1275CHAPTER 108 Life Threatening Viral Diseases and Their Treatment Viral Agent Specimen Recommended Diagnostic Testsa Adenovirus NP, BAL fluid PCR Tissue PCR, histology Serum/plasmab PCR Arboviruses[.]
1275 CHAPTER 108 Life-Threatening Viral Diseases and Their Treatment TABLE 108.2 Potential Diagnostic Tests and Corresponding Specimens for Diagnosis of Viral Pathogens Viral Agent Specimen Recommended Diagnostic Testsa Adenovirus NP, BAL fluid PCR Tissue PCR, histology Serum/plasmab PCR Serum/plasma IgM and IgG antibody,d PCR CSF IgMe and IgG antibody,d PCR Chikungunya virus Serum/plasma PCR, IgM and IgG antibodyd Coronaviruses (OC43, 229E, HKU1, NL63, SARS, and MERS)c,f NP aspirate (preferred for SARS/MERS) or swab, OP swab, BAL, stool (SARS/MERS), tissues (SARS/MERS) PCR Arboviruses (California encephalitis, Colorado tick fever, EEE, SLE, WEE, West Nile)c c Serum/plasma (SARS/MERS) PCR, IgM and IgG antibody Ebola virusc Whole blood, oral secretions PCR Enteroviruses (echoviruses, coxsackie viruses, enteroviruses)c CSF, NP, pharynx PCR Stoolg Culture b Hantavirusc Hepatitis viruses Hepatitis A virus (HAV) Hepatitis B virus (HBV) Hepatitis C virus (HCV) Hepatitis E virus (HEV) Herpesviruses CMV Serum/plasma PCR (enterovirus D68 may not be detected by these methods) Serum IgM and IgG antibodyd Whole blood PCR Tissue (lung, kidney, spleen preferred; antemortem— lung or bone marrow) PCR, immunohistochemistry Serum Serology for all Serum Anti-HAV IgM b Serum/plasma HBsAg, anti-HBcAb IgM, PCR Liver PCR Serum/plasma Anti-HCV IgG, PCR Liver PCR b Serum/plasma Anti-HEV IgM, PCR Liver PCR Stool PCR Shell vial or rapid culture, PCRi NP or BAL b EBV Serum/plasma PCR Tissue IgM and IgG antibodyd Urine PCR, histology Serum Viral capsid antibody (VCA) panel or slide agglutination test (Monospot) Plasma, CSF PCR Tissue HHV-6B HSV types and VZV PCR, immunohistochemistry b Serum/plasma, CSF PCR Tissue PCR b CSF, serum/plasma PCR Base of lesion, NP, conjunctiva, tissue PCR, culture Serum IgG antibodyd Base of lesion, tissue PCR, FA, and culture Serum IgM and IgG antibodyd Serum/plasma,b CSF PCR Continued 1276 S E C T I O N X I Pediatric Critical Care: Immunity and Infection TABLE 108.2 Potential Diagnostic Tests and Corresponding Specimens for Diagnosis of Viral Pathogens—cont’d Viral Agent Specimen Recommended Diagnostic Testsa Influenza types A and B NP, pharynx, BAL fluid PCR Tissue PCR Serum/plasmab PCR, IgM, and IgG antibodyd CSF IgM, PCR Serum IgM and IgG antibodyd LCMVc Measles (rubeola)c Urine, blood, NP PCR SSPE CSF Oligoclonal bands, IgG Metapneumovirus NP, BAL fluid PCR Mumpsc Buccal swab, saliva PCR Serum IgM and IgG antibodyd CSF, pharynx, saliva b PCR Parechoviruses CSF, serum/plasma, NP, stool PCR Parainfluenza viruses NP, BAL fluid, tissue PCR Parvovirus Serum/plasma b PCR, IgM and IgG antibodyd Polyomaviruses BK virus Serum, urine, CSF PCR JC virusc Brain biopsy,h CSF PCR Serum, CSF Rabies-specific antibody by neutralization assay Saliva, brain, tissues, urine PCR Punch biopsy (nape of neck), brain Direct fluorescent antibody (DFA; consult ID) Serum HIVAg/Ab combination immunoassays Whole blood RNA/DNA PCR Plasma, CSF RNA PCR Serum, CSF Anti-HTLV antibodies Rabies virusc Retroviridae HIV HTLV Whole blood, tissue PCR Rotavirus Stool PCR, EIA, or latex particle agglutination assays RSV NP, BAL, tissue PCR, DFA, IA Serum IgM and IgG antibodyd NP, CSF, urine PCR Serum IgM and IgG antibodies NP, stool, sputum PCR c Rubella SARS-CoV-2 Choice of test depends on clinical setting, including organ system involved and immune status of host anti-HBcAb, Anti-hepatitis B virus core antibody; BAL, bronchoalveolar lavage; CPE, cytopathic effect; CSF, cerebrospinal fluid; CMV, cytomegalovirus; DNA, deoxyribonucleic acid; EBV, Epstein-Barr virus; EEE, Eastern equine encephalitis; EIA, enzyme immunoassay; FA, fluorescence assay; HBsAg, hepatitis B surface antigen; HIV, human immunodeficiency virus; HTCL, human T-cell lymphotropic virus; IA, immunoassay; ID, infectious disease; IgG, immunoglobulin G; IgM, immunoglobulin; LCMV, lymphocytic choriomeningitis virus; MERS, Middle East respiratory syndrome; NP, nasopharyngeal secretions; OP, oropharyngeal; RNA, ribonucleic acid; RSV, respiratory syncytial virus; SARS, severe acute respiratory syndrome; SLE, St Louis encephalitis; SSPE, subacute sclerosing panencephalitis; WEE, Western equine encephalitis a Multiple diagnostic tests are available for each pathogen Commonly recommended diagnostic tests are listed; however, if results are negative or specimens are not available, infectious disease consultation may be helpful for additional or special testing b PCR is usually run on plasma, though some laboratories may run serum samples c Pathogen may have significant public health implications Testing should be performed in consultation with infectious disease and/or local public health department (for enteroviruses, if enterovirus 68/71 suspected) Testing is often not available without assistance of the Public Health Department, and recommended specimens and tests are frequently evolving; see www.cdc.gov for updates d IgM and IgG antibody may also be referred to as “serology” on laboratory request forms For most viral pathogens, when testing for IgG, it is optimal to collect acute and convalescent sera approximately weeks apart e IgM antibody does not cross the blood-brain barrier If found in CSF, IgM antibody denotes central nervous system infection f For suspected SARS or MERS, specimens should be collected from several locations at different time points following symptom onset See http://www.cdc.gov/sars/clinical/index.html for updated diagnostic information g Enteroviruses are shed in the stool for weeks and may not be diagnostic h Gold standard i Because shedding of CMV occurs in the lungs of seropositive stem cell transplant recipients without overt CMV disease, the recovery of CMV DNA by PCR from BAL fluid (which is considerably more sensitive than culture) without shell vial or culture positivity is of uncertain significance Thus, PCR testing for CMV DNA in BAL or biopsy fluid should not be ordered routinely CHAPTER 108 Life-Threatening Viral Diseases and Their Treatment 1277 TABLE 108.3 Antiviral Agents and Indications for Use Virus Drug of Choice/Dosea Alternate Agents/Dose Adenovirus No currently approved therapy Cidofovir may be considered for immunocompromised patients with disseminated disease or severe pneumonia.189,190 Coronavirus No currently approved therapy Enterovirus No currently approved therapy Hantavirus No currently approved therapy Herpesviruses CMV Ganciclovir (5 mg/kg q12h 2–3 wk, then mg/kg q24h) is primary therapy for CMV disease Valganciclovir—limited pediatric dosing information available Dose varies by age and indication Acyclovir (20 mg/kg/dose IV q8h) for encephalitis in neonates and children ,12 y and for neonates with disseminated disease; 10 mg/kg/dose IV q8h for children 12 y Foscarnet (90 mg/kg q12h 2–3 wk, then 90 mg/kg q24h), cidofovir (5 mg/kg/wk; high risk of renal toxicity, use with probenecid and saline hydration) in children >2 years HHV-6B No currently approved therapy Foscarnet and ganciclovir have in vitro activity Case reports and series show variable clinical response with one or both drugs in combination VZV Acyclovir (10–12 mg/kg/dose IV q8h); high-dose acyclovir (10 mg/kg/dose) could be used for VZV encephalitis or for disease in immunocompromised children HSV No specific dosing recommendations are available for HSVassociated hepatitis and pneumonitis At least 10 mg/kg/dose should be considered outside the neonatal period Influenza A/B Oseltamivirb or zanamivir (5 y) 10 mg (2 oral inhalations) q12h days or peramivir IV (2 y) 12 mg/kg dose, up to 600 mg maximum dose for uncomplicated influenza Baloxavir (12 y) 40 to ,80 kg: one 40-mg dose; 80 kg: one 80-mg dose for uncomplicated influenza Rimantadine or amantadine Generally not recommended due to widespread resistance Combination empiric therapy may be indicated for severely ill immunosuppressed patients.191,192 JCV No effective therapy In HIV infection, treatment with combination antiretroviral therapy may improve survival Potential role for cidofovir.193 Metapneumovirus No currently approved therapy Case reports suggest that ribavirin and IVIG may be used successfully in immunosuppressed patients.97,194–196 Parechoviruses No currently approved therapy Parainfluenza virus No currently approved therapy Treatment for PIV pneumonia should include coverage for copathogens.85 Ribavirin is active in vitro and in animal models; thus, it has been used for treatment of PIV pneumonia in immunocompromised hosts Anecdotal reports of the benefit of ribavirin have been highly variable, and a retrospective series of stem cell transplant recipients showed no benefit.85,197 RSV Aerosolized ribavirin (2 g reconstituted in 33 mL tid) d has been used with modest efficacy in patients with severe RSV pneumonia and in immunocompromised patients76; not recommended for uncomplicated disease or in otherwise healthy subjects Oral ribavirin may improve outcomes of RSV pneumonia in immunocompromised and high-risk patients but data are limited in pediatrics.198,199 CMV, Cytomegalovirus; HHV, human herpesvirus; HIV, human immunodeficiency virus; HSV, herpes simplex virus; IVIG, intravenous immunoglobulin; JCV, John Cunningham virus; PIV, parainfluenza virus; RSV, respiratory syncytial virus; VZV, varicella zoster virus a These agents are generally recommended with infectious disease consultation for the infection listed However, please note that not all of these agents are US Food and Drug Administration approved for the indicated use b Dosing varies by age and weight See http://www.cdc.gov/flu/professionals/antivirals/antiviral-dosage.htm for specific recommendations In an influenza pandemic or some outbreak situations, treatment should not wait for laboratory confirmation of influenza because this may delay treatment and a negative rapid test does not rule out influenza 1278 S E C T I O N X I Pediatric Critical Care: Immunity and Infection identified, viruses account for most cases.5 The spectrum of disease is varied and myocardial involvement may be focal or diffuse.6 Establishing a definitive diagnosis can be difficult; therefore, the true incidence of viral myocarditis is unknown Although the pathogenesis of viral myocarditis is not well understood, viruses enter cardiac myocytes through specific receptors Myocardial damage is thought to occur, at least in part, as a direct result of infection, with active viral replication leading to myocardial necrosis.7 Both humoral and cellular immune responses contribute to the pathogenesis of myocarditis8 through postinfectious autoimmune processes,9 cytotoxic T lymphocytes, antibody-dependent cell-mediated cytotoxicity,10 and cytokines.11 With persistent viremia and/or the accompanying immune response, progression to dilated cardiomyopathy may occur.12 Up to 27% of dilated cardiomyopathy in children may be attributable to preceding viral myocarditis.13 PCR testing of cardiac tissue from endomyocardial biopsy specimens in 34 children with a clinical diagnosis of myocarditis identified adenovirus in 44%, enterovirus in 24% and HSV in 6%.14 Parvovirus B19 and parechovirus have also been commonly found.6 The expression of coxsackie virus and adenovirus receptors on myocytes is highest in the neonatal period, potentially resulting in increased susceptibility and severe presentation in this age group.15 Many other viruses have caused myocarditis in children, including influenza A, human immunodeficiency virus (HIV), cytomegalovirus (CMV), respiratory syncytial virus (RSV), and the mumps and measles viruses, before the widespread use of the measles-mumps-rubella (MMR) vaccine (see Table 108.1) Recently, reports of myocardial inflammation have been reported in patients with SARS-CoV-2 infection Pathologic data are sparse; therefore, whether this represents true viral infection of cardiac cells or a complication of severe infection is unknown.15a Clinical Presentation The clinical presentation of myocarditis can range from asymptomatic to acute fulminant disease Infants may have nonspecific symptoms, including poor feeding, fever, and listlessness Physical examination findings may be consistent with congestive heart failure Enteroviral myocarditis in infancy frequently occurs in conjunction with hepatitis and/or pneumonitis16 and can be difficult to distinguish from bacterial sepsis Severe dysrhythmias have been described in infants with myocardial involvement from RSV.17 Older children and adolescents are more likely to present after a prodromal viral illness with nonspecific respiratory or gastrointestinal symptoms, often without chest pain or cardiac symptoms; thus, diagnosis is often delayed.18 Resting tachycardia is common and an apical systolic murmur may be heard A subset of patients have fulminant myocarditis, characterized by rapid onset of symptoms, severe hemodynamic compromise, and fever, mimicking sepsis or dehydration Aggressive fluid resuscitation in this setting may lead to pulmonary edema and cardiac collapse.15,19 Myocarditis has also been implicated in cases of sudden death.3,20 In addition, several reports have described children presenting with an inflammatory syndrome with clinical features overlapping with Kawasaki disease, including cardiac involvement, which is now been named multisystem inflammatory syndrome in children (MIS-C) and is associated with SARS-CoV-2 infection Information on this entity is evolving.20a Diagnosis and Management Laboratory abnormalities in myocarditis may include elevated white blood cell count, erythrocyte sedimentation rate,21 and serum aspartate aminotransferase (AST) levels.18,22 Initial workup includes biomarkers, electrocardiogram (ECG), chest radiography, and echocardiogram (ECHO) Normal biomarkers cannot exclude myocarditis, but troponin T is associated with a sensitivity of 71% and specificity of 86%.12,23,24 A recent study reported an association between elevated troponin levels in the first 72 hours of hospitalization and need for extracorporeal membrane oxygenation (ECMO) but not with mortality or need for cardiac transplantation.25 ECG abnormalities are almost always present in acute myocarditis (93%–100%).18 Findings include sinus tachycardia, lowvoltage QRS complexes, and nonspecific ST- and T-wave changes Both atrial and ventricular arrhythmias may be present as well as conduction abnormalities ECHO may reveal left ventricular dysfunction, in most cases with either segmental wall motion abnormalities or global hypokinesis Pericardial effusions are common Pulmonary edema, enlarged cardiac silhouette, and prominent pulmonary vasculature may be seen on chest radiography Contrast-enhanced cardiac magnetic resonance imaging (MRI) can define the location and extent of inflammation and is increasingly used to assist in diagnosis or to guide endomyocardial biopsy.26 In a setting in which myocarditis is clinically suspected, a consensus group proposed the following diagnostic criteria using cardiac MRI features: myocardial edema (regional or global increase in T2 signal), hyperemia or capillary leak (early gadolinium enhancement), or myocardial fibrosis (late gadolinium enhancement) If two or more of these were present, cardiac MRI correlated with histology 78% of the time.13,27 Controversy now exists as to whether biopsy and histologic confirmation will continue to be recommended in myocarditis given the availability of cardiac MRI and the risks associated with biopsy.28 Isolation of virus from the myocardium provides a definite viral diagnosis of myocarditis; however, the sensitivity is very low, even in cases of histologically proven myocarditis Viral PCR of peripheral specimens or the demonstration of a fourfold rise in specific viral antibody titers provides an indirect determination of causality.14,29 Given the increased sensitivity of PCR testing, its application in myocardial tissue provides a virologic diagnosis in up to 60% of cases.14 The mainstay of treatment for myocarditis is supportive care Severe cases may require circulatory support in the form of ECMO or a ventricular assist device (VAD), both of which may also serve as a bridge to cardiac transplantation in cases of dilated cardiomyopathy Aggressive therapy is warranted because those who survive have a good prognosis for return to normal ventricular function.30–32 Cardiac transplantation may be necessary for those children refractory to other management Current recommendations not support the use of immunosuppressive therapy, including steroids.4,6,13,21 Utilization of IVIG varies between centers High-dose IVIG has been associated with improved left ventricular function in small studies in children33,34; however, it showed no survival benefit in an evaluation of multi-institutional data.2 In adults, a controlled study found IVIG to be no better than placebo for acute dilated cardiomyopathy34 and a Cochrane Review found no role for the routine use of IVIG in presumed viral myocarditis.35 More recently, a retrospective study of children found no association between IVIG or steroids and mortality, transplantation, or readmission.4 Specific antiviral therapy may be indicated when the inciting viral agent has been identified However, because most patients present weeks after the acute infection, the benefit is unclear CHAPTER 108 Life-Threatening Viral Diseases and Their Treatment Acute Liver Failure Epidemiology and Etiology Acute liver failure (ALF) in children is defined as severe impairment of liver function with or without encephalopathy that occurs in a child with no history of chronic liver disease The causes of ALF in children can be metabolic, toxic, drug related, immune mediated or infectious (see also Chapter 96) The percentage of ALF caused by viral infections varies significantly by age and geographic location, with viral causes identified in 6% to 20% of pediatric ALF in series from North America and Europe36–38 but 50% to 60% in other regions.39–41 While less than 1% of infections due to hepatitis A virus (HAV) and hepatitis B virus (HBV) result in ALF, these viruses comprise the majority of cases with a definitive viral diagnosis.39,41–43,46 Although rare, there are case reports of ALF with both postnatally and perinatally acquired hepatitis C virus (HCV) in children.44,45 Other viruses identified in pediatric ALF include adenovirus, CMV, enterovirus, HSV, Epstein-Barr virus (EBV), human herpesvirus-6 (HHV-6), parvovirus B19,36,37,47–49 VZV,50,51 influenza,52,53 and hepatitis E virus (HEV), an enterically transmitted virus that causes epidemic hepatitis in many areas of the world, particularly in Asia.41,54 ALF can also occur in severe dengue55 and yellow fever infections56; these entities should be considered when the appropriate epidemiologic risk factors are present ALF in infants is most frequently associated with systemic illness due to HSV, enterovirus, echovirus, or CMV.43,47,57–60 Immunosuppression is a risk factor for HSV-, CMV-, adenovirus-, and VZV-associated ALF Clinical Presentation Symptoms of acute hepatitis include jaundice, anorexia, fatigue, nausea, and vomiting.47,61 In fulminant disease, there is rapid progression to hepatic failure and encephalopathy Physical examination may demonstrate fever, hepatosplenomegaly with liver tenderness, scleral or cutaneous icterus, and mucosal bleeding Laboratory studies include elevated hepatic enzymes (10- to 100fold increases in AST and alanine aminotransferases), hyperbilirubinemia, prolonged prothrombin time, and elevated ammonia levels As hepatocyte necrosis progresses, hepatic enzyme levels may decrease and hepatomegaly may resolve Renal failure is a common complication.62,63 Diagnosis and Management Viral diagnosis relies on serology, detection of viral nucleic acid in blood, and detection of viral antigens or nucleic acids in tissue obtained from liver biopsy Systematic viral testing at the time of presentation has been shown to decrease the percentage of ALF cases with an indeterminate diagnosis.64 HAV infection is confirmed by demonstrating anti-HAV IgM antibodies, which can be detected in the serum at the onset of symptoms, peak week later, and become undetectable by to months postinfection Active HBV infection is diagnosed by the presence of hepatitis B surface antigen (HBsAg) in serum Owing to the destruction of actively infected hepatocytes, HBsAg may be absent in ALF and the only marker of acute HBV infection may be anti-HBcAb (anti-HBV core antibody) IgM antibodies HBV DNA can be found by PCR in serum and liver tissue.65 When the epidemiology suggests 1279 possible infection with HCV, serum and liver tissue should be analyzed for HCV RNA by PCR HSV hepatitis is frequently a result of newly acquired infection; thus, serology may not be helpful Blood and swabs from lesions and mucosal surfaces or liver tissue, if obtained, should be assayed for HSV by PCR Both serology and tissue or blood PCR can be used to diagnose infection with EBV, CMV, HHV-6, HEV, and parvovirus Diagnosis of adenovirus and enterovirus generally requires PCR of blood and tissue The role of antiviral therapy in ALF is limited Acyclovir should be initiated if HSV is suspected or confirmed High-dose acyclovir (60 mg/kg per day divided q hours) should be used for neonates with HSV.66 There are reports of successful use of tenofovir, entecavir, and lamivudine for treatment of severe acute hepatitis caused by HBV.67–70 Liver transplantation may be required for some patients.36,62,63 For a detailed discussion of the management of ALF, see Chapter 96 Viral Pneumonia/Pneumonitis Epidemiology and Etiology Pneumonia is a leading cause of death in children worldwide Respiratory viruses—in particular, influenza—are significant contributors to the incidence of pneumonia Recent data from the United States demonstrate that viruses account for the majority of community-acquired pneumonia cases in children and adults requiring hospitalization.71,72 Globally, an estimated 14.9 million episodes of severe acute lower respiratory infection (ALRI) resulted in hospital admissions in children younger than years in 2010.73 In the United States, the annual incidence of pneumonia is estimated to be 15.7 cases per 10,000 children, with the highest rate among children younger than years (62.2 cases per 10,000 children) with an estimated 66% of these hospitalizations attributable to viral etiologies.71 The etiologic agents of viral pneumonia are listed in Table 108.1 RSV is the primary cause of hospitalization for respiratory tract illness in young children.71 In a national surveillance study, most children with RSV infection had no coexisting medical conditions or characteristics that identified them as being at significantly greater risk for severe RSV disease, except for being younger than years.74 In healthy hosts other than infants, infections are localized to the upper respiratory tract Among immunocompromised children and adults, however, RSV infections can progress to fatal pneumonia, with the greatest mortality risk in patients with severe lower tract disease and in those who not receive treatment.75,76 Influenza epidemics occur annually, with significant morbidity and death in young children and older individuals The highest rate of hospitalization occurs in the to 5-month age group.77 Since 2004, the total number of reported pediatric influenza deaths has ranged from 37 to 358, peaking with the 2009 H1N1 pandemic (https://www.cdc.gov/flu/weekly/index.htm) Among immunocompromised patients, risk factors for more severe influenza disease include lymphopenia and infection early after hematopoietic stem cell transplant.78 Immunocompromised hosts have more complications, longer viral shedding, and more antiviral resistance while demonstrating fewer clinical symptoms and signs.79 The 2009 H1N1 pandemic resulted in a greatly increased burden of influenza disease worldwide Unlike seasonal influenza, children and young adults were at a disproportionate risk for infection and hospitalization; 60% of infections occurred in those younger than 18 years.80–82 The 2009 ... host anti-HBcAb, Anti-hepatitis B virus core antibody; BAL, bronchoalveolar lavage; CPE, cytopathic effect; CSF, cerebrospinal fluid; CMV, cytomegalovirus; DNA, deoxyribonucleic acid; EBV, Epstein-Barr... outbreak situations, treatment should not wait for laboratory confirmation of influenza because this may delay treatment and a negative rapid test does not rule out influenza 1278 S E C T I O... the neonatal period, potentially resulting in increased susceptibility and severe presentation in this age group.15 Many other viruses have caused myocarditis in children, including influenza A,