Infectious Diseases Flashcards
An immunocompromised patient with a particularly severe humoral immune deficiency will be at greater risk from invasive infections particularly those involving encapsulated organisms that need to be opsonised for eradication.
What is opsonisation and what are the 3 more common bacterial infections requiring opsonisation that this patient is at risk of?
Opsonisation in the tagging of a pathogen with complements or antibodies to signal that it needs to be removed.
Macrophages and other cells will then target these pathogens and remove them.
The bacterial infections that are encapsulated and need to be opsonised for removal are:
- Strep pneumoniae
- H. Influenzae
- Neisseria meningitidis
Correctly link the CDX with the MHC X and state their role generally.
CD4 and MHC II
T Helper Cells and MHC-II: T helper cells express CD4 molecules that specifically recognize antigens presented by the MHC class II complex. MHC-II molecules are primarily found on professional antigen-presenting cells (APCs) such as macrophages, dendritic cells, and B cells. These APCs capture, process, and present extracellular pathogens to CD4+ T helper cells.
Immune Response Initiation: Once the CD4+ T helper cells recognize the MHC-II antigen complex, they become activated. Activated T helper cells then secrete various cytokines, including interleukin-2 (IL-2), to orchestrate a broader immune response.
Role in Immune System: CD4+ T helper cells play a crucial role in mediating the immune response against extracellular pathogens. They help in activating and recruiting other immune cells, enhancing both the cell-mediated and humoral immune responses.
IL-2 and Immune Recruitment
IL-2 Function: Interleukin-2 (IL-2) is a critical cytokine released by activated CD4+ T cells. It is pivotal in promoting the proliferation and activation of immune cells, including both CD4+ T cells and CD8+ cytotoxic T cells.
Recruitment of CD8 T Cells: IL-2 is instrumental in supporting the growth and activity of CD8+ cytotoxic T cells, which are essential for controlling and eliminating intracellular pathogens. It helps these cells proliferate and become effective in their cytotoxic functions.
CD8 and MHC I
CD8 T Cells and MHC-I: CD8+ cytotoxic T cells are designed to recognize antigens presented by MHC class I molecules. MHC class I molecules are expressed on almost all nucleated cells and present protein fragments derived from intracellular proteins, including those from intracellular pathogens such as viruses.
Antigen Presentation to CD8 T Cells: When a cell is infected internally, peptides from viral proteins or abnormal host proteins are presented on the cell surface by MHC class I molecules. CD8+ T cells recognize these MHC-I/antigen complexes and are activated to destroy the infected or dysfunctional cells.
Role in Immune System: This recognition mechanism is crucial for the immune system’s ability to combat intracellular pathogens and to eliminate cells that are infected, transformed, or otherwise dysfunctional.
Summary
Extracellular vs. Intracellular Pathogens: CD4+ T helper cells and MHC-II interactions are crucial for defense against extracellular pathogens by facilitating a broad immune response involving various immune cells. In contrast, CD8+ cytotoxic T cells and MHC-I interactions are vital for eliminating cells infected by intracellular pathogens, ensuring direct cell-mediated cytotoxicity against cells harboring infectious agents or malignancies.
What are the differences in response, t cell subtype, and molecules released e.g. IL-2, IL-4 during a response by the CD4 cells to extracellular bacteria, viruses, fungi, and parasites?
- Response to Extracellular Bacteria
T Cell Subtype: Th17 and Th1 cells are primarily involved in the response against extracellular bacteria.
Cytokines Released:
IL-17 (from Th17 cells): Helps in recruiting neutrophils and monocytes to the site of infection, crucial for combating bacterial infections.
IFN-γ (from Th1 cells): Activates macrophages and enhances their bactericidal activities.
IL-22: Promotes mucosal defenses which are effective against bacterial invasion at epithelial barriers.
Mechanism: Th17 cells respond to bacterial signals by producing IL-17, driving inflammation and mobilizing neutrophil responses to prevent bacterial spread. Th1 cells, through IFN-γ production, fortify macrophage responses to engulf and destroy the bacteria.
- Response to Viruses
T Cell Subtype: Th1 cells are predominantly involved in responding to viral infections.
Cytokines Released:
IFN-γ: Key in stimulating macrophages and enhancing the cytotoxic activities of NK cells and CD8+ T cells, crucial for clearing virus-infected cells.
IL-2: Supports the growth and differentiation of T cells, including cytotoxic T cells that directly kill virus-infected cells.
Mechanism: Th1 cells recognize viral peptides presented by infected cells and produce IFN-γ and IL-2, promoting a strong cytotoxic response to eliminate virus-infected cells and inhibit viral replication.
- Response to Fungi
T Cell Subtype: Th17 cells (and to some extent, Th1 cells) are crucial in fighting fungal infections.
Cytokines Released:
IL-17: Enhances the recruitment of neutrophils and macrophages to the site of infection, important for fungal clearance.
IL-22: Helps in maintaining barrier integrity against fungal invasion.
IFN-γ: Augments the fungicidal capacity of phagocytes.
Mechanism: Th17 cells respond to fungi by releasing IL-17 and IL-22, promoting mucosal defenses and mobilizing neutrophils. Th1-derived IFN-γ also plays a role by boosting the innate cell-mediated response against fungi.
- Response to Parasites
T Cell Subtype: Th2 cells are primarily responsible for combating parasitic infections.
Cytokines Released:
IL-4 and IL-5: IL-4 stimulates B-cell differentiation and antibody production, crucial for neutralizing parasites. IL-5 is vital for eosinophil activation and recruitment, key in combating larger parasites.
IL-13: Similar to IL-4, promotes B-cell responses and enhances mucosal barriers against parasites.
Mechanism: Th2 cells respond to parasitic infections by promoting a humoral response and eosinophilic activity. IL-4 and IL-13 promote antibody production that can neutralize and opsonize parasites, while IL-5 specifically mobilizes eosinophils, which are particularly effective against helminthic parasites.
Summary
Each subtype of CD4+ T helper cells (Th1, Th2, Th17) plays specialized roles in immune responses, tailored to effectively combat specific groups of pathogens through distinct cytokine profiles. This specialization ensures that the immune response is appropriate for the type of invading pathogen, whether it be viruses, bacteria, fungi, or parasites.
What are the differences in response, t cell subtype, and molecules released e.g. IL-2, IL-4 during a response by the CD8 cells to extracellular bacteria, viruses, fungi, and parasites?
CD8+ cytotoxic T lymphocytes (CTLs) are essential players in the immune response against intracellular pathogens, including viruses and certain bacteria such as mycobacteria (e.g., Mycobacterium tuberculosis). These cells recognize infected cells via peptides presented by MHC class I molecules and are pivotal in containing and clearing infections. Here’s an outline of the CD8+ T cell responses to viruses and mycobacteria, detailing their activation, effector functions, and the cytokines they release:
CD8+ T Cell Responses to Viruses
Activation:
Antigen Presentation: Virally infected cells present viral peptides via MHC class I molecules.
Recognition and Priming: CD8+ T cells recognize these antigens through their T-cell receptors (TCRs). They are primed and activated by costimulatory signals from antigen-presenting cells (APCs), particularly dendritic cells, which present viral antigens and provide necessary secondary signals.
Effector Functions:
Cytotoxic Activity: Once activated, CD8+ T cells differentiate into cytotoxic T lymphocytes. They kill infected cells primarily through the secretion of cytotoxic granules containing perforin and granzymes. Perforin forms pores in the target cell membrane, allowing granzymes to enter and induce apoptosis.
IFN-γ Production: CD8+ T cells also produce interferon-gamma (IFN-γ), a cytokine that has antiviral effects, including the inhibition of viral replication and activation of other immune cells.
Cytokines Released:
IFN-γ: Enhances the antimicrobial activities of macrophages, upregulates MHC class I and II expression, and modulates the immune response to be more effective against viruses.
TNF-α: Contributes to inflammation and can induce apoptosis in virally infected cells.
CD8+ T Cell Responses to Mycobacteria (e.g., Tuberculosis)
Activation:
Antigen Presentation: Mycobacteria-infected macrophages and dendritic cells present mycobacterial antigens via MHC class I molecules.
Recognition and Activation: Similar to viral infections, CD8+ T cells are activated upon recognizing these antigens. This process is often facilitated by the presence of IL-12 and type I interferons produced by APCs in response to bacterial infection.
Effector Functions:
Cytotoxic Activity: CD8+ T cells kill mycobacteria-infected cells by inducing apoptosis through the same mechanisms used against viruses (perforin and granzyme pathway).
Macrophage Activation: Beyond direct cytotoxicity, CD8+ T cells produce IFN-γ and TNF-α, which are crucial for activating macrophages. Activated macrophages enhance their phagocytic abilities and are better able to contain and kill intracellular mycobacteria.
Cytokines Released:
IFN-γ: Vital for the containment of mycobacterial infections. It activates macrophages to kill intracellular mycobacteria and induces the production of reactive nitrogen and oxygen intermediates.
TNF-α: Works synergistically with IFN-γ to activate macrophages. It is also involved in the formation of granulomas, which are essential for containing mycobacterial infections.
Summary
CD8+ T cells are crucial in controlling and eliminating intracellular pathogens by directly killing infected cells and by producing cytokines that modulate the immune response. For viral infections, their role is predominantly cytotoxic, while in mycobacterial infections, such as tuberculosis, they not only perform cytotoxic functions but also significantly contribute to activating macrophages and forming granulomas, critical for controlling chronic bacterial infections. This multifaceted response highlights the adaptability of CD8+ T cells in addressing different pathogenic challenges.
List the 3 main categories of immunosuppressive agents and attempt to list at least 1-2 in each category.
- Corticosteroids
Mechanism: Corticosteroids such as prednisone and methylprednisolone inhibit genes that code for pro-inflammatory proteins and promote genes that encode anti-inflammatory proteins. They inhibit the NF-kB pathway, which is crucial for the transcription of many inflammatory cytokines.
Effects: They broadly suppress immune function including T-cell activation, decrease cytokine production, and reduce the overall activity of the immune system. - Calcineurin Inhibitors
Examples: Cyclosporine, Tacrolimus
Mechanism: These drugs bind to the cytosolic proteins cyclophilin (cyclosporine) and FKBP-12 (tacrolimus). The resulting drug-protein complex then inhibits calcineurin, which is a key phosphatase involved in activating the transcription of IL-2, a cytokine that promotes T-cell proliferation.
Effects: By inhibiting calcineurin, these drugs effectively reduce T-cell activation and proliferation, significantly dampening the immune response. - mTOR Inhibitors
Examples: Sirolimus (Rapamycin), Everolimus
Mechanism: mTOR inhibitors bind to FKBP-12, similar to tacrolimus, but the drug-protein complex inhibits the mammalian target of rapamycin (mTOR), another key kinase involved in T-cell proliferation and survival.
Effects: Inhibition of mTOR leads to blocked T-cell activation and proliferation, particularly affecting the response to IL-2. - Antimetabolites
Examples: Azathioprine, Mycophenolate mofetil, Methotrexate
Mechanism:
Azathioprine is metabolized into 6-mercaptopurine which inhibits DNA synthesis, affecting primarily proliferating cells like lymphocytes.
Mycophenolate mofetil inhibits inosine monophosphate dehydrogenase, crucial for purine synthesis in lymphocytes.
Methotrexate inhibits dihydrofolate reductase, leading to reduced folate and thus inhibition of DNA synthesis.
Effects: These drugs preferentially target and suppress proliferating immune cells, reducing immune reactivity and inflammation. - Biologics (Monoclonal Antibodies)
Examples: Infliximab, Adalimumab, Rituximab, Belatacept
Mechanism: These are antibodies engineered to target specific molecules involved in the immune response:
TNF-alpha inhibitors (e.g., Infliximab, Adalimumab) bind and neutralize TNF-alpha, a potent inflammatory cytokine.
Rituximab targets CD20 on B cells, leading to their depletion.
Belatacept blocks T-cell co-stimulation by binding to CD80 and CD86, inhibiting their interaction with CD28.
Effects: Biologics specifically target components of the immune system to suppress particular aspects of the immune response, such as inflammation or cell-mediated immunity. - Integrin Inhibitors
Examples: Natalizumab
Mechanism: These drugs block integrin receptors on the surface of lymphocytes, preventing their migration from the bloodstream into inflamed tissue or the central nervous system.
Effects: This reduces the ability of immune cells to reach and damage sites of inflammation.
Explain the generic pathway of T cell activation through APC presentation to T cell activation, calcineurin pathway activity, IL-2 gene promotion and eventual activation of TOR pathway and then immune response.
Step-by-Step T Cell Activation and Immunosuppressive Drug
Actions:
Antigen Presentation:
Process: Antigen-presenting cells (APCs) such as dendritic cells, macrophages, and B cells process foreign antigens and present peptide fragments on their surface using MHC (Major Histocompatibility Complex) molecules. MHC class II molecules present antigens to CD4+ T cells, and MHC class I to CD8+ T cells.
Immunosuppressive Influence: While no major immunosuppressives directly inhibit antigen presentation, the efficacy of subsequent T cell responses can be indirectly affected by drugs that modulate T cell activation thresholds (e.g., Belatacept inhibiting co-stimulatory signals).
T Cell Receptor (TCR) Engagement:
Process: The TCR on the T cell surface binds to the antigen-MHC complex on the APC. This primary signal is necessary but not sufficient for full T cell activation.
Co-stimulation:
Process: A second signal is required for T cell activation, typically involving the interaction between CD28 on the T cell and CD80/86 (B7) on the APC.
Immunosuppressive Influence: Drugs like Belatacept block this co-stimulatory interaction, effectively preventing T cell activation despite antigen recognition.
Calcineurin Pathway Activation:
Process: TCR engagement and co-stimulation lead to an increase in intracellular calcium, which activates calcineurin. Calcineurin then dephosphorylates the transcription factor NFAT (nuclear factor of activated T-cells), enabling it to enter the nucleus.
Immunosuppressive Influence: Calcineurin Inhibitors such as Cyclosporine and Tacrolimus bind to cyclophilin and FKBP-12, respectively, forming complexes that inhibit calcineurin’s phosphatase activity, thus preventing NFAT activation and subsequent transcription of activation genes, including those for cytokines like IL-2.
IL-2 Production and Release:
Process: Activated NFAT promotes the transcription of the IL-2 gene, leading to IL-2 production and secretion. IL-2 is crucial for T cell proliferation and survival.
Immunosuppressive Influence: By inhibiting calcineurin, the aforementioned drugs reduce IL-2 production, crucially diminishing T cell proliferation and the immune response.
IL-2 Receptor Activation and mTOR Pathway:
Process: IL-2 binds to its receptor on T cells, triggering the PI3K/Akt and mTOR signaling pathways, which promote cell cycle progression and T cell proliferation.
Immunosuppressive Influence: mTOR inhibitors such as Sirolimus (Rapamycin) and Everolimus bind to FKBP-12, similar to tacrolimus, but instead of affecting calcineurin, the drug-FKBP-12 complex inhibits mTOR. This inhibition blocks the downstream effects of IL-2 receptor signaling, particularly affecting cell growth, proliferation, and survival.
Summary
In the cascade from antigen presentation to T cell proliferation, immunosuppressive drugs strategically inhibit key steps, particularly T cell activation (via co-stimulation blockade and calcineurin inhibition) and proliferation (via mTOR inhibition). Each drug targets specific components of the immune response, allowing for tailored immunosuppression based on the clinical context, whether for preventing organ transplant rejection or treating autoimmune diseases. This pathway-focused approach helps in managing the immune system’s response while attempting to minimize potential side effects.
What vaccinations are recommended for a patient who is or soon will be immunocompromised?
`Seasonal influenza
Pneumococcal vaccination (Prevenar 13, Pneumovax23)
dTPa
HPV
HBV - important for non immune
DO NOT GIVE THESE LIVE ATTENUATED ONES. If given they must only be given more than 4 weeks prior to any immunosuppressive treatments.
- MMR
- Varicella
- Zostavax
What is the recommended prophylaxis treatment for possible latent TB infections?
Isoniazid 300mg daily + pyridoxine 25mg daily for 9 months.
This is recommended for any patients at risk of having a latent TB infection who are planned for immunosuppressive treatments.
- With known TB contacts
- Born or lived in high risk country
- Any previous TB treatment for actual or possible infections
- Occupational risk e.g. HCW
- Any abnormalities on CXR (calcified lesions, apical scarring, granuloma)
- Anyone getting TNFa inhibitors
What is the clinical course of HBV after immunosuppression?
Initially patients may have low HBV DNA. During chemotherapy or other immunosuppressive treatments the HBV levels increase. It is not until the treatments are stopped and the immune system starts to respond again that you will actually see the symptoms of HBV. When the immune system restarts you may see symptoms of infection as well as raised LFTs.
Screen every patient for HBV prior to any immunosuppressive treatments.
What is the management of HBV?
What is the best antibiotic choice for surgical prophylaxis?
1st generation cephalosporins (cephazolin) offer the greatest benefit.
Add vancomycin for MRSA cover if needed.
- Pneumonia
Community-Acquired Pneumonia (CAP)
Outpatients (previously healthy, no antibiotic use within 3 months):
Amoxicillin or
Doxycycline or
Macrolides (azithromycin, clarithromycin) if there is concern for atypical pathogens.
Good choice is penicillin + doxy or Macrolide
Outpatients (comorbidities or antibiotic use within 3 months):
Respiratory fluoroquinolones (levofloxacin, moxifloxacin) or
Combination therapy with a beta-lactam (amoxicillin-clavulanate or cephalosporin) plus a macrolide.
Inpatients (non-ICU):
Respiratory fluoroquinolone or
Combination therapy with a beta-lactam plus a macrolide.
Inpatients (ICU):
Beta-lactam (ceftriaxone, cefotaxime, or ampicillin-sulbactam) plus either azithromycin or a respiratory fluoroquinolone.
Hospital-Acquired Pneumonia (HAP) and Ventilator-Associated Pneumonia (VAP)
Coverage for MRSA and Pseudomonas depending on local resistance patterns, typically includes:
Vancomycin or linezolid for MRSA,
Piperacillin-tazobactam, cefepime, or carbapenems for Pseudomonas,
Consideration of local resistance and risk factors for multi-drug resistant organisms.
- Gastrointestinal Tract Infections
Acute Gastroenteritis
Generally supportive care; antibiotics not routinely recommended except in certain conditions:
Traveler’s diarrhea: Fluoroquinolones (ciprofloxacin), azithromycin, or rifaximin.
Clostridioides difficile infection: Oral vancomycin or fidaxomicin.
Diverticulitis
Mild cases managed outpatient: Amoxicillin-clavulanate or a combination of ciprofloxacin with metronidazole.
Peritonitis with perforation - Gentamicin + ampicillin + metronidazole. Pip taz also an option. - Urinary Tract Infections (UTI)
Uncomplicated UTI
First-line: Nitrofurantoin, trimethoprim-sulfamethoxazole (unless local resistance exceeds 20%), or fosfomycin.
Alternatives: Fluoroquinolones (ciprofloxacin, levofloxacin), but generally reserved due to resistance concerns.
Complicated UTI
Depends on local resistance patterns; typically a broader spectrum antibiotic such as ceftriaxone, fluoroquinolones, or aminoglycosides, sometimes followed by an oral agent based on culture results. - Cellulitis
Beta haemolytic streptococci (e.g. staph Aureus) most common cause. So use narrow spectrum B lactams.
Non-purulent Cellulitis (e.g., streptococci predominant)
Oral: Cephalexin or dicloxacillin.
IV: Cefazolin or nafcillin.
Purulent Cellulitis (e.g., suspect MRSA)
Oral: Clindamycin, trimethoprim-sulfamethoxazole, doxycycline, or linezolid.
IV: Vancomycin, daptomycin, or linezolid.
Considerations
Allergic Reactions: Alternatives should be considered for patients with allergies to the first-line antibiotics.
Culture and Sensitivity Tests: Ideally, treatment should be guided by culture results, especially in severe or complicated cases.
Which of these drugs are ideal for IV to oral switch:
- Fluroquinolones (-floxacins)
- Metronidazole
- Trimethoprim + sulphamethoxazole (Bactrim)
- Clindamycin / Azithromycin
- Fluconazole
All are good. They have great oral bioavailability. So switch IV to oral as soon as you can.
Why should aminoglycosides be monitored.
E.g. gentamicin, amikacin
They are nephrotoxic and ototoxic
Aim for once daily dosing.
High peak and low trough
Check levels if ever used for >48 hours.
Gentamicin - very effective blood-stream but potentially toxic antibiotics
– Broad Gram -ve cover
– E. coli, Pseudomonas, Enterobacter, Klebsiella
– Use in potential Gram -ve sepsis, pyelonephritis
– 5 mg/kg daily.
– Less useful in focal infection (abscess)
– Reduce duration of use to minimise exposure (<48-72 hours)
– Avoid in renal impairment, balance/hearing problems
What are the major risk factors for infective endocarditis?
IVDU
Previous infective endocarditis
Prosthetic heart valves (1-4% at time of implant, 1% each year after)
Nosocomial Endocarditis (2nd to bacteraemia or invasive procedure e.g. vascular device)
Structural heart disease (75% of patients with IE have some pre-existing cardiac abnormality) Bicuspid aortic valve is most common predisposing factor for IE (20-30%)
Degenerative valvular disease: Those with Mitral valve prolapse - 5-8% x risk compared with average population.
Aortic valve disease (stenosis +/- regurgitation) present in 12-30% of cases.
What are the most common causes of infective endocarditis?
How does the microbiology of prosthetic valve infective endocarditis differ to that of normal infective endocarditits?
S aureus and S intermedius are coagulase positive. All other staphylococci are coagulase negative. They are salt tolerant and often hemolytic. Identification requires biotype analysis.
Coagulase-negative staphylococci are an important cause of prosthetic valve endocarditis, particularly within the first 2 months of valve placement. Many of these strains are methicillin resistant and require vancomycin, in combination with rifampin, for at least 6 weeks of treatment and 2 weeks of gentamicin.
Coagulase-negative staphylococci (CoNS) are aerobic, Gram-positive coccus occurring in clusters.
Predominantly found on the skin and mucous membranes.
Heterogeneous group
Catalase positive but coagulase negative (S. aureus is coagulase positive).
Major pathogens:
S. epidermidis: colonies typically small, white-beige (about 1-2 mm in diameter).
S. haemolyticus: colonies typically small, golden yellow (about 1-2 mm in diameter).
S. lugdunensis: colonies are usually sticky, smooth, glossy, yellow-orange (2-4 mm).
Perhaps the most virulent of CoNS, it behaves similarly to S. aureus.
Over 40 recognized species of CoNS are capable of causing human disease.
Others seen on occasion: Staphylococcus auricularis, Staphylococcus capitis, Staphylococcus hominis, S. pettenkoferi, Staphylococcus saprophyticus, and Staphylococcus simulans.
Many strains tend to produce biofilm, allowing for adherence to medical devices.
Susceptibility profile for CoNS. Breakpoints vary by species.
Vancomycin (CLSI): MIC cutoffs
Sensitive: ≤ 4 mg/L
Intermediate: 8-16 mg/L
Resistant: ≥ 32 mg/L
Note: EUCAST states resistance is MIC > 4 mg/L
Oxacillin (CLSI)
S. epidermidis sensitive if ≤ 0.25 mg/L and Resistant if ≥ 0.5 mg/L.
S. lugdunensis sensitive if ≤ 2 mg/L and resistant if ≥ 4 mg/L.
Usually resistant to penicillin and typically (> 80%) to methicillin (oxacillin, nafcillin).
mecA gene encodes for low-affinity penicillin-binding protein.
Resistance can be heterotypic, so multiple isolates should be obtained to determine whether they are susceptible to beta-lactams, as only a minority of isolates typically express resistance phenotypes.
Linezolid resistance is described but remains rare.
What are the Duke Criteria for Infective Endocarditis?
Hint:
- BE TIMER
What is the antibiotic of choice for staph aureus (MSSA) infective endocarditis?
Flucloxacillin
Treatment of MSSA bacteraemia generally consists of a beta-lactam agent such as nafcillin (2 g IV every four hours), oxacillin (2 g IV every four hours), flucloxacillin (2 g IV every six hours), or cefazolin (2g IV every eight hours)
This is just some information about resistant organisms
