Infectious Diseases, Part II

Camille Sabella

Johanna Goldfarb

This chapter includes discussions of selected viral, fungal, and mycobacterial infections.

VIRAL INFECTIONS

Human Parvovirus Infection

Human parvovirus (HPV) is a small DNA virus that replicates in human precursor red blood cells.

Primary infection most commonly occurs in schoolaged children (5 to 15 years old) in the late winter and spring. At least 60% of adults are seropositive and immune to infection. Transmission is by respiratory spread and rarely by transfusion of blood from an acutely infected person. Vertical transmission during pregnancy is also possible. The secondary attack rate is approximately 50% with household contact and 20% to 30% with school exposure.

Most infections with HPV are asymptomatic. Erythema infectiosum (slapped cheek or fifth disease) is the most recognizable form of infection. This is characterized by an intensely erythematous rash on the cheeks, with mild systemic signs of illness developing approximately 1 week after a mild prodrome of fever, headache, and myalgias. A systemic, lace-like maculopapular rash, which may be pruritic, may also appear on the trunk and extremities (see Fig. 1.20). The rash is often evanescent for weeks, changing with varying temperature and exposure to sunlight.

The appearance of the rash in erythema infectiosum signifies an immune response to the infection. Therefore, children with the rash are not contagious, and may attend school or child care centers.

Other manifestations of HPV infection include:

Arthritis
Transient aplastic crisis in children with hemolytic anemia
Chronic bone marrow infection in immunodeficient persons
Fetal hydrops
Papulopurpuric gloves-and-socks syndrome

Transient aplastic crisis occurs in persons who depend on rapid red cell production and whose hemoglobin levels are low, such as those who have hemolytic anemia associated with sickle cell disease. The aplastic crisis typically lasts 7 to 10 days, and children may require red blood cell transfusions to prevent or treat congestive heart failure. Children with aplastic crisis are highly contagious, and should be placed in droplet isolation when hospitalized.

Chronic bone marrow failure can develop in an immunodeficient child, resulting in severe anemia and, at times, thrombocytopenia and neutropenia. Intravenous immunoglobulin therapy may be effective.

The papulopurpuric gloves-and-socks syndrome is an atypical rash that can occur during parvovirus B19 infection. Its characteristics include a painful and pruritic papular, petechial and purpuric rash occurring symmetrically on the distal extremities. The rash may be accompanied by fever and perioral lesions. These manifestations occur during the period of viremia, and thus patients with this syndrome should be considered contagious.

Fetal hydrops is a potential consequence of maternal infection during pregnancy. The risk of fetal death associated with parvovirus B19 maternal infection is 2% to 6% and appears to be highest when maternal infection occurs in the first half of pregnancy.

Human Herpesvirus 6 Infection

Human herpesvirus 6 (HHV-6) is a ubiquitous herpesvirus that is the cause of exanthem subitum (roseola). Like all herpesviruses, HHV-6 causes a primary infection and then establishes latency. The distribution of HHV-6 is worldwide and nonseasonal, and primary infection most often occurs in children between the ages of 6 months and
2 years. Almost all children are seropositive for the virus by the age of 2 years. Transmission is thought to be from asymptomatic salivary shedding.

Classic roseola develops in approximately 20% of children infected with HHV-6. It is characterized by a high fever that lasts for 3 to 7 days, often associated with toxicity, followed by an erythematous maculopapular rash. HHV-6 also is a very common cause of febrile illness without rash or localizing signs in children aged 6 to 18 months. Other clinical features of HHV-6 infection include:

Cervical and occipital adenopathy
Respiratory symptoms and otitis media
Gastrointestinal symptoms
Bulging fontanelle
Febrile seizures

Febrile seizures are thought to occur in approximately 15% of children who have a primary infection with HHV-6. Reactivation of the virus in immunocompromised persons may result in hepatitis, pneumonitis, and encephalitis.

Human Immunodeficiency Virus Infection in Children

Perinatal Transmission

Most cases of human immunodeficiency virus (HIV) infection in children are the result of perinatal transmission. The overall transmission rate from an infected mother to her infant if neither the mother nor the infant is treated with antiretroviral therapy ranges from 14% to 27% in developed countries. Transmission can occur:

In utero (30% of cases)
At the time of delivery (70% of cases)
Postpartum (rarely)

Transmission in utero is associated with early onset of disease in the infant and decreased survival. By definition, infants infected in utero have a blood culture positive for HIV or evidence of HIV DNA on polymerase chain reaction (PCR) testing within 7 days of birth. A large maternal viral load and a low count of CD4+ lymphocytes in the mother are risk factors for in utero transmission; primary infection during pregnancy carries the highest risk.

Peripartum transmission accounts for most cases of infection. The clinical course of these infants is much more variable. By definition, they do not have evidence of HIV on blood culture or PCR testing within the first 7 days of life. Risk factors for peripartum transmission include advanced maternal disease (large viral load, low count of CD4+ lymphocytes), prolonged rupture of membranes, obstetric complications, and first-born twin.

Postpartum transmission occurs mainly through breastfeeding, mostly by mothers with acute seroconversion. Breastfeeding remains the recommended method of feeding in developing countries, whereas in the United States, breastfeeding is contraindicated if the mother is infected, given the availability of safe alternatives and the risk for transmission.

The perinatal transmission of HIV can be reduced by two thirds when the pregnant mother is treated with oral zidovudine beginning in the second trimester of pregnancy and intravenous zidovudine during delivery, and the infant is treated with oral zidovudine for the first 6 weeks of life. The transmission rate can be reduced further when mothers are treated more aggressively with antiretroviral agents during pregnancy. Other approaches utilizing shorter duration of antiretroviral agents in the mother at the time of delivery, using nevirapine therapy alone or in combination with other antiretroviral agents in the mother, and a single dose of nevirapine in the infant at birth, offer some benefit, but are less effective than the three-part zidovudine regimen or combination antiretroviral therapy during pregnancy. Cesarean delivery prior to rupture of membranes in mothers receiving zidovudine decreases the risk of perinatal transmission (2%), as compared to mothers on zidovudine therapy undergoing vaginal delivery (7%). However, the additional benefits of cesarean delivery in mothers who have low HIV viral loads (<1000/mL) are unknown and may not outweigh the added risk of an operative delivery for the infected woman. In the developing world, postpartum antiretroviral therapy for the mother is being evaluated to prevent breastfeeding transmission of infection.

Diagnosis

HIV infection is difficult to diagnose in young infants because maternal antibodies may persist until 18 months of age. Therefore, tests that reveal the presence of HIV antibodies are not useful for infants. The detection of HIV DNA by PCR is the most reliable test for diagnosing HIV infection in a young infant. Almost all infected infants will have a positive HIV DNA by the time they are 1 month of age. Antibody tests, such as enzyme immunoassay and Western blot, are reliable in older children (>18 months) unless they are severely malnourished or hypogammaglobulinemic and unable to mount an antibody response. Two tests should be done to confirm the diagnosis. The use of other modalities of diagnosis of HIV infection in infants and children, such as culture and detection of p24 antigen, are not recommended.

Clinical Features

The clinical features of HIV infection in children include:

Failure to thrive
Recurrent invasive bacterial infections
Chronic lymphadenopathy
Parotitis
Recurrent diarrhea
Oral candidiasis
Hepatosplenomegaly
Opportunistic infections
Central nervous system disease, including developmental delay
Lymphoid interstitial pneumonitis

Common opportunistic infections in children infected with HIV include:

Pneumocystis pneumonia (PCP)
Candidiasis of the lower respiratory tract or esophagus
Chronic diarrhea secondary to cryptosporidiosis or isosporiasis
Cytomegalovirus disease and retinitis
Severe herpes simplex virus and varicella-zoster virus infections
Invasive fungal infections
Mycobacterial infections

PCP is one of the most common serious opportunistic infection in HIV-infected infants and children. It generally develops between 3 and 6 months of life and may be the presenting manifestation of HIV infection. An acute presentation, in which tachypnea and oxygen desaturation lead to respiratory failure, is not uncommon in these infants. Mortality from PCP infection in HIV-infected infants is high despite specific therapy. Trimethoprim/sulfamethoxazole is the drug of choice for the treatment of PCP in infants and children.

General Care of the Child Infected with Human Immunodeficiency Virus

Children with HIV infection should be allowed and encouraged to attend school. The physician and family are not required to reveal the diagnosis to the school or teachers, unless the child has a behavioral issue such as biting or is an infant in diapers. All schools should implement routine infection control procedures for managing exposure to blood or blood-containing fluids, regardless of the source of the blood. Schools should notify all parents when contagious diseases such as varicella and measles are reported in a school.

Most routine childhood vaccines should be administered to HIV-infected children at the appropriate age. Measles-mumps-rubella vaccine should be administered at 12 months of age unless the child has severe immunosuppression, defined as a low percentage (<15%) of CD4⁺ lymphocytes. The second dose of measles-mumps-rubella vaccine should be administered as soon as 4 weeks after the first dose rather than waiting until school entry. Varicella vaccine should be administered for the HIV-infected child who is asymptomatic or mildly symptomatic and whose percentage of CD4⁺ lymphocytes is normal.

Prevention of Opportunistic Infections

PCP prophylaxis with trimethoprim/sulfamethoxazole is recommended for all infants with suspected or proven HIV infection:

Prophylaxis should be initiated at 4 to 6 weeks of age for all HIV-exposed infants until the diagnosis is excluded.
Children 1 to 5 years infected with HIV should continue PCP prophylaxis unless the count and percentage of CD4⁺ lymphocytes is greater than 500 cells/μL or >15%, respectively.
Children 5 years and older, who are infected with HIV, should continue PCP prophylaxis unless the count and percentage of CD4⁺ lymphocytes is >200 cells/μL or >15%.

Tuberculosis prophylaxis should be utilized for HIVinfected persons whose tuberculin skin test results are positive without evidence of active disease. Varicella-zoster immunoglobulin (or intravenous immune globulin) should be given to an HIV-infected child who is exposed to varicella. Immune globulin is indicated for the HIVinfected child who is exposed to measles, regardless of immunization status.

Antiretroviral Therapy

Antiretroviral therapy is indicated for most HIV-infected children. Recommendations regarding antiretroviral therapy are rapidly changing. In general, treatment is indicated for children who are symptomatic, have evidence of immunosuppression, or are <12 months of age. Treatment should consist of at least three antiretroviral agents, which is more effective than monotherapy. A protease inhibitor or a non-nucleoside reverse transcriptase inhibitor should be part of the regimen whenever possible. The desired goal of therapy is to decrease the viral load in the blood to undetectable levels.

FUNGAL INFECTIONS

Infections Caused by Dimorphic Pathogenic Fungi

Histoplasma, Blastomyces, and Coccidioides can cause localized and disseminated disease in normal and immunocompromised hosts, but most frequently cause asymptomatic infection. Sporothrix schenckii causes lymphocutaneous and cutaneous disease, usually without systemic signs and symptoms. The epidemiology and major clinical features of the dimorphic pathogenic fungi are summarized in Table 49.1.

Histoplasma capsulatum infection is endemic in the Ohio, Mississippi, and Missouri river valleys, and the skin test results of more than 50% of persons living in areas of endemicity are positive for the organism. H. capsulatum can be found in caves, attics, old buildings, and animal roosts. Person-to-person or animal-to-human transmission does not occur.

Ninety-five percent of infections are asymptomatic. Symptomatic infection may present with pulmonary, cutaneous, or disseminated disease. Most pulmonary disease is mild and brief and may be accompanied by hilar adenopathy and a mediastinal mass. More severe disease can develop, and may be accompanied by erythema nodosum,
hepatosplenomegaly, and migratory arthritis. Disseminated disease may be acute, subacute, or chronic and most commonly involves the liver, spleen, lymph nodes, adrenal glands, and bone marrow. Eighty percent of cases of disseminated disease occur in immunosuppressed hosts, especially patients with malignancy and HIV infection. An acute form of histoplasmosis, most common in infants, manifests as overwhelming infection associated with high fever, hepatosplenomegaly, lymphadenopathy, pneumonia, and pancytopenia.

TABLE 49.1 EPIDEMIOLOGY AND CLINICAL FEATURES OF DIMORPHIC PATHOGENIC FUNGI

Organism	Epidemiology	Clinical Features of Symptomatic Infection
Histoplasma capsulatum	Ohio and Mississippi river valleys; bat or bird droppings; caves	Acute influenza-like pulmonary illness
		Hilar adenopathy, mediastinal mass
		Disseminated disease in infants: fever, hepatosplenomegaly, adenopathy, pancytopenia
Blastomyces dermatitidis	Southeastern and central states; Uncommon in children	Acute pneumonia
	Southeastern and central states; Uncommon in children	Cutaneous and bone involvement
		Chronic forms common
Coccidioides immitis	Southwestern United States	Acute pneumonia
		Disseminated disease with meningitis
		Bone and cutaneous involvement
		Hypersensitivity reactions (erythema nodosum, arthralgias/ arthritis)
Sporothrix schenckii	Missouri and Mississippi river valleys. Rosebushes, barberry, grass species. Disease of gardeners, farmers	Lymphocutaneous or cutaneous disease
		Papule at inoculation site
		Ulcers and nodules along lymphatic chain. Satellite lesions