1. Infection in immuncompromized patient Dr.Mustafa Nema Baghdad College of Medicine 2014

2. Objectives Describe the main types of immunocompromised conditions Review the causes of immune suppression List the major types of infections associated with altered immunity Outline management of such infections Dr.Mustafa Nema/Baghdad College of Medicine 2014

3. Immunity Two Intrinsic Defense Systems 1. Innate (nonspecific) system. Responds quickly and consists of: – First line of defense – intact skin and mucosae prevent entry of microorganisms – Second line of defense – antimicrobial proteins, phagocytes, and other cells Dr.Mustafa Nema/Baghdad College of Medicine 2014

4. 2. Adaptive (specific) defense system If the innate immune system fails to provide effective protection against an invading pathogen, the adaptive immune system is mobilised – Include humoral immunity ( B cells, Ab producing) and cell- mediated immunity (T cells non-Ab producing ). Dr.Mustafa Nema/Baghdad College of Medicine 2014

5. Immune-competent and immune-compromised body When immune system function is normal = immune-competent and vice versa with immune- compromised. Immunodeficiency (or immune deficiency) is a state in which the immune system's ability to fight infectious disease is compromised or entirely absent. Immune deficiency may arise through primary (intrinsic) defects in immune function, but is much more commonly due to secondary causes, including drug therapy, malignancy and ageing. Dr.Mustafa Nema/Baghdad College of Medicine 2014

6. Immunocompromising conditions Primary (Congenital) conditions Congenital conditions most commonly affect the newborn and children. Classes of congenital conditions include the following syndromes: – Primary phagocyte deficiencies – Complement pathway deficiencies – Primary deficiencies of the adaptive immune system Primary T-lymphocyte deficiencies Combined B- and T-lymphocyte immune deficiencies Primary antibody deficiencies Dr.Mustafa Nema/Baghdad College of Medicine 2014

7. Examples of primary immune deficiency Example 1 Primary T-lymphocyte deficiencies: – These are characterised by recurrent viral, protozoal and fungal infections. – The immune deficiency is characterised by very low numbers of circulating T cells. – These disorders generally present in childhood e.g. DiGeorge syndrome Dr.Mustafa Nema/Baghdad College of Medicine 2014

8. – DiGeorge syndrome : associated with multiple abnormalities, including congenital heart disease, hypocalcaemia tracheo-oesophageal fistulae, cleft lip and palate, and absent thymic development. Dr.Mustafa Nema/Baghdad College of Medicine 2014

9. Example 2 Primary antibody deficiency: Selective IgA deficiency: Is the most common primary immune deficiency that can also present in adulthood. In most patients, low or undetectable IgA is an incidental finding with no clinical sequelae. However, 30% of individuals experience recurrent mild respiratory and gastrointestinal infections. In some patients, there is a compensatory increase in serum IgG levels. Specific treatment is generally not required. Dr.Mustafa Nema/Baghdad College of Medicine 2014

10. Investigations Investigations include serum immunoglobulins, and B and T lymphocyte counts in blood. Management With the exception of individuals with selective IgA deficiency, patients with other antibody deficiencies ( like IgG, IgM) require aggressive treatment of infections, and prophylactic antibiotics may be indicated. The mainstay of treatment is life-long immunoglobulin replacement therapy. Immunisation is generally not effective. Why? Dr.Mustafa Nema/Baghdad College of Medicine 2014

11. Secondary immune deficiencies Secondary immune deficiencies are much more common than primary immune deficiencies. Dr.Mustafa Nema/Baghdad College of Medicine 2014

12. Causes of secondary immune deficiency Physiological Ageing Prematurity Pregnancy Infection HIV Measles Mycobacterial infection Dr.Mustafa Nema/Baghdad College of Medicine 2014

13. Iatrogenic Immunosuppressive therapy Antineoplastic agents Corticosteroids Stem cell transplantation Radiation injury Some anti-epileptic agents Malignancy B-cell malignancies including leukaemia, lymphoma and myeloma Solid tumours Thymoma Dr.Mustafa Nema/Baghdad College of Medicine 2014

14. Biochemical and nutritional disorders Malnutrition Renal insufficiency/dialysis Diabetes mellitus Specific mineral deficiencies, e.g. iron, zinc Other conditions Burns Asplenia/hyposplenism Dr.Mustafa Nema/Baghdad College of Medicine 2014

15. Common causes of secondary immune defeciency include infections, such as HIV and measles, and cytotoxic and immunosuppressive drugs, particularly those used in the management of transplantation, autoimmunity and cancer. Physiological immune deficiency occurs at the extremes of life. Dr.Mustafa Nema/Baghdad College of Medicine 2014

16. How can a patient with immune deficiency presents to you and how can you manage? Dr.Mustafa Nema/Baghdad College of Medicine 2014

17. Most patients with an immune deficiency present with: Recurrent Infections. An immunocompromised person may be particularly vulnerable to opportunistic infections, in addition to normal infections that could affect everyone. Dr.Mustafa Nema/Baghdad College of Medicine 2014

18. In primary immune deficiency.. Many warning signs may help in suspecting the presence of primary immune deficiency in newborn /childhood. The presence of ≥ 2 warning signs may indicate an underlying primary immunodeficiency: o ≥ 4 new ear infections within 1 yr o ≥ 2 serious sinus infections within 1 yr o ≥ 2 months on antibiotics with little effect o ≥ 2 pneumonias within 1 yr Dr.Mustafa Nema/Baghdad College of Medicine 2014

19. o Failure of an infant to gain weight or grow normally o Recurrent, deep skin or organ abscesses o Persistent thrush in mouth or fungal infection on skin o Need for intravenous antibiotics to clear infections o ≥ 2 deep-seated infections, including septicaemia o A family history of primary immune deficiency Dr.Mustafa Nema/Baghdad College of Medicine 2014

20. In patient with infection and secondary immune deficiency suspected.. The following should be addressed in the history: Identification of the immunosuppressant factors, and nature of the immune defect. Any past infections and their treatment. Exposure to infections, including opportunistic infections that would not cause disease in an immunocompetent host. Prophylactic medicines and vaccinations administered. Dr.Mustafa Nema/Baghdad College of Medicine 2014

21. Examination: Examination should include inspection of the normal physical barriers provided by skin and mucosal surfaces and, in particular, central venous catheters, the mouth, sinuses, ears and perianal area. ( Do Not forget hidden areas ) The areas around fingernails and toenails should also be inspected closely. Dr.Mustafa Nema/Baghdad College of Medicine 2014

22. Investigations If the clinical features do not suggest a specific infection, then initial investigations should include: – A full blood count with differential count. – Blood glucose, urea and liver function tests. – Inflammatory markers: erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). – A test for antibodies to HIV-1 – Autoantibodies, including antinuclear antibodies (ANA). Dr.Mustafa Nema/Baghdad College of Medicine 2014

23. Chest X-ray and chest CT scan should be considered when respiratory symptoms occur. Abdominal imaging may also be warranted, particularly if there is right lower quadrant pain, which may indicate typhlitis (inflammation of the caecum) in neutropenic patients. Culture of the blood, central venous catheter site, urine, and stool if related symptoms and sign present. Dr.Mustafa Nema/Baghdad College of Medicine 2014

24. Specific conditions Dr.Mustafa Nema/Baghdad College of Medicine 2014

25. Neutropenic fever Neutropenia is a common complication of malignancy. It is usually secondary to chemotherapy but may occur with radiotherapy if large amounts of bone marrow are irradiated. It may also be a component of pancytopenia due to malignant infiltration of the bone marrow. Dr.Mustafa Nema/Baghdad College of Medicine 2014

26. A reduction in neutrophil count (usually less than 1.5 × 10 9 /L, but dependent on age and race) is called neutropenia The risk of bacterial infection is related to the degree of neutropenia, with counts lower than 0.5 × 10 9 /L considered to be critically low. The risk of sepsis is related to the severity and duration of neutropenia and the presence of other risk factors such as intravenous or bladder catheters. Dr.Mustafa Nema/Baghdad College of Medicine 2014

27. Neutropenic fever is an emergency in cancer patients as, if left untreated, it can result in septicaemia with a high mortality rate. Dr.Mustafa Nema/Baghdad College of Medicine 2014

28. Clinical features The typical presentation is high fever and affected patients are often non-specifically unwell. Examination is usually unhelpful in defining a primary source of the infection. Hypotension is an adverse prognostic feature and may progress to systemic circulatory shutdown and organ failure Dr.Mustafa Nema/Baghdad College of Medicine 2014

29. Investigations and Treatment An infection screen should be performed. Typical first-line empirical therapy consists of an anti-pseudomonal β-lactam (ceftazidime, cefotaxime or meropenem), or a combination of an aminoglycoside and a broad-spectrum penicillin with anti-pseudomonal activity (gentamicin and piperacillin). Dr.Mustafa Nema/Baghdad College of Medicine 2014

30. Metronidazole should be added if anaerobic infection is suspected, and flucloxacillin or vancomycin or teicoplanin when Gram-positive infection is suspected (for example, in patients with central lines). If there is no response after 36–48 hours, treatment with amphotericin B or voriconazole should be considered to cover fungal infection. Other supportive therapy, including intravenous fluids and dialysis, may be required. Dr.Mustafa Nema/Baghdad College of Medicine 2014

31. Infections in transplant recipients Infections in solid transplant recipients are grouped according to the time of onset. Those in the first month are related to the underlying condition or surgical complications. Those occurring 1–6 months after transplantation are characteristic of impaired T-cell function. Dr.Mustafa Nema/Baghdad College of Medicine 2014

32. Time post- transplantation Infections Solid organ recipients 0–1 mth Bacterial or fungal infections related to the underlying condition or surgical complications 1–6 mthsCMV, other opportunistic infections (e.g. Pneumocystis jirovecii pneumonia) > 6 mthsBacterial pneumonia, other bacterial community-acquired infections, shingles, cryptococcal infection. Dr.Mustafa Nema/Baghdad College of Medicine 2014

33. Types of immune deficiency, causes and resultant infection Dr.Mustafa Nema/Baghdad College of Medicine 2014

34. Humoral immune deficiency B cells, plasma cells or antibodies o Primary humoral o Multiple myeloma o Chronic lymphoid leukemia o AIDS o Streptococcus pneumoniae o Hemophilus influenzae o Pneumocystis jirovecii o Giardia intestinalis o Cryptosporidium parvum Type of immune deficiency Affected components Main causesMain pathogens of resultant infections Dr.Mustafa Nema/Baghdad College of Medicine 2014

35. Cryptosporidium parvum Strept pneuomonia Dr.Mustafa Nema/Baghdad College of Medicine 2014

36. T cell deficiency T cells Marrow and other transplantation AIDS Cancer chemotherapy Lymphoma Glucocorticoid therapy Intracellular pathogens, including Herpes simplex virus, Mycobacterium, Listeria, and intracellular fungal infections. Dr.Mustafa Nema/Baghdad College of Medicine 2014

37. Miliary TB Dr.Mustafa Nema/Baghdad College of Medicine 2014

38. Neutropenia Neutrophil granulocytes o Chemotherapy o Bone marrow transplantation o Dysfunction, such as chronic granulomatous disease o Oral Streptococci o Pseudomonas aeruginosa o Enterococcus species o Candida species o Aspergillus species Dr.Mustafa Nema/Baghdad College of Medicine 2014

39. Aspergillus lung infection Dr.Mustafa Nema/Baghdad College of Medicine 2014

40. Asplenia Spleen o Splenectomy o Trauma o Sickle-cell anemia Polysaccharide encapsulated bacteria,particularly: Streptococcus pneumoniae Haemophilus influenzae Neisseria meningitidis o Plasmodium species o Babesia species Dr.Mustafa Nema/Baghdad College of Medicine 2014

41. Complement deficiency Complement system Congenital deficiencies o Neisseria species o Streptococcus pneumoniae Dr.Mustafa Nema/Baghdad College of Medicine 2014

42. Opportunistic infections Bacterial Mycobacterial infections including M.avium complex Legionellosis Nocardia Actinomycetes Salmonellosis Campylobacter infection Viral CMV Herpes simplex Adenovirus Dr.Mustafa Nema/Baghdad College of Medicine 2014

43. Parasitic Pneumocystis jirovecii pneumonia (PJP). the old name is P.carinii pneomonia (PCP) Toxoplasmosis Cryptosporidiosis Isosporiasis Generalised strongyloidiasis Fungal Candidosis Cryptococcosis Aspergillosis Histoplasmosis Dr.Mustafa Nema/Baghdad College of Medicine 2014

44. Pneumocystis jirovecii pneumonia Dr.Mustafa Nema/Baghdad College of Medicine 2014

45. Vaccine New guidelines recommend that most immunocompromised patients should be vaccinated. Dr.Mustafa Nema/Baghdad College of Medicine 2014

46. Readings Davidson clinical and practice of medicine 22th ed. 2014. www.emedicine.medscape.com Dr.Mustafa Nema/Baghdad College of Medicine 2014