This therapy was endorsed as the preferred treatment for over 25 years, until widespread antimicrobial resistance was documented. After the abandonment of sulfonamide treatment for meningococcal disease, the study and use of penicillin and chloramphenicol persisted until second and third-generation cephalosporins were demonstrated to be the safest and most effective antibiotic therapies.
This still holds true today. If meningitis is suspected or meningococcal disease is known to be present, health care providers will immediately administer antibiotics, sometimes even before a diagnosis is confirmed. The rapid progression of meningiococcal disease necessitates quick action, and the lifesaving potential of properly administered antibiotics supports such empirical therapy. During times of N. meningitidis outbreak, susceptibility of circulating strains must be determined and taken into account when selecting antibiotics or combination therapies to treat resistant strains. Depending on how serious the infection is, people with meningococcal disease may also need other treatments, including breathing support, medications to treat low blood pressure, surgery to remove dead tissue and wound care for parts of the body that are damaged by disseminated disease.
Meningiococcal Vaccines
A pivotal discovery in the 1960s paved the way for meningiococcal vaccine development. Immunology research, led by Irving Goldschneider and colleagues, demonstrated that the capsular polysaccharide of some N. meningiditis serotypes induced production of protective antibodies against disease caused by the same serotype. Thus, development of vaccines against meningococcal disease began with simple polysaccharide formulations, starting with a monovalent type A vaccine, followed by monovalent type C and then bivalent A and C.
Plain polysaccharide vaccines were helpful, but limited by poor or nonexistent protection in children under 2 years, and no protection against organism carriage (i.e., having the organism in the respiratory tract without disease). The development of conjugate vaccines was a major breakthrough that addressed some of these limitations. In 1981, scientists developed a bivalent Y and W135 vaccine, which led to the tetravalent A, C, Y and W135 vaccine in 1982.
Today, the best way to prevent meningococcal disease is to get vaccinated. The CDC recommends meningococcal vaccination for all preteens and teens, as well children and adults at increased risk for meningococcal disease. There are currently 3 types of meningococcal vaccines available in the United States:
- Meningococcal conjugate or MenACWY vaccines (Menveo® and MenQuadfi®).
- Serogroup B meningococcal or MenB vaccines (Bexsero® and Trumenba®).
- Pentavalent meningococcal or MenABCWY vaccine (PenbrayaTM).
For the most up-to-date vaccination recommendations, see the CDC Meningococcal Vaccination site.
Modern Diagnostics and Lab Considerations
Meningococcal disease can be diagnosed by the microbiology lab using culture and PCR techniques. For patients who present with meningitis only, a CSF specimen should be collected and sent for testing. For patients with other presentations (e.g., a bloodstream infection caused by N. meningiditis) a blood sample may also be necessary.
Still, bacterial culture is considered the gold standard test for the diagnosis of N. meningiditis and has nearly 100% specificity. Advantages of culture include, the ability to perform serotyping and susceptibility testing, or sequencing from isolates if necessary. Limitations include, the organism's fastidious growth characteristics and the risk of infection associated with laboratory handling. To reduce the risk to medical laboratory scientists, appropriate personal protective equipment (PPE) and biosafety cabinets should be used when handling the organism.
Once the organism is grown in culture, it may be identified by PCR, sequencing, biochemical methods or MALDI-TOF. It is important to note that the genetic relatedness of N. meningiditis to other species may make identification on MALDI-TOF challenging. There are currently 3 commercially available multiplex PCR tests that can detect N. meningiditis from CSF or blood, along with other pathogens that may infect these sterile body sites. The advantages of PCR for diagnosis of meningococcal disease include, increased sensitivity and rapid turnaround time, as well as reducing the risk of infection to medical laboratory scientists thanks to decreased handling and closed testing systems. The major disadvantage of performing PCR directly from clinical specimens suspected of having N. meningiditis is that susceptibility testing cannot be performed.
Recent Meningococcal Meningitis Outbreaks and Trends
To this day, meningococcal meningitis remains endemic in many parts of the world and occurs worldwide. The highest incidence of infection occurs in the "meningitis belt" of Africa, where large epidemics occur every 5-12 years. Serotypes of N. meningiditis that circulate regularly may differ between countries. B, C, W and Y regularly circulate in the U.S.
Meningococcal outbreaks, in a way, require a "perfect storm," and the concurrent drivers of each epidemic are not always clear. Key elements required for meningococcal epidemics include, immunological susceptibility of the population, either due to waning immunity or lack of vaccination, special climatic conditions (e.g., dust storms), low socioeconomic status and transmission of a virulent strain.
Several recent outbreaks in the U.S. and globally have occurred, or are ongoing, and demonstrate how meningococcal infection can occur and spread. In March 2024, the CDC released a Health Advisory Network alert (HAN) describing an increased rate of invasive meningococcal disease in the U.S. that is disproportionately affecting people between the ages of 30-60 years, Black or African American people and people living with HIV. In most cases, sequencing of isolates identified the causative strain as serotype Y, sequence type (ST) 1466-the same type that was responsible for at least 422 cases in 2023 (the highest number of cases to occur in the U.S. since 2014). As of March 25, 2024, 143 cases of meningococcal disease have been reported in the U.S. During the same period in 2023, only 81 cases were reported.
Notably, most cases of invasive meningococcal disease that occurred between 2023-2024 did not present as meningitis, but rather as bacteremia and septic arthritis. Furthermore, the case-fatality rate in the 2024 outbreak is 18%, higher than the historical case-fatality rate of 11% that was reported for serogroup Y cases between 2017-2021.The combination of waning immunity or lack of vaccination in vulnerable populations, lack of access to care and less obvious clinical presentation are all suspected to be factors contributing to the significant increase in cases, as is increased travel to and from endemic regions of the world. As a result, the CDC has provided specific recommendations for quadrivalent meningococcal (MenACWY) conjugate vaccination of travelers to countries where meningococcal disease is hyperendemic or epidemic.
Although we have made significant advances in our knowledge of meningococcal immunity, diagnostics, therapeutics and vaccines, deadly outbreaks of invasive meningococcal disease persist due to complex factors including climate, socioeconomic conditions and war. Recent outbreaks demonstrate that without appropriate health care access, immunization or living conditions, diseases like meningococcal meningitis will persist in the modern era.
Are you interested in learning about the history of other infectious diseases? Check out this next article about how the deadly history of scarlet fever, the disease caused by a Streptococcus pyogenes toxin, prevails today.
