1594 PART 5 Infectious Diseases

be compliant. Plasma HIV RNA levels should be monitored within

2–4 weeks after initiation of ART or following a change in regimen,

every 4–8 weeks until HIV RNA levels are suppressed to <200 copies/mL, and then every 3–6 months during therapy.

In order to determine an optimal therapeutic regimen for initial therapy or for a patient on a failing regimen, one may attempt

to measure antiretroviral drug susceptibility through genotyping

or phenotyping of HIV quasispecies and to determine adequacy

of dosing through measurement of drug levels. Genotyping may

be done through cDNA sequencing. Phenotypic assays typically

measure the enzymatic activity of viral enzymes in the presence

or absence of different concentrations of different drugs and have

also been used to determine co-receptor tropism. These assays

will generally detect quasispecies present at a frequency of ≥10%.

Next-generation sequencing may allow detection of quasispecies

at frequencies down to 1%. It is generally recommended that

resistance testing be used in selecting initial therapy in settings

where the risk of transmission of resistant virus is high (such as the

United States and Europe) and in determining new regimens for

patients experiencing virologic failure while on therapy. Resistance

testing may be of particular value in distinguishing drug-resistant

virus from poor patient compliance. Due to the rapid rate at which

drug-resistant viruses revert to wild-type, it is recommended that

resistance testing performed in the setting of drug failure be carried

out while the patient is still on the failing regimen. Measurement

of plasma drug levels can also be used to tailor an individual

treatment. The inhibitory quotient, defined as the trough blood

level/IC50 of the patient’s virus, is used by some to determine the

adequacy of dosing of a given treatment regimen. Despite the best

of efforts there will still be patients with ongoing high levels of HIV

replication while receiving the best available therapy. These patients

will receive benefit from remaining on antiretroviral therapy even

though it is not fully suppressive.

In addition to the licensed medications discussed above, a large

number of experimental agents are being evaluated as possible

therapies for HIV infection. Therapeutic strategies are being developed to interfere with virtually every step of the replication cycle of

the virus (Fig. 202-3) and in an attempt to eliminate the reservoir

of infected cells to “cure” HIV infection. In addition to directly

acting antiviral drugs, other strategies, generically referred to as

“immune-based therapies,” are being developed as a complement

to antiviral therapy. Among the antiviral agents in early clinical

trials are additional nucleoside and nucleotide analogues, protease

inhibitors, fusion inhibitors, receptor and co-receptor antagonists,

and integrase inhibitors—as well as new antiviral strategies including antisense nucleic acids and maturation inhibitors. Among the

immune-based therapies being evaluated are monoclonal antibodies, IFN-α, bone marrow transplantation, adoptive transfer of

lymphocytes genetically modified to resist infection or enhance

HIV-specific immunity, active immunotherapy with inactivated

HIV or its components, IL-7, and IL-15. Strategies directed toward

cure are examining the role of latency-reversing agents such as histone-deacetylase inhibitors.

HIV AND THE HEALTH CARE WORKER

Health care workers, especially those who deal with large numbers

of HIV-infected patients, have a small but definite risk of becoming

infected with HIV as a result of professional activities (see “Occupational Transmission of HIV: Health Care Workers, Laboratory Workers, and the Health Care Setting,” above).

In the United States, 58 health care workers for whom case investigations have been completed have had documented seroconversions to

HIV following occupational exposures. Only one of these has occurred

since 1999. Approximately 85% of the exposures resulting in infection

have been due to percutaneous (puncture/cut injury) exposures to

HIV-infected blood. In addition, at least 150 possible cases of occupationally acquired HIV infection have been reported among health

care personnel in the United States. The number of these workers

who actually acquired their infection through occupational exposures

is not known. Taken together, data from several large studies suggest

that the risk of HIV infection following a percutaneous exposure to

HIV-contaminated blood is ~0.23%, and after a mucous membrane

exposure, ~0.09%. Although episodes of HIV transmission after

nonintact skin exposure have been documented, the average risk for

transmission by this route has not been precisely quantified but is

estimated to be less than the risk for mucous membrane exposures.

The risk for transmission after exposure to body fluids or tissues other

than HIV-infected blood also has not been quantified but is probably

considerably lower than for blood exposures. A seroprevalence survey of 3420 orthopedic surgeons, 75% of whom practiced in an area

with a relatively high prevalence of HIV infection and 39% of whom

reported percutaneous exposure to patient blood, usually through an

accident involving a suture needle, failed to reveal any cases of possible occupational infection, suggesting that the risk of infection with a

suture needle may be considerably less than that with a blood-drawing

(hollow-bore) needle.

Most cases of health care worker seroconversion occur as a result

of needle-stick injuries. When one considers the circumstances that

result in needle-stick injuries, it is immediately obvious that adhering

to the standard guidelines for dealing with sharp objects would result

in a significant decrease in this type of accident. In one study, 27% of

needle-stick injuries resulted from improper disposal of the needle

(over half of these were due to recapping the needle), 23% occurred

during attempts to start an IV line, 22% occurred during blood drawing, 16% were associated with an IM or SC injection, and 12% were

associated with giving an IV infusion.

Occupational exposures to HIV should be considered as a medical

emergency to ensure timely postexposure management and administration of postexposure antiretroviral prophylaxis (PEP). Recommendations regarding PEP must take into account that a variety of

circumstances determine the risk of transmission of HIV following

occupational exposure. In this regard, several factors have been associated with an increased risk for occupational transmission of HIV

infection, including deep injury, the presence of visible blood on

the instrument causing the exposure, injury with a device that had

been placed in the vein or artery of the source patient, and advanced

TABLE 202-25 Indications for Changing Antiretroviral Therapy in

Patients with HIV Infectiona

Less than a 1-log drop in plasma HIV RNA by 4 weeks following the initiation

of therapy

A reproducible significant increase (defined as threefold or greater) from

the nadir of plasma HIV RNA level not attributable to intercurrent infection,

vaccination, or test methodology

Persistently declining CD4+ T-cell numbers

Clinical deterioration

Side effects

a

Generally speaking, a change should involve the initiation of at least two drugs felt

to be effective in the given patient. The exception to this is when change is being

made to manage toxicity, in which case a single substitution is reasonable.

Source: Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and

Adolescents, USPHS.

TABLE 202-24 Initial Combination Regimens Recommended for Most

Treatment-Naïve Patients Regardless of HIV RNA Level or CD4 Count

Dolutegravir + tenofovir*

 + emtricitabine†

Raltegravir + tenofovir*

 + emtricitabine†

Bictegravir + tenofovir*

+ emtricitabine†

Elvitegravir + cobicistat + tenofovir*

 + emtricitabine†

Dolutegravir + abacavir + lamivudine†

 (only for those HLA-B*

5701 negative)

*

Tenofovir alafenamide and tenofovir disoproxil fumarate are two forms of tenofovir

approved by FDA. Tenofovir alafenamide has fewer bone and renal toxicities while

tenofovir disoproxil fumarate is associated with lower lipid levels. †

Lamivudine may

substitute for emtricitabine and vice versa.

Source: Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and

Adolescents, USPHS.

1595CHAPTER 202 Human Immunodeficiency Virus Disease: AIDS and Related Disorders

HIV disease in the source patient. Other important considerations

when considering PEP in the health care worker include known or

suspected pregnancy or breast-feeding, the possibility of exposure

to drug-resistant virus, and the toxicities of different PEP regimens.

Regardless of the decision to use PEP, the wound should be cleansed

immediately and antiseptic applied. If a decision is made to offer PEP,

U.S. Public Health Service guidelines recommend that PEP regimens

contain three (or more) antiretroviral drugs administered for a 4-week

duration for all occupational exposures to HIV. Detailed guidelines are

available from the Updated U.S. Public Health Service Guidelines for the

Management of Occupational Exposures to HIV and Recommendations

for Postexposure Prophylaxis (CDC, 2015). The report emphasizes

the importance of adherence to PEP when it is indicated, and close

follow-up of exposed workers should be provided including counseling, baseline and follow-up HIV testing, and monitoring for drug

toxicity. Follow-up appointments should begin within 72 h of an HIV

exposure and may be concluded 4 months after exposure. For consultation on the treatment of occupational exposures to HIV and other

bloodborne pathogens, the clinician managing the exposed patient

can call the National Clinicians’ Post-Exposure Prophylaxis Hotline

(PEPline) at 888-448-4911. This service is available 24 hours a day at

no charge. (Additional information on the Internet is available at www

.nccc.ucsf.edu.) PEPline support may be especially useful in challenging

situations, such as when drug-resistant HIV strains are suspected or if

the health care worker is pregnant.

Health care workers can minimize their risk of occupational HIV

infection by following the CDC guidelines of June 2015, which include

adherence to universal precautions and assuming that blood and other

body fluids from all patients are potentially infectious. Therefore, the

following infection control precautions should be adhered to at all

times: (1) routinely use barriers (such as gloves and/or goggles) when

anticipating contact with blood or body fluids; (2) immediately wash

hands and other skin surfaces after contact with blood or body fluids;

and (3) carefully handle and dispose of sharp instruments during and

after use. For further information contact the CDC at 800-CDC-INFO

(232-4636) or see www.cdc.gov/cdc-info/. The risk of HBV infection following a needle-stick injury from a hepatitis antigen–positive patient

is much higher than the risk of HIV infection (see “Transmission,”

above). There are multiple examples of needle-stick injuries where the

patient was positive for both HBV and HIV and the health care worker

became infected only with HBV. For these reasons, it is advisable, given

the high prevalence of HBV infection in HIV-infected individuals, that

all health care workers dealing with HIV-infected patients be immunized with the HBV vaccine.

TB is another infection common to HIV-infected patients that can

be transmitted to the health care worker. For this reason, all health

care workers should know their PPD status, have it checked yearly,

and, where appropriate, receive 6 months of isoniazid treatment if

their skin test converts to positive. In addition, all patients in whom a

diagnosis of active pulmonary TB is being entertained should be placed

immediately in respiratory isolation, pending results of the diagnostic

evaluation. The emergence of drug-resistant organisms, including

extensively drug-resistant TB strains, has made TB an increasingly

important problem for health care workers. This is particularly true for

the health care worker with preexisting HIV infection.

HIV PREVENTION

Many proven interventions, usually applied in combination, have a role

in preventing the transmission of HIV (Fig. 202-48). Education, counseling, and behavior modification are the cornerstones of any HIV prevention strategy. A major problem in the United States and elsewhere is

that many infections are passed on by those who do not know that they

are infected. Of the ~1.2 million persons in the United States who are

HIV-infected, it is estimated that ~13% do not know their HIV status

and that a substantial proportion of all new infections are transmitted

by those people. In this regard, the CDC has recommended that HIV

testing become part of routine medical care and that all individuals

between the ages of 13 and 64 years be tested at least one time. These

individuals should be informed of the testing and be tested without the

need for written informed consent. Each individual can “opt out” of

testing; however, testing should otherwise be routinely administered.

Individuals who are practicing high-risk behavior should be tested

more often and should use pre-exposure prophylaxis (PrEP) (see

below). Partners engaged in monogamous sexual relationships who

wish to be assured of safety should both be tested for HIV antibody.

If both are negative, it must be understood that any divergence from

monogamy puts both partners at risk; open discussion of the importance of honesty in such relationships should be encouraged.

When the HIV status of either partner is not known, or when one

partner is positive, there are a number of options. Use of condoms

can markedly decrease the chance of HIV transmission. It should be

remembered that condoms are not 100% effective in preventing transmission of HIV infection, and there is a ~10% failure rate of condoms

used for contraceptive purposes. Most condom failures result from

breakage or improper usage, such as not wearing the condom for

the entire period of intercourse. Latex condoms are preferable since

virus has been shown to leak through natural skin condoms. Petroleum-based gels should never be used for lubrication of the condom,

since they increase the likelihood of condom rupture.

Microbicides composed of gels or rings containing antiretroviral

drugs have been shown to be variably efficacious in preventing acquisition of HIV infection in women engaging in vaginal intercourse. The

considerable degree of variability in efficacy relates to the generally poor

adherence of participants to the use of the intervention. One product,

a vaginal ring that releases the antiretroviral drug dapivirine from the

ring into the vagina slowly over 28 days, has been recommended by

WHO as an additional prevention choice for women at substantial risk

of HIV infection as part of combination prevention approaches.

Large, prospective clinical trials have clearly demonstrated that

ART for people with HIV has an important role in HIV prevention.

The initial results of the HPTN 052 clinical trial published in 2011

demonstrated a 96% reduction in HIV transmission risk among heterosexual HIV-discordant couples where the partner with HIV started

ART immediately versus delayed ART initiation. The final results of

HPTN 052, published in 2016, reported no HIV transmissions within

these couples when the partner with HIV had a suppressed viral

load (defined as having a viral load of <400 copies of HIV RNA per

milliliter). Three subsequent studies reported similar results, with no

genetically linked infections while the partner with HIV was virally

suppressed even though couples were engaging in sex without a

condom and not using PrEP. These three studies included >500 HIVdiscordant heterosexual couples and >1100 HIV-discordant couples

of men who have sex with men. Combined, these couples engaged in

over 125,000 sex acts without a condom or PrEP over more than 2600

Treatment as

Prevention

Education/

Behavior

Modification

Condoms

Treatment/

Prevention of

Drug/Alcohol

Abuse

Clean

Syringes Microbicides STI

Treatment

Medical Male

Circumcision

HIV Testing/

Counseling

Blood

Supply

Screening

PMTCT PrEP

FIGURE 202-48 The HIV prevention “toolkit.” See text for detailed description. PrEP,

pre-exposure prophylaxis with antiretroviral drugs; PMTCT, prevention of motherto-child transmission of HIV. (From RW Eisinger et al Clin Infect Dis 69:2122, 2019.)

1596 PART 5 Infectious Diseases

couple-years of observation. Collectively, the studies demonstrated that

if the viral load of the infected partner is decreased to below detectable

levels by antiretroviral therapy, sexual transmission to the uninfected

partner does not occur. This is true for heterosexuals and men who

have sex with men, leading, as noted above, to the commonly used

phrase “undetectable equals untransmittable” or U=U.

Pre-exposure prophylaxis (PrEP) with antiretroviral medication also

is highly effective in preventing HIV acquisition by at-risk uninfected

men who have sex with men and heterosexual men and women.

Accumulated data indicate that high adherence to a PrEP regimen of

emtricitabine + tenofovir disoproxil fumarate, taken as 1 pill per day or

on demand (immediately before and following a sexual encounter), is

99% effective in preventing HIV acquisition if subjects adhere strictly

to the regimen. Subsequent studies indicated similar, if not better,

efficacy with cabotegravir injections given every 2 months as a maintenance regimen. More limited data demonstrate the utility of PrEP for

people who inject drugs. CDC estimates that approximately 1.2 million

people in the United States are at “substantial” risk for HIV infection

and should be counseled about PrEP.

Adult male circumcision, which has been shown to result in a 50–65%

reduction in HIV acquisition in the circumcised subject, is currently

being pursued, particularly in developing nations, as a component of

HIV prevention (see above). The most effective way to prevent transmission of HIV infection among IDUs is to stop the use of injectable

drugs. Unfortunately, that is extremely difficult to accomplish unless

the individual enters a treatment program. For those who will not or

cannot participate in a drug treatment program and who will continue

to inject drugs, the avoidance of sharing of needles and other paraphernalia (“works”) is the next best way to avoid transmission of infection.

However, the cultural and social factors that contribute to the sharing

of paraphernalia are complex and difficult to overcome. Under these

circumstances, paraphernalia should be cleaned after each usage with

a virucidal solution, such as undiluted sodium hypochlorite (household bleach). Needle exchange programs have been highly successful

in decreasing HIV transmission among injection drug users without

increasing the use of injection drugs. As noted, above, oral PrEP also

is effective in preventing acquisition of HIV infections among IDUs. It

is important for IDUs to be tested for HIV infection and counseled to

avoid transmission to their sexual partners. Prevention of transmission

through blood or blood products and prevention of mother-to-child

transmission are discussed in “Transmission,” above.

■ HIV VACCINES

There is currently no safe and effective vaccine approved for the prevention of HIV infection. Successful vaccines for other diseases are

predicated on the assumptions that the body can mount an adequate

immune response to the microbe or virus in question during natural

infection and that the vaccine will mimic the natural response to

infection. Even with serious diseases, such as smallpox, poliomyelitis,

measles, and influenza among others, the body in the vast majority

of cases clears the infectious agent and provides protection, which is

usually life-long against future exposure against the same pathogen.

Unfortunately, this is not the case with HIV infection since the natural

immune response to HIV infection is unable to clear the virus from the

body and cases of superinfection are not rare.

Some of the factors that contribute to the problematic nature of

developing a preventive HIV vaccine are (1) the high mutability of the

virus; (2) the fact that the infection can be transmitted by cell-free or

cell-associated virus; (3) the fact that the HIV provirus integrates itself

into the genome of the target cell and may remain in a latent form unexposed to the immune system; (4) the likely need for the development of

effective mucosal immunity; and, importantly, (5) the difficulty that the

immune system has in readily mounting broadly neutralizing antibodies in response to natural infection with HIV (see below).

Early attempts to develop a vaccine with the envelope protein gp120

aimed at inducing neutralizing antibodies in humans were unsuccessful; the elicited antisera failed to neutralize primary isolates of HIV. In

this regard, two phase 3 trials were undertaken in the United States and

Thailand using soluble gp120, and the vaccines failed to protect human

volunteers from HIV infection. In addition, two separate vaccine trials

aimed at eliciting CD8+ T-cell responses to prevent infection and, if

unsuccessful in preventing infection, to control postinfection viremia,

also failed at both goals. In 2009, a vaccine using a poxvirus vector

prime expressing various viral proteins followed by an envelope protein

boost was tested in a 16,000-person clinical trial (RV144) conducted

in Thailand among predominantly low-HIV-prevalence heterosexuals. The vaccine provided the first positive, albeit very modest, signal

ever reported in an HIV vaccine trial, showing 31% protection against

acquisition of infection. Such a result is certainly not sufficient justification for clinical use of the vaccine; however, it served as an important

first step in the direction of the development of a safe and effective

vaccine against HIV infection.

Follow-up studies of RV144 indicate that nonneutralizing or weakly

neutralizing antibody responses against certain constant epitopes in

the otherwise highly variable V1–V2 region of the HIV envelope may

be associated with the modest degree of protection observed in that

clinical trial. Additional similar studies were undertaken in high-HIVprevalence countries in sub-Saharan Africa as well as in the Americas

and certain European countries in attempts to improve on the results

of RV144 by a variety of approaches, including increasing the number

of vaccine boosts with envelope protein, the use of mosaic antigens,

and the addition of adjuvant. Unfortunately, two recent phase 3 studies

of candidate vaccines failed to show efficacy. A third phase 3 trial is

underway in the Americas and Europe with results expected in 2024.

An area of HIV vaccine research that is currently being actively

pursued is the attempt to induce broadly neutralizing antibodies by

developing as immunogens for vaccination certain epitopes on the HIV

envelope that are the targets of naturally occurring broadly neutralizing

antibodies during HIV infection (Fig. 202-30). It is curious that only

about 20% of HIV-infected individuals develop broadly neutralizing

antibodies in response to natural infection and they do so only after

2–3 years of ongoing infection. By the time these antibodies appear,

they can neutralize a broad range of primary HIV isolates, but they

appear to be ineffective against the autologous virus in the infected

subject. Upon close examination, these broadly neutralizing antibodies

manifest a high degree of somatic mutations that were accumulated

over time and are responsible for their affinity maturation and broadly

neutralizing capacity. The goal of current efforts is to develop the conformationally correct HIV envelope epitopes that, when used as immunogens, would direct the immune response of an uninfected individual

to the production of broadly neutralizing antibodies over a reasonable

time frame by sequential immunizations. It remains to be seen whether

this approach will be feasible.

■ FURTHER READING

Bekker LG et al: The complex challenges of HIV vaccine development

require renewed and expanded global commitment. Lancet 395:384,

2020.

Centers for Disease Control and Prevention (CDC): HIV risk

and prevention. Available at www.cdc.gov/hiv/risk/.

Centers for Disease Control and Prevention (CDC): HIV prevention in the United States: Mobilizing to end the epidemic. Available at www.cdc.gov/hiv/pdf/policies/cdc-hiv-prevention-bluebook.pdf.

Cohn LB et al: Biology of the HIV-1 latent reservoir and implications

for cure strategies. Cell Host Microbe 27:519, 2020.

Collins DR et al: CD8+ T cells in HIV control, cure and prevention.

Nat Rev Immunol 20:471, 2020.

Eisinger RW et al: Ending the human immunodeficiency virus pandemic: Optimizing the prevention and treatment toolkits. Clin Infect

Dis 69:2212, 2019.

Eisinger RW et al: HIV viral load and transmissibility of HIV infection: Undetectable equals untransmittable. JAMA 321:451, 2019.

Elliott T et al: Challenges of HIV diagnosis and management in the

context of pre-exposure prophylaxis (PrEP), post-exposure prophylaxis (PEP), test and start and acute HIV infection: A scoping review.

J Int AIDS Soc 22:e25419, 2019.

Fauci AS, Lane HC: Four decades of HIV/AIDS—much accomplished, much to do. N Engl J Med 383:1, 2020.

1597CHAPTER 203 Viral Gastroenteritis

Haynes BF et al: Multiple roles for HIV broadly neutralizing antibodies. Sci Transl Med 11:eaaz2686, 2019.

Kazer SW: Evolution and diversity of immune responses during acute

HIV Infection. Immunity 53:908, 2020.

Moir S, Fauci AS: B-cell responses to HIV infection. Immunol Rev

275:33, 2017.

Panel on Opportunistic Infections in Adults and

Adolescents with HIV: Guidelines for the Prevention and

Treatment of Opportunistic Infections in Adults and Adolescents

with HIV. Available at clinicalinfo.hiv.gov/en/guidelines/adult-andadolescent-opportunistic-infection/whats-new-guidelines.

Saez-Cirion A, Sereti I: Immunometabolism and HIV-1 pathogenesis: Food for thought. Nat Rev Immunol 21:5, 2021.

Thompson ME et al: Primary care guidance for persons with human

immunodeficiency virus: 2020 update by the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis

Nov 6, 2020 [Epub ahead of print].

UN Joint Programme On HIV/AIDS (UNAIDS): 2021 UNAIDS

Global AIDS Update – Confronting inequalities – Lessons for pandemic responses from 40 years of AIDS. Available at https://www.

unaids.org/en/resources/documents/2021/2021-global-aids-update.

U.S. Department of Health and Human Services Panel on

Antiretroviral Guidelines for Adults and Adolescents:

Guidelines for the use of antiretroviral agents in adults and adolescents living with HIV. Available at clinicalinfo.hiv.gov/en/guidelines/

adult-and-adolescent-arv/whats-new-guidelines.

Section 15 Infections Due to RNA Viruses

203

Acute infectious gastroenteritis is a common illness that affects persons

of all ages worldwide. It is a leading cause of death among children in

developing countries, accounting for an estimated 0.5 million deaths

each year, and is responsible for up to 6–8% of all hospitalizations

among children in industrialized countries, including the United States.

Elderly persons, especially those with debilitating health conditions,

also are at risk of severe complications and death from acute gastroenteritis. Among healthy young adults, acute gastroenteritis is rarely fatal

but incurs substantial medical and social costs, including those of time

lost from work.

Several enteric viruses have been recognized as important etiologic

agents of acute infectious gastroenteritis (Table 203-1, Fig. 203-1).

Although most viral gastroenteritis is caused by RNA viruses, the

DNA viruses that are occasionally involved (e.g., adenovirus types 40

and 41) are included in this chapter. Illness caused by these viruses is

characterized by the acute onset of vomiting and/or diarrhea, which

may be accompanied by fever, nausea, abdominal cramps, anorexia,

Viral Gastroenteritis

Umesh D. Parashar, Roger I. Glass

TABLE 203-1 Viral Causes of Gastroenteritis Among Humans

VIRUS FAMILY GENOME

PRIMARY AGE GROUP

AT RISK

CLINICAL

SEVERITY DETECTION ASSAYS

Group A rotavirus Reoviridae Double-strand segmented RNA Children <5 years + + + EM, EIA (commercial), PAGE, RT-PCR

Norovirus Caliciviridae Positive-sense single-strand RNA All ages + + EM, RT-PCR

Sapovirus Caliciviridae Positive-sense single-strand RNA Children <5 years + EM, RT-PCR

Astrovirus Astroviridae Positive-sense single-strand RNA Children <5 years + EM, EIA, RT-PCR

Adenovirus (mainly

types 40 and 41)

Adenoviridae Double-strand DNA Children <5 years +/+ + EM, EIA (commercial), PCR

Abbreviations: EIA, enzyme immunoassay; EM, electron microscopy; PAGE, polyacrylamide gel electrophoresis; PCR, polymerase chain reaction; RT-PCR, reverse-transcription PCR.

and malaise. As shown in Table 203-2, several features can help distinguish gastroenteritis caused by viruses from that caused by bacterial

agents. However, the distinction based on clinical and epidemiologic

parameters alone is often difficult, and laboratory tests are required to

confirm the diagnosis.

■ HUMAN CALICIVIRUSES

Etiologic Agent The Norwalk virus is the prototype strain of a

group of small (27–40 nm), nonenveloped, round, icosahedral viruses

with relatively amorphous surface features on visualization by electron

microscopy. Molecular cloning and characterization have demonstrated that the viruses have a single, positive-strand RNA genome

~7.5 kb in length and possess a single virion-associated protein—

similar to that of typical caliciviruses—with a molecular mass of 60

kDa. On the basis of these molecular characteristics, these viruses

are presently classified into two genera belonging to the family

Caliciviridae, the noroviruses and the sapoviruses (previously called

Norwalk-like viruses and Sapporo-like viruses, respectively), which are

further classified into genogroups and genotypes. Of the 10 recognized

norovirus genogroups in humans and animals, 35 different genotypes

belonging to 5 genogroups (GI, GII, GIV, GVIII, and GIX) are known

to infect humans.

Epidemiology Infections with the Norwalk and related human

caliciviruses are common worldwide, and most adults have antibodies

to these viruses. Antibody is acquired at an earlier age in developing

countries—a pattern consistent with the presumed fecal–oral mode

of transmission. Infections occur year-round, although, in temperate

climates, a distinct increase has been noted in cold-weather months.

Noroviruses may be the most common infectious agents of mild gastroenteritis in the community and affect all age groups, whereas sapoviruses primarily cause gastroenteritis in children. Noroviruses also

cause traveler’s diarrhea, and outbreaks have occurred among military

personnel deployed to various parts of the world. The limited data

available indicate that norovirus may be the second most common viral

agent (after rotavirus) among young children and the most common

agent among older children and adults. In the United States and some

other developed countries, with the decline in severe rotavirus disease

following implementation of a rotavirus vaccination program, norovirus has become the leading cause of medically attended gastroenteritis

in young children. Noroviruses are also recognized as the major cause

of epidemics of gastroenteritis worldwide. In the United States, ~50%

of all reported outbreaks of gastroenteritis are caused by noroviruses.

Norovirus is transmitted predominantly by the fecal–oral route

but is also present in vomitus. Because an inoculum with very few

viruses can be infectious, transmission can occur by aerosolization, by

contact with contaminated fomites, and by person-to-person contact.

Viral shedding and infectivity are greatest during the acute illness, but

challenge studies with Norwalk virus in volunteers indicate that viral

antigen may be shed by asymptomatically infected persons and also

by symptomatic persons before the onset of symptoms and for several

weeks after the resolution of illness. Viral shedding can be prolonged

in immunocompromised individuals.

Pathogenesis The exact sites and cellular receptors for attachment of viral particles have not been determined. Data suggest that

1598 PART 5 Infectious Diseases

incubation period of 24 h (range, 12–72 h). The illness generally lasts

12–60 h and is characterized by one or more of the following symptoms: nausea, vomiting, abdominal cramps, and diarrhea. Vomiting is

more prevalent among children, whereas a greater proportion of adults

develop diarrhea. Constitutional symptoms are common, including

headache, fever, chills, and myalgias. The stools are characteristically

loose and watery, without blood, mucus, or leukocytes. White cell

counts are generally normal; rarely, leukocytosis with relative lymphopenia may be observed. Death is a rare outcome and usually results

from severe dehydration in vulnerable persons (e.g., elderly patients

with debilitating health conditions).

Immunity Approximately 50% of persons challenged with Norwalk

virus become ill and acquire short-term immunity against the infecting

strain. In early human volunteer studies, immunity to Norwalk virus

appeared to correlate inversely with level of antibody; i.e., persons

with higher levels of preexisting antibody to Norwalk virus were more

susceptible to illness on rechallenge. This paradoxical observation was

later explained by data indicating that some individuals have a genetic

carbohydrates that are similar to human histo-blood group antigens

(HBGA) and are present on the gastroduodenal epithelium of individuals with the secretor phenotype may serve as ligands for the attachment

of Norwalk virus. Additional studies must more fully elucidate norovirus–

carbohydrate interactions, including strain-specific variations. After

the infection of volunteers, reversible lesions are noted in the upper

jejunum, with broadening and blunting of the villi, shortening of the

microvilli, vacuolization of the lining epithelium, crypt hyperplasia,

and infiltration of the lamina propria by polymorphonuclear neutrophils and lymphocytes. The lesions persist for at least 4 days after

the resolution of symptoms and are associated with malabsorption of

carbohydrates and fats and a decreased level of brush-border enzymes.

Adenylate cyclase activity is not altered. No histopathologic changes

are seen in the stomach or colon, but gastric motor function is delayed,

and this alteration is believed to contribute to the nausea and vomiting

that are typical of this illness.

Clinical Manifestations Gastroenteritis caused by Norwalk and

related human caliciviruses has a sudden onset following an average

FIGURE 203-1 Viral agents of gastroenteritis. NV, norovirus; SV, sapovirus.

TABLE 203-2 Characteristics of Gastroenteritis Caused by Viral and Bacterial Agents

FEATURE VIRAL GASTROENTERITIS BACTERIAL GASTROENTERITIS

Setting Incidence similar in developing and developed

countries

More common in settings with poor hygiene and sanitation

Infectious dose Low (10–100 viral particles) for most agents High (>105

 bacteria) for Escherichia coli, Salmonella, Vibrio; medium (102

–105

 bacteria) for

Campylobacter jejuni; low (10–100 bacteria) for Shigella

Seasonality In temperate climates, winter seasonality for most

agents; year-round occurrence in tropical areas

More common in summer or rainy months, particularly in developing countries with a high

disease burden

Incubation period 1–3 days for most agents; can be shorter for

norovirus

1–7 days for common agents (e.g., Campylobacter, E. coli, Shigella, Salmonella); a few hours

for bacteria producing preformed toxins (e.g., Staphylococcus aureus, Bacillus cereus)

Reservoir Primarily humans Depending on bacterial species, human (e.g., Shigella, Salmonella), animal

(e.g., Campylobacter, Salmonella, E. coli), and water (e.g., Vibrio) reservoirs exist

Fever Common with rotavirus and norovirus; uncommon

with other agents

Common with agents causing inflammatory diarrhea (e.g., Salmonella, Shigella)

Vomiting Prominent and can be the only presenting feature,

especially in children

Common with bacteria producing preformed toxins; less prominent in diarrhea due to other

agents

Diarrhea Common; non-bloody in almost all cases Prominent and occasionally bloody with agents causing inflammatory diarrhea

Duration 1–3 days for norovirus and sapovirus; 2–8 days for

other viruses

1–2 days for bacteria producing preformed toxins; 2–8 days for most other bacteria

Diagnosis This is often a diagnosis of exclusion in clinical

practice. Commercial enzyme immunoassays are

available for detection of rotavirus and adenovirus,

but identification of other agents is limited to

research and public health laboratories.

Fecal examination for leukocytes and blood is helpful in differential diagnosis. Culture of

stool specimens, sometimes on special media, can identify several pathogens. Molecular

techniques are useful epidemiologic tools but are not routinely used in most laboratories.

Treatment Supportive therapy to maintain adequate hydration

and nutrition should be given. Antibiotics and

antimotility agents are contraindicated.

Supportive hydration therapy is adequate for most patients. Antibiotics are recommended

for patients with dysentery caused by Shigella or diarrhea caused by Vibrio cholerae and for

some patients with Clostridium difficile colitis.

1599CHAPTER 203 Viral Gastroenteritis

predisposition to illness, with specific HBGA phenotypes influencing

susceptibility to norovirus infection. Contemporary data show that

functional antibodies that block norovirus binding to HBGAs correlate with protective immunity in human volunteer challenge and

vaccination studies. Furthermore, initial studies have demonstrated

that norovirus grown in vitro in the newly developed human intestinal

enteroid (HIE) cell-based system can be neutralized by sera containing

blocking antibodies.

Diagnosis Cloning and sequencing of the genomes of Norwalk and

several other human caliciviruses have allowed the development of

assays based on polymerase chain reaction (PCR) for detection of virus

in stool and vomitus. Virus-like particles (VLPs) produced by expression

of capsid proteins in a recombinant baculovirus vector have been used

to develop enzyme immunoassays (EIAs) for detection of virus in stool

or a serologic response to a specific viral antigen. These newer diagnostic techniques are considerably more sensitive than previous detection

methods, such as electron microscopy, immune electron microscopy,

and EIAs based on reagents derived from humans. However, given that

these single-stranded RNA viruses show great antigenic and genetic

diversity, no currently available single assay can detect all human caliciviruses. In addition, the assays are still cumbersome and are available

primarily in research laboratories, although they are increasingly being

adopted by public health laboratories for routine screening of fecal specimens from patients affected by outbreaks of gastroenteritis. Commercial EIA kits have limited sensitivity and usefulness in clinical practice

and are of greatest utility in outbreaks, in which many specimens are

tested and only a few need be positive to identify norovirus as the cause.

TREATMENT

Infections with Norwalk and Related Human

Caliciviruses

The disease is self-limited, and oral rehydration therapy is generally

adequate. If severe dehydration develops, IV fluid therapy is indicated. No specific antiviral therapy is available.

Prevention Epidemic prevention relies on situation-specific measures, such as control of contamination of food and water, exclusion of

ill food handlers, and reduction of person-to-person spread through

good personal hygiene and disinfection of contaminated fomites. The

role of immunoprophylaxis is not clear, given the lack of long-term

immunity from natural disease, but efforts to develop norovirus vaccines are ongoing. Vaccines based on VLPs are being tested in human

volunteers. In a proof-of-concept trial, the efficacy of a monovalent

GI.1 VLP vaccine was 47% among volunteers who received the vaccine

intranasally and were then challenged with a homologous strain. In a

second trial, norovirus disease severity was reduced in volunteers who

received a bivalent G1.1/GII.4 VLP vaccine intramuscularly (with the

GII.4 component including a consensus sequence from three different

GII.4 strains) and were subsequently challenged with a GII.4 norovirus

strain. Data from the first field efficacy study of this bivalent vaccine

conducted in ~4700 healthy U.S. Navy recruits given one intramuscular

injection of the bivalent vaccine were recently reported. While the primary endpoint of protection against homotypic infection could not be

evaluated because only six total moderate/severe cases due to GI.1 or

GII.4 norovirus strains occurred during the trial, the vaccine efficacy

was 61.8% (95.01% confidence interval, 20.8–81.6%) for moderate/

severe norovirus acute gastroenteritis due to any type. These initial data

are encouraging; however, key issues to be further studied include the

duration of protection and the level of heterotypic protection against

antigenically distinct strains, particularly given the continuing and rapid

natural evolution leading to the emergence of novel norovirus strains.

■ ROTAVIRUS

Etiologic Agent Rotaviruses are members of the family Reoviridae. The viral genome consists of 11 segments of double-strand RNA

that is enclosed in a triple-layered, nonenveloped, icosahedral capsid

75 nm in diameter. Viral protein 6 (VP6), the major structural protein, is the target of commercial immunoassays and determines the

group specificity of rotaviruses. Seven major groups of rotavirus (A

through G) exist; human illness is caused primarily by group A and,

to a much lesser extent, by groups B and C. Two outer-capsid proteins,

VP7 (G-protein) and VP4 (P-protein), determine serotype specificity,

induce neutralizing antibodies, and form the basis for binary classification of rotaviruses (G and P types). The segmented genome of rotavirus allows genetic reassortment (i.e., exchange of genome segments

between viruses) during co-infection—a property that plays a role in

viral evolution and that has been utilized in the development of reassortant animal/human rotavirus–based vaccines.

Epidemiology Worldwide, nearly all children are infected with

rotavirus by 3–5 years of age. Neonatal infections are common but

are often asymptomatic or mild, presumably because of protection by

maternal antibody or breast milk. Compared with rotavirus disease in

industrialized countries, disease in developing countries occurs at a

younger age, is less seasonal, is more frequently caused by uncommon

or multiple rotavirus strains, and is more often fatal. Moreover, because

of suboptimal access to hydration therapy, rotavirus is a leading cause

of diarrheal death among children in the developing world, with the

highest mortality rates among children in sub-Saharan Africa and

southern Asia (Fig. 203-2).

First infections after 3 months of age are likely to be symptomatic,

and the incidence of disease peaks among children 4–23 months of

age. Reinfections are common, but the severity of disease decreases

with each repeat infection. Therefore, severe rotavirus infections are

less common among older children and adults than among younger

individuals. Nevertheless, rotavirus can cause illness in parents and

caretakers of children with rotavirus diarrhea, immunocompromised

persons, travelers, and elderly individuals and should be considered in

the differential diagnosis of gastroenteritis among adults.

In tropical settings, rotavirus disease occurs year-round, with less

pronounced seasonal peaks than in temperate settings, where rotavirus

disease occurs predominantly during the cooler fall and winter months.

Before the introduction of rotavirus vaccine in the United States, the

rotavirus season each year began in the Southwest during the autumn

and early winter (October through December) and migrated across

the continent, peaking in the Northeast during late winter and spring

(March through May). The reasons for this characteristic pattern are

not clear but may be correlated with state-specific differences in birth

rates, which could influence the rate of accumulation of susceptible

infants after each rotavirus season. After the implementation of routine

vaccination of U.S. infants against rotavirus in 2006, the characteristic

prevaccine geotemporal pattern of U.S. rotavirus was dramatically

altered, and these changes were accompanied by substantial declines

in rotavirus detections by a national network of sentinel laboratories.

In addition, a pattern of biennial increases in rotavirus activity has

emerged during postvaccine seasons.

During episodes of rotavirus-associated diarrhea, virus is shed in

large quantities in stool (107

–1012/g). Viral shedding detectable by EIA

usually subsides within 1 week but may persist for >30 days in immunocompromised individuals; it may be detected for longer periods by

sensitive molecular assays, such as PCR. The virus is transmitted predominantly through the fecal–oral route. Spread through respiratory

secretions, person-to-person contact, or contaminated environmental

surfaces has been postulated to explain the rapid acquisition of antibody

in the first 3 years of life, regardless of sanitary conditions.

At least 10 different G serotypes of group A rotavirus have been identified in humans, but only 5 types (G1 through G4 and G9) are common.

While human rotavirus strains that possess a high degree of genetic

homology with animal strains have been identified, animal-to-human

transmission appears to be uncommon.

Group B rotaviruses have been associated with several large epidemics of severe gastroenteritis among adults in China since 1982 and have

also been identified in India. Group C rotaviruses have been associated

with a small proportion of pediatric gastroenteritis cases in several

countries worldwide.

1600 PART 5 Infectious Diseases

Rates per 100,000 PY: 0 to <10

10 to <50

50 to <100

≥100

FIGURE 203-2 Rotavirus mortality rates by country, per 100,000 children <5 years of age. (From JE Tate et al: Global, regional, and national estimates of rotavirus mortality

in children <5 years of age, 2000-2013. Clin Infect Dis 62(Suppl 2):S96, 2016.)

Pathogenesis Rotaviruses infect and ultimately destroy mature

enterocytes in the villous epithelium of the proximal small intestine.

The loss of absorptive villous epithelium, coupled with the proliferation of secretory crypt cells, results in secretory diarrhea. Brush-border

enzymes characteristic of differentiated cells are reduced, and this

change leads to the accumulation of unmetabolized disaccharides and

consequent osmotic diarrhea. Studies in mice indicate that a nonstructural rotavirus protein, NSP4, functions as an enterotoxin and

contributes to secretory diarrhea by altering epithelial cell function and

permeability. In addition, rotavirus may evoke fluid secretion through

activation of the enteric nervous system in the intestinal wall. Data

indicate that rotavirus antigenemia and viremia are common among

children with acute rotavirus infection, although the antigen and RNA

levels in serum are substantially lower than those in stool.

Clinical Manifestations The clinical spectrum of rotavirus infection ranges from subclinical infection to severe gastroenteritis leading

to life-threatening dehydration. After an incubation period of 1–3 days,

the illness has an abrupt onset, with vomiting frequently preceding the

onset of diarrhea. Up to one-third of patients may have a temperature

of >39°C. The stools are characteristically loose and watery and only

infrequently contain red or white cells. Gastrointestinal symptoms

generally resolve in 3–7 days.

Respiratory and neurologic features in children with rotavirus

infection have been reported, but causal associations have not been

proven. Moreover, rotavirus infection has been associated with a variety of other clinical conditions (e.g., sudden infant death syndrome,

necrotizing enterocolitis, intussusception, Kawasaki disease, and type 1

diabetes), but no causal relationship has been confirmed with any of

these syndromes.

Rotavirus does not appear to be a major opportunistic pathogen in

children with HIV infection. In severely immunodeficient children,

rotavirus can cause protracted diarrhea with prolonged viral excretion

and, in rare instances, can disseminate systemically. Persons who are

immunosuppressed for bone marrow transplantation also are at risk

for severe or even fatal rotavirus disease.

Immunity Protection against rotavirus disease is correlated with

the presence of virus-specific secretory IgA antibodies in the intestine

and, to some extent, the serum. Because virus-specific IgA production

at the intestinal surface is short-lived, complete protection against

disease is only temporary. However, each infection and subsequent

reinfection confers progressively greater immunity; thus, severe disease

is most common among young children with first or second infections.

Immunologic memory is believed to be important in the attenuation of

disease severity upon reinfection.

Diagnosis Illness caused by rotavirus is difficult to distinguish

clinically from that caused by other enteric viruses. Because large quantities of virus are shed in feces, the diagnosis can usually be confirmed

by a wide variety of commercially available EIAs or by techniques for

detecting viral RNA, such as gel electrophoresis, probe hybridization,

or PCR.

TREATMENT

Rotavirus Infections

Rotavirus gastroenteritis can lead to severe dehydration. Thus,

appropriate treatment should be instituted early. Standard oral rehydration therapy is successful for most children who can take fluids

by mouth, but IV fluid replacement may be required for patients

who are severely dehydrated or are unable to tolerate oral therapy

because of frequent vomiting. The therapeutic roles of probiotics,

bismuth subsalicylate, enkephalinase inhibitors, and nitazoxanide

have been evaluated in clinical studies but are not clearly defined.

Antibiotics and antimotility agents should be avoided. In immunocompromised children with chronic symptomatic rotavirus disease,

orally administered immunoglobulins or colostrum may result in

the resolution of symptoms, but the best choices regarding agents

and their doses have not been well studied, and treatment decisions

are often empirical.

Prevention Efforts to develop rotavirus vaccines were pursued

because it was apparent—given the similar rates in less developed and

industrialized nations—that improvements in hygiene and sanitation

were unlikely to reduce disease incidence. The first rotavirus vaccine

1601CHAPTER 203 Viral Gastroenteritis

licensed in the United States in 1998 was withdrawn from the market

within 1 year because it was linked with a low incidence of intussusception, a form of bowel obstruction.

In 2006, promising safety and efficacy (85−98% against severe

rotavirus disease) data for two new rotavirus vaccines—RotaTeq

(Merck, United States) and Rotarix (GlaxoSmithKline, Belgium)—

were reported from large clinical trials conducted in North America,

Europe, and Latin America. Both vaccines are now recommended for

routine immunization of all U.S. infants, and their use has rapidly led

to a >70–80% decline in rotavirus hospitalizations and emergency

department visits at hospitals across the United States. Somewhat

unexpectedly, rotavirus vaccination of young infants has also resulted

in the added benefit of declines in rotavirus disease among children

who miss vaccination and even among older children and adults who

are not eligible for vaccination in some settings. The reason is likely

to be a reduction in community transmission of rotavirus because of

vaccination—i.e., herd protection. In April 2009, the World Health

Organization (WHO) recommended the use of rotavirus vaccines in all

countries worldwide. As of May 2020, nearly 100 countries, including

several low-income countries in Africa and Asia, have incorporated

rotavirus vaccine into their national childhood immunization programs (Fig. 203-3). Large declines in severe morbidity and mortality

from childhood diarrhea have been documented in many countries.

Postmarketing surveillance has identified a low risk of intussusception in some countries; however, the benefits of vaccination exceed

the risks, and no changes in vaccine administration policy have been

implemented.

The different epidemiology of rotavirus disease and the greater

prevalence of co-infection with other enteric pathogens, of comorbidities, and of malnutrition in developing countries may adversely affect

the performance of oral rotavirus vaccines, as is the case with oral

vaccines against poliomyelitis, cholera, and typhoid in these regions.

Therefore, evaluation of the efficacy of rotavirus vaccines in resourcepoor settings of Africa and Asia was specifically recommended, and

these trials have now been completed. As anticipated, the efficacy of

rotavirus vaccines was moderate (50–65%) in these settings when compared with that in industrialized countries. Despite modest efficacy,

routine use of rotavirus vaccines in low-income African countries with

a heavy disease burden has yielded substantial public health benefits.

Several manufacturers in emerging markets, including India, China,

Vietnam, Indonesia, and Brazil, are developing candidate rotavirus

vaccines. Beginning in 2016, two Indian-made rotavirus vaccines—Rotavac

(Bharat Biotech, India) and Rotasiil (Serum Institute, India)—were

implemented in India’s routine childhood immunization program,

which has since expanded to all Indian states with a birth cohort of

>25 million. In trials conducted in low-income countries, the efficacy

of Rotavac and Rotasiil ranged from 36 to 66%, similar to the efficacy

of multinational vaccines in these settings. In 2018, these two vaccines

were prequalified by WHO, allowing their procurement with funding

support from Gavi, the Vaccine Alliance, in low-income countries

outside India.

■ OTHER VIRAL AGENTS OF GASTROENTERITIS

Enteric adenoviruses of serotypes 40 and 41 belonging to subgroup F

are 70- to 80-nm viruses with double-strand DNA that cause ~2–12%

of all diarrhea episodes in young children. Unlike adenoviruses that

cause respiratory illness, enteric adenoviruses are difficult to cultivate

in cell lines, but they can be detected with commercially available

EIAs. Adenovirus types 31 and 42–49 have been linked to diarrhea in

HIV-infected and other immunocompromised persons.

Astroviruses are 28- to 30-nm viruses with a characteristic icosahedral structure and a positive-sense, single-strand RNA. At least seven

serotypes have been identified, of which serotype 1 is most common.

Astroviruses are primarily pediatric pathogens, causing ~2–10% of

cases of mild to moderate gastroenteritis in children. The availability

of simple immunoassays to detect virus in fecal specimens and of

molecular methods to confirm and characterize strains will permit

more comprehensive assessment of the etiologic role of these agents.

Toroviruses are 100- to 140-nm, enveloped, positive-strand RNA

viruses that are recognized as causes of gastroenteritis in horses (Berne

virus) and cattle (Breda virus). Their role as a cause of diarrhea in

humans is still unclear, but studies from Canada have demonstrated

associations between torovirus excretion and both nosocomial gastroenteritis and necrotizing enterocolitis in neonates. These associations require further evaluation.

Picobirnaviruses are small, bisegmented, double-strand RNA viruses

that cause gastroenteritis in a variety of animals. Their role as primary

causes of gastroenteritis in humans remains unclear, but several studies

have found an association between picobirnaviruses and gastroenteritis

in HIV-infected adults.

Several other viruses (e.g., enteroviruses, reoviruses, pestiviruses,

aichivirus, and parvovirus B) have been identified in the feces of

patients with diarrhea, but their etiologic role in gastroenteritis has

not been proven. Diarrhea has also been noted as a manifestation of

Rotavirus Vaccine

Status

Introduced

Not Introduced

FIGURE 203-3 Countries that have implemented national rotavirus vaccination programs, December 31, 2019. (Source: View-Hub, http://www.view-hub.org/viz/.)

1602 PART 5 Infectious Diseases

infection with recently recognized viruses that primarily cause severe

respiratory illness: the SARS-CoV, influenza A/H5N1 virus, and the

current pandemic strain of influenza A/H1N1 virus.

■ FURTHER READING

Banyai K et al: Viral Gastroenteritis. Lancet 392:175, 2018.

Burke R et al: Current and new rotavirus vaccines. Curr Opin Infect

Dis 32:435, 2019.

Burke R et al: The burden of norovirus in the United States, as estimated based on administrative data: Updates for medically attended

illness and mortality, 2001–2015. Clin Infect Dis 14:ciaa438, 2020.

Burnett E et al: Global impact of rotavirus vaccination on diarrhea

hospitalizations and deaths among children <5 years old: 2006-2019.

J Infect Dis 222:1731, 2020.

Tate JE et al: Global, regional, and national estimates of rotavirus mortality in children <5 years of age, 2000–2013. Clin Infect Dis 62(Suppl 2):

S96, 2016.

ENTEROVIRUSES

■ CLASSIFICATION AND CHARACTERIZATION

Enteroviruses, members of the family Picornaviridae, are so designated

because of their ability to multiply in the gastrointestinal tract. Despite

their name, these viruses are not a prominent cause of gastroenteritis.

Enteroviruses encompass more than 115 human serotypes: 3 serotypes of poliovirus, 23 serotypes of coxsackievirus A, 6 serotypes of

coxsackievirus B, 29 serotypes of echovirus, enteroviruses 68–71, and

multiple new enteroviruses (beginning with enterovirus 73) that have

been identified by molecular techniques. Human enteroviruses have

been reclassified into four species designated A–D. Echoviruses 22

and 23 have been reclassified as parechoviruses 1 and 2 on the basis

of low nucleotide homology and differences in viral proteins. Enterovirus and parechovirus surveillance conducted in the United States by

the Centers for Disease Control and Prevention (CDC) in 2014−2016

showed that the most common enteroviruses and parechoviruses were

enterovirus D68 (55.9% of cases), followed in frequency by echovirus

30, coxsackievirus A6, echovirus 18, and coxsackievirus B3, which

accounted for 75% of all isolates.

Human enteroviruses contain a single-stranded RNA genome surrounded by an icosahedral capsid comprising four viral proteins. These

viruses have no lipid envelope and are stable in acidic environments,

including the stomach. They are susceptible to chlorine-containing

cleansers but resistant to inactivation by standard disinfectants (e.g.,

alcohol, detergents) and can persist for days at room temperature.

■ PATHOGENESIS AND IMMUNITY

Much of what is known about the pathogenesis of enteroviruses has

been derived from studies of poliovirus infection. After ingestion,

poliovirus is thought to infect epithelial cells in the mucosa of the

gastrointestinal tract and then to spread to and replicate in the submucosal lymphoid tissue of the tonsils and Peyer’s patches. The virus next

spreads to the regional lymph nodes, a viremic phase ensues, and the

virus replicates in organs of the reticuloendothelial system. In some

cases, a second episode of viremia occurs and the virus replicates further in various tissues, sometimes causing symptomatic disease.

It is uncertain whether poliovirus reaches the central nervous system

(CNS) during viremia or whether it also spreads via peripheral nerves.

204 Enterovirus, Parechovirus,

and Reovirus Infections

Jeffrey I. Cohen

Since viremia precedes the onset of neurologic disease in humans, it

has been assumed that the virus enters the CNS via the bloodstream.

The poliovirus receptor is a member of the immunoglobulin superfamily. Poliovirus infection is limited to primates, largely because their

cells express the viral receptor. Studies demonstrating the poliovirus

receptor in the end-plate region of muscle at the neuromuscular junction suggest that, if the virus enters the muscle during viremia, it could

travel across the neuromuscular junction up the axon to the anterior

horn cells. Studies of monkeys and of transgenic mice expressing the

poliovirus receptor show that, after IM injection, poliovirus does not

reach the spinal cord if the sciatic nerve is cut. Taken together, these

findings suggest that poliovirus can spread directly from muscle to the

CNS by neural pathways.

Poliovirus can usually be cultured from the blood 3–5 days after

infection, before the development of neutralizing antibodies. While

viral replication at secondary sites begins to slow 1 week after infection,

it continues in the gastrointestinal tract. Poliovirus is shed from the

oropharynx for up to 3 weeks after infection and from the gastrointestinal tract for as long as 12 weeks; hypogammaglobulinemic patients

can shed poliovirus for >20 years. During replication in the gastrointestinal tract, attenuated oral poliovirus can mutate, reverting to a

more neurovirulent phenotype within a few days; however, additional

mutations are probably required for full neurovirulence. One patient

with hypogammaglobulinemia who had been infected 12 years earlier

and was receiving IV immune globulin suddenly developed quadriplegia and respiratory muscle paralysis and died; analysis showed that the

virus had reverted to a more wild-type sequence.

Humoral and secretory immunity in the gastrointestinal tract is

important for the control of enterovirus infections. Enteroviruses

induce specific IgM, which usually persists for <6 months, and specific

IgG, which persists for life. Capsid protein VP1 is the predominant

target of neutralizing antibody, which generally confers lifelong protection against subsequent disease caused by the same serotype but

does not prevent infection or virus shedding. Enteroviruses also induce

cellular immunity of uncertain significance. Patients with impaired

cellular immunity are not known to develop unusually severe disease

when infected with enteroviruses. In contrast, the severe infections

in patients with agammaglobulinemia emphasize the importance of

humoral immunity in controlling enterovirus infections. Disseminated

enterovirus infections have occurred in hematopoietic cell transplant

recipients. IgA antibodies are instrumental in reducing poliovirus

replication in and shedding from the gastrointestinal tract. Breast milk

contains IgA specific for enteroviruses and can protect humans from

infection.

■ EPIDEMIOLOGY

Enteroviruses have a worldwide distribution. More than 50% of nonpoliovirus enterovirus infections and >90% of poliovirus infections are

subclinical. When symptoms do develop, they are usually nonspecific

and occur in conjunction with fever; only a minority of infections are

associated with specific clinical syndromes. The incubation period for

most enterovirus infections ranges from 2 to 14 days but usually is

<1 week.

Enterovirus infection is more common in socioeconomically disadvantaged areas, especially in those where conditions are crowded

and in tropical areas where hygiene is poor. Infection is most common

among infants and young children; serious illness develops most often

during the first few days of life and in older children and adults. In

developing countries, where children are infected at an early age,

poliovirus infection has less often been associated with paralysis; in

countries with better hygiene, older children and adults are more likely

to be seronegative, become infected, and develop paralysis. Passively

acquired maternal antibody reduces the risk of symptomatic infection

in neonates. Young children are the most frequent shedders of enteroviruses and are usually the index cases in family outbreaks. In temperate climates, enterovirus infections occur most often in the summer

and fall; no seasonal pattern is apparent in the tropics.

Most enteroviruses are transmitted primarily by the fecal–oral or

oral–oral route. Patients are most infectious shortly before and after