INFECTIONS IN THE IMMUNOCOMPROMISED HOST

Dr. Mohammad Abdul MatinMRCP(Ire) MRCP(UK) FACP FRCP(Edin)

Consultant, Internal Medicine

Agenda:

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

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:

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

Romani et al 2004

Clinical Immunodeficiency:

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

B lymphocyte deficiency

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

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:

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

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

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)

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

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.

The x-linked SCID is due to a defect in gamma-chain 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

DiagnosisIs based on enumeration of T and B cells

and immunoglobulin measurement.

Severe combined immunodeficiency can be treated with bone marrow transplant

Ataxia-telangiectasia:

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.

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:

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.

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.

Chronic granulomatous disease (CGD):

Leukocyte Adhesion Deficiency:

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:

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:

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 drugs-

Organ 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:

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 Immunocompromis

ed 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

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

ChemotherapyMyealoablative therapyImmunosuppresive drugs

Neutropenia Escherichia coliKlebsiella pneumoniaeStaph aureusStaph epidermisAspergillus speciesCandida species

Causes continue…….

Causes Deficiency Organisms

HIV infectionLymphomaMyealoablative therapyCongenital syndrome

Cellular Immune defects

RSVCMVEBVHerpes simplex and zosterSalmonella speciesMycobacterium species(esp MAI)Cryptococcus NeoformansCandida speciesCryptosporidiumPneumocystis JiroveciiToxoplasma gondi

Causes Deficiency Organisms

Congenital syndromeChronic Lymphocytic LeukaemiaCorticosteroids

Humoral immunodeficiency

Hemophylus influenzaStreptococcus pneumoniaEnteroviruses

Cause Deficiency Organisms

Congenital syndrome

Terminal complements deficiency(C5-C9)

N.MeningitisN.gonorrhoeae

Causes Deficiency

SurgeryTrauma

Splenectomy Strep. PneumoniaeN. MeningitisH. InfluenzaeMalaria

Specific infections associated with HIV:

Fungal Infections: Pneumocystis jirovecii Cryptococcus Candida Aspergillus Histoplasmosis, blastomycosis ,

coccidioidomycosis

Protozoal Infections: Toxoplasmosis Cryptosporidiosis Microsporidiosis Leishmaniasis

Viral Infections:HBV & HCVCMVHerpes Viruses- Herpes simplex virus, Varicella

zoster, HHV-8(Kaposis Sarcoma)EBVHPVPolyoma Virus(JC virus)Bacterial InfectionsMycobaterium- MTB, MAI

Post-transplant Infections

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

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.

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:

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 lactumIf 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 Granulocyte-

Macrophage Colony stimulating factor (GM-CSF) used in high isk patients.

Thanks