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Case 7: Anatomical Pathology (Immunodeficiency Diseases), Types of Stains …
Case 7: Anatomical Pathology (Immunodeficiency Diseases)
Causes of Immunodeficiency
Outline the Causes of Immunodeficiency
There are various causes of Immunodeficiency
Primary Immunodeficiency
Primary Immunodeficiency refers to causes that are Hereditary or Congenital
These are ALL uncommon and include diseases such as:
X-linked agammaglobulinaemia (of Bruton)
Common variable immunodeficiency
Isolated IgA deficiency
DiGeoge's Syndrome (Thymic Hypoplasia)
Severe Combined Immunodeficiency (SCID)
Secondary Immunodeficiency
Secondary Immunodeficiency refers to causes that have been acquired through the patient's lifetime
These causes are much more common, and are seen more often in clinical practice
They include Iatrogenic causes that are due to treatment with immunosuppressive agents such as:
Steroids
Radiation
Chemotherapy (for cancer)
Cyclosporin which are drugs used post-transplantation
Other Secondary or Acquired Causes of Immunodeficiency include:
Infections such as AIDS, and Measles
Malignancy such as Hodgkin's Disease
Other causes such as malnutrition, Autoimmune Disease, Chronic Renal Failure (CRF) and Sarcoidosis
Acquired immunodeficiency Syndrome (AIDS)
Define the condition: Acquired immunodeficiency Syndrome (AIDS)
AIDS is defined as severe immunodeficiency resulting from an infection with the Human Immunodeficiency Virus (HIV), which belongs to the group of viruses known as the Retrovirus
AIDS is characterized by Opportunistic Infection and increased incidence of Malignancies
Opportunistic Infections in AIDS
Describe Opportunistic Infections in AIDS
Opportunistic Infections are infections caused by organisms that rarely cause severe disease in immunocompetent individuals.
In AIDS they can cause severe, often lethal disease.
The presence of these infections in an HIV Positive person, as well as the presence of certain malignancies, indicates that the person has Full-Blown AIDS (as per the AIDS defining Criteria)
Opportunistic Infections Associated with HIV and AIDS
List the Opportunistic Infections associated with HIV and AIDS according to the Aetiological Agents
Opportunistic Infections associated with HIV and AIDS according to the Aetiological Agent are as follows:
Fungal Infections:
Pneumocystis jiroveci
Candida
Cryptococcus
Histoplasmosis
Protozoal Infections:
Cryptosporidium, Microsporidium, and Isospora belli
Cryptosporidiosis is a disease that causes watery diarrhoea and is caused by Cryptosporidium
Toxoplasmosis
Bacterial Infections:
Tuberculosis
BCG adenitis - Mycobacterium bovis
Severe, recurrent Bacterial Pneumonia
Viral Infections:
Cytomegalovirus
Human Papovavirus (JC virus)
Herpes Simplex
Opportunistic Fungal Infections: Pneumocystis jiroveci
Describe the characteristics of Pneumocystis jiroveci
Pneumocystis jiroveci is a fungal organisms which causes Pneumonia in AIDS
This is the presenting feature in at least 20% of cases
50% of AIDS patient develop it at some stage of their illness
Caption: The image shows Heavy Pale Lungs as a result of the fungal organism, Pneumocystis jiroveci
Describe the microscopic features of Pneumocystis jiroveci
Pneumocystis jiroveci causes Alveolar spaces to become filled with pink, foamy, amorphous material composed of proliferating fungi and cell debris
Pneumocystis jiroveci causes bubbly secretions in the alveoli
Fungi are within the foamy intra-alveolar material
Image indicated Pneumocystis stained with a Silver Stain
This is Cytology of bronchioalveolar Lavage showing the Fungi which appear black
Opportunistic Fungal Infection in AIDS: Candida
Describe the characteristics of the Fungal Infection: Candida
Candida also known as Thrush is common in AIDS, and be severe involving the Mouth, Oesophagus and Skin
Candida may disseminate to visceral organs
Caption: In the image, Tan-Yellow plaques are seen in the lower oesophagus, along with the Mucosal Hyperemia are due to Candida
Describe the Microscopic Features of Candida
Candida involving the Small Intestine
There is an ulcer showing Superficial Slough in the small intestine
Candida involving the small intestine
A Silver Stain has been used to identify Candida Yeast and Pseudo-hyphae in the small intestine
Candida involving the Lung
Multiple pale nodular lesions visible on the cut surface of the Lung as a result of Candida Infection
Opportunistic Fungal Infections in AIDS: Cryptococcus
Describe the characteristics of Cryptococcus
Cryptococcus neoformans is a Fungus which can cause opportunistic infection in the setting of AIDS
Cryptococcus Meningitis is the major manifestation of Cryptococcus neoformans, typically a Basal Meningitis with a Gelatinous Appearance
Caption: Image shows Cryptococcus yeast forms with a soap bubble appearance, the features are consistent with Mucormycosis
Describe the macroscopic and microscopic features of Cryptococcus
Cryptococcus involving the Spleen
Cryptococcus involving the Spleen results in the Spleen showing a gelatinous cut section
Cryptococcus involving the Spleen
Cryptococcus involving the Spleen results in a microscopy indicating a soap bubble appearance due to the extensive Cryptococcus
High power staining showing the encapsulated spherical Cryptococcus yeast
Special stain highlights the Mucoid Capsule Pink
Opportunistic Fungal Infections in AIDS: Histoplasmosis
Describe the characteristics of Histoplasmosis
Histoplasmosis causes Pneumonia or a Disseminated Disease in the setting of AIDS
Caption: Silver staining highlighting Histoplasmosis yeast black
Describe the microscopic features of Histoplasmosis
The image below shows a kidney with an abscess at the upper pole
Infarction of most of the kidney, sparring part of the upper pole
Histoplasmosis involving Kidney
Microscopy of the Kidney shows numerous Fungal Hyphae seen on the silver stain
Hyphae show right-angle branching in keeping with Mucormycosis
Histoplasmosis involving the Kidney
Vascular invasion in the kidney as a result of Histoplasmosis
Fungal occlusion of blood vessels with resultant thrombosis and infarction
Opportunistic Protozoal Infections in AIDS: Cryptosporidium, Microsporidium and Isospora belli
Describe the characteristics of Cryptosporidium, Microsporidium and Isospora belli
Persistent Diarrhoea is very common in AIDS, and is characterized as profuse, watery and debilitating, and is caused by Cryptosporidium, Microsporidium and Isospora belli.
Describe the microscopic features of Cryptosporidium
Cryptosporidium involving the small intestine results in cryptosporidium oocyst on the surface of the epithelium
Opportunistic Protozoal Infections in AIDS: Toxoplasmosis
Describe the characteristics of Toxoplasmosis
Toxoplasmosis may cause Pneumonia, Encephalitis and CNS Masses
Describe the Macroscopic and Microscopic features of Toxoplasmosis
Toxoplasmosis involving the brain
Toxoplasmosis causes a necrotic lesion on the cut surface of the brain
Slow-growing protozoa is formed and is called a Bradyzoites encased in a cyst with a cyst wall
There are multiple basophilic dot-like parasites that can be seen in the cyst
Opportunistic Bacterial Infection: Tuberculosis
Describe the characteristics of Tuberculosis
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Describe the Macroscopic and microscopic features of Tuberculosis
Tuberculosis involving the Lung
Multiple pale/white tubercles visible on the cross section of the lung due to Tuberculosis
Pale areas
Tuberculosis involving the Mediastinal Lymph Nodes
Tuberculosis causes multiple white/pale tubercles on mediastinal lymph nodes
White areas
Tuberculosis involving the Lung Lymph Node
Multiple white tubercles visible on the lymph node of a lung as a result of Tuberculosis
Tuberculosis involving the Spleen
Tuberculosis causes multiple pale tubercles on the cut surface of the Spleen
Tuberculosis Meningitis (Tuberculosis involving Brain)
TB Meningitis is associated with a thick gelatinous exudate at the base of the brain
Tuberculosis involving the Brain
Tuberculosis can result in the formation of a mass in the brain called a Tuberculoma
Necrotising Granulomatous Inflammation
Provide a caption of the pathology in the image
Necrotising Granulomatous Inflammation
Langerhans type giant cell in centre (Multi-nucleated Giant Cells)
List the components of a Granulomatous Inflammation
Granulomatous inflammation is composed of:
Aggregates of Epithelioid histiocytes
Peripheral lymphocytes
Langerhans giant type cells
Sometimes or most times Central Necrosis
Opportunistic Bacterial Infections: BCG Adenitis - Mycobacterium bovis
Describe the characteristics of BCG adenitis
The immune reconstitution inflammatory syndrome (IRIS) may explain the BCG complications in HIV positive children on Highly Active Antiretroviral Therapy (HAART)
Possible manifestations include:
Persistent ulceration and discharge from the vaccination site
Regional lymphadenitis with or without abscess formation and/or fistula formation
Disseminated BCG Infection
In HIV-infected children not on Highly Active Antiretroviral Therapy (HAART) possible manifestations include:
Localised disease of the vaccine site with or without Ipsilateral Axillary Lymphadenitis is mainly described
Describe the Macroscopic and Microscopic features of Axillary Lymphadenopathy
Axillary Lymphadenopathy
Microscopic image of an axillary lymph node with Axillary Lymphadenopathy
The Lymph Node shows Necrotising Granulomatous Inflammation
Ziehl-Neelsen Stain
Ziehl-Neelsen stain shows numerous pink Acid-Fast bacilli
Opportunistic Bacterial Infection: Bacterial Pneumonia
Describe the characteristics of Bacterial Pneumonia in AIDS
Patients with AIDS are also susceptible to severe, recurrent Bacterial Pneumonias
Opportunistic Viral Infections in AIDS: Cytomegalovirus
Describe the characteristics of Cytomegalovirus
Cytomegalovirus is associated with Pneumonia, GIT involvement with Oesophagitis and Colitis, Chorioretinitis, and brain infection in the setting of HIV and AIDS
Chorioretinitis an inflammation of the choroid (thin pigmented vascular coat of the eye) and retina of the eye.
It is a form of posterior uveitis
Describe the macroscopic and microscopic features of Cytomegalovirus
Ulcers in colon due to Cytomegalovirus
Microscopic features of Cytomegalovirus
Enlarged cell
Enlarged nucleus
Owl's eye intranuclear occlusion
Basophilic granular inclusions in the cytoplasm
Cytomegalovirus viral inclusions in the lung
Enlarged cell
Enlarged nucleus
Owl's eye intranuclear inclusions
Basophilic granular inclusions in the cytoplasm
Opportunistic Viral Infections in AIDS: Human Papovavirus (JC Virus) and Herpes Simplex Virus
Describe the characteristics of the Human Papovavirus (JC Virus) and Herpes Simplex Virus
Human papovavirus (JC Virus) causes Progressive Multifocal Encephalopathy
"Encephalopathy" means damage or disease that affects the brain
Herpes Simplex virus causes local mucocutaneous lesions or disseminated disease
Caption: Oesophageal ulcer
Describe the macroscopic and microscopic features of the Herpes Simplex Virus
Herpes virus inclusions
Large cell with nuclear viral inclusions and multinucleation, margination of chromatin and moulding in keeping with Herpes Simplex Virus inclusions
Malignant Neoplasms in AIDS
List the types of Malignant neoplasms associated with AIDS
There are various types of neoplasms associated with AIDS
These include:
High grade B-cell Lymphoma
Burkitt's Lymphoma
Diffuse large B-cell Lymphoma
Primary CNS and body cavities Lymphoma
Kaposi's Sarcoma
Squamous carcinoma of Conjunctiva
Carcinoma of the Cervix
Describe the pathology identified in the following images
Lymphoma of the small bowel, this is noted as a polypoid mass
Burkitt's Lymphoma
Burkitt's Lymphoma which causes a diffuse lymphoid infiltrate with a starry sky appearance
Malignant Neoplasms in AIDS: Kaposi's Sarcoma
Describe the characteristics of Kaposi's Sarcoma
Kaposi's sarcoma is a vascular neoplasm, which is quite rare outside of AIDS
Kaposi's sarcoma is caused by a Human Herpesvirus Type 8 (HHV8)
Kaposi's sarcoma results in multiple reddish-purple skin lesions, nodal involvement and dissemination to visceral organs occurs
Describe the macroscopic and microscopic features of Kaposi's Sarcoma
Violaceus plaques due to Kaposi's
Sarcoma
Kaposi's Sarcoma in the Stomach
Macroscopic Image: Kaposi's sarcoma in the stomach results in a Haemorrhagic surface of the stomach
Microscopic image: Vascular proliferation in keeping with Kaposi's Sarcoma
Kaposi's sarcoma in the Bowel
Haemorrhagic areas in the bowel are due to the presence of Kaposi's Sarcoma
Haemorrhagic lymph nodes in keeping with nodal involvement as a result of Kaposi's sarcoma
Vascular Tumour
Microscopy of a vascular tumour and the tumour staining Positive with HHV8
Spindle-cell proliferation with intervening cleft spaces containing red blood cells due to Kaposi's Sarcoma
CNS Manifestations of HIV and AIDS
Outline the CNS manifestations of HIV and AIDS
CNS manifestations of HIV and AIDS include:
Infections such as Cryptococcus and Toxoplasmosis
Cryptococcus neoformans with spherical, encapsulated yeast
B cell Lymphoma
Meningitis from HIV itself and Subacute Encephalitis with memory loss, apathy, depression and dementia
Progressive Multifocal Leukoencephalopathy (PML) with:
Destruction of white matter with progressive demyelination
Progressive neurologic deterioration
Describe the pathology for the following CNS manifestations of HIV and AIDS
Progressive Multifocal Encephalopathy
Image indicates degenerative change within the subcortical white matter associated with Progressive Multifocal Encephalopathy
Progressive Multifocal Leukoencephalopathy (PML) - Viral inclusions
Microscopy indicates nuclear viral inclusions associated with Progressive Multifocal Leukoencephalopathy (PML)
Lymph Node Findings associated with HIV and AIDS
Describe the Lymph Node Findings associated with HIV and AIDS
The changes are not specific, and are non-diagnostic, but the following stages have been recognised which correlates with increasing immunosuppression and worsening of the prognosis:
Explosive Follicular Hyperplasia - with Large irregular lymphoid follicles
Mixed Hyperplasia and Involution
Follicular Involution - with Small burnt out follicles
Describe the macroscopic and microscopic finding of Lymph Node Findings associated with HIV and AIDS
Enlarged para-aortic lymph nodes
Microscopic images depicting the various features of HIV-related Lymphadenopathy
A: Enlarged irregular germinal centre in HIV associated lymphadenopathy
B: Follicle-lysis and germinal centre haemorrhage
C: Follicle involution
D: Positive P24 Immunochemistry - P24 stains HIV infected cells
HIV Transmission
List the ways in which HIV is transmitted
HIV can be transmitted in the following ways:
Sexual contact
Parenteral inoculation
Parental Inoculation can occur via the use of infected blood and blood products, shared needles, and needle stick injuries
Perinatal Transmission
Perinatal Transmission occurs in Utero, During birth or Post partum via breast milk
Increasing number of infected children as a result of Perinatal transmission, Child abuse or Sex with virgins
Pathogenesis of HIV Infection
Outline the Pathogenesis of HIV Infection
CD4+ Molecules have a high affinity receptor for HIV
High affinity receptor is found on subset T-Lymphocytes (CD4+ Helper T cells) and Monocytes/Macrophages
And HIV gains access to these cells via the CD4 molecules
Once the HIV has entered the cell, it uses an enzyme called Reverse Transcriptase to transcribe its viral RNA to host pro-viral DNA
Pro-Viral DNA then directs the cell to replicate the virus
Viral Replication causes destruction of CD4+ T Cells, leading to severe T-Cell Depletion
Depletion of T Cells is central to the pathogenesis of AIDS (Lysis, Apoptosis/Pyroptosis, Cytotoxic T cell)
Chronic latent infection of T-cells and Macrophages may persist for months to years, without any clinical symptoms
This accounts for the long variable incubation period before AIDS occurs
When the CD4 count drops below 200, then clinical AIDS occurs
Monocytes and Macrophages also become infected with HIV, but they are not destroyed
Instead Monocytes and Macrophages act as a reservoir for the virus, and are able too transport the virus around the body, including across the Blood-Brain Barrier
They are probably responsible for the CNS infection by HIV, although direct infection of Neurons and Glial Cells also occurs
Major Abnormalities of the Immune System, in AIDS
List the Major Abnormalities of the Immune System, in AIDS
Lymphopaenia lysis, Apoptosis/Pyroptosis, Cytotoxic T-cells
Decreased T-cell function in vivo (opportunistic infections and neoplasms)
Altered T-cell function in vivo
Polyclonal B-cell activation
Altered monocyte and macrophage function
Natural History of HIV Infection: HIV Phases
List and Outline the Phases of HIV Infection
The 3 Phases of HIV Infection:
Early Acute phase
Middle Chronic phase
Final Crisis phase
Early Acute Phase
Early acute phases involves the initial response by an immunocompetent person
An anti-viral response occurs with development of anti-HIV antibodies in the blood at 3-17 weeks following exposure and cytotoxic T-cell response
Seroconversion may be accompanied by a self-limited flu-like illness, with rash, lymphadenopathy, sore throat and diarrhoea (30-50%)
Middle Chronic Phase
Middle chronic phase is the clinically latent phase that can last for 2-8 years or longer
Virus is relatively contained and the host is still immunocompetent, but there is steady loss of CD4 cells over this period
Most patients are asymptomatic in this phase, but some patients have persistent generalised lymphadenopathy (with mild constitutional symptoms and mild CD4 depletion)
PGL - Persistent Extra-inguinal Lymphadenopathy in two or more contiguous (neighbouring) sites, of greater than three months duration, and of no known Aetiology other than HIV infection
Final Crisis Phase
In the Final crisis phase, Full-blow AIDS develops
Host defence breaks down, the Viral load is high, and the CD4 count is low (below 200) and there is reversal of CD4:CD8 ratio
AIDS - related complex - patient's present with fever, weight loss, fatigue. diarrhoea, opportunistic infections and neoplasms
Anaemia, Thrombocytopaenia and Hypergammaglobulinaemia are often present
Thrombocytopenia is a condition in which you have a low blood platelet count.
Types of Stains
Ziehl-Neelsen Stain used for Acid-Fast Bacilli
Silver Stain
Eosinophilic Stain
Grocott stain, is a special stain used for Fungi
Cryptococcoma is caused by Cryptococcus neoformans
Cryptococcomas are granulomas caused by cryptococcus within the brain parenchyma
