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7,401 | of developing antimicrobial resistance. Susceptibility testing of myco bacterial isolates often can aid in therapeutic decision making. AGENTS USED AGAINST MYCOBACTERIUM TUBERCULOSIS Commonly Used Agents Isoniazid Isoniazid (INH) is a hydrazide form of isonicotinic acid and is bac tericidal for rapidly growing M. tuberculosis. The primary target of INH involves the INHA gene, which encodes the enoyl acyl carrier protein (ACP) reductase needed for the last step of the mycolic acid biosynthesis pathway of cell wall production. Resistance to INH occurs after pathogenic variants in the INHA gene or in other genes encoding enzymes that activate INH, such as katG. INH is indicated for the treatment of M. tuberculosis, M. kansasii, and M. bovis. The pediatric dosage is 10 15 mgkgday orally (PO) in a single dose, not to exceed 300 mgday. The adult dosage is 5 mgkgday PO in a single dose, not to exceed 300 mgday. Alternative pediatric dosing is 20 30 mgkg PO in a single dose, not to exceed 900 mgdose, given twice weekly under directly observed therapy (DOT), in which patients are observed to ingest each dose of antituberculosis medica tion to maximize the likelihood of completing therapy. The duration of treatment depends on the disease being treated (Table 260.1). INH needs to be taken 1 hour before or 2 hours after meals because food decreases absorption. It is available in liquid, tablet, intravenous (IV; not approved by the U.S. Food and Drug Administration FDA), and intramuscular (IM) preparations. Major adverse effects include hepatotoxicity in 1 of children and approximately 3 of adults (increasing with age) and dose related peripheral neuropathy. Pyridoxine can prevent the peripheral neu ropathy and is indicated for breastfeeding infants and their mothers, children and youth on milk or meat deficient diets, pregnant adoles cents, and symptomatic HIV infected children. Minor adverse events include rash, worsening of acne, epigastric pain with occasional nausea and vomiting, decreased vitamin D levels, and dizziness. The liquid formulation of INH contains sorbitol, which often causes diarrhea and stomach upset. INH is accompanied by significant drug drug interactions (Table 260.2). The metabolism of INH is by acetylation. Acetylation rates have minimal effect on efficacy, but slow acetylators have an increased risk for hepatotoxicity, especially when INH is used in combination with rifampin. Routine baseline liver function testing or monthly monitor ing is only indicated for persons with underlying hepatic disease or those receiving concomitant hepatotoxic drugs, including other anti mycobacterial agents, acetaminophen, or alcohol. Monthly clinic visits while taking INH alone are encouraged to monitor adherence, adverse effects, and worsening of infection. Rifamycins The rifamycins (rifampin, rifabutin, rifapentine) are a class of macro lide antibiotics developed from Streptomyces mediterranei. Rifampin is a synthetic derivative of rifamycin B, and rifabutin is a derivative of rifamycin S. Rifapentine is a cyclopentyl derivative. The rifamycins inhibit the DNA dependent RNA polymerase of mycobacteria, result ing in decreased RNA synthesis. These agents are generally bacteri cidal at treatment doses, but they may be bacteriostatic at lower doses. Resistance is from |
7,402 | a pathogenic variant in the DNA dependent RNA polymerase gene (rpoB) that is often induced by previous incomplete therapy. Cross resistance between rifampin and rifabutin has been demonstrated. Rifampin is active against M. tuberculosis, M. leprae, M. kansa sii, and M. avium complex. Rifampin is an integral drug in standard combination treatment of active M. tuberculosis disease and can be used as an alternative to INH in the treatment of latent tuberculo sis infection in children who cannot tolerate INH. Rifabutin has a similar spectrum, with increased activity against M. avium complex. Rifapentine is undergoing pediatric clinical trials and appears to have activity similar to the activity of rifampin. The pediatric dosage of rifampin is 10 15 mgkgday PO in a single dose, not to exceed 600 mgday. The adult dosage of rifampin is 5 10 mgkgday PO in a single dose, not to exceed 600 mgday. Commonly used rifampin preparations include 150 and 300 mg capsules and a suspension that is usually formulated at a concentration of 10 mgmL. The shelf life of rifampin suspension is short (approximately 4 weeks), so it should not be compounded with other antimycobacterial agents. An IV form of rifampin is also available for initial treatment of patients who can not take oral preparations. Dosage adjustment is needed for patients with liver failure. Other rifamycins (rifabutin and rifapentine) have been poorly studied in children and are not recommended for pedi atric use. Rifampin can be associated with adverse effects such as transient elevations of liver enzymes; gastrointestinal (GI) upset with cramps, nausea, vomiting, and anorexia; headache; dizziness; and immuno logically mediated fever and flulike symptoms. Thrombocytopenia and hemolytic anemias can also occur. Rifabutin has a similar spectrum of toxicities, except for an increased incidence of rash (4) and neutro penia (2). Rifapentine has fewer adverse effects but is associated with hyperuricemia and cytopenias, especially lymphopenia and neutrope nia. All rifamycins can turn urine and other secretions (tears, saliva, stool, sputum) orange, which can stain contact lenses. Patients and families should be warned about this common but otherwise innocu ous adverse effect. Rifamycins induce the hepatic cytochrome P450 (CYP) isoen zyme system and are associated with the increased metabolism and decreased level of several drugs when administered concomitantly. These drugs include digoxin, corticosteroids such as prednisone and dexamethasone, dapsone, fluconazole, phenytoin, oral contraceptives, warfarin, and many antiretroviral agents, especially protease inhibitors and nonnucleoside reverse transcriptase inhibitors. Rifabutin has less of an effect on lowering protease inhibitor levels. The use of pyrazinamide in combination with rifampin for short course latent tuberculosis therapy has been associated with serious liver dysfunction and death. This combination has never been well studied or recommended for pediatric patients and should not be used. Chapter 260 Principles of Antimycobacterial Therapy Stacene R. Maroushek Section 7 Mycobacterial Infections Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter |
7,403 | 260 u Principles of Antimycobacterial Therapy 1831 No routine laboratory monitoring for rifamycins is indicated unless the patient is symptomatic. In patients with signs of toxicity, complete blood count (CBC) and kidney and liver function tests are indicated. Pyrazinamide Pyrazinamide (PZA) is a synthetic pyrazine analog of nicotinamide that is bactericidal against intracellular M. tuberculosis organisms in acidic environments, such as within macrophages or inflammatory lesions. A bacteria specific enzyme (pyrazinamidase) converts PZA to pyrazinoic acid, which leads to low pH levels not tolerated by M. tuber culosis. Resistance is poorly understood but can arise from bacterial pyrazinamidase alterations. PZA is indicated for the initial treatment phase of active tuberculo sis in combination with other antimycobacterial agents. The pediatric dosage is 3040 mgkgday PO in a single dose, not to exceed 2,000 mg day. Twice weekly dosing with DOT only is with 50 mgkgday PO in a single dose, not to exceed 4,000 mgday. It is available in a 500 mg tablet and can be made into a suspension of 100 mgmL. Adverse effects include GI upset (e.g., nausea, vomiting, poor appetite) in approximately 4 of children, dosage dependent hepatotoxicity, and elevated serum uric acid levels that can pre cipitate gout in susceptible adults. Approximately 10 of pediat ric patients have elevated uric acid levels but with no associated clinical sequelae. Minor reactions include arthralgias, fatigue, and, rarely, fever. Use of PZA in combination with rifampin for short course treat ment of latent tuberculosis is associated with serious liver dysfunction and death, and this combination should be avoided. Table 260.1 Recommended Usual Treatment Regimens for Drug Susceptible Tuberculosis in Infants, Children, and Adolescents INFECTIONDISEASE CATEGORY REGIMEN COMMENTS LATENT MYCOBACTERIUM TUBERCULOSIS INFECTION Isoniazid susceptible 12 wk of isoniazid plus rifapentine once a wk or 4 mo of rifampin once a day or Continuous daily therapy is required. Intermittent therapy even by DOT is not recommended. 9 mo of isoniazid once a day If daily therapy is not possible, DOT twice a week can be used for 9 mo. Isoniazid resistant 4 mo of rifampin once a day Continuous daily therapy is required. Intermittent therapy even by DOT is not recommended. Isoniazid rifampin resistant Consult a tuberculosis specialist. Moxifloxacin or levofloxacin with or without ethambutol or pyrazinamide. PULMONARY AND EXTRAPULMONARY INFECTION Except meningitis 2 mo of isoniazid, rifampin, pyrazinamide, and ethambutol daily or twice weekly, followed by 4 mo of isoniazid and rifampin by DOT for drug susceptible M. tuberculosis Some experts recommend a three drug initial regimen (isoniazid, rifampin, and pyrazinamide) if the risk of drug resistance is low. DOT is highly desirable. If hilar adenopathy only and the risk of drug resistance is low, 6 mo course of isoniazid and rifampin is sufficient. Drugs can be given 2 or 3 timeswk under DOT. 9 12 mo of isoniazid and rifampin for drug susceptible Mycobacterium bovis Meningitis 2 mo of isoniazid, rifampin, pyrazinamide and an aminoglycoside or ethionamide once daily, followed by 7 10 mo of isoniazid and rifampin once daily |
7,404 | or twice weekly (9 12 mo total) for drug susceptible M. tuberculosis At least 12 mo of therapy without pyrazinamide for drug susceptible M. bovis For patients who may have acquired tuberculosis in geographic areas where resistance to streptomycin is common, kanamycin, amikacin, or capreomycin can be used instead of streptomycin. Positive TST or IGRA result, no disease. See text for comments and additional acceptablealternative regimens. Duration of therapy may be longer for human immunodeficiency virus (HIV)infected people, and additional drugs and dosing intervals may be indicated Medications should be administered daily for the first 2 wk to 2 mo of treatment and then can be administered 2 3 timeswk by DOT. (Twice weekly therapy is not recommended for HIV infected people.) If initial chest radiograph shows pulmonary cavities and sputum culture after 2 mo of therapy remains positive, the continuation phase is extended to 7 mo, for a total treatment duration of 9 mo. Streptomycin, kanamycin, amikacin, or capreomycin. DOT, Directly observed therapy; IGRA, interferon release assay; TST, tuberculin skin test. Adapted from American Academy of Pediatrics: Red Book: 20182021 report of the Committee on Infectious Diseases, 31st ed. Elk Grove Village, IL: AAP, 2018: Table 3.85. Table 260.2 Isoniazid Drug Drug Interactions DRUG USED WITH ISONIAZID EFFECTS Acetaminophen, alcohol, rifampin Increased hepatotoxicity of isoniazid or listed drugs Aluminum salts (antacids) Decreased absorption of isoniazid Carbamazepine, phenytoin, theophylline, diazepam, warfarin Increased level, effect, or toxicity of listed drugs due to decreased metabolism Itraconazole, ketoconazole, oral hypoglycemic agents Decreased level or effect of listed drugs due to increased metabolism Cycloserine, ethionamide Increased central nervous system adverse effects of cycloserine and ethionamide Prednisolone Increased isoniazid metabolism Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1832 Part XV u Infectious Diseases No routine laboratory monitoring for PZA is required, but monthly visits to reinforce the importance of therapy are desirable. Ethambutol Ethambutol is a synthetic form of ethylenedi imino di 1 butanol dihy drochloride that inhibits RNA synthesis needed for cell wall formation. At standard dosages, ethambutol is bacteriostatic, but at dosages 25 mgkg, it has bactericidal activity. The mechanism of resistance to eth ambutol is unknown, but resistance develops rapidly when ethambutol is used as a single agent against M. tuberculosis. Ethambutol is indicated for the treatment of infections caused by M. tuberculosis, M. kansasii, M. bovis, and M. avium complex. Etham butol should only be used as part of a combination treatment regimen for M. tuberculosis. Daily dosing is 15 25 mgkg PO in a single dose, not to exceed 2,500 mgday. Twice weekly dosing is with 50 mgkg PO in a single dose, not to exceed 2,500 mgday. Dosage adjustment is needed in renal insufficiency. Ethambutol is available in 100 and 400 mg tablets. The major adverse effect with ethambutol is optic neuritis, and thus ethambutol should generally be reserved for children old |
7,405 | enough to have visual acuity and color discrimination reliably monitored. Visual changes are usually dosage dependent and reversible. Other adverse events include headache, dizziness, confusion, hyperuricemia, GI upset, peripheral neuropathy, hepatotoxicity, and cytopenias, espe cially neutropenia and thrombocytopenia. Routine laboratory monitoring includes baseline and periodic visual acuity and color discrimination testing, CBC, serum uric acid levels, and kidney and liver function tests. Less Commonly Used Agents Aminoglycosides The aminoglycosides used for mycobacterial infections include strep tomycin, amikacin, kanamycin, and capreomycin. Streptomycin is isolated from Streptomyces griseus and was the first drug used to treat M. tuberculosis. Capreomycin, a cyclic polypeptide from Streptomyces capreolus, and amikacin, a semisynthetic derivative of kanamycin, are newer agents that are recommended when streptomycin is unavail able. Aminoglycosides act by binding irreversibly to the 30S subunit of ribosomes and inhibiting subsequent protein synthesis. Streptomycin exhibits concentration dependent bactericidal activity, and capreomy cin is bacteriostatic. Resistance results from a pathogenic variant in the binding site of the 30S ribosome, by decreased transport into cells, or by inactivation by bacterial enzymes. Cross resistance between amino glycosides has been demonstrated. The aminoglycosides are indicated for the treatment of M. tuber culosis and M. avium complex. All are considered second line drugs in the treatment of M. tuberculosis and should be used only when resistance patterns are known. Aminoglycosides are poorly absorbed orally and are administered by IM injection. Pediatric dosing ranges for streptomycin are 20 mgkgday if given daily and 20 40 mgkgday if given twice weekly; dosing is IM in a single daily dose. Capreomycin, amikacin, and kanamycin dosages are 15 30 mgkgday IM in a single dose, not to exceed 1 gday. Dosage adjustment is necessary in renal insufficiency. Aminoglycosides have adverse effects on proximal renal tubules, the cochlea, and the vestibular apparatus of the ear. Nephrotoxicity and ototoxicity account for most of the significant adverse events. Rarely, patients exhibit fever or rash with administration of aminoglycosides. Concomitant use of other nephrotoxic or ototoxic agents should be avoided, because adverse effects may be additive. An infrequent but serious synergistic, dosage dependent aminoglycoside effect with non depolarizing neuromuscular blockade agents can result in respiratory depression or paralysis. Hearing and kidney function should be monitored at baseline and periodically. Early signs of ototoxicity include tinnitus, vertigo, and hearing loss. Ototoxicity appears to be irreversible, but early kid ney damage may be reversible. As with other aminoglycosides, peak and trough drug levels are helpful in dosing and managing early toxicities. Cycloserine Cycloserine, derived from Streptomyces orchidaceous or Streptomyces garyphalus, is a synthetic analog of the amino acid d alanine that inter feres with bacterial cell wall synthesis through competitive inhibition of d alanine components to be incorporated into the cell wall. It is bac teriostatic, and the mechanism of resistance is unknown. Cycloserine is used to treat M. tuberculosis and M. bovis. The dosage is 10 20 mgkgday PO divided into two doses, not to exceed 1 gday. It is available in a 250 mg capsule. The major adverse effect |
7,406 | is neurotoxicity with significant psycho logic disturbance, including seizures, acute psychosis, headache, con fusion, depression, and personality changes. The neurotoxic effects are additive with ethionamide and INH. Cycloserine has also been associ ated with megaloblastic anemia. It must be dosage adjusted in patients with kidney impairment and should be used with caution in patients with underlying psychiatric illness. Routine laboratory monitoring includes kidney and hepatic func tion, CBC, and cycloserine levels. Psychiatric symptoms are less com mon at blood levels 30 gmL. Ethionamide Ethionamide is structurally related to INH and is an ethyl derivative of thioisonicotinamide that inhibits peptide synthesis by an unclear mechanism thought to involve nicotinamide adenine dinucleotide (NAD) and NAD phosphate dehydrogenase disruptions. Ethionamide is bacteriostatic at most therapeutic levels. Resistance develops quickly if ethionamide is used as a single agent therapy, although the mecha nism is unknown. Ethionamide is used as an alternative to streptomycin or ethambutol in the treatment of M. tuberculosis and has some activity against M. kansasii and M. avium complex. A metabolite, ethionamide sulfoxide, is bactericidal against M. leprae. Ethionamide has been shown to have good central nervous system (CNS) penetration and has been used as a fourth drug in combination with rifampin, INH, and PZA. The pediat ric dosing is 15 20 mgkgday PO in two divided doses, not to exceed 1 gday. It is available as a 250 mg tablet. GI upset is common, and other adverse effects include neurologic disturbances (anxiety, dizziness, peripheral neuropathy, seizures, acute psychosis), hepatic enzyme elevations, hypothyroidism, hypoglycemia, and hypersensitivity reaction with rash and fever. Ethionamide should be used with caution in patients with underlying psychiatric or thyroid disease. The psychiatric adverse effects can be potentiated with con comitant use of cycloserine. In addition to close assessment of mood, routine monitoring includes thyroid and liver function tests. In diabetic patients taking ethionamide, blood glucose levels should be monitored. Fluoroquinolones The fluoroquinolones are fluorinated derivatives of the quinolone class of antibiotics. Ciprofloxacin is a first generation fluoroquino lone, and levofloxacin is the more active l isomer of ofloxacin. Moxi floxacin and gatifloxacin are agents with emerging use in pediatric mycobacterial disease. Fluoroquinolones are not indicated for use in children 18 years old, but studies of their use in pediatric patients continue to indicate that they may be used in special circumstances. Fluoroquinolones are bactericidal and exert their effect by inhibition of DNA gyrase. The alterations in DNA gyrase result in relaxation of supercoiled DNA and breaks in double stranded DNA. The mecha nism of resistance is not well defined but likely involves pathogenic variants in the DNA gyrase. Levofloxacin is an important second line drug in the treatment of multidrug resistant (MDR) M. tuberculosis. Ciprofloxacin has activity against M. fortuitum complex and against M. tuberculosis. The pediat ric dosage of ciprofloxacin is 20 30 mgkgday PO or IV, not to exceed 1.5 mgday PO or 800 mgday IV. The adult dosage of ciprofloxacin is 500 750 mgdose PO in two divided doses or 200 400 mgdose |
7,407 | IV every 12 hours. Ciprofloxacin is available in 100 , 250 , 500 , and 750 mg tablets and can be made in 5 (50 mgmL) or 10 (100 mgmL) suspensions. The dosage of levofloxacin for children is 5 10 mgkgday Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 260 u Principles of Antimycobacterial Therapy 1833 given once daily either PO or IV, not to exceed 1,000 mgday, and for adults, 500 1,000 mgday PO or IV, not to exceed 1,000 mgday. Levo floxacin is available in 250 , 500 , and 750 mg tablets, and a 50 mgmL suspension can be extemporaneously compounded. The suspension has a shelf life of only 8 weeks. The most common adverse effect of fluoroquinolones is GI upset, with nausea, vomiting, abdominal pain, and diarrhea, including pseu domembranous colitis. Other less common adverse effects include bone marrow depression, CNS effects (e.g., lowered seizure threshold, confusion, tremor, dizziness, headache), elevated liver transaminases, photosensitivity, and arthropathies. The potential for arthropathies (e.g., tendon ruptures, arthralgias, tendinitis) is the predominant rea son that fluoroquinolones are not recommended for pediatric use. The mechanism of injury appears to involve the disruption of extracellu lar matrix of cartilage and depletion of collagen, a particular concern related to the bone and joint development of children. Fluoroquinolones induce the CYP isoenzymes that can increase the concentrations of dually administered theophylline and warfarin. Non steroidal antiinflammatory drugs (NSAIDs) can potentiate the CNS effects of fluoroquinolones and should be avoided while taking a fluo roquinolone. Both ciprofloxacin and levofloxacin should be dosage adjusted in patients with significant renal dysfunction. While taking fluoroquinolones, patients should be monitored for hepatic and renal dysfunction, arthropathies, and hematologic abnormalities. Linezolid Linezolid is a synthetic oxazolidinone derivative. This drug is not cur rently approved for use against mycobacterial infection in pediatric or adult patients but has activity against some mycobacterial species. Studies on efficacy of treatment of mycobacterial infections are under way. Linezolid inhibits translation by binding to the 23S ribosomal component of the 50S ribosome subunit, preventing coupling with the 70S subunit. Resistance is thought to be from a point a pathogenic vari ant at the binding site but is poorly studied because only a few cases of resistance have been reported. The approved indications for linezolid are for bacterial infections other than mycobacteria, but studies reveal in vitro activity against rapidly growing mycobacteria (M. fortuitum complex, M. chelonae, M. abscessus), M. tuberculosis, and M. avium complex. The dosage for 0 to 11 year old children is 10 mgkgday PO or IV in divided doses every 8 12 hours. For persons 12 years old, the dosage is 600 mg PO or IV every 12 hours. Linezolid is available in 400 and 600 mg tablets and as a 20 mgmL suspension. Adverse effects of linezolid include GI upset (e.g., nausea, vomit ing, diarrhea), |
7,408 | CNS disturbances (e.g., dizziness, headache, insomnia, peripheral neuropathy), lactic acidosis, fever, myelosuppression, and pseudomembranous colitis. Linezolid is a weak inhibitor of mono amine oxidase A, and patients are advised to avoid foods with high tyramine content. Linezolid should be used cautiously in patients with preexisting myelosuppression. In addition to monitoring for GI upset and CNS perturbations, rou tine laboratory monitoring includes CBC at least weekly. Paraaminosalicylic Acid Paraaminosalicylic acid (PAS) is a structural analog of paraaminoben zoic acid (PABA). It is bacteriostatic and acts by competitively inhibit ing the synthesis of folic acid, similar to the action of sulfonamides. Resistance mechanisms are poorly understood. PAS acts against M. tuberculosis. The dosage is 150 mgkgday PO in two or three divided doses. PAS is dispensed in 4 g packets, and the granules should be mixed with liquid and swallowed whole. Common adverse effects include GI upset, and less common events include hypokalemia, hematuria, albuminuria, crystalluria, and eleva tions of hepatic transaminases. PAS can decrease the absorption of rifampin, and co administration with ethionamide potentiates the adverse effects of PAS. In addition to monitoring for weight loss, routine laboratory moni toring includes liver and kidney function tests. Bedaquiline Fumarate This oral diarylquinoline has been recommended for the treatment of MDR tuberculosis. Bedaquiline fumarate should be used as part of combination therapy and administered by direct observation. Although approved for patients 18 years old, bedaquiline may be considered for children on a case by case basis. Serious adverse effects include hepatotoxicity and a prolonged QT interval. Delamanid Delamanid is a dihydro nitroimidazooxazole derivative recently approved for use in the treatment of MDR tuberculosis. It acts by inhibiting the synthesis of mycobacterial cell wall compounds such as methoxymycolic acid and ketomycolic acid. Limited studies are avail able in the pediatric population, and delamanid should be used only in conjunction with a tuberculosis specialist. Adverse effects include nausea, vomiting, dizziness, anxiety, shak ing, and QT prolongation. AGENTS USED AGAINST MYCOBACTERIUM LEPRAE Dapsone Dapsone is a sulfone antibiotic with characteristics similar to sulfonamides. Similar to other sulfonamides, dapsone acts as a competitive antagonist of PABA, which is needed for the bacterial synthesis of folic acid. Dapsone is bacteriostatic against M. leprae. Resistance is not well understood but is thought to occur after alterations at the PABA binding site. Dapsone is used in the treatment of M. leprae in combination with other antileprosy agents (rifampin, clofazimine, ethionamide). The pediatric dosage is 1 2 mgkgday PO as a single dose, not to exceed 100 mgday, for a duration of 3 10 years. The adult dosage is 100 mg day PO as a single dose. Dapsone is available in 25 and 100 mg scored tablets and as an oral suspension of 2 mgmL. The dosage should be adjusted in renal insufficiency. Dapsone has many reported adverse effects, including dosage related hemolytic anemia, especially in patients with glucose 6 phosphate dehydrogenase (G6PD) deficiency, pancreatitis, renal complications (acute tubular necrosis, acute renal failure, albumin uria), increased liver enzymes, psychosis, tinnitus, peripheral |
7,409 | neuropa thy, photosensitivity, and a hypersensitivity syndrome with fever, rash, hepatic damage, and malaise. Treatment may produce a lepra reaction, which is a nontoxic, paradoxical worsening of lepromatous leprosy with the initiation of therapy. This hypersensitivity reaction is not an indication to discontinue therapy. Dapsone should be used with cau tion in patients with G6PD deficiency or taking other folic acid antago nists. Dapsone levels can decrease with concomitant rifampin use and can increase with concomitant clotrimazole use. Routine laboratory monitoring includes CBC weekly during the first month of therapy, weekly through 6 months of therapy, and then every 6 months thereafter. Other periodic assessments include kidney func tion with creatine levels, urinalysis, and liver function tests. Clofazimine Clofazimine is a synthetic phendimetrazine tartrate derivative that acts by binding to the mycobacterial DNA at guanine sites. It has slow bac tericidal activity against M. leprae. Mechanisms of resistance are not well studied. No cross resistance between clofazimine and dapsone or rifampin has been shown. Clofazimine is indicated as part of a combination therapy for the treatment of M. leprae. It appears there may be some activity against other mycobacteria such as M. avium complex, although treatment failures are common. The safety and efficacy of clofazimine are poorly studied in children. The pediatric dosage is 1 mgkgday PO as a sin gle dose, not to exceed 100 mgday, in combination with dapsone and rifampin for 2 years and then additionally as a single agent for 1 year. The adult dosage is 100 mgday PO. Clofazimine should be taken with food to increase absorption. The most common adverse effect is a dosage related, reversible, pink to tan brown discoloration of the skin and conjunctiva. Other adverse Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1834 Part XV u Infectious Diseases effects include a dry, itchy skin rash, headache, dizziness, abdominal pain, diarrhea, vomiting, peripheral neuropathy, and elevated hepatic transaminases. Routine laboratory monitoring includes periodic liver function tests. AGENTS USED AGAINST NONTUBERCULOUS MYCOBACTERIA Cefoxitin Cefoxitin, a cephamycin derivative, is a second generation cephalospo rin that, like other cephalosporins, inhibits cell wall synthesis by linking with penicillin binding proteins to create an unstable bacterial cell wall. Resistance develops by alterations in penicillin binding proteins. Cefoxitin is often used in combination therapy for mycobacterial disease (Table 260.3). Pediatric dosing is based on disease severity, with a range of 80 160 mgkgday divided every 4 8 hours, not to exceed 12 gday. Adult dosages are 1 2 gdose, not to exceed 12 gday. Cefoxitin is available in IV and IM formulations. Increased dosing intervals are needed with renal insufficiency. Adverse effects are primarily hematologic (eosinophilia, granulocy topenia, thrombocytopenia, hemolytic anemia), GI (nausea, vomiting, Table 260.3 Treatment of Nontuberculous Mycobacteria Infections in Children ORGANISM DISEASE INITIAL TREATMENT SLOWLY GROWING SPECIES Mycobacterium avium complex (MAC); Mycobacterium haemophilum; Mycobacterium lentiflavum Lymphadenitis Complete excision |
7,410 | of lymph nodes; if excision incomplete or disease recurs, clarithromycin or azithromycin plus ethambutol andor rifampin (or rifabutin). Pulmonary infection Clarithromycin or azithromycin plus ethambutol with rifampin or rifabutin (pulmonary resection in some patients who fail to respond to drug therapy). For severe disease, an initial course of amikacin or streptomycin often is included. Clinical data in adults with mild to moderate disease support that 3 times weekly therapy is as effective as daily therapy, with less toxicity. For patients with advanced or cavitary disease, drugs should be given daily. Mycobacterium chimaera Prosthetic valve endocarditis Valve removal, prolonged antimicrobial therapy based on susceptibility testing. Disseminated See text. Mycobacterium kansasii Pulmonary infection Rifampin plus ethambutol with isoniazid daily. If rifampin resistance is detected, a three drug regimen based on drug susceptibility testing should be used. Osteomyelitis Surgical debridement and prolonged antimicrobial therapy using rifampin plus ethambutol with isoniazid. Mycobacterium marinum Cutaneous infection None, if minor; rifampin, TMP SMX, clarithromycin, or doxycycline for moderate disease; extensive lesions may require surgical debridement. Susceptibility testing not routinely required. Mycobacterium ulcerans Cutaneous and bone infections Daily intramuscular streptomycin and oral rifampin for 8 wk; excision to remove necrotic tissue, if present; potential response to thermotherapy. RAPIDLY GROWING SPECIES Mycobacterium fortuitum group Cutaneous infection Initial therapy for serious disease is amikacin plus meropenem IV, followed by clarithromycin, doxycycline, TMP SMX, or ciprofloxacin PO on the basis of in vitro susceptibility testing; may require surgical excision. Up to 50 of isolates are resistant to cefoxitin. Catheter infection Catheter removal and amikacin plus meropenem IV; clarithromycin, TMP SMX, or ciprofloxacin orally on the basis of in vitro susceptibility testing. Mycobacterium abscessus Otitis media; cutaneous infection There is no reliable antimicrobial regimen because of variability in drug susceptibility. Clarithromycin plus an initial course of amikacin plus cefoxitin or imipenemmeropenem; may require surgical debridement on the basis of in vitro susceptibility testing (50 are amikacin resistant). Pulmonary infection (in cystic fibrosis) Serious disease; clarithromycin, amikacin, and cefoxitin or imipenem meropenem on the basis of susceptibility testing; most isolates have very low MIC to tigecycline; may require surgical resection. Mycobacterium chelonae Catheter infection, prosthetic valve endocarditis Catheter removal; debridement, removal of foreign material; valve replacement; and tobramycin (initially) plus clarithromycin, meropenem, and linezolid. Disseminated cutaneous infection Tobramycin and meropenem or linezolid (initially) plus clarithromycin. Doxycycline can be used for short durations (i.e., 21 days) without regard to patient age but is not recommended for longer treatment durations in children 8 yr old. Only 50 of isolates of M. marinum are susceptible to doxycycline. IV, Intravenously; MIC, minimum inhibitory concentration; PO, orally (by mouth); TMP SMX, trimethoprim sulfamethoxazole. From Kimberlin DW, Barnett ED, Lynfield R, Sawyer MH, eds. Red Book: 20212024 Report of the Committee on Infectious Diseases, 32nd ed. Itasca, IL: American Academy of Pediatrics; 2021. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter |
7,411 | 261 u Tuberculosis (Mycobacterium tuberculosis) 1835 diarrhea with possible pseudomembranous colitis), and CNS related (dizziness, vertigo). Potential additive adverse effects can occur when cefoxitin is used with aminoglycosides. Routine laboratory monitoring with long term use includes CBC and liver and renal function tests. Doxycycline Doxycycline is in the tetracycline family of antibiotics and has lim ited use in pediatrics. As with other tetracyclines, doxycycline acts to decrease protein synthesis by binding to the 30S ribosome and to trans fer RNA. It can also cause alterations to the cytoplasmic membrane of susceptible bacteria. Doxycycline is used to treat M. fortuitum (see Table 260.3). Although it can be used to treat M. marinum, adult treatment failures have occurred. Pediatric dosing is based on age and weight. For children 8 years old who weigh 45 kg, the dosage is 4.4 mgkgday divided twice daily. Dosing for larger children and adults is 100 mg twice daily. Doxycycline is available as 50 and 100 mg capsules or tablets and in 25 mg5 mL and 50 mg5 mL suspensions. Doxycycline use in children is limited by a permanent tooth dis coloration, which becomes worse with long term use. Other adverse effects include photosensitivity, liver and kidney dysfunction, and esophagitis, which can be minimized by dosing with large volumes of liquid. Doxycycline can decrease the effectiveness of oral contracep tives. Rifampin, carbamazepine, and phenytoin can decrease the con centration of doxycycline. Routine laboratory monitoring with long term use includes kidney and liver function tests as well as CBC. Macrolides Clarithromycin and azithromycin belong to the macrolide family of antibiotics. Clarithromycin is a methoxy derivative of erythromy cin. Macrolides act by binding the 50S subunit of ribosomes, sub sequently inhibiting protein synthesis. Resistance mechanisms for mycobacteria are not well understood but might involve binding site alterations. Clarithromycin appears to have synergistic antimy cobacterial activity when combined with rifamycins, ethambutol, or clofazimine. Clarithromycin is widely used for the prophylaxis and treatment of M. avium complex disease and also has activity against M. absces sus, M. fortuitum, and M. marinum. Azithromycin has significantly different pharmacokinetics compared with other macrolide agents and has not been studied and is not indicated for mycobacterial infections. The pediatric dosage of clarithromycin for primary prophylaxis of M. avium complex infections is 7.5 mgkgdose PO given twice daily, not to exceed 500 mgday. This dosage is used for recurrent M. avium complex disease in combination with ethambu tol and rifampin. The adult dosage is 500 mg PO twice daily to be used as a single agent for primary prophylaxis or as part of combi nation therapy with ethambutol and rifampin. Dosage adjustment is needed for renal insufficiency but not liver failure. Clarithromycin is available in 250 and 500 mg tablets and suspensions of 125 mg5 mL and 250 mg5 mL. The primary adverse effect of clarithromycin is GI upset, includ ing vomiting (6), diarrhea (6), and abdominal pain (3). Other adverse effects include taste disturbances, headache, and QT prolon gation if used with inhaled anesthetics, clotrimazole, |
7,412 | antiarrhythmic agents, or azoles. Clarithromycin should be used cautiously in patients with renal insufficiency or liver failure. Routine laboratory monitoring with prolonged use of clarithromy cin includes periodic liver enzyme tests. Diarrhea is an early sign of pseudomembranous colitis. Trimethoprim Sulfamethoxazole Trimethoprim sulfamethoxazole (TMP SMX) is formulated in a fixed ratio of one part TMP to five parts SMX. SMX is a sulfonamide that inhibits synthesis of dihydrofolic acid by competitively inhibiting PABA, similar to dapsone. TMP blocks production of tetrahydrofolic acid and downstream biosynthesis of nucleic acids and protein by reversibly binding to dihydrofolate reductase. The combination of the two agents is synergistic and often bactericidal. TMP SMX is often used in combination therapy for mycobacte rial disease (see Table 260.3). Oral or IV pediatric dosage for serious infections is TMP 15 20 mgkgday divided every 6 8 hours, and for mild infections, TMP 6 12 mgkgday divided every 12 hours. The adult dosage is 160 mg TMP and 800 mg SMX every 12 hours. Dosage reduction may be needed in renal insufficiency. TMP SMX is available in single strength tablets (80400 mg TMP SMX) and double strength tablets (160800 mg TMP SMX) and in a suspension of 40 mg TMP and 200 mg SMX per 5 mL. The most common adverse effect with TMP SMX is myelosuppres sion. It must be used with caution in patients with G6PD deficiency. Other adverse effects include renal abnormalities, rash, aseptic men ingitis, GI disturbances (e.g., pancreatitis, diarrhea), and prolonged QT interval if co administered with inhaled anesthetics, azoles, or macrolides. Routine laboratory monitoring includes monthly CBC and periodic electrolytes and creatinine to monitor renal function. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Mycobacterium tuberculosis has caused human disease for more than 4,000 years and is one of the most important infectious diseases world wide. There are five closely related mycobacteria in the Mycobacterium tuberculosis complex: M. tuberculosis, M. bovis, M. africanum, M. microti, and M. canetti. M. tuberculosis is the most important cause of tuberculosis (TB) disease in humans. The tubercle bacilli are non spore forming, nonmotile, pleomorphic, weakly gram positive curved rods 1 5 m long, typically slender, and slightly bent. They can appear beaded or clumped under microscopy. They are obligate aerobes that grow in synthetic media containing glycerol as the carbon source and ammonium salts as the nitrogen source (Lwenstein Jensen culture media). These mycobacteria grow best at 3741C (98.6105.8F), produce niacin, and lack pigmentation. A lipid rich cell wall accounts for resistance to the bactericidal actions of antibody and complement. A hallmark of all mycobacteria is acid fastnessthe capacity to form stable mycolate complexes with arylmethane dyes (crystal violet, car bolfuchsin, auramine, and rhodamine). They resist decoloration with ethanol and hydrochloric or other acids. M. tuberculosis grows slowly, with a generation time of 12 24 hours. Isolation from clinical specimens on solid synthetic media usually takes 3 6 weeks, and drug susceptibility testing requires an additional 2 4 weeks. Growth can be detected in 1 3 weeks |
7,413 | in selective liquid medium using radiolabeled nutrients (e.g., BACTEC radiometric sys tem), and drug susceptibilities can be determined in an additional 3 5 days. Once mycobacterial growth is detected, the species of mycobac teria present can be determined within hours using high pressure liq uid chromatography analysis (identifying the mycolic acid fingerprint of each species) or DNA probesnucleic amplification tests (NAATs). Chapter 261 Tuberculosis (Mycobacterium tuberculosis) Lindsay H. Cameron and Jeffrey R. Starke Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1836 Part XV u Infectious Diseases NAATs are used to identify genes associated with M. tuberculosis drug resistance and complement phenotypic drug susceptibility testing. Results are available in hours, which expedites management decisions. Phenotypic drug susceptibility testing is necessary to confirm suscepti bility to each drug. Restriction fragment length polymorphism genetic profiling of mycobacteria is a helpful tool to study the epidemiology of TB strain relatedness in both outbreaks and routine epidemiology of TB in a community. CLINICAL STAGES There are three major clinical stages of TB: exposure, infection, and disease. Exposure means a child has had recent significant contact (shared the air) with an adult or adolescent with infectious TB but lacks proof of infection. In this stage, the tuberculin skin test (TST) or interferon release assay (IGRA) result is negative, the chest radiograph is normal, the physical examination is normal, and the child lacks signs or symptoms of disease. However, the child may be infected and develop TB disease rapidly, because there may not have been enough time for the TST or IGRA to turn positive. Tuberculosis infection (TBI) occurs when the individual inhales droplet nuclei containing M. tuberculosis, which survive intracellularly within the lung and associated lymphoid tissue. The hallmark of TBI is a positive TST or IGRA result. In this stage the child has no signs or symptoms and has a normal physical examination, and the chest radiograph is either normal or reveals only granuloma or calcifications in the lung parenchyma. Disease occurs when signs or symptoms or radio graphic manifestations caused by M. tuberculosis become apparent. Not all infected individuals have the same risk of developing disease. An immunocompetent adult with untreated TBI has approximately a 510 lifetime risk of developing disease. In contrast, an infected child 1 year old has a 40 chance of developing TB disease within 9 months. EPIDEMIOLOGY TB remains a leading cause of death from an infectious disease world wide. The global burden of TB is influenced by several factors, includ ing the HIV pandemic; the development of multidrug resistant (MDR) tuberculosis; the disproportionately low access of populations in low resource settings worldwide to both diagnostic tests and effec tive medical therapy; and the COVID 19 pandemic. The World Health Organization (WHO) 2020 Global Tuberculosis Report estimates that the COVID 19 pandemic could have a significant impact on access to essential TB services |
7,414 | (human capital, financial), which may increase the rates of TB associated morbidity and mortal ity. Many countries have had to allocate public health resources from TB prevention efforts toward COVID 19 prevention, including con tact tracing and using GeneXpert machines for COVID 19 testing. The WHO predicts that this resource diversion from TB case finding, test ing, treatment, and prevention may result in an increase of global TB associated deaths by 0.2 0.4 million per year. Approximately 95 of TB cases occur in the developing world. In 2019, the 30 high TB burden countries accounted for 87 of incident cases (Fig. 261.1). Two thirds of cases occurred in eight countries, including India, Indonesia, China, the Philippines, Pakistan, Nigeria, Bangladesh, and South Africa. An estimated 10 million incident cases and 1.4 million TB associated deaths occurred worldwide in 2019. The WHO 2020 Global Tuberculosis Report estimates that in 2019 there were 1.2 million childhood incident cases and 230,000 TB associated deaths among children, including 32,000 TB associated deaths among children living with HIV. The incidence of drug resistant TB has increased in some areas of the world in both adults and children. In 2019, the WHO reported a global total of 206,030 cases of multidrug or rifampicin resistant TB, a 10 increase from 2018 (Fig. 261.2). Isoniazid (INH)mono resistant TB is resistance to INH alone, rifampicin resistant TB (RR TB) is resistance to at least rifampin, MDR TB is defined as resistance to at least isoniazid and rifampin, and extensively drug resistant tuberculosis TB (XDR TB) includes MDR TB plus resistance to any fluoroquinolone and at least one of three injectable drugs (kanamy cin, capreomycin, or amikacin). In 2014, the worldwide estimate for MDR TB in children was 2.9 of all cases and 0.1 for XDR TB. The highest incidence of MDR TB in children occurs in the Southeast Asian, African, and Western Pacific regions; however, the proportion of drug resistant cases is highest in countries belonging to the Rus sian Federation, where over 30 of children with TB have a drug resistant organism. In the United States, TB case rates decreased steadily during the first half of the 20th century, long before the advent of antituberculosis drugs, as a result of improved living conditions and likely genetic selec tion favoring persons resistant to developing disease. A resurgence of TB in the late 1980s was associated primarily with the HIV epidemic, transmission of the organism in congregate settings including health care institutions, disease occurring in recent immigrants, and poor conduct of community TB control. Since 1992, the TB incidence in the Number of incident cases 100 000 500 000 1 000 000 2 000 000 India China Indonesia Philippines Pakistan Nigeria Bangladesh Democratic Republic of the Congo Fig. 261.1 Countries that had at least 100,000 incident cases of TB in 2021. The countries that rank first to eighth in terms of numbers of cases and that accounted for about two thirds of global cases in 2021 are labeled. (From the World |
7,415 | Health Organization: Global Tuberculosis Report 2022. Geneva: World Health Organization; 2022, Fig 12. License: CC BY NC SA 3.0 IGO.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 261 u Tuberculosis (Mycobacterium tuberculosis) 1837 United States has decreased over time. In 2020, the case rate was at the all time low of 2.2 per 100,000 persons (Fig. 261.3). In 2017, the incidence rate of TB among children 15 years was 0.7 cases per 100,000 person years, a decline of 41 from 1993. The TB incidence rates were highest in children less than 12 months of age (1.3 per 100,000 person years), followed by children age 1 4 years (1.1 per 100,000 person years), and were lowest among children age 5 14 years (0.5 per 100,000 person years) (Fig. 261.4). From 1993 to 2017, non United Statesborn children, children born to non United Statesborn parents, and children of racial or ethnic minority status were disproportionately affected by TB. Non United Statesborn children accounted for approximately 25 of the total number of childhood TB cases, the majority being from Mexico, fol lowed by the Philippines, Somalia, Vietnam, Ethiopia, and Haiti (Fig. 261.5). According to data reported to the National TB Surveillance System from 2007 to 2017, among United Statesborn children, the incidence rates of TB if both parents were non United Statesborn and if one parent was non United Statesborn were eight and three times higher, respectively, compared to United Statesborn children with both par ents being United Statesborn. This is supported by prior research that found that 75 of United Statesborn children with TB had some international connection through a family member or previous travel or residence in a TB endemic country. Similar to adults in the United Number of cases 1000 10 000 100 000 India China Indonesia Philippines Pakistan South Africa Russian Federation Fig. 261.2 Percentage of new TB cases with MDR RR TB. The seven countries with the highest burden in terms of numbers of MDRRR TB cases and that accounted for two thirds of global MDR RR TB cases in 2021 are labeled. (From the World Health Organization: Global Tuberculosis Report 2022. Geneva: World Health Organization; 2022, Fig 17. License: CC BY NC SA 3.0 IGO.) 30,000 25,000 20,000 15,000 10,000 5,000 0 N um be r of c as es 19 93 19 95 19 97 19 99 20 01 20 03 20 05 20 07 Year 20 09 20 11 20 13 20 15 20 17 20 19 12 10 8 6 4 2 0 C as es p er 1 00 ,0 00 p er so ns Number of cases Incidence rate Fig. 261.3 Reported tuberculosis cases in the United States for 1993 2019 (as of October 29, 2020). (From Centers for Disease Control and Prevention. Trends in Tuberculosis, 2019. Atlanta: U.S. Department of Health and Human |
7,416 | Services; 2020.) Age 1 year Age 14 years Age 59 years Age 1014 years N22,037 1000 100 10 1 0.1 0.01 C as es p er 1 00 ,0 00 P er so n Y ea rs 19 93 19 95 19 97 19 99 20 01 20 03 20 05 20 07 20 09 20 11 20 13 20 15 20 17 Fig. 261.4 Reported pediatric tuberculosis (TB) cases in the United States by age group for the years 1993 2017. Rates are presented on a logarithmic scale. (From Centers for Disease Control and Prevention, National Center for HIVAIDS, Viral Hepatitis, STD and TB Prevention. Pediatric Tuberculosis in United States, 19932017. Atlanta: U.S. De partment of Health and Human Services; 2018.) Mexico Philippines Somalia Vietnam Ethiopia Haiti 1993 1995 1997 1999 2001 2003 2005 2007 2009 2011 2013 2015 2017 400 350 300 250 200 150 100 50 0 Fig. 261.5 Top six countries of birth for nonUnited Statesborn pediatric TB cases for the years 1993 2017. Non United Statesborn refers to persons born outside the United States or its territories or not born to a US citizen. Cases in United Statesborn children of non United Statesborn parents are included in United Statesborn counts and thus not displayed in this figure. (From Centers for Disease Control and Prevention, National Center for HIVAIDS, Viral Hepatitis, STD and TB Prevention. Pediatric Tuberculosis in United States, 19932017. At lanta: U.S. Department of Health and Human Services; 2018.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1838 Part XV u Infectious Diseases States, TB among children of racial ethnic minority status occurs dis proportionately. The incidence rates of TB among children of Native Hawaiian or Pacific Islander, Asian, Native American or Native Alas kan, Black, and Hispanic children were 144, 44, 22, 19, and 18 times higher, respectively, than among non Hispanic White children. The rates of drug resistant TB in children in the United States remain low. A total of 89 childhood cases of MDR TB were reported in the United States in 2015; of those, 70.8 were non United States born. Among children with culture confirmed TB in the United States in 2015, 15.2 had organisms with resistance to at least one first line drug and 0.9 had MDR organisms. Most children are infected with M. tuberculosis in their home by someone close to them, but outbreaks of childhood TB also have occurred in elementary and high schools, nursery schools, daycare centers and homes, churches, school buses, and sports teams. Adults living with HIV who have pulmonary TB can transmit M. tuberculo sis to children, and children living with HIV are at increased risk for developing TB after infection. Other specific groups are at high risk for acquiring TBI and progressing to tuberculosis disease (Table 261.1). TRANSMISSION Transmission of M. tuberculosis is usually by inhalation |
7,417 | of airborne mucus droplet nuclei, particles 1 5 m in diameter that contain M. tuberculosis. Transmission rarely occurs by direct contact with an infected discharge or a contaminated fomite. The chance of transmission increases when the patient has a positive acid fast smear of sputum, an extensive upper lobe infiltrate or cavity, copious production of thin spu tum, and severe and forceful cough (although the absence of cough does not eliminate the risk of TBI). Environmental factors such as poor air circulation enhance transmission. Within several days to 2 weeks after beginning adequate chemotherapy, most adults no longer transmit the organism, but some patients remain infectious for many weeks. Young children with TB rarely infect other children or adults; tubercle bacilli are sparse in their endobronchial secretions, and cough is often absent or lacks the tussive force required to suspend infectious particles of the correct size. However, adolescents often present with adult type cavity or endobronchial TB and can easily transmit the organism. Airborne transmission of M. bovis and M. africanum also occurs rarely. M. bovis can penetrate the gastrointestinal (GI) mucosa or invade the lymphatic tissue of the oropharynx when large numbers of the organism are ingested. Human infection with M. bovis is rare in developed countries as a result of the pasteurization of milk and effective TB control programs for cattle. Approximately 46 of culture proven childhood TB cases from the San Diego, Califor nia, region since 1994 were caused by M. bovis, likely acquired by children when visiting Mexico or another country or consuming dairy products from countries with suboptimal veterinary TB con trol programs. Zoonotic transmission is an uncommon source of M. tuberculosis that has been reported in adults exposed to elephants and potentially cattle. PATHOGENESIS The primary complex (or Ghon complex) of TB includes local infec tion at the portal of entry and the regional lymph nodes that drain the area. The lung is the portal of entry in 98 of cases. The tubercle bacilli multiply initially within alveoli and alveolar ducts. Most of the bacilli are killed, but some survive within nonactivated macrophages, which carry them through lymphatic vessels to the regional lymph nodes. When the primary infection is in the lung, the hilar lymph nodes usually are involved, although an upper lobe focus can drain into paratracheal nodes. The tissue reaction in the lung parenchyma and lymph nodes intensifies over the next 2 12 weeks as the organisms grow in number and tissue hypersensitivity develops. The parenchy mal portion of the primary complex often heals completely by fibrosis or calcification after undergoing caseous necrosis and encapsulation (Fig. 261.6). Occasionally, this portion continues to enlarge, resulting in focal pneumonitis and pleuritis. If caseation is intense, the center of the lesion liquefies and empties into the associated bronchus, leaving a residual cavity. Table 261.1 Groups at High Risk for Acquiring Tuberculosis Infection and Developing Disease in Countries with Low Incidence RISK FACTORS FOR TUBERCULOSIS INFECTION Children exposed to high risk adults Foreign born persons from |
7,418 | high prevalence countries Homeless persons Persons who inject drugs Present and former residents or employees of correctional institutions, homeless shelters, and nursing homes Healthcare workers caring for high risk patients (if infection control is not adequate) RISK FACTORS FOR PROGRESSION OF TUBERCULOSIS INFECTION TO TUBERCULOSIS DISEASE Infants and children 4 yr old, especially those 2 yr old Adolescents and young adults Persons co infected with human immunodeficiency virus Persons with skin test conversion in the past 1 2 yr Persons who are immunocompromised, especially in cases of malignancy and solid organ transplantation, immunosuppressive medical treatments including antitumor necrosis factor therapies, diabetes mellitus, chronic renal failure, silicosis, and malnutrition RISK FACTORS FOR DRUG RESISTANT TUBERCULOSIS Personal or contact history of treatment for tuberculosis Contacts of patients with drug resistant tuberculosis Birth or residence in a country with a high rate of drug resistance Poor response to standard therapy Positive sputum smears (acid fast bacilli) or culture 2 mo after initiating appropriate therapy Fig. 261.6 Posteroanterior (A) and lateral (B) chest radiographs of an ado lescent showing a 7 mm calcified gran uloma in the left lower lobe (arrows). (From Lighter J, Rigaud M. Diagnosing childhood tuberculosis: traditional and innovative modalities. Curr Probl Pedi atr Adolesc Health Care. 2009;39:55 88.) A B Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 261 u Tuberculosis (Mycobacterium tuberculosis) 1839 The foci of infection in the regional lymph nodes develop some fibrosis and encapsulation, but healing is usually less complete than in the parenchymal lesion. Viable M. tuberculosis can persist for decades within these foci. In most cases of initial TBI, the lymph nodes remain normal in size. However, hilar and paratracheal lymph nodes that enlarge significantly as part of the host inflammatory reaction can encroach on a regional bronchus (Figs. 261.7 and 261.8). Par tial obstruction of the bronchus caused by external compression can cause hyperinflation in the distal lung segment. Complete obstruction results in atelectasis. Inflamed caseous nodes can attach to the bron chial wall and erode through it, causing endobronchial TB or a fistula tract. The caseum causes complete obstruction of the bronchus. The resulting lesion is a combination of pneumonitis and atelectasis and has been called a collapse consolidation lesion or segmental lesion (Fig. 261.9). During the development of the primary complex, tubercle bacilli are carried to most tissues of the body through the blood and lymphatic vessels. Although seeding of the organs of the reticuloendothelial sys tem is common, bacterial replication is more likely to occur in organs with conditions that favor their growth, such as the lung apices, brain, kidneys, and bones. Disseminated tuberculosis occurs if the number of circulating bacilli is large and the hosts cellular immune response is inadequate. More often, the number of bacilli is small, leading to clinically inapparent metastatic foci in many organs. These remote foci usually become |
7,419 | encapsulated, but they may be the origin of both extra pulmonary tuberculosis and reactivation pulmonary tuberculosis. The time between initial infection and clinically apparent TB disease is variable. Disseminated and meningeal TB are early manifestations, often occurring within 2 6 months of acquisition. Significant lymph node or endobronchial TB usually appears within 3 9 months. Lesions of the bones and joints take several years to develop, whereas renal lesions become evident decades after infection. Extrapulmonary mani festations are more common in children than in adults and develop in 2535 of children with TB vs approximately 10 of immunocompe tent adults. Pulmonary TB that occurs 1 year after the primary infection is usu ally caused by endogenous regrowth of bacilli persisting in partially encapsulated lesions. This reactivation TB is rare in young children but is common among adolescents and young adults. The most com mon form is an infiltrate or cavity in the apex of the upper lobes, where oxygen tension and blood flow are highest. The risk for dissemination of M. tuberculosis is very high in persons living with HIV. Reinfection also can occur in persons with advanced HIV or AIDS. In immunocompetent persons, the response to the ini tial infection with M. tuberculosis usually provides protection against reinfection when a new exposure occurs. However, exogenous reinfec tion has been reported to occur in adults and children without immune compromise in highly endemic areas. Immunity Conditions that adversely affect cell mediated immunity predispose to progression from TBI to disease. Rare specific genetic defects (Mende lian susceptibility to mycobacterial disease MSMD) associated with deficient cell mediated immunity in response to mycobacteria include interleukin (IL) 12 receptor B1 deficiency TYK2 pathogenic gene vari ants; 15 other genes associated with primary immunodeficiencies such as NEMO, STAT1, JAK1, and RORC; and complete and partial interferon (IFN) receptor 1 chain deficiencies. TBI is associated with a humoral antibody response, which plays a little known role in host defense. Shortly after infection, tubercle bacilli replicate in both free alveolar spaces and inactivated alveolar macrophages. Sulfatides in the A B Fig. 261.7 A 14 yr old child with proven primary tuberculosis. Frontal (A) and lateral (B) views of the chest show hyperinflation, prominent left hilar lymphadenopathy, and alveolar consolidation involving the pos terior segment of the left upper lobe and the superior segment of the left lower lobe. (From Hilton SVW, Edwards DK, eds. Practical Pediatric Radiology, 3rd ed. Philadelphia: Saunders; 2003:334.) Fig. 261.8 An 8 yr old child with a history of cough. A single frontal view of the chest shows marked right hilar and paratracheal lymphadenopathy with alveolar disease involving the right middle and lower lung fields. This was also a case of primary tuberculosis. (From Hilton SVW, Edwards DK, eds. Practical Pediatric Radiology, 3rd ed. Philadelphia: Saunders; 2003:335.) Fig. 261.9 Right sided hilar lymphadenopathy and collapse consolidation lesions of primary tuberculosis in a 4 yr old child. (From Kimberlin DW, Bar nett ED, Lynfield R, Sawyer MH (eds). Red Book: 20212024 Report of the |
7,420 | Committee on Infectious Diseases, 32nd ed. Itasca, IL: American Academy of Pediatrics, 2021. p 805806; with data from Furin J, Seddon J, Becerra M, et al. Management of MultidrugResistant Tuberculosis Children: A Field Guide, 4th ed. Boston: The Sentinel Project for Pediatric DrugResistant Tuberculosis, 2019. Available at: http:sentinelproject.orgwpcontentup loads201902UpdatedDRTBFieldGuide2019V3.pdf ) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1840 Part XV u Infectious Diseases mycobacterial cell wall inhibit fusion of the macrophage phagosome and lysosomes, allowing the organisms to escape destruction by intra cellular enzymes. Cell mediated immunity develops 2 12 weeks after infection, along with tissue hypersensitivity (Fig. 261.10). After bacilli enter macrophages, lymphocytes that recognize mycobacterial antigens proliferate and secrete lymphokines and other mediators that attract other lymphocytes and macrophages to the area. Certain lymphokines activate macrophages, causing them to develop high concentrations of lytic enzymes that enhance their mycobactericidal capacity. A discrete subset of regulator helper and suppressor lymphocytes modulates the immune response. Development of specific cellular immunity prevents progression of the initial infection in most persons. The pathologic events in the initial TBI seem to depend on the bal ance among the mycobacterial antigen load; cell mediated immunity (which enhances intracellular killing); and tissue hypersensitivity, which promotes extracellular killing. When the antigen load is small and the degree of tissue sensitivity is high, granuloma formation results from the organization of lymphocytes, macrophages, and fibroblasts. When both antigen load and degree of sensitivity are high, granuloma formation is less organized. Tissue necrosis is incomplete, resulting in formation of caseous material. When the degree of tissue sensitivity is low, as often occurs in infants or immunocompromised persons, the reaction is diffuse and the infection is not well contained, leading to dissemination and local tissue destruction. Tumor necrosis factor (TNF) and other cytokines released by specific lymphocytes promote cellular destruction and tissue damage in susceptible persons. CLINICAL MANIFESTATIONS Primary Pulmonary Disease The primary complex includes the parenchymal pulmonary focus and the regional lymph nodes. Approximately 70 of lung foci are subpleural, and localized pleurisy is common. The initial parenchymal inflammation usually is not visible on chest radiograph, but a local ized, nonspecific infiltrate may be seen before the development of tis sue hypersensitivity. All lobar segments of the lung are at equal risk for initial infection. Two or more primary foci are present in 25 of cases. The hallmark of primary TB in the lung is the relatively large size of the regional lymphadenitis compared with the relatively small size Crosspriming M. tuberculosis M. tuberculosis PRR PRR CD8 CD8Direct presentation PNGMHC I MHC I MHC II MHC II DC DC IL17 T T IFN M M M M M IFN IFN IL10 TGF? IFN Th1Th17 CD4 CD4 IL2 IL4 B Th2 Treg Suppression Active disease Caseous granuloma Latent infection Solid granuloma Protection Protection Exhaustion TNF CD4 Teff CD8 Teff CD8 CTLLysis Lysis CD8 |
7,421 | TM CD8 TM Th1 TM Fig. 261.10 Overview of the immune response in tuberculosis. Control of Mycobacterium tuberculosis is mainly the result of productive teamwork between T cell populations and macrophages (M). M. tuberculosis survives within macrophages and dendritic cells (DCs) inside the phagosomal compartment. Gene products of major histocompatibility complex (MHC) class II are loaded with mycobacterial peptides that are presented to CD4 T cells. CD8 T cell stimulation requires loading of MHC I molecules by mycobacterial peptides in the cytosol, either by egression of mycobacterial antigens into the cytosol or cross priming, by which macrophages release apoptotic bodies carrying mycobacterial peptides. These vesicles are taken up by DCs and peptides presented. The CD4 T helper (Th) cells polarize into different subsets. DCs and macrophages express pattern recogni tion receptors (PRRs), which sense molecular patterns on pathogens. Th1 cells produce interleukin (IL) 2 for T cell activation, interferon (IFN ), or tumor necrosis factor (TNF) for macrophage activation. Th17 cells, which activate polymorphonuclear granulocytes (PNGs), contribute to the early formation of protective immunity in the lung after vaccination. Th2 cells and regulatory T cells (Treg) counterregulate Th1 mediated protection via IL 4, transforming growth factor (TGF ), or IL 10. CD8 T cells produce IFN and TNF, which activate macrophages. They also act as cytolytic T lymphocytes (CTLs) by secreting perforin and granulysin, which lyse host cells and directly attack M. tuberculosis. These effector T cells (Teff) are succeeded by memory T cells (TM). TM cells produce multiple cytokines, notably IL2, IFN , and TNF. During active containment in solid granuloma, M. tuberculosis recesses into a dormant stage and is immune to attack. Exhaustion of T cells is mediated by interactions between T cells and DCs through members of the programmed death 1 system. Treg cells secrete IL 10 and TGF , which suppress Th1. This process allows resuscitation of M. tuberculosis, which leads to granuloma caseation and active disease. B, B cell. (From Kaufman SHE, Hussey G, Lambert PH. New vaccines for tuberculosis. Lancet. 2010;375:21102118.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 261 u Tuberculosis (Mycobacterium tuberculosis) 1841 of the initial lung focus (see Figs. 261.7 and 261.8). As delayed type hypersensitivity develops, the hilar lymph nodes continue to enlarge in some children, especially infants, compressing the regional bronchus and causing obstruction. The usual sequence is hilar lymphadenopathy, focal hyperinflation, and then atelectasis. The resulting radiographic shadows have been called collapse consolidation or segmental TB (see Fig. 261.9). Rarely, inflamed caseous nodes attach to the endobronchial wall and erode through it, causing endobronchial TB or a fistula tract. The caseum causes complete obstruction of the bronchus, resulting in extensive infiltrate and collapse. Enlargement of the subcarinal lymph nodes can cause compression of the esophagus and, rarely, a broncho esophageal fistula. Most cases of tuberculous bronchial obstruction in children resolve fully |
7,422 | with appropriate treatment. Occasionally, there is residual calcifi cation of the primary focus or regional lymph nodes. The appearance of calcification implies that the lesion has been present for at least 6 12 months. Healing of the segment can be complicated by scarring or con traction associated with cylindrical bronchiectasis, but this is rare. Children can have lobar TB pneumonia without impressive hilar lymphadenopathy. If the primary infection is progressively destructive, liquefaction of the lung parenchyma can lead to formation of a thin walled primary TB cavity. Rarely, bullous tuberculous lesions occur in the lungs and lead to pneumothorax if they rupture. Erosion of a parenchymal focus of TB into a blood or lymphatic vessel can result in dissemination of the bacilli and a miliary pattern, with small nodules evenly distributed on the chest radiograph (Fig. 261.11). The symptoms and physical signs of primary pulmonary TB in chil dren are surprisingly meager considering the degree of radiographic changes often present. When active case finding is performed, up to 50 of infants and children with radiographically moderate to severe pulmonary TB have no physical findings. Infants are more likely to experience signs and symptoms. Nonproductive cough and mild dys pnea are the most common symptoms. Systemic complaints such as fever, night sweats, anorexia, and decreased activity occur less often. Some infants have difficulty gaining weight or develop a true failure to thrive syndrome that often does not improve significantly until several months of effective treatment have been taken. Pulmonary signs are even less common. Some infants and young children with bronchial obstruction have localized wheezing or decreased breath sounds that may be accompanied by tachypnea or, rarely, respiratory distress. These pulmonary symptoms and signs are occasionally alleviated by antibiot ics, suggesting bacterial superinfection. Progressive Primary Pulmonary Disease A rare but serious complication of TB in a child occurs when the primary focus enlarges steadily and develops a large caseous center. Liquefaction can cause formation of a primary cavity associated with large numbers of tubercle bacilli. The enlarging focus can slough necrotic debris into the adjacent bronchus, leading to further intrapulmonary dissemination. Significant signs or symptoms are common in locally progressive disease in children. High fever, severe cough with sputum production, weight loss, and night sweats are common. Physical signs include diminished breath sounds, rales, and dullness or egophony over the cavity. The prog nosis for full recovery is excellent with appropriate therapy. Reactivation Tuberculosis Pulmonary TB in adults usually represents endogenous reactivation of a site of TBI established previously in the body. This form of TB is rare in childhood but can occur in adolescence. Children with a healed TBI acquired when they were 2 years old rarely develop chronic reactiva tion pulmonary disease, which is more common in those who acquire the initial infection when they are 7 years old. The most common pulmonary sites are the original parenchymal focus, lymph nodes, and the apical seedings (Simon foci) established during the hematogenous phase of the early infection. This form of |
7,423 | TB disease usually remains localized in the lungs, because the established immune response pre vents further extrapulmonary spread. The most common radiographic findings are extensive infiltrates and thick walled cavities in the upper lobes. Older children and adolescents with reactivation TB are more likely to experience fever, anorexia, malaise, weight loss, night sweats, pro ductive cough, hemoptysis, and chest pain than children with primary pulmonary TB. However, physical examination findings usually are minor or absent, even when cavities or large infiltrates are present. Most signs and symptoms improve within several weeks of starting effective treatment, although the cough can last for several months. This form of TB may be highly contagious if there is significant sputum production and cough. The prognosis for full recovery is excellent with appropriate therapy. Pleural Effusion Tuberculous pleural effusions, which can be local or general, origi nate in the discharge of bacilli into the pleural space from a subpleural pulmonary focus or caseated lymph node. Asymptomatic local pleu ral effusion is so common in primary TB that it is considered part of the primary complex. Larger and clinically significant effusions occur months to years after the primary infection. Tuberculous pleural effu sion is uncommon in children 6 years old and rare in children 2 years old. Effusions are usually unilateral but can be bilateral. They are rarely associated with a segmental pulmonary lesion and are uncom mon in disseminated TB. Often the radiographic abnormality is more extensive than would be suggested by physical findings or symptoms (Fig. 261.12). Clinical onset of tuberculous pleurisy is often sudden and charac terized by low to high fever, shortness of breath, chest pain on deep inspiration, and diminished breath sounds. The fever and other symp toms can last for several weeks after the start of antituberculosis che motherapy. The TST is positive in 7080 of cases. The prognosis is Fig. 261.11 Posteroanterior (A) and lateral (B) chest radiographs of an in fant with miliary tuberculosis. The childs mother had failed to complete treatment for pulmonary tuberculosis twice within 3 years of this childs birth. A B Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1842 Part XV u Infectious Diseases excellent, but radiographic resolution often takes months. Scoliosis is a rare complication from a long standing effusion. Examination of pleural fluid and the pleural membrane is important to establish the diagnosis of tuberculous pleurisy. The pleural fluid is usually yellow and only occasionally tinged with blood. The specific gravity is usually 1.012 1.025, the protein level is usually 2 4 gdL, and the glucose concentration may be low, although it is usually in the low normal range (20 40 mgdL). Typically, there are several hundred to several thousand white blood cells per microliter (WBCsL), with an early predominance of polymorphonuclear leukocytes (PMNs) fol lowed by a high percentage of lymphocytes. Acid fast smears |
7,424 | of the pleural fluid are rarely positive. Cultures of the fluid are positive in 30 of cases. Measurement of adenosine deaminase (ADA) levels may enhance the diagnosis of pleural TB. Biopsy of the pleural mem brane is more likely to yield a positive acid fast stain or culture, and granuloma formation can be demonstrated. Pericardial Disease The most common form of cardiac TB is pericarditis. It is rare, occur ring in 0.54 of TB cases in children. Pericarditis usually arises from direct invasion or lymphatic drainage from subcarinal lymph nodes. The presenting symptoms are nonspecific, including low grade fever, malaise, and weight loss. Chest pain is unusual in children. A pericar dial friction rub or distant heart sounds with pulsus paradoxus may be present. The pericardial fluid is typically serofibrinous or hemorrhagic. Acid fast smear of the fluid rarely reveals the organism, but cultures are positive in 3070 of cases. ADA levels are elevated in TB pericar ditis. The culture yield from pericardial biopsy may be higher, and the presence of granulomas often suggests the diagnosis. Partial or com plete pericardiectomy may be required when constrictive pericarditis develops. Lymphohematogenous (Disseminated) Disease Tubercle bacilli are disseminated to distant sites, including the liver, spleen, skin, and lung apices, in all cases of TBI. Lymphohematogenous spread is usually asymptomatic. Rare patients experience protracted hematogenous TB caused by the intermittent release of tubercle bacilli as a caseous focus erodes through the wall of a blood vessel in the lung. The clinical picture subsequent to lymphohematogenous dissemina tion depends on the burden of organisms released from the primary focus to distant sites and the adequacy of the hosts immune response. Although the clinical picture may be acute, more often it is indolent and prolonged, with spiking fever accompanying the release of organisms into the bloodstream. Multiple organ involvement is common, leading to hepatomegaly, splenomegaly, lymphadenitis in superficial or deep nodes, and papulonecrotic tuberculids appearing on the skin. Bones and joints or kidneys also can become involved. Meningitis occurs only late in the course of the disease. Early pulmonary involvement is surprisingly mild, but diffuse involvement becomes apparent with prolonged infection. The most clinically significant form of disseminated TB is miliary disease, which occurs when massive numbers of tubercle bacilli are released into the bloodstream, causing disease in two or more organs. Miliary tuberculosis usually complicates the primary infection, occur ring within 2 6 months of the initial infection. Although this form of disease is most common in infants and young children, it is also found in adolescents and older adults, resulting from the breakdown of a pre viously healed primary pulmonary lesion. The clinical manifestations of miliary TB are protean, depending on the number of organisms that disseminate and where they lodge. Lesions are often larger and more numerous in the lungs, spleen, liver, and bone marrow than in other tissues. Because this form of TB is most common in infants and mal nourished or immunosuppressed patients, the hosts immune incom petence likely plays a |
7,425 | role in pathogenesis. Rarely, the onset of miliary TB is explosive, and the patient can become gravely ill in several days. More often, the onset is insidious, with early systemic signs, including anorexia, weight loss, and low grade fever. At this time, abnormal physical signs are usually absent. Generalized lymphadenopathy and hepatosplenomegaly develop within several weeks in approximately 50 of cases. The fever can then become higher and more sustained, although the chest radiograph usu ally is normal and respiratory symptoms are minor or absent. Within several more weeks, the lungs can become filled with tubercles, and dyspnea, cough, rales, or wheezing occur. The lesions of miliary TB are usually 2 3 mm in diameter when first visible on chest radiograph (see Fig. 261.11). The smaller lesions coalesce to form larger lesions and sometimes extensive infiltrates. As the pulmonary disease progresses, an alveolar air block syndrome can result in frank respiratory distress, hypoxia, and pneumothorax or pneumomediastinum. Signs or symp toms of meningitis or peritonitis are found in 2040 of patients with advanced disease. Chronic or recurrent headache in a patient with miliary TB usually indicates the presence of meningitis, whereas the onset of abdominal pain or tenderness is a sign of tuberculous peritoni tis. Cutaneous lesions include papulonecrotic tuberculids, nodules, or purpura. Choroid tubercles occur in 1387 of patients and are highly specific for the diagnosis of miliary TB. Unfortunately, the TST is non reactive in up to 40 of patients with disseminated TB. Diagnosis of disseminated TB can be difficult, and a high index of suspicion by the clinician is required. Often the patient presents with fever of unknown origin (FUO). Early sputum or gastric aspirate cul tures have a low sensitivity. Biopsy of the liver or bone marrow with appropriate bacteriologic and histologic examinations more often yields an early diagnosis. The most important clue is usually a history of recent exposure to an adult with infectious TB. The resolution of miliary TB is slow, even with proper therapy. Fever usually declines within 2 3 weeks of starting chemotherapy, but the chest radiographic abnormalities might not resolve for many months. Occasionally, corticosteroids hasten symptomatic relief, especially when air block, peritonitis, or meningitis is present. The prognosis is excellent with early diagnosis and adequate chemotherapy. Upper Respiratory Tract Disease TB of the upper respiratory tract is rare in developed countries but is still observed in developing countries. Children with laryngeal TB have a crouplike cough, sore throat, hoarseness, and dysphagia. Most children with laryngeal TB have extensive upper lobe pulmonary dis ease, but occasional patients have primary laryngeal disease with a normal chest radiograph. TB of the middle ear results from aspiration of infected pulmonary secretions into the middle ear or from hematog enous dissemination in older children. The most common signs and symptoms are painless unilateral otorrhea, tinnitus, decreased hearing, facial paralysis, and a perforated tympanic membrane. Enlargement of Fig. 261.12 Pleural tuberculosis in 16 yr old female. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California |
7,426 | from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 261 u Tuberculosis (Mycobacterium tuberculosis) 1843 lymph nodes in the preauricular or anterior cervical chains can accom pany this infection. Diagnosis is difficult, because stains and cultures of ear fluid are often negative, and histology of the affected tissue often shows a nonspecific acute and chronic inflammation without granu loma formation. Lymph Node Disease TB of the superficial lymph nodes, often referred to as scrofula, is the most common form of extrapulmonary TB in children (Figs. 261.13 261.15). Historically, scrofula was usually caused by drinking unpas teurized cows milk laden with M. bovis. Most current cases occur within 6 9 months of initial infection by M. tuberculosis, although some cases appear years later. The tonsillar, anterior cervical, submandibular, and supraclavicular nodes become involved secondary to extension of a primary lesion of the upper lung fields or abdomen. Infected nodes in the inguinal, epitrochlear, or axillary regions result from regional lymphadenitis associated with TB of the skin or skeletal system. The nodes usually enlarge gradually in the early stages of lymph node dis ease. They are discrete, nontender, and firm but not hard. The nodes often feel fixed to underlying or overlying tissue. Disease is most often unilateral, but bilateral involvement can occur because of the cross over drainage patterns of lymphatic vessels in the chest and lower neck. As infection progresses, multiple nodes are infected, resulting in a mass of matted nodes. Systemic signs and symptoms other than a low grade fever are usually absent. The TST is usually reactive. The chest radio graph is often normal (in 70 of cases). The onset of illness is occasion ally more acute, with rapid enlargement, tenderness, and fluctuance of lymph nodes and with high fever. The initial presentation is rarely a fluctuant mass with overlying cellulitis or skin discoloration. Lymph node TB can resolve if left untreated but more often pro gresses to caseation and necrosis. The capsule of the node breaks down, resulting in the spread of infection to adjacent nodes. Rupture of the node usually results in a draining sinus tract that can require surgi cal removal. Tuberculous lymphadenitis can usually be diagnosed by fine needle aspiration (FNA) of the node and responds well to antitu berculosis therapy, although the lymph nodes do not return to normal size for months or even years. Surgical removal is not usually necessary and must be combined with antituberculosis medication, because the lymph node disease is only one part of a systemic infection. A definitive diagnosis of tuberculous adenitis usually requires histo logic, bacteriologic, or molecular confirmation, which is best accom plished by FNA for culture, molecular testing, stain, and histology. If FNA is not successful in establishing a diagnosis, excisional biopsy of the involved node is indicated. Culture of lymph node tissue yields the organism in only approximately 50 of cases. Many other condi tions can be confused |
7,427 | with tuberculous adenitis, including infection caused by nontuberculous mycobacteria (NTM), cat scratch disease (Bartonella henselae), tularemia, brucellosis, toxoplasmosis, pyogenic infection, or noninfectious causes, including tumor, branchial cleft cyst, and cystic hygroma. The most common problem is distinguish ing infection caused by M. tuberculosis from lymphadenitis caused by NTM in geographic areas where NTM are common. Both conditions are usually associated with a normal chest radiograph and a reactive TST. An important clue to the diagnosis of tuberculous adenitis is an epidemiologic link to an adult with infectious TB. In areas where both diseases are common, culture or PCR testing of the involved tissue may be necessary to establish the exact cause of the disease. Central Nervous System Disease TB of the central nervous system (CNS) is the most serious complica tion in children and is fatal without prompt and appropriate treatment. Tuberculous meningitis usually arises from the formation of a meta static caseous lesion in the cerebral cortex or meninges that develops Fig. 261.13 Scrofula. Axial CT image of the neck in 8 yr old male shows calcified right cervical lymphadenopathy (black arrow) and tonsil lar swelling (white arrow). (From Lighter J, Rigaud M. Diagnosing child hood tuberculosis: traditional and innovative modalities. Curr Probl Pediatr Adolesc Health Care. 2009;39:5588.) A B Fig. 261.14 Scrofula. A, Ulcerative lesion 3.2 2.1 cm with under mined edges and necrotic base with surrounding induration. B, Acid fast bacilli. (From Sharawat IK. Scrofula. J Pediatr. 2017;189:236.) Fig. 261.15 Scrofula. Tuberculous lymphadenitis with fistula in 4 yr old male associated with scrofuloderma (arrows). (From Pereira C, Cascais M, Felix M, Salgado M. Scrofula in a child. J Pediatr. 2017;189:235.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1844 Part XV u Infectious Diseases during the lymphohematogenous dissemination of the primary infec tion. This initial lesion increases in size and discharges small numbers of tubercle bacilli into the subarachnoid space. The resulting gelati nous exudate infiltrates the corticomeningeal blood vessels, producing inflammation, obstruction, and subsequent infarction of the cerebral cortex. The brainstem is often the site of greatest involvement, which accounts for the commonly associated dysfunction of cranial nerves III, VI, and VII. The exudate also interferes with the normal flow of cerebrospinal fluid (CSF) in and out of the ventricular system at the level of the basilar cisterns, leading to a communicating hydrocepha lus. The combination of vasculitis, infarction, cerebral edema, and hydrocephalus results in the severe damage that can occur gradually or rapidly. Profound abnormalities in electrolyte metabolism from salt wasting or the syndrome of inappropriate antidiuretic hormone secre tion (SIADH) also contribute to the pathophysiology of tuberculous meningitis. Tuberculous meningitis complicates approximately 0.3 of untreated TBIs in children. It is most common in children 6 months to 4 years old. Occasionally, tuberculous meningitis occurs many years after the infection, when rupture of one or more of the subependy |
7,428 | mal tubercles discharges tubercle bacilli into the subarachnoid space. The clinical progression of tuberculous meningitis may be rapid or gradual. Rapid progression tends to occur more often in infants and young children, who can experience symptoms for only several days before the onset of acute hydrocephalus, seizures, and cerebral edema. More often, the signs and symptoms progress slowly over weeks and are divided into three stages. The first stage typically lasts 1 2 weeks and is characterized by non specific symptoms such as fever, headache, irritability, drowsiness, and malaise. Focal neurologic signs are absent, but infants can experience a stagnation or loss of developmental milestones. The second stage usually begins more abruptly. The most common features are lethargy, nuchal rigidity, seizures, positive Kernig and Brudzinski signs, hyper tonia, vomiting, cranial nerve palsies, and other focal neurologic signs. The accelerating clinical illness usually correlates with the develop ment of hydrocephalus, increased intracranial pressure, and vasculitis. Some children have no evidence of meningeal irritation but can have signs of encephalitis, such as disorientation, movement disorders, or speech impairment. The third stage is marked by coma, hemiplegia or paraplegia, hypertension, decerebrate posturing, deterioration of vital signs, and eventually death. The prognosis of tuberculous meningitis correlates most closely with the clinical stage of illness at the time treatment is initiated. The major ity of patients in the first stage have an excellent outcome, whereas most patients in the third stage who survive have permanent disabili ties, including blindness, deafness, paraplegia, diabetes insipidus, or mental retardation. The prognosis for young infants is generally worse than for older children. It is imperative that antituberculosis treat ment be considered for any child who develops basilar meningitis and hydrocephalus, cranial nerve palsy, or stroke with no other apparent etiology. Often the key to the correct diagnosis is identifying an adult who has infectious TB and is in contact with the child. Because of the short incubation period of tuberculous meningitis, the illness has not yet been diagnosed in the adult in many cases. The diagnosis of tuberculous meningitis can be difficult early in its course, requiring a high degree of suspicion on the part of the clinician. The TST is nonreactive in up to 50 of cases, and 2050 of children have a normal chest radiograph. The most important laboratory test for the diagnosis of tuberculous meningitis is examination and culture of the lumbar CSF. The CSF leukocyte count usually ranges from 10 to 500 cellsL. PMNs may be present initially, but lymphocytes predominate in the majority of cases. The CSF glucose is typically 40 mgdL but rarely 20 mgdL. The protein level is elevated and may be extremely high (400 5,000 mgdL) secondary to hydrocephalus and spinal block. Although the lumbar CSF is grossly abnormal, ventricular CSF can have normal chemistries and cell counts because this fluid is obtained from a site proximal to the inflammation and obstruction. During early stage one, the CSF can resemble that of viral aseptic meningitis, only to progress to the more |
7,429 | severe CSF profile over several weeks. The success of the microscopic examination of acid faststained CSF and myco bacterial culture is related directly to the volume of the CSF sample. Examinations or culture of small amounts of CSF are unlikely to dem onstrate M. tuberculosis. It is recommended that serial collections of large volume lumbar CSF (up to 15 mL) be obtained for acid fast stain and culture. When 5 10 mL of lumbar CSF can be obtained, the acid fast stain of the CSF sediment is positive in up to 30 of cases and the culture is positive in 5070 of cases. Polymerase chain reaction (PCR) testing of the CSF and ADA levels can improve the diagnosis. Cultures of other body fluids can help confirm the diagnosis. Radiographic studies can aid in the diagnosis of tuberculous men ingitis. CT or MRI of the brain of patients with tuberculous meningitis may be normal during early stages of the disease. As the disease pro gresses, basilar enhancement and communicating hydrocephalus with signs of cerebral edema or early focal ischemia are the most common findings (Fig. 261.16). Some young children with tuberculous menin gitis have one or several clinically silent tuberculomas, occurring most often in the cerebral cortex or thalamic regions. Another manifestation of CNS TB is the tuberculoma, a tumor like mass resulting from aggregation of caseous tubercles that usually manifests clinically as a brain tumor. Tuberculomas account for up to 30 of brain tumors in some areas of the world but are rare in North America. In adults, tuberculomas are most often supratentorial, but in children, they are often infratentorial, located at the base of the brain near the cerebellum (Fig. 261.17). Lesions are most often singular but may be multiple. The most common symptoms are headache, fever, focal neurologic findings, and convulsions. The TST is usually reac tive, but the chest radiograph is usually normal. Surgical excision is sometimes necessary to distinguish tuberculoma from other causes of brain tumor. However, surgical removal is not necessary because most tuberculomas resolve with medical management. Corticoste roids are administered during the first few weeks of treatment or in the immediate postoperative period to decrease cerebral edema. On CT or MRI of the brain, tuberculomas usually appear as discrete lesions with a significant amount of surrounding edema. Contrast medium enhancement is often impressive and can result in a ringlike lesion. Since the advent of CT, the paradoxical development of tuberculomas in patients with tuberculous meningitis who are receiving ultimately effective chemotherapy has been recognized. The cause and nature of these tuberculomas are poorly understood, but they do not represent failure of antimicrobial treatment. This phenomenon should be con sidered whenever a child with tuberculous meningitis deteriorates or develops focal neurologic findings during treatment. Corticosteroids A B Fig. 261.16 Tuberculous meningitis in a child. A and B, Postcontrast CT images demonstrate intense enhancement in the suprasellar cistern, sylvian cistern, and prepontine cistern. Dilation of the ventricular system is seen, consistent with associated hydrocephalus. (From |
7,430 | Lerner A, Ra jamohan A, Shiroishi MS, et al. Cerebral infections and inflammation. In Haaga JR, Boll DT, eds. CT and MRI of the Whole Body, 6th ed. Phila delphia: Elsevier; 2017: Fig 10 20.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 261 u Tuberculosis (Mycobacterium tuberculosis) 1845 can alleviate the occasionally severe clinical signs and symptoms that occur. These lesions can persist for months or years. Cutaneous Disease Cutaneous TB is rare in the United States but occurs worldwide and accounts for 12 of tuberculosis (see Chapter 706). Bone and Joint Disease TB involving bone or joints is most likely to involve the vertebrae. The classic manifestation of tuberculous spondylitis is progression to Pott disease, in which destruction of the vertebral bodies leads to gibbus deformity and kyphosis (Fig. 261.18) (see Chapter 720.4). Skeletal tuberculosis is a late complication of TB and has become a rare entity since the availability of antituberculosis therapy but is more likely to occur in children than in adults. Tuberculous bone lesions can resemble pyogenic and fungal infections or bone tumors. Multifocal bone involvement can occur. A bone biopsy is essential to confirm the diagnosis. Surgical intervention is generally not necessary for cure, and the prognosis is excellent with adequate medical treatment. A sterile polyarticular (large joint) arthritis may also be noted in patients with active TB at another site. Abdominal and Gastrointestinal Disease TB of the oral cavity or pharynx is quite unusual. The most common lesion is a painless ulcer on the mucosa, palate, or tonsil with enlarge ment of the regional lymph nodes. TB of the parotid gland has been reported rarely in endemic countries. TB of the esophagus is rare in children but may be associated with a tracheoesophageal fistula in infants. These forms of TB are usually associated with extensive pul monary disease and swallowing of infectious respiratory secretions. They can occur in the absence of pulmonary disease, by spread from mediastinal or peritoneal lymph nodes. Tuberculous peritonitis occurs most often in young males and is uncommon in adolescents and rare in children. Generalized peritoni tis can arise from subclinical or miliary hematogenous dissemination. Localized peritonitis is caused by direct extension from an abdominal lymph node, intestinal focus, or genitourinary TB. Rarely, the lymph nodes, omentum, and peritoneum become matted and can be palpated as a doughy, irregular, nontender mass. Abdominal pain or tenderness, ascites, anorexia, and low grade fever are typical manifestations. The TST is usually reactive. The diagnosis can be confirmed by paracen tesis with appropriate stains and cultures, but this procedure must be performed carefully to avoid entering a bowel that is adherent to the omentum. Tuberculous enteritis is caused by hematogenous dissemination or by swallowing tubercle bacilli discharged from the patients own lungs. The jejunum and ileum near Peyer patches and the appendix are the most common |
7,431 | sites of involvement. The typical findings are shallow ulcers that cause pain, diarrhea or constipation, weight loss, and low grade fever. Mesenteric adenitis usually complicates the infection. The enlarged nodes can cause intestinal obstruction or erode through the omentum to cause generalized peritonitis. The clinical presentation of tuberculous enteritis is nonspecific, mimicking other infections and conditions that cause diarrhea. The disease should be suspected in any child with chronic GI complaints and a reactive TST or positive IGRA. Biopsy, acid fast stain, and culture of the lesions are usually necessary to confirm the diagnosis. Genitourinary Disease Renal TB is rare in children because the incubation period is several years or longer. Tubercle bacilli usually reach the kidney during lym phohematogenous dissemination. The organisms often can be recov ered from the urine in cases of miliary TB and in some patients with pulmonary TB in the absence of renal parenchymal disease. In true renal TB, small caseous foci develop in the renal parenchyma and release M. tuberculosis into the tubules. A large mass develops near the renal cortex that discharges bacteria through a fistula into the renal pel vis. Infection then spreads locally to the ureters, prostate, or epididy mis. Renal TB is often clinically silent in its early stages, marked only by sterile pyuria and microscopic hematuria. Dysuria, flank or abdominal pain, and gross hematuria develop as the disease progresses. Superin fection by other bacteria is common and can delay recognition of the underlying TB. Hydronephrosis or ureteral strictures can complicate the disease. Urine cultures for M. tuberculosis are positive in 8090 of cases, and acid fast stains of large volumes of urine sediment are positive in 5070 of cases. The TST is nonreactive in up to 20 of patients. A pyelogram or CT scan often reveals mass lesions, dilation of the proximal ureters, multiple small filling defects, and hydronephrosis if ureteral stricture is present. Disease is most often unilateral. Genital tract TB is uncommon in prepubescent males and females. This condition usually originates from lymphohematogenous spread, although it can be caused by direct spread from the intestinal tract or bone. Adolescent females can develop genital tract TB during the pri mary infection. The fallopian tubes are most often involved (90100 of cases), followed by the endometrium (50), ovaries (25), and cervix (5). The most common symptoms are lower abdominal pain and dysmenorrhea or amenorrhea. Systemic manifestations are usually absent, and the chest radiograph is normal in the majority of cases. The TST is usually reactive. Genital TB in adolescent males causes epididymitis or orchitis. The condition usually manifests as a painless, unilateral nodular swelling of the scrotum. Involvement of the glans Fig. 261.18 Tuberculosis of the spine in a toddler. (From Feder HM Jr, Rigos L, Teti K. Potts disease in a Connecticut toddler. Lancet. 2016;388:504505.) Fig. 261.17 MRI of brain of 3 yr old child showing multiple pontine tuberculomas. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For |
7,432 | personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1846 Part XV u Infectious Diseases penis is extremely rare. Genital abnormalities and a positive TST in an adolescent male or female suggest genital tract TB. Pregnancy and the Newborn Pulmonary and particularly extrapulmonary TB other than lymph adenitis in a pregnant woman is associated with increased risk for prematurity, fetal growth retardation, low birthweight, and perinatal mortality. Congenital TB is rare because the most common result of female genital tract TB is infertility. Primary infection in the mother just before or during pregnancy is more likely to cause congeni tal infection than is reactivation of a previous infection. Congenital transmission usually occurs from a lesion in the placenta through the umbilical vein, when tubercle bacilli infect the fetal liver, where a pri mary focus with periportal lymph node involvement can occur. Organ isms pass through the liver into the main fetal circulation and infect many organs. The bacilli in the lung usually remain dormant until after birth, when oxygenation and pulmonary circulation increase signifi cantly. Congenital TB can also be caused by aspiration or ingestion of infected amniotic fluid. However, the most common route of infection for the neonate is postnatal airborne transmission from an adult with infectious pulmonary TB. Perinatal Disease Symptoms of congenital TB may be present at birth but usually begin by the second or third week of life. The most common signs and symp toms are respiratory distress, fever, hepatic or splenic enlargement, poor feeding, lethargy or irritability, lymphadenopathy, abdominal distention, failure to thrive, ear drainage, and skin lesions. The clini cal manifestations vary in relation to the site and size of the caseous lesions. Many infants have an abnormal chest radiograph, most often with a miliary pattern. Some infants with no pulmonary findings early in the course of the disease later develop profound radiographic and clinical abnormalities. Hilar and mediastinal lymphadenopathy and lung infiltrates are common. Generalized lymphadenopathy and men ingitis occur in 3050 of infants. The clinical presentation of TB in newborns is similar to that caused by bacterial sepsis and other congenital infections, such as syphilis, toxoplasmosis, and cytomegalovirus. The diagnosis should be suspected in an infant with signs and symptoms of bacterial or congenital infection whose response to antibiotic and supportive therapy is poor and in whom evaluation for other infections is unre vealing. The most important clue for rapid diagnosis of congenital TB is a maternal or family history of TB. Often, the mothers disease is discovered only after the neonates diagnosis is suspected. The infants TST is negative initially but can become positive in 1 3 months. A positive acid fast stain of an early morning gastric aspirate from a newborn usually indicates TB. Direct acid fast stains on middle ear discharge, bone marrow, tracheal aspirate, or tissue biopsy (especially liver) can be useful. The CSF should be examined, cultured, and sent for PCR testing. The mortality rate of congenital TB remains very high |
7,433 | because of delayed diagnosis. Many children have a complete recovery if the diagnosis is made promptly and adequate chemother apy is started. Tuberculosis Disease in Children Living with HIV In the United States, the rate of TB disease in children living with untreated HIV is 30 times higher than in children without HIV. Estab lishing the diagnosis of TB in a child living with HIV may be difficult because TST reactivity can be absent (also with a negative IGRA), cul ture confirmation is difficult, and the clinical features of TB are similar to many other HIV related opportunistic infections and conditions. TB in children living with HIV is often more severe, progressive, and likely to occur in extrapulmonary sites. Radiographic findings are similar to those in children with normal immune systems, but lobar disease and lung cavitation are more common. Nonspecific respiratory symptoms, fever, and weight loss are the most common complaints. Rates of drug resistant TB tend to be higher in adults living with HIV and probably are also higher in children living with HIV. Recurrent TB disease and relapsed TB occur more frequently in children living with HIV. The prognosis generally is good if TB disease is not far advanced at diagno sis and appropriate antituberculosis drugs are available. The mortality rate of children living with HIV with TB is high, espe cially as the CD4 lymphocyte numbers decrease. In adults, the host immune response to TBI appears to enhance HIV replication and accelerate the immune suppression caused by HIV. Increased mortal ity rates are attributed to progressive HIV infection rather than TB. Therefore children living with HIV with potential TB exposures and or recent TBI should be promptly evaluated and treated for TB. Con versely, all children with TB disease should be tested for HIV infection. Children living with HIV who are given highly active antiretroviral therapy (HAART) are at high risk of developing immune reconstitu tion inflammatory syndrome (IRIS). IRIS should be suspected in patients who experience a worsening of TB symptoms while receiving antituberculosis therapy (paradoxical IRIS) or who develop new onset TB symptoms and radiographic findings after initiation of HAART (unmasking IRIS). Factors suggesting IRIS are temporal association (within 3 months of starting HAART), unusual clinical manifesta tions, unexpected clinical course, exclusion of alternative explanations, evidence of preceding immune restoration (rise in CD4 lymphocyte count), and decrease in HIV viral load. The most common clinical manifestations of IRIS in children are fever, cough, new skin lesions, enlarging lymph nodes in the thorax or neck, and appearance or enlargement of tuberculomas in the brain, with or without accompany ing meningitis. The treatment of TB associated IRIS in children living with HIV often included steroids but should be undertaken by a clini cian with specific expertise in TB treatment. IMMUNE BASED TESTING (TESTS OF TUBERCULOSIS INFECTION) Tuberculin Skin Testing The development of delayed type hypersensitivity in most persons infected with the M. tuberculosis complex organisms makes the TST a useful diagnostic tool. The Mantoux TST is |
7,434 | the intradermal injec tion of 0.1 mL purified protein derivative stabilized with Tween 80. T cells sensitized by prior infection are recruited to the skin, where they release lymphokines that induce induration through local vasodilation, edema, fibrin deposition, and recruitment of other inflammatory cells to the area. The amount of induration in response to the test should be measured by a trained person 48 72 hours after administration. In some patients, the onset of induration is 72 hours after placement; this is also a positive result. Immediate hypersensitivity reactions to tuberculin or other constituents of the preparation are short lived (24 hours) and not considered a positive result. Tuberculin sensitivity develops 3 weeks to 3 months (most often in 4 8 weeks) after inhala tion of organisms. Host related factors, including very young age, malnutrition, immunosuppression by disease or drugs, viral infections (measles, mumps, varicella, influenza), vaccination with live virus vaccines, and overwhelming TB, can depress the skin test reaction in a child infected with M. tuberculosis. Corticosteroid therapy can decrease the reaction to tuberculin, but the effect is variable; TST done at the time of initiating corticosteroid therapy is usually reliable. Approximately 10 of immunocompetent children with TB disease (up to 50 of those with meningitis or disseminated disease) do not react initially to purified protein derivative; most become reactive after several months of antituberculosis therapy. False positive reactions to tuber culin can be caused by cross sensitization to antigens of NTM, which generally are more prevalent in the geographic environment as one approaches the equator. These cross reactions are usually transient over months to years and produce 10 12 mm of induration, but larger areas of induration can occur. Previous vaccination with bacille Calmette Gurin (BCG) also can cause a reaction to a TST, especially if a person has received two or more BCG vaccinations. Approxi mately 50 of the infants who receive a BCG vaccine never develop a reactive TST, and the reactivity usually wanes in 2 3 years in those with initially positive skin test results. Older children and adults who receive a BCG vaccine are more likely to develop tuberculin reactivity, but most lose the reactivity by 5 10 years after vaccination. However, Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 261 u Tuberculosis (Mycobacterium tuberculosis) 1847 some individuals maintain tuberculin reactivity from BCG vaccine for many years. When present, skin test reactivity usually causes 10 mm of induration, although larger reactions occur in some persons. The appropriate size of induration indicating a positive Mantoux TST result varies with related epidemiologic and risk factors. In children with no TB risk factors, skin test reactions are usually false positive results. The American Academy of Pediatrics (AAP) and Centers for Disease Control and Prevention (CDC) discourage routine testing of all children and recommend targeted tuberculin testing of children at risk |
7,435 | identified through periodic screening questionnaires (Table 261.2). Possible exposure to an adult with or at high risk for infectious pulmonary TB is the most crucial risk factor for children. Reaction size limits for determining a positive TST result vary with the persons risk for infection (Table 261.3). In those at highest risk of progression to TB disease, TST sensitivity is most important, whereas specificity is more important for persons at low risk of progression. Interferon Release Assay Two blood testsT SPOT.TB (Oxford Immunotec; Marlborough, MA) and QuantiFERON TB GoldGold Plus (QFT, Qiagen; Ger mantown, MD) detect IFN generation by the patients T cells in response to specific M. tuberculosis antigens (ESAT 6, CFP 10, and TB7.7). The QFT test measures whole blood concentrations of IFN , and the T SPOT.TB test measures the number of lymphocytes monocytes producing IFN . The test antigens are not present on M. bovisBCG (vaccine) and M. avium complex, the major group of environmental mycobacteria, so one would expect higher specificity compared with the TST and fewer false positive results. Both IGRAs have internal positive and negative controls. Internal positive con trols allow for detection of an anergic test response, which is useful in children who are young and immunocompromised. Indeterminate (QFT)invalid (T SPOT.TB) responses occur when the test sample is negative but the positive control has insufficient activity or if the negative control has high background activity. Indeterminateinvalid results are also caused by technical factors (e.g., insufficient shaking of QFT tubes, delayed processing time). Most studies report indeter minate or invalid rates in children of 010, which is influenced by a childs age and immune status. In children 2 years old, indetermi nate rates can be as high as 8.1 vs 2.7 in older children, although more recent studies generally report much lower rates. An indetermi nate or invalid IGRA result is neither negative nor positive and cannot be used to guide treatment decisions. Some IGRAs cannot differentiate between TBI and TB disease. If available, certain IGRA tests will test CD4 and CD8 T cell reactiv ity, which may help differentiate latent from active disease. Two clear advantages of the IGRAs are the need for only one patient encounter (vs two with TST) and the lack of cross reaction with BCG vaccination and most other mycobacteria, thereby increasing test specificity for TBI. Studies comparing IGRA and TST performance in children have shown comparable sensitivity (85 in culture confirmed children) between the two tests and superior IGRA specificity (95 vs 49) in BCG immunized, low risk children. Neither the TST nor the IGRAs perform well in infants and young children who are malnourished, severely immunocompromised, or have disseminated TB disease. It is now standard to use an IGRA in the evaluation of healthy young children 2 years of age, and most experts use IGRAs in younger children who are at low risk of TB infection, especially in those who have received a BCG vaccine. Both TST and Table 261.2 Tuberculin Skin Test (TST) or Interferon |
7,436 | Release Assay (IGRA): Recommendations for Infants, Children, and Adolescents CHILDREN FOR WHOM IMMEDIATE TST OR IGRA IS INDICATED Contacts of people with confirmed or suspected contagious tuberculosis (contact investigation) Children with radiographic or clinical findings suggesting tuberculosis disease Children immigrating from countries with endemic infection (e.g., Asia, Middle East, Africa, Latin America, countries from former Soviet Union), including international adoptees Children with travel histories to countries with endemic infection and substantial contact with indigenous people from such countries Children who should have annual TST or IGRA: Children infected with human immunodeficiency virus CHILDREN AT INCREASED RISK FOR PROGRESSION OF TUBERCULOSIS INFECTION TO TUBERCULOSIS DISEASE Children with other medical conditions, including diabetes mellitus, chronic renal failure, malnutrition, and congenital or acquired immunodeficiencies, and children receiving tumor necrosis factor (TNF) antagonists deserve special consideration. Without recent exposure, these children are not at increased risk of acquiring tuberculosis infection. Underlying immune deficiencies associated with these conditions theoretically would enhance the possibility for progression to severe disease. Initial histories of potential exposure to tuberculosis should be included for all of these patients. If these histories or local epidemiologic factors suggest a possibility of exposure, immediate and periodic TST or IGRA should be considered. An initial TST or IGRA should be performed before initiation of immunosuppressive therapy, including prolonged corticosteroid administration, organ transplantation, or use of TNF antagonists or blockers, or immunosuppressive therapy in any child requiring these treatments. Bacille Calmette Gurin immunization is not a contraindication to a TST. Beginning as early as 3 mo of age. If the child is well and has no history of exposure, the TST or IGRA should be delayed up to 10 wk after return. From Kimberlin DW, Barnett ED, Lynfield R, Sawyer MH, eds. Red Book: 20212024 Report of the Committee on Infectious Diseases, 32nd ed. Itasca, IL: American Academy of Pediatrics; 2021:789. Table 261.3 Definitions of Positive Tuberculin Skin Test (TST) Results in Infants, Children, and Adolescents INDURATION 5 MM Children in close contact with known or suspected contagious people with tuberculosis disease Children suspected to have tuberculosis disease: Findings on chest radiograph consistent with active or previously tuberculosis disease Clinical evidence of tuberculosis disease Children receiving immunosuppressive therapy or with immunosuppressive conditions, including HIV infection INDURATION 10 MM Children at increased risk of disseminated tuberculosis disease: Children 4 yr old Children with other medical conditions, including Hodgkin disease, lymphoma, diabetes mellitus, chronic renal failure, or malnutrition (see Table 261.2) Children with increased exposure to tuberculosis disease: Children born in high prevalence regions of the world Children often exposed to adults with HIV infection, homeless, users of illicit drugs, residents of nursing homes, incarcerated or institutionalized, or migrant farm workers Children who travel to high prevalence regions of the world INDURATION 15 MM Children 4 yr old without any risk factors These definitions apply regardless of previous BCG immunization; erythema at TST site does not indicate a positive test result. Tests should be read at 48 72 hr after placement. Evidence by physical examination or laboratory |
7,437 | assessment that would include tuberculosis in the working differential diagnosis (e.g., meningitis). Including immunosuppressive doses of corticosteroids or tumor necrosis factor antagonists. BCG, Bacille Calmette Gurin; HIV, human immunodeficiency virus. From Kimberlin DW, Barnett ED, Lynfield R, Sawyer MH, eds. Red Book: 20212024 Report of the Committee on Infectious Diseases, 32nd ed. Itasca, IL: American Academy of Pediatrics; 2021:788. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1848 Part XV u Infectious Diseases IGRA testing should be considered in children whose initial TST or IGRA result is negative for whom the risk of TB is high (to enhance the sensitivity of the combination of the two tests). Technical advantages of the IGRAs over the TST include the need for a single patient encounter (vs two spaced in time with the TST), the lack of cross reaction with BCG vaccination and most environ mental mycobacteria, and eliminating the need for experience in correctly interpreting the TST. IGRAs are also useful for those who are unlikely to return for TST interpretation, those whose family is reluctant to treat a child with TBI based on a TST result alone, and those with a positive TST result in whom NTM disease is suspected (Table 261.4). Most studies have shown no consistent, significant difference between the two commercially available IGRAs, and the CDC recom mends no preference. Because of cost constraints, the WHO does not endorse IGRA use in low and middle income countries, even in those with a high prevalence of tuberculosis. MYCOBACTERIAL SAMPLING, SUSCEPTIBILITY, AND CULTURE The most specific confirmation of pulmonary TB is isolation of M. tuberculosis from a clinical sample. Sputum specimens for culture should be collected from adolescents and older children who are able to expectorate. Induced sputum with a jet nebulizer, inhaled saline, and chest percussion followed by nasopharyngeal suctioning is effec tive in children as young as 1 year. Sputum induction provides samples for both culture and acid fast bacilli (AFB) staining. The traditional culture specimen in young children is the early morning gastric acid obtained before the child has arisen and peristalsis has emptied the stomach of the pooled respiratory secretions that have been swallowed overnight. However, even under optimal conditions, three consecu tive morning gastric aspirates yield the organisms in 50 of cases. The culture yield from bronchoscopy is even lower, but this procedure can demonstrate the presence of endobronchial disease or a fistula. To improve the sensitivity of a diagnosis of TB in children, in high burden TB settings, there is an increasing trend to collect nontraditional speci mens, including stool, nasopharyngeal, and urine specimens. These specimens are easier to obtain than respiratory specimens but less sensitive in diagnosing TB in children compared to sputum or serial gastric aspirate specimens. Their diagnostic utility is increased when multiple specimens are collected in conjunction with traditional respi ratory specimens. Negative cultures |
7,438 | never exclude the diagnosis of TB in a child. The presence of a positive TST or IGRA, an abnormal chest radiograph consistent with TB, and history of recent exposure to an adult with infectious TB is highly suggestive of the clinical diagnosis of TB disease. If a likely adult source case has been identified, drug susceptibility test results of the isolate from the adult source usually can be used to determine the best therapeutic regimen for the child, except in very high incidence areas, where the apparent source case might not be the actual one. Cultures should be always obtained from the child whenever the source case is unknown, there are multiple pos sible source cases, or the source case has possible or confirmed drug resistant TB. Confirmation of extrapulmonary TB is best achieved with a positive culture or PCR testing. However, for many forms of TB, the culture yield is only 2550, and probable diagnosis is by a combination of clinical signs and symptoms, analysis of body fluids when possible, radiographic or histopathologic evidence of TB, PCR testing, and elim ination of other possible diagnoses. Nucleic Acid Amplification Tests The main NAAT studied in children with TB is PCR, which uses spe cific DNA sequences as markers for microorganisms. Compared with a clinical diagnosis of pulmonary TB in children, the sensitivity of PCR has varied from 25 to 83, and specificity has varied from 80 to 100. A negative PCR result never eliminates the diagnosis of TB, and the diagnosis is not confirmed by a positive PCR result. NAAT identifies genes associated with drug resistance and is used to supplement culture based (phenotypic) methods for drug susceptibil ity testing. It also decreases the time to identification of drug resistance from weeks to hours, which expedites the initiation of optimal therapy. Culture based, phenotypic, drug susceptibility testing is necessary to confirm susceptibility to each drug; the absence of resistance genes is not always predictive of drug susceptibility. The interpretation of molecular based drug susceptibility testing is constantly evolving, and an expert in the management of pediatric TB should be involved when drug resistance is suspected. Gene Xpert MTBRIF cartridge and Xpert MTB Ultra cartridge (Xpert; Cepheid, Sunnyvale, CA) are real time PCR assays for M. tuberculosis that simultaneously detect rifampin resistance, which is often used as a proxy for MDR TB. These assays use a self contained cartridge system, which yields results from direct specimens in 2 hours and is less operator dependent than traditional PCR detection methods. Sensitivity and specificity of Xpert MTBRIF have averaged 7277 and 99 in AFB sputum smearnegative adults and 9899 and 99100 in AFB sputum smearpositive adults, respectively. Pediatric studies reveal that, compared to culture, the sensitivity and specificity of Xpert MTBRIF is 62 and 98 on induced or expectorated sputa and 66 and 98 on gastric aspirates, respectively. For other specimen types (nasopharyngeal aspirate and stool), Xpert MTBRIF pooled sen sitivity for pulmonary TB ranges between 46 and 73 with a pooled specificity |
7,439 | of 98 and 100. Compared with smear microscopy, Xpert improved the sensitivity of detecting pediatric TB cases by 3644. For lymph node aspirates or biopsies, Xpert MTBRIF compared with culture had a sensitivity and specificity of 90. Compared to culture, Xpert MTBRIFs sensitivity and specificity to detect rifampin resis tance in respiratory specimens collected from children with suspected pulmonary TB are 86 and 98, respectively. Xpert Ultra is a next generation assay that has enhanced perfor mance in children who often have paucibacillary or smear negative TB. The pooled sensitivity of Ultra for detection of M. tuberculosis was 73 in sputum samples, 64 in gastric aspirate samples, 53 in stool speci mens, and 46 in nasopharyngeal samples. The pooled specificity was 98 in sputum samples, 98 in nasopharyngeal aspirate specimens, 98 in stool samples, and 95 in gastric aspirate samples. The WHO recommends use of Xpert Ultra in sputum and nasopharyngeal spec imens collected from children for the diagnosis of TB and rifampin resistance, in addition to the use of Xpert MTBRIF in sputum, gastric aspirate, nasopharyngeal aspirate, and stool specimens. Although car tridges for the Xpert systems are expensive, they offer advantages in rapid detection of MDR TB and are especially useful in settings lacking Table 261.4 Recommendations for Use of Tuberculin Skin Test (TST) and Interferon Release Assay (IGRA) in Children TST preferred, IGRA acceptable: Children 2 yr of age IGRA preferred, TST acceptable: Children 2 yr of age who have received BCG vaccine Children 2 yr of age who are unlikely to return for TST reading TST and IGRA should be considered when: The initial and repeat IGRAs are indeterminate or invalid The initial test (TST or IGRA) is negative and: Clinical suspicion for TB disease is moderate to high The child has a TB risk factor and is at high risk of progression and poor outcome (especially therapy with an immunomodulating biologic agent, e.g., TNF antagonist) The initial TST is positive and: 2 yr old and history of BCG vaccination Additional evidence needed to increase adherence with therapy Some experts do not use an IGRA for children younger than 2 yr because of a relative lack of data for this age group and the high risk of progression to disease. Positive result of either test is considered significant in these groups. BCG, Bacille Calmette Gurin; TB, tuberculosis, TNF, tumor necrosis factor. Adapted from Starke JR, AAP Committee of Infectious Diseases. Interferon release assays for diagnosis of tuberculosis infection and disease in children. Pediatrics. 2014;134(6):e17631773. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 261 u Tuberculosis (Mycobacterium tuberculosis) 1849 laboratory infrastructure. In many low resource settings, Xpert has replaced smear microscopy; however, it has not replaced mycobacte rial cultures and drug susceptibility studies. TREATMENT The basic principles of management of TB disease in children and ado lescents are the same |
7,440 | as in adults. Several drugs are used to effect a rela tively rapid cure and prevent the emergence of secondary drug resistance during therapy (Tables 261.5 to 261.8). The choice of regimen depends on the extent of TB disease, the host, and the likelihood of drug resis tance (see Chapter 260, Table 260.1). As recommended by the WHO and AAP, the standard therapy of intrathoracic, presumed or confirmed drug susceptible TB (pulmonary disease andor hilar lymphadenopathy) in children is a 4 to 6 month regimen of multidrug therapy. The ini tial treatment regimen includes isoniazid, rifampin, pyrazinamide, and ethambutol. The ethambutol can be discontinued once the organism is known to be susceptible to the other first line drugs. Pyrazinamide is discontinued after 2 months, and isoniazid and rifampin are continued for an additional 2 4 months. Several clinical trials have shown that a 6 month regimen yields a success rate approaching 100, with an inci dence of clinically significant adverse reactions of 2. Data from the SHINE trial (Shorter Treatment for Minimal Tuberculosis in Children) found that a 4 month treatment regimen in children age 0 16 years (3 kg) with nonsevere, smear negative, presumed drug susceptible TB was noninferior to a 6 month course. Based on the results of this trial, the WHO supports the use of a 4 month treatment regimen in eligible children. Most experts recommend that all drug administra tion be either directly observed or electronically observed, meaning that a healthcare worker watches when the medications are adminis tered toor taken by the patients. When in person directly observed therapy (DOT) or video directly observed therapy (VDOT) is used, intermittent (twice or thrice weekly) administration of drugs after an initial period as short as 2 weeks of daily therapy is as effective for drug susceptible TB in children as daily therapy for the entire course. Table 261.5 Dosage Recommendations for the Treatment of TB in Adults and Children1 DOSE IN MGKG (MAXIMUM DOSAGE IN PARENTHESES) DRUG ADULTSCHILDREN2 DAILY 1 TIMEWK3 2 TIMESWK3 3 TIMESWK3 Isoniazid Adults 5 mgkg (300 mg) 15 mgkg (900 mg) 15 mgkg (900 mg) 15 mgkg (900 mg) Children 10 15 mgkg (300 mg) 20 30 mgkg (900 mg) Rifampin Adults 10 mgkg (600 mg) 10 mgkg (600 mg) 10 mgkg (600 mg) Children 10 20 mgkg (600 mg) 10 20 mgkg (600 mg) Rifabutin Adults 5 mgkg (300 mg) 5 mgkg (300 mg) 5 mgkg (300 mg) Children 12 yr Appropriate dosing for children unknown Rifapentine Adults 10 mgkg (600 mg; continuation phase) Children Pyrazinamide Adults (weight) 40 55 kg 18.2 25 mgkg (1000 mg) 36.4 50 mgkg (2000 mg) 27.3 37.5 mgkg (1500 mg) 56 75 kg 20 26.8 mgkg (1500 mg) 40 53.6 mgkg (3000 mg) 33.3 44.6 (2500 mg) 76 90 kg 22.2 26.3 mgkg (2000 mg) 44.4 52.6 mgkg (4000 mg) 33.3 39.5 mgkg (3000 mg) Children 40 kg 30 40 mgkg (2000 mg) 50 mgkg (2000 kg) Ethambutol 4 Adults (weight) 40 55 kg 14.5 20 |
7,441 | mgkg (800 mg) 36.4 50 mgkg (2000 mg) 21.8 30 mgkg (1200 mg) 56 75 kg 16 21.4 mgkg (1200 mg) 37.3 50 mgkg (2800 mg) 26.7 35.7 mgkg (2000 mg) 76 90 kg 17.8 21.1 mgkg (1600 mg) 44.4 52.6 mgkg (4000 mg) 26.7 31.6 mgkg (2400 mg) Children 15 20 mgkg (1000 mg) 50 mgkg (2500 mg) 1Although these regimens are broadly applicable, modifications may be needed for certain circumstances (patients on antiretroviral therapy ART). For more information, refer to treatment of tuberculosis guidelines. MMWR 2003; 52 (No.RR 11). 2For purposes of this document, adult dosing begins at age 15 years. Children weighing more than 40 kg should be dosed as adults. Adjust doses as the patients weight changes. 3All patients prescribed an intermittent regimen should be given DOT. 4Ethambutol should be used with caution in young children since it is difficult to monitor their vision. However, if they have TB that is resistant to INH or RIF, a dose of 15 mgkg per day can be used. From Centers for Disease Control and Prevention. Core Curriculum on Tuberculosis: What the Clinician Should Know, 7th ed. Atlanta: CDC, 2021. Table 6.4. https:www.cdc.govtbe ducationcorecurrpdfchapter6.pdf Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1850 Part XV u Infectious Diseases Table 261.6 Common Adverse Reactions to TB Drugs CAUSED BY ADVERSE REACTION SIGNS AND SYMPTOMS SIGNIFICANCE OF REACTION Any drug Allergic Skin rash May be serious or minor Ethambutol Eye damage Blurred or changed vision Changed color vision Serious Isoniazid Pyrazinamide Rifampin Hepatic toxicity Abdominal pain Abnormal liver function test results Dark urine Fatigue Fever for 3 or more days Flu like symptoms Lack of appetite Nausea Vomiting Yellowish skin or eyes Serious Isoniazid Nervous system damage Dizziness; tingling or numbness around the mouth Serious Peripheral neuropathy Tingling sensation in hands and feet Serious Pyrazinamide Stomach upset Stomach upset Vomiting Lack of appetite May be serious or minor Gout Abnormal uric acid level Joint aches Serious Rifampin Bleeding problems Easy bruising Slow blood clotting Serious Discoloration of body fluids Orange urine, sweat, or tears Permanently stained soft contact lenses Minor Drug interactions Interferes with certain medications such as birth control pills, birth control implants, and methadone treatment May be serious or minor Sensitivity to the sun Frequent sunburn Minor Patients should stop medication for serious adverse reactions and consult a clinician immediately. Patients can continue taking medication if they have minor adverse reactions. Asymptomatic elevated uric acid levels are expected with PZA treatment. Acute gouty arthritis, which is rare without preexisting gout, is a contraindication to PZA use. EMB, ethambutol; INH, isoniazid; PZA, pyrazinamide; RIF,. From Centers for Disease Control and Prevention. Core Curriculum on Tuberculosis: What the Clinician Should Know, 7th ed. Atlanta: CDC, 2021. Table 6.11. https:www.cdc.govtb educationcorecurrpdfchapter6.pdf Table 261.7 Commonly Used Drug Regimens and Dosages for Treatment in Pediatric Patients with TB |
7,442 | Infection (TBI) DRUGS DOSAGE FORMS AND AGE GROUP ADMINISTRATION DURATION (MO) AGE RESTRICTION COMMENTS Isoniazid Rifapentine (3HP) Age 12 yr INH: 15 mgkg rounded up to the nearest 50 or 100 mg (max 900 mg) Rifapentine (by weight): 10 14 kg: 300 mg 14.1 25 kg: 450 mg 25.1 32 kg: 600 mg 32.1 49.9 kg: 750 mg 50 kg: 900 mg Age 2 11 yr INH: 25 mgkg, rounded up to the nearest 50 or 100 mg (max 900 mg) Rifapentine (see above) Weekly (DOT) 3 Not for children 2 yr Take with food, containing fat if possible, pyridoxine for selected patients RFP has drugdrug interactions Rifampin (4R) Adult: 10 mgkg (max 600 mg) Child: 15 20 mgkg (max 600 mg) Daily (SAT) 4 None Drug drug interactions INH Rifampin Same daily doses as when the drugs are used individually Daily (SAT) 3 None RIF has drug drug interactions INH Adult: 5 mgkg (max 300 mg) Child 10 15 mgkg (max 300 mg) Adult: 15 mgkg (max 900 mg) Child: 20 30 mgkg (max 900 mg) Daily (SAT) Twice weekly (DOT) 6 or 9 None Seizures with overdose; pyridoxine for selected patients Exclusively breastfed infants and for children and adolescents on meat and milk deficient diets; children with nutritional deficiencies, including all asymptomatic children living with HIV infection; and pregnant adolescents and women. From Kimberlin DW, Barnett ED, Lynfield R, Sawyer MH, eds. Red Book: 20212024 Report of the Committee on Infectious Diseases, 32nd ed. Itasca, IL: American Academy of Pediatrics; 2021:805806; and Nolt D, Starke JR. Tuberculosis infection in children and adolescents: testing and treatment. Pediatrics. 2021;148(6):e2021054663. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 261 u Tuberculosis (Mycobacterium tuberculosis) 1851 Extrapulmonary tuberculosis is usually caused by small numbers of mycobacteria. In general, the treatment for most forms of extrapulmo nary TB in children, including cervical lymphadenopathy, is the same as for pulmonary TB. Exceptions are bone and joint, disseminated, and CNS TB, for which there are inadequate data to recommend 6 months of therapy; these conditions are usually treated for 9 12 months. Surgical debridement in bone and joint disease and ventriculoperitoneal shunt ing in CNS disease may be necessary adjuncts to medical therapy. The optimal treatment of TB in children living with HIV has not been established. Adults living with HIV with TB disease can be treated successfully with standard regimens that include isoniazid, rifampin, pyrazinamide, and ethambutol. The total duration of therapy should be 6 9 months or 6 months after culture of sputum becomes sterile, which ever is longer. Data for children are limited to relatively small series. Most experts believe that children living with inadequately controlled HIV who have drug susceptible TB should receive the standard four drug regimen for the first 2 months followed by isoniazid and rifampin for a total duration of at least |
7,443 | 9 months. However, all treatment should be daily, not intermittent. Children living with HIV appear to have more frequent adverse reactions to antituberculosis drugs and must be mon itored closely during therapy. Co administration of rifampin and some antiretroviral agents results in subtherapeutic blood levels of protease inhibitors and nonnucleoside reverse transcriptase inhibitors and toxic levels of rifampin. Concomitant administration of these drugs is not recommended. Treatment of children living with HIV with TB is often empirically based on epidemiologic and radiographic information because the radiographic appearance of other pulmonary complica tions of HIV in children, such as lymphoid interstitial pneumonitis and bacterial pneumonia, may be similar to that of TB. Therapy should be considered when TB cannot be excluded. Drug Resistant Tuberculosis The incidence of drug resistant TB is increasing in many areas of the world, including North America. There are two major types of drug resistance. Primary resistance occurs when a person is infected with M. tuberculosis that is already resistant to a particular drug. Second ary resistance occurs when drug resistant organisms emerge as the dominant population during treatment. The major causes of sec ondary drug resistance are poor adherence to the medication by the patient or inadequate treatment regimens prescribed by the physi cian. Nonadherence to one drug is more likely to lead to secondary resistance than is failure to take all drugs. Secondary resistance is rare in children because of the small size of their mycobacterial popu lation. Consequently, most drug resistance in children is primary, and patterns of drug resistance among children tend to mirror those found among adults in the same population. The main predictors of drug resistant TB among adults are history of previous antitubercu losis treatment, co infection with HIV, and exposure to another adult with infectious drug resistant TB. Treatment of drug resistant TB is successful only when at least two bactericidal drugs are given to which the infecting strain of M. tubercu losis is susceptible. When a child has possible drug resistant TB, usu ally at least four or five drugs should be administered initially until the susceptibility pattern is determined and a more specific regimen can be designed. The specific treatment plan must be individualized for each patient according to the results of susceptibility testing on the isolates from the child or the adult source case. Treatment duration of 9 months with rifampin, pyrazinamide, and ethambutol is usually adequate for isoniazid resistant TB in children. High dose isoniazid is often added in those with low level isoniazid resistant TB. The recommendations for the treatment of MDR TB have rapidly evolved in recent years. In 2019, the WHO advocated for the use of all oral (injectable free) regimens and reprioritized the order of the available oral drugs (Tables 261.8 and 261.9). Treatment regimens should prioritize administering group A and B drugs in addition to delamanid for children older than 3 years of age. Bedaquiline can be used in those older than 6 years of age. First line treatment includes |
7,444 | an all oral regimen using three group A drugs and at least one group B drug. If only one or two group A medications are used, then group B drugs should be added to make a regimen of four drugs. Group C drugs are only used if the isolate is susceptible and when drugs from groups A and B cannot be used. The WHO recommends treatment of those with severe MDR TB disease for 12 18 months; however, in children younger than 15 years with less severe MDR TB disease, the treatment duration can be shortened to 9 12 months. The WHO defines severe MDR TB disease as children with cavities or bilateral parenchymal disease on chest radiography or extrapulmonary forms of disease other than lymphadenopathy. Those with severe malnutrition; advanced immunosuppression; or positive smear, NAAT, or culture are also often treated with a longer course of therapy. The second line drugs require close monitoring for adverse effects and toxicity (see Table 261.9). The prognosis of single drugresistant or MDR TB in children with nonsevere disease is good if the drug resistance is identified early in the treatment, if appropriate drugs are administered under DOT, if adverse reactions from the drugs are minor, and if the child and family are in a supportive environment. The treatment of drug resistant TB in children always should be under taken by a clinician with specific expertise in TB treatment. Corticosteroids Corticosteroids are useful in treating some children with TB disease. They are most beneficial when the host inflammatory reaction contrib utes significantly to tissue damage or impairment of organ function. There is convincing evidence that corticosteroids decrease mortality rates and long term neurologic sequelae in some patients with tuber culous meningitis by reducing vasculitis, inflammation, and ulti mately intracranial pressure. Lowering the intracranial pressure limits tissue damage and favors circulation of antituberculosis drugs through Table 261.8 Drug Grouping for the Treatment of MDR TB GROUP INSTRUCTIONS DRUG Group A Include all three drugs (unless they cannot be used), add delamanid if age 3 yr Levofloxacin OR moxifloxacin Bedaquiline Linezolid Group B Add both drugs (unless they cannot be used) Clofazimine Cycloserine or terizidone Group C Add to complete regimen (of four to five agents) Add when drugs from groups A or B cannot be used Ethambutol Delamanid Pyrazinamide Imipenem cilastatin Meropenem Amikacin OR streptomycin Ethionamide OR prothionamide p Aminosalicylic acid Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1852 Part XV u Infectious Diseases Table 261.9 Drugs Used for Treating Drug Resistant Tuberculosis in Infants, Children, and Adolescents DRUGS DOSAGE, FORMS DAILY DOSAGE (mgkg) MAXIMUM DOSE ADVERSE REACTIONS Amikacin Vials: 500 mg, 1 g 15 20 (IV or IM administration) 1 g Auditory and vestibular toxic effects, nephrotoxic effects Amoxicllin clavulanate (Strength expressed in terms of amoxicillin component) Syrup: 50 mgmL 80 mgmL 120 mgmL (ES 600) |
7,445 | Tablets: 500 mg 875 mg 1000 mg (XR tablet) 40 (amoxicillin component), twice daily 4 g (amoxicillin) 500 mg (clavulanate) Abdominal pain, diarrhea, rash Bedaquiline Tablets: 20 mg, 100 mg Adults and children 5 yr, 15 to 30 kg weeks 12: 200 mg day; weeks 324: 100 mg 3x week 30 kg weeks 12: 400 mg day; weeks 324: 200 mg 3x week 600 mgweek QTc prolongation, reduced levels with efavirenz co administration Clofazimine Gelcaps: 50 mg 100 mg 2 5 per day 100 mg QTc prolongation, reversible skin pigmentation Cycloserine or terizidone Capsules: 250 mg 10 20, given in 2 divided doses 1 g Psychosis, personality changes, seizures, rash Delamanid Tablets: 50 mg 100 mg 611 years: 50 mg 2xday 1217 years: 100 mg 2xday 100 mgdose QTc prolongation, adverse events with hypoalbuminemia, avoid if metronidazole allergic Ethambutol Tablets: 100 mg 400 mg Children 40 kg: 1525 Children 40 kg: 4055 kg: 800 mg day PO 5675 kg: 1200 mg day PO 7690 kg: 1600 mg day PO 2.5 g Optic neuritis (usually reversible), decreased red green color discrimination, gastrointestinal tract disturbances, hypersensitivity Ethionamide Tablets: 125 mg 250 mg 15 20, given in 12 divided doses 1 g GI tract disturbances, hepatotoxic effects, hypersensitivity reactions, hypothyroidism Imipenem cilastatin 60 100 per day, divided in 4 doses 4 g Anemia, thrombocytopenia, eosinophilia, elevated liver enzymes Levofloxacin Tablets: 250 mg 500 mg 750 mg Oral solution: 25mL Vials: 25 mgmL Adults: 750 1000 mg (daily) Children: 15 20 mgkg daily 1 g Theoretic effect on growing cartilage, joint pain, GI tract disturbances, rash, headache, restlessness, confusion Linezolid Tablets: 400 mg 600 mg Syrup: 20 mgmL Children 16 kg: 15 mgkg once daily Children 16 kg: 10 12 mg kgday once daily 600 mg if 12 yr 300 mg if 12 yr Bone marrow suppression, peripheral neuropathy, lactic acidosis, potential overlapping toxicity with nucleoside reverse transcriptase inhibitors Moxifloxacin Tablets: 400 mg IV solution: 400 mg250 mL in 0.8 saline Adultsadolescents: 400 mg Children: 10 15 mgkg daily 400 mg; maximum doses of 600800 mg per day are used for higher MIC or in malabsorption Arthropathy, arthritis p Aminosalicylic acid (PAS) Packets: 3 g 200 300 (2 4 times a day) 10 g GI tract disturbances, hypersensitivity, hepatotoxic effects Prothionamide Tablets: 250 mg 500 mg 15 20 (divided twice daily) 1 g GI tract disturbances, hepatotoxic effects, hypersensitivity reactions, hypothyroidism Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 261 u Tuberculosis (Mycobacterium tuberculosis) 1853 Table 261.9 Drugs Used for Treating Drug Resistant Tuberculosis in Infants, Children, and Adolescentscontd DRUGS DOSAGE, FORMS DAILY DOSAGE (mgkg) MAXIMUM DOSE ADVERSE REACTIONS Pyrazinamide Scored tablets: 500 mg 30 40 2 g Hepatotoxic effects, hyperuricemia, arthralgias, gastrointestinal tract upset Streptomycin Vials: 1 g 4 g 20 40 (IM administration) 1 g Auditory and vestibular toxic effects, nephrotoxic effects, rash These drugs |
7,446 | should be used in consultation with a specialist in tuberculosis. Dose adjustment in renal insufficiency. GI, Gastrointestinal; IM, intramuscular; IV, intravenous. From Kimberlin DW, Barnett ED, Lynfield R, Sawyer MH, eds. Red Book: 20212024 Report of the Committee on Infectious Diseases, 32nd ed. Itasca, IL: American Academy of Pediatrics; 2021:805806; and Furin J, Seddon J, Becerra M, et al. Management of Multi drug Resistant Tuberculosis Children: A Field Guide, 4th ed. Boston: The Sentinel Project for Pediatric Drug Resistant Tuberculosis; 2019. Available at: http:sentinel project.orgwp contentuploads201902UpdatedDRTB Field Guide 2019 V3.pdf the brain and meninges. Short courses of corticosteroids also may be effective for children with endobronchial tuberculosis that causes respiratory distress, localized emphysema, or segmental pulmonary lesions. Several randomized clinical trials have shown that cortico steroids can help relieve symptoms and constriction associated with acute tuberculous pericardial effusion. Corticosteroids can cause dra matic improvement in symptoms in some patients with tuberculous pleural effusion and shift of the mediastinum. However, the long term course of the disease is probably unaffected. Some children with severe miliary tuberculosis have dramatic improvement with corticosteroid therapy if the inflammatory reaction is so severe that alveolocapillary block is present. There is no convincing evidence to support a specific corticosteroid preparation. The most common regimen is prednisone 1 2 mgkgday in one to two divided doses orally for 4 6 weeks fol lowed by a taper. Supportive Care Children receiving TB treatment should be followed carefully to pro mote adherence to therapy, to monitor for toxic reactions to medica tions, and to ensure that the TB is being adequately treated. Adequate nutrition is important. Patients should be seen at monthly intervals and should be given just enough medication to last until the next visit. Anticipatory guidance with regard to the administration of medications to children is crucial. The physician should foresee dif ficulties that the family might have in introducing several new medi cations in inconvenient dosage forms to a young child. The clinician must report all cases of suspected TB in a child to the local health department to be sure that the child and family receive appropriate care and evaluation. Nonadherence to TB treatment is the major problem. The patient and family must know what is expected of them through verbal and written instructions in their primary language. Approximately 3050 of patients taking long term treatment are significantly nonadherent with self administered medications, and clinicians are usually not able to determine in advance which patients will be nonadherent. Prefer ably, DOT should be instituted by the local health department. Mycobacterium tuberculosis Infection The following aspects of the natural history and treatment of TBI, often referred to as latent TB infection, in children must be considered in the formulation of recommendations about therapy: 1. Infants and children 5 years old with TBI who have been infected recently. 2. The risk for progression to disease is high. 3. Untreated infants with TBI have up to a 40 chance of development of TB disease. 4. The risk for |
7,447 | progression decreases gradually through childhood un til adolescence, when the risk increases. 5. Infants and young children are more likely to have life threatening forms of TB, including meningitis and disseminated disease. 6. Children with TBI have more years at risk for development of dis ease than adults. Because of these factors and the excellent safety profile of isoniazid, rifampin, and rifapentine in children, there is a tendency to err on the side of overtreatment in infants, young children, and adolescents. The main TBI treatment regimens used in children are summarized in Table 261.7. The regimens include 6 9 months of isoniazid (daily or twice weekly by DOT), 3 months of daily rifampin and isoniazid, 4 months of daily rifampin, and once weekly isoniazid and rifapen tine (3HP) for 12 total doses. Because of improved treatment comple tion rates and noninferiority, the rifamycin based, shorter treatment regimens are often favored over isoniazid monotherapy. The main indication for the use of isoniazid is if the child is at risk of drug drug interactions with rifamycins. Isoniazid therapy for TBI appears to be more effective for children than for adults, with several large clinical trials demonstrating a risk reduction of 7090. The risk of isoniazid related hepatitis is mini mal in infants, children, and adolescents, who tolerate the drug bet ter than adults. Analysis of data from several studies demonstrates that the efficacy decreased significantly if isoniazid was taken for 9 months. However, the international standard is 6 months of treat ment with isoniazid because of resource considerations. Isoniazid given twice weekly has been used extensively to treat TBI in children, especially schoolchildren and close contacts of case patients. DOT or VDOT should be considered when it is unlikely that the child and family will adhere to daily self administration or if the child is at increased risk for rapid development of disease (newborns and infants, recent contacts, immunocompromised children). For healthy children taking isoniazid but no other potentially hepatotoxic drugs, routine biochemical monitoring and supplementation with pyridox ine are not necessary. Rifampin alone for 4 months is now frequently used for the treatment of TBI in infants, children, and adolescents. This regimen is most often used when a shorter, self administered treatment regimen is preferred, when isoniazid cannot be toler ated, or the child has had contact with a source case infected with an isoniazid resistant but rifamycin susceptible organism. If a child is identified with TBI during a contact investigation or if the cost of rifampin is prohibitive for families, administration of the medica tion through VDOT programs offered by health departments should be considered. Rifapentine is a rifamycin with a very long half life, allowing for weekly administration in conjunction with high dose isoniazid. Studies have demonstrated that 12 doses of once weekly isoniazid and rifapentine (3HP) are as effective for treating TBI and as safe as 9 months of daily isoniazid in children as young as 2 years. This is becoming the preferred regimen for the treatment of |
7,448 | TBI in age eligible children who are exposed to a contact with presumed pan susceptible TB. Given the risk of selecting for drug resistant isolates by missing intermittent doses of rifamycins, this treatment regimen currently is recommended only with DOT under the super vision of local health departments. The main reason children or ado lescents are unable to complete this regimen is the inability to crush the tablets and the high pill burden. In these situations, the children are often transitioned to an alternative treatment regimen. A 3 month daily regimen of rifampin and isoniazid has been used throughout Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1854 Part XV u Infectious Diseases Europe. Although this regimen has not been used regularly in the United States, experts believe it is favorable in children less than 5 years of age in whom the pill burden of 3HP is difficult. Studies have revealed that the shorter treatment regimens for TBI in children are equally efficacious as 9 months of isoniazid and are associated with superior treatment completion rates. For children with MDR TB, the regimen will depend on the drug susceptibility profile of the contract cases organism; an expert in TB should be consulted. There are data that support the use of levofloxacin or moxifloxacin for treatment of MDR TBI. Few controlled studies have been published regarding the efficacy of any form of treatment for TBI in children living with HIV. A 9 month course of daily isoniazid is recommended. Most experts recommend that routine monitoring of serum hepatic enzyme concentrations be performed and pyridoxine be given when children living with HIV are treated with isoniazid. The optimal duration of rifampin therapy in children living with HIV with TBI is not known, but many experts recommend at least a 6 month course. Isoniazid or rifampin should be given to children 5 years old who have a negative TST or IGRA result but who have a known recent exposure to an adult with potentially contagious TB disease. This prac tice is often referred to as window prophylaxis. By the time delayed hypersensitivity develops (2 3 months), an untreated child already may have developed severe TB. For these children, TST or IGRA is repeated 8 10 weeks after contact with the source case for TB has been broken (broken contact is defined as physical separation or adequate initial treatment of the source case). If the second test result is posi tive, the child should complete a treatment course for TBI (either 9 months of isoniazid or 4 months of rifampin). There is a benefit to using rifampin over isoniazid for window prophylaxis (unless con traindicated because of drug drug interactions or prohibitive because of cost). By the time of the second test result (8 10 weeks later), if positive, the child receiving rifampin has approximately 2 months of |
7,449 | therapy to complete compared to 7 months of isoniazid. Alternatively, if a new, shorter TBI treatment course is started after the second test result becomes positive (either 4 months of rifampin if isoniazid was given as window prophylaxis, 12 weekly doses of isoniazid and rifa pentine, or 3 months of isoniazid and rifampin), the treatment start date is day 1 of the new regimen. If the second test result is negative, TBI treatment can be stopped. PREVENTION The highest priority of any TB control program should be case find ing and treatment, which interrupt transmission of infection between close contacts. All children and adults with symptoms suggestive of TB disease and those in close contact with an adult with suspected infec tious pulmonary TB should be tested for TBI (by TST or IGRA) and examined as soon as possible. On average, 3050 of household con tacts to infectious cases are also infected, and 1 of contacts already have overt disease. This scheme relies on effective and adequate public health response and resources. Children, particularly young infants, should receive high priority during contact investigations because their risk for infection is high and they are more likely to rapidly develop severe forms of TB. Mass testing of large groups of children for TBI is an inefficient process. When large groups of children at low risk for TB are tested, the vast majority of TST reactions are actually false positive reactions because of biologic variability or cross sensitization with NTM. How ever, testing of high risk groups of adults or children should be encour aged because most of these persons with positive TST or IGRA results have TBI. Testing should take place only if effective mechanisms are in place to ensure adequate evaluation, follow up, and treatment of the persons who test positive. Bacille Calmette Gurin Vaccination The only available vaccine against TB is the BCG vaccine. The origi nal vaccine organism was a strain of M. bovis attenuated by subcul ture every 3 weeks for 13 years. This strain was distributed to dozens of laboratories that continued to subculture the organism on different media under various conditions. The result has been production of many BCG vaccines that differ widely in morphology, growth charac teristics, sensitizing potency, and animal virulence. The administration route and dosing schedule for the BCG vac cines are important variables for efficacy. The preferred route of administration is intradermal injection with a syringe and needle because it is the only method that permits accurate measurement of an individual dose. The BCG vaccines are extremely safe in immunocompetent hosts. Local ulceration and regional suppurative adenitis occur in 0.11 of vaccine recipients. Local lesions do not suggest underlying host immune defects and do not affect the level of protection afforded by the vaccine. Most reactions are mild and usually resolve spontaneously, but chemotherapy is needed occasionally. Surgical excision of a suppura tive draining node is rarely necessary and should be avoided if possible. Osteitis is a rare complication of BCG vaccination |
7,450 | that appears to be related to certain strains of the vaccine that are no longer in wide use. Systemic complaints such as fever, convulsions, loss of appetite, and irritability are extraordinarily rare after BCG vaccination. Profoundly immunocompromised patients can develop disseminated BCG infec tion after vaccination. Children living with HIV appear to have rates of local adverse reactions to BCG vaccines that are comparable with rates in immunocompetent children. However, the incidence in these children of disseminated infection months to years after vaccination is currently unknown. Recommended vaccine schedules vary widely among countries. The official WHO recommendation is a single dose administered during infancy in populations where the risk for TB is high. However, infants with known or suspected HIV infection should not receive a BCG vacci nation. In some countries, repeat vaccination is universal, although no clinical trials support this practice. In others, it is based on either TST or the absence of a typical scar. The optimal age for BCG administra tion and dosing schedule are unknown because adequate comparative trials have not been performed. Although dozens of BCG trials have been reported in various human populations, the most useful data have come from several controlled trials. The results of these studies have been disparate. Some demon strated substantial protection from BCG vaccines, but others showed no efficacy at all. A meta analysis of published BCG vaccination trials suggested that BCG is 50 effective in preventing pulmonary TB in adults and children. The protective effect for disseminated and menin geal TB appears to be slightly higher, with BCG preventing 5080 of cases. A variety of explanations for the varied responses to BCG vac cines have been proposed, including methodologic and statistical vari ations within the trials, interaction with NTM that either enhances or decreases the protection afforded by BCG, different potencies among the various BCG vaccines, and genetic factors for BCG response within the study populations. BCG vaccination administered during infancy has little effect on the ultimate incidence of TB in adults, suggesting waning protection with time. BCG vaccination has worked well in some situations but poorly in others. Clearly, BCG vaccination has had little effect on the ulti mate control of TB throughout the world, because 5 billion doses have been administered, but TB remains epidemic in most regions. BCG vaccination does not substantially influence the chain of transmission, because cases of contagious pulmonary TB in adults that can be prevented by BCG vaccination constitute a small frac tion of the sources of infection in a population. The best use of BCG vaccination is to prevent life threatening forms of TB in infants and young children. BCG vaccination has never been adopted as part of the strategy for TB control in the United States. Widespread use of the vaccine would render subsequent TSTs less useful. However, BCG vaccina tion can contribute to TB control in select population groups. BCG is recommended for TST negative, HIV negative infants and chil dren who are at high risk for intimate |
7,451 | and prolonged exposure to persistently untreated or ineffectively treated adults with infectious Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 262 u Hansen Disease (Mycobacterium leprae) 1855 pulmonary TB and who cannot be removed from the source of infection or placed on long term preventive therapy. It also is rec ommended for those who are continuously exposed to persons with TB who have bacilli that are resistant to isoniazid and rifampin. Any child receiving BCG vaccination should have a documented negative TST before receiving the vaccine. After receiving the vac cine, the child should be separated from the possible sources of infection until it can be demonstrated that the child has had a vac cine response, as evidenced by tuberculin reactivity, which usually develops within 1 3 months. Prevention of Perinatal Tuberculosis The most effective way of preventing TB infection and disease in the neonate or young infant is through appropriate testing and treatment of the mother and other family members. High risk pregnant women should be tested with TST or IGRA, and those with a positive test result should receive a chest radiograph with appropriate abdominal shield ing. If the mother has a negative chest radiograph and is clinically well, no separation of the infant and mother is needed after delivery. The child needs no special evaluation or treatment if the child remains asymptomatic. Other household members should undergo testing for TBI and further evaluation as indicated. If the mother has suspected TB at the time of delivery, the new born should be separated from the mother until the chest radiograph is obtained. If the mothers chest radiograph is abnormal, separation should be maintained until the mother has been evaluated thor oughly, including examination of the sputum. If the mothers chest radiograph is abnormal but the history, physical examination, spu tum examination, and evaluation of the radiograph show no evi dence of current active TB, it is reasonable to assume that the infant is at low risk for infection. The mother should receive appropriate TB treatment, and she and her infant should receive careful follow up care. If the mothers chest radiograph or AFB sputum smear shows evi dence of current TB disease, additional steps are necessary to protect the infant. Isoniazid therapy for newborns has been so effective that separation of the mother and infant is no longer considered man datory. Separation should occur only if the mother is ill enough to require hospitalization, has been or is expected to become nonadher ent to treatment, or has suspected drug resistant TB. Isoniazid treat ment for the infant should be continued until the mother is sputum culture negative for 3 months. At that time, a TST should be placed on the child. If the test is positive, isoniazid is continued for a total duration of 9 12 months; if the TST is |
7,452 | negative, isoniazid can be dis continued. Once the mother and child are taking adequate therapy, it is usually safe for the mother to breastfeed, because the medications, although found in milk, are present in low concentrations. If isoniazid resistance is suspected or the mothers adherence to medication is in question, continued separation of the infant from the mother should be considered. The duration of separation must be at least as long as is necessary to render the mother noninfectious. A TB expert should be consulted if the young infant has potential exposure to the mother or another adult with TB disease caused by an isoniazid resistant strain of M. tuberculosis. Although isoniazid is not thought to be teratogenic, the treatment of pregnant women who have asymptomatic TBI is often deferred until after delivery. However, symptomatic pregnant women or those with radiographic evidence of TB disease should be appropriately evalu ated. Because pulmonary TB is harmful to both the mother and the fetus and represents a great danger to the infant after delivery, TB in pregnant women always should be treated. The most common regi men for drug susceptible TB is isoniazid, rifampin, and ethambutol. The aminoglycosides and ethionamide should be avoided because of their teratogenic effect. The safety of pyrazinamide in pregnancy has not been established. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Leprosy (Hansen disease HD) is a heterogeneous, curable infection caused by Mycobacterium leprae that primarily affects the upper air way, skin, and peripheral nerves. Disease manifestations are mainly determined by the hosts immunologic response to infection, resulting in a wide clinical spectrum. The majority of exposed individuals never develop clinical disease. HD is currently the accepted designation of leprosy, and contrary to popular folklore, HD is not highly transmis sible and is treatable. In addition, the associated morbidity and disabil ity can be prevented with early diagnosis and appropriate treatment. MICROBIOLOGY M. leprae is an obligate, intracellular, acid fast, gram positive bacillus of the family Mycobacteriaceae measuring 1 8 m in length. It grows optimally at 2733C (80.691.4F) yet cannot be cultured in vitro. The bacillus multiplies slowly, with a doubling time of 11 13 days. It is the only bacterium known to infect Schwann cells of peripheral nerves. Identification of acid fast bacilli (AFB) in peripheral nerves is pathog nomonic of leprosy. EPIDEMIOLOGY The prevalence of leprosy is variable, with most cases being identi fied in tropical and subtropical areas. The World Health Organization (WHO) goal to eliminate leprosy as a public health problem, defined as a reduction in its prevalence to less than 1 case per 10,000 popula tion, was achieved at the global level in 2000. Despite an overall decline in reported prevalence, HD continues to afflict more than 2 million people worldwide. In 2022, 174,059 new cases were reported globally, with most cases occurring in Southeast Asia (mostly India), Africa, and South America (mostly Brazil). Of those, 5.92 occurred in children 15 years. In 2018, the WHO reviewed the available evidence on key |
7,453 | issues related to the elimination of leprosy and developed a guidance WHO Guidelines for the Diagnosis, Treatment and Prevention of Lep rosy. More recently, the WHO released Towards Zero Leprosy Global Leprosy (Hansens Disease) Strategy 2021 2030, which was aligned with the 2021 2030 road map for neglected tropical diseases during the same period. Since 1984, HD has been a notifiable disease in the United States, with about 14,000 cases recorded since then. Since the 1990s, an aver age of 175 new cases are reported annually. Of the 159 new U.S. cases reported in 2020, 69 were identified in Texas, Louisiana, Hawaii, Cal ifornia, Florida, and New York. Most new cases (75) in the United States were identified among immigrants from HD endemic countries or in citizens who have worked abroad in endemic areas. However, over one third of U.S. cases are autochthonous and do not report con tact with foreign countries or people with leprosy. The likelihood of developing HD is determined by several variables: age (with two incidence peaks: 10 14 years and 30 years), gender (male female ratio 2:1, with no differences observed in children), genetics, immune status, type of leprosy (with higher risk in those exposed to patients with multibacillary disease), and possibly through exposure to armadillos. Whole genome sequencing has allowed identification of genes and polymorphisms associated with increased susceptibil ity to leprosy and found that approximately 5 of people are geneti cally susceptible to M. leprae infection. HD in immunocompromised Chapter 262 Hansen Disease (Mycobacterium leprae) Cristina Tomatis Souverbielle and Asuncion Mejias Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1856 Part XV u Infectious Diseases hosts has been reported in solid organ and bone marrow transplant recipients and patients receiving tumor necrosis factor (TNF)block ing monoclonal antibodies. Patients with HIV infection do not appear to be at increased risk of acquiring leprosy, increased disease severity, or poor response to treatment. However, clinicians should be aware that concomitant HIV infection and leprosy can result in worsening of symptoms of leprosy during HIV treatment as a result of an immune reconstitution inflammatory syndrome. The exact mechanism of transmission is not fully understood but is thought to occur primarily by the respiratory route. Natural infec tion occurs in humans and armadillos, which are the only recognized nonhuman reservoir. The risk of transmission from armadillos to humans seems low, and again, the mechanism is not fully understood. The incubation period between natural infection and overt clinical dis ease in humans ranges from 3 months to 20 years, with a mean of 4 years for tuberculoid leprosy and 10 years for lepromatous leprosy. Up to 107 viable bacilli per day can be shed in respiratory secretions of patients with multibacillary leprosy. The relative risk for developing disease in household contacts is 8 to 10 fold for lepromatous disease and 2 to 4 |
7,454 | fold for the tuberculoid form. Transmissions by breast milk, the transplacental route, and through broken skin have been reported. Environmental factors and subclinically infected humans may also play a role in disease transmission. The infectivity of patients with HD becomes negligible within 24 hours of the first administration of effec tive therapy. PATHOGENESIS In the skin, M. leprae shows affinity for keratinocytes, macrophages, and histiocytes, and in peripheral nerves, the organism can be found in the Schwann cells. The mechanism of mycobacterial dissemination from the respiratory tract to the skin and nerves is thought to occur hematogenously but has not been completely elucidated. M. leprae induces demyelination and binds to the laminin 2 glycoprotein pres ent in the basal lamina of Schwann cells in peripheral nerves, where it replicates slowly over several years. Infection stimulates the dedif ferentiation of Schwann cells to immature cells through the activa tion of the Erk12 pathway. This reprogramming of Schwann cells seems to be linked to disease dissemination. In addition to the direct nerve invasion, the immune response to infection also contributes to nerve damage. Schwann cells express human leukocyte antigen (HLA) class II molecules and present mycobacterial peptides to the HLA class II restricted CD4 T cells, which initiate an inflammatory response. These events explain the nerve damage seen in paucibacil lary disease and in reversal reactions. Swelling within the perineu rium leads to ischemia, further nerve damage, and eventually fibrosis and axonal death. DISEASE CLASSIFICATION Disease classification is important to determine potentially infec tious cases and prognosis. Based on the cellular immune response and disease dissemination, two classification schemes for leprosy are fre quently used: the Ridley Jopling scale and the WHO classification: A. The Ridley Jopling scale is used in the United States and describes the five types of leprosy, according to clinical spectrum of disease, bacillary load, and findings on histopathology. 1. Tuberculoid form: Patients usually have a vigorous and specific cellular immune response to M. leprae antigens and have a small number of skin lesions, generally one to three well demarcated macules or plaques with elevated borders (Fig. 262.1) and re duced or absent sensation. The lesions are infiltrated by T helper 1 (Th1) cells producing abundant interferon (IFN) and TNF , forming well demarcated granulomas, with few, if any, bacilli found within the lesions. 2. Borderline tuberculoid form 3. Borderline form 4. Borderline lepromatous 5. Lepromatous form: Patients have an absence of specific cellular immunity to M. leprae (but intact immunity to Mycobacterium tuberculosis) and present the most severe form of disease. They manifest clinically apparent infiltration of peripheral nerves and skin lesions (usually many lesions and not all hypoesthetic or an esthetic), with a high load of bacilli in the absence of an effective cell mediated immune response. Skin biopsies reveal extensive infiltration of the skin and nerves, containing messenger RNA for Th2 cytokines such as interleukin (IL) 4 and IL 10, poorly formed granulomas, and uncontrolled proliferation of bacilli within foamy macrophages. A large amount of |
7,455 | circulating anti body to M. leprae is present but does not confer protective im munity. Over time, patients with the lepromatous form develop a systemic disease with symmetric peripheral nerve involvement and a diffuse infiltrative dermopathy that includes thickening of the facial skin and hair loss of the eyelashes and eyebrows (ma darosis), leading to the classic presentation of the leonine facies. They also have involvement of the nasal mucosa causing nasal congestion and epistaxis. 6. The majority of patients will present with a borderline form. From borderline tuberculoid to borderline lepromatous forms, there is a progressive reduction in cellular immune responses, an increase in bacillary load, more frequent hypopigmented skin lesions and nerve involvement, and higher antibody titers (Fig. 262.2). Patients with the extreme forms of the disease (tu berculoid and lepromatous) are considered to have stable cell mediated immunity, because their disease manifestations do not change much over time. In contrast, patients with border line disease have unstable cell mediated immunity and demon strate changes in their clinical manifestations over time toward the polar forms (downgrade) or present sudden reversal reac tions (upgrade). Indeterminate leprosy is the earliest form of the disease and is seen most frequently in young children. Patients usually have a single hypopigmented macule with poorly defined borders, without erythema or induration. Anesthesia is minimal or absent, especially if the lesion is on the face. The diagnosis is Fig. 262.1 Tuberculous leprosy in a patient who has a single skin le sion with a raised border and flattened center. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. usually one of exclusion in the setting of a contact investigation. Tissue biopsies show diagnostic evidence of leprosy but do not meet sufficient criteria for classification. Up to 5075 of these lesions will heal spontaneously, and the rest will progress to an other form of leprosy. B. The WHO classification can be used when histologic evaluation and confirmatory diagnosis is unavailable, a common scenario in the field. This simplified scheme is based on the number of skin le sions: 1. Paucibacillary (1 5 patches) 2. Multibacillary (5 patches) CLINICAL MANIFESTATIONS The host immune response determines the clinical spectrum of lep rosy. Skin and serologic studies suggest that up to 90 of infected people develop immunity after exposure, without manifesting clini cal disease. In genetically susceptible individuals with sufficient expo sure to become infected, the cellular hosts immunologic response to infection and unique tropism for peripheral nerves determine the wide spectrum of clinical (and histologic) manifestations. Regard less of the disease subtype, HD affects the skin and peripheral nerves. Leprosy lesions usually do not itch or hurt. Polymorphisms in vita min D and its receptor have been proposed to play a role in the mani festations of leprosy. Skin Involvement The most common skin lesions are macules or plaques with unclear outer limits, |
7,456 | with or without neurologic symptoms. Diffuse infil trative lesions and subcutaneous nodules are less common. Initial lesions are insidious hypopigmented macules, although they may appear erythematous on pale skin. Lesions may involve any area of the body, are more pronounced in cooler areas (e.g., earlobes, nose), and occur less frequently in the scalp, axillae, or perineum. Approx imately 70 of skin lesions have reduced sensation; the degree of hypoesthesia depends on the location and size of the lesion and the degree of Th1 immune response. Examination of the skin should ideally be performed in natural sunlight and include testing for hypoesthesia to light touch, pinprick, temperature, and anhidrosis. Studies in endemic areas in children 15 years old have shown a predominance of paucibacillary forms, with a predominance of single lesions. Nerve Involvement Peripheral nerves are most frequently affected early in the disease and should be palpated for thickness and tenderness (Fig. 262.3), as well as evaluated for both motor and sensory function, particularly temperature and light touch. The posterior tibial nerve (medial malleolus) is the most common nerve affected, followed by the ulnar (elbow), median (wrist), lateral popliteal (fibular neck), and facial nerves. The skin lesions overlying a nerve trunk distribution predict the involvement of nerves in the vicinity. There is a pure neuritic form of leprosy, usually occurring in India and Nepal, in which patients present with asymmetric neuropathy but lack skin lesions. Other Organ Involvement Ocular involvement leading to vision loss results from both direct bacillary invasion of the eye and optic nerve damage. Lagophthalmos occurs when there is destruction of the facial nerve (cranial nerve VII), and trigeminal nerve (cranial nerve V) destruction causes anesthesia of the cornea and conjunctiva, leading to abrasions. Facial skin lesions are associated with a 10 fold higher risk of facial nerve damage. Systemic involvement of other organs is seen mainly in patients with leproma tous leprosy, where a high bacillary burden leads to infiltration of the nasal mucosa, bones, and testes. Renal involvement and amyloidosis are rare findings. Immunologic Reactions Leprosy reactions are acute clinical exacerbations reflecting distur bances of the immunologic balance to M. leprae infection and occur ring in 3050 of all leprosy patients. These sudden changes occur in patients with borderline and lepromatous leprosy, typically during the initial years after infection (sometimes as the initial presentation), but can occur before, during, or after completion of treatment. There are two main types of leprosy reactions, which require immediate treatment to prevent long term complications. In children 15 years old, leprosy reactions range from 1 to 30 and are mainly type 1 reactions. Type 1 reactions (also known as reversal reactions) occur in one third of patients with borderline disease. These reactions are characterized by acute edema and increased erythema, warmth, and painful inflammation of preexisting cutaneous plaques or nodules, with acute swelling and tenderness of peripheral nerves that can quickly progress to cause nerve abscesses and necrosis. There may be a peripheral lymphocytosis and an increased cytokine response, but |
7,457 | systemic symptoms are uncommon and appear to be associated with an increase in Th1 mediated reactivity to mycobacterial anti gens. Increased serum concentrations of CXCL10 have been found in type 1 reactions. Rapid and sustained reversal of the inflamma tory process using corticosteroids is essential to prevent continued nerve damage. Type 2 reactions, or erythema nodosum leprosum (ENL), occur in borderline lepromatous and lepromatous forms, as these patients have the highest levels of M. leprae antigens and antibodies, most often in the first 2 years after starting therapy. ENL is distinguished from reversal reactions by the development of new painful, ery thematous subcutaneous nodules with an accompanying systemic inflammatory response. ENL is accompanied by high circulating concentrations of TNF . Patients develop high fever and signs Chapter 262 u Hansen Disease (Mycobacterium leprae) 1857 Fig. 262.3 Thickened, superficial peroneal nerve of leprosy. Fig. 262.2 Borderline leprosy in a patient who has numerous hypo pigmented lesions with poorly defined borders. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1858 Part XV u Infectious Diseases of systemic toxicity, and in severe cases, ENL can be life threaten ing, presenting with features similar to septic shock. Deposition of extravascular immune complexes leads to neutrophil infiltra tion and activation of complement in the skin and other organs. Tender, erythematous dermal papules or nodules (resembling erythema nodosum) occur in clusters, typically on extensor sur faces of the lower extremities and face. Immune complex deposi tion also contributes to migrating polyarthralgias, painful swelling of lymph nodes and spleen, iridocyclitis, vasculitis, orchitis, and, rarely, nephritis. Patients may present with a single acute episode, a relapsing form comprising multiple acute episodes, or a chronic continuous form. Management of type 2 reactions is usually more complicated because of recurrence and systemic involvement. Lucio phenomenon (erythema necroticans) is an uncommon but potentially fatal reaction distinct from type 1 or 2 reactions and occurs in patients with untreated lepromatous leprosy and in patients whose ancestry is from Mexico. It is a necrotizing vasculitis caused by M. lep rae directly invading the endothelium. Clinically, patients develop vio laceous or hemorrhagic plaques, followed by ulcerations in the absence of systemic complaints. Secondary bacterial infections are common. DIAGNOSIS The diagnosis of HD requires high clinical suspicion and should be considered in any patient with a hypoesthetic or anesthetic skin lesion that does not respond to standard treatment, especially if there is a history of travel or residence in an endemic region or a his tory of contact with leprosy patients or armadillos. There are no reli able tests to diagnose subclinical leprosy. Full thickness skin biopsy and polymerase chain reaction (PCR) are the main laboratory tests to aid in the diagnosis. Patients are considered to have HD if they have one or more of the three cardinal signs: loss of sensation in a localized skin lesion (pale or |
7,458 | erythematous), thickened peripheral nerve with loss of sensation andor weakness of muscles enervated by that nerve, or the presence of AFB on biopsy. The positive predic tive value for the diagnosis of leprosy in patients meeting all three criteria is 98. To confirm the diagnosis and determine the extent of nerve involve ment and the type of infiltrate, a full thickness skin biopsy from the most active lesion should be performed. M. leprae is best identified in tissue using the Fite stain. Lesions from patients with the leproma tous form reveal numerous AFB in clumps (globi), whereas patients with the tuberculoid form rarely have mycobacteria identified, but the diagnosis can be made by demonstration of well formed noncaseating granulomas and nerve involvement. The presence of neural inflam mation differentiates leprosy from other granulomatous disorders. Mycobacterial culture of lesions should be performed to exclude M. tuberculosis and nontuberculous cutaneous infections. If no resources are available, slit skin (skin smear) biopsies represent an alternative. Slit skin smears have high specificity but low sensitivity; only 30 of adults and 1030 of children 15 years old are smear positive (usu ally patients with the lepromatous form). The bacterial index can range from 0 (no bacilli in 100 oil immersion fields), as generally seen in paucibacillary disease, to 6 (1,000 bacillifield), as can be seen in multibacillary disease. Diagnostic and histopathologic consultation in the United States is available through the National Hansens Disease Program (NHDP; http:www.hrsa.govhansens or 800 642 2477). Specimens (formalin or paraffin embedded) can be sent to the NHDP for pathologic analysis free of charge. A PCR test for M. leprae is not readily available in clini cal practice but may be performed at the NHDP. In nonendemic areas, PCR may be useful for diagnosis when AFB are discernible in tissue but clinical and histopathologic features are not typical. M. leprae DNA is detectable by PCR in 95 of lepromatous disease and 55 of tuber culoid lepra. PCR has also allowed detection of the organism in nasal secretions from asymptomatic people. Molecular testing for mutations causing drug resistance is also available through the NHDP and is usu ally used in the setting of relapse. Antibodies to M. leprae are present in 90 of patients with untreated lepromatous disease, 4050 of patients with paucibacillary disease, and 15 of healthy controls. However, serologic testing is insensitive and is not used for diagnosis. TREATMENT The primary goal of treatment is early antimicrobial therapy to prevent permanent neuropathy. Leprosy is curable. Effective treatment requires multidrug therapy (MDT) with dapsone, clofazimine, and rifampin. Combination therapy is employed to prevent antimicrobial resistance. In the United States, clinical providers considering a diagnosis and treatment of a patient with HD should obtain consultation from the NHDP. The recommended combination MDT can be obtained free of charge from the NHDP (Table 262.1) and in other countries through the WHO (Table 262.2). Compared with the WHO, the NHDP advo cates for a longer duration of treatment and daily rather than monthly administration of |
7,459 | rifampin because shorter antimicrobial regimens have been associated with a greater risk of relapse. The recommended duration by the WHO for tuberculoid disease is 6 months and for lep romatous disease is 12 months. Since 2018, the WHO has advocated for a three drug regimen for all leprosy forms; however, NHDP guide lines recommend two drugs (dapsone and rifampin) for the treatment of paucibacillary disease. Before starting combination MDT, patients should be tested for glucose 6 phosphate dehydrogenase deficiency, have a baseline Table 262.1 NHDP Recommended Multidrug Therapy Regimens for Hansen Disease in the United States TYPE OF LEPROSY PATIENT POPULATION ANTIMICROBIAL THERAPY DURATION OF THERAPY Multibacillary (LL, BL, BB) Adult Dapsone 100 mgday and rifampin 600 mgday and clofazimine 50 mgday 24 mo Pediatric Dapsone 1 mgkgday and rifampin 10 20 mgkgday and clofazimine 1 mgkgday Paucibacillary (TT, BT) Adult Dapsone 100 mgday and rifampin 600 mgday 12 mo Pediatric Dapsone 1 mgkgday and rifampin 10 20 mgkgday Rifampin is taken monthly if the patient is on prednisone. Daily pediatric mgkg dose should not exceed the adult daily maximum. Clofazimine is only available through NHDP Investigational New Drug (IND) program; minimum formulation is 50 mg, and capsules should not be cut. Alternative dosing includes clofazimine 2 mgkg every other day NHDP, National Hansens Disease Program; BB, borderline; BL, borderline lepromatous; BT, borderline tuberculoid; LL, lepromatous; TT, tuberculoid. NHDP multidrug therapy is daily and of longer duration than WHO recommended regimen. All drugs are administered orally. For immunologically compromised or elderly patients, these protocols may be modified. Consultation with the NHDP is advised. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 262 u Hansen Disease (Mycobacterium leprae) 1859 complete blood cell count and liver function testing, and be evalu ated for evidence of active tuberculosis, in which monotherapy with rifampin should be avoided. Response to therapy is seen clinically as flattening or disappearance of skin lesions and improvement in nerve function, usually within 1 2 months after initiating MDT. Complete resolution or improvement may take 6 12 months, depending on the severity of infection. Most skin lesions heal without scarring. Identifi cation of biomarkers for the optimal identification and management of leprosy continue to be under study. CXCL10 (IP 10) has been identi fied as a potential marker to help monitor treatment efficacy in patients with multibacillary disease, as higher levels of CXCL 10 are important for the control of bacillary load. Alternative agents to treat HD include minocycline, clarithromy cin, and some fluoroquinolones (levofloxacin, ofloxacin, moxifloxa cin). Given limited data, these alternative antimicrobials are used in selected cases of intolerance to the routine combination MDT regimen or for documented resistance. It is important to note that some patients who have been adequately treated for HD may later show evidence of chronic reversal reactions and late neuropathies, but these are bacillus negative and |
7,460 | thus should not be considered relapses. Neuritis must be treated promptly to minimize nerve injury and disability. Treatment with corticosteroids appears to improve nerve function in two thirds of patients. Bone marrow suppression and hepatotoxicity have been reported and should be monitored every 3 months during therapy. A screening urinalysis should be performed annually. Other reactions, such as met hemoglobinemia and hypersensitivity reactions to dapsone, are rare. An ophthalmologic evaluation should routinely be performed in all patients with HD because ocular complications can occur. Given the proclivity for testicular invasion in multibacillary leprosy with resul tant testicular dysfunction and infertility, males should be screened for elevated follicle stimulating hormone or luteinizing hormone concen trations and decreased testosterone levels. After completion of MDT, annual follow up for 5 years for pauci bacillary and 10 years for multibacillary disease is warranted. Relapse of the disease after completion of MDT is rare (0.011.4) and must be distinguished from the more common leprosy immunologic reactions. Patients who have a bacillary index of 4 pre MDT or 3 at the com pletion of MDT have the highest risk of relapse (approximately 20). When relapse occurs, it is usually within 5 10 years of MDT comple tion and a result of reactivation of drug susceptible mycobacteria. Thus patients who are expected to relapse are generally treated with the same MDT regimen. Resistance to all three drugs has been documented, although it rarely occurs with combination therapy. There is no role for routine baseline resistance testing, but the NHDP can provide it if needed. Leprosy Reactions Immunologic reactions can occur before, during, and years after treat ment and should be treated aggressively to prevent peripheral nerve damage. In general, antimycobacterial drugs should be continued. Fatigue, malaise, or fever can be present, and the inflammation associ ated with these reactions can cause severe nerve injury. Prompt therapy with corticosteroids with or without other antiinflammatory agents, adequate analgesia, and physical support are essential for patients with active neuritis to prevent nerve damage. If corticosteroids are indi cated for a prolonged time, the frequency of rifampicin administra tion should be decreased from daily to monthly administration (to avoid drug interactions). In 2020, to aid with the management of lep rosy reactions, the WHO published the technical guide: LeprosyHan sen Disease: Management of Reactions and Prevention of Disabilities. For severe type 1 reactions, prednisone is recommended, 1 mg kgday orally (40 60 mg) with a slow taper (decreasing by 5 mg every 2 4 weeks after evidence of improvement over 3 6 months) in addition to standard MDT. If there is evidence of peripheral nerve deteriora tion, higher doses and longer tapers may be needed. Nerve function improves after corticosteroid treatment in 3080 of patients who did not have preexisting neuritis. In patients not responding to corticoste roids, cyclosporine may be used as a second line agent. For severe type 2 reactions, prednisone is routinely used at 1 mg kgday for 12 weeks. However, given the recurrence and chronicity of ENL, |
7,461 | corticosteroid sparing agents should be considered to avoid complications associated with their prolonged use. Thalidomide (100 400 mgdaily for 48 72 hours, tapering over 2 weeks to 100 mgdaily) is effective in treating these types of reactions. Given the teratogenicity of thalidomide (contraindicated for children 12 years old and women of childbearing age), the drug is only available through a restrictive distribution program approved by the U.S. Food and Drug Adminis tration (FDA). Clofazimine (300 mgday for several months, tapering to 100 mgday, within a year) alone or in combination with cortico steroids, has also been useful in managing patients with chronic ENL and is generally used until all signs of the reaction have abated. Other immunosuppressive drugs have been used to treat type 2 reactions with inconsistent results, including cyclosporine, mycophenolate, and methotrexate. Lucio phenomenon is managed similarly to ENL and treatment of underlying infections. Table 262.2 WHO Recommended Multidrug Therapy (MDT) Regimens for Hansen Disease TYPE OF LEPROSY PATIENT POPULATION ANTIMICROBIAL THERAPY DURATION OF THERAPY Multibacillary (LL, BL, BB) Adult Rifampicin 600 mg once monthly and dapsone 100 mgday and clofazimine 300 mg once monthly and 50 mgday 12 mo Pediatric Rifampicin 450 mg once monthly and dapsone 50 mgday and clofazimine 150 mg once monthly and 50 mg every other day Paucibacillary (TT, BT) Adult Rifampicin 600 mg once monthly and dapsone 100 mgday and clofazimine 300 mg once monthly and 50 mgday 6 mo Pediatric Rifampicin 450 mg once monthly and dapsone 50 mgday and clofazimine 150 mg once monthly and 50 mg every other day In children 10 yr old, or than 40Kg, MDT dosages should be in mgkg, not to exceed the adult daily maximum: rifampicin 10 mgkg once monthly, dapsone 2 mgkgday, and clofazimine100 mg once a month, 50 mg twice weekly. WHO, World Health Organization; BB, borderline; BL, borderline lepromatous; BT, borderline tuberculoid; LL, lepromatous; TT, tuberculoid. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1860 Part XV u Infectious Diseases LONG TERM COMPLICATIONS Leprosy is a leading cause of permanent physical disability among com municable diseases worldwide. The major chronic complications and deformities of leprosy are caused by nerve injury. Nerve impairment may be purely sensory, motor, or autonomic or may be a combination. The prognosis for arresting progression of tissue and nerve damage is good if therapy is started early, but recovery of lost sensory and motor function is variable and frequently incomplete. Nerve function impair ment can occur before diagnosis, during MDT, or after MDT and can develop without overt signs of skin or nerve inflammation (silent neu ropathy). Patients at highest risk of nerve impairment are those with multibacillary leprosy and preexisting nerve damage. These patients should undergo regular monthly surveillance during therapy and for at least 2 years from the time of diagnosis. In children, deformities can occur in 310 of |
7,462 | cases and mainly in those with nerve enlargement. Other factors contributing to risk of deformities include increasing age in children, delay in accessing medical care, multiple skin lesions, mul tibacillary disease, smear positivity, multiple nerve involvement, and leprosy reaction at presentation. PREVENTION In addition to treating active leprosy cases, control measures for HD include the management of contacts of index patients. In endemic countries, close monitoring of household contacts of HD patients, particularly HD patients with multibacillary disease, is warranted to ensure that early treatment can be implemented if evidence of early HD develops. These household contacts should be examined at base line and then yearly for 5 years. In nonendemic areas, disease pre senting in the contacts of patients with HD is rare. A single dose of bacille Calmette Gurin (BCG) vaccine has variable protective efficacy against leprosy, ranging from 10 to 80; an additional dose results in increased protection. Any suspected or newly diagnosed case of lep rosy in the United States should be reported to local and state public health departments, the Centers for Disease Control and Prevention (CDC), and NHDP. There are no leprosy vaccines available or recom mended for use in the United States. In the hospital setting, standard precautions should be implemented. Hand hygiene is recommended for all people in contact with a patient with lepromatous leprosy. The use of chemoprophylaxis with a single dose of rifampin (SDR) within endemic areas is recommended by the WHO, but not the NHDP, for adults and children 2 years in contact with leprosy patients. Because leprosy is a highly stigmatized disease, caution must be exercised when implementing SDR in contacts, particularly for those outside the patients family. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Nontuberculous mycobacteria (NTM), also referred to as atypical mycobacteria and mycobacteria other than tuberculosis (MOTT), are all members of the genus Mycobacterium and include species other than Mycobacterium tuberculosis complex and Mycobacterium leprae. The NTM constitute a highly diverse group of bacteria that differ from M. tuberculosis complex bacteria in their pathogenicity, interhuman transmissibility, nutritional requirements, ability to produce pigments, Chapter 263 Nontuberculous Mycobacteria Ericka V. Hayes enzymatic activity, and drug susceptibility. In contrast to the M. tuber culosis complex, NTM are acquired from environmental sources and not by person to person spread, although the latter is under debate, especially in patients with cystic fibrosis (CF). Their omnipresence in the environment means that the clinical relevance of NTM isola tion from clinical specimens is sometimes unclear; a positive culture might reflect occasional presence or contamination rather than true NTM disease. NTM are associated with pediatric lymphadenitis, oto mastoiditis, serious lung infections, and, rarely, disseminated disease. Treatment is long term and cumbersome and often requires adjunc tive surgical intervention. Comprehensive guidelines on diagnosis and treatment are provided by the American Thoracic Society (ATS) and British Thoracic Society (BTS). ETIOLOGY NTM are ubiquitous in the environment all over the world, existing as saprophytes in soil and water (including municipal water supplies, tap water, hot tubs, |
7,463 | and shower heads), environmental niches that are the supposed sources of human infections. With the introduction of molecular identification tools such as 16S recombinant DNA gene sequencing, the number of identified NTM species has grown to more than 150; the clinical relevance (i.e., percentage of isolates that are caus ative agents of true NTM disease, rather than occasional contaminants) differs significantly by species. Mycobacterium avium complex (MAC; i.e., M. avium, Mycobacte rium intracellulare, and several closely related but rarer species) and Mycobacterium kansasii are most often isolated from clinical samples, yet the isolation frequency of these species differs significantly by geo graphic area. MAC bacteria have been frequently isolated from natural and synthetic environments, and cases of MAC disease have been suc cessfully linked to home exposure to shower and tap water. Although the designation M. avium suggests that human infections are acquired from birds (Latin avium), molecular typing has established that M. avium strains that cause pediatric lymphadenitis and adult pulmo nary disease represent the M. avium hominis suis subgrouping, mainly found in humans and pigs and not in birds. Some NTM have well defined ecologic niches that help explain infection patterns. The natural reservoir for Mycobacterium marinum is fish and other cold blooded animals, and the fish tank granuloma, a localized skin infection caused by M. marinum, follows skin injury in an aquatic environment. Mycobacterium fortuitum complex bacteria and Mycobacterium chelonae are ubiquitous in water and have caused clusters of nosocomial surgical wound and venous catheterrelated infections. Mycobacterium ulcerans is associated with severe, chronic skin infections (Buruli ulcer disease) and is endemic mainly in West Africa and Australia, although other foci exist. Its incidence is high est in children 15 years old. M. ulcerans had been detected in envi ronmental samples by polymerase chain reaction (PCR) and has been recovered by culture from a water strider (an insect of the Gerris genus) from Benin. EPIDEMIOLOGY Humans are exposed to NTM on a daily basis. In rural U.S. counties, where M. avium is common in swamps, the prevalence of asymp tomatic infections with M. avium complex, as measured by skin test sensitization, approaches 70 by adulthood. Still, the incidence and prevalence of the various NTM disease types remain largely unknown, especially for pediatric NTM disease. In Australian chil dren, the overall incidence of NTM infection is 0.84 per 100,000, with lymphadenitis accounting for two thirds of cases. The incidence of pediatric NTM disease in the Netherlands is estimated at 0.77 infections per 100,000 children per year, with lymphadenitis making up 92 of all infections. In comparison, estimations of the prevalence of NTM from respi ratory samples in adults are 5 15 per 100,000 persons per year, with important differences between countries or regions. Because pulmo nary NTM disease progresses slowly, over years rather than months, and usually takes several years to cure, the prevalence of pulmonary NTM disease is much higher than incidence rates would suggest. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by |
7,464 | Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 263 u Nontuberculous Mycobacteria 1861 The paradigm that NTM disease is a rare entity limited to resource rich countries is changing. In recent studies in African countries with a high prevalence of HIV infection, it has been found that NTM might play a much larger role as a cause of tuberculosis like disease of chil dren and adults than previously assumed and thus confuse the diagno sis of tuberculosis. Although it is generally believed that NTM infections are contracted from environmental sources, whole genome sequence analysis of Mycobacterium abscessus strains of patients in a CF clinic in the United Kingdom supports the possibility of nosocomial horizontal transmis sion among CF patients. PATHOGENESIS The histologic appearances of lesions caused by M. tuberculosis and NTM are often indistinguishable. The classic pathologic lesion consists of caseating granulomas. Compared with M. tuberculosis infections, NTM infections are more likely to result in granulomas that are non caseating, poorly defined (nonpalisading), irregular or serpiginous, or even absent, with only chronic inflammatory changes observed. The histology likely reflects the immune status of the patient. In patients with AIDS and disseminated NTM infection, the inflam matory reaction is usually scant, and tissues are filled with large numbers of histiocytes packed with acid fast bacilli (AFB). These dis seminated NTM infections typically occur only after the number of CD4 T lymphocytes has fallen below 50L in children 6 years, below 75L in children 2 to 6 years, below 500L in children 1 to 2 years, and below 750L in children 1 year, suggesting that specific T cell products or activities are required for immunity to mycobacteria. The pivotal roles of interferon (IFN) , interleukin (IL) 12, and tumor necrosis factor (TNF) in disease pathogenesis are demon strated by the high incidence of mostly disseminated NTM disease in children with IFN and IL 12 pathway deficiencies and in persons treated with agents that neutralize TNF . Observed differences in pathogenicity, clinical relevance, and spectrum of clinical disease associated with the various NTM spe cies emphasize the importance of bacterial factors in the pathogen esis of NTM disease, although exact virulence factors remain largely unknown. CLINICAL MANIFESTATIONS Lymphadenitis of the superior anterior cervical or submandibular lymph nodes is the most common manifestation of NTM infection in children (Table 263.1). Preauricular, posterior cervical, axillary, and inguinal nodes are involved occasionally. Lymphadenitis is most Table 263.1 Major Clinical Syndromes Associated with Nontuberculous Mycobacterial Infection SYNDROME MOST COMMON CAUSES LESS FREQUENT CAUSES Chronic nodular disease (adults with bronchiectasis; cystic fibrosis) MAC (M. intracellulare, M. avium), M. kansasii, M. abscessus M. xenopi, M. malmoense, M. szulgai, M. smegmatis, M. celatum, M. simiae, M. goodii, M. asiaticum, M. heckeshornense, M. branderi, M. lentiflavum, M. triplex, M. fortuitum, M. arupense, M. abscessus subsp. bolletii, M. phocaicum, M. aubagnense, M. florentinum, M. abscessus subsp. massiliense, M. nebraskense, M. saskatchewanense, M. seoulense, M. senuense, M. paraseoulense, M. |
7,465 | europaeum, M. sherrisii, M. kyorinense, M. noviomagense, M. mantenii, M. shinjukuense, M. koreense, M. heraklionense, M. parascrofulaceum, M. arosiense Cervical or other lymphadenitis (especially children) MAC M. scrofulaceum, M. malmoense (northern Europe), M. abscessus, M. fortuitum, M. lentiflavum, M. tusciae, M. palustre, M. interjectum, M. elephantis, M. heidelbergense, M. parmense, M. bohemicum, M. haemophilum, M. europaeum, M. florentinum, M. triplex, M. asiaticum, M. kansasii, M. heckeshornense Skin and soft tissue disease M. fortuitum group, M. chelonae, M. abscessus, M. marinum, M. ulcerans (Australia, tropical countries only) M. kansasii, M. haemophilum, M. porcinum, M. smegmatis, M. genavense, M. lacus, M. novocastrense, M. houstonense, M. goodii, M. immunogenum, M. mageritense, M. abscessus subsp. massiliense, M. arupense, M. monacense, M. bohemicum, M. branderi, M. shigaense, M. szulgai, M. asiaticum, M. xenopi, M. kumamotense, M. setense, M. montefiorense (eels), M. pseudoshottsii (fish), M. shottsii (fish) Skeletal (bone, joint, tendon) infection M. marinum, MAC, M. kansasii, M. fortuitum group, M. abscessus, M. chelonae M. haemophilum, M. scrofulaceum, M. heckeshornense, M. smegmatis, M. terraechromogenicum complex, M. wolinskyi, M. goodii, M. arupense, M. xenopi, M. triplex, M. lacus, M. arosiense Disseminated infection M. genavense, M. haemophilum, M. xenopi HIV seropositive host M. avium, M. kansasii M. marinum, M. simiae, M. intracellulare, M. scrofulaceum, M. fortuitum, M. conspicuum, M. celatum, M. lentiflavum, M. triplex, M. colombiense, M. sherrisii, M. heckeshornense HIV seronegative host M. abscessus, M. chelonae M. marinum, M. kansasii, M. haemophilum, M. chimaera, M. conspicuum, M. shottsii (fish), M. pseudoshottsii (fish) Catheter related infections M. fortuitum, M. abscessus, M. chelonae M. mucogenicum, M. immunogenum, M. mageritense, M. septicum, M. porcinum, M. bacteremicum, M. brumae Hypersensitivity pneumonitis (metal workers; hot tub users) M. immunogenum, M. avium The available information is sparse for selected pathogens such as M. xenopi, M. malmoense, M. szulgai, M. celatum, and M. asiaticum and the newly described species. HIV, Human immunodeficiency virus; MAC, Mycobacterium avium complex. From Brown Elliott BA, Wallace RJ Jr. Infections caused by nontuberculous mycobacteria other than Mycobacterium avium complex. In Bennett JF, Dolin R, Blaser MJ, eds. Mandell, Douglas, and Bennetts Principles and Practice of Infectious Diseases, 8th ed. Philadelphia: Elsevier; 2015: Table 254 1. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1862 Part XV u Infectious Diseases common in children 1 5 years of age and has been related to soil exposure (e.g., playing in sandboxes) and teething, although exact predisposing conditions have not been identified. Given the constant environmental exposure to NTM, the occurrence of these infections might also reflect an atypical immune response of a subset of the infected children during or after their first contact with NTM. How ever, in healthy children with isolated NTM lymphadenitis, immuno deficiency is quite rare. Affected children usually lack constitutional symptoms and present with a unilateral, subacute, and slowly enlarging lymph node or group of closely approximated nodes 1.5 cm in diameter |
7,466 | that are firm, pain less, freely movable, and not erythematous (Fig. 263.1). The involved nodes occasionally resolve without progression, but most undergo rapid suppuration after several weeks (Fig. 263.2). The center of the node becomes fluctuant, and the overlying skin thins and becomes erythematous and often even violaceous. Eventually, the nodes rupture and can form cutaneous sinus tracts that can drain persistently, remi niscent of scrofula from tuberculosis (Fig. 263.3). In the United States and Western Europe, MAC accounts for approx imately 80 of NTM lymphadenitis in children. M. kansasii accounts for most other cases of lymphadenitis in the United States. M. mal moense and M. haemophilum have also been described as causative agents of lymphadenitis. M. malmoense is most common in North western Europe. For M. haemophilum, underestimation of its impor tance is likely because the bacteria require specific culture conditions (hemin enriched media, low incubation temperatures). On the basis of PCR analysis of lymph node samples from lymphadenitis cases in The Netherlands, M. haemophilum is the second most common cause of this infection, after MAC. One study suggests that children with MAC lymphadenitis are significantly younger than those infected by M. hae mophilum, possibly related to age specific environmental exposures. Mycobacterium lentiflavum is also an emerging NTM associated with lymphadenitis. Cutaneous disease caused by NTM is rare in children (see Table 263.1). Infection usually follows percutaneous inoculation with fresh or salt water contaminated by M. marinum. Within 2 6 weeks after exposure, an erythematous papule develops at the site of minor abra sions on the elbows, knees, or feet (swimming pool granuloma) and on the hands and fingers of fish tank owners, mostly inflicted during tank cleaning (fish tank granuloma). These lesions are usually non tender and enlarge over 3 5 weeks to form violaceous plaques. Nodules or pustules can develop and occasionally will ulcerate, resulting in a serosanguineous discharge. The lesions sometimes resemble sporotri chosis, with satellite lesions near the site of entry, extending along the superficial lymphatics. Lymphadenopathy is usually absent. Although most infections remain localized to the skin, penetrating M. mari num infections can result in tenosynovitis, bursitis, osteomyelitis, or arthritis. M. ulcerans infection is the third most common mycobacterial infec tion in immunocompetent patients, after M. tuberculosis and M. leprae infection, and causes cutaneous disease in children living in tropical regions of Africa, South America, Asia, and parts of Australia. In some communities in West Africa, up to 16 of people have been affected. Children 15 years old are particularly affected in rural tropical coun ties, accounting for 48 of infected individuals in Africa. Infection fol lows percutaneous inoculation from minor trauma, such as pricks and cuts from plants or insect bites. After an incubation period of approxi mately 3 months, lesions appear as an erythematous nodule, usually on the legs or arms. The lesion undergoes central necrosis and ulceration. The lesion, often called a Buruli ulcer after the region in Uganda where a large case series was reported, has a characteristic undermined edge, |
7,467 | expands over several weeks, and can result in extensive, deep soft tis sue destruction or bone involvement (Fig. 263.4). Lesions are typically painless, and constitutional symptoms are unusual. Lesions might heal slowly over 6 9 months or might continue to spread, leading to defor mities, contractures, and disability. Depending on the location of the ulcer, these can be significantly disfiguring. Skin and soft tissue infections caused by rapidly growing myco bacteria, such as M. fortuitum, M. chelonae, or M. abscessus, are rare in children and usually follow percutaneous inoculation from puncture or surgical wounds, minor abrasions, or tattooing. There has been a large outbreak of M. fortuitum furunculosis related to nail salon footbaths. Clinical disease usually arises after a 4 to 6 week incubation period and manifests as localized cellulitis, painful nodules, or a draining abscess. M. haemophilum can cause painful subcutaneous nodules, which often ulcerate and suppu rate in immunocompromised patients, particularly after kidney transplantation. Fig. 263.1 Enlarging cervical lymph node infected with Mycobacte rium avium complex infection. The node is firm, painless, freely mov able, and not erythematous. Fig. 263.2 Suppurating cervical lymph node infected with Mycobac terium avium complex. Fig. 263.3 Ruptured cervical lymph node infected with Mycobacteri um avium complex, which resembles the classic scrofula of tuberculosis. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 263 u Nontuberculous Mycobacteria 1863 NTM are an uncommon cause of catheter associated infections but are becoming increasingly recognized in this respect. Infections caused by M. fortuitum, M. chelonae, or M. abscessus can manifest as bactere mia or localized catheter tunnel infections. Otomastoiditis, or chronic otitis media, is a rare extrapulmonary NTM disease type that specifically affects children with tympanostomy tubes and a history of topical antibiotic or steroid use. M. abscessus is the most common causative agent, followed by MAC (see Table 263.1). Patients present with painless, chronic otorrhea resistant to antibiotic therapy. CT can reveal destruction of the mastoid bone with mucosal swelling (Fig. 263.5). Delayed or unsuccessful treatment can result in permanent hearing loss. In unusual circumstances, NTM cause other bone and joint infections that are indistinguishable from those pro duced by M. tuberculosis or other bacterial agents. Such infec tions usually result from operative incision or accidental puncture wounds. M. fortuitum infections from puncture wounds of the foot resemble infections caused by Pseudomonas aeruginosa and Staphylococcus aureus. Pulmonary infections are the most common form of NTM illness in adults but are rare in children. MAC bacteria, the most commonly identified organisms (see Table 263.1), are capable of causing acute pneumonitis, chronic cough, or wheezing associated with paratracheal or peribronchial lymphadenitis and airway compression in normal children. Associated constitutional symptoms such as fever, anorexia, and weight loss occur in 60 of these children. Chest radiographic findings are similar to those for primary tuberculosis, with unilateral infiltrates and hilar lymphadenopathy (Fig. 263.6). |
7,468 | Pleural effusion is A B C D Fig. 263.4 Buruli ulcer lesions in patients from West Africa (A and B) and Japan (C and D). (A, B from Rltgen K, Pluschke G. Buruli ulcer: history and disease burden. In: Pluschke G, Rltgen K, eds. Buruli Ulcer. Cham: Springer; 2019; C, D courtesy Dr Mikio Ohtsuka, Fukushima Medical University.) Fig. 263.5 CT images of the middle ear of 6 yr old child infected with My cobacterium abscessus, demonstrating extensive bone destruction in the right mastoid and associated right sided mucosal swelling. A, Bone tissue win dow setting. B, Soft tissue window set ting. A B Fig. 263.6 Chest radiograph of 2 yr old child infected with Mycobac terium avium complex, demonstrating a left upper lobe infiltrate and left hilar lymphadenopathy. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1864 Part XV u Infectious Diseases Table 263.2 American Thoracic Society Clinical and Microbiologic Criteria for Diagnosis of Nontuberculous Mycobacteria (NTM) Pulmonary Disease CLINICAL PULMONARY OR SYSTEMIC SYMPTOMS Radiologic Nodular or cavitary opacities on chest radiograph or a high resolution computed tomography (HRCT) scan that shows bronchiectasis with multiple small nodules AND Appropriate exclusion of other diagnoses Microbiologic 1. Positive culture results from at least two separate expectorated sputum samples. If the results are nondiagnostic, consider repeat sputum AFB smears and cultures. or 2. Positive culture results from at least one bronchial wash or lavage. or 3. Transbronchial or other lung biopsy with mycobacterial histologic features (granulomatous inflammation or AFB) and positive culture for NTM or biopsy showing mycobacterial histologic features (granulomatous inflammation or AFB) and one or more sputum or bronchial washings that are culturepositive for NTM. Note: Both clinical and radiologic criteria are required. AFB, Acid fast bacilli. From Daley CL, Iaccarino JM, Lange C, et al. Treatment of nontuberculous mycobacterial pulmonary disease: an official ATSERSESCMIDIDSA Clinical Practice Guideline published correction appears in Clin Infect Dis. 2020 Dec 31;71(11):3023. Clin Infect Dis. 2020;71(4):e1e36. uncommon. Rare cases of progression to endobronchial granulation tissue have been reported. Pulmonary infections usually occur in adults with underlying chronic lung disease. The onset is insidious and consists of cough and fatigue, progressing to weight loss, night sweats, low grade fever, and generalized malaise in severe cases. Thin walled cavities with mini mal surrounding parenchymal infiltrates are characteristic, but radio graphic findings can resemble those of tuberculosis. A separate disease manifestation occurs typically in postmenopausal women and is radio logically characterized by bronchiectasis and nodular lesions, often affecting the middle lobe and lingula (Lady Windemeres syndrome). Chronic pulmonary infections specifically affect children with CF and are generally caused by M. abscessus or MAC. M. abscessus pri marily affects children, and MAC is most common among adults. The percentage of CF patients with at least one sputum culture positive for NTM is 68.1 overall and increases with age; in CF patients 12 |
7,469 | years old, a prevalence of 3.9 has been reported. The strong representa tion of M. abscessus in these patients is remarkable, because this bac terium is an uncommon isolate in other categories of patients. There are indications that NTM infections in CF patients further accelerate the decline in lung function; antimycobacterial therapy can result in weight gain and improved lung function in affected patients. Disseminated disease is usually associated with MAC infection and occurs in immunocompromised children. The first category of patients with disseminated disease includes persons with mutations in genes coding for the interferon receptor (IFNGR) or the IL 12 receptor or for IL 12 production. Patients with complete IFNGR deficiency have severe, difficult to treat disease. Those with partial IFNGR deficiency or IL 12 pathway mutations have milder disease that can respond to IFN and antimycobacterial therapy. Multifocal osteomyelitis is particularly prevalent in persons with the IFNGR1 818del4 mutation. Recurrences, even years after a course of treatment, and multiple infec tions are well documented. The second category of patients affected by disseminated disease is patients with AIDS. Disseminated NTM disease in patients with AIDS usually appears when CD4 cell counts are 50L for children 6 years , 75L in children 2 to 6 years, 500L in children 1 to 2 years, and 750L in children 1 year. The most recent estimate of the incidence of disseminated NTM dis ease is 0.14 0.2 episodes per 100 person years, a 10 fold decrease from its incidence before combination antiretroviral therapy (cART) was available. Colonization of the respiratory or gastrointestinal (GI) tract prob ably precedes disseminated MAC infections, but screening studies of respiratory secretions or stool samples are not useful to predict dissem ination. Continuous high grade bacteremia is common, and multiple organs are infected, typically including the lymph nodes, liver, spleen, bone marrow, and GI tract. The thyroid, pancreas, adrenal gland, kid ney, muscle, and brain can also be involved. The most common signs and symptoms of disseminated MAC infections in patients with AIDS are fever, night sweats, chills, anorexia, marked weight loss, wasting, weakness, generalized lymphadenopathy, and hepatosplenomegaly. Jaundice, elevated alkaline phosphatase or lactate dehydrogenase lev els, anemia, and neutropenia can occur. Imaging studies usually dem onstrate massive lymphadenopathy of hilar, mediastinal, mesenteric, or retroperitoneal nodes. Successful treatment of disseminated infection in children with AIDS requires immune reconstitution and cART in addition to specific NTM therapy. The survival in children with AIDS has improved considerably with the availability of cART. Disseminated disease in children without any apparent immunode ficiency is exceedingly rare. DIAGNOSIS For infections of lymph nodes, skin, bone, and soft tissues, isolation of the causative NTM bacteria by Mycobacterium culture, preferably with histologic confirmation of granulomatous inflammation, normally suffices for diagnosis. The differential diagnosis of NTM lymphad enitis includes acute bacterial lymphadenitis, tuberculosis, cat scratch disease (Bartonella henselae infection), mononucleosis, toxoplasmo sis, brucellosis, tularemia, and malignancies, especially lymphomas. Differentiation between NTM and M. tuberculosis may be difficult, but children with NTM lymphadenitis usually have a Mantoux tubercu |
7,470 | lin skin test reaction of 15 mm induration, unilateral anterior cervi cal node involvement, a normal chest radiograph, and no history of exposure to tuberculosis. Definitive diagnosis requires excision of the involved nodes for culture and histology. Fine needle aspiration for PCR and culture can enable earlier diagnosis, before excisional biopsy. The diagnosis of pulmonary NTM infection in children is difficult because many species of NTM, including MAC, are omnipresent in our environment and can contaminate clinical samples or be present but not causative of disease. As a result, isolation of these bacteria from nonsterile specimens (respiratory and digestive tract) does not neces sarily reflect true disease. To determine the clinical relevance of isola tion of NTM, the ATSBTS diagnostic criteria are an important support (Table 263.2). These criteria take into consideration clinical features and radiologic, pathologic, and microbiologic findings. Their hallmark is the need for multiple positive cultures yielding the same NTM spe cies to make a definitive diagnosis of pulmonary NTM disease, though a single culture from bronchoalveolar lavage (BAL)bronchial lavage is acceptable in patients who meet clinical and radiologic criteria. In chil dren, definitive diagnosis often requires invasive procedures such as bronchoscopy and pulmonary or endobronchial biopsy; in CF patients, more aggressive sample pretreatment in the clinical microbiology labo ratory is necessary to prevent overgrowth by other species, especially Pseudomonas. The chance of NTM isolation being clinically relevant differs significantly by species; some species are more likely causative agents of true pulmonary disease (M. avium, M. kansasii, M. abscessus, M. malmoense), whereas others are more likely contaminants (M. gor donae, M. fortuitum, M. chelonae). Blood cultures are 9095 sensitive in AIDS patients with dissemi nated infection. MAC may be detected within 7 10 days of inocula tion in almost all patients by automated blood culture systems. In adults, some studies have shown that liver biopsy cultures and stains are more sensitive than blood culture or bone marrow biopsy workup. Commercially available DNA probes differentiate NTM from M. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 263 u Nontuberculous Mycobacteria 1865 tuberculosis. If DNA probes cannot identify the causative mycobacte ria, DNA sequencing of bacterial housekeeping genes can yield a clue to the identity of these NTM. Identification of histiocytes containing numerous AFB from bone marrow and other biopsy tissues provides a rapid presumptive diagnosis of disseminated mycobacterial infection. TREATMENT Therapy for NTM infections is long term and cumbersome; expert consultation is advised. Therapy involves medical, surgical, or often combined treatment (see Chapter 260, Table 260.3). Isolation of the infecting strain followed by drug susceptibility testing is ideal, because it provides a baseline for drug susceptibility. Important discrepancies exist between in vitro drug susceptibility and in vivo response to treat ment, explained in part by synergism, mainly among first line antitu berculosis drugs. In vitro, slow growers (M. kansasii, M. marinum, |
7,471 | M. xenopi, M. ulcerans, M. malmoense) are usually susceptible to the first line antituberculosis drugs rifampin and ethambutol; MAC bacteria are often resistant to these drugs alone but susceptible to the combina tion and have variable susceptibility to other antibiotics, most impor tantly the macrolides. Rapid growers (M. fortuitum, M. chelonae, M. abscessus) are highly resistant to antituberculosis drugs and often have inducible macrolide resistance mechanisms. Susceptibility to macro lides, aminoglycosides, carbapenems, tetracyclines, and glycylcyclines are most relevant for therapy guidance. In all NTM infections, multi drug therapy (MDT) is essential to avoid development of resistance. The preferred treatment of NTM lymphadenitis is complete sur gical excision. Clinical trials revealed that surgery is more effective than antibiotic treatment (see Table 260.3). Nodes should be removed while still firm and encapsulated. Excision is more difficult if extensive caseation with extension to surrounding tissue has occurred, and com plications of facial nerve damage or relapse of infection are more likely in such cases. Incomplete surgical excision is not advised, because chronic drainage can develop. If there are concerns or risk factors for possible M. tuberculosis infection, therapy with isoniazid, rifampin, ethambutol, and pyrazinamide should be administered until cultures confirm the cause to be NTM (see Chapter 261). If surgery of NTM lymphadenitis cannot be performed, or removal of infected tissue is incomplete, or recurrence or chronic drainage develops, a 3 month trial of antibiotic therapy should be considered. Clarithromycin or azithromycin combined with rifampin or ethambutol are the most common therapy regimens reported for MAC lymphadenitis (see Table 260.3). Suppuration may still occur on appropriate antibiotic therapy. In immunocompetent patients, an observational approach to NTM lymphadenitis can be chosen without antibiotic therapy, although resolution will take up to 12 months. Posttraumatic cutaneous NTM lesions in immunocompetent patients usually heal spontaneously after incision and drainage without other therapy. M. marinum is susceptible to rifampin, amikacin, etham butol, sulfonamides, trimethoprim sulfamethoxazole, and tetracycline. Therapy with a combination of these drugs, particularly clarithromy cin and ethambutol, may be given until 1 month after the lesion has disappeared. Corticosteroid injections should not be used. Superficial infections with M. fortuitum or M. chelonae usually resolve after sur gical incision and open drainage, but deep seated or catheter related infections require removal of infected central lines and therapy with parenteral amikacin plus cefoxitin, ciprofloxacin, or clarithromycin. Some localized forms of M. ulcerans skin disease (Buruli ulcer) can heal spontaneously; for most forms, excisional surgery with pri mary closure or skin grafting is recommended. The combination of rifampin (10 mgkg once daily) and clarithromycin (7.5 mgkg twice daily) for 8 weeks results in excellent outcomes and is now the rec ommended treatment for early limited Buruli ulcer. Another agent that shows great promise is telacebec (also known as Q203), a novel first in class antituberculosis drug targeting cellular energy production through inhibition of the mycobacterial cytochrome bc1 complex; ani mal studies have demonstrated significant potency against M. ulcerans, possibly allowing for shorter courses of treatment. In January 2021, the |
7,472 | U.S. Food and Drug Administration granted orphan drug designation (ODD) to telacebec for Buruli ulcer treatment. Physiotherapy after surgery is essential to prevent contractures and functional disabilities. For patients who meet diagnostic criteria for pulmonary NTM infections (see Table 263.2), treatment rather than observation is rec ommended, particularly with persistently positive sputum smears andor cavitary lung disease. Although treatment offers possibility of cure, there can be significant adverse effects of treatment and low cure rates for some forms of infection. Patients who require treatment for NTM pulmonary disease should have isolates sent for susceptibility testing, with the caveat that this testing is helpful for NTM for anti biotics where there is a well documented correlation between in vitro activity and microbiologic response to therapy. Drugs for which this correlation exist include macrolides (azithromycin, clarithromycin) and amikacin for MAC and M. abscessus and rifampin for M. kansasii. For macrolide susceptible MAC pulmonary disease, treatment with three drugs for at least 12 months after culture conversion is rec ommended, generally azithromycin, rifampin, and ethambutol. For macrolide resistant isolates, parenteral amikacin is often used, as MAC isolates are usually susceptible in vitro to this agent. Macrolides are a mainstay in the treatment of M. abscessus pulmo nary disease. However, macrolide resistance can develop via chro mosomal mutation or through induction of the erm(41) gene. For M. abscessus disease caused by strains without inducible or chro mosomal macrolide resistance, a macrolide containing treatment regimen is recommended, typically with at least three active drugs. If macrolide resistance (chromosomal or inducible) is present, at least four active drugs are recommended. Treatment regimens for M. abscessus are complex, usually with oral plus parental drugs. Regimens typically include two to three oral agents, which may include azithromycin, clofazimine, or linezolid, and at least one parenteral agent, with options including amikacin, imipenem, and tigecycline. In CF patients, inhaled agents may also have a role. Choice of treatment regimens and duration of therapy should be guided by expert consultation. For select patients, surgical resec tion of severely diseased lung in addition to medical therapy may be indicated. For M. kansasii pulmonary disease, susceptibility based treatment for rifampin is recommended over empirical therapy. The recom mended treatment regimen for rifampin susceptible M. kansasii infec tions is rifampin, ethambutol, and either isoniazid or a macrolide for at least 12 months. Fluoroquinolones also have good activity against M. kanasasii but are reserved for rifampin resistant M. kansasii infection treatment and for patients who have intolerance to one of the first line antibiotics. Patients with disseminated MAC and IL 12 pathway defects or IFNGR deficiency should be treated for at least 12 months with clar ithromycin or azithromycin combined with rifampin or rifabutin and ethambutol. In vitro susceptibility testing for macrolides is impor tant to guide therapy. Once the clinical illness has resolved, lifelong daily prophylaxis with azithromycin or clarithromycin is advisable to prevent recurrent disease. The use of IFN adjunctive therapy is deter mined by the specific genetic defect. In children with AIDS, |
7,473 | prophylaxis with azithromycin or clarithro mycin is indicated to prevent infection with MAC. Although few pedi atric studies exist, the U.S. Public Health Service recommends either azithromycin (20 mgkg once weekly PO, maximum 1,200 mgdose or 5 mgkg once daily PO, maximum 250 mgdose in patients intolerant of the larger dose) or clarithromycin (7.5 mgkgdose twice daily PO; maximum 500 mgdose) for HIV infected children with significant immune deficiency, as defined by the CD4 count (children 6 years old, CD4 count 50 cellsL; 2 to 6 years old, 75L; 1 to 2 years old, 500L; 1 year old, 750L). Rifabutin may also be used. Pri mary prophylaxis may be safely discontinued in children 2 years old receiving stable highly active antiretroviral therapy (HAART) for 6 months and experiencing sustained (3 months) CD4 cell recovery well above the age specific target for initiation of prophylaxis: 100 cellsL for children 6 years old and 200L for children 2 5 years old. For children 2 years old, no specific recommendations for dis continuing MAC prophylaxis exist. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1866 Part XV u Infectious Diseases Syphilis is a chronic systemic sexually or vertically (mother to child) transmitted infection that can be easily treated if detected early but manifests with protean clinical symptoms and significant morbidity if left unchecked. (Please note that the terms mother and maternal are used to designate the birthing parent throughout this chapter and are not intended to exclude other birthing parents.) ETIOLOGY Syphilis is caused by Treponema pallidum, a delicate, tightly spiraled, motile spirochete with finely tapered ends belonging to the family Spi rochaetaceae. The pathogenic members of this genus include T. pallidum subspecies pallidum (venereal syphilis), T. pallidum subspecies pertenue (yaws), T. pallidum subspecies endemicum (bejel or endemic syphilis), and T. pallidum subspecies carateum (pinta). Because these microor ganisms stain poorly and are below the detection limits of conventional light microscopy, detection in clinical specimens requires dark field, phase contrast microscopy or direct immunofluorescent or silver stain ing. T. pallidum has only recently been successfully grown in vitro via coculture with mammalian tissue culture cells, and a method has now been described for inoculation of fresh and frozen needle aspirates from primary experimental syphilis lesions onto culture plates but remains to be developed for clinical use. Use of nucleic acid amplification testing by polymerase chain reaction (PCR) may have a role in diagnosis, particu larly in seronegative patients or those with discrepant serology results. EPIDEMIOLOGY Acquired syphilis is transmitted almost exclusively by sexual contact, including vaginal, anal, and oral exposure. Less common modes of trans mission include transfusion of contaminated blood or direct contact with infected tissues. Syphilis in men who have sex with men (MSM) may be acquired in the absence of visible lesions. DNA based T. pallidum testing |
7,474 | has identified organisms in oral rinse or swab samples and in anal canal swabs, urine, semen, and peripheral blood; the risk is highest in secondary and early latent syphilis. The incubation period for acquired primary syphilis is about 3 weeks (range 10 90 days). After an epidemic resurgence of primary and secondary syphilis in the United States that peaked in 1989, the annual rate declined 90 to the lowest ever rate by 2000. The total number of cases of primary and secondary syphilis has subsequently rebounded since 2000 (Fig. 264.1). MSM have been dis proportionately impacted: 46 of cases in 2021. Rates of primary and secondary syphilis in women remain lower than in men yet still have increased 55 during 2021. Cases of congenital syphilis reached an his toric low in 2005 but have subsequently increased annually since 2013, reflecting the rates among women. In 2021, the US national congenital syphilis rate was 77.9 cases per 100,000 live births, representing a 30.5 increase from 2020 and a 219.3 increase from 2017 (Fig. 264.2); syphi litic still births also increased over this period. The increase occurs across every region and all races and ethnicities, but marked disparities exist, with minority groups, gay and bisexual men, and youth most affected. The COVID 19 pandemic disrupted screening programs and access to care, and increased cases are expected. Congenital syphilis results from transplacental transmission of spiro chetes or occasionally by intrapartum contact with infectious lesions or possibly involved mucosa without obvious lesions. Women with primary and secondary syphilis and spirochetemia are more likely to transmit infection to the fetus than are women with latent infection. Transmis sion can occur at any stage of pregnancy, resulting in early fetal loss, pre term or low birthweight infants, stillbirths, neonatal deaths, or infants born with congenital disease. The incidence of congenital infection in offspring of untreated or inadequately treated infected women remains highest during the first 4 years after acquisition of primary infection, secondary infection, and early latent disease. Maternal (parental) factors associated with congenital syphilis include limited access to healthcare, late or no prenatal care, drug use, multiple sex partners, unprotected sex ual contact, incarceration, work in the sex trade, and inadequate treat ment of syphilis during pregnancy. Congenital syphilis may be seen in the context of untreated, inadequately treated, or undocumented treat ment before or during pregnancy. In addition, the mother may have been treated appropriately but did not have an adequate serologic response to therapy and the infant was inadequately evaluated, or the infant had documented congenital syphilis. Confirmed cases of both acquired and congenital syphilis must be reported to the local health department. CLINICAL MANIFESTATIONS AND LABORATORY FINDINGS Many persons infected with syphilis are asymptomatic for years, or do not recognize the early signs of disease, or do not seek or have access C as es 60,000 45,000 30,000 15,000 0 2017 2018 2019 Year 2020 2021 MSM Women MSW MSU Fig 264.1 Primary and secondary syphilis Reported cases by sex and sex |
7,475 | of sex partners 20172021. Note: Over the 5 yr period, 0.2 of cases were missing sex and were not included. MSM, Gay, bisexual, and other men who have sex with men; MSU, Men with unknown sex of sex partners; MSW, men who have sex with women only. (From Centers for Disease Control and Prevention. Sexually transmitted disease surveil lance. National overview of STDs, 2021. https:www.cdc.govstdstat istics2021overview.htm) 3,000 2,400 1,800 1,200 600 0 2012 2015 2018 Year 2021 CS Cases PS Syphilis rate 18 15 12 9 6 3 0 CS cases Female (1544 years) PS syphilis rate Fig. 264.2 Congenital syphilis Reported cases by year of birth and rates of reported cases of primary and secondary syphilis among women age 15 44 years, United States, 20122021. Per 100,000. CS, Congenital syphilis; PS syphilis, Primary and secondary syphilis. (From Centers for Disease Control and Prevention. Sexually transmitted dis ease surveillance. National overview of STDs, 2021. https:www.cdc.g ovstdstatistics2021overview.htm) Chapter 264 Syphilis (Treponema pallidum) Alice I. Sato and H. Dele Davies Section 8 Spirochetal Infections Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 264 u Syphilis (Treponema pallidum) 1867 to treatment. The Centers for Disease Control and Prevention (CDC) recommends testing all pregnant persons and selective testing of adolescents, based on lesions or risk factors (those with other sexu ally transmitted diseases including HIV, MSM, incarcerated individu als, or persons who exchange sex for money or drugs). CDCMMWR sexually transmitted infection (STI) guidelines should be consulted to ensure that all appropriate screening is performed. All 50 states and the District of Columbia explicitly allow minors to consent for STI services, though as of 2022, 18 states allow (but do not require) physi cians to notify parents of STI services provided to a minor (https: www.cdc.govhivpolicieslawstatesminors.html). Periods of active clinical disease alternate with periods of latency (Fig. 264.3). Primary syphilis is characterized by a chancre and regional lymphadenitis. A painless papule (which may be overlooked) appears at the site of entry (usually the genitalia) 2 6 weeks after inoculation and develops into a clean, painless but highly contagious ulcer with raised borders (chan cre) containing abundant T. pallidum. Extragenital chancres can occur at other sites of primary entry and pose a diagnostic challenge. Oral lesions can be mistaken for aphthous ulcers or herpes. Lesions on the nipple can be confused with cellulitis or eczema. Adjacent lymph nodes are generally enlarged and nontender. The chancre heals spontaneously within 4 6 weeks, leaving a thin scar. Untreated patients develop manifestations of secondary syphilis related to spirochetemia 2 10 weeks after the chancre heals. Manifes tations of secondary syphilis include a generalized nonpruritic macu lopapular rash, notably involving the palms and soles (Fig. 264.4). Pustular lesions can also develop. Condylomata lata, gray white to erythematous wartlike plaques, can occur in moist areas around the anus, scrotum, or vagina, and white |
7,476 | plaques (mucous patches) may be found in mucous membranes. Secondary syphilis should be con sidered in the differential diagnosis of virtually any rash of unknown etiology. A flulike illness with low grade fever, headache, malaise, anorexia, weight loss, sore throat, myalgias, arthralgias, and general ized lymphadenopathy is often present. Renal, hepatic, or ocular mani festations may be present. Meningitis occurs in about 30 of patients with untreated syphilis, occurring at any stage but most commonly in Exposure Incubation (1090 days; mean 21) Primary syphilis (chancre formation) lasts 26 weeks Early latent syphilis (asymptomatic) (1 year or less postinfection) Late latent syphilis (asymptomatic) (1 yr or unknown duration postinfection) Tertiary syphilis Incubation (48 weeks after appearance of chancre) Secondary syphilis Infectious via sexual or mothertochild transmission (1 year) Infectious via mothertochild transmission (5 years) Noninfectious Recurrence 2030 Central nervous system invasion 2560 80 clearance Cardiovascular syphilis 10 (Onset 10 years postinfection) Gummatous disease 15 (Onset 5 years postinfection) Tertiary syphilis Late neurosyphilis General paresis 25 (Onset 15 years postinfection) Tabes dorsalis 29 (Onset 15 years postinfection) Early neurosyphilis Asymptomatic Symptomatic 5 Acutesubacute aseptic meningitis Cranial neuritis Ocular involvement Meningovascular disease (stroke) Fig. 264.3 Natural course of untreated syphilis. As of January 2018, the Centers for Disease Control and Prevention renamed early and late latent syphilis early syphilis, nonprimary, nonsecondary and syphilis, unknown duration or late, respectively. HIV infection may modify the progression of syphilis; the chancre may coexist with the secondary syphilis stage, suggesting a more rapid progression to the secondary stage. (Modified from Radolf JD, Tramont EC, Salazar JC. Syphilis Treponema pallidum. In: Bennett JE, Dolin R, Blaser MJ, eds. Mandell, Douglas, and Bennetts Principles and Practice of Infectious Diseases, 9th ed. Philadelphia: Elsevier; 2020: Fig. 237.5, p. 2874.) Fig. 264.4 Secondary syphilis. Ham colored palmar macules on an adolescent with secondary syphilis. (From Weston WL, Lane AT, Morelli J. Color Textbook of Pediatric Dermatology, 3rd ed. St. Louis: Mosby; 2002.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1868 Part XV u Infectious Diseases secondary syphilis (see Fig. 264.3). It is characterized by cerebrospinal fluid (CSF) pleocytosis and elevated protein level. Patients with men ingitis might not show neurologic symptoms. Even without treatment, secondary infection becomes latent within 1 2 months after onset of rash. Relapses with secondary manifestations can occur during the first year of latency (the early latent period). Late syphilis follows and may be either asymptomatic (late latent) or symptomatic (tertiary). Tertiary disease follows in about one third of untreated cases and is marked by neurologic, cardiovascular, and gummatous lesions (non suppurative granulomas of the skin, bone, and liver resulting from the host cytotoxic T cell response). In the preantibiotic era, neurologic manifestations of tertiary syphilis (tabes dorsalis and paresis) were common. The clinical course of syphilis and its tissue manifestations reflect the immunopathobiology of the host humoral and delayed |
7,477 | type hypersensitivity responses. A robust timeline of progression through the overlapping stages occurs in immunocompromised HIV patients Congenital Infection Untreated syphilis during pregnancy results in a vertical transmission rate approaching 100, with profound effects on pregnancy outcome, reflecting obliterating endarteritis. Fetal or perinatal death occurs in 40 of affected infants. Premature delivery can also occur. Neonates can also be infected at delivery by contact with an active genital lesion. Most infected infants are asymptomatic at birth, including up to 40 with CSF seeding, and are identified only by routine prenatal screen ing. In the absence of treatment, symptoms develop within weeks or months. Among infants symptomatic at birth or in the first few months of life, manifestations have traditionally been divided into early and late stages. All stages of congenital syphilis are characterized by a vas culitis, with progression to necrosis and fibrosis. The early signs appear during the first 2 years of life, and the late signs appear gradually dur ing the first 2 decades. Early manifestations vary and involve multiple organ systems, resulting from transplacental spirochetemia, and are analogous to the secondary stage of acquired syphilis. Hepatospleno megaly, jaundice, and elevated liver enzymes are common. Histologi cally, liver involvement includes bile stasis, fibrosis, and extramedullary hematopoiesis. Lymphadenopathy tends to be diffuse and resolve spontaneously, although shotty nodes can persist. Coombs negative hemolytic anemia is characteristic. Thrombocyto penia is often associated with platelet trapping in an enlarged spleen. Characteristic osteochondritis and periostitis (Fig. 264.5) and a mucocutaneous rash (Fig. 264.6A and B) manifesting with erythema tous maculopapular or vesiculobullous lesions followed by desqua mation involving the hands and feet (see Fig. 264.6C) are common. Mucous patches, persistent rhinitis (snuffles), and condylomatous lesions (Fig. 264.7) are highly characteristic features of mucous mem brane involvement containing abundant spirochetes. Blood and moist, open lesions from infants with congenital syphilis and children with acquired primary or secondary syphilis are infectious until 24 hours of appropriate treatment. Bone involvement is common. Roentgenographic abnormalities include Wimberger lines (demineralization of the medial proxi mal tibial metaphysis); multiple sites of osteochondritis at the wrists, elbows, ankles, and knees; and periostitis of the long bones and, rarely, the skull. The osteochondritis is painful, often resulting in irritabil ity and refusal to move the involved extremity (pseudoparalysis of Parrot). Congenital neurosyphilis is often asymptomatic in the neona tal period, although CSF abnormalities can occur even in asymp tomatic infants. Failure to thrive, chorioretinitis, nephritis, and nephrotic syndrome can also be seen. Manifestations of renal involvement include hypertension, hematuria, proteinuria, hypo proteinemia, hypercholesterolemia, and hypocomplementemia, probably related to glomerular deposition of circulating immune complexes. Less common clinical manifestations of early congenital syphilis include gastroenteritis, peritonitis, pancreatitis, pneumo nia, eye involvement (glaucoma and chorioretinitis), nonimmune hydrops, and testicular masses. Late manifestations (children 2 years of age) are rarely seen in developed countries. These result primarily from chronic granuloma tous inflammation of bone, teeth, and the central nervous system and are summarized in Table 264.1. Skeletal changes are caused by persis tent |
7,478 | or recurrent periostitis and associated thickening of the involved Fig. 264.5 Osteochondritis and periostitis in a newborn with congeni tal syphilis. A B C Fig. 264.6 A and B, Papulosquamous plaques in two infants with syphilis. C, Desquamation on the palm of a newborns hand. (A and B from Eichenfeld LF, Frieden IJ, Esterly NB, eds. Textbook of Neonatal Dermatology. Philadelphia: WB Saunders, 2001: p. 196; courtesy Dr. Patricia Tread well.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 264 u Syphilis (Treponema pallidum) 1869 bone. Dental abnormalities, such as Hutchinson teeth (Fig. 264.8), are common. Defects in enamel formation lead to repeated caries and eventual tooth destruction. Saddle nose (Fig. 264.9) is a depression of the nasal root and may be associated with a perforated nasal septum. Other late manifestations of congenital syphilis can manifest as hypersensitivity phenomena. These include unilateral or bilateral inter stitial keratitis and the Clutton joint (see Table 264.1). Other common ocular manifestations include choroiditis, retinitis, vascular occlusion, and optic atrophy. Soft tissue gummas (identical to those of acquired disease) and paroxysmal cold hemoglobinuria are rare hypersensitivity phenomena. DIAGNOSIS Fundamental limitations of the currently available tests for syphilis are vexing, but results must always be interpreted in the context of patient history and physical examination. Physicians should remain aware of their local prevalence rates and treat presumptively when syphilis is suspected by clinical and epidemiologic data. The diagnosis of primary syphilis is confirmed when T. pallidum is demonstrated by dark field microscopy or direct fluorescent antibody testing on specimens from skin lesions, placenta, or umbilical cord. Nucleic acidbased amplifica tion assays, such as PCR, are also used in some specialized laborato ries but are not commercially available. Despite the absence of a true Fig. 264.7 Perianal condylomata lata. (From Karthikeyan K, Thappa DM. Early congenital syphilis in the new millennium. Pediatr Dermatol. 2002;19:275276.) Table 264.1 Late Manifestations of Congenital Syphilis SYMPTOMSIGN DESCRIPTIONCOMMENTS Olympian brow Bony prominence of the forehead caused by persistent or recurrent periostitis Clavicular or Higoumenakis sign Unilateral or bilateral thickening of the sternoclavicular third of the clavicle Saber shins Anterior bowing of the midportion of the tibia Scaphoid scapula Convexity along the medial border of the scapula Hutchinson teeth Peg shaped upper central incisors; they erupt during sixth yr of life with abnormal enamel, resulting in a notch along the biting surface Mulberry molars Abnormal first lower (6 yr) molars characterized by small biting surface and excessive number of cusps Saddle nose Depression of the nasal root, a result of syphilitic rhinitis destroying adjacent bone and cartilage Rhagades Linear scars that extend in a spokelike pattern from previous mucocutaneous fissures of the mouth, anus, and genitalia Juvenile paresis Latent meningovascular infection; it is rare and typically occurs during adolescence with behavioral changes, focal seizures, or loss of intellectual function Juvenile tabes Rare spinal cord involvement |
7,479 | and cardiovascular involvement with aortitis Hutchinson triad Hutchinson teeth, interstitial keratitis, and eighth cranial nerve deafness Clutton joint Unilateral or bilateral painless joint swelling (usually involving the knees) from synovitis with sterile synovial fluid; spontaneous remission usually occurs after several weeks Interstitial keratitis Manifests with intense photophobia and lacrimation, followed within weeks or months by corneal opacification and complete blindness Eighth cranial nerve deafness May be unilateral or bilateral, appears at any age, manifests initially as vertigo and high tone hearing loss, and progresses to permanent deafness A perforated nasal septum may be an associated abnormality. Fig. 264.8 Hutchinson teeth as a late manifestation of congenital syphilis. Fig. 264.9 Saddle nose in a newborn with congenital syphilis. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1870 Part XV u Infectious Diseases gold standard serologic assay, serologic testing for syphilis remains the principal means for diagnosis and traditionally involves a two step screening process with a nontreponemal test followed by a con firmatory treponemal test (Fig. 264.10A). Both test types are required for serologic based diagnosis. False negative tests may occur in early syphilis, and high risk individuals may need repeat testing in 2 4 weeks if clinically indicated. The Venereal Disease Research Laboratory (VDRL) and rapid plasma reagin (RPR) tests are sensitive nontreponemal tests that detect antibodies against phospholipid antigens on the treponeme surface that cross react with cardiolipin lecithin cholesterol antigens of damaged host cells. The quantitative results of these tests are help ful both in screening and in monitoring therapy. Titers increase with active disease, including treatment failure or reinfection, and decline with adequate treatment (Fig. 264.11). Nontreponemal tests usually become nonreactive within 1 year of adequate therapy for primary syphilis and within 2 years of adequate treatment for secondary disease. Fifteen to twenty percent of patients become serofast (nontreponemal titers persisting at low levels for long periods). In congenital infection, nontreponemal tests become nonreactive within a few months after adequate treatment. Certain conditions such as infectious mononucle osis and other viral infections, autoimmune diseases, and pregnancy can give false positive VDRL results. False positive results are less common with the use of purified cardiolipin lecithin cholesterol anti gen. All pregnant women should be screened early in pregnancy and at delivery. All positive maternal (parental) serologic tests for syphilis, regardless of titer, necessitate thorough investigation. Antibody excess can give a false negative reading unless the serum is diluted (prozone effect) as the formation of the antigen antibody lattice needed to visualize a positive flocculation test is disrupted. False negative results can also occur in early primary syphilis, in latent syphilis of long duration, and in late congenital syphilis. Treponemal tests traditionally are used to confirm diagnosis and measure specific T. pallidum antibodies (immunoglobulin Ig G, IgM, and IgA), which appear earlier than nontreponemal antibodies. Treponemal tests include the T. pallidum particle agglutination |
7,480 | test (TP PA, which is the preferred treponemal test) and the fluorescent treponemal antibody absorption test (FTA ABS). Treponemal anti body titers become positive soon after initial infection and usually remain positive for life, even with adequate therapy (see Fig. 264.11). These antibody titers do not correlate with disease activity. Tradition ally they are useful for diagnosis of a first episode of syphilis and for distinguishing false positive results of nontreponemal antibody tests but cannot accurately identify length of time of infection, response to therapy, or reinfection. There is limited cross reactivity of treponemal antibody tests with other spirochetes, including the causative organisms of Lyme disease (Borrelia burgdorferi), yaws, endemic syphilis, and pinta. Only venereal syphilis and Lyme disease are found in the United States. Nontrepo nemal tests (VDRL, RPR) are uniformly nonreactive in Lyme disease. Various enzyme linked, chemiluminescence, and multiplex flow immunoassays to detect treponemal IgG and IgM have been devel oped. These assays have increased sensitivity and are amenable to automation and high volume use. Rapid point of care tests are avail able to allow quality screening programs in resource limited settings where the World Health Organization otherwise relies on syndromic management of STIs and patients are treated for all likely causes of their constellation of signs and symptoms. In the United States, use of immunoassays has confounded screening because it switches the traditional algorithm: the treponemal specific testing is done before the nontreponemal testing. Because the former remain positive for life, clinical and epidemiologic data are required to provide guidelines to distinguish cured disease, early syphilis, untreated late latent dis ease, and true false positive tests. Benefits of reverse screening are Treponemal (immunoassay) Supplemental treponemal Reactive Reactive Nonreactive Nonreactive Step 1 Step 2 Step 3 Lab interpretation The supplemental treponemal test should use a unique platform andor antigen, different from the first treponemal test. Nonreactive Nontreponemal Reactive Consistent with current or past syphilis infection Consistent with past or potential early syphilis infection Inconclusive for syphilis infection; potentially early infection or false positive No laboratory evidence of syphilis infection RPR or VDRL (Nontreponemal test) Nontreponemal test No syphilis or very recent infection testing concludes Treponemal test Biologic falsepositive (see text for significance) Treponemal test Syphilis new case or previously treated case Nontreponemal test Treponemal test EIACIA, TPPA, TPHA, or FTAABS A B Fig. 264.10 A, Traditional laboratory testing algorithm for syphilis. B, Suggested alternative testing algorithm. EIACIA, Enzyme immunoassay chemiluminescence immunoassay; FTA ABS, fluorescent treponemal antibody absorption; RPR, rapid plasma reagin; TP HA, Treponema pallidum hemagglutination; TP PA, Treponema pallidum particle agglutination; VDRL, Venereal Disease Research Laboratory. If nontreponemal test is posi tive qualitatively, a titer is then quantitated. (A based on data from Workowski KA, Berman S; Centers for Diseases Control and Prevention. Sexually transmitted diseases treatment guidelines, 2010. MMWR Recomm Rep 2010;59RR 12:1110. pp. 2629.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier |
7,481 | Inc. All rights reserved. Chapter 264 u Syphilis (Treponema pallidum) 1871 Fig. 264.11 Common patterns of serologic reactiv ity in syphilis patients. FTA Abs, fluorescent trepone mal antibody absorption (test); RPR, rapid plasma reagin (test); TPHA, Treponema pallidum hemaggluti nation assay; VDRL, Venereal Disease Research Labo ratory (test). IgM by immunoassay. (From Peeling R, Ye H. Diagnostic tools for preventing and managing maternal and congenital syphilis: an overview. Bull World Health Organ. 2004;826:439446.) 100 80 60 40 20 o f p at ie nt s w ho te st p os iti ve 2 4 6 8 10 12 2 10 20 Time of infection Weeks Years Time postinfection Primary Primary lesion Secondary Secondary lesion Latent (asymptomatic) TertiaryClinical stages of syphilis IgM by ELISA or FTAABS 195 or immunoblot. FTAAbs TPHA Untreated Treated VDRLRPR IgM increased detection of transmissible early syphilis and of late latent disease to afford monitoring for tertiary disease. Although the CDC and American Academy of Pediatrics (AAP) Red Book continue to rec ommend the traditional screen (conventional diagnostic approach; see Fig. 264.10A), they have provided guidelines for interpretation of the reverse screening algorithm (see Fig. 264.10B). Reverse screening may yield false positive results, particularly in low prevalence popula tions where testing results should be interpreted with caution, as false positive testing in children may have serious adverse consequences. If reverse testing yields a positive treponemal result but a negative nontreponemal result, a second treponemal test targeting a different treponemal antigen is needed for confirmation. Interpretation of non treponemal and treponemal serologic tests in the newborn can be con founded by maternal IgG antibodies transferred to the fetus. Passively acquired antibody is suggested by a neonatal titer at least fourfold (i.e., a two tube dilution) less than the maternal (parental) titer. This conclu sion can be verified by a gradual decline in antibody in the infant, usu ally becoming undetectable by 3 6 months of age. Conversely, an infant nontreponemal titer fourfold higher than the mothers at the time of delivery or a persistent or rising nontreponemal titer in the infant sug gests congenital infection. Neurologic involvement can occur at any stage of syphilis. The diagnosis of neurosyphilis remains difficult but is often established by demonstrating pleocytosis and increased protein in the CSF and a positive CSF VDRL test along with neurologic symptoms. The CSF VDRL test is specific but relatively insensitive (2269) for neurosyphilis. CSF PCR and IgM immunoblot tests are being stud ied but not currently recommended for use in making the diagnosis of neurosyphilis. Dark field or direct fluorescent antibody microscopy of scrap ings from primary lesions or congenital or secondary lesions can reveal T. pallidum, often before serology becomes positive, but these modalities are usually not available in clinical practice. Since 2015 dif ferent methods of PCR, including routine PCR, nested PCR, reverse transcriptase PCR, and quantitative PCR targeting different DNA gene sequences, have been used by many laboratories as methods to detect T. pallidum in primary disease. However, there are currently no |
7,482 | commercially available test kits, and each test must be validated for use in each laboratory. Furthermore, these tests are not useful for asymptomatic patients, and interpretation may be complicated by the fact that they amplify both dead and living organisms. Placen tal examination by gross and microscopic techniques can be useful in the diagnosis of congenital syphilis. The disproportionately large placentas are characterized histologically by focal proliferative villitis, endovascular and perivascular arteritis, and focal or diffuse immatu rity of placental villi. Congenital Syphilis A diagnosis of congenital syphilis requires a thorough review of mater nal (parental) history of syphilis treatment preconception and the testing, treatment, and dynamics of response during the current preg nancy. Regardless of maternal (parental) treatment and the presence absence of symptoms in the infant, proactive evaluation and treatment of exposed neonates is critical (Fig. 264.12 and Table 264.2). Symptom atic infants should be thoroughly evaluated and treated. Figure 264.12 and Table 264.3 describe the guidelines for evaluating and managing asymptomatic infants who are considered at risk for congenital syphi lis because the maternal (parental) nontreponemal and treponemal serology is positive. Internationally adopted, refugee, and immigrant children should also be screened, regardless of history or report of treatment. Diagnostic testing risk stratifies infants to probability of congenital infection: proven or highly probable congenital syphilis, possible congenital syphilis, congenital syphilis less likely, or congeni tal syphilis unlikely. A diagnosis of neurosyphilis in the newborn with syphilitic infec tion is confounded by poor sensitivity of the CSF VDRL test in this age group and lack of CSF abnormalities. A positive CSF VDRL test in a newborn warrants treatment for neurosyphilis, even though it might reflect passive transfer of antibodies from serum to CSF. It is now accepted that all infants with a presumptive diagnosis of con genital syphilis should be treated with regimens effective for neuro syphilis because central nervous system involvement cannot be reliably excluded. A diagnosis of syphilis beyond early infancy should lead to consideration of possible child abuse. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1872 Part XV u Infectious Diseases For infants with proven or highly probable disease or abnormal physical findings, complete evaluation, including serologic tests (RPR or VDRL), complete blood count with differential and platelet count, liver function tests, long bone radiographs, ophthalmology examina tion, auditory brainstem response, and other tests as indicated, should be performed. If possible, pathologic examination of the placenta and or umbilical cord with specific fluorescent antitreponemal antibody staining is recommend by the AAP. For infants with a positive VDRL or RPR test result and normal physical examination whose mothers were inadequately treated, further evaluation is not necessary if 10 days of parenteral therapy are administered. TREATMENT The goals of early detection and treatment include treatment of current infection and prevention of both late stage disease and sexual or verti cal transmission. |
7,483 | T. pallidum remains extremely sensitive to penicillin, with no evidence of emerging penicillin resistance, and thus penicillin remains the treatment drug of choice (additional information available in Table 264.4 and at http:www.cdc.govstdtreatment for patients over 1 month old). Parenteral penicillin G is the only documented effective treatment for congenital syphilis, syphilis during pregnancy, and neurosyphilis and is recommended for treatment of syphilis in persons with HIV. Aqueous crystalline penicillin G is preferred over Conventional diagnostic approach Reversesequence screening approach Initial reactive maternal RPRVDRL Nonreactive maternal treponemal testa Reactive maternal treponemal testa,b Initial positive maternal treponemal EIACIA screening test Reactive maternal RPRVDRL Nonreactive maternal RPRVDRL Falsepositive reaction: no further evaluation (if pregnant, treponemal repeat testing may be appropriate) Reactive alternative maternal treponemal test (eg, TPPA)a,b Nonreactive alternative maternal treponemal test (eg, TPPA)a If epidemiologic risk and clinical probability of syphilis is low, no further evaluation is required If not low, consider repeat RPRVDRL in 24 wk to differentiate early primary infection from false positive Evaluate mothers treatment history for syphilis Maternal treatment: None, OR Undocumented, OR Less than 4 wk before delivery, OR Nonpenicillin drug, OR Maternal evidenceconcern of reinfectionrelapse (fourfold or greater increase in maternal titers)c Partner recently diagnosed with syphilis Maternal penicillin treatment during pregnancy AND 4 wk or more before delivery, AND no evidenceconcern of maternal reinfection or relapse Adequate maternal treatment before pregnancy with low stable (serofast)d or negative titer AND infant examination normal; if infant examination is abnormal, proceed with evaluatione Reactive maternal RPRVDRL at 24 wk Evaluatee Infant physical examination normal; AND evaluation normal; AND infant RPRVDRL same or less than fourfold the maternal RPRVDRL titerc Infant physical examination abnormal; OR evaluation abnormal or incomplete; OR RPRVDRL at least fourfold greater than maternal RPRVDRLc Proven or highly probable congenital syphilis Possible congenital syphilis Congenital syphilis unlikely Congenital syphilis less likely Proven or highly probable congenital syphilis Infant RPRVDRL not fourfold or greater than maternal RPRVDRLc Infant physical examination abnormal Infant physical examination normal Infant RPRVDRL fourfold or greater than maternal RPRVDRL titerc Evaluatee Infant physical examination normal; AND evaluation normal; AND infant RPRVDRL same or less than fourfold the maternal RPRVDRL titerc Infant physical examination abnormal; OR evaluation abnormal or incomplete; OR RPRVDRL at least fourfold greater than maternal RPRVDRLc Possible congenital syphilis Proven or highly probable congenital syphilis Fig. 264.12 Algorithm for the diagnostic approach of infants born to mothers (birthing parents) with reactive serologic tests for syphilis. aTre ponema pallidum particle agglutination (TP PA) (which is the preferred treponemal test) or fluorescent treponemal antibody absorption (FTA ABS). bTest for human immunodeficiency virus (HIV) antibody. Infants of HIV infected mothers do not require different evaluation or treatment for syphilis. cA fourfold change in titer is the same as a change of two dilutions. For example, a titer of 1:64 is fourfold greater than a titer of 1:16, and a titer of 1:4 is fourfold lower than a titer of 1:16. When comparing titers, the same type of nontreponemal test should be used (e.g., if |
7,484 | the initial test was an RPR, the follow up test should also be an RPR). dStable VDRL titers 1:2 or less or RPR 1:4 or less beyond 1 year after successful treatment are con sidered low serofast. eComplete blood cell (CBC) and platelet count; cerebrospinal fluid (CSF) examination for cell count, protein, and quantitative VDRL; other tests as clinically indicated (e.g., chest radiographs, long bone radiographs, eye examination, liver function tests, neuroimaging, and auditory brainstem response). For neonates, pathologic examination of the placenta or umbilical cord with specific fluorescent antitreponemal anti body staining, if possible. RPR, Rapid plasma regain; VDRL, Venereal Disease Research Laboratory. (From American Academy of Pediatrics. Syphilis. In Kimberlin DW, Barnett ED, Lynfield R, Sawyer MH, eds. Red Book: 20212024 Report of the Committee on Infectious Diseases, 32nd ed. Itasca, IL: American Academy of Pediatrics; 2021: Fig. 3.15, p. 734.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 264 u Syphilis (Treponema pallidum) 1873 procaine penicillin, because it better achieves and sustains the mini mum concentration of 0.018 gmL (0.03 unitsmL) needed for 7 10 days to achieve the prolonged treponemicidal levels required for the long dividing time of T. pallidum. In 2023, due to manufacturing limitations and increased demand, the United States entered a period of penicillin G shortage, requir ing prioritization of pregnant persons to receive this antibiotic, as no other medication is proven to prevent vertical transmission. Penicil lin G is often preferred for IM injection in treatment of other syphilis infections as an approach to ensure adherence to therapy, and thus the shortage may lead to increased transmission. For proven or highly probable congenital syphilis, procaine penicillin G (50,000 Ukg IM daily 10 days) should only be used if access to IV penicillin G is limited (such as in a low resource setting) or if IV access cannot be obtained. For infants with possible congenital syphilis, aqueous penicillin G (50,000 Ukg IV every 12 hours when 1 wk or younger, then every 8 hours for infants older than 1 wk, for a total of 10 days of therapy) is preferred, though procaine penicillin G (50,000 Ukg IM daily x 10 days) may be given. Benzathine penicillin G (50,000 Ukg IM) as a single dose can be considered but only if all components of the evaluation are normal and followup is certain. Infants in whom congenital syphilis is less likely may be treated with benzathine penicillin G (50,000 Ukg IM) as a single dose. If no treatment is given, infants must be closely followed until the nontreponemal test becomes nonreactive. If any portion of the assessment for congenital syphilis is abnormal or not obtained, or the CSF studies are uninterpretable, or outpatient follow up cannot be assured, treatment with procaine penicillin G is preferred. Patients with persistent or increasing titers require repeat evaluation and treatment with a |
7,485 | 10day course of par enteral penicillin G, even if previously treated. Although nonpenicillin regimens are available to the penicillin allergic patient, desensitization followed by standard penicillin ther apy is the most reliable strategy. Success of treatment also depends on the integrity of the host immune response. A transient acute systemic febrile reaction called the Jarisch Herxheimer reaction (caused by massive release of endotoxin like antigens during bacterial lysis) occurs in 1520 of patients with acquired or congenital syphilis treated with penicillin. It is not an indication for discontinuing penicillin therapy. Use of other agents for congenital syphilis should only be done in con sultation with a pediatric infectious diseases specialist and requires close clinical and serologic follow up. Acquired Syphilis Primary, secondary, and early latent disease is treated with a single dose of benzathine penicillin G (50,000 unitskg IM, maximum 2.4 mil lion units, in a single dose). Persons with late latent or tertiary disease require three doses at 1 week intervals. Nonpregnant penicillin allergic patients without neurosyphilis may be treated with either doxycycline (4.4 mgkg divided in 2 doses, max 200 mg per day, orally twice a day for 14 days) or tetracycline (2550 mgkg divided in 4 doses, max 2 g per day, orally for 14 days, for age 8 years). Emerging azalide and mac rolide resistance has been documented throughout the United States (a 23S ribosomal NA rRNA point mutation at position 2058) and, more recently, worldwide (a 23S rRNA point mutation at position 2059), compromising the effective use of these antibiotics. Careful serologic follow up is always necessary. Documentation of serologic cure is an essential part of syphilis treatment. Less than a fourfold decline in titer reflects treatment failure. The CDC recommends that all persons with syphilis be tested for HIV and other STIs. Patients diagnosed with syphilis with a negative HIV test should undergo repeat testing 3 months later. Diagnosis of syphilis in high risk individuals, particularly men or transgender women who have sex with men, is associated with increased risk of Table 264.2 Clues that Suggest a Diagnosis of Congenital Syphilis EPIDEMIOLOGIC BACKGROUND CLINICAL FINDINGS Untreated early syphilis in the mother Untreated latent syphilis in the mother An untreated mother who has contact with a known patient with syphilis during pregnancy Mother treated less than 30 days before delivery Mother treated for syphilis during pregnancy with a drug other than penicillin Mother treated for syphilis during pregnancy without follow up to demonstrate fourfold decrease in titer Mother coinfected with HIV Osteochondritis, periostitis Snuffles, hemorrhagic or mucopurulent rhinitis Condylomata lata Bullous lesions, palmar or plantar rash Mucous patches Hepatomegaly, splenomegaly Jaundice, hepatitis Nonimmune hydrops fetalis Generalized lymphadenopathy Central nervous system signs; elevated cell count or protein in cerebrospinal fluid Hemolytic anemia, diffuse intravascular coagulation, thrombocytopenia Pneumonitis Nephrotic syndrome Placental villitis or vasculitis (unexplained enlarged placenta) Intrauterine growth restriction Arranged in decreasing order of confidence of diagnosis. Modified from Remington JS, Klein JO, Wilson CB, et al., eds. Infectious Diseases of the Fetus and Newborn Infant, |
7,486 | 6th ed. Philadelphia: WB Saunders; 2006:556. Table 264.3 Confirmed Proven or Highly Probable Congenital Syphilis DIAGNOSIS AND TREATMENT Any neonate with: An abnormal physical examination that is consistent with congenital syphilis; A serum quantitative nontreponemal serologic titer that is fourfold (or greater) higher than the mothers titer at delivery (e.g., maternal titer 1:2, neonatal titer 1:8 or maternal titer 1:8, neonatal titer 1:32); or A positive dark field test or PCR of placenta, cord, lesions, or body fluids or a positive silver stain of the placenta or cord. Recommended evaluation: CSF analysis for VDRL, cell count, and protein Complete blood count (CBC) and differential and platelet count Long bone radiographs Other tests as clinically indicated (e.g., chest radiograph, liver function tests, neuroimaging, ophthalmologic examination, and auditory brainstem response) Recommended regimens, confirmed or highly probable congenital syphilis: Aqueous crystalline penicillin G 100,000 150,000 unitskg body weightday, administered as 50,000 unitskg body weightdose by IV every 12 hr during the first 7 days of life and every 8 hr thereafter for a total of 10 days OR Procaine penicillin G 50,000 unitskg body weightdose IM in a single daily dose for 10 days If 1 day of therapy is missed, the entire course should be restarted. Data are insufficient regarding use of other antimicrobial agents (e.g., ampicillin). When possible, a full 10 day course of penicillin is preferred, even if ampicillin was initially provided for possible sepsis. Using agents other than penicillin requires close serologic follow up for assessing therapy adequacy. Preferred therapy per the 20212024 AAP Red Book From Centers for Disease Control and Prevention. Congenital syphilis. Sexually Transmitted Diseases and Treatment Guidelines, 2021. Scenario 1. https:www.cdc.gov stdtreatment guidelinescongenital syphilis.htm. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1874 Part XV u Infectious Diseases subsequent HIV acquisition, and preexposure prophylaxis (PrEP) should be considered. Patients coinfected with HIV are at increased risk for neurologic complications and higher rates of treatment fail ure. CDC guidelines recommend the same treatment of primary and secondary syphilis as for patients who are not infected with HIV, but some experts recommend three weekly doses of benzathine penicil lin G. HIV infected patients with late latent syphilis or latent syphilis of unknown duration should have a CSF evaluation for neurosyphilis before treatment. Sex partners of infected persons of any stage should be evaluated and treated. Persons exposed for 90 days or less preceding diagnosis in a sex partner should be treated presumptively even if seronegative. Persons exposed for more than 90 days before the diagnosis in a sex partner should be treated if seropositive or if serologic tests are not available. Follow up serology should be performed on treated patients to estab lish adequacy of therapy, and all patients should be tested for other sexually transmitted diseases, including HIV. Children with acquired primary, secondary, or latent syphilis should undergo evaluation for |
7,487 | possible sexual assault or abuse. Syphilis in Pregnancy When clinical or serologic findings suggest active infection or when the diagnosis of active syphilis cannot be excluded with certainty, treatment is indicated. The goals of treatment of the pregnant per son include eradication of maternal (parental) disease, prevention of parent to child transmission, and treatment of fetal infection. Patients should be treated immediately with the penicillin regimen appropri ate for the pregnant persons stage of syphilis. Those who have been Table 264.4 Recommended Treatment for Syphilis in People Older Than 1 Mo STATUS CHILDREN ADULTS Congenital syphilis in patients 1 mo old; OR children 2 mo with late and previously untreated congenital syphilis Aqueous crystalline penicillin G 200,000 300,000 Ukgday IV administered as 50,000 Ukg, every 4 6 hr for 10 days Primary, secondary, and early latent syphilis Penicillin G benzathine 50,000 Ukg IM, up to the adult dose of 2.4 million U in a single dose If allergic to penicillin and not pregnant, Doxycycline 4.4 mgkg divided in 2 doses, max 200 mg per day, orally twice a day for 14 days (for ages 8 yr) OR Tetracycline 25 50 mgkg divided in 4 doses, max 2 g per day, orally for 14 days (for ages 8 yr) Penicillin G benzathine 2.4 million U IM in a single dose OR If allergic to penicillin and not pregnant, doxycycline 100 mg orally twice a day for 14 days OR Tetracycline 500 mg orally 4 timesday for 14 days Late latent syphilis Penicillin G benzathine 50,000 Ukg IM, up to the adult dose of 2.4 million U, administered as 3 single doses at 1 wk intervals (total 150,000 Ukg, up to the adult dose of 7.2 million U) If allergic to penicillin and not pregnant, Doxycycline 4.4 mgkg divided in 2 doses, max 200 mg per day, orally twice a day for 4 weeks (for ages 8 yr) OR Tetracycline 25 50 mgkg divided in 4 doses, max 2 g per day, orally for 4 weeks (for ages 8 yr) Penicillin G benzathine 7.2 million U total, administered as 3 doses of 2.4 million U IM, each at 1 wk intervals; pregnant women who have delays in any dose of therapy beyond 9 days between doses should repeat the full course of therapy OR If allergic to penicillin and not pregnant, Doxycycline 100 mg orally twice a day for 4 wk OR Tetracycline 500 mg orally, 4 timesday for 4 wk Tertiary Penicillin G benzathine 7.2 million U total, administered as 3 doses of 2.4 million U IM at 1 wk intervals If allergic to penicillin and not pregnant, consult an infectious diseases expert Neurosyphilis Aqueous crystalline penicillin G 200,000 300,000 Ukgday IV every 4 6 hr for 10 14 days, in doses not to exceed the adult dose Aqueous crystalline penicillin G 18 24 million U per day, administered as 3 4 million U IV every 4 hr for 10 14 days OR Penicillin G procaine 2.4 million U IM once |
7,488 | daily PLUS probenecid 500 mg orally 4 timesday, both for 10 14 days If the patient has no clinical manifestations of disease, the cerebrospinal fluid (CSF) examination is normal, and the CSF Venereal Disease Research Laboratory (VDRL) test result is negative, some experts would treat with up to 3 weekly doses of penicillin G benzathine 50,000 Ukg IM. Some experts also suggest giving these patients a single dose of penicillin G benzathine 50,000 Ukg IM after the 10 day course of intravenous aqueous penicillin. Early latent syphilis is defined as being acquired within the preceding year. Penicillin G benzathine and penicillin G procaine are approved for intramuscular administration only. Late latent syphilis is defined as syphilis beyond 1 years duration. Patients who are allergic to penicillin should be desensitized. Some experts administer penicillin G benzathine 2.4 million U IM once per week for up to 3 weeks after completion of these neurosyphilis treatment regimens. IV, Intravenously; IM, intramuscularly. From American Academy of Pediatrics. Syphilis. In: Kimberlin DW, Barnett ED, Lynfield R, Sawyer MH, eds. Red Book: 20212024 Report of the Committee on Infectious Diseases, 32nd ed. Itasca, IL: American Academy of Pediatrics; 2021: Table 3.67, pp. 741742. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 264 u Syphilis (Treponema pallidum) 1875 adequately treated in the past do not require additional therapy unless quantitative serology suggests evidence of reinfection (fourfold eleva tion in titer). Penicillin G is the only agent known to be effective for treating fetal infection and for prevention of congenital infection. Pregnant patients who are allergic to penicillin should be desensitized and treated with penicillin. If doses for late latent syphilis are delayed beyond 9 days from the prior dose, the full course of therapy needs to be repeated. Additional therapy may be considered for pregnant persons with primary, secondary, or early latent syphilis or when syphilis is diag nosed during the second half of pregnancy and sonographic evidence of fetal or placental syphilis is noted. In these cases, a second dose of benzathine penicillin G (2.4 million units IM given 1 week after the initial dose) may decrease the risk of vertical transmission. Jarisch Herxheimer reaction in the second half of pregnancy may induce pre mature labor or fetal distress, and patients with reactions should seek obstetric attention promptly. Congenital Syphilis Adequate maternal (parental) treatment at least 30 days before deliv ery is likely to prevent congenital syphilis. All infants born to pregnant persons with syphilis should be followed until nontreponemal serol ogy is negative. The infant should be treated if there is any uncertainty about the adequacy of maternal (parental) treatment. The goal of infant treatment is prevention of organ damage, skeletal deformity, and developmental delay. Any infant at risk of congenital syphilis should be evaluated for HIV. Congenital syphilis is treated in infants up to 1 month of |
7,489 | age with aqueous penicillin G (100,000 150,000 unitskg24 hr IV divided every 12 hours for the first week of life and every 8 hours thereafter) or pro caine penicillin G (50,000 unitskg IM once daily) given for 10 days. Both penicillin regimens are recognized as adequate therapy for con genital syphilis, but higher concentrations of penicillin are achieved in the CSF of infants treated with intravenous aqueous penicillin G than in those treated with intramuscular procaine penicillin. Treated infants should be closely monitored at 2 , 4 , 6 , and 12 month well child care visits and serologic nontreponemal titers repeated every 2 3 months until nonreactive. Titers generally decrease by 3 months of age and become nonreactive by 6 months of age if adequately treated or if antibody was merely transplacentally acquired without infection. Infants diagnosed and treated for congenital syphilis after 1 month of age should be treated with aqueous crystalline penicillin G 200,000 300,000 Ukgday IV administered as 50,000 Ukg, every 46 hr for 10 days (Table 264.4). Nontreponemal titers may resolve more slowly if the patient was treated after 1 month old. Increasing or persistent stable titers 6 12 months after initial treatment suggest possible ongo ing infection, and repeat evaluation, including CSF, is indicated. Repeat treatment (penicillin G IV for 10 days) may be indicated. Infants with a negative nontreponemal test born to a person seroreactive at the time of delivery could have incubating congenital infection and so should be retested at 3 months. Infants with initial abnormal CSF studies only require repeat lumbar puncture if they have persistent nontreponemal serologic titers at 6 12 months old. If CSF has a persistent positive VDRL or abnormal indices not attributable to another ongoing illness, retreatment is indicated after 2 years of follow up. At age 2 previously treated infants should receive a full developmental assessment. In a very low risk neonate who is asymptomatic and whose mother was treated appropriately, without evidence of relapse or reinfection but with a low and stable VDRL titer (serofast), no evaluation is necessary. Some specialists, however, would treat such an infant with a single dose of benzathine penicillin G 50,000 unitskg IM. PREVENTION Syphilis, including congenital syphilis, is a reportable disease in all 50 states and the District of Columbia. Testing is indicated at any time for persons with suspicious lesions, a history of recent sexual exposure to a person with syphilis, or diagnosis of another sexu ally transmitted infection, including HIV infection. Screening for syphilis in asymptomatic, nonpregnant persons at increased risk for infection has received an A recommendation from the US Preven tive Services Task Force (USPSTF) as providing significant benefit. Directtoconsumer test services for STIs (or home tests) have become more acceptable following consumer experience with simi lar testing during the COVID19 pandemic, and best practices for implementation are an area of intense research. As of late 2023, the US CDC had posted request for comment on proposed guidelines for the use of doxycycline as postexposure |
7,490 | prophylaxis for bacterial STI prevention, including syphilis, to be offered to MSM and trans gender women with a history of at least one bacterial STI in the last 12 months; insufficient evidence is currently available to give recom mendations for other groups, including children, cisgender women or heterosexual men, transgender men, or other queer and nonbinary individuals. The resurgence of syphilis compels clinicians to remain cognizant of its protean manifestations to avoid missed or late diag nosis. Timely treatment lessens risk of community spread. Despite the genome sequencing of T. pallidum in 1998, vaccine development remains elusive, confounded by the treponemes ability to evade the immune system. Congenital Syphilis Congenital syphilis is a preventable disease, a sentinel event indi cating multiple missed opportunities. Primary prevention is tied to prevention of syphilis in women of childbearing age, and secondary prevention with early diagnosis and prompt treatment of women and their partners. Access to and use of comprehensive prenatal care is key, with careful history taking (including interim sexual partners) at each visit. Routine prenatal screening for syphilis remains the most important factor in identifying infants at risk for developing congeni tal syphilis. Screening all women at the beginning of prenatal care is an evidence based standard of care and legally required in all states. In pregnant women without optimal prenatal care, serologic screen ing for syphilis should be performed at the time pregnancy is diag nosed. Any person who is delivered of a stillborn infant at 20 weeks or fewer of gestation should be tested for syphilis. In communities and populations with a high prevalence of syphilis and in patients at high risk (pregnant persons with a history of incarceration, drug use, or multiple or concurrent partners), testing should be performed at least two additional times: at the beginning of the third trimes ter (28 weeks) and at delivery. Some states mandate repeat testing at delivery for all pregnant persons, underscoring the importance of preventive screening. Those at high risk for syphilis should be screened even more frequently, either monthly or, pragmatically (in the case of inconsistent prenatal care), at every medical encounter because they can have repeat infections during pregnancy or rein fection late in pregnancy. Follow up serologic testing of all treated pregnant persons should be done after treatment to document titer decline, relapse, or reinfection. No newborn should leave the hospital without the mothers (par ents) syphilis status having been determined at least once during pregnancy or at delivery. In states conducting newborn screening for syphilis, both the parents and infants serologic results should be known before discharge. Appropriate follow up for the treated or exposed infant should be arranged. In addition, all previously unin vestigated infants of an infected mother should be screened. Strong linkages between clinicians and public health practitioners remain essential for comprehensive prevention of acquired and congenital syphilis. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For |
7,491 | personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1876 Part XV u Infectious Diseases Nonvenereal treponemal infectionsyaws, bejel (endemic syphilis), and pintaare caused by different subspecies of Treponema pallidum and occur in tropical and subtropical areas. The causative agents of nonve nereal treponematosesT. pallidum pertenue, T. pallidum subspecies endemicum, and Treponema carateumcannot be distinguished from T. pallidum subspecies pallidum by morphologic or serologic tests. In general, nonvenereal treponematoses have prominent cutaneous manifestations and relapsing courses, as in venereal syphilis, but they are not found in urban centers, they are not sexually transmitted, and they are not congenitally acquired. Transmission is primarily through body contact, poor hygiene, crowded conditions, and poor access to healthcare. Children also serve as the primary reservoirs for these organisms, spreading infection via skin to skin and skintomucous membrane contact, and possibly via fomites as well. Penicillin remains the treatment of choice for syphilis and nonvenereal treponemal infections. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 265.1 Yaws (Treponema pertenue) Stephen K. Obaro and H. Dele Davies Yaws is the most prevalent nonvenereal treponematosis. The caus ative agent, Treponema pertenue, bears very close genomic resem blance to T. pallidum subspecies pallidum. The overall sequence identity between the genomes of T. pallidum pertenue and T. pal lidum subspecies pallidum is 99.8. Yaws is a contagious, chronic, relapsing infection involving the skin and bony structures caused by the spirochete T. pertenue, which is identical to T. pallidum micro scopically and serologically. This disease occurs in tropical regions with heavy rainfall and annual temperatures 27C (80F). Almost all cases occur in children in tropical and subtropical countries. It is also referred to as framboesia, pian, parangi, and bouba. A high percentage of the population is infected in endemic areas. T. pertenue is transmitted by direct contact from an infected lesion through a skin abrasion or laceration. Transmission is facili tated by overcrowding and poor personal hygiene in the rainfor est areas of the world. Yaws predominantly affects children, with approximately 75 of cases being reported in children younger than 15 years of age. This population also constitutes the reservoir for disease transmission. The initial papular lesion, which constitutes primary yaws, also described as the mother yaw, occurs 2 8 weeks after inoculation. This lesion typically involves the buttocks or lower extremities. The papule develops into a raised, raspberry like papilloma and is often accompanied by regional lymphadenopathy. The skin pathology is similar to that of venereal syphilis, consisting of epidermal hyperplasia and papillomatosis (Fig. 265.1). Healing of the mother yaw leaves a hypopigmented scar. The secondary stage lesions can erupt anywhere on the body before or after the healing of the mother yaw and may be accompanied by lymphadenopathy, anorexia, and malaise. Multiple cutaneous lesions (daughter yaws, pianomas, or framboesias) appear, spread diffusely, ulcerate, and are covered by exudates containing treponemes. Secondary lesions heal without scarring. Recurrent lesions are common within 5 years after the primary lesion. The lesions are often associated with bone |
7,492 | pain resulting from underlying periostitis or osteomyelitis, especially of the fingers, nose, and tibia. The initial period of clinical activity is followed by a 5 to 10 year period of latency. The appearance of tertiary stage lesions develops in approximately 10 of infected patients, with onset typically at puberty, with solitary and destructive lesions. These lesions occur as painful papillomas on the hands and feet, gummatous skin ulcerations, or osteitis. Bony destruction and deformity, juxtaarticular nodules, depigmentation, and painful Chapter 265 Nonvenereal Treponemal Infections Stephen K. Obaro and H. Dele Davies A B C 100 m Fig. 265.1 Yaws lesions in a patient with treatment failure associated with macrolide resistant T p pertenue. A, Primary lesion (red, moist 2.5 cm ulcer) on the left leg of an 11 yr old patient with yaws observed at the 30 mo survey. Lesional swab PCR was positive for T p pertenue with wild type 23S rRNA. B, Secondary yaws papillomas (multiple nodules with yellow granular surface) seen at 36 mo survey. These lesions were PCR positive for T p pertenue with A2059G mutation in 23S rRNA. C, Photomicrograph of skin biopsy of the larger papilloma lesion in panel B with abundant spiro chete organisms stained bright red by the Treponema pallidum immunohistochemical stain (400 magnification). T p pertenue, Treponema pallidum subspecies pertenue. (From Mitja O, Godornes C, Houinei W, et al. Re emergence of yaws after single mass azithromycin treatment followed by targeted treatment: a longitudinal study. Lancet. 2018;391:15991606, Fig. 2.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 265 u Nonvenereal Treponemal Infections 1877 hyperkeratosis (dry crab yaws) of the palms and soles are common. Approximately 10 of patients may progress and develop tertiary stage lesions after 5 years or more of untreated infection, although this outcome is now rare. The diagnosis is based on the characteristic clinical manifesta tions of the disease in an endemic area. Dark field examination of cutaneous lesions for treponemes and both treponemal and non treponemal serologic tests for syphilis, which are positive because of cross reactivity, are used to confirm the diagnosis. The nontrepo nemal agglutination tests, such as the rapid plasma reagin and Vene real Diseases Research Laboratory tests, are positive in untreated cases, and these tests can be used for test of cure, because they revert to negative after treatment. However, the treponemal tests (T. pallidum hemagglutination assay, T. pallidum particle aggluti nation assay, and fluorescent treponemal antibody absorption) are more specific and remain positive for life. New immunochromato graphic test strips that can be applied for testing both whole blood and serum are simple, cheap, and easy to use and do not require refrigeration. However, they have lower sensitivity compared with the antibody assays and appear to work best in persons with more active disease. The differential diagnosis includes other conditions with similar cutaneous manifestations such |
7,493 | as eczema, psoriasis, excoriated chronic scabies, tungiasis, leishmaniasis, tropical ulcer cutaneous mycoses, and verrucae. Involvement of the bone may mimic dactylitis that is com monly associated with sickle cell disease. Treatment of yaws consists of a single dose of the long acting benzathine penicillin G (1.2 million units IM for adults and 0.6 mil lion units for children 10 years) for index patients and all contacts. Patients allergic to penicillin may be treated with erythromycin, doxycycline, or tetracycline at appropriate doses for venereal syphilis (see Chapter 264). One oral dose of azithromycin (30 mgkg; maxi mum: 2 g) is as effective as benzathine penicillin. Treatment cures the lesions of active yaws, renders them noninfectious, and prevents relapse. Family members, contacts, and patients with latent infection should receive the same dose as those with active disease. Eradication of yaws from some endemic areas has been accomplished by treating the entire population (mass treatment) with azithromycin, although reemergence has been reported in those who did not receive mass treatment. In 2023, due to manufacturing limitations and increased demand, the United States entered a period of penicillin G shortage, potentially causing treatment to shift to erythromycin, doxycycline, or tetracycline until the shortages are resolved. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 265.2 Bejel (Endemic Syphilis; Treponema pallidum endemicum) Stephen K. Obaro and H. Dele Davies Bejel, or endemic syphilis, affects children in remote rural com munities living in poor hygienic conditions. Unlike yaws, bejel can occur in temperate and dry, hot climates. Infection with T. palli dum subspecies endemicum follows penetration of the spirochete through traumatized skin or mucous membranes. In experimen tal infections, a primary papule forms at the inoculation site after an incubation period of 3 weeks. A primary lesion is almost never visualized in human infections; however, primary ulcers have been described surrounding the nipples of nursing mothers with infected children. The clinical manifestations of the secondary stage typically occur 3 6 months after inoculation and are confined to the skin and mucous membranes. They consist of highly infectious mucous patches on the oral mucosa and condyloma like lesions on the moist areas of the body, especially the axilla and anus. These mucocutaneous lesions resolve spontaneously over a period of sev eral months, but recurrences are common. The secondary stage is followed by a variable latency period before the onset of late or ter tiary bejel. The tertiary stage can occur as early as 6 months or as late as several years after resolution of initial symptoms. The lesions in the tertiary stage are identical to those of yaws and include gumma formation in skin, subcutaneous tissue, and bone, resulting in painful destructive ulcerations, swelling, and deformity. The diagnosis is based on the characteristic clinical manifestations of the disease in an endemic area. Dark field examination of cutaneous lesions for treponemes and both treponemal and nontreponemal sero logic tests for syphilis, which are positive because of cross reactivity, are used to confirm the diagnosis. Differentiation from venereal syphilis is extremely |
7,494 | difficult in an endemic area. Bejel is distinguished by the absence of a primary chan cre and lack of involvement of the central nervous system and cardio vascular system during the late stage. Treatment of early infection consists of a single dose of benza thine penicillin G (1.2 million units IM for adults and 0.6 million units for children 10 years). Late infection is treated with three injections of the same dosage at intervals of 7 days. Patients aller gic to penicillin may be treated with erythromycin or tetracycline. Similarly, when penicillin G is unavailable because of manufac turing limitations, treatment with erythromycin or tetracycline is appropriate. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 265.3 Pinta (Treponema carateum) Stephen K. Obaro and H. Dele Davies Pinta is a chronic, nonvenereally transmitted infection caused by T. pallidum subsp. carateum, a spirochete morphologically and serologi cally indistinguishable from other human treponemes. This is perhaps the mildest of the nonvenereal treponematoses. The disease is endemic in Mexico, Central America, South America, and parts of the West Indies and largely affects children younger than 15 years of age. Infection follows direct inoculation of the treponeme through abraded skin. After a variable incubation period of days, the pri mary lesion appears at the inoculation site as a small asymptomatic erythematous papule resembling localized psoriasis or eczema. The regional lymph nodes are often enlarged. Spirochetes can be visu alized on dark field examination of skin scrapings or from biopsy of the involved lymph nodes. After a period of enlargement, the primary lesion disappears. Unlike primary yaws, the lesion does not ulcerate but can expand with central depigmented resolution. Sec ondary lesions follow within 6 8 months and consist of small mac ules and papules on the face, scalp, and other sun exposed portions of the body. These pigmented, highly infectious lesions are scaly and nonpruritic and can coalesce to form large plaquelike eleva tions resembling psoriasis. In the late or tertiary stage, atrophic and depigmented lesions develop on the hands, wrists, ankles, feet, face, and scalp. Hyperkeratosis of palms and soles is uncommon. The diagnosis is based on the characteristic clinical manifestations of the disease in an endemic area. Dark field examination of cutaneous lesions for treponemes and both treponemal and nontreponemal sero logic tests for syphilis, which are positive because of cross reactivity, are used to confirm the diagnosis. Treatment consists of a single dose of benzathine penicillin G (1.2 million units IM for adults and 0.6 million units for chil dren 10 years). Tetracycline and erythromycin are alternatives for patients allergic to penicillin and during periods when penicillin G is unavailable because of manufacturing limitations. Treatment campaigns and improvement of standards of living are necessary for reduction and elimination of the disease. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1878 Part XV u Infectious Diseases Leptospirosis is |
7,495 | a common and widespread zoonosis caused by aerobic, motile spirochetes of the genus Leptospira. ETIOLOGY Leptospira spp. are thin, helix shaped members of the phylum Spiro chaetes. There are 22 species identified within the genus Leptospira, and these are further divided into over 300 serovars. There are at least 10 pathogenic Leptospira species, with serovars demonstrating prefer ential host specificity. EPIDEMIOLOGY Leptospirosis has a worldwide distribution, but most human cases occur in tropical and subtropical countries with disease burden disproportionately affecting resource poor populations. Lepto spires survive for days to weeks in warm and damp environmental conditions, including water and moist soil. In the United States, the CDC estimates 100 200 annual cases; Hawaii reports about 50 of U.S. cases, with Pacific Coast and Southern states having a higher incidence than the remainder of the country. Leptospires infect many species of animals, including rats, mice, and moles; livestock such as cattle, goats, sheep, horses, and pigs; wild mam mals like raccoons or opossums; and domestic dogs. Infected animals excrete spirochetes in their urine for prolonged periods. Globally, most human cases result from exposure to water or soil contaminated with rat urine; however, the major animal reservoir in the United States is the dog. Groups at high risk for leptospi rosis include persons exposed occupationally or recreationally to contaminated soil, water, or infected animals. High risk occupa tions include agricultural workers, veterinarians, abattoir workers, meat inspectors, rodent control workers, laboratory workers, sewer workers, and military personnel. Cases are more frequent in the Chapter 266 Leptospira H. Dele Davies and Kari A. Simonsen Fig. 266.1 Stages of anicteric and icteric leptospirosis. Cor relation between clinical findings and presence of leptospires in body fluids. CSF, Cerebrospinal fluid. (From Feigin RD, An derson DC. Human leptospirosis. CRC Crit Rev Clin Lab Sci. 1975;5:413467. Copyright CRC Press, Inc., Boca Raton, FL.) Anicteric Leptospirosis F ev er Im po rt an t C lin ic al F in di ng s Le pt os pi re s P re se nt First Stage 37 days (Septicemic) Second Stage 0 days1 mo (Immune) Myalgia Headache Abdominal pain Vomiting Conjunctival suffusion Fever Meningitis Uveitis Rash Fever Blood CSF Urine Blood CSF Urine Icteric Leptospirosis (Weil Syndrome) Jaundice Hemorrhage Renal failure Myocarditis First Stage 37 days (Septicemic) Second Stage 1030 days (Immune) late summer and fall and often after heavy rainfalls. Exposure to contaminated floodwaters is also a documented source of infec tion. Transmission via animal bites and directly from person to person has been rarely reported. PATHOLOGY AND PATHOGENESIS Leptospires enter human hosts through mucous membranes (primar ily the eyes, nose, and mouth), transdermally through abraded skin, or by ingestion of contaminated water. After penetration, they circulate in the bloodstream, causing endothelial damage of small blood vessels with secondary ischemic damage to end organs. CLINICAL MANIFESTATIONS The spectrum of human leptospirosis ranges from asymptomatic infection to severe disease (510 of infections) with multiorgan dysfunction and death. The onset is usually abrupt, and the ill ness may follow a |
7,496 | monophasic or the classically described bipha sic course (Fig. 266.1). The incubation period ranges from 2 to 30 days, after which there is an initial or septicemic phase last ing 2 7 days, during which leptospires can be isolated from the blood, cerebrospinal fluid (CSF), and other tissues. This phase may be followed by a brief period of well being before onset of a sec ond symptomatic immune or leptospiruric phase. This phase is associated with the appearance of circulating IgM antibody, disap pearance of organisms from the blood and CSF, and appearance of signs and symptoms associated with localization of leptospires in the tissues. Despite the presence of circulating antibody, lepto spires can persist in the kidney, urine, and aqueous humor. The immune phase can last for several weeks. Symptomatic infection may be anicteric or icteric. Anicteric Leptospirosis The septicemic phase of anicteric leptospirosis has an abrupt onset with flulike signs of fever, shaking chills, lethargy, severe headache, malaise, nausea, vomiting, and severe debilitating myalgia most prominent in the lower extremities, lumbosacral spine, and abdo men. Bradycardia and hypotension can occur, but circulatory col lapse is uncommon. Conjunctival suffusion with photophobia and orbital pain (in the absence of chemosis and purulent exudate), Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 266 u Leptospira 1879 generalized lymphadenopathy, and hepatosplenomegaly may also be present. A transient (24 hours) erythematous maculopapular, urticarial, petechial, purpuric, or desquamating rash occurs in 10 of cases. Rarer manifestations include pharyngitis, pneumonitis, arthritis, carditis, cholecystitis, and orchitis. The second or immune phase can follow a brief asymptomatic interlude and is character ized by recurrence of fever and aseptic meningitis. Although 80 of infected children have abnormal CSF profiles, only 50 have clinical meningeal manifestations. CSF abnormalities include a modest elevation in pressure, pleocytosis with early polymorpho nuclear leukocytosis followed by mononuclear predominance rarely exceeding 500 cellsmm3, normal or slightly elevated protein lev els, and normal glucose values. Encephalitis, cranial and peripheral neuropathies, papilledema, and paralysis are uncommon. A self limited unilateral or bilateral uveitis can occur during this phase, rarely resulting in permanent visual impairment. Central nervous system symptoms usually resolve spontaneously within 1 week, with almost no mortality. Icteric Leptospirosis (Weil Syndrome) Weil syndrome is a severe form of leptospirosis seen more com monly in adults (30 years) than in children. The initial manifes tations are similar to those described for anicteric leptospirosis. However, the immune phase is characterized by jaundice, acute renal dysfunction, thrombocytopenia, and, in fulminant cases, pul monary hemorrhage and cardiovascular collapse. Hepatic involve ment leads to right upper quadrant pain, hepatomegaly, direct and indirect hyperbilirubinemia, and modestly elevated serum levels of hepatic enzymes. Liver function usually returns to normal after recovery. Patients have abnormal findings on urinalysis (hematuria, proteinuria, and casts), and azotemia is common, often associated with oliguria or anuria. Acute kidney failure occurs |
7,497 | in 1640 of cases. Abnormal electrocardiograms are present in 90 of cases, but congestive heart failure is uncommon. Transient thrombocytopenia occurs in 50 of cases. Rarely, hemorrhagic manifestations occur, including epistaxis, hemoptysis, and pulmonary, gastrointestinal, and adrenal hemorrhage. Patients with pulmonary hemorrhage syndrome may have 50 mortality rate, although the overall mor tality rate for severe disease is lower, about 515. DIAGNOSIS Leptospirosis should be considered in the differential diagnosis of acute flulike febrile illnesses with a history of direct contact with ani mals or with soil or water contaminated with animal urine. The dis ease may be difficult to distinguish clinically from dengue or malaria in endemic areas. The diagnosis is most often confirmed by serologic testing and less often confirmed by isolation of the infecting organism from clinical specimens. The gold standard diagnostic method is the microscopic agglutination test, a serogroup specific assay using live antigen suspension of leptospiral serovars and dark field microscopy for agglutination. A fourfold or greater increase in titer in paired sera confirms the diagnosis. Agglutinins usually appear by the 12th day of illness and reach a maximum titer by the third week. Low titers can persist for years. Approximately 10 of infected persons do not have detectable agglutinins, presumably because available antisera do not identify all Leptospira serotypes. Additionally, enzyme linked immunosorbent assay (ELISA) meth ods, latex agglutination, and immunochromatography are commer cially available, and DNA PCR diagnostics have been developed. Phase contrast and dark field microscopy are insensitive for spi rochete detection, but organisms may be identified using Warthin Starry silver stain or fluorescent antibody staining of tissue or body fluids. Unlike other pathogenic spirochetes, leptospires can be recovered from the blood or CSF during the first 10 days of ill ness and from urine after the second week by repeated culture of small inoculum (i.e., one drop of blood or CSF in 5 mL of medium) on commercially available selective media. However, the inoculum in clinical specimens is small, and growth can take up to 16 weeks. TREATMENT Leptospira spp. demonstrate in vitro susceptibility to penicillin and tetracyclines, but in vivo effectiveness of these antibiotics in treating human leptospirosis is unclear because of the naturally high sponta neous recovery rates. Some studies suggest that initiation of treatment before the seventh day shortens the clinical course and decreases the severity of the infection; thus treatment with penicillin G, ceftriaxone, or doxycycline (in children 8 years of age) should be instituted early when the diagnosis is suspected. There is evidence that a short (2 weeks) course of doxycycline may be safely used in children 2 years of age. Parenteral penicillin G (6 8 million Um2day divided every 4 hours IV for 7 days) is recommended, with doxycycline 2 mgkg day divided in two doses with a maximum of 100 mg twice daily as an alternative for patients allergic to penicillin. Ceftriaxone, and azithromycin have been evaluated in clinical trials and have dem onstrated equivalent effectiveness with doxycycline. These antibiot ics can be used |
7,498 | as alternatives in patients for whom doxycycline is contraindicated. In mild illness, oral doxycycline, amoxicillin, and ampicillin have been used successfully. In severe illness, support ive care with specific attention given to cardiopulmonary status, renal function, coagulopathy, and fluid and electrolyte balance is warranted. PREVENTION Prevention of human leptospirosis infection is facilitated through rodent control measures and avoidance of contaminated water and soil. Immunization of livestock and domestic dogs is recommended as a means of reducing animal reservoirs. Human vaccine develop ment has been challenging because of the diversity of Leptospira serovars and their variable geographic distribution. Protective clothing (i.e., boots, gloves, and goggles) should be worn by persons at risk for occupational exposure. In hospital settings, in addition to standard precautions, contact precautions are recommended for potential exposures to infected urine. Leptospirosis was successfully prevented in American soldiers stationed in the tropics by admin istering prophylactic doxycycline (200 mg PO once a week). This approach may be similarly effective for travelers to highly endemic areas for short periods; however, there are no specific pediatric data to support any prophylaxis regimen. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 1880 Part XV u Infectious Diseases Relapsing fever is characterized by recurring fevers and flulike symp toms such as headaches, myalgia, arthralgia, and rigors. ETIOLOGY Relapsing fever is an arthropod (lice or tick) transmitted infection caused by spirochetes of the genus Borrelia. Louse borne (epidemic) relapsing fever is caused by Borrelia recur rentis and is transmitted from person to person by Pediculus humanus, the human body louse. Human infection occurs as a result of crush ing lice during scratching, facilitating entry of infected hemolymph through abraded or normal skin or mucous membranes. Tick borne (endemic) relapsing fever is caused by several species of Borrelia and is transmitted to humans by Ornithodoros ticks. Borrelia hermsii and Borrelia turicatae are the common species in the western United States, whereas Borrelia dugesii is the major cause of disease in Mexico and Central America. Human infection occurs when saliva, coxal fluid, or excrement is released by the tick during feeding, thereby permitting spirochetes to penetrate the skin and mucous membranes. Borrelia miyamotoi has been identified in the Japanese Ixodes per sulcatus tick and in the Ixodes dammini tick, the agent that transmits Lyme disease in the northeastern United States. This Borrelia species causes a Lyme diseaselike illness rather than relapsing fever. EPIDEMIOLOGY Louse borne relapsing fever tends to occur in epidemics associated with war, poverty, famine, and poor personal hygiene, often in associa tion with typhus. This form of relapsing fever is no longer seen in the United States but is endemic in parts of East Africa. Using 16S ribo somal RNA (rRNA) polymerase chain reaction assays for molecular detection, up to 20.5 of all unexplained fever in the Horn of Africa, |
7,499 | including northwestern Morocco where the population traditionally lives in mud huts, is caused by tick borne relapsing fever, making this the most common cause of bacterial infections. Ornithodoros ticks, which transmit endemic relapsing fever and are distributed worldwide, including in the western United States, prefer warm, humid environments and high altitudes and are found in rodent burrows, caves, and other nesting sites (Fig. 267.1). Rodents (e.g., squirrels and chipmunks) are the principal reservoirs. Infected ticks gain access to human dwellings on the rodent host. Human contact is often unnoticed because these soft ticks have a painless bite and detach immediately after a short blood meal. PATHOLOGY AND PATHOGENESIS Relapsing fever is cyclical because the Borrelia organisms undergo anti genic (phase) variation. Multiple variants evolve simultaneously dur ing the first relapse, with one type becoming predominant. Spirochetes isolated during the primary febrile episode differ antigenically from those recovered during a subsequent relapse. During febrile episodes, spirochetes enter the bloodstream, induce the development of specific immunoglobulin M and G antibodies, and undergo agglutination, immobilization, lysis, and phagocytosis. During remission, Borrelia spi rochetes may remain in the bloodstream, but spirochetemia is insuffi cient to produce symptoms. The number of relapses in untreated patients depends on the number of antigenic variants of the infecting strain. CLINICAL MANIFESTATIONS Relapsing fever is characterized by febrile episodes lasting 2 9 days, separated by afebrile intervals of 2 7 days. Louse borne disease has an incubation period of 2 14 days, longer periods of pyrexia, fewer relapses, and longer remission periods than tick borne disease. The incubation period of tick borne disease is usually 7 days (range: 2 9 days). Each form of relapsing fever is characterized by sudden onset of high fever, lethargy, headache, photophobia, nausea, vomiting, myal gia, and arthralgia. Additional symptoms may appear later and include abdominal pain, a productive cough, mild respiratory distress, and bleeding manifestations, including epistaxis, hemoptysis, hematuria, and hematemesis. During the end of the primary febrile episode, a dif fuse, erythematous, macular, or petechial rash lasting up to 2 days may develop over the trunk and shoulders. There may also be lymphade nopathy, pneumonia, and splenomegaly. Hepatic tenderness associated with hepatomegaly is a common sign, with jaundice in half of affected children. Central nervous system manifestations include lethargy, stu por, meningismus, convulsions, peripheral neuritis, focal neurologic deficits, and cranial nerve paralysis and may be the principal feature of late relapses in tick borne disease. Severe manifestations include myo carditis, hepatic failure, and disseminated intravascular coagulopathy. The initial symptomatic period characteristically ends with a crisis in 2 9 days, marked by abrupt diaphoresis, hypothermia, hypoten sion, bradycardia, profound muscle weakness, and prostration. In untreated patients, the first relapse occurs within 1 week, followed by usually 3 but up to 10 relapses, with symptoms during each relapse becoming milder and shorter as the afebrile remission period lengthens. DIAGNOSIS Diagnosis depends on demonstration of spirochetes by dark field microscopy or in thin or thick blood smears stained with Giemsa or Wright stain and by |
7,500 | blood culture (Fig. 267.2). During afebrile remis sions, spirochetes are not found in the blood. Serologic tests have not been standardized, are generally not available, and produce cross reac tions with other spirochetes, including Borrelia burgdorferi, the agent of Lyme disease. Central nervous system involvement may be asso ciated with lymphocytic pleocytosis. Molecular methods, including nested polymerase chain reaction or 16S rRNA polymerase chain reac tion assays, have been used for detection of tick borne and louse borne recurrent fever and have been found to have improved sensitivity and specificity compared with blood smears. However, these assays are not yet routinely available for commercial use. TREATMENT Oral or parenteral tetracycline or doxycycline is the drug of choice for louse borne and tick borne relapsing fever. For children older than 8 years of age and young adults, tetracycline 500 mg PO every 6 hours or doxycycline 100 mg PO every 12 hours for 10 days is effective. Single dose treatment with tetracycline (500 mg PO) or Chapter 267 Relapsing Fever (Borrelia) Stephen K. Obaro and H. Dele Davies Each dot, placed randomly within the county of exposure (where known), represents one case. Each dot, placed randomly within the county of residence, represents one case. Fig. 267.1 Cases of tickborne relapsing feverUnited States, 1990 2011. During the years 19902011, 483 cases of tickborne relapsing fever were reported in the western United States, with infections being transmitted most frequently in California, Washington, and Colorado. (From Centers for Disease Control and Prevention CDC. Tick borne re lapsing fever: distribution. Available at: http:www.cdc.govrelapsing feverdistribution) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 268 u Lyme Disease (Borrelia burgdorferi) 1881 erythromycin is efficacious in adults, but experience in children is limited. In children younger than 8 years of age, erythromycin (50 mgkgday divided every 6 hours PO) for a total of 10 days is rec ommended, although there is evidence that doxycycline given for durations of less than 2 weeks is safe in children 2 years of age. Penicillin and chloramphenicol are also effective. Central nervous system involvement is usually responsive to intravenous ceftriaxone or penicillin. Resolution of each febrile episode either by natural crisis or as a result of antimicrobial treatment is often accompanied by the Jarisch Herxheimer reaction, which is caused by massive antigen release. Corticosteroid or antipyretic pretreatment does not prevent this reaction. PROGNOSIS With adequate therapy, the mortality rate for relapsing fever is 5. A majority of patients recover from their illness with or without treat ment after the appearance of anti Borrelia antibodies, which agglu tinate, kill, or opsonize the spirochete. However, pregnant women and their neonates are at increased risk for tick borne recurrent fever associated complications, including adult respiratory distress syndrome, Jarisch Herxheimer reaction, and precipitous or prema ture delivery. Neonates have up to a 33 case fatality rate. The risk of |
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