SH/Lectures/Infection and pathology in the immunocompromised

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Definitions

  • Immunocompromised host - an individual with impaired immunity
  • Immunodeficiency disorder - a condition associated with impaired immunity
  • Immunosuppression - therapeutic measures to reduce the activity of the immune system
    • Immunosuppression is a cause of immunodeficiency.

Causes of immunodeficiency

Primary immunodeficiency Acquired immunodeficiency

≈ Congenital immunodeficiency

  • Usually caused by a single gene disorder

Much more common than congenital immunodeficiency

Modern medicine is discovering more single gene disorders causing immune diseases.

Primary immunodeficiency disorders

See SH/Pracs/Immunology for examples of this.

  • Severe cases present in the first year after birth.
    • Immune system is not needed in utero. (Mother shields us from infections -- don't need immune system)
    • Maternal antibody from placenta and lactation provides protection in the first few months of life. (So B cell disorders don't present in this time)
  • Disorders may affect T cells, B cells, neutrophils or complement.
    • T cell disorders are generally associated (or “combined”) with defects in antibody production.
  • Most disorders have been linked to abnormalities in a single gene.
    • Several examples are X-linked. (60% of patients are male).

The boy in the bubble

1971-84. He had severe combined immunodeficiency, a congenital disorder that prevented him from making T cells. His older brother had died in infancy from the same disorder.

To shield him from pathogens, he lived in a plastic bubble with filtered air. He was given a NASA- designed suit for walks.

He died after acquiring EBV from a bone marrow transplant from his unaffected sister.

Point = normally we depend on the immune system to protect us; if it doesn't work, we die.

Management of primary immunodeficiency disorders

  • Infections must be diagnosed and treated aggressively.
  • Primary antibody deficiency responds well to passive immunization with iv or sc IgG pooled from healthy blood donors.
  • Primary T cell deficiencies and neutrophil disorders can be treated with haematopoietic stem cell transplantation, provided an MHC-matched donor is available.
  • In principle, primary immunodeficiencies are good candidates for gene therapy. Small numbers of patients have responded successfully to gene therapy, but some of these developed leukaemia related to the therapy.

Causes of acquired immunodeficiency

  • AIDS
  • Malnutrition
  • Old age
  • Medically caused
  • Associated with other diseases, for example:
    • Malignancy
    • Tuberculosis
    • Diabetes mellitus (esp bacterial infections and candida because of impaired neutrophil function/defective neutrophils)
    • Renal failure
  • Reduced/absent spleen

Vicious circle: Protein calorie malnutrition --> immunodeficiency --> increased infections --> protein calorie malnutrition (due to medical and social factors)

Old age and immunodeficiency

  • Increased infections
  • Pneumonia called “the old man’s friend”
  • Poorer response to vaccines
  • T cell function especially affected
  • Total T cell numbers do not decline, but
    • Thymus produces fewer new naïve T cells
    • Memory cell compartment becomes dominated by cells specific for a limited number of pathogens, esp cytomegalovirus
    • Sort of like a monoculture in ecology
  • Established antibody responses less affected

Medical causes of immunodeficiency

  • Glucocorticoids (“steroids”) -
    • Widely used to inhibit unwanted immune responses in:
      • Autoimmune diseases e.g. rheumatoid arthritis
      • Allergic disorders e.g. steroid puffers for asthma (the use of puffers limits the location of adverse effects -- medically we actually want to suppress the immune system)
      • Transplantation
  • Immunosuppressive drugs e.g. cyclosporin A are used in transplantation and severe autoimmune diseases
  • The above drugs inhibit all immune responses, not only unwanted ones.
    • T cell-dependent responses are especially affected.
  • Cytotoxic drugs in cancer chemotherapy
    • Cytotoxic drugs kill rapidly dividing cells, both malignant and non-malignant.
    • Non-malignant rapidly dividing cells in the immune system include:
      • Neutrophil precursors, which proliferate rapidly, especially during infection.
      • Lymphocytes, which proliferate rapidly after activation by antigen.

Reduced/absent spleen

  • Causes of hyposplenism:
    • Surgical removal
      • Abdominal trauma, lymphoma
  • Medical causes of impaired function:
    • Sickle cell disease, many other causes
  • Congenital absence (rare)
  • Spleen is important in defence against circulating encapsulated bacteria
  • Patients are at increased risk of infections with S. pneumoniae, H. influenzae, N. meningitidis
    • Risk of overwhelming sepsis
  • Management
    • Prompt and vigorous treatment of infections
    • Maintain vaccination against encapsulated bacteria

General features of immunodeficiency disorders

  • Increased risk of infection
    • Major consequence of immunodeficiency disorders.
  • Increased risk of certain types of cancers
    • Especially virus induced
  • Increased risk of autoimmune disorders
    • Paradoxical
      • possibly caused by loss of regulatory T cells? (Impaired regulation of the immune system)

Infection in immunodeficiency disorders

  • Infections with organisms that normally do not cause disease (opportunistic infections)
  • Infections with conventional pathogens have unusual features, and may be:
    • more severe or recurrent
    • incompletely responsive to standard treatment
    • at unusual sites e.g. osteomyelitis
  • Patterns of infection reflect degree and nature of immunodeficiency.

Patterns of infection

  • Deficiency of all T cells or CD4 T cells:
    • impairment of macrophage function, cytotoxic T cell function, antibody production
    • many different pathogens:
      • intracellular bacteria eg M. tuberculosis
      • viruses
      • various fungi, bacteria, protozoa
    • live vaccines may cause systemic infection
  • B cell, neutrophil, complement deficiencies - infections by extracellular bacteria

The moral of the story

  • Don't give live vaccines to people with impaired immune function

Malignancy in immunodeficiency disorders

  • Incidence of selected cancers is greatly increased in long- standing immunodeficiency, eg AIDS, transplant recipients.
  • AIDS patients have 100-fold increased risk of B cell lymphoma.
    • Risk is proportional to the degree of reduction of CD4 count
  • Often these cancers are associated with viruses, e.g.:
Cancer Virus
B cell lymphoma Epstein-Barr virus
Kaposi's sarcoma Human herpesvirus type 8 (HHV-8)
  • Incidence of most common cancers (eg breast, colon) is little changed.

Development of malignancy

  • Malignancy (cancer) arises from a single abnormal cell which divides in an uncontrolled fashion
  • Malignancy is caused by abnormal genes
  • Theory - need a minimum of 3 abnormal genes in the same cell for it to become malignant
  • Some viruses (oncogenic or cancer-causing viruses) can provide an abnormal gene which can co-operate with abnormal mutated cellular genes
  • Cells chronically infected with such viruses need fewer mutations of cellular genes to become malignant.

Development of malignancy in the immunocompromised host

VirusesCausingCancer.png

  • Persistent viral infection will by random chance result in a cell with mutations that cooperate with the virus, and that these affected genes may cause malignancy

Opportunistic infections in HIV

What is an opportunistic infection?

  • Definition: Infections which generally do not cause symptomatic disease in those with a normal immune system. The patterns of infections and malignancy seen are proportional to the precise nature and extent of the immune dysfunction

Nature of immune defects

  • T-cells: ↓ number, DTH (delayed-type hypersensitivity), cytotoxic response
  • neutrophils: ↓number,phagocytosis
  • B-cells: ↓antibodyresponsiveness, ↑ autoimmune
  • macrophages: ↓ phagocytosis & chemotaxis
  • NKcells: ReducedIL-2→↓T-cellexpansion
  • As you lose your CD4 cells, certain infections come in at predictable points in time.
  • Similar graphs are shown in SH/SGs/Introduction to HIV
    • When we see a sick patient, it is very unlikely that anyone with 500 CD4 cells are going to have any of the severe infections (you don't see them until <200 CD4/microliter)

OI in HIV patients

  • Skin infections
  • Respiratory infections
  • Systemic viral infections
  • Gastrointestinal infections
  • CNS infections
  • Haematological manifestations

Dermatologic manifestations

  • Rashes are common in viral infections
  • Rashes on the palm and soles only happen in: HIV, secondary syphilis and drug reactions
  • Rash associated with seroconversion illness (palms and soles!)
  • Staphylococcal infections - persistent folliculitis, superficial abscesses
  • Fungal lesions - onychomycosis, tinea corporis, tinea capitis (increased extent and severity of lesions)
  • Herpes zoster (especially in a young adult or if recurrent)
  • Herpes simplex (recurrent or severe cases)
  • Molluscum contagiosum
  • Cutaneous cryptococcosis - disseminated diseases causing lung pathology and meningitis, but also skin lesions

Mucosal lesions

Oral

  • oral hairy leukoplakia
  • oral candidiasis (pseudomembranousor erythematous) (thrush)
  • oral ulceration (broad differential diagnosis including HSV, CMV, aphthous ulceration, histoplasmosis and squamous cell carcinoma
  • Kaposi’s sarcoma

Genital

  • candidiasis
  • HSV
  • cervical dysplasia (HPV)
  • carcinoma in situ (anal or cervical)
  • perianal ulceration (HSV)

Moderate immunodeficiency

Bacterial infections

  • S. pneumoniae
  • S. aureus
  • H. influenzae
  • salmonella
  • Mycobacterium tuberculosis
    • In poor countries where TB is endemic, at least 50% of HIV patients contract TB

Anyone can catch these, but are more common in the immunocompromised host

Advanced immunodeficiency

Bacteria
  • gram negative organisms, especially salmonella
Fungi
  • Pneumocystis carinii/Pneumocystis jiroveci pneumonia (="PCP")
  • endemic fungi (histoplasmosis) cryptococcosis
  • Candida spp
  • Penicillium marneffei (fungus causing skin infections; Thailand)
Protozoa
  • Toxoplasma gondii (50% of adults carry this latently -- can get infected if you get HIV)
  • Leishmania donovani
  • Isospora, Microsporidium spp,
  • Cryptosporidium parvum
Viruses
  • HIV
  • HHV8
  • EBV

Have to get the patient on HAART ASAP, so that CD4 count increases and a lot of these things will improve

Late stage HIV

  • Bacteria
  • Viruses
    • CMV (retinitis, polyradiculopathy,meningitis)
    • JC virus (PML)
  • Tumours
    • 1o cerebral lymphoma
    • Kaposi’s sarcoma

Aetiology of common OIs

  • Bacteria
    • Streptococcus pneumoniae
    • Non-typhi salmonellae
    • Mycobacteria tuberculosis
    • Mycobacteria avium complex
  • Fungi
    • Pneumocystis carinii
    • Cryptococcus neoformans
    • Candida spp
  • Protozoa
    • Toxoplasma gondii
    • Crytosporidium/Microsporidium
  • Viruses
    • CMV

Bacteria: Pneumococcus

  • ↑20-50x in HIV infection
  • any stage of HIV,↑ if CD4+ <500
  • smokers,alcohol,underlying respiratory disease
  • Presentation:
    • lobar pneumonia
    • sinusitis
    • septicaemia
    • meningitis
  • Treatment:
    • as for non-HIV; use penicillin, add vancomycin if the penicillin doesn't get into the CSF (Cerebrospinal fluid)
  • Prevention:
    • Pneumovax (23 valent) every
    • 5 years
    • ? role for penicillin prophylaxis

Bacteria: Mycobacterium avium complex (MAC)

  • Everyone's exposed to it, but it's very wimpy and it doesn't get anyone with CD4>50
  • Advanced immunodeficiency, CD4 <50
  • 1/3 will develop MAC without prophylaxis
  • Presentation: unwell
  • Symptoms: fever, sweats, weight loss, anaemia
  • Signs: wasting, lymphadenopathy, anaemia, hepatosplenomegaly
  • Diagnosis:
    • MAC PCR and blood cultures
    • bone marrow biopsy or lymph node biopsy --> microscopy and culture
    • Need to get CD4 up to 200 or more

Fungi: Pneumocystis jiroveci

  • Still the most common ADI
  • CD4+ < 200 (mean 110)
  • Rarer in developing world, die earlier (TB)
  • Sites:
    • pulmonary
    • extra-pulmonary: skin, adrenals, sinuses
  • Presentation: insidious, often over weeks;
    • fever >39oC
    • dry cough rarely productive (if purulent sputum present – think of another diagnosis)
    • increasing shortness of breath on exertion (SOBOE) – may be subtle decrease in exercise tolerance in early stages – take a careful history! "Can't run as far as normal!"
    • other features of HIV: wasting, oral candida
  • Signs:
    • fever
    • ↑RR
    • desaturation with exercise
    • chest often clear to auscultation
  • Diagnosis:
    • CXR: bilateral peri-hilar shadowing (sparing bases/apices) 10% normal, 10% focal Δ ie cystic, coarse, lobar
    • induced sputum/BAL:silver methanamine or fluorescent stain using monoclonal Ab, organism not culturable
    • ABG (arterial blood gas)
    • PCR on sputum-unde rinvestigation; can pick up normal flora! Too sensitive?!

Fungi: Cryptococcus neoformans

  • CD4+<100
  • geographic variation++
  • inhaled encapsulated yeast
  • Sites:
    • meninges+/-brain(rare)
    • lung
    • skin (implies fungaemia)
    • bone (rare in HIV)
    • prostate (focus for reactivation)
    • liver, myocardium, adrenal-all rare
  • Presentation: insidious
    • low grade fever
    • headache,meningism in less than 50%
    • focal signs common
    • mass effect/cranial nerve involvement
  • Diagnosis:
    • CT brain with contrast
    • CXR
    • LP with opening pressure,Indiaink,CRAG (cryptococcal polysaccharide antigen )

Fungi: Candida species

  • CD4+200-350
  • Candida albicans
  • other species including Candida tropicalis, glabrata, dubliniensis
  • Diagnosis: clinical,fungal culture,endoscopy
  • Treatment: azoles
  • multi-drug resistance in late stage -> add terbinafine to azole agent
    • Others: new azole agents (posaconazole, voriconazole), amphotericin, topical gentian violet
    • New: liposomal nystatin, echinocandins

Protozoa: Toxoplasma gondii

  • CD4<100
  • bradyzoites become active--> tachyzoites (latent form becomes active)
  • Presentation:
    • 70% altered mental state
    • 60% hemiparesis and other focal signs
    • 50% headache
    • 30% fits
    • Other: fever, confusion, coma
  • CT = well circumscribed lesion in brain -- cryptococcal brain abscess

Intestinal protozoa: Cryptosporidium parvum

  • CD4 < 100
  • Transmission: H2O, person-to-person
  • Symptoms:
    • diarrhoea (10% >2L/d)
    • wasting, abdominal pain, nausea
    • cholangiopathy
    • URTI
  • Diagnosis:
    • stool (ZN), small bowel biopsy
  • Treatment: no proven effective therapy
    • HAART of most benefit
    • nutrition
    • symptomatic --> opiates, octreotide
    • therapeutic agents – paromomycin, azithromycin, bovine colostrum, nitazoxanide

HSV-2 in HIV positive individuals

  • HSV-2 seroprevalence 63-77%
  • Coinfection
  • Transmission
    • Genital ulcer disease

Immunocompromised HSV

  • almost always reactivation
  • more frequent recurrences
  • more severe
    • larger and more painful
    • more prolonged
    • viral shedding and lesions last for weeks to months
  • spread to surrounding structures
    • eg. oesophagus and lungs
  • increased risk of dissemination but still rare

Oncogenic viruses in HIV

  • EBV
    • Burkitt’s lymphoma
    • NHL (Non-Hodgkin Lymphomas)
    • 1o cerebral lymphoma
  • HHV8
    • Kaposi sarcoma
    • Castleman’s syndrome
    • Body cavity lymphoma
  • HPV(16,18)
    • Squamous carcinoma cervix and anus

HHV8

  • gamma herpesvirus resembling simian herpesvirus
  • B-lymphocyte trophic
  • seropositivity ranges from 0 - 20% in healthy adult population to 80% in patients with KS

HHV8 The virus that causes KS

  • Epidemiology
    • notaubiquitousagent
    • geographicspecificityeghighincidence in Africa and Southern Italy
  • Transmission
    • sexual
    • transplantedorgans
    •  ??transplacental

HHV8 related syndromes

  • Kaposis’ sarcoma : HHV8 found in KS tissue regardless of HIV status of the host
  • primary effusion lymphoma : HHV8 found regardless of HIV status
  • multicentric Castleman’s disease : HHV8 found only in HIV infected host

Multicentric Castleman’s Disease (MCD)

  • lymphoproliferative disorder characterised by lymph node hyperplasia with germinal centre formation and marked capillary proliferation
  • B cell proliferation secondary to IL-6 production
  • MCD - evidence of multisystem involvement histologically both clinically and
  • progressive, fatal course in context of HIV - most cases reported dead within 6 months
  • outlook dramatically improved by antiretroviral therapy

Old notes

Primary Immunodeficiencies

Severe primary immune disorders present in the first year of birth, as the immune system in not required in utero and maternal antibody provides protection in the first months of life. Most primary immunodeficiencies have been linked to abnormalities in a single gene, which may affect T-cells, B-cells, neutrophils or complement. Management includes aggressive treatment of infections, passive immunization with IgG, or stem cell transplantation.

Acquired Immunodeficiencies

Acquired immunodeficiency can be caused by:

  • AIDS
  • Malnutrition
  • Old age- t-cell function especially affected
  • Medically caused (immunosuppression) by:
    • Glucocorticoids used in autoimmune and allergic diseases and in transplants
    • Cytotoxic drugs in cancer chemotherapy which affect rapidly dividing cells including haematopoietic tissue
  • Associated with other diseases, for example:
    • Malignancy
    • Tuberculosis
    • Diabetes mellitus
    • Renal failure
  • Reduced/absent spleen (congenital asplenia), increasing risk of infection by circulating encapsulated bacteria.

Features of Immunodeficiency

Immunodeficiency is characterised by an increased risk of infection by conventional and opportunistic organisms, certain cancers and, paradoxically, an increased risk of autoimmune diseases (due to a lack of regulatory t-cells). Opportunistic pathogens are pathogens which would not cause disease in a normal, healthy human host.

The likelihood of some cancers is increased because some viruses (oncogenic or cancer-causing viruses) can provide an abnormal gene which can co-operate with abnormal mutated cellular genes. Cells chronically infected with such viruses need fewer mutations to become malignant. These cancers include cervical cancer, B-cell lymphomas and Kaposi’s sarcoma.

Opportunistic Infections in HIV

Dermatologic:

  • Seroconversion rash
  • Staph folliculitis and abcesses
  • Fungal lesions
  • Herpes zoster
  • Herpes simplex

Mucosa associated:

  • Oral hairy leukoplakia
  • Oral candidiasis
  • Oral ulceration (HSV, CMV)
  • Kaposi’s sarcoma
  • Cervical dysplasia
  • Perianal ulceration