Clinical Information

Bacteria:

Escherichia coli K1 strains account for nearly 80% of E coli isolated from cerebrospinal fluid (CSF). While most E coli are harmless enteric organisms residing in the intestines of humans and animals, some cause gastrointestinal illness and extraintestinal infections (eg, urinary tract infections, bacteremia, and meningitis). E coli associated with meningitis contain virulence factors that contribute to their pathogenesis by allowing them to spread through the blood, hijack normal host cell functions, infiltrate endothelial cells, and gain access to the tissues of the central nervous system (CNS). The K1 antigen is a capsule that protects the bacteria from the immune system. These infections are of particular concern for preterm babies and neonates, and they are responsible for nearly 45% and 30% of meningitis cases in these age groups with a mortality rate of 13% and 25%, respectively. Infections in adults are less common and generally opportunistic in nature, following exposure of sterile organs to contents of the gastrointestinal tract following trauma or surgical procedures; the mortality rate for adults is reported to be 28% to 36%.

Haemophilus influenzae is a gram-negative coccobacillus that is isolated exclusively from humans. Strains of H influenzae are divided into 2 groups based on the presence or absence of a polysaccharide capsule. Encapsulated strains are further divided into 6 serotypes (a through f). Prior to widespread use of the H influenzae type b (Hib) conjugate vaccines, Hib caused more than 80% of invasive H influenzae infections, predominantly in children under the age of 5, with a mortality rate of 3% to 6% and a further 20% to 30% developing permanent sequelae ranging from mild hearing loss to intellectual disability. In areas with routine vaccination, the majority of invasive H influenzae infections are caused by nontypeable strains and remain an important cause of meningitis, particularly for persons with predisposing conditions such as otitis or sinusitis, diabetes, immune deficiency, or head trauma with CSF leakage. Meningitis due to H influenzae occurs at an estimated rate of 0.08 cases per 100,000 in the United States, and it has been reported as the etiologic agent of bacterial meningitis in 20% to 50% of cases worldwide over the last several decades.

Listeria monocytogenes, the causative agent of listeriosis, is a gram-positive bacillus that is ubiquitous in soil and water and can be found in the gastrointestinal tract of up to 5% of healthy human adults. Listeriosis is considered one of the most severe bacterial foodborne infections due to its high mortality rate, even with early antibiotic treatment (11%-60%). Invasive listeriosis can result in abortion, sepsis, meningitis, and meningoencephalitis. Populations at risk for developing invasive listeriosis include individuals who are immunosuppressed, pregnant women, neonates, fetuses, and older adults. Meningitis due to L monocytogenes is reported to be approximately 0.05 cases per 100,000 persons in the United States per year, and causes from 0.5% to 2.0% of bacterial meningitis cases in non-United States countries.(1)

Neisseria meningitidis (encapsulated) is a fastidious, aerobic, gram-negative diplococcus that is transmitted by contact with mucus or respiratory droplets, often from asymptomatic carriers. There are at least 12 different serogroups of N meningitidis, 6 of which are associated with epidemics (groups A, B, C, W135, X, and Y). The serogroup refers to types of capsular antigens, generally only encapsulated N meningitidis are considered pathogenic. Meningococcal disease (meningitis and meningococcemia) is rare in developed countries, but it can occur in outbreaks and is a public health issue in developing countries. It is most common in infants, children, and young adults, and appears in places with crowded living conditions (eg, college dormitories and military barracks). Seasonal incidence peaks in late winter and early spring with an annual incidence of about 0.2 cases per 100,000 in the United States. The disease can progress extremely quickly (<24 hours), with hypotension, multiorgan dysfunction, shock, peripheral ischemia, and limb loss, and has a mortality rate of approximately 5% to 10%. There are licensed meningococcal vaccines available in United States that may be used in persons of all ages, depending on the vaccine. Despite extensive vaccination efforts worldwide, several serogroups of N meningitidis still cause seasonal outbreaks, particularly in sub-Saharan Africa. Extreme reductions in serogroup C meningococcal meningitis have been observed in countries where vaccines providing protection for this serogroup have been introduced.

Streptococcus agalactiae (group B Streptococcus or GBS) is an important cause of meningitis in neonates, particularly those that are preterm, and is often coincident with neonatal sepsis. The most important risk factor for neonatal disease is maternal colonization with GBS. Since 1996, the Centers for Disease Control and Prevention guidelines (updated in 2010) have called for prophylactic antibiotic treatment several hours before delivery in at-risk deliveries, resulting in declining rates of neonatal GBS. In adult patients, GBS is associated with advanced age or severe underlying health conditions. Overall incidence in the United States is estimated to be 0.25 infections per 100,000 and neonatal GBS disease has ranged from 0.2 to 2.4 per 1000 births in Europe over the last few decades. Mortality rates range from 10% for neonates to 25% to 30% in adults.

Streptococcus pneumoniae colonizes the upper respiratory tract and is the most frequently isolated respiratory pathogen in community-acquired pneumonia. It is also a major cause of meningitis, particularly in pediatric and older adult patients, and especially in those with underlying medical conditions, with an incidence rate of approximately 0.8 infections per 100,000 in the United States and causes 20% to 31% of bacterial meningitis cases in non-United States countries. The mortality rate is also high: 8% to 15% for children and 20% to 37% for adults. Mortality approaches 50% in resource-poor countries, especially where HIV coinfection is a factor. Neurological sequelae (cognitive impairment, deafness, epilepsy) are reported in up to 40% of survivors. Vaccines have helped reduce the risk of both invasive disease and pneumococcal pneumonia by 50% to 80%.

Viruses:

Human cytomegalovirus (CMV) is a double-stranded DNA virus of the Herpesviridae family. Seroprevalence data show that infection is nearly ubiquitous in the population worldwide, with rates approaching 100% in developing countries and 36% to 90% in the United States depending on age and race/ethnicity. While severe illness in immunocompetent patients is rare, CMV is an opportunistic pathogen in individuals who are immunocompromised or immunosuppressed, either as an initial infection or activation of a latent infection. In some patients (eg, transplant recipients), CMV may infect the central nervous system and cause meningoencephalitis.

Enteroviruses (EV) are small RNA viruses that are members of the Picornaviridae family and associated with human illnesses ranging from asymptomatic or mild infections to serious CNS illnesses requiring hospitalization. Infection rates are highest in children, with the majority of infections occurring during summer months. The most common EV serotypes are coxsackie viruses A9 and B1, and echoviruses 6, 9, and 18, which account for over 50% of serotyped detections. Infections are spread via fecal-oral and respiratory routes and can spread quickly in community settings, particularly in areas with poor sanitation. EV is one of the commonly identified causes of infectious encephalitis/meningitis, with prevalence rates reported between 5.5% and 30% depending on location and patient demographics.

Herpes simplex viruses 1 and 2 (HSV-1 and HSV-2) are DNA viruses of the Herpesviridae family named for the spreading skin ulcerations caused by infection with these viruses. HSV-1 infections usually occur early in childhood and manifest primarily as oral lesions. However HSV-2 is primarily associated with genital lesions, and infections are acquired later in life and are associated with sexual activity. HSV establishes residency in nerve cells following initial infection, which is asymptomatic in most cases. Viral activation resulting in lesions or other severe disease outcomes (such as CNS infection) may occur throughout life and are associated with fever, injury, exposure to ultraviolet irradiation (sunlight), emotional stress, hormone irregularities, and changes in immune status. In the United States, overall seroprevalence for HSV-1 is around 60%. The overall seroprevalence for HSV-2 is around 16% but varies with age, sex, and ethnicity. Worldwide, approximately 90% of people are infected with HSV-1; HSV-2 is less common with 15% to 80% of people infected. HSV is one of the most common causes of viral encephalitis and is a significant cause of meningitis. In a large study of over 1600 CSF specimens in the United Kingdom, HSV-1 was found in 25 (1.5%) patients (almost all of whom had encephalitis), and HSV-2 was found in 33 (1.9%) patients (almost all of whom had meningitis). This overall prevalence of approximately 3% in CSF is similar to that seen in a recent study of CSF patients in New York state. This study also saw a similar distribution of HSV-1 and HSV-2 in encephalitis versus meningitis.

Human herpesvirus 6 (HHV-6) was discovered in the mid-1980s, when the rise of patients who are immunocompromised led to an increase in the population susceptible to severe disease outcome. There are 2 species: HHV-6A and HHV-6B. Studies have shown that over 95% of persons over the age of 2 are positive for 1 or both variants, and the infection establishes latency due to viral integration into host cells. While primary infection with HHV-6B causes roseola in infants, the clinical manifestations of primary infection with HHV-6A remain somewhat undefined; however, some studies have suggested that HHV-6A infection may be linked to inflammatory or neurological disease, and HHV-6A may have an increased neurotropism compared to HHV-6B. This hypothesis is supported by the finding that HHV-6 inhabits CNS tissues, including the brain, where it may cause tissue damage leading to encephalitis or meningitis. Furthermore, HHV-6 was identified in CSF of 1.8% of patients with encephalitis or meningitis in a recent study. CNS disease associated with HHV-6 is found in both children and adults, suggesting CNS invasion during primary infection is possible. While immunocompetent patients may experience CNS infection, it is much more common in individuals who are severely immunosuppressed. However, HHV-6 is known to reactivate in asymptomatic patients and can be detected by polymerase chain reaction (PCR) analysis in otherwise healthy individuals without signs of active HHV-6 infection. Studies of HHV-6 in normal brain tissue have identified HHV-6 DNA via PCR in up to 85% of patients without signs of active infection, and HHV-6 DNA may persist in the CSF after acute infection. In a study of 56 allogeneic stem cell transplant patients, HHV-6 DNA was detected in the CSF of 14 (27%) patients without CNS symptoms. Given the prevalence of latent infection and potential for asymptomatic reactivation, positive HHV-6 results should be carefully interpreted in association with clinical symptoms and supplemental laboratory testing.

Human parechoviruses (HPeV) comprise another genus of the Picornaviridae family. HPeV were originally classified as enterovirus upon their discovery in the 1950s, and at least a dozen serotypes have been identified. Seroprevalence for HPeV-1 approaches 100% in adult populations, with most infections occurring during early childhood. As with EV, infections are spread via fecal-oral and respiratory routes, with the most common symptoms being mild respiratory or gastrointestinal illness. CNS disease from HPeV-1 is rare, but HPeV-3 is associated with severe disease outcomes, such as sepsis, encephalitis, meningitis, and hepatitis in children younger than 3 months of age. Recent studies of CSF from infants with suspected CNS illness or sepsis have demonstrated HPeV at a prevalence of 3% to 17%, nearly all of which were HPeV-3. Magnetic resonance imaging studies of infants who survive HPeV CNS disease show damage to the white matter of the brain and developmental disabilities later in life.

Varicella zoster virus (VZV) is a double-stranded DNA virus of the Herpesviridae family that usually causes infections in childhood (chicken pox) and establishes latent presence in cells that can reactivate later in life (zoster or shingles). VZV is primarily spread through respiratory secretions or direct contact with lesions of an infected individual, and infection of new hosts begins within the epithelial cells of the respiratory tract. Following primary infection (fever and malaise accompanied with a maculopapular rash), VZV establishes itself in the sensory ganglia of the nervous system where it remains latent. In the United States, nearly 90% of the population had been infected with VZV before the advent of vaccines. Similar rates have been reported in European countries. Of those infected, between 10% and 30% develop zoster (a painful rash along the dorsal ganglia), primarily later in life. It is estimated that the median global incidence of zoster is 4.0 to 4.5 per 1000 person-years, which highlights the frequency of VZV reactivation worldwide. Studies have shown that VZV is transiently detectable by PCR in the blood of older, asymptomatic individuals (both immunocompetent and immunocompromised), suggesting reactivation occurs throughout life but is usually managed by the immune system. Encephalitis and meningitis are complications of both varicella and zoster infections. In 1 study, VZV was the third most detected virus among patients with signs and symptoms of encephalitis or meningitis, with a reported prevalence of 1.9% in the study population. There are live, attenuated VZV vaccines licensed for use in the United States for the vaccination of children against varicella and adults against zoster.

Yeast:

Cryptococcus neoformans and Cryptococcus gattii are pathogenic fungi that are acquired by inhalation and can spread to other organ systems (particularly the brain and meninges). C neoformans is considered an opportunistic pathogen of individuals who are immunocompromised. It is the AIDS-defining illness in up to 50% of patients with AIDS. C gattii infections are relatively rare but appear to be increasing. While typically associated with tropical and subtropical climates, since the 1990s, C gattii infections have been reported in British Columbia, Canada, the United States Pacific Northwest region, the Northeastern United States, and in Europe. In addition to those with reduced immune function, C gattii can also cause disease in the immunocompetent, particularly in persons with underlying health conditions. Mortality from cryptococcal meningitis is high, ranging from 10% to nearly 50% in immunocompromised patients.(1)