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What is primary immunodeficiency?

Inherited (so quite rare)
- due to exposure in utero to environmental factors


What is secondary immunodeficiency?

An underlying disease state or treatment for a disease that inhibits/wipes out part of the immune system
- common


Why are numbers of immunocompromised patients increasing?

Improved survival at the extremes of life
Improved cancer treatment
Developments in transplant techniques
Developments in intensive care
Management of chronic inflammatory conditions
- immunomodulatory agents including steriods


What is the most common cause of morbidity and mortality in the immunocompromised host?

Infections - a specific deficiency increases susceptibility to pathogens normally eradicated by that defense mechanism


A specific deficiency increases susceptibility to pathogens
normally eradicated by that defense mechanism, but why is it not always that straightforward?

Basic patterns are recognisable, but organisms are unpredictable
Isolated deficiencies are rare as there is a complex interplay of pathways
- malfunction of one part often influences another
Underlying diseases and their treatment affect a range of mechanisms


Which parts of the immune system do cytotoxic drugs, irradiation and steroids affect?

Neutrophil function
- Chemotaxis
- Phagocytic activity
- Intracellular killing


If netrophil function is affected, which pathogens are most likely to infect a patient?

Gram positive cocci
- staph aureus
- coagulase negative staph
- viridans strep
- enterococci
- bacteriodes
- clostridia
Gram negative bacilli
- E.coli
- pseudomonas aeruginosa
- klebisella pneumoniae
- enterobacter
- cadida
- aspergillus


Describe chronic granulomatous disease.

An X-linked inherited disorder (most common inherited)
Defect in gene coding for NADPH oxidase
- deficient production of oxygen radicals
- defective intracellular killing
Recurrent bacterial and fungal infections
- abscesses in the lungs, lymph nodes and skin
- inflammatory responses; widespread granuloma formation


What are the most common pulmonary infections in chronic granulomatous disease?

Staph aureus


What conditions/drugs suppress cellular immunity?

DiGeorge syndrome - failure of T-cell proliferation
Malignant lymphoma
Cytotoxic chemotherapy
Extensive irradiation
Immunosuppressive drugs
Allogenic stem cell transplantation, especially in GvHD
- because of high dose steriod treatment
Infections - HIV, mycobacterial infections, measles, EBV and CMV


Which kinds of immunosuppresive drugs cause suppression of cellular immunity?

Cyclosporin - immunosuppressant used to prevent organ rejection
Tacrolimus - more potent than cyclosporin
Alemtuzumab - anti-CD52 monoclonal
Rituximab - anti-CD20 monoclonal used in rheumatoid arthritis
Purine analogues (fludarabine) - causes profound lymphopaenia used in cytotoxic chemotherapy


What are some causes of humoral immunity suppression?

Bruton agammaglobinaemia (primary, rare)
Lymphoproliferative disorders cause decreased antibody production
- CLL, multiple myeloma
- preserved in acute leukemia
Intensive radio/chemotherapy


What happens if someone doesn't have a spleen, or it is under active?

Splenic macrophages eliminate non-opsonised microbes (encapsulated bacteria) with a specific opsonising antibody required for phagocytosis of encapsulated bacteria
- lack of this impairs activity of all phagocytic cells


What bacteria/viruses are most likely to affect someone with humoral deficiency, splenectomy or hyposplenism?

Strep pneumoniae
Haemophilus influenzae type B
Neisseria meningitidis


What are the physical barriers against microbial invasion?

Mucous membranes
- gut
- respiratory tract
- GU tract


How do we protect out mucosal surfaces from colonisation?

Colonisation resistance occurs due to our normal flora
- they coat our mucous surfaces and stop colonisation of pathogenic organisms (e.g. C.diff)


How is our skin effective at preventing pathogenic invasion?

Desquamates - high turnover physically removes organisms from the skin surface
Slightly acidic pH
Temperature 5C cooler than the body, so the organisms can't live
Secretory IgA in sweat


What impairs the integrity of the skin?

Surgical incisions - cellulitis common


Why are lines and needles important methods of infection in an immunocompromised host in a hospital environment?

Hickman lines - chemotherapy administration
- used and wiggled too often
- organisms can travel up the venflon or sit in the port and wait for it to be opened
- S.aureus
- cellulitis due to disseminated S.aureus


How can organisms be introduced into the body and enter through mucosal surfaces?

Ventialtion - direct lines of access into respiratory tract


How can chemotherapy and irradiation impair the integrity of the GI tract?

High mitotic index and inflammatory response in the lymphoid tissue.
This causes mucositis -> pain, dysphagia, xerostomia and ulceration
- if the pH is affected, the organisms may be able to survive the stomach
This impairs GI function and its permeability
Nutritional status is altered


How does impaired nutritional status cause immunodeficiency?

Compromise integrity of the host defences
- Anorexia
- Nausea and vomiting
- Mucositis
- Metabolic derangements
Iron deficiency reduces microbial capacity of neutrophils and T-cell function


What is the clinical definition of severe nutritional deficiency?

less than 75% ideal body weight
rapid weight loss and hypoalbuminaemia


How can organ dysfunction lead to increased susceptibility for infection

Obstruction - build up of secretions increases susceptibility
CNS tumors/spinal cord compression
- loss of cough/swallow reflex
- incomplete bladder emptying
Diabetes mellitus - reduced opsonisation, chemotaxis
Stress - reduced T-cell function


Why are premature babies more at risk of immunosuppression?

Intubation risks
- no surfactant means they can't breath properly
Can't develop normal gut flora like most babies do when they go home with their families
- hospital flora, which are very resistant
Chronic lung disease and infection are biggest risks


What is the greatest risks to remember when thinking about infection in solid organ transplantation?

Normal signs and symptoms of infection are diminished/not present due to the immunosuppressive drugs the patient is on
- no antibody response


How should infection in solid organ transplantation be managed?

Prophylactic therapy is most important
- bacterial
- fungal
- viral
Empirical therapy is the only option for treatment
- choice is complicated due to drug interactions/toxicities
- resistance is common


What infections are most common less than one month after a transplant?

Donor associated infections
- latent (TB, syphilis, HIV)
- active at time of procurement (staph, E.Coli)
Pathogens in patient at the time of transplant


What infections are most common 2-6 months after a transplant?

Opportunistic infections
- community acquired
- aspergillus
- pneumocystis


How can pneumocytis jerovecii be identified?

Respiratory infection
- cough, dyspnoea, wheeze, shortness of breath
Fine mottled appearance on lung fields


What is the most concerning feature of aspergillus infections?

This spore producing fungus that erodes into large blood vessels and causes hemorrhage
- can disseminate widely
- stroke


If an immunocompromised patient comes in with neutropaenic fever, what is the diagnosis?

Infection until proven otherwise


What is septic shock?

Sepsis induced hypotension requiring inotropic support
Hypotension that is unresponsive to adequate fluid resuscitation


What is the definition of febrile neutropenia?

A neutrophil count of less than 0.5 (or less than one is they have recent chemotherapy
Fever/hypothermia or SIRS or SEPSIS/SEPTIC SHOCK


What is the immediate clinical management of neutropenic sepsis (fibrile netropenia)?

Deliver high flow oxygen
IV fluid resuscitation
Blood cultures before antibiotics
IV antibiotics as per risk category
Serum lactate and PBC
Urine output and consider catheter


When assessing someone for neutropenic sepsis, what things must you remember?

Don't wait for confirmation of neutropenia in patients who are haemodynamically compromised
Assess with 15 mins of presentation
Assess sepsis severity with NEWS
Institute SEPSIS 6 withing one hour


What antibiotics are given in cases of neutropenic sepsis?

IV Piperacillin/tazobactam (Tazocin)
IV Vancomycin and ciprofloxacin or azteronam
- consider gentamicin


What antibiotics are given in cases of neutropenic sepsis with septic shock or a NEWS greater than 5?

IV Piperacillin/tazobactam (tazocin) and gentamicin
or if allergic
IV Vancomycin, gentamicin and ciprofloxacin or azternam


What antibiotics are used for known ESBL carriers, acute leukemia or an AlloSTC?

IV meropenem (for intoropic support)
an aminoglycoside