Haematology - Neutropenic fever

Question 1

Host immune defense in skin and mucosa?

Answer 1

Physicochemical barrier:
 Skin: pH, sIgA, normal flora, osmotic pressure

 Mucosa: pH, sIgA, normal flora, bile, digestiveenzymes, lysozyme, flushing/ peristalsis, lactoferrin, peroxidase

Question 2

Immune defense against microbes in local tissues

Answer 2

Cellular arm of the innate immune response

 Infiltration by phagocytes (neutrophil, macrophages, Langhan cells)
 Exudation
 Local inflammatory response (LIRS)

Question 3

Examples of 4 pathogens that are not virulent but cause disease in immunocompromised host

Answer 3

Opportunistic: 
Candida albicans
Bacillus cereus
Staphylococcus epidermidis
Cytomegalovirus (CMV)

Question 4

Define immunocompromised host

Examples of immunocompromised state

Answer 4

Compromised host:

• Has >1 significant alterations in body’s natural defense mechanisms (innate & adaptive immunity)
• As a result of underlying diseases & their therapy
• Which predispose the host to severe infections / neoplasia

E.g.:
o Leukaemia, lymphoma
o Organ/ bone marrow transplant, use of immunosuppressives (e.g. steroid, anti-TNF)
o Severe burn, massive trauma
o Alcoholism, under-nutrition & intravenous drug abuse

Question 5

Examples of acquired immunocompromised state

Answer 5

Most common = HIV

From most to least severe:
 BMT
 Solid organ transplant (heart and lung > liver > kidneys)
 Cancers (hematological (leukemia, lymphoma) are more suppressed than the solid tumour)
 Autoimmune disorder
 Chronic diseases/ major organ failure (e.g. liver/ kidney failure)
 Splenectomy
 Malnutrition

Question 6

Major mechanisms in compromising host immunity **

14

Answer 6

1. Granulocytopenia (neutropenia = commonest, e.g. chemotherapy-induced)
2. Cellular immune dysfunction (low CD4 T lymphocytes, e.g. AIDS, immunosuppressives)
3. Humoral immune dysfunction (related to antibody, B lymphocytes)
4. Anatomic-barrier damage involving the mucosa/ skin
   - Severe burn/ massive trauma
   - Chemotherapy-/ radiotherapy-induced mucositis Neutropenic fever most common
5. Complement deficiency
6. Autoantibody against cytokines (e.g. IFN-γ, IL-6, GM-CSF)
7. Medical/surgical procedures, indwelling devices, implant devices
8. Antimicrobial therapy: Suppress normal flora
9. Gastric hypochlorhydria
10. Therapeutic biologics
11. Obstruction of conducting systems
    - draining from a normally sterile anatomical site to a non-sterile one
12. Central nervous system dysfunction e.g. aspiration pneumonia
13. Major organ dysfunction
14. Others:
    o Thrombocytopenia
    o Malnutrition
    o Chronic blood transfusion/ poorly controlled diabetes mellitus

Question 7

Pathogenesis of chemo-/ radiotherapy induced mucositis and subsequent infection

Answer 7

Cytoreductive chemotherapy acts on rapidly replicating cells
(e.g. blood cells, epithelial cells in GIT), e.g. chemotherapy mucositis affecting GI tract

> > Damage to mucosa throughout the alimentary system

> > endogenous bacterial/ fungal flora (or transient flora acquired from hospital environment) translocates across the mucosa

> > seeds the bloodstream and causes the majority of neutropenic fever cases

Question 8

Clinical presentation of chemo/ radiotherapy induced mucositis

Answer 8

1. Oral mucositis (sore throat; erythema, ulceration)
2. Oesophagitis (retrosternal pain on swallowing)
3. Enterocolitis (watery diarrhea)
4. Narrowest part of GI tract which undergo frequent distension: cricopharyngeal junction, oesophagogastric junction, ileocecal junction, anus

Question 9

Sources of bacteria causing chemo/radiotherapy-induced mucositis

Answer 9

o Feces (bacteremia)
o Skin (e.g. Hickman catheter exit site)
o Air (pulmonary aspergillosis)

Question 10

Post-chemotherapy neutropenia

• Explain why neutropenic fever must occur if neutropenia is not corrected after weeks
• What determines the recovery of neutrophil count

Answer 10

Neutrophil half-life is only 8 hours
Neutrophil count is maintained by bone marrow reserves for up to 2 weeks
If WBC does not return to normal, then mucositis and infection will occur during neutropenic state

Determinants of neutrophil recovery:
- Intensity of chemotherapy
- Hematopoietic stem cell function and proliferation rate to re-populate BM
- Type of chemotherapy affects quality (function) of neutrophils: O2-dependent
microbicidal activity, complement receptor, adhesiveness, motility,
chemotaxis, loss of sialic acid…

Question 11

Neutropenic fever

• Define absolute neutrophil counts for severities of neutropenia

Answer 11

Absolute neutrophil count (ANC):
 ANC<1.5:
neutropenia (abnormal)

 ANC<0.5 (<500/μL):
severe neutropenia – rate of infections start to increase

 ANC<0.1 (<100/μL):
profound neutropenia – when most bacteraemia occurr

Question 12

First-line investigations for neutropenic fever

Answer 12

Full Hx & P/E (daily): Focus on SKIN, GIT, RESPIRATORY tract
 Skin, perianal skin (fungal cellulitis/ abscess: pain on defecation), surgical site infections S/S
 Oral, abdomen exam (ask for mucositis, esophagitis, enterocolitis, bowel habits)
 Lung, sinus (Respiratory S/S, Sinusitis S/S e.g. fungal sinusitis from inspiration)

Ix:
 General (CBP, LFT, RFT)
 Blood cultures from central venous catheter through 2 different ports

Abdomen:
 Abdomen CT scan
 stool culture: Add-on Clostridium difficile cytotoxin & culture

Lungs:
 CXR (low risk); CT thorax (high risk)
 BAL for sampling, culture

Others:
 Urine, skin, sputum culture

Question 13

Neutropenic fever causes and predisposing conditions

Answer 13

conditions that decrease neutrophil production or increase neutrophil destruction:
- severe active infections such as sepsis, hepatitis, or tuberculosis
- bone marrow disorders like aplastic anemia or myelofibrosis;
- autoimmune diseases like systemic lupus erythematosus or rheumatoid arthritis.
- cancer treatments such as chemotherapy, radiation therapy, and hematopoietic stem cell transplant (HSCT)

Predisposing conditions:
o Chemotherapy induced mucositis
o Indwelling vascular catheter

Question 14

Neutropenic fever presentation

Answer 14

Fever may be only symptom

Other S/S:
abdominal pain, mucositis of the gastrointestinal tract, and perirectal pain.
complications such as severe sepsis or septic shock

Question 15

Treatment of neutropenic fever

Answer 15

Oral: Ciprofloxacin + Augmentin

IV:
- Piperacillin/Tazobactam
- Meropenem
+/- Glycopeptide, FLuoroquinolone

Question 16

Explain how antimicrobial therapy can compromise host immunity and predispose nosocomial infection

Answer 16

Antimicrobial therapy:
o Suppress normal flora (anaerobes, relatively non-invasive)&raquo_space; flora fails to resist colonization by the more virulent and antibiotic-resistant hospital-acquired organisms (e.g. Pseudomonas aeruginosa, Corynebacterium jeikium, yeasts)

Hospital-acquired organisms: introduced into the patient during hospitalization by:
 Hands of medical personnel
 Various diagnostic/therapeutic procedures (e.g. endoscopy, surgery, nursing activities)

Question 17

Explain how biologics can compromise host immunity and predispose opportunistic infections

Answer 17

Biologics: treat autoimmune diseases, e.g. inflammatory bowel disease, rheumatoid arthritis

MoA:
 Monoclonal antibodies against cytokine, chemokine (e.g. anti-TNF [infliximab], anti-IL-2, anti-IL-6 receptor, anti-IL-12/IL-23)
 Kinase inhibitors of the JAK-STAT signaling pathway (Ruxolitinib, Tofacitinib)

Result: interfere with the immune response (immunosuppression) – especially intracellular pathogens related to T cell immunity

Question 18

Types of ductal obstruction that lead to infection

Answer 18

o Urinary (ureter)
o Respiratory (e.g. bronchogenic carcinoma partially obstructing a bronchus > stasis of secretions > pneumonia)
o Biliary tree

Question 19

Types of organ failure that lead to infection

Answer 19

cirrhosis (liver failure), uraemia (renal failure), heart failure, chronic obstructive pulmonary disease, Splenectomy

Question 20

Conditions that lead to iron overload

Why does iron overload increase susceptibility to infection

Answer 20

Chronic blood transfusion/ poorly controlled diabetes mellitus

Siderophilic bacteria infection:
Klebsiella, Yersinia enterocolitica, Salmonella & Rhizopus infections

Question 21

5 unique features of infection in immunocompromised host vs normal host

Answer 21

1. The spectrum of pathogens involved is highly predictable from the specific immune defect
2. Unusual pathogens:
   o Ubiquitous organisms (environmental/ normal commensals)
   o Reactivation of latent organisms (e.g. Herpes viruses, Toxoplasma, Mycobacterium tuberculosis)
3. Unusual/ non-specific clinical presentation:
   o Absence/ marked blunting of characteristic inflammatory symptoms & signs (subtle presentation)
   o Unusual sites are involved (e.g. perirectal cellulitis in neutropenic patients)
4. Polymicrobial infections in severe immunity defects (e.g. bone marrow transplant patients)
5. Oncogenic viruses may develop virus associated cancer

Question 22

3 virus associated cancers

Answer 22

o EBV-related post-transplant lymphoproliferative diseases;
o HHV8-related Kaposi’s sarcoma; or
o HPV-related ano-genital cancers

Question 23

7 principles in management of immunocompromised host infection

Answer 23

1. Recognize specific immune defects
2. High clinical suspicion of minimal symptoms (e.g. low grade fever, mental dullness)
3. Always sample clinical specimen for microbiological tests
4. Early, aggressive empirical antimicrobials before culture results
5. Monitor drug therapy for efficacy and side effects
6. Monitor paradoxical deterioration during recovery of immune defects
7. Consult clinical microbiologist always

Question 24

Fever

• Temperature definition
• Pathophysiology
• Importance of fever in immunocompromised host

Answer 24

Fever:
Definition:
 Oral temperature >37.6oC >once within a day; or
 (Single oral temperature >38.3oC; or
 (Sustained 38oC >1 hr)

Due to release of pro-inflammatory cytokines from endothelial cells/macrophages (IL1, TNF, IL4,6)

Often the only manifestation of infection in immunosuppressed host (e.g. may not have sore throat, diarrhea)

Blunted by steroid, chemotherapy, NSAID

Question 25

List types of sampling and biopsy for Ix of infection in immunocompromised host

Answer 25

``` clinical specimens for: o Cultures (blood culture = minimal) - Blood cultures from central venous catheter - Urine, skin, sputum - BAL - Stool ``` o Direct microscopy/ visualization (e.g. gram staining, Z-N staining) o Antigen detection (e.g. latex agglutination test for Clostridium difficile, Cryptococcus neoformans)

Question 26

Which conditions can present with paradoxical deterioration during recovery of immune defct

Answer 26

Paradoxical deterioration: e.g. fever, new inflammatory focus, progression of a preexisting inflammatory focus **Immune Reconstitution Inflammatory Syndrome (IRIS):** recovery of CD4 lymphocyte count after antiretroviral treatment) **Myeloid Reconstitution Syndrome**: recovery of ANC after chemotherapy

Question 27

Prevention measures against infections in immunocompromised host

Answer 27

1. **Avoid unecessary invasive procedures and antimicrobial therapies** 2. **Treat potential/ established infections before immunosuppressive therapy** e.g. dental carries, anal fissures, chronic sinusitis and lung infections... 3. Serological **screening for latent infections** before transplant (e.g. HSV, CMV, HIV, HBV, Toxoplasma) 4. **Total parenteral nutrition for chemotherapy-induced severe mucositis**

Question 28

Neutropenic fever Causative organisms

Answer 28

0-30 days after transplant – pathogens from mucosa with high microbial count (e.g. alimentary tract, skin, airway): (Think about quantitative neutrophil defect. Always GPC, GNR, Fungal) Pyogenic bacterial infection  bacteremia: **Gram-positive cocci:**  Staphylococcus epidermidis, S. aureus  Viridans streptococci (esp. S. mitis) (dental plaque)  Enterococcus spp. **Gram-negative bacilli**:  Gut flora (large intestine): Escherichia coli, Klebsiella pneumoniae  Pseudomonas aeruginosa **Fungi:** o Yeasts: Candida spp., Trichosporon spp., Torulopsis spp. o Moulds/ filamentous: Aspergillus, Fusarium spp, Zygomycetes, Mucoraceae Virus: o D0-14: HSV 1&2 o D20-27: HHV 6&7

Question 29

Special preventative measures against neutropenic fever

Answer 29

1. **Oral prophylactic antibiotics:**  E.g. fluoroquinolones, septrin for pneumocystis jerovecii 2. **Prophylactic antifungal: Azoles**  Fluconazole for Candida species  Voriconazole/ posaconazole for yeasts and molds 3. Granulocyte colony stimulating factor (**G-CSF**) to speed up the quantitative and functional recovery of these phagocytes High risk (e.g. bone marrow transplant): **To prevent aspergillosis:**  **Protective isolation rooms** (e.g. high efficiency particulate air (HEPA) filter  **Low-microbe food**  Passive immunisation – **intravenous immunoglobulin (IVIG)**

Question 30

Cellular immune dysfunction (CD4 helper T lymphocyte related) –quantitative and/or qualitative defect Causes

Answer 30

Hodgkin’s disease AIDS childhood acute lymphoblasticleukaemia (ALL) Solid organ transplant, engrafted bone marrow transplants recipients Treatment with steroid, cyclosporin & other cytotoxic (e.g. chlorambucil for CLL) Auto-antibody against INF-γ

Question 31

Cellular immune dysfunction (CD4 helper T lymphocyte related) Pathophysiology of Th cell dysfunction

Answer 31

Helper T lymphocytes fail to activate the macrophage/monocyte by IFN-γ to kill the ingested intracellular pathogens: - Herpes viruses - Toxoplasma gondii - Mycobacterium abscessus Cannot activate CD8+ cytotoxic T lymphocytes/ natural killer cells to kill off virus-infected host cells

Question 32

Cellular immune dysfunction (CD4 helper T lymphocyte related) Types of pathogens causing infection

Answer 32

Viruses: - CMV, HSV, VZV, HHV6,7, EBV, respiratory viurses, HPV Intracellular bacteria: Mainly aerobic Gram-positive rods: - Listeria monocytogenes - Nocardia, Rhodococcus - Mycobacterium (both TB, MOTT) Gram-negative rods: - Salmonella spp., - Burkholderia pseudomallei, - Legionella Fungi: Yeast: Pneumocystis jirovecii (carinii; PCP), Cryptococcus neoformans (meningitis), Microsporidia Mould: Aspergillus species Dimorphic fungi: Penicillium marneffei, Histoplasma, Coccidioides Parasites Protozoa: Toxoplasma gondii, Cryptosporidum, Cyclospora, Isospora Helminth: Strongyloides, stercoralis

Question 33

Cellular immune dysfunction (CD4 helper T lymphocyte related) Preventative measures against infection

Answer 33

**Prophylactic antiviral:**  Acyclovir for HSV  Ganciclovir for CMV  Entecavir for HBV **Prophylactic antifungal:**  Voriconazole/ posaconazole for yeasts and molds  Septrin for PCP **Prophylactic antiparasitic:**  Septrin for Toxoplasma gondii Some bone marrow transplant patients:  **Passive immunisation** – intravenous immunoglobulin (IVIG)  Adoptive transfer of **virus specific ex-vivo expanded T lymphocytes** for preventing or treating PTLD/ resistant CMV/ adenovirus infections

Question 34

Cellular immune dysfunction (CD4 helper T lymphocyte related) Preventative measures against infection

Answer 34

Prophylactic antiviral:  Acyclovir for HSV  Ganciclovir for CMV  Entecavir for HBV Prophylactic antifungal:  Voriconazole/ posaconazole for yeasts and molds  Septrin for PCP Prophylactic antiparasitic:  Septrin for Toxoplasma gondii Some bone marrow transplant patients:  Passive immunisation – intravenous immunoglobulin (IVIG)  Adoptive transfer of virus specific ex-vivo expanded T lymphocytes for preventing or treating PTLD/ resistant CMV/ adenovirus infections

Question 35

Humoral immune dysfunction Causes Pathophysiology of increased susceptibility to infections

Answer 35

```  Chronic lymphocytic leukaemia  Multiple myeloma  Rituximab  Agammaglobulinaemia  Splenectomized patients (including functional asplenia) ```  Decreased opsonising antibody production; or  Clearing of immune complexes (Note: B cells need activation by CD4 helper T cells, hence mixed immunodysfunction are common)

Question 36

Humoral immune dysfunction Pathogens causing infections

Answer 36

``` Increased risk of sepsis from:  Encapsulated bacteria: o Streptococcus pneumoniae o Haemophilus influenzae type b o Neisseria meningitidis o Capnocytophaga canimorsus (e.g. children, licked by dogs) ```  Other bacteria: Salmonella  Protozoa: Babesia microti (children)  Plasmodium

Question 37

Humoral immune dysfunction Methods for prevention of infection

Answer 37

Chronic lymphocytic leukaemia: passive immunisation – intravenous immunoglobulin (IVIG)

Question 38

Post-splenectomy/ hyposplenism Pathophysiology of increased susceptibility to infection Types of pathogens causing infection Prevention methods

Answer 38

(Spleen is critical in clearing/ filtering bacteraemic organisms which an individual has no prior contact and is non-immune)  Cannot clear encapsulated bacteria  Cannot produce opsonizing antibody (IgM), opsonins (tuftsin, properdin) ``` Increased risk of sepsis from:  Encapsulated bacteria: o Streptococcus pneumoniae o Haemophilus influenzae type b o Neisseria meningitidis o Capnocytophaga canimorsus (e.g. children, licked by dogs)  Other bacteria: Salmonella  Protozoa: Babesia microti (children)  Plasmodium ``` Prevention: With/before splenectomy: active immunisation – pneumococcal vaccine (especially children)

Question 39

Complement deficiency Increased susceptibility to which infections

Answer 39

Encapsulated bacteria (S. pneumoniae, H. influenzae), esp. Neisseria meningitidis

Question 40

Name 3 indwelling devices that increase risk of opportunistic infections

Answer 40

a) Implanted vascular catheters (e.g. Hickman)  Exit site infections (erythema, dirty granuloma)  Tunnel infections  Catheter-related bacteraemia/ fungaemia b) Foley’s catheter - Urinary tract infection c) Endotracheal tube  Pneumonia  Sinusitis

Question 41

Pathogens related to indwelling device infections

Answer 41

``` a) Implanted vascular catheters (e.g. Hickman)  S. epidermidis  S. aureus  Bacillus spp.  Candida spp. ``` b) Foley’s catheter UTI  Aerobic Gram-negative bacilli: Enterobacteriaceae, Vibrionaceae and other genera, non-fermenters, etc.  Enterococcus c) Endotracheal tube  Aerobic Gram-negative bacilli: Enterobacteriaceae, Vibrionaceae and other genera, non-fermenters, etc.