Articles on Medical Diseases and Conditions

Category: Viral Infections

Viral Infections

  • Hepatitis Viruses

    Hepatitis A virus (HAV)

    Hepatitis A virus (HAV) was originally called “infectious hepatitis” or “short-incubation hepatitis,” and has an incubation period of 3-4 weeks (range, 2-6.5 weeks). HAV is highly contagious. During active infection it is excreted in the stool and is usually transmitted via fecal contamination of water or food. However, infection by fecal contamination can also spread from person to person. Although urine and saliva are less infectious than stool, they can transmit HAV infection. The greatest quantity of virus excretion in stool occurs before clinical symptoms develop, although much lower levels of excretion may occur for a few days after onset of clinical illness. Clinical illness is usually not severe, and fatality is rare. However, cases of severe HAV hepatitis with a high fatality rate have been reported. There usually is complete recovery in 1-3 weeks and no carrier state. Occasional patients may have more prolonged illness, lasting as long as a year. One report indicates that 8%-10% of cases have a fluctuating clinical and laboratory test course, sometimes for as long as 12-15 months.

    There is increased incidence of HAV infection in children, and epidemics occur within institutions for mentally retarded children, day-care centers, and orphanages. These children frequently infect institution staff, and day-care patients infect parents and other household contacts. Occasional epidemics are confined to adults, usually associated with eating contaminated food or shellfish from contaminated water. About 40%-50% (range, 30%-60%) of adults in the United States who have been tested have antibody against HAV; in some “third world” countries, this may be as high as 90%-100%. More than 50% of acute HAV infections are subclinical (“anicteric hepatitis”), including almost all infants, 75% of children less than 2 years old, and 60% of those 4-6 years old. In adults, only about 10% are asymptomatic (range, 0-60%).

    Tests for HAV infection

    At present, serologic tests are not available to detect HAV antigen. Electron microscopy (EM) can detect HAV virus in stool as early as 1-2 weeks after exposure; this period ends about 1-4 days after onset of symptoms (range, 1 week before to 2 weeks after symptoms). Virus in stool is not detectable on admission in 40%-65% of patients. Presence of HAV in blood terminates just before or at the beginning of symptoms, too late to be detected in most patients.

    Antibody testing currently is the best method for diagnosis. Both RIA and ELISA methods have been used. Tests for HAV antigen are not yet commercially available. When they do become available, the major problem will be the disappearance of antigen before or shortly after onset of clinical symptoms. Two types of antibody to HAV antigen are produced. One is a macroglobulin (IgM), which appears about 3-4 weeks after exposure (range, 15-60 days), or just before the beginning of the AST increase (range, 10 days before to 7 days after the beginning of the AST increase). Peak values are reached approximately 1 week after the rise begins, with return to normal (nondetectable) in about 2 months (range, 1-5 months or 1-2 weeks after clinical symptoms subside to about 4 months after symptoms subside). However, in a few cases detectable IgM antibody has remained as long as 12-14 months. The second type of antibody is IgG, which appears about 2 weeks after the beginning of the IgM increase (between the middle stages of clinical symptoms and early convalescence), reaches a peak about 1-2 months after it begins to rise, and then slowly falls to lower titer levels, remaining detectable for more than 10 years (Fig. 17-2).

    Serologic tests in HAV infection

    Fig. 17-2 Serologic tests in HAV infection.

    If the IgM antibody is elevated but the IgG antibody is not, this proves acute HAV infection. If the IgM antibody is nondetectable and the IgG antibody is elevated, this could mean residual elevation from old HAV infection or a recent infection in the convalescent stage. If clinical symptoms began less than 1 week before the specimen was obtained, an old HAV infection is more likely. If the test for IgM antibody is not done and the IgG antibody is elevated, this could mean either a recent infection or residual elevation from a previous infection. A rising titer is necessary to diagnose recent infection using the IgG antibody alone. If the test for IgM antibody is not done and the IgG test is nonreactive, it could mean either no infection by HAV or that the specimen was drawn before the IgG antibody titer began to rise. Whether another specimen should be drawn 2 weeks later to rule out a rising titer depends on the length of time that elapsed since clinical symptoms began or ended. Therefore, interpretation of HAV antibody test results depends on when the specimen was obtained relative to onset of clinical symptoms and which antibody or antibodies are being assayed.

    HAV Antibodies

    HAV-IgM ANTIBODY
    Appearance

    About the same time as clinical symptoms (3-4 weeks after exposure, range 14-60 days), or just before beginning of AST/ALT elevation (range, 10 days before 7 days after)

    Peak

    About 3-4 weeks after onset of symptoms (1-6 weeks)

    Becomes nondetectable

    3-4 months after onset of symptoms (1–6 months). In a few cases HAV-IgM antibody can persist as long as 12-14 months.

    HAV-TOTAL ANTIBODY

    Appearance

    About 3 weeks after IgM becomes detectable (therefore, about the middle of clinical symptom period to early convalescence)

    Peak

    About 1-2 months after onset

    Becomes nondetectable

    Remains elevated for life, but can slowly fall somewhat

    Summary
    HEPATITIS A ANTIGEN AND ANTIBODIES

    HAV-Ag by EM (in stool)

    Shows presence of virus in stool early in infection

    HAV-Ab (IgM)

    Current or recent HAV infection

    HAV-Ab (total)

    Convalescent or old HAV infection

    Summary: Diagnosis of HAV Infection

    Best all-purpose test(s) to diagnose acute HAV infection = HAV-Ab (IgM)
    Best all-purpose test(s) to demonstrate past HAV infection/immunity = HAV-Ab (Total)
    (see also the box)

  • Rubella

    Rubella (German measles) is a very common infection of childhood, although primary infection can occur in adults. The major clinical importance of rubella is maternal infection during pregnancy, which may produce the congenital rubella syndrome in the fetus. The congenital rubella syndrome includes one or more of the following: congenital heart disease, cataracts, deafness, and cerebral damage. Diagnosis is made by documenting active rubella infection in the mother during early pregnancy and by proving infection of the infant shortly after birth. Rubella antibody tests are used to determine (1) if a woman is susceptible to rubella infection (and, therefore, should be immunized to prevent infection during pregnancy), (2) to prove that a woman is immune (and therefore, does not have to be immunized or be concerned about rubella infection), (3) to determine if possible or actual exposure to rubella infection during pregnancy actually produced maternal infection, (4) to determine if an infant has been infected, (5) to determine if symptoms that might be rubella (such as a rash) really are due to rubella or to something else.

    Serologic tests in rubella infection

    Fig. 17-1 Serologic tests in rubella infection.

    Rubella has an incubation period of about 14 days (range, 10-23 days), followed by development of a skin rash that lasts about 3 days (range, 1-5 days). Illness can be subclinical in up to 25% of cases. The patients are contagious for about 2 weeks (range, 12-21 days), beginning 7 days (range, 5-7 days) before and ending about 7 days (range, 5-10 days) after onset of the rash. Subclinical illness is also infective. Virus can be cultured in the nasopharynx (posterior end of the nose is best) about 7 days before the rash until about 7 days (range, 4-15 days) after onset of the rash. Serologic tests have mostly replaced culture except for epidemiologic purposes.

    Commercially available kits for antigen are not available. Those for antibody include hemagglutination inhibition (HI or HAI), indirect hemagglutination (IHA), ELISA, and LA. Most of the kits detect only IgG antibody, but some ELISA kits for IgM are also available. Some kits detect both IgM and IgG. Most current IgG kits appear to have greater than 95% sensitivity, although there is some variation between kits. There sometimes is confusion due to the large variety of kits and methods. Some kits detect both IgM and IgG, but do not differentiate between them and generally behave as though they detect IgG alone. Also, some procedures are reported as a titer and some as positive or negative. Also, HI (HAI) used to be the standard method but has been mostly replaced by ELISA and LA. Hemagglutination inhibition-reacting antibodies appear during the first week after onset of a rash; they are sometimes detectable after only 2-3 days. Peak levels are reached near the beginning of the second week after onset of the rash. Afterward the titer slowly falls, but an elevated titer persists for many years or for life. Although the standard HI test detects both IgM and IgG antibodies, the HI time sequence just described is similar to that of rubella IgG antibodies. Complement fixation-reacting or immunofluorescent-demonstrable antibodies develop in the more conventional time of 7-14 days after onset of the rash, reach a peak about 14-21 days after the rash and usually disappear in a few years.

    Serologic tests for rubella IgM antibody are available. Immunoglobulin M antibody titer begins to rise about the time of onset of the rash, peaks about 1 week after onset of the rash, and becomes nondetectable about 4-5 weeks after onset of the rash (range 21 days-3 months). Therefore, the rubella IgM and IgG antibody rise and peak are relatively close together, in contrast to serologic behavior in most other viral diseases, in which IgG usually follows IgM by at least 1 week. Some IgM procedures, but not others, may be affected by IgM produced against nonrubella antigen (e.g., rheumatoid factor). If so, this might lead to a false positive result. Besides primary infection, rubella reinfection can occur. If this happens there is often a rise in IgG antibody, but IgM antibody is not produced. Reinfection of the mother during pregnancy is not dangerous to the fetus, in marked contrast to primary infection. The ELISA method generally detects about 94%-97% of nonneonatal patients with well-established rubella compared to the HI method and can be modified to detect either IgG or IgM or both together. Most LA kits detect over 95% of cases but detect only IgG.

    Vaccination produces immune (IgM and IgG) response in about 95% of persons. Antibodies develop 10-28 days after vaccination. Some persons take up to 8 weeks to respond. Most of those who do not respond originally will do so if revaccinated. IgG elevation declines significantly in 10% of vaccinated persons by 5-8 years and becomes nondetectable in a small number of these persons (one study found about one third had no detectable IgG antibody at 10 years). IgM lasts longer than usual in vaccinated persons; in one study 72% still had detectable IgM at 6 months. Reinfection can occur, usually subclinical, more often in vaccinated persons than in those who had previous wild-type virus infection. Reinfection does not produce a detectable IgM response but may elevate the preexisting IgG level. Reinfection apparently does not harm a fetus.

    When a test is reported either as positive or negative, this is a screen for immunity to rubella infection and is performed on a 1:8 serum dilution (the 1:8 dilution is the HI titer level that has become accepted as demonstrable of an immune IgG antibody response). If multiple serum dilutions are tested, the antibody responses detected by LA are similar in time sequence to the IgG response of HI.

    Summary of Rubella Antibodies
    HAI (HI): IS A TOTAL ANTIBODY TEST (IgM + IgG)
    Appearance

    1-3 days after onset of rash

    Peak

    About 14 days (range, 10-17 days) after onset of rash

    Becomes nondetectable

    Usually decreases about 2 serial dilutions by 1 year, then stable for life
    Titer of 1:8 considered adequate immune level

    IgM ANTIBODIES

    Appearance

    About 1-2 days after onset of rash

    Peak

    About 10 days (range, 7-21 days) after onset of rash

    Becomes nondetectable

    About 5-6 weeks (range, 10 days-12 weeks) after onset of rash; in congenital rubella, remains elevated after birth for 3-6 months

    IgG ANTIBODIES

    Appearance

    About 3-4 days after onset of rash

    Peak

    About 14 days (range, 10-21 days) after onset or rash

    Becomes nondetectable

    Remains elevated for life

    Absence of HI IgG (1:8 level) or LA antibody indicates susceptibility to rubella since elevated IgG levels usually persist for many years, whereas titers of other antibodies return to normal. Presence of LA antibody means either past or recent infection. In a person who is clinically well, this means immunity to subsequent infection. In a person with clinically suspected rubella, an immediate serum specimen and a second one drawn 2 weeks later should be obtained, the standard procedure for all serologic tests. A fourfold rise in titer confirms very recent (active) infection. However, if the first serum specimen was not obtained until several days after onset of a rash, the LA antibody titer peak may already have been reached, and no further increase may occur. If tests for rubella IgM antibody are available, presence of this antibody means recent acute infection. Absence of IgM antibody in a single specimen, however, does not completely rule out acute or recent infection, since the specimen could have been obtained either before antibody rise or after antibody fall. If IgM antibody tests are not available, a significant two-tube dilution or fourfold rise in titer of CF or fluorescent antibody may be demonstrable, since these antibodies develop later than LA. However, if both the LA and CF antibodies are at their peak, it is impossible with this information alone to differentiate between recent infection and infection occurring months or even years previously. Height of titers by itself is not reliable in differentiating acute from old infection; only a sufficient change in titer can provide this information.

    Infants with congenital rubella infection can produce both IgM and IgG antibody before birth, beginning in the late second trimester. In addition, the fetus acquires passively transferred maternal IgG antibody, whether or not the mother acquired the infection during pregnancy, so that neonatal serum IgG antibodies could represent either old or current maternal infection. Therefore, neonatal serum IgG antibodies might originate from the infant, the mother, or both. By age 6-8 months, maternal antibody in the child has disappeared, and persistence of IgM or IgG antibody past this time indicates congenital or neonatal infection. For some reason, however, at least 20% of children with congenital rubella lose their HI titer by age 5 years. Congenital rubella can also be diagnosed by detection of specific rubella IgM antibody in the blood of the newborn. If the specimen is drawn before 10 days of life (the incubation period of rubella acquired during or just after birth before postnatal antibody has a chance to rise), specific rubella IgM antibody is diagnostic of intrauterine infection. If the specimen is obtained later, this antibody may be highly suggestive of congenital rubella but is not absolutely diagnostic, since there could be a small chance that infection was acquired after delivery.

    The ELISA and LA tests are, in general, more reliable than the HI test in the average laboratory. However, false positive or negative results may occur for various reasons, just as they may occur with any test in any laboratory. If the patient is pregnant and test results may lead to some action, it may be advisable to split each sample, keeping part of each frozen, if the specimens are sent to an outside laboratory, in case a recheck is desired. If the tests are performed in-house, immediate redraw of a specimen that suggests active maternal infection might be useful. Because of technical factors, most laboratories list a specific titer below which the antibody level is not considered significant. This depends to some extent on the test being used. The cutoff titer level most frequently is 1:8 or 1:10. This fact is mentioned because theoretically any antibody titer ought to be significant in terms of indicating previous infection. However, in actual practice, antibody levels below the cutoff value are considered negative since it is not certain how much artifact is involved in very low titers.

    Summary of Rubella Testing
    For immune status = Single IgG antibody test
    For primary acute infection diagnosis = IgM (if negative, repeat in 2 weeks) or IgG (using acute and convalescent specimens)
    For congenital infection diagnosis = fetal/maternal IgM
    For possible reinfection = IgG acute and convalescent (assuming IgG was known to have been elevated before the presumed reinfection occurred)

    Summary of rubella test results
    To test for immunity to rubella in a pregnant or nonpregnant woman, an LA test (or other standard rubella test) is obtained. If the result is negative, the woman is susceptible to infection. A positive test result means immunity; and in a nonpregnant woman and in many pregnant women, this is usually enough information. However, a positive test result could either be due to past infection or recent infection. If there is some reason to rule out recent infection in a pregnant or nonpregnant woman, a rubella IgM titer could be obtained. An alternative could be a titer of the original specimen plus another specimen for titer in 2 weeks. To determine whether recent infection took place, the time relationship of two critical events—date of exposure or date of rash—is extremely important regarding what test to use and when to obtain the test specimen or specimens. To determine the presence or absence of immunity only, such timing is not important.

    If a pregnant woman has been exposed to someone with rubella, and the question is whether infection has been acquired, serum should be obtained immediately for rubella antibody titer. A significant titer obtained less than 10 days after exposure usually means immunity because of previous disease (the incubation period of rubella is 10-21 days). If the result is negative or a borderline low titer, a second specimen should be obtained 3-4 weeks later to detect a rising titer (to permit sufficient time for antibody to be produced if infection did occur). If exposure was more than 10 days previously and the LA titer is borderline or elevated, a second specimen should be obtained 2-3 weeks later to detect a possible rising titer. Alternatively, a rubella IgM antibody test could be obtained about 3 weeks after exposure. Significantly elevated IgM proves recent primary infection.

    If a person develops a rash, and the question is whether it was due to rubella, two specimens for rubella antibody titer should be drawn, one immediately and the other 2 weeks later. Alternatively, a rubella IgM antibody test could be obtained 7 days after the rash onset.

  • Diagnosis of Viral Diseases

    Culture. Until the 1980s, except in a relatively few cases the only available laboratory methods were culture and serologic tests for antibodies. There have been significant advances in culture techniques in the past few years, but most virus culture still is difficult and expensive. Culture is performed using living cell preparations or in living tissues. This fact in itself rules out mass production testing. Partly for this reason, facilities for culture are limited and are available mainly at sizable medical centers, regional reference laboratories, or large public health laboratories. In addition, culture and identification of the virus takes several days. Finally, cultural isolation of certain viruses does not absolutely prove that the virus is causing actual patient disease, since many viruses are quite prevalent in the general clinically healthy population. In these instances, confirmation of recent infection is helpful, such as presence of IgM antibodies or a fourfold rising titer of antibodies.

    Antigen detection. In the 1980s, several other diagnostic techniques that can detect viral antigen have appeared. These include electron microscopy, fluorescent antibody (FA or IFA) methods, enzymelinked immunoassay (ELISA), latex agglutination (LA) methods, and, even more recently, nucleic acid (DNA) probes (Chapter 14). These methods can provide same-day results. However, many of them are relatively expensive, especially the DNA probes, particularly when only one patient specimen is tested at a time. Except in large-volume reference laboratories, most institutions do not receive a large number of orders for virus tests in general; and with the possible exception of rubella, hepatitis B virus (HBV), human immunodeficiency virus type 1 (HIV-1), Epstein-Barr virus (EBV), and possibly rotavirus, laboratories usually receive very few requests for diagnosis of any one particular virus. This makes it difficult for the average laboratory to keep reagents for testing many different viruses; and without having the advantage of testing many specimens at the same time, costs (and therefore, prices) are much higher.

    Antibody detection. In addition to culture and tests for viral antigen, serologic tests for antibody are available for most viruses. There are many techniques, including complement fixation (CF), hemagglutination (HA or HAI), radioimmunoassay (RIA), ELISA, FA, and LA. Some of these methods can be adapted to detect either antigen or antibody and either IgM or IgG antibody. Although they are considerably less exacting than culture, most techniques other than LA and ELISA monoclonal spot test modifications are still somewhat tedious and time-consuming. Therefore, these tests are not immediately available except at reference laboratories. Serologic tests have the additional disadvantage that antibodies usually take 1-2 weeks to develop after onset of illness, and unless a significantly (fourfold or two-tube) rising titer is demonstrated, they do not differentiate past from recent infection by the viral agent in question. One serum specimen is obtained as early in the disease as possible (“acute” stage) and a second sample is obtained 2-3 weeks later (“convalescent” stage). Blood should be collected in sterile tubes or Vacutainer tubes and serum processed aseptically to avoid bacterial contamination. Hemolyzed serum is not acceptable. To help prevent hemolysis, serum should be separated from blood clot as soon as possible. The serum should be frozen as soon as possible after collection to minimize bacterial growth and sent still frozen (packed in dry ice) to the virus laboratory. Here a variety of serologic tests can be done to demonstrate specific antibodies to the various organisms. A fourfold rise in titer from acute to convalescent stage of the disease is considered diagnostic. If only a single specimen is taken, an elevated titer could be due to previous infection rather than to currently active disease. A single negative test result is likewise difficult to interpret, since the specimen might have been obtained too early (before antibody rise occurred) or in the case of short-lived antibodies such as IgM, a previously elevated antibody value may have decreased to nondetectable levels.

    There is one notable exception to the rule of acute and convalescent serologic specimens. In some circumstances, it is desirable to learn whether a person has an antibody titer to a particular virus that is sufficient to prevent onset of the disease. This is especially true for a woman in early pregnancy who might be exposed to rubella. A single significant antibody titer to rubella suggests immunity to the virus.

    Two types of antibodies are produced in most, but not all, bacterial or viral infections. A macroglobulin (IgM) type appears first, usually shortly before or just after onset of clinical illness; reaches a peak titer about 1-2 weeks after clinical symptoms begin; and then falls to normal levels within a few weeks (usually in less than 6 months). A gamma-globulin (IgG) type appears 1 or more weeks after detection of IgM antibody. The IgG antibody reaches a peak 1-3 weeks (sometimes longer) after the peak of the IgM antibody. The IgG antibody typically persists much longer than the IgM antibody (several years or even for life). Therefore, presence of the IgM antibody usually indicates recent acute infection. Presence of the IgG antibody usually requires that a rising titer be obtained to diagnose acute infection (although in some diseases there are circumstances that alter this requirement), since without a rising titer one does not know whether the IgG antibody elevation is due to recent or to old infection.

    Special stains. The Tzanck test is sometimes requested in certain skin diseases associated with vesicles or bullae. One of the vesicles is carefully unroofed, and the base and undersurface of the vesicle membrane is scraped; the scrapings are gently smeared on glass slides. The smear can be stained with Wright’s stain or Giemsa stain; if so, the slide can either be methanol-fixed or air-dried. Papanicolaou (Pap) stain can also be used, in which case the slide must be immediately fixed in a cytology fixative. The slide is then examined microscopically for multinucleated giant cells or characteristic large abnormal rounded epithelial cells. If found, these are suggestive of herpes simplex or varicella-zoster infection.

    Viral test specimens

    The type of specimen needed for viral culture depends on the type of illness. In aseptic meningitis, a CSF specimen should be obtained. In addition, stool culture for virus should be done, since enteroviruses are frequent causes of meningitis. In enterovirus meningitis, stool culture is 2-3 times more effective than CSF culture.

    In any kind of meningitis with negative spinal fluid cultures or severe respiratory tract infection of unknown etiology it is a good idea to freeze a specimen of serum as early in the disease as possible. Later on, if desired, another specimen can be drawn and the two sent for virus studies. As noted, serum specimens are generally drawn 2 weeks apart.

    In suspected cases of (nonbacterial) encephalitis, whole blood should be collected for virus culture during the first 2 days of illness. During this short time there is a chance of demonstrating arbovirus viremia. This procedure is not useful in aseptic meningitis. Spinal fluid should also be sent for virus culture. Although the yield is relatively small in arbovirus infections, the specimen results sometimes are positive, and culture also helps to rule out other organisms, such as enterovirus. In upper respiratory tract illness, throat or nasopharyngeal swabs are preferred. These should be placed in trypticase broth (standard bacterial medium). Swabs not preserved in some type of medium such as trypticase or Hank’s solution are usually not satisfactory, since they dry out quickly, and most viruses are killed by drying. Throat washings or gargle material can be used but are difficult to obtain properly. In viral pneumonia, sputum or throat swabs are needed. If throat swabs are used, they should be placed in acceptable transport solutions. Whether throat swab or sputum is used, the specimen must be frozen immediately and sent to the virus laboratory packed in dry ice. In addition, a sputum specimen (or throat swab) should be obtained for Mycoplasma culture (Chapter 14).

    In possible viral gastroenteritis, the most logical specimen is stool. At present, rotavirus and Norwalk viruses cannot be cultured from stool, but stool can be examined for Norwalk virus by immune electron microscopy and for rotavirus antigen by RIA, ELISA, or slide LA. Serologic tests on serum can be used for diagnosis of rotavirus infection, but only a few laboratories are able to do this. Whenever a stool culture for virus is needed, actual stool specimens are preferred to rectal swabs, since there is a better chance of isolating an organism from the larger sample. Stool samples should be collected as soon as possible—according to the U.S. Centers for Disease Control (CDC), no later than 48 hours after onset of symptoms (to ensure the best chance of success). The stool specimen should be refrigerated, not frozen; and if sent to an outside laboratory, the specimen should be shipped the day of collection (if possible), and kept cool with dry ice. However, it is better to mail any virus specimens early in the week to avoid arrival on weekends. An insulated container helps prolong effects of the dry ice.

    An adequate clinical history with pertinent physical and laboratory findings should accompany any virus specimen, whether for culture or serologic studies. As a minimum, the date of clinical illness onset, collection date of each specimen, and clinical diagnosis must be included. The most likely organism should be indicated. This information helps the virus laboratory to decide what initial procedures to use. For example, some tissue culture cell types are better adapted than others for certain viruses. Considerable time and effort can be saved and a meaningful interpretation of results can be provided.

    Certain viruses deserve individual discussion. The method of diagnosis or type of specimen required for some of these organisms is different from the usual procedure, whereas in other cases it is desirable to emphasize certain aspects of the clinical illness that suggest the diagnosis.

  • Viral Diseases

    Viral upper respiratory tract diseases

    Respiratory disease may take several forms, and the predominant etiologies are different in different age groups. Incidence statistics also vary depending on the geographic area and the population selected. Of the known viruses, rhinoviruses are predominantly associated with acute upper respiratory tract disease (including the common cold) in adults, whereas in children, rhinovirus, adenovirus, parainfluenza virus, and the enteroviruses are important. Acute bronchitis in children is most often due to respiratory syncytial virus and parainfluenza virus. In croup, parainfluenza is said to be the most important virus.

    Viral pneumonia

    Respiratory syncytial virus is the predominant cause of pneumonia in infants and young children, beginning at age 1 month with a peak incidence at about age 6 months, followed by adenovirus or parainfluenza virus. In older children or adults, bacterial pneumonia (most often due to Pneumococcus or Mycoplasma pneumoniae) is more common than viral pneumonia. Among viral agents known to cause pneumonia in adults, the most common is probably influenza. In any study, a large minority of cases do not yield a specific etiologic agent.

    Viral meningitis

    Viruses are an important cause of meningitis, especially in children. They typically produce the laboratory picture of aseptic meningitis: the classic cerebrospinal fluid (CSF) findings are variable, but often include mildly increased protein levels, increased cell counts with mononuclear cells predominating, normal glucose levels, and no organisms found on culture. It should be remembered, however, that tuberculous meningitis gives similar findings, except for a decreased CSF glucose level, and likewise shows a sterile culture on ordinary bacterial culture media. Some patients with mumps meningoencephalitis may have decreased CSF glucose levels in addition to CSF lymphocytosis. Enteroviruses are the largest etiologic group causing aseptic meningitis. Among the enteric viruses, poliomyelitis used to be the most common organism, but with widespread polio vaccination programs, echovirus and coxsackievirus have replaced polio in terms of frequency.

    After the enteroviruses, mumps is the most important. A small but significant number of patients with mumps develop clinical signs of meningitis, and a large number show CSF changes without demonstrating enough clinical symptoms to warrant a diagnosis and workup for meningitis. Changes in CSF or the clinical picture of meningitis may occur in patients without parotid swelling or other evidence of mumps. Lymphocytic choriomeningitis and leptospirosis are uncommon etiologies for aseptic meningitis.

    Encephalitis is a syndrome that frequently has CSF alterations similar to those of meningitis. The two cannot always be separated, but the main difference is clinical; encephalitis features depression of consciousness (lethargy, coma) over a prolonged period, whereas meningitis usually is a more acute illness with manifestations including fever, headache, vomiting, lethargy, stiff neck, and possibly convulsions. In severe bacterial infection, encephalitis may follow meningitis. Encephalitis is most often caused by viruses, of which the more common are mumps, herpes simplex type 1 (HSV-1), measles, and the arboviruses. Sometimes encephalitis is a complication of vaccination.

    Viral gastroenteritis

    Viruses are likely to be blamed for diarrhea that cannot be explained otherwise. In most cases, definitive evidence is lacking because enteric virus is present in a significant number of apparently healthy children. Bacterial infection should always be carefully ruled out. Two clinical types of viral gastroenteritis have been described. One type usually occurs in epidemics, more often in older children and in adults, with clinical signs of an acute self-limited gastroenteritis of 1-2 days’ duration. The most commonly associated etiology is the Norwalk-type group of viruses. The other type of illness is sporadic and affects mostly infants and younger children. There is severe diarrhea, usually accompanied by fever and vomiting, which lasts for 5-8 days. Rotavirus is the most frequently isolated virus in these patients. About 5%-10% of gastroenteritis in infants less than 2 years old is said to be caused by adenovirus types 40 and 41

    Viral infections in pregnancy

    By far the most dangerous viral disease during pregnancy is rubella. Statistics are variable, but they suggest about a 15%-25% risk of fetal malformation when rubella infection occurs in the first trimester (literature range, 10%-90%). The earlier in pregnancy that maternal infection occurs, the greater the risk that the fetus will be infected. However, not all infected fetuses develop congenital malformation. When the fetus is infected early in the first trimester, besides risk of congenital malformation, as many as 5%-15% of fetuses may die in utero. Risk of fetal malformation in second trimester infections is about 5%. After the fourth month of pregnancy, there is no longer any danger to the fetus. Cytomegalovirus (CMV) infection is more frequent than rubella, but CMV has a lower malformation rate. Cytomegalovirus damage is more severe in the first two trimesters. Other viruses may cause congenital malformations, but evidence is somewhat inconclusive as to exact incidence and effects. Herpes simplex and the hepatitis viruses are in this group.