Presentation on theme: "Ngoc-Yen Nguyen, PharmD February, 2014"— Presentation transcript:
1 Ngoc-Yen Nguyen, PharmD February, 2014 Pharmacologic management of viral and fungal infections in the immunocompromised hostNgoc-Yen Nguyen, PharmDFebruary, 2014
2 ObjectivesReview risks for viral and fungal infections in the immunocompromised hostIdentify pharmacologic treatments for viral and fungal infectionsApply appropriate therapeutic agents to specific patient scenarios
5 Types of invasive fungal infections YeastsCandida spp.Fourth most common nosocomial bloodstream infection in the U.S.Most common invasive fungal infection in critically-ill nonneutropenic patientsPortals of entryGastrointestinal tractIntravascular cathetersTypes of Candida spp.Candida albicans- most commonCandida non-albicansCandida glabrata – most common non-albicans Candida spp. associated with bloodstream infectionCandida krusei – more frequent cause of fungemia in patients with hematologic malignancyCryptococcus neoformansOnly pathogenic species in the genus CryptococcusSource – contaminated soil with pigeon droppingsPortal of entry – Inhalation of yeasts
6 Types of invasive fungal infections Aspergillus spp.Ubiquitous environmental mold with airborne sporesMost common cause of invasive mycotic infections in the severely immunocompromised populationCommon species: A. fumigatus, A. flavus, A. terreusFrequent sites of infectionLungsCentral nervous systemSinusesOther difficult to treat organismsFusarium spp.Second most frequent cause of invasive mycotic infections in the severely immunocompromised populationFound in the soil known to cause localized skin infections in immunocompetent personsCommon species: F. solani; F. oxysporum; F. moniliformeMucor spp.Found in soil, plants, and decaying fruitsCommon species: M. amphibiorum; M. circinelloides; M. indicus
8 Diagnosis Blood culture Biopsy Fungitell assay detects (1-3)--D-glucan in the diagnosis of invasive fungal infection, (1,3)- ß-D- glucan is sloughed from the cell walls during the life cycle of most pathogenic fungiassay detects the following pathogens: Candida spp., Aspergillus spp., Coccidioides immitis, Fusarium spp., Histoplasma capsulatum, Saccharomyces cerevisiae, and Pneumocystis jiroveci.does not detect Cryptococcus, Zygomycetes, such as Mucor, and Rhizopus, nor Blastomyces dermatitidisAspergillus Galactomannan EIAassay uses EBA-2 monoclonal antibodies to detect Aspergillus galactomannan, in the diagnosis of invasive Aspergillosisconcomitant use of mold-active, anti fungal therapy in some patients with invasive Aspergillosis may result in reduced sensitivity of this assaypositive galactomannan test has result in patients receiving pip/tazo
11 PolyenesMOA: binds to the ergosterol component of the fungal cell membrane and cause the fungus to leak electrolytes and dieMainstay of therapy for certain invasive systemic fungal infectionsUse is limited by the risks for nephrotoxicity and hypokalemia – but SE may be improved with newer dosage formsAgentsAmphotericin B deoxycholate (conventional)Amphotericin B colloidal dispersionAmphotericin B lipid complexAmphotericin B liposomalControlled comparative trials of original form to the newer formulations are lackingNote different dosing with different productsPremedication may help prevent/decrease infusion related rxnswith combination of acetaminophen, diphenhydramine, +/- hydrocortisone and +/- meperidineABLC - As a modification of dimyristoyl phosphatidylcholine:dimyristoyl phosphatidylglycerol 7:3 (DMPC:DMPG) liposome, amphotericin B lipid-complex has a higher drug to lipid ratio and the concentration of amphotericin B is 33 M. ABLC is a ribbon-like structure, not a liposome.Ambisome - Amphotericin B (liposomal) is a true single bilayer liposomal drug delivery system. Liposomes are closed, spherical vesicles created by mixing specific proportions of amphophilic substances such as phospholipids and cholesterol so that they arrange themselves into multiple concentric bilayer membranes when hydrated in aqueous solutions. Single bilayer liposomes are then formed by microemulsification of multilamellar vesicles using a homogenizer. Amphotericin B (liposomal) consists of these unilamellar bilayer liposomes with amphotericin B intercalated within the membrane. Due to the nature and quantity of amphophilic substances used, and the lipophilic moiety in the amphotericin B molecule, the drug is an integral part of the overall structure of the amphotericin B liposomal liposomes. Amphotericin B (liposomal) contains true liposomes that are <100 nm in diameter.Controlled comparative trials of original form to the newer formulations are lacking Thus, comparative data discussing differences among the formulations should be interpreted cautiously
12 The TriazolesMOA: inhibition of cytochrome P-450-dependent ergosterol synthesis and inhibition of cell membrane formation. These agents are metabolized by the CyP450 system and may affect/may be affected by drugs that are dependent on this systemAgentsFluconazoleItraconazoleVoriconazolePosaconazole
13 FluconazolePlace in therapy: Most often used as prophylaxis or treatment agent against C. albicansMost frequently seen adverse effect is elevation of LFTs (particularly hepatic transaminases)80% of drug is renally eliminated – thus dosage adjustments may be needed in renal insufficiencySubstrate and inhibitor of CYP450 - beware of drug interactionsDosage forms: oral and intravenousInhibits CYP1A2 (weak), CYP2C19 (strong), CYP2C9 (moderate), CYP3A4 (moderate)
14 ItraconazoleHas broad spectrum of activity including Aspergillus, Blastomyces, Candida, Coccidioides, Cryptococcus, Histoplasma capsulatum, and Sporotrichosis speciesSubstrate and inhibitor of CPY3A4 – high risk for significant drug interactionsSide effectsIncreased LFTsCase of new or exacerbation of heart failure has been reportedUse with caution in renal impairment due to wide variations in plasma concentrationsAvailable as oral capsule, tablet, and solutionCapsule and oral solution formulations are not bioequivalentCapsule and tablet absorption is best if taken with foodSolution should be taken on an empty stomachSubstrate of CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP3A4 (strong), P-glycoproteinHas negative inotropic propertiesThe benefit:risk for therapy in the treatment of other types of fungal infections should be carefully considered in each patient, particularly those with HF and in heart transplant recipients. If indicated after cardiac, renal, or liver transplantation, itraconazole can increase cyclosporine levels by up to 50% at high doses. It also increases serum levels of lovastatin and simvastatin by up to 20-fold, as well as other HMG-CoA reductase inhibitors (except fluvastatin and rosuvastatin), by inhibiting CYP3A4. This is important since many post-transplantation patients are also hyperlipidemic and on HMG-CoA reductase inhibitors. Itraconazole may also increase levels of digoxin, disopyramide, dofetilide, and quinidine. The simultaneous administration of these medications may increase the risk of cardiotoxicity. Edema has been reported in patients concurrently receiving itraconazole and calcium channel blockers (CCBs). CCBs may cause additive negative inotropic effects when used concurrently with itraconazole. Use caution with concurrent use of itraconazole and CCBs due to an increased risk of HF. Concurrent use of itraconazole and dofetilide, nisoldipine and quinidine is contraindicated.
15 Voriconazole Place in therapy Dosing considerations Side effects Drug of choice for invasive aspergillosisUsed in treatment of infections caused by Scedosporium apiospermum and Fusarium spp in patients intolerant of, or refractory to other therapyMore active than fluconazole against Candida sp and has more activity than amphotericin B, except C. glabrataDosing considerationsOptimal doses in children is not well established – may require higher dosages than adults to achieve comparable serum levels; may need to monitor drug levelDecrease dose by 50% in patients with mild to moderate hepatic dysfunction per Child- Pugh ScoreFor CrCl < 50 ml/minute, consider changing IV to oral, as the accumulation of IV formulation vehicle(SBECD) occursSide effectsVisual changes reported in 30% of patients in clinical trialsIncrease in liver function enzymes (AST, ALT, Alk Phos)Substrate and inhibitor of CYP450 - beware of drug interactionsDosage forms: oral and intravenousVisual changes such as blurred vision, photophobia, changes in visual acuity and color have been reported in 30% of patients in clinical trials.sulfobutylether-β-cyclodextrinSubstrate of CYP2C19 (major), CYP2C9 (major), CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP2C19 (moderate), CYP2C9 (moderate), CYP3A4 (strong
16 Posaconazole Place in therapy PK studies in pediatric is limited Prophylaxis of invasive Aspergillus and Candida infections in severely- immunocompromised patientsTreatment of oropharyngeal candidiasis (including patients refractory to itraconazole and/or fluconazole)Excellent activity against both yeast and mould infections, specifically against zygomycosis in which voriconazole has no efficacyPK studies in pediatric is limitedInhibitor of CYP3A4 – beware of drug interactionDosage forms:Available as an oral suspension onlyBioavailability increased approximately 3-4 times when administered with a meal or an oral liquid nutritional supplement.Prophylaxis of invasive Aspergillus and Candida infections in severely-immunocompromised patients [eg, hematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD) or those with prolonged neutropenia secondary to chemotherapy for hematologic malignancies]
17 EchinochandinsMOA: block the synthesis of 1-3-D-glucan, a critical component of the fungal cell wallAvailable as intravenous preparations onlyAgentsFDA indicationsPK considerationsDrug interactionsCaspofunginInvasive candidiasis; salvage therapy for aspergillosis; neutropenic fever; oroesophageal candidiasisUndergo hepatic metabolismMay require dose adjustmentin moderate to severe hepaticdysfunctionDose adjustment not needed inrenal impairmentReduces tacrolimus AUCby 20%Rifampin, phenytoin,nevirapine, etc. caspotrough by 30%MicafunginInvasive candidiasis; prophylaxis in HSCT; oroesophageal candidiasisMay bloodconcentration of drugsmetabolized byCYP450AnidulafunginInvasive candidiasis; oroesophageal candidiasisUndergo slow nonhepatic,chemical degradation
18 FlucytosineConverted within the fungal cell to 5-fluorouracil, which inhibits thymidylate synthetase, thus inhibits DNA synthesisAdjunctive treatment IFI caused by susceptible strains of Candida or Cryptococcus, often synergistically with amphotericin BWidely distributed including to the CSFAdverse effectsNausea, vomiting , diarrhea, severe enterocolitisNeutropenia, thrombocytopenia, bone marrow aplasia– possibly irreversibleRenal and hepatic toxicitiesDosage form: capsuleFlucytosine appeared on the market in theearly 1970s, followed by the systemic azoles ketoconazolein 1980 and fluconazole and itraconazole in the early1990s.Antimetabolite - cytotoxic drugSystemic fungistaticFlucytosine is metabolized to fluorouracil which may cause adverse events if administered during pregnancy; refer to the fluorouracil monograph for additional information.
22 What is a virus? Very small infectious agent Some are smaller than ribosomeApprox 10x smaller than bacteriaConsist of nucleic acid (DNA or RNA)Surrounded by a protein coat, which is often surrounded by another protective envelopeLack membranes, a cytoplasm, & any means to produce energyRely on host cell to replicate, mutate and maintain genetic continuityViruses are quite different from cells. They contain only one type of nucleic acid, DNA or RNA, never both. They lack membranes and a cytoplasm, as well as ribosomes and any means to produce energy. Although viruses can replicate, mutate and maintain genetic continuity, they depend entirely upon a host cell to supply a habitat, energy and raw materials (precursors) for viral replication. Thus, viruses must exist as obligate intracellular parasites of cellsA.
24 Stages of virus replication Attachment and penetrationUncoating and releasing of viral genome into cellTranscription of the viral genomeAssembly of virion particlesStages of virus replication and possible targets for antiviral activityTranslation & modification of viral proteinsRelease of new viruses
25 Pathogenesis of Selected Virus Infections DiseaseCommon Site of ImplantationRoute of SpreadTarget Organ(s)Site of SheddingAIDSInjection, trauma, intestineBloodImmune system, brainBlood, semenChickenpoxRespiratory tractBlood, nerves (site of latency)Skin, lungsRepiratory tract, skinHepatitis AAlimentary TractLiverAlimentary tractHepatitis BPenetration of skinHSV1AcuteNerves, leukocytesMany (brain, liver, skin)Respiratory tract,epithelial surfacesRecurrentGanglionNerves (to site of latency)Skin, eyeSkin, eyesHSV2Genital tractMeaslesSkin, lungs, brainPoliomyelitisCNSRabiesSubcutaneously (bite)NervesBrainSalivary glandsRubellaSkin, lymph nodes, fetusRespiratory tract, excreted in newbornThis table list some viruses the sites of implantation, how they are spread, the organs they attack, and site of shedding
26 Virus effect on cells Lytic Infection Persistent Infection Causes destruction of host cellE.g. HSV, poxvirusesPersistent InfectionVirions are released continuouslyHost cell may not be lysed causes little adverse effectE.g. Lassa, retroviruses, rubellaLatent InfectionDelay between infection and appearance of symptomsE.g. fever blisters due to HSV-1Cellular TransformationChanges normal cell into a tumor cellE.g. HPV, EBVThere are several possible consequences to a cell that is infected by a virus, and ultimately this may determine the pathology of a disease caused by the virus. Lytic infections result in the destruction of the host cell. Lytic infections are caused by virulent viruses, which inherently bring about the death of the cells that they infect. Acute cytolytic infection, the most common form of virus-host cell interaction results in destruction of the infected cell. (e.g., herpesviruses, poxviruses, and paramyxoviruses)When enveloped viruses are formed by budding, the release of the viral particles may be slow and the host cell may not be lysed. Such infections may occur over relatively long periods of time and are thus referred to as persistent infections. Viruses may also cause latent infections. The effect of a latent infection is that there is a delay between the infection by the virus and the appearance of symptoms. Fever blisters (cold sores) caused by herpes simplex type 1 result from a latent infection; they appear sporadically as the virus emerges from latency, usually triggered by some sort of stress in the host. Some animal viruses have the potential to change a cell from a normal cell into a tumor cell, the hallmark of which is to grow without restraint. This process is called transformation. Viruses that are able to transform normal cells into tumor cells are referred to as oncogenic viruses .
28 Host factors Presence of target receptors on host cells Availability of enzymes essential for viral entry and replicationSpecific immunity against certain viral epitopesState of immunocompetence, i.e. ability of the immune system to control the viral replication effectivelyPresence of target receptors on host cellsAvailability of enzymes in host cells which are essential for viral entry and replicationState of immunocompetence of the individual hostSpecific immunity against certain viral epitopes in the individual host and target populationAbility of the immune system to control the viral replication effectively without causing serious collateral damage to the host by its inflammatory response
29 Defenses against infections Non-specificSpecificAnatomic barriersNonspecific inhibitorsPhagocytic cellsFeverInflammationInterferonHumoral immunityCellular immunityMost viral infections are limited by defenses that are antigen nonspecific and/or specific.Nonspecific defenses act sooner than specific defenses. Some are always in place (anatomic barriers, nonspecific inhibitors, and phagocytic cells); others are evoked by the infection (fever, inflammation, and interferon).Specific defenses include humoral and cellular immunity
30 Diagnosis Clinical symptoms Blood tests and cultures Blood may be tested for antibodies to viruses or for antigensPolymerase chain reaction (PCR)DiagnosisCommon viral infections may be diagnosed based on symptoms. For infections that occur in epidemics (such as influenza), the presence of other similar cases may help doctors identify a particular infection.For other infections, blood tests and cultures may be done. Blood may be tested for antibodies to viruses or for antigens (proteins on or in viruses that trigger the body's defenses).Polymerase chain reaction (PCR) techniques may be used to make many copies of the viral genetic material.
31 Treatment Antivirals interfere with replication of viruses Target only limited cellular metabolic functionsCause many toxic side effectsDevelopment of resistanceStrengthening the immune response of patientsInterferonsImmunoglobulinsVaccinesCompared to viruses, bacteria are relatively large organisms, commonly reproduce by independently outside of cells, and have many metabolic functions that antibacterial drugs (antibiotics) can target.In contrast, viruses are small and replicate inside host cells using the cells' own metabolic functions, there are only a limited number of metabolic functions that antiviral drugs can target. Therefore, antiviral drugs are much more difficult to develop than antibacterial agents. Many antiviral drugs work by interfering with replication of viruses. Other challenges in the treatment of viral infection include:toxic side effects of antivirals andthe development of viral resistance to antiviral drugs.Another strategy used is strengthening the immune response to the viral infection. Agents used include several types of interferons, immunoglobulins, and vaccines.Interferon drugs are replicas of naturally occurring substances that slow or stop viral replication.Immune globulin is a sterilized solution of antibodies (also called immunoglobulins) collected from a human donors.Vaccines are materials that help prevent infection by stimulating the body's natural defense mechanisms.Many immune globulins and vaccines are given before exposure to a virus to prevent infection. Some immune globulins and some vaccines, such as those for rabies and hepatitis B, are also used after exposure to the virus to help prevent infection from developing or reduce the severity of infection. Immune globulins may also help treat some established infections and also prevent infection after exposures to the virus.
32 Respiratory Syncytial Virus (RSV) Causes acute respiratory tract illness in all agesMost children are infected by 2nd year of ageSeasonal outbreaks between October – MayHighly contagiousPrevious infection does not protect against reinfectionTransmissionDirect contact with infected dropletsRSV can survive for several hours outside the bodyViral shedding ~ 3 – 8 days, up to 4 weeksIncubation ranges from 2 – 8 days
33 RSV: High Risk Groups Infants (< 12 months) 1 -2 % require hospitalizationMean age of infants hospitalized: 3 monthsDuration of illness: up to 12 days10% remain ill after 4 weeksFatal in < 1%Immunocompromised patientsElderlySolid organ transplantBone marrow transplant - Mortality of 70 to 100 %For most people, RSV produces only mild symptom, often very similar to the common cold. However, according to the CDC, it is the “most common cause of bronchiolitis and pneumonia among infants and children under 1 year of age. In these patients who develop brionchiolitis, leading to severe respiratory illness requiring hospitalization and rarely, causing death. This is more likely to occur in patients that are immunocompromised or infants born prematurely.It is associated with up to 120,000 pediatric hospitalizations each year, and is increasing in frequency.Data compiled by the Centers for Disease Control, RSV pneumonia has been blamed or an average of 2700 adult and pediatric deaths each year.
34 RSV: Clinical Presentation Usually self-limited processInfants and young children usually present with LRTIBronchiolitisBronchospasmPneumoniaAcute respiratory failureWheezingApnea - 20% of hospitalized infantsThe clinical manifestations vary depending upon the patient's age, health status, and whether the infection is primary or secondary.Infants and young children with primary infections usually present with LRTIApnea may be the presenting symptom in approximately 20 percent of infants hospitalized with RSV, and may be the cause of sudden unexpected death.
35 RSV: Clinical Presentation Older children and adults usually have upper respiratory tract symptomsCoughRhinorrheaConjunctivitisHigh risk groups may develop LRTIRSV pneumonia can lead to respiratory failureOlder children and adults typically have primarily upper respiratory tract symptoms, but may develop LRTI, particularly if they are elderly or immunocompromised.RSV pneumonia leading to respiratory failure can be a significant cause of acute morbidity and mortality in the immunocompromised host, with mortality rates of 70 to 100 percent being described in bone marrow transplant patientsLong-term pulmonary sequelae in these patients have not been adequately studied. However, chronic pulmonary dysfunction as a result of RSV infection does not appear to be a problem in lung or renal transplant patients, as indicated by the following observations:Lung transplant patients showed a return to baseline spirometry five months after RSV infection.Pediatric renal transplant patients showed a return to baseline pulmonary function three months after RSV infection.
36 RSV: Prevention exposure and the risk of acquiring RSV Avoidance of exposure to tobacco smokeRestricting participation in child care setting during RSV season for high- risk infantsHandwashing in all settingsImmunoprophylaxis with palivizumabHumanized monoclonal antibody against the RSV F glycoproteinIndicated for use inselected infants and children younger than 24 months with BPDpreterm birth (≤35 weeks)hemodynamically significant congenital heart diseaseDose scheduled monthly x 5 doseslower risk of hospitalizationfewer hospital days requiring oxygenfewer total hospital daysThe virus is spread through droplets when a person coughs or sneezes (breathing in the droplets.) The virus can also live on surfaces such as contertops or doorknobs, and on hands and clothing. It can be easily spread when a person touches a contaminated object or surface. (Hand to mouth.)Because RSV is highly contagious and can cause serious infections , preventive measure should be practice to minimize the impact, especially in high risk patients. Prevention is most important for infants with congenital heart or lung disease, bone marrow and lung transplant recipients, and the frail elderly with multiple underlying conditions.Patients/Families should be advised to avoid tobacco smoke, ….Immunoprophylaxis also should continue even if the infant experiences breakthrough infection . This is because high-risk infants may be hospitalized more than once during an RSV season and more than one strain of RSV may cocirculate in a community.Efficacy and effectiveness — The efficacy of palivizumab for preventing severe RSV infection in infants and children with prematurity, BPD, and congenital heart disease has been demonstrated in randomized controlled trials:In the IMpact-RSV Trial, 1502 patients with BPD and/or prematurity (<35 weeks) were randomly assigned to monthly treatment with palivizumab or placebo . Palivizumab was associated with significantly fewer RSV-associated hospitalizations (4.8 versus 10.6 percent with placebo, a 55 percent reduction).In another trial, 1287 children with hemodynamically significant congenital heart disease were randomly assigned to monthly treatment with palivizumab or placebo. Palivizumab was associated with fewer RSV-associated hospitalizations (5.3 versus 9.3 percent, a 45 percent reduction), fewer hospital days requiring oxygen (178 versus 658, a 73 percent reduction) and fewer total hospital days (367 versus 876, a 56 percent reduction). The mortality rates were similar in both groups (3.3 versus 4.3 percent). No deaths or adverse events were attributed to palivizumab.
37 RSV: Treatment Supportive therapy Ribavirin IH Racemic epinephrine BronchodilatorsOxygenRibavirin IHRoutine use is not recommendedMust be given within 48 hours of onset of symptomsRandomized controlled trials yielded mix resultsUncontrolled studies on combination with IVIG improved survival, ventilator days, & incidence of bronchiolitis obliteransAAP recommends that use of ribavirin be based on clinical circumstancesCHDLung diseaseBMT (Early use resulted in morbidity and mortality)Need for mechanical ventilationContraindication — pregnant womenAdverse effects — headache , conjunctivitis , dizziness, pharyngitis, lacrimation, bronchospasm and/or chest painThe routine use of nebulized ribavirin in infants and children with RSV LRTI is not recommended.efficacy of ribavirin in this population has not been clearly provenribavirin is expensivemust be given early in the course to be effectiveconcerns regarding occupational exposureRandomized controlled trials comparing ribavirin to placebo in children with RSV LRTI have yielded mixed results.Some studies have demonstrated decreased severity of illness, decreased duration of mechanical ventilation, oxygentherapy and hospital stay, and decreased viral sheddingOther studies have not demonstrated these benefitsstudies of children with RSV infection and LRTI found that trials of ribavirin lack sufficient powerThe efficacy of ribavirin for patients with solid-organ transplants is unknown.Contraindications — contraindicated in pregnant women. Ribavirin is a known teratogen in rodent species. However, it has not been shown to be teratogenic in primates, and no adverse effects have been found in the human fetus.Adverse effects — Adverse effects related to occupational exposure to ribavirin have not been reported. However, the National Institute of Occupational Safety and Health has published recommendations to reduce the ambient air concentrations of ribavirin and limit occupational exposure to hospital personnel.
38 Herpes Simplex Virus (HSV) Double stranded DNA virus with an envelopeInfects > 40 million Americans between 15 and 75 yrs oldSubtypesHSV-1: resides in trigeminal ganglionHSV-2: resides in sacral gangliaLife cycleEntry into the body replicates kills surface cells enters and remains dormant in the cell end-plates at skin surface (connected to internal nerve cells and eventually lead to a ganglion)(HSV) is a double-stranded DNA virus with an enveloped, icosahedral capsid.a common cause of infections of the skin and mucous membranes, manifesting itself as tiny, clear, fluid-filled blisters usually around the mouth or genitals. The virus infects more than 40 million Americans between the ages of 15 and 75, and in extreme cases, can appear in and about the eyes, esophagus, trachea, brain, and arms and legs Both types of herpes simplex virus (HSV), HSV-1 and HSV-2, can cause oral or genital infection. Most often, HSV-1 causes gingivostomatitis, herpes labialis, and herpes keratitis. HSV-2 usually causes genital lesions. Transmission of HSV occurs from close contact with an individual who is actively shedding virus. Viral shedding generally occurs from lesions but can occur even when lesions are not apparent.After the initial infection, HSV remains dormant in nerve ganglia from which it can periodically emerge, causing symptoms. Recurrent herpetic eruptions are precipitated by overexposure to sunlight, febrile illnesses, physical or emotional stress, immunosuppression, or unknown stimuli. Recurrent eruptions are generally less severe, and generally occur less frequently over time.
39 HSV: Clinical presentation Primary InfectionTransmitted from human-to-human contactManifests as tiny, clear, fluid filled blistersRecurrent Infection (occurs in %)Triggers: sunlight, fever, stress, immunosuppressionFrequency of occurrence variesLesions appear at same siteDiseases caused by HSVMucocutaneousHerpes keratitisCNSNeonatal herpesDisseminated infectionPrimary infection refers to the first time an individual is infected with any type of HSV. This primary event may or may not be accompanied by clinical symptoms and the individual may be unaware of the infection. The primary infection can be accompanied by blisters, ulcers, or red inflamed areas (lesions), which may occur at a variety of body sites including the eye and the internal and external areas of the mouth or genitals.Recurrent infection occur as often as every few weeks or as seldom as once a year, and they usually appear at the same site. Many factors can initiate a recurrence, such as sunlight, menstruation, wind, fever, suppression of immune system, emotional stress, and intense dental work. Importantly, the immune system can never fully eliminate the virus; however, people with immunocompetent systems can have less severe and less frequent outbreaks.Mucocutaneous infection is most common. Ocular infection (herpes keratitis), CNS infection, and neonatal herpes are unusual but more serious manifestations. HSV rarely causes fulminant hepatitis in the absence of cutaneous lesions. In patients with HIV infection, herpetic infections can be particularly severe. Progressive and persistent esophagitis, colitis, perianal ulcers, pneumonia, encephalitis, and meningitis may occur.HSV outbreaks may be followed by erythema multiforme possibly from an immune reaction to the virus. Eczema herpeticum is a complication of HSV infection in which patients have severe disease in skin regions with eczema.
40 Neonatal Herpes Occurs in 1/3000 to 1/20,000 births HSV-2 accounts for 80% of casesUsually transmitted during delivery15% transmissionS from another neonate or familySymptoms & signs appears in 1st and 2nd weekLocal or disseminated diseaseSkin vesicles in 55% of casesCNS disease in those with no skin vesiclesMore serious forms of disease will follow within 10 days if localized disease is left untreatedNeonatal herpes simplex virus (HSV) infection has high mortality and significant morbidity. Incidence estimates range from 1/3,000 to 1/20,000 births. HSV type 2 causes about 80% of cases; 20% are caused by HSV type 1.HSV is usually transmitted during delivery through an infected maternal genital tract. Transplacental transmission of virus and hospital-acquired spread from one neonate to another by hospital personnel or family may account for about 15% of cases. Mothers of neonates with HSV infection tend to have no history or symptoms of genital infection at the time of delivery.Symptoms and SignsManifestations generally occur between the 1st and 2nd wk of life but may not appear until as late as the 4th wk. Patients may present with local or disseminated disease. Skin vesicles are common in either form, occurring in about 55% overall. Those with no skin vesicles usually present with localized CNS disease. In patients with isolated skin or mucosal disease, progressive or more serious forms of disease frequently follow within 7 to 10 days if left untreated.PrognosisThe mortality rate of untreated disseminated disease is 85%; among those with untreated local disease and encephalitis, it is about 50%. At least 95% of survivors have severe neurologic sequelae. Death is uncommon in those with local disease but without CNS or organ disease, except as the result of concomitant medical problems, but about 30% develop neurologic impairment, which may not manifest until 2 to 3 yr of age.
41 Neonatal Herpes: Prognosis Localized infection:Mortality: 50%30% develop neurologic impairment, which may not manifest until 2 to 3 yr of age.Desseminated infection:Mortality: 85%Most survivors are neurologically impaired92% if untreated86% if treatedPrognosisThe mortality rate of untreated disseminated disease is 85%; among those with untreated local disease and encephalitis, it is about 50%. At least 95% of survivors have severe neurologic sequelae. Death is uncommon in those with local disease but without CNS or organ disease, except as the result of concomitant medical problems, but about 30% develop neurologic impairment, which may not manifest until 2 to 3 yr of age.Mortality without treatment is >80%, with treatment 57% (9), all but a few survivors impaired (abnormal neurologic status at one year 92% in untreated patients and 86% in treated patients with disseminated disease).
42 Immunocompromised Host Incidence of reactivation60 – 80% in solid organ tranplants> 80% after bone marrow transplantCan be local or disseminatedLesions at multiple sitesLesions may take 3 -5 weeks to healLonger viral shedding periodPatients whose immune responses are suppressed, immunocompromised, frequently suffer from recurrent HSV infections that are much more painful than infections in immunocompetent patients. The recurrences are mostly caused by reactivation of a latent infection that was acquired prior to the period of immunosuppression. The reactivated infections usually have lesions that may take 3-5 weeks to heal, a longer period of viral shedding, and are more likely to cause lesions at multiple sites compared to lesions in an immunocompetent host (Pielop et al., 2000). In addition, recurrent infections can result in local or systemic infection, dehydration, and nutritional deficiencies secondary to oral and esophageal lesions. If left untreated, HSV infections can cause severe morbidity and mortality because it is an opportunistic infection in immunocompromised patients. The reactivation rate of HSV among seropositive transplant patients is between 60 and 80% for patients with solid organ transplants and over 80% after bone marrow transplants.
43 HSV: Treatment Acyclovir First line agent for HSV infection MOA Binds to HSV DNA polymerase, incorporated into viral DNA, and prevents further elongation of the chainConverted to the active monophosphate form by herpesvirus thymidine kinaseResistance is observed in virus strains that are deficient in thymidine kinaseAdverse effectsNephrotoxicity - most significantMaintaining good hydration helps incidence
44 HSV: Treatment (cont.) Acyclovir (cont.) Ganciclovir Foscarnet Oral acyclovir - 10 – 20% bioavailableValacyclovir - 50% bioavailable; pediatric dosing not well studiedGanciclovirStructurally similar to acyclovir active against HSVCross-resistance occurs with acyclovirFoscarnetSecond line agent, when acyclovir resistance is suspectedDoes not require thymidine kinase for drug activation
45 Cytomegalovirus (CMV) Member of herpesvirus familyInfects 50-80% of adults by 40 years oldPrimary infectionUsually causes few symptomsFew long-term health consequencesSome develop a mononucleosis-like syndrome with prolonged fever and a mild hepatitisOnce infected, virus usually remain dormant for lifeRecurrence rarely occurs in a healthy personCytomegalovirus, or CMV, is found throughout all geographic locations and socioeconomic groups and infects between 50% and 80% of adults in the United States by 40 years of age.In the United States, CMV is also the virus most frequently transmitted to a developing child before birth.For most healthy persons who acquire CMV after birth, there are few symptoms and no long-term health consequences.Some persons with symptoms experience a mononucleosis-like syndrome with prolonged fever and a mild hepatitis.Once a person becomes infected, the virus remains alive, but usually dormant, within that person's body for life.Recurrent disease rarely occurs unless the person's immune system is suppressed due to therapeutic drugs or disease. Therefore, for the vast majority of people, CMV infection is not a serious problem.
46 CMV (cont.) Transmission Prevention Person-to-person contact In householdsIn day care centersVia saliva, urine, body fluid, breastmilk, transplanted organs, blood transfusionsPreventionHandwashingPregnant women to avoid direct contact with young childrenTransmission and PreventionTransmission of CMV occurs from person to person. Infection requires close contact with a person excreting the virus in their saliva, urine, or other body fluids. CMV can be sexually transmitted and can also be transmitted via breast milk, transplanted organs, and occasionally from blood transfusions.Although the virus is not highly contagious, it has been shown to spread in households and among young children in day care centers. Transmission of the virus is often preventable because it is often transmitted through infected body fluids that come in contact with hands and then are absorbed through the nose or mouth of a susceptible person. Therefore, care should be taken when interacting with children and handling items like diapers. Simple hand washing with soap and water is effective in removing the virus from the hands. Pregnant women should also be counseled to avoid direct contact with the saliva of young children through behaviors such as kissing on the lips.CMV infection without symptoms is common in infants and young children; therefore, it is unjustified and unnecessary to exclude from school or an institution a child known to be infected. Similarly, hospitalized patients do not need separate or elaborate isolation precautions.General screening of children and patients for CMV is of questionable value. The cost and management of such procedures are impractical. Children known to have CMV infection should not be singled out for exclusion, isolation, or special handling. Instead, staff education and effective hygiene practices are advised in caring for all children.
47 CMV: High-risk groups Unborn baby during pregnancy Highest risk occurs in women with primary infection during pregnancy1/3 of infants will be infected10 -15% of infected infants will have symptomsSymptoms range from enlargement of liver and spleen to fatal illness80 to 90% will have hearing loss, vision impairment, and varying degrees of mental retardation5 to 10% of asymptomatic infants will have varying degrees of hearing and mental or coordination problemsHowever, CMV infection is important to certain high-risk groups. Major areas of concern are (1) the risk of infection to the unborn baby during pregnancy, (2) the risk of infection to people who work with children, and (3) the risk of infection to the immunocompromised person, such as organ and bone marrow transplant recipients and persons infected with human immunodeficiency virus (HIV).PregnancyThe incidence of primary (or first) CMV infection in pregnant women in the United States varies from 1% to 4%. Healthy pregnant women are not at special risk for disease from CMV infection. When infected with CMV, most women have no symptoms and very few have a disease resembling mononucleosis. It is their developing unborn babies that may be at risk for congenital CMV disease. CMV remains the most important cause of congenital viral infection in the United States. For infants who are infected by their mothers before birth, two potential problems exist:Generalized infection may occur in the infant, and symptoms may range from moderate enlargement of the liver and spleen (with jaundice) to fatal illness. With supportive treatment most infants with symptomatic CMV disease usually survive. However, from 80% to 90% will have complications within the first few years of life that may include hearing loss, vision impairment, and varying degrees of mental retardation.Another 5% to 10% of infants who are infected but without symptoms at birth will subsequently have varying degrees of hearing and mental or coordination problems.These risks are highest among women who previously have not been infected with CMV and who are having their first infection with the virus during pregnancy. Even in this case, two-thirds of the infants will not become infected, and only 10% to 15% of the remaining third will have symptoms at the time of birth.Recs for pregnant women:practice good personal hygiene, especially handwashing with soap and water, after contact with diapers or oral secretions (particularly with a child who is in day care).Avoid direct contact with the saliva of young children through behaviors such as kissing on the lips, sharing food, drinks, or utensils.Women who develop a mononucleosis-like illness during pregnancy should be evaluated for CMV infection and counseled about the possible risks to the unborn child.
48 CMV: High-risk groups (cont.) People who work with childrenCMV is commonly transmitted among young children and to child care providersPrevent transmission by practice handwashing and reduce personal contactImmunocompromised personTransplant patients, patients receiving immunosuppressive drugs, & HIV patientsPneumonia, retinitis, & GI illness are common presentationsAvoid CMV+ blood productsPeople Who Work with Infants and ChildrenMost healthy people working with infants and children face no special risk from CMV infection. However, for women of child-bearing age who previously have not been infected with CMV, there is a potential risk to the developing unborn child (the risk is described above in the Pregnancy section). Contact with children who are in day care, where CMV infection is commonly transmitted among young children (particularly toddlers), may be a source of exposure to CMV.Since CMV is transmitted through contact with infected body fluids, including urine and saliva, child care providers(meaning day care workers, special education teachers, therapists, as well as mothers) should be educated aboutthe risks of CMV infection and the precautions they can take. Day care workers appear to be at a greater risk than hospital and other health care providers, and this may be due in part to the increased emphasis on personal hygiene and the lower amount of personal contact in the health care setting.Recommendations for individuals providing care for infants and children include the following:Female employees should be educated concerning CMV, its transmission, and hygienic practices, such as hand washing, which minimize the risk of infection.Immunocompromised PatientsPrimary CMV infection in the immunocompromised patient can cause serious disease. However, the more common problem is the reactivation of the dormant virus. Infection with CMV is a major cause of disease and death in immunocompromised patients, including organ transplant recipients, patients undergoing hemodialysis, patients with cancer, patients receiving immunosuppressive drugs, and HIV-infected patients.Pneumonia, retinitis (an infection of the eyes), and gastrointestinal disease are the common manifestations of disease. Because of this risk, exposing immunosuppressed patients to outside sources of CMV should be minimized.Whenever possible, patients without CMV infection should be given organs and/or blood products that are free of the virus.
49 CMV: Treatment Ganciclovir Used primarily for CMV; active against herpes virusesMOA:An inhibitor and substrate for CMV DNA polymerase inhibits DNA synthesis and prevents DNA elongationRequires thymidine kinase in CMV-infected cell to phosphorylate drug to triphosphate (active) form ganciclovir phosphorylation indicator of CMV resistanceCan be used in combination with foscarnet for synergistic activity dose when combining therapy to toxicityAdverse effectsMyelosuppressionNephrotoxicity - much less than acyclovir or foscarnetHandling of this agent requires chemotherapy precautionsMOA:An inhibitor and substrate for CMV DNA polymerase inhibits DNA synthesis and end DNA elongationRequires thymidine kinase in CMV-infected cell to phosphorylate the drug to triphosphate form (active) ganciclovir phosphorylation CMV resistance
50 CMV: Treatment Foscarnet Used for prophylaxis and treatment of CMV infectionSecond line agent for HSV refractory to acyclovirMOA:Inhibits viral RNA and DNA polymerases inhibits pyrophosphate exchange prevents elongation of DNA chainDoes not require activation by thymidine kinase; active against HSV strains that are deficient in thymidine kinaseSpectrum of activityHSV-1; HSV-2CytomegalovirusVaricella zoster virusEpstein-Barr virusInfluenza virus (A Victoria and B Hong Kong strains)MOA: Foscarnet is a pyrophosphate analogue which acts as a noncompetitive inhibitor of many viral RNA and DNA polymerases as well as HIV reverse transcriptase. Inhibitory effects occur at concentrations which do not affect host cellular DNA polymerases; however, some human cell growth suppression has been observed with high concentrations in vitro. Inhibition of DNA polymerase results in inhibition of pyrophosphate exchange which prevents elongation of the DNA chain.Because foscarnet does not require activation by thymidine kinase, it is active in vitro against herpes simplex virus mutant strains that are deficient in thymidine kinase
51 CMV: Treatment Foscarnet (cont.) Adverse effects Renally eliminated – adjust dose for impaired renal functionConsider combination tx with ganciclovir to toxicitiesAdverse effectsNephrotoxicityElectrolyte abnormalitiesHypokalemiaHypocalcemiaHyperphosphatemia OR hypophosphatemiaHypomagnesemiaNeurotoxicity (seizures with rapid infusion)
52 CMV: Treatment CMV-IVIG A preparation of IgG of pooled healthy blood donors with a high titer of CMV antibodiesProvides a passive source of antibodies against CMVProphylaxis in solid organ transplantUse in combination with antivirals for treatment of CMV pneumoniaDosing and length of therapy not well studiedProphylaxis for organ transplant: maximum total dosage for infusion is 150 mg/kg; administer according to the following schedule:Within 72 hours of transplant: 150 mg/kg2, 4, 6, and 8 weeks post-transplant: mg/kg12 and 16 weeks post-transplant: mg/kgSevere CMV pneumonia: Various regimens have been used, including 400 mg/kg CMV-IGIV in combination with ganciclovir on days 1, 2, 7, or 8, followed by 200 mg/kg CMV-IGIV on days 14 and 21.improved total survival, reduced CMV disease, and CMV-associated deaths
53 Adenovirus Non-enveloped, double-stranded DNA virus Consists of 51 distinct pathogenic typesSome serotypes are endemic to specific parts of the worldSome are usually acquired during childhoodSome cause sporadic outbreaksTransmissionDirect contact with respiratory dropletFecal-oralWaterborne
54 Adenovirus Clinical manifestations High risk groups Respiratory illness (most common )GastroenteritisConjunctivitisHemorrhagic cystitisHepatitisHigh risk groupsImmunocompromised patients (viral reactivation)Occurs in 5 -29% of BMT patientsDeaths occur in %Acute respiratory disease can be precipitated by overcrowding and stress
55 Adenovirus: Treatment Treat symptoms and complications of infectionCidofovirFDA-approved indication: CMV retinitis in AIDS patientsMOAInhibits viral DNA polymeraseDoes not depend on virus-specific thymidine kinaseSpectrum of activityHerpesvirus (HSV-1, HSV-2)CytomegalovirusBK virusAdenovirus
57 Antivirals Drug Target Virus Adverse Effects Other considerations AcyclovirHSVNephrotoxicity (require dosing adjustment in renal dysfunction)1st line agent for HSV.Must be well hydrated . Valacyclovir more bioavailable than oral acyclovir.GanciclovirHSV, CMVMyelosuppression, nephrotoxicty (< acyclovir & foscarnet)1st line agent for CMV.May use in combination with foscarnet for synergistic activity.FoscarnetHSV,CMVRenal toxicity (require dosing adjustment in renal dysfunction)Electrolyte abnormalities(K, Ca, P, Mag)Does not require thymidine kinase for activation; thus, can be used in cases of acyclovir and ganciclovir. Must be well hydrated.CidofovirHSV,CMV, adenovirusNephrotoxicity (SrCr, proteinuria, & renal tubular acidosis), granulocytopeniaIs an option when ganciclovir and foscarnet fail.Must be administered with appropriate hydration and probenecid.RibavirinBroad coverageRSV, HSV, adenovirusFDA Pregnancy Category: Category X. IH form causes headaches & conjunctivitis. IV form causes hemolytic anemia, reticulocytosis, seizures and dizzinessIV preparation available via compassionate use protocol - requires prior FDA and IRB approval.
58 ConclusionsA mature, intact immune system is the best defense against fungal viral infectionsImmunocompromised patients are most at risk for morbidity and mortalityPremature neonatesElderlyImmunosuppressed patients (HIV, SCID, transplant)Avoidance is perhaps the best prevention against infectionEarly recognition and implementation of appropriate therapy are vital to improved outcome
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