Acute Inflammation - Bacterial Meningitis

Introduction

Bacterial meningitis is an acute inflammation of the meninges (dura mater, arachnoid mater, and the pia mater) due to bacterial infection, namely that of Streptococcus pneumoniae and Neisseria meningitidis. Bacterial meningitis is spread through droplets or secretion of mucous from the throat between close contact of people. It is a highly significant disease with over 1.2 million cases occurring globally which may result in neurological damage, disability, or fatality if left untreated (Center for Disease Control and Prevention, 2016). Meningitis is a concerning disease as survival depends on the early diagnosis and treatment of the disease. A delayed diagnosis can result in death within 24 to 48 hours of clinical manifestations. There is also a high risk of complications that can occur in association with the immune response to infection such as sepsis (Center for Disease Control and Prevention, 2019).

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Nonetheless, medical research has improved the prevention and treatment of the disease, leading to a significant decrease in cases in developed countries through vaccine programs and antibiotic treatment. This is evident in the reduction of cases of meningitis caused by Haemophilius influenzae with 45 - 48% down to 7% due to the introduction of the H. influenzae type b vaccine (Brouwer, Tunkel, & van de Beek, 2010). However, there is still up to 34% mortality rate with up to 50% of survivors presenting with long-term neurological damage. (Hoffman & Weber, 2009). This can be attributed to the intensity of the inflammatory response to current use of bacteriolytic antibiotic paired with the resistance to penicillin which raises the concern for further research into alternative antibiotic treatments.

The report highlights the cause of bacterial meningitis and generally covers the pathogenesis, diagnosis, and treatment of the disease in the background information. It then goes into the identification of key features present in bacterial meningitis through an annotated image of a specimen with the disease. It then proposes a research question on the efficiency of the alternative use of nonbacteriolytic antibiotic in treatment and finally reflects on the challenge of research and understanding of the topic.

Background

Meningitis is an inflammation of the meninges, especially within the subarachnoid space. The meninges are the membrane of the brain and spinal cord and consist of the dura mater, arachnoid mater, and the pia mater. Meningitis affects people globally but is predominant in developing countries, especially those within the 'meningitis belt', an area spreading 26 countries from Senegal to Ethiopia. The risk of infection is increased in people younger than 5 years and older than 60 years. Other risk factors may include large gathering of people, pre-existing conditions such as immunodeficiency and travelling to areas of high occurrence of meningitis such as the sub-Saharan Africa (Center for Disease Control and Prevention, 2019). It is most commonly caused by Streptococcus pneumoniae (41.2%) and Neisseria meningitidis (9.1 - 36.2%). However, it may also be caused by Group B Streptococcus, Haemophilus influenzae, Listeria monocytogenes, and Escherichia coli (OordtSpeets et al, 2018).

The brain is usually protected from bacterial invasion through cellular barriers; the blood-brain barrier and the blood-cerebrospinal fluid barrier. These are physical barrier against microbial infection while also allowing for the transport of nutrients for brain function via various transport mechanisms. It is through the breakdown of the blood-brain barrier and invasion through the bloodstream that causes bacterial meningitis (Dando et al, 2014, p. 694). Bacteria spread from close contact with a person who carries the bacteria and it can enter the body via the nose or mouth. The bacteria are then allowed to colonise in the nasopharyngeal where it can be encapsulated which helps prevent the bacteria from being phagocytized by neutrophils. It then invades the vascular system and can enter the central nervous system (CNS) due to epithelial cell injury. Once in meninges of the brain, it can cause headaches and activates the inflammatory response by releasing cytokines that can lead to fever and subsequently increases the permeability of the blood-brain barrier to proteins and neutrophils which can cause neck stiffness. This increases the intensity of the inflammatory response causing swelling of the brain which leads to increased pressure in the skull which can impair blood flow. The vascular system also dilates and gets congested and may lead to neurologic injury leading to complications such as disabilities and loss of function (Tunkel & Scheld, 1993).

Diagnosis of bacterial meningitis is mainly through the identification of gram-stains which may be either positive or negative depending on the bacterial strain in cerebrospinal fluid (CSF) through extraction of CSF by lumbar puncture. This is then viewed microscopically or using polymerase chain reaction (PCR) to amplify small amounts presents. For areas with limited access to resources, urine dipsticks are also used to identify glucose and leukocyte concentration because a decreased glucose and elevated white blood cell count indicate blood-barrier disruption. Further diagnosis of meningitis can also be conducted through CT scan for complications such as swelling and infarction (Hoffman & Weber, 2009). During diagnosis, treatment of empiric antibiotics is immediately administered and after diagnosis, specific antibiotic can be administered for the bacteria identified. If the particular bacterial agent is not identifiable, the choice of antibiotic is done based on age and health status because the bacterial agents tend to infect specific age groups. Corticosteroids may also be given to treat complications and signs of inflammation such as swelling (El Bashir, Laundy & Booy, 2003).

Macroscopic Specimen

The specimen is a brain with meningitis. The superior view of the brain shows signs of acute inflammation of the meninges. The brain has a diffuse lesion of white/milky coloured exudate that largely covers the surface of the brain particularly within the sulci, indicating the meninges to be infected. This exudate is most likely caused by Streptococci during infection however due to the small size of the brain, it indicates it belonged to that of a young individual which suggest that the bacterial may have been E. coli as that is the most common in newborns. The phagocytosis of the bacteria by neutrophils in the subarachnoid space and its prevalence around the sulci indicate the disease to be meningitis. The blood vessels of the brain are also dilated which is suggests congestion of the blood vessels, especially in the occipital lobe. The gyri of the brain also appear enlarged with few spaces between each, indicating swelling of the brain.

Current medical research

A key area of current research has been in the study of the effectiveness of treatments to reduce the high mortality rate of bacterial meningitis as well as to reduce the incident of neuronal damage. These studies are conducted on mice and rabbits as the outcomes are similar to those that humans present. The main focus of current research has been in the additional effect of corticosteroids and has led to the treatment of bacterial meningitis as a combined treatment of a bacteriolytic antibiotic such as penicillin or ceftriaxone and an adjunctive agent such as dexamethasone to eliminate the bacterial agent while also reducing the inflammatory response within the subarachnoid space. These investigations have led to the extremely significant discovery of dexamethasone being an effective adjuvant agent in improving the outcome of bacterial meningitis in more wealthy countries (de Gans & van de Beek, 2002). It has improved the treatment of bacterial meningitis and allows for further investigation into the use more stronger corticosteroids for the reduction of inflammatory response for the decreased rate of long-term neural damage in developed countries such as the U.S. and Europe. However, there are issues with the effectiveness of dexamethasone as it has only been beneficial for teens and adults in developed countries whereas young children and newborns, elderly, and individuals that are affected by HIV did not show an improvement compared to in developed countries with the combined treatment (Scarborough et al, 2007). Nevertheless, the research into anti-inflammatory drugs and treatments is highly significant in a bid to reduce the cases of neural damage.

Although the rate of occurrence and mortality of bacterial meningitis has been significantly reduced since the introduction of vaccination and antibiotic treatment, it is currently still extremely high with a rate of up to 34% (Hoffman & Weber, 2009). One area in particular which needs further research is the current administration of bacteriolytic antibiotics such as penicillin for the treatment of bacterial meningitis, although effective in killing the bacteria, can cause further damage and increase complications to brain function. This is because the use of bacteriolytic antibiotics cause an increased intensity of the inflammatory response as the breakdown of the cell wall and lysis products causes the immune system to send out more cytokines and neutrophils to combat the bacterial components. This increase in intensity cause further damage to the brain as its response can damage blood vessels and neurons due to increased permeability and swelling. This can result in high rate of complications such as loss of hearing, brain function, seizures in surviving individuals. In addition, the increase in resistance to current antibiotics further highlights the need for continued research into alternative antibiotic treatment for bacterial meningitis (Woehrl et al, 2011).

It is through the potential of non-bacteriolytic antibiotics such as daptomycin in treating bacterial meningitis that the risk of fatality may be lowered. Daptomycin is a lipopeptide antibiotic which is effective against gram-positive bacteria. It works by disrupting the membrane potential through depolarization via calcium-dependent pore formation which leads to cell death. An investigation comparing the treatment of daptomycin against ceftriaxone in mice infected with bacterial meningitis showed that daptomycin was more beneficial for memory retention of objects for short-term and long-term as opposed to treatment with ceftriaxone which required increased stimulation for memory retention. Thus, indicating the preservation of neural function. Another benefit of the use of daptomycin over ceftriaxone is that it has a higher clearance of bacterial components in the CSF compared to ceftriaxone (Barichello et al, 2013). For a highly effective treatment for the prevention of bacterial meningitis complication, daptomycin could also be combined with a matrix metalloproteinases inhibitor to reduce the risk of hearing loss. This is effective because an inhibitor of matrix metalloproteinases stops the blood-brain barrier from being disrupted and therefore reduces the intensity of the inflammatory response because it would not be initiated and the vascular parts of the brain would remain functional (Muri et al, 2018). Thus, the research into the use of daptomycin instead of penicillin for the treatment of bacterial meningitis is highly significant for the decrease in mortality and increase in full term recovery from meningitis.

The problem with the treatment of bacterial meningitis is the lack of a single efficient empiric antibiotic which will not cause host inflammatory damage and is not at the risk of resistance. Although daptomycin is very efficient at eliminating bacterial components from CSF, it is only efficient at removing gram-positive bacteria, so any gram-negative bacteria would be able to persist. The increasing risk of resistant bacteria to the current empiric antibiotic is another major concern because if the invading bacteria is resistant to the empiric antibiotic, there is an increased risk of mortality as the first dose of antibiotics is meant to be given at the same time as lumbar puncture to stop the risk of progressing bacteria. Therefore, it is imperative to research for alternative treatments against bacterial meningitis.

References

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Brouwer, M. C., Tunkel, A. R., & van de Beek, D. (2010). Epidemiology, diagnosis, and antimicrobial treatment of acute bacterial meningitis. Clinical microbiology reviews, 23(3), 467–492. doi:10.1128/CMR.00070-09

Center for Disease Control and Prevention (2016). Meningitis | Lab Manual | Epidemiology. Retrieved from https://www.cdc.gov/meningitis/lab-manual/chpt02epi.html

Centers for Disease Control and Prevention (2019). Meningitis | About Bacterial Meningitis Infection. Retrieved from https://www.cdc.gov/meningitis/bacterial.html

Dando, S. J., Mackay-Sim, A., Norton, R., Currie, B. J., St John, J. A., Ekberg, J. A., Batzloff, M., Ulett, G. C., Beacham, I. R. (2014). Pathogens penetrating the central nervous system: infection pathways and the cellular and molecular mechanisms of invasion. Clinical microbiology reviews, 27(4), 691–726. doi:10.1128/CMR.00118-13 De Gans, J. & van de Beek, D. Dexamethasone in adults with bacterial meningitis.

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Muri, L., Grandgirard, D., Buri, M., Perny, M., & Leib, S. L. (2018). Combined effect of non-bacteriolytic antibiotic and inhibition of matrix metalloproteinases prevents brain injury and preserves learning, memory and hearing function in experimental paediatric pneumococcal meningitis. Journal of Neuroinflammation, 15 Oordt-Speets, A. M., Bolijn, R., van Hoorn, R. C., Bhavsar, A., & Kyaw, M. H. (2018). Global etiology of bacterial meningitis: A systematic review and meta-analysis. PloS one, 13(6), e0198772. doi:10.1371/journal.pone.0198772

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