Case Based Pediatrics For Medical Students and Residents
Department of Pediatrics, University of Hawaii John A. Burns School of Medicine
Chapter VI.1. Virology
Loren G. Yamamoto, MD, MPH, MBA
February 2003

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A 5 year old boy is seen in the office with a history of fever, body aches and nausea. His temperature at home was 39 degrees (102.2 degrees F). He was treated with acetaminophen which resulted in normalization of his temperature and improvement in his body aches. He has been taking fluids without vomiting. He has a slight cough and nasal congestion, but no sore throat, headache, diarrhea, abdominal pain, or urinary complaints.

Exam: T37.2, P80, R25, BP 90/60, oxygen saturation 100% in room air. Height and weight are at the 50th percentile. He is alert, active and cooperative. He is not toxic and not irritable. His exam findings are unremarkable except for nasal congestion.

You tell his mother that he has a virus infection, which is something like a flu type of illness. She says, "That's what he had two weeks ago. How can he keep getting the same virus over and over again? What's the name of this virus anyway? How can he get rid of it?" You explain that this is not the same virus, that there are many different viruses, and that his immune system eventually clears the virus from his system. But he is still susceptible to many other viruses. You're not really sure of the name for his current virus, but we don't have any antiviral treatments for this virus anyway.


While most clinicians have a fairly good background of bacteriology, our knowledge of viruses is usually not as good. Optimal use of antibiotics improves with knowledge of bacteriology. Since we don't have many antiviral agents, it is generally unnecessary (from a therapeutic decision standpoint) to be able to distinguish most of these viruses. However, in the future, as more antiviral agents become available, we will need to improve our knowledge of virology to optimally utilize these future antiviral agents.

Similar to bacteria which can be basically classified using gram stain and morphology, viruses can be classified based on their envelope and nucleic acid type. Viruses are obligate intracellular organisms which utilize the host cell for varying degrees of viral replication. They can only be grown in cell culture media. They are too small to see with a light microscope, but the "cytopathic effect" on the cells in the cell culture media can be seen with a light microscope. Other clinical laboratory methods to identify the presence of viruses are: immunologic assays, antibody serology, polymerase chain reaction (PCR) to detect nucleic acid, detection of reverse transcriptase and electron microscopy.

Viruses are either naked or enveloped. All naked virus have an icosahedral head shape. All enveloped viruses utilize the host cell's membrane by budding off a section to create its envelope. In general, there are four types of disease patterns produced by viruses: 1) acute infection, 2) chronic infection, 3) latent infection, and 4) post-infectious or para-infectious phenomena. Acute infection is caused by naked viruses or enveloped viruses. They kill cells as more viral particles are released. Chronic infection, which is the chronic continued release of viral particles lasting 6 months or more, can only be caused by enveloped viruses such as hepatitis B and HIV. Naked viruses cannot cause chronic infection. Latent infections result when the viral nucleic acid sequence is incorporated into the cell, but the cell is not actively producing viral particles unless it is somehow reactivated in the future. Latent infections, such as with Herpes simplex, are characterized by recurrent episodes of clinical infection. Post and para-infectious phenomena are the result of the body's immune system damaging the host cells and tissues in an effort to get rid of the virus. This is most clinically evident in encephalitis and myocarditis.

The nucleic acid of viruses can be either DNA, +RNA, -RNA, retroviral RNA, or double stranded RNA. DNA viruses usually utilize double stranded DNA (dsDNA) which separates and replicates to form new dsDNA for the new viral particles. Some viruses utilize single stranded DNA (ssDNA). +RNA contains a single stranded RNA which is directly utilized as a messenger RNA (mRNA) to synthesize viral proteins using the host ribosomes. -RNA contains a single stranded RNA which is used as a template for a virion associated polymerase to transcribe an mRNA strand which then uses the host ribosomes to synthesize viral proteins. Retroviral RNA viruses contain a single strand of RNA and a virion associated reverse transcriptase which is used to synthesize dsDNA from the RNA strand. This dsDNA is often integrated into the host cell genome. There are a few exceptions to these general classes.

DNA viruses include parvovirus, papovavirus, adenovirus, hepadnavirus, herpesvirus and poxvirus. This can be remembered by "Poor pappy adds hep to her pox". The first three are naked DNA viruses. The latter three are enveloped DNA viruses.

Parvoviruses commonly cause veterinary disease. The major human parvovirus is called human parvovirus B19. This virus causes Fifth disease (erythema infectiosum), which is a viral exanthem of childhood. Clinical manifestations of Fifth disease are pink cheeks (slapped cheeks), fever and a slight rash on the body. Human parvovirus is a more serious problem for children and adults with hemoglobinopathies (thalassemia, sickle cell disease, etc.). Human parvovirus infection is responsible for aplastic crisis in sickle cell disease. Human parvovirus seems to cause mild anemia in healthy persons, but it causes severe erythrocyte suppression in patients with hemoglobinopathies. A fetus with thalassemia may be stillborn due to hydrops fetalis if the mother is infected by human parvovirus during pregnancy.

Papovaviruses include human papillomavirus and polyomavirus. Papillomaviruses cause various types of cervical cancer and warts such as: plantar warts and genital warts (condyloma acuminata). Polyomaviruses mostly affect birds, but they also include JC virus (which causes progressive multifocal leukoencephalopathy dementia in immunocompromised patients), and BK virus (which causes kidney disease in immunocompromised patients).

Adenoviruses commonly affect children. These illnesses are usually self limited. Many different adenoviruses classified by serotype numbers, cause various combinations of fever, conjunctivitis, pharyngitis, rhinitis, pharyngitis and pneumonia. Some adenoviruses cause gastroenteritis.

The most important hepadnavirus is hepatitis B virus. Since it is an enveloped virus, it is capable of chronic disease in some hosts. Chronic hepatitis B may cause chronic hepatitis, hepatic failure and hepatocellular carcinoma.

Herpesviruses are a large family which include herpes simplex virus (HSV), varicella-zoster virus (VZV), Epstein-Barr virus (EBV) and cytomegalovirus (CMV). HSV and VZV are similar in that they both start with acute infection with subsequent latent lifelong infection and periodic reactivation of symptomatic infection. HSV-1 causes oral herpes while HSV-2 causes genital herpes. Both cause initial acute infections with fever, viremia, mucosal lesions and/or central nervous system infection. The virus survives (latent) in nerve tissue and upon lifelong periodic reactivation, mucosal or vesicular lesions recur. Similarly varicella virus causes an acute systemic infection as varicella (chickenpox), with subsequent reactivation of latent infection manifested as zoster (or shingles). HSV-1 usually causes an initial acute infection characterized by gingivostomatitis (high fever, gum swelling and multiple mouth sores on the lips and anterior tongue). However, some children may present with encephalitis. Neonates are especially prone to encephalitis with HSV-1 and HSV-2. Thus, all measures must be taken to prevent HSV exposure to neonates. Mothers with a history of genital herpes must undergo Cesarean section prior to the rupture of membranes to prevent neonatal exposure to occult genital herpes lesions.

EBV and CMV are similar in that they both cause syndromes of prolonged viral infection with fever, malaise, lymphadenopathy, and organomegaly. This EBV syndrome is known as infectious mononucleosis, which also includes tonsillitis. EBV is capable of latent infection and is associated with Burkitt's lymphoma (the cells of which contain EBV DNA).

CMV and HSV cause recognizable congenital viral syndromes, which occur when a pregnant mother acquires an initial acute infection with CMV or HSV during early pregnancy. The acute infection results in viremia which may infect the fetus and placenta. This results in a recognizable pattern of findings which include central nervous system calcification, microcephaly, thrombocytopenia, petechial rash, small for gestational age, etc. Recurrent maternal infection does not usually result in a systemic viremia, so congenital infection is not likely with anything other than an acute maternal infection. Congenital infection should be distinguished from perinatal infection in that congenital infection occurs during early gestation while perinatal infection occurs at the time of birth or just after. Thus, a mother with a history of genital herpes many years ago is at no risk for delivering an infant with congenital herpes, but this does pose a risk for perinatal herpes, which may present as an acute encephalitis or overwhelming acute viremia.

The poxviruses do not include VZV (chickenpox) which is in the herpesvirus family. The poxviruses include variola virus (smallpox), vaccinia (cowpox) and molluscum contagiosum virus. Smallpox no longer exists on the planet except in bio-warfare programs. This is a contagious virus with a fairly high mortality rate. Vaccinia virus is called cowpox because it was found in dairy cattle and milk maids would get a mild infection with vaccinia, manifested as pox lesions on their milking hands. Vaccinia virus infection elicits cross immunity against smallpox. The classic observation that milk maids never got smallpox was noticed by Edward Jenner who eventually demonstrated that inoculation with vaccinia virus, could prevent smallpox (variola virus infection), a process which he called vaccination (named after vaccinia virus).

The +RNA viruses (remembered by: "Pete can float toward the coast backward") include picornavirus, calicivirus, flavivirus, togavirus, coronavirus, and retroviruses (retro = backward in the mnemonic).

Picornaviruses include (PEECoRnA) polio, entero, echo, coxsackie, rhino and hepA virus genera. Polio is covered in a separate chapter. Enteroviruses cause viral meningitis, occasional encephalitis, gastroenteritis and myocarditis. Coxsackie virus usually causes fever and stomatitis, such as in hand-foot-mouth disease. Echovirus causes fever and rash. Rhinoviruses cause common cold symptoms.

Caliciviruses include Norwalk virus (which causes gastroenteritis) and hepatitis E virus. Flaviviruses include hepatitis C, yellow fever, dengue fever and St. Louis encephalitis. Togaviruses include the equine encephalitis viruses (such as western equine encephalitis and eastern equine encephalitis), and rubella virus (German measles). Coronaviruses include multiple serotypes which cause cold symptoms.

Retroviruses include human immunodeficiency virus (HIV) and human T-cell lymphotrophic virus.

The -RNA viruses (remembered by: "raspberry filled parfaits are often burned") include rhabdovirus, filovirus, paramyxovirus, arenavirus, orthomyxovirus and bunyavirus families. Rabies is the most important rhabdovirus. Ebola virus is the most important filovirus. Paramyxoviruses include rubeola (measles), mumps, respiratory syncytial virus (RSV), and parainfluenza virus (colds, laryngitis, croup). Arenaviruses include lymphocytic choriomeningitis virus and Lassa fever virus. Orthomyxoviruses include influenza A and B. Hanta virus is the most important bunyavirus.

The -RNA viruses include several deadly viral infections: rabies, Ebola and Hanta viruses. This group also includes many illnesses for which we are routinely immunized against: measles, mumps, and influenza. Premature and other high risk infants routinely receive passive immunity against RSV.

The double stranded RNA viruses include orbivirus, rotavirus and reovirus (ORR). Orbivirus includes Colorado tick fever. Rotavirus is a major cause of pediatric diarrhea. Reoviruses causes febrile illnesses without other specific findings.

Summary of virus classifications

I. DNA viruses (Poor pappy adds hep to her pox)

A. Naked
. . . . 1. Parvovirus (human parvovirus B19)
. . . . 2. Papovavirus (papillomavirus, polyomavirus)
. . . . 3. Adenovirus (many which cause febrile respiratory infections)

B. Enveloped
. . . . 1. Hepadnavirus (hepatitis B)
. . . . 2. Herpesvirus (HSV, VZV, EBV, CMV)
. . . . 3. Poxvirus (variola, vaccinia, molluscum contagiosum)

II. +RNA viruses (Pete can float toward the coast backward)

A. Naked
. . . . 1. Picornavirus (PEECoRnA = polio, entero, echo, coxsackie, rhino, hepA)
. . . . 2. Calicivirus (Norwalk, hepatitis E)

B. Enveloped
. . . . 1. Flavivirus (yellow fever, dengue, St. Louis encephalitis, hepatitis C)
. . . . 2. Togavirus (rubella, equine encephalitis)
. . . . 3. Coronavirus (colds)
. . . . 4. Retrovirus (HIV)

III. -RNA viruses (raspberry filled parfaits are often burned )

A. Naked - none

B. Enveloped
. . . . 1. Rhabdovirus (rabies)
. . . . 2. Filovirus (Ebola)
. . . . 3. Paramyxovirus (measles, mumps, RSV, parainfluenza)
. . . . 4. Arenavirus
. . . . 5. Orthomyxovirus (influenza)
. . . . 6. Bunyavirus (Hanta)

IV. dsRNA viruses (ORR)

A. Orbivirus (Colorado tick fever)

B. Rotavirus

C. Reovirus


Questions

1. Name the 3 naked and 3 enveloped DNA virus families.

2. In terms of the potential duration of infection, how do naked viruses differ from enveloped viruses?

3. Name 6 viruses within the picornavirus family.

4. How are members of the herpesvirus family similar?

5. Name 4 viruses which cause cold symptoms?

6. Name the +RNA viral families.

7. Name two naked (non-enveloped) viruses which cause chronic infection.

8. Name the -RNA viral families.

9. Naked viruses are mostly of what morphologic shape on light microscopy?

10. Name 4 virus families which cause central nervous system infections.


References

Hawley LB. High-Yield Microbiology and Infectious Diseases. 2000, Philadelphia: Lippincott Williams & Wilkins.


Answers to questions

1. Poor pappy adds hep to her pox: Parvovirus, papovavirus, adenovirus, hepadnavirus, herpesvirus, poxvirus. The first three are naked, the latter three are enveloped.

2. Naked viruses cause acute infection only. Some enveloped viruses are capable of chronic infection.

3. PEECoRnA: polio, entero, echo, coxsackie, rhino, hepA.

4. VZV and HSV are similar in that they both cause acute vesicular infections with lifelong latency and recurrence. EBV and CMV are similar in that they both cause infectious mononucleosis type syndromes. CMV and HSV both cause congenital viral infection malformation syndromes.

5. Rhinovirus, RSV, parainfluenza virus, coronavirus, adenovirus. Influenza virus may be included also.

6. Pete can float toward the coast backward: picorna, calci, flavi, toga, corona, retro.

7. None. Only enveloped viruses can cause chronic infection.

8. Raspberry filled parfaits are often burned: rhabdo, filo, paramyxo, arena, orthomyxo, bunya.

9. Viruses are too small to be seen on light microscopy. On electron microscopy, nearly all naked viruses have an icosahedral shape.

10. Herpesvirus (HSV, VZV, CMV), picornavirus (poliovirus, enteroviruses), flavivirus (encephalitis), togavirus (encephalitis), rhabdovirus (rabies), bunyavirus (encephalitis).


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