Infectious diseases Flashcards
Sepsis
Sepsis is an acute life-threatening condition characterized by organ dysfunction due to a dysregulated immune response to infection. The previously widely used term “systemic inflammatory response syndrome” (SIRS) is now considered outdated because its criteria were too simplified. Initial infection is generally bacterial and commonly of respiratory, genitourinary, gastrointestinal, dermatological, or soft tissue origin. Risk factors include immunocompromise, chronic comorbidities (e.g., diabetes mellitus), young or old age, and lengthy or invasive medical care. Patients may present with fever, tachycardia, confusion, and signs of the primary infection. Organ dysfunction is determined using a sequential organ failure assessment (SOFA) score that considers multiple parameters, but may be quickly evaluated and assumed if two of the following findings are present: tachypnea, hypotension, and altered mental status. Diagnostic workup focuses on determining the responsible pathogen via cultures and identifying the source of infection (e.g., via imaging, ECG, lumbar puncture). Laboratory findings are largely nonspecific. Prompt, aggressive treatment is vital to survival and consists of resuscitation, empiric antibiotic therapy, and control of the infectious source.
Sepsis
D:
R:
D:
E:
A: Common primary infections: respiratory , genitourinary, gastrointestinal, skin, and soft tissue infections
Pathogens
Bacterial: gram positive bacteria (most common in the US), gram negative bacteria
Fungal, viral, or parasitic infection (rare)
Risk factors
Age: < 1 year or > 75 years
Primary comorbidities (diabetes mellitus, cirrhosis, community acquired pneumonia, bacteremia (presence of bacteria in circulation), alcoholism)
Immunosuppression (neutropenia, corticosteroid treatment)
Intensive care or prolonged admission (nosocomial infections)
Recent antibiotic or corticosteroid treatment
Invasive medical devices (e.g., endotracheal tubes, intravenous lines, urinary catheters).
2015 criteria and SOFA classification (The third international consensus definitions for sepsis and septic shock, Sepsis-3)
Sepsis: acute and life-threatening organ dysfunction due to abnormal host response to infection
Organ dysfunction: an acute change in total SOFA score ≥ 2 points
Infection: may be confirmed (via culture) or suspected
Septic shock consists of the following parameters:
Sepsis +
Significant circulatory, metabolic, and cellular abnormalities +
Requiring vasopressor therapy to maintain a mean blood pressure of ≥ 65 mmHg and presence of increased lactate levels > 2 mmol/L (18 mg/dL) in the absence of hypovolemia
The term “severe sepsis” is no longer used
Quick SOFA criteria (qSOFA): to predict mortality in adult patients with suspected infection
Positive if ≥ 2 of the following are present:
Altered mental status (Glasgow Coma Scale < 15) [8]
Respiratory rate: ≥ 22 breaths per minute
Systolic BP: ≤ 100 mmHg
If positive then the patient should be assessed for organ dysfunction via the SOFA score.
C: Patients typically present with a poor overall condition and generalized edema (capillary leak).
Fever , chills, and diaphoresis
Tachycardia
Tachypnea
Features of organ dysfunction (see SOFA score)
CNS impairment: altered mental status
Cardiovascular failure: hypotension
Coagulopathy → disseminated intravascular coagulation → petechiae, purpura
Liver failure: jaundice
Kidney failure: oliguria
Respiratory failure: symptoms of acute respiratory distress syndrome (ARDS)
Additionally in septic shock
Severe hypotension (< 65 mmHg)
Initially warm skin and normal capillary refill time (warm shock) → cold cyanotic, pale, or mottled skin with prolonged capillary refill time (cold shock)
Features of the primary infection
P:
Sepsis is the state of a hyperinflammatory systemic reaction
Local activation of inflammatory mediators (complement system, mast cells, macrophages) results in vessel dilation and further release of proinflammatory cytokines (esp. TNFα, IL-1)
Generalized endothelial disruption → capillary leak → generalized edema due to a shift of intravascular fluid and albumin into the surrounding tissue
Intravascular hypovolemia → excessive triggering of the extrinsic coagulation cascade → disseminated intravascular coagulation (DIC) and microvascular thrombosis
Decreased oxygen utilization and tissue ischemia → widespread cellular injury → organ dysfunction (commonly multisystem)
An adequate immune response requires a balance between proinflammatory (anti-infectious) and anti-inflammatory signals!
I:
Identify the responsible pathogen
Perform Gram stain and cultures of blood and urine
Depending on symptoms, consider other body fluids for culture: e.g., sputum (if coughing), stool (if diarrhea is present), pus (soft tissue infection).
Identify the infectious focus
Imaging
Lumbar puncture if suspected CNS infection
Echocardiography if suspected endocarditis
Assess organ dysfunction
Coagulation abnormalities (see disseminated intravascular coagulation): ↑ prothrombin time, ↑ activated partial thromboplastin time, ↓ antithrombin III, later ↑ D dimer
Abnormal liver function: hyperbilirubinemia, ↑ INR, ↑ ALT, ↑ AST
Adrenal insufficiency (e.g., ACTH stimulation test)
Impaired kidney function: ↑ BUN and ↑ creatinine
Nonspecific infectious parameters
CBC
Anemia
Leukocytosis or eventual leukopenia
Thrombocytopenia → early prognostic marker of 28 day mortality due to septic shock
Procalcitonin
↑ CRP
↑ Serum lactate
Hyperglycemia (plasma glucose > 140 mg/dL or 7.7 mmol/L) in the absence of known diabetes
M: Immediate resuscitation (respiratory and circulatory support)
Intubation and mechanical ventilation may be required if the following is present: respiratory insufficiency, dyspnea, persistent hypotension, or poor peripheral perfusion
Fluid resuscitation (hypotension and hypoperfusion)
Vasopressors (catecholamines) may be necessary when patients remain hypotensive despite fluid resuscitation (e.g., norepinephrine)
Empiric antibiotic treatment: begin immediately after blood cultures have been drawn, preferably within 1 hour after recognition
Treat for MRSA until ruled out: vancomycin or linezolid/daptomycin in combination with either:
Piperacillin/tazobactam, cefepime, or carbapenems if Pseudomonas infection is likely
3rd generation cephalosporin (e.g., ceftriaxone or cefotaxime) if Pseudomonas infection is unlikely
Antifungal treatment in cases of documented fungemia (presence of a fungus in the bloodstream)
Control infectious source
Remove any foreign bodies
Surgically drain abscesses or perform debridement on infectious wounds
Manage any complications of surgery (e.g., ileus, peritonitis, anastomotic insufficiency, osteomyelitis)
Reassess the success of the therapeutic management every 48–72 hours
Other therapy considerations
Glucocorticoids (e.g., prednisone or dexamethasone): if there is an increased risk of cerebral edema
Insulin-based control of blood glucose levels: control of stress-induced hyperglycemia results in a shorter length of stay in the ICU, even in non-diabetic patients.
In addition to immediate resuscitation and empiric therapy, the infectious focus must be identified and treated!
P:
Critical illness polyneuropathy
Definition: axonal injury, particularly to the motor neurons, as a sequela of sepsis and multiple organ dysfunction
Clinical features
Predominantly distal, symmetrical, flaccid paralysis of the extremities with muscle atrophy; may affect the diaphragm
Absent or reduced reflexes
Dysesthesias in a glove-and-stocking distribution may be present
Preservation of cranial nerve function
May be associated with critical illness myopathy : flaccid quadriparesis (proximal > distal); facial muscle weakness, sensation normal, tendon reflexes normal or ↑
Diagnosis: typical clinical features, sepsis, and electrophysiological evidence of motor and sensory neuropathy
Electromyography (EMG): spontaneous activity (e.g., fibrillations)
Nerve conduction studies: normal velocity, reduced amplitude
Treatment: no specific treatment available, usually gradual spontaneous resolution (weeks to months)
Critical illness polyneuropathy is a common cause of prolonged weaning from mechanical ventilation in a patient with sepsis!
nosocomial infections
Nosocomial infections, also known as hospital-acquired infections, are newly acquired infections that are contracted within a hospital environment. Transmission usually occurs via healthcare workers, patients, hospital equipment, or interventional procedures. The most common sites of infection are the bloodstream, lungs, urinary tract, and surgical wounds. Though any bacteria may cause a nosocomial infection, there is an increasing incidence of multidrug-resistant (MDR) pathogens causing hospital-acquired infections. This rise can be explained by indiscriminate use of antibiotics and lacking hygiene measures, especially among medical staff. Commonly seen multidrug-resistant pathogens include methicillin-resistant Staphylococcus aureus (MRSA), extended-spectrum beta-lactamase-producing bacteria (ESBL), and vancomycin-resistant enterococci (VRE). The choice of antibiotic for treating infections with these pathogens is based on the individual resistance profile and often requires additional strict isolation methods for the patient.
Risk factor: Risk factors
Age > 70 years
Lengthy hospital stays → high risk of infection
Via medical staff (e.g., insufficient disinfection of hands, clothing) and contact surfaces (e.g., equipment, furniture)
Via indoor air (may be contaminated by droplets from infected patients, staff, or procedures like bronchoscopy)
Metabolic diseases (especially diabetes mellitus) and immunosuppression
Prior antibiotic use
Iatrogenic (caused by treatment or a diagnostic procedure)
Invasive instruments and foreign bodies: catheters, intravenous catheters, endotracheal tubes
Conditions which require a high amount of interventional procedures (e.g., shock, major trauma, acute renal failure, coma)
Mechanical ventilation
Multiresistant pathogens
Methicillin-resistant Staphylococcus aureus (MRSA)
Resistance: developed by forming a modified penicillin-binding protein (PBP) that inhibits binding to beta-lactam antibiotics, thereby decreasing their bactericidal effect
Occurrence: asymptomatic colonization of the nasal mucosa estimated at 0.5–5% of the population
Measures to curb MRSA
Hygiene measures: hand disinfection, protective clothing (gown, mask) , disinfection of patient rooms
Patient isolation, if necessary cohort isolation
MRSA eradication in asymptomatic carriers
Mupirocin nasal ointment, antiseptic solution for skin/hair contamination (e.g., chlorhexidine)
The resistance mechanism of MRSA is caused by modified PBPs, not the formation of beta-lactamase! Every detected case of MRSA (symptomatic or asymptomatic) requires treatment!
Extended-spectrum beta-lactamase-producing bacteria (ESBL)
Resistance: Bacteria produce beta-lactamases that have a broad spectrum and are thus able to cleave penicillins, cephalosporins, and, in isolated cases, carbapenems.
Common pathogens: particularly gram-negative bacteria (e.g., Enterobacteriaceae such as Klebsiella, Escherichia coli)
Associated with nosocomial urinary tract infections and healthcare-associated pneumonia
Isolation in separate rooms required
Vancomycin-resistant enterococci (VRE)
Definition: bacterial strains of the genus Enterococcus that are resistant to the antibiotic vancomycin (e.g., E. faecalis , E. faecium)
Resistance: acquisition of van genes → alteration of peptidoglycan synthesis pathway → inhibits binding of vancomycin to peptidoglycan
Multidrug-resistant gram-negative bacteria (MDRGNB)
Definition: A pathogen is termed as MDRGN when resistance is demonstrated to at least three antibiotic classes (see “Treatment of multiresistant pathogens” below).
Hospital hygiene and prevention of infection
Suspected cases: no isolation
In cases of pathogen detection
Basic hygiene measures in normal areas sufficient
Isolation in risk areas
Infections caused by Pseudomonas aeruginosa
Characteristics
Pseudomonas aeruginosa has a high natural resistance to antibiotics
Blue-green color (e.g., blue-green sputum or pus)
Sweet, sickly odor
Typically found in damp environments
Diseases: pneumonia, severely infected wounds, urinary tract infections, otitis externa (“swimmer’s ear”), keratitis
Treatment of multiresistant pathogens
The increased use of antibiotics in hospital settings has led to a greater antibiotic resistance of some bacterial strains. The treatment of infections caused by these strains is difficult since common broad spectrum antibiotics are ineffective and use of alternative drugs is necessary. Therefore, prophylaxis involves both preventing the spread of the causative pathogen as well as treating asymptomatic carriers.
Gram positive resistant MRSA--> first line: vancomycin, linezolid. alternative: Quinupristin/dalfopristin Daptomycin Tigecycline
vancomycin-resistant enterococci (VRE) --> first line: Linezolid, alternative: Quinupristin/dalfopristin Tigecycline Daptomycin
Gram negative
ESBL pathogens (Extended-spectrum β-lactamase): first line: MDRGN carbapenems
Psudomonas aeruginosa: first line: MDRGN: piperacillin + tazobactam.
Group 3b cephalosporins (ceftazidime)
Carbapenems
All options are potentially combinable with an aminoglycoside
HIV Dr Deac Pimp
Infection with the human immunodeficiency virus (HIV) leads to a complex disease pattern which ultimately results in chronic immunodeficiency. HIV can be transmitted sexually, parenterally, or vertically (e.g., peripartum from mother to child). Infection is most common in the young adult population between 20 and 30 years of age. The virus infects macrophages and other CD4+ cells, leading to the destruction of CD4 T cells and thereby impairing one of the key mechanisms of cellular immune defense. There are three major stages: acute infection, clinical latency, and acquired immunodeficiency syndrome (AIDS). For clinical staging, detailed classifications have been established by the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO). During the stage of acute infection, the virus reproduces rapidly in the body, which can lead to acute, nonspecific (e.g., flu-like) symptoms (also known as acute retroviral syndrome, ARS) within 2–4 weeks. However, approximately half of all infected individuals remain asymptomatic. Once the stage of acute infection subsides, the clinical latency stage begins. Again, many individuals remain asymptomatic during this period, while others develop non-AIDS-defining conditions (e.g., oral hairy leukoplakia). The last stage, AIDS, is characterized by AIDS-defining conditions (e.g., Kaposi’s sarcoma) and/or a CD4 count < 200 cells/μL. HIV infection can reliably be detected via antigen/antibody-based tests. In patients with confirmed infection, the most important parameters for monitoring the disease are CD4 count and viral load. HIV treatment involves a combination of antiretroviral drugs (combination antiretroviral therapy, cART). In addition, HIV-related complications (e.g., HIV wasting syndrome, opportunistic infections) will require management. There have been significant advances in treatment so that the average life expectancy of HIV patients receiving current antiretroviral drugs is approaching that of the general population.
Epidemiology:
Incidence (in the US)
HIV infection: peak incidence between ages 20 and 30 (∼ 35/100,000)
AIDS: peak incidence approx. age 45 (∼ 14/100,000)
Ethnicity: Incidence is significantly higher in the Black population than in other population groups.
Prevalence
US: ∼ 1.2 million
Global: ∼ 37 million
Aetiology
Pathogen (human immunodeficiency virus)
Lymphotropic lentivirus (from the family of retroviridae)
Consists of the two species HIV-1 and HIV-2
HIV-1: most common species worldwide
HIV-2: restricted almost completely to West Africa
Routes of transmission
Sexual: responsible for ∼ 80% of infections worldwide
Risk per sexual act
Risk for men who have sex with men (MSM): 0.5% for receptive partner
Risk for male-to-female sex
0.1% for female partner
0.05% for male partner
Modifying factors
Viral load: studies have shown that transmission is unlikely if viral load is < 400 copies/ml
Circumcision: reduced risk of infection for circumcised men
Coinfection: genital inflammation (e.g., as a result of coinfection with other pathogens such as HPV or genital herpes) increases local virus concentration and therefore risk of transmission
Genital mucosal damage: increases risk of transmission
Parenteral transmission
Needle sharing: 0.67% per exposure through needle-sharing contact
Needlestick injuries: 0.36% per injury
Infectious blood on mucous membranes: 0.1% per exposure
Blood transfusions: 0.00005% risk per transfusion (1 in 2 million)
Vertical transmission: from mother to child
During childbirth (∼ 5–15%)
Through breastfeeding after birth (∼ 5–20%)
Risk of transmission can be lowered significantly if HIV infection is treated consistently and viral load is below the limit of detection!
Pathophysiology:
Structure of HIV
Physical structure: icosahedral with a conical capsid and a spiked envelope
Genome : 9 genes encoding a total of 15 proteins (e.g., reverse transcriptase , integrase , and envelope proteins )
pol gene codes for a polyprotein that consists of protease, reverse transcriptase, and integrase
gag gene codes for gag protein, which consists of matrix protein, nucleocapsids, and capsid proteins
env gene codes for surface glycoproteins, gp41 and gp120
Natural history of HIV infection
Initial infection and HIV replication cycle
HIV enters the body (e.g., via mucosal lesions or via infection of mucosal/cutaneous immune cells.), then attaches to the CD4 receptor on target cells with its gp120 glycoprotein (binding)
Cells that have CD4 receptors: T lymphocytes (e.g., T helper cells), macrophages, monocytes, dendritic cells (CNS).
Viral envelope fuses with host cell, capsid enters the cell.
For fusion, CD4 receptor and a coreceptor (CCR5 in macrophages, and CCR5 or CXCR4 in T-cells) must be present.
Patients without CCR5 receptors appear to be resistant to HIV, those patients either have a homozygous CCR5 mutation (substantial resistance) or a heterozygous CCR5 mutation (slower course).
Virion’s RNA is transcribed into DNA and then integrated into the host’s DNA
Viral DNA is replicated and virions are assembled
Virion repurposes a portion of the cell’s membrane as envelope and leaves the cell (budding) → cell death
Progression to chronic immunodeficency
HIV infects CD4+ lymphocytes, then reproduces and spreads to other CD4+ lymphocytes near the original site of infection → infection of CD4+ lymphocytes concentrated in specialized lymphoid tissue (e.g., lymph nodes or gut-associated lymphatic tissue (GALT) ) → explosive growth and dissemination → acute HIV syndrome with high viral load
Window period: The time between infection and detectability of HIV antibodies.
After the acute stage, viral load decreases and remains at roughly that level for approximately 8–10 years (clinical latency stage )
→ loss of CD4+ lymphocytes (especially T cells) impairs immune function and thereby facilitates opportunistic infections and development of malignancies (AIDS) → these secondary diseases are usually the cause of death in patients with HIV
Viral load predicts the rate of disease progression! CD4 count correlates with immune function!
Acute HIV syndrome does not develop in all patients! The hallmark of HIV is chronic persistent infection!
The role of immune response
Because HIV infects cells of the immune system itself, activation of cellular immunity is a factor that paradoxically helps the virus spread and ensures chronic persistence of the infection.
HIV evades immune control via:
Genetic mutation and recombination
Downregulation of MHC class I surface molecules in infected cells
Clinical features:
General considerations
In early HIV infection, patients are often asymptomatic.
Incubation period: usually 2–4 weeks
Infectiousness: two peaks (1st peak: within the first months after infection; 2nd peak: during AIDS-stage)
Acute HIV infection
Also referred to as acute retroviral syndrome (ARS) or described as a mononucleosis-like syndrome.
Fever
Fatigue
Myalgia and arthralgia
Headache
Generalized nontender lymphadenopathy
Generalized rash
Gastrointestinal symptoms (nausea, diarrhea, weight loss)
Oropharyngeal symptoms (sore throat, ulcerations, painful swallowing)
Clinical latency and AIDS
Clinical latency
Patients may still be asymptomatic
Non-AIDS-defining conditions
Chronic subfebrile temperatures
Persistent generalized lymphadenopathy
Localized opportunistic infections (e.g., oral candidiasis , vaginal infections )
Oral hairy leukoplakia (lesions located mainly on the lateral borders of the tongue)
Chronic diarrhea (> 1 month)
Skin manifestations (e.g. molluscum contagiosum, warts, exacerbations of psoriasis, shingles)
AIDS: see article on HIV-associated conditions.
Test patients with a history of injecting drugs who present with otherwise unexplained weight loss, depression, and/or dementia for HIV!
Candidiasis in the esophagus, unlike oral candidiasis, is an AIDS-defining condition!
Stages
WHO (World Health Organization) classification
WHO classifies individuals with confirmed HIV infection according to clinical features and diagnostic findings:
Primary HIV infection: acute retroviral syndrome or asymptomatic
Clinical stage 1: persistent generalized lymphadenopathy (PGL) or asymptomatic
Clinical stage 2: e.g., unexplained moderate weight loss (< 10%), recurrent fungal/viral/bacterial infections
Clinical stage 3: e.g., unexplained severe weight loss (> 10%), unexplained chronic diarrhea (> 1 month), unexplained persistent fever (≥ 36.7°C intermittent or constant > 1 month), persistent/severe fungal/viral/bacterial infections , unexplained anemia (< 8 g/dL) and/or neutropenia (< 500 cells/mm3) and/or chronic thrombocytopenia (< 50,000/μL) for more than 1 month
Clinical stage 4: AIDS-defining conditions (e.g., Kaposi sarcoma, Pneumocystis pneumonia)
Investigations:
HIV testing
Indications
Test all patients with clinical features of acute or chronic HIV infection
All individuals with possible past exposure, especially high-risk individuals : regular testing (e.g., annually)
One-time testing is recommended early in every pregnancy
HIV-testing requires patient consent (opt-out)
Initial diagnostic approach
Both screening tests and confirmatory tests detect anti-HIV antibodies in the blood
Screening tests
Combination antigen/antibody tests : detect both HIV antigen (p24) and anti-HIV antibodies → a negative result essentially rules out HIV infection (almost 100% sensitivity)
Antibody-only tests (HIV serology)
ELISA (enzyme-linked immunosorbent assay): standard method for detecting antibodies within approx. 1–3 hours; requires laboratory
Rapid tests: can deliver results in ∼ 20 minutes and do not require a laboratory, which makes them suitable as an alternative to the more complex tests in some outpatient settings.
Confirmatory tests
HIV-1/HIV-2 antibody differentiation immunoassay : can detect both HIV-1 and HIV-2 in ∼ 20 minutes and distinguish between the two types
Western blot: tests may be negative up to 2 months after infection; results are usually available after several days and HIV subtype O is not reliably detected.
Detection of viral RNA
Can detect HIV infection earlier than antibody/antigen-based tests but FDA-approved tests are limited to HIV-1
Indications:
Neonatal HIV infection
Patients with indeterminate results
Patients presenting before seroconversion
Screening of blood donors
Post-treatment monitoring
Viral RNA load: indicator of ART response
Decrease in viral loads indicates effective treatment
Prognostic marker in long-term treatment
CD4+ count: correlates with overall immune function
CD4+ counts increase in response to successful ART therapy
Critical measurement for initiating opportunistic infection prophylaxis
CD4+:CD8+ ratio: Used in the immunological evaluation of long-term follow-up cases
Expected increase in ratio with successful ART therapy
Correlates with immune dysfunction and viral reservoir size
Natural course of HIV infection.
Additional laboratory studies
CBC: possibly lymphocytopenia
Treatment
Antiretroviral HIV therapy
General approach
All persons infected with HIV (regardless of CD4 count) should begin combined antiretroviral therapy (cART) as soon as possible.
Therapy should be determined based on the HIV genotype
Antiretroviral drugs
Nucleoside reverse transcriptase inhibitors (NRTI): e.g., zidovudine, lamivudine, emtricitabine, abacavir, stavudine, didanosine
Mechanism of action: NRTIs act as nucleoside analogs → prevent the formation of 3’ to 5’ phosphodiester linkages → inhibit reverse transcription of RNA to DNA
NRTIs require intracellular phosphorylation for activation, and their efficacy is thus reliant on kinase availability and activity, which is variable depending on cell functionality and activation state.
Side effects
Bone marrow suppression → neutropenia, anemia
Mitochondrial toxicity → myopathy, neuropathy, hepatic steatosis, and lactic acidosis
Abacavir-related hypersensitivity syndrome
Didanosine/stavudine: pancreatitis
HIV-associated lipodystrophy: abnormal distribution of fat (clinical presentation varies greatly)
Loss of subcutaneous fatty tissue (lipoatrophy) of face and extremities
Metabolic changes: impaired glucose tolerance, hyperlipoproteinemia (elevated triglycerides, elevated total cholesterol, lowered HDL)
Probable accumulation of fat in liver, muscles, abdomen, breasts and neck (buffalo hump)
Resistance: caused by mutations in the gene that codes for reverse transcriptase (pol gene)
Non-nucleoside reverse-transcriptase inhibitors (NNRTI): e.g., nevirapine, efavirenz
Mechanism of action: non-competitive inhibitors of viral reverse transcriptase
NNRTIs do not require intracellular phosphorylation for activation but are direct inhibitors.
Side effects:
Hepatotoxicity (nevirapine)
CNS toxicity (efavirenz)
Hypersensitivity reactions (including Stevens-Johnson syndrome)
Nucleotide analogs (also called nucleotide reverse-transcriptase inhibitors; NtRTI): e.g., tenofovir
Protease inhibitors (PI): e.g., indinavir, ritonavir, nelfinavir, lopinavir
Mechanism of action: inhibition of viral protease → inability to cleave viral polypeptides → generation of viral proteins impaired → only immature (non-infectious) virions are produced
Side effects:
GI intolerance (nausea, diarrhea), lipodystrophy and fat accumulation , nephrolithiasis and crystal-induced nephropathy
Hyperglycemia: inhibition of insulin-dependent glucose transporters (GLUT 4) → peripheral insulin resistance → impaired glucose tolerance
Integrase inhibitors (INI): e.g., raltegravir, dolutegravir
Mechanism of action: inhibition of the viral integrase .
Fusion inhibitor: enfuvirtide
Mechanism of action: competitively binds to the viral protein gp41 and thereby prevents fusion with the cell
CCR5-antagonist: maraviroc
Mechanism of action: blocks the CCR5 coreceptor that is essential to cell infection for some HIV genotypes (R5 viruses)
Not generally recommended because of comparatively high costs and limited clinical data
HIV replication and mechanism of action of antiretroviral drugs
Regimens
Recommended regimens
3 NRTI (e.g., zidovudine, lamivudine, abacavir) OR
2 NRTI (e.g., lamivudine + abacavir) AND
1 NNRTI (e.g., efavirenz) OR
1 PI (e.g., lopinavir) OR
1 INI (e.g., raltegravir)
Hepatotoxic drugs (e.g. nevirapine) are contraindicated if there is coinfection with HBV or HCV!
Most NRTIs end in “-ine”, protease inhibitors in “-navir”, and integrase inhibitors end in “-gravir!”
Prognosis
Morbidity and mortality among patient subsets
Untreated HIV infection has a mortality rate of > 90% (average time from infection to death approx. 8–10 years)
Progression varies among individuals: some patients may die within a few years while others remain asymptomatic for decades
Untreated individuals with advanced HIV infection usually die within a few years (median survival is 12–18 months)
Some untreated individuals show only slow progression and can remain asymptomatic for more than 20 years.
In rare cases, untreated individuals have no detectable viremia and continue to have high CD4 counts for long periods
The average life expectancy of HIV-infected patients who receive adequate antiretroviral treatment is ∼ 8 years lower than noninfected individuals of the same age.
Individual prognosis depends on various factors, including:
Adequate antiretroviral treatment
Viral set point and CD4 count
Exposure to opportunistic pathogens ,
Individual genetic properties
HIV species and subtype
Preexisting conditionsMorbidity and mortality among patient subsets
Untreated HIV infection has a mortality rate of > 90% (average time from infection to death approx. 8–10 years)
Progression varies among individuals: some patients may die within a few years while others remain asymptomatic for decades
Untreated individuals with advanced HIV infection usually die within a few years (median survival is 12–18 months)
Some untreated individuals show only slow progression and can remain asymptomatic for more than 20 years.
In rare cases, untreated individuals have no detectable viremia and continue to have high CD4 counts for long periods
The average life expectancy of HIV-infected patients who receive adequate antiretroviral treatment is ∼ 8 years lower than noninfected individuals of the same age.
Individual prognosis depends on various factors, including:
Adequate antiretroviral treatment
Viral set point and CD4 count
Exposure to opportunistic pathogens ,
Individual genetic properties
HIV species and subtype
Preexisting conditions
Prevention
HIV post-exposure prophylaxis
Indications
Injury with HIV-contaminated instruments or needles
Contamination of open wounds or mucous membranes with HIV-contaminated fluids
Unprotected sexual activity with a known or potentially HIV-infected person
Timing: Initiate as soon as possible (ideally within one to two hours after exposure)
Drugs: A three-drug regimen is recommended (similar to cART treatment). Typically, this includes a nucleoside/nucleotide combination NRTI plus an integrase inhibitor:
Tenofovir-emtricitabine + dolutegravir
Tenofovir-emtricitabine + raltegravir
Measures after needle stick injury or other contamination
Let the wound bleed.
Rinse/flush with water and soap and/or antiseptic agent.
Immediately seek medical attention.
If occupational exposure: report incident immediately.
Vaccinations in HIV-infected individuals
Efficacy of immunization is reduced in HIV-infected individuals (due to impaired immune function)
The immunization schedule should be observed with the following exceptions:
Live-attenuated varicella zoster and MMR vaccine should not be given if the CD4 count is < 200 cells/mm3 (CD4 percentage < 15% in patients ≤ 5 years) or if the patient has AIDS-defining conditions.
Live-attenuated influenza vaccine is not recommended, regardless of the CD4 count; inactivated influenza vaccine should be given instead.
The inactivated polio vaccine should be used instead of the live-attenuated polio vaccine.
Immunizations that are not part of the standard immunization schedule:
Inactivated vaccines are generally safe
Live vaccines should generally not be given to severely immunocompromised patients
HIV in pregnancy
Transmission
Highest risk during birth (perinatal vertical transmission)
Prenatal transmission is possible
Risk depends on maternal viral load
Reducing risk of transmission
Combined antiretroviral therapy (cART) is recommended throughout pregnancy
However, most antiretroviral drugs are not approved for use during pregnancy.
Delivery method
Viral load > 1,000 copies/mL (or unknown) near time of delivery: increased risk of HIV transmission
Cesarean delivery should be scheduled at 38 weeks (even if the mother received cART during pregnancy)
HIV post-exposure prophylaxis with zidovudine, lamivudine and nevirapine OR zidovudine and nevirapine
Viral load ≤ 1,000 copies/mL and mother has received cART during pregnancy: low risk of HIV transmission
Vaginal delivery may be considered as an alternative to cesarean section
HIV post-exposure prophylaxis with zidovudine for the newborn
Breastfeeding should generally be avoided , because risk of transmission is 5–20% .
Diagnosis in infants: if < 18 months, diagnosis is confirmed via PCR, not ELISA
Suspect HIV in infants with failure to thrive, diffuse lymphadenopathy, diarrhea, and thrush, especially if the mother is a high-risk parent!
Malaria dr deac pimp
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