Infectious Diseases Lecture Notes PDF

Infectious Diseases C.D. Powell, M.D., M.P.H. https://www.the-scientist.com/news- opinion/neutrophil-extracellular-traps- may-augur-severe-covid-19-67588  Outline Impact of infectious diseases Host-mic...

Infectious Diseases C.D. Powell, M.D., M.P.H. https://www.the-scientist.com/news- opinion/neutrophil-extracellular-traps- may-augur-severe-covid-19-67588  Outline Impact of infectious diseases Host-microbe interactions Pathogen classes to be discussed Bacteria Viruses Fungi and yeasts Protozoa Pathogen Identification Antimicrobial resistance https://www.flickr.com/photos/niaid/51231640152/ in/album-72157712914621487  Outline Selected pathogens Covid-19 Strep pyogenes Strep pneumoniae Staph aureus Tuberculosis Chlamydia trachomatis Neisseria gonorrhea Clostridiodes difficile Borrelia burgdorferi Influenza virus HIV Malaria Pediatric considerations Geriatric considerations https://www.nih.gov/research-training/advances-hiv/aids-research  Billy Howard: Documenting the Time of Aids  Objectives for Section 1 Understand the enormous impact of infectious diseases on human health Describe these aspects of human-microbe interactions: Colonization vs. infection, Mechanisms of host protection Portals of entry Pathogen virulence factors Host factors that influence infection acquisition Sepsis  Top 10 Causes of Death (World Health Organization), Low Income Countries Disease Number of Deaths Percent of All Deaths Lower respiratory infection 499,839 9.33 Diarrheal disease 383,400 7.16 Ischemic heart disease 349,076 6.52 HIV/AIDS 292,097 5.45 Stroke 278,310 5.19 Malaria 247,602 4.62 Tuberculosis 225,928 4.22 Preterm birth complications 212,100 3.96 Birth asphyxia and birth trauma 201,395 3.76 Road injury 193,577 3.61 Top 10 Causes of Death (World Health Organization), High Income Countries Although the risk of death from ID is less in the U.S. than in low income countries, in 2015 there were still 15.5 million office visits and 3.7 million ER visits for ID. In 2017, CDC reported mortality for influenza and pneumonia was 14.3%. Disease Number of Deaths Percent of All Deaths Ischemic heart disease 1,724,964 16.78 Stroke 741,425 7.21 Alzheimer disease + other 718,641 6.99 dementias Trachea/bronchus/lung cancer 580,003 5.64 Chronic obstructive pulmonary 554,555 5.40 disease Lower respiratory infection 438,608 4.27 Colon/rectum cancer 327,925 3.19 Diabetes 271,947 2.65 Kidney disease 220,813 2.15 Breast cancer 187,500 1.82 COVID-19 excess mortality estimates and reported deaths by WHO region, 2020 The Leading Causes of Death in the US for 2020 JAMA. 2021;325(18):1829-1830. doi:10.1001/jama.2021.5469  Human-Microbe Interactions Vaginal delivery first exposes neonate to mother’s flora (cesarean delivery exposes neonate to mother’s skin flora). Additional exposures accumulate—from breathing, eating, skin contact. Colonization of environment/mucosal interfaces populates the normal flora of eyes, nose, mouth, pharynx, skin, gastrointestinal (GI) tract, lower urinary tract, vagina. Exposure to pathogens can cause an infection OR movement of a colonizing organism from its normal niche to alternative site can cause an infection. Examples: Streptococcus pneumoniae (oropharynx), Staphylococcus aureus (skin), Escherichia coli (gut) Most infections resolve, others become chronic infections, some are fatal.  Colonization versus Infection Colonization Infection Organism documented by culture or other Organism documented by culture or other means means No evidence of inflammation Infection progresses with pathogen numbers increasing, invading tissues Limited bacterial growth, no progression to Local inflammation: redness, heat, swelling, infection pain No signs and symptoms If upper respiratory infection: cough, airway irritation, mucus production Sometimes known as “carrier state” May become systemic: bacteremia, sepsis  Mechanisms of Protection from Pathogens Normal flora contribute to: The development of the immune system, The gastrointestinal immune development and digestive function, And the reduction of infections by inhibiting growth of pathogenic microorganisms. Skin and mucosa provide barrier functions. Each body region that interfaces with the environment has its own defense mechanisms. For example, secretions such as sweat and tears contain antimicrobial compounds such as dermcidin and lysozyme. The innate and adaptive immune systems provide powerful mechanisms to kill invading pathogens and to develop specific immunity against many organisms, either following an initial infection or by immunization.  Complement Complement and the membrane attack complex. These proteins undergo automatic cleavage and self-assembly when exposed to pathogen antigens and literally poke holes in the bacterial membrane. https://www.researchgate.net/figure/Assembly-of-the-membrane-attack-complex- MAC-a-Cryo-EM-structure-of-the-membrane-attack_fig3_319111035; https://www.biorxiv.org/content/10.1101/2020.12.02.408690v1.full Neutrophils is a photograph by Dennis Kunkel Microscopy/Science Photo Library which was uploaded on October 4th, 2018. https://fineartamerica.com/featured /7-neutrophils-dennis-kunkel- microscopyscience-photo- library.html  Portals of Entry A pathogen requires a portal of entry into the host and a site of attachment in order to initiate an infection. Examples: Influenza and hemagglutinin which attach to sialic acid molecules on the membranes of respiratory tract epithelial cells Bacteria can form a biofilm on foreign material, like implanted heart valves, that is highly resistant to immune attack. https://visual-science.com/projects/influenza/illustration; https://commons.wikimedia.org/wiki/File:Influenza_virus_particle_8430_lores.jpg#/media/File:Influenz a_virus_particle_8430_lores.jpg  Portals of Entry Covid 19 uses its spike protein to bind to angiotensin converting enzyme 2 (ACE 2) receptors in the respiratory tract. It must also bind with heparin sulfate in the carbohydrate coating of the cells, which facilitates its binding to the ACE 2 receptors. The virus is then able to fuse with the cell, enter the cell, and use its machinery to reproduce. The photo is of one cell infected by covid 19 (yellow and orange spheres budding from the surface). https://www.nih.gov/news-events/nih-research-matters/sars-cov-2-may- use-key-carbohydrate-infect-cells  Pathogen Virulence Factors Mobility—ability to adhere to membranes and migrate along them or move to other tissue layers and organs Ability to adapt to new environments (Helicobacter pylori can thrive in the acidic gastric pits in the stomach) Ability to evade immune detection or destruction (Staphylococcus aureus can live inside of neutrophils, evading lysosomal destruction) Secretion of exotoxins that destroy host cells and organ functions Rupture and release of endotoxins that provoke hyperactive immune reactions Release of superantigens that further provoke immune reactions  Host Factors Influencing Pathogen Success Age and general level of health Youngest and oldest are often most vulnerable Immunosuppression due to endogenous disease (HIV) or immune-disrupting medications (chemotherapy/neutropenia; steroids/general immunosuppression) Chronic disease—poorly controlled diabetes impairs immune defenses against infections Paradoxically, the magnitude of the host immune response can also amplify the severity of disease presentation. The Spanish flu epidemic in 1918 and the H1N1 epidemic of 2009 had high mortality rates in healthy young adults in addition to young children and older adults, likely due to the robust inflammatory response in the young adults, which was so intense that the massive cytokine release resulted in septic shock and ARDS.  Sepsis Sepsis — A 2016 SCCM/ESICM task force has defined sepsis as life-threatening organ dysfunction caused by a dysregulated host response to infection as evidenced by the following: Organ dysfunction – Organ dysfunction is defined by the 2016 SCCM/ESICM task force as an increase of two or more points in the SOFA score [Sequential (Sepsis-related) Organ Failure Assessment score]. The presence of infection, based upon clinical suspicion derived from the signs and symptoms of infection as well as supporting radiologic and microbiologic data and response to therapy. Septic shock is a type of vasodilatory or distributive shock, and it has circulatory, cellular, and metabolic abnormalities that are associated with a greater risk of mortality than sepsis alone. Clinically, this includes patients who, despite adequate fluid resuscitation, require vasopressors to maintain a mean arterial pressure (MAP) ≥65 mmHg and have a lactate >2 mmol/L (>18 mg/dL). Patients who fulfill these criteria for septic shock have a higher mortality than those who do not (≥40 versus ≥10 percent). Sepsis can be caused by bacteria, viruses, or fungi.  Epidemiology and Impact of Sepsis The Global Burden of Disease Study reported that in 2017, an estimated 48.9 million incident cases of sepsis were reported. Approximately 11 million deaths were reported, representing 19.7 percent of all global deaths. A retrospective population-based analysis reported increased rates of sepsis and septic shock in the U.S. from 13 to 78 cases per 100,000 between 1998 and 2009. Globally, the overall mortality associated with sepsis decreased by almost 53 percent between 1990 and 2017, highlighting the success of early detection and treatment strategies, but also pointing to the need to do more. The reasons for a possible increased rate of sepsis include advancing age, immunosuppression, and multidrug-resistant infections, and possibly increased detection of early sepsis from education and awareness campaigns, although this hypothesis is unproven. Older patients ≥65 years of age account for the majority (60 to 85 percent) of all episodes of sepsis; with an increasing aging population, it is likely that the incidence of sepsis will continue to increase in the future.  Objectives for Section 2 List the 7 categories of infectious pathogens Describe the typical characteristics of the following organism classes and their associated antimicrobial targets: Bacteria and how antibiotics exploit these characteristics to treat bacterial infections Viruses and the targets of antivirals Fungi and yeast and antifungals Protozoa and treatment angles Differentiate between the lab methods of identification of organisms State the impact of antimicrobial resistance and the importance of the good stewardship of these compounds  Pathogen Classes There are an estimated trillion microbial species on earth. Only ~ 1,400 are pathogenic. Pathogen classes: Bacteria Viruses Fungi and yeasts Prion protein. Coloured transmission electron micrograph (TEM) of prion Protozoa protein. A group of diseases which cause brain degeneration, including scrapie, Multicellular organisms like BSE (bovine spongiform encephalopathy or mad cow disease) and human helminths Creutzfeldt-Jakob disease (CJD) seem to be caused by an agent without genetic Prions material. They are thought to be transmitted by prions, abnormal versions of a protein that is normally found in nerves and some other tissues. The prion can Algae convert the normal protein to the abnormal form, which accumulates within nerve cells, destroying them. https://www.sciencephoto.com/media/249603/view/prion-proteins-tem A typical “florid” plaque of a Creutzfeldt-Jacob disease case. https://link.springer.com/protocol/10.1007/978-1-4939-7211-1_7 Characteristics of Bacteria Small prokaryotes ~ 1/10 size of human cells Many different shapes—spheres (cocci), rods (bacilli), spiral shaped (spirochetes) Rapidly reproduce by binary fission—not mitosis No nucleus—DNA in the form of a nucleoid, coiled in cytoplasm, no nuclear membrane Ribosomes-protein translation, a target of drugs Cell wall is external to the cell membrane—properties influence Gram https://www.sciencephoto.com/media/875964/view/staphylococcus- stain, positive or negative bacteria-sem by Steve Gschmeissner. Projections assist adhesion and motility, tissue invasion: pili, flagellae  Bacteria Have Characteristic Shapes and Other Properties Cocci are spheres found as unitary bacteria or in typical clusters such as diplococci (2), staphylococci (clumps), streptococci (chains) Bacilli are rod-shaped More complex shapes include helical and budding forms Further classified by gram staining (+/-) and aerobic vs. anaerobic metabolism Gram (+) cell walls have peptidoglycan that retains stain  Typical Bacterial https://pixels.com/featured/2- neisseria-gonorrhoeae- Features kwangshin-kim.html Three outer layers are possible: Plasma membrane Cell wall Capsule (adds virulence when present, particularly in patients who have undergone splenectomy) Pili allow adhesion. Ex: Neisseria gonorrhoeae Flagellum allows motion Nucleoid in cytoplasm—replication and transcription both happen in cytoplasm  Clinical Aspects of Bacterial Infections Many bacteria duplicate rapidly by binary fission Doubling rates (generation time) allow for exponential growth soon after infection, some bacteria can divide every 20 minutes (in laboratory culture)—growth projections in the body during infection are not known and are probably slower The presence of bacteria stimulates a host response by macrophages, mast cells, and neutrophils—release of cytokines (particularly interleukin-1 and tumor necrosis factor alpha) activates immune responses and causes signs and symptoms (fever, malaise, anorexia) Some bacteria release exotoxins that act on target organs, causing additional signs and symptoms. Ex: cholera and botulinum toxins. Cell walls of gram negative bacteria release endotoxins (ETX), such as lipopolysaccharide, from the cell wall when lysed. This further stimulates white blood cell cytokine secretion and sickness-associated signs and symptoms, such as septic shock.  Question 1 Infectious disease pathologies resulting from endotoxin release are most common in these infections: a. Fungal infections, due to the presence of ergosterol in the cell membrane b. Gram-negative infections, due to the presence of lipopolysaccharide in the cell membrane c. Gram-positive infections, due to the presence of peptidoglycan in the cell wall d. Viruses, due to the presence of hemagglutinin in the viral envelope  Antimicrobial Drug Mechanisms of Action Antimicrobial drugs target differences between prokaryotic cells and eukaryotic cells by disrupting: Cell wall synthesis—penicillin and other early antimicrobials containing a beta- lactam ring disrupt cell wall formation Nucleic acid synthesis—some antimicrobials, such as the sulfonamides, disrupt purine production by blocking folate synthesis. Others, such as the quinolones, block bacterial DNA gyrase or RNA polymerase. Protein synthesis—some antimicrobials block bacterial ribosomal subunits (macrolides, clindamycin, linezolid, chloramphenicol, streptogramins, tetracyclines, aminoglycosides).  Typical Features of Viruses Nucleic acid core Capsid (protein) coat —icosahedral, helical, or complex structures Many have membrane-like envelope, often acquired while budding from host cells. Capsid proteins (for nonenveloped viruses) and spike proteins projecting from the membranes of enveloped viruses are the antigenic determinants that provoke the host immune response to form neutralizing antibodies and to activate cytotoxic T cells to kill host virus- infected cells displaying those proteins.  Ebola Has an Unusual Filamentous Shape https://www.flickr.com/photos/niaid/14440817981/in https://www.flickr.com/photos/niaid/14712446017/in/photo /photostream/ https://www.flickr.com/photos/niaid/16 stream/ 436410472/in/photostream/  HIV budding from a T lymphocyte https://phys.org/news/2009-01-protein-receptors- cells.html  Some viruses exhibit Typical Viral Life Cycle a latent phase during which no viral replication and release Endocytosis take place. At a later time, exposure to stress or altered immunity allows resumption of the viral life cycle. Ex. include cytomegalovirus, Epstein–Barr virus, and several herpesviruses responsible for cold sores (herpes simplex virus [HSV]-1), genital herpes (HSV-2), and shingles (herpes zoster). Others can become chronic infections, such as HIV and hepatitis C.  Key Elements of the Viral Life Cycle Each virus has a core of nucleic acid—DNA or RNA Complexity is added by the protein coat called a “capsid” Further complexity is added if an outer membrane-like envelope is present The virus must attach to and enter a host cell, use the host cell’s machinery to replicate its genome and synthesis capsid proteins. Viral particles are assembled and released from cells by budding. As intracellular pathogens, they are more difficult drug targets Vaccines can be very effective against many viruses Virus Budding from Mammalian Cells http://cammer.net/historical/aif/ gallery/sem/sem.htm  Targets of Antiviral Drugs Example: Drugs to Treat Influenza Infection. Antiviral drugs can target: -the uncoating phase after virus entry (adamantanes; e.g.,amantadine), -RNA production (ribavirin), and -virion release (neuraminidase inhibitors; e.g., oseltamivir). -In addition, viral RNA polymerase is inhibited by acyclovir, vidarabine, foscarnet, and ganciclovir.  Key Elements of Fungi and Yeasts 200,000 known species of fungi; fewer than 400 are pathogenic to humans. Fungi are eukaryotic cells with defined nuclei and organelles. Membranes have the lipid ergosterol—target of antifungal drugs Fungi are multicellular, can grow by branching, and can reproduce sexually or asexually. Yeasts are fungi that are unicellular. Fungal infections can be superficial (common, dermatophytes—target skin, hair) or systemic (less common, more lethal) Fungal and yeast infections are more common in the immunocompromised patient. Candida glabrata, Candida parapsilosis, and C. albicans are the most common organisms associated with invasive candidiasis.  Cryptococcus Neoformans http://cammer.net/historical/aif/gallery/sem/ sem.htm https://www.pnas.org/content/99/5/3165:https://jgi.doe.gov/yeast- formations-got-started/cneoformans-ppat-v06-i06-g001/  Candida Albicans: A Pleomorphic Fungus https://en.wikipedia.org/wiki/ Candida_albicans  Key Elements of Protozoa Single-celled eukaryotic organisms, abundant in the environment, not usually pathogenic Protozoal diseases that are highly prevalent. Amebiasis affects more than 700 million people worldwide; Malaria, 300 million people; Giardiasis, trichomoniasis, and schistosomiasis, more than 200 million people each; And trypanosomiasis (including Chagas disease), more than 60 million. Giardiasis Some classification schemes are organized by site of infection, including intestinal protozoa, urogenital protozoa, and blood and tissue protozoa (including Plasmodium species that cause malaria). Metronidazole treats intestinal Giardia infections and vaginal Trichomonas infections Entamoeba Histolytica https://www.sciencephoto.com/media/255966/view/colo https://pixels.com/featured/3-parasitic-amoeba- ured-sem-of-entamoeba-histolytica-in-colon entamoeba-histolytica-dennis-kunkel-microscopyscience- photo-library.html  Pathogen Identification Direct identification—swab, microscopic examination Gram staining Peripheral blood smear, as for Plasmodium falciparum Culture Multistep process of inoculation, incubation, isolation, inspection, and identification. Pathogen identification using metabolic assays, antibody binding, and genetic analysis. Testing for antibiotic sensitivity Antigen or antibody identification Antibody-based detection methods for specific pathogen antigens Measurement of antibody levels in the blood Nucleic acid amplification testing (NAAT) for molecular signatures using polymerase chain reactions (PCR)  Question 2 Which of the following is correct about nucleic acid amplification testing (NAAT) to identify a pathogen? a. It is performed by an enzyme-linked immunoassay and detects pathogen proteins b. It is performed by an enzyme-linked immunoassay and detects host antibody titers c. It is performed by polymerase chain reaction and chip hybridization and detects pathogen DNA or RNA d. It is performed by culture and gram stain and detects bacterial cell wall properties  Antimicrobial Resistance Many human pathogens have rapid proliferation and high mutation rates, favoring the development of drug resistance Bacterial drug resistance is facilitated by small DNA elements (plasmids) that can carry resistance genes and be shared by bacteria during binary fission Examples of mechanisms of drug resistance: Genes that encode proteins that disable an antibiotic, such as beta- lactamases Mutations in antibiotic targets, such as penicillin binding proteins that help to synthesize cell walls Blocking antibiotic entry into the cell, as occurs when porins change in number, type, or function Efflux pumps that remove antibiotics from cells  Timeline of antibiotic resistance As antibiotics have developed, resistant strains have also been identified, some within just a few years of development. PDR, pan-drug resistant; R, resistant; XDR, extensively drug resistant. Note: Authoritative sources state that methicillin was introduced in 1959 and resistance was identified in 1960, within the first year of the drug’s use. Source: From the Centers for Disease Control and Prevention. https://www.cdc.gov/drugresistance/thre at-report-2013/pdf/ar-threats-2013-508.pdf  Threat Level Species Urgent Carbapenem-resistant Acinetobacter, Candida auris, Clostridioides difficile (formerly known as Clostridium difficile) CRE Drug-resistant Neisseria gonorrhoeae Serious Drug-resistant Campylobacter, Drug-resistant Candida Extended-spectrum, β-lactamase-producing Enterobacteriaceae VRE Multidrug-resistant Pseudomonas aeruginosa CDC-Identified Threats From Antimicrobial- Resistant Pathogens Drug-resistant non typhoidal Salmonella CRE, carbapenem- resistant Drug-resistant Salmonella serotype typhi Enterobacteriaceae; MRSA, methicillin- Drug-resistant Shigella resistant Staphylococcus aureus; VRE, vancomycin- resistant Enterococcus; VRSA, vancomycin- MRSA resistant Staphylococcus aureus. Drug-resistant Streptococcus pneumoniae Drug-resistant tuberculosis Concerning Erythromycin-resistant group A Streptococcus Clindamycin-resistant group B Streptococcus  Molluscum Contagiosum http://www.virology.uct.ac.za/vir/teaching/linda- stannard/electron-micrograph-images https://www.sciencephoto.com/media/608571/view/m olluscum-contagiosum-sem Pathogenesis of Selected Microbes https://en.wikipedia.org/wiki/File:Neutrophil_with_anthrax_copy.jpg  Objectives for Section 3 Describe the pathogenesis of the following specific organisms: Covid-19 Strep pyogenes Strep pneumoniae Staph aureus Tuberculosis Chlamydia trachomatis Neisseria gonorrhea Clostridiodes difficile Borrelia burgdorferi Influenza virus HIV Malaria  SARS-CoV-2 (COVID-19) On 12/30/20, Dr. Li Wenliang, an ophthalmologist in Wuhan, China, typed into a chat group with his former medical school classmates that a novel coronavirus had emerged similar to SARS. He was told by authorities to stop his warnings because they disrupted the social order. He continued to describe what he was witnessing. During the first week of February, 2020, he died of Covid-19 in Wuhan at the hospital where he worked.  1/21/20: The First Case of COVID-19 Is Described in America on the West Coast By 3/14/20, the Emory University Hospital had opened a specialized ICU for COVID-19 patients. It had 5 patients the day it opened. By the next week, it had 14. The first cohort of patients were largely from nursing and retirement homes. 7 more ICU beds were added, then 9 more, then 9 more again. ICUs across the Emory hospitals began to partition patient beds into COVID and nonCOVID. Elective admissions and surgeries were cancelled. A COVID command center was established that coordinated the care of these patients across the entire Emory system hour by hour. Cases, wins, losses, and observations were reported via text messages and emails in real time and relayed to the managing physicians and senior administrators handling the crisis. COVID study groups were formed, focusing on the pulmonary, cardiac, renal, and hematologic complications that we were seeing. We divided the world’s literature to process it among ourselves, combined it with what we were observing, and published recommendations on the web. Mostly we did everything we could to keep our patients alive and to survive Including using humor wherever possible… Halloween 2020 3/20: early handmade mask to cover N-95 and hat to match.  SARS-CoV-2 It is a corona virus that likely had zoonotic origins, although the exact source is still under investigation. It has an airborne pattern of spread. It contains RNA as its genetic material, and spike proteins on the surface that attach to Angiotensin Converting Enzyme 2 receptors which are abundant in the lungs. The spike proteins are wrapped in a protective lipid layer, which is why soap is helpful at destroying it. It binds to the cell, injects its RNA, and can cause the cell to efficiently replicate tens of thousands of virions within hours. Unlike other causes of pneumonia, the viral RNA is found in tissue many days after infection in severely ill hosts. Some carriers are asymptomatic. Others manifest symptoms within 2-14 days.  COVID-19 Pathology in the Lung Exudative phase of Organizing diffuse alveolar microthrombus damage with hyaline (arrow). membranes (arrow). Concomitant interstitial pneumonia, intra-alveolar Early proliferative phase scattered multinucleated of diffuse alveolar giant cells (top, left), and damage with many outstanding epithelial hyperplastic, and rarely proliferation around a atypical, type 2 bronchiole pneumocytes. Advanced proliferative phase Intermediate phase of of diffuse alveolar damage diffuse alveolar damage with interstitial myofibroblastic with initial organizing reaction, diffuse lymphocytic aspects (arrow) and interstitial infiltrate, and interstitial pneumonia with residual scattered hyperplastic marked lymphocytic type 2 cells. infiltrate.  Reference for Covid-19 Autopsy Findings The Lancet Pulmonary post-mortem findings in a series of COVID-19 cases from northern Italy: a two-centre descriptive study Luca Carsana, MD Aurelio Sonzogni, MD Ahmed Nasr, MD Roberta Simona Rossi, MD Alessandro Pellegrinelli, MD Pietro Zerbi, MD et al. Published:June 08, 2020DOI:https://doi.org/10.1016/S1473-3099(20)30434-5 https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(20)30434-5/fulltext Radiographic Images of COVID-19 Infections  The Early Emory Efforts Reported in Critical Care Medicine ICU and Ventilator Mortality Measurements and Main Results: Among Critically Ill Adults With Among 217 critically ill patients, mortality Coronavirus Disease 2019* for those who required mechanical ventilation was 35.7% (59/165), with 4.8% Auld, Sara C. MD, MSc ; Caridi-Scheible, Mark 1–3 of patients (8/165) still on the ventilator MD ; Blum, James M. MD 1,4 1,4,5,6 ; Robichaux, at the time of this report. Overall Chad MPH ; Kraft, Colleen MD, MSc7,8; Jacob, 5,6 mortality to date in this critically ill cohort Jesse T. MD, MSc3,7; Jabaley, Craig S. MD1,4; is 30.9% (67/217) and 60.4% (131/217) Carpenter, David PA1; Kaplow, Roberta PhD, patients have survived to hospital RN9; Hernandez-Romieu, Alfonso C. MD, MPH7; Adelman, Max W. MD7; Martin, Greg S. MD, discharge. MSc1,2,6; Coopersmith, Craig M. MD1,10; Prior to this report, the mortality rate for Murphy, David J. MD, PhD1,2,11; and the Emory patients requiring mechanical ventilation COVID-19 Quality and Clinical Research had been stated to be > 60%, and in some Collaborative cases as high as 80%, worldwide. Author Information Critical Care Medicine: September 2020 - Volume 48 - Issue 9 - p e799-e804  The Researchers Who Saved the World Katalin Kariko’, PhD, and Drew Weissman, MD, PhD receiving the mRNA vaccine they created https://www.nytimes.com/2021/04/08/health/coronavirus- mrna-kariko.html https://www.pennmedicine.org/news/news-releases/2021/september/penn-mrna-scientists-drew- weissman-and-katalin-kariko-receive-2021-lasker-award Strep pyogenes: A Group A Beta-Hemolytic Strep Most common cause of bacterial pharyngitis, can also cause: Rheumatic heart disease Poststreptoccal glomerulonephritis Cellulitis, necrotizing fasciitis Virulence factors Entry into epithelial cells evades phagocytes Thick, protective capsule also limits immune destruction M protein on fimbriae blocks binding of complement proteins—evades lysis Exotoxin production- streptolysin S Identified by rapid strep test, throat culture Most strains are sensitive to penicillin https://www.researchgate.net/figure/Scanning-electron-microscopy-of-S-pyogenes- cells-Late-exponential-phase-bacterial_fig1_6657374, https://www.sciencephoto.com/media/12966/view/chains-of-streptococcus-pyogenes- bacteria Strep pyogenes Schematic of Streptococcus pyogenes. The hyaluronic capsule assists with immune evasion, whereas virulence factors include the M protein of fimbriae, lipoteichoic acid, and secreted substances that assist with invasion, cell lysis and tissue damage, and fever.  Streptococcus pneumoniae S. pneumoniae is a gram-positive, alpha- hemolytic bacterium that often exists in pairs. The most common cause of community acquired pneumonia in adults, followed by Haemophilus influenza. CAP is the 3rd most common reason for hospitalization in > 65 yo’s and is the leading cause of sepsis. S. pneumoniae, first identified in 1881, is part of the normal oral and upper respiratory flora and can enter the lower respiratory passages by inhalation and by aspiration. It’s role in lobar pneumonia was noted in the 1880’s. Osler’s triad: pneumonia, endocarditis, and meningitis. Also causes otitis media. SEM of Streptococcus pneumoniae colony. Debbie Marshall. Attribution 4.0 International (CC BY 4.0)  Streptococcus pneumoniae SEM of pneumococci attaching to a human lung cell. Pneumococci rarely make pili or fimbriae in order to adhere to cells. Rather, they decorate their cell wall with proteins that bind to human cell carbohydrates or the receptor for platelet activating factor, creating direct contact between the bacteria and the host cell over a large area. UpToDate. Microbiology and pathogenesis of Streptococcus pneumoniae.  Streptococcus pneumoniae Respiratory compromise in pneumonia is due to the inflammatory response that promotes fluid entry into alveoli, limiting gas exchange. This is exacerbated when viral and bacterial coinfection occur, synergizing to enhance inflammatory responses. Virulence: Pneumococcal capsular antigens protect the bacteria from phagocytosis and define serotypes, and several of the antigens are the targets of pneumococcal vaccines. Additional pneumococcal virulence elements include: Pneumolysin, a pore- forming toxin that promotes host cell damage and death and exacerbates inflammation. Bacterial proteases are able to cleave and inactivate host IgA as well as the mucus protective barrier, disabling mucociliary clearance. Other surface and secreted proteins block complement binding and degrade complement https://doi.org/10.1590/S1806- proteins. 37132015000000010  Streptococcus pneumoniae: Virulence The teichoic acid and lipoteichoic acid of the cell wall contribute strongly to host defense responses associated with acute inflammation. These components have the following effects: Activate procoagulant activity on the surface of endothelial cells Induce production of cytokines, nitric oxide, and PAF upon binding to epithelial and endothelial cells and macrophages Activate the alternative pathway of the complement cascade Bind the acute-phase reactant C-reactive protein Initiate the influx of neutrophils Brooks, L.R.K. & Mias, G.I., https://www.frontiersin.org/articles/10.3389/fimmu.2018.01366/full  Question 3 Which of the following patients is least likely to develop a disseminated Strep pneumoniae infection, such as Osler’s triad (pneumonia, endocarditis, meningitis)? A. HIV patients with CD4 counts < 200 B. Patients who have had a splenectomy C. Patients with multiple myeloma on chemotherapy D. Adults in the 30-50 age range E. Adults over 65 years old  Staphylococcus aureus https://www.cdc.gov/mrsa/community/photos/photo- mrsa-1.html https://www.eurekalert.org/news-releases/857922  Staphylococcus aureus A gram-positive, facultative anaerobic, extracellular pyogenic bacterium Causes skin infections, can cause toxic shock syndrome, often hospital- acquired Includes Methicillin resistant S. aureus Frequently associated with abscesses and boils Can cause endocarditis, septic arthritis, osteomyelitis Diagnosed by gram stain, culture, nucleic acid amplification test (NAAT) Produces inflammation with infiltration of polymorphonuclear leukocytes, macrophages, and fibroblasts, and the infected region can become walled off by fibrin and collagen deposition, sometimes forming an abscess  Staphylococcus aureus Virulence factors Produces β-lactamase that degrades penicillin and similar drugs. Resistant strains carry the mecA staphylococcal cassette chromosome (SCC) gene. Additional drug resistance due to mecA gene—alters cell wall penicillin-binding proteins Fibronectin-binding protein facilitates cell adhesion by recognizing the amino acid sequence arginine–glycine–aspartate in fibronectin α-toxin kills host cells by pore formation—increased membrane permeability Produces several exotoxins, including one that produces toxic shock Synthesizes catalase and other enzymes that neutralizes neutrophil reactive oxygen species and lysosomal degradative enzymes Some strains produce a Panton–Valentine leukocidin that destroys neutrophils and platelets.  Staphylococcus aureus Cellular mechanisms of Staphylococcus pathology. Staphylococcus FnBPs mediate cellular attachment, whereas secreted α-toxin forms pores in host cells, ultimately destroying them. Clfs contribute to aggregate formation, and fibrinogen conversion to fibrin is promoted, leading to a walling-off process that can contribute to boil formation. Clf, clumping factor; FnBP, fibronectin-binding protein; PMN, polymorphonuclear leukocyte. Mycobacterium tuberculosis Today, TB infects about one-third of the human population and remains among the leading infectious causes of death worldwide. Nonmotile, non–spore-forming, aerobic bacterium that appears as a thin, straight, or slightly curved rod and fixes acid stain Have complex, waxy cell walls composed of peptidoglycans, polysaccharides, and mycolic acids that protect against host defenses and common antibiotics. Exposure is often followed by effective clearance or latency Host responses reduce risk of infection: lung protective mechanisms, mucociliary clearance, cough Progression to disease occurs in vulnerable populations, including children, those who are immunosuppressed, people with chronic disease. https://en.wikipedia.org/wiki/Tuberculosis#/media/File :TB_in_sputum.png  Interaction of M. tuberculosis with the Surface of Pulmonary M Cells http://cammer.net/historical/aif/gallery/ sem/sem.htm Mycobacterium tuberculosis Droplets containing MTB bacilli are inhaled and deposit in alveoli, where they are engulfed by alveolar macrophages. Macrophage activation leads to cytokine release, attracting additional immune cells, including T and B lymphocytes, natural killer cells, and neutrophils. A solid granuloma forms around the core of infected macrophages, foam cells, giant cells, epithelioid macrophages, and dendritic cells, surrounded by lymphocytes, neutrophils, and natural killer cells. Macrophage death leads to transition of the solid granuloma to a caseating granuloma with a liquefying center. From this stage, the granuloma may ultimately collapse, releasing the bacilli into the circulation and perpetuating spread of the infection.  Alveolar Macrophages and MTB https://www.flickr.com/photos/zeissmicro/87655124 https://www.researchgate.net/figure/Transmission-electron- 96/in/photostream/ photomicrograph-of-M-tuberculosis-infected-J774-mouse- macrophages_fig1_14502810  Latent TB to Clinically Evident TB Disease In immunocompetent individuals with latent TB infection, there is an average 10% lifetime risk of developing clinical TB disease. Individuals with latent TB and uncontrolled HIV coinfection have an estimated annual risk of up to 10% of going on to develop the disease. They also have a higher burden of bacteria and spread the disease more easily. Tumor necrosis factor–inhibiting drugs used for autoimmune diseases reduce the effectiveness of innate immune responses and also increase the risk of TB disease progression. Tuberculosis: CXR of Reactivated TB, and Caseating Granuloma https://en.wikipedia.org/wiki/Tuberculosis  Diagnosing TB A chest x-ray showing areas of infiltration and cavity formation may be the first indication of active TB infection. In high-resource settings, NAAT is currently used for diagnosing TB and identifying pharmacological susceptibility. In other regions, sputum smear for acid-fast staining and microscopy is commonly used. Culture can be done, but the slow division rate of the bacteria requires at least 2 to 5 weeks of incubation. Screening for latent TB infection can be done by tuberculin skin testing or the interferon-γ release assay, which measure the amount of interferon released when white blood cells isolated from the person being screened are exposed to TB antigens.  Treating TB TB treatment relies on a separate class of antibiotics that are able to penetrate cells and specifically target mycobacteria. Among these, isoniazid, rifampin, ethambutol, and pyrazinamide are often used in combination, and treatment must be prolonged to eradicate the slow- growing mycobacteria. MTB strains readily develop resistance, and early regimens that relied heavily on isoniazid fostered development of strains with resistance to that drug (monoresistance). Multidrug-resistant TB is becoming more common and is characterized by resistance to (at least) isoniazid and rifampin. Extremely drug-resistant TB strains add resistance to fluoroquinolone and at least one second-line drug.  Question 4 Which of the following is true regarding the difference between infection with tuberculosis (TB) and TB disease? a. Infection always leads to the disease, although there is considerable variability in the latent phase. b. The immune system is sometimes capable of completely clearing the TB infection. c. Adults are the most likely to develop primary TB disease after TB infection. d. Once infected with TB reinfection is unlikely.  Case Study in Reactivation of TB: The Town Barber  History of Illness Onset: At age 23 he developed severe malaise, weight loss, fevers, and night sweats. He had a slight, dry cough at the time, and hemoptysis was not present. As he grew weaker, his local doctor referred him to Emory University Hospital in 1950, where it took over a month to make a diagnosis of military TB. At Emory, one night when it appeared he would die, his Ivs were removed and he was placed on comfort care. But he did not die…  Past Medical History: Childhood and Adolescent Exposure His childhood was spent in extreme poverty during the Great Depression. His father died when he was 2 yo, causing financial instability and episodes of homelessness throughout his adolescence, with periods in crowded housing conditions with other poor people. He worked as a young man in a café serving the public in a small town until he fell ill at 23 yo. Miliary TB Miliary TB  The Sanatorium Movement As there were no very effective treatments for TB early in the 20th century before 1945, the sanatorium movement began in Europe. Edward Trudeau, a physician who had TB and who suffered multiple relapses and remissions throughout his life, is credited with beginning the movement in America. He also founded the American Sanatorium Association (later to become the American Thoracic Society) and the National Association for the Study and Prevention of Tuberculosis (later to become the American Lung Association). https://doi.org/10.1513/AnnalsATS.201509- 632PS  Battey State Hospital in Rome, Georgia, became a TB sanitorium in 1946 when the state purchased it for 1$ from the federal government. It had 2,000 beds. Robert Battey, M.D. Aerial view of Battey from 1950’s  The Sanatorium Years The Emory patient with military TB survived and later in 1950 was sent to Battey State Hospital and where he remained an inpatient for 3 years, being treated for active TB. In 1946 Schatz, Bugie, and Waksman had discovered a new antibiotic they isolated from soil microbes called streptomycin. They would later receive the Nobel prize for their discovery. Other researchers in TB, Feldman and Hinshaw ,obtained 10 g of the new drug from Waksman and found that it killed the bacteria. The 23 yo Battey patient was treated initially with Para-aminosalicyclic acid, developed in Sweden by Jorgen Lehman, and streptomycin together. Unfortunately, they both had severe side effects, including severe ototoxicity. The young man developed complete sensorineural deafness. In 1952, simultaneously 2 American and 1 German pharmaceutical company ”discovered” Isoniazid. The original drug has been synthesized in 1912 by 2 Czech predoctoral students. It has proven to be the most effective drug against TB to this day. The Battey patient began treatment with Isoniazid in 1953.  Isoniazid in Patient 1 “Graphs showing the dramatic effects of isoniazid alone on temperature and weight in a single patient in the first clinical study of isoniazid in treating pulmonary tuberculosis. Although this is one of a group of “selected patients” whose data are displayed from among 44 patients in the study, the average weight gain for the group treated for at least 8 weeks was more than 20 pounds. ” https://doi.org/10.1513/AnnalsATS.201509- 632PS  Release The young man, now 26 yo, had such profound hearing loss that his hearing did not register on any available audiology equipment. He was recovering from TB on isoniazid on 7/4/53 when a fellow inmate threw a firecracker beneath his bed. He heard it. He was fitted with a body box hearing aid, the most powerful available, and when released, entered a government rehabilitation program where he learned to be a barber. The town barber would go on to put his second daughter through medical school at Emory University, using the receipts from his $8.50 hair cuts.  She would become a pulmonary/critical care physician in postgraduate training from ‘90-’96, the height of the HIV epidemic. In the midst of that battle with a novel virus, she would witness the resurgence of TB caused by the weakening of the population’s immune system by HIV. HIV patients had a 7 fold increase in the probability of developing TB. The TB resurgence peaked in ‘92-’93, increasing its prevalence by 20%, while adding drug resistant strains. By the end of her residency in 1993, over 30% of her co-residents would have contracted active or latent TB while battling the twin AIDS/TB epidemics.  Patient with HIV and TB: Often the apical infiltrates expected in TB, where the oxygen tension was higher, were more diffuse in HIV patients. Patient with HIV and TB. Patient with TB. Case courtesy of Dr Rahul Kulkarni, Radiopaedia.org, rID: 21102  Chlamydia trachomatis Most common sexually transmitted infection, can cause pelvic inflammatory disease (PID) in women. Leading cause of blindness globally via trachoma eye disease, and it also causes lymphogranuloma venereum. Obligate intracellular pathogen that requires host cell energy production for adenosine triphosphate (ATP) and certain metabolites Two forms: Elementary body—small, transmits the infection, able to adhere to and enter cells of the genitourinary tracts. Reticulate body—larger, active form that acquires nutrients and replicates in host cell, forming elementary bodies. The elementary bodies released by exocytosis or host cell rupture infect adjacent cells. C. trachomatis Life Cycle Exposure to the Chlamydia elementary body can occur by sexual transmission or vertical transfer (mother to neonate). Upon entering genitourinary epithelial cells, the bacterium enlarges and transforms to a reticulate body capable of binary fission and rapid enlargement. Within a few days, the reticulate bodies revert to elementary body form and burst out, lysing the cell and spreading infection.  C. Trachomatis Elementary and Reticulate Bodies https://www.sciencephoto.com/media/12269/view  Chlamydia trachomatis Antibodies against the chlamydial major outer membrane protein (MOMP) are a component of the protective host immune response. Antibodies to other proteins, such as the chlamydial 60-kDa heat shock proteins 60 and 10 (cHSP60 and cHSP10), exert both a protective effect and a pathological effect. In as many as 70% of primary genital tract infections due to C. trachomatis, the immune response is sufficient to clear the pathogen. In men, it initially causes urethritis, then epididymitis and proctitis. In women, it initially causes cervicitis, urethritis, or endometritis. If infection progresses to the female upper genital tract, pelvic inflammatory disease can develop, causing chronic pain, tubal occlusion, and infertility. Chlamydial infection also has an associated risk of cervical carcinoma. NAAT of urine samples is the test of choice CDC recommends azithromycin and doxycycline.  Neisseria gonorrhoeae Common sexually transmitted infection, often coinfection with chlamydia, identified by NAAT. CDC recommends testing for coinfection. Presentation: In males—intense, purulent urethritis In women—asymptomatic cervicitis in up to 80%, ascent to Fallopian tubes can cause PID, a leading cause of infertility and ectopic pregnancy. Host response as infection proceeds may promote local inflammation and symptoms. Dissemination of the pathogen can also lead to arthritis, endocarditis, and https://pixels.com/featured/2-neisseria- meningitis. gonorrhoeae-kwangshin-kim.html Neisseria gonorrhoeae Aerobic or anaerobic conditions. Like Chlamydia, N. g. organisms are primarily intracellular pathogens. Diplococci with membrane-attached pili for mucosal invasion and motility Known for its ability to rapidly change its surface structures, such as pili, lipooligosaccharides, and various membrane proteins, to avoid host defenses. It has been proposed that the urethral epithelial cells house and protect the bacteria during early infection. It has many mechanisms of immune evasion, including producing enzymes which neutralize neutrophil reactive oxygen species. A membrane endotoxin-like molecule, lipooligosaccharide, contributes to inhibition of neutrophils, cytokine activation, and host inflammatory response.24  Question 5 Which statement is correct regarding Neisseria gonorrhoeae? a. N. gonorrhoeae infections are restricted to genitourinary tissues b. N. gonorrhoeae use pili for motility and tissue invasion c. N. gonorrhoeae evade neutrophil killing by secreting neutrophil-targeting exotoxins d. N. gonorrhoeae infections are generally symptomatic in women, while producing few symptoms in men  Clostridiodes difficile https://www.researchgate.net/figure/Scanning-electron-micrograph-of-C-difficile-The-primary-magnification-is-38000- the_fig1_316522614  Spores of C. difficile imaged by TEM and SEM. (A and B) TEM on Coloured Transmission electron micrograph of Clostridium spore (C) TEM on negatively stained whole spores of strain M7404 difficile bacterium forming an endospore , with the inset showing a magnified view of the spore edge. (D to F) https://pharmaceutical-journal.com/article/ld/clostridium- SEM on spores of strains CD196 (D), 630E (E), and CD47 (F). Ex, difficile-diagnosis-and-treatment-update exosporium; HP, hair-like projections; IM, inner membrane; GCW, germ cell wall; Cx, cortex; OC, outer coat; IC, inner coat. Bars, 0.5 m (A and C to F) and 0.1 m (B and C inset). https://www.researchgate.net/figure/Spores-of-C-difficile-imaged-by-TEM-and-SEM-A- and-B-TEM-on-spore-section-of-strain_fig5_320228747  C. diff Anaerobic, gram positive rod—most common healthcare-acquired infection Disease manifestations result from bacterial exotoxins. Identification by culture, PCR, or detection of Toxin A (TcdA) or Toxin B (TcdB) Spore-forming capability allows survival for prolonged periods and eases transmission. It is inhibited by bile salts. Ingestion of spores by a vulnerable hosts reactivates pathogen in the acidic gastric environment. https://www.nature.com/articles/nrdp201620?WT.feed_name=subjects_micro biota  C. diff Likelihood of infection is increased by: Treatment with broad-spectrum antibiotics that kill normal flora, proton pump inhibitors Healthcare exposure/hospitalization Older age Bacterial proliferation accompanies exotoxin synthesis and secretion— targeting the gut mucosa. Host inflammatory response causes widespread epithelial damage and pseudomembrane formation. https://imagebank.hematology.org/image/3999/itc- difficileit-colitis--1 C. diff -The presence of normal microbiota and gut function tends to resist the transformation of Clostridioides difficile colonization to infection and diarrhea (top). -Inhibition or loss of these mechanisms, by proton pump inhibitors that reduce gastric acid secretion, or changes in microbiota due to aging or antibiotic use, can initiate the transition from the spore colonization state to the active expansion state of the C. difficile bacteria. -This results in infection and diarrhea production.  C. diff Infection The formal definition of CDI is based on both clinical and laboratory findings, including the presence of diarrhea (defined as three or more unformed stools in 24 consecutive hours) and a stool test positive for the presence of toxigenic C. difficile, its toxins, or colonoscopic or histopathologic findings consistent with pseudomembranous colitis. Diarrhea is typically watery, though it may be associated with mucus or occult blood. Associated symptoms may include fever, cramping, and abdominal pain. Leukocytosis may be present, and it is recommended that CDI be considered in the differential diagnosis of hospitalized patients with unexplained leukocytosis. The most severe complications of CDI may include hypotension, shock, toxic megacolon, intestinal perforation, and acute peritonitis. Recurrence is common, and occurs in up to 25% of patients.  Phases of a C. diff infection The pathogenesis of C. difficile diarrhea can be differentiated into three phases. The first process is the loss of colonization resistance. The 2nd phase is colonization of the anaerobic colonic environment (this is thought to involve more than 500 genes) and the production of toxins TcdA and TcdB, which damage the mucosal epithelial cells. The toxins are taken up by the cells through receptor-mediated endocytosis. Following cleavage, the active subunit is transferred to the host cell cytosol, where it glycosylates cytoskeletal regulatory proteins called guanosine triphosphatases. This action disrupts the cytoskeleton, causing dissociation of the tight junctions between cells and increased cell permeability, leading to apoptosis and cell death.30 The final phase of C. difficile pathogenesis involves the host response to infection. Damage to the host mucosal epithelium, as well as the subsequent translocation of gut bacteria into deeper tissues, initiates a rapid and profound host immune response. The inflammatory process further adds to the epithelial damage.29 In fact, the diarrhea burden of CDI has been correlated with the degree of intestinal inflammation and not pathogen burden.31  Question 6 Which of the following is not true regarding the pathology of Clostridioides difficile? a. C. difficile colonization can result in a carrier state in a person without causing any disease manifestations b. Intestinal mucosal damage by C. difficile is caused by endotoxin released when the bacteria are lysed by complement c. Recurrence is common and often occurs 1 to 3 weeks after completion of therapy d. Treatment with broad-spectrum antibiotics that eradicate normal flora is a major risk factor for C. difficile infection  Borrelia burdorferi B. burgdorferi, the organism that causes Lyme disease, is a gram-negative spirochete bacterium that can live in ticks, mice, deer, and humans. It is a motile parasite whose transmission relies on the complex 2-year life cycle of the Ixodes tick, as well as the ability to move between tissues of the host. The bacterial DNA is composed of both linear chromosomes and many plasmids that are important for adaptation to various host species. https://www.globallymealliance.org/news Expression of surface proteins varies depending /yale-scientists-unlock-new-insight-into- on tick life cycle stage and host species. the-lyme-disease-bacterium  B. burgdorferi—Complex 2-year Life Cycle Ticks lay eggs in the spring (1) New tick larvae ingest first blood meal, usually from infected mice (2) Nymphs take another blood meal from any available hosts—complete their growth while infecting humans (usually occurs in spring) (3) Adult ticks usually feed on deer, most actively in fall (4) Adult ticks lay eggs the following spring (5)  Borrelia burdorferi Once a human is infected, the earliest cutaneous sign is often erythema migrans, a gradually enlarging “bull’s eye” rash. Afterwards, bacteria can migrate to the joints, heart, and brain. Lyme carditis can present with atrioventricular block, myocarditis, and LV dysfunction. Identification depends on enzyme immunoassay, followed up by Western blot if indicated Lack of early symptoms may allow development of later phase with more extensive bacterial invasion and more severe symptoms Prompt antibacterial treatment usually https://en.wikipedia.org/wiki/Erythema_migrans#/medi provides complete pathogen eradication a/File:Bullseye_Lyme_Disease_Rash.jpg  Influenza Virus Common pathogen of respiratory infections. Influenza A—most common, but A, B, and C infect humans. Enveloped negative RNA virus, variable hemagglutinin/neuraminidase composition (H/N). Severe epidemics and pandemics have occurred, including the major epidemics that have been associated with the H1N1 virus (1918 Spanish flu pandemic, 2009 flu pandemic). Immunization efficacy depends on strains covered Must be decided before season starts Varying match with actual annual strains Genes for viral proteins mutate rapidly, changing antigenic targets. Antigenic shift and antigenic drift  Influenza Virus Detection: both NAAT and immunoassay tests for influenza are available, including a rapid influenza diagnostic test. Host cell death and sloughing from airways contributes to cough and other symptoms Host immune defenses contribute to manifestations—fever, malaise, myalgias, arthralgias Potential to progress to viral or https://www.cdc.gov/h1n1flu/images.htm superimposed bacterial pneumonia  Influenza Virus The envelope proteins hemagglutinin (blue) and neuraminidase (red), and the M2 ion channel, play functional roles in the viral life cycle of host cell infection.  Influenza Virus Life Cycle cRNA, complementary RNA; mRNA, messenger RNA; NEP, nuclear export protein; RNP, ribonucleoprotein; vRNA, viral RNA. Source: (a) From Centers for Disease Control and Prevention. Influenza (flu). https://www.cdc.gov/flu/resource- center/freeresources/graphics/images.htm.  Question 7 Typing of influenza A virus depends on identification of its hemagglutinin protein and this molecule: a. The M2 protein, a channel protein that assists with membrane fusion and viral uncoating b. The neuraminidase protein c. Ribonucleoprotein, which contains the viral RNA that will be transcribed in the nucleus of the host cell d. The envelope sialic acid July 11, 1989  Kaposi’s Sarcoma and the Heprpes 8 Virus https://www.genengnews.com/topics/translational-medicine/3d- structure-of-virus-linked-to-kaposis-sarcoma-may-open-door-to- https://www.semanticscholar.org/paper/Kaposi%27s-sarcoma- new-antiviral-therapies/ associated-herpesvirus-(human- Schulz/25320fd14f8f1b5d0be535557475f8b258b8c678 HIV Retrovirus RNA-based virus Reverse transcriptase enzyme converts to a single-strand, then to double-stranded DNA. Integrase inserts this DNA into the host cell genome. Identification tests for presence of the HIV P24 antigen, and antibodies to HIV. Viral load is tracked, as well as CD4 count https://www.sciencephoto.com/media/248367/vi ew/coloured-tem-of-hiv-viruses-cause-of-aids  Antiretroviral therapies (ART) target: HIV reverse transcriptase (RT; nucleoside RT inhibitors or non- nucleoside RT inhibitors); integrase inhibition; protease inhibition; fusion inhibition; block of coreceptor The goal of ART is to achieve low or undetectable viral copies, at which point it is not possible to transmit the virus to others https://www.science.org.au/curious/people-medicine/zero-hiv- transmissions-australia-2020  HIV Life Cycle Virus attachment occurs when GP120 binds to target cells, primarily macrophages and CD4+ T-helper lymphocytes. The host cell membrane protein CD4 is the initial docking site for GP120, and this binding is complemented by binding to a co-receptor, either CCR5 or CXCR4. The first stage of binding allows the transmembrane protein GP41 to bind to the host cell and draw the virion close to the target cell, initiating fusion and entry of the nucleocapsid into the host cell. Uncoating releases the single-stranded viral RNA and enzyme reverse transcriptase. The proviral nucleic acid is synthesized—double-stranded DNA coding for HIV proteins. Proviral DNA is integrated into the host’s chromosomal DNA by the viral integrase protein. Transcription of messenger RNA (mRNA) for viral proteins begins; additional transcription reproduces the viral RNA needed to produce daughter virions Translation produces the viral pro-protein—a single transcript containing all of the required viral proteins as one long polypeptide strand. Limited proteolysis by viral protease produces the proteins that will be packaged inside the virion, including reverse transcriptase, integrase, and protease. Additional translation produces GP120 and GP41 for insertion into the host cell membrane. Budding gives the nucleocapsid a membrane coat that contains the appropriate glycoproteins. HIV Life Cycle  Time course of HIV viremia and CD4+ T-cell count (blue dashed line) after HIV infection. Within weeks of primary infection there is a dramatic rise in viral load (red line) and substantial drop in CD4+ T lymphocyte numbers (blue line). This is followed by recovery in T lymphocyte population and drop in viral copies that may last for years. In the absence of treatment, viral load gradually increases and lymphocyte numbers gradually drop until a critical level is achieved in which symptoms and opportunistic diseases occur, resulting in death due to AIDS.  Question 8 Following infection with the HIV virus there is a 2- to 3-week incubation period during which the number of CD4 T cells declines. In the absence of diagnosis and treatment, which of the following occurs next? a. CD8 T cells develop the viral infection b. CD4 T cell counts relentlessly decline and opportunistic infections begin c. CD4 T cell counts initially recover, but then slowly begin to decline d. Viral RNA and protein levels become undetectable in blood samples  CDC Listing of AIDS-Defining Conditions (1) Bacterial infections, multiple or recurrent* Candidiasis of bronchi, trachea, or lungs Candidiasis of esophagus† Cervical cancer, invasive‡ Coccidioidomycosis, disseminated or extra- pulmonary Cryptococcosis, extrapulmonary Cryptosporidiosis, chronic intestinal (>1 month duration) Cytomegalovirus disease (other than liver, spleen, or nodes), onset at age >1 month Cytomegalovirus retinitis (with loss of vision)† Encephalopathy, HIV related Herpes simplex: chronic ulcers (>1 month duration) or bronchitis, pneumonitis, or esophagitis (onset at age >1 month) Histoplasmosis, disseminated or extrapulmonary Isosporiasis, chronic intestinal (>1 month duration)  CDC Listing of AIDS-Defining Conditions (2) Kaposi sarcoma† Lymphoid interstitial pneumonia or pulmonary lymphoid hyperplasia complex*† Lymphoma, Burkitt (or equivalent term) Lymphoma, immunoblastic (or equivalent term) Lymphoma, primary, of brain Mycobacterium avium complex or Mycobacterium kansasii, disseminated or extrapulmonary† Mycobacterium tuberculosis of any site, pulmonary,†‡ disseminated,† or extrapulmonary† Mycobacterium, other species or unidentified species, disseminated† or extrapulmonary† Pneumocystis jiroveci pneumonia† Pneumonia, recurrent†‡ Progressive multifocal leukoencephalopathy Salmonella septicemia, recurrent Toxoplasmosis of brain, onset at age >1 month† Wasting syndrome attributed to HIV  Question 9 Which of the following is not usually an opportunistic disease associated with HIV infection? a. Kaposi sarcoma b. Hodgkin lymphoma c. Mycobacterium avium infection d. Toxoplasmosis of the brain  Malaria Protozoal parasite of five pathogenic Plasmodium species Transmission by the female Anopheles mosquito—organism proliferation is sexual (in mosquito) and asexual (in vertebrate host). This photo shows oocytes, of a malaria parasite developing on a mosquito's intestinal wall. When these oocytes rupture, they release sporozoites that travel to the mosquito's salivary glands. From there, they can infect a vertebrate https://scopeblog.stanford.edu/2012/04/29/image-of- host. the-week-malaria-developing/  Malaria In humans, infection begins in liver, then shifts to red blood cells Periods of red cell lysis with release of merozoites result in gametocyte production (taken into mosquito with next blood meal), and with classic symptoms. Several genetic blood disorders that are common in individuals of African descent appear to have been evolutionarily favored owing to conferring resistance to malaria infection—these include sickle cell trait, thalassemia, and glucose-6-phosphate https://www.thelancet.com/journals/lancet/article/PIIS01 dehydrogenase deficiency. 40-6736(16)30299-9/references Plasmodium Life Cycle  Malaria Identification: microscopy for red blood cell inclusions, polymerase chain reaction (PCR) for parasite DNA, immune-based rapid detection test, host antibodies. Parasites have a high degree of resistance to drugs. Prophylaxis is given to travelers to high-risk areas. Prevention with protective clothing, mosquito nets are essential. High-risk groups: children, pregnant women, concurrent HIV infection. https://pixels.com/featured/red-blood-cell- with-the-malaria-parasite-dennis-kunkel- microscopyscience-photo-library.html A Giemsa-stained thin blood smear shows ring- form Plasmodium malariae parasites.  Objectives for Section 4 List common childhood diseases caused by pathogens and describe clinical manifestations and potential complications Predict the impact of infection on older adults  Pediatric Considerations Common pediatric infections: Viral gastroenteritis—norovirus most common cause (before vaccinations, it was rotavirus). ID—immune-based detection or NAAT Despite vaccination—other diseases are reappearing Measles—fever, cough, maculopapular rash Mumps—affects respiratory tract, nervous system, pancreas, testes, salivary glands; may occur in young adult/college age persons  Pediatric Considerations (continued) Infectious agents capable of vertical transmission: Group B streptococcus, Treponema pallidum (syphilis), rubella virus, hepatitis B virus, HIV, C. trachomatis, and N. gonorrhoeae. Depending on maternal geographical, travel, and sexual history, screening for Zika virus may also be appropriate. Other infections that can be transmitted across the placenta include toxoplasmosis, cytomegalovirus infection, and herpes simplex. Treatment of the mother before and during birth or the neonate at birth is often effective at reducing or eliminating vertical transmission of many pathogens.  Pediatric Considerations (continued) Rubella was eliminated from the United States in 2004, and recent cases have been reported in visitors to the United States, rather than being caused by local outbreaks. Maternal rubella during pregnancy may result in miscarriage, fetal demise, or a constellation of congenital anomalies. Common anomalies of congenital rubella syndrome include cataracts, pigmentary retinopathy, microphthalmos, congenital glaucoma, patent ductus arteriosus, peripheral pulmonary artery stenosis, sensorineural hearing impairment, behavioral disorders, meningoencephalitis, microcephaly, and intellectual disability.  Gerontological Considerations Community-acquired pneumonia (CAP) or healthcare-acquired pneumonia (HCAP) Vaccination for pneumococcus and influenza are recommended CAP may have atypical presentations in older adults: Absence of cough, fever, leukocytosis does not rule out CAP Unusual presentations: altered mental status, falls, anorexia, incontinence, general decline in function Diagnosis—opacities on chest radiograph, sputum gram stain + culture, respiratory biofire, urine legionella, urine and CSF strep pneumo immunochromatographic membrane test detects soluble bacterial C-polysaccharide. Causative organism may not be identified Pneumonia Severity Index and CURB-65 prognostic scales  Gerontological Considerations (Continued Varicella-zoster virus reactivation Older adults are at higher risk for shingles and postherpetic neuralgia—vaccine is recommended HIV—reduced awareness of risk increases incidence, and diagnosis may be delayed. CD4 counts are already reduced in older adults, and will be further reduced by disease and later entry into treatment Older adults have greater severity at HIV presentation, and more rapid trajectory of CD4 decline and transition to AIDS Survival  Answers Question 1: b 2: c 3: d 4: b 5: b 6: b 7: b 8: c 9: b