Infectious Diseases of Blood PDF

Defenses in blood circulation Microbes that successfully invade blood gain access to every part of the body, and every system may be affected. For this reason, bloodstream infections are called systemic infections. Multiple defenses against infection reside in the bloodstream:...

Defenses in blood circulation Microbes that successfully invade blood gain access to every part of the body, and every system may be affected. For this reason, bloodstream infections are called systemic infections. Multiple defenses against infection reside in the bloodstream: The blood is full of leukocytes, with approximately 5,000 to 10,000 white blood cells per milliliter of blood. The various types of white blood cells include the lymphocytes responsible for specific immunity, and the phagocytes which are responsible for nonspecific immunity. Specific immune responses No normal microbiota in blood and lymphs Medical conditions involving the blood often have the suffix -emia. For example: Bacterial presence in the blood is called bacteremia Viral presence in the blood is called viremia Fungal presence in the blood is called fungemia Infectious diseases of blood 1- Viral infections 1- Infectious mononucleosis (kissing disease) Infectious mononucleosis is an acute, self-limited disease of adolescents and young adults that is caused by Epstein-Barr virus (EBV). Viral properties EBV is a member of the family Herpesviridae. EBV is a ds-DNA and has icosahedral shape. It is enveloped virus As a herpes virus, it has a tegument Transmission EBV is transmitted mainly via direct contact with patient Transmission through blood transfusions, sexual contact, and organ transplants is also possible. More than 90% of the world’s population has been infected with EBV. 30% to 77% of infection during the teen years have mononucleosis symptoms. Pathogenesis Virus initially infects oropharyngeal epithelial cells and then spreads to underlying lymphoid tissue (tonsils and adenoids). When virus enters tonsils and adenoids, it infects resting B cells. The infection of B cells takes one of two forms. More commonly, the infection is nonproductive and the virus persists in latent form. In a minority of cells, the infection is lytic, leading to viral replication and release of virions. CD8+ T cells are activated and proliferate to control the infection. Virus-specific CD8+ T cells appear in the circulation as atypical lymphocytes, a finding that is characteristic of infectious mononucleosis. At any time, the latent virus can become reactivated and new virions may be shed into saliva. Only people who are immunocompromised tend to have symptoms during a reactivation. Signs and symptoms Fever, headache, extreme fatigue, severe sore throat, enlarged lymph nodes, splenomegaly, and a rash may develop. Lab diagnosis Leukocytosis (12,000-25,000/cm3) with absolute lymphocytosis, monocytosis and atypical lymphocytes. Paul-Bunnell test (mono-spot test): to detect presence of heterophil antibodies by agglutination with sheep RBCs Detection of IgM antibodies against viral capsid antigen (VCA) by ELISA. VCA-IgG persists for the rest of a person’s life. Detection of IgG antibodies against early antigen (Anti-EA IgG). They appear in the acute phase of illness. In many people, detection of antibody to EA is a sign of active infection. Detection of EBV nuclear antigen (EBNA): Antibody to EBNA is not seen in the acute phase of EBV infection but slowly appears 2-4 months after onset of symptoms and persists for the rest of a person’s life. Interpretation of EBV antibody tests and diagnosis of EBV infection If patient has anti-VCA IgM but do not have antibody to EBNA, it suggests primary infection If patient has both VCA and EBNA antibodies, it suggests persistent infection. Treatment - Disease is self-limited - Acyclovir has little activity against EBV, but administration of high doses may be useful in life- threatening EBV infections. Prevention: There is no EBV vaccine. Note EBV is oncogenic virus. It is associated with tumors such as Burkitt's lymphoma, Hodgkin's lymphoma, nasopharyngeal carcinoma and gastric cancer. 2- Dengue fever Dengue fever is caused by dengue viruses (serotypes 1, 2, 3, or 4). Dengue virus is an enveloped, single- stranded RNA which belonged to Flaviviridae family. Transmission Virus is transmitted via bites of two mosquitoes: female Aedes aegypti or Aedes albopictus. Pathogenesis The virus infects leukocytes. The presence of dengue virus nonstructural protein 1 (NS1) provokes cytokine release and inflammatory response. Inflammatory response causes plasma leakage through capillaries. Signs and symptoms WHO classified dengue infection into 3 phases: dengue fever without warning signs, dengue with warning sings, and severe dengue. 1- Dengue without warning signs (classic dengue fever) It occurs in the majority of patients. Patient has: high grade fever (>38°C) myalgia and arthralgia (break bone fever) rash which appears on the 3rd or 4th day and lasts for 1–5 days. retro-orbital pain frequently enlarged lymph nodes positive tourniquet test leukopenia Patients recovered without any complications. Patient has lifelong immunity. The immunity is serotype specific. 2- Dengue with warning signs Some patients develop warning signs such as: Abdominal pain or tenderness Persistent vomiting Mucosal bleeding Hepatomegaly Clinical fluid accumulation Increasing hematocrit concurrent with rapid decrease in platelet count Patients at risk include: immunocompromised patients, infants less than 1 year, patient with previous dengue history. Severe forms of dengue Not all dengue cases are severe. Approximately 10% of dengue cases progress to severe disease. Commonly occurs in patients infected with another dengue virus serotype (secondary infection) and in infants who have maternal Abs. A- Dengue hemorrhagic fever (DHF) Patient has severe bleeding. Platelets count is lower than 100,000 mm3. Patient has low hematocrit. B- Dengue shock syndrome (DSS) Patient has severe plasma leakage and shock. Diagnosis A- Serology tests include: Detection of IgM in primary infection (acute) (appears after 4-5 days) Detection of IgG (7-10 days) Detection of non-structural protein 1 (NS1) for early diagnosis (0-7 days) B- RT-PCR: for viral genome C- Positive tourniquet test: A blood pressure cuff is applied to the forearm of the patient for five minutes. If red patchy skin appears, it indicates that the patient’s capillaries have become leaky due to the viral infection. 4- HIV infection The causative agent is human immunodeficiency virus (HIV). Infection with HIV leads to acquired immunodeficiency syndrome (AIDS) due to depletion of CD4 T helper cells. Virus properties It belongs to retroviridiae family and genus lentivirus It is non-transforming retrovirus It has 2 positive ss-RNA segments It has 3 enzymes: reverse transcriptase (RT), integrase, and protease It is enveloped virus with 2 important glycoproteins (Gp 120 and Gp41) Spherical with cone-shaped nucleocapsid HIV structure 2 copies of RNA, reverse transcriptase, integrase, protease, capsid, envelp, gp120, gp41 HIV genome Pol, env, gag Serotypes and genotypes There are two HIV species HIV-1 and HIV-2. Most of the reported cases are caused by HIV-1. There are four groups of HIV-1 with different geographical distributions. 1. HIV-1 group M (major): which is responsible for most of the infections in world (90% of cases). It has been further subdivided into subtypes (clades) from A-K. 2. HIV-1 group O (outlier): relatively rare (less than 1%) 3. HIV-1 group N (neither M nor O): very rare 4. HIV-1 group P: only 2 cases in Cameroon There are many variants (quasispecies) of HIV in a single infected patient. Transmission Virus is transmitted sexually (especially homosexual; 50% of all cases). IV drug users (20% of cases) Virus also transmitted via blood and blood products (e.g. in hemolytic anemia and hemophilia) It can be transmitted from infected mother to her fetus: transplacenta, during birth, or via breast milk. Needle stick injury Pathogenesis While HIV can infect many tissues, the two major targets of HIV infection are the immune system and the central nervous system. HIV virus uses CD4 as a receptor for attachment and subsequently for fusion and entry into the cell. CD4 is expressed on T helper cells, macrophages, monocytes and dendritic cells. HIV virus also uses two co-receptors CCR5 and CXCR4. The initial step in infection is the binding of gp120 envelope glycoprotein to CD4 molecules, which leads to a conformational change that creates a new recognition site on gp120 for the coreceptors CCR5 or CXCR4. Binding to the coreceptors induces conformational changes in gp41 leading to fusion of the virus with the host cell membrane. After fusion, the virus core containing the HIV genome enters the cytoplasm of the cell and starts to replicate. RNA genome of the virus undergoes reverse transcription, leading to the synthesis of leading to the synthesis of double stranded complementary DNA (cDNA; proviral DNA). In quiescent T cells, HIV cDNA may remain in the cytoplasm in a linear episomal form. In dividing T cells, the cDNA circularizes, enters the nucleus, and is then integrated into the host genome. After integration, the provirus may be silent for months or years, a form of latent infection. Alternatively, proviral DNA may be transcribed, leading to the expression of viral proteins that are required for the formation of complete viral particles. New virus particles leave infected cell by budding figure 5. HIV infection leads to low levels of CD4+ T cells through two main mechanisms: 1) Direct killing of infected cells by cytopathic effects of HIV virus 2) Killing of infected CD4+ T cells by CD8+ T cells that recognize infected cells When CD4+ T cell numbers decline below a critical level (200 cell/cm3), cell-mediated immunity is lost, and the body becomes susceptible to opportunistic infections. Clinical features HIV infection has three basically stages: 1- Acute infection Acute infection begins 3-6 weeks after infection. All patients have high levels of viremia measured by several millions of HIV-RNA copies per mL blood. Viremia lasts for several weeks and contributes to more virus dissemination in the body. The patient in this stage is highly infectious. Acute infection in 50 % of individuals can include symptoms such as fever, myalgia, sore throat, malaise, rash, lymphadenopathy, mouth and esophageal sores. Because these symptoms are non-specific, most of cases are misdiagnosed. The viremia is associated in all patients with the activation of CD8+ T cells and production of anti-HIV. Good T cells immune response is very important in controlling virus level in the blood which peaks and then declines while CD4+ T cell counts fall and then quickly return to around normal, figure 1. Seroconversion occurs 3-7 weeks after infection. The period after virus infection and before seroconversion is termed window period. 2- Chronic infection Patient shows few or no symptoms and this stage can last from two weeks to twenty years or more. During this period, the virus is not dormant and there is active viral replication. More than 1011 new HIV particles are produced each day but they are rapidly cleared. There can be up to 102 to 107 virus particles per ml of blood. Most of this virus is coming from recently infected proliferating CD4+ cells. The infected cells are destroyed either by the CD8+ T cells or by the virus. However, the rate of production of CD4+ cells can compensate for the loss of cells. Nevertheless, there is a continuous decline in the CD4+ T cell counts per μL, figure 6. Patient in this stage is still infectious to others. At this stage, the virus reaches what called the set point. The set point determines the time of onset of clinical disease. With fewer than 200 copies/ml, disease does not appear to occur at all (non- progressive). With less than 1000 copies/ml of blood, disease will probably occur with a latency period of more than 10 years. Most patients with more than 100,000 copies per ml, lose their CD4+ cells more rapidly and progress to AIDS before 10 years. 3- Onset of AIDS AIDS, the final stage of HIV infection, shows symptoms of various opportunistic infections and malignancies (e.g. Kaposi Sarcoma) associated with the progressive failure of the immune system due to loss of CD4+ T cells (less than 200 cells/μL). Examples opportunistic infections are candidiasis, pneumonia, and TB. Examples of malignancies are Kaposi sarcoma and lymphoma. Effect of HIV on CNS: Many patients have neurologic problems. Lab diagnosis ▪ Multiple tests are available for HIV testing. The most common is the ELISA test. This test is used to screen for HIV, but it is not considered as a confirmatory test due to both false-negative and false- positive results. ▪ Routine ELISA tests detect antibodies to HIV, not HIV antigens. Negative ELISA test does not exclude HIV infection. Since the test may be done in window period as well as anti-HIV titers often fall in patients with AIDS. ▪ In window period, patient is diagnosed by detection of P24 or by PCR test. P24 test becomes negative after appearing of HIV antibodies. Newborns for HIV-positive mothers are tested for P24 or viral nucleic acid using PCR technique. ELISA or any other serological tests are not used because they have anti-HIV from their mothers. Anti-HIV antibodies last about 18 months in the child blood. Confirmatory test: Nowadays, the confirmation of HIV infection is made by PCR test. PCR are used either to diagnose HIV infections or to follow up the patients. HIV-PCR of 2 types: 1- HIV-RNA PCR This is used to diagnose acute infection and then to monitor the progression of disease and treatment response. All infected patients are monitored at three-monthly intervals. 2- HIV DNA PCR: This looks for the viral DNA integrated in the cells (provirus). This is now being replaced by HIV RNA PCR as it is equally sensitive in diagnosing infection. Monitoring 1- Viral load: The concentration of virus is measured in the plasma of infected individuals. The higher the concentration (e.g.106 copies/ml), the more rapid will be progression to AIDS. The lower the concentration (the lowest level of detection is 500 copies/ml), the slower the disease progression. 2- CD4 counts: The concentration of T helper correlates with the stage the patient's immune system has reached in its battle with HIV. Normal CD4 count is 500-1200 cells/μL. The lower the CD4 count, the more likely the individual has illness. The risk is rising progressively as the count falls below 200 and then below 100 cells/ μL. Treatment Antiretroviral therapy has greatly decreased the incidence of opportunistic infections and tumors but also has numerous complications. There are three types of drugs that can be used for patient treatment and are given in combination 1- RT-inhibitors: Zidovudine (azidothymidine, AZT) and viramune 2- Protease inhibitors: ritonavir 3- Entry inhibitors: Maraviroc binds to gp120 preventing viral entry. Prevention No vaccine Avoid adultery Blood banks have to test for the presence of p24 antigen to detect presence of virus during window period Post-exposure prophylaxis after needle-stick injury by zidovudine, lamivudine and protease inhibitor Infected pregnant women should receive AZT or nevirapine during pregnancy Delivery by caesrean section Neonates should receive the same drugs Infected mothers should not breast feed their infants 4- Yellow fever It is caused by Yellow fever virus. Virus properties It belongs to family Flaviviridae It has ssRNA with positive polarity It has icosahedral shape It is enveloped Mode of transmission It is transmitted via female mosquito Aedes aegypti. Aedes feeds during daylight hours. Pathogenesis The virus is deposited into tissue by mosquito bite; dendritic cells take up the virus and then move to the lymph nodes where the virus can kill dendritic cells, releasing more virus to infect macrophages. Infected macrophages migrate through blood and lymph, where they die and release more viruses to the patient’s organs (particularly the liver). Signs and symptoms Most yellow fever infections are asymptomatic or mild. However, some patients develop symptoms. Symptomatic yellow fever has three stages. Stage 1 (early stage): involves a slight fever, headache, myalgia, and vomiting. Stage 2 (remission): Fever and other symptoms disappear. Most people will recover at this stage. Stage 3 (intoxication): 15% of patients proceed to the most severe disease characterized by delirium, seizures, coma, and degeneration of the liver, kidneys, and heart, as well as massive hemorrhaging accompanied by high fever, nausea, nosebleed, and shock.