Pathogenesis

The primary HSV infection is usually acquired through direct contact with affected area or through secretions. The virus once attached to the cells at inoculation site through specific receptors; it replicates too many virions to the maximum number and discharges to neighboring cells. Subsequently it affects adjacent cells, spreads to distant sensory nerve endings and autonomic axons, further to adjacent related ganglia, and remains latent there. The lymph node is involved through viral proteins by mobile dendritic cells and begins its primary immune response. The reason for the wide anatomical distribution and multiple crops may be due to descending spread of virions back to periphery from various neuronal site. Initial or primary infection is asymptomatic and occurs commonly in childhood or infancy. This disease manifests as characteristic vesicles containing desquamated cells, multinucleated giant cells, and free viruses with edema fluid. Though both subtypes produce orofacial and genital lesions, which are clinically indistinguishable, HSV-1 predominantly affects the face, lips, the oral cavity, and upper body skin; and HSV-2 usually affects the genitals and skin of the lower half of the body. Primary infection resolves and the virus can no longer be recovered from ganglia but viral DNA can be found in the ganglion cells. Both humoral and cell mediated immunity is responsible for the clinical manifestation, latency, and recurrence of the disease. Immune-compromised individuals, especially with impaired cellular immunity, are more prone for dissemination and recurrence of the primary disease.

An in-depth summary of the structure, composition, growth cycle, and cytopathogenic effects of HSV-1 has been published by Hicks and Terezhalmy. Gruter was among the first to offer evidence that the herpes simplex infection was caused by an infectious agent and that the fluid of vesicles from patients with herpes simplex would produce keratitis when inoculated on scarified rabbit cornea. Subsequently, the virus has been found to multiply well on the chorioallantoic membrane of the chick embryo. Andrews and Carmichael, in 1930, found that neutralizing antibodies against the herpes simplex virus were present in the circulating blood of most normal adults and persisted throughout life, but that recurrent herpetic lesions frequently developed in these persons.

These and other studies have finally led to the established principle that two types of infection with the herpes simplex virus occur. The first is a primary infection in a person who does not have circulating antibodies, and the second is a recurrent infection in persons who have such antibodies. It is impossible to differentiate clinically between the lesions of a primary and a recurrent attack, although the primary infection is accompanied more frequently by severe systemic manifestations and is occasionally fatal. It has been shown; however, that most adults have circulating antibodies in the blood, but have never exhibited a severe primary illness. Thus, it is reasoned, subclinical primary infections must be common. The relation between the primary and secondary forms of the herpes simplex infection is shown in Figure 6-1.

Herpes genitalis, caused by HSV-2, is a relatively common disease of the uterine cervix, vagina, vulva, and penis. The incidence of this form of the infection has increased precipitously in the United States within the past decade, and in fact, is now often termed the ‘new epidemic venereal disease,’ since it is transmitted through sexual contact. This virus differs immunologically from type 1 herpes virus, which is responsible for most cases of herpetic infection of the oral cavity. The type 2 virus of genital herpes is somewhat more virulent than type 1, and significantly, has been associated repeatedly with carcinoma of the uterine cervix, thus suggesting a possible cause and effect relationship. However, because of changing sexual practices, there has been rather widespread translocation in the usual habitats of type 1 and type 2 HSV. Thus, it is not unusual today to find HSV-2 on the lips or oral mucous membranes and HSV-1 on the genitalia.

Herpetic meningoencephalitis is a serious form of this infection, characterized by sudden fever and symptoms of increased intracranial pressure. Paralysis of various muscle groups occurs, while convulsions and even death may ensue. It is difficult to differentiate clinically between meningoencephalitis caused by the herpes virus and that produced by other viruses.

Herpetic conjunctivitis, or keratoconjunctivitis, is a rather common disease and is characterized by swelling and congestion of the palpebral conjunctiva, although keratitis and corneal ulceration also may occur. Herpetic vesicles of the eyelids are typical, but these eye lesions usually heal rapidly.

Herpetic eczema (Kaposi’s varicelliform eruption) is an epidermal form of the herpetic infection superimposed upon a pre-existing eczema (possibly an example of anachoresis) and is characterized by diffuse vesicular lesions of the skin, usually of an extremely serious nature. In addition to this atopic dermatitis, the herpetic infection may also be superimposed on severe seborrheic dermatitis, impetigo, scabies, Darier’s disease, and pemphigus vulgaris or foliaceus. It is most frequently due to the primary herpetic attack and may be fatal. The patients, usually children, exhibit a high fever, coincident with the typical umbilicated vesicles as well as other systemic manifestations.

Disseminated herpes simplex of the newborn is a relatively uncommon disease in which the newborn baby acquires the infection during passage through the birth canal of a mother who is suffering from herpetic vulvovaginitis. However, occasional cases of transplacental infection by the virus have been reported. These infants usually manifest the disease by the fourth to seventh day of life, exhibit a wide variety of signs and symptoms of the disease and with few exceptions, usually die on the 9th to 12th day of life. Surviving infants frequently show residual neurological involvement.

Herpetic whitlow occurs in fingers due to autoinoculation.

Herpes gladiatorum occurs in wrestlers.

Clinical Features

Herpetic stomatitis is a common oral disease transmitted by droplet spread or contact with the lesions. It affects children and young adults. However, it has been suggested by Sheridan and Herrmann that the primary form of the disease is probably more common in older adults than was once thought. It rarely occurs before the age of six months, apparently because of the presence of circulating antibodies in the infant derived from the mother. The disease occurring in children is frequently the primary attack and is characterized by the development of fever, irritability, headache, pain upon swallowing, and regional lymphadenopathy. Within a few days, the mouth becomes painful and the gingiva which is intensely inflamed appears erythematous and edematous. The lips, tongue, buccal mucosa, palate, pharynx, and tonsils may also be involved. Shortly, yellowish, fluid-filled vesicles develop. These vesicles rupture and form shallow, ragged, extremely painful ulcers covered by a gray membrane and surrounded by an erythematous halo (Fig. 6-2). It is important to recognize that the gingival inflammation precedes the formation of the ulcers by several days. The ulcers vary considerably in size, ranging from very tiny lesions to lesions measuring several millimeters or even a centimeter in diameter. They heal spontaneously within 7–14 days and leave no scar.

Utilizing culture techniques, August and Nordlund found that the HSV-1 could be isolated from facial, labial, and oral herpetic lesions for a mean duration of three-and-a-half days, with a range of 2–6 days, after the onset of the lesions, while HSV-2 could be isolated from genital lesions for a mean duration of five-and-a-half days, with a range of 2–14 days, after onset. They also noted that viral persistence in lesions did not seem to differ between mild primary infection and recurrent infection. In addition, Turner and his colleagues have shown that HSV could survive for two to four hours on environmental surfaces such as cloth and plastic as well as on the skin of the hands contaminated by direct contact with labial or oral lesions.

It is now well established that the HSV does not remain latent at the site of the original infection in the skin or oral mucosa. Instead, the virus reaches nerve ganglia supplying the affected areas, presumably along nerve pathways, and remains latent there until reactivated. The usual ganglia involved are the trigeminal for HSV-1 and the lumbosacral for HSV-2. Viral DNA can be demonstrated in these ganglia. Unfortunately, this incorporation of viral DNA into host DNA ensures a lifelong infection beyond the reach of antibody, cell mediated immune responses or chemotherapy.

Mode of Transmission

The fact that the herpes virus may be recovered from the saliva of patients during the course of the disease leads to the assumption that transmission may occur by droplet infection, although some workers believe that direct contact is necessary. There is no animal reservoir for this virus. It has been reported in one series of patients that a history of contact with affected persons was present in nearly 50% of the cases. After such contact, the incubation period appears to range from 2–20 days, with an average of six days before development of lesions. There also have been occasional epidemics of herpetic stomatitis, such as that reported by Hale and his associates in an orphanage nursery. In addition, it has been noted that primary herpetic eruptions are commonly associated with pneumonia, meningitis, and common cold.

Histologic Features

The herpetic vesicle is an intraepithelial blister filled with fluid. The infected cells are swollen and have pale eosinophilic cytoplasm and large vesicular nuclei, described as ‘ballooning degeneration,’ while others characteristically contain intranuclear inclusions known as Lipschütz bodies. These are eosinophilic, ovoid, homogeneous structures within the nucleus, which tend to displace the nucleolus and nuclear chromatin peripherally. The displacement of chromatin often produces a peri-inclusion halo. Cytoplasm of the infected cells forms giant cells. The subjacent connective tissue is usually infiltrated by inflammatory cells. When the vesicle ruptures, the surface of the tissue is covered by exudates made up of fibrin, polymorphonuclear leukocytes, and degenerated cells. The lesions heal by peripheral epithelial proliferation.

Diagnosis

It can be diagnosed both clinically and by laboratory procedures. Scrapings obtained from the base of the lesions are stained with Wright’s, and Giemsa stain. Pap stain demonstrates balloon cells, multinucleated giant cells and intranuclear inclusions. Though cytological procedures give a quick result but it will not differentiate between HSV and varicella zoster virus (VZV). More than that, identification of giant cells requires experience.

HSV can be demonstrated in the laboratory by isolation of virus in tissue culture or by DNA in the scrapings from lesions. The most sensitive and accurate method for diagnosing these lesions is PCR technique.

Treatment

Antiviral drugs have significant impact on the course of the disease, if it is diagnosed early. Antibiotic therapy helps in the prevention of secondary infection. Nonsteroidal anti-inflammatory drugs and topical anesthetic gel may relieve the discomfort considerably.

Clinical Features

Recurrent herpes simplex infection may occur at widely varying intervals, from nearly every month in some patients to only about once a year or even less in others. The lesions may develop either at the site of primary inoculation or in the adjacent area supplied by the involved ganglion. It may develop on the lips (recurrent herpes labialis, Fig. 6-3) or intraorally (Fig. 6-4). In either location, the lesions are frequently preceded by a burning or tingling sensation and a feeling of tautness, swelling or slight soreness at the location in which the vesicles subsequently develop. These vesicles are generally small (1 mm or less in diameter), tend to occur in localized clusters, and may coalesce to form somewhat larger lesions. These gray or white vesicles rupture quickly, leaving a small red ulceration, sometimes with a slight erythematous halo. On the lips, these ruptured vesicles become covered by a brownish crust. The degree of pain present is quite variable.

It has been emphasized by Weathers and Griffin that the recurrent intraoral herpetic lesions almost invariably develop on the oral mucosa that is tightly bound to periosteum. Seldom do they occur on mobile mucosa, in contrast to the recurrent aphthous stomatitis (q.v.) which almost invariably occurs only on mobile mucosa. Thus, the most common sites for the recurrent intraoral herpetic lesions are the hard palate and attached gingiva or alveolar ridge. Interestingly, herpes labialis is seldom seen concurrently with intraoral lesions.

The lesions gradually heal within 7–10 days and leave no scar.

Histologic Features

A number of investigators, beginning with Blank and his associates, have shown that the Papanicolaou smear, using fresh scrapings from the base of a vesicle, is a reliable technique for the diagnosis of active herpes simplex infection if herpes zoster/varicella infection is ruled out, since no other conditions produce a similar cytopathic effect. ‘Ballooning degeneration,’ chromatin margination and typical Lipschütz bodies as described earlier are all seen in smears from these lesions, as well as characteristic multi-nucleated giant cells originally observed by Tzanck (Fig. 6-5). Nowakovsky and her coworkers have thoroughly reviewed the manifestations of viral infections in exfoliated cells. The histologic findings in biopsy specimens from the recurrent lesions are identical to those described under the primary form of the disease.

Laboratory Findings

Isolation of the herpes simplex virus can be accomplished in tissue culture, particularly in the early stages of the recurrent infection. According to Tokumaru, the virus is easily isolated when there is a low production of γ-A globulin, but there is a rapid clearing of the virus, often within one day, after a rebound production of γ-A globulin. Similarly, smears would be positive for only a short time after the virus has cleared because of the rapid degeneration of the affected cells.

Current diagnostic methods for herpes viral diagnosis have been reviewed by Burns. These have included:

Treatment

Until recently, little could be provided in the way of actual therapy except for symptomatic relief, although many drugs have been tested over the years.

Several specific antiviral chemotherapeutic agents are presently available for use under certain conditions and with certain forms of HSV infection. The most prominent of these are: (1) acyclovir (9– [2– hydroxyethoxymethyl] guanine); (2) vidarabine (adenine arabinoside); and (3) idoxuridine (5–iodo-2’-deoxyuridine). However, these must only be used according to prescribed indications and do not represent curative drugs for this disease.

Differential Diagnosis

A consideration of differential diagnosis is of great importance, since numerous diseases may bear some resemblance to herpes simplex. Thus, some difficulty may be encountered in distinguishing herpes simplex particularly from the recurrent aphthous stomatitis (q.v.). Other conditions to be considered are herpes zoster, impetigo, erythema multiforme, and related diseases, smallpox, pemphigus, epidermolysis bullosa, food or drug allergies, and chemical burns.

Clinical Features

The incubation period is probably 2–10 days. It is most commonly seen in young children; older children and adults are only occasionally affected. Herpangina is chiefly a summer disease, and many children may actually harbor the virus at this time without exhibiting clinical manifestations of the disease.

The clinical manifestations of herpangina are comparatively mild and of short duration. It begins with sore throat, cough, rhinorrhea, low-grade fever, headache, sometimes vomiting, prostration, and abdominal pain. The patients soon exhibit small vesicles which rupture to form crops of ulcers, each showing a gray base and an inflamed periphery on the anterior faucial pillars and sometimes on the hard and soft palates, posterior pharyngeal wall, buccal mucosa; and tongue (Fig. 6-6). Vesicles preceding the ulcers are small and of short duration, and are frequently overlooked by the examiner. The ulcers do not tend to be extremely painful, although dysphagia may occur. The systemic symptoms resolve within few days. Ulcers generally heal within 7–10 days.

Children have been affected several times in one season by infection with different strains of the Coxsackie virus. A permanent immunity to the infecting strain usually develops rapidly, and most adults have neutralizing antibodies against numerous strains.

Laboratory Findings

The Coxsackie virus can be isolated in suckling mice or hamsters by inoculation of scrapings from the throat lesions or stool specimens of nearly all patients who manifest clinical signs and symptoms of the disease or who have had contact with infected patients. Although there are distinct immunologic differences between various strains of herpangina virus, animal inoculation of any type produces the same manifestations—destruction of skeletal muscles followed by death. Even after the disappearance of clinical manifestations of the disease in the human patient, the virus may still be isolated from him/her for one to two months.

Treatment

No treatment is necessary, since the disease appears to be self-limiting and presents few complications. Those reported have consisted of acute parotitis, meningitis, hemolytic anemia, and hemorrhagic diathesis.

Clinical Features

The disease affects predominantly children and young adults, although older adults are also occasionally involved. The chief complaints consist of sore throat, an elevation of temperature varying from 100°–105° F, mild headache, and anorexia. Typically, the patients do not manifest rhinorrhea, cough, tracheitis, gingivostomatitis, skin eruptions, arthralgia, otitis media, or lymphadenopathy.

The symptomatic course varies from 4–14 days and the local oral lesions resolve within 6–10 days, although a residual ring of fading erythema may sometimes be seen for several days. The estimated incubation period of the disease is 2–10 days.

Oral Manifestations

The lesions, characteristic of the disease, are raised, discrete, whitish or yellowish to dark pink solid papules or nodules, surrounded by a narrow zone of erythema (Fig. 6-7). The lesions are not vesicular and do not ulcerate. The lesions characteristically appear on the uvula, soft palate, anterior pillars, and posterior oropharynx.

Laboratory Findings

Primary isolation of Coxsackie A10 virus can be established in suckling mice by inoculation of throat swab or fecal material. Serologic evidence of infection by this virus is also positive.

Histologic Features

The papules or nodules consist of hyperplastic lymphoid aggregates. In some cases the overlying epithelium show inclusion of bodies which in some instances are intranuclear but in others, cytoplasmic.

Treatment

No specific treatment is necessary as the disease is self-limiting. It has been found that antibiotic therapy is of no benefit.

Clinical Features

The disease is primarily one affecting young children, the majority of cases occurring between the ages of six months and five years. It is characterized by the appearance of maculopapular, exanthematous, and vesicular lesions of the skin, particularly involving the hands, feet, legs, arms, and occasionally the buttocks. The patients commonly manifest anorexia, low-grade fever, coryza and sometimes lymphadenopathy, diarrhea, nausea, and vomiting.

Oral Manifestations

A sore mouth and refusal to eat is one of the most common findings in the disease. This is due to the small, multiple vesicular, and ulcerative oral lesions that are more numerous than seen in herpangina. In the series of cases reported by Adler and his associates, sore mouth was the principal symptom in 90% of the patients, and oral lesions were present in 100% of the patients. The most common sites for the oral lesions were the hard palate, tongue, and buccal mucosa, with a much smaller percentage of patients showing involvement of the lips, gingiva and pharynx, including the tonsils. The tongue may also become red and edematous.

Laboratory Findings

Intracytoplasmic viral inclusions can sometimes be demonstrated in vesicular scrapings of the lesions. It has been found that these inclusions are indistinguishable from those found in vaccinia. In addition, viral isolates may usually be obtained from rectal or throat swabs from vesicular fluid itself. Finally, there is generally a remarkable rise in acute or convalescent serum antibody titer to Coxsackie A16. In a few patients there is concomitant rise in herpes simplex virus antibody titer, but this is probably a fortuitous occurrence. Nevertheless, the clinical findings of hand, foot and mouth disease and of herpes simplex infection may be remarkably similar so that the two may be separated only with appropriate laboratory viral tests.

Treatment

No specific treatment is necessary since the disease is self-limiting and generally regresses within one to two weeks.

Differential Diagnosis

There is an obvious similarity in the clinical appearance of the oral lesions of hand, foot and mouth disease and a variety of other conditions which may be encountered. In an excellent review of this disease, McKinney has listed several such conditions to be considered in the differential diagnosis, including herpetic gingivostomatitis, herpangina, erythema multiforme, recurrent aphthous ulcers, and animal foot-and-mouth disease.

Clinical Features

When it is transmitted to the human, foot-and-mouth disease manifests itself clinically by fever, nausea, vomiting, malaise, and the appearance of ulcerative lesions of the oral mucosa and pharynx. Development of vesicles on the skin also occurs in some cases. These vesicular lesions appear most commonly on the palms and soles.

Oral Manifestations

The lesions of the oral mucosa may occur at any site, although the lips, tongue, palate, and oropharynx appear to be those chiefly affected. These lesions begin as small vesicles, which rapidly rupture, but heal usually within two weeks.

Epidemiology

Measles has a worldwide distribution but incidence is more in developing countries. In Asia, incidence was reduced after the introduction of a vaccine schedule, but resurgence of measles may be due to failure to immunize infants and young children, and failure of vaccination or waning immunity. The mortality rate is high among children and adults. It varies from 1–10% in developing countries. It is contagious from first or second day even before the onset of serious illness or appearance of rash. It is transmitted mainly through respiratory secretions and also through direct contact of droplets. The incubation period is generally from 8–12 days. It is mainly transmitted in large families, crowded homes and slums. It is a self-limiting disease in healthy immune competent children, but morbidity and mortality is high in malnourished and immunocompromised individuals.

Pathogenesis

Upon invasion of respiratory epithelium it reaches reticuloendothelial system through blood stream and thereby infect skin, respiratory tract, and other organs. The invasion of T lymphocytes and increased levels of suppressive cytokines leads to transient suppression of cellular immunity. Monocyte is mainly infected. Symptoms show mainly due to the infection of the entire respiratory epithelia and the secondary infection with bacteria. Viremia develops, but specific antibodies are not developed before the onset of rash. Cellular immunity plays a major role in host defense against measles.

Clinical Features

There are three stages in measles namely pre-eruptive stage or prodromal stage, eruptive stage and post-eruptive stage. Incubation period of 8–10 days, is characterized by the onset of fever, malaise, cough, conjunctivitis, photophobia, lacrimation, and eruptive lesions of the skin and oral mucosa. Skin eruptions usually begin on the face, in the hair line and behind the ears, and spread to the neck, chest, back, and the extremities. These appear as tiny red macules or papules which enlarge and coalesce to form blotchy, discolored, irregular lesions which blanch upon pressure and gradually fade away in four to five days with a fine desquamation.

Oral Manifestations

The oral lesions are prodromal, frequently occurring two to three days before the cutaneous rash, and are pathognomonic of this disease. These intraoral lesions are called Koplik’s spots and have been reported to occur in as high as 97% of all patients with measles. The Koplik’s spots are white papules resembling table salt like crystals with red base which appear usually on the buccal mucosa opposite to first and second molar teeth. Immune reaction to the virus in the endothelial cells of dermal capillaries plays a role in the development of spots. The spots disappear after the onset of rash. In actual practice, they are seldom seen unless the affected child has had a known contact with measles and the dentist or parent watches carefully, since the child is often well at the time they appear. These characteristic spots are small, irregularly shaped flecks which appear as bluish, white specks surrounded by a bright red margin. These macular lesions increase in number rapidly and coalesce to form small patches. Palatal and pharyngeal petechiae as well as generalized inflammation, congestion, swelling, and focal ulceration of the gingiva, palate and throat may also occur.

Histopathological features show pathognomonic multinucleated giant cells called Warthin–Finkeldey giant cells.

Complications

Measles is a disease which lowers the general body resistance, and for this reason, often leads to complications. These may include diarrhea, bronchial pneumonia, encephalitis, otitis media, and occasionally, noma. In addition, it has been recognized that measles has an immunosuppressive effect through impairment of cell-mediated immunity. Thus, while it may result in a delay in wound healing, it may also cause induction of remission of leukemia and Hodgkin’s disease. The disease is rarely fatal except in the case of secondary complications.

Control Measures

Measles vaccines are available as single or in combination (MMR). In Asian countries, especially in India, the Edmonton–Zagreb (E-Z strain) 5 ml of vaccine is given subcutaneously. Studies have suggested the age for vaccination as nine months. A second dose should be given in the form of MMR at 15–18 months for adequate immunity.