D&D3.1 Flashcards

Question

dsDNA virus genome replication

Answer 1

replication is exclusively nuclear. The replication of these viruses is relatively dependent on cellular factors, but may involve viral polymerases and accessory factors. Another strategy is replication in the cytoplasm (poxvirus) and have all the necessary factors for replication of their genomes and are therefore largely independent of the cellular machinery.

Answer 2

replication occurs in the nucleus, involving the formation of a ds intermediate that serves as a template for the synthesis of ssDNA.

Answer 3

uses a virally encoded reverse transcriptase to copy viral genomes from mRNAs transcribed from the template genome.

Answer 4

transcription and genome replication is integrated. Replication uses anti-genome as the template. Production of the anti-genome, as well as the replicated genomes is performed by RdRp.

Answer 5

for icosahedral capsids packaging of the genome can either be accomplished by assembling the capsid around the virus genome or by feeding the genome into preformed capsids. For helical nucleocapsids, viral genome is usually coated with nucleocapsid protein during its synthesis. Assembly often results in significant cytopathic effect (CPE) because capsid proteins are produced in very high numbers. The abundance can result in the appearance of either cytoplasmic or nuclear inclusions (depending on the cellular location). These inclusions can be detected by electron microscope and the size and location is often highly characteristic of particular viral infections.

Answer 6

exit from the infected cell for naked viruses often occurs with lysis of cell due to the volume of the virus in the cell. Viruses with envelopes can acquire their envelopes from budding. Viruses that bud into the plasma membrane are released into the extracellular environment directly. Viruses that bud into the membranes of golgi apparatus or ER are secreted from the infected cell.

Answer 7

when a certain virus is likely to infect specific tissues and not others. Enterotropic viruses replicate in the gut and neurotropic viruses in the nervous system tissue. Tropism is determined by a combination of factors including access to the tissue in which it can replicate, receptors required for binding and entry, expression of host genes required for virus infection and production of new progeny virus, and a relative failure of host defenses. Tropism can drive virus population variants among or within individuals particularly in viruses with highly error prone replication systems.

Answer 8

for local infections, shedding occurs at initial site of infection. For disseminated or systemic diseases, shedding could take place from multiple or distant site. Viral transmission may be in a single host or in multiple hosts as in insect to human transmission. The means of transmission depends on the site of viral replication/release and the stability of virus particle in the environment. Enveloped viruses are fragile and sensitive to many environmental stresses, such as pH, and are often transmitted by close contact. Non-envoloped viruses are hardier and can sustain drying, low pH, detergents, and high temperature and therefore can be transmitted via virus associated objects or formites and use respiratory or fecal/oral routes. Most transmission is horizontal, but vertical (parent/child) and germ-line transmission does sometimes occur. Some viruses are seasonal or geographical, which may indicate the need for particular animal or vector host or may indicate a susceptible or naïve population.

Answer 9

these factors include expression of appropriate receptors for virus entry, accessibility and permissively (ability of cells to support viral replication) of infected cells, age of host, genetic background, and immune status.

Answer 10

some viral diseases are mediated by host immune response, which can include antibody (immune complex diseases), cell mediated response (rash, fever, and malaise), autoimmunity (possibly due to cross-reactivity with virus), and transient immune modulation such as immune suppression.

Answer 11

is characterized by a high viral replication rate and production of a large number of progeny. Replication is transient in a specific host and is limited by either death of the host (and/or cell death) or by the host immune responses. Local or systemic depends on initial events of infection and viral tropism.

Answer 12

usually infections of epithelial cells at body surface (gut, respiratory tract, eyes). Often have short incubation times and many are serotypes (rapidly mutating). This results in short lived immunity primarily via secretory IgA. Re-infections are common. E.g. colds and diarrheal disease.

Answer 13

primary infection site is also often epithelial cells but viremia and systemic infection leads to secondary replication at various sites. Immune response includes both IgA and IgG and leads to lifelong immunity. E.g. measles and smallpox.

Answer 14

ongoing virus infection and/or replication, usually with mild or unapparent disease in host. Manifestation of disease is often a result of immune suppression or other complications. Chronic infections can be persistent, latent, or slow.

Answer 15

usually refers to virus infections that continue to produce new viruses over a long period of time. Last for longer periods of time and may be the result of an acute primary infection that never clears and the ability of the virus to spread to other organisms or offspring of the host.

Answer 16

involve substantial periods in which the host produces no detectable viruses. They are different from dead end infections in that they retain their ability to re-initiate transcription and replication to produce new virus. This is reactivation or recrudescence. (VZV in nerves)

Answer 17

no symptoms on initial infection, long incubation period, may or may not induce an immune response, and eventual disease is followed by progressive deterioration and death. (AIDS and cancer)

Answer 18

some retroviruses integrate into host genome and activate viral or host oncogenes. Other viruses may integrate to cause host DNA breakage and oncogene activation or inactivation of tumor suppressor. Finally, some infections (in particular persistent infections) may cause ongoing inflammation and so contribute to tumorigenesis.

Answer 19

1) abortive infection or failed infection (no virus produced/ no apparent effects on the cell). 2) lytic infection resulting in production of virus and death of the infected cell. 3) persistent infection- chronic (production of virus), latent (no virus produced), and transforming (may produce virus). These outcomes are characteristic of certain viruses in their target tissues, however they are not hard-wired and are dependent on virus, host, target tissue, and immune status at time and site of virus entry. A virus that is cytolytic in epithelial cells may be latent in neurons (tissue dependent). A latent virus in neurons may be reactivated upon immune suppression and resume productive lytic infection (dependent on immune status).

Answer 20

includes any detectable morphological change in host cell. Retroviruses do not generally cause cell death, being released by budding and causes persistent infections. Conversely, picornaviruses cause lysis and death of cells, leading to fever and increased mucous secretions in rhinoviruses and paralysis or death for poliovirus.

Answer 21

may result from diversion of cell’s energy, turning off of cell marcromolecular synthesis, competition of viral mRNA for cellular ribosomes, competition of viral promoters and enhancers for cellular factors and inhibition of the interferon defense mechanisms.

Answer 22

can result from integration of viral genome, induction of mutations in the host genome, inflammation, and host immune response. The immune response has the greatest effect on the outcome of infection and the pathological effects. Cellular immunity plays the major role in clearing virus infection and humoral immunity protects against reinfection.

Answer 23

permissive cells provide machinery and components required for replication, non- permissive do not and does not always result in efficient production of virus. It can also result in a latent or transforming infections. There is a continuum between the two.

Answer 24

cellular proteins that can block post-entry steps of certain virus infections. They are not apart of the adaptive immune response but there is specificity for certain viruses. These factors are potent, widely expressed, and intracellular blocks to viral replication. These exists due to evolutionary pressures but viruses evolve faster than the host. E.g Trim5 blocks retroviruses and APOBEC blocks HIV and HCV.

Answer 25

recognize PAMPs and induces signaling pathways which lead to activation of innate immunity and instructs development of antigen specific acquired immunity

Answer 26

ligand is dsRNA (viruses)

Answer 27

ligand is LPS, fusion protein (respiratory syncytial virus), and envelope protein (mouse mammary- tumor virus)

Answer 28

imidazoquinoline (synthetic compounds) and ssRNA (viruses)

Answer 29

imidazoquinoline (synthetic compounds) and ssRNA (viruses)

Answer 30

CpG containing DNA (bacteria and viruses)

Answer 31

recognize viral nucleic acids within infected cells. RLH proteins coordinate many of the same signaling pathways as TLRs.

Answer 32

include alpha-IFN and beta-IFN. Antiviral cytokines transiently produced and secreted by most infected cells within hours. They induce resistance to viral replication in all cells, increase MHC class I expression and antigen presentation in all cells, and activate NK cells to kill virus-infected cells.

Answer 33

gamma-IFN. Produced by T cells and NK cells, and some others (but more restrictive than type I).

Answer 34

respond to IFN binding to IFN receptors and control genes whose transcription is regulated by interferon-stimulated response elements (ISREs) for the type 1 IFNs and by gamma activated site (GAS) elements for type II IFN.

Answer 35

a cells response to IFN in order to block viral replication by altering transcription of over 100 genes. dsRNA activates a number of IFN responsive genes. Results in temporary blockade of cell proliferation, reduces cellular metabolism, potentiates NK cell activity including gamma-IFN production, increases expression of antigen presentation molecules, and may lead to apoptosis. Most viruses can induce IFN production resulting in “flu-like” syndrome. Large amounts of IFN can have severe physiological effects but have been used in treatment against hep C as well as tumors.

Answer 36

phosphorylates and inactivates a cellular translation initiation factor, resulting in decreased protein synthesis.

Answer 37

activates a cellular ribonuclease that degrades mRNA.

Answer 38

apart of innate defense. Phagocytosis, release of inflammatory mediators, antigen presentation

Answer 39

apart of innate defense. Migratory cells found in every tissue except the brain, present antigens to T cells, stimulate B cell differentiation and proliferation. They are key modulators in the development of that adaptive immune response during viral infections and secrete a large variety of antiviral and immunoregulatory cytokines. They are important in initiating T cell response to viruses, which fail to induce co-stimulatory activity in other types of antigen presenting cells. Pathogens that escape recognition receptor specific phagocytosis, get taken up by tissue DCs through macropinocytosis allowing their peptides to be presented to T cells.

Answer 40

apart of innate defense. Are activated in response to IFNs or macrophage dependent cytokines and serve to contain virus infections while adaptive immunity response generate antigen-specific cytotoxic T cells that can clear the infection.

Answer 41

are also called PMNs, include neutrophils, basophils, eosinophils, and mast cells.

Answer 42

chemoattractant for leukocytes, recruiting monocytes, neutrophils, and other effector cells from blood to site of infection. E.g IL-8, IP10, MIP1-alpha.

Answer 43

Viral pathogens are recognized by the cells in which they replicate, leading to the production of interferons that serve to inhibit viral replication and to activate NK cells. The induced innate responses either succeed in clearing the infection or contain it while an adaptive response develops. Adaptive immunity harnesses many of the same effector mechanisms used in the innate system, but is able to target them with greater precision. Thus antigen-specific T cells activate the microbicidal and cytokine-secreting properties of macrophages harboring pathogens, while antibodies activate complement, act as direct opsonins for phagocytes, and stimulate NK cells to kill infected cells. In addition, the adaptive immune response uses cytokines and chemokines, in a manner similar to that of innate immunity, to induce inflammatory responses that promote the influx of antibodies and effector lymphocytes to sites of infection.

Answer 44

B lymphocytes are the effectors of the humoral response and produce Ig, both surface bound and secreted. When their receptors are bound that cell divides and there is amplification and competition for antigen, promoting antibody affinity maturation (selection of B cells with the highest affinity antibody) and differentiation of those cells into plasma cells. Stimulation also leads to isotype switching (IgM to IgG, IgE, or IgA). Antibodies produced during primary virus infection are usually lower affinity than those produced later on. IgA inhibits virion/host attachement, neutralizes toxins and enzymes. IgG inhibits fusion of enveloped viruses with host membranes. IgG and IgM opsonize virions to enhance phagocytosis and can facilitate complement lysis of enveloped viruses. IgM can coat and agglutinate some virions. Neutralizing antibodies binds to virus and prevents it from budding or fusion. Abs can also target infected cells for complement-mediated lysis or for enhaced killing of KN and phagocytes as in antibody-dependent cell mediated cytotoxicity (ADCC).

Answer 45

necessary for getting virus after it is inside the cell. They need to be powerful and accurate to minimize damage to healthy tissue. T helper cells generally bind to class II and produce cytokines that regulate proliferation and activity of other cells. T cytotoxic cells generally bind peptide with class I and can kill virus infected cell.

Answer 46

secretion of IFN by helper and cytotoxic T cells and activated NK cells. CTLs lyse virus infected cells. NK cells and macrophages kill infected cells directly or by antibody-dependent cell mediated cytotoxicity (ADCC).

Answer 47

consists of preformed immune reactants (cells, Ab, and cytokines) and immunological memory. Antibody levels and effector T-cell activity gradually decline after an infection is cleared. An early reinfection is rapidly cleared by these immune reactants. There are few symptoms but levels of immune reactants increase. Reinfection at later times leads to rapid increases in antibody and effector T cells owing to immunological memory (the anamnestic response), and infection can be mild or even inapparent. Viral infections may be controlled by the host immune system with or without clearance of the virus.

Answer 48

is critical for recognition of virions. Cell-mediated response is critical for recognizing and eliminating virally infected cells. Th1 cells skews immune response towards cell mediated immunity and Th2 cells favor humoral response.

Answer 49

includes point mutation in antigenic drift (HIV and influenza A) and genome shuffling in antigenic shift (influenza). These rapid changes allow viruses to be unrecognizable to the immune system.

Answer 50

molecular mimicry or infection prior to competent immune system. Virus proteins that resemble host proteins may escape the immune system.

Answer 51

going invisible to the host defenses as in latent infections (HIV).

Answer 52

such as cytokines, receptors, and Ab’s (pox and herpesviruses). Viruses produce proteins which can bind and block cellular mediators or can mimic cellular mediators. Those mimics have evolved to omit certain functions of their cellular counterparts (such as stimulatory) and retain only those functions which benefit them (such as suppressive functions).

Answer 53

such as MHC class I or adhesion molecules (pox and herpesviruses). Since class I is required for CTL recognition, down regulation protects virus infected cells from detection. Class I down regulation however, is also a trigger for NK cell detection, so some sophisticated viruses also express a viral homolog of class I molecules to avoid NK recognition.

Answer 54

such as the brain (HSV)

Answer 55

HIV and EBV

Answer 56

(e.g. SV40 large T antigen and Adenovirus E1A). Many viruses affect these two pathways, and these two pathways are also often involved in tumorigenesis.

Answer 57

envelope, linear dsDNA that is protected by an icosahedral capsid, includes HSV-1 (oral and some genital lesions, spontaneous temporal lobe encephalitis, keratoconjunctivitis), HSV-2 (genital and some oral lesions), VSV (HHV-3, chickenpox, zosters- shingles), EBV (HHV-4, mononucleosis, burkitt lymphoma, hodgkin lymphoma, nasopharyngeal carcinoma), CMV (HHV-5, infection in immunosuppressed patients- AIDS retinitis, especially transplant recipients, congenital defects), HHV-6 (roseola- exanthema subitum), HHV-7 (less common cause of roseola), HHV-8 (Kaposi sarcoma). In this family there is latency after initial infection and may reactivate later and is sometimes but not always associated with further disease. Tends to occur during immunosuppression. Herpesviruses are classified into three subfamilies based on their site of latency.

Answer 58

(HSV-1, HSV-2, VZV) establish latency in sensory ganglia.

Answer 59

(CMV, HHV-6, HHV-7) establish latency in monocytes and lymphocytes.

Answer 60

(EBV, KSHV) establish latency in B cells.

Answer 61

targets mucosal epithelium, latency in neuron ganglia, transmitted by respiratory secretions and saliva, can cause gingivostomatitis, keratoconjunctivitis, herpes labialis, temporal lobe encephalitis (most common cause of sporadic encephalitis, can present with altered mental status, seizures, and/or aphasia), Herpes whitlow, neonatal herpes.

Answer 62

target mucosal epithelium, latent in sacral neuron ganglia, transmitted by sexual contact and perinatally. Clinical manifestations include herpes genitalis and some orofacial lesions, neonatal herpes, encephalitis, herpes whitlow, herpes keratitis.

Answer 63

varicella-zoster (chicken pox and shingles), encephalitis, pneumonia. Targets mucosal epithelium, latency in dorsal root or trigeminal ganglia. Most common complication of shingles is post-herpetic neuralgia. Transmitted by respiratory secretions.

Answer 64

mononucleosis. Characterized by fever, hepatosplenomegaly, pharyngitis, and lymphadenopathy (especially in posterior cervical nodes). Transmitted by respiratory secretions and salivia, also called kissing disease since is common in teens and young adults. Infect B cells through CD21. Atypical lymphocytes seen on peripheral blood smear that are not infected B cells but are reactive cytotoxic T cells, detect by positive monospot test- heterophile antibodies detected by agglutination of sheep or horse RBCs. Associated with lymphomas (endemic Burkitt lymphoma), and nasopharyngeal carcinoma. Targets both B lymphocytes and epithelia. Latency in B lymphocytes. In immunocompromised patients it can cause central nervous system lymphoma.

Answer 65

congenital infection, mononucleosis (negative monospot). Targets Epithelia monocytes, lymphocytes and others. Latency in monocytes, lymphocytes and possibly others. Transmitted congenitally and by transfusion, sexual contact saliva, urine, and transplant. In immunocompromised patients, can cause retinitis, pneumonia, colitis. In newborns, can cause congenital CMV.

Answer 66

targets and latency in T lymphocytes and other. HHV-6 is transmitted through contact and respiratory route transmission for HHV-7 is unknown. Can cause roseola-high fevers for several days that can cause seizures, followed by a diffuse macular rash.

Answer 67

targets endothelial cells, latency in B lymphocytes. Transmitted by sexual contact (exchange of body fluids?). clinical presentation includes Kaposi sarcoma- a neoplasm of endothelial cells. Seen in HIV/AIDS and transplant patients. Can also cause dark/violaceous plaques of nodules representing vascular proliferations. Can also affect GI tract and lungs.

Answer 68

viral culture for skin.genitalia. CSF PCR for herpes encephalitis. Tzanck test- a smear of an opened skin vesicle to detect multinucleated giant cells commonly seen in HSV1 and 2 and VZV infection. Intranuclear inclusions also seen with HSV-1 and 2 and VZV

Answer 69

entry occurs through binding to surface receptors-> fusion. Nucleocapsid enters cytoplasm and is transported to nucleus via microtubules where genome enters through pores. Herpesviruses replication occurs in an organized, temporal manner. Immediate early (IE) genes are expressed prior to protein synthesis (brought in with the virus). IE genes are required for the expression of the early (E) and late (L) genes, which are de novo synthesized. Many IE genes encode transcriptional activators. E genes encode proteins involved in DNA replication, such as viral DNA polymerase, thymidine kinase (TK), helicase, etc. Many drug targets are to these virally-encoded proteins. For example, acyclovir and ganciclovir act on TK, and foscarnet acts on viral DNA polymerase. Finally, L genes encode structural proteins, such as capsid and glycoproteins. Virus assembly occurs in the nucleus. Capsids self-assemble and newly synthesized DNA gets packaged. Nucleocapsids assembled in the nucleus bud through the nuclear membrane and acquire their glycoprotein-rich envelope as they pass through the Golgi complex. Virions leave the cell through exocytosis or cell lysis.

Answer 70

HSV 1 and 2. Lesions are infectious. It penetrates through cracks in the skin. Washing with soap and water readily inactivates HSV. Incubation period is 2-12 days (average is 4 day). Primary infection has no serum antibody present when symptoms first appear. Most HSV infections are asymptomatic. If they are symptomatic, primary disease is likely to be more severe than recurrences. After primary infection, the virus spreads from infected epithelial cells to nearby sensory nerve endings and travels to the nerve cell body in the sensory ganglion. For facial HSV it is the trigeminal ganglion. For genital, it is the sacral ganglion. The virus then enters the nucleus, where it lies latent. With reactivation, it travels from the infected ganglion or neuronal body down the axons to cause recurrence of disease in skin or mucous membrane supplied by that nerve. Lesions occur on face, cornea or perineum. Reactivation can be triggered by illness, sunlight, stress, menstruation, and immunosuppression. Reactivation is commonly asymptomatic, but the virus still sheds and is transmissible. If lesions do develop they are less in number and heal more quickly than primary lesions and may go unnoticed. Primary HSV-1 usually occur in childhood and are often asymptomatic.

Answer 71

most common primary infection with HSV-1, wide spectrum of severity. The child develops painful mouth vesicles and ulcerations of the gums, lips and tongue. These ulcers are usually in the anterior part of the mouth. Fever is common and can be quite high. There is often swelling of the lips and drooling. Cervical lymph node swelling is commonly seen.

Answer 72

occurs from inoculation of HSV from oral secretions onto the fingers. The virus gains entry into the skin via small cut or abrasion. This is an occupational hazard for doctors, nurses, and dentists. Wearing gloves whenever there is the potential to get oral secretions on your hands is necessary. This includes suctioning tracheostomies, obtaining nasal specimens from patients etc. This entity is also sometimes seen when a child injures his/her finger and mother (who has a cold sore or who is asymptomatically shedding HSV from her oral secretions) kisses it. Often the area of entry is near the fingernail but does not have to be. The area of virus entry develops erythema, swelling and grouped vesicles on an erythematosus base. The vesicles quickly evolve into pustules, with cloudy fluid. The finger is tender to touching. Frequently, a whitlow is mistaken for a bacterial infection and the patient is given antibiotics.

Answer 73

is a sexually transmitted infection that is usually caused by HSV-2, but HSV-1 causes about 30% of infections. Primary HSV genital infections are most commonly asymptomatic. However, if symptoms occur, painful vesicles and ulcers develop in the genital and sometimes perianal region. These lesions are quite painful and last 10-14 days. In women with primary lesions, swelling of the vulva and perineal tissues is often seen. Urinating may be very painful as the more acidic urine irritates the lesions. In some women, urinating is so painful, acute urinary retention develops requiring placement of a catheter.

Answer 74

is a condition where HSV infects the cornea of the eye. Herpes keratitis can be the result of a primary infection or from reactivation. It can be caused by HSV-1 or HSV-2, but HSV-1 is the more common pathogen. HSV-2 may rarely infect the eye by means of orofacial contact with genital lesions and occasionally is transmitted to neonates as they pass through the birth canal of a mother with genital HSV-2 infection. HSV produces dendritic lesions of the cornea, which can cause scarring and blindness. HSV keratitis is one of the leading causes of blindness in the US. Topical and sometimes systemic antivirals are used for therapy.

Answer 75

can be caused by primary disease or reactivation. This is an extremely serious manifestation of herpes disease. Herpes encephalitis can occur either through blood-borne (hematogenous) spread or neuronal transmission of the virus. Herpes infection of the brain results in a fulminant and hemorrhagic, necrotizing encephalitis. There is a strong predilection for the temporal lobes of the brain. As a consequence, it is common to observe altered mental status. Mortality is about 30% with treatment. HSV-1 causes most cases of childhood and adult encephalitis. HSV-2 is the more common cause of neonatal herpes encephalitis, which is associated with maternal genital herpes infections.

Answer 76

is a primary infection of the neonate that can be acquired intrauterine (in utero), peripartum (perinatal) or postpartum (postnatal). The majority of transmissions occur during the peripartum period, e.g. during birth from exposure to maternal secretions with HSV 1 or 2 present (active lesions or asymptomatic viral shedding). Since most genital herpes lesions are caused by HSV-2, most (but not all) neonatal HSV is caused by HSV-2. Because maternal infections can be asymptomatic and because asymptomatic viral shedding can occur, neonatal herpes frequently is diagnosed in babies whose mothers have no history of a known herpes infection. There are three forms of disease: 1) skin, eye and mucous membrane (SEM), 2) CNS, and 3) disseminated, with disseminated being the most severe. Because of the morbidity and mortality associated with neonatal herpes disease, finding a vesicle in a neonate less than 4 weeks of age (without a definitive alternative explanation) is a medical emergency. Herpes should be high on the differential and treated until proven otherwise.

Answer 77

in many, viral shedding may occur 1-3 days prior to development of a symptomatic outbreak. Herpes labialis (cold sores) most common with HSV-1.

Answer 78

(inflammation/infection of the cornea)- Primary infection of any of the 3 (ophthalmic, maxillary, mandibular) branches of cranial nerve V leads to latent infection of nerve cells in the trigeminal ganglion. When keratitis occurs as a result of reactivation, the virus, which has been latent in the trigeminal ganglion, migrates down the nerve axon to cause corneal disease. Interneuronal spread of HSV within the ganglion can occur and this allows patients to develop subsequent keratitis without ever having had a primary ocular HSV infection. HSV produces dendritic lesions of the cornea, which can cause scarring and blindness. These lesions are usually dendritic in appearance. HSV keratitis is one of the leading causes of blindness in the US. Topical and sometimes systemic antivirals are used for therapy.

Answer 79

Women or men may reactivate and shed HSV virus from their mucous membranes, anus or perineum. In some cases, recurrent lesions may be so small and trivial that they are not noticed. Recurrences of genital herpes cause terrible psychological stress on patients and their partners. Regular condom use and daily antiviral suppressive therapy will decrease transmission to uninfected partners. In many patients, symptomatic recurrences will become less frequent with time and may disappear. But most patients continue to shed virus asymptomatically intermittently, even if their symptomatic outbreaks disappear. Up to 70% of new genital HSV infections are transmitted by asymptomatic reactivation and shedding.

Answer 80

In encephalitis due to reactivation, neuronal spread of the latent virus occurs in retrograde fashion to the brain, usually through the trigeminal tract. Presentation is similar to that seen during primary infection.

Answer 81

Herpes gingivostomatitis and herpes labialis can often be diagnosed clinically, without laboratory testing. Laboratory testing may be desired in some cases to confirm the diagnosis. Genital herpes can also often be diagnosed clinically, but there are issues to consider that make obtaining a definitive diagnosis a good idea. Specifically, patients that are diagnosed with genital herpes feel stigmatized. There are issues with potential transmission to partners. Consideration should be given to regular condom use and/or antiviral suppressive therapy (in some patients). Definitive diagnosis for herpes simplex viruses can be obtained by: Viral culture of lesions (easiest and best bet for oral or genital lesions), Direct fluorescent antibody stain of lesions (fluorescent stain adheres to HSV antigens in a sample indicating their presence), and PCR of lesions (most expensive). None of these tests can distinguish between a primary or recurrent infection.

Answer 82

There are a group of nucleoside analog drugs used to treat herpes infections, some of which have high specificity since they take advantage of activation of the drug by a viral enzyme, thymidine kinase (remember HSV encodes a viral thymidine kinase).

Answer 83

The most common nucleoside analog for HSV treatment, but there are other similar agents. Severe HSV infections are treated with intravenous acyclovir. The following groups should be treated with intravenous acyclovir therapy: Patients with neonatal herpes, Herpes infections in immunocompromised hosts, and Patients with encephalitis or meningoencephalitis. Oral antiviral therapy (acyclovir or a related antiviral) can be used for oral or genital HSV outbreaks.

Answer 84

In certain patients who will be compliant, oral antiviral suppressive therapy is considered for patients with frequent painful oral or genital herpes recurrences. It is also considered for those patients who have genital herpes and are sexually active with an uninfected partner (or do not have a stable sexual partner). For successful viral suppression, patients must be willing to take medicine once or twice daily and not miss days.

Answer 85

is primarily transmitted by the respiratory route via droplet or aerosolized secretions (coughing, sneezing). Chickenpox can also be acquired from direct contact with lesions or aerosolization of virus from skin lesions. A person with chickenpox is contagious 1-2 days before the rash appears and until all blisters have formed scabs.  Incubation period: It takes from 10-21 days after exposure for someone to develop chickenpox. Symptoms start with fever, malaise, headache and sometimes cough. The rash appears in “crops” or waves. The initial lesions might be flat and rose colored, but they quickly mature into the classic “dew drop on a rose petal” which is a vesicle on an erythematosus base. The rash first appears on the face or trunk, then spreads to the extremities. As successive crops appear, lesions will be noted to be in various stages of development. Vesicles mature to pustules (with cloudy centers), which then rupture and scab. A hallmark of chickenpox is the finding of lesions in multiple stages of evolution (vesicles, pustules, crusts and scabs). The rash is described as itchy. The distribution of the rash is notable in that there are more lesions on the trunk and face then on the arms and legs. It takes about 7 days for all lesions to scab—at the time all lesions are scabbed the patient is no longer infectious. If the patient does not pick at the lesions and they don’t become secondarily infected, there is usually no scarring. Adolescents and adults often have much more severe disease than do young children. Pregnancy is a special situation. Pregnant women who contract chickenpox are at high risk for development of severe disease including varicella pneumonia and death. Many need intensive care and mechanical ventilation.

Answer 86

The virus gains entry via the respiratory tract and spreads to the regional lymphoid system. Viral replication takes place in regional lymph nodes over the next 2-4 days and is followed by a primary viremia occurring 4-6 days after initial infection. The virus then replicates in the liver, spleen, and possibly other organs. A secondary viremia, spreads viral particles to the skin 14-16 days after initial exposure, and causes the typical vesicular rash.

Answer 87

includes secondary infection or cellulitis, pneumonia, necrotizing fasciitis, encephalitis or encephalomyelitis, hepatitis, and congenital varicella syndrome

Answer 88

this is the most common complication seen with chickenpox. Group A Streptococcus is the most common bacteria to cause secondary skin and soft tissue infections (cellulitis) after chickenpox. While keeping lesions clean certainly decreases risk of secondary infection, we see this complication even in children whose families have been meticulous with wound care.

Answer 89

Bacterial pneumonia-This is the second most common complication that occurs with chickenpox. Group A streptococcal infections and Staphylococcus aureus are the most common pathogens responsible. While usually treatable, this can be a fatal complication in some individuals. Viral VZV pneumonia-usually occurs only in immunocompromised patients and pregnant women. This is a serious development and often requires intensive care management. This is a potentially fatal complication.

Answer 90

a rare but very serious complication where the infection extends deeper into the fascia. As the infection progresses along fascial planes, it shears off nerve endings and blood supply to the skin causing necrosis of the overlying skin. This is sometimes a fatal complication and when necrotizing fasciitis occurs as a complication of varicella, it is usually due to Group A Streptococcus.

Answer 91

these are rare but serious complications of VZV. If they are due to acute infection with spread of virus to the CNS, they usually occur in immunocompromised hosts with chickenpox. A more common form of encephalitis occurs during the convalescent stage of varicella and is thought to be antibody mediated. It may occur up to 2-3 weeks after the illness and is likely due to antibodies to VZV that cross react with certain brain antigens. This antibody mediated form of the disease does not involve any replicating virus in the brain.

Answer 92

Mild elevations of liver function tests are sometimes seen with chickenpox but significant abnormalities or fulminant liver failure may occur. Severe hepatitis and/or fulminant liver failure usually occur only in immunocompromised hosts.

Answer 93

Rare disorder that occurs when varicella is contracted by a pregnant woman in her first 8-20 weeks of pregnancy. The fetus can exhibit multiple tissue and organ abnormalities, such as microcephaly, mental retardation, hypoplasia of extremities, microphthalmia and hypopigmentation.

Answer 94

Varicella in normal children is usually a benign self-limited disease that does not mandate therapy. However, if therapy is instituted within the first 48-72 hours of onset, antiviral therapy can shorten the course. Acyclovir can be given orally to outpatients. For those patients sick enough to require inpatient management, acyclovir can be given intravenously. All patients who are immunocompromised, pregnant, or have severe varicella disease should be treated with antiviral therapy. Most immunocompromised and pregnant patients will require hospitalization and intravenous therapy. Teenagers and adults who develop varicella should be considered high risk for severe disease, and most physicians would start acyclovir even if beyond the 48-72 hour period from onset of disease.

Answer 95

Live attenuated varicella zoster virus vaccine (chickenpox vaccine) is currently recommended for prevention of chickenpox. It is given to children as part of the routine immunization schedule as a 2-dose series. The vaccine is given by subcutaneous injection: Initial dose at 12-15 months of age and Booster dose given at 4-6 years of age. Live attenuated vaccines may cause disease in patients who are immunocompromised. In general, the varicella vaccine is contraindicated in immunocompromised patients.

Answer 96

The virus remains in the ganglia during the latent period, which for many people is life-long. In 1/3 of infected individuals, virus reactivation results in shingles. The virus may be reactivated by stress, immune suppression, or other unknown factors. Once the virus reactivates in the ganglion it tracks down the sensory nerve to the area of the skin that nerve innervates, producing a varicella-form rash in the distribution of a dermatome. Inflammation and necrosis of cells in the ganglion occurs, and neuropathic pain (sometimes excruciating) is felt in the dermatome of the sensory nerve. VZV is the only Herpesvirus (Herpesviridae virus) that does not exhibit asymptomatic viral shedding in normal hosts that experience reactivation. Other members of the Herpesvirus family may manifest reactivation only by asymptomatic viral shedding. During VZV reactivation in normal hosts, virus is shed only from the shingles lesions.

Answer 97

The first symptom of shingles is often radicular pain in the area innervated by the nerve in which the latent infection has now reactivated. Pain may precede development of lesions by several days. Once, the lesions emerge, they are grouped vesicles on an erythematous base. They are confined to the single involved dermatome and do not cross the midline of the body. Lesions usually heal in about 2 weeks. Reactivation can affect the eye via the trigeminal nerve.

Answer 98

The major complication of shingles is chronic burning, itching, or shooting pain, which is seen primarily in the elderly. The pain may last weeks to months after the rash has healed. Often associated with post-herpetic neuralgia is increased sensitivity to touch (hyperesthesia). Post-herpetic neuralgia is a neuropathic pain which is sometimes severe and can last weeks to months. Pain control is often needed.

Answer 99

Usually chickenpox and shingles can be diagnosed clinically. If the diagnosis is unclear (i.e. differentiation between shingles and herpes) there are ways to distinguish the viruses: Direct fluorescent antibody (swab the base of the lesion and look for antigens by way of a fluorescent tagged antibody), VZV polymerase chain reaction (PCR) , and Viral culture (HSV grows readily, VZV grows slowly so culture is usually used  to “rule in” herpes)  

Answer 100

Acyclovir (or an acyclovir-like drug) given within 48-72 hours of onset may decrease lesions and pain.

Answer 101

A shingles vaccine (Zostavax) is approved for individuals 50 years of age or older. It is a live-attenuated vaccine and is given as 1 dose. This vaccine effectively “boosts” the immune response to VZV and decreases likelihood of developing shingles. Studies show Zostavax reduces risk for developing shingles by 70% in those greater than 50 years. In those who were vaccinated but who developed shingles, it reduced the risk of postherpetic neuralgia by 66%.

Answer 102

There is evidence that lowered cell-mediated immunity to varicella is the critical piece that puts people at risk for shingles. The fact that shingles is more common in the elderly may reflect declining cell mediated immunity in old age. Declining cell-mediated immunity may also be due to fewer exposures to naturally occurring chickenpox in the community (now that most children are vaccinated). Routine exposures used to serve to “boost immunity” in persons regularly.

Answer 103

Primary infection in the mother leads to viremia and possible transplacental infection of the fetus. Two thirds of the infants whose mothers contract primary CMV during pregnancy will NOT be infected in utero---1/3 are infected. Fortunately, most of those infected will be asymptomatic. Only 10-15% of the infected infants will have symptoms at birth --this is about 3-5% of the infants born to mothers with primary infections. These babies have congenital CMV. Infection of the fetus can also occur if a pregnant women reactivates CMV, but the risk is much lower (<1% of babies will become infected and even fewer are symptomatic).

Answer 104

The following signs are seen in infants with congenital CMV syndrome: Low birth weight, Microcephaly, Hearing loss, Mental impairment, Hepatosplenomegaly, Skin rash (blueberry muffin spots)-due to extramedullary hematopoiesis in the skin, Jaundice, Chorioretinitis. CMV may also be transmitted perinatally. Travel through the birth canal may result in infection by aspiration of CMV infected cervical/vaginal secretions. Or the infant may be infected by breastfeeding. More than 50% of infants fed with breast milk that contains infectious virus become infected with CMV. Infants that are infected during the birth process or after delivery (breast milk) do not have the congenital CMV syndrome. These infants usually have asymptomatic infection.

Answer 105

is another common pathogen that is a double-stranded DNA virus. This pathogen also infects the majority of people by adulthood. Transmission may occur in utero, perinatally or postnatally. In developed countries (i.e. US) with a high standard of hygiene, 60% of adolescents have been infected and ultimately 80% of the population is infected. In developing countries, over 90% of people are ultimately infected.

Answer 106

A person can become infected with CMV when they come in contact with infected body fluids: Saliva, breast milk, sexual contact, blood, tears, respiratory secretions, contact with urine, stool etc.; Blood transfusions and organ transplantations; Infected pregnant women can pass the virus to their unborn babies

Answer 107

2 weeks to 2 months

Answer 108

Upon initial infection, CMV infects the epithelial cells of the salivary gland or the genital tract, resulting in a persistent infection and intermittent viral shedding. There is likely viremia causing wide distribution of the virus to other organs and tissues. Infection of the genitourinary system leads to CMV being shed in the urine.

Answer 109

in persons with normal immune systems are usually asymptomatic. If symptoms occur, the illness can take 2 forms: 1) a mild febrile illness or 2) mononucleosis- like illness (similar to Epstein-Barr virus) with fever, swollen nodes and a mild hepatitis. Primary infections in immunocompromised persons are serious and CMV can infect most organs including causing pneumonia, colitis, hepatitis, encephalitis, retinitis, etc.

Answer 110

Once infected, the virus remains latent for life (latent infection) and may be reactivated from time to time, during which infectious virions appear in the urine and the saliva. Reactivation can lead to vertical transmission (mother to baby in utero), but vertical transmission is more common in mothers with primary CMV infections. Reactivation in persons with normal immune systems is asymptomatic. The virus is shed in body secretions, typically the saliva and the urine. Reactivation in immunocompromised individuals may produce serious disease including pneumonia, colitis, hepatitis, encephalitis, and retinitis.

Answer 111

The severity of CMV disease in immunocompromised patients parallels the degree of impairment of cell-mediated immunity. Patients with organ transplantation, bone marrow transplantation, or HIV (with very low CD4 counts) are most likely to have severe disease. CMV can affect most organs, but the most frequent clinical manifestations include CMV pneumonia, colitis, retinitis and hepatitis.

Answer 112

in persons with normal immune systems is not indicated- resolution without sequelae is expected. Immunocompromised persons with CMV infections are treated with an antiviral, Ganciclovir. CMV-IG, an immunoglobulin preparation with high titer of CMV antibodies, together with Ganciclovir are sometimes used to treat CMV pneumonia. Ganciclovir treatment of infants with congenital CMV is being studied in a clinical trial to see if outcomes are improved, but currently there is no recommendation to treat those infants.

Answer 113

There is no available vaccine. CMV-IG is given intravenously once monthly to some severely immunocompromised patients who are at very high risk for CMV to prevent CMV disease.

Answer 114

Viral culture , PCR, Fluorescent antibody staining, serology, and histology

Answer 115

For primary CMV disease (mononucleosis-like syndrome or pregnant  woman with febrile illness), serology can establish the diagnosis. Unlike the previous tests, this one can distinguish between primary and recurrent infection. In persons with a primary CMV infection, the CMV IgM will be positive and there will be a negative CMV IgG. Serology is also useful in establishing whether a person has EVER had a CMV infection. CMV IgG is positive for life, once the person has been infected. The following can be used to interpret serology: Positive IgM, negative IgG = acute CMV disease. Negative IgM, negative IgG= patient has never been infected with CMV. Negative IgM, positive IgG= patient has previously been infected with CMV  at some time in their life. Positive IgM, positive IgG = recent CMV reactivation.

Answer 116

with organ involvement (i.e. hepatitis, pneumonia, colitis), a tissue biopsy is sometimes done for diagnostic purposes. CMV-infected cells will have a characteristic “owl’s eye” appearance, which is diagnostic for CMV infection. The owl’s eye is a dense, dark nuclear body surrounded by a halo. These represent intranuclear inclusions (accumulation of viral proteins or virions). There may also be smaller intracytoplasmic inclusions noted.

Answer 117

an RNA virus with a segmented genome made up of eight different pieces of ssRNA, which encode several different viral proteins. Surrounding the core is a lipid envelope, with a lining of matrix protein on the inner side of the envelope, the two most common viral proteins are hemagglutinin (H) and neuraminidase (N) glycoproteins. Both H and N are surface proteins and different types are designated by numbers (e.g. H1, H2, N1, and N2). Influenza viral subtypes are identified by the combination of H and N proteins on the viral coat (e.g. H1N1). There are three types. Type A and B strains circulate in the population every year. Type C strains cause mild or clinically-insignificant illness. Type A strains cause both epidemics and pandemics and can infect other animals. With the nomenclature, the first letter says the type (e.g. A). this is followed by the strain number, the year the strain was isolated and the virus subtype. For non-human strains, the animal is listed between the virus type and the geographic origin. Influenza epidemics continue to persist because the type A and B viruses undergo constant and rapid change due to antigenic drift.

Answer 118

cause respiratory infections and contains an F-protein that causes formation of multicunleated giant cells (syncytial cells). This virus differs from the rest of its kin by lacking bot the HA and NA glycoproteins. It is the number one cause of pneumonia in young children, especially in infants less than 6 months of age. It is highly contagious with outbreaks occurring in the winter and spring. It is hard to treat and efforts focus on prevention. Can be prevented in many cases with palivizumab, a monoclonal antibody against RSV that is produced by a recombinant DNA method. Previously infected individuals are not completely immune but the subsequent infections are usually limited to the upper respiratory tract. Spreads through large droplets. It lives on surfaces for 1 hour and 40-60% of attacks are in children under the age of two. Yearly epidemics, with both A and B subtypes, can circulate during one season, but also in alternative seasons. Usually one of the subtypes in dominant. Even when there are two strains circulating, there is often temporal and geographic clustering. It is the most common cause of bronchiolitis. It can result in severe disease requiring hospitialization, usually in children less than a year of age but can be severe in anyone, particularly high-risk groups (immunocompromised, elderly). RSV infection in a child may predispose children to wheezing as adults.

Answer 119

it is a ssRNA, non-segmented virus. There are two types, A and B. there is antigenic variability within the groups. Drift occurs over time, like in influenza. Type A has shown to cause more severe disease in studies and is more prevalent in epidemiologic studies. F protein is for fusion of viral envelope to host cell; fusion of membranes of infected cells to each other to cause syncytia. G protein causes initial binding of virus to the host cell.

Answer 120

invades conjunctiva and nasopharynx. 3-5 day incubation. Causes constriction of smooth muscles in bronchioles, which leads to edema and inflammation of the airway, ventilation and perfusion mismatch (hypoxia), hyperexpansion by mucous plugging (visible with chest x-ray). Clinical presentation includes respiratory distress, wheezing and rhonchi breath sounds, hypoxia, and copious secretions.

Answer 121

cell culture (takes time), direct antigen detection rapid test (not very sensitive/ accurate), nucleic acid/ genomic amplification mostly PCR (most accurate).

Answer 122

RSV immunoprophylaxis. Respigam is a human pooled antibody with high RSV titers, shown to have a decrease in disease severity and hospitalization. Once monthly IM injection during RSV season for high-risk groups of young children. Very expensive

Answer 123

Either called EVD or EBOV. It is in the family filoviridae. Ebola species include Zaire (current outbreak), Sudan, Bundibugyo, Tai Forest, and Reston.

Answer 124

Ebola outbreaks result from spillover events from animal reservoirs with subsequent human-to-human transmission. Initial cases often tied to hunters or slaughtering animals. Then get human-to-human transmission; health care workers at very high risk. There have been 25 outbreaks in Africa, current outbreak in W. Africa is the largest ever; W. Africa has a more mobile population than C. Africa, this is the first time Ebola has been in cities. In W. Africa, a 2-yo boy has been identified as the index case, not sure how he got it but the family hunted bats. All cases linked back to this one and have been human-to-human. The epidemiology of Ebola has changed since early on in the outbreak. Compare initial projections versus what we see now. The numbers we see are underestimations – there is no reporting system, it’s  still shameful to have it, so people don’t want to get diagnosed or admit people in the family have died from Ebola; makes it difficult to get good numbers  

Answer 125

Filovirus comes from word filament. Enveloped, negative-strand RNA, replicates in the cytoplasm. 7 structural proteins and 2 non-structural proteins. Virions are polyploid – with multiple genomes strung together (filamentous shape). Structures include Viral membrane, RNA (genetic material), Glycoprotein – part of viral envelope, also a secreted form; functions in attachment/entry, important for pathogenicity, and Matrix proteins VP40 and VP24. VP40 is the main part of the virion/matrix, important for structure, stability, assembly, budding. VP24 is involved in assembly, budding, nucleocapsid assembly, immune defense. Nucleocapsid and nucleoprotein (VP30 and nucleoproteins) form the nucleocapsid. Polymerase complexes (VP35 and L) function in replication, RNA-dependent RNA polymerase

Answer 126

Enters body through mucosal surfaces or cuts to the skin. You only need a few virions for infection. Ebola initially enters phagocytic cells, sends signal for more cells to come, which facilitates infecting those cells; also spreads efficiently when cells go to lymph nodes, which allows ebola to infect more immune cells. When it infects cells it replicates VERY efficiently. Once in the cell, induces a massive cytokine storm – cytokines and similar molecules desctory vascular endothelium, induce disseminated intravascular coaculation (DIC). After initial infection of phagocytes, then goes to infect many other cells/organs in the body including: endothelial cells, liver, spleen, lungs. When Ebola infects parenchymal cells, get significant cell destruction/necrosis. With infection of endothelial cells, get leakage of fluids, severe fluid loss, hypovolemic shock, organ failure (hypovolemia and direct invasion). People die from hypovolemia +/- organ failure

Answer 127

After someone is infected, it is believed that he/she is protected from future infections; antibodies found out to 10 years after infection. Antibody response to the surface glycoprotein is associated with better survival. Ebola has many ways to evade the human immune system including glycoproteins, VP35 and VP24. Glycoprotein (surface) masks antibody binding sites. Parts exposed to immune system against which we make antibodies are  highly variable/dispensible. Glycoproteins physically blocks the MHC and other cell surface proteins in order to block  their role in triggering an immune response. Glycoprotein (secreted) secreted by the cell, act as decoys; antibodies against secreted GP aren’t very good at neutralizing the virus. VP35 and VP24 are both interfere with the cell’s interferon production, which plays a role in signaling for “help” and also inhibits the cell from apoptosis. In general, the immune system becomes overwhelmed and, therefore, dysregulated. Initial cytokine release signaling for more immune cells to come to the area  of initial infection, helps ebola to spread. Some antibodies may enhance cell entry of the virus. Other immune cells are prompted to die (apoptosis). The liver is infected early on, which is an important organ for shutting off the  immune response by clearing the cytokines from circulation

Answer 128

are non-specific – GI, fever, fatigue/weakness; very similar to other illness which are common (malaria, typhoid, dysentery). People develop significant 3rd spacing, loose a lot of fluids through capillary leak, vomiting and diarrhea (can loose 5-10 liters/day)

Answer 129

Management is symptomatic – there are no Ebola tratments (Fluid repletion, Electrolyte corrections, Renal replacement, ventilation, Need critical care, Need to isolate patients). Ebola can be found in many body fluids and may last longer than symptoms. Older age associated with worse outcome. Treatments – no approved treatments, but in 3 categories:  Antibodies from Ebola survivors – we used this in the US, not clear that it works; difficult in medical systems already stretched to their limits. Vaccines – in Phase I/II studies currently, plan large Phase III study soon; target is the GP. Drugs – several in development, none in clinical trials prior to this epidemic. Favipiravir and brincidofovir are both under investigation. Zmapp was given to several US patients. It is a monoclonal antibody against 3  targets on the GP

Answer 130

fever (94%), diarrhea (80%), weakness (74%), dysphagia (41%), hiccups (15%), and bleeding from mucous membranes.

Answer 131

presentation tends to resemble that of bacterial sepsis, including lethargy, decreased eating and mottling. A high incidence of apnea (cessation of breathing) may also occur. Infants and toddlers tend to present with gastrointestinal symptoms (nausea, vomiting and diarrhea); fever; anorexia; and various respiratory syndromes, including undifferentiated febrile upper respiratory illness, acute laryngotracheobronchitis (croup), bronchiolitis, bronchitis and febrile convulsions.

Answer 132

is transmitted primarily by the respiratory route. Also, contact with infectious particles can occur by contamination of hands or inanimate objects (fomites). Virus lives on human hands for about 5 minutes, on steel or plastic for 24-48 hours, and cloth or paper tissues for 8-12 hours. Therefore, touching a contaminated object and then touching a mucosal surface (eye, nose, mouth) can transmit virus. The incubation period is relatively short, typically 1-3 days.

Answer 133

can use both matric protein inhibitors (e.g. amantadine and rimantadine, only for subtype A) and neuraminidase inhibitors

Answer 134

this vaccine is an injectable, killed vaccine; licensed for all individuals 6 months of age and older. There are both trivalent and quadrivalent IIVs approved and available. The quadrivalent is newer, but it will likely completely replace all trivalent vaccines. The additional strain is a second B virus.

Answer 135

this is delivered intranasally via a small, needle-free syringe that delivers a fine mist into the nose; this is a live, attenuated (weakened strain) vaccine; licensed for healthy persons 2 yrs through 49 years of age. This contains the same influenza strains as IIV, however, it is only quadrivalent (initially was trivalent, but quadrivalent approved in 2012 and that’s all that is manufactured). The additional strain is a second B virus.

Answer 136

a gradual change in the virus that occurs through a slow series of mutations, substitutions or deletions in amino acids constituting the hemagglutinin or neuraminidase surface antigens. Occurring only after a particular viral strain has become established in humans, antigenic drift represents an adaptation to the development of host antibodies. Newly developed antigenic strains of influenza then prevail for a period of 2 to 5 years, only to be replaced by the next emerging strain. This new strain can then trigger a new epidemic, since it is now unfamiliar to the antibody repertoire of the population. The development of yet another set of host antibodies eventually protects the population–at the same time it puts pressure on the virus to drift yet again.

Answer 137

occurs when a type A influenza virus with a completely novel hemagglutinin or neuraminidase gene segment is introduced into humans. The new gene segment is usually acquired from other host species (i.e. birds or swine). Gene reassortment can occur when two or more influenza viruses infect a single human or animal. Because influenza has a segmented genome, some gene segments can be “swapped” between strains – producing a new virus that has gene segments from both viral strains. Pigs are unusual because they have can be infected with influenza strains that usually infect three different species: pigs, birds and humans. If a pig were to become infected with 2 different strains of influenza virus at the same time (for example a human strain and a bird strain), those strains might both infect the same cell, allowing for reassortment of gene segments to occur between the human and avian strains. This might create a predominately human strain that now contains a “novel” hemagglutinin or neuraminidase gene from the bird strain. Therefore, pigs can serve as a “mixing vessel” where influenza viruses might exchange genes, producing new and dangerous strains. Antigenic shift of type A influenza viruses occurs less frequently than antigenic drift, but with more dramatic impact. The result of global immunologic susceptibility to a new influenza virus is often a pandemic. Influenza type B viruses are not subject to antigenic shift as they infect only humans.

Answer 138

the virus’ gene segments were similar to influenza viruses that were known to circulate in pigs and it is believed that this virus strain was created from reassortment (antigenic shift). The rate of Pandemic H1N1 infection in the United States, during the 2009-2010 season, was highest among children and young adults ≤24 years of age. Pandemic H1N1 influenza A infections were less common in persons older than 65 years. This may be due to older people having preexisting immunity against antigenically-similar influenza viruses that circulated prior to 1957.

Answer 139

Avian influenza is an infectious disease of birds caused by influenza A subtypes. These viruses circulate in wild bird populations but rarely cause mortality. Wild birds are largely asymptomatic when infected but shed large amounts of virus in their stool – usually into lakes or waterways. There are 16 types of hemagglutinin and 9 types of neuraminidase and wild birds can be infected with all combinations. (They are the only species that can be infected with all influenza strains.) So, birds are a reservoir for influenza strains. Domesticated poultry can also be infected and avian influenza, which can have a huge toll on the poultry industry, as entire flocks may have to be culled to prevent spread to other farms. Currently, there is a highly virulent strain, H5N1, circulating in some bird populations that can cause severe disease in wild birds, domesticated birds, and can occasionally be transmitted to humans.

Answer 140

was isolated and is referred to as Highly pathogenic avian influenza A (H5N1) virus, also referred to as HPAI H5N1, and often shortened to H5N1. The HPAI H5N1 occurs mainly in birds and can be deadly, particularly to domestic poultry. Avian influenza viruses and human influenza viruses have some species specificity that is conferred by the way the hemagglutinin binds to the receptor. Avian viruses bind in an alpha 2, 3 linkage, whereas human viruses bind in an alpha 2, 6 linkage. This explains why many people with close contact with infected birds do not get infected. However, avian viruses with avian receptor specificity do occasionally infect humans, and this has been seen in the sporadic cases world wide. For efficient human-to-human transmission, the hemagglutinin from an avian virus must preferentially recognize the human receptor. A mutation in the hemagglutinin gene might confer such a change in the preferred binding. For example, an avian virus might mutate such that the preferred receptor binding is in a alpha 2, 6 (human) configuration. If this occurred, the avian virus would preferentially infect humans. There is another way an avian influenza pandemic could emerge and that is through reassortment (as occurred with the pandemic H1N1 infection) using pigs as the mixing vessel for the avian and human strains. If reassortment occurred such that the human hemagglutinin gene assorted with predominately avian segments, a novel strain would be produced that had the ability to bind to human receptors. Because in SE Asia, people live so closely to their animals and have a lot of animal contact, this scenario is a real concern.

Answer 141

1. Emergence of a new influenza subtype. 2. The virus must infect humans and cause serious illness. 3. Virus must have sustained human-to-human transmission and spread easily(without interruption) among humans.

Answer 142

Host cell is lysed - typically RNA virus-mediated response (e.g., influenza). Host cell is persistently infected - host cell survives initial infection; low levels of disease are detected  chronically and may recur. Host cell is latently infected - host cell survives initial infection; disease is undetectable and may recur;  latent infections are not targeted by current antiviral therapies

Answer 143

Influenza binds to the cell surface of an airway epithelial cell and is endocytosed and internalized into endosomes. The acidified endosomal environment promotes a conformational change in hemagglutinin structure that mediates fusion between the influenza viral envelope and the endosomal membrane. Activation of and proton influx through the viral M2 proton channel elicits the release of the RNA genome and its subsequent replication and assembly into new virus particles. Egress of newly synthesized virions results in their being tethered to the plasma member via the interaction with hemagglutinin and cellular sialic acid moieties. Viral envelope-bound neuraminidases cleave the sequestered sialic acid moieties, resulting in virion release.

Answer 144

Oseltamivir (Tamiflu) / Zanamivir (Relenza), Peramivir (Rapivab)

Answer 145

it works by inhibiting the enzyme neuraminidase (NA) that cleaves N-acetyl neuraminic acid (sialic acid) from host cell receptors for the influenza virus (A and B). The egress of newly synthesized virions results in their tethering to the plasma membrane via interaction of hemagglutinin with sialic acid moieties. Without NA activity, virus aggregates at cell surface decreasing both intracellular viral translocation and viral budding, resulting in reduced viral infectivity. Inhibition of NA also impairs viral penetration through mucin secretions, reducing the infection of other respiratory epithelial cells. Resistance: Relatively rare (1-4%), from mutations in either viral hemagglutinin or neuraminidase.

Answer 146

Administered orally as prodrug. Eliminated via renal tubular secretion with plasma half- life of 6-10 hours (given twice daily) x 5 days.

Answer 147

Poor oral bioavailability, administered via inhalation twice daily x 5 days. Renal elimination.

Answer 148

Given as single IV dose but hospitalized, critically ill or immunocompromised patients may be treated longer (off-label use)

Answer 149

FDA approval for uncomplicated influenza. Started within 48 hours of symptom onset can decrease the severity and duration (by 1-2 days) of symptoms caused by either influenza A or B in adults and children. Effective (80-90%) as prophylactic measure in contacts; indicated to control influenza institutional outbreaks and protect high-risk individuals until vaccination effective.

Answer 150

minor, occasional nausea and vomiting (reduced by taking with food)

Answer 151

bronchospasm reported uncommonly in patients with asthma or COPD

Answer 152

diarrhea and GI effects; neutropenia has occurred; rarely serious skin reactions

Answer 153

Amantadine (Symmetrel) and Rimantadine (Flumadine)

Answer 154

They block virally-encoded H+ ion channel (M2 protein) preventing changes in intracellular pH necessary for uncoating. This prevents the subsequent release of the virion ribonucleoprotein and RNA genome for replication in the cytosol. Resistance: Occurs to both amantadine and rimantadine in response to mutations in transmembrane domains of M2 proton channel.

Answer 155

Effective orally with accumulation in lungs. Amantadine is excreted unchanged in urine (90%) requiring dosage adjustment if impaired renal function. Hepatic elimination for rimantadine (t1/2 ∼ 12 hrs, 1-2 daily doses). Excreted in breast milk: Not recommended if breast feeding due to potential to cause urinary retention, vomiting, skin rash in the nursing infant.

Answer 156

For prophylaxis and treatment of influenza A infections (influenza B lacks M2 protein target). Can be given for 2-3 weeks in conjunction with flu vaccine in high risk populations. If given 1-2 days prior to and 6-7 days during infection will reduce incidence and severity of symptoms. If given 48 hours after, only slight therapeutic effect seen. In 2014, most seasonal A H3N2 and A H1N1 isolates were resistant limiting current use.

Answer 157

may cause insomnia, concentration difficulty, lightheadedness / dizziness, headache

Answer 158

better tolerated due to poor CNS penetration (more highly protein bound)

Answer 159

Herpes cellular attachment and entry is followed by viral uncoating. Transfer of viral DNA into host nuclei wherein viral immediate-early genes are transcribed to direct the synthesis of viral genome replicating genes (e.g., thymidine kinase, DNA polymerase, etc.). Upon completion of viral genome replication, late viral encoded genes direct the assembly and packaging of virion progeny. Progeny undergo budding to facilitate their ultimate release from host cells

Answer 160

The vast majority of antiviral agents are nucleoside analogs that specifically target viral genome replication by inactivating viral DNA polymerases, or viral reverse transcriptases. Antiviral actions of purine and pyrimidine analogs involve passage of the lipid soluble analog across the cell membrane where it is then converted to the active triphosphate form by intracellular kinases. The highest degree of selective toxicity is seen with those analogs (e.g., acyclovir) that are activated by viral kinases rather than host cell kinases. Selective toxicity can also be achieved with differences in the affinity of the analog for viral vs mammalian enzymes.

Answer 161

Acyclovir (Zovirax), Valacyclovir (Valtrex), Penciclovir (Denavir), Famciclovir (Famvir), Trufluridine (Viroptic)

Answer 162

Initial phosphorylation is mediated by viral thymidine kinase. This is the primary mechanism of viral vs. host selectivity (i.e., 200-fold difference in affinity). In addition, acyclovir-TP binds with greater affinity to viral DNA polymerase vs the host enzyme, providing further selectivity. Cellular protein kinases convert acyclovir-MP (monophosphate) to its TP (triphosphate) form. Acyclovir-TP competes with cellular dGTP for viral DNA polymerase, which then incorporates the nucleotide analog into replicating viral DNA strands. Once incorporated, acyclovir-TP terminates further DNA replication and strand elongation. DNA containing acyclovir-TP also irreversibly binds and inactivates viral DNA polymerase (i.e., suicide inactivation)

Answer 163

Mainly seen in immunosuppressed patients receiving extended treatment regimens. Most commonly due to reduced or loss of expression of viral thymidine kinase. Altered viral thymidine kinase substrate specificity (kinase loses activity). Altered affinity of viral DNA polymerase activity

Answer 164

Oral absorption poor (15-30%); not affected by food. Also available in topical and intravenous formulations. Acyclovir is renally excreted (adjust dosage if renal impairment). Neonatal (< 1 yr) clearance only 1/3 of adults.

Answer 165

Valyl ester prodrug of acyclovir; given orally achieves plasma levels 3-5 times higher than acyclovir (equivalent to IV administration)

Answer 166

Acyclic guanosine analog; poor oral absorption, topical only (more effective than topical acyclovir)

Answer 167

Penciclovir prodrug that increases oral bioavailability to 70%

Answer 168

Only administered topically due to toxicity associated with IV use

Answer 169

For treatment, ORAL acyclovir shortens symptom duration of primary and recurrent genital herpes and reduces mean duration of pain (not time to healing) in recurrent herpes labialis. Topical therapy much less effective. Also effective in secondary prevention (lower daily dose). Intravenous acyclovir: Treatment of choice for herpes simplex encephalitis, neonatal HSV infections, and serious HSV or VZV infections, especially in immunocompromised patients. Topical vidarabine and trifluridine are limited to use for HSV keratoconjunctivitis and recurrent epithelial keratitis. Effective against acyclovir-resistant strains

Answer 170

Oral acyclovir decreases number of lesions and duration of varicella (chicken pox) and zoster (shingles) but higher doses are required. Suppression with oral acyclovir reduces VZV reactivation in immunocompromised patients

Answer 171

Minor toxicities include headache, nausea, vomiting, reversible renal dysfunction (rare with adequate  hydration). IV acyclovir has been associated with encephalopathy (tremors, hallucinations, seizures, and coma). Classified as category B for use in pregnancy

Answer 172

includes Docosanol

Answer 173

Long chain saturated alcohol that inhibits replication of many lipid-enveloped viruses (including HSV). Acts to prevent fusion between cellular and viral envelop membranes that blocks viral entry into cell. Topical treatment (5X daily to lips or face) begun within 12 hours of prodomal symptoms or lesion onset reduces healing time about one day (4.8 days to 4.1 days, similar to penciclovir). Administration  at papular or later stages fails to elicit therapeutic responses. Appears to be well tolerated  

Answer 174

Ribavirin (oral: Copegus, Rebetol; aerosolized: Virazole). A purine nucleoside analog

Answer 175

Converted to ribavirin-TP by cellular kinases. Ribavirin-TP inhibits GTP-dependent 5’ capping of viral mRNA, which decreases their stability and translatability. Ribavirin also may increase viral mutagenesis rates, ultimately leading to viral suicide. Resistance has not been observed to date

Answer 176

Ribavirin oral bioavailability is relatively good (45-64%), increases with fatty meals. Elimination via hepatic metabolism and renal excretion of unchanged drug. Half-life varies with route of administration: inhalation (children) - 6-11 hours; oral (adults) - initial plasma t1/2 ~43 hours, increases at steady-state to > 150 hours

Answer 177

Inhalation: Generally well tolerated but can cause conjunctival or bronchial irritation; acute deterioration of respiratory function reported in patients with bronchospastic lung disease. Oral-systemic: High incidence of hemolytic anemia. When given with interferon causes higher incidence of cough, pruritus, and rash than interferon alone. Teratogenic and should not be administered during pregnancy (category X). Pregnant health care workers should not care for patients taking aerosolized ribavirin.

Answer 178

can fight respiratory syncitial virus. Aerosolized ribavirin is effective against RSV and pneumonia, but because of potential adverse effects, reserve use for severe RSV and immunocompromised patients. can also fight hepatitis C. Oral ribavirin combined with interferon-α2a or α2b. Formerly the standard of care for chronic HCV infection – now largely replaced by direct-acting antiviral agents

Answer 179

is a humanized monoclonal antibody to RSV F glycoprotein that is indicated for RSV immunoprophylaxis in infants and young children with congenital heart disease. It is expensive – benefits vary among risk groups. Given IM monthly - max of 5 doses – before beginning of RSV season (usually November). Well tolerated – rarely severe hypersensitivity reactions (<1 per 100,000)

Answer 180

Ganciclovir (Cytovene) and Valganciclovir (Valcyte) and Foscarnet (Foscavir).

Answer 181

All of the agents currently utilized in the treatment of CMV infections exert their antiviral activity via inhibition of viral DNA polymerase. There are differences between agents in the activation step, which can limit cross-resistance between agents in some instances. CMV infections occur primarily in the setting of advanced immunosuppression (HIV and organ transplantation), most commonly as a result of reactivation of latent infection. Infection results in end organ disease including retinitis, colitis, esophagitis, CNS disease, and pneumonitis. With the availability of oral valganciclovir and intraocular ganciclovir the usage of intravenous ganciclovir and foscarnet has decreased

Answer 182

Cellular uptake and initial phosphorylation is mediated by the viral protein kinase UL97 in CMV (or by viral thymidine kinase in HSV). This is the primary mechanism of viral vs. host selectivity. Cellular protein kinases then convert ganciclovir-MP (mono-phosphate) to its TP (triphosphate) form, which is 10-fold higher than in non-CMV-infected cells. Ganciclovir-TP competes with cellular dGTP for viral DNA polymerase, which then incorporates the nucleotide analog into replicating viral DNA strands. Ganciclovir incorporation into replicating DNA eventually slows and ceases further viral DNA chain elongation.

Answer 183

Mutations in UL97 protein kinase decrease ganciclovir phosphorylation and activation (most common) and mutations in viral DNA polymerase activity (UL54) that alters its activity. Cross-resistance to cidofovir possible with UL 54 mutations.

Answer 184

Ganciclovir has poor oral bioavailability, but exhibits good distribution in bodily fluids; usually  administered intravenously. Valganciclovir prodrug is rapidly deesterified and converted to  ganciclovir by GI and hepatic esterases. Ganciclovir is primarily excreted unchanged via the urine (clearance related to renal function) with a  t1/2 of 4 hours (intracellular half-life of 16-24 hours)

Answer 185

Effective for treatment and chronic suppression of CMV retinitis in immuno-compromised patients. Also effective in controlling CMV in transplant patients. Ophthalmic gel is effective in treating HSV keratitis. Some activity against HBV when administered orally

Answer 186

Less selective toxicity than acyclovir because host kinase can also perform first phosphorylation step. Myelosuppression with neutropenia and thrombocytopenia is the major side effect and concern (20- 40%). Can be reversed by drug cessation. GI disturbances and nausea also are reported. Rarely, CNS toxicity (headache, mental status changes, seizures) and abnormal liver function. Ganciclovir is classified as Category C (risk cannot be ruled out) for use in pregnancy Foscarnet (Foscavir). Inorganic pyrophosphate analog, unique amongst all antiviral agents

Answer 187

Foscarnet does not require cellular activation. Noncompetitively binds to the pyrophosphate binding site of RNA and DNA polymerases. Appears to inhibit cleavage of pyrophosphate from deoxy-TPs resulting in a block of viral replication.

Answer 188

Resistant strains exhibit alterations in DNA polymerase. Combined use of ganciclovir  and foscarnet can benefit some CMV patients, but strains resistant to both agents have been reported.

Answer 189

Oral bioavailability is poor; primarily administered via IV infusion. Primarily eliminated unchanged in the urine. Plasma half-life is bimodal and complex – initial t1/2 is  4-8 hours, while the terminal t1/2 is 3-4 days

Answer 190

Effective against CMV retinitis, particularly in immunocompromised patients. Also effective against ganciclovir-resistant CMV infections and acyclovir resistant HSV and VZV  infections

Answer 191

Major side effect is nephrotoxicity and hypocalcemia, can be quite severe or even fatal. CNS abnormalities also have been reported and include headache, tremor, seizures, and even  hallucinations. Other reported side effects include rash, fever, and nausea.

Answer 192

are eukaryotic, aerobic, unicellular or filamentous, heterotrophic organisms encased in a rigid cell wall. Fungi may reproduce by sexual and/or asexual mean and the nature reproduction is used in classification. As eukaryotes, fungal cells contain membrane bound organelles including nuclei, mitochondria, golgi apparatus, endoplasmic reticulum, and lysosomes. As heterotrophic organisms, fingi lack chlorophyll and are not photosynthetic (autotrophic) like plants and algae, but instead obtain necessary organic substrates from their surroundings. Like plants, fungi have rigid cell walls, which separates them from animals. These cell walls contain chitin (also in the exoskeleton of insects) and cellulose (found in plant matter). Fungi also have a cell membrane inside of the cell wall, which contains ergosterol. Only a very small number of specialized fungi (Chytridiomycota) are motile and none of the medically-relevant species are motile. Fungal species may be subclassified as saprobes, symbionts, commensals or parasites (this is the same system of classification also applies to bacteria and protozoa).

Answer 193

live upon dead and decaying organic matter. 

Answer 194

live upon another organism to the mutual advantage of both.

Answer 195

live upon another organism with no detriment to the host.

Answer 196

live upon another organism with clear detriment to the host.

Answer 197

fungi phylum of Mucor, Rhizomucor, and Rhizopus

Answer 198

fungi phylum of dermatophytes

Answer 199

fungi phylum of Cryptococcus

Answer 200

fungi phylum of asexual/ imperfect fungi

Answer 201

a unicellular growth form where the fungus reproduces via budding to form blastoconidia, or by dividing in half through fission. Colonies of yeast are usually moist or mucoid in appearance. Medically relevant yeast includes Cryptococcus neoformans and Candida albicans.

Answer 202

a filamentous growth form where the fungus reproduces via formation of spores or conidia. These filamentous elements are called hyphae. A mass of hyphae is referred to collectively as mycelium. Hyphae are often branched, and grow by apical extension. Medically relevant molds include common dermatophytes and Aspergillosis.

Answer 203

are thread like, branching, cylindrical, tubules composed of fungal cells attached end to end and grow by extending in length from the tips of the tubules. They may be septate (with internal divisions) or non-septate. Septa divide hyphae into compartments, but do not strictly divide the fungus into “cells,” as cytoplasm or even organelles may flow between compartments via pores within the septa.

Answer 204

are simply elongated yeast linked together like sausages. Typically pseudohyphae demonstrate some degree of rounding and DO NOT have cytoplasmic connections between the compartments. Common Candida albicans is an organism that often forms pseudohyphae.

Answer 205

fungi that do not have a fixed morphology but may exist in a yeast or hyphal form are referred to as dimorphic. Typically, an environmental change, such as a change in atmosphere, temperature, or food supply, triggers a transition from one form to another. Thermal dimorphism refers to dimorphism that is dictated by temperature, and it is in this context that the word “dimorphism” is most often used.

Answer 206

a disease that is caused by Histoplasmosa capsulatum, a thermally dimorphic fungi that is often found in bird feces or bat guano. In this fecal material at ambient material sitting in the environment, the fungus exists as a mold and saprophyte, but if inhaled, it can transform inside the body into a parasitic yeast of macrophages at body temperature. This thermal dimorphism is a different sub property from simple general dimorphism, which is the ability to grow in two phases – the yeast and hyphal phases - because of any stimulus.

Answer 207

S–some C–can H–have B–both P – phases. Sporothrix schenckii, Coccidioides immiti,s Histoplasmosa capsulatum Blastomyces dermatitidis, and Paracoccidioides brasiliensis

Answer 208

a specialized from of hyphal elements that grow like roots from larger hyphae. These rhizoids are seen in only a limited number of medically-relevant fungi (e.g. Rhizopus).

Answer 209

those that demonstrate complete cell walls that subdivide the hyphae into compartments. These subdivisions are NOT equivalent to “cells,” as microscopic pores in the septae allow for the free exchange of cytoplasm and nuclei between compartments. Aspergillus fumigatus is an example of a septate hyphal fungus, as are the dermatophytes.

Answer 210

have no cell walls compartmentalizing the hyphae. In truth, sometime very sparse or incomplete septae may be present, but the fungus is still considered to be aseptate (e.g. Rhizopus).

Answer 211

Sexual and asexual fungi may reproduce via spore formation, yet at an introductory level, the spores useful to identify and classify the medically-relevant fungi are asexual spores. Examples of the important types of asexual spores include conidia, sporangia, chlamydospores, arthrospores, spherules, blastocondia, and sclerotic bodies.

Answer 212

asexual spores usually borne off of specialized aerial hyphae (upward-projecting hyphae) called conidophores. A conidium may be large and multinucleated (macroconidia) or small and unicellular (microconidia). Some fungal species may produce both macroconidia and microconidia.

Answer 213

similar to macroconidia, except that the asexual spores (endospores) are enclosed in a membranous sac that breaks and the entire structure is borne by a sporangiphore. The shapes and or colors of a sporangium may be useful in speciation.

Answer 214

thick-walled, round spores that are highly resistant to adverse environmental conditions. Chlamydospores are further classified based upon where they form along hyphae. Terminal chlamydospores form at the ends of hyphae, while intercalary chlamydospores form along and within hyphae

Answer 215

like chlamydospores, arthrospores develop along the hyphae, but in general they are more numerous and elongated, often with a shape likened to a “barrel.” The mycelial phase of Coccidioides immitis classically demonstrates barrel-shaped arthospores. Incidentally, it is inhalation of these arthospores from the environment that yields the disease.

Answer 216

large, asexual spores that develop during the yeast phase of some organisms growth. The yeast form of the dimorphic fungus Coccidioides immitis forms spherules in tissue that are filled with endospores.

Answer 217

yeasts that bud asymmetrically

Answer 218

thick-walled, environmentally protective forms of yeast that are produced by some medically-relevant fungi that reproduce by fission

Answer 219

another name for a fungal colony growing on a culture dish.

Answer 220

the obverse is the top side of the growing thallus, while the converse is the flip-side (seen by looking through the media, and also known as the reverse). The color of the obverse/converse, or other characteristics (“mucoid”, “tangled”, “cerebriform”) of the growing thallus may be used in speciation

Answer 221

confined predominately to humans (and typically less inflammatory).

Answer 222

occurs predominately in animals but can be transmitted to humans (typically more inflammatory).

Answer 223

occurs predominately in the soil but can be transmitted to humans (often less relevant clinically).

Answer 224

a fungus, which produces its own pigment, usually melanin.

Answer 225

Tinea (dermatophytes, dermatophytosis – “ringworm”), Candida (candidiasis, thrush, “[vaginal] yeast infections”), and  Pityrosporum (pityrosporum versicolor/tinea versicolor)

Answer 226

Sporotrichosis, Cryptococcosis, Coccidioidomycosis, North American Blastomycosis, Histoplasmosis, Paracoccidiodomycosis, Lobomycosis, and Mucormycosis. The deep mycoses are characterized by their ability to cause systemic infection. Many of them begin in the lungs (through inhalation of arthrospores and the like) and then later disseminated widely to a variety of tissues. Often the extent of the disease depends upon the immunological status of the host.

Answer 227

defined as a group of hyphal fungi that utilizes keratin as a substrate for growth. This is a rather unique property of this group of fungi and it (obviously) limits the areas of the body where the organism will be found (skin, hair, nails) and it also predicts its behavior as you will seen in later lectures. These enzymes secrete an enzyme called keratinase, which digests keratin. The most common dermatophytes are Microsporum, Trichophyton, and Epidermophyton

Answer 228

a non-dermatophyte yeast that prefers the glucose of interstitial fluids for growth. While candida also causes superficial fungal infections, its need for glucose explains subtle differences in its body distribution and behavior.

Answer 229

another non-dermatophyte yeast that prefers breakdown products of sebum (“skin oil”) for growth and this substrate dependence explains differences in its body distribution and behavior.

Answer 230

365nm, causes some fungal species to autofluoresce under black light. Certain species of microsporum will fluoresce.

Answer 231

may be added, which denatures human material and leaves the chitinous walls of fungi more visible, and this allows for direct observation for the presence of yeast and hyphae indicative of a superficial fungal infection. The addition of chlorazol E black stain to KOH or DMSO stains the chitinous fungal cell walls a grey-green color and this makes the direct microscopic examination easier for many inexperienced practitioners.

Answer 232

cryptococcosis is a systemic infection prevalent in HIV/AIDS patients. This yeast has a thick mucoid capsule surrounding it. If cryptococcosis is suspected, the CSF from a lumbar puncture may be identified by mixing the fluid with India ink which stains everything EXCEPT the mucoid capsule, thereby highlighting the organism

Answer 233

A simple Gram stain, used to highlight bacteria on clinical material also highlights the yeast, Candida albicans.

Answer 234

Just as for bacterial cultures, clinical material (skin, hair, nails, soft tissue, etc.) may be cultured for growth of fungal organisms. The chief advantage of culture is that it allows for direct speciation of the infecting organism, although in many clinical situations the sensitivity of culture may be less than direct examination or histological examination (via biopsy). Cultures may be performed using a variety of different media including: Sabouraud’s agar Mycosel/Mycobiotic agar Dermatophyte Test Medium. Sometimes special agar may be used for a specific purpose or to grow a fastidious organism. For example, cornmeal agar induces Candida albicans to produce chlamydospores

Answer 235

the most sensitive to fungi growth, as it will allow for growth of both dermatophytes and non-dermatophytes. Unfortunately, unrelated contaminants also grow well, and may obscure the primary pathogen.

Answer 236

fungal media impregnated with chloramphenicol and chlorheximide to inhibit the growth of bacteria and saprobes. Dermatophyte Test Medium (DTM) is essentially mycosel-like media with a pH indicator that turns the agar from red in the presence of a dermatophyte

Answer 237

is often used on fungal specimens taken from colonies grown via culture. It is not a stain that is used in any clinical setting outside of the examination of cultured fungi.

Answer 238

highlights the chitinous cell wall of fungi, yielding a magenta/purple color. Most human tissue does not stain with PAS-D and glycogen rich material will stain with PAS; but this staining is lost with diastase digestion, while fungal chitin is not affected by diastase.

Answer 239

another special fungal stain that utilizes silver to highlight fungus a jet black color

Answer 240

this mucin stain is useful to highlight the mucoid capsule of Cryptococcus a red color.

Answer 241

may be used for direct examination of most specimens using fluorescent microscopy. The cell walls of fungi bind the stain and fluoresce blue-white or apple-green depending upon the fluorescent light source used on the fluorescent microscope

Answer 242

Skin testing works using principles similar to that of TB screening. Killed antigenic material, such as histoplasmin derived from Histoplasmosa capsulatum s is placed under the skin. A delayed- type hypersensitivity response is checked for in 48-72 hours. Just like a TB screen, a positive reaction is only indicative of prior exposure and not necessarily active disease.

Answer 243

For some types of fungal infections, blood tests may be useful. For example, in patients with disseminated cryptococcosis, a serological test of cryptococcal antigen is positive in 75% of cases.

Answer 244

a circular molecule consisting of a hydrophobic and hydrophilic region, creating an amphoteric molecule. Polyenes bind with ergosterol in the fungal cell membrane, and react with animal sterols to much lesser extent. They are considered to be fungicidal, leading directly to fungal cell death. Examples of this drug using this mechanism are Amphotericin B and Nystatin

Answer 245

binds to ergosterol, creating a pore in the fungal membrane, which causes ions and other molecules to leak out of the cell. This medication has many side-effects including fever, seizures, and kidney damage. In fact, amphotericin B used to be referred to as the “shake and bake treatment” or “amphoterrible.” Newer liposomal formulations have made amphotericin better tolerated, but with a greater financial cost. Despite its side effects, amphotericin remains a common medication for life-threatening fungal infections.

Answer 246

another polyene used topically for Candida infections, although it is not absorbed when given by mouth, and is too toxic for intravenous use.

Answer 247

inhibit the enzyme, 14α-demethylase. This enzyme converts lanosterol to ergosterol, and it is required in fungal cell membrane synthesis. These drugs block steroid synthesis in humans too, but to a much lesser extent. Imidazoles and triazoles are generally considered to be fungistatic, but not fungicidal. Oral imidazoles and triazoles also often interfere with cytochrome P450 enzymes, leading to potentially fatal drug interactions with certain medications. Topical imidazoles are not absorbed to any significant extent and are considered free of worry with regard to drug-drug interactions, and this is why they are available over the counter. Triazoles are similar to imidazoles but are simply newer, and for the most part, are better tolerated.

Answer 248

clotrimazole, miconazole, econazole, sertaconazole

Answer 249

ketoconazole

Answer 250

itraconazole, fluconazole, vorivonazole, posaconazole.

Answer 251

inhibit the enzyme squalene epoxidase, another enzyme required for ergosterol synthesis. The inhibition of this enzyme leads to accumulation of squalene within the fungal cell and this is directly toxic, making these agents fungicidal, rather than fungistatic. The most common allylamine is terbinafine, a medication which is available in topical and oral form. There are a significant number of reports of unmasking of lupus-like conditions with oral terbinafine making it a poor choice for those with a pre-existing history of connective tissue disease. Butenafine is a related topical benzylamine.

Answer 252

the newest class of antifungal agents, with capsofungin. These agents inhibit the synthesis of glucan in the cell walls of some fungi, probably via inhibition of the enzyme 1,3-β glucan synthase. The strengths of echinocandins include low toxicity, rapid fungicidal activity against most isolates of Candida and favorable kinetics that allow for once daily dosing. In addition to fungicidal activity against Candida, echinocandins are fungistatic against Aspergillus, but are not useful against many other forms of fungus.

Answer 253

inhibits fungal cell mitosis by disrupting mitotic spindle formation, a critical step in cellular division. Griseofulvin is well tolerated and has been around for many decades. It is still used in children with tinea capitis because of its long record of safety, but in many other indications it has been replaced by newer triazole medications. Griseofulvin is fungistatic.

Answer 254

a small molecule that is transported into fungal cells by a specific enzyme, cytosine permease, and is then converted in the cytoplasm by cytosine deaminase to 5-fluorouracil (5-FU). 5-FU is a pyrimidine anti-metabolite that interrupts DNA synthesis, inhibiting fungal growth. Flucytosine is fungistatic.

Answer 255

Unlike the other topical antifungals already discussed, ciclopirox olamine does not affect ergosterol metabolism. Instead this medication is thought to chelate polyvalent metal cations, such as Fe3+ and Al3+ leading to inhibition of many different fungal enzymes, including cytochromes. Important cellular activities such as mitochondrial electron transport and energy production are inhibited. Ciclopirox exhibits fungistatic and/or fungicidal activity in vitro against a broad spectrum of fungal organisms.

Answer 256

Binds to ergosterol in fungal cell membrane opening pores that result in leakage of cellular constituents (Na+, K+, and H+ ions) and subsequent cell death (fungicidal). LESS selective toxicity because it also binds to cholesterol components in mammalian cells

Answer 257

Poor oral absorption (used IV or topically). Rapidly sequestered in tissues (liver, spleen, lymph nodes, lungs) - slowly released (little to CNS). Slowly excreted by kidney, major route through biliary tract (terminal t1/2 about 15 days). Also as bladder irrigation or intraventricularly/ intracisternally/ intralumbarly (fungal meningitis)

Answer 258

Broad spectrum, including opportunistic (Candida, Aspergillus) and systemic (Histoplasma, Cryptococci, Blastomyces, Coccidioides) fungal infections

Answer 259

``` Drug of choice for nearly all life-threatening systemic fungal infections, commonly seen in immunosuppressed patients (cancer patient with neutropenia). Often used as initial induction therapy then replaced by one of newer, less toxic azoles for maintenance therapy. Deep candidiasis, aspergillosis, mucormycosis, cryptococcosis, extracutaneous sporotrichosis ```

Answer 260

Very toxic drug. Nephrotoxicity is major limiting factor. Occurs in nearly all patients, can be attenuated somewhat with pretreatment saline infusion. Infusion-related toxicities: Chills, fever, vomiting, rigor, hypotension with IV use (premedicate with acetaminophen/diphenhydramine or administer with hydrocortisone; meperidine can shorten duration of rigors). Anemia (75%) occurs secondary to bone marrow depression (via decreased erythropoeitin). Liposomal preparations may reduce renal and infusion toxicities. Lipid vehicle serves as amphotericin reservoir reducing non-specific binding to human cell membranes (in theory). [AmBisome, Abelcet]

Answer 261

Similar to Amphotericin B, but toxicity limits use to topical treatment of Candidal infections of skin, mucous membranes, and GI tract. Safe and effective for this indication; no appreciable absorption from GI tract; toxicities limited to mild and transient GI upset.

Answer 262

Caspofungin (Cancidas), Anidulafungin (Eraxis), Micafungin (Mycamine). New class of antifungal agents called echinocandins.

Answer 263

Inhibits the synthesis of β (1,3)-D-glucan, an essential component of fungal cell walls, leading to  disruption of cell wall assembly. High level of selective toxicity due to absence of these enzymes in mammalian cells

Answer 264

Administered by IV infusion. Dosage reduction required for patients with hepatic insufficiency (NOT for anidulafungin), but not in presence of renal dysfunction. Dosage increase may be necessary if patient is also taking inducers of cytochrome P450 (phenytoin, rifampin, carbamazepine, certain HIV drugs)

Answer 265

Indicated for treatment of invasive aspergillosis in patients who are refractory or intolerant to other therapies (amphotericin B, itraconazole) D. Adverse Reactions: Histamine-mediated symptoms (rash, facial swelling, pruritus) are possible during administration. Other effects can include fever, nausea/vomiting, headache, phlebitis.

Answer 266

(Triazoles and Imidazoles) Triazoles: Fluconazole (Diflucan), Itraconazole (Sporanox), Voriconazole (Vfend) - Terconazole (Terazole) is topical only. Imidazoles: Ketoconazole (Nizoral) can be used systemically and topically. Clotrimazole (Lotrimin / Mycelex) and Miconazole (Monistat) are available topical only due to extreme systemic toxicity. Terbinafine (Lamisil)- synthetic allylamine. Flucytosine (Ancobon). Griseofulvin (Fulvicin). Pentamidine (Pentam)

Answer 267

Highly selective inhibition of fungal cytochrome P450 (14α-demethylase) reducing normal sterol synthesis; fungistatic. Greater selectivity for fungal vs mammalian cytochrome enzymes than seen with imidazoles (ketoconazole), resulting in less hepatotoxicity, fewer hepatic enzyme interactions, and a wider therapeutic index

Answer 268

Oral bioavailability is 90-99%; itraconazole absorbed best with food. Fluconazole cleared primarily by renal excretion of unchanged drug (80%) requiring dosage reduction  in impaired renal function; itraconazole eliminated primarily by hepatic metabolism. T1/2 of 30-40 hrs allows once daily dosing of each. Fluconazole can enter CSF for treatment of meningitis

Answer 269

Vaginal candidiasis in patients who fail treatment with topical agents. Oropharyngeal and esophageal candidiasis; also used in Itraconazole has potential benefit in treatment of aspergillosis, histoplasmosis, sporotrichosis. Agent of choice in dermatophytoses and onychomycosis if systemic therapy chosen.

Answer 270

new agent useful in serious invasive aspergillosis; less toxicity than amphotericin

Answer 271

Reported more frequently in HIV patients (21% vs 13%); overall very well tolerated. GI distress most common; also headaches, allergic rash, elevation of liver enzymes, transient visual changes (voriconazole). No inhibition of mammalian CYP450 steroid biosynthesis

Answer 272

Interference with drug metabolism by itraconazole is similar to ketoconazole; inhibition by fluconazole somewhat less, but possible. Voriconazole levels reduced by CYP450 inducers

Answer 273

Inhibits P450-dependent enzyme (14α-demethylase) resulting in decreased levels of ergosterol. Disruption in synthesis of cell membrane sterols leads to alterations in membrane permeability (fungistatic / fungicidal depending on concentration)

Answer 274

Only ketoconazole used systemically (oral and IV). Poorly absorbed, maximal absorption with low pH. Well-distributed, but enters CNS poorly (5%); crosses placenta. Eliminated by hepatic metabolism (primarily by oxidation). Excreted in breast milk

Answer 275

(decline in systemic use of ketoconazole due to availability of safer agents). Chronic mucocutaneous candidiasis and other systemic fungal infections (ketoconazole, oral); less toxic than Amphotericin B but also less effective. May antagonize amphotericin effect by preventing synthesis of ergosterol binding targets. Oral and vaginal candidiasis (miconazole / clotrimazole, topically as creams and troches as high systemic toxicity occurs if these agents are given parenterally)

Answer 276

(use of systemic ketoconazole). Side effect profile leading to decline in systemic use. Anorexia, nausea / vomiting most common; tolerance improves by taking with food or at bedtime. Pruritus, rash, and dizziness can occur. Hepatotoxicity. Mild jaundice common, serious toxicity rare (but some fatalities). Generally avoid if  preexisting liver dysfunction. Avoid in pregnancy (teratogenic in rat). Can inhibit mammalian testosterone synthesis leading to impotence, decreased libido, and gynecomastia due to  greater propensity to inhibit mammalian CYP450 than the triazole antifungal agents. High doses may also inhibit adrenal steroidogenesis and decrease plasma cortisol concentrations (therapeutic use).

Answer 277

Antacids / Cimetidine: Elevation of pH leads to decreased oral absorption. Cyclosporine / Phenytoin / Anticoagulants: Ketoconazole is strong inhibitor of CYP3A4 drug metabolism leading to increased drug effect (or toxicity). Rifampin: Decreases effect of ketoconazole by inducing metabolism

Answer 278

Interferes with ergosterol synthesis by inhibiting squalene oxidase; toxic effects also from accumulation of squalene. Fungicidal, accumulates in keratin (like griseofulvin).

Answer 279

Agent of choice in once daily oral dose for toe / finger nail infections (onychomycosis). Available topically for athlete’s foot (tinea cruris, tinea corporis)

Answer 280

GI upset, rash, headache, taste disturbances. Interference with CYP450 metabolism

Answer 281

Converted in fungal cell into 5-fluorouracil (via cytosine deaminase) which interferes with DNA  synthesis leading to cell death. High selective toxicity (mammalian cells lack deaminase). Resistance occurs in fungi that lack cytosine deaminase.

Answer 282

Well absorbed after oral administration; given in 4 equally spaced doses. Excellent distribution to tissues (including CNS). 90% excreted unchanged in urine; requires decreased dosage if diminished renal function

Answer 283

Effective agent, but rarely given alone (with Amphotericin B due to resistance development). Used for serious infections of cryptococcosis, candidiasis, and chromoblastomycosis

Answer 284

Relatively non-toxic, but toxicities frequent when given with Amphotericin B. Nausea, vomiting, skin rashes occasionally. Prolonged high levels leading to bone marrow depression, abnormal liver function, hair loss. Probably due to bacterial conversion of flucytosine to 5-FU in intestine.

Answer 285

Binds to microtubules inhibiting fungal mitosis and interfering with processing of new cell wall components; fungistatic.

Answer 286

Oral absorption generally poor but can be improved by reducing particle size (microsize/ultramicrosize)  and administration with fatty foods. Absorbed drug has affinity for diseased skin (binds to keratin making it resistant to fungal growth); as  keratinized structures shed, tend to be replaced by uninfected ones; topical use has little effect. Little griseofulvin present in body fluids or tissues; excreted chiefly in feces.

Answer 287

Indicated for severe dermatophytosis (superficial) involving skin and hair (3-6 weeks) or fingernails (3- 6 months) or toenails (6-12 months). Infrequently used, replaced by shorter course of therapy with itraconazole or terbinafine (3 months)

Answer 288

Hypersensitivity reactions most common (skin rashes, urticaria, angioneurotic edema). Occasionally headache (can be severe), GI distress, mental confusion

Answer 289

Inhibits protein and nucleic acid synthesis.

Answer 290

Usually given IV/IM; inhalation can produce higher levels and lower toxicity in treating P. jirovici (carinii) pneumonia (common opportunistic fungal infection in AIDS patients).

Answer 291

Effective against wide variety of protozoa (concentrated in organisms). Agent of choice in treatment of P. jirovici (carinii) pneumonia in AIDS patients (or trimethoprim / sulfamethoxazole [Bactrim]). Bactrim preferred for treatment in non-AIDS patients and for prophylaxis in all patients.

Answer 292

Severe toxicities often limit use with 50% of patients receiving pentamidine show some adverse effect. Leukopenia, hypoglycemia, hypotension (IV use). Nephrotoxicity / hepatotoxicity more common, less severe.

Answer 293

Uncommon in healthy, immunocompetent individuals with exception of mucosal candidiasis and dermatophyte skin infections (e.g., athlete’s foot). These infections affect 10- 20% of population at any given time and account for > 2 million office visits a year. Superficial [pityriasis versicolor, tinea nigra, black piedra, white piedra]. Limited to outermost layers of the skin and hair that do not elicit a cellular response from the host. Usually produce only cosmetic problems that are easily diagnosed and treated.

Answer 294

Removal from the skin with keratolytic agents (selenium, salicylic acid) and / or topical azole-antifungal agents [ketoconazole (cream-shampoo-gel-foam), miconazole, clotrimazole]

Answer 295

include dermatophytes and candida

Answer 296

Microsporum, Tricophyton, Epidermophyton, e.g., tinea corporis (ringworm), tinea pedis (Athlete’s Foot), tinea cruris (Jock Itch), tinea capitis (scalp); tricophyton rubrum (nails). Includes infections that are deeper in the epidermis and its integuments, the hair and nails. Generally restricted to the keratinized layers of the integument and its appendages. Clinical manifestations of these infections are referred to as ringworm or tinea.

Answer 297

Generally conservative with use of topical antifungal agents (clotrimazole, miconazole, butenafine, terbinafine). Hair infections, griseofulvin can be given orally. Nail infections (onychomychosis) generally requires systemic therapy of 6 weeks to 6 months duration (itraconazole, terbinafine). Topical therapy (ciclopirox) is of low efficacy. Fingernail infections will usually always clear, while toenail infections respond in about 60-70 % of cases.

Answer 298

(esp. albicans): Part of normal human flora. Includes disease that affect mucosal surfaces of mouth, vagina, esophagus, and bronchial tree in addition to diseases of skin and nails mimic dermatophyte infections.

Answer 299

Topical nystatin, clotrimazole, butoconazole, terconazole for mucocandidiasis. Can try fluconazole via systemic (oral) route if no response

Answer 300

[Sporotrichosis, Chromoblastomycosis]. Relatively rare infections. Infections that involve the dermis, subcutaneous tissues, muscle, and fascia. Characterized by development of lesions on skin surface, usually sites of trauma where organism is implanted in tissue.

Answer 301

Oral itraconazole and parenteral amphotericin B (severe systemic infection)

Answer 302

[Blastomycosis, Coccidioidomycosis, Cryptococcosis, Histoplasmosis]. Infections that originate primarily in the lung but may spread to many organ systems. Causative organisms are inherently virulent and cause disease in healthy humans. Respiratory infections are generally asymptomatic and it is the secondary spread to other organs that causes a patient to seek medical attention. The host’s immune status determines severity of disease, which can be life- threatening in immunocompromised patients if therapy is not instituted rapidly.

Answer 303

Long term therapy with systemic amphotericin B infusions generally required

Answer 304

amphotericin B > itraconazole > voriconazole > fluconazole > ketoconazole

Answer 305

amphotericin B, maintenance with fluconazole or itraconazole 

Answer 306

amphotericin B ± flucytosine, fluconazole

Answer 307

amphotericin B, itraconazole

Answer 308

[Candida albicans, Aspergillus fumigatus, Pneumocystis carinii]. Host debilitation increases susceptibility to fungal infections. Becoming more common and medically significant due to AIDS and increased use of radiation and cytotoxic drug therapy in cancer and transplant patients

Answer 309

fluconazole, micafungin-caspofungin, posaconazole

Answer 310

amphotericin B, caspofungin, voriconazole, itraconazole

Answer 311

TMP-SMX, pentamidine

Answer 312

an organism that lives upon or within another living organism at whose expense it obtains some advantage. The ability of parasites to infect specific tissues (tropism) is often essential for their life cycles. The geographic occurrence of parasitic diseases is often restricted by the availability of host species that are essential for the life cycles of the parasites. Most protozoan parasites can replicate and increase their numbers in humans. In contrast, many worms undergo development but do not replicate in humans, and the worm burden of such parasites in humans reflects the intensity of their exposure to infection. A detailed medical history, including specifics of travel and activities that could place the patient at risk for exposure to parasitic diseases, is essential for evaluation of patients with diseases caused by parasites. Many parasites evade or subvert the protective immune responses of their hosts, and damage to host tissues is often the result of host immune responses. In addition, diseases caused by many parasites become clinically apparent when the number of parasites (the parasite burden) is high or when infection persists for long periods of time. Development of effective vaccines against the major parasitic diseases of humans has been difficult and remains an important goal for world health. Because parasitic diseases are caused by eukaryotic pathogens, the biological bases for selective toxicity of anti-parasite drugs are quite different from those described previously for anti-bacterial and anti-viral drugs. Discussion of the drugs used to treat parasitic diseases will be covered in lectures given by the pharmacology faculty.

Answer 313

the species in which that parasite undergoes sexual replication

Answer 314

other species in which asexual replication

Answer 315

that cause parasitic diseases in humans occur within several major biological groups. These include: roundworms/nematodes, flatworm/ Trematodes/Flukes, and Tapeworms/Cestodes

Answer 316

(Ascaris, pinworms, whipworms, hookworms, Strongyloides, Echinococcus, Trichinella, filarial worms, etc.)

Answer 317

(Schistosomes, lung fluke, etc.)

Answer 318

(beef tapeworm, pork tapeworm, fish tapeworm, etc.)

Answer 319

occur also within several major biological groups. These include: Amebas, Flagellates, Ciliates, Sporozoa, and Microsporidia

Answer 320

(Entamoeba histolytica, etc.)

Answer 321

(Giardia, Trichomonas, Trypanosoma, Leishmania, etc.)

Answer 322

(Balantidium coli)

Answer 323

(Cryptosporidium, Cyclospora, Plasmodium, Toxoplasma, etc.).

Answer 324

(Enterocytozoon, Septata, etc.)

Answer 325

transmitted to humans by exposure to contaminated fresh water. It causes acute manifestations and progresses to chronic disease affecting the intestinal or urinary system. Schistosomiasis is estimated to affect 200-300 million people and to cause up to 200,000 deaths per year on a global basis, second only to malaria among parasitic diseases. Among the infected people, 120 million are symptomatic and 20 million have severe disease. 85% of affected people live in sub-Saharan Africa. Schistosomes are trematodes/flatworms. Three species are widely distributed and cause most infections in humans: Schistosoma mansoni (primarily in Africa, South America and the Middle East), S. japonicum (primarily in China, the Philippines and Indonesia), and S. haematobium (primarily in Africa and the Middle East). Two species have more restricted geographic distributions: Schistoma intercalatum (West Africa) and Schistoma mekongi (Southeast Asia). Schistosomiasis in the United States is seen only in immigrants or travelers, and a history of residence in or travel to an endemic area is important for considering the correct diagnosis.

Answer 326

is complex. Eggs shed in the feces or urine of infected humans hatch in fresh water and release miracidia, which infect snails. Following further development as sporocysts in the snails, free-swimming cercariae are released. The cercariae are capable of penetrating the skin of humans to initiate infection. The cercariae lose their tails and develop into schistosomulae in the tissues of the human host. The schistosomulae gain access to the circulation, migrate to the portal blood, and mature into adult worms that migrate to the mesenteric veins (S. mansoni, S. japonicum, S. intercalatum, and S. mekongi) or to the venous plexus of the bladder (primarily S. haematobium), where mating occurs. The eggs that are produced circulate in the venous blood to the liver and are also released into the intestine or urinary bladder, depending on the anatomic location of the adult worms. Release of the eggs into the environment perpetuates the cycle of infection.

Answer 327

Cercarial invasion into the skin can cause dermatitis (swimmers itch) within 2-3 days. The acute phase of schistosomiasis (also called Katayama fever) is a serum-sickness like illness that occurs 4-8 weeks after skin invasion, coincident with worm maturation and onset of oviposition, and often accompanied by lymphadenopathy and hepatosplenomegaly. The chronic stage of schistosomiasis involves granulamatous and fibrotic changes in the liver (from S. mansoni, S. japonicum, S. mekongi or S. intercalatum) or in the bladder (from S. hematobium). These pathological changes in chronic schistosomiasis are the consequence of host reactions to deposited eggs, leading to formation of infiltrates containing large numbers of eosinophils and eventually to scarring of the liver or urinary bladder. Patients with light infestations may be asymptomatic, while those with heavier infestations often present with symptoms such as diarrhea, abdominal pain, or ascites for intestinal schistosomiasis, and symptoms ranging from bloody urine (hematuria) to bladder cancer (for urinary schistosomiasis). The diagnosis is often made by microscopic examination of stool or urine for schistosome eggs with characteristic sizes and shapes or by detection of similar schistosome eggs in tissue biopsies.

Answer 328

public health education (avoiding contact with infected water, building wells and latrines to provide potable water and avoiding contamination of environmental water sources), use of molluscicides and environmentasl modification to control snail intermediate hosts for schistosomes, mass treatment of populations with anti-schistosome drugs (usually praziquantel), and research on diagnostic tests, improved therapeutics, and vaccines for schistosomiasis. Even in regions where control of schistosomiasis has been effective, the parasite has not been eliminated and transmission of infection continues to occur, albeit at a lower frequency.

Answer 329

Malaria is the most important parasitic disease. It affects > 1 billion people and causes 1-3 million deaths/year. Four species of protozoa in the genus Plasmodium cause malaria in humans: P. vivax, P. ovale, P. malariae, and P. falciparum. P. falciparum causes most of the deaths. P. vivax is widely distributed from tropical to temperate zones, but P. falciparum occurs primarily in the tropics and subtropics. Malaria has been eliminated from the United States, Canada, Europe and Russia (except for imported cases), but global malaria and resistance to anti-malarial drugs are still major problems.

Answer 330

Infected mosquitos bite humans and inject sporozoites into the blood. The asexual phase of development (schizogony) occurs in humans. Sporozoites of all malaria parasites can infect liver cells and replicate, but only P. vivax and P. ovale can establish a dormant hepatic phase with non-dividing forms called hypnozoites that can initiate late relapses. After primary replication in the liver, merozoites are released into the blood, infect erythrocytes, and undergo additional asexual replication. Gametes (macro- and micro-gametocytes) are formed in some infected erythrocytes. The sexual phase of development (sporogony) occurs in the infected mosquito where the gametes fuse in the intestine to form zygotes. Development of the parasite in mosquitoes eventually leads to the production of sporozoites in the salivary gland. Introduction of the sporozoites into a susceptible human by the bite of an infected mosquito initiates a repetition of the life cycle of the parasite. Acquired immune responses that help to control the development of malaria parasites in humans are also shown.

Answer 331

The symptoms of malaria are primarily associated with the rupture of infected erythrocytes and release of merozoites. P. falciparum invades erythrocytes of all ages, and it can therefore achieve the highest parasitemia and mortality. P. vivax and P. ovale invade only young erythrocytes, while P. malariae invades only old erythrocytes. In untreated patients with malaria, this process often becomes synchronized, and fever paroxysms may then have a regular periodicity (48 hr for benign tertian malaria caused by P. vivax or P. ovale; 72 hr. for quartan malaria caused by P. malariae; and 36-48 hr. for malignant tertian malaria caused by P. falciparum). Anemia, which may be disproportionate to the parasitemia, results not only from the lysis of RBCs, but also from their phagocytosis by the stimulated reticuloendothelial system, their sequestration in the enlarged spleen, and depressed bone marrow function. Hemolysis can be extreme, resulting in hemoglobinuria (blackwater fever). Physical examination reveals jaundice, hypotension and tachycardia in addition to fever and hepatosplenomegaly. Especially with P. falciparum infections, vasodilation causes hypotension and inadequate blood supply to vital organs. P. falciparum-infected red blood cells bind to the microvascular endothelium, which is especially significant in cerebral malaria (up to 50% mortality). Multi-organ failure is the major cause of death in adults. With P. malariae infections, immune complex deposition leading to glomerulonephritis is common. The patient generally mounts an immune response that makes subseqent episodes of symptomatic disease less severe. Both B and T cell responses are involved. Within a few weeks of infection, stage specific anti-plasmodium antibodies are produced. Natural immunity is short-lived, and continual re-infection is required to maintain it. People returning to endemic areas following a long absence may therefore be quite susceptible to re-infection.

Answer 332

The diagnosis of malaria is usually established by detecting the asexual forms of the parasites in stained thick or thin blood films. Morphological features of the intracellular parasites and the infected erythrocytes are used to differentiate the four species from each other and from other protozoan that also can replicate in erythrocytes. Rapid monoclonal antibody-based tests for the PfHRP2 antigen or for Plasmodium LDH antigens are also useful in diagnosis of P. falciparum infections.

Answer 333

P. vivax is widely distributed from tropical to temperate zones, but P. falciparum occurs primarily in the tropics and subtropics. Splenic enlargement is common in apparently healthy individuals with repeated infections and is often used to estimate the prevalence of malaria in populations in endemic areas. The widespread and lethal nature of malaria has apparently selected for traits that protect against plasmodia but are otherwise undesirable, including sickle cell anemia, the thalassemias and glucose-6- phosphate dehydrogenase deficiency. The parasites do not appear to thrive in the hemoglobin S associated with sickle cell disease, nor in certain other abnormal hemoglobins. In thalassemia, there is increased production of fetal hemoglobin, which retards maturation of P. falciparum, while in G6PD deficiency oxidative stress may inhibit parasite growth. HLA-B53, which is associated with recovery from falciparum malaria, is very common in West Africa. Prevention by minimizing mosquito contact is used in endemic areas. The efforts at mosquito control and malaria eradication during the 1950’s and 1960’s by using DDT and drugs were eventually frustrated by the concurrent appearance of DDT-resistant mosquitoes, cessation of DDT use due to its environmental effects, and development of drug resistant plasmodia. An array of drugs is used for prophylaxis and treatment of malaria. Extensive efforts are underway to develop effective vaccines against the various forms of malaria.

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