SPR L16 Infections in the Immunocompromised Host

Question 1

Learning Outcomes

Answer 1

• Host defence overview
• Factors that make a host compromised
• Microbes that infect the compromised host

Question 2

Definitions

Define the following…

1. Pathogen
2. Primary Pathogen
3. Opportunisitc Pathogen

Answer 2

1. a micro-organism causing disease
2. common cause of disease in healthy non-immune hosts e.g. S. aureus, S. pneumoniae
3. rare cause of disease in healthy individuals, causes serious disease in compromised hosts e.g. Pseudomonas aeruginosa, Pneumocystis jirovecii,

Question 3

Source of infection

Outline the following sources

1. Endogenous
2. Exogenous

Answer 3

1. Micro-organisms originating from the patient’s own body which cause harm when they move to another body site
2. Micro-organisms originating from an external source (e.g. other human) which are transmitted by a variety of possible mechanisms to the host, eg. Direct contact, airborne route etc.

Question 4

Define a ‘compromised person’

Answer 4

A compromised person is one whose normal defenses against infection are defective

Question 5

What can compromised patients be
infected with?

Answer 5

Pathogens capable of infecting immunocompetent individuals AND Opportunist pathogens

Question 6

Host defence overview

What do the following involve?

1. Innate immunity
2. Adaptive immunity

Answer 6

1. Defences against entry into the body→ physical & chemical factors & normal bacterial flora

Defenses once the microorganism penetrates the body - Soluble factors: lyzozymes- complement- acute phase proteins- IFN AND Cells of innate immunity: phagocytes- NK cells

2. Antibody

T-lymphocytes

Question 7

What may immunodeficiency involve?

Answer 7

The immunodeficiency may involve the innate or adaptive systems and may be primary or secondary

Question 8

Primary immunodeficiencies
(defects in innate immunity)

Give examples

Answer 8

• Phagocytic cells defects eg. Chronic granulomatous disease (CGD) & Leukocyte Adhesion Deficiency (LAD) → recurrent bacterial & fungal infections
• Complement deficiencies => Deficiencies of terminal complement components => severe Neisseria infections

Question 9

Primary immunodeficiencies
(defects in adaptive immunity)

Generally, outline the following

1. T cell defects
2. B cell defects
3. Combined T & B cells deficiency (SCID)

Answer 9

1. viral , fungal & protozoal infections
2. pyogenic infections (pus forming)
3. all kinds of infections

Question 10

Secondary immunodeficiencies
(defects in innate immunity)

How can these arise?

Answer 10

• Disruption of mechanical barriers
  
  • Burns (Damage to mechanical barriers of the body, Abnormalities in neutrophil function, Highly nutritious surface for organisms)
  • Trauma
  • Major surgery
  • Devices or procedures
  • Foreign bodies
• Obstruction → interference with clearance mechanisms → infection
• Malnutrition
  
  • inadequate cell-mediated response
• Infections – immunosuppressive viruses (HIV→ AIDS), measles and many others
• Neoplasia → reduced immunoreactivity
• Splenectomy => phagocytosis of antibody coated bacteria
• Drugs/treatment
  
  • Cytotoxic agents
  • Corticosteroids & antibiotics–Radiation therapy

Question 11

Secondary immunodeficiencies
(defects in innate immunity)

What are the important pathogens involved?

Answer 11

• P aeruginosa : particular problem in these patients
• Staph aureus
• Fungi
• Others

Question 12

Secondary immunodeficiency-
physical factors

Define how the following bring about immunodeficiency

1. Traumatic injury & surgical wound infections
2. In situ devices (prosthetic valves and joints, pacemakers)
3. Compromised clearance mechanism

Answer 12

1. Destroy integrity of body – make it vulnerable to infections, staph. aureus commonest cause of surgical wound infection
2. Gain access during surgery or subsequent bacteremia. Staph. epidermidis is an important pathogen.
3. Ciliary escalator damage, Obstruction of urine flow.

Question 13

Secondary immunodeficiency-
physical factors
Splenectomy

1. What are these patients susceptible to?
2. What actions need to be taken?

Answer 13

1. capsulate bacteria
2. Prevention of infection

• vaccination (preferably before splenectomy)
• Prophylactic antibiotics against Streptococcus pneumoniae

Question 14

Secondary immunodeficiency-
physical factors
Neutropenia

1. What are the causes?
2. Major problem infections with neutropenia are…?
3. What is important to remember?

See picture - where pt drops and levels is unpredictable: important to monitor - daily white cell counts

Answer 14

1. Iatrogenic (Post chemotherapy, Post BMT) Aplastic anaemia
2. Bacterial : gram negative rods & gram positive

Fungal: if neutropenia > 21 days

3. infection or suspicion of infection in a neutropenic patient is an absolute clinical emergency
   
   1. ​Instead of source isolation, protective isolation

Question 15

Secondary immunodeficiency
AIDS infections

1. What does the clinical definition of AIDS include?
2. What has led to a decline in the incidence of these infections in HIV-positive patients?

Answer 15

1. the presence of one or more opportunistic infections
2. The arrival of highly active antiretroviral therapy, or HAART

Question 16

Opportunist infections & tumors in AIDS

Give examples of these…

1. Viruses
2. Bacteria
3. Protozoa
4. Fungi
5. Tumors

Answer 16

see picture

TB

Salmonella - prolonged infections

Kaposi’s Sarcoma - common tumor in AIDs driven by HHV8).

Tumours have an infective origin. See these late. CD4+ count almost non-existent.

Question 17

Secondary immunodeficiency
AIDS infections

Spectrum of infecting organisms relates to what?

Answer 17

to disease progression (CD4 count)*

• 0.5 X 109/l M. tuberculosis
• <0.2 X 109/l , P. jiroveci pneumonia, Toxoplasmosis
• <0.10 X 109/l CMV, MAI
  
  • CD4 count boosted by HAART
  • Rational prophylaxis offered for P. jiroveci pneumonia , Mycobacterium Avium-Intracellulare (MAI), CMV with falling counts
  • (Normal Ratio of CD4:CD8 is 0.9-1.9)

Question 18

Candida (yeast)

What may this cause?

What is candidiais?

Answer 18

site may depend on type of immunodeficiency

• vaginal and oral thrush
• skin infections
• endocarditis

Candidiais

• chronic mucotaneous
• oropharyngeal and esophageal
• gastrointestinal

Disseminated - through GI tract but also intravascular catheter related infections

Question 19

Cryptococcus neoformans (yeast)

Who is this seen in? What does it result in?

Answer 19

• People with impaired cell-mediated immunity
• Lung infections and mengioencephalitis
• Sometimes bone and joints

Question 20

Other Fungi

Outline the following…

1. Histoplasma
2. Aspergillius

Answer 20

1. mainly tropical- ‘histo belt’ central USA, Ohio, Misissippi spores in soil – deposited in alveoli and germinate- fungi and spreads to lymph nodes and then other tissues
2. lung infection but increasingly reported in profoundly neutropenic patients

Question 21

What does Pneumocystis jirovecii
(formerly P carinii) cause?

Answer 21

• Atypical fungus
• Pneumonia
• Cell-mediated immune deficiences
• Hard to diagnose-symptoms resemble other infections or non-infectious diseases

Question 22

Protozoa

Describe the following…

1. Cryptosporidium
2. Isopora Belli

Answer 22

1. Protozoan, animal pathogen, severe chronic diahorrea in the immunocompromised
2. similar organism- in AIDS patients

Question 23

Protozoa-Toxoplasma gondii

1. What is the host?
2. What will it give rise to?

Answer 23

1. Cat
2. Ring-enhancing lesions on CT/MRI scan and

Toxoplasma- IgG antibody

Question 24

Examples of opportunist infections & tumors associated with HIV infection

Give examples

Answer 24

A) Hairy cell leukoplakia (EBV)

(B) Extensive oral candidiasis.

(C) Kaposi’s sarcoma (HHV 8)

(human herpsesvirus 8)

Question 25

**Viruses** List the clinically important viruses in the immunosuppressed

Answer 25

* Herpesviruses - reactivate when immunosuppressed. * CMV * Prophylaxis given for CMV (can be own virus or e.g acquired from transplant). * EBV- tumour development-non-Hodgkin’s lymphomas.

Question 26

**CMV in the transplant setting** CMV is an issue in both Solid organ and Bone marrow (Stem cell) transplants in the weeks or months post transplant How does it present?

Answer 26

CMV infection post transplant: * leukopenia (unexplained) * shivery, fever, hepatitis * occasionally retinitis * very occasionally pneumonitis

Question 27

**CMV in the transplant setting** CMV is an issue in both Solid organ and Bone marrow (Stem cell) transplants in the weeks or months post transplant 1. Which type of infection is associtated with more severe infections? 2. What is tested? 3. What is the most risky situation?

Answer 27

1. Primary infection 2. “CMV status” IgG positive or negative * Approximately 50 % of the adult population are CMV positive (CMV status positive i.e. IgG positive). Infected at somestage at the past. Still latent because it is a herpesvirus. If an organ donor - CMV will be in the organ and will be transplanted in the organ. * Once infected, virus is in all tissues for rest of life. And will be in any harvested organ. 3. **For solid organ transplants Donor positive Recipient negative is most risky situation =\> primary CMV infection via the graft.**

Question 28

**Solid Organ vs Bone marrow** 1. What is the most severe situation now?

Answer 28

1. Most severe situation is different Solid organ = Donor CMV positive, Recipient CMV negative Bone marrow transplant = Donor CMV negative, Recipient CMV positive Need to think with respect to the immune system! =\> primary infection of a naïve bone marrow

Question 29

**Solid Organ vs Bone marrow** 1. What is the most severe situation now?

Answer 29

1. Most severe situation is different Solid organ = Donor CMV positive, Recipient CMV negative Bone marrow transplant = Donor CMV negative, Recipient CMV positive Need to think with respect to the immune system! =\> primary infection of a naïve bone marrow

Question 30

**Diagnosis of CMV disease post transplant** How is CMV diagnosed here?

Answer 30

CMV PCR (on blood sample) * Quantitative (copies per ml or IU per ml) * Measures amount of CMV DNA in blood * Also used for monitoring – response to treatment 2 key tests: **“CMV Status”** = CMV IgG – used to look at donor and recipient prior to transplant **CMV PCR** – used to diagnose and monitor CMV infection post transplant

Question 31

**CMV in transplant setting** 1. How is it treated? 2. What does prophylaxis involve?

Answer 31

1. **ganciclivir** (IV) used to treat symptomatic CMV infection 2. oral **valganciclovir** (can be given for 3 or 6 months post transplant in risky situations – donor recipient CMV mismatch) - Aim is to delay the CMV infection and make it clinically less severe

Question 32

What other Viruses are important in immunosuppressed patients?

Answer 32

**Respiratory viruses** * RSV, parainfluenza, influenza, adenovirus, measles. **Polyomaviruses** (BK, JC)- JC causes progressive multifocal leucoencephalopathy (PML). Slow progressive –multiple neurological signs.

Question 33

**Case presentation** An 8-year-old girl with sickle cell disease combined with ß-thalassemia received an allogeneic hematopoietic stem cell transplant. Cyclosporine and methotrexate were given as prophylaxis against graft-versus-host disease. A suspension of cotrimoxazole and amphotericin B was given as anti-infective prophylaxis. Seventeen days after transplant, patient developed persistent fever unresponsive to broad-spectrum antibacterial agents while the patient was still profoundly neutropenic (\< 0.1 x 109/L) so intravenous amphotericin B (30 mg) was empirically added. Germ tube–producing organism was isolated from two sets of blood cultures drawn 6 hours apart from a peripheral vein and from two sets through the central venous catheter. Once the results of the positive blood cultures became known, 5-flucytosine (100 mg/kg) was added to the regimen. 1. What is the likely diagnosis of this condition? 2. How may the girl have become infected?

Answer 33

1. Disseminated candidiasis 2. Central Intravascular catheter