Systems based pathophysiology global overview of select infectious diseases

Prepared and presented by Marc Imhotep Cray, M.D.

Companion study tools: Case-based Q&A: ICM_ Systems-based Pathophysiologic High Yield Cases.pdf (Case numbers inside refer to this document.)

Textbook: Hammer GD & McPhee SJ (Eds.). Pathophysiology of Disease: An Introduction to Clinical Medicine, 7th Ed. New York, NY: McGraw-Hill Education, 2014.

Marc Imhotep Cray, M.D.

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What is Pathophysiology? Pathophysiology includes four interrelated topics: etiology, pathogenesis, clinical manifestations, and treatment implications

 Etiology refers to study of proposed cause or causes of a particular disease process o Etiology is a complex concept b/c most diseases are multifactorial resulting from interplay between genetic constitution and environmental influences

 Pathogenesis refers to proposed mechanisms whereby an etiologic stimulus leads to typically observed clinical manifestations o Pathogenesis describes direct effects of initiating event, as well as usual physiologic responses and compensatory mechanisms Marc Imhotep Cray, M.D.

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What is Pathophysiology? cont.  Clinical manifestations describe signs and symptoms that typically accompany a particular pathophysiologic process o Manifestations may vary depending on stage of disorder, individual variation, and acuity or chronicity

 Treatment implications An understanding of etiology, pathogenesis, and clinical consequences of a disorder may imply that certain treatments could be helpful Marc Imhotep Cray, M.D.

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Etiologic Classification of Diseases            

Congenital (inborn) diseases or birth defects Degenerative diseases Iatrogenic diseases Idiopathic diseases Immunologic diseases Infectious diseases Inherited diseases Metabolic diseases Neoplastic diseases Nutritional deficiency diseases N.B: Four major causes of deathPhysical agent–induced diseases injury, infection, degenerative Psychogenic diseases

Marc Imhotep Cray, M.D.

disease and cancer

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Differential Diagnosis Mnemonic (Note the relationship to previous slide.)

IS THE PROCESS… VASCULAR - SUDDEN ONSET INFLAMMATORY- CARDINAL SIGNS/SYMPTOMS NEOPLASTIC - MASS DRUGS - HISTORY INFECTION- CARDINAL SIGNS/SYMPTOMS CONGENITAL- FROM BIRTH AUTOIMMUNE - SYSTEMIC TRAUMATIC - HISTORY - Sn/Sx E NDOCRINE / METABOLIC “VINDICATE” Marc Imhotep Cray, M.D.

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Disorders of the Immune System Case 10

Marc Imhotep Cray, M.D.

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Clinical Case: Make the Diagnosis  A 40-year-old male was seen by his internist with chief complaints of fever, night sweats, increased episodes of diarrhea during the past month, and a 30-pound weight loss over the previous 4 months. On physical exam, he had oral thrush and cervical lymphadenopathy.

Laboratory findings were significant for a CD4+ cell count of 100 cells/mL.

Marc Imhotep Cray, M.D.

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Acquired immunodeficiency syndrome (AIDS) Capsule AIDS is an infectious disease caused by human immunodeficiency viruses (HIV) AIDS is characterized by a profound suppression of immune system and susceptibility to infections, neurologic disorders, and malignancies Main characteristics of HIV  Two genetically different, but closely related forms of human pathogens are recognized: HIV-1 and HIV-2  Both are RNA viruses belonging to retrovirus family (lentivirus genus)  HIV expresses cell surface protein gp120, which binds to CD4+ surface molecule of T helper lymphocytes  Proviral DNA synthesized by a reverse transcription in infected cells is Marc integrated Imhotep Cray, M.D.into host’s nuclear DNA

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Human Immunodeficiency Virus (HIV) What is HIV?  HIV is an RNA retrovirus of lentivirus genus  This virus causes acquired immunodeficiency syndrome (AIDS) Causes There are two types of HIV: 1. HIV-1:  Type M: A-J prevalent in Europe, America, Australia and sub-Saharan Africa  Type O: mainly in Cameroon 2. HIV-2: predominantly confined to West Africa Marc Imhotep Cray, M.D.

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Prevalence of human immunodeficiency virus (HIV) infection among the adult population worldwide.

World Health Organization (WHO) figures from 2006 demonstrate extent of HIV pandemic throughout world.

Marc Imhotep Cray, M.D.

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HIV (2) Structure (simplified)

Ireland KA. Visualizing Human Biology, 3rd ed. New Jersey: Wiley & Sons, 2011.

Marc Imhotep Cray, M.D.

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HIV (3) HIV genes, gene products & structure of HIV-1 virion HIV is a group of related retroviruses, whose RNA encodes for nine genes

Modified from: Hammer GD and McPhee JS, Eds. Pathophysiology of Disease : An Introduction to Clinical Medicine, 7th Ed. 2014

Kumar V and Abbas AK. Robbins and Cotran Pathologic Basis of Disease 8th ed. 2014

Human Immunodeficiency Virus (4) Etiology and Epidemiology: HIV-1 causes AIDS Transmission  Unprotected sexual intercourse o Homosexual contact is major mode of HIV-1 transmission in the United States o Heterosexual transmission is most common in the rest of world

 Shared contaminated needles (IVDAs)  Contaminated blood transfusions  Vertical transmission from mother to child virus crosses placenta and is transmitted through breast milk Marc Imhotep Cray, M.D.

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HIV (5) Reproduction/ infection process 1. Virus attaches to host cell at CD4 receptor 2. Viral RNA is injected into cell and using reverse transcriptase makes a complementary DNA strand (cDNA) 3. Viral cDNA makes a second strand of DNAďƒ double-stranded viral DNA enters nucleus and is inserted into host DNA where it can remain dormant for many years as a provirus 4. Viral cDNA is transcribed into viral RNA and exported into cytoplasm.

5. Viral RNA is translated into new viral particles 6. Assembled virus buds from cell membrane and is released

Helper TLymphocyte (CD4+ Cell)

Modified from: Ireland KA. Visualizing Human Biology, 3rd ed. New Jersey: Wiley & Sons, 2011

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Human immunodeficiency virus-1 (HIV-1) seen budding from infected cells (arrows)

Rubin R and Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 2012

Marc Imhotep Cray, M.D.

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HIV (6) HIV-1 pathogenesis  HIV-1 attaches via envelope glycoprotein gp120 to CD4 molecule and a second coreceptor (chemokine receptor) on helper T lymphocytes, monocytes-macrophages, and mucosal dendritic cells  HIV-1 may infect both activated and nonactivated CD4+ cells in draining lymph node  Virus remains latent in nonactivated (resting) T cells but replicates in and kills T cells activated by infection or cytokines or both Note: chemokine=any of a family of low Marc Imhotep Cray, M.D.

molecular weight (8–10 kD) cytokines that induce chemotaxis or chemokinesis in leukocytes (or in particular populations of leukocytes).

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HIV (7) AIDS pathogenesis AIDS is consequence of infection with HIV-1 which infects multiple cell lines, including lymphocytes, monocytes, macrophages, and dendritic cells  With HIV infection, there is an absolute reduction of CD4 T lymphocytes, an accompanying deficit in CD4+ T-lymphocyte function and an associated increase in CD8+ cytotoxic T lymphocytes (CTLs)  “Reversal of the OKT4/T8 Ratio” Marc Imhotep Cray, M.D.

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HIV (8) AIDS pathogenesis cont.  In addition to cell-mediated immune defects (T lymphocytes ) B-lymphocyte function (humoralmediated immunity) is altered  such that many infected individuals have marked hypergammaglobulinemia but impaired specific antibody responses Resultant immunosuppression predisposes patients to constellation of opportunistic infections that characterizes AIDS Marc Imhotep Cray, M.D.

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Human Immunodeficiency Virus (9)  Clinical Manifestations: HIV disease is characterized by  an acute phase with a “flu-like” or infectious mononucleosislike syndrome, followed by  an asymptomatic phase of clinical latency characterized by fatigue, weight loss, night sweats, or lymphadenopathy with a median time of 7-10 years to development of AIDS

Symptomatic phase and AIDS is end-stage disease  AIDS is characterized by a CD4+ T lymphocyte count below 200 cells/mL (normal = 800–1200/mL)  Opportunistic protozoal, fungal, bacterial, & viral infections  Malignancies  Neurological disorders Marc Imhotep Cray, M.D.

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HIV (10)  Diagnostic Test:  Bloods: CBC, Lytes, LFTs, lipids, glucose, lymphocyte subsets  HIV specific: o Enzyme-linked immunosorbent assay (ELISA) o Western blot test o Immunofluorescence assay (IFA) o Nucleic acid testing  Virology screen: HIV antibody, HIV viral load, HIV genotype, hepatitis serology, cytomegalovirus (CMV) antibody, syphilis screen  Other infection, e.g. tuberculosis if indicated Marc Imhotep Cray, M.D.

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Natural History (NH) & Phases of HIV infection Four major stages of HIV infection: 1. Early, acute phase: Self-limited acute illness 3 to 6 weeks after infection  High level of virus production and widespread infection of lymphoid organs 2. Middle, chronic phase: No symptoms or persistent lymphadenopathy for several years

3. Minor infections

4. Final, crisis: Long-lasting fever, severe opportunistic infections, secondary neoplasms, and neurologic disorders  This usually develops after 7 to 10 years of chronic phase Marc Imhotep Cray, M.D.

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Four major stages of HIV infection cont.

1) With acute HIV infection, individual may remain asymptomatic or develop an acute illness that resembles influenza or infectious mononucleosis Sx usually develop within 2 to 6 weeks after infection  During this stage, antibodies to HIV are generally undetectable 2) Seroconversion usually occurs during clinical latency, an asymptomatic period that would last approx. 7 to 10 years in an untreated patient  Low-level (but persistent) replication of HIV causes a gradual decrease in CD4+ T cells, and minor opportunistic infections may occur 3) During crisis phase, escalation of viral replication leads to a more rapid T-cell decline  clinically apparent as weight loss, fever, fatigue, and lymphadenopathy 4) Acquired immunodeficiency syndrome (AIDS) is diagnosis for a person who is HIVpositive and has a T-cell count below 200 cells/ uL ( or 200/ mm3) or presents with one of AIDS defining opportunistic infections /malignancies 23

NH: Typical course of HIV infection (1) Acute HIV infection may present as a self-limited, febrile viral syndrome characterized by:  fatigue  pharyngitis  myalgias  maculopapular rash  lymphadenopathy and  significant viremia  without detectable anti-HIV antibodies Marc Imhotep Cray, M.D.

Kumar V and Abbas AK. Robbins and Cotran Pathologic Basis of Disease 8th ed. Philadelphia: Saunders, 2014

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NH: Typical course of HIV infection (2)

Marc Imhotep Cray, M.D.

Rubin R and Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 2012

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NH: Typical course of untreated HIV infection (3)  During early period after primary infection, there is widespread dissemination of virus and a sharp decrease in number of CD4 T cells in peripheral blood  An immune response to HIV ensues, with a decrease in detectable viremia followed by a prolonged period of clinical latency 

Sensitive assays for viral RNA show that virus is present in plasma at all times

 CD4 T-cell count continues to decrease during following years until it reaches a critical level below which there is a substantial risk of opportunistic diseases

Fauci AS, Lane HC: Human immunodeficiency virus disease: AIDS and related disorders. In Longo DL, Fauci AS, Kasper DL, et al (editors). Harrison’s Principles of Internal Medicine, 18th ed. McGraw-Hill, 2012 26

Human Immunodeficiency Virus (11) Common Agents of Infection In Patients with AIDS

As indicated above,  AIDS is characterized by a profound suppression of immune system and susceptibility to o infections o neurologic disorders & o malignancies Copstead LC, Banksia JL. Pathophysiology, 5th Ed. St. Louis, Missouri: Saunders-Elsevier, 2013.

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HIV/AIDS (12) Consequences & Complications  o o o o o o o

Increased risk of opportunistic infections: Toxoplasmosis CMV, e.g. retinitis Pneumocystis jiroveci pneumonia Cryptococcal meningitis Mycobacterium avium complex Candida Aspergillosis

 o o o o

Increased risk of malignancies: Kaposi’s sarcoma Non-Hodgkin’s lymphoma Cervical cancer Anal cancer

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Consequences of HIV infection and AIDS  HIV-1 mediated destruction of cellular immune system results in  AIDS  Infectious and neoplastic complications of AIDS can affect practically every organ system

Rubin R and Strayer DS Eds. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 2012

Pneumocystis jiroveci (carinii).

HIV-associated Kaposi sarcoma in macular stage.

HIV-associated Kaposi sarcoma in nodular stage.

Copstead LC, Banksia JL. Pathophysiology, 5th Ed. St. Louis, Missouri: Saunders-Elsevier, 2013.

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Human Immunodeficiency Virus (14) Clinical Manifestations  HIV affects all body systems, particularly integumentary, pulmonary, gastrointestinal (GI), neurologic, and ocular systems  GI manifestations develop in nearly all persons with HIV b/c of major effect of HIV infection on GI system  Pulmonary and cutaneous symptoms develop in ~ 50% to 75% of all persons with HIV, and  Neurologic Sx develop in 50% to 60% Marc Imhotep Cray, M.D.

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Human Immunodeficiency Virus (15) One of most significant systemic symptoms is malnutrition or wasting syndrome  In Africa, HIV is known as “slim disease” b/c of wasting Malnutrition is defined as unintended, involuntary loss of greater than 10% body weight Systemic symptoms attributable to HIV infection malnutrition include major muscle wasting, weight loss, and loss of vitamins, minerals, and other nutrients Marc Imhotep Cray, M.D.

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HIV (16) Wasting syndrome cont. HIV malnutrition is result of a combination of factors, including  an elevated metabolic rate with increased resting energy expenditure (REE)  chronic inflammation  malabsorption  anorexia  decreased intake of food, and  effect of multiple opportunistic insults Marc Imhotep Cray, M.D.

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Human Immunodeficiency Virus (17) Treatment  Conservative: patient education including o Transmission reduction advice o Contact tracing o Psychological support

 Medical: highly active antiretroviral therapy (HAART): either 2 × NRTIs combined with 1 × NNRTI or 2 × NRTIs combined with 1 × PIs or 1 × II: o o o o

Nucleoside reverse transcriptase inhibitor (NRTI),e.g. zidovudine Non-nucleoside reverse transcriptase inhibitor (NNRTI), e.g. nevirapine Protease inhibitor (PI), e.g. indinavir Integrase inhibitor (II), e.g. raltegravir

Marc Imhotep Cray, M.D.

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HIV (18) Antiretroviral therapy Stages in life cycle of HIV in which antiretroviral therapy is effective are shown.

Copstead LC, Banksia JL. Pathophysiology, 5th Ed. St. Louis, Missouri: Saunders-Elsevier, 2013.

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Infectious Diseases Cases 11, 12 , 13, 14 & 15

Marc Imhotep Cray, M.D.

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Clinical Case: Make the Diagnosis A 30-year-old man presents to the emergency room with sudden high fever and shaking chills. A new murmur localized to the mitral valve is heard. The patient has bilateral nail-bed hemorrhages, painful nodules on the tips of his fingers and toes, an erythematous rash on his palms and soles, and white spots surrounded by hemorrhage in his retina. You immediately begin the patient on broad spectrum antibiotics and order blood cultures and an echocardiogram to confirm the diagnosis.

Marc Imhotep Cray, M.D.

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Infective Endocarditis (IE) What is infective endocarditis?  It is an infection of endocardium usually involving heart valves, with ‘vegetation’ of infectious agent  Mitral valve is more commonly affected but tricuspid valve is implicated in IV drug users (IVDAs) Risk factors  IV drug abuse  Cardiac lesions  Rheumatic heart disease  Dental treatment: requires antibiotic prophylaxis Marc Imhotep Cray, M.D.

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Infective endocarditis (2) Pathophysiology and Pathogenesis  Infective endocarditis is a rare infection that usually affects patients who already have a structural valve abnormality  Reason why heart valves are targeted is b/c valves of heart have limited blood supply and consequently WBCs cannot reach valves through blood

 Hemodynamic factors that predispose pts. to development of endocarditis include: o (1) a high-velocity jet stream causing turbulent flow o (2) flow from a high- to a low-pressure chamber, and o (3) a comparatively narrow orifice separating two chambers that creates a pressure gradient Marc Imhotep Cray, M.D.

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Infective endocarditis (3) Pathophysiology and Pathogenesis cont.  Lesions of endocarditis tend to form on surface of valve in lower pressure cardiac chamber  The predisposed, damaged endothelium of an abnormal valveor jet stream-damaged endothelium-promotes deposition of fibrin and platelets forming sterile vegetations 

When bacteremia occurs (such as after dental work) microorganisms can be deposited on these sterile vegetations

Marc Imhotep Cray, M.D.

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Infective endocarditis (4) Causative agents ď ą A variety of organisms are known to have an affinity for endocardium and cardiac valves in particular  Most common bacterial culprits are several strains of Streptococcus and Staphylococcus aureus Bacterial organisms: o o o o o o

Streptococcus viridans Staphylococcus aureus Staphylococcus epidermidis Diphtheroids Microaerophilic streptococci HACEK group: Hemophilus, Actinobacillus, Cardiobacterium, Eikenella and Kingella

Marc Imhotep Cray, M.D.

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Infective endocarditis (5) Signs and symptoms  fever, chills, night sweats, malaise, Roth spots, Janeway lesions, splinter hemorrhages, and Osler nodes Remember as FROM JANE:  Fever  Roth’s spots (seen on fundoscopy)  Osler’s nodes (painful nodules seen on fingers and toes)  Murmur (new)  Janeway lesions (painless papules seen on palms and soles)  Anemia  Nails: splinter hemorrhages  Emboli Marc Imhotep Cray, M.D.

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Infective endocarditis (6) Sn and Sx cont.  Osler node causing pain within pulp of big toe in a woman hospitalized with acute bacterial endocarditis  (Osler nodes are painful: remember “O” for Ouch and Osler.)

 Note multiple painless flat Janeway lesions over sole of foot Hammer GD & McPhee SJ (Eds.).

Pathophysiology of Disease: An Introduction to Clinical Medicine, 7th Ed. New York, NY: McGraw-Hill Education, 2014.

Marc Imhotep Cray, M.D.

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Infective endocarditis (7)  In addition to classic Sx & Sn described above, pts. w IE can develop multisystem complaints, including:           

headaches back pain focal neurologic Sx shortness of breath pulmonary edema chest pain cough decreased urine output hematuria flank pain abdominal pain

Sx & Sn reflect: (1) hemodynamic changes from valvular damage (2) end-organ damage by septic emboli (right-sided endocarditis causes emboli to lungs & left-sided endocarditis causes emboli to brain, spleen, kidney, GI tract, and extremities) (3) immune complex deposition causing acute glomerulonephritis, and (4) persistent bacteremia and distal seeding of infection, resulting in abscess formation 44

Infective endocarditis (8) ď ą Mitral valve endocarditis from subacute bacterial infection with Streptococcus viridans (friable vegetations are denoted by arrows)  Left ventricle contains numerous abscesses formed by seeding from vegetations traveling in coronary arteries

Marc Imhotep Cray, M.D.

Copstead LC, Banksia JL. Pathophysiology, 5th Ed. St. Louis, Missouri: Saunders-Elsevier, 2013.

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Infective endocarditis (9) Diagnostic Test:  Blood cultures: take 3 separate cultures from 3 different peripheral sites (before empiric abx Tx started)  Bloods for elevated WBC and anemia  Urinalysis for microscopic hematuria  CXR septic lesions  Transesophageal/ transthoracic ECHO for vegetations

Marc Imhotep Cray, M.D.

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Infective endocarditis (10) Classification of infective endocarditis Duke Criteria: 2 major criteria or 1 major and 3 minor criteria or 5 minor criteria  Major criteria: o 2 separate positive blood cultures o Endocardial involvement  Minor criteria: FIVE o Fever >38°C o IV drug user or predisposing heart condition o Immunological phenomena, e.g. Osler’s nodes or Roth’s spots o Vascular phenomena, e.g. mycotic aneurysm or Janeway lesions o Echocardiograph findings Marc Imhotep Cray, M.D.

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Acute vs Subacute infective endocarditis Acute infective endocarditis may develop in any individual if host resistance is low, if organism is highly virulent & if bacterial invasion is sufficiently large  usually affects individuals with previously normal valves and leads to death in a large percentage of patients  Intravenous drug abusers (IVDAs) are particularly susceptible to acute infective endocarditis Staphylococcus aureus & Staphylococcus epidermidis

Subacute infective endocarditis has a more insidious onset and generally affects individuals with some preexisting valvular lesion, including:  Rheumatic heart disease, congenital heart abnormalities, mitral valve prolapse, calcified valves, and prosthetic valves are important predisposing factors  Offending organisms are less virulent commonly Streptococcus viridans 48

Infective endocarditis (11) Complications  Heart failure  Arrhythmias  Abscess formation in cardiac muscle  Emboli formation: may cause stroke, vision loss or spread infection to other regions of body

Marc Imhotep Cray, M.D.

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Infective endocarditis (12) Treatment Depends on causative agent Check hospital antibiotic guidelines  Conservative: maintain good oral hygiene  Medical: empirical therapy is benzylpenicillin and gentamicin o Streptococci: benzylpenicillin and amoxicillin o Staphylococci: dicloxacillin, vancomycin (for MRSA) and gentamicin o Aspergillus: miconazole  Surgical: valve repair or valve replacement

Marc Imhotep Cray, M.D.

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Clinical Case: Make the Diagnosis A 21-year-old man presents to the emergency department complaining of a severe headache.

Physical examination reveals a fever to 102°F, nuchal rigidity, and photophobia.

You perform a lumbar puncture, which initially reveals purulent CSF infiltrated with neutrophils, increased protein content, and decreased glucose content.

While you await culture results, you admit the patient to the hospital and begin empiric broad spectrum antibiotics to treat his condition.

Marc Imhotep Cray, M.D.

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Meningitis What is Meningitis?  Inflammation of meninges (membranes covering brain and spinal cord [see next slide]), usually due to infection Etiology:  Viral meningitis tends to occur in epidemics in winter (U.S.) it is relatively mild  Bacterial meningitis is life-threatening o Mainly caused by Haemophilus Influenzae type B (HIB) (most common worldwide), Neisseria meningitides (Meningococcus) Type B & C and Streptococcus pneumoniae

Marc Imhotep Cray, M.D.

N.B. Meningitis is both an acute and chronic disease.

Bacteria and viruses cause acute disease, while Mycobacterium tuberculosis and fungi (Cryptococcus and Coccidioides) cause the chronic form.

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Meningitis (2) Etiology cont.  Bacteria that cause meningitis usually reach CNS by way of bloodstream or by extension from cranial structures such as paranasal sinuses or ears  Some of organisms responsible for causing meningitis may be normal inhabitants of nasopharynx  Pathogens can also gain access to CNS through breaks in barrier system as occur w penetrating head wounds or skull fractures or following neurosurgery in which dura is penetrated  Overall mortality rate for meningitis is highest for individuals 65 years of age and older (23%) whereas that for infants is 7%  Survivors of meningococcal disease have an 11% to 19% chance of ongoing neurologic deicits Marc Imhotep Cray, M.D.

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Meninges

Netter FH. The Netter Collection of Medical, Illustrations: Nervous System, Part I: BRAIN, Volume 7, 2nd Ed. Saunders-Elsevier, 2013.

BMA Illustrated Medical Dictionary. Dorling Kindersley, 2013.

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Meningitis (3) gross

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

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Meningitis (4) microscopic

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

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Pyogenic (bacterial) Meningitis (5) Etiology : Causative agents  Group B streptococci, E coli, Listeria in neonates and infants  H influenzae and N meningitidis in children and young adults  Pneumococcus, Listeria, and gram-negative rods in older adults Pathology: Purulent exudate within leptomeninges, engorged meningeal vessels, neutrophils within subarachnoid space Clinical Manifestations: Headache, neck stiffness, fever, irritability other clues seen in a variable proportion include N/V, photophobia, Kernig sign and Brudzinski sign Lab findings: Lumbar puncture shows cloudy CSF with neutrophils, increased protein, decreased glucose and increased opening pressure Treatment: Antibiotics and supportive care Marc Imhotep Cray, M.D.

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Pathogenic steps leading to pneumococcal meningitis A. Pneumococcus adheres to and colonizes nasopharynx  IgA1 protease protects pneumococcus from host antibody

B. Once in bloodstream, bacterial capsule helps pneumococcus to evade opsonization C. Pneumococcus accesses CSF through receptors on endothelial surface of bloodbrain barrier (BBB) Hammer GD & McPhee SJ (Eds.). Pathophysiology of Disease: 58 An Introduction to Clinical Medicine, 7th Ed. McGraw-Hill, 2014.

Pathophysiological alterations leading to neuronal injury during bacterial meningitis.

Hammer GD & McPhee SJ (Eds.). Pathophysiology of Disease: An Introduction to Clinical Medicine, 7th Ed. McGraw-Hill, 2014.

Marc Imhotep Cray, M.D.

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Viral (aseptic) meningitis (6) Most common form of acute meningitis Clinical Manifestations: Headache, photophobia, neck stiffness, fever, irritability Pathology: May be no abnormality or a mild lymphocytic infiltrate in subarachnoid space and mild edema may be present Causes: HSV virus, coxsackie virus, echoviruses, and arboviruses Lab findings: Lumbar puncture shows lymphocytosis, mildly elevated protein, and normal glucose Treatment: Self-limiting illness; acyclovir for HSV meningitis N.B. Viral encephalitis refers to infection of brain and/or meninges (meningoencephalitis)  It can be caused by many organisms, including arboviruses, herpes, cytomegalovirus, rabies, and poliovirus  Histopathologically, glial nodules, inclusion bodies in neurons, and perivascular mononuclear cell infiltrates are seen Marc Imhotep Cray, M.D.

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Meningitis: Common Cause & CSF Findings

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Clinical Case: Make the Diagnosis A 68-year-old man presents to the emergency department complaining of a fever, dyspnea, and a cough productive of green sputum. Physical examination reveals an ill-appearing man, breathing heavily. On lung examination, you note bronchial breath sounds and dullness to percussion over the right lower lung lobe.

A chest x-ray demonstrates circumscribed opacity over the region of his right lower lung lobe. You obtain sputum and blood cultures and then admit this patient to the hospital for antibiotic treatment.

Marc Imhotep Cray, M.D.

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Bacterial Pneumonia Etiology  

Lobar pneumonia: Pneumococcus (Streptococcus pneumoniae) accounts for 90%-95% of cases Bronchopneumonia: Staphylococcus aureus, Haemophilus influenzae, Klebsiella pneumoniae, Streptococcus pyogenes

Pathology 

Lobar: Generally intra-alveolar exudate leading to consolidation 4 stages: (1) congestion: heavy red lung, intra-alveolar fluid; (2) red hepatization: RBCs, fibrin and neutrophils within alveoli; (3) gray hepatization: fibrin and neutrophils within alveoli; (4) resolution: intraalveolar exudate is reabsorbed



Bronchopneumonia: Often is bilateral and multilobar neutrophil exudate extends from bronchi and bronchioles into adjacent alveoli

Marc Imhotep Cray, M.D.

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Bacterial Pneumonia (2) Clinical Manifestations:  Sx Malaise, fever, dyspnea, and productive cough  Sn Bronchial breath sounds and rales on auscultation and dullness to percussion over affected lung areas Complications include abscess, empyema, or sepsis

Imaging: CXR shows radio-opaque lobe for lobar pneumonia or patchy opacities for bronchopneumonia Treatment: Antibiotics; respiratory support N.B. Hospital-acquired pneumonias may be caused by gram-negative microorganisms (Klebsiella, Escherichia coli, Pseudomonas) as well as gramMarc Imhotep Cray, M.D. positive organisms (S aureus) and can be fatal

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Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

Marc Imhotep Cray, M.D.

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Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

Marc Imhotep Cray, M.D.

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Acute community-acquired typical pneumonias

Johnson AG, et.al. Microbiology and Immunology (Board Review Series) 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2010

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Clinical Case: Make the Diagnosis A 21-year-old woman presents to the university health clinic complaining of general weakness and a low-grade fever of 3 days duration. Upon directed history, you learn that she has had an occasional cough and dyspnea and that her two roommates have been suffering from similar symptoms. When a chest x-ray reveals patchy infiltrates, you prescribe her a course of azithromycin and schedule her for a follow-up visit to make sure that her symptoms have resolved.

Marc Imhotep Cray, M.D.

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Interstitial Pneumonia Etiology: Mycoplasma pneumoniae; viruses (influenza, RSV, adenovirus); Chlamydia psittaci; Coxiella burnetii; Legionella pneumophila Pathology: Lung: Often multilobar; patchy infiltration of mononuclear inflammatory exudate into alveolar walls; may see pink hyaline membranes lining alveoli Clinical Manifestations: Malaise; fever; muscle aches; occasional cough (clinical picture appears less severe than typical pneumonias) Imaging: CXR reveals patchy infiltration Marc Imhotep Cray, M.D.

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Interstitial Pneumonia (2) Lab findings:  Leukocytosis, elevated cold agglutinin levels in M pneumoniae infection Treatment:  Antibiotics; supportive care N.B Pneumocystis carinii pneumonia (PCP) is most common opportunistic infection seen in AIDS patients  It demonstrates an interstitial pattern of lung pathology and can be diagnosed by silver stain of a bronchial lavage

Marc Imhotep Cray, M.D.

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Mp X-ray looks worse than patient X-ray of 25-year old FM w cough due to Mycoplasma Pneumonia

http://www.medicalgrapevineasia.com/mg/2012/11/20/themycoplasma-story/ Marc Imhotep Cray, M.D.

http://www.intechopen.com/books/respiratory-diseaseand-infection-a-new-insight/pneumonia-in-children

Acute community-acquired atypical pneumonias

Johnson AG, et.al. Microbiology and Immunology (Board Review Series) 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2010

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Bacterial pneumonias: most common causative agents  Bronchopneumonia is caused by  staphylococci,  streptococci,  pneumococci,  Haemophilus influenzae,  Pseudomonas aeruginosa, and  coliform bacteria  Lobar pneumonia is most frequently (90%–95%) caused by pneumococci (Streptococcus pneumoniae)  encapsulated gram-positive coccus known for causing rustcolored sputum Marc Imhotep Cray, M.D.

73

Common causes of pneumonia (2) Neonates (< 4 Wks.) Group B streptococci E. coli

Children (4 Wks.–18 Yrs.) Viruses (RSV) Mycoplasma C. trachomatis (infants–3 yr.)

C. pneumoniae (school-aged children) S. pneumoniae

Adults (18–40 Yrs.)

Adults (40–65 Yrs.)

Elderly

Mycoplasma C. pneumoniae S. pneumoniae

S. pneumoniae H. influenzae Anaerobes Viruses Mycoplasma

S. pneumoniae Influenza virus Anaerobes H. influenzae Gram-negative rods

Redrawn and modified from: Le T and Bhushan V. First Aid for the USMLE Step 1 2015

Note: Most common pneumonias in childhood are Viral pneumonias Most commonly implicated viruses are Influenza, parainfluenza, respiratory syncytial virus, rhinovirus, and adenovirus Marc Imhotep Cray, M.D.

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Common causes of pneumonia (3) Special groups Alcoholic/IV drug user

S. pneumoniae, Klebsiella, S. aureus

Aspiration

Anaerobes (e.g., Peptostreptococcus, Fusobacterium, Prevotella, Bacteroides)

Atypical

Mycoplasma, Legionella, Chlamydia

Cystic fibrosis

Pseudomonas, S. aureus, S. pneumoniae

Immunocompromised

S. aureus, enteric gram-negative rods, fungi, viruses, P. jirovecii (with HIV)

Nosocomial (hospital acquired)

S. aureus, Pseudomonas, other enteric gram-negative rods

Postviral

S. aureus, H. influenzae, S. pneumoniae

Redrawn from: Le T and Bhushan V. First Aid for the USMLE Step 1 2016. New York, NY: McGraw-Hill Education, 2016.

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Clinical Case: Make the Diagnosis A 21-year-old woman presents with the complaint of diarrhea.

She returned from Mexico the day before her visit. The day before that, she had an acute onset of profuse watery diarrhea.

She denies blood or mucus in the stools. She has had no associated fever, chills, nausea, or vomiting. She has no other medical problems and is taking no medications. Examination is remarkable for diffuse, mild abdominal tenderness to palpation without guarding or rebound tenderness. Stool is guaiac negative.

Infectious diarrhea is suspected.

Marc Imhotep Cray, M.D.

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Infectious Diarrhea (Diarrheas & Dysentery)  Diarrheas are characterized by frequent and fluid stools that result from small intestine disease involving fluid and electrolyte loss (Watery diarrhea)   Dysentery is an inflammatory disease of large intestine with blood or pus in stool (Bloody diarrhea) 

However, clinicians frequently only apply term dysentery to infections by a Shigella bacteria or an amoeba=Entamoeba histolytica

 Thus, diarrhea can be classified  On basis of nature of diarrhea reflects pathology  Site of infection

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Infectious Diarrhea (2)  Sources of infectious agents are    

Food Water Zoonotic, or Person-to-person transfer by fecal–oral route

 Toxins play a major role in development of symptoms observed w some bacteria and rotavirus infections incubation times depend on whether  a preformed toxin  colonization and toxin synthesis, or  tissue invasion is involved Marc Imhotep Cray, M.D.

78

Infectious Diarrhea (3)  Many infections are self-limiting, but some, particularly in children without proper rehydration, can be fatal  Since it is impossible to clinically diagnose causative agents recent food and travel history as well as examination of stool is important  Specific diagnosis is dependent on laboratory analysis of stool involving Gram staining for bacteria, staining for polymorphonuclear neutrophils (PMNs), and bacterial culture and immunologic-based tests for specific pathogens Marc Imhotep Cray, M.D.

79

Infectious Diarrhea (4)  Other important considerations related to diagnosis are whether pathogen is associated with an epidemic  infection is frequently location dependent in developed countries, viral infections are most common  An identification scheme initially based on nature of diarrhea and presence or absence of vomiting is described in the following slides (i.e., watery vs bloody w or w/o vomiting) Marc Imhotep Cray, M.D.

80

Infectious Diarrhea (5) A. Watery diarrheas with vomiting  Causative pathogens are viruses and several bacteria majority of which synthesize enterotoxins involved in pathogenesis of disease  Some produce fever, but all have relatively short incubation times ranging from several hours to a few days due to associated toxins or virus multiplication in small intestine Marc Imhotep Cray, M.D.

81

Watery diarrheas with vomiting

Johnson AG, et.al. Microbiology and Immunology (Board Review Series) 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2010.

Pathogenesis of Vibrio cholerae and enterotoxigenic E coli (ETEC) in diarrheal disease

Hammer GD & McPhee SJ (Eds.). Pathophysiology of Disease: An Introduction to Clinical Medicine, 7th Ed. New York, NY: McGraw-Hill Education, 2014.

83

Infectious Diarrhea (8) B. Watery diarrhea with no vomiting  One bacterium (Clostridia Perfringens) and two protozoa (Giardia lamblia & Cryptosporidium parvum) are in this group  Variety of toxins contribute to bacterial disease  has a short (less than 24 hours) incubation period  Protozoa have longer (1 to 4 weeks) incubation periods with disease that is usually moderate but it can become chronic and serious in immunocompromised individuals  No fever is associated with these infections Marc Imhotep Cray, M.D.

84

Watery diarrhea with no vomiting

Johnson AG, et.al. Microbiology and Immunology (Board Review Series) 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2010

85

Infectious Diarrhea (10) C. Bloody diarrhea with vomiting  Two types of Escherichia coli cause this form of diarrhea  Enterohemorrhagic E. coli (EHEC) strains release a verotoxin that is cytotoxic to intestinal villi and colon epithelial cells  Enteroinvasive E. coli (EIEC) strains invade and destroy colon epithelial cells  Both have incubation periods of 2 to 5 days

Marc Imhotep Cray, M.D.

Note: There are 4 different strains of E coli, namely: Enteropathogenic E. coli (EPEC) Enterotoxigenic E. coli (ETEC) ‘‘Traveler’s’’ diarrhea Enterohemorrhagic E. coli (EHEC)’ Enteroinvasive E. coli (EIEC)

86

Bloody diarrhea with vomiting

Johnson AG, et.al. Microbiology and Immunology (Board Review Series) 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2010

Marc Imhotep Cray, M.D.

87

Infectious Diarrhea (12) D.Bloody diarrhea with no vomiting  Both bacillary and amebic dysentery cause this form of diarrhea  Gram-positive and Gram-negative rods and a protozoan are involved  PMNs in stool and fever occur with most infections  Tissue invasion is common

Marc Imhotep Cray, M.D.

88

Bloody diarrhea with no vomiting

Johnson AG, et.al. Microbiology and Immunology (Board Review Series) 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2010 89

Sepsis, Bacteremia, Septicemia & Septic Shock: Definitions  Sepsis Infection of a wound or body tissues with bacteria that leads to formation of pus or to multiplication of the bacteria in blood. (not a clinical definition)  Bacteremia Presence of bacteria in bloodstream. Occurs briefly after many minor surgical operations invasive medical and dental procedures. The immune system usually prevents bacteria from multiplying and causing damage.  Septicemia A potentially life-threatening condition in which there is rapid multiplication of bacteria and in which bacterial toxins are present in the blood.  Septic Shock A life-threatening condition in which there is tissue damage and a dramatic drop in blood pressure as a result of septicemia.

Source: The British Medical Association Illustrated Medical Dictionary. Dorling Kindersley, 2013.

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Septicemia Capsule:  Septicemia usually arises through escape of bacteria from a focus of infection such as an abscess  Septicemia is more likely to occur in:   

people with an immunodeficiency disorder, cancer, or diabetes mellitus those who take immunosuppressant drugs, and drug addicts who inject

 Symptoms include a fever, chills, rapid breathing, headache, and clouding of consciousness  Sufferer may go into life-threatening septic shock  Treatment Glucose and/or saline are given by intravenous infusion, and antibiotics by bolus injection or IV infusion  

Surgery may be necessary to remove original infection If treatment is given before septic shock develops, prognosis is good 91

Sepsis & Septic Shock Epidemiology  Sepsis is a leading cause of death in United States more than 34,000 deaths occurring annually and overall case fatality rate approaching 20%  Medical costs of sepsis In U.S. > $17 billion  Rates of sepsis continue to rise secondary to medical advances  widespread use of indwelling intravascular catheters, increased implantation of prosthetic material (e.g., cardiac valves and artificial joints), and administration of immunosuppressive drugs and chemotherapeutic agents  These interventions serve to increase risk of infect. & subsequent sepsis Marc Imhotep Cray, M.D.

92

Sepsis & Septic Shock (2) Study of sepsis has been facilitated by establishment of standardized case definitions ( See table slide 88) Systemic inflammatory response syndrome ( SIRS ) is a nonspecific inflammatory state that may be seen w infection as well as w noninfectious states (e.g. pancreatitis, pulmonary embolism, and myocardial infarction)  Leukopenia and hypothermia, included in SIRS case definition, are predictors of a poor prognosis when associated w sepsis Marc Imhotep Cray, M.D.

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Sepsis & Septic Shock (3)  Sepsis is defined as presence of SIRS associated w an infectious precipitant

 Severe sepsis occurs when there is objective evidence of organ dysfunction (e.g., renal failure, hepatic failure, altered mentation) usually associated w tissue hypoperfusion  Final stage of sepsis is septic shock defined as hypotension (SBP <90 mm Hg or a 40 mm Hg decrease below baseline SBP) unresponsive to fluid Marcresuscitation Imhotep Cray, M.D.

94

Clinical definition of sepsis

Marc Imhotep Cray, M.D.

Hammer GD & McPhee SJ (Eds.). Pathophysiology of Disease: An Introduction to Clinical Medicine, 7th Ed. New York, NY: McGraw-Hill Education, 2014.

95

Confusion about meaning of terms bacteremia, sepsis, septic shock, and SIRS prompted planning of a consensus conference to provide definitions for clinical and research purposes.

Copstead LC, Banksia JL. Pathophysiology, 5th Ed. St. Louis, Missouri: Saunders-Elsevier, 2013.

See: Levy MM, et al: 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference, Crit Care Med 31(4):1250â&#x20AC;&#x201C;1256, 2003.

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Sepsis & Septic Shock Relationship of infection, systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, and septic shock

Abbreviations: ARDS, acute respiratory distress syndrome CI, cardiac index DIC, disseminated intravascular coagulation MODS, multiple-organ dysfunction syndrome Marc Imhotep Cray, M.D.

Dipiro JT et al, editors: Pharmacotherapy: A Pathophysiologic Approach, 8th Ed. New York: McGraw-Hill, 2011.

97

Etiology of Circulatory Shock Cardiogenic Shock Myocardial infarction Cardiomyopathy Valvular heart disease Ventricular rupture Congenital heart defects Papillary muscle rupture Obstructive Shock Pulmonary embolism Cardiac tamponade Tension pneumothorax Dissecting aortic aneurysm Marc Imhotep Cray, M.D.

Hypovolemic Shock Acute hemorrhage Dehydration from vomiting, diarrhea Overuse of diuretics Burns Pancreatitis Distributive Shock Anaphylaxis Neurotrauma Spinal cord trauma Spinal anesthesia Sepsis 98

Comparison of Clinical Findings In Different Types of Shock

Copstead LC, Banksia JL. Pathophysiology, 5th Ed. St. Louis, Missouri: Saunders-Elsevier, 2013.

Marc Imhotep Cray, M.D.

99

Sepsis & Septic Shock (5) Etiology  Although evidence of infection is a diagnostic criterion for sepsis only 28% of patients w sepsis have bacteremia, and only 10% will have primary bacteremia, defined as positive blood cultures w/o an obvious source of bacterial seeding  Common sites of infection among pts. w sepsis syndrome (in decreasing order of frequency) include     

respiratory tract genitourinary tract abdominal sources (gall bladder, colon) device-related infections, and wound or soft tissue infections

Marc Imhotep Cray, M.D.

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Sepsis & Septic Shock (6) Etiology cont.

Bacteriology of sepsis: ď&#x201A;§ Gram-negative bacteria ( Enterobacteriaceae & Pseudomonas ) , previously most common cause of sepsis, have been supplanted by gram-positive organismsď&#x192; now cause more than 50% of cases o Staphylococci are most common bacteria cultured from bloodstream, b/c of an increase in prevalence of chronic indwelling venous access devices and implanted prosthetic material

Marc Imhotep Cray, M.D.

101

Sepsis & Septic Shock Pathophysiology of septic shock

Copstead LC, Banksia JL. Pathophysiology, 5th Ed. St. Louis, Missouri: Saunders-Elsevier, 2013.

102

Sepsis & Septic Shock Signs and Symptoms Associated with Sepsis  Clinical manifestations of sepsis include:  Those related to systemic response to infections (tachycardia, tachypnea, alterations in temp. and WBC count) and  Those related to specific organ system dysfunction (cardiovascular, respiratory, renal, hepatic, and hematologic abnormalities) Marc Imhotep Cray, M.D.

Early Sepsis

Late Sepsis

Fever or hypothermia Rigors, chills Tachycardia Tachypnea Nausea, vomiting Hyperglycemia Myalgias Lethargy, malaise Proteinuria Hypoxia Leukocytosis Hyperbilirubinemia

Lactic acidosis Oliguria Leukopenia DIC Myocardial depression Pulmonary edema Hypotension (shock) Hypoglycemia Azotemia Thrombocytopenia ARDS Gl hemorrhage Coma 103

Septic Shock: KEY POINTS  Septic shock results from a severe systemic inflammatory response to infection  Gram-positive bacteria, Gram-negative bacteria, and fungal infections are common causes of septic shock 

In gram-negative shock, endotoxins in bacterial cell walls stimulate massive immune system activation

 Septic shock from any organism is characterized by release of large numbers of immune mediators (e.g., cytokines) resulting in widespread inflammation  The clotting cascade, complement system, and kinin system are activated as part of immune response Marc Imhotep Cray, M.D.

104

Septic Shock: KEY POINTS (2)  Widespread inflammation leads to profound peripheral vasodilation w hypotension, maldistribution of bld flow w cellular hypoxia, and increased capillary permeability w edema formation  Initially, septic shock is characterized by abnormally high cardiac output resulting from immune-mediated vasodilation and sympathetic activation of heart  Patient is usually febrile and warm  Even though cardiac output is high, cellular hypoxia is present b/c of maldistribution of blood flow  Reduced cellular oxygen utilization is manifested as a high SvO2 Marc Imhotep Cray, M.D.

105

Septic Shock: KEY POINTS (3) ď ą Therapy for septic shock is aimed at improving distribution of blood flow and managing infection with antibiotics ď ą Administration of fluid and drugs to increase cardiac and vascular performance is done to improve distribution of blood low

Marc Imhotep Cray, M.D.

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THE END

See next slide for further study tools and resources.

107

Sources and further study:  Copstead LC, Banksia JL. Pathophysiology, 5th Ed. St. Louis, Missouri: Saunders-Elsevier, 2013.  Dipiro JT et al, eds. Pharmacotherapy: A Pathophysiologic Approach, 8th Ed. New York: McGraw-Hill, 2011.  Kishiyama JL. Ch. 3 Disorders of the Immune System, Pgs. 31-59 and Bloch KC. Ch. 4 Infectious Diseases, Pgs. 61-87 In: Hammer GD and McPhee eds. JS. Pathophysiology of Disease : An Introduction to Clinical Medicine, 7th Ed. New York: McGraw-Hill Education, 2014  Johnson AG et al. Bacterial Diseases. In: Microbiology and immunology. 4th Ed. Baltimore: Lippincott Williams & Wilkins, 2010.  Le T and Bhushan V. First Aid for the USMLE Step 1 2016, New York: McGraw-Hill, 2016. eLearning (IVMS Cloud) o Infectious Disease o Microbial biology & Immune System Textbooks:  Ryan KJ and Ray CG Eds. Sherris Medical Microbiology, 5th Ed. New York: McGraw-Hill, 2010.  Carroll KC etal. Jawetz, Melnick, & Adelberg’s Medical Microbiology 27th Ed. New York: McGraw-Hill, 2016.

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