AIDS is the most typical immunodeficiency disorder worldwide, and HIV infection is one from the best epidemics in human history. AIDS is the consequence of a chronic retroviral virus that produces extreme, life-threatening CD4 helper T-lymphocyte dysfunction, opportunistic infections, and malignancy.
Retroviruses include viral RNA that is transcribed by viral reverse transcriptase into double-stranded DNA, which can be integrated into the host genome. Cellular activation leads to transcription of HIV gene items and viral replication. AIDS is defined by serologic evidence of HIV virus with the presence of a range of indicator diseases related to medical immunodeficiency.
HIV is transmitted by coverage to infected body fluids or sexual or perinatal make contact with. Transmissibility from the HIV virus is related to subtype virulence, viral load, and immunologic host factors. Acute HIV virus may present as an acute, self-limited, febrile viral syndrome characterized by exhaustion, pharyngitis, myalgias, rash, lymphadenopathy, and significant viremia without detectable anti-HIV antibodies.
Following an initial viremic phase, individuals seroconvert along with a period of clinical latency is usually observed. Lymph tissues turn out to be centers for substantial viral replication during a "silent," or asymptomatic, stage of HIV virus despite an absence of detectable trojan in the peripheral blood. Over time, there's a progressive decline in CD4 T lymphocytes, a reversal from the regular CD4:CD8 T-lymphocyte ratio, and numerous other immunologic derangements.
The clinical manifestations are directly related to HIV tissue tropism and defective immune function. Development of neurologic complications, opportunistic infections, or malignancy signal marked immune deficiency. The time course for progression varies, but the median time before appearance of medical illness is about ten many years. Around 10% of individuals infected manifest rapid progression to AIDS within five many years after virus.
A minority of individuals are "long-term nonprogressors." Genetic elements, host cytotoxic immune responses, and viral load and virulence appear to effect susceptibility to virus and the rate of disease progression. Chemokines (chemoattractant cytokines) regulate leukocyte trafficking to sites of inflammation and have been discovered to play a significant role in the pathogenesis of HIV illness.
During the initial stages of virus and viral proliferation, virion entry and cellular infection requires binding to two coreceptors on target T lymphocytes and monocyte/macrophages. All HIV strains express the envelope protein gp120 that binds to CD4 molecules, but different viral strains display tissue "tropism" or specificity on the basis from the coreceptor they recognize. These coreceptors belong towards the chemokine receptor family.
Changes in viral phenotype throughout the course of HIV virus may lead to changes in tropism and cytopathology at different stages of disease. Viral strains isolated in early stages of infection (eg, R5 viruses) demonstrate tropism toward macrophages. X4 strains of HIV are a lot more commonly seen in later stages of illness.
X4 viruses bind to chemokine receptor CXCR4, more broadly expressed on T cells, and are related to syncytium formation. A small percentage of individuals possessing nonfunctional alleles for the polymorphic chemokine receptor CCR5 appear to be highly resistant to HIV virus or display delayed progression of disease. Mathematical models estimate that throughout HIV virus billions of virions are produced and cleared each day.
The reverse transcription step of HIV replication is error prone; mutations occur frequently, and even within an individual patient, HIV heterogeneity develops rapidly. The improvement of antigenically and phenotypically distinct strains contributes to progression of illness, medical drug resistance, and lack of efficacy of early vaccines. Cellular activation is critical for viral infectivity and reactivation of integrated proviral DNA.
Although only 2% of mononuclear cells are found peripherally, lymph nodes from HIV-infected individuals can include large amounts of trojan sequestered among infected follicular dendritic cells within the germinal centers.
The marked decline in CD4 T-lymphocyte counts-characterizing HIV infection-is due to several mechanisms, including the pursuing: (1) direct HIV-mediated destruction of CD4 T lymphocytes, (2) autoimmune destruction of virus-infected T cells, (3) depletion by fusion and development of multinucleated giant cells (syncytium formation), (4) toxicity of viral proteins to CD4 T lymphocytes and hematopoietic precursors, and (five) induction of apoptosis (programmed cell death).
CD8 CTL activity is initially brisk and effective at controlling viremia through elimination of trojan and virus-infected cells. Ultimately, viral proliferation outpaces host responses, and HIV-induced immunosuppression leads to disease development. Loss of viral containment occurs with lack of adequate helper T purpose and decreased IL-2 production leading to diminution of CD8+ T-cell-dependent cytotoxic responses.
Subsequently, there is an accumulation of viral escape mutations with general cytokine dysregulation detrimental to maintenance of lymphatic organs, bone marrow integrity, and effective immune responses. In addition to the cell-mediated immune defects, B-lymphocyte function is altered such that numerous infected individuals have marked hypergammaglobulinemia but impaired specific antibody responses.
Both anamnestic responses and individuals to neoantigens can be impaired. However, the role of humoral immunity in controlling viremia or slowing disease development is unclear. The development of assays to measure viral burden (plasma HIV-RNA quantification) has led to a better understanding of HIV dynamics and has provided a tool for assessing response to therapy.
It is now well recognized that viral replication continues all through the disease, and immune deterioration occurs despite clinical latency. The risk of progression to AIDS appears correlated with an individual's viral load after seroconversion. Data from a number of large clinical cohorts have shown that there's a direct correlation between the CD4 T-lymphocyte count and also the risk of AIDS-defining opportunistic infections.
Thus, the viral load and also the degree of CD4 T-lymphocyte depletion serve as important clinical indicators of immune status in HIV-infected people. Prophylaxis for opportunistic infections such as pneumocystis pneumonia is started when CD4 T-lymphocyte counts reach the 200-250 cells/ L variety.
Similarly, patients with HIV virus with fewer than 50 CD4 T lymphocytes/ L are at significantly increased risk for cytomegalovirus (CMV) retinitis and Mycobacterium avium complex (MAC) infection. Cells other than CD4 T lymphocytes contribute to the pathogenesis of HIV infection.
Monocytes, macrophages, and dendritic cells can be infected with HIV and facilitate transfer of trojan to lymphoid tissues and immunoprivileged sites, such as the CNS. HIV-infected monocytes will also release large quantities from the acute-phase reactant cytokines, including IL-1, IL-6, and TNF, contributing to constitutional symptomatology.
TNF, in particular, has been implicated in the severe wasting syndrome observed in patients with advanced illness. Concomitant infections might serve as cofactors for HIV infection, increasing expression of HIV through enhanced cytokine production, coreceptor surface expression, or increased cellular activation mechanisms.
The medical manifestations of AIDS are the direct consequence from the progressive and severe immunologic deficiency induced by HIV. Patients are susceptible to a wide variety of atypical or opportunistic infections with bacterial, viral, protozoal, and fungal pathogens. Common nonspecific symptoms consist of fever, night sweats, and weight loss. Weight loss and cachexia can be due to nausea, vomiting, anorexia, or diarrhea.
They often portend a poor prognosis. The incidence of infection increases as the CD4 T lymphocyte number declines. Lung virus with Pneumocystis jiroveci is the most common opportunistic infection, affecting 75% of individuals. Patients present clinically with fevers, cough, shortness of breath, and hypoxemia ranging in severity from mild to existence threatening.
A diagnosis of pneumocystis pneumonia could be made by substantiation from the medical and radiographic findings with Wright-Giemsa or silver methenamine staining of induced sputum samples. A negative sputum stain does not rule out disease in patients in whom there's a strong clinical suspicion of disease, and further diagnostic maneuvers such as bronchoalveolar lavage or fiberoptic transbronchial biopsy might be required to establish the diagnosis.
Issues of pneumocystis pneumonia include pneumothoraces, progressive parenchymal disease with severe respiratory insufficiency, and, most commonly, adverse reactions to the medications used for treatment and prophylaxis.
As a consequence of chronic immune dysfunction, HIV-infected individuals are also at high risk for other pulmonary infections, including bacterial infections with S pneumoniae and H influenzae; mycobacterial infections with M tuberculosis or M avium-intracellulare (MAC); and fungal infections with C neoformans, H capsulatum, or C immitis. Medical suspicion followed by early diagnosis of these infections should lead to aggressive treatment.
The improvement of active tuberculosis is significantly accelerated in HIV virus as a result of compromised cellular immunity. The risk of reactivation is estimated to be 5-10% per year in HIV-infected patients compared having a lifetime risk of 10% in those without having HIV. Furthermore, diagnosis may be delayed because of anergic skin responses.
Extrapulmonary manifestations occur in up to 70% of HIV-infected individuals with tuberculosis, and the emergence of multidrug resistance may compound the problem. MAC is really a less virulent pathogen than M tuberculosis, and disseminated infections usually occur only with extreme medical immunodeficiency.
Symptoms are nonspecific and typically consist of fever, weight loss, anemia, and GI distress with diarrhea. The presence on physical examination of oral candidiasis (thrush) and hairy leukoplakia is highly correlated with HIV infection and portends rapid development to AIDS.
Abnormal outgrowth of Candida from normal mouth flora is the cause of persistent oral candidiasis, whereas Epstein-Barr trojan is the cause of hairy leukoplakia. HIV-infected people with oral candidiasis are at much greater risk for esophageal candidiasis, which might existing as substernal pain and dysphagia. This infection and its characteristic medical presentation are so common that most practitioners treat with empiric oral antifungal therapy.
Should the patient not respond rapidly, other explanations for the esophageal symptoms should be explored, including herpes simplex and CMV infections. Persistent diarrhea, especially when accompanied by high fevers and abdominal pain, might signal infectious enterocolitis.
The list of potential pathogens in such cases is lengthy and includes bacteria, MAC, protozoans (cryptosporidium, microsporidia, Isospora belli, Entamoeba histolytica, Giardia lamblia), and even HIV itself. HIV-associated gastropathy and malabsorption are commonly noted in these individuals.
Because of their reduced gastric acid concentrations, individuals have an increased susceptibility to virus with Campylobacter, Salmonella, and Shigella. Co-infection with viral hepatitis (HBV, HCV, CMV) can lead to end-stage liver disease, but fortunately, institution of highly active antiretroviral therapy (HAART) can lead to a reduction in medical HBV illness.
Skin lesions commonly related to HIV virus are typically classified as infectious (viral, bacterial, fungal), neoplastic, or nonspecific. Herpes simplex virus (HSV) and herpes zoster virus (HZV) may cause chronic persistent or progressive lesions in individuals with compromised cellular immunity.
HSV commonly causes oral and perianal lesions but can be an AIDS-defining sickness when involving the lung or esophagus. The risk of disseminated HSV or HZV virus and the presence of molluscum contagiosum appear to be correlated using the extent of immunoincompetence.
Seborrheic dermatitis caused by Pityrosporum ovale and fungal skin infections (Candida albicans, dermatophyte species) are also commonly observed in HIV-infected patients. Staphylococcus including methacillin-resistant S aureus can cause the folliculitis, furunculosis, and bullous impetigo commonly observed in HIV-infected individuals, which require aggressive treatment to prevent dissemination and sepsis.
Bacillary angiomatosis is a potentially fatal dermatologic disorder of tumor-like proliferating vascular endothelial cell lesions, the result of infection by Bartonella quintana or Bartonella henselae. The lesions might resemble those of Kaposi's sarcoma but respond to treatment with erythromycin or tetracycline. CNS manifestations in HIV-infected patients consist of infections and malignancies.
Toxoplasmosis frequently presents with space-occupying lesions, causing headache, altered mental status, seizures, or focal neurologic deficits. Cryptococcal meningitis commonly manifests as headache and fever. Up to 90% of patients with cryptococcal meningitis exhibit a positive serum test for Cryptococcus neoformans antigen.
HIV-associated cognitive-motor complex, or AIDS dementia complex, is the most frequently diagnosed cause of altered mental status in HIV-infected patients. Patients typically have difficulty with cognitive tasks, poor short-term memory, slowed motor purpose, personality changes, and waxing and waning dementia. Up to 50% of patients with AIDS suffer from this disorder, perhaps caused by glial or macrophage infection by HIV resulting in destructive inflammatory changes within the CNS.
The differential diagnosis can be broad, including metabolic disturbances and toxic encephalopathy resulting from drugs. Other causes of altered mental status consist of neurosyphilis, CMV or herpes simplex encephalitis, lymphoma, and progressive multifocal leukoencephalopathy, a progressive demyelinating disease caused by a JC papovavirus.
Peripheral nervous system manifestations of HIV virus include sensory, motor, and inflammatory polyneuropathies. Almost 33% of individuals with advanced HIV disease develop peripheral tingling, numbness, and pain in their extremities. These symptoms are likely to become due to loss of nerve axons from direct neuronal HIV infection.
Alcoholism, thyroid disease, syphilis, vitamin B12 deficiency, drug toxicity (ddI, ddC), CMV-associated ascending polyradiculopathy, and transverse myelitis also cause peripheral neuropathies. Less commonly, HIV-infected patients can develop an inflammatory demyelinating polyneuropathy similar to Guillain-Barre syndrome; however, unlike the sensory neuropathies, this inflammatory demyelinating polyneuropathy typically presents before the onset of clinically apparent immunodeficiency.
The origin of this condition is not known, although an autoimmune reaction is suspected. Retinitis resulting from CMV virus is the most typical cause of rapidly progressive visual loss in HIV virus. The diagnosis could be difficult to make because Toxoplasma gondii virus, microinfarction, and retinal necrosis can all cause visual loss. HIV-related malignancies commonly seen in AIDS include Kaposi's sarcoma, non-Hodgkin's lymphoma, primary CNS lymphoma, invasive cervical carcinoma, and anal squamous cell carcinoma.
Impairment of immune surveillance and defense and increased coverage to oncogenic viruses appear to contribute towards the development of neoplasms. Kaposi's sarcoma is the most typical HIV-associated cancer. In San Francisco, 15-20% of HIV-infected homosexual men develop this tumor during the progression of their disease.
Kaposi's sarcoma is uncommon in women and children for reasons that are not clear. Unlike classic Kaposi's sarcoma, which affects elderly men within the Mediterranean, the illness in HIV-infected individuals may present with either localized cutaneous lesions or disseminated visceral involvement.
It is often a progressive disease, and pulmonary involvement could be fatal. Histologically, the lesions of Kaposi's sarcoma consist of a mixed cell population that includes vascular endothelial cells and spindle cells within a collagen network.
Human herpesvirus 8 is associated with Kaposi's sarcoma in patients with AIDS. HIV itself appears to induce cytokines and growth factors that stimulate tumor cell proliferation rather than causing malignant cellular transformation. Clinically, cutaneous Kaposi's sarcoma typically presents as a purplish nodular skin lesion or painless oral lesion.
Sites of visceral involvement include the lung, lymph nodes, liver, and GI tract. In the GI tract, Kaposi's sarcoma can produce chronic blood loss or acute hemorrhage. In the lung, it often presents as coarse nodular infiltrates bilaterally, frequently related to pleural effusions.
Non-Hodgkin's lymphoma is particularly aggressive in HIV-infected individuals and usually indicative of substantial immune compromise. The majority of these tumors are high-grade B-cell lymphomas with a predilection for dissemination. The CNS is frequently involved either as a primary site or as an extranodal site of widespread disease.
Anal dysplasia and squamous cell carcinoma are also more commonly found in HIV-infected homosexual men. These tumors appear to become related to concomitant anal or rectal infection with human papillomavirus (HPV). In HIV-infected women, the incidence of HPV-related cervical dysplasia is as high as 40%, and dysplasia can progress rapidly to invasive cervical carcinoma.
Adherence to multidrug regimens remains a challenge, but clearly antiretroviral therapy improves immune purpose. For reasons that are not clear, HIV-infected patients have an unusually high rate of adverse reactions to a wide variety of antibiotics and frequently develop severe debilitating cutaneous reactions.
Drug hypersensitivity and toxicity can be severe, potentially life-threatening, and limiting with certain agents. Immune reconstitution syndrome is really a described reaction occurring days to weeks following initiation of HAART.
Medical relapse or worsening of mycobacterial, pneumocystis, hepatitis, or neurological infections occurs as a result of a resurgence of immune activity, causing paradoxical worsening of inflammation, possibly as residual antigens or subclinical pathogens are attacked.
Other issues of HIV-infection include arthritides, myopathy, GI syndromes, dysfunction of the adrenal and thyroid glands, hematologic cytopenias, and nephropathy. Since the illness was first described in 1981, medical knowledge of the underlying pathogenesis of AIDS has increased at a rate unprecedented in medical background.
This knowledge has led towards the rapid improvement of therapies directed at controlling HIV virus as well as the multitude of complicating opportunistic infections and cancers.
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