Meningitis Dr Michael Prentice.ppt by tongxiamy

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									Infections in Immunocompromised
         and Special Hosts

       Professor Mark Pallen
                      Overview

•   Immunodeficiency
•   Infections in Pregnancy
•   Congenital Infections
•   Infections in Neonates
                     Definitions

• Pathogen: a micro-organism causing disease
• Primary pathogen: common cause of disease
  in healthy non-immune hosts,
  – e.g. S. aureus, S. pneumoniae
• Opportunistic pathogen: rare cause of
  disease in healthy individuals, causes serious
  disease in compromised hosts
  – e.g. Pseudomonas aeruginosa
                 Host Defence Overview

• Defence is not just                 • Compromise caused by
  immunological                          – damage to physical defence
• anatomical integrity and                 against infection
  physiological defences of                  • Burns, trauma, breaching
                                               skin, iatrogenic damage to
  body surfaces                                physical defences (e.g.
   – e.g. peristalsis, muco-ciliary            surgery), foreign body
     escalator, normal flora,                  insertion, intubation,
     normal urinary flow                       urinary catheterisation
                                         – Other defence disruption
                                             • antimicrobiotics disturb
                                               normal flora
                                             • cytotoxics damage gut
                                               mucosa
                            Burns

• Infections with            • Prevention of infection
  Pseudomonas                   – topical prophylactic use
  aeruginosa and                  of silver sulfadiazine
  Staphylococcus aureus           (flammazine)
  common                        – Burn wound excision
   – Can spread to
     bloodstream
   – Treatment includes
     topical and systemic
     agents
                           Immunodeficiency

• Primary                                   • Secondary
  Immunodeficiency                            Immunodeficiency
     –   Neutrophil defects: CGD              – AIDS
     –   Humoral: B cell defects              – Neutropenia
     –   Humoral: Complement                     • Post-transplant
     –   Cell-mediated: T cells                  • BMT
     –   Severe combined                         • chemotherapy
         immunodeficiency                     – Splenectomised patient

see http://www.ncbi.nlm.nih.gov/Omim/
for details of primary immunodeficiencies
              Primary Immunodeficiency
                            Pathogens
• Humoral defects             • Cell-mediated
   – Capsulated bacteria         – intracellular bacteria
      •   S. pneumoniae              • Mycobacteria, Salmonella,
      •   H. influenzae                Listeria, Legionella
      •   N. meningitidis        – Viruses
      •   S. aureus                  • Herpes, Respiratory &
   – Enteroviruses                     Enteric viruses
   – mycoplasma                  – Fungi & protozoa
                                     • Candida, Aspergillus,
                                       Pneumocystis,
 • Neutrophil defects                  Cryptococcus,
    – S. aureus, Candida,              Cryptosporidium,
      Aspergillus                      Toxoplasma
         Primary Immunodeficiency
                      Management
– Correct defect
   • Immunoglobulin, cytokines
   • BMT
   • Gene therapy?
– Early aggressive antibiotic treatment
– Prophylaxis
   • Daily co-trimoxazole
   • Penicillin if complement deficiency
   • Flucloxacillin in some neutrophil disorders
                    Acquired Immunodeficiency
                                        AIDS
• Many “AIDS-defining                   • Diagnosis
  illnesses” in HIV-positive               – many pathogens difficult or
  individual                                 impossible to grow
    – Western presentation                 – or inaccessible e.g.
        • (pre-HAART)                        intracerebral
          Pneumocystis carinii             – multiple infections are the
          pneumonia.                         rule
    – In Africa                            – Antigen detection (PCR,
        • TB or slim disease                 DNA probe) + tissue
          (prolonged diarrhoea with a        diagnoses may be required
          wasting illness)

                  Note:
                  • stunning effect of HAART!
                  • meanness of drug companies
          Acquired Immunodeficiency
                      AIDS
• Spectrum of infecting organisms relates to disease
  progression (CD4 count)

      0.5 X 109/L M. tuberculosis

             <0.2 X 109/L PCP, Toxoplasmosis

                   <0.10 X 109/l CMV, MAI
• CD4 count boosted by HAART (triple therapy)
• Rational prophylaxis offered for PCP, MAI, CMV with
  falling counts
                Infections in AIDS patients
                                    Pathogens

• Fungi                                 • Bacteria
    – Pneumocystis carinii                   – Mycobacterium avium
    – Candida spp.                           – Mycobacterium
    – Cryptococcus                             tuberculosis
      neoformans                             – Salmonella
• Parasites                             • Viruses
    – Cerebral toxoplasmosis                 – CMV
    – Cryptosporidiosis                      – HSV
                                             – HHV8/KSHV

 STOP PRESS
 The arrival of highly active antiretroviral therapy, or HAART, has led to a
 stunning decline in the incidence of these infections in HIV-positive patients
           Pneumocystis
              carinii

•   Ubiquitous uncultivable fungus:    •   Diagnosis
    opportunistic pathogen                  – Silver stain/monoclonal
     – 60% of people infected by the          antibody detection in BAL or
       age of four                            biopsy.
     – complex life cycle involving    •   Treatment
       cysts and trophozoites               – High dose cotrimoxazole
     – most common infection in AIDS        – ventilation
•   Presentation                            – If sulphonamide allergy:
     – non productive cough,                  pentamidine, dapsone,
       dyspnoea, fever                        clindamycin plus primaquine,
     – Perihilar infiltrates                  atovaquone.
     – may progress to severe          •   Chemoprophylaxis
       respiratory distress                 – cotrimoxazole or inhaled
     – extrapulmonary infection               pentamidine
                                            – ?? Still needed on HAART
             Mycobacterium tuberculosis

• 2-10% annual risk of              • Hospital outbreaks
  infection if HIV positive            – in AIDS patients from smear-
    – Worldwide, most illness is         negative individuals
      reactivation of latent             (bronchoscopy and
      infection                          aerosolised pentamidine)
    – In Africa, 50% of HIV            – Multiple drug resistant (MDR)
      infected are MTB infected          TB outbreaks with spread to
                                         hospital staff in USA
• Presentation
    – Rapidly progressive disease   • Therapy
      on primary infection             – in the absence of drug
    – Extrapulmonary disease             resistance is standard for the
      more likely as CD4 cells           site of infection but given for
      decline                            longer e.g. six months after
                                         culture negative
            Mycobacterium avium-intracellulare
                     (MAI) complex
•   M. avium - “TB in birds”            •   Diagnosis
•   M. intracellulare - atypical             – culture after 1-4 incubation of
    human isolate                              sample from a sterile site,
                                                  • blood culture, bone marrow,
     – Ubiquitous (soil, water, food,
                                                    lymph node, liver biopsy
       animals)
                                        •   Therapy
•   Presentation
                                             – Problematic: resistance to
     – Pulmonary infection in non-
                                               antituberculous drugs
       AIDS patients
                                             – Clarithromycin or azithromycin
     – Disseminated in advanced
                                               (macrolides) and ethambutol
       AIDS (CD4<0.1 X 109/l)
                                               plus rifabutin (+/- clofazamine
     – Fever, night sweats, weight             rifampicin ciprofloxacin
       loss. Organ infiltration.               amikacin)
                                        •   Prophylaxis
                                             – rifabutin at CD4<0.1 X 109/l
          Cerebral Toxoplasmosis

•   T. gondii
     – Protozoal infection, usually
       asymptomatic (50% infected by
       middle age) or glandular fever    •   Histology and culture of brain
     – Zoonosis: from cats                   biopsy may be required if no
•   Presentation in AIDS                     response at 10 days
     – main cause of focal CNS           •   Therapy:
       lesions in AIDS                        – Pyrimethamine plus folinic acid
     – Pneumonitis and chorioretinitis          and sulphadiazine or
       may also occur                           clindamycin for 3-6 weeks
                                                acutely (expert advice needed!)
•   Empirical antitoxoplasma
    therapy IF                           •   Prophylaxis
     – 1. Ring-enhancing lesions on           – Secondary: to prevent relapse
       CT/MRI scan and                          pyrimethamine/dapsone
     – 2. Toxoplasma IgG antibody             – Primary: in seropositive patients
       (dye test/ELISA) are present             with low CD4 counts
               Cryptococcus neoformans

• Capsulate urease-positive           • Diagnosis
  yeast                                  – microscopy of CSF with india
   – found in bird droppings               ink (50% sensitive)
   – asymptomatic infection by           – antigen detection by latex
     pulmonary route                       agglutination in serum or
                                           urine (>90%sensitive)
• Leading systemic fungal
  infection in AIDS                      – CSF or blood culture
   – insidious meningitis             • Treatment
       • Capsule inhibits alternate      – amphoteracin B or
         pathway of complement             fluconazole
       • Little inflammation             – lifelong fluconazole
   – skin and bone infections              maintenance therapy required
     less common                           (even with HAART?)
                    Cryptosporidiosis

• C. parvum protozoan           • Diagnosis
  parasite                         – Modified acid-fast stain
• Water-borne outbreaks,           – Monoclonal based
  faecal-oral spread, esp.           immunofluorescence
  from farm animals             • Prevention
• Self-limiting infection (2-      – Boil water if at risk
  3 weeks) in normal            • Treatment
  children                         – Difficult
• Chronic watery                   – Azithromycin with
                                     paromomycin shows
  diaarhoea in AIDS, can             promise
  be life-threatening
               Viral infections in AIDS

• HSV                               • CMV
  – Chronic mucocutaneous             – Sites
    infection (oral & anogenital)         •   retinitis
  – Treatement: acyclovir                 •   encephalitis
• VZV                                     •   hepatitis
                                          •   pneumonia
  – shingles
                                      – Treatment: ganciclovir
                                      – Paradoxical worsening
                                        of retinitis after HAART
                                    • HHV8
                                      – Kaposi’s sarcoma
                   Acquired Immunodeficiency
                              Neutropenia
• Causes                            • Empirical therapy:
    – Iatrogenic                       – Febrile neutropenic cannot
        • Post-chemotherapy              await culture results
        • Post-BMT                     – URGENT bactericidal
    – Aplastic anaemia (e.g. post        broad-spectrum agents
      Chloramphenicol).                    • anti-pseudomonal penicillin
    – Other drugs (rarely high               + aminoglycoside
      dose beta-lactams)               – Add vancomycin (anti-
                                         Gram-positive), then
• Diagnostic difficulty
                                         antifungal if no improvement
    – absence of pus/localisation
                                       – Other measures: HEPA
    – rely on fever as cardinal          filtered air, G-CSF, gut
      sign                               decontamination
                   Acquired Immunodeficiency
                          Neutropenia
          Cytotoxic
Neutro                                        Onset
phils                                         maximum risk
X 109/l

   0.5
   0.1
                                              Time (days)
               2      4   6   8   10   12

• Timely admission in cyclical chemotherapy
    – <0.5 x 109/l risk of infection
    – <0.1 x 109/l high risk of septicaemia
              Opportunistic mycoses in
                    neutropenia
• Aspergillus fumigatus           • Candida albicans:
   – saprophytic mould in soil      yeast-like fungus:
   – inhaled spores infect lung      – endogenous infection;
     in prolonged neutropenia        – predisposition by
   – necrotising pneumonia             diabetes, iv feeding,
     and dissemination                 antibiotics
   – filamentous septate             – Blood cultures positive in
     hyphae in tissues                 40%.
   – Common contaminant of           – Treatment: Amphoteracin
     culture media.                    B, Fluconazole
   – Treatment: Amphoteracin
     B (liposomal less toxic)
                         Splenectomy

• Susceptible to capsulate bacteria
   – Risk of systemic pneumococcal disease 25x (fatal infection
     75x)
   – Functional splenectomy in sickle cell disease
• Prevention of infection
   – vaccination (preferably before splenectomy)
   – Prophylactic antibiotics
      • Pen V or amoxycillin
                      Infections in Pregnancy
•   Increased risk of infection with            •   Puerperal sepsis
     – Ascending UI TI                               – Classically Group A beta-
     (see UTI lecture)                                 haemolytic streps
     – Listeria monocytogenes (a                       (Semmelweiss)
        Gram-positive rod)                           – Now group B most important:
         • causes miscarriage, stillbirth or             • Maternal speticaemia, neonatal
           severe illness in newborn,                      septicaemia and meningitis
           septicaemia and meningitis in                 • Higher risk in US than UK
           mother                                        • Prophylaxis with ampicilin
         • Prevention                                      during labour
               – Pregnant women should               – Mixed pelvic infections
                 avoid eating paté and mould-
                 ripened or blue-veined soft
                                                       including anaerobes if retained
                 cheese, e.g. Brie,                    products: need broad spectrum
                 Camembert, Stilton, Danish            cover
                 blue (hard cheeses, cheese
                 spreads are OK) and raw
                 chilled ready meals
         • Treatment: ampicillin
                 Congenital Infections

•   Toxoplasmosis           • Seek expert advice on
•   Rubella                   management & diagnosis
•   CMV                     • Prevention
•   HSV                        – Vaccination
                                   • rubella, hep B
•   Hepatitis B, HIV
                               – Treatment
•   Parvovirus B19                 • Antimicrobial (anti-retrovirals,
•   Syphilis                         syphilis, acyclovir, spiramycin for
                                     toxo, silver nitrate eye drops etc.)
•   Ophthalmia neonatorum
                                   • Other (intra-uterine blood
                                     transfusion for B19)
                               – Screening (syphilis, HIV, hep B),
                                 Vigilance , Avoidance (e.g. of
                                 slapped cheek syndrome)
                Infections in Neonates

• Early onset (<12 hours from birth)
   – more severe, acquired in womb or at birth, usually
     disseminated infection (Listeria or GBS)
   – Increased risk if PROM, meconium-stained liquor, maternal
     sepsis
• Late, acquired after birth (E. coli, GBS)
   – Outbreaks of GBS can occur in NICUs
• Diagnosis: gastric aspirate, blood culture, CSF
• Treatment (empirical): ampicillin and gentamicin
                           Overview

• Immunodeficiency
  – Primary
  – Secondary
     • AIDS, neutropenia
     • P. carinii, M. tb, MAI, cerebral toxo, cryptococcus,
       cryptosporidiosis, CMV, Aspergillus, Candida
• Infections in Pregnancy
  – Listeria, GBS
• Congenital Infections
• Infections in Neonates

								
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