1280 SECTION XI Pediatric Critical Care Immunity and Infection pandemic H1N1 strain continues to circulate with seasonal influenza globally Parainfluenza viruses (PIVs) are also significant causes of[.]
1280 S E C T I O N X I Pediatric Critical Care: Immunity and Infection pandemic H1N1 strain continues to circulate with seasonal influenza globally Parainfluenza viruses (PIVs) are also significant causes of ALRI in children and immunocompromised patients.83–86 PIVs account for 50% of hospitalizations for acute laryngotracheitis (croup) and at least 15% of cases of bronchiolitis and pneumonia PIV types and cause more cases of croup, whereas PIV type is more likely to infect the small air passages and cause pneumonia or bronchiolitis However, any PIV can cause lower respiratory tract disease, particularly during primary infection or in immunocompromised hosts In the latter, PIV pneumonia has a 30-day attributable mortality rate of greater than 30%.85,87,88 Other respiratory viruses that can cause pneumonia, particularly in young children and immunocompromised hosts, include human metapneumovirus (HMPV), adenovirus, human rhinoviruses (HRVs), and human coronaviruses (HCoVs) Since it was first described in 2001,89 HMPV has been shown to be a common cause of croup, bronchiolitis, and pneumonia in children, the elderly, and immunocompromised patients.90–98 The clinical manifestations of HMPV are indistinguishable from RSV Adenovirus pneumonia can occur as an isolated event or as part of disseminated disease Risk factors for adenovirus pneumonia include compromised immune function, chronic underlying respiratory or cardiac disease, and age younger than years.71,99 HRVs occasionally cause lower respiratory tract disease requiring admission to the ICU among pediatric and immunosuppressed patients, although a causative role is sometimes difficult to define because HRVs frequently occur in association with copathogens.100–105 Among pediatric patients, a new species of rhinovirus (HRV-C) has been discovered that may cause more severe disease than HRV-A or HRV-B, although this association is not yet clearly elucidated.106–111 In 2014, enterovirus-D68 (EV-D68) was associated with an outbreak of severe respiratory illness and potentially acute flaccid paralysis in children and immunocompromised adults in North America112–116; EV-D68 continues to circulate in the United States in the late summer and early fall (https://www cdc.gov/non-polio-enterovirus/hcp/ev-d68-hcp.html) The HCoV family includes several viruses that are known to infect humans Severe acute respiratory syndrome-CoV (SARSCoV), SARS-CoV-2, and Middle East respiratory syndrome-CoV (MERS-CoV) are recently emerged viruses that can cause significant morbidity and mortality; updates to the case definition, epidemiology, and current management guidelines can be found at www cdc.gov Other HCoVs strains (OC43, 229E, HKU1, and NL63) have been reported to cause pneumonia in children and immunocompromised patients treated for hematologic malignancies.117–122 Although CMV usually causes relatively benign disease in immunocompetent hosts, it is frequently severe and often fatal in immunocompromised hosts, including patients with acquired immunodeficiency syndrome (AIDS), malignancy, congenital immunodeficiencies, and transplant recipients Among allogeneic stem cell transplant recipients, the risk of CMV pneumonia is high With the introduction of routine antiviral prophylaxis and preemptive therapy strategies, CMV disease during the first months after hematopoietic stem cell transplantation has been reduced from 20% to 30% to less than 5% in most studies and CMV disease now primarily occurs late after transplant.123 Among solid-organ transplant recipients, the risk of CMV disease is greatest for lung transplant recipients, followed by liver, heart, and renal transplant recipients.124,125 Hantaviruses are a cause of hemorrhagic fevers and acute severe respiratory infection They are acquired by exposure to aerosolized feces, urine, or other secretions of infected rodents Though rare in the United States, hantaviruses can cause severe disease with high mortality by causing leakage of plasma and erythrocytes through the vascular endothelium in the lung (hantavirus pulmonary syndrome [HPS]) or kidneys (hemorrhagic fever with renal syndrome [HFRS]).126,127 Clinical Presentation The clinical presentation of viral pneumonia/pneumonitis usually consists of fever, increased respiratory rate, cough, and increased work of breathing, with grunting, flaring, retracting, and use of accessory muscles in infants and young children Decreased oral intake with increased insensible loss due to the tachypnea may lead to dehydration Some patients have centrally mediated apnea; other patients have an overwhelming sepsis-like syndrome, especially young infants Rhinorrhea, conjunctivitis, otitis media, and previous exposure to an ill child or adult should raise suspicion of a viral cause However, many patients with influenza pneumonia have no preceding upper respiratory illness Radiographic findings generally include evidence of hyperinflation and peribronchial cuffing, and a focal or diffuse infiltrate may or may not be present Bacterial coinfection may appear after, or concomitantly with, the viral infection Diagnosis and Management If available, PCR testing on nasal respiratory specimens is the initial diagnostic test of choice for respiratory viruses because most of these pathogens are concentrated in the nasopharynx However, a lower respiratory sample by bronchoscopy may provide the best yield and may be positive even with a negative nasopharyngeal sample Most centers now have rapid PCR testing that will facilitate fast and sensitive results Many commercial multiplex assays are now available Shell vial assays can be performed for CMV, RSV, and adenovirus The diagnosis of hantavirus can be made by PCR testing for viral RNA from serum, plasma, or tissues, or serologic testing.127 A review of diagnostic testing options for etiologies of viral pneumonia is provided in Table 108.2 With the exception of influenza, the cornerstone of treatment for most viral infections in the respiratory tract remains supportive with supplemental oxygen, fluids, bronchodilators, and mechanical ventilation Corticosteroids are generally of no proven benefit in viral-mediated pneumonia or bronchiolitis.128,129 The use of empiric broad-spectrum antibiotics may be important until a diagnosis can be established and because some viral infections caused by PIVs, HRVs, and HCoVs may occur in the context of a bacterial coinfection For certain immunocompromised patients, fungal copathogens should also be considered Early isolation and infection control measures for suspected viral infections should be implemented The mainstay of treatment of severe influenza is with neuraminidase inhibitors; currently available agents in the United States include oral oseltamivir, inhaled zanamivir, and intravenous peramivir Baloxavir, a cap endonuclease, is a recently approved oral agent for treatment of uncomplicated influenza infection; its use in severe disease remains to be evaluated Widespread resistance to adamantanes (amantadine and rimantadine) has developed; thus, these agents are no longer recommended National surveillance data on influenza viruses circulating in the United States is available at http://www.cdc.gov/flu/ Combination therapy and/or use of investigational agents may be considered during CHAPTER 108 Life-Threatening Viral Diseases and Their Treatment periods of concomitant circulating viruses or for severely ill immunosuppressed patients.130–132 A number of antiviral strategies have been investigated or employed on an anecdotal basis to treat other viruses that cause pneumonia These are reviewed in Table 108.3 Central Nervous System Infections Epidemiology and Etiology Aseptic meningitis, encephalitis, and myelitis are inflammatory conditions of the central nervous system (CNS) involving the meninges, brain, and spinal cord, respectively Disease is caused by a variety of infectious pathogens; viruses are responsible for most cases when an etiology is identified Viruses gain entry to the CNS via the bloodstream (enteroviruses and arboviruses) or by direct neuronal spread (HSV and rabies) Pathogenesis may involve direct viral invasion or a virus-specific immune response, resulting in damage to neurons, oligodendroglia, or the myelin components, commonly termed postinfectious encephalomyelitis or acute disseminated encephalomyelitis (ADEM) Individuals of all ages are at risk for viral CNS infections However, in general, neonates, the elderly, and immunocompromised individuals are prone to more frequent and more serious infections Recent studies have demonstrated that mutations or polymorphisms in genes important in adaptive and/or innate immunity may influence susceptibility to various viral pathogens.133 Enteroviruses, herpesviruses, and arboviruses are responsible for most viral CNS disease (see Table 108.1) Enteroviruses account for up to 99% of cases of aseptic meningitis when a cause is identified.134 Enterovirus meningitis in older children and adults is typically self-limited and associated with few complications, whereas in neonates, enteroviral CNS involvement is often manifested as encephalitis and accompanied by a sepsis-like syndrome Parechovirus, another cause of meningoencephalitis in neonates, is a close relative of enteroviruses and clinical manifestations are similar.135 Specific enterovirus strains, such as EV-D68 and enterovirus 71, may cause acute flaccid paralysis (associated with anterior myelitis) in children and present as large outbre aks.114,136,137 HSV is a common cause of CNS infection in all ages During the neonatal period, HSV, especially type 2, can cause encephalitis due to vertical transmission of the virus.138 In contrast, in older children and adults, most HSV encephalitis is caused by type HSV-2 can also cause benign aseptic meningitis in association with primary and recurrent genital infections.139 Other members of the herpesvirus family (CMV, EBV, VZV, and HHV-6) can also cause aseptic meningitis and encephalitis CMV encephalitis occurs most often in immunocompromised individuals.140,141 EBV CNS infection can present with or without the classic findings of infectious mononucleosis.142 Acute cerebellar ataxia is a common and usually benign complication of VZV infection.143,144 VZV encephalitis may occur following or preceding varicella zoster and can be complicated by small- or large-vessel vasculitis (granulomatous arteritis), which carries the potentially serious consequence of infarction.143–146 While rarely a cause of encephalitis in healthy children,147 HHV-6B is the most common cause of encephalitis in hematopoietic stem cell transplantation recipients and is especially common in cord blood transplant recipients.148,149 Arboviruses (arthropod-spread viruses) are important causes of aseptic meningitis and encephalitis.150 The specific arbovirus 1281 determines the epidemiology, morbidity, and risk of death of associated disease The La Crosse and St Louis encephalitis viruses account for most arboviral CNS infections in the United States The La Crosse virus is found mainly in the Midwest; infection typically occurs in the summer and early fall and is associated with a relatively low mortality rate The St Louis encephalitis virus occurs in every state but is most common in the Midwest, Florida, and Texas and has been responsible for large urban outbreaks.151,152 Eastern equine virus occurs less frequently, mainly in the eastern United States, but carries high rates of morbidity and death.153,154 West Nile virus encephalitis first appeared in the summer of 1999 in New York state155 and has subsequently moved across the United States Most West Nile virus infections are asymptomatic or cause flulike illness However, older or immunocompromised individuals may develop encephalitis that can be fatal Acute flaccid paralysis has also been associated with West Nile virus infection.156 There has been a resurgence and co-circulation of dengue and chikungunya viruses, which are increasingly recognized as potential causes of meningitis, encephalitis, and myelitis.157,158 Influenza has not traditionally been considered a common cause of encephalitis However, the 2009 H1N1 influenza A pandemic challenged this thinking, as 1% to 2% of infected individuals were demonstrated to have encephalopathy/encephalitis.159,160 Children, especially those with underlying neurologic disease, appeared to be at higher risk of neurologic manifestations Lymphocytic choriomeningitis virus (LCMV) is an infrequently recognized cause of meningoencephalitis Disease in humans arises after exposure to the urine, droppings, and saliva of infected rodents.161 Symptoms may last for several weeks, but most patients fully recover Measles and mumps are two vaccinepreventable causes of encephalitis Though now infrequent, mumps virus accounted for a large proportion of aseptic meningitis and encephalitis cases in the United States in the prevaccine era.162,163 Acute measles encephalitis presents with or shortly following the rash in approximately out of 1000 cases of measles while subacute sclerosing panencephalitis (SSPE) is a chronic demyelinating disease that follows to 10 years after natural measles in in every 10,000 cases.164,165 Poor vaccination coverage has led to large outbreaks in the United States and Europe, including cases of encephalitis.166 The polyomaviruses, BK virus and JC virus (John Cunningham virus), may cause encephalitis in immunocompromised hosts BK virus causes a more acute onset while JC virus results in a subacute or chronic demyelinating process.167 Postinfectious encephalomyelitis refers to an acute self-limited demyelinating process most commonly following viral respiratory infections or varicella Transverse myelitis has been most frequently associated with enteroviruses However, VZV,168,169 CMV, influenza A,170 and HAV170 have also been reported as causes, even in immunocompetent individuals Travel and exposure history, along with physical findings, can be helpful in focusing the search for an etiologic agent of viral CNS infections Travel or residence in areas where arboviruses are endemic during the appropriate season for arthropod transmission should raise suspicion Enteroviral diseases are also more prevalent during summer and fall months History of a mother with recent viral illness should raise suspicion of enterovirus in a neonate Finally, history of exposure to a bat in the appropriate clinical setting should raise the concern for rabies 1282 S E C T I O N X I Pediatric Critical Care: Immunity and Infection Clinical Presentation Viral meningitis is characterized by acute onset of fever, headache, photophobia, vomiting, and nuchal rigidity A more chronic presentation might indicate enteroviral disease in an immunocompromised host, whereas recurrent aseptic meningitis is often associated with HSV-2 Encephalitis is characterized by acute onset of fever and depressed consciousness, focal neurologic findings, and seizures A chronic progressive presentation might indicate more unusual causes, such as progressive multifocal leukoencephalopathy (PML) and SSPE Transverse myelitis is characterized by an abrupt onset of weakness of the limbs progressing to flaccid paralysis Diminished deep tendon reflexes progress to nonexistent, and there is associated sensory deficit CSF findings in aseptic meningitis typically include a normal glucose level, normal to slightly elevated protein level, and pleocytosis of up to 1000 cells/mL Though the pleocytosis is classically monocytic, there can be an initial predominance of polymorphonuclear cells in the first 48 hours of illness.172 The results of brain computed tomography and MRI studies are usually normal in viral meningitis In general, MRI is the more sensitive study for detecting acute encephalitis Early findings include edema with minimal contrast enhancement As disease progresses, edema and enhancement become more obvious and may be accompanied by mass effect, hemorrhagic changes, and necrosis As the inflammation resolves, atrophy may become prominent Focal versus generalized disease patterns based on clinical features and brain imaging findings may give a clue to the etiology of the infection While not specific, this approach may help guide testing.133 For instance, in HSV, VZV, and HHV-6B, CNS imaging findings often first involve the temporal lobes In contrast, postinfectious encephalomyelitis lesions may be seen throughout the CNS and primarily involve the white matter, although gray matter may also be involved Diagnosis and Management Arboviruses are typically diagnosed through detection of serum and/or CSF antibodies in acute and convalescent serum specimens PCR and immunohistochemistry have also been used to diagnose arboviral infections and are available in some settings Diagnosis of LCMV is made through serologic testing JC virus can be detected in CSF with PCR; this appears to be a relatively sensitive and specific method for diagnosing PML.175,176 Definitive diagnosis, however, is usually made with brain biopsy Diagnosis of SSPE is made with the evaluation of the CSF for oligoclonal bands, IgG level, and specific measles antibody titer Next-generation sequencing is a promising new technology that may be used to identify pathogens in the CSF or brain tissue However, additional research is needed to understand how to best apply this technology.133 Given the high morbidity and mortality associated with HSV encephalitis and that early identification of patients and rapid initiation of acyclovir have been associated with better outcome.177,178 unless an alternative cause is clear, high-dose acyclovir should be initiated in all children with encephalitis until HSV is ruled out After the acute phase of treatment, oral suppressive acyclovir therapy for months has been shown to improve developmental outcomes in infants with neonatal HSV and CNS involvement.179 Based on lower-strength evidence, it is recommended that hematopoietic cell transplant (HCT) recipients with evidence of HHV-6B encephalitis receive high-dose ganciclovir and/or foscarnet.180,181 Extrapolating from HSV, some experts recommended that antiviral therapy be started empirically while waiting for diagnostic results Other specific antiviral therapy may be directed as outlined in Table 108.3 Emerging Viral Diseases With the increase in global travel and the threat of bioterrorism, the potential to treat a child with an emerging or reemerging viral disease exists The relevant pathogens include Andes virus, B virus, monkeypox, and the hemorrhagic fever viruses (Ebola, Marburg, Lassa, Crimean-Congo, Argentine, and Bolivian) If one of these agents is suspected, the patient should be isolated and infection control and public health authorities should be notified immediately.182–184 While a full discussion of these agents is beyond the scope of this chapter, a few pathogens deserve mention, given the 2014 to 2015 Ebola outbreak in West Africa and ongoing concerns in other parts of Africa, the emergence of chikungunya virus in the Western hemisphere, and the evolving threat of the SARS-CoV-2 pandemic Like adult patients with Ebola virus disease, children often present with a history of abrupt onset of nonspecific symptoms and signs, such as fever, malaise, headache, myalgias, and abdominal pain.185 As the illness progresses, vomiting and diarrhea often develop and may lead to significant fluid loss and dehydration Patients with severe disease are commonly hypotensive and have electrolyte imbalances leading to shock and multiorgan failure, sometimes accompanied by hemorrhage.186 Chikungunya has caused large outbreaks in Asia and Africa More recently, the Caribbean has been experiencing a heavy burden of disease.187 Imported cases to the United States have been well recognized and now more recently isolated cases originating in the United States have been documented.188 This mosquitoborne infection typically presents with high fever, headache, photophobia, myalgias, and arthralgias, which can be severe A maculopapular rash may also occur In some patients, disabling arthralgias may persist for years Chikungunya virus is also now increasingly recognized as a potential cause of meningitis, encephalitis, and myelitis.158 A new human coronavirus, SARS-CoV-2, emerged late in 2019 Symptoms of coronavirus disease 2019 (COVID-19) range from asymptomatic infection to severe respiratory failure Elderly patients and those with underlying comorbidities such as cardiovascular and pulmonary disease, diabetes, and obesity, seem to be at highest risk for severe disease and death Children generally are asymptomatic or tend to have mild disease; however, in some instances they can have significant illness,200 including a potentially related postinfectious syndrome, MIS-C As of summer 2020, according to the World Health Organization, the virus has infected close to million people and caused close to half a million deaths globally Efforts to develop effective treatments and vaccines are ongoing CHAPTER 108 Life-Threatening Viral Diseases and Their Treatment Key References Butts RJ, Boyle GJ, Deshpande SR, et al Characteristics of clinically diagnosed pediatric myocarditis in a contemporary multi-center cohort Pediatr Cardiol 2017;38(6):1175-1182 Cooper Jr LT Myocarditis N Engl J Med 2009;360(15):1526-1538 Tunuguntla H, Jeewa A, Denfield SW Acute myocarditis and pericarditis in children Pediatr Rev 2019;40(1):14-25 Bitar R, Thwaites R, Davison S, Rajwal S, McClean P Liver failure in early infancy: aetiology, presentation, and outcome J Pediatr Gastroenterol Nutr 2017; 64(1):70-75 Squires JE, McKiernan P, Squires RH Acute liver failure: an update Clin Liver Dis 2018;22(4):773-805 Narkewicz MR, Horslen S, Hardison RM, et al A learning collaborative approach increases specificity of diagnosis of acute liver failure in pediatric patients Clin Gastroenterol Hepatol 2018;16(11):1801-1810.e3 1283 Iwane MK, Edwards KM, Szilagyi PG, et al Population-based surveillance for hospitalizations associated with respiratory syncytial virus, influenza virus, and parainfluenza viruses among young children Pediatrics 2004;113(6):1758-1764 Englund JA Diagnosis and epidemiology of community-acquired respiratory virus infections in the immunocompromised host Biol Blood Marrow Transplant 2001;(Suppl 7):2S-4S Tyler KL Acute viral encephalitis N Engl J Med 2018;379(6):557-566 Renaud C, Harrison CJ Human parechovirus 3: the most common viral cause of meningoencephalitis in young infants Infect Dis Clin North Am 2015;29(3):415-428 The full reference list for this chapter is available at ExpertConsult.com e1 References Ghelani SJ, Spaeder MC, Pastor W, Spurney CF, Klugman D Demographics, trends, and outcomes in pediatric acute myocarditis in the United States, 2006 to 2011 Circ Cardiovasc Qual Outcomes 2012;5(5):622-627 Klugman D, Berger JT, Sable CA, He J, Khandelwal 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this appears to be a relatively sensitive and specific method for diagnosing PML.175,176 Definitive