5. Pulmonary Host Defense Flashcards
Integrated Pulmonary Defenses
- Mechanical protection
a. ____ - ____, glottis, ____
b. ____ - ____, mucous, ____, - Innate immune mechanisms
a. ____ - ____, collectins, ____
b. ____ - respiratory ____, phagocytes - Adaptive immunity
a. ____ (CD4, CD8 T cell)
b. ____ (antibody - B cells)
There are 3 levels of host defense for the respiratory tract(We think of T cells and B cells when we say host defense but for Respiratory tract, yeah it’s important but the first level of defense is 1. MECHANICAL PROTECTION
upper airway turbulence cough lower airway branching cilia
soluble complement defensins cellular epithelium
cellular immunity
humoral immunity
Integrated Pulmonary Defenses (cont.)
Within the mech protection we have the Upper airway and the Lower airway. This is responsible for the overwhelming defense of the ____. Only if this is breached, do you then call in to play the 2. ____ immune mechanism of the respiratory tract
Only if you breach Mechanical protection and only if overwhelm Innate immune mechanisms, is ____ Immunity called into play (called in to play via cellular immunity and humoral immunity
respiratory tract
innate
adaptive
Mechanical protection - the upper airway
- Nares & hypopharynx:
• ____ create turbulence which causes particulate material
to settle onto surfaces
• Nasal hairs - ____
• Rhinorrhea - ____ & sneezing
• Highly effective for particles ≥ ____ uM - Epiglotis/glottis:
• ____
• ____
• ____ - Respiratory mucus:
• Impedes bacterial ____
nasal turbinates
filtration
cellular desquamation
10
swallowing
gag
cough
adherence
Mechanical protection - the upper airway (cont.)
- Nasal turbinates are structured to create turbulence in the upper respiratory tract which causes particulate material to settle onto surfaces. The main point of the turbinates are to create ____; and to ____ the air as it is inspired into the Lower resp tract
- Nasal hairs are covered with mucous filters
- Rhinorrhea causes desquamation and sneezing
- Proximal to more distal mechanical defense is size specific. - In a hospital setting, defects here in the ____ are responsible for the majority of hospital acquired pneumonia (And even community acquired lower resp tract infections bc if you breach these, the lower defense mechs not going to have capacity to respond)
- V important function: globs up particulate matter. Its part of the ____.
In the Upper resp tract it is how body gets rid of organisms. Just like most infections, inoculum is critical. So getting rid of inoculum through these mech barriers is critical for defense of the ____
turbulent airflow warm upper resp defense mucociliary ladders lower resp tract
1.a. Mechanical protection - the upper airway
Defects of the upper airway with loss of mechanical protection:
Altered consciousness
• Drug ____, anesthesia, CNS events
Laryngeal dysfunction
• Bulbar dysfunction – ____ & neuromuscular diseases
• ____ procedures
Endotracheal tube or tracheostomy
• Major risk factor for pneumonia – ____
Oropharyngeal flora & respiratory mucosa adhesive properties
• Increased ____ flora with extensive dental disease (loss of anaerobic flora in patient without teeth)
• Within a week of illness & hospitalization, normal respiratory flora is replaced with gram negative bacteria (____)
overdose myesthenia gravis oro-pharyngeal surgical ventilator-associated pneumonia anaerobic opportunistic
1a. Mechanical protection - the upper airway
Defects that lead to Upper Resp mechanical defense being lost. (Upper respiratory= oral pharyngeal cavity) This is where your Dental field (oral pharyngeal cavity) and the lower resp tract interact/intersect.
- Also ____, coma. These are the most common causes of ____ infections.
- Neuromuscular diseases include stroke having defective ____ functions, because loss of coordinated activity. Upper resp tract, epiglottis and cough reflex is critical. During surgical procedures, if you lean a PT back, PT might aspirate something you might not what them to aspirate.
- If you put a ventilator, you are basically bypassing the ____ so now you have a risk for LRT infections
- He introduced Resp tract mucous before and it has a lot of functions; one of which is acting as a ____ - flowing out microbes, also binds microbes. When people are sick the mucous adhesive properties change and the flora that colonizes the URT changes. Healthy people mostly have ____, they get colonized by gram neg bacteria when they are ill, and that changes the type of bacteria that can enter the ____.
Within a few weeks of illness/hospitalization, the flora of URT changes due to changes in adhesive properties of the ____ That totally changes the types of infections that people who are sick are susceptible to.
Most the anaerobes colonize the gingival crevices of your teeth, it’s a growing field of study the microbiome of the oral cavity
strokes LRT swallowing upper resp defense mechanism ladder anaerobes LRT mucous
Case example 1:
Defective mechanical defense - upper airway
DH - 63 year old man with poor dentiton and history of heavy alcohol use presents to ED with fever, chest pain, cough, foul-smelling sputum
Two kinds of infections:
1) opportunistic - agent is not pathogenic unless there is a defect in ____.
Ex ____ is a opportunistic infection.
2) ____, organisms that have virulent factors that make them able to create infections
in normal hosts. Ex. ____ is virulent.
Interpreting xrays: white is tissue, bone, fluid. Black is air.
Is pointing to abscess in lung.
The mans stats are listed, he has foul smelling sputum, what causes this? ____.
host immune system pneumocytis pneumonia virulent tuberculosis anaerobes
Case example 1:
Defective mechanical defense - upper airway
Lung abscess due to aspiration of ____ caused by loss of consciousness with decreased gag / cough.
Usually mixed flora - including mouth anaerobes (foul smell) if teeth are ____.
Loss of consciousness when he drank too much and blacked out ; he aspirates the oral flora and the saliva he aspirated is full of anaerobes
“If teeth are present” – Usually people who don’t have teeth don’t get ____ because they don’t have gingival crevices
anaerobic oral flora
anaerobic abscesses
Case example 2:
Defective mechanical defense - upper airway
Ventilator-associated pneumonia (VAP) due to ____ or ____ bypass of ____ protection
VAP occurs in up to 30% of intubated patients and causes 40,000 to 70,000 deaths in the US each year
A third of the people with ventilators get VAP, its bad because they are already respiratory compromised You get VAP because you have entrance of bacteria directly bypassing the URT (____).
endotracheal tube
tracheostomy
upper airway
mechanical defense
1.b. Mechanical protection: the lower (conducting) airways
Bronchial Branching
• 20 orders of bronchial branching from trachea to alveolar ducts
• Increased____ lead to decreased ____, and increased ____ with mucosal surface
• Effective for particles ____ uM
Mucous
• Lower ____ layer
• Mucinous layer (____)
Cilia
• 200 per cell at 12 - 15 beats per second
• Propel particulates & mucoid layer up
Mechanical protection and muco-cilliary ladder require coordination with the ____.
total CSA
forward velocity
contact
5-10
sol (liquid)
proteoglycans
cough reflex
- b. mechanical protection: the lower (conducting airways)
- Cross-sectional area becomes exponentially ____. If you breath in a certain amount of air per min, and your cross sectional area as that air moves towards the distal lung gets greater and greater, the forward velocity will ____. Particulates that are suspended in gas are more likely to hit ____ or settle.
-Branching works in concert with the mucociliary function Airways lined with mucous which has two
layers
-lower sol in contact with ____ and interacts w/ cilia. & floating on top of the lower sol layer we have ____ layer - v good at binding microorganisms
- Respiratory epithelia are lined by cilia, they have rhythmic beating. When cilia beats, it is able to push the mucous layer bc it has this nice watery lower sol layer, able to push mucous layer up - gets coughed and expectorated
- Muco-cilliary ladder = ____ layer on the cilia. You need proper ____. This is why with neurological defects one is at risk for resp infections. (They not only have compromised ____ function but also when things come up they cannot ____ it out)
greater decrease resp epithelium mucinous mucinous cough reflex gag swallow cough
Case Example 3:
Defective mechanical defense – conducting airways:
AB - 19 year old man presented with fever, shortness of breath, green sputum for 7 days
Sputum gram stain: Gram positive ____ in ____
Sputum grew ____ and he was treated with cefazolin.
He improved and on discharge was instructed to find a primary care doctor.
Over the next 12 years he had multiple episodes of bronchitis including several with fever, sputum and shortness of breath. Each time he was empirically treated at a clinic with antibiotics.
Since the last episode 6 months ago, he has not regained his exercise capacity, his sputum production has persisted, and recently become ____ and occasionally ____.
Side note: Classic tuberculosis is a ____ disease.
Tuberculosis More likely to reactive in the upper lung
The 19 yo PT’s gram stain: Gram positive cocci - ____
Reads the history. He never fully got better
cocci
clusters
staph aureus
green
blood-flecked
upper lobe
staph aureus
Genetic testing - F508 / ∆I507 genotype in the CFTR gene
Abnormal pattern in both lungs. Not like before where we saw a solid area of infiltrate.
He now has cystic things.
This is a ____ bronchi = ____.
Gram negative ____ – ____. Its rare, you don’t just get it as an outpatient. So then he got tested (genetic tested) for this ____ mutation. ____ that controls flow of water across the resp epithelial cells; if it is mutated it doesnt properly transport water and mucous is ____. ____ doesnt work.
large/dilated
bronchiectasis
rod pseudomonas cystic fibrosis ion channel thick mucociliary ladder
Cystic Fibrosis - defective mechanical lower airway defense (as well as innate immune defense)
Mechanical defense:
•Defective respiratory epithelial water transport leads to ineffective ____
•Bronchial distortion with loss of airway ____
Innate defense:
•Lack of antimicrobial peptide activity (defensins) due to
____ defect
Consequence:
•Chronic airway colonization & ____ infections
•Bronchial damage (____), airway obstruction
•Self perpetuating ____ of infection and further damage
CF - defective mechanical defense of the ____
Epithelial water transport is screwed up ; the ____ layer is messed up for the mucous, it does not transport up- its too viscous and thick.
That then leads to damage to bronchial airway (loss of branching, gets big/dilated) - and you dont get the normal filtering out of particles
____ in the lower airway;
Water defect in the mucous leads to an ____ defect And these antimicrobial peptides don’t work either
Chronic airway colonization and recurrent infections leading to persistent ____. Airway obstruction because you get big dilated bronchi and things don’t clear.
mucocilliary
branching
osmotic
recurrent
bronchiectasis
cycle
lower airway
sol
defensins
osmotic
inflammation
Case Example 4:
Defective mechanical defense – conducting airways
68 year old man with whooping cough as a child (pertussis) and several episodes of LLL pneumonia
Bronchiectasis (focal)
Bronchiectasis - only in one area so its called ____ bronchiectasis
So you can have a genetic defect like CF that leads to ____ or you can get ____ like seen here with this Case.
What causes focal Bronchiectasis? ____ cough used to be #1 cause of it. ____ can cause this. Even just bad ____ can cause it.
Focal Bronchiectasis is another example of conducting airway system ____ defect
focal
diffuse
focal bronchiectasis
whooping
TB
pneumonia
mechanical
Case Example 5:
Defective mechanical defense – conducting airways:
Former heavy smoker with incomplete resolution of infiltrate following his 2nd recent episode of left-sided pneumonia
Post-obstructive pneumonia due to ____
bronchogenic carcinoma
Case Example:
Defective mechanical defense – conducting airways:
Aspirated foreign body
You have post obstructive pneumonia - whole ____ filled with infiltrate
Pneumonia due to aspirated dental prosthesis
right lower lobe
Case Example 6:
Defective mechanical defense – conducting airways: Non-draining bulla or cavity
35 year old man - treated for TB about 5 years ago, now with hemoptysis for the past year. Re-treated for TB (despite negative sputum AFB) with no improvement.
____:
Blob of fungus
fungal colonization within an old cavity
Due to defect of conducting airway, this is not ____, so it allows establishment of a aspergilloma
Causes ____, doesnt usually cause ____ infection although it can.
asperigilloma
draining
hemoptysis
systemic
- Innate immunity in the lung
Cellular
• Phagocytes
• ____ are the primary immune defense system in the lung (≥85%)
• ____ (PMN) are rare in lung (≤5%) but recruited in response to stimuli
• ____ - direct killing
- Respiratory ____ cells secrete soluble products
- ____ peptides
- mediators to recruit ____
Soluble
• ____ - aggregate, opsonize
• ____ - direct lysis, opsonize
• ____ - direct lysis
- not every innate immune cell is a specialized professional immune cell
- most cells (esp. epi cells) have ____. respiratory epithelial cells have their own innate immune system
Upper Conducting airway is critical
Mechanical defense is critical
Now, lets talk about innate immunity in the lung, which is only called in to play only if the upper ____ barriers are breached.
It can be broken down into 1) cellular factors and 2) soluble factors
Innate immune functions are generalized throughout the body but there are some specific components that are uniquely specialized to the ____.
macrophages neutrophils NK cells epithelial direct antimicrobial immune cells
surfactant (collectins)
complement
defensins
innate immune function
mech
respiratory tract
2.a. cellular innate immunity
How do cells recognize as foreign something never encountered before?
Pattern Recognition Receptors :
Toll-like receptors - bind to conserved ____ components:
• ____, flagellin, ____, peptidoglycan, etc
• Nucleic acids not in mammalian genomes - ____, ____
• In the lung: ____, respiratory epithelial cells
Lectins - surface receptors recognize ____ patterns
• In the lung: ____r
Opsonization - soluble pattern-recognition binding proteins that coat microbes
• target them for ____ & trigger immune cell activation
• In the lung: ____, complement,
Adaptive - responding to something it has seen before ,
But Innate - responds to something recognized as ____ (via things like Pattern Recognition receptors)
Macrophage mannose receptor is a lectin that is well studied in the lung.
Bacterial Carbohydrates is very different from Carbohydrates of ____
Opsonization - Soluble factors may have direct effects that are ____ or may serve as ____ in order to direct phagocytes to foreign microbes In the lung: we have collectins - ____ specific multifunctional proteins
We have complements ____ (broadly distributed opsonin)
microbial LPS (endotoxin) lipoproteins dsRNA unmethylated DNA macrophages
microbial carbohydrate
macrophage mannose receptor
phagocytosis
colelctins (surfactant)
foreign
mammals
antimicrobial
opsonins
lung
everywhere
It is not only specialized immune cells that participate in innate immunity
Immune activity of airway epithelial cells:
Input:
Pattern recognition receptors involved in recognition of ____ by airway epithelial cells
Output:
Secretory products of respiratory epithelial cells active in ____ defense
Immunity is not just carried out by immune cells, its carried out by almost every cell.
In the lung, the airway epithelial cells are critical.
The input, the afferent component, is carried out by all these ____ (points to chart).
The output is that respiratory epithelial cells in response to appropriate cells puts out ____, ____ mediators to attract inflammatory cells and antimicrobial peptides.
There is crosstalk between ____ functions, the chemotactic and inflammatory mediators increase innate immune cells but also call in ____ immune cells.
microorganism innate TLRs inflammatory chemotactic innate and adaptive adaptive
a. Defects of cellular innate immunity
____ - chemotherapy, leukemia, bone marrow transplant
• Invasive ____ disease, rapid ____ infection
• ____ and ____ in the bone marrow transplant or chemotherapy patient
Desquamated & injured respiratory epithelium
• ____ / smoke inhalation
• Post-____
• Increased susceptibility to ____ (S. pneumonia, Staphylococcus)
Now we will talk about the specialized immune cells. ____ is one of the most common causes of lung infections that we see, just because neutropenia is common. Neutrophils rapidly turn over cells, derived from the bone marrow, and most chemotherapy agents hit the white cell/ neutrophil lineage hardest, (chemotherapy also hits other cells (red cells/ and platelets but they can be transfused), and endogenously in bone marrow transplant and leukemia also results in loss of neutrophils.
Consequence of neutropenia occurs with ____ disease (that you would not see in immunocompetent host, such as gram neg pneumonia, invasive aspergillosis) or rapidly ____ infection.
Direct injury to epithelium can occur from airway burns or smoke inhalation. People with influenza actually die from ____. Many ____ infections enhance sensitivity to bacterial pneumonias.
neutropenia fungal progressive bacterial gram negative pneumonia invasive aspergillosis
airway burns
influenza
bacterial pneumonia
neutropenia fungal disease progressive bacterial post viral bacterial super infections viral
2.b. Pulmonary Innate Defense: Soluble antimicrobial proteins (large proteins)
Collectins – Specialized ____ system (multi-functional)
____ proteins - SP-A & SP-D (not just for lung physiology!) ____ (MBL)
Aggregate, opsonize, fix ____
Complement (C3a, C5a, Properdin B)
____
chemotaxis
____
Others with direct antimicrobial activity:
____
Lysozyme
____
respiratory system
surfactant
soluble mannose-binding lectin
complement
direct lysis
opsonize
lactoferrin
transferrin
2.b. pulmonary innate defense: soluble antimicrobial proteins (large proteins) (cont.)
Other proteins he will not talk about but are multifunctional proteins with antimicrobial activity He wants to mention the collectins that are a group of specialized respiratory system proteins that have antimicrobial ____ immune functions, they aggregate organisms, opsonize them and fix complement triggering the alternative pathway. The collectins have a typical structure with a ____, that binds carbohydrates of microorganisms, a ____, and another region that does the ____.
Some can aggregate together in large groups that are effective in aggregating microorganisms. There are some that are specific microbial, ____, and others with ____activity (ex blowing up a balloon is easier when its big because the surface tension is greater when its small) so if the lung is a balloon you wont be able to start inspiration without surfactant that line alveoli, that help decrease surface tension, and start out to be thick and end up being thin once the lungs are blown up, allowing the lungs to expire based on elastic recoil.
There are also secondary functions, binding ____. Overall multifunctional.
innate
lectin domain
long linker region
action
mannose-binding lectins
surfactant
microorganisms
2.b. Pulmonary Innate Defense: Soluble antimicrobial proteins (small peptides)
Defensins
• ____ and beta-defensins
• Produced by airway ____ cells
Function:
• ____ microbes directly - remarkably ____ microbicidal activity against ____ and ____ bacteria, mycobacteria, ____ and some ____
• ____
Example: Cystic fibrosis
• abnormal ____ environment leads to defective folding and function of ____
Short peptides that have antimicrobial defense. A ____ immune mechanism, the first defensin was found at Penn in toad bladder!
Many epitherlial tissues produce defensins, as an ____ antimicrobial defence.
alpha-defensins epithelial lyse broad gram-negative gram-positive fungi viruses chemotactic
osmotic
defensins
primordial
innate
Case Example 7:
Defective innate cellular immunity:
3 wk post bone marrow transplant with prolonged pancytopenia including neutropenia – now with fever, shortness of breath, hemoptysis
There is always a period of prolonged ____ because it takes time for the new marrow to engraft, sometimes longer than others, and this is a period of great danger.
Classic presentation – ____, ____, ____ (coughing out blood).
Asked to describe the x-ray
There is something in the lungs, nodules/masses. Its because this is a classic picture
for ____. Certain organisms are responsive to particular immune defects, for invassive aspergillosis its common and very bad, it results in nodules and hemoptysis because it invades ____. This is a problem because the patient will also have low ____.
Neutropenia can be associated with invasive bacterial infections but also invasive fungal infections.
neutropenia
fever
SOB
hemoptysis
invasive asperigillosis
blood vessels
platelets
- Pulmonary Defense: Specific (adaptive) immunity
- Humoral immunity
- Cell-mediated immunity
Adaptive immunity doesn’t come into play until you have breached barrier one and barrier two The lung is a delicate structure, 3 cells thick, most is alveoli epithelium, interstitial cell capillary endothelium.
Inflammation is the enemy, in the lung. If it is chronic, depending on the inflammation
you can get thickening, scarring fibrosis – ____ (bad disease). If the inflammation is driven through proteases you get destruction of lung architecture and results in ____.
pulmonary fibrosis
emphysema
Specific (adaptive) immunity: central role of antigen presenting cells & CD4 T cells
Simple cartoon of adaptive immunity – antigen presentation.
Microorganism is taken up by APC, in lungs its either ____ (____ immunity) or
____, the uptake is by pattern recognition or opsonization, and will process the antigen.
Cellular activation occurs through ____, and the antigen is presented on the surface by ____. And, with costimulatory molecules it can be presented to CD4 T cell, that has the appropriate receptor that binds to the processed peptide + class II, it will lead to activation and expansion of ____, which will lead to antigen specific activation of ____ cells (with three functions listed). The CD4 T cells in lymphoid follicles will interact with B cells to make antigen specific ____/ humoral immunity (the functions are listed, Antibody-dependent cell mediated cytotoxicity (ADCC) is important for killing cells that harbor ____ pathogens, opsonization feeds back into the innate immunity).
Cellular immunity (CD8 T cells)
• ____ killing (perforin, granzyme)
• Activation of other ____ (IFN-g, IL-2)
• ____ secretion
Humoral immunity (B cells & antibody) • \_\_\_\_ killing (lysis) • \_\_\_\_ killing (complement, ADCC) • \_\_\_\_
macrophage
innate
dendritic cell
TLRs MHC class II CD4 T antibodies intracellular
direct
immune
chemotaxin
direct
indirect
opsonization
3.a. B cell mediated immunity: antibody
Functions of antibody:
• Direct lysis (with ____ - ____ pathway)
• Opsonization for enhanced ____ (locally and in the
spleen)
• Antibody-dependent cell-mediated cytotoxicity (ADCC)
Antibody is the most important defense against ____ bacteria (____, ____, ____)
IgA - Principal antibody in ____ airways
IgG - Main antibody in ____
IgE - Mainly ____ responses
____
____
____
complement
classical
cell-mediated cytotoxicity
encapsulated
s. pneumonia
hemophilus influenza
meningococcus
upper & conducting alveolar lining fluid pathologic hypersens pneumonitis asthma allergic bronchopulmonary aspergillosis
3.a. B cell mediated immunity: antibody
Direct lysis occurs particularly through ____
Spleen is really important for opsonization, it is an important organ for B cell activity, and is the site for ____ of micro-organisms and phagocytosis.
Antibody-dependent cell mediated cytotoxicity is important for killing cells that harbor ____ pathogens.
Antibody is really critical for organisms that are encapsulated, (big thick polysaccharide capsules), are poorly killed by other mechanisms but are sensitive to antibody, and the three clinically relevant encapsulated bacteria are ____, ____, ____). Strep and Hemophilus are really important for the ____.
These three immunoglobulins are very relevant to the lung. IgA (secretory) is the principal antibody in the upper conducting airway, IgG is the main Ab within alveoli. IgE is mostly immunopathogenic, it has a role with parasitic diseases, but in the lung it is responsible for ____, and inflammation pathogenic responses. Hypersensitivity pneumonitis is an allergic reaction that can cause ____, a chronic allergic inflammatory response. Asthma. Allergic reaction against fungi that colonize the airways – Allergic bronchopulmonary aspergillosis. For defense purposes, its mainly ____
complement opsonization intracellular strep pneumonia hemophilus influenza meningococcus lung
allergic
pulmonary fibrosis
IgG and IgA
3.a. Antibody function
Defects may be ____ or ____
Inherited gamaglobulinemias - quantitative
•____ or autosomal recessive agammaglobulinemia
Acquired
•Multiple myeloma (____)
•Nephrotic syndrome (____)
•Sickle cell disease (____ antibody defect & asplenia) •Asplenia (____)
•AIDS (____ - often with hypergammaglobulinemia)
All of these are associated with susceptibility to ____ and high risk of overwhelming ____ from encapsulated bacteria – e.g., S. pneumonia
quantitative functional x-linked quantitative and functional quantitative functional functional functional pneumonia sepsis
3.a. antibody function (cont.)
Acquired defects of Ig immune function
Multiple myeloma is a malignancy of ____ cells, and what happens when you get
expanded clone of plasma cells is you get suppression of ____ plasma cells. These people get a huge spike of ____ and get suppression of other immunoglobulins. These people are susceptible to overwhelming sepsis to encapsulated bacteria.
Nephrotic syndrome where ____ is lost, including Ig, which results in a ____
loss of Ig.
Sickle cell disease – leads to ____ of the spleen, and sicklers will eventually
become functionally ____. Its important to keep this in mind when someone with sickle cell disease presents with pneumonia or might be an infection they are susceptible like anyone with an Ig deficiency.
Functional asplenia - ex. Motor vehicle accident. Also a risk factor for overwhelming sepsis.
HIV/AIDS – its not just cell mediated immunity, because if you have an issue with CD4 T cells you will have ____ affected.
plasma normal abnormal clone protein quantitative auto-infarction asplenic cellular immunity and humoral immunity
Case Example 8:
Defective humoral immunity
14 year old boy with sickle cell disease (SS) presented with fever, cough, shortness of breath, chest pain.
Sputum gram stain showed ____. Blood cultures grew ____
Functional asplenia (auto-infarction) in sickle cell disease. Defect in both \_\_\_\_ production and clearance of \_\_\_\_ organisms. Very high risk for \_\_\_\_ bacteria.
Sputum gram stain image is on the right, that shows gram negative cocco-bacilli within neutrophil. The cocco-bacilli are the small red dots within the ____.
These organisms are classic for hemophilus influenzae, and is an example of functional asplenia (auto-infarction) with pneumonia and sepsis from uncontrolled hemopilus due to ____ defect that led to susceptibility to encapsulated bacteria.
gram negative cocco-bacilli
hemophilus influenzae
antibody opsonized encapsulated neutrophil antibody
3.b. Cell Mediated Immunity in the lung
Defective Cell Mediated Immunity in the lung: • \_\_\_\_ • Corticosteroids • \_\_\_\_ immunosuppression (Cyclosporin, tacrolimus, mycofenolate)
Fungi: ____ (PCP) Histoplasmosis
Cryptococcus
Viral: ____
Kaposi’s sarcoma (HHV-8)
Bacterial: ____
M. avium
____
____ diseases should be on the list because there is a lot of immunosuppression drugs used in autoimmune diseases.
These put people at risk for ____ microorganisms, he reads out all the fungi, viral diseases –including oncogenic diseases (HHV8 – herpes virus), bacterial – various mycobacteria and unusual bacteria like Nocardia.
AIDS organ transplantation pneumocystis jiroveci cytomegalovirus tuberculosis nocardia
autoimmune
opportunistic
Case Example 9:
Defective adaptive immunity (mixed humoral and cellular):
GH - 32 year old man with pleuritic chest pain, fever, shortness of breath, rusty sputum that began 3-4 days previously
Pneumonia – chest pain, fever, SOB, rusty sputum.
He reads it all, has a fever, tachycardia, hypotensive
Doesn’t have an elevated blood count but he has a left shift, which is too many
____, and has band forming, which means he has very strong stimulus for ____ response.
Ask the class what they see on the xray: Infiltrate in the right lung.
polymorphic nuclear leukocytes
neutrophilic inflam response
Sputum gram stain: Gram positive cocci in pairs and short chains
Sputum culture was negative (“normal respiratory flora”) but blood cultures grew ____. Mr. H received IV penicillin and improved.
Because of his bacteremic pneumonia and prior history of IV drug use and hepatitis, an HIV test was done, which was positive. His CD4 count was ____ and viral load was 23,000. He improved and was discharged to be followed up in the immunodeficiency clinic.
Over the next several years Mr. H moved multiple times, was incarcerated once, and did not follow up with medical care.
s. pneumonia
390
Sputum gram stain (cont.)
Arrow pointed to ____ in pairs and short chains
The classic appearance of strep pneumonia.
Its not uncommon to not get a positive culture from sputum culture. If someone is
given ____ before sputum is collected.
This patient has a positive gram stain but nothing grew, but his blood grew strep pneumonia, he got IV penicillin and improved. But because of his bacteremic pneumonia, and he is an injection drug user and has HepC, it raised the question of HIV/AIDS, so it was tested and was found positive. CD4 is 390, is not normal but its not that low, far from the level you will see pneumocystis at. So why at 390 did he get pneumococcal pneumonia? Pneumococcal is a ____ organism, you don’t have to be immunosuppressed to get this, however if you are suppressed your susceptibility goes up even higher.
He was advised to start retroviral treatment but never showed up and ended up coming years later (next slide)
gram positive cocci
antibiotics
virulent
Advanced AIDS with defective ____ immunity
Appeared in ICU with this x-ray. There is ____ infiltrate, it is not ____ either.
He has bronchoscopy showed ____, treated with appropriate antibiotics –
trimethoprim/sulfa, and corticosteroids to decrease the inflammation.
He had quite advanced ____, a high ____, low ____ count and eventually died.
Defective ____ mediated immunity is what is seen on this slide and defective ____ was what was seen on the previous slide
cell mediated and humoral bilateral diffuse infiltrates AIDS viral CD3 cell humoral
Pneumocystis jiroveci (formerly P. carinii)
This is what pneumocystis looks like, an H&E stain, pneumocystis don’t show up, they don’t ____, all you see are alveoli filled with holes from the pneumocystis organisms that don’t stain.
If you use a ____ stain you will be able to see the pneumocysis filling up the alveoli.
stain
silver
Cell mediated immunity in the lung: Tuberculosis
TB is a ____ organism and causes disease in both ____ host & ____ hosts
Immune status determines disease manifestation:
Normal host or HIV + / high CD4
•Typical reactivation TB: ____, ____
Immunocompromised host: HIV + / low CD4 •Atypical pattern: • \_\_\_\_ • \_\_\_\_ • Adenopathy only or \_\_\_\_ CXR • \_\_\_\_ • \_\_\_\_ TB (up to 50%)
But the way it presents is determined by the immune status, in a normal host or HIV/high CD4 count they typically show ____ Tb, upper lobe disease because Tb likes ____ relationship with upper lobes of the lung
If immunocompromised, you start getting atypical patterns, reads them out, can show up on a chest x-ray, milliary is disseminated throughout the body, or extrapulmonary Tb.
virulent
normal
immunodeficient
upper lobe
cavitary
noncavitary lower lobe clear milliary extrapulmonary
reactivation
high redox
Tuberculosis
Pathology, it’s a granuloma – a large ____ cell that comes from the fusion of
many ____ together to get a giant cell. ____ stains bacilli red.
multinucleated
macrophages
acid fast
35 yo female with cough, sputum, hemoptysis, HIV+ with CD4 = ____
Classic pattern with right upper lobe TB, chronic fibro-cavitary appearance
30 yo female with fevers & weight loss for 2 months, HIV+ with CD4 = ____
Milliary TB - atypical “opportunistic” pattern of disseminated disease
On the left, classic Tb, right upper lobe has ____ process. The tb in a healthy, non-immunocompromised individual.
On the right, ____ pattern, this is ____ Tb, looks like millet(grainy), associated with low CD4 count.
600 28 fibrotic inflammatory atypical milliary
Relationship between immune deficiency (by CD4 count) and lung disease in HIV infection
Immune deficiency is roughly measured by ____ count and lung disease in ____ infection, is a story of virulent organisms that as disease progresses and the CD4 count goes down you start to become susceptible to ____ organisms.
Anyone can get bacterial pneomonia/tuberculosis. Once you start getting modest immune deficiency, you become susceptible to ____.. As you become more susceptible you can get diseminated/unusual Tb patterns, once you are lower you can see pneumocystis/cyptococcus, and really advanced end stage deficiencies you can see really oppourtunistic things, mycobacterium avium/ cytomegalovirus, that never effect normal people.
VIRULENT OPPORTUNISTIC LEVEL (high to low)
____ > histoplasmosis > diseminated & unusual TB patterns > ____ > mycobacterium avium/cytomegalovirus
CD4
HIV
opportunistic
histoplasmosis
TB/bac pneumonia
pneumocystis/cryptococcus
Key points: Pulmonary host defense
1. ____ barriers of the upper airway are the first defense of the respiratory system
• most common defects leading to ____
• frequently breached ____
- Mechanical protection by the ____ airway is the second line of defense
• compromised through primary defects or from previous infection and injury
• often sets up ____ of repeated infection and damage - Innate defense involves ____ and ____ factors
• Specialized immune system components common across all systems
• Lung-specific elements (____, ____) - Adaptive immune function is a “____”
• small ____ of immune cells in the normal lung, recruited as needed - Each of the pulmonary defense mechanisms interact to ____ and ____ each other
- Infection results from:
• organism that can breach defense (____)
• defects of defense enabling organism entry (____) - The type of ____ defect and ____ determine the clinical picture
• some diseases involve multiple defects
mechanical
lung infection
iatrogenically
conducting
cycle
soluble
cellular
resp epithelium
surfactant
last resort
minority
reinforce
augment
virulent
opportunistic
host defense
severity
Key points: pulmonary host defense
2.“compromised through primary defects” – like cystic fibrosis. “Or previous infection/injury” – like bronchiectasis from previous tuberculosis or whooping cough. The cycles of repeated infections is why cystic fibrosis is always this ____ that results in end stage lung disease.
3.“Specialized immune system components common across all systems” – ____
“Lung-specific elements (respiratory epithelium, surfactant)” – ____
4.small minority of immune cells in the normal lung, recruited as needed
If you take a normal person, broncoalveolar lavage – washing out lungs, 90% of cells are ____, the rest are small population of neutrophils, B cells, T cells, NK cells, but very innate immune centric organ.
5.Each of the pulmonary defense mechanisms interact to reinforce and augment each other
Innate defense triggers chemotaxins that bring in ____ immune function/ antibody that opsonize and enhance phagocytic. They work together.
- Infections happen from organisms that have virulent factors that are specifically designed to breach defense mechanisms OR organisms that are opportunistic and typically don’t cause infections/pathogenesis and can only do it in context of defense mechanisms that enable organism entry and growth.
- Some disease involve multiple defects, but some disease you have to think about what the pathogenesis that lead to this particular infection what are the organisms I need to cover, for example aspiration after a dental procedure, you have to cover ____. Pneumonia in a patient who lacks a spleen, you have to cover ____ organisms. Pneumonia in a patient with advanced HIV, you have to cover ____ agents.
downward spiral
generalized
organ specific
macrophages adaptive anaerobes encapsulated opportunistic
