Lecture 25: Fever and Headache Flashcards
What is meningitis?
What are the changes in CSF in people with CSF?
Meningitis is inflammation of subarachnoid space extended onto surface of brain. Cerebrospinal fluid is located in subarachnoid space, between arachnoid mater and pia mater (which is tightly adhered to surface of the brain).
In meningitis, cerebrospinal fluid contains bacteria, white blood cell_s, i_nflammatory proteins, cell debris.
In normal healthy person, it’s normal to find a few neutrophils, and also a number of proteins in CSF that serve a protective function (destroy bacteria if they enter the CSF).
Because CSF isn’t exposed to the outside world and environmental agents, it has a relatively underdeveloped immune system compared to other organs such as skin or respiratory tract.
In meningitis, cerebrospinal fluid contains
- bacteria,
- white blood cells,
- inflammatory proteins,
- cell debris.
What may have caused meningitis in Bob?
1) Viruses
- Common
- Mild
- Spontaneously improves
- Benign (no inflammation in brain)
- Enteroviruses
- Influenza
- HSV2 (herpes?)
2) Bacteria
- Common
- Serious
- Medical emergency
- Main 2 causes
- Streptococcus pneumoniae
- N.meningittidis
3) Fungi
- Rare
- often du to AIDS or cancer (immunodeficiency)
4) Protozoa
- Accidental ingestion of worm eggs or larvae
5) Other (e.g. cancer, drugs, trauma)
Describe the symptoms of Meningitis
Problem with cardinal symptoms of meningitis is that they present late (when mortality risk starts to rise exponentially). Early signs of meningitis are very non-specific and look very similar to influenza.
- Meningitis causes headache, photophobia, neck stiffness (Kernig’s sign), drowsiness.
- Systemic inflammatory response causes fever, drowsiness, septic shock, rash (Neisseria meningitis).
How do you diagnose Meningitis?
1) Clinical suspicion
2) Symptoms can be vague early in the illness
3) Signs of meningitis appear late in the illness
4) Samples
- Cerebrospinal fluid
- Blood cultures
- Throat swab
- Blood to detect bacterial DNA by PCR
Describe the signs of Meningitis
The cardinal sign of meningitis is i_ncreased white cell count in CSF._
- There is an increase in neutrophils in bacterial meningitis.
- There is an _increase in lymphocyte_s in viral meningitis or chemical meningitis.
If the infection isn’t dealt to quickly, the inflammation and infection can spread towards the surface of the brain, resulting in encephalitis (resulting in meningo-encephalitis).
Kernig’s Sign: Lift the legs slowly (neck is very stiff + have increased headache if they have meningitis)
How do you get a sample of CSF?
Lumbar Puncture
Patient is curled up in a ball lying on their left side, and spinal needle is passed between L4/5.
- Needle should be angled slightly towards umbilicus (below level of spinal cord).
- Needle will encounter resistance as it passes through spinous ligament, then pop into subarachnoid space. Because dura is innervated, pain is felt as needle passes into subarachoid space.
Describe the changes in CSF in patients with meningitis - due to bacteria vs virus
Increased White Blood Cells (and Different Types)
The first thing to look for is increased white cell count (>5x106/L CSF) for meningitis.
- If they are neutrophils, then it is more likely bacterial meningitis.
- If they are lymphocytes, then it can be bacterial meningitis, but it is more likely viral or chemical meningitis.
Number of white cells correlates with likelihood of different types of meningitis (not definitive!).
- White cell count >500x106/L suggests bacterial meningitis.
- White cell count >5x106/L but on the lower end of spectrum suggests viral meningitis.
Glucose Concentration
The next aspect to analyse is CSF glucose concentration (normal CSF glucose is 2/3 blood glucose)
- With bacterial meningitis, CSF glucose decreases relative to serum glucose. This is due to increased consumption of glucose by neutrophils and bacteria through glycolysis, also impairment of glucose transport via blood brain barrier due to inflammation. Note that serious bacterial meningitis can have CSF glucose close to 0mmol/L.
- With viral meningitis, CSF glucose is unchanged. This is because viruses do not have capacity to metabolise, and lymphocytes don’t also have much requirement for glucose.
Protein Level
CSF protein level is elevated in bacterial meningitis, but it is normal or elevated in viral meningitis.
- Increased protein is due to immune proteins produced by white blood cells, and proteins from lysed bacterial cells.
- There is high protein level in bacterial meningitis caused by S pneumoniae and M tuberculosis (due to pyogenic pathogen).
Gram Stain and Culture
Bacteria presence in CSF investigated through gram stain is confirmation of bacterial meningitis. Following this, CSF culture determines aetiology. Doctors shouldn’t base their diagnosis on negative gram stain and culture!
- Gram stain is not always positive in meningitis (~50%), but more likely to be positive in meningitis caused by pneumoniae.
- The reason is that bacterial concentration required to initiate an immune response can be low. Bacterial concentration can be so low that even after sample centrifugation, gram stain doesn’t show anything.
- Gram stain for pneumococcal types is more often positive, and this is because more S. pneumoniae are required to generate an immune response.
- CSF culture can also be negative, and this is often due to empiric antibiotic treatment of suspected bacterial meningitis. Often, single dose of antibiotics is enough to kill bacteria in CSF (then PCR can be used).
Blood Cultures
Anyone with s_uspected bacterial meningitis_ should have blood cultures taken. The yield is in order of 20-50%, but extremely useful when they are positive.
- If someone has Neisseria meningitidis DNA in their blood, then they definitely have meningococcal disease.
- If pneumococcal meningitis is suspected, then urinary antigen test is also useful (urine immunochromatography)
- If blood culture has been ruined by antibiotics, then it is often possible to detect bacterial DNA in blood through PCR.
Describe PCR
- Polymerase chain reaction, or PCR, is a technique to make many copies of a specific DNA region in vitro (in a test tube rather than an organism).
- PCR relies on a thermostable DNA polymerase, T_aq polymerase,_ and requires DNA primers designed specifically for the DNA region of interest.
- In PCR, the reaction is r_epeatedly cycled through a series of temperature changes_, which allow many copies of the target region to be produced.
- Typically, the goal of PCR is to make enough of the target DNA region that it can be analyzed or used in some other way. For instance, DNA amplified by PCR may be sent for sequencing, visualized by gel electrophoresis, or cloned into a plasmid for further experiments.
Why is using PCR to detect bacterial DNA useful?
When is it not useful?
Some infectious diseases warrant detailed molecular investigations. This include:
- Serious illness or sequelae, e.g. meningitis
- Many pathogens unable to be cultivated, e.g. URTI, almost entirely viral meningitis (viral causes are common)
-
Improving diagnostic yield, e.g. urethritis (chlamydia, gonorrhoea)
- Neisseria meningitidis, Neisseria gonorrhoeae, Streptococcus pneumoniae are fastidious bacteria (have more specific requirements for growth conditions than other bacteria). Staphylococcus aureus is a very robust bacterium (grow in many conditions).
- Chlamydia is difficult to grow since it is obligated intracellular bacteria (cannot generate its own ATP energy, requires host epithelial cells to divide). This means that it is difficult to culture chlamydia because they require host cells, which can be expensive, therefore cheaper option is PCR.
- Gonorrhoea can be cultured in lab but there is a risk of it dying along the way. The yield of diagnosis increases considerably with PCR.
This approach is not useful:
- When only a few pathogens cause an illness,
- When other means are more appropriate,
- When culture is required
- When diagnosis is known.
What are Petechial Rashes?
Presentation of Petechial Rash
Characteristic petechial rash is due to inflammation of capillaries, capillaries bursting and bleeding into skin superficial layers.
- If petechial rash is seen in children with fever and headache, they should be treated for Neiserria meningitidis disease (meningococcal septicaemia)! Since the rash is a late finding, patient will require antibiotics immediately.
- Petechial rash is not seen in streptococcal pneumoniae disease.
- Petechial rash is seen in meningococcal disease and meningococcal septicaemia (blood infection without meningitis).
- Because rash is under skin, w_hen pressure is applied to it, rash doesn’t blanch_ (textbook definition). However, early parts of rash do blanch (keep an eye out for the patient!)
If there’s no presentation of petechail rash, what does this indiciate?
What should you do?
If no characteristic rash is found, all efforts should be put in to find the aetiology, especially to exclude meningococcal disease!
If C_SF gram stain is negative_, then use:
- Streptococcus pneumoniae antigen test CSF (via ELISA)
- CSF PCR for meningococcus, pneumococcus and common viral causes
- Blood PCR for meningococcus
- Throat swab for carriage of meningococcus or pneumococcus.
What are the 2 main bacterial causes of meningococcal disease?
1) Neisseria Meningitidis
2) Streptococcus penumonae
Describe our complement cascade
Complement Cascade
There are two main ways that complement cascade can be activated by:
- Antibodies binding to antigens (classical pathway);
-
Mannose binding lectin (MBL) binding to bacterial sugars (alternative pathway).
- Mannose constitutes bacterial cell wall and does not exist in healthy humans.
- If mannose is present in human body (through infection), then MBL triggers an immune response primarily through complement cascade.
Complement can spontaneously form on surface of cells, but is quickly inactivated because of particular regulators (e.g. factor H, which M protein of S pyogenes binds to and uses as a virulence factor).
The outcomes of complement cascade are improved:
- Improve chemotaxis (neutrophils can find their way to site of infection);
- Improve anaphylaxis (vasodilation to allow immune cells to site of infection);
- Improve opsonization (complement binds to bacterial cells and tags them for removal by neutrophils and other immune cells).
Complement can form pores in bacterial cell wall, called membrane attack complex (MAC). It is only useful in gram-negative bacteria (e.g. Neisseria meningitidis), but no effect in gram-positive bacteria due to thick cell wall.
Describe the Virulence Factors of Neisseria Meningitidis
There are a number of virulence factors that allow immune evasion by Neisseria meningitidis:
- Avoids immune system by expressing host structures (different LPS that has identical structure to human blood group antigen).
- In bloodstream, meningococcus releases blebs of lipopolysaccharide (endotoxin) to decoy complement fixation.
- LPS stimulates toll-like receptors (TLPs) and strongly activate immune system, which acts as a decoy for complement fixation (so complement binds to LPS instead of bacteria itself).
- LPS concentration correlate with degree of systemic immune activation (C5a, C5b, cytokines). High LPS level can cause multi-organ failure and death due to over-activated immune system.
- Type IV pili bind _C4b-binding protei_n (C4BP), which cleaves C3 convertase of classical and lectin pathways, preventing further complement activation
- PorA also binds C4BP (inhibit complement system)
- GNA1870 on bacterial capsule b_inds factor H, which down-regulates complement cascade._
Meningococcus expresses one of 14 different polysaccharide capsules, which prevent formation of complement membrane attack complex (C5-C9), also reduces opsonization.
Describe the shock response to meningitis
It is believed that neutrophil extracellular traps are why meningococcal patients develop multi-organ failure.
- When immune system over-activates, platelets signals to neutrophils, neutrophils then apoptosis and spill out their DNA.
- DNA is very sticky, and forms a web across capillary lumen to trap bacteria and other elements of immune system. This localizes immune response and bacteria in bloodstream.
- This is b_eneficial from immune perspective_, but it is deleterious from organ perspective (causes organ hypoxia and failure).
Symptoms of Shock:
- Reduced blood pressure, tachycardia and reduced perfusion of organs
- Skin is grey and clammy
- Aches and pains
- Reduced urine output
- Confusion, agitation
- Drowsy
What is “Shock”?
Shock: In medicine, a critical condition that is brought on by a sudden drop in blood flow through the body. The circulatory system fails to maintain adequate blood flow, sharply curtailing the delivery of oxygen and nutrients to vital organs.
Reduced BP, tachycardia and reduced perfusion of organs
- Skin is grey and clammy
- Aches and pains
- Reduced urine output
- Confusion, agitation
- Drowsy
Name a broad spectrum antibiotics- that is not penicillin
Cephalosporin
