1. Infections in the compromised host

2. Learning Objectives At the end of this lecture, the student should be able to: list the main types of defects in immune system List the most common microorganisms associated with disease in each type of immunodeficiency List the main laboratory methods for most of the infections in immunocompromised patients

3. Immune system -the innate defense system (e.g. skin, mucous membranes) -the adaptive (cellular and humoral) immune system protects us from infection

4. The Immune system Immunocompetent host: intact Immunocompromised host: – has defects in their body's natural defenses – prone to severe and life-threatening infections !

5. The immunocompromised patient Defects, accidental or intentional, in the body's innate defense mechanisms deficiencies in the adaptive immune response _______________________________________ Primary immunodeficiency Acquired immunodeficiency

6. Primary immunodeficiency: rare – inherited or – occurs by exposure in utero to environmental factors or by other unknown mechanisms Secondary or acquired immunodeficiency – due to an underlying disease state or – occurs as a result of treatment for a disease.

7. Immunocompromised patients increase in number due to: – Therapy of many cancer types – Organ transplantation – HIV/AIDS

8. Innate immunity Primary defects: – congenital defects in phagocytic cells or complement synthesis Extracellular infections

9. Innate immunity Secondary defects: – disruption of the body's mechanical barriers: Burns traumatic injury major surgery Devices such as intravascular and urinary catheter procedures such as lumbar puncture or bone marrow aspiration Foreign bodies such as prostheses Obstruction

10. Burn wound infections Burns damage : – the body's mechanical barrier – neutrophil function – immune responses – The major pathogens in burns are aerobic and facultatively anaerobic bacteria and fungi – Septicemia in patients with burns is often polymicrobial.

11. The most important pathogens in burn wounds are: Pseudomonas aeruginosa and other Gram- negative rods Staphylococcus aureus Streptococcus pyogenes other streptococci enterococci. Candida spp. and Aspergillus together account for about 5% of infections. Anaerobes are rare in burn wound infections.

12. Surgical wound infections Staphylococcus aureus: the most important cause – May be severe – Invade the bloodstream – seed other sites heart valves: causing endocarditis bones:osteomyelitis – thereby further compromising the patient.

13. Urinary catheters Catheter-associated infection of the urinary tract is common Especially if catheters are left in place for >48 h. The organisms involved are usually Gram- negative rods from the patient's own fecal or periurethral flora

14. Intravenous and peritoneal dialysis catheter infections Staphylococci :the most common – coryneforms, Gram-negative rods and Candida are also implicated.

15. Infections of plastic devices in situ Coagulase-negative staphylococci, particularly Staphylococcus epidermidis, account for more than 50% of the infections These opportunists are members of the normal skin flora multiple antibiotic resistances, and agents such as a glycopeptide (vancomycin or teicoplanin) and rifampicin may be required Whenever possible the plastic device should be removed.

16. Percentage of infections caused by Staph. epidermidis in patients with plastic devices in situ Infections caused by Staph. epidermidis (%) Prosthetic heart valve Early (<2 months postoperatively)30-70 Late (>2 months postoperatively)20-30 Prosthetic hip10-40 Cerebrospinal fluid shunt30-65 Vascular grafts5-20 Peritoneal dialysis related30 Intravascular catheters10-50

17. Infections due to compromised clearance mechanisms Stasis: cystic fibrosis: Staph. aureus and Haemophilus influenzae and later with P. aeruginosa Obstruction and interruption of normal urine flow: Gram-negative organisms from the periurethral flora – Septicemia is an important complication of urinary tract infection superimposed on obstruction.

18. Adaptive immunity Primary defects: – T-cell defects – B-cell deficiencies – severe combined immunodeficiency

19. Adaptive immunity Secondary defects: malnutrition infectious diseases neoplasia irradiation chemotherapy splenectomy

20. Adaptive immunity Secondary defects: -The underlying immunodeficiency state determines -the nature -severity of any associated infection, and in some cases: - infection is the presenting clinical feature

21. Infections that cause immunosuppression ViralBacterial MeaslesMycobacterium tuberculosis MumpsMycobacterium leprae Congenital rubellaBrucella spp. Epstein-Barr virus Cytomegalovirus HIV-1, HIV-2

22. Treatment of disease can also cause immunosuppression Cytotoxic agents such as cyclophosphamide and azathioprine cause leukopenia or deranged T- and B- cell function Corticosteroids reduce the number of circulating leukocytes, monocytes and eosinophils and suppress leukocyte accumulation at sites of inflammation Radiotherapy adversely affects the proliferation of lymphoid cells.

23. Treatment for neoplastic disease – patient becomes immunocompromised as a result of both the disease and the treatment. – Due to improvements in medical technology, many immune defects, particularly immunosuppression resulting from radiotherapy or cytotoxic drugs, are transient, and patients who survive the period of immunosuppression have a good chance of a complete recovery.

24. Hematologic malignancy and bone marrow transplant infections A lack of circulating neutrophils following bone marrow failure predisposes to infection Opportunistic pathogens in neutropenic patients and organ transplant recipients: – Bacteria – Fungi – Parasites Toxoplasma gondii Strongyloides stercoralis

25. Hematologic malignancy and bone marrow transplant infections – Viruses Herpesviruses, Hepatitis B Hepatitis C Polyomaviruses, e.g. BKV, JCV Adenoviruses Cytomegalovirus (CMV) infections: associated with graft-versus-host disease as well as immunosuppressive therapy.

26. Solid organ transplant infections Most infections occur within 3-4 months of transplantation Suppression of a patient's cell-mediated immunity is necessary to prevent rejection of a grafted organ, and the cytotoxic regimens used usually suppress humoral immunity to some extent as well. In addition, high doses of corticosteroids to suppress inflammatory responses are required. The combination of these factors results in a severely compromised host

27. HIV/AIDS As the HIV-infected individual progresses to AIDS, organisms that are usually controlled by cell- mediated immunity are able to reactivate to cause disseminated infections not seen in the immunologically normal individual.

28. Opportunistic pathogens FungiCandida spp. Aspergillus spp. Cryptococcus neoformans Histoplasma capsulatum Pneumocystis jiroveci

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31. Pneumocystis jiroveci causes symptomatic disease in people whose cellular immune mechanisms are deficient. high incidence of pneumonia – in patients receiving immunosuppressive therapy to prevent transplant rejection and – in people with HIV.

32. Pneumocystis jiroveci the organism cannot be isolated in expectorated sputum using conventional culture methods invasive techniques such as bronchoalveolar lavage or open lung biopsy are required. The organism can be demonstrated by silver or immunofluorescent stains. DNA amplification by the polymerase chain reaction improves the sensitivity of the diagnostic tests.

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34. Actinomycetes contain two pathogenic genera, Actinomyces and Nocardia. The lung is usually the primary site, but infection can spread to the skin, kidney or central nervous system

35. Mycobacterium avium-intracellulare disease is often a terminal event in AIDS

36. Protozoa and helminths Cryptosporidium and Isospora belli infections cause severe diarrhea in AIDS Strongyloides stercoralis

37. Certain virus infections both more common and more severe in compromised patients, and regular surveillance is critical Many of these represent reactivation of latent infections. Pre-transplantation baseline serology is carried out to determine both the donor and recipient status for a number of virus infections, including HIV, hepatitis B and C, CMV, EBV and HSV. CMV quantitative DNA monitoring is carried out on blood samples on a regular basis post- transplantation to detect early infection and start antiviral therapy (preemptive therapy)as soon as possible.

38. HSV, VZV may reactivate HHV-8 has been associated with the development of Kaposi's sarcoma (KS) in individuals with AIDS EBV infection can lead to tumor development Respiratory viruses

39. Polyoma viruses BK and JC virus can reactivate. can cause hemorrhagic cystitis and progressive multifocal leukoencephalopathy

40. Compromised patients Infection may be due to: – any of the pathogens capable of infecting immunocompetent individuals. – opportunist pathogens. – The type of infection is related to the nature of the compromise Effective antimicrobial therapy is often difficult to achieve in the absence of a functional immune response, even when the pathogen is susceptible to the drug in vitro For microorganisms involved direct methods for detection especially nucleic acid detection techniques are prefered.

41. Reference: 7th ed 2013