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INFECTIONS IN THE IMMUNOCOMPROMISED HOST Dr. Mohammad Abdul Matin MRCP(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 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: 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 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: 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. Chronic granulomatous disease (CGD): 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: 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 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: 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 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 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 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