Download Immune Compromised Infections

INFECTIONS IN THE
IMMUNOCOMPROMISED HOST
Dr. Mohammad Abdul Matin
MRCP(Ire) MRCP(UK) FACP FRCP(Edin)
Consultant, Internal Medicine
Agenda:
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Introduction
Define Immunity
Types of Immunity
Immunodeficiency states
Infections in the Immunocompromised host
Common causes of infection in Immunocompromised host
Post Transplant Infections
How to approach an immunocompromised patient with
infection
Febrile Neutropenia
Immunocompromised host: An immunocompromised
host is a patient who does not have the ability to
respond normally to an infection due to an
impaired or weakened immune system.
What is Immunity?
Immunity can be defined as protection from infection,
whether it be due to bacteria, viruses, fungi or
multicellular parasites.
Immune system composed of cells and molecules
organized into specialized tissues.
The Immune System:
 1.The Innate Immune System: inborn and operate
throughout life.
 2. The adaptive immune System : changes in
response to the pathogens it encounter
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Non-Immunologic host defense also exists.
Main cells involved in the immune response:
Category Cells
Main function
Special features
Myeloid
Neutrophil
Immunity to bacteria and
fungi
Major 1st line defense
Eosinophils,
mast cells,
basophil
Immunity to parasite
Role in allergy
Monocytes
and
macrophages
Immunity to bacteria and
fungi and parasite
Specialised phagocytes;
cytokines secretion
Lymphoid Dendritic cells
Antigen presentation to T
Lymphocytes
Activate T lymphocytes
B lymphocytes
Antibody production
Receptor for antigen, mature
into plasma cells
T lymphocytes
Orchestrate immune
response against microbes
Have specific receptor for
antigen, CD4 & CD8 type
Other molecules involved in Immunity:
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Complement
Collectins
Pentraxins
Enzymes
Non-immunologic host defense mechanism:
Physical barriers:
-Skin and mucus membrane
- Cough reflex
- Mucosal function
- Urine flow
 Chemical barriers:
 Resistance to pathogens by commensal organism
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Romani et al 2004
Clinical Immunodeficiency:
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Primary Immunodeficiency
Secondary (acquired) Immunodeficiency
Primary Immunodeficiency:
Immune Component
Example of Diseases
Common Infrctions
T lymphocyte deficiency
DiGeorge’s syndrome
Linsteria monocytogen,
Mycobacterium species,
Candida, Aspergillus
species, Cryptococcus
neoformans, HSV, VZV
AIDS/HIV infection
(secondary Immunodeficiency)
Pneumocystis, CMV, HSV,
MAI, Cryptococcus
neoformans, candida
X-linked agammaglobulinemia
Streptococcus pneumoniae,
other streptococci
CVID
Pneumocystis, CMV,
S.Pneoumoniae, H.
Influenzae
Selective IgA deficiency
G. lamblia, Hepatitis virus,
S.Pneoumoniae, H.
Influenzae
B lymphocyte deficiency
Immune Component
Example of Diseases
Common Infrctions
Combined T and B
lymphocyte
Severe Combined
Immunodeficiency
(SCID)
S. aureus, S. pneumoniae, H.
influenzae, candida
albicans, Pneumocystis, VZV,
rubella, CMV
Ataxia Telangiectasia
S. pneumoniae, H.
influenzae, S.aureus,
rubelle, G.lamblia
Wiskot-Aldrich syndrome
Neutrophil defect
Chronic Granulomatous
Disease(CGD)
Leucocyte Adhesion
Defect(LAD)
Chediac Higashi syndrome
DiGeorge's syndrome:
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It the most understood T-cell immunodeficiency disorder
Also known as congenital thymic aplasia/hypoplasia
Associated with hypoparathyroidism, congenital heart
disease, fish shaped mouth.
Defects results from abnormal development of fetus during
6th-10th week of gestation when parathyroid, thymus, lips,
ears and aortic arch are being formed
X-linked a gammaglobulinaemia
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In X-LA early maturation of B cells fails
Affect males
Few or no B cells in blood
Very small lymph nodes and tonsils
No Ig
Small amount of Ig G in early age
Recurrent pyogenic infection
IgA and IgG subclass defeciency
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IgA deficiency is most common
Patients tend to develop immune complex disease
About 20% lack IgG2and IgG4
Susceptible to pyogenic infection
Result from failure in terminal differentiation of B
cells
Common Variable Immunodeficiency (CVID)
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There are defect in T cell signaling to B cells
Acquired a gammaglobulinemia in the 2nd or 3rd
decade of life
May follow viral infection
Pyogenic infection
80% of patients have B cells that are not functioning
B cells are not defective. They fail to receive signaling
from T lymphocytes
Unknown
SEVERE COMBINED IMMUNODEFICENCY
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In about 50% of SCID patients the immunodeficiency
is x-linked whereas in the other half the deficiency is
autosomal.
They are both characterized by an absence of T cell
and B cell immunity and absence (or very low
numbers) of circulating T and B lymphocytes.
Patients with SCID are susceptible to a variety of
bacterial, viral, mycotic and protozoan infections.
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The x-linked SCID is due to a defect in gammachain of IL-2 also shared by IL-4, -7, -11 and 15,
all involved in lymphocyte proliferation and/or
differentiation.
The autosomal SCIDs arise primarily from defects in
adenosine deaminase (ADA) or purine nucleoside
phosphorylase (PNP) genes which results is
accumulation of dATP or dGTP, respectively, and
cause toxicity to lymphoid stem cells
Diagnosis
Is based on enumeration of T and B cells and
immunoglobulin measurement.
Severe combined immunodeficiency can be treated
with bone marrow transplant
Ataxia-telangiectasia:
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Associated with a lack of coordination of movement
(ataxis) and dilation of small blood vessels of the
facial area (telangiectasis).
T-cells and their functions are reduced to various
degrees.
B cell numbers and IgM concentrations are normal
to low.
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IgG is often reduced
IgA is considerably reduced (in 70% of the cases).
There is a high incidence of malignancy, particularly
leukemia in these patients.
The defects arise from a breakage in chromosome
14 at the site of TCR and Ig heavy chain genes
Wiskott-Aldrich syndrome:
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Associated with normal T cell numbers with reduced
functions, which get progressively worse.
IgM concentrations are reduced but IgG levels are
normal
Both IgA and IgE levels are elevated.
Boys with this syndrome develop severe eczema.
They respond poorly to polysaccharide antigens and
are prone to pyogenic infection.
Chronic granulomatous disease (CGD):
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CGD is characterized by marked
lymphadenopathy, hepato- splenomegaly and
chronic draining lymph nodes.
In majority of patients with CGD, the deficiency is
due to a defect in NADPH oxidase that participate
in phagocytic respiratory burst.
Leukocyte Adhesion Deficiency:
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Leukocytes lack the complement receptor CR3 due to
a defect in CD11 or CD18 peptides and consequently
they cannot respond to C3b opsonin.
Alternatively there may a defect in integrin molecules,
LFA-1 or mac-1 arising from defective CD11a or
CD11b peptides, respectively.
These molecules are involved in diapedesis and hence
defective neutrophils cannot respond effectively to
chemotactic signals.
Chediak-Higashi syndrome:
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This syndrome is marked by reduced (slower rate)
intracellular killing and chemotactic movement
accompanied by inability of phagosome and
lysosome fusion and proteinase deficiency.
Respiratory burst is normal.
Associated with NK cell defect, platelet and
neurological disorders
Secondary (acquired) Immunodeficiency:
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Infections(HIV) : T lymphocyte deficiency
Medications: Immunosuppressive drugs, (Corticosteroids,
cyclosporin, tacrolimus, purine analogues-azathioprine, alkylating
agents etc), anti-TNF-alfa monoclonal antibody, cytotoxic anti cancer
drugsOrgan transplant
Other secondary immunodeficiency:
-Acquired neutropenia: myelosuppression by drug or diseases
-Acquired hypogammaglobulinemia: Myeloma, CLL, Lymphoma
- Impairment of defence against capsulated bacteria
especially pneumococcus following splenectomy
- Other diseases: DM, CKD, CLD, Cancer
Effect of corticosteroids on immune function:
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Potent effects on production of pro-inflammatory
cytokines IL-1 and TNF-alfa by monocytes
Blockade of T lymphocytes production of IL-2 and
IFN-GAMA
Reduced activation and migration of a range of
innate and adaptive immune cells.
Infections in
Immunocompromised
Patients:
Infections in Immunocompromised Patients:
Infections usually chronic, severe and recurrent
 Partially responsive
 Organisms are often unusual (opportunistis or
unusual)
Opportunistics organism: usually low virulence but
become invasive in immunodeficient states e.g.
atypical mycobacteria, Pneumocystis Jiroveci,
staphylococcus epidermis
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Fever, neutrophilia may be absent
Onset of symptoms usually sudden and the course is
fulminant.
A high index of suspicion is necessary to diagnose
Common causes of infection in
immunocompromised patients:
Causes
Deficiency
Organisms
Chemotherapy
Myealoablative therapy
Immunosuppresive drugs
Neutropenia
Escherichia coli
Klebsiella pneumoniae
Staph aureus
Staph epidermis
Aspergillus species
Candida species
Causes continue…….
Causes
Deficiency
Organisms
HIV infection
Lymphoma
Myealoablative therapy
Congenital syndrome
Cellular Immune defects
RSV
CMV
EBV
Herpes simplex and zoster
Salmonella species
Mycobacterium species(esp
MAI)
Cryptococcus Neoformans
Candida species
Cryptosporidium
Pneumocystis Jirovecii
Toxoplasma gondi
Causes
Deficiency
Organisms
Congenital syndrome
Chronic Lymphocytic
Leukaemia
Corticosteroids
Humoral immunodeficiency
Hemophylus influenza
Streptococcus pneumonia
Enteroviruses
Cause
Deficiency
Congenital syndrome Terminal
complements
deficiency(C5-C9)
Organisms
N.Meningitis
N.gonorrhoeae
Causes
Surgery
Trauma
Deficiency
Splenectomy
Strep. Pneumoniae
N. Meningitis
H. Influenzae
Malaria
Specific infections associated with HIV:
Fungal Infections:
 Pneumocystis jirovecii
 Cryptococcus
 Candida
 Aspergillus
 Histoplasmosis, blastomycosis , coccidioidomycosis
Protozoal Infections:
 Toxoplasmosis
 Cryptosporidiosis
 Microsporidiosis
 Leishmaniasis
Viral Infections:
HBV & HCV
CMV
Herpes Viruses- Herpes simplex virus, Varicella zoster,
HHV-8(Kaposis Sarcoma)
EBV
HPV
Polyoma Virus(JC virus)
Bacterial Infections
Mycobaterium- MTB, MAI
Post-transplant Infections
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Viral infections: HSV, CMV, VZV
In solid organ transplant ,the most common causative
organism of opportunistic sepsis is CMV with the
exception of Heart transplantation, where it is
toxoplasmosis.
Other causes: Pneumocystis Jirovecii and
reactivation of TB
Post transplantation infections:
Depends on following factors:
 The organ transplanted
 Immunosuppressive regimen used
 Development of rejection or GVHD and the
treatment used,
 Characteristics of both donor and recipient
 Time since transplantation
Phases of opportunistic infections:
 Early period ( <30 days)
- Surgical site/wound infection- usually bacterial
- nosocomial infections- central line infection, pneumonia, Clostridial
difficile infection
 After 30 days: (effect of immunosuppression on cell-mediated
immunity):
- CMV
- EBV
- Polyoma
- Hep B and C
- Legionella species
- opportunistic infections: P. jirovecii, fungal infection
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Late period:(more than few months): opportunistic
infection less common.
-CMV may occur
- EBV associated Post transplant lymphoproliferative
diseases(PTLD)
- Polyoma virus infection
- Bacterial ( Listeria, nocardia)
- Fungal infection:
- CAP
Phases of opportunistic infections in allogenic
hematopoietic stem cell transplant:
Prevention of infection in Transplant recipient:
Prophylactic antibiotics after solid organ transplantation
and hematopoietic stem cell transplantation.
- fluconazole for candida
- fluroquinolones after HSCT
- Trimethoprim-sulfamethoxazole to prevent
Pneumocystis Jirovecii
 Prophylaxis against CMV- ganciclovir or valganciclovir
 Solid organ transplant recipients generally receive all
recommended vaccination before transplantation.
 Hematopoietic stem cell transplant recipient are
revaccinated after immune system reconstitution.
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How to handle/ approach Immunocomprised patient
with infection ?
History: Ask about
 The current symptoms to ascertain the focus of sepsis
 Recurrent infections and if known, investigations
performed so far
 Other medical conditions- DM, Renal failure, HIV,
Haematological malignancy
 Details of any relevant family history
 Medications history- immunosuppressive agent
 alcohol abuse, recreational drug use
 Sexual behaviour
Examination:
 Search for focus of sepsis
 Detailed examination of the system involved
 Temperature chart, BP, HR
 Look for clues to the predisposing condition, such as
stigmata of CLD, CKD, venepuncture marks for
injecting drug use, lymohadenopathy,
hepatosplenomegaly, splenectomy scar, any history
of organ transplant, Central venous lines etc…..
How to manage:
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Early and aggressive antibiotic therapy without
waiting for investigations.
Send Culture sensitivity before starting antibiotics
but therapy should not delayed if investigation is
difficult
Choice of antibiotics according to possible
organism.
Febrile Neutropenia:
Definition: Febrile neutropenia is defined as an
absolute neutrophil count of <500/mm3, with a
single core temperature of > 38.3*C or a persistent
temperature (>1 hour) of >38*C.
Risk factors:
 Most solid tumour chemotherapy
 Leukemia
 Transplant regimen
Diagnosis:
 Physical exam including looking for mucositis, of
catheter site, and of perianal region
 NO PER Rectal Exam allowed- potential risk of
bacterial translocation
 C/S of all specimen
 CxR
Treatment:
 Immediate IV antibiotics- to cover gram negative organism
 IV antibiotics:
- Monotherapy: Ceftazidime, cefepime, Imipenem or meropenem
- 2-drug therapy: aminoglycoside +antipseudomonal B lactum
If Penicillin allergy: levofloxacin + aztreonam or aminoglycoside
 Vancomycin: if hypotyension, indwelling catheter, severe mucositis, MRSA
colonization.
 Empiric antifungal if fever pesist > 72 hours
 Gram –ve coverage should continue umtil Anc >500/mm3
 Low risk patient can be treated as an outpatient oral antibiotics.
 Reverse isolation
 Granulocyte Colony stimulating factor (G-CSF) and GranulocyteMacrophage Colony stimulating factor (GM-CSF) used in high isk patients.
Thanks