[PATHO] Immunodeficiency Disorders.pdf

PATHOLOGY 08/28/2024. MOD 4: IMMUNODEFICIENCY DISORDERS...

PATHOLOGY 08/28/2024. MOD 4: IMMUNODEFICIENCY DISORDERS Dr. Joanne Marie R. Pascual Trans Group: 6B, 7B I. INTRODUCTION COMPONENTS AND REGULATORS OF COMPLEMENT SYSTEM IMMUNODEFICIENCY DISORDERS Complement deficiencies are associated with increased Primary Almost always genetically determined susceptibility to bacterial infections (particularly C3). (Congenital) (usually X-linked) Seen during infancy (6 mos - 2 yrs) COMPLEMENT COMPONENTS Associated with recurrent infections Both are early components of the Secondary Result from altered immune function classical pathway (Acquired) which may arise as complication of: Deficiency: associated with increased Cancer C2 or C4 bacterial or viral infections Malnutrition C2 and C4 deficiency with SLE: high Infections (viral, etc.) incidence of connective tissue diseases Lymphoproliferative diseases Or as side effects of: Immunosuppression (use of drugs) Required in both classical and Irradiation alternative pathways Chemotherapy Deficiency: results in susceptibility to C3 serious and recurrent pyogenic infections Both are manifested clinically by increased infections and associated with frequent bacterial which may be newly acquired or a reactivation of latent infections infection. The terminal (late-acting) components of complement system II. PRIMARY IMMUNE DEFICIENCY DISORDERS Required for the assembly of membrane Considered as “accidents of nature” caused by attack complex (MAC) which is involved genetic or inherited defects. C5 to C9 in the lysis of organisms These defects affect the defense mechanisms of the: Deficiency: associated with increased ○ Innate Immunity susceptibility to recurrent Neisseria Phagocytes infections NK (natural kille) cells Complement Neisseria is the bacteria that causes gonorrhea and ○ Adaptive Immunity meningococcemia. Humoral: B cells/lymphocytes Cellular: T cells/lymphocytes COMPLEMENT REGULATORS Most primary immunodeficiency diseases are detected in infancy between 6 months and 2 years of life, Deficiencies in complement regulators also result in ○ Telltale sign: susceptibility to recurrent infections immune deficiency disorders. A. INNATE IMMUNITY DEFECTS C1 Deficiency: hereditary angioedema or Typically affects: Inhibitor angioneurotic edema ○ Leukocyte function ○ Complement system Hereditary angioedema is an autosomal dominant ○ Innate immune receptors (mentioned on handout) disorder characterized by episodes of edema affecting the Abnormalities in these lead to increased vulnerability skin and mucosal surfaces such as the larynx and the GI to infection. tract. May result in life-threatening asphyxia, nausea, 1. LEUKOCYTE FUNCTION DEFECTS vomiting, and diarrhea after minor trauma or May be in the form of inherited defects in: emotional stress ○ Leukocyte adhesion Acute attacks of hereditary angioedema can be ○ Phagocytosis treated with C1 INH concentrates prepared from ○ Microbicidal activity human plasma. 2. COMPLEMENT SYSTEM DEFECTS Hereditary deficiencies have been described for all the B. ADAPTIVE IMMUNITY DEFECTS components of complement system and several of their Often subclassified on the basis of the primary regulators component involved such as: ○ B cells Pathology - Mod 4 Immunodeficiency Disorders 1 of 13 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  ○ T cells ○ Both Defects are mainly concerned with the maturation and activation of these lymphocytes. IMMUNE DEFICIENCY DISORDERS DUE TO DEFECTS IN ADAPTIVE IMMUNITY 1 Severe Combined Immunodeficiency X-linked SCID Autosomal Recessive SCID 2 X-linked (Bruton’s) Agammaglobulinemia 3 DiGeorge Syndrome 4 Hyper IgM Syndrome 5 Common Variable Immunodeficiency ADA Deficiency in the Principal Pathways of Lymphocyte 6 Selective IgA deficiency Development. III. SEVERE COMBINED IMMUNODEFICIENCY (SCID) Spans a constellation of genetically distinct syndromes, all having common defects in BOTH humoral and cell-mediated immune responses. A. TWO MOST COMMON TYPES/FORMS 1. X-LINKED SCID Principal Pathways ot Scheme of Lymphocyte Development and Sites of Block in PID. Please take a look at this diagram as it will be the basis of our discussion on immune deficiency disorders due to X-linked SCID Diagram. defects in adaptive immunity Most common form (50-60% of cases) Legend: - denotes the site of block X-linked — males > females 1.1 Site of Block In SCID, due to ADA (adenosine deaminase) deficiency, Cytokine common γ-chain (mutation) the block in this area means that there will be an arrest ○ Also called as common gamma (γ) chain subunit of in the development of common myeloid lymphoid cytokine receptors progenitor cells → pro-T lymphocyte stage. ○ A transmembrane protein ○ All events after the block (i.e. maturation of T cells) will no longer ensue. 1.1.1 Normal Function Sends signals to the receptors of various interleukins which is required for the survival and proliferation of lymphoid progenitors, particularly T cell precursors 1.1.2 Mechanism Causes defective interleukin receptor signaling which results in: ○ Profound defects in the earliest stages of lymphocyte development, especially in T cell development. Pro-T cell ⇸ Immature T cell ○ Ultimately, a mark reduction in T cell lymphocyte numbers Pathology - Mod 4 🏠 Immunodeficiency Disorders 2 of 13 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  Immature T Cell ⇸ CD8+ and CD4+ (ADA def) 1.2 Clinical Manifestation Defect in T-cell development Both Hypoplastic lymphoid ○ Decreased T-cells X-linked tissues OTHER ○ Normal B-cell number BUT antibody synthesis is & Marked depletion of LYMPHOI impaired due to lack of T-cell help Autosom T-cell areas D Therefore, the humoral branch of immunity al In some cases, both T cell TISSUES is affected in some way. recessive and B cell zones are Deficiency of NK cells (ADA def) depleted 1.3 Clinical Correlation C. GENERAL EFFECTS & TREATMENT Affected infants present with prominent thrush (oral Regardless of the genetic cause, patients with SCID candidiasis), extensive diaper rash, and failure to have alterations in both the cell-mediated (↓↓) and thrive. humoral (↓↓) immune response. They are also extremely susceptible to recurrent, 2. AUTOSOMAL RECESSIVE SCID severe infections by a wide range of pathogens ○ E.g. some infants develop a morbilliform rash shortly after birth due to transfer of maternal T cells across the placenta that attack the fetus Treatment of SCID involves hematopoietic stem cell transplantation, without which death occurs within the 1st year of life. IV. X-LINKED (BRUTON’S) AGAMMAGLOBULINEMIA B-cell deficiency One of the more common forms of primary immunodeficiency Autosomal Recessive SCID Diagram. 1.1 Site of Block Adenosine deaminase (ADA) enzyme (deficiency) ○ Common lymphoid progenitor cells ⇸ Pro-T cell 1.1.1 Mechanism The mechanisms by which ADA deficiency causes SCID are not entirely clear. It is proposed that ADA deficiency leads to accumulation of deoxyadenosine and its derivatives (deoxy-ATP) ○ These are toxic to rapidly dividing immature lymphocytes especially those of the T cell lineage. B-cell deficiency: X-Linked (Bruton’s) Agammaglobulinemia. 1.2 Clinical Manifestation Reduction in both T and B lymphocyte Caused by mutations in a cytoplasmic tyrosine ○ Greater reduction in the number of T lymphocytes kinase called Bruton’s tyrosine kinase (BTK) than the reduction of B lymphocytes (T cell ○ BTK functions by delivering signals needed for reduction > B cell reduction) the maturation of B lymphocytes ○ When BTK is mutated, there is failure of B cell B. HISTOLOGIC FINDINGS OR MORPHOLOGY precursors, both pro-B and pre-B cells, to develop Depends on the underlying defects into mature B cells. As an X-linked disease, this disorder is seen almost HISTOLOGIC FINDINGS OF SCID exclusively in males. ○ The disease does not usually become apparent Both of until about 6 months of age when maternal most Small and devoid of immunoglobulins become depleted. common lymphoid cells In some cases, recurrent bacterial infections of the forms respiratory tract call attention to the underlying immune defect. ○ Almost always, the causative organisms are Lobules of undifferentiated THYMUS Haemophilus, Streptococcus or Staphylococcus X-linked epithelial cells resembling (pyogenic bacteria) fetal thymus Normally, these organisms are opsonized by antibodies and cleared by phagocytosis, but Autosom because B cells, which differentiate into Presence of remnants of al antibody-producing plasma cells are absent Hassall’s corpuscles recessive Pathology - Mod 4 🏠 Immunodeficiency Disorders 3 of 13 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  from the circulation, these organisms are not ○ This is dependent on the severity of the T-cell cleared by the body. deficiency. In general, however, most fungal, protozoal, and Treatment: thymus Graft intracellular viral infections are handled quite well by the intact T cell-mediated immunity. VI. X-LINKED HYPER IGM SYNDROME The classic form of this disease has the following Mature B cells are present but are incapable of characteristics: immunoglobulin class switching because of a defect ○ B-cells are absent or markedly decreased in the in CD4 Helper T cells or an intrinsic B cell defect. circulation. ○ Pre-B cells are found in normal numbers in the bone marrow. ○ B-cell containing areas (Peyer’s patches, germinal centers of lymph nodes, appendix, and tonsils) are underdeveloped. ○ Mature B-cells did not develop plasma cells or were absent throughout the body: Serum levels of immunoglobulins are depressed. ○ T-cell number and mediated reactions (function) are normal. V. DIGEORGE SYNDROME Hyper-IgM Syndrome. T-cell deficiency Also known as thymic hypoplasia or aplasia Affected patients have IgM antibodies but are deficient in IgG, IgA and IgE antibodies. ○ The serum of persons with this syndrome contains: Normal or elevated levels of IgM No IgA or IgE Extremely low levels of IgG Numbers of B and T cells in blood are normal Clinical manifestation: Susceptibility to recurrent pyogenic infections due to low levels of opsonizing IgG antibodies. VII. COMMON VARIABLE IMMUNODEFICIENCY (CVID) T-cell deficiency: DiGeorge Syndrome (Thymic hypoplasia or aplasia). T-cell deficiency due to failure of development of the 3rd and 4th pharyngeal pouches ○ During embryogenesis, 3rd and 4th pharyngeal pouches give rise to the thymus, the parathyroids, Common Variable Immunodeficiency. some of the C-cells of the thyroid, and the ultimobranchial body. Relatively frequent entity that encompasses a ○ In patients with DiGeorge Syndrome, these heterogenous group of disorders structures do not develop normally. Common features include hypogammaglobulinemia Individuals with the syndrome have: generally affecting all the antibodies (BUT sometimes ○ Thymic hypoplasia or aplasia → variable loss of only IgG) T-cell mediated immunity Diagnosis is based on the exclusion of all other well ○ Hypocalcemia because of parathyroid hypoplasia → defined causes of decreased antibody production. tetany Clinical manifestations are caused by antibody ○ Congenital defects of the heart and great vessels deficiency. ○ Dysmorphic facies: the appearance of the mouth, ○ Thus, they resemble those of X-linked ears, and facies may be abnormal. agammaglobulinemia. Absence of cell mediated immunity is caused by low numbers of T lymphocytes in the blood and hence, poor defense against certain fungal and viral infections DIFFERENCES BETWEEN CVID AND X-LINKED (intracellular microbes). AGAMMAGLOBULINEMIA T cell zones of lymphoid organs, like the paracortical areas of the lymph nodes and the periarteriolar sheaths X-LINKED of the spleen, are depleted. CVID AGAMMAGLOBULINEMIA The humoral branch of immunity is affected in varying degrees depending on whether immunoglobulin Normal or near normal No mature B cells in the levels are normal or reduced. Pathology - Mod 4 🏠 Immunodeficiency Disorders 4 of 13 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  B cells blood and lymphoid tissue Family Retroviridae (but unable to differentiate into plasma cells) Genus Lentivirus Affects both sexes Species Human immunodeficiency Virus 1 X-linked — M > F equally Human immunodeficiency Virus 2 Later onset (usually in childhood and 6 months of age It is postulated that SIV (Simian Immunodeficiency adolescence) Virus) of primates mutated and evolved into HIV after exposure of forest workers to Bushmeat, either as vendors or hunters. VIII. ISOLATED/SELECTIVE IGA DEFICIENCY ○ Bushmeat: meat of African wild animals. African Green Monkey (source of SIV), Sooty Mangabey (source of HIV-2), and Chimpanzee (implicated source Isolated IgA Deficiency. of HIV1). Common immunodeficiency caused by impaired Two genetically different but related forms of HIV have differentiation of naive B-lymphocytes into IgA been isolated from patients with AIDS: producing plasma cells. ○ HIV-1: most common type in associated with AIDS Extremely low levels of both serum and secretory in US, Europe, Central Africa, and Asia IgA. ○ HIV-2: causes similar disease in West Africa and Most cases are asymptomatic but because IgA is the India major antibody in mucosal secretions, mucosal defenses are weakened and infections can occur in respiratory, COMPARISON OF HIV SPECIES GIT, and urogenital tracts (higher susceptibility in these areas). Inferred When transfused with normal blood containing IgA, Virulence Infectivity Prevalence Origin some patients develop severe and even fatal anaphylactic reactions because the IgA in the donor Common blood behaves like foreign antigens. HIV-1 High High Global Chimpanzee IX. SUMMARY Sooty Primary immunodeficiency disorders are diseases HIV-2 Lower Low West Africa Mangabey caused by inherited mutations in genes involved in: ○ Innate immunity ○ Adaptive immunity — lymphocyte maturation or Earliest well-documented case of HIV in a human: function Congo, 1959 HIV first appeared in the US (1981) after an outbreak of ACQUIRED IMMUNODEFICIENCY SYNDROME Pneumocystis jirovecii pneumonia (then known as Pneumocystis carinii pneumonia) and a rare skin cancer known as kaposi sarcoma were observed among the I. INTRODUCTION homosexual population and intravenous drug users who As a group, secondary immunodeficiency is more had no history of immunosuppression. common than primary immunodeficiency. B. EPIDEMIOLOGY II. ACQUIRED IMMUNODEFICIENCY SYNDROME For a time, a rule of thumb for the epidemiological Most common secondary immunodeficiency disorder identification of cases known as 4H was used. Characterized by a profound immunosuppression that 4H stood for: leads to: ○ Haitians ○ Opportunistic infections ○ Homosexuals ○ Secondary neoplasms ○ Hemophiliacs ○ Neurologic manifestations ○ Heroin users A. ETIOLOGY EPIDEMIOLOGY OF HIV WORLDWIDE Caused by retrovirus Human Immunodeficiency Virus (HIV) United Nation AIDS program (UNAIDS) 2019 Data VIRUS CLASSIFICATION Contracted HIV 75.7 million (worldwide) Group Group VI (ssRNA-RT) AIDS related death 32.7 million Pathology - Mod 4 🏠 Immunodeficiency Disorders 5 of 13 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  HIV Cases Worldwide At Present ○ But in 2016, this remained the largest affected group Children 1.8 million constituting about 70% of new cases. TOTAL 38 million Chiefly due to contact with members of other high risk group Region Occurring most rapidly in: Heterosexual ○ Female sex workers Most affected Sub-Saharan Africa Transmission ○ Women in long term marital or cohabitating Largest population Eastern and Southern Africa relationships, particularly with HIV 20.7 million among adolescents With no previous history of Middle East and North Africa homosexuality, they are the next Lowest prevalence 240,000 cases IV Drug Users largest group. Representing about 20% of infected individuals Children of HIV positive women are HIV Infection of at risk for infection in utero, at birth, or the Newborn through breast milk 0.5% of all cases: patients with hemophilia, especially those who receive large amounts of Factor VIII or IX concentrates before 1985. Hemophiliacs Recipients of blood and blood components who are not hemophiliacs, but received transfusions of HIV-infected whole blood or components. Epidemiology Worldwide. D. TRANSMISSION The HIV pandemic has been plaguing the world long Transmission of HIV occurs under conditions that before the current COVID pandemic struck. facilitate exchange of blood or body fluids containing Compared to 2010, there has been a 207% increase in the virus or virus-infected cells. new HIV infections in the Philippines. MAJOR ROUTES OF TRANSMISSION OF HIV PHILIPPINES EPIDEMIOLOGY HIV 2019 1 Sexual Transmission HIV cases 97,000 2 Parenteral Transmission (or Inoculation) New infections 16,000 3 Infected Mother to Newborn (vertical transmission) Men having sex with men are Making up 84% of the disproportionately affected new infections 1. SEXUAL TRANSMISSION Receiving Antiretroviral Dominant mode of infection worldwide 43,020 or 44% Accounts for more than 75% of all cases of HIV Therapy (ART) transmission AIDS related deaths 1,600 Virus is carried in the semen and enters the recipient's body through abrasions or microtears in rectal, oral, or New infections are increasing vaginal mucosa or by direct contact with mucosal lining People living with HIV is increasing cells Deaths are also increasing Viral transmission occurs in two ways: ○ Direct inoculation into blood vessels breached by trauma C. HIGH RISK GROUPS ○ Infection of dendritic cells (DCs) or CD4+ T cells in Five groups of adults that have high risk in developing the mucosa AIDS. The case distribution in these groups is as Can occur in male-to-male, male-to-female, and follows: female-to-male transmission Sexual transmission of HIV is enhanced by: ○ Co-existing sexually transmitted diseases HIGH RISK GROUPS especially those associated with genital ulcerations Group Parameter 2. PARENTERAL TRANSMISSION >50% of the reported cases ○ 5% are IV drug users as well GROUPS OF INDIVIDUALS AFFECTED BY Men who have Transmission of HIV in this PARENTERAL TRANSMISSION OF HIV sex with men category appears to be on the decline Pathology - Mod 4 🏠 Immunodeficiency Disorders 6 of 13 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  Hallmark: Profound immune deficiency, primarily 1 IV Drug Users affecting cell-mediated immunity Constitutes by far the largest group ○ Results chiefly from infection and subsequent Transmission occurs by sharing of needles, death or loss of CD4+ T (helper) cells syringes, and other paraphernalia As well as impairment in the function of contaminated with HIV-containing blood surviving CD4+ T (helper) cells ○ Take note that infection of macrophages and 2 Hemophiliacs who received Factor VIII and IX dendritic cells also contribute to the immune concentrates deficiency → abnormalities of B-cell function ○ Therefore, loss of both cell-mediated and 3 Random recipients of blood transfusion humoral response. 3. INFECTED MOTHER TO NEWBORN 1. MECHANISMS OF T-CELL DEPLETION IN HIV INFECTION Major cause of pediatric AIDS Infected mothers can transmit the infection to their offspring by three different routes ○ Of these transmissions, during the intrapartum (birth) and peripartum (after birth) period is considered to be the most common mode of viral transfer. ROUTES OF TRANSMISSION FROM INFECTED MOTHER TO NEWBORN 1 In utero by transplacental spread 2 During delivery through an infected birth canal Mechanism T-Cell Depletion in HIV Infection (left to right in 3 After birth by Ingestion of breast milk numerical order). AVERAGE PER ACT RISK OF GETTING HIV BY MECHANISMS EXPOSURE ROUTE TO AN INFECTED SOURCE 1 Viral replication in infected CD4+ T cells Exposure Route Chance of Infection ↓ Death of infected cell (cytopathic effect of virus) Blood transfusion* 90% Childbirth (to child) 25% Direct cytopathic effects of the replicating virus on the infected cell Needle-sharing injection Direct killing of infected cells by the virus 0.67% Primary reason for CD4+ T cell loss drug use Percutaneous needle stick 0.30% 2 Chronic activation of uninfected CD4+ T cells (are triggered to proceed) Receptive anal intercourse 0.04 - 3.0% ↓ Insertive anal intercourse 0.03% (to a process of) Activation-induced cell death or apoptosis Receptive penile-vaginal 0.05 - 0.30% Chronic activation may be due to either: intercourse* Responding to HIV itself Insertive penile-vaginal To other infections that are common in AIDS 0.01 - 0.38% intercourse* 3 Expression of HIV peptides on Receptive oral intercourse 0 - 0.04% infected CD4+ T cells ↓ Insertive oral intercourse 0 - 0.005% Killing of infected CD4+ T cell by virus-specific cytotoxic T cells (CTLs) Receiving HIV infected blood carries the highest risk of infection. This further contributes to CD4+ T cell depletion. Receptive penile-vaginal intercourse refers to the risk of the female acquiring the infection from an infective male assuming that no condom is used. 2. COURSE OF INFECTION Insertive penile-vaginal intercourse refers to the male acquiring infection from an infected female assuming PHASES OF PATHOLOGIC AND CLINICAL no condom is used. MANIFESTATIONS OF HIV E. PATHOGENESIS 1 Acute (early) HIV Self-limited Two major targets of HIV: Immune system and CNS infection / acute Acute flu-like illness ○ Immune system retroviral syndrome ○ Can target many tissues Pathology - Mod 4 🏠 Immunodeficiency Disorders 7 of 13 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited. 2 Most are 2.1.1 Acute Retroviral Syndrome asymptomatic Middle chronic phase Rest have generalized lymphadenopathy 3 Final or crisis phase (full-blown/clinical AIDS) 2.1 Acute (Early) Infection Main Symptoms of Acute HIV Infection. Clinical presentation of early acute infection with HIV and corresponds to the initial immune response of the host. It is estimated that 40-90% of the individuals who acquire a primary infection develop this syndrome. This typically occurs 3-6 weeks after infection and Pathogenesis of HIV-1 Infection. resolves spontaneously in 2-4 weeks. This phase is marked by a nonspecific, self-limited The initial infection starts in mucosal tissues, involving acute illness with flu-like symptoms including sore mainly memory CD4+ T cells and dendritic cells. throat, myalgias, fever, weight loss, and fatigue, Dendritic cells in epithelia at sites of virus entry capture sometimes accompanied by rash, cervical adenopathy, the virus and migrate into the lymph nodes diarrhea and vomiting. ○ Once in the lymphoid tissues, dendritic cells pass HIV to CD4+ T cells and continued viral replication 2.2 Chronic Phase (Clinical Latency) leads to the spread of the virus to the blood = VIREMIA As the HIV infection spreads, the individual mounts antiviral humoral and cell mediated immune responses. Within 3 to 7 weeks of exposure, HIV specific CD8+ T cells and antibodies against HIV can now be detected in the blood. ○ Detection of these antibodies in the blood = SEROCONVERSION These events correspond to the early acute phase of HIV infection CHARACTERISTICS OF ACUTE (EARLY) HIV Chronic Phase (Clinical Latency Period). INFECTION In the chronic phase of the disease, there is some 1 Infection of memory CD4+ T cells in mucosal immune containment of viremia. lymphoid tissues (entry through mucosal tissues) The number of infected CD4+ T-cells in the blood steadily declines in this phase. 2 Death of infected cells (CD4+ T cells and dendritic ○ But in the spleen and lymphoid tissues, the virus cells) stealthily continues its destruction of the CD4+ T-cells 3 Viremia (dissemination of the virus after mucosal During this period of the disease, few or no clinical infection) manifestations of the HIV infection are present, therefore this phase of HIV disease is called the clinical latency period. 4 Immune response and seroconversion (development of host-immune response) CHARACTERISTICS OF CHRONIC (LATE) HIV INFECTION 1 Asymptomatic 2 (+/-) minor opportunistic infections (e.g., oral or vaginal candidiasis, herpes zoster, tuberculosis) Pathology - Mod 4 🏠 Immunodeficiency Disorders 8 of 13 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited. 2.3 Clinical AIDS 2. LATE PHASE Variable period where the emergence of “AIDS indicator diseases” signifies that the patient have developed AIDS: ○ Serious widespread opportunistic infections ○ Secondary neoplasms ○ Clinical neurologic disease ○ Fever ○ Weight loss ○ Generalized lymphadenopathy 2.1 Opportunistic Infection Opportunistic infections account for the majority of deaths in untreated patients with AIDS OPPORTUNISTIC INFECTIONS Develops in approximately 15-30% of untreated HIV-infected people Pneumonia Caused by Pneumocystis jirovecii (fungus) Progression of HIV infection to AIDS. Most common fungal infection in Final phase of HIV infection is progression to AIDS patients with AIDS Occurs when CD4+ T-cell count falls below 200 Most common clinical cells/mcL of blood which leads to: manifestation includes infection of: ○ Breakdown of host defenses ○ Oral cavity ○ Dramatic increase in viral load ○ Vagina Candidiasis ○ Severe life threatening clinical disease ○ Esophagus In asymptomatic HIV-infected individuals, oral candidiasis is a THREE PHASES THAT CHARACTERIZE THE sign of immunologic NATURAL COURSE OF HIV INFECTION decompensation that heralds transition to AIDS Acute HIV Chronic HIV AIDS Disseminated Occurs late in the setting of Flu-like Also Occurs bacterial severe immunosuppression symptoms that known as when CD4+ infection with Mainly involves Mycobacterium occur days to latent or T cell count atypical avium-intracellulare weeks after asympto < 200 Mycobacteria contracting HIV matic cells/mcL Non-specific stage Vulnerability Opportunistic fungal infection symptoms: Can last to Cryptococcos that infects the brain generalized for several opportunis is Occurs in about 10% of AIDS lymphadenopat years tic patients hy, sore throat, Persistent infections rash viral and replication AIDS–indic Persistent diarrhea is common in ator of untreated patients with advanced disease AIDS Often caused by infections with Diarrhea protozoans F. AIDS: CLINICAL FEATURES These patients have chronic profuse watery diarrhea with 1. EARLY/MIDDLE (LATENCY) PHASE massive fluid loss It is difficult to determine the presence of an HIV infection in the early stages. Other infections preferentially involve the GIT and Subjective clinical features are NOT sufficient for genitalia. diagnosis which are high-risk behavior, such as.: ○ Promiscuity 2.2 Secondary Neoplasm ○ IV drug abuse Patients with AIDS have high incidence of certain Objective clinical findings are NON-SPECIFIC in the tumors, especially: early and middle phases of the disease, such as: ○ Kaposi sarcoma ○ Prolonged fever ○ B-cell Lymphoma ○ Acute viral symptoms ○ Carcinomas of the uterine cervix and anus ○ Generalized lymphadenopathy (HPV-related) The only specific indicator of infection: (+) test for Cervical cancer in women HIV antibodies Anal cancer in men It is estimated that 25-40% of untreated HIV infected individuals will eventually develop a malignancy. Pathology - Mod 4 🏠 Immunodeficiency Disorders 9 of 13 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  Risk of cancer appears to increase once the CD4+ count is < 500 cells/mcL of blood 2.2.1 Kaposi Sarcoma The most common malignancy or neoplasm associated with AIDS Tumor of blood vessels Rare in immunocompetent individuals AIDS-associated kaposi sarcoma is different from sporadic form ○ In HIV infected individuals, the tumors are widely HPV-related cancer of the uterine cervix (in females) and spread and tend to be more aggressive than the anus (in males). classical Kaposi sarcoma ○ Tumors present as reddish brown patches or 2.3 CNS Manifestations (Clinical Neurologic Diseases) tumorous nodules affecting the skin, mucus membranes, GIT, lymph nodes and lungs Involvement of the CNS is a common and important manifestation of AIDS 90% of patients demonstrate some form of neurologic involvement at autopsy 40-60% with clinically apparent neurological dysfunction In some patients, neurologic manifestations may be the sole or earliest presenting feature of HIV infection CNS MANIFESTATIONS HIV-associated Most common neurocognitive Progressive encephalopathy disorder (H.A.N.D.) characterized by confusion, depression, anxiety, and difficulty in walking Believed to result from a combination of HIV infection of microglia and an immune response in the CNS Meningo- Self-limited Tumors of Kaposi sarcoma. encephalitis Occurring at the time of seroconversion 2.2.2 Lymphoma Occurs at markedly increased rate in individuals with Aseptic meningitis AIDS, making it one of several AIDS defining conditions Roughly 5% of AIDS patient presents with lymphoma Peripheral ○ Originates from persistent lymphocyte activation neuropathies and subsequent transformation of B cells G. HIV CLASSIFICATION SYSTEM Two main clinical staging systems are used to classify HIV and HIV-related disease for surveillance purposes. ○ WHO Disease Staging System for HIV Infection ○ CDC Classification System for HIV Infection 1. US CENTER FOR DISEASE CONTROL AND PREVENTION CLASSIFICATION SYSTEM FOR HIV (2008) Classifies HIV infections based on CD4+ count and Clinical manifestation of lymphoma. clinical symptoms, and describes the infections in 5 groups 2.2.3 Human Papillomavirus (HPV)-Related Cancers For surveillance purposes, the diagnosis of AIDS still Patients with AIDS are at increased risk of HPV stands even after treatment, where the CD4+ T cell associated carcinomas of the uterine cervix and anus count rises to above 200 cells/mcL of blood or other 10x more common in HIV infected women compared AIDS-defining illnesses have been cured. with uninfected women Confined to HIV infected women with CD4+ T cell counts of < 500 cells/mcL, suggesting that the risk is CDC CLASSIFICATION SYSTEM FOR HIV (2008) attributable to diminished immune surveillance 1 Stage 0 The time between a negative or indeterminate HIV test followed less than 180 days by a positive test 2 Stage 1 CD4 count ≥ 500 cells/µl and no AIDS defining conditions 3 Stage 2 CD4 count 200 to 500 cells µl and no Pathology - Mod 4 🏠 Immunodeficiency Disorders 10 of 13 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  AIDS defining conditions Removal of Decreased phagocytosis of spleen microbes 4 Stage 3 “Full-blown AIDS” CD4 count ≤ 200 cells µl OR have the presence of AIDS defining conditions (or AIDS indicator disease) 5 Unknown If insufficient information is available to make any of the above classifications H. PROGNOSIS At present, there is no cure for HIV or AIDS ○ Medications (e.g. antiretroviral drugs) can dramatically slow the progression of the disease In the absence of antiretroviral treatment, most patients with HIV infection progress to AIDS after a chronic phase lasting from 7-10 years (typical course) EXCEPTIONS TO THE TYPICAL COURSE RAPID PROGRESSORS LONG-TERM NONPROGRESSORS The middle/chronic phase Untreated HIV-1 infected is shortened to 2-3 years individuals who remain after primary infection asymptomatic for 10 years or more with stable CD4 T cell counts and low viral loads (