Life-threatening viral diseases and their treatment

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Clinicians should obtain serum to store for future serologic testing when viral pathogens are considered as the potential cause of a critical illness.
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Multiplex polymerase chain reaction panels are increasingly used to diagnose viral infections from various specimens, for example, respiratory, cerebrospinal fluid, and stool.
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Current treatment for most viral infections remains supportive, with antiviral therapy generally limited to treatment of herpes and some respiratory viruses.
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Providers should initiate empiric treatment with acyclovir rapidly when herpes simplex virus encephalitis or neonatal disease is suspected.
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Parainfluenza and influenza viruses are often associated with bacterial coinfections.
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Infection control precautions should be initiated early to prevent spread of infection to staff and other patients when viral pathogens are suspected.

Viral infections are a frequent cause of disease in individuals of all ages. In general, the spectrum of illness is varied, with young and/or immunosuppressed children at higher risk of severe disease. This chapter covers viral causes of entities commonly seen in the intensive care unit (ICU): myocarditis, hepatitis, pneumonitis, and meningitis/encephalitis, as well as certain emerging infections that may require critical care ( Table 108.1 ). This content is focused on providing the reader with guidance for the initial management of patients with viral infections, with an emphasis on diagnosis and therapy.

TABLE 108.1

Viral Etiologies of Myocarditis, Fulminant Hepatitis, Pneumonia, Meningitis, Encephalitis, and Myelitis

	Myocarditis	Liver Failure	Pneumonia	Meningitis	Encephalitis	Myelitis
Adenovirus	XXX	X ^a	XX	X	X	X
Arboviruses (arthropod-borne viruses)				XX	XX
Western equine encephalitis virus				X	X
Eastern equine encephalitis virus					X
St. Louis encephalitis virus				X	X
California encephalitis virus (La Crosse)				X	X
Colorado tick fever				X	X
West Nile encephalitis virus					X
Coronaviruses (OC43, 229E, HKU1, NL63, SARS, and MERS)			XX
Enteroviruses	XXX	X	X	XXX	XX	XX
Hantavirus			X
Hepatitis A		XXX				X
Hepatitis B		X
Hepatitis C		X
Hepatitis E		X
Herpesviruses
CMV	X	X	XXX ^a		X	XX
EBV	X	XX		X	X	XX
HSV 1 and 2	X	X ^b	X ^a	XX	XX	X
HHV-6B	X	X	X ^a		X
VZV		X ^a	XX ^a	X	X	X
HIV	X				X
HTLV					X
Influenza A	X		XXX		X	X
Influenza B			X
Lymphocytic choriomeningitis virus				X	X	X
Measles	X		X		X
Metapneumovirus			XX
Mumps	X			X	X	X
Parechoviruses ^b	XX	X	X	XXX	XXX
Parainfluenza virus types 1, 2, 3, 4			XXX
Parvovirus B19 ^c	XX
Polyomaviruses
BK virus					X ^a
JC virus					X ^a
Rabies					X
RSV	X		XXX
Rhinovirus			X
Rubella					X	X
SARS-CoV-2	X		XX

XXX, Most frequent; XX, frequent; X, less common or rare.

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 Primarily in immunocompromised hosts.

b Primarily neonates and young infants.

c Viruses detected in myocardial biopsies appear to have shifted over the past few decades.

Five primary methods are used to diagnose viral infections: (1) serologic detection of an early antibody (immunoglobulin M [IgM]) or a fourfold or higher rise in IgG antibody titers between acute phase and convalescent phase (at least 10–14 days later) serum; (2) observation of characteristic cytopathic effect in cell culture; (3) microscopic identification of viral inclusion bodies; (4) assays that link specific antibodies to viral antigens (complement fixation, neutralization, immunofluorescence assays, enzyme-linked immunosorbent assay [ELISA]); and (5) molecular techniques that amplify and quantify viral deoxyribonucleic acid (DNA) or ribonucleic acid (RNA). The latter are increasingly being used in panels of multiple pathogens for various samples, including respiratory, stool, and cerebral spinal fluid (CSF). If a viral infection is suspected, acute-phase serum should be held for later interpretation. It is critical that this specimen is drawn before administration of intravenous immunoglobulin (IVIG) or blood products. Samples for viral cultures and polymerase chain reaction (PCR) testing should be collected from the appropriate sites with specific swabs. Nasal swabs and swabs of the base of a vesicle or ulcer (for varicella zoster virus [VZV], herpes simplex virus [HSV]) should include good cellular content to improve the sensitivity of the assay. Table 108.2 outlines appropriate samples and testing for a number of specific viral pathogens.

TABLE 108.2

Potential Diagnostic Tests and Corresponding Specimens for Diagnosis of Viral Pathogens

Viral Agent	Specimen	Recommended Diagnostic Tests ^a
Adenovirus	NP, BAL fluid	PCR
	Tissue	PCR, histology
	Serum/plasma ^b	PCR
Arboviruses (California encephalitis, Colorado tick fever, EEE, SLE, WEE, West Nile) ^c	Serum/plasma	IgM and IgG antibody, ^dPCR
	CSF	IgM ^eand IgG antibody, ^dPCR
Chikungunya virus ^c	Serum/plasma	PCR, IgM and IgG antibody ^d
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
	Serum/plasma (SARS/MERS)	PCR, IgM and IgG antibody
Ebola virus ^c	Whole blood, oral secretions	PCR
Enteroviruses (echoviruses, coxsackie viruses, enteroviruses) ^c	CSF, NP, pharynx	PCR
	Stool ^g	Culture
	Serum/plasma ^b	PCR (enterovirus D68 may not be detected by these methods)
Hantavirus ^c	Serum	IgM and IgG antibody ^d
	Whole blood	PCR
	Tissue (lung, kidney, spleen preferred; antemortem—lung or bone marrow)	PCR, immunohistochemistry
Hepatitis viruses	Serum	Serology for all
Hepatitis A virus (HAV)	Serum	Anti-HAV IgM
Hepatitis B virus (HBV)	Serum/plasma ^b	HBsAg, anti-HBcAb IgM, PCR
	Liver	PCR
Hepatitis C virus (HCV)	Serum/plasma	Anti-HCV IgG, PCR
	Liver	PCR
Hepatitis E virus (HEV)	Serum/plasma ^b	Anti-HEV IgM, PCR
	Liver	PCR
	Stool	PCR
Herpesviruses
CMV	NP or BAL	Shell vial or rapid culture, PCR ⁱ
	Serum/plasma ^b	PCR
	Tissue	IgM and IgG antibody ^d
	Urine	PCR, histology
EBV	Serum	Viral capsid antibody (VCA) panel or slide agglutination test (Monospot)
	Plasma, CSF	PCR
	Tissue	PCR, immunohistochemistry
HHV-6B	Serum/plasma, ^bCSF	PCR
	Tissue	PCR
HSV types 1 and 2	CSF, serum/plasma ^b	PCR
	Base of lesion, NP, conjunctiva, tissue	PCR, culture
	Serum	IgG antibody ^d
VZV	Base of lesion, tissue	PCR, FA, and culture
	Serum	IgM and IgG antibody ^d
	Serum/plasma, ^bCSF	PCR
Influenza types A and B	NP, pharynx, BAL fluid	PCR
	Tissue	PCR
LCMV ^c	Serum/plasma ^b	PCR, IgM, and IgG antibody ^d
	CSF	IgM, PCR
Measles (rubeola) ^c	Serum	IgM and IgG antibody ^d
	Urine, blood, NP	PCR
SSPE	CSF	Oligoclonal bands, IgG
Metapneumovirus	NP, BAL fluid	PCR
Mumps ^c	Buccal swab, saliva	PCR
	Serum	IgM and IgG antibody ^d
	CSF, pharynx, saliva	PCR
Parechoviruses	CSF, serum/plasma, ^bNP, stool	PCR
Parainfluenza viruses	NP, BAL fluid, tissue	PCR
Parvovirus	Serum/plasma ^b	PCR, IgM and IgG antibody ^d
Polyomaviruses
BK virus	Serum, urine, CSF	PCR
JC virus ^c	Brain biopsy, ^hCSF	PCR
Rabies virus ^c	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)
Retroviridae
HIV	Serum	HIVAg/Ab combination immunoassays
	Whole blood	RNA/DNA PCR
	Plasma, CSF	RNA PCR
HTLV	Serum, CSF	Anti-HTLV antibodies
	Whole blood, tissue	PCR
Rotavirus	Stool	PCR, EIA, or latex particle agglutination assays
RSV	NP, BAL, tissue	PCR, DFA, IA
Rubella ^c	Serum	IgM and IgG antibody ^d
	NP, CSF, urine	PCR
SARS-CoV-2	Serum	IgM and IgG antibodies
	NP, stool, sputum	PCR

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 4 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.

In general, for most life-threatening viral infections, the primary treatment is supportive. Because of improvements in intensive medical care, death from these illnesses has decreased even without the availability of specific antiviral therapy. Although lacking for many infections, there are antivirals for most of the herpes group viruses and some respiratory viruses. For most infections, the efficacy of antiviral therapy is decreased if therapy is delayed. Thus, early diagnosis and rapid initiation of medication are essential. Consultation with an infectious disease specialist is recommended because some antiviral agents are not commercially available and new treatment modalities continue to be identified. A listing of antiviral agents, indications, and dosages is provided in Table 108.3 .

TABLE 108.3

Antiviral Agents and Indications for Use

Virus	Drug of Choice/Dose ^a	Alternate Agents/Dose
Adenovirus	No currently approved therapy	Cidofovir may be considered for immunocompromised patients with disseminated disease or severe pneumonia. ^,
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 5 mg/kg q24h) is primary therapy for CMV disease. Valganciclovir—limited pediatric dosing information available. Dose varies by age and indication.	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.
HSV	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.	No specific dosing recommendations are available for HSV-associated hepatitis and pneumonitis. At least 10 mg/kg/dose should be considered outside the neonatal period.
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.
Influenza A/B	Oseltamivir ^bor zanamivir (≥5 y) 10 mg (2 oral inhalations) q12h × 5 days or peramivir IV (≥2 y) 12 mg/kg dose, up to 600 mg maximum × 1 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. ^,
JCV	No effective therapy	In HIV infection, treatment with combination antiretroviral therapy may improve survival. Potential role for cidofovir.
Metapneumovirus	No currently approved therapy	Case reports suggest that ribavirin and IVIG may be used successfully in immunosuppressed patients. ^,
Parechoviruses	No currently approved therapy
Parainfluenza virus	No currently approved therapy	Treatment for PIV pneumonia should include coverage for copathogens. 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. ^,
RSV	Aerosolized ribavirin (2 g reconstituted in 33 mL tid) × 5 d has been used with modest efficacy in patients with severe RSV pneumonia and in immunocompromised patients ; 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. ^,