Immunocompromised Hosts

Front 1

1st hurdle for a pathogen:
2nd hurdle:

Back 1

barriers
pattern recognition receptors

Front 2

Neutrophil hematopoiesis:

Back 2

*Hematopoieses is coordinated by specific transcription factors --> G-CSF modulates the relative levels of transcriptional factors within myeloid cells --> influences differentiation
*G-CSF also influences proliferation, maturation, survival of myeloid cells and accelerates passage of neutrophil pre-cursors through the bone marrow
*Infection: G-CSF increases
*Therapeutic use: rhG-CSF (filgastrim=Neupogen; peg-filgastrim=Neulasta)

Front 3

Neutrophil Kinetics:

Back 3

*Daily production 10^9 cells/kg BW
*During infection 10 times more
*5% of the total granulocyte pool located intravascularly
-Intravascular circulating cells
-Marginating cells
*Dynamic equilibrium: cells marginate via transient endothelial interaction, then resume rapid flow
*Intravascular t1/2 6-8hrs; extravacsular t1/2 hrs-days
*Steroids shift equilibrium by decreasing neutrophil adherence from marginating to circulating pool

Front 4

Summary of steps of the inflammatory response:

Back 4

1. Recruitment
2. Ingestion
3. Intracellular disposition of ingested microbe
- Oxidative burst
- Degranulation
4. Resolution of inflammatory response

Front 5

Quantitative and Qualitative Defects in neutrophil-dependent host defense:

Back 5

*Quantitative
-Neutropenia
Chemotherapy
Radiation
Cancer related
Sequestration (hypersplenism)
Autoimmunity

*Qualitative
-Functional impairment of adhesion/chemotaxis/ingestion/microbicidal systems
-Opsonization defect (complement/immunoglobulin deficiency)

Front 6

What are infections typically like in pts with neutrophil defects?

Back 6

*Infections resulting from either defect are persistent, slowly responsive to antimicrobial therapy, and recurrent
*Quantitative defect: bacteremia with septic picture
*Qualitative defect: localized infections

*Predominant organisms: Staphylococci, Gram-negative bacteria, fungi an in case of opsonization defect encapsulated bacteria

Front 7

Neutropenia:

Back 7

*Risk of infection increases progressively with duration and magnitude of neutropenia

*Relative neutropenia 500 - 1000 cells/mm3
*Absolute neutropenia <500 cells/mm3

Front 8

Extrinsic Chemotactic Defects:

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*Extrinsic defects
-Genetic complement deficiency
C3 (prone to bacterial infections)
C5 (prone to infections due to Neisseria meningitidis/gonorrhoeae)
-Decreased complement production due to cirrhosis
-Loss of serum proteins (burns, nephrotic syndrome)
-Depression of neutrophil chemotactic response in diabetic patients
-Inhibiting factors (RA, SLE, sarcoidosis, Hodgkin’s Disease)

Front 9

What can cause opsonization defects?
What are these pts vulnerable to?
How can you prevent them from getting ill?

Back 9

*Opsonization defect
-Hypogammaglobulinemia (decreased production [i.e. Multiple Myeloma; loss of serum proteins [i.e. nephrotic syndrome])
-C3 deficiency [i.e. cirrhosis]
-Asplenia [Splenectomy/Congenital]
-Functional asplenia [i.e. due to sickle cell anemia]

*Prone to infections with encapsulated bacteria
-Haemophilus influenzae type b
-Streptococcus pneumoniae
-Neisseria meningitidis
-Salmonella typhi

*Prevention
-Vaccinate (streptococcal, meningococcal, Hib vaccine) prior to splenectomy
-Preventive antibiotic therapy (daily vs as needed for fever)

Front 10

How does the adaptive immune system normally deal with a viral infection?

Back 10

*MHC class I presentation of virally derived peptide antigens to CD8+ T-cells
 -Cytolysis or inhibition of viral replication in host cells

Front 11

How does the adaptive immune system normally deal with intracellular bacteria?

Back 11

Front 12

How does the adaptive immune system normally deal with extracellular bacteria?

Back 12

Front 13

What happens if you have damaged barrier function?

Neutropenia?

Compromised/absent splenic function?

Back 13

*Damaged barrier function
Colonizing flora of skin/oral mucosa/gut mucosa

*Neutropenia
Gram-positive cocci
Gram-negative bacilli
Fungal infections

*Compromised/absent splenic function
Encapsulated bacteria

Front 14

What happens if you have impaired cellular immunity?

Back 14

*Viral infections
-Reactivation of latent viruses (i.e. HSV, VZV, CMV)
-Newly acquired viral infections (i.e. influenza, parainfluenza, RSV, adenovirus)

*Intracellular bacterial infections
-Reactivation of latent infection (tuberculosis)
-Newly acquired bacterial infections (i.e. non-tuberculous mycobacteria, Listeria monocytogenes, Nocardia spp., Salmonella spp.)

*Fungal infections
-i.e. Pneumocystis jirovecii, Aspergillus spp., Cryptococcus spp.

*Parasitic infections
-i.e. Toxoplasma gondii

Front 15

What happens if you have impaired humoral immunity?

Back 15

Bacterial infections--> Streptococcus pneumoniae, Heamophilus influenzae

Front 16

Diabetes Mellitus:
Where is the defect?
What infections is the patient at risk for?
How can infections be prevented?

Back 16

*Depression of neutrophil chemotactic response

*Focal bacterial infections (i.e. UTI, Fournier’s gangrene, cellulitis, osteomyelitis/diabetic foot infection)
*Focal fungal infections (i.e. rhino-cerebral mucor)

*Optimized glucose control
*Vaccination (pneumococcal vaccine)
*Podiatry care

Front 17

Cirrhosis:
Where is the defect?
What infections is the patient at risk for?
How can infections be prevented?

Back 17

*Neutrophil chemotaxis and phagocytosis
*Impaired gut mucosal barrier

*Focal bacterial infections, most commonly spontaneous bacterial peritonitis (SBP), followed by urinary tract infections, pneumonia and cellulitis (Vibrio vulnificus)
*The most frequent causative organisms in community-acquired infections are gram-negative bacilli, mainly Escherichia coli

*Vaccination (pneumococcal vaccine, HBV/HAV vaccination)
*SBP prophylaxis
*Education about avoidance of raw seafood (oysters) consumption and wading in salt water

Front 18

Hematologic Malignancies:
Where is the defect?

Back 18

*Depends on the affected cell line and the drugs used for treatment

*i.e. AML disease related immune defect: neutropenia; AML treatment related immune defects: mainly neutropenia and impaired barrier(mucositis),to a lesser degree impaired cellular and humoral immunity

Front 19

Solid Organ Transplant:
Where is the defect?

Back 19

*Impaired cellular immunity
*Degree of impairment / coexistence of other immune defects depend on
-Reason for transplantation (i.e. patients transplanted for cirrhosis (especially due to autoimmune hepatitis), diabetes associated end-stage renal disease, etc. have pre-existing immune deficiencies)
-Type of transplant (some organs are more immunogenic than others and require higher degree of immunosuppression)
-Time after transplantation: 3-6 months post transplant is the time of most intense immunosuppression (dependent on drugs used for induction, pre-existing immunosuppression at time of transplant, taper of maintenance immunosuppression, treatment for episodes of rejection)

Front 20

Timeline of Infections after Solid Organ Transplantation:

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Front 21

Solid Organ Transplantation--How can Infections be prevented?

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*Pre-transplant
-Serologic screening of recipient and donor
-Treatment of latent infectious diseases prior to transplant (i.e. strongyloides, latent TB)
-Pre-transplant vaccinations
-Counseling about food/travel/outdoor activity/sexual safety

*Post-transplant
-TMP/SMX for PCP, toxoplasmosis, nocardia, listeria, Hib, pneumococcal disease prevention
-Ganciclovir/valganciclovir for CMV, HSV, VZV prevention

Front 22

Timeline of Infections after Allogeneic Hematopoietic Stem Cell Transplantation:

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Front 23

Allogeneic Hematopoietic Stem Cell Transplantation--How can Infections be prevented?

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*Acyclovir or valacyclovir for HSV/VZV prophylaxis for 1 year/until all immunosuppressive treatment discontinued
*TMP/SMX prophylaxis for 1 year/until all immunosuppressive treatment discontinued
*Pre-emptive monitoring for CMV replication until day +100 or longer if GVHD treatment
*Pre-emptive monitoring for EBV replication in T-cell depleted or umbilical cord blood transplant recipients
*Mold prophylaxis in patients with severe GVHD
*Vaccination
*Counseling

Front 24

24 yo female with AML undergoing induction chemotherapy with fever, oral pain and dysphagia.

Where is the defect?

What infections is the patient at risk for?

What to do?

Back 24

neutropenia
mucositis--impaired mucosal integrity

*Invasive infections i.e. Viridans group streptococci and other oral bacterial flora
*HSV
*Candida infections

*Physical exam and review of symptoms; COMPLETE skin exam (including perianal area-but don’t do a rectal exam as you could translocate bacteria)

*Empiric antibiotic treatment (cefepime); If HSV seropositive: add acyclovir; Labs, blood cultures, imaging

Front 25

46 yo male s/p kidney transplantation complicated by an
episode of acute rejection treated with pulse dose steroids a month ago. On tacrolimus, mycophenolate
mofetil, and prednisone Maintenance immunosuppression. Presents with progressive shortness of breath, non-productive cough, and fever.

Where is the defect?

What infections is the patient at
risk for?

Back 25

-CT scan of PCP

-Impaired cellular immunity

-Viral infections
-Intracellular bacterial infections
-Fungal infections
-Parasitic infections

Front 26

What immune defect predisposes to this infection?


How could this infection have been prevented in a patient after allogeneic bone marrow transplantation?

Back 26

Impaired cellular immunity

Acyclovir or valacyclovir prophylaxis

Front 27

65 yo m with newly diagnosed multiple myeloma not yet on treatment. Presents with fever, chills, cough productive of yellow sputum and chest pain.

Back 27

-gram pos diplococci
-pneumococcal pneumonia

Front 28

49 yo male with liver cirrhosis secondary to alcohol abuse presents with fever and painful bullous lesions on his right leg. Ate raw oysters.

Back 28

vibrio vulnificus

Front 29

37 yo female with relapsed AML undergoing re-induction
chemotherapy. Developed nosebleeds and intraoral lesion.

Back 29

-Mucormycosis (pt is deeply neutropenic from treatment)

Front 30

47 yo m presents with sepsis and the skin findings depicted in the photograph.

What might be the patient’s underlying Immune defect?

Would this infection have been preventable?

Back 30

*purpura (indicative of sepsis)

*Opsonization defect (complement or impaired splenic function)

*Preventable with antibiotic prophylaxis

Front 31

55 yo female s/p renal transplantation 7 months ago. Presents with fever, abdominal pain and non-bloody
diarrhea.

Back 31

*CMV!

Front 32

55 yo male s/p liver transplant 2 months ago for end-stage liver disease secondary to autoimmune hepatitis. Presents with fever, cough, chest pain, and confusion.
He has been compliant with his TMP/SMX and valganciclovir prophylaxis.

*He has lots of pigeons around his apartment*

Back 32

*Cryptococcus infection

Front 33

22 yo f with AML undergoing induction chemotherapy treatment. Presents with fever and a skin lesion on her right calf.

Back 33

*Neutropenia
*At risk for bacterial and fungal infections
*Ecthyma gangrenosum, pseudomonas, zygomycosis, aspergillus -- lots of options here.
*This one is actually pseudomonas

Front 34

29 yo female s/p allogeneic bone marrow transplantation for AML 28 days ago. Not yet engrafted. Developed progressive fever, chest pain and cough.

Back 34

-Aspergillus
-halo sign around the lesion

Front 35

55 yo m s/p allogeneic bone marrow transplantation 150 days ago, c/b GVHD for which he remains on treatment with tacrolimus and low dose prednisone.
Presents with fever and cough productive of yellow sputum. Patient has a sulfa allergy but has been compliant with his atovaquone and acyclovir prophylaxis.

Back 35

-Nocardia
-Gram stain gives it away.
-Chinese letter-like configuration on gram stain
-cavitations on lung