Important note: Information in this article was accurate in December 2004. The state of the art may have changed since the publication date.MMWR Recommendations and Reports - December 3, 2004 / 53(RR14);1-63
Centers for Disease Control and Prevention
Recommendations from CDC, the National Institutes of Health, and the Infectious Diseases Society of America
Prepared by
Lynne M. Mofenson, M.D.1, James Oleske, M.D.2, Leslie Serchuck, M.D.1, Russell Van Dyke, M.D.3, Cathy Wilfert, M.D.4
1National Institutes of Health, Bethesda, Maryland
2New Jersey Medical School, Newark, New Jersey
3Tulane University School of Medicine, New Orleans, Louisiana
4Elizabeth Glaser Pediatric AIDS Foundation, Chapel Hill, North Carolina
The material in this report originated in the Office of the Director, National Center for HIV, STD and TB Prevention, Janet L. Collins, M.D., Acting Director.
Corresponding author: Lynne M. Mofenson, M.D., Pediatric, Adolescent and Maternal AIDS Branch, National Institute of Child Health and Human Development, National Institutes of Health, 6100 Executive Blvd., Room 4B11, Rockville, MD 20852. Telephone: 301-435-6870; Fax: 301-496-8678.
In 2001, CDC, the National Institutes of Health, and the Infectious Diseases Society of America convened a working group to develop guidelines for therapy of human immunodeficiency virus (HIV)-associated opportunistic infections to serve as a companion to the Guidelines for Prevention of Opportunistic Infections Among HIV-Infected Persons. In recognition of unique considerations related to HIV infection among infants, children, and adolescents, a separate pediatric working group was established.
Because HIV-infected women coinfected with opportunistic pathogens might be more likely to transmit these infections to their infants than women without HIV infection, guidelines for treating opportunistic pathogens among children should consider treatment of congentially acquired infections among both HIV-exposed but uninfected children and those with HIV infection. In addition, the natural history of opportunistic infections among HIV-infected children might differ from that among adults. Compared with opportunistic infections among HIV-infected adults, which are often caused by reactivation of pathogens acquired before HIV infection when host immunity was intact, opportunistic infections among children often reflect primary acquisition of the pathogen and, among children with perinatal HIV infection, infection acquired after HIV infection has been established and begun to compromise an already immature immune system. Laboratory diagnosis of opportunistic infections can be more difficult with children. Finally, treatment recommendations should consider differences between adults and children in terms of drug pharmacokinetics, dosing, formulations, administration, and toxicities. This report focuses on treatment of opportunistic infections that are common in HIV-exposed and infected infants, children, and adolescents in the United States.
In 1995, the U.S. Public Health Service (USPHS) and the Infectious Diseases Society of America (IDSA) developed guidelines for preventing opportunistic infections among adults, adolescents, and children infected with human immunodeficiency virus (HIV) (1). These evidence-based guidelines, developed for health-care providers and patients, were revised in 1997, 1999, and 2002 (2--4). Although individual guidelines for treatment of different opportunistic infections can be found in multiple sources, a compilation of recommendations for treatment and management of common HIV-associated opportunistic infections into a single document has not been available. As a result, in 2001, the National Institutes of Health (NIH), IDSA, and CDC convened a working group to develop guidelines for therapy of HIV-associated opportunistic infections, with a goal of providing evidence-based guidelines for health-care providers on treatment and prophylaxis. In recognition of unique considerations for HIV-infected infants, children, and adolescents, including differences between adults and children in mode of acquisition, natural history, diagnosis, and treatment of HIV-related opportunistic infections, a separate pediatric guidelines writing group was established.
In 1998, the Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children, convened by the Francois-Xavier Bagnoud Center (FXBC), published guidelines for treatment of HIV and opportunistic infections among children in a special supplement to Pediatrics (5). However, since these guidelines were published, advances have been made in laboratory and clinical research related to individual opportunistic infections, and use of highly active antiretroviral therapy (HAART) has dramatically increased in HIV-infected children, changing the epidemiology and presentation of opportunistic infections among children and adults. Members of the pediatric guidelines writing group for this report, in consultation with members of the FXBC's Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children and other infectious disease specialists, have developed this document focused on treatment of HIV-associated opportunistic infections among infants and children.
An important mode of acquisition of opportunistic infections and HIV infection among children is from an infected mother to her child. HIV-infected women co-infected with opportunistic pathogens might be more likely to transmit these infections to their infants than women without HIV infection. For example, greater rates of perinatal transmission of hepatitis C and cytomegalovirus have been reported from HIV-infected than uninfected women (6,7). In addition, HIV-infected women or HIV-infected family members co-infected with certain opportunistic pathogens might be more likely to transmit these infections horizontally to their children, resulting in an increased likelihood of primary acquisition of such infections in the young child. For example, Mycobacterium tuberculosis infection among children primarily reflects acquisition from family members with active tuberculosis (TB) disease, and increase in the incidence and prevalence of tuberculosis among HIV-infected persons is well documented. HIV-exposed or -infected children in the United States might have a higher risk for exposure to M. tuberculosis than comparably aged children in the general U.S. population because of residence in households with HIV-infected adults (8). Therefore, infections with opportunistic pathogens might affect not just infants who are themselves HIV-infected but also infants who are uninfected with HIV but who become infected by the pathogen because of transmission from HIV-infected mothers or family members with co-infections. Guidelines for treatment of opportunistic infections in children must also include consideration of the treatment of infections among uninfected and HIV-infected children.
The natural history of opportunistic infections among children might differ from that observed among HIV-infected adults. Many opportunistic infections in adults are secondary to reactivation of previously acquired opportunistic pathogens, which were often acquired before HIV infection at a time when host immunity was intact. However, opportunistic infections among HIV-infected children more often reflect primary infection with the pathogen. In addition, among children with perinatal HIV infection, the primary infection with the opportunistic pathogen is occurring after HIV infection is established when the child's immune system might already be compromised. This can lead to different manifestations of disease associated with the pathogen among children than among adults. For example, young children with TB are more likely to have nonpulmonic and disseminated infection than adults, even without concurrent HIV infection.
Multiple difficulties exist in making laboratory diagnosis of various infections in children. Diagnosis is often compounded by a child's inability to describe the symptoms of disease. For infections where the primary diagnostic modality is the presence of antibody (e.g., the hepatitis viruses and cytomegalovirus), the ability to make a diagnosis in young infants is complicated by transplacental transfer of maternal antibody that can persist in the infant for 12--15 months. Assays capable of directly detecting the pathogen are required to definitively diagnose such infections in infants. In addition, diagnosing the etiology of lung infections among children can be difficult because they do not generally produce sputum, and more invasive procedures might be needed.
Data related to the efficacy of various therapies for opportunistic infections in adults can generally be extrapolated to children, but issues related to drug pharmacokinetics, formulation, ease of administration, and drug dosing and toxicity require special considerations among children. Young children in particular metabolize drugs differently from adults and older children. However, data on appropriate drug dosing recommendations for children aged <2 years often are lacking.
The frequency of different opportunistic pathogens among HIV-infected children in the pre-HAART era varied by age, pathogen, previous opportunistic infection, and immunologic status (9). In the pre-HAART era, the most common opportunistic infections among children in the United States (event rates >1.0/100 child-years) were serious bacterial infections (with pneumonia, often presumptively diagnosed, and bacteremia being most common), herpes zoster, disseminated Mycobacterium avium complex (MAC), Pneumocystis jiroveci (formerly carinii) pneumonia (PCP), and candidiasis (esophageal and tracheobronchial disease). Less commonly observed opportunistic infections (event rate <1.0/100 child-years) included cytomegalovirus disease, cryptosporidiosis, tuberculosis, systemic fungal infections, and toxoplasmosis. History of a previous acquired immunodeficiency syndrome (AIDS)-defining opportunistic infection was a predictor of developing a new infection. Although the majority of infections occurred among children who were substantially immunocompromised, serious bacterial infections, herpes zoster, and TB occurred across the spectrum of immune status.
Descriptions of opportunistic infections in the HAART era among children have been limited. As with HIV-infected adults, substantial decreases in mortality and morbidity, including opportunistic infections, have been observed among children receiving HAART (10). Although the number of opportunistic infections has decreased, the relative prevalence of AIDS-defining infections remains similar to that observed in the pre-HAART era (11).
In comparison with recurrent serious bacterial infections, few of the protozoan, fungal, or viral opportunistic infections complicating HIV are curable with available treatments. Successful implementation and maintenance of HAART, resulting in improved immune status, has been established as the most important factor in control of opportunistic infections among both HIV-infected adults and children (12). For many opportunistic infections, following treatment of the initial infectious episode, secondary prophylaxis in the form of suppressive therapy is indicated to prevent recurrent clinical disease (4).
These guidelines serve as a companion to the USPHS/IDSA Guidelines for the Prevention of Opportunistic Infections Among HIV-Infected Persons and the Guidelines for the Treatment of Opportunistic Infections in Persons Infected with the Human Immunodeficiency Virus, which is focused on HIV-infected adults. Treatment of opportunistic infections is an evolving science, and availability of new agents or clinical data on existing agents might change therapeutic options and preferences. As a result, these recommendations will need to be periodically updated.
During development of these guidelines, members of the pediatric treatment guidelines writing group and of the Working Group on Antiretroviral Therapy and Medical Management of HIV-Infected Children reviewed published manuscripts and abstracts presented at professional meetings related to treatment of selected pathogens among children and adults. Because the guidelines are targeted to HIV-exposed and infected children in the United States, the opportunistic pathogens discussed are those common to U.S. children and do not include certain pathogens (e.g., Penicillium marneffei) that might be seen more frequently in resource-poor countries. The document is organized to provide information about the epidemiology, clinical presentation, diagnosis, and treatment for each pathogen. Each treatment recommendation is accompanied by a rating that includes a letter and a Roman number and is similar to the rating systems used in other USPHS/IDSA guidelines (13). The letter indicates the strength of the recommendation, which is based on the opinion of the Working Group, and the Roman numeral reflects the nature of the evidence supporting the recommendation (Box).
Appendices at the end of this document summarize the treatment recommendations for each of the opportunistic pathogens (Appendix A), provide information on pediatric drug preparations and major toxicities (Appendix B), and provide information about clinically significant drug interactions for the drugs recommended for treatment of individual opportunistic infections among children (Appendix C).
Epidemiology
Pneumocystis microbes are classified in the fungus kingdom on the basis of DNA analysis but also share biologic characteristics with protozoa. Additional DNA analyses have demonstrated that Pneumocystis organisms in different mammals are quite different, which has led to changes in taxonomy (14). The organism that infects humans and causes PCP is now named Pneumocystis jiroveci; P.carinii refers to the organism that is found only in rats. P. jiroveci is usually acquired in childhood; serum antibodies are found in >80% of children aged 2--4 years (15). Immunocompetent infants with P. jiroveci infection might have either mild respiratory symptoms or are asymptomatic.
PCP remains the most common AIDS-indicator disease among HIV-infected children, accounting for 33% of AIDS cases overall. The highest incidence of PCP in HIV-infected children is the first year of life, with cases peaking at age 3--6 months (16,17). PCP accounts for 57% of AIDS-defining conditions among infants aged <1 year. The mortality rate among children with PCP is high. Among AIDS cases reported to CDC, before the availability of HAART therapy, 35% of children with PCP died within 2 months of diagnosis, and the estimated median survival time was 19 months (16,18).
CD4+ cell counts are not a good indicator of risk for PCP in infants aged <1 year; many young infants with PCP have CD4+ cell counts >1,500/µL, and counts can drop rapidly shortly before PCP develops in infants (19--21). Since publication of the 1995 PCP prophylaxis guidelines recommending initiation of primary PCP prophylaxis in all infants born to HIV-infected women for the first year of life (or until lack of HIV infection is documented) (18,22), PCP has become unusual among HIV-infected infants born to women who know their HIV serostatus during or soon after pregnancy. However, PCP is still seen in infants born to women with unrecognized HIV infection (19,21).
Clinical Manifestations
Clinical features of PCP among HIV-infected children are similar to those in adults (i.e., fever, tachypnea, dyspnea, and cough), and the severity of these signs and symptoms might vary from child to child. Onset can be abrupt or insidious with nonspecific symptoms (e.g., mild cough, dyspnea, poor feeding, and weight loss). Certain patients might not be febrile, but almost all patients will have tachypnea by the time pneumonitis is observed on chest radiograph (23). Physical examination might show bibasilar rales with evidence of respiratory distress and hypoxia.
Extrapulmonary pneumocystosis is seen in <2.5% of HIV-infected adults (24); it is uncommon among HIV-infected children (25,26). It can occur without concurrent PCP and can be located at multiple noncontiguous sites. Sites have included ear, eye, thyroid, spleen, gastrointestinal tract, peritoneum, stomach, duodenum, small intestine, transverse colon, liver, and pancreas and less frequently, adrenal glands, bone marrow, heart, kidney and ureter, lymph nodes, meninges and cerebral cortex, and muscle.
Infants with dual infection with cytomegalovirus (CMV) and P. jiroveci might have more severe pneumonic disease and are more likely to require assisted ventilation, receive corticosteroids, or die than those with PCP alone (27). Whether corticosteroids for PCP among children with dual P. jiroveci/CMV infection increases the risk for CMV dissemination to the lung is unclear.
Diagnosis
The majority of children with PCP have substantial hypoxia with low arterial oxygen pressure and an alveolar-arterial oxygen gradient of >30 mm/Hg. Lactic dehydrogenase (LDH) is often increased but is not specific for PCP. Serum albumin might be depressed. Chest radiographs most commonly indicate bilateral diffuse parenchymal infiltrates with "ground-glass" or reticulogranular appearance, but they also might be normal or indicate only mild parenchymal infiltrates. The earliest infiltrates are perihilar, progressing peripherally before reaching the apical portions of the lung. Rarely, lobar, cavitary, nodular or miliary lesions, pneumothorax, or pneumomediastinum are observed (23).
Definitive diagnosis of PCP requires demonstration of the organism in pulmonary tissues or fluids. Diagnostic procedures are the same as used for adults with suspected PCP, but selected procedures might be more difficult to perform in children.
Induced sputum analysis, where the patient produces sputum after inhalation of nebulized 3% hypertonic saline, might be difficult among children aged <2 years because of small airways and poor ability to produce sputum. Complications can include nausea, vomiting, and bronchospasm. Sensitivity of induced sputum analysis ranges from 25%--90%; because negative predictive value is only 48%, following a negative induced sputum sample with bronchoalveolar lavage for definitive diagnosis might be necessary.
Bronchoscopy with bronchoalveolar lavage is the diagnostic procedure of choice for infants. Sensitivity ranges from 55%--97% and might be positive for at least 72 hours after PCP treatment has been initiated; treatment should not be delayed while awaiting results. Complications included hemoptysis, pneumothorax, transient increase in hypoxemia, transient increase in pulmonary infiltrates at the lavage site, and postbronchoscopy fever.
Fiberoptic bronchoscopy with transbronchial biopsy is not recommended unless bronchoalveolar lavage is negative or nondiagnostic despite the child having a clinical picture consistent with PCP. Sensitivity is 87%--95%, and cysts can be identified up to 10 days after initiation of treatment (up to 4--6 weeks in certain patients). Complications include pneumothorax and hemorrhage; this procedure is contraindicated among children with thrombocytopenia.
Open-lung biopsy is the most sensitive diagnostic technique but because it requires thoracotomy and often chest tube drainage, is not recommended routinely. Histopathology shows alveoli filled with eosinophilic, acellular, proteinaceous material that contains cysts and trophozoites but few inflammatory cells. Complications include pneumothorax, pneumomediastinum, and hemorrhage.
Three types of stains can be used to diagnose P. jiroveci organisms in specimens. Gomori's methenamine-silver stains the cyst wall brown or black. Toluidine blue stains the cyst wall blue or lavender and also stains fungal elements. Giemsa or Wright's stains stain the trophozoites and intracystic sporozoites pale blue with a punctate red nucleus but, unlike other stains, these stains do not stain the cyst wall. Monoclonal immunofluorescent antibodies that stain the cyst wall also can be used for diagnosis and have enhanced specificity compared with the other methods.
Identification of P. jiroveci DNA sequences using polymerase chain reaction (PCR) assays in blood or serum, nasopharyngeal aspirates, and bronchoalveolar lavage specimens might be more sensitive in detecting infection in lavage specimens than standard cytologic stains among children (28). However, this is a research tool and is not available at some institutions.
Coinfection with other organisms (e.g., CMV or pneumococcus) has been reported in HIV-infected children (27,29,30). Children with dual infections might have more severe disease. Although the presence of CMV in lung secretions of children with PCP might indicate colonization that does not require therapy, the presence of P. jiroveci is always an indication for treatment.
Treatment
Trimethoprim/sulfamethoxazole (TMP/SMX) is the recommended treatment for PCP (AI). The dose for HIV-infected children aged >2 months is 15--20 mg/kg body weight/day of the TMP component (75--100 mg/kg of SMX component) adminstered intravenously in 3--4 divided doses, with the dose infused over 1 hour for 21 days (AI). After the acute pneumonitis has resolved, children with mild to moderate disease who do not have malabsorption or diarrhea can be adminstered oral treatment with the same dose of TMP/SMX in 3--4 divided doses to complete a 21--day course.
Adverse reactions to TMP/SMX reported in children include rash (including erythema multiforme and rarely Stevens Johnson syndrome), hematologic abnormalities (e.g., neutropenia, thrombocytopenia, megaloblastic, or aplastic anemia), gastrointestinal complaints (usually mild), hepatitis, and renal disorders (e.g., interstitial nephritis) (31,32). The overall frequency of adverse reactions appears to be lower among HIV-infected children than adults; approximately 15% of children have substantial adverse reactions to TMP/SMX (23). For mild or moderate skin rash, TMP/SMX can be temporarily discontinued and restarted when the rash has resolved. If an urticarial rash or Stevens-Johnson syndrome occurs, TMP/SMX should be discontinued and not readministered (EIII).
Pentamidine isothionate (4 mg/kg/day once daily administered intravenously over 60--90 minutes) is recommended for patients intolerant of TMP/SMX or who demonstrate clinical treatment failure after 5--7 days of TMP/SMX therapy (AI). No evidence exists for synergistic or additive effects on efficacy of these agents; therefore, because of potential increased toxicity, their combined use is not recommended (DIII). Among patients with clinical improvement after 7--10 days of intravenous therapy with pentamidine, an oral regimen (e.g., atovaquone) might be considered to complete a 21--day course (BIII).
The most common adverse drug reaction topentamidine is renal toxicity, which usually occurs after 2 weeks of therapy and can be averted by adequate hydration and careful monitoring of renal function and electrolytes. Severe hypotension (particularly if infused rapidly), prolonged QT interval (torsades de pointes), and cardiac arrhythmias can occur. Hypoglycemia (usually after 5--7 days of therapy) or hyperglycemia, hypercalcemia, hyperkalemia, pancreatitis, and insulin-dependent diabetes mellitus have also been reported. A metallic or bitter taste might be experienced. Serious adverse reactions to pentamidine have been reported in approximately 17% of children receiving pentamidine (33). Care should be taken if administering this drug with other nephrotoxic agents (e.g., aminoglycosides, amphotericin B, cisplatin, or vancomycin) or if coadministered with agents associated with pancreatitis (e.g., didanosine).
Atovaquone is an alternative for treatment of mild to moderately severe PCP in adults (BI). Data are limited for children; dosage is 30--40 mg/kg/day in 2 divided doses given orally with fatty foods. Food increases the bioavailability of atovaquone 1.4-fold over that achieved with the fasting state. Infants aged 3--24 months might require a higher dosage of 45 mg/kg/day (34) (AII). Atovaquone concentration is increased with coadminstration of fluconazole and prednisone and decreased by coadministration with acyclovir, opiates, cephalosporins, rifampin, and benzodiazepines. Most adverse reactions occur after the first week of therapy. Skin rashes (10%--15%), nausea, and diarrhea can occur. Elevated liver enzymes also might be observed.
Clindamycin/primaquine has been used for treatment of mild to moderate PCP among adults (BI); data for children are not available (CIII). Primaquine is contraindicated among patients with glucose-6-dehydrogenase deficiency associated with the possibility of inducing hemolytic anemia. Dose information for treatment of PCP is available only for adults. For patients weighing <60 kg, clindamycin 600 mg intravenously every 6 hours for 10 days, then 300--450 mg orally every 6 hours to complete 21 days of treatment is recommended. Primaquine is adminstered as 30 mg of the base orally for 21 days. Dosing for children is based on use of these drugs for treatment of other infections: the usual pediatric dose of clindamycin for treatment of bacterial infections is 10 mg/kg every 6 hours, and the pediatric dose of primaquine equivalent to an adult dose of 30 mg base (when used for malaria) is 0.3 mg/kg of the base daily. Adverse reactions include skin rashes, nausea, and diarrhea.
Trimetrexate glucuronate with leucovorin (folinic acid) has been used as initial therapy in severe PCP in adults (BI); data are limited for children (CIII). The dose is 45 mg/m2/day of trimetrexate glucuronate for 21 days. Leucovorin should be administered at 20 mg/m2 every 6 hours for 24 days.
Dapsone/trimethoprim is effective in treatment of mild-to-moderate PCP among adults (BI); data on toxicity and efficacy among children are not available (CIII). The dose for adults of dapsone is 100 mg orally once daily and trimethoprim 15 mg/kg divided into 3 daily doses orally, administered for 21 days. Among children aged <13 years, a dapsone dose of 2 mg/kg/day is required to achieve therapeutic levels in children (35) (AII). The pediatric dose of trimethoprim is 15 mg/kg divided into 3 daily doses. The primary adverse reaction is reversible neutropenia; other reactions include skin rashes, elevated serum transaminases, anemia, and thrombocytopenia.
On the basis of studies in adults, a short course of corticosteroids might be indicated in some cases of PCP of moderate or great severity, started within 72 hours of diagnosis (AI). Pediatric studies have indicated reduction in acute respiratory failure, decreased need for ventilation, and decrease in mortality with early use of corticosteriods in HIV-infected children with PCP (36--38). Indications for corticosteroid treatment include a PaO2 value of <70 mm Hg or an alveolar-arterial gradient of >35 mm Hg. Doses in children varied between studies. Alternative regimens include 1) prednisone on days 1--5, 40 mg twice daily; days 6--10, 40 mg once daily; days 11--21, 20 mg once daily; 2) prednisone (or methylprednisolone sodium) on days 1--5, 1 mg/kg twice daily; day 6--10, 0.5 mg/kg twice daily; days 11--21, 0.5 mg/kg once daily; or 3) methylprednisolone (intravenous) on days 1--7, 1 mg/kg every 6 hours; days 8--9, 1 mg/kg twice daily; days 10--11, 0.5 mg/kg twice daily; days 12--16, 1 mg/kg once daily.
Some case reports about children have documented improved pulmonary function with use of surfactant in cases of severe disease (e.g., respiratory distress syndrome with established respiratory failure requiring ventilation) (39--41) (CIII).
Among HIV-infected children, lifelong suppression is indicated following treatment for PCP to prevent recurrence; details on secondary prophylaxis (maintenance therapy) have been published (4). Safety of discontinuation of secondary prophylaxis after immune reconstitution with HAART in children has not been studied extensively.
Epidemiology
The major mode of transmission of Toxoplasma gondii infection among infants and young children is congenital, occurring almost exclusively among neonates born to women who sustain primary Toxoplasma infection during pregnancy. The incidence of congenital toxoplasmosis in the United States is an estimated one case per 1,000--12,000 live-born infants (42,43) and is believed to have decreased substantially during the preceding 20 years. Older children, adolescents, and adults typically acquire Toxoplasma infection by eating poorly cooked meat that contains parasitic cysts or by unintentionally ingesting sporulated oocysts in soil or contaminated food or water.
The overall risk for maternal-fetal transmission in women without HIV infection who acquire primary Toxoplasma infection during pregnancy is 29% (95% confience interval [CI] = 25%--33%) (44). The risk for congenital infection is low among infants born to women who become infected during the first trimester (range: 2%--6%) but increases sharply thereafter, with a risk as high as 81% for women acquiring infection during the last few weeks of pregnancy (44). Infection of the fetus in early gestation usually results in more severe involvement, compared with milder disease when infection occurs late in gestation.
The prevalence of latent Toxoplasma infection among women with and without HIV infection in the United States was assessed in a cross-sectional study of 2,525 non-pregnant women enrolled in the Women's Interagency Health Study (45). The prevalence of Toxoplasma seropositivity was 15% and did not differ by HIV infection status. A few cases of mother-to-infant transmission of Toxoplasma in HIV-infected women have been reported (46--50). Perinatal transmission of Toxoplasma gondii from women without HIV infection who have chronic Toxoplasma infection acquired before pregnancy is uncommon (51). However, in the setting of HIV co-infection, perinatal transmission of toxoplasma has been observed among women with chronic toxoplasma infection (transmission rate: <4%), presumably because of reactivation of replication of the organism among women with severe immune suppression (46--49).
AIDS-defining infection of the central nervous system (CNS) with Toxoplasma gondii is uncommon amongHIV-infected children. It was reported as an AIDS-indicator condition in <1% of pediatric AIDS cases, even before the advent of HAART (52). In most cases of Toxoplasma encephalitis among HIV-infected children, infection is considered to have occurred in utero (53,54). More rarely, it has also been reported among older HIV-infected pediatric patients, presumably with primary acquired toxoplasmosis (54--56).
Clinical Manifestations
In studies of nonimmunocompromised infants with congenital toxoplasmosis, the majority of infants (70%-90%) are asymptomatic at birth; however, the majority of asymptomatic children develop late sequelae (e.g., retinitis, visual impairment, and intellectual or neurologic impairment) with the interval until the onset of their symptoms ranging from several months to years. When symptoms do occur in newborns, either of two presentations can be observed: generalized disease or predominantly neurologic disease. Symptoms can include maculopapular rash, generalized lymphadenopathy, hepatosplenomegaly, jaundice, hematologic abnormalities including anemia, thrombocytopenia and neutropenia, and substantial CNS disease, including hydrocephalus, intracerebral calcification, microcephaly, chorioretinitis, and seizures (57).
Similarly, toxoplasmosis acquired after birth is most often initially asymptomatic. When symptoms occur, they are frequently nonspecific and can include malaise, fever, sore throat, myalgia, lymphadenopathy (cervical), and a mononucleosis-like syndrome featuring a maculopapular rash and hepatosplenomegaly.
Toxoplasma encephalitis should be considered among all HIV-infected children with new neurologic findings. Although focal findings are more typical, the initial presentation can be variable and reflect diffuse CNS disease. Other symptoms include fever, reduced alertness, and seizures.
Isolated ocular toxoplasmosis is rare and usually occurs in association with CNS infection. As a result, a neurologic examination is indicated for children who have had Toxoplasma chorioretinitis diagnosed. Ocular toxoplasmosis appears as white retinal lesions with little associated hemorrhage; visual loss might be observed initially.
Less frequently observed presentations among HIV-infected children with reactivated chronic toxoplasmosis include systemic toxoplasmosis, pneumonitis, hepatitis, and cardiomyopathy/myocarditis (49,58).
Diagnosis
HIV-infected women might be at increased risk for transmitting Toxoplasma gondii to their fetuses, and serologic testing for Toxoplasma should be performed on all HIV-infected pregnant women. All infants whose mothers are both HIV-infected and seropositive for Toxoplasma should be evaluated for congenital toxoplasmosis (59). Congenital toxoplasmosis can be diagnosed by using enzyme immunoassay or an immunosorbent assay to detect the presence of Toxoplasma-specific IgM, IgA, or IgE in neonatal serum within the first 6 months of life or persistence of specific IgG antibody beyond age 12 months. IgA might be more sensitive for detection of congenital infection than IgM or IgE (60--62). However, approximately 20%--30% of infants with congenital toxoplasmosis will not be identified in the neonatal period with IgA or IgM assays (63).
Serologic testing is the major method of diagnosis, but interpretation of available assays is often confusing and difficult. Using the services of a specialized reference laboratory that is capable of performing serology, isolation of organisms, and PCR, and offers assistance in interpreting results, especially when attempting to diagnose congenital toxoplasmosis, can be helpful.
Additional methods that can be used to diagnose infection in the newborn include isolation of the Toxoplasma parasite by mouse inoculation, or inoculation in tissue cultures of cerebrospinal fluid (CSF), urine, placental tissue, amniotic fluid, or infant blood. Toxoplasma gondii DNA can be detected by PCR performed in a reference laboratory on body fluids (e.g., white blood cells, CSF, amniotic fluid, or tissues) (60,62,63). If a possible diagnosis of congenital toxoplasmosis at the time of delivery is uncertain, an evaluation of the neonate should be undertaken and include ophthalmologic, auditory, and neurologic examinations; lumbar puncture; and imaging of the head (either computerized tomography or magnetic resonance imaging scans) to determine whether hydrocephalus or calcifications are present.
In the United States, routine Toxoplasma serologic screening of HIV-infected children whose mothers do not have toxoplasmosis is not recommended because of its low prevalence. However, in regions with high incidence of Toxoplasma infection, serologic testing might be selectively considered for HIV-infected children aged >12 months. HIV-infected adolescents without a history of previous Toxoplasma infection should undergo serologic testing.
A presumptive diagnosis of CNS toxoplasmosis is based on clinical symptoms, serologic evidence of infection, and the presence of a space-occupying lesion on imaging studies of the brain. Cases of Toxoplasma encephalitis have been reported in persons without Toxoplasma-specific IgG antibodies; therefore, negative serology does not exclude that diagnosis. Computerized tomography of the brain might indicate multiple, bilateral, ring-enhancing lesions in CNS toxoplasmosis, especially in the basal ganglia and cerebral corticomedullary junction. Magnetic resonance imaging is more sensitive and will confirm basal ganglia lesions in the majority of patients. F-fluoro-2-deoxyglucose-positive emission tomography can be helpful in distinguishing Toxoplasma abscesses from primary CNS lymphoma, but the accuracy is not high and this test is not widely available.
Definitive diagnosis of Toxoplasma encephalitis requires histologic or cytologic confirmation by brain biopsy, which might demonstrate leptomeningeal inflammation, microglial nodules, gliosis, and Toxoplasma cysts. Biopsy should be considered when early neurologic deterioration is present despite empiric treatment or among children who fail to respond to anti-Toxoplasma therapy after 10--14 days.
Treatment
Pregnant women with suspected or confirmed primary toxoplasmosis and newborns with possible or documented congenital Toxoplasmosis should be managed in consultation with an appropriate specialist. If an HIV-infected woman has a symptomatic Toxoplasma infection during pregnancy, empiric therapy of the newborn should be strongly considered whether or not the mother was treated during pregnancy (BIII).
The preferred treatment for congenital toxoplasmosis is pyrimethamine (loading dose of 2 mg/kg body weight/day for 2 days, then 1 mg/kg/day for 2--6 months, followed by 1 mg/kg adminstered three times a week) combined with sulfadiazine (50 mg/kg/dose twice daily), with supplementary leucovorin (folinic acid) to minimize pyrimethamine-associated hematologic toxicity (AII). Although the optimal duration of therapy is undefined, the recommended duration of treatment of congenital toxoplasmosis for infants without HIV infection is 12 months (AII). Absent definitive data, the same recommendation applies to HIV-infected children with congenital toxoplasmosis.
For children without HIV infection who have mild congenital toxoplasmosis, certain experts alternate pyrimethamine/sulfadiazine/folinic acid monthly with spiramycin (50 mg/kg orally twice daily) from the seventh through the 12th month of treatment (CIII). However, among children with moderate to severe disease and those with HIV infection, the full 12-month regimen of pyrimethamine/sulfadiazine should be administered (AII).
HIV-infected children with acquired CNS, ocular, or systemic toxoplasmosis should be treated with pyrimethamine (2 mg/kg/day for 3 days, followed by 1 mg/kg/day) and leucovorin (10--25 mg/day) plus sulfadiazine (25--50 mg/kg/dose given four times daily) (AI). Acute therapy should be continued for 6 weeks, assuming clinical and radiological improvement (BII). Longer courses of treatment might be required in cases of extensive disease or poor response after 6 weeks.
Pyrimethamine can be associated with rash (including Stevens-Johnson syndrome) and nausea. The primary toxicity of pyrimethamine is reversible bone marrow suppression (i.e., neutropenia, anemia, and thrombocytopenia). A complete blood count should be performed at least weekly while the child is on daily pyrimethamine and at least monthly while on less than daily dosing (AIII). Leucovorin (folinic acid) should always be administered with pyrimethamine; increased doses of leucovorin might be required in the event of marrow suppression. Because of the long half-life of pyrimethamine, leucovorin should be continued 1 week after pyrimethamine has been discontinued.
Adverse effects of sulfadiazine include rash, fever, leukopenia, hepatitis, gastrointestinal symptoms (nausea, vomiting, and diarrhea), and crystalluria. The primary alternative for sulfadiazine in patients who develop sulfonamide hypersensitivity is clindamycin (5.0--7.5 mg/kg orally 4 times daily; maximum 600 mg/dose), adminstered with pyrimethamine and leucovorin (AI). Clindamycin can be associated with fever, rash, and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea, including pseudomembranous colitis) and hepatotoxicity.
Azithromycin (900--1,200 mg/day) also has been used with pyrimethamine and leucovorin among sulfa-allergic adults instead of clindamycin (BII), but this regimen has not been studied among children (CIII).
Another alternative in adults is atovaquone (1,500 mg orally twice daily, adminstered with meals) plus pyrimethamine and leucovorin, or atovaquone with sulfadiazine alone, or atovaquone as a single agent among patients intolerant to both pyrimethamine and sulfadiazine (BII); however, these regimens have not been studied among children (CIII). Trimethoprim-sulfamethoxazole (5 mg/kg trimethoprim plus 25 mg/kg sulfamethoxazole intravenously or orally adminstered twice daily) alone has been used as an alternative to pyrimethamine-sulfadiazine among adults (BI), but this has not been studied among children (CIII).
Corticosteriods (e.g., dexamethasone or prednisone) have been used among children with CNS disease when CSF protein is very elevated (i.e., >1,000 mg/dL) or with focal lesions with substantial mass effects (BIII). Because of the potential immunosuppressive effects of steroids, they should be discontinued as soon as possible.
Among HIV-infected children, lifelong suppression is indicated after treatment for toxoplasmosis to prevent recurrence; details on secondary prophylaxis (i.e., maintenance therapy) have been published (4). Safety of discontinuation of secondary prophylaxis after immune reconstitution with HAART among children has not been studied extensively.
Epidemiology
Cryptosporidium species are protozoal parasites that mainly cause enteric illness in humans and animals. The three most common species infecting humans are C. hominis (formerly C. parvum genotype 1 or human genotype), C. parvum (formerly C. parvum genotype 2 or bovine genotype), and C. meleagridis. In addition, infections with C. canis, C. felis, C. muris, and Cryptosporidium pig genotype have been reported in immunocompromised patients. Cryptosporidium parasites invade the gut mucosa, causing severe profuse, nonbloody, watery diarrhea leading to dehydration and malnutrition in immunocompromised hosts.
The parasite is transmitted by ingestion of oocysts excreted in the feces of infected animals and humans. The parasite is highly infectious, with an ID50 ranging from nine to 1,042 oocysts, depending on the isolate (64). Infection occurs when the ingested oocyst releases sporozoites, which attach to and invade the intestinal epithelial cells. The parasite has a predilection for the jejunum and terminal ileum (64).
Person-to-person transmission is common in child care centers. Outbreaks have been associated with ingestion of contaminated drinking water in large metropolitan areas and with public swimming pools. Foodborne and person-to-person spread also have been documented (64). Cryptosporidiosis has been reported in 3%--4% of HIV-infected children in the United States, but occurs more frequently among children outside of the United States, particularly in Africa (65).
Microspora species are obligate, intracellular, spore-forming protozoa that primarily cause moderate to severe diarrhea among children. Enterocytozoon bieneusi and Encephalitozoon intestinalis are the most common microsporidia that cause infection among patients with HIV infection. In addition to the Enterocytozoon and Encephalitozoon microsporidia genera, Nosema, Pleistophora, Trachipleistophora, Brachiola, and Vittaforma species have been implicated in human infections. The Microspora parasites develop in enterocytes and are excreted with feces and, like C. parvum, are transmitted by the fecal-oral route, which can include ingestion of contaminated food or water (66). Microsporidiosis has been reported in up to 7% of HIV-infected Thai children with acute and chronic diarrhea (67).
Clinical Manifestations
Frequent, usually nonbloody, watery, persistent diarrhea is the most common manifestation of both cryptosporidial and microsporidial infection, with abdominal cramps, fatigue, vomiting, anorexia, weight loss, and poor weight gain. Fever and vomiting are relatively common in children, mimicking viral gastroenteritis (65). Among immunocompromised children, chronic severe diarrhea can result in malnutrition, failure to thrive, and substantial intestinal fluid losses, resulting in severe dehydration and even death. Clinical history or physical examination does not allow differentiation of cryptosporidial or microsporidial infection from those caused by other pathogens.
Cryptosporidium can migrate into the bile duct and result in inflammation of the biliary epithelium, acalculous cholecystitis, and sclerosing cholangitis. Symptoms include fever and right upper abdominal pain and elevated alkaline phosphatase. Although infection is usually limited to the gastrointestinal tract, pulmonary or disseminated infection also can occur among immunocompromised children. In addition to acute and chronic diarrhea, microsporidia species have been described in cases of hepatitis, peritonitis, keratoconjunctivitis, myositis, cholangitis, sinusitis, and disseminated CNS disease.
Diagnosis
For diagnosis of cryptosporidiosis, stool samples are concentrated by using the sucrose flotation or formalin-ethyl acetate method to concentrate the oocysts. A sample is then stained by using a modified Kinyoun acid-fast stain and examined for small (4--6 um in diameter) acid-fast positive oocysts. Monoclonal antibody-based fluorescein-conjugated stain for oocysts in stool and an enzyme immunoassay to detect antigen in stool are preferred to staining methods because of enhanced sensitivity and specificity. Oocyst excretion can be intermittent; therefore, the parasite might not be detected in every stool. At least 3 stool samples should be submitted for oocyst evaluation. Organisms also can be identified on small intestinal biopsy or intestinal fluid samples.
For diagnosis of microsporidia infection, thin smears of unconcentrated stool-formalin suspension or duodenal aspirates can be stained with modified trichrome stain. Chemofluorescent agents (e.g., Calcofluor white) are helpful for the quick identification of spores in stool samples. Microsporidia spores are stained pink to red and are 1--3 um in size and ovoid and contain a distinctive equatorial-belt-like stripe.
Urine sediment examination by light microscopy can be used to identify microsporidia spores in disseminated disease with Encephalitozoonidae and Trachipleistophora. Enterocytozoon bieneusi is not associated with disseminated disease. Transmission electron microscopy is needed for speciation.
Endoscopy should be considered for all patients with chronic diarrhea of >2 months duration and negative stool examinations. Touch preparations are useful for rapid diagnosis (i.e., within 24 hours). Sensitive assays using PCR amplification of parasite DNA sequences extracted from stool or biopsy specimens have been developed for Cryptosporidium and Enterocytozoon bieneusi (68,69), but are research tools and not commercially available.
Treatment
Immune reconstitution resulting from HAART frequently results in clearance of Cryptosporidium and Microsporidium infections. Effective HAART is the recommended treatment for these infections (70) (AII). Supportive care with hydration, correction of electrolyte abnormalities, and nutritional supplementation should be provided (AIII). Antimotility agents should be used with caution among young children (CIII).
No consistently effective therapy is available for either cryptosporidiosis or microsporidiosis, and duration of treatment among HIV-infected persons is uncertain. Certain agents have demonstrated efficacy in decreasing the severity of symptoms among children. Nitazoxanide is approved for treatment of diarrhea caused by Cryptosporidium and Giardia lamblia among children and is available in a liquid formulation (BI for uninfected children and CIII HIV-infected children). An Egyptian clinical trial among 100 HIV-uninfected patients, half of them children, randomized patients to a 3-day course of nitazoxanide or placebo. Nitazoxanide therapy reduced the duration of both diarrhea and oocyst shedding; among children, clinical response was 88% with nitazoxanide and 38% with placebo (71). No substantial adverse events were reported, and adverse events that were reported were similar in the treatment and placebo groups in this study. A study in Zambia among 100 children aged 12--35 months, half HIV-infected, reported a clinical response of 56% with treatment compared with 23% with placebo among HIV-uninfected children, but among HIV-infected children, the drug was no more effective than placebo (72). However, in a study among HIV-infected adults in Mexico, 14 days of nitazoxanide resulted in 67% response using 1,000 mg twice daily and 63% using 500 mg twice daily, compared with 25% with placebo (73). One study among HIV-infected adults demonstrated clinical response in patients with CD4 cell count >50/µL but not those with CD4 cell count <50/µL (74). The recommended dose for children is 100 mg orally twice daily for children aged 1--3 years and 200 mg twice daily for children aged 4--11 years. A tablet preparation is not yet approved.
Certain specialists recommend paromomycin (25--35 mg/kg body weight/day orally in 2--4 divided doses; maximum dose: 500 mg four times daily) for the treatment of cryptosporidiosis in HIV-infected children (CIII). However, in a placebo-controlled trial in HIV-infected adults, paromomycin was no more effective than placebo for the treatment of symptomatic cryptosporidiosis (75).
Azithromycin has demonstrated some activity against C. parvum infection in a limited number of HIV-infected children (76) (CIII). An azithromycin regimen of 10 mg/kg per day on day 1 and 5 mg/kg per day on days 2--10 was successful in rapidly resolving enteric symptoms in three of four HIV-infected children with cryptosporidiosis (76). Oral hyperimmune bovine colostrum and oral immune globulin have variable benefits among immunocompromised patients with cryptosporidiosis (CIII).
For treatment of microsporidia infection, albendazole (dosage for person weighing <60 kg is 7.5 mg/kg orally twice daily; maximum dose: 400 mg orally twice daily) decreases diarrhea, sometimes with eradication of the organism (AII). Albendazole appears to be more effective for cases caused by Encephalitozoon intestinalis (77) and other microsporidia species but is not active against Enterocytozoon bienesi. Nitazoxanide has been used for treatment of Enterocytozoon bienesi infection among HIV-infected adults (78).
Fumagillin® (Sanofi-Synthelabo Laboratories, Gentilly, France) is an antibiotic derived from the fungus Aspergillus fumigatus, which has been used to treat microsporidiosis in animals and humans. In a placebo-controlled study of immunocompromised adults (including HIV-infected adults) with Enterocytozoon bieneusi microsporidiosis, fumagillin (20 mg/dose orally three times daily for 2 weeks) was associated with decreased diarrhea and clearance of microsporidial spores, which was not observed in placebo patients (79). Dose-related bone marrow toxicity was the principal adverse effect of fumagillin, with reversible thrombocytopenia and neutropenia being the most frequent adverse events. No data are available on use of fumagillin among HIV-infected children (CIII), and the drug is not available in the United States. Ocular infections caused by microsporidia among HIV-infected adults have been treated topically with fumagillin eye drops prepared from Fumidil-B®, a commercial product (Mid-Continent Agrimarketing, Inc., Olathe, KS) used to control a microsporidial disease of honeybees.
Epidemiology
In 2002, approximately 15,000 new cases of TB disease were diagnosed in the United States. Of these, 6% were among children aged <15 years (80). Although the number of cases in this age group has been decreasing since 1992, the number coinfected with HIV is uncertain because only a limited number of U.S. children who have TB have been tested for HIV infection. In a study of TB cases in the United States during 1993--2000, more adults than children had an HIV test reported (41.4 versus 16.1%); the majority of children (83.9%) did not have a reported HIV test result (81). Overall, 12.9% of adults were reported to be coinfected with HIV, compared with 1.1% of all childhood TB cases (81).
Incident case rates of TB disease among HIV-exposed or -infected children were reported in one study from the early 1990s to be up to 100-fold higher than those in comparably aged children in the general U.S. population (8). Data from international studies indicate an increased risk for TB disease among HIV-infected children; coinfection with HIV occurred in up to 48% of hospitalized South African children with culture-proven TB (82,83). In New York City, 3% of approximately 1,400 HIV-infected children and 0.5% of HIV-exposed uninfected children had active TB diagnosed during 1989--1995 (84).
Extrapulmonary and miliary TB are more common among younger children (aged <4 years) (85,86) who do not have HIV infection.Younger children are also more likely to progress more rapidly from infection to active disease than older children and adults and might not be recognized as having TB disease because they might have negative skin tests and fewer symptoms of disease (87). Despite evidence that extrapulmonary TB occurs more frequently among HIV-infected rather than uninfected adults, this is less clear among children in areas where TB is endemic (88,89).
Congenital TB is rare but has been reported among children born to HIV-infected women with active TB (90). The true incidence and whether the rate is higher among these children compared with children born to non-HIV-infected women with active TB are unknown. Congenital TB can result from hematogenous dissemination of M. tuberculosis after maternal mycobacteremia, rupture of a placental tubercule into the fetal circulation, or ingestion of infected amniotic fluid or maternal blood at delivery. The mother might not have symptoms of TB disease, and subclinical maternal genital TB also can result in an infected neonate (90).
Children with TB disease are almost always infected by an adult in their daily environment, and their infection represents primary infection rather than the reactivation disease observed among adults (8,91). Identification and treatment of the source patient and evaluation of all exposed children is particularly important; all confirmed and suspected TB cases should be reported to state and local health departments, who will assist in contact evaluation. In addition, other exposed members of the household should be evaluated because other secondary TB cases and latent infections with M. tuberculosis often are found. Latent infections should be treated to prevent cases. HIV counseling and testing should be offered to TB contacts because coexisting HIV infection, which increases the risk for TB disease, can reduce the sensitivity of the tuberculin test.
Multidrug-resistant TB is unusual among U.S.-born TB patients. Data from U.S. surveillance during 1993--2001 among pediatric patients with TB indicate that M. tuberculosis with resistance to any of the first-line anti-TB drugs was identified in 15.2% of children with culture-positive M. tuberculosis, with higher rates among foreign-born children (19.2%) than U.S.-born children (14.1%) (81). However, the prevalence of multidrug resistance (e.g., at least isoniazid and rifampin) was lower: 2.8% in foreign-born children and 1.4% in U.S.-born children with TB.
Data are limited about the incidence of drug resistant strains of TB among HIV-infected U.S. children. In one retrospective survey study of 70 PACTG sites, multiple resistant strains of M. tuberculosis were observed in 15%--20% of HIV-infected children with TB.The majority of cases were from one state with a peak in incidence of disease (8), reflecting the increase in drug-resistant TB among adults infected with TB to which the children were exposed (92,93).
Drug-resistant M. tuberculosis is as transmissible as drug-susceptible M. tuberculosis and remains drug resistant in a new host. Contacts to drug-resistant TB should be treated under the assumption that any newly diagnosed infections are similarly drug resistant.
Clinical Manifestations
Clinical signs of infection in the infant with congenital TB disease are nonspecific. Predominant early symptoms are inadequate feeding and failure to gain weight during the first weeks of life; upper respiratory symptoms and progressive hepatosplenomegaly might appear later with fever, progressive pneumonia, and meningitis. Certain infants might present more acutely with progressive respiratory distress, apnea, jaundice, and abdominal distention (94).
Children with pulmonary TB might have little or no symptoms. Symptoms, when present, might be nonspecific (e.g., weight loss, fever, and failure to thrive). TB among young children rarely manifests with the typical apical lung infiltrates and late cavitation observed among adults with TB. More commonly, pulmonary TB appears as a localized pulmonary infiltrate with associated hilar lymphadenopathy. Multiple lobes are involved in up to 25% of children. Concomitant atelectasis might result from hilar adenopathy compressing bronchi or from endobronchial granulomas.
Clinical presentation of TB disease among children with HIV infection is similar to that among children without HIV infection (86,95). Signs and symptoms might be consistent with acute pneumonia, with nonspecific radiological opacities without hilar adenopathy (83,88,96). Older HIV-infected children and adolescents might have clinical presentations more similar to that seen in HIV-infected adults (97). In countries with a high burden of TB, the incidence of treatment failure and mortality is higher among HIV-infected children (86,98). Commonly reported sites of extrapulmonary disease among children include lymph nodes, hematogenous (military), CNS, bone, pericardium, peritoneum, and pleura (86,96,99,100).
Diagnosis
Because of the difficulty of definitively diagnosing TB disease among children, a high index of suspicion is important. M. tuberculosis can be detected in culture of gastric aspirate samples from approximately 50% of children without HIV infection who have TB disease (101). Suspicion for and diagnosis of TB in HIV-infected children is further complicated by the frequent presence of pre-existing or coincidental fever, pulmonary symptoms, and radiographic abnormalities (e.g., chronic lymphoid interstitial pneumonitis or coincident pulmonary bacterial infection) in this population (102,103).
Because of the difficulty in obtaining a definitive culture-proven diagnosis of TB disease among children, the diagnosis of TB disease usually involves linking the child to an adult with confirmed pulmonary TB together with a positive tuberculin skin test (TST) and an abnormal radiograph or physical examination in the child (101). However, a negative TST result cannot exclude TB disease among children because approximately 10% of children without HIV infection but with culture-positive TB disease do not react initially to a TST (59). HIV infection further decreases TST reactivity. Therefore, a TST result among children, particularly HIV-infected children, is less useful than in adults. Although a positive test is useful to confirm the diagnosis, a negative test would not rule out the possibility of TB disease.
Because children with HIV infection are considered at high risk for TB, annual Mantoux tuberculin skin testing of this population is recommended, beginning at age 3--12 months, using intradermally injected 5 TU purified protein derivative (PPD) (59). Among children and adults with HIV infection, >5 mm of induration is considered a positive (diagnostic) reaction. Multiple puncture TB skin tests (e.g., Tine) are not recommended.
The use of control skin antigens at the time of PPD testing to identify anergy is of uncertain value and no longer routinely recommended; however, if anergy testing is performed, mumps and candida are appropriate control antigens (104). Even without HIV infection, approximately 10% of children and adults with culture-negative TB have a negative TST, and up to 50% with miliary TB and meningitis have an initially negative TST (101). Children aged <2 years or those who have HIV infection might be more likely to have a negative skin test (99,100).
Although acid-fast stained sputum smears are positive in 50%--70% of adults with pulmonary TB, children with TB disease rarely produce sputum voluntarily and typically have a low bacterial load (101). Acid-fast stains of early morning gastric aspirates are positive in 0-20% of children with TB, and in children with extrapulmonary TB, acid-fast stains of samples such as lymph node, CSF, and joint fluid are usually positive in <25% of children. Although the sensitivity of stained specimen smears is less among children than adults, a positive smear is indicative of mycobacteria, although it does not differentiate M. tuberculosis from other mycobacterial species.
Smears of all specimens should be prepared, stained (using either the Ziehl-Neelsen method or auramine-rhodamine staining in conjunction with fluorescence microscopy), and evaluated for the presence of acid-fast organisms. Auramine-rhodamine staining followed by fluorescent microscopy is more efficient than traditional carbol fuchsin stains (101).
A definitive diagnosis of TB disease requires isolation of M. tuberculosis from expectorated sputum, bronchoalveolar lavage (BAL) fluid, aspirated gastric fluid (obtained in the early morning after the child fasts overnight), biopsied lung, peripheral lymph node or other tissue (depending on location of disease), or mycobacterial blood culture (105,106). In addition, availability of an isolate allows drug susceptibility testing to be performed.
Three consecutive morning gastric aspirates yield a positive culture of M. tuberculosis in up to 70% of infants and 30%--50% of children with clinical pulmonary TB (101). Gastric lavage samples, collected on three consecutive mornings, has a higher yield on culture (50%) than a single sample collected by bronchoalveolar lavage (10%) (107). Nasopharyngeal aspiration was evaluated in one study of 64 children aged 1 month--16 years and was found to have comparable sensitivity and specificity as gastric aspirate culture (108). Sputum induction was safe and almost twice as effective in identifying M. tuberculosis compared with gastric lavage specimens in one South African study of children aged <5 years with community-acquired pneumonia (109). The culture yield from other fluids and tissues from children with extrapulmonary TB is <50%, even with optimal samples.
Strenuous efforts should be made to obtain diagnostic specimens (three each of sputum or gastric aspirate specimens or an induced sputum for culture) whenever a presumptive diagnosis of TB is made or when it is highly suspected despite negative skin testing results (i.e., because of a history of exposure to a person with active TB). Specimens should be cultured with radiometric culture methods and DNA probes for species identification. M. tuberculosis can be isolated and identified in 7--14 days.
Antimycobacterial drug susceptibility testing should be performed on the initial M. tuberculosis isolate and on subsequent isolates if treatment failure or relapse is suspected; the radiometric culture system has been adapted to perform rapid sensitivity testing. Before obtaining results of susceptibility testing and if an organism has not been able to be isolated from specimens from the child, the antimycobacterial drug susceptibility of the M. tuberculosis isolate from the source case can be used to define the probable drug susceptibility of the child's organism and to design the empiric therapeutic regimen for the child.
Diagnosis can be facilitated by use of PCR amplification techniques that allow rapid amplification of mycobacterial-species specific target sequences that are detected by a molecular probe. Two commercial kits are available for rapid, direct detection of M. tuberculosis, and both are labeled for use on sputum only. One is labeled for use on sputum only with AFB detected on the smear. When these tests are used for other specimens, sensitivity and specificity might be unsatisfactory.
PCR assays provide adjunctive, but not primary, diagnosis for evaluation of children with TB, because a negative PCR does not rule out TB as a diagnostic possibility and a positive result does not represent absolute confirmation of M. tuberculosis infection. However, it might be useful in suggesting the diagnosis of TB among HIV-infected children with unexplained pulmonary disease, when both culture and tuberculin skin tests may be falsely negative. Although both DNA and RNA amplification systems are available, only DNA systems have been used in published pediatric studies. Results for PCR testing for M. tuberculosis on gastric aspirates from children have been disappointing with sensitivity varying between 45%--83% (110--112). In one study, PCR specificity was only 80%; false positives occurred in children with Mycobacterium avium-intracellulare disease, which is not an uncommon infection among HIV-infected children (112).
Treatment
Principles for treatment of TB in the HIV-infected child are the same as for the HIV-uninfected child. However, optimal therapy has not been defined, and modified treatment durations, schedules, and medications are recommended for specific instances. Because of overlapping drug toxicities, children being treated for both HIV and TB should be managed by a specialist with expertise in treating both these conditions (AIII).
Because of the high risk for dissemination among children aged <4 years, TB treatment should be initiated as soon as the diagnosis of TB is suspected (AIII). Although the optimal timing of initiation of antiretroviral therapy during TB treatment is unknown, in the setting of antiretroviral naïve HIV-infected children, treatment of TB should be initiated 4--8 weeks before initiating antiretroviral medications to improve adherence and better differentiate potential side effects (BIII). For children already receiving antiretroviral therapy who have had TB diagnosed, the child's antiretroviral regimen should be reviewed and altered, if needed, to ensure optimal treatment for both TB and HIV and to minimize potential toxicities and drug-drug interactions (BIII).
The major problem limiting successful treatment is inadequate adherence to prescribed treatment regimens. Use of directly observed therapy (DOT) decreases the rates of relapse, treatment failures, and drug resistance. Therefore, DOT is recommended for treatment of children and adolescents with TB in the United States (59) (AII). For the first 2 months of treatment, DOT should be adminstered daily (induction phase). After this, DOT is usually given two to three times weekly (continuation phase). For patients on rifampin- or rifabutin-based regimens and who have severe immunosuppression, three-times weekly regimens are preferred because of concerns about development of rifamycin resistance by M. tuberculosis (BII). However, data on the efficacy of three-times weekly regimens among children are limited.
Initial empiric treatment of active disease (induction phase) should generally consist of a 4-drug regimen (isoniazid, rifampin, pyrazinamide, and eitherethambutol or streptomycin) to allow for the possibility of a drug-resistant organism (AI). Ethionamide can be used as an alternative to ethambutol in cases of TB meningitis because ethionamide has better CNS penetration than ethambutol(AIII).
Subsequent modifications of therapy should be based on susceptibility testing if possible. The drug susceptibility pattern from the isolate of the adult source case might help guide treatment in cases where an isolate is not available from the child (59). If the organism is susceptible to isoniazid, rifampin, and pyrazinamide during the 2-month period of induction therapy, ethambutol can be discontinued and induction therapy completed using 3 drugs (AI).
Following the 2-month induction phase, for treatment of M. tuberculosis known to be sensitive to isoniazid and rifampin, therapy is continued with isoniazid and rifampin to complete therapy (AI); daily or intermittent (2--3 times weekly) therapy is acceptable (59,112). However, children with severe immunosuppression should receive either daily or thrice weekly treatment during the continuation phase, because TB treatment regimens with once- or twice-weekly dosing have been associated with an increased rate of acquisition of rifamycin resistance among HIV-infected adults with low CD4 cell counts (<100 cells/µL) (113) (AII).
Many clinicians report high rates of treatment failure and relapse when only 6 months of treatment is administered (the recommended duration of therapy for children without HIV infection) (59,112,114). For HIV-infected children with active pulmonary disease, the minimum recommended duration of antituberculous drug treatment is 9 months; for children with extrapulmonary disease involving the bones or joints, CNS, or miliary disease, the minimum recommended duration of treatment is 12 months (59,112,115) (AIII). These recommendations assume that the organism is susceptible to the medications, that compliance with the medications has been assured, and that the child has had a clinical and microbiologic response to therapy.
For treatment of drug-resistant TB, a minimum of three drugs should be administered, including at least 2 bactericidal drugs to which the isolate is susceptible (AII). Regimens can include three to six drugs with varying levels of activity. Children infected with multidrug-resistant TB (e.g., resistance to at least isoniazid and rifampin) should be managed in consultation with an expert in this condition (AIII). If the strain is resistant only to isoniazid, isoniazid should be discontinued and the patient treated with 9--12 months of a rifampin- or rifabutin-containing regimen (e.g., rifampin, pyrazinamide and ethambutol (BII); ethionamide or streptomycin can be substituted for ethambutol if the M. tuberculosis isolate is sensitive to these agents). If the strain is resistant only to rifampin, risk for relapse and treatment failure is increased. Rifampin should be discontinued and a 2-month induction phase of isoniazid, pyrazinamide, ethambutol and streptomycin administered, followed by an additional continuation phase of isoniazid, pyrazinamide, and ethambutol to complete a minimum of a 12-month course of therapy, with the exact length of therapy based on clinical and radiologic improvement (BIII). Among older adolescents with rifampin monoresistant strains, isoniazid, ethambutol, and a fluoroquinolone can be administered, with pyrazinamide added for the first 2 months (BIII); an injectable agent (e.g., aminoglycoside such as streptomycin or amikacin) also can be included in the first 2--3 months for patients with severe disease (BIII). When the strain is resistant to isoniazid and rifampin (multidrug-resistant TB), therapeutic regimens must be individualized based on the resistance pattern, relative activities of the drugs, extent of disease, and any co-morbid conditions. Therapy frequently requires 12--24 months.
Isoniazid (10--15 mg/kg body weight adminstered orally once daily [maximum dose: 300 mg/day]) is available as syrup, but certain specialists advise against using it because the syrup is unstable and frequently causes diarrhea. When isoniazid is adminstered in a dosage exceeding 10 mg/kg in combination with rifampin, the incidence of hepatic toxicity might be increased. Pills can be pulverized at the time of administration and mixed with a small amount of appealing food immediately before giving it to the child. Dose for two--times weekly administration is 20--30 mg/kg/dose (maximum dose: 900 mg).
Gastric upset during the initial weeks of isoniazid treatment occurs frequently. Hepatotoxicity is the most common adverse effect and includes subclinical hepatic enzyme elevation and clinical hepatitis that can be reversible when drug is discontinued or rarely progresses to hepatic failure. Hepatotoxicity is less frequent in children than in adults. Transient asymptomatic serum transaminase elevations have been noted in 3%--10% and clinical hepatitis in <1% of children receiving isoniazid, although <1% of children required treatment discontinuation (115,116). However, the rate of hepatotoxicity might be higher in children on multiple hepatotoxic medications. Other toxicities reported with isoniazid include peripheral neuritis, mild CNS effects, and rare hypersensitivity reactions. Pyridoxine is recommended for children and adolescents on meat- and milk-deficient diets and children with nutritional deficiencies, including all symptomatic HIV-infected children (AII).
Rifampin (10-20 mg/kg adminstered orally once daily [maximum dose: 600 mg/day]) is available only as a capsule. It can be administered by opening the capsule and sprinkling the contents on food. Alternatively, a suspension can be formulated by the pharmacy, although the stability of the ad hoc suspension is unknown. Dose for twice weekly administration is 10--20 mg/kg per dose (maximum dose: 600 mg).
Rifampin is excreted in urine, tears, sweat, and other body fluids and colors them orange; contact lenses may be stained. The most common adverse reaction to rifampin therapy is gastrointestinal upset. Other reactions include skin rash, hepatitis, thrombocytopenia, and cholestatic jaundice. An influenza-like syndrome, hemolytic anemia, and acute renal failure have been reported among adults receiving high doses of rifampin.
Rifampin induces hepatic cytochrome P450 enzymes and can accelerate clearance of drugs metabolized by the liver (e.g., protease inhibitors and non-nucleoside reverse transcriptase inhibitors), resulting in subtherapeutic levels of the drug. As a result, concurrent administration of rifampin and single protease inhibitors, with the exception of ritonavir, is not recommended (117) (EII). Coadministration of ritonavir-boosted saquinavir, with 400 mg ritonavir boosting, with rifampin is possible, but low-dose ritonavir-boosted dual protease inhibitor regimens should not be used. Concurrent administration of rifampin with the non-nucleoside reverse transcriptase inhibitor delavirdine also is contraindicated because of similar drug interactions (EII). However, concomitant administration of rifampin with efavirenz (and perhaps nevirapine) is possible (117). Rifampin- and nevirapine-containing regimens should be used only when no other options are available and close clinical and virologic monitoring can be performed because of the decrease in nevirapine levels that can occur with concomitant administration (117).
Rifabutin (10--20 mg/kg adminstered orally once daily) is a suitable alternative to rifampin in children on HAART that proscribes the use of rifampin; however, experience in children is limited (BIII). Major toxicities of rifabutin include leukopenia, gastrointestinal upset, polyarthralgias, rash, elevated transaminases, and skin and secretion discoloration (pseudojaundice). Anterior uveitis has been reported among adults and children receiving rifabutin as prophylaxis or a part of a combination regimen for treatment, usually when adminstered at higher doses (118).
Rifabutin also increases hepatic metabolism of many drugs but is a less potent inducer of cytochrome P450 enzymes than rifampin and has fewer problematic drug interactions than rifampin. However, adjustments in doses of rifabutin and the coadministered antiretroviral drugs might be necessary for certain combinations (117). Coadministration of rifabutin with certain protease inhibitors can result in increased rifabutin concentration and thus potential toxicity; therefore, a decrease in rifabutin dose by 50% is required when coadministered with ritonavir, indinavir, nelfinavir, amprenavir, or ritonavir-boosted saquinavir. An increased dose (by 50%--100%) of rifabutin is needed when coadministered with efavirenz (117) because of decreased rifabutin levels with coadministration. Rifabutin should not be coadministered with delavirdine or hard gel capsule saquinavir without ritonavir boosting because of substantial decreases in the concomitant protease inhibitor drug levels (EII). Other drugs that inhibit hepatic metabolism (e.g., fluconazole) also can increase concentrations of rifabutin and consequent toxicity and might require dose adjustment or discontinuation of rifabutin.
Pyrazinamide (20--40 mg/kg/day is adminstered orally once daily [maximum dose: 2 g/day]) is available only as a scored tablet. It is generally administered during the first 2 months of TB therapy. If pyrazinamide is to be continued on a two- to three-times-weekly schedule, it should be administered at a dose of 50--70 mg/kg/dose (maximum dose: 2 g). Adverse effects include hepatotoxicity and hyperuricemia, arthralgias, skin rash, and gastrointestinal intolerance.
Ethambutol (15--25 mg/kg administered orally in single oral dose [maximum dose: 1.0 g]) is available only as a scored tablet. Although not approved for use among children because of concern for optic nerve toxicity that might not be easily recognizable with pediatric use, it has been used in children without toxicity (BIII). Dose for twice weekly administration is 50 mg/kg per dose (maximum dose: 1.0 g). The major toxicity is optic neuritis, with symptoms of blurry vision, central scotomata, and red-green color blindness, which is usually reversible and rare at doses of 15 mg/kg among children with normal renal function. Children receiving ethambutol should have monthly monitoring of visual acuity and color discrimination if possible (AIII). Other toxicities include headache, nausea, peripheral neuropathy, rash, and hyperuricemia.
Secondary drugs used in treatment of resistant TB have not been well studied in children. These medications should be used in consultation with a TB specialist. Ethionamide (15--20 mg/kg adminstered orally divided into 2--3 doses per day [maximum dose: 1.0 g/day]) is available only in tablet formulation. Data are unavailable to support intermittent (e.g. twice or three times weekly) dosing of this drug. Ethionamide might be useful for children with drug-resistant TB or TB meningitis because the drug achieves increased concentration in CSF (59). Nausea, vomiting, loss of appetite, and abdominal pain are the most common adverse effects. Other adverse effects include hepatitis, arthralgias, gynecomastia, photosensitive dermatitis, and a metallic taste in the mouth. Hypothyroidism has been reported with ethionamide use, and periodic (e.g., monthly) monitoring of thyroid hormone serum concentrations is recommended (AIII).
Streptomycin (20--40 mg/kg/day adminstered intramuscularly once daily [maximum dose: 1 g/day]) is an alternative drug that can be substituted for ethambutol (BIII). It also is used in combination quadruple therapy with rifampin, isoniazid, and pyrazinamide for CNS TB (meningitis and tuberculoma). Dosage for twice weekly administration is 20 mg/kg per dose intramuscularly (maximum dose: 1 g). If streptomycin is not available, kanamycin (15--30 mg/kg adminstered intramuscularly once daily [maximum dose: 1 g/day]) or amikacin (15--30 mg/kg adminstered intravenously or intramuscularly once daily [maximum dose: 1 g/day]) are active against most strains of streptomycin-resistant M. tuberculosis. Amikacin has the advantage of a lower rate of ototoxicity and has largely replaced kanamycin in the treatment of adults. Major adverse effects of aminoglycoside drugs are oto- and nephrotoxicity. Periodic audiometry, monitoring of vestibular function (if possible), and blood urea nitrogen and creatinine are recommended.
Capreomycin (15--30 mg/kg adminstered intravenously or intramuscularly once daily [maximum dose: 1 g/day]) is a secondary drug used for drug-resistant TB. The major adverse effect is toxicity to the eighth cranial nerve. Renal toxicity also might be seen, with electrolyte disturbances secondary to tubular damage and elevated serum creatinine. Monitoring of hearing with audiograms monthly, periodic examinations of vestibular function, and regular monitoring of blood urea nitrogen and creatinine are recommended (AIII).
Quinolones such as ciprofloxacin (10--15 mg/kg adminstered orally twice daily [maximum dose: 1.5 g/day]), ofloxacin (400--800 mg total given orally once daily in adults [maximum dose: 800 mg/day]) levofloxacin (500--1,000 mg adminstered orally once daily in adults) and moxifloxacin (400 mg adminstered orally once daily in adults) can be used. Adverse effects of quinolones include gastrointestinal upset, diarrhea, rash, and headache. Cartilage damage has been observed with use of the fluoroquinolone drugs in animals and, theoretically, these drugs could have an effect on growing cartilage in children; they are not approved for persons aged <18 years and use in younger persons requires an assessment of potential risks and benefits (119) (CIII). Ciprofloxacin has had the greatest use among children and appears to be well tolerated and not associated with arthropathy (120).
Cycloserine (10--20 mg/kg adminstered orally once daily [maximum dose: 1 g]) is another second-line antimycobacterial that might be needed for treatment of drug-resistant infections. The major adverse reactions are emotional and behavioral disturbances, and periodic assessment of mental status is recommended. Convulsions and peripheral neuropathy can occur, especially if adminstered with isoniazid, and coadministration of pyridoxine (150 mg/day) is recommended (AII).
Para-amino salicylic acid (200-300 mg/kg adminstered orally divided into 3 or 4 daily doses [maximum dose: 10 g/day]) also can be used for treatment of drug-resistant TB. The adverse effects of the drug are predominantly gastrointestinal (nausea, vomiting, and diarrhea). Hypersensitivity reactions occur in 5%--10% of persons, and hepatitis can occur. Hepatic enzyme monitoring is recommended (AIII). Thiacetazone can cause severe and often fatal reactions among HIV-infected children, including severe rash and aplastic anemia, and should not be used (EIII).
Unlike the majority of children without HIV infection, HIV-infected children on anti-TB medications should have liver enzymes obtained at baseline and monthly for the first few months of therapy (AIII). If symptoms of drug toxicity develop, a physical examination and repeat liver enzyme measurement should be performed (AIII). Mild elevations in serum transaminases (e.g., 2--3 times upper limit of normal) do not require discontinuation of drugs if other findings are normal (AII).
Adjunctive treatment with corticosteriods is indicated for children with tuberculous meningitis; dexamethasone lowers mortality and long-term neurologic impairment (AII). These drugs might be considered for children with pleural or pericardial effusions, severe miliary disease, and substantial endobronchial disease (BIII). Appropriate antituberculous therapy must be administered concomitantly. Most experts use 1 to 2 mg/kg/day of prednisone or its equivalent for 6--8 weeks.
Monthly monitoring of clinical and bacteriologic response to therapy is important (AII). For children with pulmonary TB, chest radiographs should be obtained after 2--3 months of therapy to evaluate response (AIII). Hilar adenopathy might persist for as long as 2--3 years despite successful antituberculous therapy, and a normal radiograph is not a criterion to discontinue therapy. Follow-up radiographs after completion of therapy are not necessary unless clinical symptoms recur.
An immune reconstitution syndrome in patients receiving anti-TB therapy in the setting of HAART has been reported in HIV-infected adults (121--123). New onset of systemic symptoms, especially high fever, expanding CNS lesions, and worsening adenopathy, pulmonary infiltrates, or pleural effusions have been reported in the setting of HAART up to several months after starting TB therapy. Persons with mild-to-moderate symptoms of immune reconstitution syndrome have been treated symptomatically with nonsteroidal anti-inflammatory drugs while continuing anti-TB and HIV therapies. In certain cases, use of systemic corticosteriods steroids for 1--2 weeks results in improvement while continuing to receive TB/HIV therapies (121--123) (CIII).
Epidemiology
Mycobacterium avium complex (MAC) refers to multiple related species of nontuberculous mycobacteria (e.g., M. avium, M. intracellulare, M. paratuberculosis) that are widely distributed in the environment. MAC is the cause of the second most common opportunistic infection among children with HIV infection after PCP, and is presumably acquired by common environmental exposures through inhallation, ingestion, or inoculation (124). Respiratory and gastrointestinal colonization can act as portals of entry that can lead to disseminated infection (125).
The proportion of children with AIDS and disseminated MAC has been higher among children with hemophilia or transfusion-acquired HIV infection (approximately 13%--14%) than those with perinatal HIV infection (5%) (124). The median age at diagnosis of disseminated MAC in children with hemophilia or transfusion-associated AIDS is 9 years, compared with 3 years in those with perinatal infection. Data on the incidence of and risk factors for MAC among children receiving HAART are limited.
MAC can appear as isolated lymphadenitis among HIV-infected children. Presentation with isolated MAC pulmonary disease is a marker of high risk for dissemination; 72% of children develop disseminated MAC within a mean time of 8 months (126). Disseminated infection with MAC in pediatric HIV infection rarely occurs during the first year of life; its frequency increases with age and declining CD4+ count, and it is a frequent complication of advanced immunologic deterioration among HIV-infected children (124,127,128). Disseminated MAC can occur at higher CD4+ cell counts among younger HIV-infected children than older children or adults, especially among children aged <2 years. Age-related CD4+ cell counts levels considered as high risk for MAC warranting consideration of prophylaxis are <750/µL among HIV-infected children <1 year old; <500/µL for children aged 1--2 years; <75/µL for children aged 2--6 years; and <50/µL for children aged >6 years (4,129--131).
Clinical Manifestations
Respiratory symptoms are uncommon among HIV-infected children with disseminated MAC, and isolated pulmonary disease is rare (125). Symptoms commonly associated with disseminated MAC infection among children include recurrent fever, weight loss or failure to thrive, neutropenia, night sweats, fatigue, chronic diarrhea, malabsorption, and persistent or recurrent abdominal pain. Lymphadenopathy, hepatomegaly, and splenomegaly can be found. Laboratory abnormalities include anemia, leukopenia, and thrombocytopenia. Serum chemistries are usually normal, although certain children might have elevations in alkaline phosphatase or lactate dehydrogenase.
Diagnosis
Procedures used to diagnose MAC in children are the same as used in HIV-infected adults. Definitive diagnosis is accomplished by isolation of the organism from the blood or from biopsy specimens from normally sterile sites (e.g., bone marrow, lymph node, or other tissues). Multiple mycobacterial blood cultures over time might be required to yield a positive result. Recovery of organisms from blood is enhanced by use of a radiometric broth medium or lysis-centrifugation culture technique.
Histology demonstrating macrophage-containing acid-fast bacilli strongly indicates MAC in a patient with typical signs and symptoms, but culture is essential to differentiate nontuberculous mycobacteria from M. tuberculosis and to determine which nontuberculous mycobacteria are the cause of infection and the antimycobacterial drug susceptibilities of the organism. The Bactec method for radiometric susceptibility testing can be used. Susceptibility thresholds for clarithromycin are minimal inhibitory concentrations (MIC) of >32 ug/ml and an MIC of >256 ug/ml for azithromycin (132).
Identification of MAC in stool or respiratory tract secretions indicates colonization but not necessarily invasive disease. Although not available widely, use of PCR might be of future value for diagnostic purposes (133,134).
Treatment
Treatment of disseminated MAC infection should be done in consultation with a pediatric infectious disease specialist with expertise in pediatric HIV infection (AIII). Combination therapy with a minimum of 2 drugs is recommended (AI). Monotherapy with a macrolide results in emergence of high-level drug resistance within weeks.
The most effective way to prevent disseminated MAC among HIV-infected children is to preserve immune function through use of effective antiretroviral therapy. In addition, improved immunologic status is important for control of MAC disease among children with disseminated disease; potent antiretroviral therapy should be initiated among children with MAC disease who are antiretroviral-naïve. However, the optimal time to start HAART in this situation is unknown; certain clinicians treat MAC 1--2 weeks before starting HAART to try to minimize the occurrence of immune reconstitution syndrome, although whether this makes a difference is unknown (CIII). HAART should be continued and optimized for those already being treated. Prolonged survival among HIV-infected adults with MAC has been associated with receiving therapy that included clarithromycin and receiving combination antiretroviral therapy that included a protease inhibitor (135).
Initial empiric therapy should include at least two drugs: clarithromycin or azithromycin plus ethambutol (AI). Certain specialists use clarithromycin as the preferred first agent, reserving azithromycin for patients with substantial intolerance to clarithromycin or when drug interactions with clarithromycin are a concern (AII).
Rifabutin can be added as a third drug to the clarithromycin/ethambutol regimen, particularly in patients with more severe symptoms or disseminated disease (AI). A study in adult patients demonstrated a survival benefit with the addition of rifabutin to clarithromycin plus ethambutol. Drugs that can increase cytochrome P3A activity (e.g., rifabutin) can lead to increased clearance of other drugs (e.g., protease inhibitors and non-nucleoside reverse transcriptase inhibitors), and increased toxicity might be observed with concomitant administration of drugs competing for the same metabolic pathways. Therefore, drug interactions should be checked carefully, and more intensive toxicity monitoring might be warranted if such drugs are given concomitantly (AIII). A decrease in rifabutin dosage by 50% is required when coadministered with ritonavir, indinavir, nelfinavir, amprenavir, or ritonavir-boosted saquinavir; an increased dose (by 50%--100%) of rifabutin is needed when coadministered with efavirenz (117). Rifabutin should not be coadministered with delavirdine or hard gel capsule saquinavir without ritonavir boosting because of substantial decreases in the concomitant protease inhibitor drug levels (EII).
Additional drugs can be considered depending on severity of illness. In a patient with severe illness, if rifabutin cannot be administered, ciprofloxacin, levofloxacin and amikacin or streptomycin have been used (CIII). In one study in HIV-infected adults, amikacin did not provide additional clinical or microbiologic benefit in a clinical trial of disseminated MAC therapy (136,137). In other studies, clofazamine was not associated with clinical or microbiologic benefit and was associated with increased mortality and is therefore not recommended (EII).
Clarithromycin is adminstered at a dose of 7.5--15.0 mg/kg body weight orally twice daily (maximum dose: 500 mg twice daily) (AI). Major toxicities include nausea, diarrhea, and abdominal pain. Uncommon toxicities include headache, leukopenia, altered taste, and elevated transaminases. Clarithromycin can inhibit hepatic metabolism of other drugs cleared by the liver, thus potential drug interactions with concomitantly administered drugs need to be considered.
Azithromycin is adminstered at a dose of 10--12 mg/kg orally once daily (maximum dose: 500 mg daily) and can be given as an alternative to clarithromycin (AII). Major toxicities include nausea, diarrhea, abdominal pain, and possible ototoxicity; uncommon adverse effects include headache, leukopenia, and elevated transaminases. Azithromycin has a minor effect on hepatic metabolism of other drugs and has less drug interactions than clarithromycin (138).
Ethambutol is adminstered at a dose of 15--25 mg/kg and is adminstered in single oral dose (maximum dose: 1.0 g) (AI). It is available only as a scored tablet. Although not approved for use among children because of concern for optic nerve toxicity that might not be easily recognizable with pediatric use, it has been used among children without a high incidence of toxicity. The major toxicity is optic neuritis, with symptoms of blurry vision, central scotomata, and red- green color blindness, which is usually reversible and is rare at doses of 15 mg/kg. Children receiving ethambutol should have monthly monitoring of visual acuity and color discrimination if possible (AII). Other toxicities include headache, nausea, peripheral neuropathy, rash, and hyperuricemia.
Rifabutin is adminstered at a dose of 10--20 mg /kg orally once daily (maximum dose: 300 mg/day) (AI). The drug is not available in a liquid formulation, but a suspension (10 mg/mL in cherry or simple syrup) can be formulated from the contents of capsules. Major toxicities of rifabutin include leukopenia, gastrointestinal upset, polyarthralgias, rash, elevated transaminases, and skin and secretion discoloration (pseudojaundice). Anterior uveitis has been reported in adults and children receiving rifabutin as prophylaxis or a part of a combination regimen for treatment, usually when adminstered at higher doses (139).
Ciprofloxacin is adminstered at a dose of 20--30 mg/kg intravenously or orally once daily (maximum dose: 1.5 grams). Adverse effects of quinolones include gastrointestinal upset, diarrhea, rash, and headache. Cartilage damage has been observed with use of the fluoroquinolone drugs in animals, and theoretically, these drugs can have an effect on growing cartilage in children. They are not approved for persons aged <18 years and use in younger persons requires an assessment of potential risks and benefits (119) (CIII). Of the quinolone drugs, ciprofloxacin has had the greatest use among children and appears to be well-tolerated and not associated with arthropathy (120).
Amikacin can be adminstered at a total daily dose of 15--30 mg/kg/day divided every 12--24 hours (maximum dose: 1.5 grams) (CIII). Amikacin is available only for intravenous administration and might be useful as a second-line agent. Ototoxicity and renal toxicity are adverse effects.
Most patients demonstrate substantial clinical improvement during the first 4--6 weeks of therapy. Microbiologic response can be monitored by blood cultures every 4 weeks during initial therapy (BIII). However, elimination of the organism from the blood might require up to 12 weeks of effective therapy. An immune reconstitution syndrome in patients receiving MAC therapy in the setting of HAART has been reported among HIV-infected adults (140). New onset of systemic symptoms, especially fever or abdominal pain, leukocytosis, and focal lymphadenitis (cervical, thoracic, or abdominal) associated with pre-existing but relatively asymptomatic MAC infection, has been seen after starting HAART. Before initiation of HAART among HIV-infected children with low CD4+ cell counts, consideration should be given for an assessment for MAC and treatment if MAC is identified. However, recent data indicate that MAC prophylaxis with azithromycin did not prevent the development of immune reconstitution disease (141). Children with moderate symptoms of immune reconstitution syndrome can be treated symptomatically with nonsteroidal anti-inflammatory drugs or, if unresponsive to nonsteroidals, a short course (e.g., 4 weeks) of systemic corticosteroid therapy while continuing to receive HAART (CIII).
Among HIV-infected children with MAC disease, after initial therapy, lifetime chronic suppressive maintenance therapy for MAC (secondary prophylaxis) is required. Although discontinuation of secondary prophylaxis in adults receiving HAART has been evaluated, the safety of discontinuation of secondary prophylaxis after immunologic recovery with HAART among children has not been studied extensively.
Epidemiology
In an evaluation of opportunistic infections diagnosed in approximately 3,000 HIV-infected children participating in Pediatric AIDS Clinical Trials Group protocols in the pre-HAART era, serious bacterial infections were the most commonly diagnosed infection, with an event rate of 15/100 child-years (9). Pneumonia was the most common bacterial infection (11 per 100 child-years), followed by bacteremia (three/100 child-years), and urinary tract infection (two/100 child-years). Other serious bacterial infections, including osteomyelitis, meningitis, abscess, and septic arthritis, occurred at rates <0.2/100-child years.
Acute pneumonia was associated with increased risk for long-term mortality among HIV-infected children in one study, although multiple episodes of acute pneumonia probably represent a marker for progressive disease and immunologic dysfunction rather than being causally associated with increased long-term mortality (142). Because of difficulties obtaining appropriate specimens (e.g., sputum) from young children, bacterial pneumonia is most often a presumptive diagnosis in a child with fever, pulmonic symptoms, and an abnormal chest radiogram unless an accompanying bacteremia exists. In a study of intravenous immune globulin prophylaxis of bacterial infections, only 12% of acute presumed bacterial pneumonia episodes had a bacterial pathogen identified (142). Chronic lung disease might predispose persons to development of acute pneumonia; in one study, the incidence of acute lower respiratory tract infection in HIV-infected children with chronic lymphoid interstitial pneumonitis was approximately 10-fold higher than in a community-based study of non-HIV--infected children (143).
In a study of 1,215 hospitalized South African children with lower respiratory tract infections, HIV infection was identified in 45.1%; bacteremia occurred in 14.9% of HIV-infected and 6.5% of uninfected children with pneumonia (144). The estimated relative incidence of bacteremic pneumonia caused by Streptococcus pneumoniae, Haemophilus influenzae type b (Hib), Staphylococcus aureus, or Escherichia coli was higher in HIV-infected than uninfected children. These organisms were more likely to be resistant to common antibiotics (e.g., methicillin, penicillin, and trimethoprim/sulfamethoxazole) in HIV-infected children. Mortality was higher among HIV-infected than uninfected children with pneumonia (13.1% versus 2.1%, respectively).
Streptococcus pneumoniae is the most prominent invasive bacterial pathogen in children with HIV infection both in the United States and worldwide, accounting for >50% of bacterial blood-stream infections in HIV-infected children (9,145--148). HIV-infected children have a markedly increased risk for pneumococcal infection compared with those who are not HIV-infected (149,150). The incidence of invasive pneumococcal disease is 6.1 cases/100 patient-years among HIV-infected children through age 7 years (151).
In studies from Malawi and South Africa of approximately 600 children (36% HIV-infected) with acute bacterial meningitis, HIV-infected children were substantially more likely than those without HIV infection to have S. pneumoniae as the cause of their meningitis (58% and 74% of HIV-infected children in Malawi and South African studies, respectively, compared with 32% and 29% in children without HIV infection) (152,153). The high incidence of invasive pneumococcal infections among HIV-infected children does not appear to be caused by increased rates of asymptomatic colonization with S. pneumoniae (154,155).
Among children with invasive pneumococcal infections, studies vary on whether penicillin-resistant pneumococci strains are more commonly isolated from HIV-infected than uninfected persons (147,151,156--158). Although reports among children without HIV infection have not demonstrated a difference in the case-fatality rate in those with penicillin-susceptible and nonsusceptible pneumococcal infections (case-fatality rate was associated with severity of disease and underlying illness) (159), in a multivariate analysis of mortality in HIV-infected, predominantly adult patients with pneumococcal bacteremia, high-level penicillin-resistance, the severity of illness, and Hispanic ethnicity were independently associated with mortality (160).
Hib also has been reported to be more common in HIV-infected children before availability of Hib vaccine. In a study in South African children who had not received Hib conjugate vaccine, the estimated relative annual rate of overall invasive Hib disease in children aged <1 year was 5.9 times greater among HIV-infected than uninfected children, and HIV-infected children were also at greater risk for having bacteremic pneumonia (161).
Although the frequency of gram-negative bacteremia is lower than gram-positive bacteremia among HIV-infected children, gram-negative bacteremia is more common among children with advanced HIV disease or immunosuppression or those with central venous catheters. However, in children aged <5 years, gram-negative bacteremia also was observed among children with milder levels of immune suppression. In a study of 680 HIV-infected children in Miami, Florida, through 1997, a total of 72 (10.6%) had 95 episodes of gram-negative bacteremia; the predominant organisms identified in those with gram-negative bacteremia were Pseudomonas aeruginosa (26%), nontyphoidal Salmonella (15%), Escherichia coli (15%), and Haemophilus influenzae (13%) (162). The relative frequency of the organisms varied over time, with the relative frequency of P. aeruginosa bacteremia increasing from 13% before 1984 to 56% during 1995--1997 and Salmonella from 7% before 1984 to 22% during 1995--1997. However, H. influenzae was not observed after 1990 (presumably decreasing after incorporation of Hib vaccine into routine childhood vaccinations). The overall case-fatality rate for gram-negative bacteremia was 43%.
The presence of a central venous catheter increases the risk for bacterial infections in HIV-infected children, but the incidence is similar to that observed among children with cancer (163). S. aureus is the most commonly isolated pathogen in catheter-associated bacteremia in HIV-infected children (163). P. aeroginosa also is common. Other organisms associated with catheter-associated bacteremia include S. epidermidis, Enterococcus, and Bacillus cereus.
Clinical Manifestations
Clinical presentation will be dependent on the particular type of recurrent bacterial infection (e.g., bacteremia/sepsis, osteomyelitis/septic arthritis, pneumonia, meningitis, and sinusitis/otitis media) (164). HIV-infected children with invasive bacterial infections typically have a clinical presentation similar to children without HIV infection, with an acute presentation and fever (150,151,165). Studies have indicated that HIV-infected children might be less likely than children without HIV infection to have leukocytosis (151).
The classical signs, symptoms, and laboratory test abnormalities that usually indicate invasive bacterial infection (e.g., fever and elevated white blood cell count) are usually present but might be lacking among HIV-infected children having reduced immune competence (150,164). One third of HIV-infected children who experience acute pneumonia have recurrent episodes (142).
In studies in Malawian and South African children with acute bacterial meningitis, the clinical presentation of children with and without HIV infection was similar (152,153). However, in the Malawi study, HIV-infected children were 6.4-fold more likely to have recurrent meningitis than children without HIV infection, although the study did not differentiate recrudescence from new infections (152). In both studies, HIV-infected children were more likely to die of meningitis than children without HIV infection.
Diagnosis
Attempted isolation of a pathogenic organism from normally sterile sites (e.g., blood, CSF, and pleural fluid) is strongly recommended. This is particularly important because of an increasing incidence of antimicrobial resistance, including penicillin-resistant S. pneumoniae and community-acquired methicillin-resistant S. aureus.
The diagnosis of pneumonia is most typically made on the basis of clinical (e.g., fever, dyspnea, tachypnea, cough, and rales) and radiographic findings, although differenciating viral from bacterial pneumonia clinically is difficult (166). Sputum induction obtained by nebulization with hypertonic (5%) saline has been evaluated for diagnosis of pneumonia in 210 South African infants and children (median age: 6 months), 66% of whom had HIV infection (167). The procedure was well-tolerated, and identified an etiology in 63% of children with pneumonia (identification of bacteria in 101, M. tuberculosis in 19, and PCP in 12 children). Culture of blood and pleural fluid, if present, should be done.
Among children with bacterimia, a source for the bacteremia should be sought. In addition to routine chest radiographs, other diagnostic radiologic evaluations might be necessary (e.g., chest, abdomen, and ultrasound studies) among HIV-infected children with compromised immune systems to identify less apparent foci of infection (e.g., bronchiectasis and internal organ abscesses) (168--170). Among children with central venous catheters, both a peripheral and catheter blood culture should be obtained; if the catheter is removed, the catheter tip should be sent for culture. Assays for detection of bacterial antigens or evidence by molecular biology techniques are important for the diagnostic evaluation of HIV-infected children in whom unusual pathogens might be involved or difficult to identify or culture by standard techniques. For example, Bordetella pertussis and Chlamydia pneumoniae can be identified by a PCR assay of nasopharyngeal secretions (166).
Treatment
The local prevalence of resistance to common infectious agents (i.e., penicillin-resistant S. pneumoniae and methicillin-resistant S. aureus) and the recent use of prophylactic or therapeutic antibiotics should be considered when initiating empiric therapy. When the organism is identified, antibiotic susceptibility testing should be performed and therapy based on the results of susceptibility testing (AII).
HIV-infected children whose immune systems are not seriously compromised (CDC Immune Class I) and who are not neutropenic can be expected to respond similarly to HIV-uninfected children and should be treated with the usual antimicrobial agents recommended for the most likely bacterial organisms (AIII). For example, for HIV-infected children outside of the neonatal period with suspected community-acquired bacteremia, bacterial pneumonia, or meningitis, empiric therapy with an extended-spectrum cephalosporin such as ceftriaxone (80--100 mg/kg body weight in 1 or 2 divided doses [maximum daily adult dose: 4 g]), cefotaxime (150--200 mg/kg divided into 3 or 4 doses [maximum daily adult dose: 8--10 g]), or cefuroxime (100--150 mg/kg divided into 3 doses [maximum daily adult dose: 4--6 g]) is reasonable until culture results are available (166,171) (AIII).
Initial empiric therapy of HIV-infected children with suspected catheter sepsis should include coverage for both gram-positive and enteric gram-negative organisms, such as ceftazidime (125--150 mg/kg divided into 3 doses [maximum daily adult dose: 6 g]), which has anti-Pseudomonas activity, and vancomycin (40--60 mg/kg divided into 4 doses [maximum daily adult dose: 2--4 g]) to cover methicillin-resistant S. aureus (AIII). Severely immunocompromised HIV-infected children with invasive or recurrent bacterial infections might require expanded empiric antimicrobial treatment covering a broad range of resistant organisms similar to that chosen for suspected catheter sepsis pending results of diagnostic evaluations and cultures (AIII).
HIV-infected children aged <5 years should receive Hib and heptavalent pneumococcal conjugate vaccines (AII). In a placebo-controlled trial of a 9-valent pneumococcal conjugate vaccine among South African children, although vaccine efficacy was somewhat lower among children with HIV infection than those without (65% versus 85%, respectively), the incidence of invasive pneumococcal disease was substantially decreased among HIV-infected vaccine recipients (157). HIV-infected children aged >2 years also should receive the 23-valent pneumococcal polysaccharide vaccine (>2 months after their last conjugate vaccine dose), with a single revaccination with the pneumococcal polysaccharide vaccine 3--5 years later if the child is aged <10 years or after 5 years if the child is aged >10 years (4,172) (AIII).
Epidemiology
Treponema pallidum can be transmitted from mother to child at any stage of pregnancy or during delivery. Untreated or inadequately treated primary and secondary syphilis during pregnancy leads to congenital infection in 60%--100% of infants. Treatment of the mother for syphilis >30 days before delivery is required for effective in utero treatment.
Congenital syphilis has been reported despite adequate maternal treatment. Factors that contribute to treatment failure include maternal stage of syphilis (early stage), advancing gestational age at treatment, higher VDRL (Venereal Disease Research Laboratory) titers at treatment and delivery, and short interval from treatment to delivery (<30 days) (173,174). In 2000, the rate of congenital syphilis among HIV uninfected infants was 13.4 cases/100,000 live-born infants compared with 27.8 cases in 1997 (175). During that same time, the prevalence of primary and secondary syphilis in women of reproductive age also decreased substantially.
Drug use during pregnancy, particularly cocaine, is substantially associated with an increased risk for maternal and congenital syphilis (176). Infants born to HIV-infected women have a substantially higher rate for congenital syphilis than in the general population. One large U.S. study conducted during 1988--1994 reported the rate of congenital syphilis was approximately 50 times greater among infants born to HIV-infected women (177). Although mother-to-child HIV transmission does not appear to be increased when syphilis is effectively treated before pregnancy (178), concurrent coinfection during pregnancy might increase the rate for perinatal HIV transmission (177,178).
Half of all new HIV infections in the United States occur among persons aged 15--24 years, with most infections transmitted sexually. In addition, approximately two thirds of the sexually transmitted diseases diagnosed annually in the United States occur among persons aged <24 years. As a result, the prevalence and incidence of syphilis among HIV-infected youth and of HIV infection among youth with syphilis is expected to be higher than the general population. In a study of 320 HIV-infected and uninfected adolescents aged 12--19 years in the United States, the prevalence of syphilis was 9% among HIV-infected girls and 6% among HIV-infected boys (179). In a meta-analysis of 30 studies, the median HIV seroprevalence among persons infected with syphilis in the United States was 15.7% (27.5% among men and 12.4% among women with syphilis) (180).
Clinical Manifestations
Untreated early syphilis during pregnancy can lead to spontaneous abortion, stillbirth, hydrops fetalis, preterm delivery, and perinatal death in up to 40% of pregnancies (181). In a study of 148 infants born to mothers with untreated or inadequately treated syphilis, 47% had clinical, radiographic, or conventional laboratory findings consistent with a diagnosis of congenital syphilis, and 44% had a positive rabbit infectivity test, PCR assay, or IgM immunoblot of serum, blood, or CSF (182).
At birth, approximately 60% of infants with congenital syphilis are asymptomatic (183). If untreated, symptoms can occur within 3 weeks--6 months after birth and might include hepatosplenomegaly, jaundice, mucocutaneous lesions, skin rash, nasal discharge, pseudoparalysis of an extremity, anemia, thrombocytopenia, and osteochondritis. Late manifestations of congenital syphilis (after age 2 years) involve CNS, bones, teeth, eyes, and skin. Manifestations include mental retardation, interstitial keratitis, cranial nerve deafness, anterior bowing of the skin, frontal bossing, mulberry molars, Hutchinson teeth, saddle nose, rhaades, and Clutton joints. HIV-infected persons with acquired early syphilis might be at increased risk for neurological complications and uveitis and have higher rates of treatment failure.
Diagnosis
The standard serologic tests for syphilis in adults are based on the measurement of IgG antibody. Because IgG antibody in the infant reflects transplacental passively transferred antibody from the mother, interpretation of reactive serologic tests for syphilis among infants is difficult. Therefore, the diagnosis of neonatal congenital syphilis depends on a combination of results from physical, radiologic, serologic, and direct microscopic examinations.
All infants born to women with reactive nontreponemal and treponemal test results should be evaluated with a quantitative nontreponemal test (e.g., VDRL slide test, rapid plasma regain (RPR), and the automated regain test). Testing should be performed on neonatal serum because of the potential for maternal blood contamination of the umbilical cord blood specimens. Performing specific treponemal tests, such as the fluorescent treponemal antibody absorption (FTA-ABS) test and T. pallidum particle agglutination (TP-PA) test, is not necessary for evaluation of congenital syphilis in the neonate. No commercially available IgM test is recommended for diagnostic use.
Darkfield microscopic examination or direct fluorescent antibody staining of lesions or body fluids should be performed, although false-negative results are common. Definitive diagnosis of congenital syphilis can be made if T. pallidum is detected in umbilical cord, placenta, nasal discharge, or skin lesion material. Pathologic examination of placenta and umbilical cord with specific fluoroscent antitreponemal antibody staining is recommended.
Evaluation of suspected cases of congenital syphilis should include a physical examination, complete blood count, differential and platelet count, and CSF analysis for VDRL, cell count, and protein. HIV-infected infants might have increased cell counts and protein concentrations even in the absence of neurosyphilis. Other tests should be performed as clinically indicated (e.g., long-bone radiographs, chest radiograph, liver-function tests, cranial ultrasound, ophthalmologic examination, and auditory brainstem response).
A presumptive case of syphilis is defined as an infant born to a mother with untreated or inadequately treated syphilis at delivery, regardless of findings in the infant, or any infant who has a reactive treponemal test result and clinical signs or symptoms of congenital syphilis on physical examination, or an abnormal CSF finding without other cause or positive CSF VDRL.
For diagnosis of acquired syphilis, a reactive nontreponemal test must be confirmed by a specific treponemal test such as FTA-ABS or TP-PA. These tests will remain positive for life, even with successful treatment. The prozone phenomenon (a weakly reactive or falsely negative) reaction might occur more frequently in HIV-infected persons (184). Treponemal antibody titers do not correlate with disease activity and should not be used to monitor treatment response. CSF evaluation should be performed among HIV-infected adolescents with acquired syphilis who have neurologic or ocular symptoms or signs, although some clinicians recommend a CSF examination for all HIV-infected patients.
Treatment
Data are insufficient about whether infants who have congenital syphilis and whose mothers are coinfected with HIV require different evaluation, therapy, or follow-up for syphilis than is recommended for all infants (185). Some studies in adults have shown a lag in serological improvement in appropriately treated patients with HIV infection (186).
Infants should be treated if mothers have untreated or inadequately treated syphilis (including treatment with erythromycin or any other nonpenicillin regimen) or no documentation of having received treatment; received treatment <4 weeks before delivery; been treated with penicillin but titers did not decrease by four-fold; or have four-fold or greater increase in nontreponemal antibody titer suggesting relapse or reinfection (185) (AII). Infants should be treated regardless of maternal history if an abnormal examination consistent with congenital syphilis, positive darkfield or fluorescent antibody test of body fluid(s), or serum quantitative nontreponemal serologic titer that is the same or four-fold greater than maternal titer are observed (185) (AII).
Treatment for proven or highly probable congenital syphilis is aqueous crystalline penicillin G at a dose of 100,000--150,000 units/kg/day, administered as 50,000 units/kg body weight/dose intravenously every 12 hours during the first 7 days of life and every 8 hours thereafter for a total of 10 days (AII). If congenital syphilis is diagnosed after 1 month of life, the dose of aqueous penicillin G should be increased to 200,000--300,000 units/kg intravenously every 6 hours for 10 days (AII). An alternative to aqueous penicillin G is procaine penicillin G at a dose of 50,000 units/kg/dose intramuscularly/day in a single dose for 10 days (BII). However, aqueous penicillin G is preferred because of its higher penetration into the CSF.
Asymptomatic infants born to mothers who have had adequate treatment and response to therapy and normal physical examination and CSF findings but who have a serum quantitative nontreponemal serologic titer that is the same or four-fold higher than maternal titer might be treated with a single dose of benzathine penicillin G 50,000 units/kg/dose intramuscularly with careful clinical and serologic follow-up (BII). However, certain health-care providers would treat such infants with the standard 10 days of aqueous penicillin because physical examination and laboratory test results cannot definitively exclude congenital syphilis in all cases (BII).
Infants with treated congenital syphilis should be examined at age 1, 2, 3, 6, and 12 months, with serologic nontreponemal tests performed at age 3, 6 and 12 months after conclusion of treatment or until results become nonreactive (AIII). If initial CSF examination was abnormal, repeat lumbar puncture should be conducted every 6 months until results are normal. Nontreponemal antibody titers should decline by age 3 months and be nonreactive by age 6 months if the infant was adequately treated or not infected (e.g., passive ant