case study on meningitis slideshare

• Campus Directory
• Current Students
• Faculty & Staff

Acute Bacterial Meningitis Case Study

Bacterial meningitis is a life-threatening infection of the linings or meninges of the brain and spinal cord. Survivors may experience hearing loss or deafness, brain damage, seizures, and/or the retention of fluid on the brain. Symptoms may be mistaken for the flu. Find out what happens to a 14-year-old when bacteria invade his central nervous system.

Module 4: Meningitits

A 14-year old male complained to his parents of feeling quite ill with...

Meningitis - Page 1

From the information provided, coupled with the patient's...

Meningitis - Page 2

Once the patient had been admitted to the hospital's critical care unit...

Meningitis - Page 3

Case Summary

Summary of the Case

Meningitis - Summary

Answers to Case Questions

Meningitis - Answers

Professionals

Health Professionals Introduced in Case

Meningitis - Professionals

Additional Links

Optional Links to Explore Further

Meningitis - Links

Ohio State nav bar

The Ohio State University

• BuckeyeLink
• Find People
• Search Ohio State

PATIENT CASE PRESENTATION

Past Medical History:

• Currently being treated by an intense chemotherapy regimen
• Type 1 Diabetes Mellitus (diagnosed at age 7)
• Rotator Cuff tear (age 22) resolved via surgery and physical therapy

Past Surgical History:

• Rotator Cuff Surgery (age 22)
• Tonsillectomy (age 8)

Pertinent Family History:

• Mother passed away from breast cancer at the age of 40.
• Father has type 2 DM and hypertension but otherwise alive and well at the age of 55.
• Brother is alive and well at age 18.
• Sister is alive and well at age 23.
• No known history of viral meningitis.

Pertinent Social History:  

• Spends a lot of time in the hospital and various medical settings d/t the treatment of his AML.
• Does not smoke or use alcohol.

Got any suggestions?

We want to hear from you! Send us a message and help improve Slidesgo

Top searches

Trending searches

46 templates

suicide prevention

8 templates

18 templates

41 templates

cybersecurity

6 templates

28 templates

Child Meningitis Case Study

Child meningitis case study presentation, free google slides theme and powerpoint template.

Download the "Child Meningitis Case Study" presentation for PowerPoint or Google Slides. A clinical case is more than just a set of symptoms and a diagnosis. It is a unique story of a patient, their experiences, and their journey towards healing. Each case is an opportunity for healthcare professionals to exercise their expertise and empathy to help those in need. With this editable template for Google Slides or PowerPoint, you can describe in detail a clinical case, something that might be invaluable for medical students and fellow doctors.

Features of this template

• 100% editable and easy to modify
• Different slides to impress your audience
• Contains easy-to-edit graphics such as graphs, maps, tables, timelines and mockups
• Includes 500+ icons and Flaticon’s extension for customizing your slides
• Designed to be used in Google Slides and Microsoft PowerPoint
• Includes information about fonts, colors, and credits of the resources used

How can I use the template?

Am I free to use the templates?

How to attribute?

Attribution required If you are a free user, you must attribute Slidesgo by keeping the slide where the credits appear. How to attribute?

Related posts on our blog.

How to Add, Duplicate, Move, Delete or Hide Slides in Google Slides

How to Change Layouts in PowerPoint

How to Change the Slide Size in Google Slides

Related presentations.

Premium template

Unlock this template and gain unlimited access

Case-based learning: meningitis

Causes, diagnosis and initial management options for adults and children with meningitis.

JL / The Pharmaceutical Journal

Meningitis is the second leading infection-related cause of death in children in the world, second only to pneumonia [1] . It is responsible for more deaths than malaria, AIDS, measles and tetanus combined [1] . The disease is more prevalent in children under the age of four years and in teenagers. In England, there has been a decline in confirmed cases of invasive meningococcal disease over the past two decades, from 2,595 cases in 1999/2000 to 755 cases in 2017/2018, which is a small increase from the 748 cases reported in 2016 and 2017 [2] .

Pharmacists have a vital role in raising awareness of the signs and symptoms of meningitis, while also maximising the benefit of the national immunisation programme to reduce the incidence of the disease. This article will cover initial management options, with a focus on children and neonates.

Meningitis — inflammation of the membranes covering the brain and spinal cord (meninges) — can be caused by viruses, bacteria or fungi.

Meningococcal disease encompasses meningococcal septicaemia (25% of cases), meningococcal meningitis (15% of cases) or a combination of the two (60% of cases) [3] . Up to 95% of meningitis in the UK is aseptic, where there is no growth on cerebrospinal fluid (CSF) culture, usually with a viral aetiology (e.g. enteroviruses) [3] .

Bacterial meningitis is most commonly caused by Neisseria meningitidis (also known as meningococcus), although the main pathogens alter with age. As such, N. meningitidis , Streptococcus pneumoniae (also known as pneumococcus) and Haemophilus influenzae type b are the leading causes of meningitis in children older than three months; however, Streptococcus agalactiae , Escherichia coli , S. pneumoniae and Listeria monocytogenes are more common in children younger than three months [3] .

The bacteria that cause meningitis are very common — they are present in the nasopharynx in around one in ten people who may not ever show any symptoms of disease. The reasons why some people develop meningitis while others do not are not yet fully understood. However, it is thought that genetic variations in the genes for Factor H and Factor H-related proteins may have a role to play [4] . These proteins regulate a part of the body’s immune system called the complement system, which recognises and kills invading bacteria.

Risk factors

In general, young children are at the highest risk of bacterial meningitis and septicaemia, but other age groups, including older people, can also be vulnerable to specific types. One study found that meningococcal meningitis was less frequent in older patients, whereas pneumococcal, listerial and meningitis of unknown origin were more frequent [3], [5] . People with low immunity, for example, those with HIV or those having chemotherapy treatment for cancer, may also be at an increased risk.

Individual countries show seasonal patterns of bacterial meningitis. For instance, increased cases have been observed between the months of December and March in the United States, France and the UK [6] . There is also evidence that mass gatherings and exposure to cigarette and wood smoke can make people more susceptible to certain causes of meningitis and septicaemia, potentially from interference with mucosal immunity [7] .

Depending on the cause, cases of meningitis may be isolated. However, those who have been in close contact with someone with bacterial meningitis may be at increased risk of disease.

Pathophysiology

Infection occurs through transmission of contaminated respiratory droplets or saliva. Pili on the bacterial surface are thought to disrupt endothelial cell junctions in the blood–brain barrier, allowing the pathogens to penetrate it [8] . Once they have entered the subarachnoid space (the area of the brain between the arachnoid membrane and the pia mater), the pathogens replicate rapidly. This causes the production of several inflammatory mediators, including lymphocytes and inflammatory cytokines, as well as local immunoglobulin production by plasma cells. This enhances the influx of leukocytes into the CSF, which releases toxic substances that contribute to the production of cyctotoxic oedema and increased intracranial pressure. It is this process that can contribute to neurological damage and even death [9] , [10] .

Signs, symptoms and immediate management

Symptoms typically occur within 3–7 days after transmission [3] . Early, non-­specific symptoms of meningitis include:

• Irritability;
• Ill appearance;
• Refusing food/drink;
• Other aches and respiratory symptoms;
• Vomiting/nausea;

Healthcare professionals should be aware that classic signs of meningitis that include neck stiffness, bulging fontanelle and high-pitched cry are often absent in infants with bacterial meningitis [3] , [11] . Less common early symptoms include shivering, diarrhoea, abdominal pain and distention, coryza and other ear, nose and throat symptoms [3] .

General features of meningitis include a non­-blanching rash that can appear anywhere on the body, altered mental state, shock, unconsciousness and toxic or moribund state. If a patient presents with these symptoms, the glass test (also known as the ‘Tumbler test’; see Figure 1) may be used to aid diagnosis, where the side of a clear glass should be firmly pressed against the rash; if it does not fade under pressure, the patient may have septicaemia and needs urgent medical attention (see Figure 2) [3] , [12] . However, it should be noted that the National Institute for Health and Care Excellence’s Clinical Knowledge Summary states that the glass test should not be used solely for diagnosing bacterial meningitis and meningococcal septicaemia [13] .

Figure 1: Glass or ‘tumbler’ test

Source: Alamy Stock Photo / Mediscan

A rash that does not fade under pressure is a sign of meningococcal septicaemeia. However, this test should not be used solely in diagnosis.

The classic rash associated with meningitis usually looks like small, red pin pricks that spreads quickly over the body and turns into red or purple blotches. However, a rash is not always present with meningitis and may be less visible in darker skin tones. It is, therefore, important to also check the soles of the feet, palms of the hands and eyelids in the patient with suspected meningitis [3] .

Furthermore, if the patient is a child or young person, it is important for healthcare professionals to consider other non-specific features of their presentation, such as the level of parental or carer concern (particularly compared with previous illness in the child or young person or their family), how quickly the illness is progressing, and clinical judgement of the overall severity of the illness [3] .

Figure 2: Immediate management of suspected meningitis in children and neonates

Source: National Institute for Health and Care Excellence [3]

CRP: C-reactive protein; CSF: cerebrospinal fluid; CT: computerised tomography; EDTA: ethylenedianinetetraacetic acid; FBC: full blood count; GCS: Glasgow coma scale; HSV: herpes simplex virus; ICP: intracranial pressure; IV: intravenous; LFT’s: liver function tests; LP: lumbar puncture; Mg: magnesium test; PCR: polymerase chain reaction; TB: tuberculosis; U+E’s: urea and electrolytes; WBC: white blood cell.

Prevention and vaccination

As meningitis can be caused by several different pathogens, there are several vaccinations available that can offer some protection against the disease (see Table) [10] .

Case studies

Several case studies show how assessment and treatment of meningitis varies by patient. All patients, events and incidents in these case studies are fictitious and should only be used as examples in the clinical setting.

Case study 1: a toddler with mild meningitis

Eva is a three-year-old girl who is on holiday with her grandparents. Eva is unusually tired and is complaining that her legs are aching. This morning, Eva’s grandparents noticed a very small purple rash on her leg, and so they have to come to the pharmacy for advice. Eva has no fever or any other symptoms, but her grandmother has a cold sore.

Assessment and diagnosis

The rash does not fade under pressure when a glass is pressed against it.

Petechiae and purpura are significantly more common with invasive meningococcal infection than with pneumococcal meningitis, which rarely presents with a rash [13] . However, although the glass test is widely promoted in patient information leaflets, the National Institute for Health and Care Excellence (NICE) has found no evidence on its use. The test is not promoted in the NICE guidelines. Consequently, the glass test should not be used as the only test for diagnosing the condition [12] . Public Health England is also informed that Eva may have meningitis, and 999 is called.

Treatment options

On arrival at hospital, Eva is showing signs of shock — she is tachycardic with increased drowsiness and cold peripheries. After having initial tests, she is treated for shock with a fluid bolus of 20mL/kg sodium chloride 0.9% over 10 minutes. A lumbar puncture is contraindicated in shock and, therefore, Eva is empirically started on intravenous (IV) ceftriaxone and steroids. She is also started on IV aciclovir, owing to her history of contact with the herpes simplex virus.

Advice and recommendations

Eva is treated with antibiotics for ten days and her grandparents are both prescribed rifampicin as chemoprophylaxis. Antibiotic prophylaxis should be given as soon as possible (ideally within 24 hours) after the diagnosis of the index case [12] .

Case study 2: a baby with meningitis

Katherine is a mother of two young children who comes into the pharmacy and asks for advice. She has a young baby, Jacob, who is six weeks old and Esmé who is four years old. Jacob has a blocked nose and fever. Katherine explains that Esmé had gastroenteritis with cold symptoms and fever last week, but no rash. Katherine is worried about Jacob and asks for advice.

Katherine brings her children into the consultation room for further assessment. Jacob has been more unsettled than usual and does not want to feed as much as normal. Upon examination, Jacob has a rash on his stomach and back, which his mother says was not present this morning. His rash looks like red blotches and does not fade with the glass test. Owing to his age, Jacob is too young to have received any vaccinations.

It is important to remain calm and inform Katherine that you think Jacob may have meningitis, as he has the characteristic rash, as well as other known symptoms. Jacob needs to be taken to hospital for emergency assessment and an ambulance is called.

On arrival at the hospital, Jacob has blood tests taken and a lumbar puncture. He is started on intravenous (IV) cefotaxime with amoxicillin (if he was three months or older, IV ceftriaxone would be administered) with full-volume maintenance fluids and enteral feeds as tolerated [3] . Corticosteroids must not be used in children aged younger than three months with suspected or confirmed bacterial meningitis.

Jacob has hourly observations initially for heart rate, blood pressure, respiratory rate, oxygen saturation, fluid balance and Glasgow Coma Scale (GCS). The GCS is a neurological scale used to describe the level of consciousness in a person following a traumatic brain injury — the lower the number, the more severe the brain injury. Public Health England is also informed that Jacob may have meningitis.

In children younger than three months, ceftriaxone may be used as an alternative to cefotaxime (with or without ampicillin or amoxicillin); however, it should not be used in premature babies or in babies with jaundice, hypoalbuminaemia or acidosis, as it may exacerbate hyperbilirubinaemia [3] .

The microbiology consultant calls the ward to confirm that Jacob has Group B streptococcal meningitis. As per the National Institute for Health and Care Excellence’s guidelines, Jacob will need treating with IV cefotaxime for at least 14 days [3] .

Before discharge, Katherine is given the contact details of several patient support organisations, including meningitis charities that can offer support and written information to signpost her to further help. Jacob has an audiology appointment booked in two weeks and will be seen by a paediatrician after this. At this appointment, the following morbidities will be considered:

• Hearing loss;
• Orthopaedic complications;
• Skin complications (including scarring from necrosis);
• Psychosocial problems;
• Neurological and developmental problems;
• Kidney failure.

Outcome of the advice

Jacob makes a full recovery from his meningitis with no lasting effects. 

Case study 3: an adult with suspected meningitis

Jane is a paediatric haematology nurse who comes into the pharmacy asking to buy paracetamol. She says she has a terrible headache and upset stomach. She seems confused and disorientated; talking to her further highlights that something is not right.

Jane explains that she has not felt well since last night and has spent most of the day in bed, as she feels like she has no energy. However, some of what Jane also says does not make sense, and she is finding it hard to follow the conversation. She has no fever or rash.

Vomiting, severe headache and confusion are all symptoms of meningitis. Using a symptoms checker, such as the one by the Meningitis Research Foundation , to help with decision making.

Upon further questioning, it is clear that Jane must go to a hospital immediately and an ambulance is called. Jane presented with confusion and disorientation, which might indicate a stroke; however, bacterial meningitis can cause stroke.

When the paramedics arrive at the pharmacy, they find Jane has a Glasgow Coma Scale of 4/15. Once Jane arrives in hospital, they follow the stroke pathway, but she is now also febrile. Jane has a lumbar puncture and the results show she has bacterial meningitis. She also has a CT scan that shows an infarct on her right temporal lobe. Jane is treated in hospital with antibiotics and steroids, and eventually discharged to go home after three weeks.

Jane was working in the paediatric intensive care unit the week preceding the symptoms. She was looking after a child with Haemophilus influenzae type b (Hib). The patient was in a neutral pressure side room with a positive pressure lobby — this is an infection control measure to prevent the spread of microbial contaminants outside the patient’s side room. The lobby had been used to store an apheresis machine; however, the door between the side room and lobby had been left open, inadvertently leading to the exposure of Hib.

Although Jane has now fully recovered, she has to wear glasses owing to damage to her optical nerve. She also has tinnitus and occasionally suffers from severe headaches.

Recovering from meningitis/complications

Some of the most common complications associated with meningitis are [10] :

• Hearing loss, which may be partial or total — people who have had meningitis will usually have a hearing test after a few weeks to check for any problems;
• Recurrent seizures;
• Problems with memory and concentration;
• Problems with coordination, movement and balance;
• Learning difficulties and behavioural problems;
• Vision loss, which may be partial or total;
• Loss of limbs — amputation is sometimes necessary to stop the infection spreading through the body and remove damaged tissue;
• Bone and joint problems, such as arthritis;
• Kidney problems.

Overall, it is estimated that up to one in every ten cases of bacterial meningitis is fatal.

Useful resources

• Meningitis Research Foundation
• Meningitis Now
• National Institute for Health and Care Excellence clinical guideline [CG102]

[1] UNICEF, WHO, World Bank Group & United Nations. Levels and Trends in Child Mortality Report. 2017. Available at: https://www.unicef.org/publications/index_101071.html (accessed June 2019)

[2] Public Health England. Invasive meningococcal disease in England: annual laboratory confirmed reports for epidemiological year 2017 to 2018. 2018. Available at: https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/751821/hpr3818_IMD.pdf (accessed June 2019)

[3] National Institute for Health and Care Excellence. Meningitis (bacterial) and meningococcal septicaemia in under 16s: recognition, diagnosis and management. Clinical guideline [CG102]. 2015. Available at: https://www.nice.org.uk/guidance/cg102 (accessed June 2019)

[4] Davila S, Wright VJ, Khor CC et al . Genome-wide association study identifies variants in the CFH region associated with host susceptibility to meningococcal disease. Nat Genet 2010;42(9):772–776. doi: 10.1038/ng.640

[5] Domingo P, Pomar V, de Benito N & Coll P. The spectrum of acute bacterial meningitis in elderly patients.  BMC Infect Dis 2013;13:108. doi: 10.1186/1471-2334-13-108

[6] Paireau J, Chen A, Broutin H et al . Seasonal dynamics of bacterial meningitis: a time-series analysis. Lancet Glob Health 2016;4(6):e370–e377. doi: 10.1016/S2214-109X(16)30064-X

[7] Cooper LV, Robson A, Trotter CL et al . Risk factors for acquisition of mening ococcal carriage in the African meningitis belt. Trop Med Int Health 2019;24(4):392–400. doi: 10.1111/tmi.13203

[8] Kolappan S, Coureuil M, Yu X et al . Structure of the Neisseria meningitidis type IV pilus.  Nat Commun 2016;7:13015. doi: 10.1038/ncomms13015

[9] Tunkel AR & Scheld WM. Pathogenesis and pathophysiology of bacterial meningitis. Clin Microbiol Rev 1993;6(2):118–136. doi: 10.1128/CMR.6.2.118

[10] Sáez-Llorens X & McCracken GH Jr. Bacterial meningitis in children. Lancet 2003;361(9375):2139–2148. doi: 10.1016/S0140-6736(03)13693-8

[11] NHS Choices. Meningitis. 2019. Available at: https://www.nhs.uk/conditions/meningitis (accessed June 2019)

[12] Baines P, Reilly N & Gill A. Paediatric meningitis: clinical features and diagnosis. Clin Pharm 2009;1:307–310. URI: 10971150

[13] The National Institute for Health and Care Excellence. Clinical Knowledge Summaries: meningitis — bacterial meningitis and meningococcal disease. 2019. Available at: https://cks.nice.org.uk/meningitis-bacterial-meningitis-and-meningococcal-disease (accessed June 2019)

[14] NHS Choices. Pneumococcal vaccination. 2019. https://www.nhs.uk/conditions/vaccinations/pneumococcal-vaccination (accessed June 2019)

[15] Cooper LV, Robson A, Trotter C et al. Risk factors for acquisition of meningococcal carriage in the African meningitis belt. Trop Med Int Health 2019;24(4):392–400. doi: 10.1111/tmi.13203

You might also be interested in…

Whooping cough resurgence as vaccination rates slump

Case-based learning: insect bites and stings

Serious shortage protocols issued for three penicillin oral solutions

We have a new app!

Take the Access library with you wherever you go—easy access to books, videos, images, podcasts, personalized features, and more.

Download the Access App here: iOS and Android . Learn more here!

• Remote Access
• Save figures into PowerPoint
• Download tables as PDFs

9:  Bacterial Meningitis

Jonathan C. Cho

• Download Chapter PDF

Disclaimer: These citations have been automatically generated based on the information we have and it may not be 100% accurate. Please consult the latest official manual style if you have any questions regarding the format accuracy.

Download citation file:

• Search Book

Jump to a Section

Patient presentation.

• Full Chapter
• Supplementary Content

Chief Complaint

“I have severe headaches and fevers.”

History of Present Illness

DJ is a 54-year-old Caucasian female who presents to the emergency department with worsening headache, neck pain, and back pain of 2 days duration. She also complains of low-grade fevers and chills that developed over the past 24 hours. Her son, who is present during her exam, states that she seems more lethargic and has difficulty maintaining her balance. In addition, she reports 3 to 4 episodes of nausea and vomiting.

Past Medical History

CHF, COPD, HTN, epilepsy, stroke, hypothyroidism, anxiety

Surgical History

Hysterectomy, cholecystectomy

Family History

Father had HTN and passed away from a stroke 4 years ago; mother has type II DM and epilepsy; brother has HTN

Social History

Divorced but lives with her two sons who are currently attending college. Smokes ½ ppd × 27 years and drinks alcohol occasionally.

Home Medications

Advair 250 mcg/50 mcg 1 puff BID

Albuterol metered-dose-inhaler 2 puffs q4h PRN shortness of breath

Alprazolam 0.5 mg PO daily

Aspirin 81 mg PO daily

Atorvastatin 20 mg PO daily

Carvedilol 6.25 mg PO BID

Citalopram 20 mg PO daily

Divalproex sodium 500 mg PO BID

Furosemide 20 mg PO daily

Levothyroxine 88 mcg PO daily

Levetiracetam 500 mg PO BID

Lisinopril 20 mg PO daily

Physical Examination

Vital signs.

Temp 101.2°F, P 72, RR 23 breaths per minute, BP 162/87 mm Hg, pO 2 91%, Ht 5′3″, Wt 56.4 kg

Lethargic, female with dizziness and in mild to moderate distress.

Normocephalic, atraumatic, PERRLA, EOMI, pale or dry mucous membranes and conjunctiva, poor dentition

Diminished breath sounds and crackles bilaterally.

Cardiovascular

NSR, no m/r/g

Soft, non-distended, non-tender, bowel sounds hyperactive

Genitourinary

Normal female genitalia, no complaints of dysuria or hematuria

Lethargic, oriented to place and person, (–) Brudzinski’s sign, (+) Kernig’s sign

Extremities

Sign in or create a free Access profile below to access even more exclusive content.

With an Access profile, you can save and manage favorites from your personal dashboard, complete case quizzes, review Q&A, and take these feature on the go with our Access app.

Pop-up div Successfully Displayed

This div only appears when the trigger link is hovered over. Otherwise it is hidden from view.

Please Wait

• Research article
• Open access
• Published: 04 June 2021

Clinical features of bacterial meningitis among hospitalised children in Kenya

• Christina W. Obiero 1 , 2 ,
• Neema Mturi 1 ,
• Salim Mwarumba 3 ,
• Moses Ngari 1 , 4 ,
• Charles R. Newton 1 , 5 ,
• Michaël Boele van Hensbroek 2 &
• James A. Berkley 1 , 4 , 6  

BMC Medicine volume  19 , Article number:  122 ( 2021 ) Cite this article

3656 Accesses

1 Citations

7 Altmetric

Metrics details

Diagnosing bacterial meningitis is essential to optimise the type and duration of antimicrobial therapy to limit mortality and sequelae. In sub-Saharan Africa, many public hospitals lack laboratory capacity, relying on clinical features to empirically treat or not treat meningitis. We investigated whether clinical features of bacterial meningitis identified prior to the introduction of conjugate vaccines still discriminate meningitis in children aged ≥60 days.

We conducted a retrospective cohort study to validate seven clinical features identified in 2002 ( KCH-2002 ): bulging fontanel, neck stiffness, cyanosis, seizures outside the febrile convulsion age range, focal seizures, impaired consciousness, or fever without malaria parasitaemia and Integrated Management of Childhood Illness (IMCI) signs: neck stiffness, lethargy, impaired consciousness or seizures, and assessed at admission in discriminating bacterial meningitis after the introduction of conjugate vaccines. Children aged ≥60 days hospitalised between 2012 and 2016 at Kilifi County Hospital were included in this analysis. Meningitis was defined as positive cerebrospinal fluid (CSF) culture, organism observed on CSF microscopy, positive CSF antigen test, leukocytes ≥50/μL, or CSF to blood glucose ratio <0.1.

Among 12,837 admissions, 98 (0.8%) had meningitis. The presence of KCH-2002 signs had a sensitivity of 86% (95% CI 77–92) and specificity of 38% (95% CI 37–38). Exclusion of ‘fever without malaria parasitaemia’ reduced sensitivity to 58% (95% CI 48–68) and increased specificity to 80% (95% CI 79–80). IMCI signs had a sensitivity of 80% (95% CI 70–87) and specificity of 62% (95% CI 61–63).

Conclusions

A lower prevalence of bacterial meningitis and less typical signs than in 2002 meant the lower performance of KCH-2002 signs. Clinicians and policymakers should be aware of the number of lumbar punctures (LPs) or empirical treatments needed for each case of meningitis. Establishing basic capacity for CSF analysis is essential to exclude bacterial meningitis in children with potential signs.

Peer Review reports

Childhood bacterial meningitis is associated with significant mortality and neurocognitive sequelae [ 1 , 2 ]. The disease burden is highest in low- and middle-income countries (LMICs) where a quarter of children who survive vaccine-preventable meningitis develop post-discharge complications [ 2 , 3 ]. Prompt recognition and antimicrobial treatment with cerebrospinal fluid (CSF) penetration for an adequate duration are critical.

CSF culture is the gold standard for bacterial meningitis but has limited sensitivity [ 4 ] as it may be compromised by prior administration of antimicrobials [ 5 ] and is usually unavailable or unreliable in public hospitals in sub-Saharan Africa. Public hospitals also often lack adequate CSF microscopy capacity, and lumbar puncture (LP) may be commonly ordered but not done [ 6 , 7 ]. Thus, antimicrobial management decisions are often based on clinical features only.

The World Health Organization (WHO) advises suspecting bacterial meningitis if one or more of the following are present: convulsions, inability to drink, irritability, lethargy, impaired consciousness, a bulging fontanel, or neck stiffness [ 8 ]. However, this recommendation is based on limited evidence collected prior to the introduction of Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae conjugate vaccines targeting the leading causes of bacterial meningitis.

In the Gambia ~20 years ago, a set of Integrated Management of Childhood Illness (IMCI) signs (lethargy, impaired consciousness, convulsions, or a stiff neck) [ 9 ] had 98% sensitivity and 72% specificity in predicting bacterial meningitis [ 10 ]. Concurrently, among children aged ≥60 days at Kilifi County Hospital (KCH), Kenya, a bulging fontanel, neck stiffness, cyanosis, seizures outside the febrile convulsions age range, focal seizures, and impaired consciousness were identified as indicators of bacterial meningitis ( KCH-2002 ) [ 11 ]. These findings were incorporated into Kenyan national paediatric guidelines [ 12 ].

Hib and 10-valent pneumococcal conjugate vaccines at 6, 10, and 14 weeks of age without booster were introduced in Kenya in 2001 and 2011, respectively, resulting in a markedly reduced incidence and mortality from bacterial meningitis [ 13 , 14 , 15 , 16 , 17 ]. Since the early 2000’s severe malaria, which may mimic bacterial meningitis [ 18 ], has declined, with changes in age and disease profile reported at several centres in Africa [ 19 , 20 , 21 ].

Changes in epidemiology, patient profile and differential diagnoses may have altered associations between clinical features and bacterial meningitis. We therefore performed a revalidation study of the KCH-2002 and IMCI signs among children aged ≥60 days.

Location and participants

KCH is a public hospital serving a mostly rural population. Paediatric care is supported by the KEMRI/Wellcome Trust Research Programme. Children aged 60 days to 13 years hospitalised at KCH between January 1, 2012, and December 31, 2016, were included in this analysis.

All children admitted were systematically assessed using standardised demographic and clinical proforma by trained clinicians at admission, and data were entered on a database in real-time. All admissions had a complete blood count, malaria slide, and blood culture. LP was performed at admission if suggestive signs were present, or if a child developed new clinical features of meningitis according to the WHO [ 8 ] and Kenyan guidelines [ 12 ] detected through daily clinical reviews until discharge. LP was deferred in children with cardiorespiratory compromise or suspicion of raised intracranial pressure [ 22 ]. Children with suspected meningitis were treated empirically with penicillin plus chloramphenicol or ceftriaxone (as per national and WHO guidelines [ 8 , 12 ]) while awaiting LP results. Once available, treatment was modified based on culture and susceptibility profile as needed. Data collection (SSC1433) and this analysis (SSC3001) were approved by the KEMRI Scientific and Ethics Review Unit.

Laboratory analysis

CSF examination included leukocyte and red blood cell (RBC) count using the Neubauer counting chamber method, and if leukocyte count >10 cells/μl, differential leukocyte count, Gram and Indian ink staining, latex antigen agglutination tests (Wellcogen™ Bacterial Antigen kit for S. pneumoniae , H. influenzae , N. meningitidis, and CrAg Lateral Flow Assay kit Ref CR2003 for Cryptococcus neoformans ) were done. CSF and blood samples were cultured, and pathogens identified using standard methods as previously described [ 11 , 18 ]. Coagulase-negative S taphylococci were considered non-significant [ 23 ]. CSF protein, glucose, and concurrent blood glucose were measured on an ILab Aries analyser (Werfen, Germany). External quality assurance was by the United Kingdom External Quality Assessment Service, and Good Clinical Laboratory Practice was accredited by Qualogy, UK [ 11 ].

Definitions

For this analysis, we used the KCH-2002 [ 11 ] definition of bacterial meningitis: (i) positive CSF culture for a known pathogen, (ii) positive CSF antigen test, (iii) an organism observed on CSF microscopy (Gram stain or Indian Ink), (iv) CSF leucocyte count ≥50 cells/μL, or (v) CSF to blood glucose ratio <0.1. We also defined possible meningitis as CSF leucocyte count >10–49 cells/μL in the absence of the above criteria.

Statistical analysis

For the primary analysis, children who underwent LP not meeting meningitis criteria or without an LP were classified as not having meningitis, as was assumed in KCH-2002 . We initially excluded children with possible meningitis [ 11 ] and calculated the highest criterion for meningitis in the order given above.

We examined the performance of KCH-2002 [ 11 ] and IMCI signs (neck stiffness, lethargy, impaired consciousness, or seizures) [ 9 ] at admission by calculating their sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for meningitis diagnosed by LP either at admission or at any time during hospitalisation versus no meningitis, defined as negative CSF analysis or no clinical suspicion of meningitis until discharge from hospital. We calculated the number of LPs needed to identify one case of meningitis as the inverse of the risk difference obtained by subtracting the prevalence of meningitis in each group from that in the group without the indicators of interest. As sensitivity analyses, we (i) included possible meningitis cases, (ii) excluded those who died before LP, and (iii) used a narrow microbiological definition of meningitis (positive CSF culture for a known pathogen, positive CSF antigen test, an organism observed on CSF microscopy (Gram stain or Indian Ink), or CSF leucocyte count >10 cells/μL plus a positive blood culture).

Proportions were compared using the chi-squared test or Fisher’s exact test. Continuous variables were compared using Wilcoxon rank-sum test. All analyses used Stata version 15 (Stata Corp, USA).

There were 12,986 admissions aged 60 days to 13 years: 2975 (23%) <1 year, 6248 (48%) 1–4 years, and 3763 (29%) ≥5 years old; 463 (3.6%) were HIV antibody positive. Two thousand six hundred-two (20%) children had an LP, of which 409 (16%) were aged <1 year. LPs were more commonly done among children aged 1–5 years [1484/6248 (24%)] than in children aged >5 years [709/3,763 (19%)] or <1 year [409/2975 (14%)], P<0.001 . A positive malaria smear was present in 1189 (46%) children who had an LP. Of 10,384 children who did not have an LP, 565 died before an LP (193 (34%) <1 year, 230 (41%) 1–5 years and 142 (25%) ≥5 years) while 9819 survived (2373 (24%) <1 year, 4534 (46%) 1–5 years, and 2912 (30%) ≥5 years) ( P<0.001 ). Median [interquartile range (IQR)] age of 565 children who died before an LP was 21 months (8.0–60) compared to 20 months (9.5–59) in 88 children who died after an LP ( P=0.874 ).

Meningitis cases

Ninety-eight children had meningitis (Fig. 1 , Group C): 0.8% of 12,986 admissions and 3.8% of 2602 children with an LP. Fifty-one (0.4%) children had possible meningitis (Group D) and were excluded from the primary analysis. Median (IQR) ages of children with meningitis, possible meningitis, or no meningitis were 25 (7.4–77), 40 (11–83), and 29 (12–67) months, respectively (P=0.167) . Fifteen (15%) meningitis cases died during hospitalisation; 2.3% (15/653) of all inpatient deaths.

Flow chart of study participants. Abbreviation: LP, lumbar puncture

Leading CSF pathogens were S. pneumoniae (16 culture-positive and 4 antigen-positive) and H. influenzae (5 culture-positive and 3 antigen-positive) (Table 1 ). Fifty (51%) meningitis cases had CSF leukocyte count ≥50/μl only. One hundred twenty (4.8%) of 2521 children had differential leukocyte count done of which 118 (98%) had polymorphonuclear cell predominance (≥60%) and 77 had meningitis. Five (2.0%) of 249 children with CSF RBC count ≥500 cells/μL had positive CSF cultures while 4 (1.6%) children missed leukocyte counting due to grossly blood-stained CSF. Thirty-three (34%) children with meningitis had positive blood culture; 23 matched CSF isolates (13 S. pneumoniae , 4 H. influenzae , 2 Salmonella spp., and 1 each of E. coli , K. pneumoniae , P. aeruginosa , and C. neoformans ). Forty-one (42%) meningitis cases had turbid CSF.

Admission clinical features

Two thousand three hundred thirty (79%), 3762 (60%), and 2007 (54%) children aged <1, 1–5, and ≥5 years, respectively, presented with KCH-2002 signs ( P<0.001 ), while 899 (30%), 2661 (43%), and 1391 (37%) had IMCI signs ( P<0.001 ). Bulging fontanel, neck stiffness, impaired consciousness, seizures outside the febrile convulsion age range, focal seizures, history of fever, and axillary temperature ≥39°C were more common among children with meningitis than without, and malaria was less common (Table 2 ). Of 8099 children with KCH-2002 signs, 485 (6.0%) died before LP (277 (57%) within 24 h of admission). Of 4951 children with IMCI signs, 359 (7.3%) died before LP (240 (67%) within 24 h of admission).

Performance of clinical features

One or more KCH-2002 signs were present in 8099 children, of whom 84 (1.0%) had meningitis compared with 14/4836 (0.3%) without KCH-2002 signs: sensitivity 86% (95% CI 77–92), specificity 38% (95% CI 37–38), PPV 1.0% (95% CI 0.8–1.3), and NPV 100% (95% CI 99–100). One hundred thirty-four children (95% CI 99–208) presenting with ≥1 KCH-2002 signs would need to undergo an LP for each case of meningitis identified (Table 3 ).

One or more IMCI signs were present in 4951 children, of whom 78 (1.6%) had meningitis compared with 20/7984 (0.3%) without IMCI signs: sensitivity 80% (95% CI 70–87), specificity 62% (95% CI 61–63), PPV 1.6% (95% CI 1.3–2.0), and NPV 100% (99%CI 99–100). Seventy-six children (95% CI 59–104) presenting with ≥1 IMCI signs would need to undergo an LP for each case of meningitis identified (Table 3 ).

Admission versus later LP

Thirty-three (34%) meningitis cases had their LP after admission, of which 6/33 (18%) and 8/33 (24%) were not identified by KCH-2002 signs and IMCI signs, respectively, at admission. Seven (7.1%) meningitis cases were not identified by either KCH-2002 signs or IMCI signs at admission (Fig. 2 ).

Clinical features of meningitis in 98 children with definite meningitis. Abbreviations: KCH-2002, previously identified signs at Kilifi Country Hospital; IMCI, Integrated Management of Childhood Illness. a History of fever with positive malaria smear ( n =1), history of diarrhoea ( n =2), history of vomiting ( n =2), oedema ( n =1), palmar pallor ( n =1), severe acute malnutrition ( n =2), died ( n =2)

Sensitivity analysis

Excluding 565 who died before an LP (Group G) and including 51 cases with possible meningitis (Group D) as ‘meningitis’ gave similar results for KCH-2002 and IMCI signs (Table S 2 ). Fifty children with microbiologically confirmed meningitis fulfilled criteria as follows: 31 positive CSF cultures only (of which 23 had positive blood culture), 7 positive antigen tests only (of which 2 had positive blood culture), 5 positive microscopies (of which 2 had CSF leukocyte count >10), and 7 CSF leukocyte counts >10 cells/μL plus positive blood culture. For microbiologically confirmed meningitis, KCH- 2002 signs had a sensitivity of 90% (95% CI 78–97) and specificity of 39% (95% CI 38–39). IMCI signs had a sensitivity of 76% (95% CI 62–87) and specificity of 63% (95% CI 62–64).

Misdiagnosis of bacterial meningitis based on clinical signs only may result in overtreatment with prolonged courses of antimicrobials, or undertreatment of missed cases [ 24 ], both contributing to mortality and selection of resistant organisms.

We studied a large cohort of hospitalised children to validate the clinical features of bacterial meningitis. Using the same definitions and inclusion criteria as in 2002, we observed a reduction in the prevalence of bacterial meningitis among paediatric admissions at our centre from 2% in 2001–2002 [ 11 ] to 0.8% in 2012–2016. There was also a decline in annual paediatric admissions and number of LPs done. However, we observed an increase in the prevalence of KCH-2002 signs (55% in 2001–2002 vs 63% in 2012–2016, P<0.001 ) and a decrease in the prevalence of IMCI signs (42% in 2001–2002 vs 38% in 2012–2016, P<0.001 ) [ 11 ]. Although S. pneumoniae and H. influenzae remained the leading causes of bacterial meningitis, cases arising from these organisms declined over time (57 vs 20 pneumococcal, and 66 vs 8 H. influenzae cases, comparing 1994–1998 [ 25 ] to 2012-2016). These changes may be attributed to conjugate vaccination and herd immunity in older children. Our study excluded infants aged <60 days who typically have bacterial meningitis due to different pathogens [ 17 ], different clinical presentation [ 26 ], and alternative diagnoses such as birth asphyxia [ 27 ], and associated higher risk of neurological disability and mortality [ 17 ].

Clinical guidelines for limited-resource settings should comprise straightforward features, easily identifiable by clinicians [ 28 ]. Overall, we found that the clinical signs at admission had lower sensitivity and PPV in discriminating children with bacterial meningitis than in 2002 [ 11 ]. KCH-2002 and IMCI signs did not statistically significantly differ in the proportions of meningitis cases missed (14% vs 20%, P=0.258 ), although numbers were limited for this comparison. Results did not appear to be altered by the exclusion of children who died before LP or using a narrower microbiological case definition.

History of fever was common with (90%) or without meningitis (68%) and nearly half of the LPs were done in children with malaria since signs overlap. The previous KCH-2002 analysis found that exclusion of fever without malaria parasitaemia from the screening rule had lower sensitivity but higher specificity (sensitivity 79%, specificity 80%, PPV 8.0%) than when it was included (sensitivity 97%, specificity 44%, PPV 3.5%) [ 11 ]. The present analysis also shows that although the specificity of KCH-2002 signs excluding fever without malaria parasitaemia has not changed, sensitivity was again markedly reduced (to 58% from 86%). Malaria parasitaemia has been shown to augment predictive models for bacterial meningitis [ 11 , 29 ]; however, the significant morbidity and mortality associated with meningitis means a screening rule with higher sensitivity may be favourable despite lower specificity.

Although conjugate vaccination has resulted in a reduction in bacterial meningitis cases, antimicrobial resistance to penicillin [ 30 ] and chloramphenicol [ 31 , 32 ] is reported. Ceftriaxone as a first-line treatment for bacterial meningitis has been associated with lower resistance rates, and reduction in mortality and neurological complications compared to chloramphenicol [ 32 , 33 ]. Thus, clinical decision rules with optimal performance in predicting bacterial meningitis contribute to antimicrobial stewardship by guiding initiation of treatment and minimising selection of resistant microorganisms.

Limitations

An inescapable limitation is that a selective group of children underwent an LP based on clinical suspicion at admission or later during admission. It is possible that a number of bacterial meningitis cases may have been missed due to apparent recovery and discharge. However, we believe that the higher than usual clinical staffing, training oversight, and availability of laboratory resources due to the presence of the research programme helped limit the chances of missed meningitis cases. Although performing LPs in all children is diagnostically optimal and would provide an understanding of the true prevalence of meningitis, this is not possible due to the risks involved and would not be ethically justified [ 22 ]. Our dataset may not be perfect, but it addresses research gaps in similar settings. Of 2602 LPs done, 1026 (39%) were performed after admission; 33/98 (34%) meningitis cases were diagnosed after admission, underscoring the importance of daily clinical reviews following standard guidelines. Our assumption of true negatives in children who did not develop signs suggestive of meningitis during hospitalisation and were discharged home alive is valid. The highest proportion of children having an LP was in those aged 1–5 years. KCH-2002 signs were most frequent among children aged <1 year, fewer LPs done in this age group may be attributed to early deaths or more LPs being deferred due to contraindications since most deaths occurred in young infants (7.4%, 4.3%, and 4.4% deaths in children aged <1, 1–5, and ≥5 years, respectively, P<0.001 ). However, age bias in LPs may have affected our findings. Importantly, our aim was to inform clinical guidelines for empiric treatment and indications for LP rather than describe the epidemiology of meningitis for which post-mortem LPs would have been necessary.

Molecular tests for bacterial and viral causes were not routinely done, potentially missing true bacterial meningitis cases and falsely including viral meningitis cases. Although differential leukocyte count was done in some CSF samples, it was not included in our standard definition of meningitis. Polymorphonuclear cell predominance can occur in both bacterial and aseptic meningitis [ 34 ]. We lacked data on pre-hospital antibiotic exposure which may be common and has been shown to alter CSF leukocyte count and biochemical profile and impede detection of bacterial pathogens [ 5 , 35 ]. Diagnostic delay may decrease survival [ 36 ] and increase neurological sequelae in Hib meningitis [ 37 ] and may be more of a problem in settings without advanced diagnostic resources such as CSF polymerase chain reaction (PCR) [ 38 ].

Low LP rates reported in settings like ours have raised concerns regarding missing meningitis cases [ 6 , 7 ]. Knowing that a large number of LPs is needed in order to diagnose each case of bacterial meningitis is important in this regard. The KCH-2002 or IMCI signs at admission suggest an LP may be needed in ~40 to 60% of children presenting to the hospital with these signs to achieve >80% sensitivity. There are no studies evaluating the additional discriminatory value of a structured repeated evaluation of signs that develop later during admission, or of biomarkers in this context. Although traumatic LPs are common and may complicate CSF leukocyte interpretation, adjustment of CSF leukocyte count has been shown to lack additional value in predicting meningitis [ 39 ]. In our study, only 5 children with CSF RBC ≥500 cells/μL met our laboratory meningitis criteria. Our results provided important guidance for performing LPs in LMICs settings where there is a paucity of comprehensive data on this important question.

Bacterial meningitis is an uncommon but important diagnosis in children. Declining incidence is welcome but identifying children with meningitis has become more difficult. Clinicians and policymakers should be aware of the number of LPs or empirical treatments needed for each case of bacterial meningitis to be identified, and this may vary with malaria endemicity. The IMCI criteria offer a balance between the more specific KCH-2002 signs (impaired consciousness or any one of bulging fontanel, neck stiffness, cyanosis, seizures outside 6 months to 6 years, or focal seizures) and non-malarial fever. While the IMCI criteria will continue to be used, the number of LPs needed to identify a single case of bacterial meningitis has increased 3-fold from 24 to 76. Clinicians should continue to have a high index of suspicion while assessing children during daily reviews. Support to establish accurate CSF cell counting, Gram stain, and glucose measurement as a minimum in resource-poor settings to optimise antimicrobial treatment is essential to providing effective inpatient paediatric services.

Availability of data and materials

The dataset used and analysed during the current study is available from the KWTRP Data Governance Committee (DGC) on reasonable request ( [email protected] ), ensuring the protection of the privacy, rights and interests of research participants and primary researchers, and upholding transparency and accountability. KWTRP is the custodian of the data used in this analysis, and the KWTRP DGC oversees the internal data repository.

Abbreviations

• Low- and middle-income countries
• Cerebrospinal fluid
• Lumbar puncture

World Health Organization

Haemophilus influenzae type b

Integrated Management of Childhood Illness

Kilifi County Hospital

Positive predictive value

Negative predictive value

Mann K, Jackson MA. Meningitis. Pediatrics Review. 2008;29(12):417–30. https://doi.org/10.1542/pir.29-12-417 .

Article   Google Scholar  

Edmond K, Clark A, Korczak VS, Sanderson C, Griffiths UK, Rudan I. Global and regional risk of disabling sequelae from bacterial meningitis: a systematic review and meta-analysis. Lancet Infect Dis. 2010;10(5):317–28. https://doi.org/10.1016/S1473-3099(10)70048-7 .

Article   PubMed   Google Scholar  

Ramakrishnan M, Ulland AJ, Steinhardt LC, Moisi JC, Were F, Levine OS. Sequelae due to bacterial meningitis among African children: a systematic literature review. BMC Med. 2009;7(1):47. https://doi.org/10.1186/1741-7015-7-47 .

Article   PubMed   PubMed Central   Google Scholar  

Manning L, Laman M, Mare T, Hwaiwhanje I, Siba P, Davis TM. Accuracy of cerebrospinal leucocyte count, protein and culture for the diagnosis of acute bacterial meningitis: a comparative study using Bayesian latent class analysis. Trop Med Int Health. 2014;19(12):1520–4.

Article   CAS   Google Scholar  

Kanegaye JT, Soliemanzadeh P, Bradley JS. Lumbar puncture in pediatric bacterial meningitis: defining the time interval for recovery of cerebrospinal fluid pathogens after parenteral antibiotic pretreatment. Pediatrics. 2001;108(5):1169–74.

CAS   PubMed   Google Scholar  

Ayieko P, Ogero M, Makone B, Julius T, Mbevi G, Nyachiro W, et al. Characteristics of admissions and variations in the use of basic investigations, treatments and outcomes in Kenyan hospitals within a new Clinical Information Network. Arch Dis Childhood. 2016;101(3):223–9. https://doi.org/10.1136/archdischild-2015-309269 .

Herbert G, Ndiritu M, Idro R, Makani JB, Kitundu J. Analysis of the indications for routine lumbar puncture and results of cerebrospinal fluid examination in children admitted to the paediatric wards of two hospitals in East Africa. Tanzania J Health Res. 2006;8(1):7–10.

WHO. Pocket book of hospital care for children: WHO Press; 2013. Available from: http://www.who.int/maternal_child_adolescent/documents/child_hospital_care/en/ .

WHO IMCI. Integrated Management of Childhood Illness (IMCI) Chart Booklet. Distance Learn Course. 2014;(March):1–76.

Weber MW, Herman J, Jaffar S, Usen S, Oparaugo A, Omosigho C, et al. Clinical predictors of bacterial meningitis in infants and young children in The Gambia. Trop Med Int Health. 2002;7(9):722–31. https://doi.org/10.1046/j.1365-3156.2002.00926.x .

Berkley JA, Versteeg AC, Mwangi I, Lowe BS, Newton CRJC. Indicators of acute bacterial meningitis in children at a rural Kenyan District Hospital. Pediatrics. 2004;114(6):e713–e9. https://doi.org/10.1542/peds.2004-0007 .

MOH. Basic Paediatric Protocols for ages up to 5 years February 2016. Available from: https://www.tropicalmedicine.ox.ac.uk/_asset/file/basic-paediatric-protocols-2016.pdf .

Mwenda JM, Soda E, Weldegebriel G, Katsande R, Biey JN-M, Traore T, et al. Pediatric bacterial meningitis surveillance in the World Health Organization African Region using the invasive bacterial vaccine-preventable disease surveillance network, 2011–2016. Clin Infect Dis. 2019;69(Supplement_2):S49–57.

Cowgill KD, Ndiritu M, Nyiro J, Slack MPE, Chiphatsi S, Ismail A, et al. Effectiveness of haemophilus influenzae type b conjugate vaccine introduction into routine childhood immunization in Kenya. Jama. 2006;296(6):671–8. https://doi.org/10.1001/jama.296.6.671 .

Article   CAS   PubMed   PubMed Central   Google Scholar  

Gessner BD, Adegbola RA. The impact of vaccines on pneumonia: key lessons from Haemophilus influenzae type b conjugate vaccines. Vaccine. 2008;26:B3–8. https://doi.org/10.1016/j.vaccine.2008.04.013 .

Article   CAS   PubMed   Google Scholar  

Wahl B, O'Brien KL, Greenbaum A, Majumder A, Liu L, Chu Y, et al. Burden of Streptococcus pneumoniae and Haemophilus influenzae type b disease in children in the era of conjugate vaccines: global, regional, and national estimates for 2000-15. Lancet Global Health. 2018;6(7):e744–e57. https://doi.org/10.1016/S2214-109X(18)30247-X .

Zunt JR, Kassebaum NJ, Blake N, Glennie L, Wright C, Nichols E, et al. Global, regional, and national burden of meningitis, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2018;17(12):1061–82. https://doi.org/10.1016/S1474-4422(18)30387-9 .

Berkley JA, Mwangi I, Mellington F, Mwarumba S, Marsh K. Cerebral malaria versus bacterial meningitis in children with impaired consciousness. QJM : monthly journal of the Association of Physicians. 1999;92(3):151–7. https://doi.org/10.1093/qjmed/92.3.151 .

Mogeni P, Williams TN, Fegan G, Nyundo C, Bauni E, Mwai K, et al. Age, spatial, and temporal variations in hospital admissions with malaria in Kilifi County, Kenya: a 25-year longitudinal observational study. PLoS Med. 2016;13(6):e1002047. https://doi.org/10.1371/journal.pmed.1002047 .

Nkumama IN, O'Meara WP, Osier FHA. Changes in malaria epidemiology in Africa and new challenges for elimination. Trends Parasitol. 2017;33(2):128–40. https://doi.org/10.1016/j.pt.2016.11.006 .

Njuguna P, Maitland K, Nyaguara A, Mwanga D, Mogeni P, Mturi N, et al. Observational study: 27 years of severe malaria surveillance in Kilifi, Kenya. BMC Med. 2019;17(1):124. https://doi.org/10.1186/s12916-019-1359-9 .

Schulga P, Grattan R, Napier C, Babiker MO. How to use lumbar puncture in children. Arch Dis Child Educ Pract Ed. 2015;100(5):264–71. https://doi.org/10.1136/archdischild-2014-307600 .

Chun S, Kang C-I, Kim Y-J, Lee NY. Clinical Significance of Isolates Known to Be Blood Culture Contaminants in Pediatric Patients. Medicina. 2019;55(10):696. https://doi.org/10.3390/medicina55100696 .

Aipit J, Laman M, Hwaiwhanje I, Bona C, Pomat N, Siba P, et al. Accuracy of initial clinical diagnosis of acute bacterial meningitis in children from a malaria-endemic area of Papua New Guinea. Trans R Soc Trop Med Hyg. 2014;108(7):444–8. https://doi.org/10.1093/trstmh/tru067 .

Mwangi I, Berkley J, Lowe B, Peshu N, Marsh K, Newton CR. Acute bacterial meningitis in children admitted to a rural Kenyan hospital: increasing antibiotic resistance and outcome. Pediatric Infect Dis J. 2002;21(11):1042–8. https://doi.org/10.1097/00006454-200211000-00013 .

Obiero CW, Mturi N, Mwarumba S, Ngari M, Newton C, Boele van Hensbroek M, et al. Clinical features to distinguish meningitis among young infants at a rural Kenyan hospital. Archives of disease in childhood. 2021;106(2):130–6. http://dx.doi.org/10.1136/archdischild-2020-318913 .

Abdul-Mumin A, Cotache-Condor C, Owusu SA, Mahama H, Smith ER. Timing and causes of neonatal mortality in Tamale Teaching Hospital, Ghana: a retrospective study. PLoS One. 2021;16(1):e0245065. https://doi.org/10.1371/journal.pone.0245065 .

Curtis S, Stobart K, Vandermeer B, Simel DL, Klassen T. Clinical features suggestive of meningitis in children: a systematic review of prospective data. Pediatrics. 2010;126(5):952–60. https://doi.org/10.1542/peds.2010-0277 .

Laman M, Manning L, Greenhill AR, Mare T, Michael A, Shem S, et al. Predictors of acute bacterial meningitis in children from a malaria-endemic area of Papua New Guinea. Am J Trop Med Hyg. 2012;86(2):240–5. https://doi.org/10.4269/ajtmh.2012.11-0312 .

Nhantumbo AA, Gudo ES, Caierao J, Munguambe AM, Come CE, Zimba TF, et al. Serotype distribution and antimicrobial resistance of Streptococcus pneumoniae in children with acute bacterial meningitis in Mozambique: implications for a national immunization strategy. BMC Microbiol. 2016;16(1):134. https://doi.org/10.1186/s12866-016-0747-y .

Sanneh B, Okoi C, Grey-Johnson M, Bah-Camara H, Kunta Fofana B, Baldeh I, et al. Declining trends of pneumococcal meningitis in gambian children after the introduction of pneumococcal conjugate vaccines. Clin Infect Dis. 2019;69(Suppl 2):S126–S32. https://doi.org/10.1093/cid/ciz505 .

Manning L, Laman M, Greenhill AR, Michael A, Siba P, Mueller I, et al. Increasing chloramphenicol resistance in Streptococcus pneumoniae isolates from Papua New Guinean children with acute bacterial meningitis. Antimicrob Agents Chemother. 2011;55(9):4454–6. https://doi.org/10.1128/AAC.00526-11 .

Duke T, Michael A, Mokela D, Wal T, Reeder J. Chloramphenicol or ceftriaxone, or both, as treatment for meningitis in developing countries? Arch Disease Childhood. 2003;88(6):536–9. https://doi.org/10.1136/adc.88.6.536 .

Negrini B, Kelleher KJ, Wald ER. Cerebrospinal fluid findings in aseptic versus bacterial meningitis. Pediatrics. 2000;105(2):316–9. https://doi.org/10.1542/peds.105.2.316 .

Nigrovic LE, Malley R, Macias CG, Kanegaye JT, Moro-Sutherland DM, Schremmer RD, et al. Effect of antibiotic pretreatment on cerebrospinal fluid profiles of children with bacterial meningitis. Pediatrics. 2008;122(4):726–30. https://doi.org/10.1542/peds.2007-3275 .

Tadesse BT, Foster BA, Shibeshi MS, Dangiso HT. Empiric treatment of acute meningitis syndrome in a resource-limited setting: clinical outcomes and predictors of survival or death. Ethiop J Health Sci. 2017;27(6):581–8. https://doi.org/10.4314/ejhs.v27i6.3 .

Kaplan SL, OʼBrian Smith E, Wills C, Feigin RD. Association between preadmission oral antibiotic therapy and cerebrospinal fluid findings and sequelae caused by Haemophilus influenzae type b meningitis. Pediatric Infect Dis J. 1986;5(6):626–32. https://doi.org/10.1097/00006454-198611000-00005 .

Khumalo J, Nicol M, Hardie D, Muloiwa R, Mteshana P, Bamford C. Diagnostic accuracy of two multiplex real-time polymerase chain reaction assays for the diagnosis of meningitis in children in a resource-limited setting. PLoS One. 2017;12(3):e0173948. https://doi.org/10.1371/journal.pone.0173948 .

Bonsu BK, Harper MB. Corrections for leukocytes and percent of neutrophils do not match observations in blood-contaminated cerebrospinal fluid and have no value over uncorrected cells for diagnosis. Pediatr Infect Dis J. 2006;25(1):8–11. https://doi.org/10.1097/01.inf.0000195624.34981.36 .

Download references

Acknowledgements

This study is published with the permission of the Director of Kenya Medical Research Institute. Surveillance at KCH was undertaken at the KWTRP by members of the KWTRP medical, nursing, laboratory and computing team who participated in patient care, data collection, and data storage. We thank all KWTRP staff and KCH patients whose data was included in this analysis.

This work was supported by the Wellcome Trust, UK core grant to KEMRI-Wellcome Trust Research Programme (grant 203077/Z/16/Z). CWO is supported by the Drugs for Neglected Diseases initiative (grant OXF-DND02). JAB is supported by the Bill & Melinda Gates Foundation within the Childhood Acute Illness and Nutrition (CHAIN) Network (grant OPP1131320) and by the MRC/DFID/Wellcome Trust Joint Global Health Trials scheme (grant MR/M007367/1). The funders had no role in the design or conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Author information

Authors and affiliations.

Clinical Research Department, KEMRI-Wellcome Trust Research Programme, P.O. Box 230 80108, Kilifi, Kenya

Christina W. Obiero, Neema Mturi, Moses Ngari, Charles R. Newton & James A. Berkley

Department of Global Health, Faculty of Medicine, University of Amsterdam, Amsterdam, The Netherlands

Christina W. Obiero & Michaël Boele van Hensbroek

Department of Microbiology, KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya

Salim Mwarumba

The Childhood Acute Illness and Nutrition (CHAIN) Network, Nairobi, Kenya

Moses Ngari & James A. Berkley

Department of Psychiatry, University of Oxford, Oxford, UK

Charles R. Newton

Centre for Tropical Medicine & Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK

James A. Berkley

You can also search for this author in PubMed   Google Scholar

Contributions

CWO, MN, CRN, MBH, and JAB contributed to the conception and design of the study. CWO, NM, and JAB contributed to inpatient care and data collection. SM was responsible for laboratory analysis. CWO, NM, SM, MN, CRN, MBH, and JAB contributed to the analysis and interpretation of the data. CWO, MBH, and JAB contributed to the drafting of the article. The views expressed in this manuscript are those of the authors and not necessarily those of the KEMRI or the Wellcome Trust. The authors read and approved the final manuscript.

Corresponding author

Correspondence to Christina W. Obiero .

Ethics declarations

Ethics approval and consent to participate.

The collection of surveillance data included in this analysis was reviewed and approved by the Kenya Medical Research Institute Scientific Steering Committee (KEMRI SSC 1433). This retrospective analysis was reviewed and approved by the KEMRI SSC (KEMRI SSC 3001).

Consent for publication

Not applicable

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s note.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Additional file 1: table s1..

Comparison of annual admissions, lumbar punctures and meningitis cases during our study period and our previous analysis. Table S2. Sensitivity Analysis of Potential Screening Criteria at Admission for Meningitis.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ . The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/ ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Cite this article.

Obiero, C.W., Mturi, N., Mwarumba, S. et al. Clinical features of bacterial meningitis among hospitalised children in Kenya. BMC Med 19 , 122 (2021). https://doi.org/10.1186/s12916-021-01998-3

Download citation

Received : 14 January 2021

Accepted : 29 April 2021

Published : 04 June 2021

DOI : https://doi.org/10.1186/s12916-021-01998-3

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

• Clinical features
• Conjugate vaccines

BMC Medicine

ISSN: 1741-7015

• Submission enquiries: [email protected]
• General enquiries: [email protected]

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

• View all journals
• My Account Login
• Explore content
• About the journal
• Publish with us
• Sign up for alerts
• Open access
• Published: 16 March 2021

A hospital-based study on etiology and prognosis of bacterial meningitis in adults

• Jun-Sang Sunwoo 1 ,
• Hye-Rim Shin 2 ,
• Han Sang Lee 3 ,
• Jangsup Moon 3 , 4 ,
• Soon-Tae Lee 3 ,
• Keun-Hwa Jung 3 ,
• Kyung-Il Park 5 ,
• Ki-Young Jung 3 ,
• Manho Kim 3 , 6 ,
• Sang Kun Lee 3 &
• Kon Chu 3  

Scientific Reports volume  11 , Article number:  6028 ( 2021 ) Cite this article

4702 Accesses

16 Citations

Metrics details

• Central nervous system infections

Bacterial meningitis is a neurological emergency with high morbidity and mortality. We herein investigated clinical features, etiology, antimicrobial susceptibility profiles, and prognosis of bacterial meningitis in adults from a single tertiary center. We retrospectively reviewed medical records of patients with laboratory-confirmed bacterial meningitis from 2007 to 2016. Patients with recent neurosurgery, head trauma, or indwelling neurosurgical devices were classified as having healthcare-related meningitis. Causative microorganisms were identified by analyzing cerebrospinal fluid (CSF) and blood cultures, and antimicrobial susceptibility profiles were evaluated. We performed multiple logistic regression analysis to identify factors associated with unfavorable outcomes. We identified 161 cases (age, 55.9 ± 15.5 years; male, 50.9%), of which 43 had community-acquired and 118 had healthcare-related meningitis. CSF and blood culture positivity rates were 91.3% and 30.4%, respectively. In community-acquired meningitis patients, Klebsiella pneumoniae (25.6%) was the most common isolate, followed by Streptococcus pneumoniae (18.6%) and Listeria monocytogenes (11.6%). The susceptibility rates of K. pneumoniae to ceftriaxone, cefepime, and meropenem were 85.7%, 81.3%, and 100%, respectively. Among healthcare-related meningitis patients, the most common bacterial isolates were coagulase-negative staphylococci (28.0%), followed by Staphylococcus aureus (16.1%) and Enterobacter spp. (13.6%). Neurological complications occurred in 39.1% of the patients and the 3-month mortality rate was 14.8%. After adjusting for covariates, unfavorable outcome was significantly associated with old age (odds ratio [OR] 1.03, 95% confidence interval [CI] 1.00–1.06), neurological complications (OR 4.53, 95% CI 1.57–13.05), and initial Glasgow coma scale ≤ 8 (OR 19.71, 95% CI 4.35–89.40). Understanding bacterial pathogens and their antibiotic susceptibility may help optimize antimicrobial therapy in adult bacterial meningitis.

Similar content being viewed by others

Outcome of childhood bacterial meningitis on three continents

Heikki Peltola, Irmeli Roine, … Tuula Pelkonen

Longer than 2 hours to antibiotics is associated with doubling of mortality in a multinational community-acquired bacterial meningitis cohort

Damon P. Eisen, Elizabeth Hamilton, … Oyelola A. Adegboye

Predictors of unfavourable outcome in adults with suspected central nervous system infections: a prospective cohort study

Liora ter Horst, Ingeborg E. van Zeggeren, … Matthijs C. Brouwer

Introduction

Bacterial meningitis is a neurological emergency with high morbidity and mortality. Over 1.2 million cases of bacterial meningitis are estimated to occur annually worldwide 1 . Although adjunctive dexamethasone reduces the risk of unfavorable outcomes and death, neurological complications occur in approximately 30% of survivors 2 , 3 . Delayed antibiotic administration has been shown to significantly increase mortality and adverse outcomes at 3 months 4 . Therefore, early clinical suspicion and immediate antibiotic therapy are crucial in the initial management of bacterial meningitis.

Antibiotic treatments are determined empirically, based on the common causative pathogens of bacterial meningitis, age, host immune status, and predisposing conditions 5 . According to previous epidemiological studies, Streptococcus pneumoniae , Neisseria meningitidis , Haemophilus influenzae , and Listeria monocytogenes are the major bacterial pathogens responsible for community-acquired meningitis in adults 6 , 7 . On the other hand, the most common microorganisms associated with neurosurgical procedures and head trauma were coagulase-negative staphylococci (CoNS), Staphylococcus aureus , and gram-negative bacilli 8 . However, the epidemiology of bacterial meningitis has changed over the past 30 years. The introduction of conjugate vaccines significantly decreased the incidence of H. influenzae and S. pneumoniae meningitis and also shifted the age distribution of bacterial meningitis from children to older adults 9 , 10 . The increasing rate of antimicrobial resistance in S. pneumoniae is another important epidemiological trend that should be considered when selecting the appropriate antibiotic therapy 11 . However, there is little information on the etiology and antimicrobial susceptibility profiles of recent bacterial meningitis cases, especially in Korea. Therefore, we investigated the clinical, laboratory, and microbiological profiles of adult bacterial meningitis patients from a single tertiary center over a 10-year period.

Study subjects

We retrospectively reviewed the medical records of adult patients with laboratory-confirmed bacterial meningitis, who were treated in Seoul National University Hospital from 2007 to 2016. Bacterial meningitis was defined as follows according to the World Health Organization recommendation 12 . Suspected cases were defined as any person with clinical features of bacterial meningitis, such as fever, altered consciousness, and meningeal signs. Probable cases were defined as any suspected cases with cerebrospinal fluid (CSF) white blood cell (WBC) count > 100 cells/mm 3 , or CSF WBC count of 10–100 cells/mm 3 with either protein level > 100 mg/dL or glucose level < 40 mg/dL. Finally, laboratory-confirmed cases were defined as any suspected or probable cases in which bacterial pathogens were identified in CSF or blood cultures or bacterial antigen detection by CSF latex agglutination test. Only laboratory-confirmed bacterial meningitis cases were selected as study subjects and included in the analysis. Patients with tuberculous meningitis and meningoencephalitis due to non-bacterial pathogens were excluded from the study. When CSF and blood cultures showed discordant results, the isolate from the CSF culture was considered as the causative organism.

Bacterial meningitis cases were classified into community-acquired and healthcare-related meningitis, because they have a different spectrum of bacterial pathogens. Patients with recent neurosurgery (within 1 month of the onset of meningitis); head trauma; or indwelling neurosurgical devices, such as ventriculoperitoneal shunt, extraventricular drain, and lumbar drain, were classified as having healthcare-related meningitis. Patients without evidence of healthcare-related infection were classified as having community-acquired meningitis.

Clinical information

We analyzed demographic information, symptoms and signs at presentation, premorbid functional status, immunocompromised status, concurrent infection, indwelling neurosurgical devices, and recent neurosurgery or head trauma. Severe mental deterioration at admission was defined as an initial Glasgow Coma Scale (GCS) score ≤ 8. We evaluated the initial CSF profiles, including cell count with differential and protein and glucose levels. Clinical outcomes were measured using a modified Rankin Scale (mRS) score at discharge and 3 months after discharge. An unfavorable outcome was defined as an mRS score ≥ 4 at 3 months.

Antimicrobial susceptibility test

Antimicrobial susceptibility tests were performed and interpreted according to the Clinical and Laboratory Standards Institute. The results were reported as susceptible, intermediate, or resistant. A bacterial isolate was classified as non-susceptible to an antimicrobial agent when it tested as intermediate or resistant. Multi-drug resistance (MDR) was defined, according to the guidelines of the European Centre for Disease Prevention and Control 13 , as non-susceptibility to at least one agent in three or more antimicrobial categories. In particular, MDR of Streptococcus spp. was defined as non-susceptibility to penicillin and antimicrobials in two or more other non-β-lactam classes 14 .

Ethical statement

This study protocol was approved by the institutional review board (IRB) of Seoul National University Hospital (No. C-1705–016-851) and was performed in accordance with the principles of the Declaration of Helsinki. Because this was a retrospective medical chart review study, informed consent was not obtained from the participants and the IRB of Seoul National University Hospital granted a waiver of informed consent. All information gathered in this study was anonymized to preserve the participants’ privacy.

Statistical analysis

We performed a Student's t-test or a Pearson's chi-square test for between-group comparisons of continuous and categorical variables, respectively. Data that were not normally distributed are presented as median (interquartile range) and were analyzed using a Wilcoxon rank-sum test. We performed multivariate logistic regression analyses to identify factors related to clinical outcomes in bacterial meningitis patients. Dependent variables were unfavorable outcome and mortality at 3 months, analyzed separately. Patients with a premorbid disability, defined as a premorbid mRS score ≥ 3, were excluded from the analysis. Variables with P  < 0.1 in univariate logistic analyses were included as independent variables. In addition, age, sex, and type of meningitis (healthcare-related vs community-acquired) were included as covariates. A two-tailed P -value < 0.05 was considered statistically significant and statistical analyses were performed using SPSS version 25 (IBM Corp. Armonk, NY, USA).

Clinical presentation

We identified 161 cases of which 43 had community-acquired meningitis and 118 had healthcare-related meningitis. Six patients, all of whom had a healthcare-related infection, experienced a second episode of bacterial meningitis. Of these, postoperative CSF leak occurred in one patient and intraventricular devices were implanted in the other five patients. Overall, the mean age was 55.9 ± 15.5 years and 50.9% of patients were male (Table 1 ). There was no significant seasonal variation ( P  = 0.806). Regarding predisposing factors, immunocompromised conditions were present in 31 (19.3%) patients and a concurrent infection, such as pneumonia, catheter-related blood stream infection, or peritonitis, was found in 44 (27.3%) patients. Among the healthcare-related meningitis patients, 64.4% underwent recent neurosurgery and 62.7% had indwelling neurosurgical devices. At presentation, the classic triad of fever, neck stiffness, and altered mental status was found in 31.3% of patients. The initial GCS score was 12.3 ± 3.8 and severe mental deterioration was observed in 33 (20.5%) patients. Compared to healthcare-related patients, community-acquired meningitis patients were characterized by older age ( P  < 0.001), lower initial GCS scores ( P  = 0.032), and a higher rate of neck stiffness ( P  = 0.049) and the classic symptom triad ( P  = 0.003). Regarding predisposing conditions, patients with healthcare-related meningitis showed a higher prevalence of concurrent infections ( P  = 0.027) and a lower prevalence of diabetes mellitus ( P  = 0.034) than those with community-acquired meningitis.

Laboratory findings

Mean CSF opening pressure was 22.5 ± 10.6 cmH 2 O, and an elevated pressure ≥ 20 cmH 2 O was found in 54.3% of the patients (Table 2 ). Median CSF WBC count was 828.0/mm 3 (interquartile range [IQR], 256.3–2870.0), with 76.3% neutrophils and 14.0% lymphocytes. The median protein level was 201.8 mg/dL (IQR, 93.0–489.0) and CSF/blood glucose ratio was 0.28 (IQR, 0.07–0.47). Community-acquired meningitis patients showed higher CSF protein levels ( P  = 0.005) and lower CSF glucose levels ( P  = 0.002) than healthcare-related meningitis patients, although CSF WBC counts did not significantly differ between the two groups. In blood tests, thrombocytopenia, with a platelet count < 100, 000/mm 3 , was noted in 12.6% of the patients, whereas increased high-sensitivity C-reactive protein (hs-CRP) levels > 10 mg/dL were identified in 42.8% of the patients.

Causative microorganisms

Overall, CSF Gram stains and cultures were positive in 24.5% (34/139) and 91.3% (147/161) of patients, respectively. Blood cultures were positive in 30.4% (49/161) of patients and blood and CSF cultures were both positive in 21.7% (35/161) of patients. Bacterial antigen detection tests were only performed in 40 patients and six of these (15.0%) were positive, with five testing positive for S. pneumoniae and one testing positive for Streptococcus agalactiae .

The bacterial pathogens isolated from 161 bacterial meningitis cases are summarized in Table 3 . Mixed infections with two different species were found in four patients. In community-acquired meningitis patients, Klebsiella pneumoniae (25.6%) was the most common isolate, followed by S. pneumoniae (18.6%) and L. monocytogenes (11.6%). H. influenzae accounted for 4.7% of infections, but N. meningitidis was not detected. Among healthcare-related meningitis patients, the most common bacterial isolates were CoNS (28.0%), followed by S. aureus (16.1%) and Enterobacter spp. (13.6%). Streptococcus spp. were more common in community-acquired meningitis patients (34.9% vs. 4.2%, P  < 0.001), whereas Staphylococcus spp. were more frequently isolated from healthcare-related meningitis patients (44.1% vs. 4.7%, P  < 0.001). Furthermore, L. monocytogenes was only isolated from community-acquired meningitis patients, whereas CoNS and Enterobacter spp. were only isolated from healthcare-related meningitis patients.

Antimicrobial susceptibility profiles

The susceptibility rates of S. pneumoniae to penicillin G, cefotaxime, and vancomycin were 33.3%, 40.0%, and 100%, respectively (Supplementary Table S1 ). For streptococci other than S. pneumoniae , the susceptibility rates to penicillin and vancomycin were 62.5% and 100%, respectively. Among the S. aureus isolates, 85% were resistant to methicillin (oxacillin), but 100% were susceptible to vancomycin. S. epidermidis isolates showed similar profiles, with 90.5% resistant to methicillin (oxacillin), but 100% susceptible to vancomycin. The MDR rate of Staphylococcus spp. was 88.5%. Among gram-negative bacilli, the susceptibility rates of K. pneumoniae to ceftriaxone, cefepime, and meropenem were 85.7%, 81.3%, and 100%, respectively (Supplementary Table S2 ). Extended-spectrum β-lactamase (ESBL) producers were found to account for 18.8% (3/16) of the K. pneumoniae isolates, all of which were from healthcare-related meningitis patients. The MDR rates of K. pneumoniae , Pseudomonas spp., Acinetobacter spp., and Enterobacter spp. were 25.0%, 18.2%, 44.4%, and 56.3%, respectively. Overall, bacterial isolates from healthcare-related meningitis patients showed higher rates of MDR than those from community-acquired meningitis patients (69.1% vs. 25.0%, P  < 0.001).

Complications and outcomes

The mean length of stay in the hospital was 76.7 ± 97.6 days, with 52.8% of patients treated in the intensive care unit. Mechanical ventilation was used in 36.0% of patients. Neurological complications occurred in 39.1% of patients and the most common complication was hydrocephalus (19.9%), followed by seizures (13.7%). Ischemic infarction and cerebral hemorrhage were more common in community-acquired patients than in healthcare-related patients ( P  < 0.001 and 0.015, respectively; Table 4 ). Mortality rates at discharge and 3 months after discharge were 10.6% and 14.8%, respectively. Mortality rates and mRS scores at discharge and 3 months after discharge did not differ between community-acquired and healthcare-related meningitis patients, although 3-month mRS scores in healthcare-related meningitis patients tended to be higher than those in community-acquired meningitis patients ( P  = 0.075).

We then assessed factors associated with unfavorable outcomes and mortality at 3 months in adult bacterial meningitis patients. Since 19 patients had no follow-up data at 3 months after discharge, we analyzed the outcome in 142 patients. In univariate analysis, an unfavorable outcome was associated with older age, neurological complications, concurrent infection, high hs-CRP levels, and an initial GCS score ≤ 8. However, neither positive Gram staining results, the MDR status of isolates, nor immunocompromised status were associated with an unfavorable outcome (Supplementary Table S3 ). After adjusting for covariates, an unfavorable outcome was significantly associated with older age (odds ratio [OR] 1.03, 95% confidence interval [CI] 1.00–1.06), neurological complications (OR 4.53, 95% CI 1.57–13.05), and an initial GCS score ≤ 8 (OR 19.71, 95% CI 4.35–89.40; Table 5 ). Multivariate analysis for mortality at 3 months showed similar results with higher mortality rates associated with neurological complications (OR 5.67, 95% CI 1.76–18.25) and an initial GCS score ≤ 8 (OR 5.31, 95% CI 1.47–19.11).

We additionally performed subgroup analysis on the unfavorable outcome for community-acquired and healthcare-related meningitis, respectively. In healthcare-related meningitis, older age (OR 1.07, 95% CI 1.02–1.11), neurological complications (OR 4.13, 95% CI 1.12–15.25), and an initial GCS score ≤ 8 (OR 39.93, 95% CI 2.61–610.86) were associated with the unfavorable outcome, which is similar to the results from the total subjects. By contrast, an initial GCS score ≤ 8 (OR 14.23, 95% CI 1.82–111.31) only remained significantly associated with the unfavorable outcome in community-acquired meningitis (Table S4 ).

In this study, we investigated clinical, laboratory, and microbiological profiles of adult bacterial meningitis. The composition of causative microorganisms was significantly different between community-acquired and healthcare-related meningitis. Streptococcus spp. accounted for 34.9% of community-acquired meningitis patients, whereas Staphylococcus spp. accounted for 44.1% of healthcare-related meningitis patients. At the species level, K. pneumoniae (25.6%) was the most common causative bacterium in community-acquired meningitis, followed by S. pneumoniae (18.6%) and L. monocytogenes (11.6%) . In healthcare-related meningitis patients, S. epidermidis (17.8%) was the most common causative bacterium, followed by S. aureus (16.1%). Mortality during hospitalization and 3 months after discharge were 10.6% and 14.8%, respectively. Older age, any neurological complications, and severe mental deterioration at admission were significantly associated with unfavorable outcomes, which is consistent with the results of previous studies 3 , 15 .

A notable finding in this study was that K. pneumoniae was the most common pathogen in community-acquired meningitis patients. This is consistent with data from Taiwan showing that K. pneumoniae was the leading causative pathogen, accounting for 44.9% of spontaneous bacterial meningitis patients 16 . Although a high incidence of K. pneumoniae meningitis, together with a low incidence of S. pneumoniae meningitis has been reported in Taiwan in the 1980s and 1990s, the exact cause has not been determined 17 . Diabetes mellitus has been reported as a risk factor for community-acquired meningitis and liver abscesses caused by K. pneumoniae 18 . In agreement with this, 54.5% (6/11) of community-acquired K. pneumoniae meningitis patients in our study had comorbid diabetes mellitus. However, this cannot explain the sudden change in the epidemiology of bacterial meningitis in Korea. An epidemiological study in Korean adults between 1998 and 2008 showed that K. pneumoniae was the third most common pathogen, but accounted for only 7.7% of community-acquired meningitis cases 19 . Selection bias due to a single-center study design may have contributed to our results. Nevertheless, our findings suggested that K. pneumoniae infection should be considered as a possible etiology of community-acquired bacterial meningitis, at least in the tertiary hospital setting. It also cannot be concluded whether the increase in K. pneumoniae meningitis is due to regional or racial influences in East Asian countries. Further epidemiological studies in other countries are needed to address this issue. All K. pneumoniae isolates from community-acquired meningitis patients were susceptible to cefotaxime and cefepime. ESBL-producing K. pneumoniae , all of which were isolated from healthcare-related meningitis patients, were resistant to ceftazidime and cefepime, but susceptible to imipenem and meropenem. These antimicrobial susceptibility profiles are consistent with previous studies 20 , suggesting that the third- and fourth-generation cephalosporins are appropriate for antibiotic therapy against community-acquired meningitis associated with K. pneumoniae , but carbapenems should be considered for the treatment of healthcare-related meningitis.

S. pneumoniae has traditionally been reported as the most common causative organism of community-acquired bacterial meningitis in adults 3 , 21 . However, S. pneumoniae only accounted for 18.6% of cases in our study, although it was the second most common species detected. The introduction of conjugate vaccines against S. pneumoniae is a possible explanation for the low frequency of pneumococcal meningitis. Pneumococcal vaccination significantly decreased the incidence of pneumococcal meningitis in children and adults, suggesting an indirect effect of vaccination through herd immunity 22 , 23 . The high rate of resistance of S. pneumoniae to penicillin and third-generation cephalosporins confirmed that antibiotics containing vancomycin are the appropriate empirical regimen for S. pneumoniae meningitis. The low frequency of H. influenzae meningitis in this study is also thought to be the result of H. influenzae type b vaccination 6 . In Korea, the incidence of H. influenzae meningitis in children has significantly decreased since 2001 24 , and in a previous study, H. influenzae was not isolated among 196 adult patients with community-acquired meningitis 19 .

L. monocytogenes was the third most common pathogen detected in our study population. It is well known that elderly individuals and immunocompromised patients are at a high risk of contracting L. monocytogenes meningitis 25 . In our study, the mean age of L. monocytogenes meningitis patients was 73.6 years (range, 66–83 years) and two (40%) patients were immunocompromised. The two (40%) immunocompromised patients died in hospital and the other two (40%) were severely disabled (mRS score, 5) at 3 months, thus confirming the high mortality and morbidity rates previously reported for L. monocytogenes meningitis 26 .

The frequency of healthcare-related meningitis (73.3%) was higher than that of community-acquired meningitis (26.7%) in our study. These findings are likely to be caused by selecting bacterial meningitis cases from the tertiary hospital. Patients with community-acquired meningitis, especially those with mild severity, might have been treated at a lower level hospital rather than being transferred to this hospital. It is also possible that the epidemiological trend of decreasing frequencies of pneumococcal and meningococcal meningitis contributed to a decrease in the overall number of community-acquired meningitis and a relative increase in the proportion of healthcare-related meningitis 10 . However, it cannot be concluded in this study, and a nationwide epidemiological investigation is required to address this issue. The most common microorganisms causing healthcare-related bacterial meningitis were CoNS, S. aureus , and gram-negative bacilli, which were consistent with the results of previous studies 17 , 21 . Staphylococcus spp. were mostly methicillin-resistant, but all were susceptible to vancomycin. Gram-negative bacilli showed moderate susceptibility to third- and fourth-generation cephalosporins, but high susceptibility to carbapenems. These antimicrobial susceptibility profiles support the use of vancomycin plus meropenem for the empirical treatment of healthcare-related meningitis 27 . Exceptionally, Acinetobacter spp. showed high resistance (44.4%) to meropenem. Therefore, if the Acinetobacter isolates are resistant to carbapenems, colistin or polymyxin B should be administered 28 .

There are several limitations of this study. Firstly, as a single-center study, our subjects may not represent the general population of adult bacterial meningitis patients in Korea. Recruitment from a tertiary hospital may have caused selection bias toward more severe cases. Moreover, although we collected data over a 10-year period, the sample size was relatively small, especially for community-acquired meningitis. Another limitation is the retrospective chart review design, which may have resulted in incomplete or inaccurate data collection. We first investigated the results of CSF examinations and cultures, and among probable cases and culture-positive cases, we reviewed the electrical medical records and selected those who met the definition of laboratory-confirmed bacterial meningitis. Nevertheless, we might have missed some cases, which is an inevitable limitation of the retrospective study. Furthermore, although we identified the clinical factors associated with unfavorable outcomes in bacterial meningitis patients, a causal relationship cannot be inferred from this study. Although we adjusted for the effect of the type of infection in the multivariate analysis, we cannot completely rule out the effect of neurosurgery itself on the unfavorable outcome.

In conclusion, we identified a spectrum of causative microorganisms for adult bacterial meningitis cases over a recent 10-year period. The increased proportion of K. pneumoniae infections and the decreased proportion of S. pneumoniae infections among community-acquired meningitis patients was particularly noteworthy. Our data on causative microorganisms and their antibiotic susceptibility profiles may help optimize determination of the appropriate empirical antimicrobial therapy for adult bacterial meningitis patients. However, further studies are required to confirm the changing epidemiology of causative pathogens and prognostic factors in adult bacterial meningitis.

Data availability

Deidentified data are available from the corresponding author upon reasonable request.

Liu, L. et al. Global, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since 2000. The Lancet 379 , 2151–2161. https://doi.org/10.1016/s0140-6736(12)60560-1 (2012).

Article   Google Scholar  

de Gans, J., van de Beek, D. & European Dexamethasone in Adulthood Bacterial Meningitis Study Investigators. Dexamethasone in adults with bacterial meningitis. N. Engl. J. Med. 347 , 1549–1556. https://doi.org/10.1056/NEJMoa021334 (2002).

Article   CAS   PubMed   Google Scholar  

van de Beek, D. et al. Clinical features and prognostic factors in adults with bacterial meningitis. N. Engl. J. Med. 351 , 1849–1859. https://doi.org/10.1056/NEJMoa040845 (2004).

Article   PubMed   Google Scholar  

Auburtin, M. et al. Detrimental role of delayed antibiotic administration and penicillin-nonsusceptible strains in adult intensive care unit patients with pneumococcal meningitis: the PNEUMOREA prospective multicenter study. Crit. Care Med. 34 , 2758–2765. https://doi.org/10.1097/01.ccm.0000239434.26669.65 (2006).

Tunkel, A. R. et al. Practice guidelines for the management of bacterial meningitis. Clin. Infect. Dis. 39 , 1267–1284. https://doi.org/10.1086/425368 (2004).

Schuchat, A. et al. Bacterial meningitis in the United States in 1995 Active Surveillance Team. N. Engl. J. Med. 337 , 970–976. https://doi.org/10.1056/NEJM199710023371404 (1997).

Sigurdardottir, B., Bjornsson, O. M., Jonsdottir, K. E., Erlendsdottir, H. & Gudmundsson, S. Acute bacterial meningitis in adults A 20-year overview. Arch. Intern. Med. 157 , 425–430. https://doi.org/10.1001/archinte.1997.00440250077009 (1997).

Laxmi, S. & Tunkel, A. R. Healthcare-associated bacterial meningitis. Curr. Infect. Dis. Rep. 13 , 367–373. https://doi.org/10.1007/s11908-011-0190-z (2011).

Thigpen, M. C. et al. Bacterial meningitis in the United States, 1998–2007. N. Engl. J. Med. 364 , 2016–2025. https://doi.org/10.1056/NEJMoa1005384 (2011).

Castelblanco, R. L., Lee, M. & Hasbun, R. Epidemiology of bacterial meningitis in the USA from 1997 to 2010: a population-based observational study. Lancet. Infect. Dis 14 , 813–819. https://doi.org/10.1016/s1473-3099(14)70805-9 (2014).

Song, J. H. et al. Spread of drug-resistant Streptococcus pneumoniae in Asian countries: Asian Network for Surveillance of Resistant Pathogens (ANSORP) Study. Clin. Infect. Dis. 28 , 1206–1211. https://doi.org/10.1086/514783 (1999).

World Health Organization. Surveillance standards for vaccine-preventable diseases . 2nd edn, (World Health Organization, 2018)

Magiorakos, A. P. et al. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin. Microbiol. Infect. 18 , 268–281. https://doi.org/10.1111/j.1469-0691.2011.03570.x (2012).

Richter, S. S. et al. Changing epidemiology of antimicrobial-resistant Streptococcus pneumoniae in the United States, 2004–2005. Clin. Infect. Dis. 48 , e23-33. https://doi.org/10.1086/595857 (2009).

Flores-Cordero, J. M. et al. Acute community-acquired bacterial meningitis in adults admitted to the intensive care unit: clinical manifestations, management and prognostic factors. Intensive Care Med. 29 , 1967–1973. https://doi.org/10.1007/s00134-003-1935-4 (2003).

Chang, W. N. et al. Changing epidemiology of adult bacterial meningitis in southern taiwan: a hospital-based study. Infection 36 , 15–22. https://doi.org/10.1007/s15010-007-7009-8 (2008).

Lu, C. H., Chang, W. N. & Chang, H. W. Adult bacterial meningitis in Southern Taiwan: epidemiologic trend and prognostic factors. J. Neurol. Sci. 182 , 36–44. https://doi.org/10.1016/s0022-510x(00)00445-7 (2000).

Ko, W.-C. et al. Community-acquired Klebsiella pneumoniae bacteremia: global differences in clinical patterns. Emerg. Infect. Dis. 8 , 160–166. https://doi.org/10.3201/eid0802.010025 (2002).

Article   PubMed   PubMed Central   Google Scholar  

Moon, S. Y. et al. Changing etiology of community-acquired bacterial meningitis in adults: a nationwide multicenter study in Korea. Eur. J. Clin. Microbiol. Infect. Dis. 29 , 793–800. https://doi.org/10.1007/s10096-010-0929-8 (2010).

Ku, Y.-H. et al. Klebsiella pneumoniae Isolates from Meningitis: Epidemiology Virulence and Antibiotic Resistance. Sci. Rep. 7 , 6634. https://doi.org/10.1038/s41598-017-06878-6 (2017).

Article   ADS   CAS   PubMed   PubMed Central   Google Scholar  

Durand, M. L. et al. Acute bacterial meningitis in adults. A review of 493 episodes. N. Engl. J. Med. 328 , 21–28. https://doi.org/10.1056/NEJM199301073280104 (1993).

Hsu, H. E. et al. Effect of pneumococcal conjugate vaccine on pneumococcal meningitis. N. Engl. J. Med. 360 , 244–256. https://doi.org/10.1056/NEJMoa0800836 (2009).

Article   CAS   PubMed   PubMed Central   Google Scholar  

Tsai, C. J., Griffin, M. R., Nuorti, J. P. & Grijalva, C. G. Changing epidemiology of pneumococcal meningitis after the introduction of pneumococcal conjugate vaccine in the United States. Clin. Infect. Dis. 46 , 1664–1672. https://doi.org/10.1086/587897 (2008).

Cho, H. K. et al. The causative organisms of bacterial meningitis in Korean children in 1996–2005. J. Korean Med. Sci. 25 , 895–899. https://doi.org/10.3346/jkms.2010.25.6.895 (2010).

Brouwer, M. C., van de Beek, D., Heckenberg, S. G., Spanjaard, L. & de Gans, J. Community-acquired Listeria monocytogenes meningitis in adults. Clin. Infect. Dis. 43 , 1233–1238. https://doi.org/10.1086/508462 (2006).

Amaya-Villar, R. et al. Three-year multicenter surveillance of community-acquired Listeria monocytogenes meningitis in adults. BMC Infect. Dis. 10 , 324. https://doi.org/10.1186/1471-2334-10-324 (2010).

Tunkel, A. R. et al. Infectious diseases society of america’s clinical practice guidelines for healthcare-associated ventriculitis and meningitis. Clin. Infect. Dis. 64 , e34–e65. https://doi.org/10.1093/cid/ciw861 (2017).

Kim, B.-N. et al. Management of meningitis due to antibiotic-resistant Acinetobacter species. Lancet. Infect. Dis 9 , 245–255. https://doi.org/10.1016/S1473-3099(09)70055-6 (2009).

Download references

Acknowledgement

The abstract of this study was published under the title "Clinical and Microbiological Characteristics of Bacterial Meningitis in Adults" at the 145th Annual Meeting of the American Neurological Association ( https://doi.org/10.1002/ana.25865 ).

This work was supported by a research grant from Ildong Pharmaceutical, Co., Ltd, Seoul, South Korea (06-2019-1880).

Author information

Authors and affiliations.

Department of Neurosurgery, Seoul National University Hospital, Seoul, South Korea

Jun-Sang Sunwoo

Department of Neurology, Dankook University Hospital, Cheonan, South Korea

Hye-Rim Shin

Department of Neurology, Comprehensive Epilepsy Center, Biomedical Research Institute, Seoul National University Hospital, 101, Daehak-ro, Jongno-gu, Seoul, 03080, South Korea

Han Sang Lee, Jangsup Moon, Soon-Tae Lee, Keun-Hwa Jung, Ki-Young Jung, Manho Kim, Sang Kun Lee & Kon Chu

Rare Disease Center, Seoul National University Hospital, Seoul, South Korea

Jangsup Moon

Department of Neurology, Seoul National University Hospital Healthcare System Gangnam Center, Seoul, South Korea

Kyung-Il Park

Protein Metabolism and Neuroscience Dementia Medical Research Center, Seoul National University College of Medicine, Seoul, South Korea

You can also search for this author in PubMed   Google Scholar

Contributions

J.S.S., H.R.S., H.S.L., and K.C. contributed to the conception and design of the study; all authors contributed to the acquisition, analysis, or interpretation of data; J.S.S. and K.C. contributed to drafting a significant portion of the manuscript.

Corresponding author

Correspondence to Kon Chu .

Ethics declarations

Competing interests.

The authors declare no competing interests.

Additional information

Publisher's note.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Rights and permissions.

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ .

Reprints and permissions

About this article

Cite this article.

Sunwoo, JS., Shin, HR., Lee, H.S. et al. A hospital-based study on etiology and prognosis of bacterial meningitis in adults. Sci Rep 11 , 6028 (2021). https://doi.org/10.1038/s41598-021-85382-4

Download citation

Received : 17 November 2020

Accepted : 01 March 2021

Published : 16 March 2021

DOI : https://doi.org/10.1038/s41598-021-85382-4

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

This article is cited by

Bacterial meningitis in adults: a retrospective study among 148 patients in an 8-year period in a university hospital, finland.

• Sakke Niemelä
• Laura Lempinen

BMC Infectious Diseases (2023)

By submitting a comment you agree to abide by our Terms and Community Guidelines . If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Quick links

• Explore articles by subject
• Guide to authors
• Editorial policies

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

• Open access
• Published: 23 January 2023

Bacterial meningitis in adults: a retrospective study among 148 patients in an 8-year period in a university hospital, Finland

• Sakke Niemelä   ORCID: orcid.org/0000-0002-8479-9096 1 ,
• Laura Lempinen   ORCID: orcid.org/0000-0002-8568-1997 2 ,
• Eliisa Löyttyniemi   ORCID: orcid.org/0000-0002-7278-6511 3 ,
• Jarmo Oksi   ORCID: orcid.org/0000-0002-3331-997X 4 &
• Jussi Jero   ORCID: orcid.org/0000-0002-1945-4008 5  

BMC Infectious Diseases volume  23 , Article number:  45 ( 2023 ) Cite this article

4532 Accesses

6 Citations

2 Altmetric

Metrics details

Bacterial meningitis (BM) causes significant morbidity and mortality. We investigated predisposing factors, clinical characteristics, spectrum of etiological bacteria, and clinical outcome of community-acquired and nosocomial BM.

In this retrospective study we analyzed data of 148 adults (age > 16 years) with BM treated in Turku University Hospital, Southwestern Finland, from 2011 to 2018. Besides culture- or polymerase chain reaction (PCR)-positive cases we also included culture-negative cases with laboratory parameters strongly suggestive of BM and those with meningitis-related findings in imaging. We used Glasgow Outcome Scale (GOS) score 1–4 to determine unfavorable outcome.

The median age of patients was 57 years and 48.6% were male. Cerebrospinal fluid (CSF) culture for bacteria showed positivity in 50 (33.8%) cases, although pre-diagnostic antibiotic use was frequent (85, 57.4%). The most common pathogens in CSF culture were Streptococcus pneumoniae (11, 7.4%), Staphylococcus epidermidis (7, 4.7%), Staphylococcus aureus (6, 4.1%) and Neisseria meningitidis (6, 4.1%). Thirty-nine patients (26.4%) presented with the triad of fever, headache, and neck stiffness. A neurosurgical procedure or an acute cerebral incident prior BM was recorded in 74 patients (50%). Most of the patients had nosocomial BM (82, 55.4%) and the rest (66, 44.6%) community-acquired BM. Ceftriaxone and vancomycin were the most used antibiotics. Causative pathogens had resistances against the following antibiotics: cefuroxime with a frequency of 6.8%, ampicillin (6.1%), and tetracycline (6.1%). The case fatality rate was 8.8% and the additional likelihood of unfavorable outcome 40.5%. Headache, decreased general condition, head computed tomography (CT) and magnetic resonance imaging (MRI), hypertension, altered mental status, confusion, operative treatment, neurological symptoms, pre-diagnostic antibiotic use and oral antibiotics on discharge were associated with unfavorable outcome.

Conclusions

The number of cases with nosocomial BM was surprisingly high and should be further investigated. The usage of pre-diagnostic antibiotics was also quite high. Headache was associated with unfavorable outcome. The frequency of unfavorable outcome of BM was 40.5%, although mortality in our patients was lower than in most previous studies.

Peer Review reports

Bacterial meningitis (BM) is a severe, life-threatening infection, which causes notable morbidity and mortality [ 1 ]. Meningitis has many etiologies: bacteria, fungi, viruses, and parasites or additionally it may be associated with cancerous conditions, medications or autoimmune diseases [ 2 ]. Worldwide number of BM cases may exceed 16 million cases, [ 3 ] with mortality up to 30% as estimated a few years ago [ 2 , 4 , 5 ].

BM can be classified into two groups; nosocomial (including postoperative BM) or community acquired [ 6 ]. The usage of conjugate vaccines during childhood against Streptococcus pneumoniae , Neisseria meningitidis and Haemophilus influenzae B , has significantly diminished the overall incidence of BM worldwide [ 7 , 8 ]. S. epidermidis and S. aureus have been the main Gram stain positive cocci causing nosocomial meningitis [ 9 ]. Recently, however, the proportion of Gram stain negative bacteria such as Acinetobacter baumannii, Klebsiella pneumoniae and Escherichia coli has increased [ 10 , 11 ]. BM cases rose between 2006 and 2016 with poverty being a strong predisposing factor [ 2 ]. The geographical location affects the incidence significantly though; in well-developed countries the incidence has been lately 0.5–1.5/100,000/year [ 12 , 13 , 14 ], but in developing countries the incidence may peak at even 1000/100,000 cases [ 2 ] due to epidemics [ 15 , 16 , 17 , 18 ].

The incidence is highest among young children and the elderly [ 6 ]. In the past 20 years the incidence, management and epidemiology of BM has changed [ 7 ]. The risk factors of BM consist of immunosuppression, human immunodeficiency virus (HIV)-infection [ 19 ], indoor air pollution [ 20 ], overcrowded houses [ 21 ], malnutrition [ 22 ] and sickle cell anemia [ 23 ]. The typical symptom triad of meningitis consists of headache, fever and meningismus [ 6 ]. Meningitis requires instant treatment and intense medical attention. In recent years the use of adjunctive dexamethasone with antibiotics has been associated to lower incidence of neurologic sequelae in survivors [ 6 ]. The diagnosis of meningitis is confirmed by cerebrospinal fluid (CSF) culture or polymerase chain reaction (PCR) on the CSF specimen [ 6 ]. Survivors of BM often present a variety of neurological difficulties afterwards, such as hearing loss and deafness, cognitive impairment, motor deficiencies, seizures, and paralysis [ 24 ].

Our aim was to study the epidemiology of BM in Southwestern Finland and the significance of possible predisposing factors and indicators of unfavorable outcome.

The medical records of all patients over 16 years (n = 148) treated between 2011 and 2018 due to BM at Turku University Hospital, a tertiary referral center in the hospital district of Southwest Finland (480,000 inhabitants), were retrospectively reviewed.

We performed a database search with International Classification of Diseases 10th Revision (ICD-10)—codes for meningitis (Table 1 legend). From 747 hits we excluded all viral and aseptic meningitis by going through clinical findings of all patients, test results on blood and CSF specimens, and analysis of imaging data one by one. Finally, 148 adults were included with all types of BM: nosocomial and community-acquired. BM was defined nosocomial, if the patient was already admitted to hospital when developing BM or, if there was a history of surgery in the preceding 54 days. BM was defined community-acquired if the patient had no history of surgery or hospitalization during the preceding 54 days. Most of the published studies on BM has collected data on only CSF culture-positive meningitis, although it is known that a considerable proportion of BM cases may be culture-negative especially with antibiotics given pre-diagnosis [ 25 ]. In this study, besides culture- or PCR-positive cases we included cases with symptomatology of BM with neutrophilic pleocytosis and at least one of the following: decreased CSF glucose levels (< 2.2 mmol/L), high protein levels (> 1000 mg/L) or high CSF lactate levels (> 3.0 mmol/L), and those with meningitis-related findings in imaging. Neuroborreliosis cases were excluded. All methods of data collection remained consistent through 2011–2018.

A minimum of 2 ml CSF was gathered from adult patients with suspected BM. First, the appropriate chemical and cytological analyses were performed and a Gram staining was performed to screen the potentials bacterial pathogens. Then, the samples were centrifuged (2500 g ) for 15 min, and a drop of sediment was spread over culture media—chocolate agar plates and sheep blood agar plates. Moreover, a drop of sediment was added into fastidious anaerobe broth (FAB). Also, if postoperative BM was suspected, a fastidious anaerobe agar (FAA) plate was cultured. The aerobic media were incubated at 35 °C in 5% CO2 atmosphere. The aerobic plates and FAB were read on the first and second day after the inoculation. If no growth was detected, negative result was given. The FAA plates were read on the second and fourth day after the inoculation, after which the negative result was given if no growth was detected. The media were further incubated until total 7 days, and if growth was detected at that point, the clinician was informed.

When growth was detected on any media, the pathogens were identified with matrix-assisted laser-desorption-ionization time-of-flight (MALDI-TOF) mass spectrometry (MALDI Biotyper® System, Bruker Daltonics, Bremen, Germany).

Species-specific PCR-methods were not available for bacteria in our hospital. When requested by the clinician, general PCR for bacteria (16S rRNA—ribosomal ribonucleic acid-sequencing) was used to identify bacterial pathogens from CSF. Bacterial deoxyribonucleic acid (DNA) was isolated in our laboratory and sent for sequencing to Eurofins Genomics laboratory (Ebersberg, Germany) and the resulting DNA sequence was compared with BLAST-software ( https://blast.ncbi.nlm.nih.gov ) to GeneBank database.

Blood culture samples were collected into Bactec™ Plus Aerobic/F and Bactec™ Plus anaerobic/F bottles (BD Diagnostic Systems, Sparks, Maryland, USA). The bottles were incubated in Bactec™ 9240 or Bactec™ FX culture system (BD Diagnostic Systems), for 120 h or until signaled positive. The bacteria were identified by MALDI Biotyper® System (Bruker Daltonics, Bremen, Germany).

Disk diffusion, minimum inhibitory concentration (MIC) gradient -method and the VITEK® 2 Compact automated ID/AST system (bioMerieux E-test) were used to analyze susceptibility to variety of antibiotics. The results were interpreted in accordance with the European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines.

Imaging data was interpreted by radiologists. Patients with meningitis-related findings in imaging according to radiologists were included.

We defined a scale on outcome with Glasgow Outcome Scale (GOS-1 = death, 2 = vegetative state—unable to interact with the environment, 3 = severe disability—unable to live independently, 4 = moderate disability—can live independently but unable to return to previous work, 5 = mild or no disability) at discharge. Unfavorable outcome was chosen to be scores 1–4.

Statistical analysis

The categorical variables are summarized with counts and percentages (%), continuous variables with range, mean for normally distributed variable or median otherwise.

To find out factors affecting to unfavorable outcome (GOS scores 1–4), log binomial model was performed separately for each factor (univariate approach) and reported with relative risk (and it’s 95% confidence intervals, CI) together with p-value. All tested factors are presented in Additional file 1 .

Association with two categorical variables was tested with Fisher’s exact test.

The data analysis was generated using SAS software, Version 9.4 of the SAS System for Windows (SAS Institute Inc., Cary, NC, USA).

The medical records of 148 adults with BM were included in this study. There were 72 (48.6%) males and 76 (51.4%) females. Median age was 57.3 years (range 16–95). Almost all (145, 98%) of patients were of Finnish nationality. Baseline characteristics, underlying conditions, associated background infections, and signs and symptoms of patients on admission are presented in Table 1 . The age distribution is presented in Fig.  1 .

A Incidence of bacterial meningitis. B Bacteria cultured from CSF by year of meningitis. Panel C . Bacteria from CSF culture by age groups

Most patients were first contacted with hospital emergency department (120, 81.1%) and some to local health center (24, 16.2%) and a few with private medical clinics (4, 2.7%). Most individuals had nosocomial BM (82, 55.4%) and the rest (66, 44.6%) community-acquired BM. Neurosurgical procedure or acute cerebral incident prior BM were seen in 74 patients (50%). Forty-nine patients (33.1%) had no previous infection or operation. Nine patients (6.1%) had otogenic, another 9 patients (6.1%) odontogenic, and seven patients (4.7%) sinonasal etiology of BM. Seven patients (4.7%) had recurrent BM. Almost all cases were diagnosed in the hospital district of Southwest Finland (139, 93.9%), but 9 patients (6.1%) were transferred to our hospital from regional hospitals elsewhere. Vaccination coverage was poorly mentioned in the patient records, only one (0.7%) was reported to having received all vaccinations in the Finnish national vaccination program.

Active cancer, diabetes, lower and upper respiratory infections, excessive alcohol use, smoking, and skin infections were frequent (Table 1 .) Sixty-seven patients (45.3%) had previous surgery and two (1.4%) of them were ear related.

Clinical picture

The median length of symptoms before admission to hospital was one day (mean 2.34; range 0–30 days). Eight patients (5.4%) had previous seizures (3 generalized, 1 focal, 4 undefined) prior admission to hospital. In the emergency department 8 (5.4%) patients had seizures. Decreased level of consciousness was observed in 62 (41.9%) patients, 4 of them being in coma—one in a ventilator and three sedated due to difficult general condition. Eighteen patients (12.2%) had two or three neurological symptoms simultaneously. One (0.7%) monoparesis and two (1.4%) hemiparesis were observed, but those were related to acute ischemic brain attack prior to BM. Skin color changes were observed in 12 (8.1%) patients: petechiae in 9, marble skin in 2 patients (1.4%), and in one patient yellowish skin. All signs and symptoms are presented in Table 1 .

Laboratory results

Blood, plasma, and CSF laboratory results are presented in Table 2 .

Causative pathogens

Blood culture for bacteria was positive with 42 (28.4%) patients. CSF culture for bacteria was performed in 146 (98.7%) cases showing positivity in 50 (33.8%) cases. PCR of CSF samples was performed with 46 individuals (31.1%) showing positivity in 10 (20.4%) cases. Same pathogen in CSF and in blood was detected in 17 (11.5%) individuals. The most common pathogens were S. pneumoniae (11, 7.4%), S. epidermidis (7, 4.7%), S. aureus (6, 4.1%), N. meningitidis (6, 4.1%) and Klebsiella spp. (5, 3.4%). S. epidermidis was defined as a causative pathogen of BM if the patient had BM symptoms, CSF culture or PCR was positive for S. epidermidis and there was simultaneous CSF pleocytosis. Culture method was used to identify seven S. epidermidis cases and PCR was used once.

There were nine (6.1%) Gram stain negative rods cultured from CSF in our study: Five Klebsiella spp, one each H. influenzae, Citrobacter koseri, Pseudomonas aeruginosa and Capnocytophaga cynodegmi. Pasteurella multocida was detected once with PCR.

All causative pathogens cultured from CSF are presented in Fig.  1 . Besides from CSF, bacteria were cultured from other sources. Most common pathogens retrieved from blood were S. pneumoniae (12, 28.6%), S. aureus (7, 16.7%), S. pyogenes (5, 11.9%), N. meningitidis (4, 9.5%), S. epidermidis and S. agalactiae (both 3, 7.1%). Klebsiella spp, H. influenzae , S. salivarius, Anaerobic streptococci, E. cloacae, P. multocida, Staphylococcus pettenkoferi , and A. baumannii were all detected once.

Pathogens most cultured from pus (from ear, sinuses, neurosurgical wound, or abscess) were S. aureus (3, 17.6%) and S. pyogenes (2, 11.8%). S. pneumoniae, S. epidermidis, Klebsiella spp , S. agalactiae, α-haemolytic streptococci, S. intermedius, H. influenzae, P. aeruginosa, E. cloacae, Raoultella spp, Eikenella corrodens and Serratia marcescens were all detected once.

Staphylococcus epidermidis (4, 66.7%) was responsible for most cultured pathogens from intracranial material. Propionibacterium and S. aureus were detected once.

Intracranial material was defined as cannula, shunt, or suture. In 7 (4.7%) cases the bacterium was detected by PCR from a CSF specimen when culture was negative; N. meningitidis (3), S. epidermidis (1), P. multocida (1), Cellulosimicrobium (1) and Bacillus cereus (1). In three (2%) cases two different pathogens were simultaneously detected in the CSF.

Antibiotic resistance

CSF pathogens causing BM were most likely resistant to cefuroxime (10, 6.8%), ampicillin (9, 6.1%) and tetracycline (9, 6.1%). All CSF culture resistance profiles are shown in Fig.  2 Panel A. Seven (4.7%) bacteria from CSF were resistant to one antibiotic, three (2%) to two different antibiotics, one (0.7%) to three different antibiotics, five (3.4%) to four different antibiotics, two (1.4%) to six different antibiotics, three (2%) to eight different antibiotics, three (2%) to 11 different antibiotics and one (0.7%) to 12 different antibiotics. It is worth noticing that there were no species of bacteria resistant to vancomycin or ceftriaxone. Multi-drug resistance (resistance to three or more antibiotics) was seen in 13 (8.8%) patients, mostly patients with nosocomial BM (8, 5.4%).

A Antibiotic resistant bacterium species cultured from CSF. B Quantity of patients with antibiotics used intravenously after the diagnosis of bacterial meningitis

In other samples (blood, pus or intracranial material), 30 (20.3%) cases presented resistance to at least one antibiotic was detected. More specifically, 13 (8.8%) bacterial species were resistant to one antibiotic, and 4 (2.7%) to two, 2 (1.4%) to three, 5 (3.4%) to four, 2 (1.4%) to six, and 2 (1.4%) to seven different antibiotics. On one occasion each, resistance was detected to eight, nine and 11 different antibiotics. There were six (4%) coexistent fungal infections.

On admission, head CT was performed to most patients (119, 80.4%) and MRI to 26 (17.6%) patients. In 14 (9.5%) cases imaging findings were consistent with meningitis, e.g., leptomeningeal or pachymeningeal intensification, most frequently seen with MRI (8, 57.1%), but also with CT (6, 42.9%), presenting specificity of 30.8% with MRI and 5.0% with CT. In 15 (10.1%) patients imaging showed findings consistent with elevated intracranial pressure. Imaging controls were performed most frequently by MRI (62, 41.9%). CT controls were performed to 43 (29.1%) patients. Fifty (33.8%) patients had at least once imaging control performed 1 month to two years after discharge from hospital.

Pre-diagnostic antibiotics, including perioperative ones, were given to 85 (57.4%) patients. Of them, 49 (57.6%) suffered from postoperative meningitis.

Pre-diagnostic corticosteroids were used with 33 (22.3%) patients: tablets, intravenous products, inhalators, nasal sprays, and intravenous products, in 19, 10, 3, and 1 patient, respectively. The most frequent corticosteroid used was dexamethasone (12, 8.1%) followed by hydrocortisone, betamethasone, prednisolone, fluticasone propionate, methyl prednisolone, mometasone furoate and fludrocortisone, with 5, 5, 4, 3, 2, 1, and 1 patient, respectively. In 23 (15.5%) patients’ treatment with acyclovir was initiated on admission.

After the diagnosis of BM, ceftriaxone was the most frequently used empiric antibiotic regimen (117 cases, 79.1%), followed by meropenem and vancomycin with 11 (7.4%) cases each. Altogether 11 different antibiotics were used as a first choice. The most used second antibiotic in conjunction with the first one was vancomycin (93, 62.8%), meropenem (11, 7.4%), doxycycline (8, 5.4%), ampicillin and clindamycin (both 5, 3.4%). Antibiotic monotherapy was given to 13 (8.8%) patients. Eighteen patients received three-modal antibiotic therapy with the most common third antibiotic being ampicillin (8, 5.4%). The total number of intravenous antibiotics used are shown in Fig.  2 . Ceftriaxone and vancomycin were the most used empiric antibiotics among all occasions and so were them also after confirmed etiology.

The most common number of different concomitant antibiotics used were three (50, 33.8%), two (34, 23%), four (22, 14.9%), five (19, 12.8%), seven (8, 5.4%), six (6, 4.1%), eight and nine (both 3, 2%), one (2, 1.4%) and ten (1, 0.7%). The numbers include perioperative, intravenous, and in some cases oral antibiotics at discharge.

After the diagnosis of BM, corticosteroids were used in 79 patients (53.4%). Operative treatment was required for 56 (37.8%) patients with most cases being neurosurgical. Mastoidectomy was performed to six (4.1%) patients of whom all had otogenic meningitis.

The median duration of intravenous antibiotic treatment was 18 days (range 2–125). At discharge, 29 (19.6%) patients were prescribed oral antibiotics with the duration ranging commonly from 5 to 30 days, and in a few patients for 100–270 days as a suppressive antibiotic treatment for various reasons. Five most common oral antibiotics used were amoxicillin clavulanic acid (5, 3.4%) followed by clindamycin, moxifloxacin, penicillin and cefalexin (all 4, 2.7%). Median value of the days on antibiotics (combined all intravenous and oral) was 21 days.

The median length of hospital stay was 20 days. Neurological sequelae after BM a total of 49 patients (33.1%) had developed at least one neurological deficit at the time of discharge. Most common deficits were memory difficulties (15, 10.1%), mental regression (13, 8.8%), dysphasia or aphasia (9, 6.1%), visual disorders (9, 6.1%), vertigo and hydrocephalus (7, 4.7% each), decreased level of consciousness (5, 3.4%), hemiparesis and change in personality (4, 2.7%). Twelve (8.1%) patients had their hearing checked with audiogram during their hospital stay. In the period from the moment of discharge to one-year control visit, eight (5.4%) patients had permanent hearing impairment. There was no deafness diagnosed in any patient. Naturally, most of the neurological sequelae were related to neurosurgical procedures.

Fourteen patients (9.5%) died (GOS score 1), all but one directly to BM. From the survivors 5 (3.4% of all patients), 18 (12.2%), 23 (15.6%) and 89 (60.1%) patients had the GOS score 2, 3, 4, and 5, respectively. In total, 40.5% (60/148) had unfavorable outcome (GOS scores 1–4). 30-day all-cause mortality was 10.8% with one-year and two-year overall mortality being 14.2% and 19.6%, respectively.

Patients who suffered from otogenic meningitis had unfavorable outcome likelihood of 22.2%, those from sinonasal meningitis 28.6%, from odontogenic meningitis 33.3%, from neurosurgery-related meningitis 44.6% and patients with no specific source of infection 38.8%. CSF-culture appeared to be most frequently negative with neurosurgery-related meningitis with 16/58 (21.6%) individuals.

Headache (p = 0.0001, 95% CI 0.16–0.35), decreased general condition (p = 0.0001, 95% CI 0.23–0.67), head CT (p = 0.0001, 95% CI 0.073–0.64) and MRI (p = 0.040, 95% CI 0.92–4.0), hypertension (p = 0.0002, 95% CI 0.34–0.70), altered mental status (p = 0.0002, 95% CI 0.47–0.73), confusion (p = 0.0011, 95% CI 0.36–0.78), operative treatment (p = 0.012, 95% CI 0.42–0.89), neurological symptoms (p = 0.023, 95% CI 0.44–0.93), pre-diagnostic antibiotic use (p = 0.026, 95% Cl 0.40–0.97) and oral antibiotics on discharge (p = 0.039, 95% CI 0.94–3.6) were correlated with unfavorable outcome.

All statistical analyses are shown in Additional file 1 .

This study shows extensively the variety of clinical picture, pathogens, and outcome of infection with different etiologies of BM in Southwestern Finland. Our study included all types of meningitis, culture-positive and -negative cases of BM, covering larger entities than if only culture-positive meningitis were included [ 25 ]. Due to severity of the disease it’s essential to regularly evaluate possible predictors of unfavorable outcome.

S. pneumoniae was the most frequently (11, 7.4%) detected pathogen confirming the results of earlier studies [ 26 , 27 ]. In addition to S. pneumoniae , N. meningitidis is a common causative pathogen of BM in all age groups presented earlier [ 28 ], but in our study the N. meningitidis cases were most commonly seen with young adults aged 16–25 years. Surprisingly there were only one Listeria monocytogenes and H. influenzae meningitis although it is shown that these pathogens cause around 9% and 7% of BM worldwide, respectively [ 6 ]. Still, it is possible that patients with septicemia and concomitant meningitis had an ICD-10 diagnosis number of only sepsis in their patient records.

We presented median CSF leucocyte count of 566 × 10 6 /L and median protein levels of 1563 mg/L. However, even normal CSF leucocyte levels can indicate BM, especially combined with high protein levels. In those cases, the outcome may be even worse than normally, with incidence of unfavorable outcome even 59% and mortality 31% [ 29 ].

In 2011 to 2018 we found seven patients with culture-negative CSF specimens positive for bacteria with PCR, a technique shown to be a lot more sensitive than culture [ 25 ]. CSF culture has shown varying sensitivities of 43–85%, and a specificity up to 97%, at least in patients without the use of pre-diagnostic antibiotics [ 30 , 31 , 32 ]. The use of antibiotics reduces the identification of pathogens at least by 30% [ 33 ]. Compared to culture, multiplex or quantitative PCR has shown up to two-fold better sensitivities and specificities up to 100% [ 31 , 33 ]. Our results of CSF culture positivity (33.8%) are compatible with previous studies, especially with frequently used pre-diagnostic antibiotics (57.4%). Our 16sRNA based PCR method presented clearly inferior to newer methods described below. CT was used with most patients (80.4%) and MRI with only 17.6% of patients, which may be due to lack of resources for use of MRI-equipment and the need for quicker results. Our results presented 30.8% and 5.0% specificity with MRI and CT, respectively, on identifying meningitis-related findings in imaging. Previous study indicated MRI being more specific but with a lower specificity of 16% [ 34 ].

Previous studies have shown that CSF sterilization may occur in hours after using parenteral antibiotics. Meningococci may be sterilized within 2 h and pneumococci within 4 h after administering parenteral antibiotic therapy [ 35 ]. Our results showed pre-diagnostic antibiotic use correlated with both negative blood- and CSF culture. Positive blood culture was correlated with positive CSF culture. Therefore, in some cases pre-diagnostic administration of antibiotics before lumbar puncture may cause lack of detectable bacteria despite BM. However, in emergency situations such as sepsis and suspicion of BM the fast administration of antibiotics is essential [ 36 ].

Triad of fever, neck stiffness and altered mental status has been previously reported with 41–59% BM cases [ 37 , 38 ]. In our study, the prevalence of the presentation with this triad was much lower (13.5%). However, another triad—fever, neck stiffness and headache—was more frequent (39, 26.4%). Therefore, it is clear that the absence of the classical triad cannot be used to rule out the possibility of BM. In an older study headache was not reported to be correlated with unfavorable outcome [ 26 ], but with a more recent study [ 37 ] headache was correlated with unfavorable outcome, as was the case also in our study. Therefore, clinicians should pay even more attention to BM patients suffering from headache and not only altered mental status, which may be a sign of a more advanced disease.

The treatment administered after the diagnosis of BM remained highly efficacious due to the lack of resistance of bacteria to the most used antibiotics ceftriaxone and vancomycin, as proved earlier with ceftriaxone [ 37 ].

Community-acquired BM has been shown to cover most of BM cases with even proportion of 86%, with pneumococci being responsible for most of the episodes in adults. Nosocomial BM, on the other hand, has been shown to cover varying proportions of all BM with 14%-73%, most cases being staphylococci dominant. Nosocomial BM cases has seen an increase during the conjugate-vaccine era [ 39 , 40 , 41 , 42 ]. Insufficiency of antibiotic prophylaxis in neurosurgical operations may explain present considerable proportion of individuals with nosocomial BM [ 41 ].

The number of cases with nosocomial BM was relatively high. This is planned to be a topic of our further research. Pre-diagnostic antibiotic use seems to be linked with unfavorable outcome. This may be due to preoperative antibiotics given to patients with neurosurgery and the operative risks. Neurological symptoms and confusion were associated with unfavorable outcome, as presented earlier [ 39 ]. Severe symptoms on admission require more often imaging to exclude other disorders, therefore relating both logically to unfavorable outcome. Oral antibiotics prescribed at discharge were also correlated with unfavorable outcome, probably due to more severe clinical picture and the need for longer antibiotic therapy.

The frequency of unfavorable outcome of BM being 40.5% in our study was compatible with previous research showing the frequency of 38% [ 26 ], but this previous European study excluded all cases with nosocomial meningitis. Previous studies have reported overall mortality of 10–17% [ 26 , 27 ], but in our study the mortality was only 8.8%. A recent study [ 37 ] from Lithuania presented likelihood of unfavorable outcome (GOS 1–3 in their study) to be 15.7% and a mortality (GOS 1) of 5.7%. For comparison, the respective proportions in our study were 24.3% for GOS 1–3 and mortality (GOS 1) of 8.8%. However, straight comparison cannot be done, since we also included patients with nosocomial BM.

Nosocomial meningitis requires often surgical intervention with significant risks. Therefore, it could be interpreted that our results of unfavorable outcome are compatible with previous studies [ 37 , 39 , 43 ].

The worldwide disease burden of BM is high especially in developing countries. Prevention of the disease with vaccines falls behind many other vaccine-preventable notorious diseases. Despite good progress of vaccine development against pathogens of BM, corresponding figures of measles (93.0%) and tetanus (90.7%) vaccination coverage imply that against BM also this could be better [ 44 ].

Our study has limitations. The fact that it was a single center study, is a limitation due to somewhat small number of patients, but the design allows uniform data collection and reliable transfer to analyses. Retrospective nature of this study may have caused inaccurate data collection in some cases. Our patients may not represent the whole population of patients in Finland. Also, we are unable to exclude the possibility of neurosurgery itself causing unfavorable outcome on patients. In the future, comprehensive prospective studies are needed to better determine prognostic factors of BM.

Streptococcus pneumoniae was the most frequent causative pathogen of BM in our study. The proportion of nosocomial BM was surprisingly high, and so was the use of pre-diagnostic antibiotics. Ceftriaxone and vancomycin were the most used antibiotics, and no pathogen presented resistance to them. Headache was associated with unfavorable outcome. Pre-diagnostic antibiotic use predicted unfavorable outcomes, but the reasons may be multifactorial.

The likelihood of unfavorable outcome was compatible with previous studies. However, mortality in our patients was lower than in most previous studies.

The need for developing vaccines against wider spectrum of pathogens causing BM remains of utmost importance. Further research is needed on risk factors, pre- and perioperative antibiotic prophylaxis, and knowledge on different causative pathogens of meningitis to specify appropriate treatments, to recognize special populations, and to improve recovery of patients with BM [ 2 ].

Availability of data and materials

The datasets generated during the current study are available from the corresponding author on reasonable request.

Abbreviations

• Bacterial meningitis

Human immunodeficiency virus

Cerebrospinal fluid

Polymerase chain reaction

International Classification of Diseases 10th Revision

C-reactive protein

• Glasgow Outcome Scale

Matrix-assisted laser-desorption-ionization time-of-flight

Fastidious anaerobe agar

Fastidious anaerobe broth

Minimum inhibitory concentration

European Committee on Antimicrobial Susceptibility Testing

Ribosomal ribonucleic acid

Deoxyribonucleic acid

Computed tomography

Magnetic resonance imaging

van de Beek D, de Gans J, Spanjaard L, Weisfelt M, Reitsma JB, Vermeulen M. Clinical features and prognostic factors in adults with bacterial meningitis. N Engl J Med. 2004;351(18):1849–59.

Article   Google Scholar  

GBD 2016 Meningitis Collaborators. Global, regional, and national burden of meningitis, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2018;17(12):1061–82.

Global Burden of Disease Study 2013 Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet Lond Engl. 2015;386(9995):743–800.

Klinger G, Chin CN, Beyene J, Perlman M. Predicting the outcome of neonatal bacterial meningitis. Pediatrics. 2000;106(3):477–82.

Article   CAS   Google Scholar  

McGill F, Heyderman RS, Panagiotou S, Tunkel AR, Solomon T. Acute bacterial meningitis in adults. Lancet Lond Engl. 2016;388(10063):3036–47.

Davis LE. Acute Bacterial Meningitis. Contin Minneap Minn. 2018;24(5):1264–83.

Google Scholar  

McIntyre PB, O’Brien KL, Greenwood B, van de Beek D. Effect of vaccines on bacterial meningitis worldwide. Lancet Lond Engl. 2012;380(9854):1703–11.

Whitney CG, Farley MM, Hadler J, Harrison LH, Bennett NM, Lynfield R, et al. Decline in invasive pneumococcal disease after the introduction of protein-polysaccharide conjugate vaccine. N Engl J Med. 2003;348(18):1737–46.

Robinson CP, Busl KM. Meningitis and encephalitis management in the ICU. Curr Opin Crit Care. 2019;25:423–9.

Valdoleiros SR, et al. Nosocomial meningitis in intensive care: a 10-year retrospective study and literature review. Acute Crit Care. 2022;37:61–70.

Kurtaran B, et al. The causes of postoperative meningitis: the comparison of gram-negative and gram-positive pathogens. Turk Neurosurg. 2018;28:589–96.

Hasbun R, Rosenthal N, Balada-Llasat JM, Chung J, Duff S, Bozzette S, et al. Epidemiology of Meningitis and Encephalitis in the United States, 2011–2014. Clin Infect Dis Off Publ Infect Dis Soc Am. 2017;65(3):359–63.

Koelman DLH, van Kassel MN, Bijlsma MW, Brouwer MC, van de Beek D, van der Ende A. Changing epidemiology of bacterial meningitis since introduction of conjugate vaccines: 3 decades of National Meningitis Surveillance in The Netherlands. Clin Infect Dis Off Publ Infect Dis Soc Am. 2021;73(5):e1099–107.

Erdem H, Inan A, Guven E, Hargreaves S, Larsen L, Shehata G, et al. The burden and epidemiology of community-acquired central nervous system infections: a multinational study. Eur J Clin Microbiol Infect Dis Off Publ Eur Soc Clin Microbiol. 2017;36(9):1595–611.

Gessner BD, Mueller JE, Yaro S. African meningitis belt pneumococcal disease epidemiology indicates a need for an effective serotype 1 containing vaccine, including for older children and adults. BMC Infect Dis. 2010;10:22.

Paireau J, Chen A, Broutin H, Grenfell B, Basta NE. Seasonal dynamics of bacterial meningitis: a time-series analysis. Lancet Glob Health. 2016;4(6):e370-377.

Wall EC, Everett DB, Mukaka M, Bar-Zeev N, Feasey N, Jahn A, et al. Bacterial meningitis in Malawian adults, adolescents, and children during the era of antiretroviral scale-up and Haemophilus influenzae type b vaccination, 2000–2012. Clin Infect Dis Off Publ Infect Dis Soc Am. 2014;58(10):e137-145.

Mazamay S, Broutin H, Bompangue D, Muyembe JJ, Guégan JF. The environmental drivers of bacterial meningitis epidemics in the Democratic Republic of Congo, central Africa. PLoS Negl Trop Dis. 2020;14(10): e0008634.

Miller L, Arakaki L, Ramautar A, Bodach S, Braunstein SL, Kennedy J, et al. Elevated risk for invasive meningococcal disease among persons with HIV. Ann Intern Med. 2014;160(1):30–7.

Hodgson A, Smith T, Gagneux S, Adjuik M, Pluschke G, Mensah NK, et al. Risk factors for meningococcal meningitis in northern Ghana. Trans R Soc Trop Med Hyg. 2001;95(5):477–80.

Baker M, McNicholas A, Garrett N, Jones N, Stewart J, Koberstein V, et al. Household crowding a major risk factor for epidemic meningococcal disease in Auckland children. Pediatr Infect Dis J. 2000;19(10):983–90.

Müller O, Krawinkel M. Malnutrition and health in developing countries. CMAJ Can Med Assoc J J Assoc Medicale Can. 2005;173(3):279–86.

Battersby AJ, Knox-Macaulay HHM, Carrol ED. Susceptibility to invasive bacterial infections in children with sickle cell disease. Pediatr Blood Cancer. 2010;55(3):401–6.

Kohli-Lynch M, Russell NJ, Seale AC, Dangor Z, Tann CJ, Baker CJ, et al. Neurodevelopmental impairment in children after group B Streptococcal disease worldwide: systematic review and meta-analyses. Clin Infect Dis Off Publ Infect Dis Soc Am. 2017;65(suppl2):S190–9.

Başpınar EÖ, Dayan S, Bekçibaşı M, Tekin R, Ayaz C, Deveci Ö, et al. Comparison of culture and PCR methods in the diagnosis of bacterial meningitis. Braz J Microbiol Publ Braz Soc Microbiol. 2017;48(2):232–6.

Bijlsma MW, Brouwer MC, Kasanmoentalib ES, Kloek AT, Lucas MJ, Tanck MW, et al. Community-acquired bacterial meningitis in adults in the Netherlands, 2006–14: a prospective cohort study. Lancet Infect Dis. 2016;16(3):339–47.

Polkowska A, Toropainen M, Ollgren J, Lyytikäinen O, Nuorti JP. Bacterial meningitis in Finland, 1995–2014: a population-based observational study. BMJ Open. 2017;7(5): e015080.

Oordt-Speets AM, Bolijn R, van Hoorn RC, Bhavsar A, Kyaw MH. Global etiology of bacterial meningitis: a systematic review and meta-analysis. PLoS ONE. 2018;13(6): e0198772.

van Soest TM, Chekrouni N, van Sorge NM, Brouwer MC, van de Beek D. Bacterial meningitis presenting with a normal cerebrospinal fluid leukocyte count. J Infect. 2022;84:615–20.

Welinder-Olsson C, et al. Comparison of broad-range bacterial PCR and culture of cerebrospinal fluid for diagnosis of community-acquired bacterial meningitis. Clin Microbiol Infect. 2007;13:879–86.

Hasanuzzaman M, et al. Comparison of culture, antigen test, and polymerase chain reaction for pneumococcal detection in cerebrospinal fluid of children. J Infect Dis. 2021;224:S209–17.

Heckenberg SGB, Brouwer MC, van de Beek D. Bacterial meningitis. Handb Clin Neurol. 2014;121:1361–75.

Corless CE, et al. Simultaneous detection of Neisseria meningitidis , Haemophilus influenzae , and Streptococcus pneumoniae in suspected cases of meningitis and septicemia using real-time PCR. J Clin Microbiol. 2001;39:1553–8.

Bineshfar N, et al. Evaluation of the epidemiologic, clinical, radiologic, and treatment methods of patients with subacute and chronic meningitis. BMC Neurol. 2022;22:340.

Kanegaye JT, Soliemanzadeh P, Bradley JS. Lumbar puncture in pediatric bacterial meningitis: defining the time interval for recovery of cerebrospinal fluid pathogens after parenteral antibiotic pretreatment. Pediatrics. 2001;108(5):1169–74.

Sherwin R, Winters ME, Vilke GM, Wardi G. Does early and appropriate antibiotic administration improve mortality in emergency department patients with severe sepsis or septic shock? J Emerg Med. 2017;53(4):588–95.

Matulyte E, et al. Retrospective analysis of the etiology, clinical characteristics and outcomes of community-acquired bacterial meningitis in the University Infectious Diseases Centre in Lithuania. BMC Infect Dis. 2020;20:733.

van de Beek D, et al. ESCMID guideline: diagnosis and treatment of acute bacterial meningitis. Clin Microbiol Infect. 2016;22(Suppl 3):S37-62.

Sunwoo J-S, et al. A hospital-based study on etiology and prognosis of bacterial meningitis in adults. Sci Rep. 2021;11:6028.

Block N, Naucler P, Wagner P, Morfeldt E, Henriques-Normark B. Bacterial meningitis: aetiology, risk factors, disease trends and severe sequelae during 50 years in Sweden. J Intern Med. 2022;292:350–64.

Kiyani M, et al. Outcomes and health care resource utilization of adult bacterial meningitis in the United States. Neurol Clin Pract. 2021;11:117–26.

Durand ML, et al. Acute bacterial meningitis in adults. A review of 493 episodes. N Engl J Med. 1993;328:21–8.

Gudina EK, Tesfaye M, Wieser A, Pfister H-W, Klein M. Outcome of patients with acute bacterial meningitis in a teaching hospital in Ethiopia: a prospective study. PLoS ONE. 2018;13: e0200067.

GBD 2016 Causes of Death Collaborators. Global, regional, and national age-sex specific mortality for 264 causes of death, 1980–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Lond Engl. 2017;390(10100):1151–210.

Download references

Acknowledgements

We thank Juha O. Grönroos for support with microbiological methodology and Emmi Alimattila for technical support.

No funding was received for conducting this study.

Author information

Authors and affiliations.

Department of Otorhinolaryngology, Turku University Hospital and University of Turku, Savitehtaankatu 5, 20540, Turku, Finland

Sakke Niemelä

Department of Radiology, HUS Medical Imaging Center, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland

Laura Lempinen

Unit of Biostatistics, Department of Clinical Medicine, University of Turku, Turku, Finland

Eliisa Löyttyniemi

Department of Infectious Diseases, Turku University Hospital and University of Turku, Turku, Finland

Department of Otorhinolaryngology, Head and Neck Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland

You can also search for this author in PubMed   Google Scholar

Contributions

Conceptualization and design of the study: SN, LL, JO and JJ. Methodology: SN, JO and JJ Acquisition of the data: SN and JJ. Analysis and interpretation of data: all authors. Software and validation: SN, EL, JO and JJ. Drafting of the original version: SN, LL, JO and JJ. Drafting, critical revising, and editing: all authors. Visualization: SN, LL, JO and JJ. Supervision: JO and JJ. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Sakke Niemelä .

Ethics declarations

Ethics approval and consent to participate.

All methods were carried out in accordance with relevant guidelines and regulations. The informed consent is waived by Ethics Committee of the Hospital District of Southwestern Finland in view of the retrospective nature. All experimental protocols were approved by Turku Clinical Research Center.

Consent for publication

Not applicable.

Competing interests

J.O reports receiving compensations for lectures or advisory boards outside the submitted work from AstraZeneca, Biocodex, Gilead, GlaxoSmithKline, MSD-Finland, Orion, Pfizer, Roche, Rokotustutkimuskeskus, and for congress travel from UnimedicPharma. All other authors declare no conflicts of interest.

Additional information

Publisher's note.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Additional file 1.

: Table S1. All statistical analyses performed.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ . The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/ ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Cite this article.

Niemelä, S., Lempinen, L., Löyttyniemi, E. et al. Bacterial meningitis in adults: a retrospective study among 148 patients in an 8-year period in a university hospital, Finland. BMC Infect Dis 23 , 45 (2023). https://doi.org/10.1186/s12879-023-07999-2

Download citation

Received : 20 September 2022

Accepted : 10 January 2023

Published : 23 January 2023

DOI : https://doi.org/10.1186/s12879-023-07999-2

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

BMC Infectious Diseases

ISSN: 1471-2334

• Submission enquiries: [email protected]
• General enquiries: [email protected]

A Case Report of Bacterial Meningitis Caused by an Emerging Strain of Penicillin-Resistant Non-Vaccine Serotype 10A

Affiliations.

• 1 Department of General Pediatrics & Interdisciplinary Medicine, National Center for Child Health and Development, Japan.
• 2 Center for Postgraduate Education and Training, National Center for Child Health and Development, Japan.
• 3 Office of Infection Control, National Center for Child Health and Development, Japan.
• 4 Division of Infectious Diseases, National Center for Child Health and Development, Japan.
• 5 Department of Palliative Medicine, National Center for Child Health and Development, Japan.
• 6 Division of Hematology, National Center for Child Health and Development, Japan.
• 7 Department of Infectious Diseases, Medical Mycology Research Center, Chiba University, Japan.
• PMID: 33518624
• DOI: 10.7883/yoken.JJID.2020.841

The pneumococcal conjugate vaccines successfully decreased the incidence of invasive pneumococcal diseases and pneumococcal antibiotic resistance. However, they also led to serotype replacements. According to a report by the National Institute of Infectious Diseases (NIID) in 2017, 96% of pneumococcal isolates obtained from children with IPD aged < 5 years were non-PCV13 serotypes. Here, we report the case of a Japanese immunocompetent and vaccinated child who developed refractory meningitis caused by Streptococcus pneumoniae nonvaccine serotype 10A. PCR revealed genotypic penicillin-resistant Streptococcus pneumoniae (gPRSP) with triple mutations (pbp1a + 2b + 2x). Multilocus sequence typing identified the strain as a sequence type (ST) 11189. The ST11189 strain has not been reported in Japan, but it has recently been reported as a cause of invasive infections in Korea. The clinical course was complicated by the development of brain and subdural abscesses that necessitated prolonged antibiotic treatment and multiple burr hole drainages. Unfortunately, the neurological sequelae persisted. Continued molecular surveillance is needed for monitoring emerging virulent clinical strains.

Keywords: Streptococcus pneumoniae; meningitis; multilocus sequence typing; pneumococcal vaccines; serogroup.

Publication types

• Case Reports
• Anti-Bacterial Agents / pharmacology
• Anti-Bacterial Agents / therapeutic use
• Drug Resistance, Multiple, Bacterial
• Meningitis, Bacterial / diagnosis*
• Meningitis, Bacterial / drug therapy
• Multilocus Sequence Typing
• Penicillins / pharmacology
• Pneumococcal Infections / drug therapy
• Pneumococcal Infections / prevention & control*
• Pneumococcal Vaccines / administration & dosage*
• Streptococcus pneumoniae / genetics
• Streptococcus pneumoniae / isolation & purification*
• Anti-Bacterial Agents
• Penicillins
• Pneumococcal Vaccines

An official website of the United States government

The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

• Publications
• Account settings

Preview improvements coming to the PMC website in October 2024. Learn More or Try it out now .

• Advanced Search
• Journal List
• v.2015; 2015

Clinical Presentation, Aetiology, and Outcomes of Meningitis in a Setting of High HIV and TB Prevalence

Keneuoe hycianth thinyane.

1 Department of Pharmacy, National University of Lesotho, Roma 180, Lesotho

Keanole Mofona Motsemme

Varsay jim lahai cooper.

2 Department of Internal Medicine, Queen Mamohato Memorial Hospital, Maseru 100, Lesotho

Meningitis causes significant morbidity and mortality globally. The aim of this study was to study the clinical presentation, aetiology, and outcomes of meningitis among adult patients admitted to Queen Mamohato Memorial Hospital in Maseru, Lesotho, with a diagnosis of meningitis. A cross-sectional study was conducted between February and April 2014; data collected included presenting signs and symptoms, laboratory results, and clinical outcomes. Descriptive statistics were used to summarise data; association between variables was analysed using Fisher's exact test. 56 patients were enrolled; the HIV coinfection rate was 79%. The most common presenting symptoms were altered mental status, neck stiffness, headache, and fever. TB meningitis was the most frequent diagnosis (39%), followed by bacterial (27%), viral (18%), and cryptococcal meningitis (16%). In-hospital mortality was 43% with case fatalities of 23%, 40%, 44%, and 90% for TB, bacterial, cryptococcal, and viral meningitis, respectively. Severe renal impairment was significantly associated with mortality. In conclusion, the causes of meningitis in this study reflect the high prevalence of HIV and TB in our setting. Strategies to reduce morbidity and mortality due to meningitis should include improving diagnostic services to facilitate early detection and treatment of meningitis and timely initiation of antiretroviral therapy in HIV-infected patients.

1. Introduction

Meningitis is a clinical syndrome characterized by inflammation of the meninges; it is one of the most common infectious diseases of the central nervous system (CNS) [ 1 ]. Most cases of meningitis are caused by bacteria or viruses; however fungi and parasites can also cause meningitis, especially in immunocompromised patients [ 2 – 4 ]. Infection with the human immunodeficiency virus (HIV) is emerging as a major risk factor for meningitis in adults [ 5 – 7 ]. Studies show that tuberculous meningitis (TBM) and cryptococcal meningitis (CM) are among the most common CNS opportunistic infections in patients with HIV/AIDS in sub-Saharan Africa and Asia [ 8 – 11 ].

Meningitis causes significant morbidity and mortality globally [ 3 , 9 , 12 , 13 ]. Long term sequelae of bacterial meningitis in adults include hearing and visual loss, seizures, and cognitive impairment [ 14 ]. Neurological and neuropsychological deficits have also been reported in adults following cryptococcal, tuberculous, and viral meningitis [ 4 , 15 , 16 ]. Mortality from meningitis appears to be much higher in developing countries than in developed countries [ 4 , 5 , 17 ]. Factors that contribute to this high mortality include delay in diagnosis/treatment of meningitis and severe immunosuppression in HIV-infected patients [ 12 , 13 ].

In Lesotho the prevalence of HIV infection is estimated at 23% of the adult population; the country also has a high incidence of tuberculosis (TB) estimated at 633 per 100 000 of the population [ 18 , 19 ]. National data show that in 2009 the rate of TB-HIV coinfection among tested patients was 76.5%; 22% of all notified new TB cases during this period were extrapulmonary [ 19 ]. In Lesotho as in other countries with a high HIV burden, meningitis is a major cause of hospital admission among HIV-infected adults [ 8 , 19 ]. At present there are limited data on the causes of meningitis among adults in Lesotho [ 20 , 21 ]; in addition the influence of HIV infection on the pathogenesis and clinical outcomes of meningitis have not been investigated. The aim of this study was to investigate the clinical presentation, aetiology, and outcome of meningitis among patients admitted to a tertiary level hospital in Maseru, Lesotho.

A cross-sectional study was conducted at Queen Mamohato Memorial Hospital (QMMH), the national tertiary referral hospital in Maseru, Lesotho, over a three-month period between February and April 2014. Patients presenting with signs and symptoms suggestive of meningitis, headache, neck stiffness, fever, photophobia, and/or altered mental status, were screened on admission to the medical wards. All patients 18 years and older with an admission diagnosis of meningitis were eligible to participate in the study. Exclusion criteria were discharge or death within 24 hours of admission.

Prior to data collection, written informed consent was obtained from each patient; for patients who were too ill to communicate, permission to enroll the patients in the study was obtained from the next of kin. Data collected at admission included age, gender, and medical history (history of present illness and concurrent diseases including HIV infection). Prehospitalisation medical records were reviewed and history of antiretroviral therapy (ART), anti-TB therapy (ATT), isoniazid preventive therapy (IPT), and use of cotrimoxazole or other antimicrobial agents was noted. Clinical evaluation of patients for meningitis was carried out according to hospital protocols. All patients underwent a physical examination and neurological assessment on admission and when not contraindicated immediate lumbar puncture (LP) was performed prior to the first dose of antibiotics. Initial cerebrospinal fluid (CSF) analysis for all patients included macroscopy, white cell count (WCC) and differential, protein and glucose levels, Gram stain and culture, India ink stain, and CSF cryptococcal antigen test. Repeat LP was performed when necessary; additional investigations included bacterial antigen detection by CSF latex agglutination tests for Streptococcus pneumoniae , Streptococcus group B, H. influenzae B, N. meningitidis serogroups A, C, Y, and W-135, and N. meningitidis serogroup B/ E. coli K1 and bacterial culture and antibiotic susceptibility testing. Computed tomography (CT) scanning of the head was performed in some, but not all patients with focal neurological deficits and/or altered mental status prior to lumbar puncture or within 24–48 hours of admission to exclude intracranial space occupying lesions and other causes of raised intracranial pressure. Patients with clinical suspicion of TB meningitis and/or HIV infection underwent sputum acid fast bacilli (AFB) smear and culture testing and chest radiography to screen for the presence of TB. Patients with an unknown or negative HIV status on admission were offered voluntary HIV counselling and testing; consenting patients were tested for HIV infection with a rapid test or HIV ELISA. Routine biochemical investigations for all patients included full blood count, liver function tests, and urea and electrolytes.

Clinical, radiological, microbiological, and other laboratory data were evaluated and the diagnosis of meningitis was made based on a combination of clinical and CSF findings (CSF protein and glucose levels, cell count and differential, microscopy, and culture) as explained below.

2.1. Bacterial Meningitis

Bacterial meningitis was diagnosed based on a positive CSF Gram stain and culture or a positive bacterial antigen test (BAT). In patients without a definitive microbiological diagnosis, bacterial meningitis was diagnosed when patients had a compatible clinical presentation (sudden onset of fever, headache, altered mental status, or other meningeal signs) and typical CSF findings (CSF pleocytosis with polymorphonuclear cell predominance, low glucose, and elevated protein). Patient response to antibiotic therapy was closely monitored; patients showing no clinical improvement within 7–10 days of initiation of empiric antibiotic therapy underwent further diagnostic tests.

2.2. Cryptococcal Meningitis

A diagnosis of cryptococcal meningitis was made in the presence of a positive CSF India ink stain or CSF cryptococcal antigen (CSF CRAG) test.

2.3. TB Meningitis

A diagnosis of TB meningitis was made when patients had clinical features of meningitis with negative CSF Gram stain and cultures for bacteria, negative CSF cryptococcal antigen test, and at least one of the following: (i) characteristic CSF findings (CSF pleocytosis with lymphocytic predominance, low glucose, and elevated protein); (ii) evidence of active tuberculosis at another site (e.g., the lungs); or (iii) brain CT findings suggestive of TM such as basal meningeal enhancement or hydrocephalus. Patients showing resolution of constitutional symptoms within 14–21 days of starting anti-TB treatment were continued on treatment and did not undergo further investigations before discharge. CSF acid-fast bacilli smear or culture studies were not performed.

2.4. Viral Meningitis

Viral meningitis was diagnosed when patients had clinical features of meningitis with negative CSF Gram stain and cultures for bacteria, negative CSF cryptococcal antigen test, and typical CSF findings (CSF lymphocytic predominance, normal or slightly elevated protein, and normal glucose) with exclusion of nonviral causes of aseptic meningitis. CSF polymerase chain reaction (PCR) testing for viral pathogens was not done.

All data analyses were performed using SPSS version 20.0. Descriptive statistics were represented as frequencies (%) and median and interquartile range (IQR). Fisher's exact test was conducted to examine the relationship between the dependent variable (in-hospital mortality) and other categorical variables including age, HIV status, CD4 count, and estimated glomerular filtration rate (eGFR) on admission. A p value less than 0.05 was considered statistically significant.

The study was approved by the Lesotho Ministry of Health Research and Ethics Committee.

A total of 72 patients with clinical suspicion of meningitis were enrolled. 16 patients were subsequently excluded; of these 12 patients were diagnosed with other CNS diseases and 4 did not have a clear final diagnosis. Of the 56 patients included in the final analysis, 57% ( n = 32) were female and the median age was 35 years (IQR: 28–44); 79% ( n = 44) were HIV positive ( Table 1 ). 26 of the 44 HIV-infected patients (59%) were receiving antiretroviral therapy; among these, 13 patients had been on ART for less than 3 months, 7 patients for 3–6 months, and 6 patients for more than 6 months; 5 patients were taking cotrimoxazole prophylaxis and 1 patient was on IPT. 9 patients (16%) were on antituberculosis treatment on admission. The most common clinical presentation of meningitis was altered mental status followed by neck stiffness and headache; less common symptoms included vomiting ( n = 12), photophobia ( n = 5), and seizures ( n = 4). CD4 cell counts were measured for 66% (29/44) of the patients with HIV infection; the majority of these (24/29) had CD4 cell counts <200 cells/mm 3 . More than half of all patients had one or more clinical and biochemical features consistent with critical illness including severe wasting, inability to walk/talk, serum Na + <130 mmol/L ( n = 16), eGFR <30 mL/min ( n = 10), and Hb <8.0 g/dL ( n = 6).

Demographic and baseline characteristics of the study participants.

Data presented as n (%) unless otherwise stated; ALT: alanine transaminase; Hb: haemoglobin; n : number of patients; N : total number of patients for whom the analysis was performed; PLT: platelets.

Table 2 shows CSF findings and clinical outcomes among the 56 study participants: 22 patients (39%) were diagnosed with TB meningitis, 15 (27%) had bacterial meningitis, 10 (18%) had viral meningitis, and 9 (16%) had cryptococcal meningitis. HIV coinfection rates were greater than 70% for all types of meningitis; the proportion of patients with CD4 cell counts below 100 cells/mm 3 was 100% (9/9) for cryptococcal meningitis, 50% (5/10) for viral meningitis, 33% (5/15) for bacterial meningitis, and 0% (0/22) for TB meningitis. The majority of the patients had CSF parameters, CSF cell, protein, and glucose findings, characteristic of the various types of meningitis. Of the 15 patients diagnosed with bacterial meningitis, 9 had a CSF pleocytosis with a polymorphonuclear cell predominance reported in 7 patients; 5 patients had low CSF glucose, and 11 had elevated protein. Positive Gram stain results were obtained on initial CSF specimen for 9 patients. Six patients were diagnosed on the basis of CSF findings after repeat LP. A positive bacterial antigen test was reported in 4 patients ( S. pneumoniae , n = 3; H. influenzae , n = 1) and a positive Gram stain in 3; one patient had a positive Gram stain and BAT result. Two patients with microbiologically confirmed bacterial meningitis had a normal CSF study (CSF white cell count up to 5 cells/mm 3 , glucose >2.2 mmol/L, and protein <0.45 g/L). Of the 9 patients diagnosed with cryptococcal meningitis, 6 had a positive CSF India ink stain and 8 were CSF CRAG positive; 5 patients had a CSF white cell count >5 cells/mm 3 with mononuclear cell predominance in 4 patients; low CSF glucose was found in 5 and elevated protein in 8 patients. One patient had a normal CSF study at diagnosis. 22 CSF Gram stain-, bacterial antigen test-, and CSF CRAG-negative patients were diagnosed with TB meningitis. A CSF pleocytosis, median CSF WCC 217 cells/mm 3 (IQR: 58–435), was observed in all patients with TBM. 14 patients had CSF white cell counts above 100/mm 3 , and 20 had a CSF lymphocytic predominance (>90% mononuclear cells). The proportion of patients with low CSF glucose and elevated CSF protein was 12/22 and 20/22, respectively. CSF analysis in patients with viral meningitis showed acellular CSF ( n = 8) or a mild lymphocytic pleocytosis (CSF white cell count <30 cells/mm 3 ; n = 2), normal CSF glucose levels ( n = 9), and elevated protein ( n = 7).

Cerebrospinal fluid analysis and clinical outcomes.

a HIV infection rate expressed as a percentage of patients with known HIV status; b expressed as a percentage of patients with HIV infection; c positive Gram stain and bacterial antigen results reported for initial and repeat CSF specimens; d calculated as a percentage of patients with CSF white cells >5 cells/mm 3 ; BM: bacterial meningitis; CM: cryptococcal meningitis; MN: mononuclear cells; n : number of patients; N : total number of patients for whom the analysis was performed; PMN: polymorphonuclear cells; TBM: tuberculous meningitis; VM: viral meningitis.

Empirical antimicrobial therapy was started with intravenous ceftriaxone; 52% of the patients received adjunctive dexamethasone on admission. Patients diagnosed with TBM were started on a regimen of isoniazid, rifampicin, ethambutol, and pyrazinamide; bacterial meningitis was treated with ceftriaxone, cryptococcal meningitis with amphotericin B, and viral meningitis with acyclovir. Supportive therapy included analgesics/antipyretics and antiemetics. Patients were closely monitored and in cases of clinical deterioration, further investigations were performed and change in therapy was instituted as necessary. The median hospital stay for discharged patients was 11 days, range 6–25 days. The overall in-hospital mortality was 43% (24/56) with more than half of the deaths (14/24, 58%) occurring during the first 7 days of hospital admission. The case fatality was 90% for viral meningitis, around 40% each for bacterial and cryptococcal meningitis and 23% for TB meningitis. In-hospital mortality was higher although not statistically significant among older patients, 67% (4/6) versus 40% (20/50), patients with HIV infection, 48% (21/44) versus 29% (2/7), and those with altered mental status, 50% (21/42) versus 21% (3/14) ( Table 3 ). Severe renal impairment (eGFR < 30 mL/min) was significantly associated with in-hospital mortality, p = 0.008 (Fisher's exact test).

Analysis of factors associated with in-hospital mortality.

4. Discussion

We investigated the clinical presentation, aetiology, and outcomes of meningitis among adult patients admitted to a tertiary level hospital in Maseru, Lesotho. TB meningitis was the most common cause of meningitis (39%) followed by bacterial meningitis (27%), viral meningitis (18%), and cryptococcal meningitis (16%). The percentage of HIV infection was 79%, with the majority of the patients presenting with symptoms and signs of advanced HIV infection (stage III/IV events) on admission. Studies from sub-Saharan Africa show that HIV coinfection is common among adults with meningitis [ 7 , 8 , 22 ]. In a study conducted in South Africa, Jarvis et al. [ 6 ] found HIV coinfection rates above 90% among patients diagnosed with bacterial, cryptococcal, and tuberculous meningitis. The immunodeficiency caused by HIV predisposes individuals to opportunistic infections by pathogens such as Cryptococcus neoformans and Mycobacterium tuberculosis which typically do not cause CNS infections in immunocompetent hosts [ 23 ]. Research indicates that the spectrum of meningitis varies between countries: in parts of Africa and South East Asia, cryptococcal meningitis is the leading cause of adult meningitis, with most of the cases occurring in patients with CD4 counts <100 cells/mm 3 [ 10 , 24 , 25 ]. In our study, TB meningitis was the most common form of meningitis among adults, a finding which is consistent with data from other studies conducted in Southern Africa [ 5 , 22 ]. Lesotho, like South Africa, has a high HIV and TB burden with HIV/TB coinfection rates above 70%. In this study, 59% of all patients ( n = 33) were treated with anti-TB drugs during hospitalisation; of these two-thirds ( n = 22) had been diagnosed with TB meningitis and a third had other forms of TB including pulmonary tuberculosis. Patients with HIV infection and active TB are at an increased risk of extrapulmonary tuberculosis [ 26 ]; in these patients TB meningitis is caused by the hematogenous dissemination of the tubercle bacilli from the primary site of infection such as the lungs. Research indicates that starting antiretroviral therapy early in the course of HIV infection and the use of prophylactic antimicrobial regimens might help reduce the incidence of CNS opportunistic infections in HIV-infected patients [ 10 ].

88% of the patients presented with at least two of the four signs and symptoms of fever, headache, neck stiffness, and altered mental status. Studies show that about 20–70% of adults with meningitis present with varying degrees of altered mental status ranging from confusion to impaired level of consciousness [ 27 – 29 ]. Multiple studies have shown that neurological signs at presentation are prognostic of poor clinical outcomes in patients with meningitis. In this study, mortality was higher though not statistically significant among patients with altered mental status. In a recent study, Jarvis et al. [ 12 ] found that altered mental status was an independent predictor of acute mortality in patients with cryptococcal meningitis. Similar findings have been reported for patients diagnosed with bacterial meningitis [ 27 ] and TB meningitis [ 22 ]. In general CSF cell and biochemistry findings in our study were typical of the different forms of meningitis; however CSF white cell counts were lower than those reported in adult references. More than a third of all patients with microbiologically confirmed bacterial and cryptococcal meningitis had atypical CSF findings: 6 of the 15 patients with bacterial meningitis had CSF white cell counts ≤5/mm 3 and 2 had a normal CSF study; the proportions were 4/9 and 1/9, respectively, among patients with cryptococcal meningitis. These findings are similar to those reported among populations with (predominantly) HIV-associated meningitis [ 6 , 13 , 22 ]. Abnormal CSF cell and biochemistry findings may cause diagnostic uncertainty especially in the presence of negative CSF microbiology results. The diagnosis of meningitis remains difficult, particularly in resource-limited settings. In diagnosing TB meningitis, CSF AFB smear has relatively low sensitivity, reported to be less than 10% in several studies [ 4 , 13 , 22 ], and although CSF AFB culture has greater sensitivity, it can take up to 8 weeks to obtain results, leading to a delay in diagnosis and initiation of anti-TB therapy. For these reasons ancillary investigations including neuroimaging studies and chest radiography are often necessary to confirm/rule out TB meningitis. Confirmatory diagnostic tests for viral meningitis include CSF PCR for nucleic acids and CSF viral culture; however these tests are not widely available. There is a need for sensitive, rapid laboratory tests to enable prompt diagnosis of meningitis and initiation of appropriate antimicrobial therapy.

The overall mortality was 43%; severe renal impairment (eGFR < 30 mL/min) was the only variable significantly associated with in-hospital mortality among the study participants. Some studies indicate that a positive HIV status is predictive of mortality in adults with meningitis [ 8 , 26 , 28 ]. In this study, the mortality rate was higher though not statistically significant among HIV-positive patients compared to those who were HIV negative. Notably, all of the patients with severe renal impairment ( n = 10) were also HIV-infected; 6 of these patients were receiving antiretroviral therapy (tenofovir/lamivudine/efavirenz) on admission and 4 were ART naive. In the absence of other comorbidities, it is highly likely that renal impairment in these patients was HIV related; either HIV-associated nephropathy or tenofovir induced renal failure. In this study, the case fatality rate for bacterial and cryptococcal meningitis was 40% and 44%, respectively, which is similar to that reported elsewhere [ 5 , 9 , 27 ]. Despite advances in diagnosis and treatment, mortality from bacterial and cryptococcal meningitis remains high, especially in developing countries [ 12 , 17 ]. The case fatality for TBM was 23%, which is lower than that reported in other studies [ 13 , 22 ]. A possible explanation for this difference is that although the majority of the TB meningitis cases in this study were also HIV-associated, the median CD4 count among HIV-infected TBM patients (119 cells/mm 3 , IQR: 100–277) was higher than that reported in the two studies above. Severe immunosuppression is significantly associated with increased in-hospital mortality in patients with TB meningitis [ 22 ]. We found a case fatality rate of 90% for patients with viral meningitis; all of the patients with viral meningitis in this study were HIV-infected. In immunocompetent adults, viral meningitis is often a benign, self-limiting condition that resolves spontaneously without any sequelae; however in immunocompromised patients, viral meningitis is frequently associated with a significant mortality [ 30 ]. Approximately 10% of HIV-infected patients develop HIV meningitis which occurs primarily at seroconversion; other aetiologic agents in HIV-associated viral meningitis include Epstein-Barr virus (EBV), herpes simplex virus (HSV) types 1 and 2, and cytomegalovirus [ 30 , 31 ]. Limited data exists regarding the aetiology of viral meningitis in sub-Saharan Africa. In two recent studies conducted in Malawi [ 31 ] and Uganda [ 32 ], EBV was identified as the most common cause of viral meningitis among HIV-infected patients while HSV infection was rarely found. In our setting, viral PCR testing is not available to confirm the diagnosis of viral meningitis and guide antiviral therapy. Possible consequences of this may include misdiagnosis of patients with atypical CSF findings, inappropriate antimicrobial therapy, or a delay in starting appropriate antimicrobial therapy. In this study, all patients with suspected viral meningitis were treated with acyclovir. Acyclovir has been used successfully to treat HSV meningitis; however the treatment of viral meningitis remains challenging as there are often no definitive effective therapies for most pathogens including EBV [ 30 ].

This study has several limitations. First of all, although this was a cross-sectional study, we did not obtain a detailed medical history of the type and duration of symptoms and/or recent use of antimicrobial agents for some of the study participants; in addition some investigations such as CD4 counts were not done routinely thus limiting the use of such variables in further data analyses. Secondly, the limited range of diagnostic tests performed, low sensitivity of the available laboratory techniques, and the presence of atypical clinical and laboratory findings complicate the diagnosis of meningitis; this could have led to exclusion of some cases and misclassification of others. Finally, the study sample was small which limited statistical analysis. Despite these limitations, this study provides evidence of the association between HIV infection and meningitis and the relatively higher prevalence of TB meningitis in our setting and further highlights the difficulties in diagnosing meningitis in a resource-limited setting. In the current study, the primary outcome of interest was death or survival to hospital discharge; future research should include neuropsychological evaluation of patients to assess disability at discharge. In addition, long term follow-up studies are required to study the long term sequelae of meningitis and the incidence of meningitis recurrence especially in patients with HIV infection.

5. Conclusions

In conclusion, the majority of the meningitis cases in this study were HIV-associated. TB meningitis was the most common cause of meningitis followed by bacterial, viral, and cryptococcal meningitis. In-hospital mortality was high with case fatality rates of 23%, 40%, 44%, and 90% for TB, bacterial, cryptococcal, and viral meningitis, respectively. There is a need for sensitive, rapid, and affordable laboratory tests to enable prompt diagnosis and treatment of meningitis. Early diagnosis of HIV infection and timely initiation could reduce morbidity and mortality from HIV-associated meningitis in this setting.

Acknowledgments

The authors would like to thank the medical staff at QMMH and the study participants for their cooperation.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.