Microbiology JC091: Fever After Chemotherapy: Infections In Immunocompromised Hosts Flashcards
Chemotherapy on Rapidly dividing cells
- BM cells producing formed elements —> suppressed —> ***Pancytopenia
- Alimentary tract —> **Mucositis, Esophagitis, **Enterocolitis
Bacteria / Yeast in GI tract can go into submucosa / even into bloodstream + Neutrophils suppressed (∵ pancytopenia)
—> Bacteraemia / Fungaemia
—> High fever
Clinical picture: ***Neutropenic fever
What is fever
Definition:
- Oral temp >37.6oC >=once within a day
- **single oral temp >38.3oC / **sustained 38oC >1 hour
- Often the only manifestation of infection in ***immunosuppressed host
- Due to release of ***pro-inflammatory cytokines from endothelial cells / macrophages (IL1, TNF, IL4, 6)
- Blunted by steroid, chemotherapy, NSAID
***Neutropenic fever
Absolute neutrophil count (ANC)
- **ANC <1.5: Neutropenia
- **ANC <0.5: Severe neutropenia
- ANC <0.1: Profound neutropenia
—> lower ANC, longer duration —> higher susceptibility to infection
Post-chemotherapy neutropenia:
- Nadir: **7-14 days (∵ BM reserve of neutrophil)
- Duration: short to long (14-28 days)
- 14-28 days: **Mucositis + **Low neutrophil + **Catheter nutrition (portal of entry) + ***Pulmonary infiltrate (e.g. fungal spores)
—> Bacteraemia / Fungaemia
—> highest risk of neutropenic fever
- 100% of post-chemotherapy patients developed fever if neutropenic for 3 weeks
Neutrophil:
- ***Short t1/2 intravascular (deplete quickly)
- replaced by marrow reserve (Metamyelocyte —> Myelocyte —> Promyelocyte —> Myeloblast) (7 days)
Approach to management of Neutropenic fever
- Full history + P/E (**daily)
- skin
- **oral (mucositis)
- **lung (↓ air entry, crepitations)
- **abdomen (tenderness)
- ***perianal (cellulitis, abscess)
- Hickman exit
- BM biopsy / aspiration site
- nasal sinus (tenderness) - Investigations
- CBP, LRFT
- **blood culture from central venous catheter if infected catheter suspected (through 2 different ports —> central venous catheter + peripheral venous puncture —> difference in **time to positivity of culture) - ***Start empirical broad spectrum antibiotics (before culture results come back)
- ***CXR (low risk patients), CT lung (high risk / symptomatic)
- Abdomen CT scan
- abdominal pain, tenderness, diarrhoea -
**Stool for **C. difficile cytotoxin + culture
- for +ve diarrhoea - Urine, Skin swab, Sputum, BAL for testing
- only if positive symptoms / lesions
Compromised vs Immunocompromised host
Compromised:
- >=1 significant defects in body’s natural defence mechanisms (Innate/ Adaptive)
—> as a result of **underlying disease / **therapy
—> predispose host to severe **infections / **neoplasia
- e.g. leukaemia, lymphoma, organ / BM transplant, use of immunosuppressives e.g. steroid, anti-TNF as anti-inflammatory, severe burn, massive trauma, alcoholism, under-nutrition, IV drug use
Immunocompromised:
- defects in immune system (Innate / Adaptive)
- can be demonstrated by laboratory tests (e.g. **reversed T4/T8 ratio in AIDS, **hypogammaglobulinaemia with CLL)
3 sided interaction:
1. Microbes (virulence)
- highly virulent organisms: Rabies virus, Bacillus anthracis, Dimorphic fungi (severe infection regardless of hosts immunity)
- low virulent organisms: CMV, Bacillus cereus, Candida albicans (can cause infection in immunocompromised host)
2. Host defence mechanism
3. Therapeutic drugs + procedures (immunosuppression, antibiotics, indwelling catheter)
***Classification of Immunocompromised hosts
Congenital immunodeficiency
Acquired immunodeficiency (more common)
- HIV
- Non-HIV
—> Transplantation —> **BM transplant (more severe) vs Solid organ transplant (less severe)
—> Non-transplantation
——> Malignancy —> **Haematological (most severe e.g. leukaemia, MM, lymphoma (less severe)) vs Solid tumour (usually during late stage, sometimes immunosuppression is due to chemotherapy)
——> Non-malignancy —> Autoimmune disease (e.g. SLE), Chronic diseases (e.g. uraemia, cirrhosis, COPD), Splenectomy
***Clinically important mechanisms predisposing compromised host to infections
- Neutropenia (***Granulocytopenia) + other neutrophil dysfunction
- Cellular immune (***Helper T lymphocyte related) dysfunction
- ***Humoral immune (B lymphocyte-Ab related) dysfunction
- ***Anatomic-barrier damage (involving mucosa / skin)
- e.g. severe burn, massive trauma, chemotherapy, radiotherapy induced mucositis - Medical procedures, Indwelling devices, ***Antimicrobial therapy (kill normal flora —> predispose to colonisation by dangerous hospital flora which are antimicrobial resistant)
- ***Obstruction of conducting systems draining from normally sterile anatomical site to a non-sterile site
- e.g. urinary, respiratory (bronchogenic carcinoma partially obstructing a bronchus causing stasis of secretions —> pneumonia), biliary tree - ***Central NS dysfunction
- e.g. stroke —> loss of gag reflex / coughing in brainstem lesions —> aspiration + pneumonia - ***Major organ dysfunction (e.g. cirrhosis, uraemia, heart failure, COPD, gastric hypochlorhydria)
- Thrombocytopenia
- ∵ ↓ platelet function - Undernutrition with weight <75% of ideal body weight
- ↓ neutrophil + T cell function - Fe deficiency
- ↓ neutrophil + T cell function
- Fe overload also predispose to Klebsiella, Yersinia enterocolitica, Salmonella, Rhizopus infections - ***Complement deficiency (innate humoral dysfunction)
- ***AutoAb against cytokines (e.g. IFNγ)
- Therapies
- Therapeutic Ab
- **Biologics against cytokine, chemokine (e.g. Anti-TNF (Infliximab), Anti-IL2, Anti-IL6 receptor, Anti-IL12, IL23)
- **Kinase inhibitor of JAK-STAT signaling pathway (Ruxolitinib, Tofacitinib)
—> predispose to wide variety of microbial infections esp. intracellular pathogens related to T cell immunity
Recognition of immunocompromised states
Importance:
1. Spectrum of pathogens highly ***predictable from specific defect
- ***Unusual pathogens may be involved
- ubiquitous organisms can become opportunistic pathogens (e.g. Aspergillus, Candida, Pneumocystis)
- reactivation of latent organisms (e.g. Herpes virus, Toxoplasma, M. Tb) - Infection can be **rapidly fatal
- should have high index of suspicion, rapid + accurate microbiological diagnosis from relevant specimens —> **early + ***aggressive therapy - Clinical presentation of illness tend to be **unusual + **non-specific + ***subtle
- absence / marked blunting of characteristic inflammatory S/S (e.g. Leukocytosis, Pus formation, Meningeal signs)
- unusual sites may be involved (e.g. perirectal cellulitis in neutropenic patients) - ***Polymicrobial infections often present
- esp. when immune defects multiple / severe (e.g. BM transplant patients) - Patients carrying oncogenic virus may develop virus-associated cancer with prolonged immunosuppression
- **EBV-related: Post-transplant lymphoproliferative diseases
- **HHV8-related: Kaposi’s sarcoma
- HPV-related: Anogenital cancers
Common pathogens causing serious infections in immunocompromised hosts
Neutropenia (neutrophil dysfunction):
1. Bacteria
- Gram +ve: **S. epidermidis, **S. aureus, Strept. viridans (esp. mitis), Enterococcus spp.
- Gram -ve: **E. coli, K. pneumoniae, **P. aeruginosa
- Yeast
- ***Candida spp., Trichosporon spp. Torulopsis spp. - Filamentous fungi
- ***Aspergillus, Mucor, Fusarium
Cellular immune dysfunction (T helper cell):
1. Bacteria (intracellular bacteria that attack RES)
- Listeria monocytogenes, **Salmonella spp., **Tuberculous + ***NTM spp., Nocardia, Legionella, Rhodococcus, Burkholderia pseudomallei
- Fungi
- Cryptococcus neoformans, **Pneumocystis jirovecii (carinii), **Penicillium marneffei, other Dimorphic fungi (Histoplasma, Coccidioides) - Virus
- **HSV, **VZV, CMV, EBV, HPV, Resp viruses - Protozoa
- ***Toxoplasma gondii, Cryptosporidium, Microsporidia, Cyclospora, Isospora - Helminth (only extracellular pathogen)
- Strongyloides stercoralis
Humoral immune dysfunction:
1. **Encapsulated Bacteria (cannot be recognised unless opsonised by Ab)
- **Streptococcus pneumoniae, ***Haemophilus influenzae, Capnocytophaga canimorsus
- Protozoa
- Babesia microti
NB: Immunocompromised host equally prone to community-acquired infections + greater severity:
- Giant cell pneumonitis by measles virus in leukaemic child
- RSV pneumonia + respiratory failure in BM transplant patients
Neutropenia
Causes:
- **Leukaemia
- Aplastic anaemia
- **Intensive therapy with cytotoxic / irradiation
- **BM transplantation
- **Patients with neutrophil dysfunction due to genetic defects
Incidence + Severity of infection inversely proportional to ANC
- ANC <1500 / uL: Abnormal / Neutropenia
- ANC <500 / uL: Severe neutropenia —> Rate of infection ↑
- ANC <100 / uL: Profound neutropenia —> Bacteraemia
Neutropenic fever:
- single oral temp >38.3oC / sustained 38oC >1 hour in a patient with ANC <=500
Pathogenesis:
- also depends on presence of other predisposing factors e.g. mucositis, indwelling vascular catheter
- Chemotherapy-induced mucositis —> damage mucosa throughout GI tract —> allow bacterial / fungal translocation across mucosa —> endogenous bacterial / fungal flora seeds bloodstream (Bacteraemia) —> neutropenic fever
Common sites of infection:
- Periodontium
- **Oropharynx
- **Lungs
- Distal esophagus
- **Colon
- **Perianal area
- Skin
Causative organisms:
- ***Endogenous flora
- Transient flora acquired from hospital environment
Cellular immune dysfunction
T lymphocyte quantitative / qualitative defect:
- **Hodgkin’s disease
- **AIDS
- Childhood acute lymphocytic leukaemia (ALL)
- **Solid organ transplant
- Engrafted BM transplant recipients
- **Steroid, Cyclosporin, cytotoxics treatment
- ***AutoAb against IFNγ
Pathogenesis:
- Failure of **Helper T cell to activate macrophage / monocytes to kill ingested **intracellular pathogens
Causative organisms:
- **Intracellular pathogens (except Strongyloides)
- common pathogens that cause significant but seldom life-threatening disease in immunocompetent host and become latent later (e.g. Herpes viruses, Toxoplasma gondii)
- specific organism may occur more frequently in particular groups of patients (e.g. **Herpes zoster in patients with Hodgkin lymphoma after recent radiotherapy, ***Mycobacterium abscessus infection in patients with AutoAb against IFNγ)
Humoral immune dysfunction
Causes:
- **CLL
- **Multiple myeloma
- ***Agammaglobulinaemia
Pathogenesis:
- ↓ **Opsonising Ab production / **Clearing of Immune complexes in MM, CLL, (splenectomised including **asplenia patients)
—> ↑ risk of sepsis from **encapsulated organisms (e.g. Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis, Capnocytophaga canimorsus, Babesia spp.)
Causative organisms:
- ***Encapsulated organisms (e.g. Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis, Capnocytophaga canimorsus, Babesia spp.)
- Extracellular pathogens (e.g. Aspergillus)
Complement deficiency
Deficiency of membrane attack complex —> predispose to recurrent disseminated infected by **N. gonorrhoea / **N. meningitidis
Splenectomy
Pathogenesis:
- Spleen is critical in clearing ***encapsulated bacteraemic organisms which an individual has no prior contact and is non-immune
Causative organism:
- Overwhelming sepsis due to **encapsulated organisms
—> S. pneumoniae, H. influenzae, N. meningitidis, Capnocytophaga, **Babesia spp. more common in ***splenectomised children (occasionally adults)
- Others: Salmonella, Plasmodium
Medical procedures + Indwelling devices
Pathogenesis:
- Indwelling catheters, endoscopic / surgical procedures that disrupt / bypass mucosa / skin —> predispose patients to **various infections
- Difficult to eradicate without removal of device (∵ bacteria + associated glycocalyx from adherent bacterial **biofilms on the devices)
- Implanted vascular catheters
- exit site infection / tunnel infection / catheter related bacteraemia, fungaemia
- S. epidermidis, S. aureus, Bacillus spp., Candida spp. - Foley catheter
- UTI
- Aerobic Gram -ve bacilli, Enterococcus - Endotracheal tube
- Pneumonia, Sinusitis
- Aerobic Gram -ve bacilli
Effect of antimicrobial therapy on normal flora
Pathogenesis:
- Antibiotics can suppress relatively non-invasive normal flora (esp. **anaerobes which tend to resists colonisation by antibiotic-resistant hospital-acquired organisms e.g. P. aeruginosa, Corynebacterium jeikium, yeasts)
—> During hospitalisation
—> Inadvertently introduce bacteria into patient by hands of medical personnel + various diagnostic / therapeutic procedures e.g. endoscopy, surgery, nursing activities
—> **Established coloniser can produce ***life-threatening infections (difficult to treat + require use of more toxic + expensive antibiotics)
Management of infections in immunocompromised hosts
- Recognition of specific immune defects in host
- High index of suspicion about infections even symptom is ***minimal (e.g. low grade fever, mental dullness)
- early imaging e.g. CT, PET/CT - Appropriate clinical specimens (e.g. blood, BAL) sent for
- Direct visualisation (e.g. Gram stain, ZN stain)
- Ag detection (e.g. latex agglutination test for C. difficile, Cryptococcus neoformans)
- Culture - Close cooperation with clinical microbiology laboratory esp. when unusual pathogens suspected (e.g. pneumocystis, fungus, nocardia, legionella)
-
**Early aggressive + empirical therapy
- indicated in some patients before definitive culture results available (e.g. IV **imipenem in febrile neutropenic patients) - Temporary replacement of deficient immune component
- ***Buffy coat (neutrophil) transfusion to combat bacterial infection not responding to antibiotics in patients with persistent neutropenia - ***Ex-vivo expanded T lymphocytes for adoptive transfer of virus-specific immunity
- treat drug resistant viral infections / virus-induced neoplasia
- EBV-related post-transplant lymphoproliferative disease, late antiviral-resistant CMV disease, disseminated adenoviral disease
- same strategy can be used in prevention of such infections in high risk transplant patients - Monitoring
- maximal efficacy of antibiotics with minimal SE e.g. drug assays -
Immune Reconstitution Inflammatory Syndrome (IRIS)
- Paradoxical deterioration with fever + new inflammatory focus / progression of preexisting inflammatory focus can happen in temporal relationship to the recovery immune defect e.g. recovery of CD4 count after antiretroviral treatment / recovery of ANC after chemotherapy (Myeloid reconstitution syndrome)
Prevention of infections in immunocompromised host
-
**No unnecessary invasive procedures / Antimicrobial therapy
- prevent impairment of host’s defence / any disturbance of ecological balance of patient’s microbial flora
- **shorter duration of Antimicrobial therapy if appropriate - ***Potential / Established sources of infection should be sought + ideally treated before any immunosuppressive therapy is instituted
- e.g. tooth decay, chronic sinusitis, asymptomatic bacteriuria, anal fissures, recurrent boils, ingrown toe nails, chronic Salmonella carriage - ***Serological screening for latent infections in donor / recipient before transplantation (e.g. HSV, CMV, HIV, HBV, HCV, Toxoplasma)
- Specific preventive measures in particular groups of patients
- Specific preventive measures in particular groups of patients
- Protective isolation + **low-microbe food
- e.g. **HEPA filter in rooms of BM transplant patients to prevent aspergillosis - Oral prophylactic antibiotics
- e.g. **Fluoroquinolone / Septrin to suppress **aerobic bacteria while **sparing anaerobes
- **Selective decontamination —> prevent overgrowth by other aerobic bacteria + yeasts
- used in patients expected to have prolonged (>10 days) + profound neutropenic (<100) e.g. BM transplant patients
- unfortunately ↑ antibiotics resistance has severity impair usefulness of this approach - Prophylactic antimicrobial (when such infection is anticipated + life threatening)
- **Aciclovir for HSV / VZV, **Ganciclovir for CMV, **Entecavir for HBV
- **Fluconazole for Candida spp., **Voriconazole / Posaconazole for yeasts + moulds, **Septrin for pneumocystis jirovecii
- ***Septrin for Toxoplasma gondii - ***Active immunisation
- Pneumococcal vaccine (conjugated) + Hib vaccine (conjugated) for patients (esp. children) with / before splenectomy - Passive immunisation (***IVIG)
- in patients with CLL / BM transplant patients with Agammaglobulinaemia - Acceleration of recovery of immune system
- use of ***G-CSF to speed up quantitative + functional recovery of these phagocytes - Total parenteral nutrition
- for patients with chemotherapy-induced severe mucositis to maintain nutritional status - ***Ex-vivo expanded T lymphocytes for adoptive transfer of virus-specific immunity
- prevent drug resistant viral infections / virus-induced neoplasia
- EBV-related post-transplant lymphoproliferative disease, late antiviral-resistant CMV disease, disseminated adenoviral disease
Microbial invasion + Host response
- Adherence to epithelium
- **Skin: pH, osmotic pressure, normal flora, sIgA
- **Mucosa: pH, bile, sIgA, normal flora, digestive enzymes, lysozyme, flushing / peristalsis, lactoferrin, peroxidase - Local infection, penetration of epithelium
- ***Complement: alternative (CRP, MBP) in interstitial fluid —> humoral arm of innate defence - Local infection of tissues
- ***Phagocytes: PMN, macrophages, Langerhans cells
—> Exudation
—> Local inflammatory response syndrome (LIRS) (紅腫痛熱) - Lymphatic spread
- **Cellular immunity: T cells: CTL, CMI
- **Humoral immunity: B cells: IgM, IgG, IgA
- ***NK cells - Adaptive immunity
- Bacteraemia
—> **Acute phase response
—> **Systemic inflammatory response syndrome (SIRS)
