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7,801 | antibody levels inhibiting HA activity can usually be detected by the second week after infection. These antibodies are also generated by vaccines, and high HA inhibition antibody titers correlate with protection. CLINICAL MANIFESTATIONS The onset of influenza illness is often abrupt, with a predominance of systemic symptoms, including fever, myalgias, chills, headache, mal aise, and anorexia. Coryza, pharyngitis, and dry cough are also usually present at the onset of illness but may be less prominent than systemic symptoms. Respiratory manifestations can include isolated upper respiratory tract illness, including croup, or progression to lower tract disease, such as bronchiolitis or pneumonia. More than other respira tory viruses, influenza virus typically causes systemic manifestations such as high temperature, myalgia, malaise, and headache. Less com mon clinical manifestations can include parotitis and rash. Abdominal pain, vomiting, and diarrhea may also occur in children; in some studies, diarrhea was reported to be more often associated with influenza A(H1N1)pdm09 compared with influenza A(H3N2) or influenza B viruses. Influenza is a less distinct illness in younger children and infants. The infected young infant or child may be highly febrile and toxic in appearance, prompting a full diagnostic workup. The typical duration of the febrile illness is 2 4 days. Cough may persist for longer periods, and evidence of small airway dysfunction is often found weeks later. Owing to the high transmissibility of influenza, other family members or close contacts of an infected person often experience a similar illness. COMPLICATIONS Otitis media and pneumonia are common complications of influenza in young children. Acute otitis media may be seen in up to 25 of cases of documented influenza. Pneumonia accompanying influenza may be a primary viral process or a secondary bacterial infection (such as with Staphylococcus aureus) facilitated through damaged respiratory epithe lium. Influenza may cause acute myositis or rhabdomyolysis marked by muscle weakness and pain, particularly in the calf muscles, and myo globinuria. Other extrapulmonary complications include acute renal failure, myocarditis, and sepsis. Central nervous system complications, such as encephalitis, myelitis, and Guillain Barr syndrome, can occur and are seen more commonly in children than adults. Although it has essentially disappeared in the United States, Reye syndrome can result with the use of salicylates during influenza infection (see Chapter 409). Bacterial coinfection may also exacerbate respiratory complications of influenza and lead to sepsis, bacteremia, toxic shock syndrome, and other manifestations. Influenza is particularly severe in some children, including those with underlying cardiopulmonary disease, including congenital and acquired valvular disease, cardiomyopathy, bronchopulmonary dys plasia, asthma, cystic fibrosis, and neurologic conditions. Pregnant women and adolescent females are also at high risk for severe influenza. Children receiving cancer chemotherapy and children with immuno deficiency also have a higher risk of complications and may shed virus for longer periods than immunocompetent children. LABORATORY FINDINGS The clinical laboratory abnormalities associated with influenza are nonspecific. Chest radiographs may show evidence of atelectasis or infiltrate. DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS The diagnosis of influenza depends on epidemiologic, clinical, and laboratory considerations. In the context of |
7,802 | an epidemic, the clinical diagnosis of influenza in a child who has fever, malaise, and respiratory symptoms may be made based on clinical discretion; however, clini cal presentation is often indistinguishable from infection with other respiratory viruses, including SARS CoV 2, respiratory syncytial virus, parainfluenza virus, human metapneumovirus, adenovirus, and even rhinovirus. Confirmation of influenza virus infection by diagnostic testing might be helpful in certain circumstances when other viruses are co circulating, but it is not required for clinical decisions to pre scribe antiviral medications, and prompt suspicion or diagnosis of influenza may allow for early antiviral therapy to be initiated and may reduce inappropriate use of antibiotics. A number of diagnostic tests may be used for laboratory confir mation of influenza (Table 305.2). Although rapid influenza diagnos tic tests based on antigen detection are often employed because of their ease of use and fast results, they can have suboptimal sensitivity to detect influenza virus infection, particularly for novel influenza viruses. Sensitivities of rapid antigen diagnostic tests are generally 5070 compared to viral culture or reverse transcription poly merase chain reaction (RT PCR). Specificities are higher, approxi mately 95100. Therefore false negative results occur more often than false positive results, particularly when the prevalence of influ enza is high (i.e., during peak influenza activity in the community). The interpretation of negative results should consider the clinical characteristics and the patients risk for complications. If there is clin ical suspicion for influenza in a patient at high risk for complications (Table 305.3), early empirical treatment should be given regardless of a negative rapid antigen diagnostic test result, and another type of test may be performed for confirmation. RT PCR or other rapid molecular assays are now preferred for influenza diagnosis in both outpatients and hospitalized patients. TREATMENT Antiviral medications are an important adjunct to influenza vacci nation. Three classes of antiviral drugs are licensed for treatment of influenza in children. The neuraminidase inhibitors (NAIs), oral osel tamivir and inhaled zanamivir, may be used for treatment of children from birth and 7 years, respectively (Table 305.4). In December 2012, the U.S. Food and Drug Administration (FDA) approved the use of oseltamivir for the treatment of influenza in infants as young as 2 wk of age, and the Centers for Disease Control and Prevention (CDC), the American Academy of Pediatrics, and the Infectious Diseases Society of America recommend its use in infants of any age. A third NAI, pera mivir, is given as an intravenous infusion and is approved for treatment in persons 2 years of age and older. The second class of drugs is represented by a new orally administered influenza antiviral called baloxavir marboxil, which was approved by the FDA in October 2018. Baloxavir is active against both influenza A and B viruses and is a cap dependent endonuclease inhibitor that interferes with viral RNA transcription and blocks virus replication. It is approved for treatment of acute uncomplicated influenza in people 12 years and older. The third class of drugs is |
7,803 | the adamantanes, including oral amanta dine and oral rimantadine, which are effective only against influenza A viruses. Genetic variants have conferred widespread adamantane resistance among circulating influenza A viruses, including seasonal influenza viruses and many H5N1 and H7N9 avian influenza viruses; therefore this class of antivirals is not currently recommended for use. When initiated early in the course of uncomplicated influenza ill ness, antiviral agents can reduce the duration of symptoms and the likelihood of complications. Among hospitalized patients, observa tional studies suggest that early treatment reduces disease severity and mortality. Although most data regarding potential benefit are for adults, a few studies support the use of antiviral agents in children. Antiviral treatment within 2 days of illness onset has been reported to reduce illness duration, the risk of otitis media, and the likelihood of hospitalization in children. Clinical benefit is greatest when antiviral Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 305 u Influenza Viruses 2023 treatment is administered early, especially within 48 hours of influenza illness onset. The CDC recommends treatment as early as possible for (1) hospitalized patients, (2) patients with severe, complicated, or pro gressive illness, and (3) patients at high risk for influenza complica tions (see Table 305.3). Decisions about starting antiviral treatment should not wait for laboratory confirmation of influenza. Although early treatment is desired, treatment more than 48 hours from onset may be beneficial and is recommended for these three categories of patients. The recommended treatment course for uncomplicated influenza is twice daily oral oseltamivir for 5 days, twice daily inhaled zanamivir for 5 days, or a single dose of intravenous peramivir or oral baloxavir. Cur rently, for hospitalized patients and patients with severe or complicated illness, treatment with oral or enterically administered oseltamivir is recommended. The optimal duration and dose are uncertain for severe or complicated influenza, and longer courses of treatment (e.g., 10 days of treatment) may be considered. Clinical judgment considering a patients disease severity, age, underlying medical conditions, likelihood of influenza, and time since onset of symptoms is important when making antiviral treat ment decisions for outpatients at high risk for complications. Anti viral treatment can also be considered for any previously healthy, symptomatic outpatient not at high risk with confirmed or sus pected influenza, if treatment can be initiated within 48 hours of illness onset. Some influenza viruses may become resistant during antiviral treat ment, an occurrence that has been reported most often for oseltamivir resistance in influenza A(H1N1) viruses. Following treatment with baloxavir, emergence of viruses with molecular markers associated with reduced susceptibility to baloxavir has been observed in clinical trials. Antiviral resistance and reduced susceptibility can also occasion ally occur spontaneously with no known exposure to antiviral drugs. It is important to review annual recommendations and updates pub lished by CDC before prescribing influenza antiviral medications (see https:www.cdc.govfluprofessionalsantiviralsindex.htm). Table |
7,804 | 305.3 Children and Adolescents Who Are at Higher Risk for Influenza Complications for Whom Antiviral Treatment is Recommended Children younger than 2 yr of age Persons with chronic pulmonary (including asthma), cardiovascular (except hypertension alone), renal, hepatic, hematologic (including sickle cell disease), and metabolic disorders (including diabetes mellitus); or neurologic and neurodevelopmental conditions (including disorders of the brain, spinal cord, peripheral nerve, and muscle such as cerebral palsy, epilepsy seizure disorders, stroke, intellectual disability, moderate to severe developmental delay, muscular dystrophy, or spinal cord injury) Persons with immunosuppression, including that caused by medications or by HIV infection Adolescents who are pregnant, or postpartum (within 2 wk after delivery) Persons younger than 19 yr of age who are receiving long term aspirin or salicylate containing medications therapy IndigenousAlaska Natives Persons who are extremely obese (body mass index 40) Residents of long term care facilities Hospitalized patients at high risk for influenza complications Antiviral treatment is recommended for children at high risk with confirmed or suspected influenza; antivirals are also recommended for children who are hospitalized or have severe or progressive disease. Although all children younger than 5 yr of age are considered at higher risk for complications from influenza, the highest risk is for those younger than 2 yr of age, with the highest hospitalization and death rates among infants younger than 6 mo of age. Current for 20212022 influenza season. Adapted from Centers for Disease Control and Prevention (CDC): Influenza antiviral medications: summary for clinicians. https:www.cdc.govfluprofessionalsantivirals summary clinicians.htm; and from American Academy of Pediatrics Policy Statement: Recommendations for Prevention and Control of Influenza in Children, 2021 2022. For current details, consult annually updated recommendations at https:www.cdc.govflu professionalsindex.htm. Table 305.2 Influenza Virus Testing Methods METHOD ACCEPTABLE SPECIMENS TEST TIME COMMENTS Rapid influenza diagnostic tests (antigen detection) Nasopharyngeal (NP) swab, aspirate or wash, nasal swab, aspirate, or wash, throat swab 15 min Rapid turnaround; suboptimal sensitivity Rapid molecular assay (influenza nucleic acid amplification) NP swab, nasal swab 15 30 min Rapid turnaround; high sensitivity Immunofluorescence, direct (DFA) or indirect (IFA) fluorescent antibody staining (antigen detection) NP swab or wash, bronchial wash, nasal or endotracheal aspirate 1 4 hr Relatively rapid turnaround; requires laboratory expertise and experience RT PCR (singleplex and multiplex; real time and other RNA based) and other molecular assays (influenza nucleic acid amplification) NP swab, throat swab, NP or bronchial wash, nasal or endotracheal aspirate, sputum Varies by assay (generally 1 8 hr) Excellent sensitivity, relatively rapid turnaround compared with conventional methods Rapid cell culture (shell vials, cell mixtures; yields live virus) NP swab, throat swab, NP or bronchial wash, nasal or endotracheal aspirate, sputum 1 3 day Culture isolates important for strain information and antiviral resistance monitoring Viral tissue cell culture (conventional; yields live virus) NP swab, throat swab, NP or bronchial wash, nasal or endotracheal aspirate, sputum 3 10 day Not recommended for routine patient diagnosis Serologic tests (antibody detection) Paired (appropriately timed) acute and convalescent serum specimens NA (not performed during acute infection) Not recommended for routine |
7,805 | patient diagnosis; useful for research studies NA, Not applicable; RT PCR, reverse transcription polymerase chain reaction. Modified from Centers for Disease Control and Prevention (CDC): Influenza virus testing methods. Available at https:www.cdc.govfluprofessionalsdiagnosistable testing methods.htm in Information for Health Professionals (https:www.cdc.govfluprofessionalsindex.htm); and from 2018 IDSA Clinical Practice Guidelines. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 2024 Part XV u Infectious Diseases Table 305.4 Recommended Dosage and Schedule of Influenza Antiviral Medications for Treatment and Chemoprophylaxis in Children for the 20212022 Influenza Season: United States MEDICATION TREATMENT DOSING CHEMOPROPHYLAXIS DOSING ORAL OSELTAMIVIR Adults 75 mg twice daily 75 mg once daily Children 12 mo 15 kg (33 lb) 30 mg twice daily 30 mg once daily 15 23 kg (33 51 lb) 45 mg twice daily 45 mg once daily 23 40 kg (51 88 lb) 60 mg twice daily 60 mg once daily 40 kg (88 lb) 75 mg twice daily 75 mg once daily Infants 9 11 mo 3 mgkg per dose twice daily 3 mgkg per dose once daily Term infants ages 0 8 mo 3 mgkg per dose twice daily 3 mgkg per dose once daily for infants 3 8 mo old; not recommended for infants 3 mo old unless situation judged critical because of limited safety and efficacy data in this age group Preterm infants See details in footnote Not recommended INHALED ZANAMIVIR Adults 10 mg (two 5 mg inhalations) twice daily 10 mg (two 5 mg inhalations) once daily Children (7 yr old for treatment; 5 yr old for chemoprophylaxis) 10 mg (two 5 mg inhalations) twice daily 10 mg (two 5 mg inhalations) once daily INTRAVENOUS PERAMIVIR Adults 600 mg intravenous infusion once given over 15 30 min Not recommended Children (2 12 yr old) One 12 mgkg dose, up to 600 mg maximum, once via intravenous infusion for 15 30 min Not recommended Children (13 17 yr old) One 600 mg dose once via intravenous infusion for 15 30 min Not recommended ORAL BALOXAVIR Adults 40 to 80 kg One 40 mg dose One 40 mg dose 80 kg One 80 mg dose One 80 mg dose Children 2 11 yr Not recommended Not recommended 12 17 yr, 40 to 80 kg One 40 mg dose One 40 mg dose 12 17 yr, 80 kg One 80 mg dose One 80 mg dose Antiviral treatment duration for uncomplicated influenza is 5 days for oral oseltamivir or inhaled zanamivir, and a single dose for intravenous peramivir or oral baloxavir. Recommended postexposure chemoprophylaxis with oseltamivir or zanamivir in a nonoutbreak setting is 7 days after last known exposure. Oseltamivir is administered orally without regard to meals, although administration with meals may improve gastrointestinal tolerability. Oseltamivir is available as Tamiflu or as a generic formulation as capsules and as a powder for oral suspension that is reconstituted to provide a |
7,806 | final concentration of 6 mgmL. Approved by the FDA for children as young as 2 wk of age. Given preliminary pharmacokinetic data and limited safety data, oseltamivir can be used to treat influenza in both term and preterm infants from birth because benefits of therapy are likely to outweigh possible risks of treatment. CDC and U.S. Food and Drug Administration (FDA)approved dosing is 3 mgkg per dose twice daily for children age 9 11 mo; the American Academy of Pediatrics recommends 3.5 mgkg per dose twice daily. The dose of 3 mgkg provides oseltamivir exposure in children similar to that achieved by the approved dose of 75 mg orally twice daily for adults, as shown in two studies of oseltamivir pharmacokinetics in children. The AAP has recommended an oseltamivir treatment dose of 3.5 mgkg orally twice daily for infants 9 11 mo, on the basis of data that indicated that a higher dose of 3.5 mgkg was needed to achieve the protocol defined targeted exposure for this cohort as defined in the CASG 114 study. It is unknown whether this higher dose will improve efficacy or prevent the development of antiviral resistance. However, there is no evidence that the 3.5 mgkg dose is harmful or causes more adverse events to infants in this age group. Oseltamivir dosing for preterm infants. The weight based dosing recommendation for preterm infants is lower than for term infants. Preterm infants may have lower clearance of oseltamivir because of immature renal function, and doses recommended for term infants may lead to high drug concentrations in this age group. Limited data from the National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group provide the basis for dosing preterm infants by using their postmenstrual age (gestational age plus chronological age): 1 mgkg per dose orally twice daily for those 38 wk postmenstrual age; 1.5 mgkg per dose orally twice daily for those 38 40 wk postmenstrual age; and 3 mg kg per dose orally twice daily for those 40 wk postmenstrual age. For extremely preterm infants (28 wk), please consult a pediatric infectious diseases physician. Zanamivir is administered by inhalation by using a proprietary Diskhaler device distributed together with the medication. Zanamivir is a dry powder, not an aerosol, and should not be administered by using nebulizers, ventilators, or other devices typically used for administering medications in aerosolized solutions. Zanamivir is not recommended for people with chronic respiratory diseases, such as asthma or chronic obstructive pulmonary disease, which increase the risk of bronchospasm. Oral baloxavir marboxil is approved by the FDA for treatment of acute uncomplicated influenza within 2 days of illness onset in people 12 yr and older. The safety and efficacy of baloxavir for the treatment of influenza have been established in pediatric patients 12 yr and older weighing at least 40 kg. Safety and efficacy in patients 12 yr of age or weighing 40 kg have not been established. Baloxavir efficacy is based on clinical trials in outpatients 12 to 64 yr |
7,807 | of age; people with underlying medical conditions and adults 65 yr were not included in the initial published clinical trials (Hayden F et al; Clin Infect Dis 2018). There are no available data for baloxavir treatment of hospitalized patients with influenza. Adapted from Centers for Disease Control and Prevention (CDC): Influenza antiviral medications: summary for clinicians. https:www.cdc.govfluprofessionalsantiviralssummary clinicians.htm. For current details, consult annually updated recommendations at https:www.cdc.govfluprofessionalsindex.htm; 2018 IDSA Clinical Practice Guidelines; and from Kimberlin DW, Acosta EP, Prichard MN, et al. National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. Oseltamivir pharmacokinetics, dosing, and resistance among children aged 2 yr with influenza. J Infect Dis. 2013;207(5):709720. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 305 u Influenza Viruses 2025 SUPPORTIVE CARE Adequate fluid intake and rest are important in the management of influenza. Bacterial superinfections are relatively common and should be appropriately treated with antibiotic therapy. Bacterial superinfec tion should be suspected with recrudescence of fever, prolonged fever, or deterioration in clinical status. With uncomplicated influenza, people should usually start to feel better after the first 48 72 hours of symptoms. PROGNOSIS The prognosis for recovery from uncomplicated influenza is generally excellent, although full return to normal level of activity and freedom from cough may require weeks rather than days. Fatigue may also per sist for weeks. However, severe influenza disease can be associated with hospitalizations and death, even among previously healthy children. PREVENTION Influenza vaccination is the best means of preventing influenza ill ness. In studies of children who are fully vaccinated, influenza vac cine is 4060 effective in reducing the risk of laboratory confirmed influenza illness. Vaccine effectiveness can vary from year to year and among different age and risk groups. Recommendations for use of the influenza vaccine have broadened as the impact of influenza is appreci ated in such groups as pregnant women and young infants. Starting in the 20082009 influenza season, the United States Advisory Commit tee on Immunization Practices (ACIP) recommended that all children from 6 months to 18 years of age be vaccinated against influenza unless they have a specific contraindication to receiving the vaccine. Since the 20102011 season, annual flu vaccination is recommended for every one 6 months and older, with rare exception. In 2012, the Department of Health in the United Kingdom extended their influenza vaccination program to include all children between the ages of 2 and 17 years. To protect infants younger than 6 months who are too young to receive a vaccine, pregnant women, household contacts, and out of home care givers are groups for whom additional vaccination efforts should be made. Chemoprophylaxis with antiviral medications is a secondary means of prevention and is not a substitute for vaccination. Vaccines There are two main categories of seasonal influenza vaccines available for children: inactivated influenza vaccine (IIV) and live attenuated influenza |
7,808 | vaccine (LAIV). Previously referred to as the trivalent inactivated vaccine, IIV is given intramuscularly; it uses killed virus components. The LAIV vaccine uses weakened influenza virus and is administered as an intranasal spray. Neither IIV nor LAIV can cause influenza. Although in 20142015 ACIP and CDC recommended the use of the LAIV nasal spray vaccine for healthy children 2 through 8 years of age, this preferential recommendation was removed for the 20152016 season, and for the 20162017 and 20172018 seasons, ACIP and CDC made the interim recommendation that LAIV should not be used. This decision was based on concerns regarding low effec tiveness against influenza A(H1N1)pdm09 in the United States noted during the 20132014 and 20152016 seasons. After review of addi tional data, LAIV containing an updated influenza A(H1N1)pdm09 like vaccine virus, was again recommended by CDC and ACIP as an option for vaccination for the 20182019 season. Since the 20182019 season, ACIP and CDC have recommend that LAIV4 may be used. Special vaccination instructions for children 6 months to 8 years of age should be followed: children in this age group who have not previ ously received a total of at least two previous doses of trivalent or quad rivalent vaccine require two doses (at least 4 weeks apart) of the current seasons influenza vaccine to optimize immune response (Fig. 305.3). Influenza vaccines have an excellent safety profile, with the most com mon side effects being soreness, redness, tenderness, or swelling from the injection, and nasal congestion after the nasal spray. Seasonal influ enza vaccines may be co administered with other vaccines, including SARS CoV 2 vaccines. Seasonal influenza vaccines become available in the late summer and early fall each year. The formulation reflects the strains of influ enza viruses that are expected to circulate in the coming influenza sea son. Beginning in the 20132014 season, IIVs were available in both trivalent and quadrivalent formulations. The trivalent vaccine (IIV3) contains two influenza A strains and one influenza B strain; the quad rivalent vaccine (IIV4) contains a second influenza B strain of an anti genically distinct lineage. In addition to IIV and LAIV, a third vaccine category, recombinant HA influenza vaccine, became available in the 20132014 season. Since the 20202021 influenza season, all influenza vaccines used in the United States are quadrivalent. Ideally, vaccination should be given before the onset of influenza circulation in the community, so that there is time for antibodies to reach protective levels. Healthcare providers should offer vaccination by the end of October, if possible. The ACIP publishes guidelines for vaccine use each year when the vaccines are formulated and released; these guidelines should be referred to each season. The ACIP guide lines are widely publicized but appear initially in the Morbidity and Mortality Weekly Report published by CDC (https:www.cdc.govflu index.htm). Chemoprophylaxis Routine use of antiviral medications for chemoprophylaxis is not rec ommended. Examples for which the use of chemoprophylaxis may be considered to prevent influenza after exposure to an infectious person include (1) unvaccinated persons |
7,809 | at high risk of influenza complica tions, (2) persons for whom vaccine is contraindicated or expected to have low effectiveness, and (3) residentspatients in care facilities during institutional influenza outbreaks. Oral oseltamivir or inhaled zanamivir may be used for chemoprophylaxis of influenza; baloxavir is approved for postexposure prophylaxis in persons 12 years of age and older. Peramivir is not recommended for chemoprophylaxis because of a lack of data, and adamantanes are not currently recommended because of widespread adamantane resistance. Table 305.4 shows the recommendations for dosage and duration of treatment and chemo prophylaxis for the 20212022 influenza season, but updated recom mendations from the ACIP and CDC should be consulted every season (https:www.cdc.govfluprofessionalsantiviralsindex.htm). In general, postexposure chemoprophylaxis for persons at high risk of influenza complications (see Table 305.3) should be started within 48 hours of exposure to an infectious person and should be continued for 7 days after the last known exposure. An alternative to chemopro phylaxis for some persons after a suspected exposure is close monitor ing and early initiation of antiviral treatment if symptoms develop. Did the child receive 2 doses of trivalent or quadrivalent influenza vaccine before July 1, 2021? (Doses need not have been received during same or consecutive seasons) Yes No or unknown 1 dose of 20212022 influenza vaccine 2 doses of 20212022 influenza vaccine (administered 4 weeks apart) Fig. 305.3 Influenza vaccine dosing algorithm for children age 6 mo through 8 yrAdvisory Committee on Immunization Practices, United States, 20212022 influenza season. For children age 8 years who re quire two doses of vaccine, both dosages should be administered even if the child turns age 9 yr between receipt of dose 1 and dose 2. (From Grohskopf LA, Alyanak E, Ferdinands JM, et al. Prevention and control of seasonal influenza with vaccines: recommendations of the advisory committee on immunization practicesUnited States, 2021 22 Influ enza Season. MMWR Recomm Rep. 2021;70No. RR 5:128.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 2026 Part XV u Infectious Diseases For control of influenza outbreaks among high risk persons living in institutional settings, such as long term care facilities, antiviral che moprophylaxis is recommended for all vaccinated and unvaccinated residents and for unvaccinated healthcare providers. In these circum stances, CDC and the Infectious Diseases Society of America recom mend antiviral chemoprophylaxis for a minimum of 2 weeks and up to 1 week after the last known case is identified, whichever is longer. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Human parainfluenza viruses (HPIVs) are common causes of acute respiratory illness in infants and children and are important causes of lower respiratory tract disease in young children and immunocom promised persons. These viruses cause a spectrum of upper and lower respiratory tract illnesses but are particularly associated with croup (laryngotracheitis or laryngotracheobronchitis), bronchiolitis, and pneumonia. ETIOLOGY HPIVs are members of the Paramyxoviridae family. Four |
7,810 | HPIVs cause illness in humans, classified as types 1 4, with diverse manifes tations of infection. Type 4 is divided into two antigenic subtypes: 4a and 4b. HPIVs have a nonsegmented, single stranded RNA genome with a lipid containing envelope derived from budding through the host cell membrane. The major antigenic moieties are the hemagglu tinin neuraminidase (HN) and fusion (F) surface glycoproteins. EPIDEMIOLOGY By 5 years of age, most children have experienced primary infection with HPIV types 1, 2, and 3. HPIV 3 infections generally occur earliest, with half of infants infected by age 1 year and over 90 by age 5 years. HPIV 1 and HPIV 2 are more common after infancy, with approxi mately 75 infected by age 5 years. With increased use of multiplex molecular testing and more frequent addition of HPIV 4 as a panel tar get, HPIV 4 is more frequently recognized and appears to occur earlier in life than HPIV 1 and 2. In the United States and temperate climates, HPIV 1 has typically been reported to have biennial epidemics in the fall in odd numbered years, whereas HPIV 2 has biennial outbreaks in the fall of even numbered years, with peaks that are not as high as HPIV 1 or HPIV 3 (Fig. 306.1). HPIV 3 can be endemic throughout the year but typically peaks yearly in late spring or early summer. In years with less HPIV 1 activity, the HPIV 3 season has been observed to extend longer or to have a second peak in the fall (see Fig. 306.1). The epidemiology of HPIV 4 was historically less well defined, but with an increase in molecular detection, it has been found to have yearly peaks starting in the fall and peaking in winter (see Fig. 306.1). Similar to what has been observed for other nonSARS CoV 2 respiratory viruses, during the COVID 19 pandemic in 2020 and early 2021, HPIVs circulated at levels lower than prior years. However, HPIVs began increasing in the United States in spring of 2021 and, for HPIV types 1, 3, and 4, circulation patterns in 2022 and through fall 2023 were similar to prepandemic seasons; HPIV2 continued to circulate at lower levels during that period. National HPIV trends are created from weekly laboratory test result data that are reported on a voluntary basis and are available at the Centers for Disease Control and Prevention (CDC) National Respiratory and Enteric Virus Surveillance System (NREVSS) website (https:www.cdc.govsurveillancenrevss). HPIVs are spread primarily from the respiratory tract of an infected person by inhalation of large respiratory droplets or contact with infected nasopharyngeal secretions. HPIVs are notable for causing outbreaks Chapter 306 Parainfluenza Viruses Fiona P. Havers and Angela J.P. Campbell of respiratory illness in hospital wards, clinics, neonatal nurseries, and other institutional settings. The incubation period from exposure to symptom onset may range from 2 to 6 days. Children are likely to excrete virus from the oropharynx for 2 3 weeks, but shedding can be more pro longed, especially in |
7,811 | immunocompromised children, and may persist for months. Primary infection does not confer permanent immunity, and reinfections are common throughout life. Reinfections are usually mild and self limited but can cause serious lower respiratory tract illness, par ticularly in children with compromised immune systems. PATHOGENESIS HPIVs replicate in the respiratory epithelium. The propensity to cause illness in the upper large airways is presumably related to preferential replication in the larynx, trachea, and bronchi in comparison with other viruses. Some HPIVs induce cell to cell fusion. During the bud ding process, cell membrane integrity is lost, and viruses can induce cell death through the process of apoptosis. In children, the most severe illness generally coincides with the time of maximal viral shedding. However, disease severity is likely related to the host immune response to infection as much as to direct cytopathic effects of the virus. Virus specific immunoglobulin A antibody levels and serum antibodies to the surface HN and F glycoproteins are able to neutralize HPIV, and both likely contribute to host immunity. Cell mediated cytotoxicity is also important for controlling and terminating HPIV infection. CLINICAL MANIFESTATIONS The most common type of illness caused by HPIV infection consists of some combination of low grade fever, rhinorrhea, cough, pharyn gitis, and hoarseness and may be associated with vomiting or diar rhea. Rarely, HPIV infection is associated with parotitis. HPIVs have also been associated with a variety of skin manifestations, including typical maculopapular viral exanthems, erythema multiforme, and papular acrodermatitis, or Gianotti Crosti syndrome (see Chapter 708). Although often mild, more serious HPIV illness may result in hospitalization, with common discharge diagnoses of bronchiolitis, feverpossible sepsis, and apnea among younger children and croup, pneumonia, and asthma among older children (Fig. 306.2). HPIVs account for 50 of hospitalizations for croup and at least 15 of cases of bronchiolitis and pneumonia. HPIV 1 and HPIV 2 cause more cases of croup, whereas HPIV 3 is more likely to infect the small air passages of the lower respiratory tract and cause pneumonia, bronchiolitis, or bronchitis. HPIV 4 causes a similar range of illness as the other types, and with advancements in molecular diagnosis, there is evidence that HPIV 4 may be comparable to HPIV 3 and frequently associated with acute lower respiratory infection (ALRI). In fact, any HPIV can cause lower respiratory tract disease, particularly during primary infection or in patients with compromised immune sys tems. In children and adult patients with hematologic malignancies and undergoing hematopoietic stem cell transplantation, lymphopenia has repeatedly been shown to be an independent risk factor for progression from upper to lower respiratory tract disease. Recently, the first global burden estimates of HPIV associated and HPIV attributable ALRI were generated, with approximately 13 of ALRI cases, 414 of ALRI hospi tal admissions, and 4 of childhood ALRI mortality attributable to HPIV. DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS The diagnosis of HPIV infection in children is often based solely on clin ical and epidemiologic criteria. Croup is a clinical diagnosis and must be distinguished from |
7,812 | other diagnoses, including foreign body aspiration, epiglottitis, retropharyngeal abscess, angioedema, and subglottic steno sis or hemangioma. Although the radiographic steeple sign, consisting of progressive narrowing of the subglottic region of the trachea, is char acteristic of croup, differential considerations include acute epiglottitis, thermal injury, angioedema, and bacterial tracheitis. Manifestation of HPIV lower respiratory tract disease may be similar to that of a number of other respiratory viral infections; therefore virus identification should be sought by the most sensitive diagnostic means available for certain severe illnesses, such as pneumonia in immunocompromised children. Sensitive, specific, and rapid molecular assays such as multiplex polymerase chain reaction assays have become more widely available Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 306 u Parainfluenza Viruses 2027 and greatly increase sensitivity of HPIV detection. For immunocom promised patients, these highly sensitive platforms provide the critical ability to make a prompt diagnosis by detecting a wide range of viral pathogens, including HPIVs, thus allowing for early implementation of infection prevention measures and potential treatment. Other labora tory diagnosis methods are available, such as isolation in tissue culture and direct immunofluorescent staining for identification of virus anti gens in respiratory secretions, but these have been used less frequently given the increasing availability of molecular assays. TREATMENT There are no specific antiviral medications approved for the treatment of HPIV infections. For croup, the possibility of rapid respiratory com promise should influence the level of care and treatment given (see Chapter 433). The severity assessment of croup generally incorporates a number of clinical features, which include the presence and degree of chest wall retractions, whether stridor is present at rest, and evaluation of the childs mental status (e.g., for agitation, anxiety, lethargy). Humidified air has not been shown to be significantly effective in reducing symptom severity. Glucocorticoids improve symptoms at 2 hours after treatment, lessen the need for other medications, and shorten hospital stays. In general, because of its safety, efficacy, and cost effectiveness, a single dose of oral dexamethasone (0.15 to 0.6 mgkg) is the primary treatment for mild croup in the office or emergency room setting. Oral prednisolone (1 mgkg) is an accept able alternative in this setting, particularly if dexamethasone is not available; however, in a meta analysis, dexamethasone significantly reduced the rate of return visits andor (re)admissions. For obstructive airway symptoms associated with moderate to severe croup, corticosteroid therapy is recommended: oral dexa methasone (0.6 mgkg) should be given if oral intake is tolerated. A single dose of intramuscular dexamethasone or budesonide (2 mg 2 mL solution via nebulizer) may provide an alternative to oral dexamethasone for children with severe respiratory distress or vomiting. Alternatively, intravenous (IV) dexamethasone can be administered if IV access has been established. Nebulized epineph rine (either racemic epinephrine 2.25 solution, 0.05 mLkgdose up to maximum of 0.5 mLdose diluted to 3 mL with |
7,813 | normal 1200 1100 1000 900 800 700 600 500 400 300 200 100 0 07 0 9 20 11 01 0 9 20 12 07 0 9 20 12 01 0 9 20 13 07 0 9 20 13 01 0 9 20 14 07 0 9 20 14 01 0 9 20 15 07 0 9 20 15 01 0 9 20 16 07 0 9 20 16 01 0 9 20 17 07 0 9 20 17 01 0 9 20 18 07 0 9 20 18 01 0 9 20 19 07 0 9 20 19 Date D et ec tio ns HPIV1 HPIV2 HPIV3 HPIV4 Total detections Fig. 306.1 Human parainfluenza virus (HPIV) circulation, National Enteric and Respiratory Virus Surveillance System, United States Census Re gions, 20112019. (From DeGroote NP, Haynes AK, Taylor C, et al. Human parainfluenza virus circulation, United States, 20112019. J Clin Virol. 2020;124:104261. Fig. 1.) Apn ea Asth m a Bro nc hio liti s Cro up Fev er P os sib le se ps is P er ce n t w it h s p ec if ie d d is ch ar g e d ia g n o se s, b y ag e g ro u p ( m o ) Pne um on ia URI 0 A 10 20 30 40 50 0 to 5 (n58) 6 to 11 (n33) 12 to 23 (n57) 24 to 59 (n41) Apn ea Asth m a Bro nc hio liti s Cro up Fev er P os sib le se ps is P er ce n t w it h s p ec if ie d d is ch ar g e d ia g n o se s, b y H P IV t yp e Pne um on ia URI 0 B 10 20 30 40 50 HPIV1 (n73) HPIV2 (n23) HPIV3 (n95) Fig. 306.2 Selected discharge diagnoses of hospitalized children with parainfluenza (HPIV) infection, by age in months (A) and virus type (B). (Data from Weinberg GA, Hall CB, Iwane MK, et al. Parainfluenza virus infection of young children: estimates of the population based burden of hospitalization. J Pediatr. 2009;154:694699, Table II) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 2028 Part XV u Infectious Diseases saline, or l epinephrine using parenteral 1 mgml 1:1000 solu tion, 0.5 mLkgdose up to maximum 5 mLdose) is also recom mended and may provide temporary symptomatic improvement. Children should be observed for at least 2 hours after receiving epi nephrine treatment for return of obstructive symptoms. Repeated treatments may be provided, depending on the duration of symptoms. The dexamethasone dose may be repeated, but this should not be necessary on a routine basis, and there are no guidelines to compare outcomes of single and multiple dose treatment schedules. Moder ate to severe symptoms that |
7,814 | persist for more than a few days should prompt investigation for other causes of airway obstruction. Oxygen should be administered for hypoxia, and supportive care with analge sics and antipyretics is reasonable for fever and discomfort associated with HPIV infections. The indications for antibiotics are limited to well documented secondary bacterial infections of the middle ear(s) or lower respiratory tract. Ribavirin has some antiviral activity against HPIVs in vitro and in animal models. Inhaled ribavirin has been given to severely immuno compromised children with HPIV pneumonia; however, the majority of data have not shown improved outcomes, and randomized controlled studies are lacking. Some institutions use intravenous immunoglobu lin for HPIV pneumonia in children with hematologic malignancies or who have undergone hematopoietic stem cell transplantation; the impact of this treatment strategy on clinical outcomes is also limited by lack of controlled studies. Use of DAS181, a novel sialidase fusion protein inhibitor, has shown clinical potential in a phase 2 clinical trial when used for treatment of HPIV lower respiratory tract disease among solid organ and hematopoietic stem cell transplant recipients, and a phase 3 trial is ongoing. Other potential strategies for drug devel opment include hemagglutinin neuraminidase inhibitors, transcrip tion inhibitors, and synthetic small interfering RNAs. COMPLICATIONS Eustachian tube obstruction can lead to secondary bacterial invasion of the middle ear space and acute otitis media in 3050 of HPIV infec tions. Similarly, obstruction of the paranasal sinuses can lead to sinus itis. The destruction of cells in the upper airways can lead to secondary bacterial invasion and resultant bacterial tracheitis, and antecedent HPIV infection of lower airways may predispose to bacterial pneumo nia. Nonrespiratory complications of HPIV are rare but include aseptic meningitis, encephalitis, acute disseminated encephalomyelitis, rhab domyolysis, myocarditis, and pericarditis. PROGNOSIS The prognosis for full recovery from HPIV infection in the immuno competent child is generally excellent, with no long term pulmonary sequelae. Deaths may rarely occur, particularly in immunocompro mised children with lower respiratory tract infection. PREVENTION Vaccine development has focused largely on live attenuated intranasal HPIV 3 vaccines. Candidates include a recombinant human HPIV 3 virus (rcp45) derived from complementary DNA, as well as a comple mentary DNAderived chimeric bovinehuman HPIV 3 virus; these candidates are well tolerated and immunogenic in infants and young children. Constructs using chimeric bovinehuman HPIV 3 virus in addition to the F or both F and G proteins of respiratory syncytial virus (RSV) have been investigated. A combined messenger RNA (mRNA) vaccine against HPIV 3 and human metapneumovirus has completed phase 1 clinical trials. Live attenuated candidate HPIV 1 and HPIV 2 vaccines have also undergone phase 1 clinical studies (www.clinicaltria ls.gov). The measure of protection afforded by vaccines will be difficult to assess, because symptomatic reinfection occurs and the frequency of serious infection in the general population is low. Nonetheless, it is clear that prevention of acute respiratory illness caused by HPIVs, particularly lower respiratory tract infections among infants and young children, is a worthwhile goal. Visit Elsevier eBooks at eBooks.Health.Elsevier.com |
7,815 | for Bibliography. Respiratory syncytial virus (RSV) is the major cause of bronchiolitis (see Chapter 439) and viral pneumonia in children younger than 1 year of age and is the most important respiratory tract pathogen of early childhood. ETIOLOGY RSV is an enveloped RNA virus with a single stranded negative sense genome that replicates entirely in the cytoplasm of infected cells and matures by budding from the apical surface of the cell membrane. Because this virus has a nonsegmented genome, it cannot undergo antigenic shift by reassortment like the influenza viruses do. The virus belongs to the family Pneumoviridae, which comprises large enveloped, negative sense RNA viruses. This taxon was formerly a subfamily within the Paramyxoviridae but was reclassified in 2016 as a family with two genera, Orthopneumovirus (which includes RSV) and Metapneumovi rus (which includes human metapneumovirus; see Chapter 308). There are two antigenic subgroups of RSV (subgroups A and B), distinguished based primarily on sequence and antigenic variation in one of the two surface proteins, the G glycoprotein that is responsible for attachment to host cells. Sequence analysis of cDNAs of the full G glycoprotein ectodo main region allows clustering of sequence patterns and identification of molecular markers that can be used to assign genotypes, subgenotypes, and lineages. There is no unified classification scheme for genotypes, so reports differ in the number of genotypes in circulation. The observed genotypic variation, which also can alter antigenic properties at the pro tein level, is caused by point mutations from infidelity of the viral RNA polymerase and may contribute to some degree to the frequency with which RSV reinfects children and adults. However, adult human chal lenge experiments have shown that the same RSV strain can reinfect in the upper respiratory tract repetitively, suggesting that mucosal immu nity in that site is incomplete or short lived. RSV replicates in a wide variety of cell line monolayer cultures in the laboratory. In HeLa and HEp 2 cell monolayers, the virus causes cell to cell fusion that produces characteristic cytopathology called syncytia (multinucleate enlarged cells), from which the virus derives its name. Identification of syncytia in diagnostic cultures of respiratory secretions is helpful in identifying RSV, but it is not clear whether syncytium forma tion occurs to any significant degree in the airway epithelium in patients. EPIDEMIOLOGY RSV is distributed worldwide and appears in yearly epidemics. In tem perate climates, these epidemics occur each winter over a 4 to 5 month period. During the remainder of the year, infections are sporadic and much less common. In the Northern hemisphere, epidemics usually peak in January, February, or March, but peaks have been recognized as early as December and as late as June. Some areas in the United States, such as Florida, report a moderate incidence year round. In the Southern hemisphere, outbreaks also occur during the winter months in that hemisphere. RSV outbreaks often overlap with outbreaks of influenza virus or human metapneumovirus but are generally more consistent from year to year and result in |
7,816 | more disease overall, espe cially among infants younger than 6 months of age. In the tropics, the epidemic pattern is less clear. The pattern of widespread annual out breaks and the high incidence of infection during the first 3 4 months of life are unique among human viruses. The conventional seasonality of RSV outbreaks was altered in 20202021 by events associated with the COVID 19 pandemic. Delayed and out of season RSV epidemics occurred during the COVID 19 pandemic when reopening activities Chapter 307 Respiratory Syncytial Virus James E. Crowe Jr. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 307 u Respiratory Syncytial Virus 2029 occurred after a long period of reduced transmission due to nonphar maceutical interventions such as masking, distancing, and daycare and school closure reduced transmission. Transplacentally acquired anti RSV maternal immunoglobulin G (IgG) serum antibodies, if present in high concentration, appear to provide partial protection for the neonate. The age of peak incidence of severe lower respiratory tract disease and hospitalization is about 6 weeks. Maternal IgGs may account for the lower severity and inci dence of RSV infections during the first 4 6 weeks of life, except among infants born prematurely, who receive less maternal immunoglobu lin. Breastfeeding provides some protection against severe disease, an effect that may pertain only to female and not male infants. RSV is one of the most contagious viruses that affect humans. Infection is nearly universal among children by their second birthday. Reinfection occurs at a rate of at least 1020 per epidemic throughout childhood, with a lower frequency among adults. In situations of high exposure, such as daycare centers, attack rates are nearly 100 among previously unin fected infants and 6080 for second and subsequent infections. Reinfection may occur as early as a few weeks after recovery but usually takes place during subsequent annual outbreaks. Antigenic variation is not required for reinfection, as shown by the fact that a proportion of adults inoculated repeatedly with the same experimental preparation of wild type virus could be reinfected multiple times. The immune response of infants is poor in quality, magnitude, and durabil ity. The severity of illness during reinfection in childhood is usually lower than that in first infection and appears to be a function of partial acquired immunity, more robust airway physiology, and increased age. Asymptomatic RSV infection is unusual in young children. Most infants experience coryza and pharyngitis, often with fever and fre quently with otitis media caused by virus in the middle ear or bacte rial superinfection following eustachian tube dysfunction. The lower respiratory tract is involved to a varying degree, with bronchiolitis and bronchopneumonia in about a third of children. The hospitalization rate for RSV infection in otherwise healthy infants is typically 0.54, depending on region, sex, socioeconomic status, exposure to cigarette smoke, gestational age, and family history of atopy. |
7,817 | The admitting diagnosis is usually bronchiolitis with hypoxia, although this condi tion is often indistinguishable from RSV pneumonia in infants, and, indeed, the two processes frequently coexist. All RSV diseases of the lower respiratory tract (excluding croup) have their highest incidence at 6 weeks to 7 months of age and decrease in frequency thereafter. The syndrome of bronchiolitis is much less common after the first birthday. The terminology used for the diagnosis of virus associated wheezing illnesses in toddlers can be confusing, because these illnesses are vari ably termed wheezing associated respiratory infection, wheezy bronchi tis, exacerbation of reactive airways disease, or asthma attack. Because many toddlers wheeze during RSV infection but do not go on to have lifelong asthma, it is best to use the diagnostic term asthma only later in life. It is still uncertain if RSV associated wheezing illness in infancy causes asthma in later life. On the whole, prevention of severe RSV ill ness in high risk infants using RSV monoclonal antibody prophylaxis does not seem to reduce the incidence of asthma in those populations significantly. Whether a vaccine will have such an effect in the future is still to be determined. Acute viral pneumonia is a recurring problem throughout child hood, although RSV becomes less prominent as the etiologic agent after the first year. RSV plays a causative role in an estimated 4075 of cases of hospitalized bronchiolitis, 1540 of cases of childhood pneumonia, and 615 of cases of croup. Bronchiolitis and pneumo nia resulting from RSV are more common in males than in females by a ratio of approximately 1.5:1. Other risk factors with a similar impact in the United States include one or more siblings in the home, White race, rural residence, maternal smoking, and maternal education 12 years. The medical factors in infants associated with the highest risk are chronic lung disease of prematurity, congenital heart disease, immuno deficiency, and prematurity. Still, most infants admitted to the hospital because of RSV infection do not have strong, easily identifiable risk fac tors. Therefore any strategy for prophylaxis focused only on individu als with strong risk factors probably could prevent only approximately 10 of hospitalizations, even if the prophylaxis was 100 effective in treated high risk individuals. The incubation period from exposure to first symptoms is approxi mately 3 5 days. The virus is excreted for variable periods, probably depending on the severity of illness and immunologic status. Most infants with lower respiratory tract illness shed infectious viruses for 1 2 weeks after hospital admission. Excretion for 3 weeks and even longer has been documented. Spread of infection occurs when large infected droplets, either airborne or conveyed on hands or other fomi tes, are inoculated in the nasopharynx of a susceptible subject. RSV is probably introduced into most families by young schoolchildren expe riencing reinfection. Typically, in the space of a few days, 2550 of older siblings and one or both parents acquire upper respiratory tract infections, but infants become more severely ill with |
7,818 | fever, otitis media, or lower respiratory tract disease. Nosocomial infection during RSV epidemics is an important con cern. Virus is usually spread from child to child on the hands of care givers or other fomites. Adults experiencing reinfection also have been implicated in the spread of the virus. Contact precautions are sufficient to prevent spread when compliance is meticulous, because the virus is not spread by small particle aerosol to an appreciable degree, and a distance of about 6 ft is likely sufficient to avoid aerosol transmission. During the COVID 19 pandemic, widespread social measures, includ ing masking and distancing, appeared to prevent transmission of RSV on a world wide basis. However, in normal circumstances, adherence to isolation procedures by caregivers often is not complete. PATHOGENESIS Bronchiolitis is caused by obstruction and collapse of the small airways during expiration. Infants are particularly apt to experience small air way obstruction because of the small size of their normal bronchioles; airway resistance is proportional to 1radius4. There has been relatively little pathologic examination of RSV disease in the lower airways of otherwise healthy subjects. Airway narrowing likely is caused by virus induced necrosis of the bronchiolar epithelium, hypersecretion of mucus, and round cell infiltration and edema of the surrounding submucosa. These changes result in the formation of mucus plugs obstructing bronchioles, with consequent hyperinflation or collapse of the distal lung tissue. In interstitial pneumonia, the infiltration is more generalized, and epithelial shedding may extend to both the bronchi and the alveoli. In older subjects, smooth muscle hyperreactivity may contribute to airway narrowing, but the airways of young infants typi cally do not exhibit a high degree of reversible smooth muscle hyper reactivity during RSV infection. Several facts suggest that elements of the host response may cause inflammation and contribute to tissue damage. The immune response required to eliminate virus infected cells (mostly containing cytolytic T cells) is a double edged sword, reducing the cells producing virus but also causing host cell death in the process. Many soluble factors, such as cytokines, chemokines, and leukotrienes, are released in the process, and skewing of the patterns of these responses may predispose some individuals to more severe disease. There is also evidence that genetic factors may predispose to more severe bronchiolitis. Some studies have identified the presence of both RSV and human metapneumovirus viral RNA in airway secretions in a significant pro portion of infants requiring assisted ventilation and intensive care. It may be that co infection is associated with more severe disease. Positive results of polymerase chain reaction (PCR) analysis must be interpreted carefully because this positivity can remain for prolonged periods after infection, even when infectious virus can no longer be detected. It is not clear how often superimposed bacterial infection plays a pathogenic role in RSV lower respiratory tract disease. RSV bronchi olitis in infants is probably exclusively a viral disease, although there is evidence that bacterial pneumonia can be triggered by respiratory viral infection, including with RSV. A large clinical study |
7,819 | of pneumococ cal vaccine showed that childhood vaccination reduced the incidence of viral pneumonia by approximately 30, suggesting viral bacterial interactions that we currently do not fully understand. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 2030 Part XV u Infectious Diseases CLINICAL MANIFESTATIONS Typically, the first sign of infection in infants with RSV is rhi norrhea. Cough may appear simultaneously but more often does so after an interval of 1 3 days, at which time there may also be sneezing and a low grade fever. Soon after the cough develops, the child who experiences bronchiolitis begins to wheeze audibly. If the disease is mild, the symptoms may not progress beyond this stage. Auscultation often reveals diffuse fine inspiratory crackles and expiratory wheezes. Rhinorrhea usually persists throughout the ill ness, with intermittent fever. Chest radiograph findings at this stage are frequently normal. If the illness progresses, cough and wheezing worsen and air hun ger ensues, with an increased respiratory rate, intercostal and subcostal retractions, hyperexpansion of the chest, restlessness, and peripheral cyanosis. Signs of severe, life threatening illness are central cyanosis, tachypnea of 70 breathsmin, listlessness, and apneic spells. At this stage, the chest may be significantly hyperexpanded and almost silent to auscultation because of poor air movement. Chest radiographs of infants hospitalized with RSV bronchiolitis have normal findings in approximately 30 of cases, with the other 70 showing hyperexpansion of the chest, peribronchial thickening, and interstitial infiltrates. Segmental or lobar consolidation is unusual, and pleural effusion is rare. In some infants, the course of the illness may resemble that of pneu monia, the prodromal rhinorrhea and cough being followed by dys pnea, poor feeding, and listlessness. Although the clinical diagnosis is pneumonia, wheezing is often present intermittently, and the chest radiographs may show air trapping. Fever is an inconsistent sign in RSV infection. In young infants, particularly those who were born prematurely, periodic breathing and apneic spells have been distressingly frequent signs, even with rela tively mild bronchiolitis. Apnea is not necessarily caused by respiratory exhaustion but rather appears to be a consequence of alterations in the central control of breathing. RSV infections in profoundly immunocompromised hosts or those with chronic lung disease or pulmonary hypertension may be severe at any age of life. The mortality rates associated with RSV pneumonia in the first few weeks after hematopoietic stem cell or solid organ trans plantation in both children and adults are high. RSV infection does not appear to be more severe in HIV infected patients with reasonable control of HIV disease, although these patients may shed virus in respi ratory secretions for prolonged periods. Secondary (associated) bacterial infections are uncommon in most previously healthy patients with RSV bronchiolitis. However, otitis media may be present because of either RSV or bacterial middle ear infection. DIAGNOSIS Bronchiolitis is a clinical diagnosis. RSV can be suspected |
7,820 | with vary ing degrees of certainty based on the season of the year and the pres ence of the virus in the community. Other epidemiologic features that may be helpful are the presence of common colds in older household contacts and the age of the child. The other respiratory viruses that attack infants frequently during the first few months of life are human metapneumovirus, influenza viruses, parainfluenza virus type 3, rhino viruses, enteroviruses, and coronaviruses. Routine laboratory tests are of minimal diagnostic use in most cases of bronchiolitis or pneumonia caused by RSV. The white blood cell count is normal or elevated, and the differential cell count may be normal with either a neutrophilic or mononuclear predominance. Hypoxemia as measured by pulse oximetry or arterial blood gas analy sis is frequent and tends to be more marked than anticipated from the clinical findings. A normal or elevated blood carbon dioxide value in a patient with a markedly elevated respiratory rate is a sign of respira tory failure. The most important diagnostic concern is to differentiate viral infec tion from bacterial or chlamydial infection. When bronchiolitis is not accompanied by infiltrates on chest radiographs, there is little likelihood of a bacterial component. In infants 1 4 months of age, interstitial pneu monitis may be caused by Chlamydia trachomatis (see Chapter 272). With C. trachomatis pneumonia, there may be a history of conjunctivitis, and the illness tends to be of subacute onset. Coughing and inspiratory crackles may be prominent; wheezing is not. Fever is usually absent. Lobar consolidation without other signs or with pleural effusion should be considered of bacterial etiology until proved otherwise. Other signs suggesting bacterial pneumonia are neutrophilia, neutro penia in the presence of severe disease, ileus or other abdominal signs, high temperature, and circulatory collapse. In such instances, antibiot ics should be initiated. The definitive diagnosis of RSV infection is based on the detection in respiratory secretions of live virus by cell culture. Molecular diagnostic tests are more available, however. The presence of viral RNA (detected by a molecular diagnostic test using reverse transcription PCR) or viral antigens (detected by a rapid diagnostic test, usually a membrane blotting test incorporating antibody detection of viral proteins) is strongly sup portive in the right clinical setting. The antigen test is less sensitive than virus culture, whereas reverse transcription PCR analysis is more sensitive than culture. An aspirate of mucus or a nasopharyngeal wash from the childs posterior nasal cavity is the optimal specimen. Nasopharyngeal or throat swabs are less preferable but are acceptable. A tracheal aspirate is unnecessary, but endotracheal tube lavage fluid from patients intubated for mechanical ventilation can be tested. The specimen should be placed on ice, taken directly to the laboratory, and processed immediately for culture, antigen detection, or PCR analysis. RSV is thermolabile, so it degrades over relatively short periods of time unless it is frozen at a low temperature such as 80C (112F) in freezers used in research settings. TREATMENT The treatment of uncomplicated cases |
7,821 | of bronchiolitis is symptomatic. Many infants are slightly to moderately dehydrated, and therefore flu ids should be carefully administered in amounts somewhat greater than those for maintenance. Often, intravenous or tube feeding is helpful when sucking is difficult because of tachypnea. Humidified oxygen and suctioning usually are indicated for hospitalized infants who are hypoxic. High flow nasal cannula (HFNC) therapy is used for respiratory distress either before or after admission to an intensive care unit. HFNC is often started based on the subjective assessment of work of breathing; despite HFNC use, it remains uncertain if the outcome of RSV bronchiolitis has been improved with HFNC. Nasal continuous positive airway pressure is used in the intensive care unit for infants who have increased work of breathing, and mechanical ventilation is used for respiratory failure. There is disagreement among experts regarding the usefulness of aerosolized saline or hypertonic saline, epinephrine, or 2 agonists in RSV bronchiolitis. Most patients do not receive lasting benefit from prolonged therapy, which is associated with a relatively high frequency of side effects. Corticosteroid therapy is not indicated except in older children with an established diagnosis of asthma, because its use is associated with prolonged virus shedding and is of no proven clini cal benefit. The 2014 American Academy of Pediatrics bronchiolitis clinical practice guideline suggests limitations on the use of and adrenergic agents and corticosteroids. In nearly all instances of bronchiolitis, antibiotics are not useful, and their inappropriate use contributes to the development of antibiotic resistance. Interstitial pneumonia in infants 1 4 months old may be caused by C. trachomatis, and macrolide therapy may be indicated for that infection if identified by specific testing. PROGNOSIS The mortality rate of hospitalized infants with RSV infection of the lower respiratory tract is very low in the developed world. Almost all deaths occur among young, premature infants or infants with under lying disease of the neuromuscular, pulmonary, cardiovascular, or immunologic system. However, it is estimated that more than 160,000 children worldwide in resource poor settings die each year from RSV. In addition, thousands of elderly patients die of RSV infection each year in the United States. There is recurrent wheezing in 3050 of children who have severe RSV bronchiolitis in infancy, and many older children who are diag nosed with asthma have a history of severe bronchiolitis in infancy. The likelihood of the recurrence of wheezing is increased in the presence Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 307 u Respiratory Syncytial Virus 2031 of an allergic diathesis (e.g., eczema, hay fever, or a family history of asthma). With a clinical presentation of bronchiolitis in a patient older than 1 year of age, there is an increasing probability that, although the episode may be virus induced, the event is likely the first of multiple wheezing attacks that will later be diagnosed as |
7,822 | hyperreactive airways disease or asthma. Asthma is difficult to diagnose in the first year of life. It is not fully clear at this time whether early, severe RSV wheez ing disease causes some cases of asthma or whether persons destined to have asthma present with symptoms first when provoked by RSV infection during infancy. Results from a long term follow up study of infants who received palivizumab prophylaxis suggested that the pre vention of severe RSV infection may reduce the incidence of reactive airways disease later in life. PREVENTION Prevention of Nosocomial Spread In the hospital, the most important preventive measures are aimed at blocking nosocomial spread. During RSV season, highrisk infants should be separated from all infants with respiratory symptoms. Gowns, gloves, and careful handwashing (contact isolation) should be used for the care of all infants with suspected or established RSV infection. A high level of compliance with contact isolation is essential. Viral labora tory tests are adequate for diagnosis in the setting of acute disease when levels of virus are high, but they are not designed to detect low levels of virus. Therefore, contact precaution isolation should be observed for the duration of hospitalization for most patients admitted for acute disease. Rapid antigen tests should not be used to determine whether a patient still requires isolation, because low concentrations of virus may be pres ent in respiratory secretions that are infectious for humans but below the lower limit of detection for such assays. Ideally, patients with RSV or metapneumovirus infections are housed separately because coinfection with the two viruses may be associated with more severe disease. Protection of Infants Against Infection or Severe Disease Antibodies that neutralize RSV are the principal mechanism of pro tection against infection or reinfection. Antibodies are induced by natural infection but can also be provided to infants prior to a first infection in several ways. First, all mothers pass along their own natu rally occurring IgG antibodies across the placenta beginning at about 2832 weeks gestation. Second, breastfeeding may transfer maternal antibodies (including IgA antibodies) to infant mucosal surfaces, pro viding benefit in some infants. Third, antibodies manufactured as bio logic drugs can be administered directly to infants after birth. Fourth, maternal immunization with an approved RSV vaccine can increase the level of antibodies in the mothers serum and thus also the level of antibodies transferred across the placenta. The Advisory Committee on Immunization Practices (ACIP) in the United States recommends that either antibody administration to the infant or maternal vaccina tion during pregnancy should be used to prevent RSVassociated lower respiratory tract illness among all infants, but both exogenous antibod ies and maternal vaccination are not needed for most infants. Passive Immunoprophylaxis A neutralizing humanized murine monoclonal antibody against RSV given IM once a month (palivizumab) has been approved for protect ing highrisk children against serious complications from RSV disease. A nextgeneration monoclonal antibody (nirsevimab, Beyfortus, Sanofi and AstraZeneca) was subsequently approved for the prevention of lower respiratory tract infection caused by |
7,823 | RSV in the European Union, United Kingdom, United States, and Canada. Nirsevimab is an RSV fusionproteinspecific monoclonal antibody with an extended halflife because of engineered changes in the antibody Fc region. Since the anti body is longacting (with a halflife of about 3 months instead of 3 weeks as for conventional IgG), only a single dose is necessary to protect term, preterm, and highrisk infants for an entire RSV season. In the United States, nirsevimab is indicated for the prevention of RSV lower respi ratory tract disease in neonates and infants 8 months born during or entering their first RSV season and in children 819 months of age at increased risk for severe RSV disease entering their second RSV season. Nirsevimab is dispensed in prefill syringes of either 50 or 100 mg; the dose is 50 mg IM for infants 5 kg, and 100 mg IM for infants 8 months old and 5 kg. The first dose for infants 8 months of age may be given in the first week of life. For infants 819 months of age entering their second RSV season and at increased risk for severe RSV infection, the dose is 200 mg. Because of a projected shortage of the 100 mg dose, it is recom mended that only infants 5kg who are at high risk for severe RSV infection receive the 100 mg dose. High risk patients are defined as: Infants 6 months American Indian and Alaska Natives 8 months Infants age 6 to 8 months with prematurity ( 29 weeks), chronic lung disease of prematurity, hemodynamically significant congenital heart disease, severe immunocompromise, cystic fibrosis, neuro muscular disease, or congenital pulmonary abnormalities that im pair the ability to clear secretions Palivizumab should be administered only to high risk infants (819 months old) and to eligible infants 8 months old if nirsevimab is not available. Administration of palivizumab (15 mgkg intramuscularly once a month) is recommended for protecting highrisk children against serious complications from RSV disease. Palivizumab is administered from the beginning to the end of the RSV season. Palivizumab prophy laxis may be considered for the following infants and children: Infants born before 29 wk of gestation in the first year of life Infants born before 32 wk of gestation, who have chronic lung dis ease of prematurity (required 21 Fio2 fraction of inspired ox ygen for 28 days after birth), in the first year of life and in the second RSV season if continued medical support (oxygen, diuretics, steroids) is needed Infants younger than 1 yr of age with hemodynamically significant acyanotic congenital heart disease or those with moderate to severe pulmonary hypertension and those patients following cardiac trans plantation (children 2 yr of age) Children 24 mo of age or younger with profound immunocompro mising conditions during RSV season Infants in the first year of life who have either congenital abnormali ties of the airway or neuromuscular disease that compromises the handling of respiratory secretions Vaccine There are two licensed subunit protein vaccines against |
7,824 | RSV for older adults (Abrysvo, Pfizer; Arexvy, GSK) based on a prefusion conforma tion of the RSV fusion (F) protein (RSVpreF). The bivalent RSVpreF Abrysvo vaccine has subunit proteins for both the type A and type B RSV antigenic subgroups, while the Arexvy vaccine contains only subgroup A antigen combined with an adjuvant. Neither vaccine is approved for use in infants or children, but Abrysvo is used in preg nant mothers 3236 weeks pregnant during RSV season with the goal to protect infants. The mechanism of protection is that the resulting increased serum level of RSVneutralizing antibodies in the mother can enhance immunity in neonates following transplacental transfer of those maternal RSV antibodies to the fetus. In efficacy trials, this vacci nation reduced the incidence of medically attended RSV lower respira tory tract infections and hospitalization within 90 days after birth. The Abrysvo vaccine is recommended during September through January for most of the United States. since RSV typically peaks in fall and win ter. The seasonality of RSV season varies depending on location, and thus state, local, or territorial health departments may recommend dif ferent timing for administration in diverse areas. The risk of severe RSV is even greater in infants born at 32 weeks gestation. When Abrysvo was compared to placebo in clinical trials, infants born to pregnant individuals experienced low birth weight (5.1 Abrysvo compared to 4.4 placebo, a difference that was not statistically significant). The European Medicines Agency chose to approve maternal immunization with Abrysvo between weeks 24 and 36 of gestation, while the US FDA chose to approve the vaccine between weeks 32 and 36 of gestation while awaiting additional safety information from ongoing studies. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 2032 Part XV u Infectious Diseases ETIOLOGY Human metapneumovirus (HMPV) is a respiratory virus that is one of the most common causes of serious lower respiratory tract illness in children throughout the world. ETIOLOGY HMPV is an enveloped, single stranded, nonsegmented, negative sense RNA genome of the family Pneumoviridae, which comprises large enveloped negative sense RNA viruses. This taxon was formerly a subfamily within the Paramyxoviridae but was reclassified in 2016 as a family with two genera: Metapneumovirus (which includes HMPV) and Orthopneumovirus (which includes respiratory syncytial virus RSV; see Chapter 307). HMPV and the avian pneumoviruses are highly related and are separated into the separate genus Metapneumo virus because the gene order in the nonsegmented genome is slightly altered and because avian pneumovirusesHMPVs lack the genes for two nonstructural proteins, NS1 and NS2, which are encoded at the 3 end of RSV genomes. These proteins are thought to counteract host type I interferons. The absence of NS1NS2 in the metapneumoviruses (compared with RSV) may contribute to an overall slightly reduced pathogenicity relative to wild type RSV strains. The |
7,825 | HMPV genome encodes nine proteins in the order 3 N P M F M2 (orf1 and 2) SH G L 5. The genome also contains noncoding 3 leader, 5 trailer, and intergenic regions, consistent with the organization of most paramyxoviruses, with a viral promoter con tained in the 3 end of the genome. The F (fusion), G (glycosylated), and SH (short hydrophobic) proteins are integral membrane proteins on the surfaces of infected cells and virion particles. The F protein is a classic type I integral membrane viral fusion protein that contains two heptad repeats in the extracellular domain that facilitate membrane fusion. There is a predicted protein cleavage site near a hydrophobic fusion peptide that likely is cleaved by an extracellular protease, acti vating the F protein for fusion. The predicted attachment (G) protein of HMPV exhibits the basic features of a glycosylated type II mucin like protein. The HMPV G protein differs from the RSV G protein that inhibits innate immune responses in that the HMPV G lacks a cysteine noose structure. The internal proteins of the virus appear similar in function to those of other paramyxoviruses. EPIDEMIOLOGY HMPV outbreaks occur in annual epidemics during late winter and early spring in temperate climates, often overlapping with the second half of the annual RSV epidemic (Fig. 308.1). Sporadic infections occur year round. A near total decline of HMPV infections occurred in the 20202021 winter associated with COVID 19 public health measures, followed by a delayed or interseasonal outbreak in 2021. The usual period of viral shedding is likely to be many days or even several weeks after primary infection in infants. The incubation period is approximately 3 5 days. Humans are the only source of the virus; there is no known ani mal or environmental reservoir. Transmission occurs by close or direct contact with contaminated secretions involving large particle aerosols, droplets, or contaminated surfaces. Nosocomial infections have been reported, and contact isolation with excellent handwashing for health care providers is critical in medical settings. This virus also affects the elderly, immunocompromised patients, and patients with reactive air ways disease more severely than otherwise healthy individuals. PATHOLOGY Infection is usually limited to the superficial layer of airway epithelial cells and is associated with a local inflammatory infiltrate consisting of lymphocytes and macrophages. Immunocompromised individuals have evidence of both acute and organizing injuries during prolonged infection. PATHOGENESIS Infection occurs via inoculation of the upper respiratory tract. Infec tion can spread rapidly to the lower respiratory tract, but it is not clear whether the dissemination is mediated by cell to cell spread or by aspiration of infected materials from the upper tract. Severe lower respiratory tract illness, especially wheezing, occurs mainly during the first year of life, at a time when the airways are of a very small diameter and thus a high resistance. Maternal serum neutralizing anti bodies that cross the placenta may afford a relative protection against severe disease for several weeks or months after birth. Once infection is established, it |
7,826 | is likely that cytotoxic T cells recognize and eliminate virus infected cells, thus terminating the infection but also causing some cytopathology. The virus appears to have specific mechanisms for inhibiting T cell responses during acute infection. Individuals with an underlying predisposition for reactive airways disease (including adults) are susceptible to severe wheezing during reinfection later in life, suggesting that HMPV may cause smooth muscle hyperactivity, inflammation, or increased mucus production in such individuals. Infection in otherwise healthy individuals resolves without apparent long term consequences in most cases. HMPV infection is associated with exacerbations of asthma later in life. CLINICAL MANIFESTATIONS HMPV is associated with the common cold (complicated by otitis media in approximately 30 of cases) and with lower respiratory tract illnesses such as bronchiolitis, pneumonia, croup, and exacerbation of reactive airways disease. The profile of signs and symptoms caused by HMPV is similar to that caused by RSV (Table 308.1). Approximately 510 of outpatient lower respiratory tract illnesses in otherwise healthy young children are associated with HMPV infection, which is second in incidence only to RSV. Children with RSV or HMPV infec tion require supplemental oxygen and medical intensive care at similar frequencies. About half of the cases of HMPV lower respiratory tract illness in children occur in the first 6 months of life, suggesting that young age is a major risk factor for severe disease. Both young adults and the elderly can have HMPV infection that requires medical care, including hospi talization, but severe disease occurs at much lower frequencies in adults than in young children. Severe disease in pediatric and older subjects is most common in immunocompromised patients or those with com plications of preterm birth, congenital heart disease, and neuromus cular disease and can be fatal. A significant number of both adult and pediatric patients with asthma exacerbations have HMPV infection; it is not clear whether the virus causes long term wheezing. RSV and HMPV co infections have been reported; co infections may be more severe than infection with a single virus, resulting in pediatric intensive care unit admissions. It is difficult to define true co infections because these viral RNA genomes can be detected by a reverse transcriptase polymerase chain reaction (PCR) in respiratory secretions for at least several weeks after illness, even when virus shedding has terminated. LABORATORY FINDINGS The virus can be visualized only with electron microscopy. The virus grows in primary monkey kidney cells or LLC MK2 cell line or Vero cell line monolayer cultures in reference or research laboratories, but efficient isolation of the virus requires an experienced labora tory technician. Conventional bright field microscopy of infected cell monolayer cultures often reveals a cytopathic effect only after multiple passages in the cell culture. The characteristics of the cytopathic effect are not sufficiently distinct to allow identification of the virus on this basis alone, even by a trained observer. The most sensitive test for iden tification of HMPV in clinical samples is reverse transcriptase PCR, usually performed with primers directed to conserved |
7,827 | viral genes. Detection by this modality is also available in some multiplex PCR tests for panels of respiratory viruses. Real time reverse transcriptase PCR tests offer enhanced sensitivity and specificity, including assays designed to detect viruses from the four known genetic lineages. Direct Chapter 308 Human Metapneumovirus James E. Crowe Jr. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 308 u Human Metapneumovirus 2033 antigen tests for identification of HMPV antigens in nasopharyngeal secretions are available but are less efficient than nucleic acidbased detection. Some laboratories have success with the use of immuno fluorescence staining with monoclonal or polyclonal antibodies to detect HMPV in nasopharyngeal secretions and shell vial cultures or in monolayer cultures in which virus has been cultivated, with reported sensitivities varying from about 65 to 90. A fourfold rise in serum antibody titer to HMPV from the acute to convalescent time point can be used in research settings to confirm infection. DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS In temperate areas, the diagnosis should be suspected during the late winter in infants or young children with wheezing or pneumonia and a negative RSV diagnostic test result. The diseases caused by RSV and HMPV cannot be distinguished clinically. Many other common respi ratory viruses, such as parainfluenza viruses, influenza viruses, ade noviruses, rhinoviruses, enteroviruses, and coronaviruses, can cause similar disease in young children. Some of these viruses can be identi fied by PCR genetic testing or conventional cell culture means. Chest radiographs are not very specific, mostly showing parahilar opacities, hyperinflation, atelectasis, and, occasionally, consolidation but not pleural effusion or pneumothorax. COMPLICATIONS Bacterial superinfection of the lower airways is unusual but does occur. The local complication of otitis media is common, likely a result of eustachian tube dysfunction caused by the virus. TREATMENT There is no specific treatment currently for HMPV infection. A single small molecule drug inhibitor for HMPV is in clinical trials as of early 2022. Management consists of supportive care like that used for RSV (see Chapter 307). The rate of bacterial lung infection or bacteremia associated with HMPV infection is not fully defined but is suspected to be low. Antibiotics are usually not indicated in the treatment of infants hospitalized for HMPV bronchiolitis or pneumonia. Supportive Care Treatment is supportive and includes careful attention to hydration; monitoring of respiratory status by physical examination and measure ment of oxygen saturation; the use of supplemental oxygen, high flow nasal cannula therapy, and nasal continuous positive airway pressure in an intensive care unit for increased work of breathing; and, in the case of respiratory failure, mechanical ventilation. PROGNOSIS Most infants and children recover from acute HMPV infection without apparent long term consequences. Many experts believe an association exists between severe HMPV infections in infancy and the risk for recurrent wheezing or the development of asthma; however, it is not clear whether the virus |
7,828 | causes these conditions or precipitates their first manifestations. PREVENTION The only method of prevention of HMPV infection is reduction of exposure. Contact precautions are recommended for the duration of HMPV associated illness among hospitalized infants and young chil dren. The near total absence of HMPV infections during the first year of the COVID 19 pandemic suggests that nonpharmacologic interven tions (such as masking and distancing) are effective when compliance is high. Patients known to have HMPV infection should be housed in single rooms or with a cohort of HMPV infected patients. When feasi ble, it is wise to care for patients with RSV infection in a separate cohort from HMPV infected patients to prevent co infection, which may be associated with more severe disease. Preventive measures include lim iting exposure to contagious settings during annual epidemics (such as daycare centers) as much as possible and an emphasis on hand hygiene in all settings, including the home, especially during periods when the contacts of high risk children have respiratory infections. However, providers should keep in mind that infection is universal in the first several years of life. Therefore reduction of exposure makes the most sense during the first 6 months of life, when infants are at the highest risk for severe disease. Experimental HMPV vaccine candidates using live attenuated viruses or a messenger RNA (mRNA)encoded HMPV fusion protein gene are under study. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 60.0 50.0 40.0 30.0 20.0 10.0 0.0 o f e ac h vi ru s Novem ber 01 Decem ber 01 January 02 February 02 M arch 02 April 02 M ay 02 June 02 July 02 August 02 Septem ber 02 October 02 HMPV (n?68) RSV (n?101) FluA (n?77) Parainfluenza (n?36) Adenovirus (n?11) Fig. 308.1 Temporal distribution of respiratory viruses among chil dren hospitalized with lower respiratory tract infections from November 2001 through October 2002. Data are displayed as the proportion of each virus detected monthly. FluA, influenza A; HMPV, human metap neumovirus; RSV, respiratory syncytial virus. (From Wolf DG, Greenberg D, Kalkstein D, et al. Comparison of human metapneumovirus, respira tory syncytial virus and influenza A virus lower respiratory tract infections in hospitalized young children. Pediatr Infect Dis J. 2006;25:320324.) Table 308.1 Clinical Manifestations of Human Metapneumovirus in Children COMMON (50) Fever 38C (100.4F) Cough Rhinitis, coryza Wheezing Tachypnea, retractions Hypoxia (O2 saturation 94) Chest radiograph demonstration of infiltrates or hyperinflation LESS COMMON Otitis media Pharyngitis Rales RARE Conjunctivitis Hoarseness Encephalitis Fatal respiratory failure in immunocompromised children Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 2034 Part XV u Infectious Diseases Human adenoviruses (HAdVs) are a common cause of human dis ease. Conjunctivitis is a familiar illness associated with the HAdVs, but these viruses also cause upper and lower respiratory disease, pharyngi tis, gastroenteritis, and hemorrhagic cystitis. HAdVs can cause severe disease in immunocompromised |
7,829 | hosts. Outbreaks of HAdV infection occur in communities and closed populations, notably the military. No currently approved antiviral drugs are highly effective against HAdVs. Vaccines are available for HAdV types 4 and 7 but are used only in military populations. ETIOLOGY Adenoviruses are nonenveloped viruses with an icosahedral protein capsid. The double stranded DNA viral genome is contained within the particle complexed with several viral proteins. Antigenic variability in surface proteins of the virion and genomic sequencing define over 100 types, grouped into seven species. HAdV species differ in their tissue tropism and target organs, causing distinct clinical infections (Table 309.1). HAdVs can be shed from the gastrointestinal and respiratory tracts for prolonged periods and can establish persistent infection in mucosal lymphoid tissue. EPIDEMIOLOGY HAdVs circulate worldwide and cause endemic infections year round in immunocompetent hosts. Asymptomatic infections are also com mon. Epidemics of conjunctivitis (often severe), pharyngitis, and respiratory disease can occur, especially in schools, congregate living arrangements, and military settings. Outbreaks of febrile respiratory illness caused by HAdV 4 and HAdV 7 are major sources of morbidity in military barracks, with attack rates ranging from 25 to over 90. HAdV spread occurs by respiratory and fecal oral routes. An impor tant factor in HAdV transmission, especially in epidemics, is the ability of the nonenveloped particle to survive on inanimate objects in the environment. Nosocomial outbreaks have been reported. PATHOGENESIS HAdVs bind to cell surface receptors and trigger internalization by endocytosis. Acidification of the endosome induces conformational changes in the capsid, leading to eventual translocation of the genome to the cell nucleus. Viral messenger RNA transcription and genomic replication occur in the nucleus. Progeny virion particles assemble in the nucleus. Lysis of the cell releases new infectious particles and causes damage to epithelial mucosa, sloughing of cell debris, and inflammation. Host responses to HAdV infection include the recruit ment of neutrophils, macrophages, and natural killer cells to the site of infection and the elaboration by those cells of numerous cytokines and chemokines. This host immune response is likely to contribute to the symptoms of HAdV infection, but the strict species specificity of the adenoviruses has hindered detailed studies of HAdV pathogenesis in animal models. Studies using HAdV in Syrian hamsters, which are permissive for HAdV replication, and in a humanized mouse model have provided some insight. Mouse adenoviruses have also been used to study adenovirus pathogenesis using a murine model. CLINICAL MANIFESTATIONS HAdVs cause a variety of common clinical syndromes in both immu nocompetent and immunocompromised hosts. These syndromes are difficult to reliably distinguish from similar illnesses caused by other pathogens, such as respiratory syncytial virus, human metapneumo virus, human rhinovirus, rotavirus, group A Streptococcus, and other common viral and bacterial pathogens. Acute Respiratory Disease Respiratory tract infections are common manifestations of HAdV infections in children and adults. HAdVs cause an estimated 510 of all childhood respiratory diseases. Primary infections in infants may manifest as bronchiolitis or pneumonia. HAdV pneumonia may pres ent with features more typical of bacterial |
7,830 | disease (lobar infiltrates, high fever, parapneumonic effusions). HAdV 14 has emerged as a sig nificant cause of severe acute respiratory disease in military and civil ian populations, in some cases leading to hospitalization and death. Pharyngitis caused by HAdV infection typically includes symptoms of coryza, sore throat, and fever. The virus can be identified in 1520 of children with isolated pharyngitis, mostly in preschool children and infants. Ocular Infections The common follicular conjunctivitis caused by HAdV infection is self limiting and requires no specific treatment. A more severe form called epidemic keratoconjunctivitis involves the cornea and conjunctiva. Pharyngoconjunctival fever is a distinct syndrome that includes a high temperature, pharyngitis, nonpurulent conjunctivitis, and preau ricular and cervical lymphadenopathy. Gastrointestinal Infections HAdV can be detected in the stools of 510 of children with acute diarrhea. Most cases of acute diarrhea are self limiting, although severe disease can occur. Enteric infection with HAdV is often asymptomatic, and shedding of virus after acute infection can be prolonged, so the causative role in these episodes is frequently uncertain. HAdV infec tion may also cause mesenteric adenitis. Hemorrhagic Cystitis Hemorrhagic cystitis consists of a sudden onset of hematuria, dysuria, frequency, and urgency with negative urine bacterial culture results. Urinalysis may show sterile pyuria in addition to hematuria. This ill ness occurs more frequently in young males and typically resolves on its own in 1 2 weeks. Other Complications Less frequently, HAdVs are associated with myocarditis, hepatitis, or meningoencephalitis in immunocompetent individuals. Adenoviruses in Immunocompromised Patients Immunocompromised persons, particularly recipients of hematopoi etic stem cell transplants (HSCTs) and solid organ transplants, are at high risk for severe and fatal disease caused by HAdV. These patients may experience primary HAdV infection, but reactivation of persistent virus in a transplant recipient or transmission of virus from a donor organ may also occur. Organ failure as a consequence of pneumonia, hepatitis, gastroenteritis, andor disseminated infection can occur in these immunocompromised patients. HAdV infection in HSCT recipi ents commonly manifests as pulmonary or disseminated disease and is most likely to occur in the first 100 days after transplantation. Hem orrhagic cystitis caused by HAdV can be severe in HSCT recipients. Infections caused by HAdV in solid organ transplant recipients usu ally involve the transplanted organ. Immunocompromised children are at greater risk than immunocompromised adults for complicated HAdV infection, presumably because of a lack of preexisting immu nity. Additional risk factors include T celldepleted grafts, high level immunosuppression, and the presence of graft versus host disease. Some experts advocate a preemptive screening approach to detect and treat HAdV infection early in immunocompromised patients, with the intent to prevent dissemination and severe illness in this vulnerable population, though no highly effective antiviral therapy exists. DIAGNOSIS HAdV may be suspected as the etiology of an illness on the basis of epidemiologic or clinical features, but neither of these categories is spe cific enough to firmly establish the diagnosis. The frequency of asymp tomatic shedding of HAdV makes assigning causality to this pathogen Chapter 309 |
7,831 | Adenoviruses Terri L. Stillwell and Jason B. Weinberg Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 310 u Rhinoviruses 2035 difficult. Although most HAdV serotypes grow well in culture, culture based identification requires several days and thus is not helpful for early identification, and most clinical microbiology laboratories no longer perform viral cultures on a routine basis. Cells from respira tory or ocular specimens can be tested using immunofluorescent stain ing with antibodies to detect HAdV protein. Commercially available enzyme linked immunoassays can be used to rapidly detect HAdV in patient specimens, usually in stool. Multiplex molecular assays capable of identifying HAdV, in addition to other pathogens, are increasingly available and useful for rapid diagnosis. Specific diagnosis of HAdV infections are most clinically useful in immunocompromised hosts. In these patients, measurement of the HAdV genome copy number (viral load) using quantitative real time polymerase chain reaction can facilitate diagnosis, and repeated measurements can aid in assessing a patients response to treatment. Serology is generally useful only in epidemiologic investigations. COMPLICATIONS HAdV pneumonia can lead to respiratory failure requiring mechani cal ventilation, especially in immunocompromised patients. Secondary bacterial pneumonia does not appear to be as common after HAdV infection as it is after influenza infection, but data that address this issue are limited. Severe HAdV pneumonia has been linked to chronic lung disease and bronchiolitis obliterans in a minority of cases. Epi demic keratoconjunctivitis is a vision threatening form of HAdV infection. Nearly any form of HAdV infection can be fatal in an HSCT or solid organ transplant recipient. Refractory severe anemia requiring repeated blood transfusions can develop in HSCT recipients with hem orrhagic cystitis. Mortality rates of up to 6080 have been reported in transplant recipients with disseminated HAdV or HAdV pneumonia. TREATMENT Supportive care is the mainstay of treatment for HAdV infections. Patients with severe HAdV conjunctivitis should be referred for oph thalmologic consultation. The nucleoside analog cidofovir has in vitro activity against most HAdV serotypes. Cidofovir is used topically to treat epidemic keratoconjunctivitis, often in conjunction with topical steroids or other immunosuppressive agents to limit the inflammatory component of the disease process. Cidofovir may be used intravenously for HAdV infections in immunocompromised patients. Cidofovir is highly nephrotoxic, but prehydration, concomitant administration of probenecid, and weekly dosing may reduce nephrotoxicity. Clinical studies suggest some benefit from cidofovir, but there are no prospec tive randomized controlled trials of cidofovir for HAdV infection. In addition, no formal guidelines or recommendations for treatment exist. The cidofovir derivative brincidofovir is better tolerated than cidofovir and has been evaluated as treatment of HAdV disease in immuno compromised patients, but it is not currently available for clinical use. Adoptive immunotherapy involving the infusion of HAdV specific T cells may also provide some benefit for immunocompromised patients with life threatening HAdV infections. PREVENTION Environmental and fomite transmission of HAdV |
7,832 | occurs readily; therefore simple measures such as handwashing and cleaning are likely to reduce spread. Live attenuated HAdV 4 and HAdV 7 vaccines were used effectively in the U.S. military from the 1970s until 1999. Cessa tion of their use led to widespread outbreaks in barracks, and those vaccines were subsequently reintroduced into military use. However, no HAdV specific vaccines are available for routine use. HAdVs are highly immunogenic and have been used as gene therapy vectors and vaccine vectors for other pathogens, including malaria, HIV, and SARS CoV 2. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Table 309.1 Examples of Human Adenovirus Types and Common Manifestations of Disease SPECIES TYPE COMMON DISEASE ASSOCIATIONS A 12, 18, 31, 61 Gastroenteritis B 3, 7, 11, 14, 16, 21, 34, 35, 50, 55, 66 Pharyngitis, pharyngoconjunctival fever, acute respiratory disease, pneumonia, hemorrhagic cystitis C 1, 2, 5, 6, 57 Pharyngitis D 8 10, 13, 15, 17, 19, 20, 22 30, 32, 33, 36 39, 42 49, 51, 53, 54, 56, 58 60, 63 67, 69, 70 75 Epidemic keratoconjunctivitis E 4 Acute respiratory disease F 40, 41 Gastroenteritis G 52 Gastroenteritis Human rhinoviruses (HRVs) are the most frequent cause of the com mon cold in both adults and children. Although HRVs were once thought to cause only the common cold, it is now known that they are also associated with lower respiratory infections in adults and children. Many HRVs do not grow in culture. Recent studies using molecular diagnostic tools such as the polymerase chain reaction (PCR) have revealed that HRVs are leading causes of both mild and serious respi ratory illnesses in children. ETIOLOGY HRVs are members of the Picornaviridae family (pico small; rna RNA genome). Traditional methods of virus typing using immune antiserum have identified approximately 100 serotypes, classified into HRVA, HRVB, and, recently, HRVC species based on the genetic sequence similarity. HRVCs can be detected by reverse transcriptase PCR but have been cultured only using highly specialized methods. Virus gene sequence analysis demonstrates that HRVCs are a geneti cally distinct and diverse species. The increased proportions of HRV reported in recent PCR based studies are likely the result of detection of these previously unknown HRVC viruses in addition to improved detection of known HRVA and HRVB strains. Chapter 310 Rhinoviruses Katherine M. Richardson and Jennifer E. Schuster Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 2036 Part XV u Infectious Diseases EPIDEMIOLOGY Rhinoviruses are distributed worldwide. There is no consistent correla tion between serotypes and epidemiologic or clinical characteristics. Several studies suggest that HRVCs may be more strongly associated with lower respiratory infection and asthma, and HRVC has been associated with children admitted to intensive care units with asthma exacerbations, bronchiolitis, and pneumonia. However, more studies are needed to determine severity compared with other HRVs. Multiple types circulate in a community simultaneously, and |
7,833 | HRV strains may be isolated during consecutive epidemic seasons, suggesting persis tence in a community over an extended period. In temperate climates, the incidence of HRV infection peaks in the fall, with another peak in the spring, but HRV infections occur year round. HRVC appears to circulate with seasonal variation, exchanging dominance with HRVA. HRVs are the major infectious trigger for asthma among young chil dren, and numerous studies have described a sharp increase in asthma attacks in this age group when school opens in the fall. The peak HRV incidence in the tropics occurs during the rainy season, from June to October. HRVs are present in high concentrations in nasal secretions and can be detected in the lower airways. HRV particles are nonenveloped and quite hardy, persisting for hours to days in secretions on hands or other surfaces such as telephones, light switches, doorknobs, and stethoscopes. Sneezing and coughing are inefficient methods of trans fer. Transmission occurs when infected secretions carried on contami nated fingers are rubbed onto the nasal or conjunctival mucosa. HRVs are present in aerosols produced by talking, coughing, and sneezing. Children are the most important reservoir of these viruses. PATHOGENESIS The majority of HRVs infect respiratory epithelial cells via intercellu lar adhesion molecule 1, but some HRV strains utilize the low density lipoprotein receptor. The receptor for HRVC is cadherin related fam ily member 3 (CDHR3); however, distinct genetic alleles encoding this protein confer different susceptibility to HRVC infection. Infection begins in the nasopharynx and spreads to the nasal mucosa and, in some cases, to bronchial epithelial cells in the lower airways. There is no direct cellular damage from the virus, and it is thought that many of the pathogenic effects are produced by the host immune response. Infected epithelial cells release a number of cytokines and chemokines, which induce an influx of neutrophils to the upper airway. Both innate and adaptive immune mechanisms are important in HRV pathogen esis and clearance. HRV specific nasal immunoglobulin (Ig) A can be detected on day 3 after infection, followed by the production of serum IgM and IgG after 7 8 days. Neutralizing IgG to HRVs may prevent or limit the severity of illness after reinfection. However, cross protec tion by antibodies to different HRV serotypes is limited in breadth and duration, allowing recurrent infection. Both allergen exposure and elevated IgE values predispose patients with asthma to more severe respiratory symptoms in response to HRV infection. Abnormalities in the host cellular response to HRV infection that result in impaired apoptosis and increased viral replication may be responsible for the severe and prolonged symptoms in individuals with asthma. CLINICAL MANIFESTATIONS Most HRV infections produce clinical symptoms, but many are asymp tomatic. Symptomatic HRV infection induces a much more robust host immune response in the blood than asymptomatic infection. After an incubation period of 1 4 days, typical symptoms of sneezing, nasal congestion, rhinorrhea, and sore throat develop. Cough and hoarse ness are present in one third of cases. Fever |
7,834 | is less common with HRV than with other common respiratory viruses, including influenza virus, respiratory syncytial virus (RSV), and human metapneumovirus. However, HRV was detected in 35 of febrile infants less than 90 days of age. Symptoms are frequently more severe and last longer in chil dren, with 70 of children compared with 20 of adults still reporting symptoms by day 10. Virus can be shed for as long as 3 weeks. When HRV is detected 30 days from the initial illness, it is more likely to be a genotypically different strain of HRV. HRVA and HRVC are more commonly associated with symptomatic HRV infection compared with HRVB. HRVs are the most prevalent agents associated with acute wheez ing, otitis media, and hospitalization for respiratory illness in children and are an important cause of severe pneumonia and exacerbation of asthma or chronic obstructive pulmonary disease in adults. HRV associated hospitalizations are more frequent in young infants than in older children and in children with a history of wheezing or asthma. Children hospitalized with HRV bronchiolitis are more likely to be older and have a history of wheezing than children with bronchiolitis caused by RSV. HRV infection in immunocompromised hosts may be life threatening. Certain strains or species of HRV, namely HRVC, may be more pathogenic than others. DIAGNOSIS Culturing HRVs is labor intensive and of relatively low yield. Sensitive and specific diagnostic methods based on reverse transcriptase PCR are commercially available. However, because commercially available reverse transcriptase PCR tests do not identify the HRV types, it can be difficult to distinguish prolonged shedding from newly acquired infec tion. An important caveat of HRV detection is the fact that HRV infec tion can be asymptomatic, and thus the presence of the virus does not prove causality in all cases. Serology is impractical because of the great number of HRV serotypes. A presumptive clinical diagnosis based on symptoms and seasonality is not specific, because many other viruses cause similar clinical illnesses. Rapid detection techniques for HRV might lessen the use of unnecessary antibiotics or procedures. COMPLICATIONS Possible complications of HRV infection include sinusitis, otitis media, asthma exacerbation, bronchiolitis, pneumonia, and, rarely, death. HRV associated wheezing during infancy is a significant risk factor for the development of childhood asthma. In particular, this association has been noted with HRVA and HRVC, which have been associated with greater risk for recurrence of both wheezing and new infection with HRV. This effect appears to remain until adulthood, but the mechanisms have not been elucidated. One large study determined that genetic variants at the 17q21 locus were associated with asthma in children who had experienced HRV wheezing illnesses during infancy. A prospective study on a preterm cohort showed that a single nucleo tide polymorphism on the gene coding for the vitamin D receptor was associated with development of lower respiratory infection with HRV. Further studies are required to determine the likely multiple genetic and environmental factors that contribute to HRV related asthma. TREATMENT Supportive care is the |
7,835 | mainstay of HRV treatment. The symptoms of HRV infection are commonly treated with analgesics, decongestants, antihistamines, or antitussives. Data are limited on the effectiveness of such nonprescription cold medications for children. If bacterial super infections are highly suspected or diagnosed, antibiotics may be appro priate. Antibiotics are not indicated for uncomplicated viral upper respiratory infection. There are no licensed antivirals. PREVENTION Good handwashing remains the mainstay of the prevention of HRV infection and should be reinforced frequently, especially in young children, the predominant vectors for disease. Vaccines have not been successfully developed because of the numerous HRV sero types and limited cross protection between serotypes. However, a polyvalent inactivated vaccine showed promise in a nonhuman primate. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 311 u Coronaviruses 2037 Coronaviruses are increasingly recognized as important human pathogens. Currently there are seven known coronaviruses that have been found to infect humans. Four coronaviruses are endemic in humans: human coronaviruses (HCoVs) 229E, OC43, NL63, and HKU1. These CoVs cause up to 15 of common colds and have been implicated in more serious diseases, including croup, asthma exacerbations, bronchiolitis, and pneumonia. Evidence also sug gests that coronaviruses may cause enteritis and might also be agents of meningitis or encephalitis. The fifth identified HCoV, SARS associated coronavirus (SARS CoV), the etiologic agent of severe acute respiratory syndrome (SARS), emerged in 2003 and caused a world wide pandemic resulting in over 8,000 cases with an estimated case fatality rate of 10 before circulation ceased because of implementation of world wide public health measures. Similarly, Middle East respiratory syndrome coronavirus (MERS CoV), the sixth identified HCoV, first emerged in 2012 causing significant respiratory distress with very high mortality rates. MERS CoV con tinues to cause local cases and outbreaks likely as a result of con tinued emergent events from its animal reservoir. Likely because of their high mortality, lower transmissibility, and lack of asymptom atic or presymptomatic spread, neither SARS CoV nor MERS CoV became endemic viruses. In 2019 a seventh human coronavirus, SARS CoV 2, emerged as the etiologic agent of novel coronavirus disease 2019 (COVID 19), resulting in a multiyear and ongoing global pandemic with mul tiple waves of circulating variants and disease burden exceeding any prior respiratory virus pandemic, including the 1918 influenza pan demic. The ultimate trajectory of SARS CoV 2 global circulation is unclear, but it is likely that this virus will evolve to become the fifth endemic human coronavirus. The emergence of three distinct human coronaviruses resulting in world wide pandemics in the past 2 decades emphasizes the potential for coronaviruses to emerge from animal hosts and become important human pathogens. ETIOLOGY Coronaviruses are enveloped viruses of medium to large size (80 220 nm) that possess the largest known single stranded positive sense RNA genomes. These viruses |
7,836 | encode the protein nsp14 ExoN, which is the first known RNA proofreading enzyme and is likely responsible for the evolution of the large and complex coronavi rus genome. Coronaviruses derive their name from the character istic surface projections of the spike protein, giving a corona or crownlike appearance on negative stain electron microscopy. The human coronaviruses are all part of the order Nidovirales, suborder Cornidovirineae, family Coronaviridae, and subfamily Orthocoro navirinae. The subfamily Orthocoronavirinae is further subdivided into four genera based on genomic phylogenetic relationships. The genus alphacoronavirus includes HCoV 229E and HCoV NL63. The remaining 5 HCoVs fall within the genus betacoronavirus. HCoV OC43 and HCoV HKU1 are in the subgenus Embecovirus, MERS CoV is in the subgenus Merbecovirus, and SARS CoV 1 and SARS CoV 2 are in the subgenus Sarbecovirus (species severe acute respiratory syndrome related coronavirus). Gammacoronaviruses and deltacoronaviruses presently include exclusively nonhuman pathogens. Coronaviruses received international attention during the SARS outbreak, which was responsible for more than 800 deaths in 30 countries. SARS CoV, a novel coronavirus at the time of the epi demic, was found to be the causative agent of SARS. The detection of SARS like coronaviruses in a live animal market in the Guang dong province in Southern China, along with serologic evidence of exposure in food handlers in the same market, suggest that these markets facilitated the spread of SARS CoV to humans from an animal reservoir. Subsequent studies identified SARS like corona viruses in fecal specimens from asymptomatic Chinese horseshoe bats that are very closely related to SARS CoV and are capable of infecting human cells. Thus SARS CoV likely originated in bats and was transmitted to humans via an intermediary animal host such as the palm civet. Another novel coronavirus, MERS CoV, was first isolated from a man with acute pneumonia and renal failure in Saudi Arabia. As of late 2023, the World Health Organization (WHO) had recorded 2,605 confirmed cases of MERS in 27 countries, with 937 deaths worldwide (36 mortality rate). MERS CoV differs from SARS in that it seems to be less communicable, although human to human transmission has been documented. MERS CoV uses dipeptidyl peptidase 4 and carcinoembryonic antigenlike cell adhesion mol ecule 5 as its cellular receptor and co receptor, respectively, whereas SARS CoV and SARS CoV 2 use the angiotensin converting enzyme 2 receptor. With this receptor specificity, MERS CoV can infect cells from several animal lineages, including human, pig, and bat, suggesting the possibility of movement between multiple species. EPIDEMIOLOGY Endemic Coronaviruses Seroprevalence studies have demonstrated that antibodies against endemic coronaviruses 229E and OC43 increase rapidly during early childhood, so that by adulthood 90100 of persons are seropositive. Although less information is available for HKU1 and NL63, available studies demonstrate similar patterns of seroconver sion to these viruses during early childhood. Seroprevalence studies have also suggested that prevalence rates may differ by geographic region. Although some degree of strain specific protection may be afforded by recent infection, reinfections are common and occur |
7,837 | despite the presence of strain specific antibodies. Attack rates are similar in different age groups. Although infections occur through out the year, there is a peak during the winter and early spring for each of these HCoVs. In the United States, outbreaks of OC43 and 229E have occurred in 2 to 3 year alternating cycles. Independent studies of viral etiologies of upper and lower respiratory infections during the same period, but from different countries, have con firmed that all known HCoVs have a worldwide distribution. Stud ies using both viral culture and polymerase chain reaction (PCR) multiplex assays demonstrate that coronaviruses often appear in co infections with other respiratory viruses. Volunteer studies demon strated that OC43 and 229E are transmitted predominantly through the respiratory route. Droplet spread appears to be most important, although aerosol transmission may also occur. SARS CoV There have been no identified natural or laboratory acquired cases of SARS CoV since 2004, but the mechanisms of introduction, spread, and disease remain important for potential animal to human transmission and disease. The primary mode of SARS CoV transmission occurred through direct or indirect contact of mucous membranes with infectious droplets or fomites. Aerosol trans mission was less common, occurring primarily in the setting of endotracheal intubation, bronchoscopy, or treatment with aerosol ized medications. Fecal oral transmission did not appear to be an efficient mode of transmission but may have occurred because of the profuse diarrhea observed in some patients. The seasonality of SARS CoV remains unknown. SARS CoV is not highly infectious, Chapter 311 Coronaviruses Samuel R. Dominguez and Roberta L. DeBiasi Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 2038 Part XV u Infectious Diseases with generally only two to four secondary cases resulting from a single infected adult. During the SARS epidemic, a small number of infected individuals, superspreaders, transmitted infection to a much larger number of persons, but the mechanism for this high degree of spread remains unknown. In contrast, persons with mild disease, such as children younger than 12 years of age, rarely transmitted the infection to others. Infectivity correlated with dis ease stage; transmission occurred almost exclusively during symp tomatic disease. During the 2003 outbreak, most individuals with SARS CoV infection were hospitalized within 3 4 days of symptom onset. Consequently, most subsequent infections occurred within hospitals and involved either healthcare workers or other hospital ized patients. MERS CoV As of late 2023, the WHO had recorded cases of MERS CoV in 27 countries, all of which were linked to exposures in the Arabian Penin sula (80 in Saudi Arabia). Though the route of transmission between animals and humans is not fully understood, MERS CoV is proposed to have repeatedly entered the human population through contact with respiratory secretions of dromedary camels and possibly with raw camel products (e.g., unpasteurized milk). Antibodies to MERS CoV are found |
7,838 | in dromedaries throughout the Middle East, and strains identical to human MERS CoV isolates have been found in camels in Egypt, Oman, Qatar, and Saudi Arabia. These strains do not appear to be highly pathogenic or virulent in camels and have likely circulated within dromedaries for 30 years. Despite well documented zoonotic transmission, most reported cases occur through linked human to human transmission in healthcare settings, including outbreaks in Jor dan, South Korea, and Saudi Arabia in 2015 and 2016. Risk factors for nosocomial MERS CoV outbreaks include overcrowded emergency departments, delayed diagnosis or isolation, and poor infection control practices. Transmission most likely occurs through respiratory drop lets and is thus a greater risk during aerosol generating procedures. Outside of healthcare settings, human to human transmission has been infrequently documented and is primarily associated with close contact within households. CLINICAL MANIFESTATIONS Endemic Coronaviruses: Respiratory Manifestations Even though up to 50 of respiratory tract infections with OC43 and 229E are asymptomatic, coronaviruses are still responsible for up to 15 of common colds and can cause fatal disease. Cold symp toms caused by HCoVs are indistinguishable from those caused by rhinoviruses and other respiratory viruses. The average incubation period is 2 4 days, with symptoms typically lasting 4 7 days. Rhi norrhea, cough, sore throat, malaise, and headache are the most common symptoms. Fever occurs in up to 60 of cases. Corona virus NL63 is a cause of croup in children younger than 3 years of age. Coronavirus infections are linked to episodes of wheezing in asthmatic children, albeit at a lower frequency and severity than observed with rhinovirus and respiratory syncytial virus infections. Lower respiratory tract infections, including bronchiolitis and pneumonia, are also reported in immunocompetent and immu nocompromised children and adults. As with respiratory syncytial virus or rhinovirus, coronavirus detection in upper respiratory infections is frequently associated with acute otitis media and can be isolated from middle ear fluid. Endemic Coronaviruses: Nonrespiratory Manifestations There is prior evidence to support a role for coronaviruses in human gastrointestinal disease, particularly in young children. Coronavirus like particles have been detected by electron micros copy in the stools of infants with nonbacterial gastroenteritis. In addition, several outbreaks in neonatal intensive care units (ICUs) of gastrointestinal disease characterized by diarrhea, bloody stools, abdominal distention, bilious gastric aspirates, and classic necro tizing enterocolitis have also been associated with the presence of coronavirus like particles in stools. In older children and adults, coronavirus like viruses have been observed with similar frequency in symptomatic and asymptomatic individuals, making it difficult to discern if they are pathogenic in the gastrointestinal tract. Addi tionally, more recent studies using PCR assays of stool from children with gastroenteritis have infrequently found HCoVs. Coronaviruses are well known causes of neurologic disease in animals, including demyelinating encephalitis, but their role in causing human neuro logic disease remains unclear. Several studies have found an asso ciation of HCoVs, particularly HCoV HKU1, with febrile seizures in young children. HCoVs have been detected by culture, in situ |
7,839 | hybridization, and reverse transcriptase PCR (RT PCR) in brain tissue from a few patients with multiple sclerosis. HCoV OC43 has been detected by RT PCR in the spinal fluid, nasopharynx, or brain biopsy specimens of two children with acute encephalomyelitis. However, coronavirus RNA has also been recovered from the spinal fluid and brain tissue of adults without neurologic disease. Severe Acute Respiratory SyndromeAssociated Coronavirus During the 20022003 global outbreak of SARS, the incubation period for SARS CoV ranged from 1 14 days, with a median of 4 6 days. SARS CoV infections in teenagers and adults included a viral replication phase and an immunologic phase. During the viral rep lication phase, there was a progressive increase in viral load that reached its peak during the second week of illness. The appearance of specific antibodies coincided with peak viral replication. Clini cal symptoms were nonspecific, most commonly consisting of fever, cough, malaise, coryza, chills or rigors, headache, and myalgia. Gas trointestinal symptoms, including diarrhea and nausea or vomiting, occurred in up to one third of cases. The clinical deterioration that typified the second and third week of illness was characterized by a decline in the viral load and evidence of tissue injury, likely from cytokine mediated immunity. Seroepidemiologic studies suggest that asymptomatic SARS CoV infections were uncommon. The clinical course of SARS CoV infection varied with age. Adults were most severely affected, with initial onset of fever, cough, chills, myalgia, malaise, and headache. Following an initial improvement at the end of the first week, fever recurred, and respiratory distress developed, with dyspnea, hypox emia, and diarrhea. These symptoms progressed in 20 of patients to acute respiratory distress syndrome and respiratory failure. Adolescents manifested increasing severity in direct correlation to increasing age; respiratory distress and hypoxemia were observed in 1020 of patients, one third of whom required ventilator support. Acute renal failure with histologic acute tubular necrosis was pres ent in 6.9 of patients overall, likely a result of hypoxic kidney dam age. Of SARS patients, 28.8 had abnormal urinalysis, with viral genome detectable by quantitative RT PCR. The case fatality rate from SARS CoV infection during the 2003 outbreak was 1017. No pediatric deaths were reported. The estimated case fatality rate according to age varied from 1 for those younger than 20 years of age to 50 for those older than 65 years of age. In contrast, children younger than 12 years of age had a relatively mild nonspecific illness, with only a minority experiencing significant lower respiratory tract disease and illness typically lasting less than 5 days. Some young children had no respiratory symptoms. Coryza was more common in children younger than 12 years of age, whereas systemic symptoms were seen more often in teenagers. There were no deaths or cases of acute respiratory distress syndrome in children younger than 12 years of age from SARS CoV infection. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. |
7,840 | No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 311 u Coronaviruses 2039 Middle East Respiratory Syndrome Coronavirus The incubation period of MERS CoV is 2 14 days. The syndrome usually presents with nonspecific clinical features typical of acute febrile respiratory illnesses, including low grade fever, rhinorrhea, sore throat, and myalgia. In mildly symptomatic cases, radiographic findings are typically normal. Severe disease is characterized by the acute respiratory distress syndrome with multilobular airspace dis ease, ground glass opacities, and occasional pleural effusions on radiography. The median time between hospitalization and ICU transfer for critical illness is 2 days. Risk factors for severe disease include age 50 years and comorbidities such as obesity, diabetes, chronic obstructive pulmonary disease (COPD), end stage renal disease, cancer, and immunosuppression. Specific host genetic risk factors have not been identified. Variation in clinical outcomes does not appear to be explained by viral strain specific sequence vari ability. As with SARS, extrapulmonary manifestations are common in severe MERS disease. Gastrointestinal symptoms such as nausea, vomiting, and diarrhea occur in one third of patients, and acute kidney injury has been documented in half of critically ill patients. Encephalitis like neurologic manifestations have been observed in three cases. Laboratory analyses typically detect leukopenia and lymphopenia, with occasional thrombocytopenia, anemia, and aminotransferase elevations. The case fatality rate remains at 35, though the true incidence of MERS CoV infection is likely under estimated by existing data. Most patients have been adults, although children as young as 9 months of age have been infected. It is not known whether children are less susceptible to MERS CoV or pres ent with a different clinical picture. DIAGNOSIS With the advent of commercially available, syndromic, multiplex PCR respiratory panels, respiratory infections due to the four endemic HCoVs are now easily diagnosed and widely available in most clinical settings. These panels have rapid turnaround times, excellent sensitivity and specificity, and most commonly use upper respiratory tract specimens. Virus culture of primary clinical specimens remains a challenge for HCoVs HKU1, OC43, 229E, and NL63, even though the epidemic coronaviruses can successfully be grown in culture from respiratory samples. Sero diagnosis with complement fixation, neutralization, hemaggluti nation inhibition, enzyme immunoassay, and Western blots have been used in the research setting. The diagnosis of SARS CoV infection can be confirmed by serologic testing, detection of viral RNA using RT PCR, or isolation of the virus in cell culture. Even though the serology for SARS CoV has a sensitivity and specific ity approaching 100, antibodies are not detectable until 10 days after the onset of symptoms, and immunoglobulin (Ig) G serocon version may be delayed for up to 4 weeks. The diagnosis of MERS CoV should be guided by clinical features and an epidemiologic link. The mainstay for laboratory confirmation of MERS CoV infection is real time RT PCR. The best diagnostic sensitivity is achieved from lower respiratory tract samples collected within the first week of infection, though MERS CoV RNA can be detected in upper |
7,841 | respiratory and blood samples. Alternatively, serocon version can be documented by screening enzyme linked immuno sorbent assays followed by immunofluorescence microscopy. For all known endemic and emerging HCoVs, respiratory specimens (nasopharyngeal swabs or aspirates) are most likely to be positive, but in a setting of a possible novel coronavirus, saliva, serum, or stool may also be positive. TREATMENT AND PREVENTION Several antiviral agents are available for clinical use against coro naviruses targeting the conserved coronavirus protease and poly merase. Ribavirin was extensively used during the 2003 SARS CoV outbreak but is of questionable benefit given its poor in vitro activ ity against SARS CoV at clinically relevant concentrations. Challenges for the development of effective vaccines targeted against OC43, 229E, HKU1, and NL63 include the fact that infec tions are rarely life threatening and reinfection is the rule, even in the presence of natural immunity from previous infections. The durability of immunity to SARS CoV and MERS CoV is poorly understood. Nevertheless, effective vaccines for SARS CoV and MERS CoV are highly desirable but not yet available. Visit Elsevier eBooks at eBooks.Health.Elsevier.com Bibliography. 311.1 COVID 19 Samuel Dominguez and Roberta L. DeBiasi New variants may evolve: recommendations for treatment and preven tion may change. See Centers for Disease Control and Prevention for updates. SARS CoV 2 first emerged in Wuhan China in December 2019 as the etiologic agent of a severe respiratory illness termed COVID 19. Despite measures to contain transmission, SARS CoV 2 rapidly spread globally, resulting in declaration of a worldwide pandemic by March 2020. As of late 2023, over 770 million cases and nearly 7 million deaths have occurred globally due to SARS CoV 2. Ongo ing transmission has led to the emergence of sequential variants (e.g., Delta, Omicron, BA.2, BA.5, BQ, XBB1.5 variants) with pro gressively unique gene variants in the receptor binding domain of the spike protein, conferring increased transmissibility compared to the parent strain (Alpha variant). Gene changes in some variants have been associated with reduced susceptibility to monoclonal antibody therapeutics andor reduced neutralization by convales cent and vaccine induced antibodies, promoting immune escape and breakthrough infections in previously infected andor immu nized individuals and ongoing community transmission. EPIDEMIOLOGY SARS CoV 2 transmission occurs from human to human primarily by respiratory droplet, as well as by aerosol transmission, with the highest rates of transmission occurring from 2 days prior to 2 3 days after symptom onset. Transmission is quite common among asymptomatic or presymptomatic infected patients. Close contact (conversation distance) increases the risk; normal conversation as well as coughing, sneezing, singing, or just breathing are mecha nisms. Immunocompromised hosts may shed infectious virus for longer periods of time, up to 21 days or more after symptom onset. Spread within households and close communal settings is com mon; transmission has been confirmed from infants, toddlers, and school age children (who may have very high viral loads in the anterior nares even with asymptomatic or mild infection) and from adolescents to adult household members as well as |
7,842 | from adults to children. A metanalysis of household secondary transmission has identified household secondary attack rates of nearly 17, which exceeds that for SARS CoV (7.5) and MERS CoV (4.7). Second ary attack rates within households are increased from symptom atic compared to asymptomatic index cases, in adults compared to children, in spouses compared to other household members, and in households with three or more contacts. Throughout the pandemic, it has been noted that transmission is increased in unvaccinated compared to vaccinated individuals. Young children were initially reported to be less likely to be infected or more likely to be asymptomatic with SARS CoV 2 (alpha, delta strains) than adults and unlikely to develop severe disease. However, despite overall lower rates of hospitalization and death, children are efficiently infected and can develop severe dis ease (usually older children and adolescents) that results in hospi talization, ICU admission, and occasional death (mortality 0.5); the majority of young children experience mild to moderate illness. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 2040 Part XV u Infectious Diseases As of spring 2023, over 15 million laboratory confirmed infections and nearly 40,000 hospitalizations have occurred cumulatively in U.S. children 18 years of age, representing 13 of overall infec tions and up to 4.5 of hospitalizations in the United States. Young children under 5 years of age have made up a relatively increased proportion of cases and hospitalizations during later stages of the pandemic (late variants) presenting more with upper respiratory infection, croup, or bronchiolitis (Fig. 311.1). Milder illness may be due to less virulent variants or prior immunity from vaccination or infection; morbidity and mortality have remained low compared to adults, despite the increased transmissibility of more recent variants. Early in the pandemic, a post infectious hyperinflammatory com plication of SARS CoV 2 infection termed multisystem inflammatory syndrome of children (MIS C; also referred to as pediatric inflamma tory multisystem syndrome temporally associated with COVID19, PIMSTS) was recognized. MIS C is associated with higher acuity in older children and initially was associated with higher rates of mor tality due to hemodynamic instability, myocardial dysfunction, and cardiovascular collapse. With better recognition of this syndrome, key 0 25 50 75 100 Jan 2022 Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec Jan 2023 Feb Mar Apr May Month and year of specimen collectionA B P er ce nt ag e of to ta l li ne ag es Percentage of SARSCoV2 variants 0.2 0.4 0.6 0.8 1 2 3 4 5 Jan 2022 Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec Jan 2023 Feb Mar Apr May Month and year of specimen collection N o. o f c as es ( m ill io ns ) B.1.617.2 B.1.1.529 BA.1.1 BA.2 BA.2.12.1 BA.2.75 BA.2.75.2 BA.4 BA.4.6 BA.5 CH.1.1 BN.1 BF.7 BF.11 BA.5.2.6 BQ.1 BQ.1.1 |
7,843 | XBB XBB.1.5 XBB.1.5.1 XBB.1.9.1 XBB.1.9.2 FD.2 XBB.1.16 XBB.2.3 Other Estimated number of variantattributed COVID19 cases Mar 19, 2022 Fig. 311.1 National weekly proportion estimates of SARS CoV 2 variants (A) and estimated number of variantattributed cases (B) United States, January 2, 2022May 13, 2023. Sequences are reported to CDC through NS3, contract laboratories, public health laboratories, and other U.S. institutions. Variant proportion estimation methods use a complex survey design and statistical weights to account for the probability that a specimen is sequenced. Lineages reaching a prevalence of 1 with spike protein substitutions of potential therapeutic relevance and separated out on the COVID Data Tracker website. Estimated numbers of COVID19 cases attributable to variants were calculated by multiplying weekly numbers of reported positive nucleic acid amplification tests from CELR with estimated variant proportions. (From Ma KC, Shirk P, Lambrou AS, et al: Genomic surveillance for SARSCoV2 variants: circulation of omicron lineagesUnited States, January 2002May 2023. MMWR 2023;72,:651656. Fig. 1, p. 653.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 311 u Coronaviruses 2041 Table 311.1 Case Definition for Multisystem Inflammatory Syndrome in Children (MIS C) Any illness in a person 21 years that meets: The clinical AND the laboratory criteria (Confirmed), OR The clinical criteria AND epidemiologic linkage criteria (Probable), OR The vital records criteria (Suspect) CLINICAL CRITERIA LABORATORY CRITERIA FOR SARS COV 2 INFECTION EPIDEMIOLOGIC LINKAGE CRITERIA VITAL RECORDS CRITERIA An illness characterized by all of the following, in the absence of a more likely alternative diagnosis Subjective or documented fever (temperature 38.0C) Clinical severity requiring hospitalization or resulting in death Evidence of systemic inflammation indicated by C reactive protein 3.0 mgdL (30 mgL) New onset manifestations in at least two of the following categories: 1. Cardiac involvement indicated by: Left ventricular ejection fraction 55 OR Coronary artery dilatation, aneurysm, or ectasia, OR Troponin elevated above laboratory normal range, or indicated as elevated in a clinical note 2. Mucocutaneous involvement indicated by: Rash, OR Inflammation of the oral mucosa (e.g., mucosal erythema or swelling, drying or fissuring of the lips, strawberry tongue), OR Conjunctivitis or conjunctival injection (redness of the eyes), OR Extremity findings (e.g., erythema redness or edema swelling of the hands or feet) 3. Shock 4. Gastrointestinal involvement indicated by: Abdominal pain, OR Vomiting, OR Diarrhea 5. Hematologic involvement indicated by: Platelet count 150,000 cellsL OR Absolute lymphocyte count (ALC) 1,000 cellsL Detection of SARS CoV 2 RNA in a clinical specimen up to 60 days before or during hospitalization, or in a postmortem specimen using a diagnostic molecular amplification test (e.g., polymerase chain reaction PCR), OR Detection of SARS CoV 2 specific antigen in a clinical specimen up to 60 days before or during hospitalization, or in a postmortem specimen, OR Detection of SARS CoV 2specific antibodies in serum, plasma, or whole blood associated with current illness resulting in or |
7,844 | during hospitalization Close contact with a confirmed or probable case of COVID 19 disease in the 60 days before hospitalization A person whose death certificate lists MIS C or multisystem inflammatory syndrome as an underlying cause of death or a significant condition contributing to death If documented by the clinical treatment team, a final diagnosis of Kawasaki Disease should be considered an alternative diagnosis. These cases should not be reported to national multisystem inflammatory syndrome in children (MIS C) surveillance. Positive molecular or antigen results from self administered testing using over the counter test kits meet laboratory criteria. Includes a positive serology test regardless of COVID 19 vaccination status. Detection of anti nucleocapsid antibody is indicative of SARS CoV 2 infection, and antispike protein antibody may be induced either by COVID 19 vaccination or by SARS CoV 2 infection. Clinician documentation of shock meets this criterion. Close contact is generally defined as being within 6 feet for at least 15 min (cumulative over a 24 hr period). However, it depends on the exposure level and setting; for example, in the setting of an aerosol generating procedure in healthcare settings without proper personal protective equipment (PPE), this may be defined as any duration. From Centers for Disease Control and Prevention. Information for healthcare providers about multisystem inflammatory syndrome in children (MIS C). https:www.cdc.govmismis chcpindex.html discriminatory diagnostic criteria, and institution of rapid immuno modulatory treatment, outcomes have improved (Table 311.1; Table 208.4 in Chapter 208). As of late 2023, there have been 9500 cases and 79 deaths due to MIS C in the United States. The incidence of MIS C has substantially decreased with the appearance of the late pandemic viral variants. Pathogenesis of COVID 19 Severe disease in COVID 19 likely results from both direct virologic damage and subsequent immunopathology (Fig. 311.2). Postmor tem exams have demonstrated COVID 19 virus in almost all tissues (lung, blood vessels, brain, gastrointestinal tract, heart, etc.). Sub stantial viral loads can be detected in the upper and lower respiratory tracts, stool, and blood. Late progression to severe disease appears independent of the quantity and timing of viremia; excessive host immune responses likely play an important role in the progression to lower respiratory disease, acute respiratory distress syndrome, and MIS C (see Fig. 311.2). COVID 19 is associated with massive elabo ration of inflammatory cytokines and recruitment of inflammatory cells. The roles for inflammatory cells are controversial, with cyto toxic T cells and macrophages implicated in both immune protection and immunopathology. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 2042 Part XV u Infectious Diseases Stage I (early infection) Viral response phase Host inflammatory response phaseS ev er ity o f i lln es s Stage II (pulmonary phase) IIA IIB Mild constitutional symptoms Fever 99.6F Dry cough Lymphopenia Shortness of breath without (IIA) and with hypoxia (IIB) Abnormal chest |
7,845 | imaging Transaminitis Lownormal procalcitonin ARDS SIRSshock Cardiac failure Elevated inflammatory markers (CRP, LDH, IL6, Ddimer, ferritin) Troponin, NTproBNP elevation Clinical symptoms Clinical signs Time course Stage III (hyperinflammation phase) Fig. 311.2 Staging of acute COVID 19 infection. Classification of COVID 19 disease states and potential therapeutic targets. The figure illustrates three escalating phases of COVID 19 disease progression, with associated signs, symptoms. ARDS, Acute respiratory distress syndrome; JAK, Janus kinase; LDH, lactate dehydrogenase; NT proBNP, N terminal pro B type natriuretic peptide; SIRS, systemic inflammatory response syndrome. (Modi fied from Siddiqi HK, Mehra MR. COVID 19 illness in native and immunosuppressed states: a clinical therapeutic staging proposal. J Heart Lung Transpl. 2020;395:405407. Fig. 1.) Table 311.2 Clinical Spectrum of SARS CoV 2 Infection Asymptomatic or presymptomatic infection: Individuals who test positive for SARS CoV 2 using a virologic test (i.e., a nucleic acid amplification test NAAT or an antigen test) but have no symptoms consistent with COVID 19. Mild illness: Individuals who have any of the various signs and symptoms of COVID 19 (e.g., fever, cough, sore throat, malaise, headache, muscle pain, nausea, vomiting, diarrhea, loss of taste and smell) but do not have shortness of breath, dyspnea, or abnormal chest imaging. Moderate illness: Individuals who show evidence of lower respiratory disease during clinical assessment or imaging and who have an oxygen saturation measured by pulse oximetry (SpO2) 94 on room air at sea level. Severe illness: Individuals who have SpO2 94 on room air at sea level, a ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (Pao2Fio2) 300 mm Hg, a respiratory rate 30 breathsmin, or lung infiltrates 50. Critical illness: Individuals who have respiratory failure, septic shock, andor multiple organ dysfunction. Spo2 is a key parameter for defining the listed illness categories. However, pulse oximetry has important limitations. Clinicians who use Spo2 when assessing a patient must be aware of those limitations and conduct the assessment in the context of that patients clinical status. Underlying conditions associated with a higher risk of severe COVID 19 include asthma, cancer, cardiovascular disease, chronic kidney disease, chronic liver disease, chronic lung disease, diabetes, advanced or untreated HIV infection, obesity, pregnancy, cigarette smoking, and being a recipient of immunosuppressive therapy or a transplant. The initial evaluation for patients may include chest imaging (e.g., x ray, ultrasound or computed tomography scan) and an electrocardiogram. Laboratory testing should include a complete blood count with differential and a metabolic profile, including liver and renal function tests. Although inflammatory markers such as C reactive protein (CRP), D dimer, and ferritin are not routinely measured as part of standard care, results from such measurements may have prognostic value. In children with COVID 19, radiographic abnormalities are common and, for the most part, should not be the only criteria used to determine the severity of illness. The normal values for respiratory rate also vary with age in children; therefore hypoxemia should be the primary criterion used to define severe COVID 19, especially in younger |
7,846 | children. In a small subset of children and young adults, SARS CoV 2 infection may be followed by the severe inflammatory condition multisystem inflammatory syndrome in children (MIS C). From Centers for Disease Control and Prevention. Clinical spectrum of SARS CoV 2 infection. https:www.covid19treatmentguidelines.nih.govoverviewclinical spectrum CLINICAL MANIFESTATIONS In both children and adults, the spectrum of clinical manifestations of SARS CoV2 infection ranges from asymptomatic infection to mild, moderate, or severe, life threatening pulmonary and extra pulmonary manifestations (Table 311.2). Children are more likely than adults to experience asymptomatic (up to 40) or mild disease (all variants) but can also experience moderate and severe illness, including need for critical care support (MIS C or early variants in older children or adolescents). Mild, moderate, or severe illness can include nonspecific symptoms such as fever, headache, myalgias, and fatigue (Table 311.3). Respiratory manifestations of COVID 19 in children are similar to those in adults and may include mild upper respiratory tract symptoms such as rhinorrhea, congestion, cough, and sore throat and lower respiratory symptoms such as shortness of breath and chest pain. Patients with severe or critical pulmonary and systemic features are at risk for venous thrombosis; Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 311 u Coronaviruses 2043 prophylactic doses of enoxaparin are recommended. Chest imag ing is essential in those with respiratory symptoms (Fig. 311.3). Croup and bronchiolitis presentations have been observed in asso ciation with the Omicron and later variants. Anosmia and ageu sia have been reported in 1015 of cases in children as well as adults. Gastrointestinal symptoms such as abdominal pain (pseudo appendicitis), diarrhea, and vomiting may be more prominent in pediatric patients (COVID 19 andor MIS C) compared to adults (Fig. 311.4). Although children with and without underlying medi cal conditions may be infected, up to 60 of hospitalized children have one or more underlying medical conditions and up to 80 of children with severe disease requiring critical care support have an underlying condition. Cutaneous lesions have often been reported in pediatric patients with COVID 19 and pediatric patients with MIS C (Table 311.4 and Fig. 311.5). SARS CoV 2 is a neurotropic virus; 1020 of pediatric patients with COVID 19 andor MIS C have central or peripheral nervous system manifestations during the acute illness. The most common neurologic manifestations include seizures (including status epi lepticus), headaches, behavioral changes, myalgias, and encepha lopathy (30 with reversible splenial lesions). Other identifiable syndromes include stroke, acute disseminated encephalomyelitis (ADEM) (50 are myelin oligodendrocyte glycoprotein MOG antibody positive), Guillain Barr syndrome (also reported with the vaccine), optic neuritis, psychosis, and cerebellar or brainstem lesions. Neuroimaging findings associated with neurologic complications in children with COVID19 are shown in Fig. 311.6. Cerebrospinal fluid (CSF) findings include a pleocytosis. Neonates are often hospitalized because of SARS CoV 2 infection due to febrile illness with less prominent |
7,847 | respiratory complaints, primarily to exclude neonatal bacterial sepsis or neonatal herpes simplex virus (HSV) infection. Although nearly 15 of women presenting in labor during the early phase of the COVID19 pandemic were found to be SARS CoV 2 PCR positive (majority are asymptomatic), very few infants born to these women are PCR positive at birth or become infected perinatally. Preterm birth and stillbirth due to effects on the placenta, placental inflammation, and other specific abnormalities have been reported in pregnant women with symptomatic SARS CoV 2 infection. Congenital abnormalities or intrauterine growth restriction have not been observed in live born infants with in utero SARS CoV 2 exposure; potential long term neuro developmental effects are not yet known. Over the course of the pandemic, extrapulmonary manifestations and complications of SARS CoV 2 infection have increasingly been appreciated, including new onset or exacerbation of type 1 and type 2 diabetes, intestinal inflammation (pseudo appendicitis) and mesen teric lymphadenitis (see Fig. 311.4), and vascular complications such as thrombosis of vessels in the extremities as well as cerebral vasculature. SARS CoV 2 infection has been associated with sickle cell vasoocclu sive crises and acute chest syndrome in patients with sickle cell disease and increased seizures in children with seizure disorders. MIS C The primary clinical manifestations of MIS C occur 2 6 weeks after SARS CoV 2 infection and consist of unremitting fever, involvement of two or more organ systems (cardiac, renal, respiratory, hemato logic, gastrointestinal, dermatologic, or neurologic), clinical severity requiring hospitalization, and laboratory evidence of inflammation (see Table 311.1). In addition, there is evidence for recent SARS CoV 2 infection by RT PCR, serology, or antigen test; or exposure to a suspected or confirmed COVID 19 case within the 4 weeks before the onset of symptoms. The median age for children with MIS C is 8 10 years (range 4 14 years), but MIS C can affect any age group, including adolescents and rarely infants. A similar syndrome, MIS A, has been reported in adults (21 years). The vast majority of cases of MIS C have occurred in children with no underlying medical conditions or immunodefi ciency. Cardiac manifestations including myocardial dysfunction, coronary artery dilatation, and aneurysm formations (Fig. 311.7), valvular dysfunction, reduced left ventricular ejection fraction, shock, cardiac arrhythmias, and pericardial effusion are present in up to 50 of children at presentation. With institution of rapid Table 311.3 Clinical Criteria for COVID 19 In the absence of a more likely diagnosis: At least two of the following symptoms: Fever (measured or subjective) Chills Rigors Myalgia Headache Sore throat Nausea or vomiting Diarrhea Fatigue Congestion or runny nose OR Any one of the following symptoms: Cough Shortness of breath Difficulty breathing New olfactory disorder New taste disorder OR Severe respiratory illness with at least one of the following: Clinical or radiographic evidence of pneumonia Acute respiratory distress syndrome (ARDS) LABORATORY CRITERIA (SEE TABLE 311.10) EPIDEMIOLOGIC LINKAGE One or more of the following exposures in the prior 14 days: 1. Close contact |
7,848 | with a confirmed or probable case of COVID 19 disease 2. Member of a risk cohort as defined by public health authorities during an outbreak CASE CLASSIFICATION Suspect Meets supportive laboratory evidence with no prior history of being a confirmed or probable case. Probable Meets clinical criteria AND epidemiologic linkage with no confirmatory laboratory testing performed for SARS CoV 2 Meets presumptive laboratory evidence Meets vital records criteria with no confirmatory laboratory evidence for SARS CoV 2 Confirmed Meets confirmatory laboratory evidence VITAL RECORDS CRITERIA A death certificate that lists COVID 19 disease or SARS CoV 2 as an underlying cause of death or a significant condition contributing to death. Close contact is generally defined as being within 6 feet for at least 15 min. However, it depends on the exposure level and setting; for example, in the setting of an aerosol generating procedure in healthcare settings without proper personal protective equipment (PPE), this may be defined as any duration. Data are insufficient to precisely define the duration of exposure that constitutes prolonged exposure and thus a close contact. The terms confirmatory, presumptive, and supportive are categorical labels used here to standardize case classifications for public health surveillance. The terms should not be used to interpret the utility or validity of any laboratory test methodology. For suspect cases (positive serology only), jurisdictions may opt to place them in a registry for other epidemiologic analyses or investigate to determine probable or confirmed status. From Centers for Disease Control and Prevention. Coronavirus disease 2019 (COVID 19): 2020 interim case definition. Approved August 5, 2020. https:ndc.services.cdc. govcasedefinitionscoronavirusdisease2019covid19 Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. A HG B C D E F Fig. 311.3 Chest radiography and chest CT findings of children with COVID 19 in conjunction with symptom and time interval between imaging studies. A, Posteroanterior chest radiograph of a 13 yr old patient who presented with fever for 2 days. Chest radiography and chest CT images were obtained on the same day. Chest radiograph was normal. B, Chest CT image in the axial plan revealed a single, peripheral located, ground glass opacity (GGO) at the posterobasal segment of the right lower lobe. The opacity was obscured with the right liver lobe and diaphragm on chest radiography. C, Posteroanterior chest radiograph of a 10 yr old patient who presented with cough and fever for 2 days. Chest radiography and chest CT images were obtained on the same day. Chest radiograph revealed peripheral GGO (arrow) at the basal segments of the right liver lobe. D, Axial section chest CT examination revealed bronchovascular distributed GGOs at the periphery of the basal segments of the right lower lobe. E, Posteroanterior chest radiograph of a 13 yr old patient who presented with cough and fever for 2 days. Chest radiography and chest CT images were obtained on the same day. |
7,849 | Chest radiograph was interpreted as normal. F, Axial chest CT image without contrast demonstrates bilateral, multifocal, peripheral, and perivascular distributed millimetric nodular shaped GGOs. The opacities were not detected on chest radiography due to the smaller size and lower density. G, Posteroanterior chest radiograph of a 16 yr old patient who presented with cough and fever for 3 days. Chest radiography and chest CT images were obtained on the same day. Chest radiograph demonstrates paramediastinal GGO at the right upper lobe (red box). H, Axial chest CT image without contrast demonstrates peripherally distributed GGO at the right upper lobe with an interlobular interstitial thickening. (From Bayramoglu Z, Canpek E, Comert RG, et al. Imaging features of pediatric COVID 19 on chest radiography and chest CT: a retrospective, single center study. Acad Radiol. 2021;28:1827. Fig. 1.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 311 u Coronaviruses 2045 UB A B C Fig. 311.4 A 14 yr old with multisystem inflammatory syndrome in children (MIS C). Imaging findings showed bowel wall thickening, acute kidney injury, ascites, and mesenteric adenopathy. A, Axial contrast enhanced CT image shows diffuse mural thickening and mild mucosal hyperenhance ment of colon (arrows). B, Coronal image from same CT examination as A shows mesenteric lymphadenopathy (black arrows) and pelvic ascites (arrowheads). Wall of urinary bladder (UB) is thickened, and thickening of colon (white arrow) is again noted. C, Supine anteroposterior abdominal radiograph obtained 15 hours after CT (A and B) shows retention of IV contrast material in kidneys (asterisks) (termed delayed nephrogram) in setting of acute kidney injury. Residual oral contrast material is present in descending colon and sigmoid (arrows) and shows wall thickening and irregularity. (From Blumfield E, Levin TL, Kurian J, et al. Imaging findings in multisystem inflammatory syndrome in children (MIS C) associated with coronavirus disease (COVID 19). AJR. 2021;216:507518. Fig. 7.) immunomodulation, short term outcomes appear to be favorable, including resolution of coronary abnormalities in the majority of cases. Studies to evaluate the long term prognosis for cardiac func tion are in progress, including studies using sensitive measures such as cardiac MRI. Patients with severe cardiac dysfunction must be followed by a pediatric cardiologist and abstain from sports for 3 6 months or until cleared by the cardiologist. Sub phenotypes of MIS C include cases that appear very similar to Kawasaki disease (marked conjunctival injection, adenopathy, and or prominent rash Table 208.4 in Chapter 208) and cases lacking Kawasaki disease features but with prominent abdominal symptoms mimicking an acute abdomen. Analysis of cytokine responses in chil dren with MIS C has identified elevation of a variety of biomarkers, confirming the hyperinflammatory nature of this illness (Table 311.5). Rapid institution of immunomodulatory therapy has been shown to be lifesaving in the setting of MIS C and has included intravenous immunoglobulin (IGIV) with methylprednisolone andor other bio logics |
7,850 | such as anakinra, tocilizumab, or infliximab (Table 311.6). The incidence of MIS C has dramatically decreased with the appearance of newer variants. Infectious complications are uncommon and are noted in Table 311.7. Another complication is rebound (recurrence) of COVID 19 symptoms after an initial episode (Table 311.8). Post Acute Sequelae of SARS CoV 2 Infection (Long COVID) An estimated 1040 of adults and a much lower percentage of children who have recovered from recognized or unrecognized SARS CoV 2 infection may develop long standing and in some cases severe symptoms that are not specifically related to their orig inal symptoms (Table 311.9). These may include ill defined pain syndromes, headaches, abdominal pain, fatigue and postexertional malaise, shortness of breath, chronic cough, palpitations, dizziness syncope, among others, as well as anxiety, depression, and posttrau matic stress disorder. The pathogenesis of long COVID is not yet known but may include genetic determinants related to immune dysregulation, autonomic instability, or persistent indolent viral effects. Long COVID may occur in individuals with mild symp toms, as well as those with moderate or severe infection. Affected individuals may benefit from multidisciplinary and coordinated evaluation in centers that can coordinate subspecialty evaluations Table 311.4 Rashes Reported in COVID 19 Infected Patients Common. Modified from Dinulos JE, Dinulos JG. Cutaneous coronavirus disease 2019 in children: a clinical primer for diagnosis and treatment. Curr Opin Pediatr. 2021;33:691703. Table 1. Morbilliform Chilblain likepernio Urticarial Macular papular erythema Vesicular Acrocyanosis Acral desquamation Papulosquamous Livedo reticularislike Erythema multiforme like Erythroderma Grover like Retiform purpura Petechial Bullous Palpable purpuravasculitis (leukocytoclastic) Dengue like Pressure injury Erythema nodosum Livedo racemose Miliaria rubra Acneiform Enanthem Anagen effluvium Erythema elevatum diutinum Photo distributed Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 2046 Part XV u Infectious Diseases at a single visit, with focus on the symptoms that are most disrup tive to quality of life and function. DIAGNOSIS Numerous diagnostic assays have been developed for the diagnosis of SARS CoV 2, including laboratory based and rapidpoint of care nucleic acid amplification tests, rapid antigen tests, and sero logic assays (Table 311.10). Multiple platforms targeting different aspects of the viral spike and nucleocapsid genes or proteins have been used for direct viral detection. Antibody to the spike protein may develop with either natural infection or vaccination, but pres ence of nucleocapsid antibody indicates natural infection. Virus may be detected by PCR or antigenbased methods for many days after the onset of symptoms, but immunocompetent individuals are generally not contagious after 10 days and immunocompro mised patients are generally not contagious after 21 days, with late viral detection representing nonviable, replication incompetent remnants. Cycle time (Ct) in nonquantitative PCR assays cannot directly correlate with disease or likelihood of disease severity or progression but can be used as a rough estimate of viral load and shedding over time within a single patient, with |
7,851 | lower Ct represent ing high viral loads and high Ct more likely representing shedding of nonviable virus. Antibodies usually develop within 2 weeks of infection, but there is great variability in antibody responses to natural infection. Some infected individuals mount high antibody responses that are durable over many months, but others may not mount an effective or long lived response after natural infection, highlighting the importance of vac cination for reliable immunity. Antibody responses have been docu mented to wane over time in both naturally infected and vaccinated individuals, leading to the recommendation for booster doses of vac cine. Vaccination has continued to be highly effective in prevention of severe disease, hospitalization, and death and in reducing the likeli hood of MIS C. TREATMENT AND PREVENTION Therapeutic agents for SARS CoV 2 include antivirals that inhibit viral replication such as intravenous remdesivir, oral nirmatrelvir ritonavir combination therapy, and oral molnupiravir. These antivi rals reduce morbidity and mortality in hospitalized patients (5 10 day courses of intravenous remdesivir) as well as nonhospitalized high risk children and adults (oral agents and shorter 3 day courses of intravenous remdesivir). High risk conditions associated with severe disease include obesity, diabetes, chronic lung disease, neuro logic disorders, cardiovascular disease, sickle cell disease, or immu nosuppression because of underlying conditions or medications. Systemic corticosteroid therapy (dexamethasone) has been shown to significantly reduce morbidity and mortality in the treatment of hos pitalized patients with COVID 19 pulmonary disease. Several mono clonal antibodies were developed and found to be effective during the early phase of the pandemic in preventing progression to severe disease in individuals with highrisk conditions. However, these antibodies have not retained activity against more recent variants of SARSCoV2. High titer immune plasma has demonstrated variable efficacy with the original variant and is not recommended. Other biologics, such as the interleukin 6 inhibitor tocilizumab, have been used in critically ill adults unresponsive to first line therapies but are used less commonly in children. Multiple vaccines have been developed to combat spread of SARS CoV 2, including novel platforms such as mRNA based vac cines and adenovirus vector based vaccines (see Chapter 215). For the majority of these SARS CoV 2 vaccines, the primary target is the viral spike protein. The FDA had granted EUA approval for SARS CoV 2 vaccines in the United States in children 6 months of age and adults. Guidelines in late 2023 regarding isolation and precautions for people with COVID19 are summarized in Table 311.11. However, guidelines continue to evolve and are available at the Centers for Disease Control and Prevention website (https:www.cdc.govcoronavirus2019ncov yourhealthisolation.html). Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. C B A Fig. 311.5 Dermatologic manifestations of COVID 19. A, Petechial rash. B, Chilblains of the foot. C, Livedo reticularis of the lower extrem ity. (A and B from Gottlieb M, Long B. Dermatologic manifestations and complications of COVID 19. Am J Emerg Med. 2020;38:1715 1721. Figs. 4 and 5; C from Nantsupawat T, Mankongpaisarnrung C, Soontrapa S, et al. |
7,852 | Obscure severe infrarenal aortoiliac stenosis with severe transient lactic acidosis. J Investig Med High Impact Case Rep. 2013;1(1):2324709613479940. Fig. 2.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 311 u Coronaviruses 2047 A J I B C D E F G H Fig. 311.6 MRI scans showing a range of neurologic complications. A C, MRI brain and spine scans from 2 yr old child with acute disseminated encephalomyelitis. Multiple hyperintense foci on axial T2 weighted (A) and T2 FLAIR (B) images involve both cerebral hemispheres, including the basal ganglia, thalami, and subcortical and periventricular white matter (arrowheads). C, Sagittal T2 weighted image of the spine shows a focus of hyperintensity within the cord close to the conus (arrowhead). D F, MRI brain scans from 11 yr old child who presented with MISC, encephalopathy, and MERS. D, Axial T2 weighted image shows a focus of hyperintensity involving the splenium of the corpus callosum along the midline (arrowhead). The B1000 (E) and the ADC maps (F) from diffusion weighted imaging show subtle diffusion restriction involving the lesion. G J, MRI spine scans from a 16 mo old infant who presented with Guillain Barr syndrome. Sagittal T1 weighted images before (G) and after contrast (H) show enhance ment of the lumbosacral nerve roots (arrowheads). I, J, Axial T1 weighted postcontrast images show bilateral enhancement of the nerve roots. ADC, Apparent diffusion coefficient;; FLAIR, fluid attenuated inversion recovery; MERS, mild encephalopathy with reversible splenial lesion; MISC, multisystem inflammatory syndrome in children. (Modified from Ray ST, Abdel Mannon O, Sa M, et al. Neurological manifestations of SARS CoV 2 infection in hospitalised children and adolescents in the UK: a prospective national cohort study. Lancet Child Adolesc. 2021;5:631641. Fig. 2.) A B C V V Fig. 311.7 Early cardiac imaging. Echocardiography (day 21) showing a giant (z score 26) left anterior descending artery aneurysm (A) and a large (z score 8.5) right coronary artery aneurysm (B, arrow). C, Three dimensional reconstruction of coronary architecture. (Modified from Villacis Nunez DS, Hashemi S, Nelson MC, et al. Giant coronary aneurysms in multisystem inflammatory syndrome in children associated with SARS CoV 2 infection. JACC Case Rep. 2021;313:14991508. Fig. 2.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 2048 Part XV u Infectious Diseases Table 311.5 Evaluation of MIS C LABORATORY TESTING A C reactive protein 3.0 mgdL (30 mgL) is required for the CSTECDC MIS C surveillance case definition; other laboratory tests may also indicate evidence of inflammation (e.g., erythrocyte sedimentation rate, fibrinogen, procalcitonin, and ferritin). Similarly, SARS CoV 2 laboratory testing is indicated. Although detection of anti nucleocapsid antibody or anti spike protein antibody fulfill criteria for the case definition, when feasible SARS CoV 2 |
7,853 | anti nucleocapsid antibody testing is recommended, particularly in children with a history of COVID 19 vaccination because anti nucleocapsid antibody is indicative of SARS CoV 2 infection, whereas antispike protein antibody may be induced either by COVID 19 vaccination or by SARS CoV 2 infection. Serology testing should be obtained before administering intravenous immunoglobulin or any other exogenous antibody treatments whenever possible. IMAGING Given the frequent association of MIS C with cardiac involvement, the following tests are usually performed: Echocardiogram Electrocardiogram Other imaging should be directed by patient signs or symptoms but could include: Imaging to evaluate for acute appendicitis Imaging to evaluate for pharyngeal space infection OTHER EVALUATIONS It is important to evaluate children with suspected MIS C for alternative diagnoses, particularly because MIS C clinical manifestations overlap with those of other etiologies. Testing to evaluate for other potential diagnoses should be directed by patient signs or symptoms. Alternative diagnoses to consider include: Acute viral infection (e.g., SARS CoV 2, influenza, adenovirus) Acute viral infection myocarditis (e.g., influenza, enteroviruses) Kawasaki disease Rickettsial disease (e.g., typhus) CSTECDC, Council of State and Territorial EpidemiologistsCenters for Disease Control and Prevention; MIS C, multisystem inflammatory syndrome in children. From Centers for Disease Control and Prevention. Information for healthcare providers about multisystem inflammatory syndrome in children (MIS C). https:www.cdc.govmismis chcpindex.html Table 311.6 Treatment of MIS C Initial treatment is tailored according to the patients presenting signs and symptoms and may include: Fluid resuscitation Inotropic support Respiratory support Antiinflammatory measures have included the frequent use of intravenous immunoglobulin and steroids. There is some evidence that multisystem inflammatory syndrome in children (MIS C) with milder manifestations can be treated with steroid monotherapy and that prolonged duration of outpatient steroids should be avoided. The use of other antiinflammatory medications (e.g., anakinra) and the use of anticoagulation treatments have been variable. Aspirin has commonly been used because of concerns for coronary artery involvement, and antibiotics are routinely used to treat potential sepsis while awaiting bacterial cultures. Thrombotic prophylaxis is often used given the hypercoagulable state typically associated with MIS C. From Centers for Disease Control and Prevention. Information for healthcare providers about multisystem inflammatory syndrome in children (MIS C). https:www.cdc.govmismis chcpindex.html Table 311.7 Infectious Complications in Patients with COVID 19 Coinfections at presentation: Although most individuals present with only SARS CoV 2 infection, concomitant viral infections, including influenza and other respiratory viruses, have been reported. Community acquired bacterial pneumonia also has been reported, but it is uncommon, with a prevalence that ranges from 0 to 6 of people with SARS CoV 2 infection. Antibacterial therapy is generally not recommended unless additional evidence for bacterial pneumonia is present (e.g., leukocytosis, the presence of a focal infiltrate on imaging). Reactivation of latent infections: There are case reports of underlying chronic hepatitis B virus and latent tuberculosis infections reactivating in patients with COVID 19 who receive immunomodulators as treatment, although the data are currently limited. Reactivation of herpes simplex virus and varicella zoster virus infections have also been reported. Cases of |
7,854 | severe and disseminated strongyloidiasis have been reported in patients with COVID 19 during treatment with tocilizumab and corticosteroids. Many clinicians would initiate empirical treatment (e.g., with the antiparasitic drug ivermectin), with or without serologic testing, in patients who require immunomodulators for the treatment of COVID 19 and have come from areas where Strongyloides is endemic (i.e., tropical, subtropical, or warm temperate areas). Nosocomial infections: Hospitalized patients with COVID 19 may acquire common nosocomial infections, such as hospital acquired pneumonia (including ventilator associated pneumonia), line related bacteremia or fungemia, catheter associated urinary tract infection, and Clostridioides difficileassociated diarrhea. Early diagnosis and treatment of these infections are important for improving outcomes in these patients. Opportunistic fungal infections: Invasive fungal infections, including aspergillosis and mucormycosis, have been reported in hospitalized patients with COVID 19. Although these infections are relatively rare, they can be fatal, and they may be seen more commonly in patients who are immunocompromised or receiving mechanical ventilation. The majority of mucormycosis cases have been reported in India and are associated with diabetes mellitus or the use of corticosteroids. From Centers for Disease Control and Prevention. Clinical spectrum of SARS CoV 2 infection. https:www.covid19treatmentguidelines.nih.govoverviewclinical spectrum Table 311.8 Viral or Symptom Rebound Soon After COVID 19 Observational studies and results from clinical trials of therapeutic agents have described SARS CoV 2 viral or COVID 19 symptom rebound in patients who have completed treatment for COVID 19. Viral and symptom rebounds have also occurred when antiSARS CoV 2 therapies were not used. Typically, this phenomenon has not been associated with progression to severe COVID 19. From Centers for Disease Control and Prevention. Clinical spectrum of SARS CoV 2 infection. https:www.covid19treatmentguidelines.nih.govoverviewclinical spectrum Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 311 u Coronaviruses 2049 Table 311.9 Adjusted Hazard Ratios of Selected Potential PostCOVID 19 Symptoms and Conditions Among Children and Adolescents Age 2 17 Years With and Without COVID 19, by Age Group: HealthVerity Medical Claims Database, United States, March 1, 2020January 31, 2022 OUTCOME ADJUSTED HAZARD RATIO (95 CI) 2 4 YR 5 11 YR 12 17 YR SYMPTOM Smell and taste disturbances 1.22 (0.70 2.15) 0.94 (0.83 1.07) 1.23 (1.16 1.31) Circulatory signs and symptoms 1.17 (1.12 1.23) 1.11 (1.08 1.13) 1.04 (1.02 1.06) Malaise and fatigue 1.13 (1.05 1.22) 1.08 (1.05 1.12) 1.03 (1.01 1.04) Musculoskeletal pain 1.16 (1.10 1.21) 1.06 (1.04 1.07) 1.00 (0.99 1.01) Dizziness and syncope 1.08 (0.90 1.29) 1.03 (0.99 1.08) 1.00 (0.98 1.02) GI and esophageal disorders 1.15 (1.10 1.20) 1.02 (1.00 1.04) 0.97 (0.95 0.99) Sleeping disorders 0.99 (0.93 1.06) 0.89 (0.86 0.92) 0.91 (0.89 0.94) Respiratory signs and symptoms 1.07 (1.04 1.10) 0.93 (0.92 0.94) 0.88 (0.87 0.89) Symptoms of mental conditions 1.03 (0.97 1.10) 0.92 (0.90 0.95) 0.89 (0.86 0.91) CONDITION Acute pulmonary embolism 2.03 (1.61 2.56) Myocarditis and cardiomyopathy 2.39 (1.573.65) 2.84 (2.39 3.37) 1.66 |
7,855 | (1.48 1.88) Venous thromboembolic event 2.69 (1.73 4.19) 1.52 (1.22 1.91) Acute and unspecified renal failure 1.52 (1.072.14) 1.38 (1.161.63) 1.27 (1.151.40) Type 1 diabetes 1.01 (0.57 1.78) 1.31 (1.13 1.53) 1.20 (1.091.33) Coagulation and hemorrhagic disorders 1.47 (1.20 1.80) 1.28 (1.15 1.43) 1.10 (1.031.19) Type 2 diabetes 1.24 (0.85 1.81) 1.14 (1.02 1.28) 1.18 (1.11 1.24) Cardiac dysrhythmias 1.44 (1.22 1.70) 1.23 (1.14 1.32) 1.12 (1.08 1.17) Cerebrovascular disease 1.66 (0.85 3.23) 1.14 (0.79 1.64) 1.18 (0.93 1.48) Chronic kidney disease 0.86 (0.54 1.36) 1.04 (0.83 1.31) 1.12 (0.96 1.31) Asthma 1.12 (1.07 1.18) 1.02 (1.00 1.05) 0.96 (0.94 0.98) Muscle disorders 0.87 (0.77 0.98) 0.86 (0.82 0.91) 0.96 (0.93 0.99) Neurologic conditions 0.98 (0.93 1.04) 0.96 (0.93 0.98) 0.91 (0.89 0.93) Anxiety and fear related disorders 0.91 (0.83 1.00) 0.86 (0.83 0.88) 0.84 (0.82 0.85) Mood disorders 0.82 (0.62 1.08) 0.73 (0.69 0.77) 0.80 (0.77 0.83) Each adjusted hazard ratio was obtained from a single Cox proportional hazards model stratified by age group, with the specific symptom or condition as the outcome and the following covariates: presence of COVID 19, age (continuous variable), sex, race, U.S. Census Bureau region, payor type, previous medical complexity, and previous hospitalization. P value 0.05. Age stratified analyses were performed only when there were at least 10 patients with COVID 19 and at least 10 patients without COVID 19 in that age group with the specific symptom or condition. From Kompaniyets L, Bull Otterson L, Boehmer TK, et al. Post COVID 19 symptoms and conditions among children and adolescentsUnited States, March 1, 2020 January 21, 2022. Morb Mortal Wkly Rep. 2022;71(31):993998. Table 3. Table 311.10 Laboratory Evidence for COVID 19 Infection Laboratory evidence using a method approved or authorized by the U.S. Food and Drug Administration (FDA) or designated authority: CONFIRMATORY LABORATORY EVIDENCE Detection of SARS CoV 2 ribonucleic acid (RNA) in a clinical or postmortem specimen using a diagnostic molecular amplification test performed by a Clinical Laboratory Improvement Amendments (CLIA) certified provider OR Detection of SARS CoV 2 RNA in a clinical or postmortem specimen by genomic sequencing PRESUMPTIVE LABORATORY EVIDENCE Detection of SARS CoV 2specific antigen in a clinical or postmortem specimen using a diagnostic test performed by a CLIA certified provider. SUPPORTIVE LABORATORY EVIDENCE Detection of SARS CoV 2 specific antigen by immunocytochemistry, OR Detection of SARS CoV 2 RNA or specific antigen using a test performed without CLIA oversight. The terms confirmatory, presumptive, and supportive are categorical labels used here to standardize case classifications for public health surveillance. The terms should not be used to interpret the utility or validity of any laboratory test methodology. Includes those tests performed under a CLIA certificate of waiver. Some genomic sequencing tests that have been authorized for emergency use by the FDA do not require an initial polymerase chain reaction (PCR) result to be generated. Genomic sequencing results may be all the public health agency receives. Modified from Centers for Disease Control and Prevention. Coronavirus disease 2019 (COVID 19) 2023 Case Definition. |
7,856 | https:ndc.services.cdc.govcase definitionscoronavirus disease 2019 covid 19 Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 2050 Part XV u Infectious Diseases Table 311.11 Isolation and Precautions for People with COVID 19 WHEN TO ISOLATE If you test negative: You can end your isolation. If you test positive: Follow the full isolation recommendations below. When you have COVID 19, isolation is counted in days, as follows. If You Had No Symptoms Day 0 is the day you were tested (not the day you received your positive test result). Day 1 is the first full day following the day you were tested. If you develop symptoms within 10 days of when you were tested, the clock restarts at day 0 on the day of symptom onset. If You Had Symptoms Day 0 of isolation is the day of symptom onset, regardless of when you tested positive. Day 1 is the first full day after the day your symptoms started. Isolation If you test positive for COVID 19, stay home for at least 5 days and isolate from others in your home. You are likely most infectious during these first 5 days. Wear a high quality mask if you must be around others at home and in public. Do not go places where you are unable to wear a mask. For travel guidance, see CDCs Travel webpage. Do not travel. Stay home and separate from others as much as possible. Use a separate bathroom, if possible. Take steps to improve ventilation at home, if possible. Do not share personal household items, such as cups, towels, and utensils. Monitor your symptoms. If you have an emergency warning sign (like trouble breathing), seek emergency medical care immediately. Learn more about what to do if you have COVID 19. ENDING ISOLATION End isolation based on how serious your COVID 19 symptoms were. Loss of taste and smell may persist for weeks or months after recovery and need not delay the end of isolation. If You Had No Symptoms You may end isolation after day 5. If You Had Symptoms and Your Symptoms Are Improving You may end isolation after day 5 if you are fever free for 24 hr (without the use of fever reducing medication). Your Symptoms Are Not Improving Continue to isolate until: You are fever free for 24 hr (without the use of fever reducing medication). Your symptoms are improving. If You Had Symptoms and Had Moderate illness (you experienced shortness of breath or had difficulty breathing) You need to isolate through day 10. Severe Illness (You Were Hospitalized) or Have a Weakened Immune System You need to isolate through day 10. Consult your doctor before ending isolation. Ending isolation without a viral test may not be an option for you. If you are unsure if your symptoms are moderate or severe or if you have a weakened |
7,857 | immune system, talk to a healthcare provider for further guidance. Regardless of When You End Isolation Until at least day 11: Avoid being around people who are more likely to get very sick from COVID 19. Remember to wear a high quality mask when indoors around others at home and in public. Do not go places where you are unable to wear a mask until you are able to discontinue masking (see below). For travel guidance, see CDCs Travel webpage. Removing Your Mask After you have ended isolation, when you are feeling better (no fever without the use of fever reducing medications and symptoms improving): Wear your mask through day 10. OR If you have access to antigen tests, you should consider using them. With two sequential negative tests 48 hr apart, you may remove your mask sooner than day 10. Note: If your antigen test results are positive, you may still be infectious. You should continue wearing a mask and wait at least 48 hours before taking another test. Continue taking antigen tests at least 48 hr apart until you have two sequential negative results. This may mean you need to continue wearing a mask and testing beyond day 10. After you have ended isolation, if your COVID 19 symptoms recur or worsen, restart your isolation at day 0. Talk to a healthcare provider if you have questions about your symptoms or when to end isolation. As noted in the U.S. Food and Drug Administration labeling for authorized over the counter antigen tests, negative test results do not rule out SARS CoV 2 infection and should not be used as the sole basis for treatment or patient management decisions, including infection control decisions. From Centers for Disease Control and Prevention. Isolation and precautions for people with COVID 19. https:www.cdc.govcoronavirus2019 ncovyour healthisolation.html Diarrhea is a leading cause of childhood death in the world, account ing for 5 10 million deaths per year. In early childhood, the single most important cause of severe dehydrating diarrhea is rotavirus infection. Rotavirus and other gastroenteric viruses are not only major causes of pediatric deaths but also lead to significant morbidity. Before rotavirus Chapter 312 Rotaviruses, Caliciviruses, and Astroviruses Dorsey M. Bass vaccines were available, children in the United States were estimated to have a risk of hospitalization for rotavirus diarrhea of 1:43, corre sponding to 80,000 hospitalizations annually. ETIOLOGY Rotaviruses, astroviruses, caliciviruses such as the Norwalk agent, and enteric adenoviruses are the medically important pathogens of human viral gastroenteritis (see Chapter 387). Rotaviruses are in the Reoviridae family and cause disease in virtu ally all mammals and birds. These viruses are wheel like, triple shelled icosahedrons containing 11 segments of double stranded RNA. The diameter of the particles on electron microscopy is approximately 80 nm. Rotaviruses are classified by serogroup (A, B, C, D, E, F, and G) and subgroup (I or II). Rotavirus strains are species specific and do not cause disease in heterologous hosts. Group A includes the common human pathogens and |
7,858 | a variety of animal viruses. Group B rotavirus is reported as a cause of severe disease in infants and adults in China Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 312 u Rotaviruses, Caliciviruses, and Astroviruses 2051 only. Occasional human outbreaks of group C rotavirus are reported. The other serogroups infect only nonhumans. Subgrouping of rotaviruses is determined by the antigenic structure of the inner capsid protein, VP6. Serotyping of rotaviruses, described for group A only, is determined by classic cross neutralization testing and depends on the outer capsid glycoproteins, VP7 and VP4. The VP7 serotype is referred to as the G type (for glycoprotein). There are 10 G serotypes, of which 4 cause most illness and vary in occurrence from year to year and region to region. The VP4 serotype is referred to as the P type. There are 11 P serotypes. Although both VP4 and VP7 elicit neutralizing immunoglobulin (Ig) G antibodies, the relative role of these systemic antibodies compared with mucosal IgA antibodies and cellular responses in protective immunity remains unclear. Caliciviruses, which constitute the Caliciviridae family, are small, 27 to 35 nm viruses and are the most common cause of gastroenteri tis outbreaks in older children and adults. Caliciviruses also cause a rotavirus like illness in young infants. They are positive sense, single stranded RNA viruses with a single structural protein. Human calici viruses are divided into two genera, the noroviruses and sapoviruses. Caliciviruses have been named for locations of initial outbreaks: Norwalk, Snow Mountain, Montgomery County, Sapporo, and oth ers. Caliciviruses and astroviruses are sometimes referred to as small, round viruses on the basis of their appearance on electron microscopy. Astroviruses constitute the Astroviridae family and are important agents of viral gastroenteritis in young children, with a high incidence in both the developing and developed worlds. Astroviruses are positive sense, single stranded RNA viruses. They are small particles, approxi mately 30 nm in diameter, with a characteristic central five or six pointed star when viewed on electron microscopy. The capsid consists of three structural proteins. There are eight known human serotypes. Enteric adenoviruses are a common cause of viral gastroenteritis in infants and children. Although many adenovirus serotypes exist and are found in human stool, especially during and after typical upper respiratory tract infections (see Chapter 309), only serotypes 40 and 41 cause gastroenteritis. These strains are very difficult to grow in tissue culture. The virus consists of an 80 nmdiameter icosahedral particle with a relatively complex double stranded DNA genome. Aichi virus is a picornavirus that is associated with gastroenteri tis and was initially described in Asia. Several other viruses that may cause diarrheal disease in animals have been postulated but are not well established as human gastroenteritis viruses. These include coro naviruses, toroviruses, and pestiviruses. The picobirnaviruses are an unclassified group of small (30 nm), single |
7,859 | stranded RNA viruses that have been found in 10 of patients with HIV associated diarrhea. EPIDEMIOLOGY Worldwide, rotavirus is estimated to cause more than 111 million cases of diarrhea annually in children 5 years. Of these, 18 million cases are consid ered at least moderately severe, with approximately 200,000 deaths per year. Rotavirus caused 3 million cases of diarrhea, 80,000 hospitalizations, and 20 40 deaths annually in the United States before widespread vaccine use. Rotavirus infection is most common in winter months in temperate climates. In the United States, the annual winter peak historically spread from west to east. Unlike the spread of other winter viruses, such as influ enza, this wave of increased incidence was not caused by a single prevalent strain or serotype. Since widespread adoption of rotavirus vaccines, this geographic phenomenon has vanished and peaks have decreased. Typi cally, several serotypes predominate in a given community for one or two seasons, but nearby locations may harbor unrelated strains. Disease tends to be most severe in patients 3 24 months of age, although 25 of the cases of severe disease occur in children older than 2 years of age, with serologic evidence of infection developing in virtually all children by 4 5 years of age. Infants younger than 3 months are relatively protected by transpla cental antibody and possibly breastfeeding. Infections in neonates and in adults in close contact with infected children are generally asymptomatic. Some rotavirus strains have stably colonized newborn nurseries for years, infecting virtually all newborns without causing any overt illness. Rotavirus and the other gastrointestinal viruses spread efficiently by the fecal oral route, and outbreaks are common in childrens hos pitals and childcare centers. The virus is shed in stool at a very high concentration before and for days after the clinical illness. Very few infectious virions are needed to cause disease in a susceptible host. The epidemiology of astroviruses is not as thoroughly studied as that of rotavirus, but these viruses are a common cause of mild to moderate watery winter diarrhea in children and infants and are an uncommon pathogen in adults. Hospital outbreaks are common. Enteric adenovi rus gastroenteritis occurs year round, mostly in children younger than 2 years. Nosocomial outbreaks occur but are less common than with rotavirus and astrovirus. Calicivirus is best known for causing large, explosive outbreaks among older children and adults, particularly in settings such as schools, cruise ships, and hospitals. Often a single food, such as shellfish or water used in food preparation, is identified as a source. Like astrovirus and rotavirus, caliciviruses are also commonly found in winter infantile gastroenteritis and are now the leading cause of significant pediatric viral diarrhea in communities with high rates of rotavirus vaccination. PATHOGENESIS Viruses that cause human diarrhea selectively infect and destroy villus tip cells in the small intestine. Biopsies of the small intestines show variable degrees of villus blunting and round cell infiltrate in the lam ina propria. Pathologic changes may not correlate with the severity of |
7,860 | clinical symptoms and usually resolve before the clinical resolution of diarrhea. The gastric mucosa is not affected despite the commonly used term gastroenteritis, although delayed gastric emptying has been docu mented during Norwalk virus infection. In the small intestine, the upper villus enterocytes are differentiated cells, which have both digestive functions, such as hydrolysis of disac charides, and absorptive functions, such as the transport of water and electrolytes via glucose and amino acid cotransporters. Crypt entero cytes are undifferentiated cells that lack the brush border hydrolytic enzymes and are net secretors of water and electrolytes. Selective viral infection of intestinal villus tip cells thus leads to (1) decreased absorp tion of salt and water and an imbalance in the ratio of intestinal fluid absorption to secretion and (2) diminished disaccharidase activity and malabsorption of complex carbohydrates, particularly lactose. Most evidence supports altered absorption as the more important factor in the genesis of viral diarrhea. It has been proposed that a rotavirus non structural protein (NSP4) functions as an enterotoxin. Viremia may occur in severe, primary infections, but symptomatic extraintestinal infection is extremely rare in immunocompetent per sons. In contrast, immunocompromised patients may occasionally experience central nervous system, hepatic, or renal involvement. The increased vulnerability of infants (compared with older children and adults) to severe morbidity and mortality from gastroenteritis viruses may relate to a number of factors, including decreased intestinal reserve function, lack of specific immunity, and decreased nonspecific host defense mechanisms such as gastric acid and mucus. Viral enteri tis greatly enhances intestinal permeability to luminal macromolecules and has been postulated to increase the risk for food allergies and celiac disease. CLINICAL MANIFESTATIONS Rotavirus infection typically begins after an incubation period of 48 hours (range: 1 7 days) with mild to moderate fever as well as vomiting, followed by the onset of frequent, watery stools. All three symptoms are present in about 5060 of cases. Vomiting and fever typically abate during the second day of illness, but diarrhea often con tinues for 5 7 days. The stool is without gross blood or white blood cells. Dehydration may develop and progress rapidly, particularly in infants. The most severe disease typically occurs among children 4 36 months of age. Malnourished children and children with underly ing intestinal disease, such as short bowel syndrome, are particularly likely to acquire severe rotavirus diarrhea. Rarely, immunodeficient children experience severe and prolonged illness. Rotavirus has rarely been associated with mild encephalopathy that may progress to cereb ellitis and with reversible splenium lesions. Although most newborns infected with rotavirus are asymptomatic, some outbreaks of necrotiz ing enterocolitis have been associated with the appearance of a new rotavirus strain in the affected nurseries. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 2052 Part XV u Infectious Diseases The clinical course of astrovirus infection appears to be similar to that of rotavirus |
7,861 | gastroenteritis, with the notable exception that the dis ease tends to be milder, with less significant dehydration. Adenovirus enteritis tends to cause diarrhea of longer duration, often 10 14 days. The Norwalk virus has a short (12 hour) incubation period. Vomit ing and nausea tend to predominate in an illness associated with the Norwalk virus, and the duration is brief, usually consisting of 1 3 days of symptoms. The clinical and epidemiologic picture of Norwalk virus often closely resembles so called food poisoning from preformed tox ins such as Staphylococcus aureus and Bacillus cereus. DIAGNOSIS In most cases, a satisfactory diagnosis of acute viral gastroenteritis can be made on the basis of the clinical and epidemiologic features. Many hospitals now offer multiplex PCR stool testing for multiple diarrheal pathogens, including a variety of bacterial and protozoan and all five common viral agents in one test. Enzyme linked immunosorbent assays, which offer 90 specificity and sensitivity, are available for the detection of group A rotaviruses, caliciviruses, and enteric adeno viruses in stool samples. Research tools include electron microscopy of stools, RNA polymerase chain reaction analysis to identify G and P antigens, and culture. The diagnosis of viral gastroenteritis should always be questioned in patients with persistent or high fever, blood or white blood cells in the stool, or persistent severe or bilious vomiting, especially in the absence of diarrhea. LABORATORY FINDINGS Isotonic dehydration with acidosis is the most common finding in chil dren with severe viral enteritis. The stools are free of blood and leuko cytes. Although the white blood cell count may be moderately elevated secondary to stress, the marked left shift seen with invasive bacterial enteritis is absent. DIFFERENTIAL DIAGNOSIS The differential diagnosis includes other infectious causes of enteritis, such as bacteria and protozoa. Occasionally, surgical conditions such as appendicitis, bowel obstruction, and intussusception may initially mimic viral gastroenteritis. TREATMENT Avoiding and treating dehydration are the main goals in the treatment of viral enteritis. A secondary goal is maintenance of the nutritional status of the patient (see Chapters 74 and 387). There is no routine role for antiviral drug treatment of viral gastroen teritis. Controlled studies show limited benefits for antidiarrheal drugs, and there is a significant risk for serious side effects with these types of agents. Antibiotics are similarly of no benefit. Antiemetics such as ondansetron may help alleviate vomiting in children older than 2 years. Immunoglobulins have been administered orally to both normal and immunodeficient patients with severe rotavirus and norovirus gas troenteritis, but this treatment is currently considered experimental. Therapy with probiotic organisms such as Lactobacillus spp. has been shown to be helpful only in mild cases and not in dehydrating disease. Supportive Treatment Rehydration via the oral route can be accomplished in most patients with mild to moderate dehydration (see Chapters 74 and 387). Severe dehydration requires immediate intravenous therapy followed by oral rehydration. Modern oral rehydration solutions containing appropri ate quantities of sodium and glucose promote the optimum absorp tion of fluid from the |
7,862 | intestine. There is no evidence that a particular carbohydrate source (rice) or the addition of amino acids improves the efficacy of these solutions for children with viral enteritis. Other clear liquids, such as flat soda, fruit juice, and sports drinks, are inappropri ate for the rehydration of young children with significant stool loss. Rehydration via the oral (or nasogastric) route should be done over 6 8 hours, and feedings should be initiated immediately thereafter. Providing the rehydration fluid at a slow, steady rate, typically 5 mL min, reduces vomiting and improves the success of oral therapy. Rehy dration solution should be continued as a supplement to make up for ongoing excessive stool loss. Initial intravenous fluids are required for the infant in shock or the occasional child with intractable vomiting. After rehydration has been achieved, resumption of a normal diet for age has been shown to result in a more rapid recovery from viral gastroenteritis. Prolonged (12 hours) administration of exclusive clear liquids or dilute formula is without clinical benefit and actually prolongs the duration of diarrhea. Breastfeeding should be continued even during rehydration. Selected infants may benefit from lactose free feedings (e.g., soy formula and lactose free cows milk) for several days, although this step is not necessary for most children. Hypocaloric diets low in protein and fat such as BRAT (bananas, rice, cereal, applesauce, and toast) have not been shown to be superior to a regular diet. PROGNOSIS Most fatalities occur in infants with poor access to medical care and are attributed to dehydration. Children may be infected with rotavirus each year during the first 5 years of life, but each subsequent infec tion decreases in severity. Primary infection results in a predominantly serotype specific immune response, whereas reinfection, which is usu ally with a different serotype, induces a broad immune response with cross reactive heterotypic antibody. After the initial natural infection, children have limited protection against subsequent asymptomatic infection (38) and greater protection against mild diarrhea (73) and moderate to severe diarrhea (87). After the second natural infec tion, protection increases against subsequent asymptomatic infection (62) and mild diarrhea (75) and is complete (100) against moder ate to severe diarrhea. After the third natural infection, there is even more protection against subsequent asymptomatic infection (74) and near complete protection against even mild diarrhea (99). PREVENTION Good hygiene reduces the transmission of viral gastroenteritis, but even in the most hygienic societies, virtually all children become infected as a result of the efficiency of infection of the gastroenteritis viruses. Good handwashing and isolation procedures can help control nosocomial outbreaks. The role of breastfeeding in prevention or ame lioration of rotavirus infection may be slight, given the variable protec tion observed in a number of studies. Vaccines offer the best hope for control of these ubiquitous infections. Vaccines A trivalent rotavirus vaccine was licensed in the United States in 1998 and was subsequently linked to an increased risk for intussusception, especially during the 3 to 14 day period after the |
7,863 | first dose and the 3 to 7 day period after the second dose. The vaccine was withdrawn from the market in 1999. Subsequently, two new live, oral rotavirus vaccines have been approved in the United States after extensive safety and efficacy testing. A live, oral, pentavalent rotavirus vaccine was approved in 2006 for use in the United States. The vaccine contains five reassortant rotaviruses isolated from human and bovine hosts. Four of the reassortant rotavi ruses express one serotype of the outer protein VP7 (G1, G2, G3, or G4), and the fifth expresses the protein P1A (genotype P8) from the human rotavirus parent strain. The pentavalent vaccine protects against rotavi rus gastroenteritis when administered as a three dose series at 2, 4, and 6 months of age. The first dose should be administered between 6 and 12 wk of age, with all three doses completed by 32 weeks of age. The vaccine provides substantial protection against rotavirus gastroenteritis, with a primary efficacy of 98 against severe rotavirus gastroenteritis caused by G1 G4 serotypes and 74 efficacy against rotavirus gastroenteritis of any severity through the first rotavirus season after vaccination. It pro vides a 96 reduction in hospitalizations for rotavirus gastroenteritis through the first 2 years after the third dose. In a study of more than 70,000 infants, the pentavalent vaccine did not increase the risk for intus susception, although other studies suggest a slight increased risk. Another monovalent rotavirus vaccine was licensed in the United States and also appears to be safe and effective. It is an attenuated mon ovalent human rotavirus and is administered as two oral doses at 2 and 4 months of age. The vaccine has 85 efficacy against severe gastroen teritis and was found to reduce hospital admissions for all diarrhea by Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 313 u Human Papillomaviruses 2053 42. Despite being monovalent, the vaccine is effective in prevention of all four common serotypes of human rotavirus. Preliminary surveillance data on the rotavirus incidence from the U.S. Centers for Disease Control and Prevention suggest that rota virus vaccination greatly reduced the disease burden in the United States during the 20072008 rotavirus season and thereafter. Given the incomplete vaccine coverage during this period, the results suggest a degree of herd immunity from rotavirus immunization. Studies from several developed countries show greater than 90 protection against severe rotavirus disease. Studies from developing countries show 5060 protection from severe disease. Vaccine associated disease has been reported in vaccine recipients who have severe combined immu nodeficiency disease (a contraindication). In addition, vaccine derived virus may undergo reassortment and become more virulent, producing diarrhea in unvaccinated siblings. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. See also Chapter 708. Human papillomaviruses (HPVs) cause a variety of proliferative cutaneous and mucosal lesions, including common skin warts, benign and malignant anogenital |
7,864 | tract lesions, oral pharyngeal cancers, and life threatening respiratory papillomas. Most HPV related infections in children and adolescents are benign (see also Chapter 708). ETIOLOGY The papillomaviruses are small (55 nm), DNA containing viruses that are ubiquitous in nature, infecting most mammalian and many non mammalian animal species. Strains are almost always species specific. Viral DNA is divided into an early region, which encodes proteins associated with viral replication and transcription, and a late region, which encodes capsid proteins necessary for virion assembly. These structural proteins are also the immunodominant antigens leading to type specific immune responses. More than 100 different types of HPVs have been identified through the comparison of sequence homologies. The different HPV types typically cause disease in spe cific anatomic sites; more than 30 HPV types have been identified from genital tract specimens. EPIDEMIOLOGY HPV infections of the skin are common, and most individuals are probably infected with one or more HPV types at some time. There are no animal reservoirs for HPV; all transmission is presumably from per son to person. There is little evidence to suggest that HPV is transmit ted by fomites. Common warts, including palmar and plantar warts, are frequently seen in children and adolescents and typically infect the hands and feet, common areas of frequent minor trauma. HPV is also the most prevalent viral sexually transmitted infection in the United States. Up to 80 of sexually active women will acquire HPV through sexual transmission; most have their first infection within 3 years of beginning sexual intercourse. Thus HPV dispropor tionately affects youth, with 75 of new infections occurring in 15 to 24 year olds. The greatest risk for HPV in sexually active adolescents is exposure to new sexual partners, but HPV can still be acquired even with a history of one partner, underscoring the ease of transmission of this virus through sexual contact. It is estimated that after 11 acts of sexual intercourse, 100 of all HPV types infecting an individual will be transmitted to the other sexual partner. Couple studies show that Chapter 313 Human Papillomaviruses Kristen A. Feemster there is high concordance in the genital area as well as between the hand and the genital area in the other partner. Whether the DNA detected in HPV on the hand is capable of transmitting infectious particles is unknown. Unlike other sexually transmitted infections, female to male transmission appears greater than male to female transmission. This may be because males in general have superficial transient infec tions or deposition. In turn, males do not develop an adequate immune response, so reinfections are quite common. The prevalence of HPV in women decreases with time, suggesting immune protection, whereas in men, the prevalence of HPV remains high across all ages. As with many other genital pathogens, perinatal transmission to newborns can occur. Transmission from caregiver to child during the early childhood years has also been documented. However, both perinatal and early childhood infections appear transient. It remains unclear whether these HPV DNA detections |
7,865 | are simply a deposition of caregiver DNA or a true infection. Detection of HPV DNA in older preadolescent children is rare. HPV DNA detection in nonsexually active adolescents has been reported, but a history of sexual activity in adolescents is not always disclosed and is therefore difficult to confirm. Although caregivers can spread HPV to young children, if lesions are detected in a child older than 3 years of age, the possibility of sexual transmission should be raised. In adolescents, HPV DNA is most commonly detected without evi dence of any lesion. Some of these detections are thought to be the result of partner deposition and hence do not represent a true infec tion. In older women, detection of HPV DNA is more commonly asso ciated with a lesion. This is because the HPV DNA detected in older women reflects those HPV infections that became established persis tent infections. Persistence is now the known necessary prerequisite for the development of significant precancerous lesions and cervical cancer. Approximately 1520 of sexually active adolescents have detect able HPV at any given time and have normal cytologic findings. The most common clinically detected lesion in adolescent women is the cervical lesion termed low grade squamous intraepithelial lesion (LSIL) (Table 313.1). LSILs can be found in 2530 of adolescents infected with HPV. External genital warts are much less common, occurring in 1 of adolescents; the incidence has decreased since introduction of HPV vaccines, but approximately 10 of individu als will develop genital warts in their lifetime. LSIL is a cytologic and histologic term to reflect the benign changes caused by an active viral infection and is likely present in most, if not all, women with HPV infection. However, the majority of women have very minute or subtle lesions not easily detected by cytology. As with HPV DNA detection, most LSILs regress spontaneously in young women and do not require any intervention or therapy. Less commonly, HPV can induce more severe cellular changes, termed high grade squamous intraepithelial lesions (HSILs) (see Chapter 590). Although HSILs are considered precancerous lesions, they rarely progress to invasive cancer. HSILs occur in approximately 0.43 of sexually active women, whereas invasive cervical cancer occurs in 8 cases per 100,000 adult women. In the United States, there are approxi mately 12,000 new cases (7 cases100,000) and 4,000 deaths from cer vical cancer each year. Worldwide, cervical cancer is the fourth most common cause of cancer deaths among women. HPV is also associated with a range of other anogenital cancers, including an estimated 9,000 cases of anal cancer and 44,000 cases of oropharyngeal cancers in men and women. Some infants may acquire papillomaviruses during passage through an infected birth canal, leading to recurrent juvenile laryngeal pap illomatosis (JLP; also referred to as respiratory papillomatosis). Cases also have been reported after cesarean section. The incubation period for emergence of clinically apparent lesions (genital warts or laryngeal papillomas) after perinatally acquired infection is unknown but is esti mated to be around 3 6 months |
7,866 | (see Chapter 438.2). It may be that infections can also occur during hygienic care from an infected parent. Genital warts may represent a sexually transmitted infection even in some very young children. Therefore genital warts appearing in childhood should raise suspicion for possible sexual abuse with HPV Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 2054 Part XV u Infectious Diseases transmission during the abusive contact. A child with genital warts should thus be provided with a complete evaluation for evidence of possible abuse (see Chapter 17.1), including the presence of other sexu ally transmitted infections (see Chapter 163). However, the presence of genital warts in a child does not confirm sexual abuse, because peri natally transmitted genital warts may go undetected until the child is older. Typing for specific genital HPV types in children is not helpful in diagnosis or to confirm sexual abuse status, because the same genital types occur in both perinatal transmission and abuse. In true virginal populations, including children who are not sexually abused, rates of clinical disease are close to zero. PATHOGENESIS Initial HPV infection of the cervix or other anogenital surfaces is thought to begin by viral invasion of the basal cells of the epithelium, a process that is enhanced by disruption of the epithelium caused by trauma or inflammation. It is thought that the virus initially remains relatively dormant because virus is present without any evidence of clinical disease. The life cycle of HPV depends on the differentiation program of keratinocytes. The pattern of HPV transcription varies throughout the epithelial layer and through different stages of dis ease (LSIL, HSIL, invasive cancer). Understanding of HPV transcrip tion enhances understanding of its ability to behave as an oncovirus. Early region proteins, E6 and E7, function as transactivating factors that regulate cellular transformation. Complex interactions between E6 and E7 transcribed proteins and host proteins result in the per turbation of normal processes that regulate cellular DNA synthesis. The perturbations caused by E6 and E7 are primarily disruption of the anti oncoprotein p53 and retinoblastoma protein (Rb), respectively, contributing to the development of anogenital cancers. Disruption of these proteins results in continued cell proliferation, even under the circumstances of DNA damage, which leads to basal cell proliferation, chromosomal abnormalities, and aneuploidy, hallmarks of squamous intraepithelial lesion (SIL) development. Evidence of productive viral infection occurs in benign lesions such as external genital warts and LSILs, with the abundant expression of viral capsid proteins in the superficial keratinocytes. The appearance of the HPV associated koilocyte is a result of the expression of E4, a struc tural protein that causes collapse of the cytoskeleton. Low level expres sion of E6 and E7 proteins results in cell proliferation seen in the basal cell layer of LSILs. LSILs are a manifestation of active viral replication and protein expression. In HSILs, expression of E6 and |
7,867 | E7 predomi nates throughout the epithelium, with little expression of the structural proteins L1 and L2. This results in the chromosomal abnormalities and aneuploidy characteristic of the higher grade lesions. The critical events that lead to cancer have not been verified; however, several mechanisms are thought to be critical, including viral integration into the host chro mosome and activation of telomerase to lengthen chromosomes and avoid physiologic cell senescence. Over 150 HPV types have been doc umented and are classified by extent of their DNA homology into 5 genera, with the different types having different life cycle and disease characteristics. The predominant group is HPV types, which are asso ciated with cutaneous and mucosal anogenital infections and cancers. , , , and cause predominantly benign cutaneous lesions but can be difficult to manage in severely immunocompromised individuals. types are commonly detected on the skin without any apparent lesions but are associated with the development of skin cancers in those with epidermodysplasia verruciformis or other forms of immunodeficien cies. Genital lesions caused by the HPV types may be broadly grouped into those with little to no malignant potential (low risk) and those with greater malignant potential (high risk). Low risk HPV types 6 and 11 are most commonly found in genital warts and are rarely found isolated in malignant lesions. High risk HPV types are those types that are asso ciated with anogenital cancers, specifically cervical cancer. HPV 16 and 18 are thought to be more oncogenic than other HPV types because they comprise 70 of cervical cancers, whereas each of the other 12 high risk types (31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, and 73) con tribute less than 19. HPV 16 appears to be even more important in anal and HPV associated oropharyngeal cancers, comprising close to 90 of these cancers. HPV 16 is also commonly found in women without lesions or in those with LSILs, making the connection with cancer confusing. Genital warts and SIL are commonly associated with the detection of multiple HPV types, including a combination of low and high risk HPV types. Data show that it is likely that a single lesion arises from a single HPV type. Detection of multiple HPV types reflects the presence of cervical and anal coexisting lesions. Almost all (95) incident low risk and high risk HPV DNA detections, with or without detectable SIL, will spontaneously resolve within 1 3 years. Although HPV 16 has a slower rate of regression than some of the other high risk types, the majority of incident HPV 16 detections also will resolve. Data suggest that clearance of an HPV type results in natural immune protection against reinfection with that same type. Redetections of the same type are not common and when found are often associated with a history of a new sexual partner, suggesting that these are not reactivated infections but are due to new exposures. These redetections rarely result in high grade disease. Persistent high risktype infections are associ |
7,868 | ated with increased risk for development of HSILs and invasive cancer. Progression of HSIL to invasive cancer is still rare, with only 515 showing progression. Approximately 50 of HPV 16associated HSILs and 80 of nonHPV 16 HSILs will spontaneously regress in young women. Genital and common warts in general also resolve without therapy but may take years to do so. Genital warts in only extremely rare conditions can become malignant. Most infants with recognized genital warts are infected with the low risk types. In contrast, children with a history of sexual abuse have a clinical picture more like that of adult genital warts, consist ing of mixed low and high risk types. There are rare reports of HPV associated genital malignancies occurring in preadolescent children and adolescents. On the other hand, precancerous HSILs do occur in sexually active adolescents. There is a concern that younger age of sexual debut has contributed to the increase in invasive cervical can cers seen in women younger than 50 years of age in the United States, specifically cervical adenocarcinomas. Persistent HPV infections are considered necessary but not sufficient for the development of invasive Table 313.1 Terminology for Reporting Cervical Cytology and Histology DESCRIPTIVE DIAGNOSIS OF EPITHELIAL CELL ABNORMALITIES EQUIVALENT TERMINOLOGY SQUAMOUS CELL Atypical squamous cells of undetermined significance (ASC US) Squamous atypia Atypical squamous cells, cannot exclude HSIL (ASC H) Low grade squamous intraepithelial lesion (LSIL) Mild dysplasia, condylomatous atypia, HPV related changes, koilocytic atypia, cervical intraepithelial neoplasia (CIN) 1 High grade squamous intraepithelial lesion (HSIL) Moderate dysplasia, CIN 2, severe dysplasia, CIN 3, carcinoma in situ GLANDULAR CELL Endometrial cells, cytologically benign, in a postmenopausal woman Atypical Endocervical cells, NOS Endometrial cells, NOS Glandular cells, NOS Endocervical cells, favor neoplastic Glandular cells, favor neoplastic ENDOCERVICAL ADENOCARCINOMA IN SITU Adenocarcinoma Endocervical Endometrial Extrauterine NOS NOS, Not otherwise specified. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 313 u Human Papillomaviruses 2055 Fig. 313.1 Common warts of the left hand and the chest wall. (From Meneghini CL, Bonifaz E. An Atlas of Pediatric Dermatology, Chicago: Year Book; 1986:45.) Fig. 313.2 Common warts of the hand in a mother and perianal con dylomata acuminata in her son. (From Meneghini CL, Bonifaz E. An At las of Pediatric Dermatology, Chicago: Year Book; 1986:44.) cancers. Other risk factors for which there is relatively strong sugges tive evidence of association include smoking cigarettes, prolonged oral contraceptive use, greater parity, and Chlamydia trachomatis and her pes simplex virus infections. CLINICAL MANIFESTATIONS The clinical findings in HPV infection depend on the site of epithelial infection. Skin Lesions The typical HPV induced lesions of the skin are proliferative, papular, and hyperkeratotic. Common warts are raised circinate lesions with a keratinized surface (Fig. 313.1). Plantar and palmar warts are practi cally flat. Multiple warts are common and may create a mosaic pattern. Flat warts appear as |
7,869 | small (1 to 5 mm), flat, flesh colored papules. Genital Warts Genital warts may be found throughout the perineum around the anus, vagina, and urethra, as well as in the cervical, intravaginal, and intraanal areas (Fig. 313.2). Intraanal warts occur predominantly in patients who have had receptive anal intercourse, in contrast with perianal warts, which may occur in men and women without a history of anal sex. Although rare, lesions caused by genital genotypes can also be found on other mucosal surfaces, such as the conjunctivae, tongue, gingivae, and nasal mucosa. They may be single or multiple lesions and are frequently found in multiple anatomic sites, including the cervix. External genital warts can be flat, dome shaped, keratotic, pedunculated, and cauliflower shaped and may occur singly, in clusters, or as plaques. On mucosal epithelium, the lesions are softer. Depending on the size and anatomic location, lesions may be pruritic and painful, may cause burning with urination, may be friable and bleed, or may become superinfected. Adolescents are frequently disturbed by the development of genital lesions. Other rarer lesions caused by HPV of the external genital area include Bowen disease, bowenoid papulosis, squamous cell carcinomas, Buschke Lwenstein tumors, and vulvar intraepithelial neoplasias. Squamous Intraepithelial Lesions and Cancers SILs detected with cytology are usually invisible to the naked eye and require the aid of colposcopic magnification and acetic acid. With aid, the lesions appear white and show evidence of neovascularity. SILs can occur on the cervix, vagina, vulva, penis, and intraanus. HPV associated squamous cell lesions can also be found in the oropharynx. Invasive cancers tend to be more exophytic, with aberrant appearing vasculature. These lesions are rarely found in nonsexually active individuals. Laryngeal Papillomatosis The median age at diagnosis of recurrent laryngeal papillomatosis is 3 years. Children present with hoarseness, an altered cry, and sometimes stridor. Rapid growth of respiratory papillomas can occlude the upper airway, causing respiratory compromise. These lesions may recur within weeks of removal, requiring frequent surgery. The lesions do not become malignant unless treated with irradiation. DIAGNOSIS The diagnosis of external genital warts and common warts may be reliably determined by visual inspection of a lesion by an experienced observer and does not require additional tests for confirmation. A biopsy should be considered if the diagnosis is uncertain, the lesions do not respond to therapy, or the lesions worsen during therapy. Screening for cervical cancer in young women begins with cytol ogy, which is performed by either Papanicolaou smear or liquid based cytology and may also include high risk HPV DNA testing for women age 30 65 years. Screening guidelines were updated in 2018 by the U.S. Preventive Services Task Force (USPSTF) and recommend starting screening at age 21 years. Screening earlier is more likely to result in unnecessary referrals for colposcopy, because most lesions, including both LSILs and HSILs in this age group, are likely to regress. Guide lines recommend screening with cytology every 3 years through 29 years of age. For women age 30 65 |
7,870 | years of age, USPSTF recommends screening every 3 years with cervical cytology alone, or every 5 years with high risk HPV testing alone or high risk HPV testing with cytol ogy (cotesting). High risk HPV testing is not recommended earlier than age 30 years, because HPV infections are extremely common in young women, resulting in a very low positive predictive value in this age group. These recommendations apply to all persons who have a cervix, regardless of sexual history of HPV vaccination history. The recommended terminology used for cytologic evaluation is based on the Bethesda system (see Table 313.1). Recent updates to the terminology used for histology uses similar terms. Many clinicians still prefer the World Health Organization terminology using cervical intraepithelial neoplasia (CIN) 1, 2, and 3 (see Table 313.1). Although the purpose of screening is to identify CIN 3 lesions, the majority of CIN lesions are found in women who were referred for atypical squamous cells of undetermined significance (ASC US) or LSILs on cytology. On the other hand, few CIN 3 or cancers exist in women younger than 24 years of age. Thus, for women 21 24 years of age, ASC US and LSILs are treated the same. Consensus guidelines from the American Society of Colposcopy and Cervical Pathology for the management of cervical cancer screening abnormalities were updated in 2019 and used a risk based (related to Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 2056 Part XV u Infectious Diseases a patients risk of CIN 3) rather than test based algorithm. Treatment guidelines are also dichotomized by age group, 21 24 years and 25 years or older. Women age 21 24 years with ASC US or LSIL should have repeat cytology at 12 months and 24 months after the initial abnormal result. For persistent ASC US or LSILs at 2 years of follow up or for HSIL at any point, referral for colposcopy is recommended. If colpos copy results show LSIL, cytology should be repeated in 1 year. If there are two negative cytology results, routine age based screening can be resumed. If repeat cytology shows HSIL with CIN2, observation with repeat colposcopy every 6 months should be performed. If HSIL per sists for 2 years or if CIN 3 is identified, treatment with an excisional procedure is recommended. In women 25 years of age and older, HSIL can be treated without histologic confirmation. However, this approach should be avoided in those 21 24 years of age, because HSIL is often misdiagnosed in this group or will resolve spontaneously. In all women age 21 years and older, high risk HPV testing is accept able to assist in ASC US triage. This recommendation is based on the observations that adult women with ASC US and a positive HPV test result for high risk types are more likely to have CIN |
7,871 | 23 than women with a negative HPV test result. However, in women with ASC US and a positive HPV test for high risk types, repeat cytology is recom mended for confirmation. In women 21 24 years of age referred for colposcopy and found to have no lesion or biopsy confirmed LSIL after ASC US or LSIL cytology, repeat cytology is recommended at 12 month intervals as described previously. In women with biopsy confirmed LSIL after atypical squamous cells of high grade (ASC H) or HSIL, observation with cytology and colposcopy is recommended at 6 month intervals for up to 2 years. For persistent ASC H or HSIL at 2 years or progression at any time, treatment is recommended. These guidelines and updates can be found at http:www.asccp.org. Very sensitive tests for the presence of HPV DNA, RNA, and pro teins are becoming generally available, although they are not required for the diagnosis of external genital warts or related conditions. There are no indications for HPV DNA testing in women younger than 21 years of age or children. HPV DNA testing is also not recommended in women 21 29 years of age but is acceptable for ASC US triage. Diagno sis of JLP is made based on laryngeal examination. There are no routine screening recommendations for noncervical or oropharyngeal lesions. DIFFERENTIAL DIAGNOSIS A number of other conditions should be considered in the differen tial diagnosis of genital warts, including condyloma latum, sebor rheic keratoses, dysplastic and benign nevi, molluscum contagiosum, pearly penile papules, neoplasms, Bowen disease, bowenoid papulosis, Buschke Lwenstein tumors, and vulvar intraepithelial neoplasias. Condyloma latum is caused by secondary syphilis and can be diag nosed with darkfield microscopy and standard serologic tests for syphilis. Seborrheic keratoses are common, localized, hyperpigmented lesions that are rarely associated with malignancy. Molluscum conta giosum is caused by a poxvirus, is highly infectious, and is often umbil icated. Pearly penile papules occur at the penile corona and are normal variants that require no treatment. TREATMENT Most common (plantar, palmar, skin) warts eventually resolve spon taneously (see Chapter 708). Symptomatic lesions should be removed. Removal includes a variety of self applied therapies, including salicylic acid preparations and provider applied therapies (cryotherapy, laser therapy, electrosurgery). Genital warts are benign and usually remit, but only over an extended period. It is recommended that genital lesions be treated if the patient or the parent requests therapy. Treat ments for genital warts are categorized into self applied and provider applied. No one therapy has been shown to be more efficacious than any other. Recommended patient applied treatment regimens for external genital warts include topical podofilox, imiquimod, and sine catechins. Podofilox 0.5 solution (using a cotton swab) or gel (using a finger) is applied to visible warts in a cycle of applications twice per day for 3 days followed by 4 days of no therapy, repeated for up to a total of four cycles as needed. The total volume of podofilox used per day should not exceed 0.5 mL, and |
7,872 | patients should wash hands before and after each application. Imiquimod 5 cream is applied at bedtime, 3 times per week, every other day, for up to 16 weeks. Imiquimod 3.75 cream is applied at bedtime every night for up to 8 weeks. For both for mulations, the treated area should be washed with mild soap and water 6 10 hours after treatment. Sinecatechins (15 ointment) is a topical product from green tea extract used for external genital wart treatment that is applied 3 times daily until warts have completely resolved but no longer than 16 weeks. A 0.5 cm strand of ointment should be applied to each wart as a thin layer. Provider applied therapies include surgical treatments (electrosur gery, tangential scissor or shave excision, curettage, laser surgery), cryotherapy with liquid nitrogen or a cryoprobe and office based appli cation of bichloroacetic (BCA) or trichloroacetic acid (TCA) 8090 solution. Surgical treatments require appropriate training and equip ment but can be most beneficial for patients with large or extensive warts. Surgical removal or cryotherapy are also recommended for urethral meatus warts, while surgical removal, cryotherapy or BCA TCA is recommended for vaginal, cervical, and intraanal warts. BCA or TCA treatment should be applied only to warts and can be repeated once per week for 3 6 weeks. Alternative regimens include podophyllin resin, intralesional inter feron, photodynamic therapy, and topical cidofovir, but there are few available data regarding their efficacy. Intralesional interferon is asso ciated with significant adverse effects and is reserved for treatment of recalcitrant cases. Podophyllin resin is no longer recommended because of the availability of other, safer regimens but may be consid ered for provider administered treatment if there can be strict adher ence to recommendations to prevent complications from systemic absorption. Many therapies are painful, and children should not undergo pain ful genital treatments unless adequate pain control is provided. Par ents and patients should not be expected to apply painful therapies themselves. None of the patient applied therapies are approved for use during pregnancy, and podofilox is contraindicated in pregnancy. For any of the nonsurgical treatments, prescription is contraindicated in a patient with any history of hypersensitivity to any product constituents. If HPV exposure as a result of sexual abuse is suspected or known, the clinician should ensure that the childs safety has been achieved and is maintained. When indicated, the most common treatments for CIN 23 are abla tive and excisional treatments, including cryotherapy, laser, and loop electrosurgical excisional procedures. Once confirmed by histology with CIN 1, LSILs can be observed as described previously. The deci sion to treat a persistent CIN 1 rests between the provider and patient. Risks of treatment, including premature delivery in a future pregnancy, should be discussed before any treatment decision. Treatment in preg nancy is not recommended unless invasive cancer is present. JLP is commonly treated with surgical removal of lesions, but laser and microdebriders are also used. However, because of the incidence of scar formation after repeat debridement procedures, |
7,873 | medical therapies have been increasingly investigated. Adjunctive treatments have included interferon , antivirals such as cidofovir administered locally or systemically, photodynamic therapy, antiinflammatory drugs (celecoxib), heat shock protein, human monoclonal antibodies (beva cizumab), and HPV vaccination. However, the effectiveness of adjunc tive therapies is not consistent. COMPLICATIONS The presence of HPV lesions in the genital area may be a cause of pro found embarrassment to a child or parent. Complications of therapy are uncommon; chronic pain (vulvodynia) or hypoesthesia may occur at the treatment site. Lesions may heal with hypopigmentation or hyperpigmentation and less commonly with depressed or hypertrophic scars. Surgical therapies can lead to infection and scarring. Premature delivery and low birthweight in future pregnancies are complications of excisional therapy for CIN. It is estimated that 515 of untreated CIN 3 lesions will progress to cervical cancer. Most cancer is prevented by early detection and treat ment of these lesions. Despite screening, cervical cancer develops rap idly in a few adolescents and young women. The reason for the rapid Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 313 u Human Papillomaviruses 2057 development of cancer in these rare cases remains unknown, but host genetic defects are likely underlying causes. JLPs rarely become malig nant, unless they have been treated with irradiation. Vulvar condylo mas rarely become cancerous. HPV associated cancers of the vagina, vulva, anus, penis, and oral cavity are much rarer than cervical tumors, and therefore screening for noncervical lesions is not currently recom mended. However, anal, vaginal, and vulvar cancers are more com mon in women with cervical cancer; thus it is recommended to screen women with cervical cancer for other anogenital or oropharyngeal tumors with visual andor digital inspection PROGNOSIS With all forms of therapy, genital warts commonly recur, and approxi mately half of children and adolescents require a second or third treat ment. Recurrence is also evident in patients with JLP. Patients and parents should be warned of this likelihood. Combination therapy for genital warts (imiquimod and podofilox) does not improve response and may increase complications. Prognosis of cervical disease is bet ter, with 8590 cure rates after a single treatment with the loop elec trosurgical excision procedure. Cryotherapy has a slightly lower cure rate. Recalcitrant disease should prompt an evaluation and is common in immunocompromised individuals, specifically men and women infected with HIV. PREVENTION The only means of preventing all types of HPV infection is to avoid direct contact with lesions. Condoms may reduce the risk for HPV transmission; condoms also prevent other sexually transmitted infec tions, which are risk factors associated with SIL development. In addi tion, condoms appear to hasten the regression of LSILs in women. Avoiding smoking cigarettes is important in preventing cervical can cer. Prolonged oral contraceptive use and parity have been shown to be risks for cervical cancer. However, the mechanisms associated |
7,874 | with these factors have not been identified, and consequently no change in counseling is recommended. HPV vaccines show efficacy against type specific persistence and development of type specific disease, including the cervix, vagina, vulva, and anus. A quadrivalent HPV vaccine containing types 6, 11, 16, and 18 was licensed in the United States in 2006, and a bivalent HPV vaccine containing types 16 and 18 was licensed in the United States in 2009. A 9 valent vaccine containing types 6, 11, 16, 18, 31, 33, 45, 52, and 58 was approved in 2014. Initial licensure was for vaccina tion of persons age 9 26 years. In 2018, the FDA expanded licensure to include men and women age 27 45 years based on quadrivalent HPV vaccine clinical trial results in women age 27 45 years and bridging immunogenicity and safety data in women and men. The bivalent vac cine is indicated for the prevention of cervical precancer and cancer in females. The 4 and 9 valent HPV vaccines are indicated for the pre vention of anal, cervical, vaginal, and vulvar precancerscancers, as well as genital warts in females and anal precancer cancer and genital warts in males. The indication for the 9 valent HPV vaccine was expanded to include oropharyngeal and other head and neck cancers in 2021. The types targeted by the nonavalent vaccine account for up to 85 of cervical cancer cases. The efficacy of these vaccines is medi ated by the development of neutralizing antibodies. Prelicensure stud ies demonstrate 90100 efficacy in the prevention of persistent HPV infection, CIN 23, adenocarcinoma in situ, anogenital warts, and pre cancerous vaginal and vulvar lesions. Since vaccine introduction, data from Sweden and Australia show a decrease in national rates of geni tal warts within 4 years of implementing vaccination programs. Data from the United States show significant reductions in the prevalence of the HPV types contained in the quadrivalent vaccine among ado lescent and young adult females in the years 20092012 (postvaccine) compared with 20032006 (prevaccine). Additionally, the HPV vac cinetype prevalence was 2.1 in vaccinated compared with 16.9 in unvaccinated 14 to 24 year old sexually active females. A systematic review of 20 studies conducted in nine high income countries showed reductions of at least 68 in the prevalence of HPV 16 and 18 among 13 to 19 year olds in countries with HPV vaccination rates 50. Recent data also demonstrate significant reductions in cervical cancer rates and CIN 3 with the highest reductions among women who were vaccinated at age 12 13 years after implementation of a national HPV vaccination program in the United Kingdom. A 29 reduction in cer vical cancer annual incidence rates from 20032006 to 20112014 was observed among females age 15 24 years in the United States. Addi tionally, an analysis of data from a population based cancer registry showed a decline in the incidence of squamous cell carcinoma and adenocarcinoma among young women age 15 29 years, with the larg est reductions in the |
7,875 | 15 to 20 year age group. Available effectiveness data suggest that HPV vaccination confers herd immunity in addition to individual protection. Vaccination in the United States is recommended routinely for all adolescents at 11 12 years of age and is administered intramuscularly in the deltoid region in a two dose series at 0 and 6 12 months. A two dose series was approved and recommended in 2016 for younger ado lescents who initiate the HPV vaccine series before age 15 years based on immunogenicity data showing a comparable immune response among younger adolescents who receive a two dose series compared with older adolescents, who receive a three dose series. The effective ness of one dose has also been evaluated in observational and post hoc analyses from clinical trials. It is important that vaccination take place in children before they become sexually active, because the rate of HPV acquisition is high shortly after the onset of sexual activity. Vaccine can be given to ado lescents as young as 9 years of age, and catch up vaccination is now recommended in all persons through 26 years of age. Vaccination is also recommended for adults 27 45 years using shared clinical decision making if they have not been previously vaccinated. For any adolescent who receives his or her first HPV vaccine dose at age 15 years or older, a three dose series at 0, 1 2, and 6 months is recommended. The three dose series is also recommended for adolescents and young adults 9 26 years of age who have an immunocompromising condition. Individu als who are already infected with one or more vaccine related HPV types before vaccination are protected from clinical disease caused by the remaining vaccine HPV types. Therefore a history of prior HPV infection is not a contraindication to vaccine receipt. Currently licensed HPV vaccines are not therapeutic. However, there are thera peutic HPV vaccines under development that are primarily designed to generate a cell mediated immune response to target infected cells. Post licensure vaccine safety surveillance has not identified any seri ous adverse events attributable to HPV vaccine receipt. Three large observational studies and safety monitoring through active and pas sive surveillance networks among more than 1 million individuals have not identified any association between HPV vaccination and outcomes such as autoimmune disorders, stroke, or venous thrombotic emboli. Vaccination can cause fever in approximately 1 in 60 and discomfort at the injection site in 1 in 30 vaccine recipients. Syncope has also been found to be correlated with vaccine administration in 0.1 of vaccine recipients. Therefore it is advised that adolescents remain seated for 15 minutes after vaccination. Despite an excellent safety and efficacy profile, HPV vaccine uptake has been slow. Immunization rates have consistently lagged behind rates for the other vaccines included in the adolescent immunization platform. In 2020, 75 of 13 to 17 year olds had received at least one HPV vaccine dose compared with 89 who received at least one dose of the quadrivalent meningococcal |
7,876 | vaccine and 92 who received tetanusdiphtheriaacellular pertussis (Tdap) vaccine. Reasons for the slow uptake include inconsistent provider recommendation, lack of knowledge about HPV, parental belief that vaccination is not nec essary for younger adolescents, and misconceptions about vaccine safety, among others. There is a growing body of literature evaluating interventions to improve HPV vaccine uptake. One important strategy is a strong, consistent recommendation in which HPV vaccines are presented in the same way as Tdap and meningococcal vaccines. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 2058 Part XV u Infectious Diseases The arthropod borne viral infections are caused by a group of mosquito or tick transmitted viral pathogens of several taxa and manifest clinically mostly as neurologic infections, influenza like illnesses, or acute viral exanthems. In temperate countries, arbovi ruses are transmitted during warmer weather; however, in tropical and subtropical countries, arboviruses may be transmitted year round either in an urban cycle (human to mosquito to human) or by arthropods that feed on other vertebrate species and then feed on humans. ETIOLOGY The principal arthropod borne viral infections in North America are West Nile encephalitis (WNE), St. Louis encephalitis (SLE), Powassan (POW) encephalitis, a complex of California encephali tis group viruses, and, less frequently, western equine encephalitis (WEE), eastern equine encephalitis (EEE), and Colorado tick fever (Fig. 314.1). In 2013, chikungunya virus (CHIK) emerged from its original African zoonosis via Asia into the tropical and subtropi cal Western Hemisphere, exposing indigenes and many visitors who were traveling in the region. A few cases occurred in southern United States. In 2015, Zika virus (ZIKV), a flavivirus also main tained in Africa zoonoses, was introduced into the Americas, again from endemic areas in Asia. Limited transmission occurred within the continental United States. The major source of infection among Americans for each of these viruses has been travel to tropical and subtropical countries. CHIK appears to be endemic now, whereas ZIKV illnesses have decreased dramatically. Throughout the world outside North America, there are many arboviruses that pose major health problems (Fig. 314.2). In descend ing order, these are the dengue viruses (DENV; Chapter 315), trans mitted in all subtropical and tropical countries; Japanese encephalitis (JE), transmitted in northern, southern, and Southeast Asia; tick borne encephalitis (TBE), transmitted across Europe and into north ern and eastern Asia; yellow fever (YF; Chapter 316), transmitted from zoonotic cycles in Africa and South America; and Venezuelan equine encephalitis (VEE), transmitted in parts of South and Central America. The etiologic agents belong to different viral taxa: alphaviruses of the family Togaviridae (CHIK, EEE, VEE, WEE), flaviviruses of the family Flaviviridae (DENV, JE, POW, SLE, TBE, WNE, YF, ZIKV), the California complex of the family Bunyaviridae (California encephalitis), and Reoviridae (Colorado tick fever virus). Alpha viruses are 69 nm, enveloped, positive sense RNA viruses. Studies |
7,877 | suggest that this group of viruses had a marine origin (specifically the southern ocean) and has subsequently spread to both the Old and New Worlds. VEE circulates in nature in six subtypes. Virus types I and III have multiple antigenic variants. Types IAB and IC have caused epizootics and human epidemics. Flaviviruses are 40 to 50 nm, enveloped, positive sense RNA viruses that evolved from a common ancestor. They are mosquito borne (WNE, SLE, JE, YF, DENV, ZIKV) and tick borne (POW, TBE) agents, globally distrib uted, and responsible for many important human viral diseases. The California serogroup, 1 of 16 Bunyavirus groups, are 75 to 115 nm enveloped viruses possessing a three segment, negative sense RNA genome. Reoviruses are 60 to 80 nm double stranded RNA viruses. DIAGNOSIS For arboviral infections not described separately, the etiologic diag nosis is established by testing either an acute phase serum to detect the virus, viral antigen, or viral RNA (influenza like illnesses or viral exanthems) or by recovery of virus from central nervous system (CNS) tissue or cerebrospinal fluid (CSF). More commonly, the diag nosis is established serologically. Serum obtained 5 days after the onset of illness is tested for the presence of virus specific immuno globulin (Ig) M antibodies using an enzyme linked immunosorbent assay IgM capture test, an indirect immunofluorescence test, or a pre cipitin test. Alternatively, acute and convalescent sera can be tested for a fourfold or greater increase in enzyme linked immunosorbent assay, hemagglutination inhibition, or neutralizing antibody titers. Commercial serologic diagnostic kits are marketed for DENV, CHIK, JE, TBE, WNE, YF, and ZIKV viral infections. The serum and CSF should be tested for JE or WNE virusspecific IgM. However, IgM may reflect past infection, because it may be present up to 12 months after infection. For suspected flavivirus infections, including ZIKV, it may be possible to establish infection using a serologic test, calling on the specificity of neutralizing antibodies. The most common of these is the plaque or focus reduction neutralizing antibody test. Reference laboratories offer tests for all of the pathogenic flaviviruses. The diag nosis may also be established by the isolation of virus in cell cultures, by identification of viral RNA, or by detection of viral proteins (e.g., dengue NS1) from blood, brain tissue obtained by brain biopsy, or tissues obtained at autopsy. PREVENTION Several vaccines for JE and TBE are licensed in endemic and non endemic countries. An experimental vaccine for VEE is available to protect laboratory workers. Travelers who plan to be in rural areas of Asia during the expected period of seasonal transmission should receive JE vaccine. Similarly, travelers who plan to travel, camp, or picnic in rural areas of Europe and East Asia should con sult local health authorities concerning the need to be vaccinated against TBE. An inactivated JE vaccine manufactured in Japan by intracerebral injection of young mice once available throughout the world was taken off the market owing to a high incidence of adverse events. In 20082009, tissue |
7,878 | culturebased JE vaccine (Ixi aro) was licensed in Europe, Australia, and the United States. In the United States, this vaccine, licensed for use in children and adults, distributed by Novartis (Basel), is administered intramuscularly as two doses of 0.5 mL each, 28 days apart. The final dose should be completed at least 1 week before the patients expected arrival in a JE endemic area. This vaccine contains alum and protamine sulfate and has exhibited only mild adverse events. Chimerivax JE, mar keted by Sanofi Pasteur and licensed in Australia and several Asian countries, is a live attenuated two dose vaccine composed of the structural gene of JE inserted into the YF 17D vaccine backbone. A highly efficacious live attenuated single dose JE vaccine, SA 14 14 2, developed in China for children is licensed and marketed in Asian countries. This vaccine can be co administered with live attenuated measles vaccine without altering the immune responses to either vaccine. In humans, prior DENV infection provides partial protection against clinical JE. No TBE vaccines are licensed or available in the United States. Two inactivated cell culturederived TBE vaccines are available in Europe, in adult and pediatric formulations: FSME IMMUN (Baxter, Austria) and Encepur (Novartis, Germany). The adult for mulation of FSME IMMUN is also licensed in Canada. Two other inactivated TBE vaccines are available in Russia: TBE Moscow (Chumakov Institute, Russia) and EnceVir (Microgen, Russia). Immunogenicity studies suggest that the European and Russian vaccines should provide cross protection against all three TBE virus subtypes. For both FSME IMMUN and Encepur, the primary vac cination series consists of three doses. The specific recommended Chapter 314 Arboviral Infections Scott B. Halstead Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 314 u Arboviral Infections 2059 intervals between doses vary by country and vaccine. Because the routine primary vaccination series requires 6 months for comple tion, most travelers to TBE endemic areas will find avoiding tick bites to be more practical than vaccination. For all viral diseases discussed in this chapter, personal measures should be taken to reduce exposure to mosquito or tick bites, especially for short term residents in endemic areas. These measures include avoiding evening outdoor exposure, using insect repellents, covering the body with clothing, and using bed nets or house screening. Com mercial pesticides, widely used by rice farmers, may be useful in reduc ing populations of vector mosquitoes or ticks. Fenthion, fenitrothion, and phenthoate are effectively adulticidal and larvicidal. Insecticides may be applied from portable sprayers or from helicopters or light aircraft. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Human Eastern Equine Encephalitis Cases by State, 19642010 EEE Human cases VT 1 1 53 16 13 13 94 4 2 2 3 4 17 13 28 70 76 17 2 10 37 6 20 3 3 36 173 16 27 7 6 1 1 2 |
7,879 | 43 78 40 26 5 16 1 2 3 4 602 1 123 2 4 4 3 2 1 1 41 7 127 14 5 19 88 12 1021 168 79 77 25 8 5 33 697 369 441 37 10 68 8 6 3 141 348 150 5 380 1 1 2 5 25 5 14 134 367 586 31 241 143 918 8 58 23 28 237 163 14 7 27 4 1 131 1 9 9 12 NH MA RI CT NJ DE MD DC WV Puerto RicoHI AK A B C D Human Western Equine Encephalitis Cases by State, 19642007 WEE Human cases VT NH MA RI CT NJ DE MD DC WV Puerto RicoHI AK Human Saint Louis Encephalitis Cases by State, 19642010 SLE Human cases Powassan Virus Neuroinvasive Disease Cases Reported by State, 20012012 POWV Human cases VT NH MA RI CT NJ DE MD DC WV Puerto RicoHI AK Human California Serogroup Viral Encephalitis Cases by State, 19642010 CAL Human cases VT NH MA RI CT NJ DE MD DC WV Puerto Rico The majority of reported California serogroup cases are La Crosse virus (LAC). HI AK 19 10 1 1 13 2 1 E VT NH MA RI CT NJ DE MD DC WV Puerto RicoHI AK 1 Fig. 314.1 The distribution and incidence of reported cases of eastern equine encephalitis (A), western equine encephalitis (B), St. Louis encepha litis (C), California serogroup encephalitis (D), and Powassan encephalitis; (E), reported by state to the Centers for Disease Control and Prevention, 1964 to 2010. (From Division of Vector Borne Diseases, Centers for Disease Control and Prevention. http:www.cdc.govncidoddvbidarborarbo casehtm) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 2060 Part XV u Infectious Diseases 314.1 Eastern Equine Encephalitis Scott B. Halstead In the United States, EEE is a disease with a very low incidence, with a median of eight cases occurring annually in the Atlantic and Gulf states from 1964 to 2007. A severe outbreak in 2019 resulted in 19 fatalities among 38 cases (see Fig. 314.1). Transmission occurs often in focal endemic areas of the coast of Massachusetts, the six southern counties of New Jersey, and northeastern Florida. In North America, the virus is maintained in freshwater swamps in a zoonotic cycle involving the Culiseta melanura mosquito and birds. Various other mosquito species obtain viremic meals from birds and transmit the virus to horses and humans. Virus activity varies markedly from year to year in response to still unknown ecologic factors. Most infections in birds are silent, but infections in pheasants are often fatal, and epizootics in these species are used as sentinels for periods of increased viral activity. Cases have been recognized on Caribbean islands. The case:infection ratio is low est in children (1:8) and somewhat higher in adults (1:29). EEE virus infections result in fulminant encephalitis |
7,880 | with a rapid progression to coma and death in one third of cases. In infants and children, abrupt onset of fever, irritability, and headache are followed by lethargy, confusion, seizures, and coma. High temperature, bulg ing fontanel, stiff neck, and generalized flaccid or spastic paralysis are observed. There may be a brief prodrome of fever, headache, and diz ziness. Unlike most other viral encephalitides, the peripheral white blood cell count usually demonstrates a marked leukocytosis and the CSF may show marked pleocytosis. Pathologic changes are found in the cortical and gray matter, with viral antigens localized to neurons. There is necrosis of neurons, neutrophilic infiltration, and perivascular cuffing by lymphocytes. The prognosis in EEE is better for patients with a prolonged pro drome; the occurrence of convulsions conveys a poor prognosis. Patient fatality rates are 3375 and are highest in the elderly. Residual neurologic defects are common, especially in children. The diagnosis of encephalitis may be aided by CT or MRI and by electroencephalography. Focal seizures or focal findings on CT or MRI or electroencephalography should suggest the possibility of her pes simplex encephalitis, which should be treated with acyclovir (see Chapter 299). Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 314.2 Western Equine Encephalitis Scott B. Halstead WEE infections occur principally in the United States and Canada west of the Mississippi River (see Fig. 314.1). Cases occur mainly in rural areas where water impoundments, irrigated farmland, and nat urally flooded land provide breeding sites for the Culex tarsalis mos quito. The virus is transmitted in a cycle involving mosquitoes, birds, and other vertebrate hosts. Humans and horses are susceptible to encephalitis. The case:infection ratio varies by age, having been esti mated at 1:58 in children younger than 4 years of age and 1:1,150 in adults. Infections are most severe at the extremes of life; one third of cases occur in children younger than 1 year of age. Recurrent human epidemics have been reported from the Yakima Valley in Washington State and the Central Valley of California; the largest outbreak on record resulted in 3,400 cases and occurred in Minnesota, North and South Dakota, Nebraska, and Montana, as well as Alberta, Manitoba, and Saskatchewan, Canada. Epizootics in horses precede human epi demics by several weeks. For the past 20 years, only three cases of WEE have been reported, presumably reflecting successful mosquito abatement. In WEE, there may be a prodrome with symptoms of an upper respi ratory tract infection. The onset is usually sudden with chills, fever, diz ziness, drowsiness, increasing headache, malaise, nausea and vomiting, Flaviviridae Zika Virus Japanese encephalitis virus Yellow fever virus West Nile virus Saint Louis encephalitis virus Tickborne encephalitis virus Dengue virus CrimeanCongo hemorrhagic fever virus Toscana virus La Crosse virus Rift Valley fever virus Bunyaviridae Venezuelan equine encephalitis virus Sindbis virus ONyongnyong virus Ross River virus Chikungunya virus Togaviridae (alphaviruses) BA C Fig. 314.2 World distribution of major arbovirus infections. (From Charlier C, Beaudoin MC, Couderc T, et al. Arboviruses and pregnancy: mater nal, fetal, |
7,881 | and neonatal effects. Lancet Child Adolesc. 2017;1:134146. Fig. 1.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 314 u Arboviral Infections 2061 stiff neck, and disorientation. Infants typically present with the sudden cessation of feeding, fussiness, fever, and protracted vomiting. Convul sions and lethargy develop rapidly. On physical examination, patients are somnolent, exhibit meningeal signs, and have generalized motor weakness and reduced deep tendon reflexes. In infants, a bulging fon tanel, spastic paralysis, and generalized convulsions may be observed. On pathologic examination, disseminated small focal abscesses, small focal hemorrhages, and patchy areas of demyelination are distinctive. Patient fatality rates in WEE are 39 and are highest in the elderly. Major neurologic sequelae have been reported in up to 13 of cases and may be as high as 30 in infants. Parkinsonian syndrome has been reported as a residual in adult survivors. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 314.3 St. Louis Encephalitis Scott B. Halstead Cases of SLE are reported from nearly all states; the highest attack rates occur in the gulf and central states (see Fig. 314.1). Epidemics frequently occur in urban and suburban areas; the largest occurred in 1975 and involved 1,800 persons living in Houston, Chicago, Memphis, and Denver. Cases often cluster in areas where there is ground water or septic systems, which support mosquito breeding. The principal vec tors are Culex pipiens and Culex quinquefasciatus mosquitoes in the central gulf states, Culex nigripalpus in Florida, and Culex tarsalis in California. SLE virus is maintained in nature in a bird mosquito cycle. Viral amplification occurs in bird species abundant in residential areas (e.g., sparrows, blue jays, and doves). Virus is transmitted in the late summer and early fall. The case:infection ratio may be as high as 1:300. Age specific attack rates are lowest in children and highest in individu als older than 60 years. The most recent small outbreaks were in Florida in 1990 and Louisiana in 2001. For the past 15 years, there have been a mean of 18 cases annually. Clinical manifestations of SLE vary from a mild flulike illness to fatal encephalitis. There may be a prodrome of nonspecific symptoms with subtle changes in coordination or mentation of several days to 1 week in duration. Early signs and symptoms include fever, photophobia, headache, malaise, nausea, vomiting, and neck stiffness. About half of patients exhibit an abrupt onset of weakness, incoordination, disturbed sensorium, restlessness, confusion, lethargy, and delirium or coma. The peripheral white blood cell count is modestly elevated, with 100 200 white blood cellsL found in the CSF. On autopsy, the brain shows scattered foci of neuronal damage and perivascular inflammation. The principal risk factor for fatal outcome of SLE is advanced age, with patient fatality rates being as high as 80 in early outbreaks. In children, mortality rates are 25. In adults, underlying hypertensive cardiovascular disease |
7,882 | has been a risk factor for fatal outcome. Recov ery from SLE is usually complete, but the rate of serious neurologic sequelae has been reported to be as high as 10 in children. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 314.4 West Nile Encephalitis Scott B. Halstead West Nile virus (WNV) was imported into the United States in 1999 and survives in a broad enzootic cycle across the United States and Canada. Every state in the continental United States plus nine provinces in Canada have reported mosquito, bird, mammalian, or human WN virus infection, most frequently during the summer or fall months. Through the end of 2015, a total of 43,937 cases had been reported in the United States, 4050 of which were neuroin vasive, with 1,911 deaths (Fig. 314.3). In 2020, there were 505 WNV cases, 159 of which were neuroinvasive, resulting in 52 deaths. WNV transmission cycles have come to resemble JE with large epizootics and human cases occurring every 5 10 years. WNV has entered the blood supply through asymptomatic viremic potential blood donors. Since 2003, blood banks screen for WNV RNA. Dur ing the major outbreak of 2012, 597 viremic potential blood donors were identified and the donation was rejected. WNV has also been transmitted to humans via the placenta, breast milk, and organ transplantation. Throughout its range, the virus is maintained in nature by transmission between mosquitoes of the Culex genus and various species of birds. In the United States, human infections are largely acquired from C. pipiens. Horses are the nonavian verte brates most likely to exhibit disease with WNV infection. During the 2002 transmission season, 14,000 equine cases were reported, with a mortality rate of 30. Disease occurs predominantly in indi viduals 50 years of age. WNV has been implicated as the cause of sporadic summertime cases of human encephalitis and meningi tis in Israel, India, Pakistan, Romania, Russia, Canada, the United States, and parts of Central and South America. All North and South American WNVs are genetically similar and are related to a virus recovered from a goose in Israel in 1998. West Nile encephalitis (WNE) may be asymptomatic, but when clinical features appear, they include an abrupt onset of high fever, headache, myalgias, and nonspecific signs of emesis, rash, abdomi nal pain, or diarrhea. Most infections manifest as a flulike febrile illness, whereas a minority of patients demonstrate meningitis or encephalitis or both. Rarely there may be cardiac dysrhythmias, myocarditis, rhabdomyolysis, optic neuritis, uveitis, retinitis, orchi tis, pancreatitis, or hepatitis. WNV disease in the United States has been accompanied by prolonged lymphopenia and an acute asym metric polio like paralytic illness with CSF pleocytosis involving the anterior horn cells of the spinal cord. A striking but uncom mon feature has been parkinsonism and movement disorders (with tremor and myoclonus). WNV infections have been shown to lead to chronic kidney disease in a small group of patients. Cases of WNE and deaths due to the disease occur mainly in the elderly, although |
7,883 | many serologic surveys show that persons of all ages are infected. In 2015, among a total of 2,175 human cases, 1,455 were neuroinvasive disease with 146 deaths, a 10 mortality rate (see Fig. 314.2). Paralysis may result in permanent weakness. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Per 100,000 population. 1.00 0.50.99 0.250.49 0.010.24 0.00 Fig. 314.3 Rate (per 100,000 population) of reported cases of West Nile virus neuroinvasive disease, United States, 2016. (From Burakoff A, Lehman J, Fischer M, et al. West Nile virus and other nationally notifi able arboviral diseases, United States, 2016. MMWR Morb Mortal Wkly Rep. 2018;671L1317.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 2062 Part XV u Infectious Diseases 314.5 Powassan Encephalitis Scott B. Halstead POW virus is transmitted by Ixodes cookei among small mammals in eastern Canada and the United States; it has been responsible for 39 deaths in the United States since 2008 (see Fig. 314.1). Other ticks may transmit the virus in a wider geographic area, and there is some concern that Ixodes scapularis (also called Ixodes dammini), a compe tent vector in the laboratory, may become involved as it becomes more prominent in the United States. In a limited experience, POW encephalitis has occurred mainly in adults with vocational or recreational exposure and has a high fatality rate. POW encephalitis has occurred mostly in adults living in enzootic areas with vocational or recreational exposure; it is associated with sig nificant long term morbidity and has a case fatality rate of 1015. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 314.6 La Crosse and California Encephalitis Scott B. Halstead La Crosse viral infections are endemic in the United States, occurring annually from July to September, principally in the north central and central states (see Fig. 314.1). Infections occur in peridomestic envi ronments as the result of bites from Aedes triseriatus mosquitoes, which often breed in tree holes. The virus is maintained vertically in nature by transovarial transmission and can be spread between mosquitoes by copulation and amplified in mosquito populations by viremic infec tions in various vertebrate hosts. Amplifying hosts include chipmunks, squirrels, foxes, and woodchucks. A case:infection ratio of 1:22 300 has been surmised. La Crosse encephalitis is principally a disease of chil dren, who may account for up to 75 of cases. A mean of 100 cases has been reported annually for the past 10 years. The clinical spectrum includes a mild febrile illness, aseptic menin gitis, and fatal encephalitis. Children typically present with a prodrome of 2 3 days of fever, headache, malaise, and vomiting. The disease evolves with clouding of the sensorium, lethargy, and, in severe cases, focal or generalized seizures. On physical examination, children are lethargic but not disoriented. Focal neurologic signs, including weak ness, aphasia, and focal or generalized seizures, have been reported in 1625 of cases. CSF shows low |
7,884 | to moderate leukocyte counts. On autopsy, the brain shows focal areas of neuronal degeneration, inflam mation, and perivascular cuffing. Recovery from California encephalitis is usually complete. The case fatality rate is approximately 1. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 314.7 Colorado Tick Fever Scott B. Halstead Colorado tick fever virus is transmitted by the wood tick Dermacentor andersoni, which inhabits high elevation areas of states extending from the central plains to the Pacific coast. The tick is infected with the virus at the larval stage and remains infected for life. Squirrels and chipmunks serve as primary reservoirs. Human infections typically occur in hikers and campers in indigenous areas during the spring and early summer. Colorado tick fever begins with the abrupt onset of a flulike illness, including high temperature, malaise, arthralgia and myalgia, vomiting, headache, and decreased sensorium. Rash is uncommon. The symp toms rapidly disappear after 3 days of illness. However, in approximately half of patients, a second identical episode reoccurs 24 72 hours after the first one, producing the typical saddleback temperature curve of Colorado tick fever. Complications, including encephalitis, meningoen cephalitis, and a bleeding diathesis, develop in 37 of infected persons and may be more common in children younger than 12 years of age. Recovery from Colorado tick fever is usually complete. Three deaths have been reported, all in persons with hemorrhagic signs. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 314.8 Chikungunya Fever Scott B. Halstead Chikungunya virus is enzootic in several species of African subhuman primates but also is endemic in urban Aedes aegypti or Aedes albopictus transmission cycles in Africa, Asia, and the Americas. From the 18th century, chikungunya exited Africa eastward, producing Asian pan demics in 1790, 1824, 1872, 1924, 1963, and 2005. In 1827, chikungu nya went the other direction via the slave trade, reaching the Western Fig. 314.4 Algorithm showing diagnostic criteria for chikungunya virus fever. (From Burt FJ, Rolph MS, Rulli NE, et al. Chikungu nya: a re emerging virus. Lancet. 2012;379:662668. Fig. 6.) Criteria Definition 1 Clinical criteria: Acute onset of fever ?38.5C and severe arthralgia or arthritis Possible case when not explained by other medical condition: dengue or alphaviral infection, arthritic disease, endemic malaria Probable case if clinical and epidemiologic criteria are met: other pathogens with similar clinical manifestations can cocirculate within the same geographic region Confirmed case if a patient tests positive for 1 of the laboratory criteria, irrespective of clinical manifestations 3 Laboratory criteria: After acute phase Virus isolation Presence of viral RNA Specific IgM antibodies Fourfold increase in IgG titers in paired samples 2 Epidemiologic criteria: Residing in or visited epidemic area within 15 days before onset of symptoms Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 314 u Arboviral Infections 2063 Hemisphere predominantly in the Caribbean. In 2005, proceeding again in an easterly direction, virus appeared on |
7,885 | Reunion Island and then traveled to Asia across the Indian Ocean. In 2013, chikungunya virus from this epidemic was introduced into the Americas, where it is now endemic. Clinical manifestations begin 3 7 days after a mosquito bite; the onset is abrupt, with high fever and often severe joint symptoms (hands, feet, ankles, wrists) that include symmetric bilateral polyar thralgia or arthritis. Infections in children are often asymptomatic, but all ages are vulnerable to classic disease. There may be headache, myalgias, conjunctivitis, weakness, lymphopenia, and a maculopapular rash. Mortality is rare; some individuals develop prolonged joint symp toms (tenosynovitis, arthritis) lasting over a year. The acute episode lasts 7 10 days. The differential diagnosis includes dengue, West Nile, enterovirus diseases, leptospirosis, rickettsial disease, measles, parvovi rus disease, rheumatologic diseases, and other alphavirus diseases (e.g., Ross River virus) in endemic areas. Figure 314.4 lists the diagnostic criteria. The incidence of febrile convulsions is high in infants. The progno sis is generally good, although in large outbreaks in Africa and India, severe disease and deaths have been attributed to chikungunya infec tions, predominantly in adults. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 314.9 Venezuelan Equine Encephalitis Scott B. Halstead VEE virus was isolated from an epizootic in Venezuelan horses in 1938. Human cases were first identified in 1943. Hundreds of thousands of equine and human cases have occurred over the past 70 years. During 1971, epizootics moved through Central America and Mexico to south ern Texas. After 3 decades of quiescence, epizootic disease emerged again in Venezuela and Colombia in 1995. Between December 1992 and January 1993, the Venezuelan state of Trujillo experienced an out break of this virus. Overall, 28 cases of the disease were reported, along with 12 deaths. A bigger outbreak occurred in June 1993, resulting in the death of 55 humans and 66 horses. A much larger outbreak in Venezuela and Colombia occurred in 1995. On May 23, 1995, equine encephalitis like cases were reported in the northwest portion of the country. Eventually, the outbreak spread toward the north, as well as to the south. The outbreak caused about 11,390 febrile cases in humans, as well as 16 deaths. About 500 equine cases were reported with 475 deaths. The incubation period is 2 5 days, followed by the abrupt onset of fever, chills, headache, sore throat, myalgia, malaise, prostration, pho tophobia, nausea, vomiting, and diarrhea. In 510 of cases, there is a biphasic illness; the second phase is heralded by seizures, projectile vomiting, ataxia, confusion, agitation, and mild disturbances in con sciousness. There is cervical lymphadenopathy and conjunctival suf fusion. Cases of meningoencephalitis may demonstrate cranial nerve palsy, motor weakness, paralysis, seizures, and coma. Microscopic examination of tissues reveals inflammatory infiltrates in lymph nodes, spleen, lung, liver, and brain. Lymph nodes show cellular depletion, necrosis of germinal centers, and lymphophagocytosis. The liver shows patchy hepatocellular degeneration, the lungs demonstrate a diffuse interstitial pneumonia with intraalveolar hemorrhages, and the brain shows patchy cellular infiltrates. Vertical transmission from mother to |
7,886 | fetus has been documented. Ten fetal autopsies performed during an outbreak demonstrated VEE virus in the brains of aborted fetuses. https:www.ncbi.nlm.nih.govbooksNBK559332. Infants born to mothers with VEE may have neurologic sequelae or fatal cerebral lesions. There is no specific treatment for VEE. The treatment is intensive supportive care (see Chapter 82), including control of seizures (see Chapter 633). In patients with VEE meningoencephalitis, the fatality rate ranges from 1025. Sequelae include nervousness, forgetfulness, recurrent headache, and easy fatigability. Several veterinary vaccines are available to protect equine animals. VEE virus is highly infectious in laboratory settings, and biosafety level 3 containment should be used. An experimental vaccine is available for use in laboratory workers. Several vaccine constructs are in the pipe line for potential use in humans. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 314.10 Japanese Encephalitis Scott B. Halstead JE is a mosquito borne viral disease of humans, as well as horses, swine, and other domestic animals. The virus causes human infections and acute disease in a vast area of Asia, from Indochina through the Indian subcontinent, northern Japan, Korea, China, Taiwan, the Philippines, and the Indonesian archipelago. Culex tritaeniorhynchus summarosus, a night biting mosquito that feeds preferentially on large domestic ani mals and birds but only infrequently on humans, is the principal vector of zoonotic and human JE in northern Asia. A more complex ecology prevails in southern Asia. From Taiwan to India, C. tritaeniorhynchus and members of the closely related Culex vishnui group are vectors. Before the introduction of JE vaccine, summer outbreaks of JE occurred regularly in Japan, Korea, China, Okinawa, and Taiwan. Over the past decade, there has been a pattern of steadily enlarging recurrent seasonal outbreaks in Vietnam, Thailand, Nepal, and India, with small outbreaks in the Philippines, Indonesia, and the northern tip of Queensland, Aus tralia. Seasonal rains are accompanied by increases in mosquito popu lations and JE transmission. Pigs serve as an amplifying host. The annual incidence in endemic areas ranges from 1 10 per 10,000 population. Children younger than 15 years of age are prin cipally affected, with nearly universal exposure by adulthood. The case:infection ratio for JE virus has been variously estimated at 1:25 to 1:1,000. Higher ratios have been estimated for populations indigenous to enzootic areas. JE occurs in travelers visiting Asia; therefore a travel history in the diagnosis of encephalitis is critical. After a 4 to 14 day incubation period, cases typically progress through the following four stages: prodromal illness (2 3 days), acute stage (3 4 days), subacute stage (7 10 days), and convalescence (4 7 weeks). The onset may be characterized by an abrupt onset of fever, headache, respiratory symptoms, anorexia, nausea, abdominal pain, vomiting, and sensory changes, including psychotic episodes. Grand mal seizures are seen in 1024 of children with JE; parkinsonian like nonintention tremor and cogwheel rigidity are seen less frequently. Particularly characteristic are rapidly changing central nervous system signs (e.g., hyperreflexia followed by hyporeflexia or plantar responses that change). The sensory status of the |
7,887 | patient may vary from confu sion through disorientation and delirium to somnolence, progressing to coma. There is usually a mild pleocytosis (100 1,000 leukocytesL) in the cerebrospinal fluid, initially polymorphonuclear but in a few days predominantly lymphocytic. Albuminuria is common. Fatal cases usually progress rapidly to coma, and the patient dies within 10 days. JE should be suspected in patients reporting exposure to night biting mosquitoes in endemic areas during the transmission season. The etiologic diagnosis of JE is established by testing acute phase serum collected early in the illness for the presence of virus specific IgM anti bodies or, alternatively, demonstrating a fourfold or greater increase in IgG antibody titers by testing paired acute and convalescent sera. The virus can also be identified by polymerase chain reaction (PCR). There is no specific treatment for JE. The treatment is intensive sup portive care (see Chapter 82), including control of seizures (see Chap ter 633). Patient fatality rates for JE are 2442 and are highest in children 5 9 years of age and in adults older than 65 years of age. The frequency Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 2064 Part XV u Infectious Diseases of sequelae is 570 and is directly related to the age of the patient and severity of disease. Sequelae are most common in patients younger than 10 years at the onset of disease. The more common sequelae are mental deterioration, severe emotional instability, personality changes, motor abnormalities, and speech disturbances. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 314.11 Tick Borne Encephalitis Scott B. Halstead TBE refers to neurotropic tick transmitted flaviviral infections occur ring across the Eurasian land mass. In the Far East, the disease is called Russian spring summer encephalitis; the milder, often biphasic form in Europe is simply called TBE. TBE is found in all countries of Europe except Portugal and the Benelux countries. The incidence is particularly high in Austria, Poland, Hungary, Czech Republic, Slovakia, former Yugoslavia, and Russia. The incidence tends to be very focal. Seropreva lence is as high as 50 in farm and forestry workers. The majority of cases occur in adults, but even young children may be infected while playing in the woods or on picnics or camping trips. The seasonal distri bution of cases is midsummer in southern Europe, with a longer season in Scandinavia and the Russian Far East. TBE can be excreted in the milk of goats, sheep, or cows. Before World War II, when unpasteurized milk was consumed, milk borne cases of TBE were common. Viruses are transmitted principally by hard ticks, Ixodes ricinus in Europe and Ixodes persulcatus in the Far East. Viral circulation is main tained by a combination of transmission from ticks to birds, rodents, and larger mammals and transstadial transmission from larval to nymphal and adult stages. In some parts of Europe and |
7,888 | Russia, ticks feed actively during the spring and early fall, giving rise to the name spring summer encephalitis. After an incubation period of 7 14 days, the European form begins as an acute nonspecific febrile illness that is followed in 530 of cases by meningoencephalitis. The Far Eastern variety more often results in encephalitis with higher case fatality and sequelae rates. The first phase of illness is characterized by fever, headache, myalgia, malaise, nau sea, and vomiting for 2 7 days. Fever disappears but after 2 8 days may return, accompanied by vomiting, photophobia, and signs of menin geal irritation in children and more severe encephalitic signs in adults. This phase rarely lasts more than 1 week. There is no specific treatment for TBE. The treatment is intensive supportive care (see Chapter 82), including control of seizures (see Chapter 633). The main risk for a fatal outcome is advanced age; the fatality rate in adults is approximately 1, but sequelae in children are rare. Tran sient unilateral paralysis of an upper extremity is a common finding in adults. Common sequelae include chronic fatigue, headache, sleep disorders, and emotional disturbances. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 2016 Florida: First outbreak in continental USA 201516 Spread in 48 countries in the Americas and Caribbean First reported local circulation in the Americas, Brazil May, 2015 French Polynesia: Second outbreak; first severe complications; nonvectorborne transmission 200812 2013 Yap Island: First outbreak No reported outbreaks 201416 2007 201516 Cape Verde: First African outbreak 2016 Singapore: First Asian outbreak Asian endemic areas before 2007 African outbreaks African endemic areas before 2007 Asian outbreaks Pacific outbreaks American outbreaks 201416 Spread in 20 Pacific countries Fig. 314.5 Zika virus outbreaks from 2007 to 2016. (From Baud D, Gubler DJ, Schaub B, et al. An update on Zika virus infection. Lancet. 2017;390:20992109. Fig. 2.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 314 u Arboviral Infections 2065 314.12 Zika Virus Scott B. Halstead EPIDEMIOLOGY ZIKV, a member of the Flavivirus genus, is maintained in complex African zoonotic cycles, spilling over from time to time into the Aedes aegyptiA. albopictus urban transmission cycles, possibly over a period of many years (Fig. 314.5). After the virus was discovered in Africa in 1947, human antibodies were found widely dispersed throughout tropical Asia. However, in all these locations, human ZIKV disease was mild and rare until 2007, when there was an out break of a mild febrile exanthem on the Yap Islands in the western Pacific. Soon thereafter an outbreak on Tahiti in 20132014 was fol lowed in 4 weeks by a small outbreak of Guillain Barr syndrome (GBS). In 2015 a massive epidemic in South America was accom panied by focal reports, particularly in Brazil, of ZIKV infections of pregnant women that produced infected and damaged fetuses or newborns. The epidemiology of ZIKV infections |
7,889 | is essentially identi cal to that of the DENV and CHIK. Residents of urban areas, particu larly those without adequate sources of piped water, are at highest risk. A. aegypti, the principal vector mosquito, is very abundant and widespread throughout South and Central America, Mexico, and the Caribbean region. During the North, Central, and South American pandemic, ZIKV was found to infect the male reproductive tract, be secreted in urine and saliva, and be sexually transmitted. By 2017, the ZIKV epidemic in the American tropics appeared to wane, with few cases reported since then. During 20152016, large numbers of imported ZIKV infections, some in pregnant women, were reported in the United States and other temperate zone developed coun tries. Small outbreaks of endogenous human ZIKV infections were reported in South Florida during the summer of 2016. From the pediatric perspective, the most important outcome of human ZIKV infection is termed the congenital Zika syndrome (CZS), which consists of microcephaly, facial disproportion, hypertonia spasticity, hyperreflexia, irritability, seizures, arthrogryposis, ocular abnormalities, and sensorineural hearing loss (Table 314.1). A compre hensive understanding of the precise antecedents to CZS is not known. It appears that the earlier during pregnancy that ZIKV infections occur, the greater the likelihood of and the more severe is the CZS. Vertical transmission appears to follow viremia with ZIKV, transiting the uterus to infect the placenta and then the fetus. However, factors that affect the occurrence or severity of CZS, such as age, ethnicity, or prior immune status of the mother, are not known. In vitro studies have demonstrated that DENV antibodies can enhance ZIKV infection in vitro, in Fc receptorbearing cells. In Nicaraguan children, a prior DENV infec tion did not enhance Zika disease, and, as yet, there is no evidence that a prior DENV infection alters the chance of ZIKV crossing the placenta or increases the risk of CZS. Maternalfetal transmission of ZIKV can occur during labor and delivery. There are no reports of ZIKV infection acquired by an infant at the time of delivery leading to microcephaly. There are no data to contraindicate breastfeeding, although the virus has been identified in breast milk. Maternal and newborn laboratory testing is indicated during the first 2 weeks of life if the mother had relevant epidemiologic exposure within 2 weeks of delivery and had clinical manifestations of ZIKV infection (e.g., rash, conjunctivitis, arthralgia, or fever). Infants and children who acquire ZIKV infection postnatally appear to have a mild course, similar to that seen in adults. CLINICAL FEATURES Congenital Zika syndrome may be defined in a fetus with diagnostic evidence of ZIKV infection, including (1) severe microcephaly (3 SD below the mean), partially collapsed skull, overlapping cranial sutures, prominent occipital bone, redundant scalp skin, and neurologic impairment; (2) brain anomalies, including cerebral cortex thinning, abnormal gyral patterns, increased fluid spaces, subcortical calcifica tions, corpus callosum anomalies, reduced white matter, and cerebellar vermis hypoplasia; (3) ocular findings, such as macular scarring, focal pigmentary retinal mottling, structural anomalies (microphthalmia, Table 314.1 Surveillance Case |
7,890 | Classification: Children, Neonate to 2 Years of Age, Born to Mothers with Any Evidence of Zika Virus Infection During Pregnancy ZIKA ASSOCIATED BIRTH DEFECTS Selected structural anomalies of the brain or eyes present at birth (congenital) and detected from birth to age 2 yr. Microcephaly at birth, with or without low birthweight, was included as a structural anomaly. Selected congenital brain anomalies: intracranial calcifications; cerebral atrophy; abnormal cortical formation (e.g., polymicrogyria, lissencephaly, pachygyria, schizencephaly, gray matter heterotopia); corpus callosum abnormalities; cerebellar abnormalities; porencephaly; hydranencephaly; ventriculomegaly hydrocephaly. Selected congenital eye anomalies: microphthalmia or anophthalmia; coloboma; cataract; intraocular calcifications; chorioretinal anomalies involving the macula (e.g., chorioretinal atrophy and scarring, macular pallor, and gross pigmentary mottling), excluding retinopathy of prematurity; optic nerve atrophy, pallor, and other optic nerve abnormalities. Microcephaly at birth: birth head circumference 3rd percentile for infant sex and gestational age based on INTERGROWTH 21st online percentile calculator (http:intergrowth21.ndog.ox.ac.uk). NEURODEVELOPMENTAL ABNORMALITIES POSSIBLY ASSOCIATED WITH CONGENITAL ZIKA VIRUS INFECTION Consequences of neurologic dysfunction detected from birth (congenital) to age 2 yr. Postnatal onset microcephaly was included as a neurodevelopmental abnormality. Hearing abnormalities: Hearing loss or deafness documented by testing, most frequently auditory brainstem response (ABR). Includes sensorineural hearing loss, mixed hearing loss, and hearing loss not otherwise specified. Failed newborn hearing screening is not sufficient for diagnosis. Congenital contractures: Multiple contractures (arthrogryposis) and isolated clubfoot documented at birth. Brain anomalies must be documented for isolated clubfoot but not for arthrogryposis. Seizures: Documented by electroencephalogram or physician report. Includes epilepsy or seizures not otherwise specified; excludes febrile seizures. Body tone abnormalities: Hypertonia or hypotonia documented at any age in conjunction with (1) a failed screen or assessment for gross motor function; (2) suspicion or diagnosis of cerebral palsy from age 1 2 yr; or (3) assessment by a physician or other medical professional, such as a physical therapist. Movement abnormalities: Dyskinesia or dystonia at any age; suspicion or diagnosis of cerebral palsy from age 1 2 yr. Swallowing abnormalities: Documented by instrumented or noninstrumented evaluation, presence of a gastrostomy tube, or physician report. Possible developmental delay: Abnormal result from most recent developmental screening (i.e., failed screen for gross motor domain or failed screen for two or more developmental domains at the same time point or age); developmental evaluation; or assessment review by developmental pediatrician. Results from developmental evaluation are considered the gold standard if available. Possible visual impairment: Includes strabismus (esotropia or exotropia), nystagmus, failure to fix and follow at age 1 yr; diagnosis of visual impairment at age 1 yr. Postnatal onset microcephaly: Two most recent head circumference measurements reported from follow up care 3rd percentile for childs sex and age based on World Health Organization child growth standards; downward trajectory of head circumference percentiles with most recent measurement 3rd percentile. Age at measurement was adjusted for gestational age in infants born at 40 wk of gestational age through age 24 mo chronological age. From Rice ME, Galang RR, Roth NM, et al. Vital signs: Zika associated birth defects and neurodevelopmental abnormalities |
7,891 | possibly associated with congenital Zika virus infectionUS territories and freely associated states, 2018. MMWR Morb Mortal Wkly Rep. 2018;67(31):858866. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 2066 Part XV u Infectious Diseases coloboma, cataracts, and posterior anomalies), chorioretinal atro phy, or optic nerve hypoplasiaatrophy; (4) congenital contractures, including unilateral or bilateral clubfoot and arthrogryposis multi plex congenita; and (5) neurologic impairment, such as pronounced early hypertoniaspasticity with extrapyramidal symptoms, motor dis abilities, cognitive disabilities, hypotonia, irritabilityexcessive crying, tremors, swallowing dysfunction, vision impairment, hearing impair ment, and epilepsy (see Table 314.1). Acquired ZIKV infection may present with nonspecific viral syn dromelike features. Nonetheless, patients are at increased risk of myelitis and GBS. In addition, the virus may remain present in the blood and body fluids for months after resolution of clinical symptoms. MANAGEMENT For infants with confirmed ZIKV infection, close follow up is neces sary. The appropriate follow up evaluation depends on whether the infant has clinical signs and symptoms of congenital ZIKV syndrome. All infants should have close monitoring of growth and development, repeat ophthalmologic examinations, and auditory brainstem response testing (see Table 314.1). LABORATORY DIAGNOSIS Laboratory testing for ZIKV infection in the neonate includes the following: serum and urine for ZIKV RNA by real time reverse tran scription polymerase chain reaction (rRT PCR) and serum ZIKV IgM enzyme linked immunosorbent assay. If the IgM is positive, the plaque reduction neutralization test is used to confirm the specificity of the IgM antibodies against ZIKV and to exclude a false positive IgM result. If CSF is available, it should be tested for ZIKV RNA (via rRT PCR), as well as ZIKV IgM. CSF specimens need not be collected for the sole purpose of ZIKV testing but may be reasonable for the evaluation of infants with microcephaly or intracranial calcifications. A definitive diagnosis of congenital ZIKV infection is confirmed by the presence of ZIKV RNA in samples of serum, urine, or CSF collected within the first 2 days of life; IgM antibodies may be positive or negative. A negative rRT PCR result with a positive ZIKV IgM test result indicates probable congenital ZIKV infection. Fetuses or infants born to mothers who test positive for ZIKV infection should be studied sonographically or for clinical evidence of congenital Zika syndrome; a comprehensive evaluation (including ophthalmologic examination, laboratory tests, and specialist consulta tion) should be performed before hospital discharge. PROGNOSIS The prognosis of newborns with congenital Zika syndrome is unclear. Reported acute mortality rates among live born infants range from 46. The combination of ZIKV related microcephaly and severe cere bral abnormalities generally has a poor prognosis, but little is known about the prognosis for congenitally infected infants with less severe or no apparent abnormalities at birth. DIFFERENTIAL DIAGNOSIS The differential diagnosis for congenital ZIKV infection includes other congenital infections and other causes of microcephaly. PREVENTION The prevention |
7,892 | of the congenital Zika syndrome includes avoidance of travel to endemic regions, if possible; if travel to endemic regions cannot be avoided, careful contraception (male and female) is essen tial, especially with the knowledge that ZIKV can persist in semen for months after a primary infection (Table 314.2). Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Table 314.2 CDC Recommendations for Preconception Counseling and Prevention of Sexual Transmission of Zika Virus Among Persons with Possible Zika Virus Exposure: United States, August 2018 EXPOSURE SCENARIO RECOMMENDATIONS (UPDATE STATUS) Only the male partner travels to an area with risk for ZIKV transmission and couple is planning to conceive The couple should use condoms or abstain from sex for at least 3 mo after the male partners symptom onset (if symptomatic) or last possible ZIKV exposure (if asymptomatic). (Updated recommendation) Only the female partner travels to an area with risk for ZIKV transmission and couple is planning to conceive The couple should use condoms or abstain from sex for at least 2 mo after the female partners symptom onset (if symptomatic) or last possible ZIKV exposure (if asymptomatic). (No change in recommendation) Both partners travel to an area with risk for ZIKV transmission and couple is planning to conceive The couple should use condoms or abstain from sex for at least 3 mo from the male partners symptom onset (if symptomatic) or last possible ZIKV exposure (if asymptomatic). (Updated recommendation) One or both partners have ongoing exposure (i.e., live in or frequently travel to an area with risk for ZIKV transmission) and couple is planning to conceive The couple should talk with their healthcare provider about their plans for pregnancy, their risk for ZIKV infection, the possible health effects of ZIKV infection on a baby, and ways to protect themselves from ZIKV. If either partner develops symptoms of ZIKV infection or tests positive for ZIKV infection, the couple should follow the suggested time frames listed previously before trying to conceive. (No change in recommendation) Men with possible ZIKV exposure whose partner is pregnant The couple should use condoms or abstain from sex for the duration of the pregnancy. (No change in recommendation) Petersen EE, Meaney Delman D, Neblett Fanfair R, et al. Update: interim guidance for preconception counseling and prevention of sexual transmission of Zika virus for persons with possible Zika virus exposureUnited States, September 2016. MMWR Morb Mortal Wkly Rep. 2016;65:10771081. From Polen KD, Gilboa SM, Hills S, et al. Update: interim guidance for preconception counseling and prevention of sexual transmission of Zika virus for men with possible Zika virus exposure: United States, August 2018. MMWR Morb Mortal Wkly Rep. 2018;67(31):868870. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 315 u Dengue Fever, Dengue Hemorrhagic Fever, and Severe Dengue 2067 Dengue fever is a benign syndrome caused by several arthropod borne viruses and is characterized by |
7,893 | biphasic fever, myalgia or arthralgia, rash, leukopenia, and lymphadenopathy. Dengue hem orrhagic fever (Philippine, Thai, or Singapore hemorrhagic fever; hemorrhagic dengue; acute infectious thrombocytopenic purpura) is a severe, often fatal, febrile disease caused by one of four dengue viruses. It is characterized by capillary permeability, abnormalities of hemostasis, and, in severe cases, a protein losing shock syndrome (dengue shock syndrome), which is thought to have an immuno pathologic basis. A revised case definition adopted by the World Health Organization (WHO) in 2009 includes as severe dengue those cases accompanied by fluid loss leading to shock, fluid loss with respiratory distress, liver damage evidenced by elevations of ALT or AST to 1000 UL, severe bleeding, and altered consciousness or significant heart abnormalities. ETIOLOGY There are at least four distinct antigenic types of dengue virus (dengue 1, 2, 3, and 4), members of the family Flaviviridae. In addition, three other arthropod borne viruses (arboviruses) cause similar dengue fever syndromes with rash (Table 315.1; see also Chapter 314). EPIDEMIOLOGY Dengue viruses are transmitted by mosquitoes of the Stegomyia family. Aedes aegypti, a daytime biting mosquito, is the principal vector, and all four virus types have been recovered from it. Transmission occurs from viremic humans by bite of the vector mosquito in which virus multiplies during an extrinsic incubation period and then by bite is passed on to a susceptible human in what is called the urban trans mission cycle. In most tropical areas, A. aegypti is highly urbanized, breeding in water stored for drinking or bathing and in rainwater col lected in any container. Dengue viruses have also been recovered from A. albopictus, as in the 2001 and 2015 Hawaiian epidemics, whereas outbreaks in the Pacific area have been attributed to several other Aedes species. These species breed in water trapped in vegetation. In South east Asia and West Africa, dengue virus may be maintained in a cycle Chapter 315 Dengue Fever, Dengue Hemorrhagic Fever, and Severe Dengue Scott B. Halstead Table 315.1 Vectors and Geographic Distribution of Dengue Like Diseases VIRUS GEOGRAPHIC GENUS AND DISEASE VECTOR DISTRIBUTION Togavirus Chikungunya Aedes aegypti Africa, India, Southeast Asia, Latin America, United States Aedes africanus Aedes albopictus Togavirus Onyong nyong Anopheles funestus East Africa Flavivirus West Nile fever Culex molestus Europe, Africa, Middle East, India Culex univittatus involving canopy feeding jungle monkeys and Aedes spp, which feed on monkeys. In the 19th and early 20th centuries, epidemics were common in temperate areas of the Americas, Europe, Australia, and Asia. After several decades of virus control in the Americas, dengue fever and dengue like disease are now endemic in tropical Asia, the South Pacific Islands, northern Australia, tropical Africa, the Arabian Peninsula, the Caribbean, and Central and South America (Fig. 315.1). The wide dis tribution of A. aegypti is frequently attributed to global warming, but this view is mistaken. This mosquito was widely dispersed during the little ice age in the 1700s, supporting yellow fever epidemics in New York and continental Europe. Mosquito breeding depends on access |
7,894 | to stored fresh water, not temperature. Dengue fever occurs frequently among travelers to endemic areas. Locally acquired disease has been reported in Florida, Arizona, and Texas, and imported cases in the United States occur in travelers to endemic areas. More than 390 mil lion dengue infections occur annually; approximately 96 million have clinical disease. Dengue outbreaks in urban areas infested with A. aegypti may be explosive; in virgin soil epidemics, up to 7080 of the population may be involved. Most overt disease occurs in older children and adults. Because A. aegypti has a limited flight range, spread of an epidemic occurs mainly through viremic human beings and follows the main lines of transportation. Sentinel cases may infect household mos quitoes; a large number of nearly simultaneous secondary infections give the appearance of a contagious disease. Where dengue is highly endemic, indigenous children and susceptible foreigners may be the only persons to acquire overt disease, because adults have become immune. Dengue Like Diseases Dengue like diseases may occur in epidemics. Epidemiologic features depend on the vectors and their geographic distribution (see Chapter 314). Chikungunya virus is enzootic in subhuman primates through out much of West, Central, and South Africa. Periodic introductions of virus into the urban transmission cycle have led to pandemics, result ing in widespread endemicity in the most populous areas of Asia. In Asia, A. aegypti is the principal vector; in Africa, other Stegomyia spp. may be important vectors. In Southeast Asia, dengue and chikungu nya outbreaks occur concurrently in the urban cycle. Outbreaks of onyong nyong fever usually involve villages or small towns, in contrast to the urban outbreaks of dengue and chikungunya. West Nile virus is enzootic in Africa. Chikungunya is now endemic in urban cycles in tropical countries throughout the world. Intense transmission in Caribbean and Central and South American countries beginning in 2013 results in the emergence of limited chikungunya transmission in the United States. Dengue Hemorrhagic Fever Dengue hemorrhagic fever occurs where multiple types of dengue virus are simultaneously or sequentially transmitted. It is endemic in tropical America, Asia, the Pacific Islands, and parts of Africa, where warm temperatures and the practices of water storage in homes plus outdoor breeding sites result in large, permanent populations of A. aegypti. Under these conditions, infections with dengue viruses of all types are common. A first infection, referred to as a primary infection, may be followed by infection with a different dengue virus, referred to as a secondary infection. In areas of high endemicity, secondary infec tions are frequent. Secondary dengue infections are relatively mild in the majority of instances, ranging from an inapparent infection through an undiffer entiated upper respiratory tract or dengue like disease, but may also progress to dengue hemorrhagic fever. Nonimmune foreigners, both adults and children, who are exposed to dengue virus during outbreaks of hemorrhagic fever have classic dengue fever or even milder disease. The differences in clinical manifestations of dengue infections between natives and foreigners in Southeast Asia are related to |
7,895 | immunologic status. Dengue hemorrhagic fever is unusual in patients with pri mary dengue infection, with the exception of infants whose mothers Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 2068 Part XV u Infectious Diseases are immune to dengue. Dengue hemorrhagic fever or severe dengue occurs rarely in individuals of African ancestry because of an as yet incompletely described resistance gene. This gene is thought to have originated in populations with long standing exposure to yellow fever and explains the low incidence of severe dengue throughout much of Africa and among African populations in the American tropics despite high rates of dengue infection. PATHOGENESIS The pathogenesis of dengue hemorrhagic fever is incompletely understood, but epidemiologic studies strongly associate this syn drome with second heterotypic infections with dengue types 1 4 or in infants born to mothers who have had two or more lifetime dengue infections. Retrospective studies of sera from human moth ers whose infants acquired dengue hemorrhagic fever and prospec tive studies in children acquiring sequential dengue infections have shown that the circulation of infection enhancing antibodies at the time of infection is the strongest risk factor for development of severe disease. The absence of dengue neutralizing antibodies in the presence of enhancing antibodies from passive transfer or active production is the best correlate of risk for dengue hemorrhagic fever. Monkeys that are infected sequentially or have received enhancing antibodies experience enhanced viremias. In humans studied early during the course of secondary dengue infections, viremia levels directly predicted disease severity. When dengue virus immune complexes attach to monocytemacrophage Fc receptors, a signal is sent that suppresses innate immunity, resulting in enhanced viral production. In the Americas, dengue hemorrhagic fever and den gue shock syndrome have been associated with dengue types 1 4 strains of recent Southeast Asian origin. Outbreaks of dengue hem orrhagic fever in all areas of the world are correlated with secondary dengue infections. Early in the acute stage of secondary dengue infections, there is rapid activation of the complement system. Shortly before or dur ing shock, blood levels of soluble tumor necrosis factor receptor, interferon , and interleukin 2 are elevated, C1q, C3, C4, C5 C8, and C3 proactivators are depressed, and C3 catabolic rates are elevated. All of these outcomes are attributed to circulating viral nonstructural protein 1 (NS1), a viral toxin that activates myeloid cells to release cytokines by attaching to tolllike receptor 4. NS1 also contributes to increased vascular permeability by activating complement and, most importantly, interacting with and damag ing endothelial cells and interacting with blood clotting factors and platelets. The mechanism of bleeding in dengue hemorrhagic fever is not fully understood, but a mild degree of disseminated intravas cular coagulopathy, liver damage, and thrombocytopenia may oper ate synergistically. NS1 mediated capillary damage allows fluid, electrolytes, small proteins, and, in some instances, red blood cells to |
7,896 | leak into extravascular spaces. This internal redistribution of fluid, together with deficits caused by fasting, thirsting, and vomit ing, results in hemoconcentration, hypovolemia, increased cardiac work, tissue hypoxia, metabolic acidosis, and hyponatremia. Usually no pathologic lesions are found to account for death. In rare instances, death may be a result of gastrointestinal or intra cranial hemorrhages. Minimal to moderate hemorrhages are seen in the upper gastrointestinal tract, and petechial hemorrhages are common in the interventricular septum of the heart, on the peri cardium, and on the subserosal surfaces of major viscera. Focal hemorrhages are occasionally seen in the lungs, liver, adrenals, and subarachnoid space. The liver is usually enlarged, often with fatty changes. Yellow, watery, and at times blood tinged effusions are present in serous cavities in approximately 75 of patients at autopsy. Dengue virus is frequently absent in tissues at the time of death; viral antigens or RNA have been localized to hepatocytes and macrophages in the liver, spleen, lung, and lymphatic tissues. CLINICAL MANIFESTATIONS Dengue Fever The incubation period is 1 7 days. The clinical manifestations are variable and are influenced by the age of the patient. In infants and young children, the disease may be undifferentiated or character ized by fever for 1 5 days, pharyngeal inflammation, rhinitis, and mild cough. A majority of infected older children and adults experi ence sudden onset of fever, with temperature rapidly increasing to 39.441.1C (103106F), usually accompanied by frontal or retro orbital pain, particularly when pressure is applied to the eyes. Occa sionally, severe back pain precedes the fever (back break fever). A transient, macular, generalized rash that blanches under pressure may be seen during the first 24 48 hours of fever. The pulse rate may be slow relative to the degree of fever. Myalgia and arthralgia occur soon after the onset of fevers and increase in severity over time. From the second to sixth day of fever, nausea and vomiting are apt to occur, and generalized lymphadenopathy, cutaneous hyperes thesia or hyperalgesia, taste aberrations, and pronounced anorexia may develop. Approximately 1 2 days after defervescence, a generalized, morbil liform, maculopapular rash appears that spares the palms and soles. It disappears in 1 5 days; desquamation may occur. Rarely there is edema of the palms and soles. About the time this second rash appears, the body temperature, which has previously decreased to normal, may become slightly elevated and demonstrate the characteristic biphasic temperature pattern. Presence of dengue High Medium Low 10degree isotherms Jan isoth 10C July isoth 10C Fig. 315.1 Global dengue burden, 2014. (From Guzman MG, Harris E. Dengue. Lancet. 2015;385:453462. Fig. 1.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 315 u Dengue Fever, Dengue Hemorrhagic Fever, and Severe Dengue 2069 Fig. 315.2 Suggested dengue case classification and levels of severity. (From World Health Organization WHO and Special Programme for Research |
7,897 | and Train ing in Tropical Diseases TDR. Dengue: guidelines for diagnosis, treatment, prevention and control, 2009. Fig. 1.4, http:apps.who.intirisbitstreamhandle1066544 1889789241547871eng.pdf?sequence1) Probable dengue live intravel to dengue endemic area. Fever and two of the following criteria: Nausea, vomiting Rash Aches and pain Tourniquet test positive Leukopenia Any warning sign Abdominal pain or tenderness Persistent vomiting Clinical fluid accumulation Mucosal bleed Lethargy, restlessness Liver enlargement 2 cm Laboratory: increase in HCT concurrent with rapid decrease in platelet count Liver: AST or ALT 1000 CNS: Impaired consciousness Heart and other organs Shock (DSS) Fluid accumulation with respiratory distress Laboratoryconfi rmed dengue (important when no sign of plasma leakage) Warning signs (requiring strict observation and medical intervention) Severe plasma leakage leading to: Severe bleeding as evaluated by clinician Severe organ involvement CRITERIA FOR DENGUE WARNING SIGNS CRITERIA FOR SEVERE DENGUE DENGUE WARNING SIGNS SEVERE DENGUE 1. Severe plasma leakage 2. Severe hemorrhage 3. Severe organ impairmentwithout with warning signs Dengue Hemorrhagic Fever and Dengue Shock Syndrome The differentiation between dengue fever and dengue hemorrhagic fever is difficult early in the course of illness. A relatively mild first phase with abrupt onset of fever, malaise, vomiting, headache, anorexia, and cough may be followed after 2 5 days by rapid clinical deterioration and collapse. In this second phase, the patient usually has cold, clammy extremities, a warm trunk, flushed face, diaphore sis, restlessness, irritability, mid epigastric pain, and decreased uri nary output. There may be scattered petechiae on the forehead and extremities; spontaneous ecchymoses may appear, and easy bruis ing and bleeding at sites of venipuncture are common. A macular or maculopapular rash may appear, and there may be circumoral and peripheral cyanosis. Respirations are rapid and often labored. The pulse is weak, rapid, and thready, and the heart sounds are faint. The liver may enlarge to 4 6 cm below the costal margin and is usu ally firm and somewhat tender. Approximately 2030 of cases of dengue hemorrhagic fever are complicated by shock (dengue shock syndrome). Dengue shock can be subtle, arising in patients who are fully alert, and is accompanied by increased peripheral vascular resistance and raised diastolic blood pressure. Shock is not from congestive heart failure but from venous pooling. With increasing cardiovascular compromise, the diastolic pressure rises toward the systolic level and the pulse pressure narrows. Fewer than 10 of patients have gross ecchymosis or gastrointestinal bleeding, usually after a period of uncorrected shock. After a 24 to 36 hour period of crisis, convalescence is fairly rapid in the children who recover. The temperature may return to normal before or during the stage of shock. Bradycardia and ventricular extrasystoles are common dur ing convalescence. Dengue with Warning Signs and Severe Dengue In hyperendemic areas, dengue hemorrhagic feverdengue shock syn drome (DHFDSS) is the life threatening event during a dengue infec tion that challenges the identifying physician. When the four dengue viruses spread to the American hemisphere and to South Asia, there were millions of primary and secondary dengue infections in individu als |
7,898 | of all ages. Dengue disease in these areas presented a wider clinical spectrum resulting in a new diagnostic algorithm and case definitions (see later). DIAGNOSIS A clinical diagnosis of dengue fever derives from a high index of sus picion and knowledge of the geographic distribution and environmen tal cycles of causal viruses (for nondengue causes see Chapter 314). Because clinical findings vary and there are many possible causative agents, the term dengue like disease should be used until a specific diagnosis is established. A case is confirmed by virologic diagnosis, which can be established by serologic tests, by detection of viral pro teins or viral RNA, or by the isolation of the virus from blood leuko cytes or acute phase serum. A probable case is a typical acute febrile illness with supportive serology and occurrence at a location where there are confirmed cases. The WHO criteria for dengue hemorrhagic fever are fever (2 7 days in duration or biphasic); minor or major hemorrhagic manifestations, including a positive tourniquet test, thrombocytopenia (100,000L), and objective evidence of increased capillary permeability (hematocrit increased by 20); pleural effusion or ascites (by chest radiography or ultrasonography); or hypoalbuminemia. Dengue shock syndrome criteria include those for dengue hemorrhagic fever as well as hypoten sion, tachycardia, narrow pulse pressure (20 mm Hg), and signs of poor perfusion (cold extremities). In 2009, the WHO promulgated guidelines for the diagnosis of prob able dengue, dengue with warning signs, and a category called severe dengue (Fig. 315.2). The presence of warning signs in an individual with probable dengue alerts the physician to the possible need for hos pitalization. Severe dengue is a mixture of the syndromes that are asso ciated with dengue infection, including classic DHFDSS, but also rare instances of encephalitis or encephalopathy, liver damage, or myocar dial damage. Severe dengue also includes respiratory distress, a harbin ger of pulmonary edema caused by overhydration, an all too common outcome of inexpert treatment (see Treatment and Complications sections). After primary and secondary dengue infections, there is an appearance of anti dengue (immunoglobulin Ig M) antibod ies. These disappear after 6 12 weeks, a feature that can be used to date a dengue infection. In secondary dengue infections, most dengue antibody is of the IgG class. Serologic diagnosis depends on a fourfold or greater increase in IgG antibody titer in paired sera by hemagglutination inhibition, complement fixation, enzyme immu noassay, or neutralization test. Carefully standardized IgM and IgG capture enzyme commercial immunoassays are now widely used to identify acute phase antibodies from patients with primary or secondary dengue infections in single serum samples. Usually such samples should be collected not earlier than 5 days and not later than 6 weeks after onset. It may not be possible to distinguish the infecting virus by serologic methods alone, particularly when there has been prior infection with another member of the same arbo virus group. Virus can be recovered from acute phase serum after inoculating tissue culture or living mosquitoes. Viral RNA can be |
7,899 | Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 2070 Part XV u Infectious Diseases detected in blood or tissues by specific complementary RNA probes or amplified first by polymerase chain reaction or by real time polymerase chain reaction. A viral nonstructural protein, NS1, is released by infected cells into the circulation and can be detected in acute stage blood samples using monoclonal or polyclonal antibod ies. The detection of NS1 is the basis of commercial tests, includ ing rapid lateral flow tests. These tests offer a reliable point of care diagnosis of acute dengue infection. DIFFERENTIAL DIAGNOSIS The differential diagnosis of dengue fever includes dengue like diseases, viral respiratory and influenza like diseases, including COVID19, the early stages of malaria, mild yellow fever, scrub typhus, viral hepatitis, and leptospirosis. Four arboviral diseases have dengue like courses but without rash: Colorado tick fever, sandfly fever, Rift Valley fever, and Ross River fever (see Chapter 314). Colorado tick fever occurs sporadically among campers and hunters in the western United States; sandfly fever in the Mediterranean region, the Middle East, southern Russia, and parts of the Indian subcontinent; and Rift Valley fever in North, East, Central, and South Africa. Ross River fever is endemic in much of eastern Aus tralia, with epidemic extension to Fiji. In adults, Ross River fever often produces protracted and crippling arthralgia involving weight bearing joints. Because meningococcemia, yellow fever (see Chapter 316), other viral hemorrhagic fevers (see Chapter 317), many rickettsial diseases, and other severe illnesses caused by a variety of agents may produce a clinical picture similar to that of dengue hemorrhagic fever, the etio logic diagnosis should be made only when epidemiologic or serologic evidence suggests the possibility of a dengue infection. LABORATORY FINDINGS In patients with dengue fever, pancytopenia may develop after the 3 4 days of illness. Neutropenia may persist or reappear during the latter stage of the disease and may continue into convalescence, with white blood cell counts 2,000L. Platelet counts rarely fall below 100,000L. Venous clotting, bleeding and prothrombin times, and plasma fibrinogen values are within normal ranges. The tourniquet test result may be positive. Mild acidosis, hemoconcentration, increased transaminase values, and hypoproteinemia may occur during some primary dengue virus infections. The electrocardiogram may show sinus bradycardia, ectopic ventricular foci, flattened T waves, and pro longation of the P R interval. In dengue hemorrhagic fever, dengue shock syndrome, and severe dengue, the most common hematologic abnormalities are hemoconcentration with an increase of 20 in the hematocrit, thrombocytopenia, a prolonged bleeding time, and a moderately decreased prothrombin time that is seldom 40 of control. Fibrin ogen levels may be subnormal, and fibrin split product values are elevated. Other abnormalities include moderate elevations of serum transaminase levels, depressed complement levels, mild metabolic acidosis with hyponatremia, occasional hypochloremia, slight ele vation of blood urea nitrogen, and hypoalbuminemia. Chest x |
7,900 | ray reveals pleural effusions (right left) in nearly all patients with den gue shock syndrome. Ultrasonography can be used to detect serosal effusions of the thorax or abdomen. Thickening of the gallbladder wall and the presence of perivesicular fluid, ascites, or pleural effu sions are characteristic signs of increased vascular permeability. TREATMENT Dengue Treatment of uncomplicated dengue fever is supportive. Bed rest is advised during the febrile period. Antipyretics should be used to keep the body temperature 40C (104F). Analgesics or mild sedation may be required to control pain. Aspirin is contraindicated and should not be used because of its effects on hemostasis. Fluid and electrolyte replacement is required for deficits caused by sweating, fasting, thirst ing, vomiting, and diarrhea. Dengue Hemorrhagic Fever and Dengue Shock Syndrome Shock syndrome is a medical emergency that may occur in any child who lives in or has a recent travel history to a tropical destination. Management begins with diagnostic suspicion and the understand ing that shock often accompanies defervescence. Detailed instruc tions for case management are available at the Centers for Disease Control and Prevention web site: https:www.cdc.govdengueheal thcareprovidersindex.html. Management of dengue hemorrhagic fever and dengue shock syndrome includes immediate evaluation of vital signs and degrees of hemoconcentration, dehydration, and elec trolyte imbalance. Close monitoring is essential for at least 48 hours because shock may occur or recur precipitously, usually several days after the onset of fever. Patients who are cyanotic or have labored breathing should be given oxygen. Rapid intravenous replacement of fluids and electrolytes can frequently sustain patients until spontane ous recovery occurs. Normal saline is more effective than the more expensive Ringer lactated saline in treating shock. When the pulse pressure is 10 mm Hg or when elevation of the hematocrit persists after the replacement of fluids, plasma or colloid preparations are indicated. Oral rehydration of children who are being monitored is useful. Prophylactic platelet transfusions have not been shown to reduce the risk of hemorrhaging or improve low platelet counts and may be associated with adverse effects. Care must be taken to avoid overhydration, which may contribute to cardiac failure. Transfusions of fresh blood may be required to con trol bleeding but should not be given during hemoconcentration and should be administered only after evaluation of hemoglobin or hema tocrit values. Salicylates are contraindicated because of their effect on blood clotting. Sedation may be required for children who are markedly agitated. Use of vasopressors has not resulted in a significant reduction of mortality rates over that observed with simple supportive therapy. Disseminated intravascular coagulation may require treatment (see Chapter 532). Corticosteroids do not shorten the duration of dis ease or improve the prognosis in children receiving careful support ive therapy. COMPLICATIONS Hypervolemia during the fluid reabsorptive phase may be life threatening and is heralded by a decrease in hematocrit with wide pulse pressure. Diuretics and digitalization may be necessary. Primary infections with dengue fever and dengue like diseases are usually self limited and benign. Fluid and electrolyte losses, hyperpyrexia, |
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