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Infections in the immunocompromised: with particular reference to Haematological malignancy patients Aims & Objectives • To give overview of the types of immunodeficiency and associated infections • Describe clinical presentations of opportunistic infections with emphasis on Haematological patients • List preventative measures employed in transplantation Romani et al 2004 Rare inherited immunodeficiency states • Di George syndrome, SCID associated with T cell defects (PCP, CMV, mycobacteria) • Hypogammaglobulinaemia: B cell defects ( pyogenic infections) • Phagocyte disorders: Chronic granulomatous disorder (Staph aureus, fungal infections) • Complement deficiency states (encapsulated bacteria) Acquired immunodeficiency states • Primary: AIDS, hypogammaglobulinaemia • Secondary: to immunosuppression eg, transplantation Immunocompromised Hosts Leukaemia therapy Bone marr. transplant Myelofibrosis Cyclophosphamide Alcoholism Chr Gr Disease Leukaemia Lymphoma Transplant AIDS Steroids Cyclosporin A Staph epidermidis E coli, klebsiella Pseudomonas Enterococci Candida Herpes Tuberculosis Legionella Nocardia Cryptococcus Pneumocystis CLL Myeloma Splenectomy Complement def Late transplant Pneumococcus Neisseria Mycoplasma Enteroviruses Giardia Categories of transplant patients • Bone marrow/ stem cell transplants • Solid organ transplants -kidney -liver -heart/ heart-lung • Other tissue transplants Bone marrow and stem cell transplantation: why does infection occur? • The underlying disease itself may result in a high risk of infection eg, leukaemia, aplasia • Prior to the transplant the patient needs to be immunosuppressed • There follows a prolonged period of immunocompromise • Graft versus host disease and therapeutic immunosuppression may increase the risk further • General support measures may be complicated by infection eg, indwelling catheters Risk periods for infection after transplantation • Neutropenic phase: generally lasts 3 weeks • 1-3 months: acute immunosuppression • 4-12 months chronic immunosuppression Factors increasing risk of infection during neutropenia • Lack of circulating and tissue neutrophils to phagocytose invading bacteria and fungi • Mucositis due to chemotherapy/irradiation causing breach in mucosal barriers • Indwelling catheter providing portal of entry for skin organisms • Broad spectrum antibiotics reducing colonization resistance Infections complicating the neutropenic period • Bacteraemia: gram negative and gram positive • Herpes mucositis: herpes simplex virus • Invasive mycosis: Candida and Aspergillus Clinical presentations of these infections • Febrile neutropenia: fever greater than 380C for 2 hours or longer. • There may be rigors, drop in blood pressure, septic shock • Herpes: mouth ulceration which may be complicated by bacteraemia by oral bacteria • Candida sepsis; Aspergillus lung infiltrates Approaches to treatment at this stage • Initial empirical therapy with a broad spectrum of intravenous antibiotics • Clinical trials (EORTC studies suggest either beta lactam + aminoglycoside or cephalosporin or carbapenem) support this approach • Failure of fever to resolve by 5 days prompts initiating empirical antifungal therapy eg: amphotericin B • Herpes mucositis treated with acyclovir Algorythm for therapy of febrile neutropenia Broad spectrum antibiotics eg tazocin +gentamicin No reponse in 2-3 days? Change to 2nd line Eg ceftazidime +teicoplanin No response by 5-7 days? Change to antifungal Eg: amphotericin B Blood culture pathogens that we commonly isolate during neutropenia • • • • • Coagulase negative staphylococci Enterobacteria Ps aeruginosa Corynebacteria (JK coryneforms significant) “oddies”: Stenotrophomonas maltophilia, environmental bacteria • Candida Further infectious complications: days 30-100 • Pneumonia: “interstitial” • Bacterial sepsis with prolonged neutropenia • Fungaemia, dissemination, chronic hepatic candidiasis • Reactivation of latent viruses eg, CMV, BK THE IMPORTANCE OF PNEUMONIA • A major killer in both developed and developing countries • Accounts for more deaths than other infectious diseases • Mortality rates vary but can be as high as 25% • A major cause of death in children in developing countries • Incidence here (?) 2-5/1000 population TYPES OF COMMUNITY ACQUIRED PNEUMONIA • In a previously healthy individual • Here the infection may have been acquired by droplet spread from another • Alternatively, in patients with underlying diseases endogenous colonizing bacteria may be the cause • These are more likely to be resistant to firstline antibiotics MICROBIOLOGICAL CAUSES (%) OF COMMUNITY ACQUIRED PNEUMONIA FROM HOSPITAL BASED STUDIES (N=3,000) • • • • • • • • • No cause found Pneumococcus Influenza virus Legionella spp*. Haem. Influenzae Other viruses Psittacosis/Q fever Gram neg. bacilli Staph aureus* CAP Severe CAP 36 25 8 7 5 5 33 27 2.3 17 5 8 3 2 2.7 2 2 5 TYPICAL GRAM APPEARANCE OF Strep pneumoniae IN SPUTUM GRAM POSITIVE CHAINS DIPLOCOCCI Streptococcus pneumoniae (pneumococcus) • A gram positive coccus that grows in short chains • Alpha haemolytic on blood agar • Identified by its susceptibility to optochin • Polysaccharide capsule confers pathogenicity-at least 80 serotypes • There are multivalent vaccines for prevention of pneumococcal disease SOME COMPLICATIONS OF PNEUMOCOCCAL SEPSIS • Bacteraemia (10%+) • Empyema (1%) • Meningitis (<0.5%) • Mortality rates of 10-25% • Splenectomy or asplenia a major risk factor Pneumococcal vaccine is recommended for: • • • • • • • Age >65 years Underlying chronic lung disease Asplenia Alcoholism Diabetes mellitus Chronic renal failure HIV infection VIRUSES THAT CAUSE COMMUNTIY ACQUIRED PNEUMONIA INFLUENZA OTHER VIRAL CAUSES • • • • Respiratory syncytial virus (RSV) Parainfluenza viruses Enteroviruses (Cytomegalovirus) Principal causes of interstitial pneumonia (immunocompromised) • Cytomegalovirus • Pneumocystis carinii • Respiratory viruses -RSV -Parainfluenza -Infleunza Legionnaires’ disease • A severe pneumonia due to Legionella pneumophila • Can be community or hospital acquired • Organism is acquired from environmental sources eg, humidified air conditioning, showers • Usually attacks debilitated individuals RISK FACTORS • • • • • • Male sex Advanced age Cigarette smokers Alcoholism Chronic lung disease Immmunosuppression, malignancy ACID ALCOHOL FAST RODS SUGGESTING TUBERCULOSIS PNEUMONIA IN THE IMMUNOCOMPROMISED HOST • Cause depends on the underlying immunodeficiency • More likely to present as a diffuse interstitial pneumonia • Treatment often empirical as establishing the cause is often difficult MAJOR CAUSES OF PNEUMONIA IN IMMUNOCOMPROMISED • • • • • Pneumocystis jirovecii (carinii) Cytomegalovirus Other respiratory viruses Tuberculosis Fungi How we investigate undiagnosed pneumonia o CT scan o Bronchoalveolar lavage -culture for bacteria, fungi -immunofl. For PCP -culture for viruses o Transbronchial biopsy o Legionella urinary antigen o Look for evidence of CMV infection Approach to treatment…. o Cover the most likely pathogens with high mortality: PCP, fungi, broad spectrum antibiotics o Adjust according to changing clinical picture and investigation findings Late complications: days 100-12 months o Usually associated with ongoing immunosuppression for GVHD o Infections with capsulate bacteria a major risk eg, pneumococcus o Reactivation of varicella zoster virus not uncommon o Other opportunistic infections occur as in chronic immunosuppression Infections complicating solid organ transplantation • Early infections complicate the surgical procedure eg, wound infection, post-op pneumonia • After 1 month the risk of opportunistic infections increases and correlates with the level of immunosuppression • Infections are more often due to “intracellular” pathogens Some examples of opportunistic pathogens in organ tr. recipients o o o o o o o o Legionella pneumophila (pneumonia) Nocardia asteroides (pneumonia, dissem.) Listeria monocytogenes (meningitis) Myco.tuberculosis (pneumonia, dissem.) Pneumocystis jirovecii (pneumonia) Crypto. neoformans (meningitis) Aspergillus fumigatus (pneum. Dissem.) Toxoplasma gondii (pneum. Encephalitis) Viral infections complicating organ transplantation o Cytomegalovirus pneumonia, disseminated infection, retinitis o HSV oropharyngeal or oesophageal infection, disseminated, encephalitis o VZV rash, disseminated o EBV pulmonary, hepatic disease, lymphoma o Others: papilloma virus, HHV 6, resp viruses Strategies to protect the immunocompromised Identify the patient and perform a risk assessment • Most common groups are patients with acquired immunocompromise due to underlying disease and its treatment • A good example is acute leukaemia • This may be treated by either chemotherapy or stem cell transplant A risk assessment in an acute leukaemic patient:undergoing remission induction chemotherapy • They may have infection on presentation , therefore full clinical examination • Neutropenia will last for c. 3 weeks therefore antibacterial prophylaxis is appropriate • Antifungal prophylaxis controversial • Antiviral prophylaxis for HSV reactivation Do prophylactic antibiotics work? • There have been many trials that have shown benefit from antibiotic prophylaxis • The concept adopted is selective depletion of gut flora leaving the colonization resistance intact • Ciprofloxacin widely used for this purpose • Antifungals eg, fluconazole reduce mucosal infections due to candida Additional approaches • Protective environment: single room isolation • Care of indwelling catheter • General avoidance of risks after chemo completed Protecting the stem cell transplant patient • Allogeneic transplant carries a higher risk than autologous • More prolonged period of immunosuppression • Greater risk of airborne fungal infection and CMV Protective measures for the SCT patient • Protected environment: positive pressure HEPA filtered room • Antibiotic and antifungal prophylaxis • HSV prophylaxis (acyclovir) • Measures to prevent CMV infection: screened blood products, ganciclovir • Cotrimoxazole prophylaxis on engraftment for P jirovecii prevention • Penicillin prophylaxis in chronic GVHD • Vaccination: ‘killed’ vaccines General measures to prevent infection • Avoid contact with respiratory infections • Physiotherapy with bacterial chest infections • Avoid live vaccines • Irradiate blood • Use CMV seronegative blood • Promptly treat infections Splenectomy/hyposplenism carries an increased risk of overwhelming sepsis • • • • • • Sickle cell disease Coeliac disease GVHD ITP Splenic irradiation Surgical removal Causes of infection after splenectomy • • • • • • • Strep pneumoniae H influenzae Meningococcus Salmonella spp Capnocytophaga canimorsus (dog bites) Babesia microti (tick borne or transfusion) Plasmodium malaria Preventive measures • Delay elective splenectomy • Vaccinate before splenectomy • Vaccinate with: pneumococcal; meningococcal; H influenzae • Penicillin prophylaxis (children main benefit) • Early empirical therapy • Alert bracelet