JC91 (Microbiology) - Neutropenic fever Flashcards
Host immune defense in skin and mucosa?
Physicochemical barrier:
Skin: pH, sIgA, normal flora, osmotic pressure
Mucosa: pH, sIgA, normal flora, bile, digestiveenzymes, lysozyme, flushing/ peristalsis, lactoferrin, peroxidase
Immune defense against microbes in local tissues
Cellular arm of the innate immune response
Infiltration by phagocytes (neutrophil, macrophages, Langhan cells)
Exudation
Local inflammatory response (LIRS)
Examples of 4 pathogens that are not virulent but cause disease in immunocompromised host
Opportunistic: Candida albicans Bacillus cereus Staphylococcus epidermidis Cytomegalovirus (CMV)
Define immunocompromised host
Examples of immunocompromised state
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
Examples of acquired immunocompromised state
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
Major mechanisms in compromising host immunity **
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- Granulocytopenia (neutropenia = commonest, e.g. chemotherapy-induced)
- Cellular immune dysfunction (low CD4 T lymphocytes, e.g. AIDS, immunosuppressives)
- Humoral immune dysfunction (related to antibody, B lymphocytes)
-
Anatomic-barrier damage involving the mucosa/ skin
- Severe burn/ massive trauma
- Chemotherapy-/ radiotherapy-induced mucositis Neutropenic fever most common - Complement deficiency
- Autoantibody against cytokines (e.g. IFN-γ, IL-6, GM-CSF)
- Medical/surgical procedures, indwelling devices, implant devices
- Antimicrobial therapy: Suppress normal flora
- Gastric hypochlorhydria
- Therapeutic biologics
-
Obstruction of conducting systems
- draining from a normally sterile anatomical site to a non-sterile one - Central nervous system dysfunction e.g. aspiration pneumonia
- Major organ dysfunction
- Others:
o Thrombocytopenia
o Malnutrition
o Chronic blood transfusion/ poorly controlled diabetes mellitus
Pathogenesis of chemo-/ radiotherapy induced mucositis and subsequent infection
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
Clinical presentation of chemo/ radiotherapy induced mucositis
- Oral mucositis (sore throat; erythema, ulceration)
- Oesophagitis (retrosternal pain on swallowing)
- Enterocolitis (watery diarrhea)
- Narrowest part of GI tract which undergo frequent distension: cricopharyngeal junction, oesophagogastric junction, ileocecal junction, anus
Sources of bacteria causing chemo/radiotherapy-induced mucositis
o Feces (bacteremia) o Skin (e.g. Hickman catheter exit site) o Air (pulmonary aspergillosis)
Post-chemotherapy neutropenia
- Explain why neutropenic fever must occur if neutropenia is not corrected after weeks
- What determines the recovery of neutrophil count
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…
Neutropenic fever
- Define absolute neutrophil counts for severities of neutropenia
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
First-line investigations for neutropenic fever
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
Neutropenic fever causes and predisposing conditions
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
Neutropenic fever presentation
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
Treatment of neutropenic fever
Oral: Ciprofloxacin + Augmentin
IV:
- Piperacillin/Tazobactam
- Meropenem
+/- Glycopeptide, FLuoroquinolone
Explain how antimicrobial therapy can compromise host immunity and predispose nosocomial infection
Antimicrobial therapy:
o Suppress normal flora (anaerobes, relatively non-invasive)»_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)
Explain how biologics can compromise host immunity and predispose opportunistic infections
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
Types of ductal obstruction that lead to infection
o Urinary (ureter) o Respiratory (e.g. bronchogenic carcinoma partially obstructing a bronchus > stasis of secretions > pneumonia) o Biliary tree
Types of organ failure that lead to infection
cirrhosis (liver failure), uraemia (renal failure), heart failure, chronic obstructive pulmonary disease, Splenectomy
Conditions that lead to iron overload
Why does iron overload increase susceptibility to infection
Chronic blood transfusion/ poorly controlled diabetes mellitus
Siderophilic bacteria infection:
Klebsiella, Yersinia enterocolitica, Salmonella & Rhizopus infections
5 unique features of infection in immunocompromised host vs normal host
- The spectrum of pathogens involved is highly predictable from the specific immune defect
-
Unusual pathogens:
o Ubiquitous organisms (environmental/ normal commensals)
o Reactivation of latent organisms (e.g. Herpes viruses, Toxoplasma, Mycobacterium tuberculosis) - 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) - Polymicrobial infections in severe immunity defects (e.g. bone marrow transplant patients)
- Oncogenic viruses may develop virus associated cancer
3 virus associated cancers
o EBV-related post-transplant lymphoproliferative diseases;
o HHV8-related Kaposi’s sarcoma; or
o HPV-related ano-genital cancers
7 principles in management of immunocompromised host infection
- Recognize specific immune defects
- High clinical suspicion of minimal symptoms (e.g. low grade fever, mental dullness)
- Always sample clinical specimen for microbiological tests
- Early, aggressive empirical antimicrobials before culture results
- Monitor drug therapy for efficacy and side effects
- Monitor paradoxical deterioration during recovery of immune defects
- Consult clinical microbiologist always
Fever
- Temperature definition
- Pathophysiology
- Importance of fever in immunocompromised host
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
List types of sampling and biopsy for Ix of infection in immunocompromised host
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)
Which conditions can present with paradoxical deterioration during recovery of immune defct
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
Prevention measures against infections in immunocompromised host
- Avoid unecessary invasive procedures and antimicrobial therapies
- Treat potential/ established infections before immunosuppressive therapy e.g. dental carries, anal fissures, chronic sinusitis and lung infections…
- Serological screening for latent infections before transplant (e.g. HSV, CMV, HIV, HBV, Toxoplasma)
- Total parenteral nutrition for chemotherapy-induced severe mucositis
Neutropenic fever
Causative organisms
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
Special preventative measures against neutropenic fever
-
Oral prophylactic antibiotics:
E.g. fluoroquinolones, septrin for pneumocystis jerovecii -
Prophylactic antifungal: Azoles
Fluconazole for Candida species
Voriconazole/ posaconazole for yeasts and molds - 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)
Cellular immune dysfunction
(CD4 helper T lymphocyte related) –quantitative and/or qualitative defect
Causes
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
Cellular immune dysfunction
(CD4 helper T lymphocyte related)
Pathophysiology of Th cell dysfunction
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
Cellular immune dysfunction
(CD4 helper T lymphocyte related)
Types of pathogens causing infection
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
Cellular immune dysfunction
(CD4 helper T lymphocyte related)
Preventative measures against infection
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
Cellular immune dysfunction
(CD4 helper T lymphocyte related)
Preventative measures against infection
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
Humoral immune dysfunction
Causes
Pathophysiology of increased susceptibility to infections
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)
Humoral immune dysfunction
Pathogens causing infections
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
Humoral immune dysfunction
Methods for prevention of infection
Chronic lymphocytic leukaemia: passive immunisation – intravenous immunoglobulin (IVIG)
Post-splenectomy/ hyposplenism
Pathophysiology of increased susceptibility to infection
Types of pathogens causing infection
Prevention methods
(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)
Complement deficiency
Increased susceptibility to which infections
Encapsulated bacteria (S. pneumoniae, H. influenzae), esp. Neisseria meningitidis
Name 3 indwelling devices that increase risk of opportunistic infections
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
Pathogens related to indwelling device infections
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.
