Infections in Immunocompromised and Special Hosts

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Infections in Immunocompromised and Special Hosts

• Professor Mark Pallen

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Overview

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

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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

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Host Defence Overview

• Defence is not just immunological
• anatomical integrity and physiological defences
  of body surfaces
• e.g. peristalsis, muco-ciliary escalator, normal
  flora, normal urinary flow

• Compromise caused by
• damage to physical defence against infection
• Burns, trauma, breaching skin, iatrogenic damage
  to physical defences (e.g. surgery), foreign body
  insertion, intubation, urinary catheterisation
• Other defence disruption
• antimicrobiotics disturb normal flora
• cytotoxics damage gut mucosa

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Burns

• Infections with Pseudomonas aeruginosa and
  Staphylococcus aureus common
• Can spread to bloodstream
• Treatment includes topical and systemic agents

• Prevention of infection
• topical prophylactic use of silver sulfadiazine
  (flammazine)
• Burn wound excision

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Immunodeficiency

• Primary Immunodeficiency
• Neutrophil defects CGD
• Humoral B cell defects
• Humoral Complement
• Cell-mediated T cells
• Severe combined immunodeficiency
• see http//www.ncbi.nlm.nih.gov/Omim/
• for details of primary immunodeficiencies

• Secondary Immunodeficiency
• AIDS
• Neutropenia
• Post-transplant
• BMT
• chemotherapy
• Splenectomised patient

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Primary ImmunodeficiencyPathogens

• Humoral defects
• Capsulated bacteria
• S. pneumoniae
• H. influenzae
• N. meningitidis
• S. aureus
• Enteroviruses
• mycoplasma

• Cell-mediated
• intracellular bacteria
• Mycobacteria, Salmonella, Listeria, Legionella
• Viruses
• Herpes, Respiratory Enteric viruses
• Fungi protozoa
• Candida, Aspergillus, Pneumocystis, Cryptococcus,
  Cryptosporidium, Toxoplasma

• Neutrophil defects
• S. aureus, Candida, Aspergillus

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Primary ImmunodeficiencyManagement

• Correct defect
• Immunoglobulin, cytokines
• BMT
• Gene therapy?
• Early aggressive antibiotic treatment
• Prophylaxis
• Daily co-trimoxazole
• Penicillin if complement deficiency
• Flucloxacillin in some neutrophil disorders

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Acquired Immunodeficiency AIDS

• Many AIDS-defining illnesses in HIV-positive
  individual
• Western presentation
• (pre-HAART) Pneumocystis carinii pneumonia.
• In Africa
• TB or slim disease (prolonged diarrhoea with a
  wasting illness)

• Diagnosis
• many pathogens difficult or impossible to grow
• or inaccessible e.g. intracerebral
• multiple infections are the rule
• Antigen detection (PCR, DNA probe) tissue
  diagnoses may be required

• Note
• stunning effect of HAART!
• meanness of drug companies

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Acquired Immunodeficiency AIDS

• Spectrum of infecting organisms relates to
  disease progression (CD4 count)
• 0.5 X 109/L M. tuberculosis
• lt0.2 X 109/L PCP, Toxoplasmosis
• lt0.10 X 109/l CMV, MAI
• CD4 count boosted by HAART (triple therapy)
• Rational prophylaxis offered for PCP, MAI, CMV
  with falling counts

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Infections in AIDS patientsPathogens

• Fungi
• Pneumocystis carinii
• Candida spp.
• Cryptococcus neoformans
• Parasites
• Cerebral toxoplasmosis
• Cryptosporidiosis

• Bacteria
• Mycobacterium avium
• Mycobacterium tuberculosis
• Salmonella
• Viruses
• CMV
• 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
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Pneumocystis carinii

• Ubiquitous uncultivable fungus opportunistic
  pathogen
• 60 of people infected by the age of four
• complex life cycle involving cysts and
  trophozoites
• most common infection in AIDS
• Presentation
• non productive cough, dyspnoea, fever
• Perihilar infiltrates
• may progress to severe respiratory distress
• extrapulmonary infection

• Diagnosis
• Silver stain/monoclonal antibody detection in BAL
  or biopsy.
• Treatment
• High dose cotrimoxazole
• ventilation
• If sulphonamide allergy pentamidine, dapsone,
  clindamycin plus primaquine, atovaquone.
• Chemoprophylaxis
• cotrimoxazole or inhaled pentamidine
• ?? Still needed on HAART

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Mycobacterium tuberculosis

• 2-10 annual risk of infection if HIV positive
• Worldwide, most illness is reactivation of latent
  infection
• In Africa, 50 of HIV infected are MTB infected
• Presentation
• Rapidly progressive disease on primary infection
• Extrapulmonary disease more likely as CD4 cells
  decline

• Hospital outbreaks
• in AIDS patients from smear-negative individuals
  (bronchoscopy and aerosolised pentamidine)
• Multiple drug resistant (MDR) TB outbreaks with
  spread to hospital staff in USA
• Therapy
• in the absence of drug resistance is standard for
  the site of infection but given for longer e.g.
  six months after culture negative

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Mycobacterium avium-intracellulare (MAI) complex

• M. avium - TB in birds
• M. intracellulare - atypical human isolate
• Ubiquitous (soil, water, food, animals)
• Presentation
• Pulmonary infection in non-AIDS patients
• Disseminated in advanced AIDS (CD4lt0.1 X 109/l)
• Fever, night sweats, weight loss. Organ
  infiltration.

• Diagnosis
• culture after 1-4 incubation of sample from a
  sterile site,
• blood culture, bone marrow, lymph node, liver
  biopsy
• Therapy
• Problematic resistance to antituberculous drugs
• Clarithromycin or azithromycin (macrolides) and
  ethambutol plus rifabutin (/- clofazamine
  rifampicin ciprofloxacin amikacin)
• Prophylaxis
• rifabutin at CD4lt0.1 X 109/l

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Cerebral Toxoplasmosis

• T. gondii
• Protozoal infection, usually asymptomatic (50
  infected by middle age) or glandular fever
• Zoonosis from cats
• Presentation in AIDS
• main cause of focal CNS lesions in AIDS
• Pneumonitis and chorioretinitis may also occur
• Empirical antitoxoplasma therapy IF
• 1. Ring-enhancing lesions on CT/MRI scan and
• 2. Toxoplasma IgG antibody (dye test/ELISA) are
  present

• Histology and culture of brain biopsy may be
  required if no response at 10 days
• Therapy
• Pyrimethamine plus folinic acid and sulphadiazine
  or clindamycin for 3-6 weeks acutely (expert
  advice needed!)
• Prophylaxis
• Secondary to prevent relapse pyrimethamine/dapson
  e
• Primary in seropositive patients with low CD4
  counts

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Cryptococcus neoformans

• Capsulate urease-positive yeast
• found in bird droppings
• asymptomatic infection by pulmonary route
• Leading systemic fungal infection in AIDS
• insidious meningitis
• Capsule inhibits alternate pathway of complement
• Little inflammation
• skin and bone infections less common

• Diagnosis
• microscopy of CSF with india ink (50 sensitive)
• antigen detection by latex agglutination in serum
  or urine (gt90sensitive)
• CSF or blood culture
• Treatment
• amphoteracin B or fluconazole
• lifelong fluconazole maintenance therapy required
  (even with HAART?)

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Cryptosporidiosis

• C. parvum protozoan parasite
• Water-borne outbreaks, faecal-oral spread, esp.
  from farm animals
• Self-limiting infection (2-3 weeks) in normal
  children
• Chronic watery diaarhoea in AIDS, can be
  life-threatening

• Diagnosis
• Modified acid-fast stain
• Monoclonal based immunofluorescence
• Prevention
• Boil water if at risk
• Treatment
• Difficult
• Azithromycin with paromomycin shows promise

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Viral infections in AIDS

• HSV
• Chronic mucocutaneous infection (oral
  anogenital)
• Treatement acyclovir
• VZV
• shingles

• CMV
• Sites
• retinitis
• encephalitis
• hepatitis
• pneumonia
• Treatment ganciclovir
• Paradoxical worsening of retinitis after HAART
• HHV8
• Kaposis sarcoma

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Acquired ImmunodeficiencyNeutropenia

• Causes
• Iatrogenic
• Post-chemotherapy
• Post-BMT
• Aplastic anaemia (e.g. post Chloramphenicol).
• Other drugs (rarely high dose beta-lactams)
• Diagnostic difficulty
• absence of pus/localisation
• rely on fever as cardinal sign

• Empirical therapy
• Febrile neutropenic cannot await culture results
• URGENT bactericidal broad-spectrum agents
• anti-pseudomonal penicillin aminoglycoside
• Add vancomycin (anti-Gram-positive), then
  antifungal if no improvement
• Other measures HEPA filtered air, G-CSF, gut
  decontamination

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Acquired ImmunodeficiencyNeutropenia
Cytotoxic
Neutro phils X 109/l
Onset maximum risk
0.5 0.1
Time (days)
2
4
6
8
10
12

• Timely admission in cyclical chemotherapy
• lt0.5 x 109/l risk of infection
• lt0.1 x 109/l high risk of septicaemia

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Opportunistic mycoses in neutropenia

• Aspergillus fumigatus
• saprophytic mould in soil
• inhaled spores infect lung in prolonged
  neutropenia
• necrotising pneumonia and dissemination
• filamentous septate hyphae in tissues
• Common contaminant of culture media.
• Treatment Amphoteracin B (liposomal less toxic)

• Candida albicans yeast-like fungus
• endogenous infection
• predisposition by diabetes, iv feeding,
  antibiotics
• Blood cultures positive in 40.
• Treatment Amphoteracin B, Fluconazole

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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

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Infections in Pregnancy

• Increased risk of infection with
• Ascending UITI
• (see UTI lecture)
• Listeria monocytogenes (a Gram-positive rod)
• causes miscarriage, stillbirth or severe illness
  in newborn, septicaemia and meningitis in mother
• Prevention
• Pregnant women should avoid eating paté and
  mould-ripened or blue-veined soft cheese, e.g.
  Brie, Camembert, Stilton, Danish blue (hard
  cheeses, cheese spreads are OK) and raw chilled
  ready meals
• Treatment ampicillin

• Puerperal sepsis
• Classically Group A beta-haemolytic streps
  (Semmelweiss)
• Now group B most important
• Maternal speticaemia, neonatal septicaemia and
  meningitis
• Higher risk in US than UK
• Prophylaxis with ampicilin during labour
• Mixed pelvic infections including anaerobes if
  retained products need broad spectrum cover

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Congenital Infections

• Toxoplasmosis
• Rubella
• CMV
• HSV
• Hepatitis B, HIV
• Parvovirus B19
• Syphilis
• Ophthalmia neonatorum

• Seek expert advice on management diagnosis
• Prevention
• Vaccination
• rubella, hep B
• Treatment
• Antimicrobial (anti-retrovirals, syphilis,
  acyclovir, spiramycin for toxo, silver nitrate
  eye drops etc.)
• Other (intra-uterine blood transfusion for B19)
• Screening (syphilis, HIV, hep B), Vigilance ,
  Avoidance (e.g. of slapped cheek syndrome)

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Infections in Neonates

• Early onset (lt12 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

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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