Infection in Immunocompromised Hosts PDF

Infection in immunocompromised hosts Dr. Xin Li Department of Microbiology School of Clinical Medicine Li Ka Shing Faculty of Medicine Learning objectives Describe the components of host immune system. List the common infections complications associated with different types of immunodeficiencie...

Infection in immunocompromised hosts Dr. Xin Li Department of Microbiology School of Clinical Medicine Li Ka Shing Faculty of Medicine Learning objectives Describe the components of host immune system. List the common infections complications associated with different types of immunodeficiencies. List the microbes typically associated with: - Neutropenic fever. - Solid organ or haemopoietic stem cell transplantation. The ‘Infective triad’ Bacteria, virus, fungi, parasites, prions Agent Physical barrier Innate immunity Adaptive immunity Host Environment Drugs and procedures: • Chemotherapy • Radiotherapy • Indwelling catheters • Surgery • Antibiotics Clinical Infectious Diseases Human host Microbes Immunocompetent vs immunocompromised Endogenous vs exogenous Host immune system Drugs and procedures Commensal vs pathogen https://doi.org/10.1264/jsme2.ME17017 Types of microbes • Commensal: a microorganism that is a normal inhabitant of the human body. • Pathogen: a microorganism capable of causing disease. • Primary pathogen: a pathogen that regularly causes disease in some proportion of susceptible individuals with apparently intact defence system. • Opportunistic pathogen: a pathogen that causes disease mostly in immunocompromised individuals. Key difference: inherent ability to breach the host immunity Primary pathogen: Opportunistic pathogen: • • Corynebacterium diphtheriae Staphylococcus epidermidis • Bacillus anthracis • • Bordetella pertussis Stenotrophomonas maltophilia • Candida spp. • Staphylococcus aureus • Streptococcus pneumoniae • Mycobacterium tuberculosis • Pseudomonas aeruginosa Host status • Immunocompetent: having the ability to mount a normal immune response. • Immunocompromised / immunosuppressed: having a weakened immune system, due to one or more defects in body’s natural defence against microbial infections and disease. Components of host immune system • Barriers: • Innate immunity: • Neutrophils, macrophages, NK cells, cytokines. • Anatomical: skin, mucous membrane; • Physiological: temperature, pH; • Chemical: lysozyme, defensins; • Mechanical: cilia, urinary flow; • Antibodies / immunoglobulins (B lymphocytes); • Biological: commensal flora. • Cell mediated immunity / CMI (T lymphocytes). • Adaptive immunity: Innate immunity • • Adaptive immunity Pre-existing barriers and induced • All mechanisms are induced. mechanisms. • Adaptive leukocytes express an Innate leukocytes express a small almost infinite number of number of pattern recognition diverse antigen receptors, each molecules that collectively of which recognises a specific recognise a wide range of antigen. pathogens. • Slower response. • Fast response. • Responding cells proliferate and • Responding cells do not proliferate and are short-lived. • are long-lived. • Level of response is stronger Level of response similar upon and faster with repeated repeated exposure to the same exposure to the same pathogen. pathogen. Netea, Mihai G. et al. Innate and Adaptive Immune Memory: an Evolutionary Continuum in the Host’s Response to Pathogens Cell Host & Microbe, Volume 25, Issue 1, 13 - 26 Causes of immunodeficiency • Primary immunodeficiency: the individual is born with a genetic mutation that results in a defect in the innate or adaptive immune response. • Rare (~1 in 5,000 live births), many seen in infancy, but some may not manifest till adulthood. • Secondary immunodeficiency: the individual is born with intact immune system but later experiences an event that damages the immune system in some way. • More common, seen through all age groups. Common causes of secondary immunodeficiency • Infection: e.g., human immunodeficiency virus (HIV) infection. • Malignancy: e.g., leukaemia, lymphoma. • Haemopoietic stem cell or solid organ transplantation and anti-rejection therapy. • Immunosuppressive treatment: e.g., chemotherapeutic agents, corticosteroid, biologics. • Trauma or surgery, severe burn. • Malnutrition and other metabolic disruption: e.g., diabetes mellitus, Cushing’s syndrome. Importance of infection in immunocompromised hosts • Increasing number of immunocompromised hosts due to advance in medical treatment, especially treatment for cancers and rheumatological conditions. • Immunocompromised patients are predisposed to infection by various pathogens, including unusual opportunistic pathogens. • Severe infection or atypical presentation are common. • Differing management approach. Common types of B cell immunodeficiency T cell immunodeficiency Neutropenic fever Haemopoietic stem cell or solid organ transplantation immunodeficiencies encountered clinically Case 1 • Male, 38 years old. • B-cell lymphoma on chemotherapy including rituximab (anti-CD20 monoclonal antibody). • Presented with persistent right lower quadrant abdominal pain, chronic diarrhoea, and weight loss for 4 months. • Colonoscopy and biopsy showed inflammation and ulcer in caecum. • Not responding to repeated courses of ciprofloxacin and oral budesonide. By Olek Remesz (wiki-pl: Orem, commons: Orem) - Own work, CC BY-SA 2.5, https://commons.wikimedia.org/w/index.php?curid=2599426 Case 1 Case 1 Case 1 Nathan Reading from Halesowen, UK, CC BY 2.0 <https://creativecommons.org/licenses/by/2.0>, via Wikimedia Commons B cell immunodeficiency • Both primary (e.g., X-linked agammaglobulinaemia) and secondary (e.g., rituximab) causes. • Defects in immunoglobulin production and/or composition. • Predisposes to infection by: • Encapsulated bacteria: S. pneumoniae, Haemophilus influenzae, Neisseria meningitidis. • Enterovirus. • Campylobacter spp., Salmonella spp. • Giardia lamblia Case 2 • Male, 40 years old. • Newly diagnosed HIV infection with CD4 count of 50 cells/µL, not yet started on combined antiretroviral treatment (cART). • Presented with low-grade fever, dry cough and increasing shortness of breath for 1 week. • On admission temperature 38.1°C, requiring 2L/min O2 via nasal cannula. Case 2 T cell immunodeficiency • Both primary (e.g., severe combined immunodeficiency) and secondary (e.g., HIV infection) causes. • Defects in T cells and cell-mediate immunity. • Predispose to infection mainly by intracellular organisms: • Mycobacteria, Listeria monocytogenes, Salmonella • P. jirovecii, Cryptococcus, Talaromyces marneffei • Cytomegalovirus, herpes simplex virus, respiratory viruses (e.g., adenovirus) • Toxoplasma gondii https://doi.org/10.1007/s11046-019-00395-y Case 3 Ecthyma gangrenosum • Female, 60 years old. • Acute myeloid leukaemia on chemotherapy. • Presented with sudden onset fever and chills 10 days after chemotherapy, no localising symptoms of infection. • Septic shock requiring high-dose inotrope infusion. • Absolute neutrophil count 0.02 x 109/L. https://doi.org/10.1016/S1473-3099(03)00522-X Blood culture: Stefan Walkowski, CC BY-SA 4.0 <https://creativecommons.org/licenses/by-sa/4.0>, via Wikimedia Commons Case 3 Neutropenic fever • Definitions: • Fever: a single oral temperature of ≥38.3°C (101°F) or a temperature of ≥38.0°C (100.4°F) sustained over a one-hour period. • Neutropenia: absolute neutrophil count (ANC) <1,000 cells/µL. • Severe neutropenia: ANC <500 cells/µL or expected to decrease to <500 cells/µL over the next 48 hours. • Profound neutropenia: ANC <100 cells/µL. Approach to patients with neutropenic fever • History taking: localising symptoms of infection (usually none!). • Physical examination: pulmonary, abdominal, skin, sinuses, mucosa. • Microbiological investigation: blood culture, urine culture, sputum culture etc. • Radiological investigation: chest X-ray, computed tomography (CT) thorax +/- abdomen. • Start empirical antimicrobial with broad-spectrum coverage without delay! Microbial biomass in the mucosal surfaces of alimentary tract & skin Spectrum of organisms causing neutropenic fever Bacteria: skin, GI tract Gram-negative bacilli: • Enterobacteriaceae: E. coli, Klebsiella spp., Enterobacter spp. • Non-fermenters: Pseudomonas aeruginosa, Acinetobacter spp. Gram-positive cocci: • S. aureus, S. epidermidis • Viridans streptococci • Enterococcus spp. Yeasts: GI tract, GU tract Candida spp. Moulds: air Aspergillus spp., Mucorales, Fusarium spp. Common sites of infection • Primary bacteraemia. • Catheter-related bloodstream infection. • Oral mucositis. • Neutropenic enterocolitis (typhlitis). • Pulmonary infection. • Urinary tract infection. Miller LM, Clark E, Dipchand C, Hiremath S, Kappel J, Kiaii M, Lok C, Luscombe R, Moist L, Oliver M, MacRae J; Canadian Society of Nephrology Vascular Access Work Group. Hemodialysis Tunneled Catheter-Related Infections. Can J Kidney Health Dis. 2016 Sep 27;3:2054358116669129. doi: 10.1177/2054358116669129. https://www.aaom.com/index.php?option=com_content&view=article&id=149:oral-mucositis&catid=22:patient-condition-information&Itemid=120 Case 4 • Male, 44 years old. • Received liver related liver transplant for cirrhosis related to hepatitis B virus. • On prednisolone, cyclosporin A and mycophenolate mofetil. • 6 months after transplantation, he presented with lowgrade fever, abdominal pain, and bloody diarrhoea for 5 days. • On admission ANC 3.5 x 109/L, lymphocyte 0.3 x 109/L. • A colonoscopy was arranged. https://doi.org/10.1097/MIB.0b013e31828075ce Transplant-related infections Neutropenic phase Post-engraftment phase Late phase HSCT Transplant D30 D60 D100 SOT Early post-op period Post-op 1-6 months >6 months Mucositis Typhlitis Central lines Neutropenic phase Post-engraftment phase Late phase HSCT Transplant D30 D60 D100 SOT Early post-op period Surgery-related infections Nosocomial infections Donor-related infections Post-op 1-6 months >6 months Mucositis Typhlitis Central lines Impaired immunity, esp cellular immunity Engraftment syndrome GVHD Neutropenic phase Post-engraftment phase Late phase HSCT Transplant D30 D60 D100 SOT Early post-op period Surgery-related infections Nosocomial infections’ Donor-related infections Post-op 1-6 months Rejections requiring pulse steroid / increase in immunosuppressant >6 months Stage-specific host defect: cellular immunity Bacteria (usually intracellular) Fungi Viruses Parasites • Listeria monocytogenes • Salmonella spp. • Legionella pneumophila • Mycobacteria, including M. tuberculosis and non-tuberculous mycobacteria • Nocardia spp. • Pneumocystis jirovecii • Cryptococcus neoformans • Aspergillus spp. • Herpesviruses: VZV, CMV, EBV, HSV 1/2, HHV-6 • BK virus • Respiratory viruses: adenovirus • Toxoplasma gondii Mucositis Typhlitis Central lines Impaired immunity, esp cellular immunity Engraftment syndrome GVHD Recovering immunity but still quite deficient humoral immunity Neutropenic phase Post-engraftment phase Late phase HSCT Transplant D30 D60 D100 SOT Early post-op period Surgery-related infections Nosocomial infections’ Donor-related infections Post-op 1-6 months Rejections requiring pulse steroid / increase in immunosuppressant >6 months Pitfalls in transplant recipients • Fever may be the only manifestation of infection in transplant recipients, but it is also a poor indicator of infection. • Immune response is dampened, leading to atypical presentation or atypical radiological / histological findings. • Always think about false-positive and false-negative reaction in serological assays. Assays based on antibody detection can be unreliable in these patients. • ‘One man one disease’ may not hold true. Type of immunodeficiency Response to treatment Infectious syndrome / site of infection Duration of immunosuppression Antimicrobial prophylaxis References 1) Relman DA, Falkow S, Ramakrishnan L. A Molecular Perspective of Microbial Pathogenecity. In: Bennett JE, Dolin R, Blaser MJ eds. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 9th ed. Philadelphia, Elsevier/Churchill Livingstone, 2020: Ch. 1. 2) Mak TW, Jett BD. Introduction to the Immune Response. In: Mak TW, Saunders ME, Jett BD eds. Primer to the Immune Response. 2nd ed. Burlington, MA, AP Cell Press, 2014: Ch. 1. 3) Mak TW, Jett BD. Immunodeficiency. In: Mak TW, Saunders ME, Jett BD eds. Primer to the Immune Response. 2nd ed. Burlington, MA, AP Cell Press, 2014: Ch. 15.