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7,501 | JarischHerxheimer reaction appears to be much higher in louse borne relapsing fever (LBRF) (55.8) compared to TBRF (19.3). However, they have similar overall case fatality rates, TBRF (6.5) and LBRF (410.2). PREVENTION No vaccine is available. Disease control requires avoidance or elimi nation of the arthropod vectors. In epidemics of louse borne disease, good personal hygiene and delousing of persons, dwellings, and cloth ing with commercially available insecticides can prevent dissemina tion. The risk for tick borne disease can be minimized in endemic areas by maintaining rodent free dwellings. Giving prophylactic dox ycycline for 4 days after a tick bite may prevent tick borne relapsing fever caused by Borrelia persica. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Fig. 267.2 Stained thin smear of a newborns peripheral blood show ing the presence of numerous spirochetes (indicated by arrows) at 63 magnificationColorado, 2011. (From Centers for Disease Control and Prevention CDC. Tickborne relapsing fever in a mother and newborn childColorado, 2011. MMWR Morb Mortal Wkly Rep. 2012;61:174 176.) Lyme disease is the most common vector borne disease in the United States and is an important public health problem. ETIOLOGY Lyme disease is a zoonotic infection caused by the transmission of the spirochete Borrelia burgdorferi sensu lato (broad sense) to humans via the bite of an infected tick of the Ixodes genus. In North America, B. burgdorferi sensu stricto (strict sense) causes almost all cases; another species in the upper Midwestern United States, Borrelia mayonii (belonging to the group B. burgdorferi sensu lato), also causes Lyme disease, but the illness is slightly different, with more diffuse rashes and gastrointestinal symptoms. In Europe, the species Borrelia afzelii and Borrelia garinii also cause disease. The three major outer surface pro teins, called OspA, OspB, and OspC (which are highly charged basic proteins of molecular weights of about 31, 34, and 23 kDa, respec tively), and the 41 kDa flagellar protein are important targets for the immune response. Differences in the molecular structure of the differ ent species are associated with differences in the clinical manifestations of Lyme borreliosis in Europe and the United States. These differences include the higher incidence of radiculoneuritis in Europe. TRANSMISSION In the eastern and midwestern United States, the vector for Lyme disease is Ixodes scapularis, the black legged tick that is commonly known as the deer tick. It is responsible for most cases in the United States. The vector on the Pacific Coast is Ixodes pacificus, the western black legged tick. Ixodes ticks have a 2 year, three stage life cycle. The larvae hatch in the early summer and are usually uninfected with B. burgdorferi. The tick can become infected at any stage of its life cycle by feeding on a host, usually a small mammal such as the white footed mouse (Peromyscus leucopus), which is a natural reservoir for B. burg dorferi. The larvae overwinter and emerge the following spring in the nymphal stage, which is the stage of the tick most likely to transmit the infection. The nymphs |
7,502 | molt to adults in the fall, and then adults spend the second winter attached to white tailed deer (Odocoileus virginia nus). The females lay their eggs the following spring before they die, and the 2 year life cycle begins again. Several factors are associated with increased risk for transmission of B. burgdorferi from ticks to humans. The proportion of infected ticks varies by geographic area and by the stage of the ticks life cycle. In endemic areas in the northeastern and midwestern United States, 1525 of nymphal ticks and 3550 of adult ticks are infected with B. burgdorferi. By contrast, I. pacificus often feeds on lizards, which are not a competent reservoir for B. burgdorferi, reducing the chance that these ticks will be infected. The risk for transmission of B. burgdorferi from infected Ixodes ticks is related to the duration of feeding. Experi ments in animals show that infected nymphal ticks must feed for 36 48 hours and infected adults must feed for 48 72 hours before the risk for transmission of B. burgdorferi becomes substantial. If the tick is recog nized and removed promptly, transmission of B. burgdorferi will not occur. Most patients with Lyme disease do not remember the tick bite that transmitted the infection. The habitat of tick species that carry B. burgdorferi may be geo graphically expanding in the United States because of climate change. I. scapularis also transmits other microorganisms, namely Anaplasma Chapter 268 Lyme Disease (Borrelia burgdorferi) Sanjeev K. Swami 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. 1882 Part XV u Infectious Diseases Fig. 268.1 The geographic distribution of Lyme disease cases in the United States. (From the Centers for Disease Control and Preven tion. Reported cases of Lyme diseaseUnited States, 2019. Available at: https:www.cdc. govlymedatasurveillancemaps recent.html) phagocytophilum and Babesia microti, as well as Borrelia miyamo toi. Simultaneous transmission can result in co infections with these organisms and B. burgdorferi. EPIDEMIOLOGY Lyme disease has been reported in more than 50 countries, including forested areas of Asia; northwestern, central, and eastern Europe; and eastern and midwestern United States. In Europe, most cases occur in the Scandinavian countries and in central Europe, especially Germany, Austria, and Switzerland, whereas in the United States, 92 of cases occurred in 16 states in 2019: Connecticut, Delaware, Maine, Mary land, Massachusetts, Minnesota, New Hampshire, New Jersey, New York, North Carolina, Pennsylvania, Rhode Island, Vermont, Virginia, West Virginia, and Wisconsin (Fig. 268.1). In 2019, the most recent year for which U.S. data are available, more than 23,000 confirmed cases and more than 11,000 probable cases were reported. The 3 year averaged national incidence is estimated at 7.8 cases per 100,000 population, and in recent years the national incidence has ranged from a low of 7.0 cases per 100,000 (2012) to a high of 9.1 cases per 100,000 (2017). In endemic areas, the reported annual |
7,503 | incidence ranges from 20 to 100 cases per 100,000 population, although this figure may be as high as 600 cases per 100,000 popula tion in hyperendemic areas. The reported incidence of disease by age is bimodal. There is an initial peak among children age 5 14 followed by a second peak among adults 55 69. In the United States, Lyme dis ease is diagnosed in males slightly more often than in females. Early Lyme disease usually occurs from spring to early fall, corresponding to deer tick activity. Late disease (primarily arthritis) occurs year round. Among adults, outdoor occupation and leisure activities are risk fac tors; for children, location of residence in an endemic area is the most important risk for infection. Lyme disease is designated a nationally notifiable disease by the CDC and Council for State and Territorial Epidemiologists. Health care providers, hospitals, laboratories, and other parties are required by law to notify local health departments when a confirmed or prob able case of Lyme disease occurs. The local health departments report cases to the state and territorial health departments; it is voluntary in turn for these authorities to report data to the CDC, and there fore the actual number of Lyme disease cases and incidence are likely underreported and underestimated. Lyme disease was the sixth most common notifiable disease reported to the CDC in 2019 (following Chlamydia trachomatis, gonorrhea, syphilis, campylobacteriosis, and salmonellosis). PATHOLOGY AND PATHOGENESIS Similar to other spirochetal infections, untreated Lyme disease is characterized by asymptomatic infection, clinical disease that can occur in stages, and a propensity for cutaneous and neurologic mani festations. The skin is the initial site of infection by B. burgdorferi. Disseminated Lyme disease results from the spread of spirochetes through the bloodstream to tissues throughout the body. The spiro chete adheres to the surfaces of a wide variety of different types of cells, but the principal target organs are the skin, central and periph eral nervous systems, joints, heart, and eyes. Because the organism can persist in tissues for prolonged periods, symptoms can appear very late after initial infection. The symptoms of disseminated Lyme disease are a result of inflam mation mediated by interleukin 1 and other lymphokines in response to the presence of the organism. It is likely that relatively few organisms actually invade the host, but cytokines serve to amplify the inflamma tory response and lead to much tissue damage. Lyme disease is charac terized by inflammatory lesions that contain both T and B lymphocytes, macrophages, plasma cells, and mast cells. The refractory symptoms of disseminated Lyme disease can have an immunogenetic basis. Per sons with certain HLA DR allotypes may be genetically predisposed to develop chronic Lyme arthritis. An autoinflammatory response in the synovium can result in clinical symptoms long after the bacteria have been killed by antibiotics. CLINICAL MANIFESTATIONS The clinical manifestations of Lyme disease are divided into early and disseminated stages. Older nomenclature included early localized dis ease, early disseminated disease, and late disease; early disseminated and late |
7,504 | disease have been combined into disseminated disease in the current nomenclature (Table 268.1). Untreated patients can progres sively develop clinical symptoms of each stage of the disease, or they can present with disseminated disease without having had any symp toms of the early Lyme disease. Early Disease The first clinical manifestation of Lyme disease in many patients is erythema migrans (Fig. 268.2). Although it usually occurs 7 14 days after the bite, the onset of the rash has been reported from 3 to 30 days later. The initial lesion occurs at the site of the bite. The rash is generally either uniformly erythematous or a target lesion with central clearing; rarely, there are vesicular or necrotic areas 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. in the center of the rash. Occasionally the rash is itchy or painful, although usually it is asymptomatic. The lesion can occur anywhere on the body, but the most common locations are the axilla, perium bilical area, thigh, and groin. It is not unusual for the rash to occur on the neck, face, or hairline, especially in young children. Without treatment, the rash gradually expands (hence the name migrans) to an average diameter of 15 cm and typically remains present for 1 2 weeks. Erythema migrans may be associated with systemic fea tures, including fever, myalgias, arthralgias, headache, or malaise; gastrointestinal symptoms are rare. Coinfection with B. microti or A. phagocytophilum during early infection with B. burgdorferi is associated with more severe systemic symptoms. Co infections should be suspected with unusual features of Lyme disease, poor response to appropriate antibiotics, prolonged fever, or laboratory abnormalities that include anemia, leukopenia, thrombocytopenia, or elevated liver enzymes. Disseminated Disease In the United States, approximately 20 of patients with acute B. burgdorferi infection develop secondary (multiple) erythema migrans lesions, a common manifestation of disseminated Lyme disease, caused by hematogenous spread of the organisms to multiple skin sites (Fig. 268.3). The secondary lesions, which can develop several days or weeks after the first lesion, are usually smaller than the pri mary lesion and are often accompanied by more severe constitutional symptoms. The lesions may not have the classic appearance of ery thema migrans; they may lack central clearing, appear oval in shape, or have irregular borders. The most common neurologic manifesta tions are peripheral facial nerve palsy and meningitis. Peripheral (or cranial) nerves other than the facial nerve may be affected, and patients can present with multiple concurrent nerve palsies. Lyme meningitis usually has an indolent onset with days to weeks of symp toms (longer than viral meningitis) that can include headache, neck pain and stiffness, and fatigue. Fever is variably present. Patients can present with both peripheral nerve palsy and meningitis, but typi cally they have either central nervous system or peripheral nervous system disease. The clinical findings of papilledema, cranial neuropathy (especially |
7,505 | cranial nerve VII), and erythema migrans, which are present individu ally or together in up to 90 of cases, help differentiate Lyme meningi tis from viral meningitis, in which these findings are rarely present. The aseptic meningitis caused by Lyme disease can be accompanied by sig nificant elevations of intracranial pressure, which can sometimes last weeks or even months. All the cranial nerves except the olfactory have been reported to be involved with Lyme disease, but the most common are VI and especially VII. In endemic areas, Lyme disease is the leading cause of peripheral facial nerve palsy. It is often the initial or the only manifestation of Lyme disease and is sometimes bilateral. The facial paralysis usually lasts 2 8 weeks and resolves completely in most cases. Radiculoneuritis and other peripheral neuropathies can occur but are more common in Europe. Cardiac involvement occurs in 515 of disseminated Lyme disease (overall 1 of Lyme infections) and usually takes the form of heart block, which can be first, second, or third degree, and the rhythm can fluctuate rapidly. Rarely, myocardial dysfunction (myocarditis) can occur. Patients presenting with suspected or proven disseminated Lyme disease should have a careful cardiac examination, and elec trocardiography should be strongly considered, especially if patients report chest pain, palpitations, or presyncopal symptoms. Lyme cardi tis is a treatable condition and is the only manifestation of Lyme disease that has been fatal. Papilledema and uveitis are most common ocular conditions associ ated with Lyme disease; optic neuritis has also been reported. Arthritis is the most common manifestation of disseminated Lyme disease and begins weeks to months (possibly years) after the initial infection. Lyme arthritis is classically a monoarticular, nonmigratory arthritis affecting the large joints. The knee is the Chapter 268 u Lyme Disease (Borrelia burgdorferi) 1883 Fig. 268.3 Multiple erythema migrans in early disseminated Lyme disease. Table 268.1 Clinical Stages of Lyme Disease DISEASE STAGE TIMING AFTER TICK BITE TYPICAL CLINICAL MANIFESTATIONS Early localized 3 30 days Erythema migrans (single), variable constitutional symptoms (headache, fever, myalgia, arthralgia, fatigue) Disseminated 3 12 wk Erythema migrans (single or multiple), worse constitutional symptoms, cranial neuritis, meningitis, carditis, ocular disease Disseminated 2 mo Arthritis A B Fig. 268.2 Skin manifestations of Lyme borreliosis. A, Erythema mi grans on the upper leg, showing central clearing. B, Erythema migrans of the arm showing bulls eye appearance. (A from Stanek G, Strle F. Lyme borreliosis. Lancet. 2003;362:16391647.) 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. 1884 Part XV u Infectious Diseases most commonly infected joint followed by the hip. Lyme arthritis can occasionally be oligoarticular or migratory. The hallmark of Lyme arthritis is joint swelling, which is a result of synovial effu sion and sometimes synovial hypertrophy. The swollen joint may be only mildly symptomatic, or less often, it may be painful and tender, although patients usually do not |
7,506 | experience the severe pain and sys temic toxicity that are common with pyogenic arthritis. Micromo tion tenderness is rare with Lyme arthritis. If untreated, the arthritis can last several weeks, resolve, and then be followed by recurrent attacks in the same or other joints. Other manifestations of Lyme disease involving the central nervous system, sometimes termed late neuroborreliosis, are rarely reported in children. In adults, chronic encephalitis and polyneuritis have been attributed to Lyme disease. The term Lyme encephalopathy has been used to describe chronic encephalitis (demonstrable by objective measures), but other literature has also used this term in reference to memory loss and other cognitive sequelae after Lyme disease has been treated. At times, the vague and mistaken term chronic Lyme disease has been used to describe symptomatology in persons who might have never had well documented infection with B. burgdorferi at all, have serologic evidence of prior infection but current symptoms not con sistent with Lyme disease, or have persistent symptoms after having received appropriate antibiotic therapy. Prolonged treatment does not treat the chronic neuropsychiatric symptoms and at times has harmed the patient. Some patients experience prolonged symptoms after treatment of early or disseminated Lyme disease; these symptoms frequently include fatigue, headaches, myalgias, arthralgias, and difficulty thinking. This phenomenon is termed posttreatment Lyme disease syndrome. The etiology for this process is unclear, but prolonged antibiotic treatment has not been shown to hasten recovery and has been associated with harm. Most patients have symptom resolution by 6 months without antibiotic therapy. Congenital Lyme Disease In endemic areas, infection can occur during pregnancy, and although congenital infection appears to be a rare event, there is no recognized congenital infection syndrome associated with Lyme disease. B. burg dorferi has been identified from several abortuses and from a few live born children with congenital anomalies; however, the tissues in which the spirochete has been identified usually have not shown histologic evidence of inflammation. Severe skin and cardiac manifestations have been described in a few cases, but studies conducted in endemic areas have indicated that there is no difference in the prevalence of congeni tal malformations among the offspring of women with serum anti bodies against B. burgdorferi and the offspring of those without such antibodies. LABORATORY FINDINGS Standard laboratory tests rarely are helpful in diagnosing Lyme disease because any associated laboratory abnormalities usually are nonspe cific. The peripheral white blood cell count may be either normal or elevated. The erythrocyte sedimentation rate (ESR) may be mildly elevated. Liver transaminases are occasionally mildly elevated. In Lyme arthritis, the white blood cell count in joint fluid can range from 25,000 to 100,000mL, often with a preponderance of polymorphonuclear cells. A lower ESR (40) and C reactive protein and a peripheral blood absolute neutrophil count of less than 10,000 may help to differentiate Lyme from septic arthritis. When meningitis is present, there usually is a low grade pleocytosis with a lymphocytic and monocytic predomi nance. The cerebrospinal fluid (CSF) protein level may be elevated, but |
7,507 | the glucose concentration usually is normal. Gram stain and routine bacterial cultures are negative. Imaging of the central nervous system (e.g., magnetic resonance imaging and single photon emission com puted tomography) occasionally reveals abnormalities, but there is no definitive pattern in Lyme disease. The main role of imaging is to exclude other diagnoses. DIAGNOSIS In the appropriate epidemiologic setting (endemic area, season), typi cal erythema migrans is pathognomonic. Occasionally, the diagno sis of erythema migrans may be difficult because the rash initially can be confused with nummular eczema, tinea corporis, granuloma annulare, an insect bite reaction, southern tickassociated rash illness, or cellulitis. The relatively rapid expansion of erythema migrans helps distinguish it from these other skin lesions. The other clinical manifestations of Lyme disease are less specific and may be confused with other conditions; the monoarticular or oligoar ticular arthritis sometimes is confused with a septic joint or other causes of arthritis in children, such as juvenile idiopathic arthritis or rheumatic fever; the facial nerve palsy caused by Lyme disease is clinically indistinguishable from Bell palsy, although bilateral involvement is much more common with Lyme disease; Lyme men ingitis generally occurs in the warmer months, the same period that enteroviral meningitis is prevalent. Therefore for all disease mani festations other than erythema migrans, it is recommended to have laboratory confirmation of infection with B. burgdorferi. Although B. burgdorferi has been isolated from the blood, skin, CSF, myocardium, and synovium of patients with Lyme disease, the organism is difficult to isolate in culture (cultivation is largely rele gated to research laboratories). Infection is usually identified by the detection of antibody in serum. Although some laboratories offer polymerase chain reaction as a diagnostic test for Lyme disease, its sensitivity is poor because of the low concentrations of bacteria in many sites, especially CSF. Other antigen based tests, including a test for B. burgdorferi antigens in urine, are unreliable. Clinicians should be aware that some laboratories use alternative diagnostic tests andor alternative interpretive criteria that are not evidence based, leading to a false diagnosis of Lyme disease. The CDC and the Food and Drug Administration recommend against using these tests. Serology After the transmission of B. burgdorferi from a tick bite, specific immunoglobulin (Ig) M antibodies appear first, usually within 2 weeks, peak at 6 8 weeks, and subsequently decline. Sometimes a pro longed or recurrent elevation of IgM antibodies occurs despite effec tive antimicrobial treatment. Elevated IgM levels after 6 8 weeks are often false positives. Specific IgG antibodies usually appear between 2 and 6 weeks, peak after 4 6 months, and can remain elevated for years, particularly in patients with arthritis. The antibody response to B. burgdorferi may be blunted in patients with early Lyme disease who are treated promptly with an effective antimicrobial agent. Sero diagnosis during the first 4 weeks of infection is not sensitive and may need to be repeated. Historically, the most common method used to detect IgG and IgM antibodies has been the enzyme linked immunosorbent |
7,508 | assay (ELISA). This method is sensitive but not optimally specific. The ELISA sometimes produces false positive results because of antibodies that cross react with other spirochetal infections (e.g., B. miyamotoi, syphi lis, leptospirosis, or relapsing fever), or certain viral infections (e.g., Epstein Barr virus), or that occur in certain autoimmune diseases (e.g., systemic lupus erythematosus). The positive predictive value of the ELISA result depends primarily on the plausibility that the patient has Lyme disease based on the clinical and epidemiologic history and the physical examination (the pretest probability). For patients who have been in endemic areas with opportunities for Ixodes tick expo sure and who have typical clinical manifestations of Lyme disease, the pretest probability is high, and positive ELISA results are usually true positives. For patients who are from nonendemic areas andor who have little risk for Ixodes tick exposures andor have nonspecific symp toms (low pretest probability), rates of false positive results are high. Infection with B. miyamotoi may cause false positive ELISA tests for Lyme disease. This syndrome of relapsing fever, headache, and myalgia 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) 1885 but no rash with neutropenia or thrombocytopenia is uncommon in Lyme disease. Western immunoblotting is well standardized, and there are accepted criteria for interpretation. Five of 10 IgG bands and 2 of 3 IgM bands are considered reactive. The Western blot is not as sensi tive as ELISA, especially in early infection, but is highly specific. Any positive or equivocal ELISA can be confirmed with Western blotting. The CDC recommends using IgM and IgG Western blot confirmation when symptoms have been present 30 days and IgG only when symptoms have been present longer than 30 days. Two tier testing is the recommended laboratory evaluation of most cases of Lyme disease and is associated with a high degree of sensitivity and specificity when used appropriately. Two tier assays using serial ELISAs have been developed that have similar or better sensitivity and specificity when compared with ELISA followed by Western blot. The serial ELISA methodology can have improved turn around time and has two quantitative tests rather than a quantitative test followed by a test that requires interpretation. Stand alone ELISAs have also been developed that have similar sensitivity and specificity when compared with two tier testing. Clinicians should be aware that Lyme disease might not be the cause of a patients symptoms despite the presence of antibodies to B. burgdorferi. The test result may be falsely positive (as described for ELISA), or the patient might have been infected previously. Antibodies to B. burgdorferi that develop with infection can per sist for many years despite adequate treatment and clinical cure of the disease. In addition, because some people who become infected with B. burgdorferi are asymptomatic, the background rate of sero positivity among |
7,509 | patients who have never had clinically apparent Lyme disease may be substantial in endemic areas. Finally, because antibodies against B. burgdorferi persist after successful treatment, there is no reason to obtain follow up serologic tests. TREATMENT Table 268.2 provides treatment recommendations. Most patients can be treated with oral antibiotics. Young children are generally treated with amoxicillin. Doxycycline has the advantages of good central nervous system penetration and activity against A. phago cytophilum, which may be transmitted at the same time as B. burg dorferi in certain geographic areas. Historically, children 8 years were not treated with doxycycline because of the risk of staining of the permanent teeth. Data from the CDC have shown that this is not a concern for treatment courses 2 weeks. Doxycycline oral solution is still challenging to find, so most younger children are prescribed amoxicillin. There are no data that show a difference in efficacy between amoxicillin and doxycycline for the treatment of Lyme disease. Patients who are treated with doxycycline should be alerted to the risk for developing photosensitivity in sun exposed areas while taking the medication; thus long sleeves, long pants, and a hat are recommended for activities in direct sunlight. The only oral cephalosporin proved to be effective for the treatment of Lyme disease is cefuroxime axetil, which is an alternative for persons who cannot take doxycycline or who are allergic to penicillin. There is no reported resistance of B. burgdorferi to these antibiotics. Mac rolide antibiotics, including azithromycin, appear to have limited activity and are only recommended for patients allergic to all of the other active medications. Parenteral therapy is usually recommended for patients with higher degrees of heart block or central nervous system involve ment, although oral therapy for meningitis is also considered acceptable for ambulatory patients. Patients with arthritis that fails to resolve after an initial course of oral therapy can be retreated with an oral regimen or can receive intravenous antibiotic therapy. Ceftriaxone is favored because of its excellent anti Borrelia activity, tolerability, and once daily dosing regimen, which can usually be done on an outpatient basis. Peripheral facial nerve palsy can be treated using an oral antibiotic. Experts are divided on whether every patient with Lyme associated facial palsy needs a CSF analysis, but clinicians should consider lumbar puncture for patients with significant headache, neck pain or stiffness, or papilledema. Patients with symptomatic cardiac disease, second or third degree heart block, or significantly prolonged PR interval should be hospital ized and monitored closely. These patients should receive a parenteral antibiotic for their initial treatment. Patients with first degree heart block can be treated with an oral antibiotic, and patients with high degrees of heart block can be transitioned to oral treatment as their heart block resolves. Some patients develop a Jarisch Herxheimer reaction soon after treatment is initiated; this results from lysis of the Borrelia. The mani festations of this reaction are low grade fever and achiness. These symptoms resolve spontaneously within 24 48 hours, and administra tion |
7,510 | of nonsteroidal antiinflammatory drugs often is beneficial. Nonste roidal antiinflammatory drugs also may be useful in treating symptoms of early Lyme disease and of Lyme arthritis. Co infections with other pathogens transmitted by Ixodes ticks should be treated according to standard recommendations. There is no clear evidence that posttreatment Lyme disease syn drome is related to persistence of the organism. Studies in adults have Table 268.2 Recommended Treatment of Lyme Disease DRUG PEDIATRIC DOSING Amoxicillin 50 mgkgday in 3 divided doses (max: 1,500 mgday) Doxycycline 4.4 mgkgday in 2 divided doses (max: 200 mgday) (see text regarding doxycycline use in children) Cefuroxime axetil 30 mgkgday in 2 divided doses (max: 1,000 mgday) Ceftriaxone (IV), 50 75 mgkgday once daily (max: 2,000 mgday) Azithromycin 10 mgkgday once daily 7 days RECOMMENDED THERAPY BASED ON CLINICAL MANIFESTATION Erythema migrans Doxycycline 10 days Amoxicillin 14 days Cefuroxime 14 days Meningitis, radiculopathy Doxycycline 14 21 days or Ceftriaxone 14 days (14 21 for hospitalized patients) Cranial nerve palsy Doxycycline 14 21 days Cardiac disease Oral regimen or ceftriaxone 14 21 days (see text for specifics) Arthritis Oral regimen 28 days Persistent or recurrent arthritis after initial treatment Oral regimen 28 days or Ceftriaxone 14 28 days Borrelial lymphocytoma Doxycycline, amoxicillin, cefuroxime 14 days Penicillin G is an alternative parenteral agent but requires more frequent dosing. Doses of 100 mgkgday should be used for meningitis. For those unable to take amoxicillin or doxycycline. Treatment is to prevent late disease, not to treat the cranial palsy; avoid corticosteroids. 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. 1886 Part XV u Infectious Diseases not shown benefit with prolonged or repeated treatment with oral or parenteral antibiotics. PROGNOSIS There is a widespread misconception that Lyme disease is difficult to cure and that chronic symptoms and clinical recurrences are common. The most likely reason for apparent treatment failure is an incorrect diagnosis of Lyme disease. The prognosis for children treated for Lyme disease is excellent. Children treated for erythema migrans rarely develop symptoms of late Lyme disease. The long term prognosis for patients who are treated beginning in the later stages of Lyme disease also is excellent. Although chronic and recurrent arthritis may occur, especially among patients with certain human leukocyte antigen allotypes (an autoimmune pro cess), most children who are treated for Lyme arthritis are cured and have no sequelae. Although there are rare reports of adults who have developed late neuroborreliosis, usually among persons with Lyme dis ease in whom treatment was delayed for months or years, similar cases in children are rare. PREVENTION The best way to avoid Lyme disease is to avoid tick infested areas (Table 268.3). Children should be examined for deer ticks after known or potential exposure (although many people are not able to identify the species or the stage of the tick). If a tick attachment |
7,511 | is noted, the tick should be grasped at the mouthparts with a forceps or tweezers; if these are not available, the tick should be covered with a tissue (Table 268.4). The recommended method of tick removal is to pull directly outward without twisting; infection is usually preventable if the tick is removed before 36 hours of attachment; at this time the ticks are flat and nonen gorged (Fig. 268.4). The overall risk for acquiring Lyme disease after a tick bite is low (13) in most endemic areas. If the tick is engorged and present for 72 hours (a high risk tick bite), the risk of infection may increase to 25 in hyperendemic areas. Patients and families should be advised to watch the area for development of erythema migrans and to seek medi cal attention if the rash or constitutional symptoms occur. If infection develops, early treatment of the infection is highly effective. Prophy laxis after a high risk tick bite with a single dose of oral doxycycline in adults (200 mg) or 4.4 mgkg in children is effective in reducing the risk of Lyme disease. The routine testing of ticks that have been removed from humans for evidence of B. burgdorferi is not recommended because the value of a positive test result for predicting infection in the human host is unknown. Personal protective measures that may be effective in reducing the chance of tick bites include wearing protective clothing (long pants tucked into socks, long sleeved shirts) when entering tick infested areas, checking for and promptly removing ticks, and using tick repellents such as N,N diethyl 3 methylbenzamide (DEET) (see Table 268.3). This chemical can safely be used on pants, socks, and shoes; care must be used with heavy or repeated application on skin, Table 268.3 Personal Prevention Measures BEFORE VENTURING OUTSIDE DURING ANDOR AFTER EXPOSURE TO TICK HABITAT Personal prevention measures Conduct a thorough tick check of extremities, torso, and areas where ticks may be visually obscured (e.g., axilla, nape of neck, hairline, in and around ears, umbilicus, groin, popliteal fossa) Avoid risky habitats Bathe or shower within 2 hr Wear light colored clothing Dry clothes on high heat for at least 10 min; if not possible, wash clothes in hot water Wear long sleeves and pants Tuck pants into socks or footwear Wear permethrin treated clothing Use an EPA approved repellent or insecticide as per manufacturers instructions If an attached tick is detected Remove properly and clean bite area DEET https:www.cdc.govlyme removalindex.html Picaridin Tip: Store tick (e.g., in sealed containerplastic bag, wrapped in clear tape, or taped to a piece of paper). Label with date and likely geographic location of exposure. IR3535 See clinician and show tick if concerned that it is an Ixodes spp. and has fed at least 36 hr. Oil of lemon eucalyptus (OLE) Monitor health for symptoms of Lyme disease and other tick borne diseases p Methane 3,8 diol (PMD) 2 undecanone Permethrin (for application to clothing and gear only) Tip: Have handy a |
7,512 | fine tipped tweezers, tick storage container, and hand sanitizer. Continue to conduct a tick check whenever possible to detect and remove feeding ticks as soon as possible. DEET, N,N Diethyl meta toluamide; EPA, Environmental Protection Agency. From Lantos PM, Rumbaugh J, Bockenstedt LK, et al. Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA), American Academy of Neurology (AAN), and American College of Rheumatology (ACR): 2020 Guidelines for the Prevention, Diagnosis and Treatment of Lyme Disease. Clin Infect Dis. 2021;72(1):e1e48, Table 5, p. e13. Table 268.4 Management of a Suspected Ixodes Tick Bite in the United States DO DO NOT 1. Remove tick with clean fine tipped tweezers (or other comparable device). 1. Do not use other nonmechanical methods for tick removal. 2. Identify tick. Send to a laboratory, refer to an online resource. 2. Do not test tick for pathogens (e.g., send for PCR). 3. Determine if tick meets high risk criteria. a. Identified as Ixodes vector species b. Bite occurred in a highly endemic area c. Attached for 36 hr 3. Do not initiate prophylaxis in any other scenario. Consider initiating prophylaxis if a, b, and c are met AND it is within 72 hr of tick removal. See dosing in the footnote. Doxycycline is given as a single oral dose, 200 mg for adults and 4.4 mgkg (up to a maximum dose of 200 mg) for children. PCR, Polymerase chain reaction. From Lantos PM, Rumbaugh J, Bockenstedt LK, et al. Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA), American Academy of Neurology (AAN), and American College of Rheumatology (ACR): 2020 Guidelines for the Prevention, Diagnosis and Treatment of Lyme Disease. Clin Infect Dis. 2021;72(1):e1e48, Table 6, p. e13. 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 269 u Mycoplasma pneumoniae 1887 Wait and watch Consider for prophylaxis Wait and watch Consider for prophylaxis Unfed Day 1.5 Day 2 Day 2.5 Day 3 Day 4 Unfed Day 1.5 Day 2 Day 3 Day 4 Day 7 Fig. 268.4 Relative sizes of engorging nymphal and adult female Ixodes scapularis (black legged deer tick) as a function of time spent feeding ( attachment time). Transmission of Borrelia burgdorferi requires 36 48 hr of feeding, and therefore antibiotic prophylaxis is recommended only if the tick has been attached for at least 36 hr, or 1.5 days. By itself, duration of feeding is insufficient for recommending antibiotic prophylaxis. (Top) Nymphs (Feeding time: Unfed 0 hr; Day 1.5 36 hr; Day 2 48 hr; Day 2.5 60 hr; Day 3 72 hr; Day 4 96 hr). (Bottom) Adult females over the same period. Unfed nymph and adult female are the sizes of poppy and sesame seeds, respectively. Not actual size. (Courtesy of URI TickEncounter Resource Center, TickEncounter.org; From Lantos PM, Rumbaugh J, Bockenstedt LK, et al. Clinical Practice Guidelines by the |
7,513 | Infectious Diseases Society of America IDSA, American Academy of Neurology AAN, and American College of Rheumatology ACR: 2020 Guidelines for the Preven tion, Diagnosis and Treatment of Lyme Disease. Clin Infect Dis. 2021;721:e1e48, Fig. 6.) Among the few Mycoplasma species isolated from the human respira tory tract, Mycoplasma pneumoniae remains the most common species causing respiratory infections in school age children and young adults and is associated with a variety of clinical manifestations. THE ORGANISM Mycoplasmas are the smallest self replicating prokaryotes known to cause disease in humans. Their size of 150 250 nm is more on the order of viruses than bacteria. M. pneumoniae is a fastidious double stranded DNA bacterium that is distinguished by a small genome (800,000 base pairs) and a long doubling time, which makes culturing it a slow Chapter 269 Mycoplasma pneumoniae Asuncion Mejias and Octavio Ramilo Section 9 Mycoplasmal Infections process (5 20 days) compared to other bacteria. M. pneumoniae iso lates can be classified in two major genetic groups (subtypes 1 and 2) based on the P1 adhesion protein. Distinguishing these two subtypes is important for epidemiologic purposes. Like other mycoplasmas, M. pneumoniae is distinguished by the complete absence of a cell wall, resulting in (1) their dependence on host cells for obtaining essential nutrients, (2) their intrinsic resistance to lactam agents, and (3) their pleomorphic shape and lack of visibility on Gram staining. EPIDEMIOLOGY M. pneumoniae infections occur worldwide and throughout the year. This organism is a frequent cause of community acquired pneumonia (CAP) in children 5 years of age and adults, accounting for 20 of all CAP in middle school and high school children and up to 50 of CAP in college students and military recruits. The proportion of cases increases accord ing to age, as recently shown in a large population based study of CAP conducted in the United States (3 in 5 years, 17 in 5 9 years, and 24 in 10 17 years). In contrast to the acute, short lived epidemics associated with some respiratory viruses, M. pneumoniae infection occurs endemically world wide. Epidemic outbreaks of variable intensity occur every few years and are likely related to the alternative circulation of the two M. pneumoniae subtypes. Transmission occurs through the respiratory route by large droplet spread during close contact with a symptomatic person. Commu nity outbreaks have been described in closed settings (colleges, boarding schools, military bases) and can spread largely through school contacts. Attack rates within families are high, with transmission rates of 4080 for household adult and children contacts, respectively. In contrast to many other respiratory infections, the incubation period is 2 3 weeks; hence, the course of infection in a specific population (family) may last several weeks. The occurrence of mycoplasma illnesses is related, in part, to age and preexposure immunity. Overt illness is less common before 3 years of age but can occur. Children younger than 5 years of age appear to have milder illnesses associated with upper respiratory tract involvement, vomiting, and diarrhea. |
7,514 | Immunity after infection is not long lasting, as evidenced by the frequency of reinfections over time. Other pathogens particularly in infants, because of the risk of systemic absorption and toxicity. Permethrin treatment of clothing is also an effective preven tion strategy. 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. 1888 Part XV u Infectious Diseases are frequently co detected in children with M. pneumoniae, especially in those younger than 2 years of age, where viral co infections have been identified in up to 30 of cases. Asymptomatic carriage after infection can last up to 4 months despite antibiotic therapy and may contribute to prolonged outbreaks. Children are often the reservoir from whom mycoplasma spreads. In the clinical setting, there are no available tools yet to differentiate carriage vs infection. PATHOGENESIS The pathogenicity of M. pneumoniae is dependent on its extracellular attachment and the initiation of the host cell immune response. The mechanisms by which M. pneumoniae causes disease include (1) direct bacterial invasion that initiates in the cells of the ciliated respiratory epithelium, the target cells of M. pneumoniae infection; (2) toxin medi ated through the production of the adenosine diphosphateribosyl ating and vacuolating toxin termed community acquired respiratory distress syndrome (CARDS), an exotoxin that may damage the respira tory tract and has been associated with more severe or even fatal dis ease; and (3) indirect immune mediated effects, by altering antigens in the cell surface and inducing the production of autoantibodies. The organism is an elongated snakelike structure with a one end organ elle, which mediates the attachment to sialic acid receptors in the cilia through a complex set of adhesion transmembrane proteins (P1, P30, proteins B and C, P116, and HMW1 3). Virulent organisms attach to cili ated respiratory epithelial cell surfaces located in the bronchi, bronchioles, alveoli, and possibly upper respiratory tract and burrow down between cells, resulting in ciliostasis and eventual sloughing of the cells. This bacte rium is capable of forming biofilms, with strain specific phenotypic differ ences, which hinder antibiotic penetration and recognition by the immune system. Once M. pneumoniae reaches the lower respiratory tract, it pro motes the polyclonal activation of B lymphocytes and CD4 T cells and amplifies the immune response with the production of various proin flammatory and antiinflammatory cytokines and chemokines, such as tumor necrosis factor , interleukin (IL) 8, IL 1, Il 6, and IL 10. Although it is well documented that specific cell mediated immu nity and antibody titers against M. pneumoniae increase with age (and therefore probably follow repeated infections), the immune mecha nisms that protect against or clear the infection are not well defined. In humans, nasal IgA antibodies correlated with protection after experi mental challenge. A distinct aspect of M. pneumoniae is its ability to induce the production of cold agglutinins (IgM |
7,515 | antibodies) directed against the I antigen on the erythrocytes surface. Even though anti body responses do not confer complete protection against reinfections, the importance of a robust humoral response is apparent, because patients with congenital antibody deficiencies, such as those with hypogammaglobulinemia, can develop severe and prolonged disease and have a higher risk of extrapulmonary manifestations. In children with sickle cell disease or sickle related hemoglobinopathies, M. pneu moniae is a common infectious trigger of acute chest syndrome. These children and also children with Down syndrome can develop severe Mycoplasma pneumonia. On the other hand, M. pneumoniae does not seem to be a common infectious agent in patients with AIDS. M. pneumoniae has been detected by polymerase chain reaction (PCR) in many nonrespiratory sites, including blood, pleural fluid, cerebrospinal fluid (CSF), and synovial fluid. The mechanisms of extra pulmonary disease associated with M. pneumoniae are unclear and appear to be different according to the duration of symptoms at the time of presentation: direct invasion vs immune mediated. CLINICAL MANIFESTATIONS M. pneumoniae is a frequent cause of upper and lower respiratory tract infections in children and adolescents. The clinical manifestations of M. pneumoniae can be divided into respiratory (more common) and extrapulmonary (less common). Respiratory Tract Disease Tracheobronchitis and atypical pneumonia are the most commonly rec ognized clinical syndromes associated with M. pneumoniae. This agent is responsible for up to 20 of all cases of CAP. The clinical manifestations of M. pneumoniae pneumonia evolve according to the stage of the disease. The onset is usually characterized by gradual development of headache, malaise, fever, and sore throat, followed by progression of lower respiratory symptoms, including hoarseness and nonproductive cough. The gradual onset in children with atypical pneumonia is in contrast to the sudden onset of lobar pneumonia. Coryza and gastrointestinal manifestations are unusual and suggest a viral etiology, if present. Approximately 10 of children will develop a cutaneous maculopapular rash. Although the clini cal course in untreated patients is variable, cough, the clinical hallmark of M. pneumoniae infection, usually worsens during the first week of illness. Symptoms generally resolve within 2 weeks, although cough can last up to 4 weeks and may be accompanied by wheezing. Chest examination may be unrevealing, even in patients with severe cough. There may be no auscultative or percussive findings or only mini mum dry rales. Clinical findings are often less severe than suggested by the chest radiograph, explaining why the term walking pneumonia is often used to describe CAP caused by M. pneumoniae. Radiographic findings are variable and nonspecific, not allowing differentiation from viral or bacterial pathogens. Bilateral diffuse infiltrates, lobar pneumonia, or hilar lymphadenopathy can occur in up to 30 of patients. Although unusual, large pleural effusions associated with lobar infiltrates and necrotizing pneumonia have been described in patients with immunodeficiency, Down syndrome, chronic cardiopulmonary disease, and sickle cell disease. The white blood cell and differential counts are usually normal, whereas the erythrocyte sedimentation rate and C reactive protein are often ele vated. Appropriate antibiotics |
7,516 | shorten the duration of illness but do not reliably eradicate the organism from the respiratory tract. Other respiratory illnesses occasionally caused by M. pneumoniae include undifferentiated upper respiratory tract infections; intractable, nonproductive cough; pharyngitis (usually without marked cervical lymphadenopathy); sinusitis; croup; and bronchiolitis. M. pneumoniae is a common trigger of wheezing in asthmatic children and can cause chronic colonization in the airways, resulting in lung dysfunction in adolescent and adult asthmatic patients. Otitis media and bullous myringitis, which also occur with other viral and bacterial infections, have been described but are rare, and their absence should not exclude the diagnosis of M. pneumoniae. Extrapulmonary Disease Despite the reportedly rare isolation of M. pneumoniae from non respiratory sites, the improved sensitivity of PCR for M. pneumoniae DNA detection has led to increasing identification of this bacterium in nonrespiratory sites, particularly the central nervous system (CNS). Patients with or without respiratory symptoms can have involvement of the skin, CNS, blood, heart, gastrointestinal tract, and joints. Extra pulmonary manifestations have been documented in 1126 of chil dren with M. pneumoniae infection and include: 1. CNS disease: Occurs in 0.1 of all patients with M. pneumoniae infection and in 7 of those requiring hospitalization. Manifesta tions include encephalitis, acute disseminated encephalomyelitis (ADEM), transverse myelitis, cerebellar ataxia, aseptic meningitis, Guillain Barr syndrome, Bell palsy, and peripheral neuropathy. CNS disease manifestations occur 3 23 days (mean: 10 days) after onset of respiratory illness but may not be preceded by any signs of respiratory infection in up to 20 of cases. Studies in children suggest that there are two pathogenic mechanisms for M. pneumo niaeassociated neurologic disease: the first pattern is characterized by almost absent or no prodromal respiratory symptoms (7 days) and nonreactive IgM responses. On the other hand, the second pat tern is characterized by the presence of respiratory symptoms (most commonly cough) for 7 days and reactive IgM in acute serum. In the first group M. pneumoniae is usually identified in CSF by PCR but not in the respiratory tract, whereas in children presenting with 7 days of respiratory symptoms, the opposite is true. These stud ies suggest that encephalitis occurring more than 7 days after onset of prodromal symptoms is more likely to be caused by an autoim mune response to M. pneumoniae, whereas its occurrence early in the course of the disease may be associated with direct bacterial in vasion of the CNS. Involvement of the brainstem can result in severe 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 269 u Mycoplasma pneumoniae 1889 dystonia and movement disorders. The CSF may be normal or have mild mononuclear pleocytosis andor increased CSF protein con centrations with normal glucose. Diagnosis is confirmed with posi tive CSF PCR, positive PCR from a throat swab, or demonstration of seroconversion. Findings on MRI include focal ischemic changes, ventriculomegaly, diffuse edema, |
7,517 | or multifocal white matter inflam matory lesions consistent with postinfectious ADEM. Long term sequelae have been reported in 2364 of cases. 2. Mucocutaneous disease: Up to 25 of children with M. pneumoniae infections can have associated skin and mucosal exanthems, most no tably maculopapular rashes, urticaria, and Mycoplasma induced rash and mucositis syndrome (MIRM) or Stevens Johnson syndrome (SJS). Gianotti Crosti syndrome and erythema nodosum are also associated with M. pneumoniae infections. Approximately 10 of children with M. pneumoniae CAP will exhibit a maculopapular rash. Mycoplasma induced rash and mucositis usually develop 3 21 days after initial res piratory symptoms, last less than 14 days, and are rarely associated with severe complications (Figs. 269.1 and 269.2). M. pneumoniae may also produce an isolated oral mucositis in absence of a rash. 3. Hematologic abnormalities: Include mild degrees of hemolysis with a positive Coombs test and minor reticulocytosis 2 3 weeks after the onset of illness. Severe hemolysis is associated with high titers of cold hemagglutinins (1:512) and occurs rarely. Thrombocyto penia, aplastic anemia, hemophagocytic syndrome, and coagulation defects occur occasionally. 4. Musculoskeletal: Arthritis appears to be less common in children than in adults, but monoarthritis, polyarthritis, and migratory ar thritis have been described. Rhabdomyolysis has also been docu mented, often associated with other organ system manifestations. 5. Other conditions, such as mild hepatitis, gastroenteritis, pancreati tis, acute glomerulonephritis, iritis or uveitis, and cardiac complica tions (pericarditis, myocarditis, and rheumatic feverlike syndrome, most commonly seen in adults) are also described. Fatal M. pneumo niae infections are rare. DIAGNOSIS No specific clinical, epidemiologic, or laboratory parameters allow for a definite diagnosis of M. pneumoniae infection. Nevertheless, pneumo nia in school age children and young adults with a gradual onset and cough as prominent findings suggests M. pneumoniae infection. The best method for diagnosis is a combination of PCR from respiratory samples and serology (acute and convalescent), as M. pneumoniae colonizes the airway and has been identified in 1725 of asymptomatic children. Cultures on special media (SP4 agar media) of the throat or sputum might demonstrate the classic M. pneumoniae mulberry colonies, but growth generally requires incubation for more than 2 3 weeks. The fas tidious nutritional requirements of Mycoplasma make cultures slow and impractical, and few laboratories maintain the capability of culturing M. pneumoniae. Serologic tests (immunofluorescence tests, enzyme linked immune assays EIAs) to detect serum immunoglobulin (Ig) M, IgA, and IgG antibodies against M. pneumoniae are commercially available. IgM anti bodies have a high rate of false positive and false negative results. In most cases, IgM antibodies are not detected within the first week after symptom onset or in children with recurrent infections and may be posi tive for up to 6 12 months after infection, or even years, and thus may not indicate acute infection. A fourfold or greater increase in IgG anti body titers against M. pneumoniae between acute and convalescent sera obtained 2 4 weeks apart is diagnostic. Complement fixation assays are less sensitive and specific than EIA or |
7,518 | immunofluorescent assays. Cold hemagglutinins (cold reacting antibodies IgM against red blood cells) can be detected in approximately 50 of patients with M. pneumoniae pneumonia. These antibodies are nonspecific, especially at titers 1:64, as modest increases in cold hemagglutinins can be observed in other viral infections. Cold agglutinin antibodies should not be used for the diagnosis of M. pneumoniae infections if other methods are available. Nucleic acid amplification test (NAATs) for M. pneumoniae have replaced other diagnostic tests. PCR of a nasopharyngeal or throat swab (the combination of both increases sensitivity) for M. pneumoniae genomic DNA carries a sensitivity and a specificity of 80 to 97. Different prim ers have been used to identify gene sequences of the P1 cytoadhesion pro tein or the ribosomal (r) 16S RNA. PCR allows a more rapid diagnosis in acutely ill patients and can be positive earlier in the course of infection than serologic tests. Identification of M. pneumoniae by PCR (or culture) from a patient with compatible clinical manifestations suggests causation. The diagnosis of extrapulmonary disease associated with M. pneu moniae is challenging. Although M. pneumoniae has been identified by PCR in the CSF of children with encephalitis, there are currently no reliable tests for the diagnosis of CNS or other nonrespiratory sites associated with M. pneumoniae. Because the extrapulmonary manifes tations of M. pneumoniae may have an immunologic base, measuring acute and convalescent IgM and IgG antibody levels is advisable. TREATMENT M. pneumoniae illness is usually mild, and most cases of pneumonia can be managed without the need for hospitalization. Because myco plasmas lack a cell wall, they are inherently resistant to lactam agents that act by inhibiting the cell wall synthesis. In addition, drugs from other classes, such as trimethoprim, rifampin, or linezolid, are inactive against M. pneumoniae. Studies regarding the effectiveness of antimi crobial therapy for M. pneumoniae infections in children are contradic tory. Nevertheless, empiric treatment is often initiated in hospitalized children with CAP or severe extrapulmonary manifestations based on clinical suspicion because of the difficulty of a definitive diagnosis. Fig. 269.1 Lip changes found in Mycoplasma pneumoniaeassoci ated mucositis. Fig. 269.2 Classic skin lesions found in Mycoplasma pneumoniae associated rash. 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. 1890 Part XV u Infectious Diseases Antimicrobial Therapy M. pneumoniae is typically sensitive to macrolides (erythromycin, clarithromycin, azithromycin), tetracyclines, and quinolones in vitro. Treatment of Mycoplasma does not assure eradication. Data from observational studies showed that macrolide treatment of children with M. pneumoniae CAP shortened the course of illness. Treatment may be more effective when started within 3 4 days of illness onset. Although macrolides do not have bactericidal activity, they are pre ferred in children younger than 8 years of age. Two multicenter studies of pediatric CAP demonstrated comparable clinical and bacteriologic success rates between erythromycin and clarithromycin or azithromy cin. However, the newer |
7,519 | macrolides were better tolerated. The recom mended treatment is clarithromycin (15 mgkgday divided into two doses PO for 10 days; maximum daily dose 1 g) or azithromycin (10 mgkg PO once on day 1 maximum dose 500 mg and 5 mgkg once daily maximum dose 250 mg PO on days 2 5). Doxycycline (2 4 mgkgday PO twice a day for 7 days, maximum daily dose 200 mg) in children of all ages and fluoroquinolones such as levofloxacin (10 mg kg per dose twice a day in children 5 years; 10 mgkgday once a day in children 5 yearsmaximum daily dose 750 mgfor 7 10 days) are effective but have higher minimum inhibitory concentrations (MICs) compared with macrolides and currently are not recommended as a first line therapy in children. Macrolide resistant M. pneumoniae infections should be sus pected in patients with severe infections not responding to macro lide therapy within the first 48 hours of treatment, especially if they have a history of exposure to macrolides. Macrolide resistant M. pneumoniae strains have been reported in Asia (7090 in Japan and China), Europe (with great variability from country to country: 0 in the Netherlands vs 26 in Italy), and Israel. In the United States and Canada, the rates of resistance have varied from 2.8 to 13 of cases. The clinical significance of macrolide resistant infec tions has not been completely elucidated. However, if macrolide resistant M. pneumoniae is suspected, switching to a nonmacrolide antimicrobial regimen such as doxycycline or levofloxacin might be prudent. Adjunctive Therapy There is no evidence that treatment of upper respiratory tract or non respiratory tract disease with antimicrobial agents alters the course of illness. However, patients with severe manifestations of extrapulmo nary disease may benefit from antimicrobial treatment because direct involvement of the bacterium cannot be excluded. Oftentimes antibiot ics are administered in combination with immunomodulatory therapy. In this regard, corticosteroids with or without intravenous immuno globulin are the most commonly used agents for managing severe M. pneumoniae extrapulmonary manifestations, particularly for patients with CNS involvement or rash and mucositis. Although definitive data are lacking, case studies suggest the associated clinical benefit of ste roids in the management of severe lung disease, SJS, and hemolytic anemia. PREVENTION Trials with inactivated and live attenuated vaccines for M. pneu moniae have been conducted with disappointing results. In hospital ized patients, standard and droplet precautions are recommended for the duration of symptoms. It is important to emphasize that Myco plasma infection remains contagious as long as cough persists and despite successful antibiotic therapy. Prophylaxis with tetracyclines or azithromycin substantially reduces the secondary attack rates in institutional outbreaks and family close contacts. Antimicrobial pro phylaxis is not recommended routinely; however, it can be consid ered in patients at high risk for severe disease, such as children with sickle cell disease. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. ETIOLOGY Mycoplasma species are small pleomorphic bacteria that typically lack a cell wall and are bound by a cell membrane. Many of the |
7,520 | biologic properties of mycoplasmas are in fact the result of the absence of a rigid cell wall, including resistance to lactam antibiotics. These ubiq uitous organisms are difficult to cultivate using routine media and belong to the family Mycoplasmataceae in the class Mollicutes and represent the smallest self replicating organisms known to date. The entire genome of many of the Mycoplasma species is among the small est of the prokaryotic genomes. The family Mycoplasmataceae is com posed of two genera responsible for human infection: Mycoplasma and Ureaplasma. Of those, Mycoplasma hominis, Mycoplasma genitalium, and Ureaplasma spp., which include Ureaplasma urealyticum (biovar 2) and Ureaplasma parvum (biovar 1), are considered human urogenital pathogens and are reviewed in this chapter. The main feature that dis tinguishes Ureaplasma spp. from Mycoplasma spp. is the ability of the former to hydrolyze urea for energy production. Genital mycoplasmas are often associated with sexually transmit ted infections such as cervicitis and nongonococcal urethritis (NGU) or with puerperal infections such as endometritis. M. hominis and Ureaplasma spp. commonly colonize the female genital tract and can cause chorioamnionitis, colonization of neonates, and perinatal infections. The role of M. genitalium in pregnant women has not been well defined. EPIDEMIOLOGY Genital mycoplasmas are part of the normal flora and are commonly present in the genitourinary (GU) tract of postpubertal women and men and the upper respiratory tract. The prevalence of genital colo nization with these bacteria has been directly associated with low socioeconomic status, hormonal changes, and ethnicity and increases proportionally according to sexual activity, being highest among indi viduals with multiple sexual partners. Female colonization is greatest in the vagina (and less in the endocervix, urethra, and endometrium), with rates varying from 40 to 80 for Ureaplasma spp. and 2150 for M. hominis among sexually active asymptomatic women. Urea plasma is isolated less often from urine than from the cervix, but M. hominis is present in the urine and in the cervix with approximately the same frequency. Male colonization is less common and occurs pri marily in the urethra. Among prepubertal children and sexually inac tive adults, colonization rates are 10. M. genitalium is implicated in approximately 1520 of NGU cases in men and in 1030 of women with cervicitis and also plays a role in pelvic inflammatory disease in women. Studies using polymerase chain reaction (PCR) show that col onization of the female lower urogenital tract with M. genitalium is less common than with M. hominis or Ureaplasma spp. Chapter 270 Genital Mycoplasmas (Mycoplasma hominis, Mycoplasma genitalium, and Ureaplasma urealyticum) Mara I. Snchez Cdez 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. Chapter 270 u Genital Mycoplasmas 1891 Table 270.1 Clinical Syndromes and Antibiotic Therapy for Ureaplasmas and Mycoplasmas Infection UREAPLASMA SPP. M. HOMINIS M. GENITALIUM INTRAUTERINE AND NEONATAL INFECTIONS Chorioamnionitis Preterm delivery Postpartum fever UK BPD UK CNS |
7,521 | infections UK NEC UK UK GENITOURINARY INFECTIONS NGU (acutechronic) Cervicitis PID NON NEONATALNONGENITOURINARY INFECTIONS CNS disease Bacteremia Surgical wound infections Arthritis TREATMENT Macrolides Quinolones Clindamycin Tetracyclines (doxycycline) Only Ureaplasma urealyticum (not parvum). CNS disease include meningitis, hydrocephalus, brain abscess, subdural empyema, intraventricular hemorrhage, and nonfunctioning CNS shunts. The most commonly used quinolones are ciprofloxacin, levofloxacin, and moxifloxacin. BPD, Bronchopulmonary dysplasia; CNS, central nervous system; NEC, necrotizing enterocolitis; NGU, nongonococcal urethritis; PID, pelvic inflammatory disease; UK, unknown. TRANSMISSION Genital mycoplasmas are transmitted by sexual contact or by vertical transmission from mother to infant. As with other perinatal infec tions, vertical transmission can occur through ascending intrauterine infection or hematogenous spread from placental infection but most often occurs through a colonized birth canal at the time of delivery. Transmission rates among neonates born to women colonized with Ureaplasma spp. range from 18 to 88. Neonatal colonization rates are higher among infants who weigh 1,000 g, infants who are born in the presence of chorioamnionitis, and infants born to mothers who are heavily colonized and of lower socioeconomic status. Neonatal colonization is transient and decreases proportionally with age. Organ isms may be recovered from the newborns throat, vagina, rectum, and, occasionally, conjunctiva and respiratory tract. PATHOGENESIS Genital mycoplasmas can cause chronic inflammation of the GU tract and amniotic membranes. These bacteria usually live in a state of adherence to the respiratory or urogenital tract but can disseminate to other organs when there is a disruption of the mucosa or a weakened or immature immune system, such as in premature infants. Ureaplasma spp. can infect the amniotic sac early in gestation without rupturing the amniotic membranes, resulting in a clinically silent, chronic cho rioamnionitis characterized by an intense inflammatory response. In addition, mycoplasmas and Ureaplasma spp. hydrolyze arginine or urea into ammonium for energy production. Ammonium causes an increase in the genital pH that leads to bacterial dysbiosis with a reduc tion in Lactobacillus and overgrowth of other genital bacteria that can promote preterm labor, premature rupture of membranes, and chorioamnionitis. Attachment to fetal human tracheal epithelium can cause ciliary disarray, clumping, and loss of epithelial cells. In vitro studies show that Ureaplasma spp. stimulates macrophage production of interleukin (IL) 6 and tumor necrosis factor . In addition, high concentrations of proinflammatory cytokines possibly associated with development of bronchopulmonary dysplasia (BPD) of prematurity, such as monocyte chemoattractant protein 1 and IL 8, have been found in tracheal secre tions from very low birthweight infants colonized with Ureaplasma spp. Immunity appears to require serotype specific antibody. Thus lack of maternal antibodies might account for a higher disease risk in pre mature newborns. CLINICAL MANIFESTATIONS The main syndromes associated with Ureaplasma spp., M. genitalium, and M. hominis are displayed in Table 270.1. Intrauterine and Neonatal Infections Chorioamnionitis and Early Onset Infections Genital mycoplasmas are associated with a variety of fetal and neonatal infections. Ureaplasma spp. have been associated with clinically inap parent chorioamnionitis, resulting in spontaneous abortion, increased fetal death, or premature delivery, although the causative |
7,522 | role remains uncertain. Studies have shown that women with Ureaplasma spp. detected by PCR in amniotic fluid in the first or second trimester of gestation have an increased risk of preterm labor and delivery. In addi tion, Ureaplasma spp. are the microorganism most commonly iden tified by PCR in women with premature rupture of membranes, and data suggest that U. parvum plays a bigger role than U. urealyticum in prematurity. 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. 1892 Part XV u Infectious Diseases Ureaplasma spp. can also be recovered from tracheal, blood, cere brospinal fluid (CSF), or lung biopsy specimens in up to 50 of sick infants younger than 34 weeks of gestation. In a study of 351 mother infant dyads, isolation of Ureaplasma spp. or M. hominis from cord blood was documented in 23 of infants born between 23 and 32 weeks of gestation and correlated with the development of systemic inflammatory response syndrome. Bronchopulmonary Dysplasia The role of these organisms in causing severe respiratory insufficiency, the need for mechanical ventilation, the development of BPD, or death remains controversial. Nevertheless, meta analyses of published stud ies have identified respiratory colonization with Ureaplasma spp. as an independent risk factor for the development of BPD. However, tri als using erythromycin or azithromycin therapy in high risk preterm infants with tracheobronchial colonization of Ureaplasma spp. have failed to show any difference in the development of BPD in treated vs. nontreated infants. Similarly, treatment with azithromycin in pregnant women colonized with Ureaplasma spp. did not show a reduction in the risk of BPD in neonates. To date there is not enough evidence to support the use of antibiotic therapy in preterm infants at risk for or with confirmed Ureaplasma spp. infection to prevent the development of BPD. Central Nervous System Infections M. hominis and Ureaplasma spp. have been isolated from the CSF of premature infants and, less commonly, full term infants. These bac teria may represent true pathogens and may be associated with CNS disease based on the host susceptibilitygestational age and bacteria pathogenicity. However, the clinical significance of recovering M. hom inis and Ureaplasma spp. from the CSF is uncertain, as most infants have no overt signs of CNS disease, CSF pleocytosis is not consistent, and spontaneous clearance of mycoplasmas has been documented without specific therapy. Ureaplasma spp. have been associated with the development of subdural empyema and meningitis associated with intraventricular hemorrhage (IVH) and hydrocephalus. Limited data suggest that men ingitis caused by M. hominis can also be associated with IVH, hydro cephalus, and brain abscess, particularly in low birthweight or preterm neonates and in infants with neural tube defects. In a review of 29 reported neonatal cases with M. hominis meningitis, 8 (28) neonates died and 8 (28) developed neurologic sequelae. The age of onset of meningitis ranges from 1 to 196 days |
7,523 | of life, and organisms can persist in the CSF without therapy for days to weeks. Pachymeningitis may be evident on MRI. Other: M. hominis and Ureaplasma spp. have also been associated with neonatal conjunctivitis, abscesses (mainly at the scalp electrode site and associated with M. hominis), pneumonia, bacteremia, and nec rotizing enterocolitis (NEC). Genitourinary Infections In sexually active adolescents and adults, genital mycoplasmas are associated with sexually transmitted diseases and are rarely associ ated with focal infections outside the genital tract. U. urealyticum (not U. parvum) and M. genitalium are recognized etiologic agents of NGU, mainly in men, and represent the second most common cause of urethritis after Chlamydia trachomatis. M. genitalium has been identified in 30 of patients with persistent or recurrent NGU, because this bacterium is relatively resistant to the antibiotics rec ommended for the treatment of NGU. Rare complications of NGU include epididymitis and prostatitis. Salpingitis, cervicitis, pelvic inflammatory disease, and endometritis have been described in women associated with M. genitalium and, to a lesser extent, with M. hominis. Nongenital Infections Ureaplasma spp. and M. hominis infections are rarely described outside the neonatal period. These infections have been reported in both immunocompetent and immunocompromised children, including patients with hypogammaglobulinemia, lymphoma, or solid organ transplant recipients, who appear to be at higher risk of infection. Cases of Ureaplasma spp. pneumonia, osteomyelitis, arthritis, men ingitis, mediastinitis, bacteremia, infection of aortic grafts, and surgical site infections have been reported. Recent data suggest that Ureaplasma spp. is associated with posttransplant hyperammonemia syndrome, a rare but potentially fatal complication. M. hominis is most commonly reported in systemic infections and has been associated with CNS disease (including meningitis, brain abscesses, subdural empyema, and nonfunctioning shunts), surgi cal wound infections, arthritis (associated in up to 50 of cases with prior manipulation of the GU tract), prosthetic and nave endocardi tis, osteomyelitis, and pneumonia. There are reports of life threatening mediastinitis, sternal wound infections, pleuritis, peritonitis, and peri carditis, with high mortality rates in patients after organ transplanta tion. These infections should be suspected in culture negative systemic or local infections, when samples have been properly collected and before initiation of antibiotic therapy. DIAGNOSIS All Mollicutes lack a cell wall and are therefore not visible on Gram stain. M. hominis and Ureaplasma spp. can grow in cell free media and require sterols for growth, producing characteristic colonies on agar. Colonies of M. hominis are 200 300 m in diameter with a fried egg appearance, whereas colonies of Ureaplasma spp. are smaller (16 60 m in diameter). M. genitalium is a fastidious organism and can be isolated with difficulty in cell culture systems, requiring up to 8 weeks to be detected. Most clinical microbiology laboratories do not rou tinely test for these pathogens, and nucleic acidbased tests are the pre ferred method for diagnosis. PCR based assays have greater sensitivity than culture (90 vs 40, respectively) and provide a more practical method for detection. Serologic assays for genital mycoplasmas have limited value in the clinical setting |
7,524 | and are not commercially available for diagnostic purposes. In addition, serologic studies for Ureaplasma spp. are not useful because of the high prevalence of colonization in healthy children and adults. Genital Tract Infection Confirmation of genital tract infection is challenging because of the high colonization rates in the vagina and urethra. NGU is typi cally defined as new onset urethral discharge or dysuria with Gram stain of urethral discharge showing 5 polymorphonuclear leuko cytes per oil immersion field in the absence of gram negative dip lococci (i.e., Neisseria gonorrhoeae). The lack of cell wall prevents the identification of these bacteria by routine Gram stain. Detection of Ureaplasma spp. or M. hominis by PCR is available for a variety of specimens, including urine and swabs of the cervix, urethra, and vagina. M. genitalium is often identified by nucleic acid amplifica tion tests (NAATs) of first void urine specimens in men and vaginal swabs in women. Neonates Ureaplasma spp. and M. hominis have been isolated from urine, blood, CSF, tracheal aspirates, pleural fluid, abscesses, and lung tis sue. Premature neonates who are clinically ill with pneumonitis, focal abscesses, or CNS disease (particularly progressive hydrocephalus with or without pleocytosis) for whom bacterial cultures are negative or in whom there is no improvement with standard antibiotic therapy warrant further workup to rule out genital mycoplasmas. Isolation of Ureaplasma spp. and M. hominis requires special media using urea for the former and arginine for the latter, and clinical specimens must be cultured immediately or frozen at 70C (94F) to prevent loss of organisms. M. hominis can also be detected sometimes using routine laboratory media such as blood agar or chocolate agar. When inocu lated into broth containing arginine (for M. hominis) or urea (for Urea plasma spp. ), growth is indicated by an alkaline pH. Identification of 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 271 u Chlamydia pneumoniae 1893 Ureaplasma spp. on agar requires 1 3 days of growth and visualization with the dissecting microscope, whereas M. hominis is apparent to the eye but can require 2 7 days to grow. PCR based assays are available and will shed light on the causality of these pathogens when sterile sites are tested (e.g., CSF, joint fluid). TREATMENT These organisms lack a cell wall, and thus lactam agents or glyco peptides are not effective. These bacteria are also resistant to sulfon amides and trimethoprim because they do not synthesize folic acid. Rifamycins do not have activity against Mollicutes (see Table 270.1). Unlike other mycoplasmas and ureaplasmas, M. hominis is resis tant to macrolides but generally susceptible to clindamycin and quinolones. Most Ureaplasma spp. are susceptible to macrolides and advanced generation quinolones, such as levofloxacin or moxi floxacin, but are intrinsically resistant to aminoglycosides and often resistant to ciprofloxacin and clindamycin. Susceptibility to tetra cyclines is variable for both organisms, |
7,525 | with increasing resistance being reported. M. genitalium is typically susceptible to macro lides and moxifloxacin, with variable resistance to tetracyclines and clindamycin. Adolescents and Adults Recommended treatment for NGU should include antibiotics with activity against C. trachomatis with either doxycycline (100 mg PO twice daily for 7 days) or azithromycin (1 g PO as a single dose). If adherence to a multiday regimen is not a concern, azithromycin administered over a 5 day course (500 mg on day 1 followed by 250 mg daily for 4 days) is an alternative and may limit the develop ment of resistance. Recurrent NGU after completion of treatment suggests the presence of doxycycline or azithromycin resistant M. genitalium. If the initial empiric regimen did not include macro lides, retreatment with an azithromycin based regimen may be indicated. Azithromycin is also preferred in children younger than 8 years and in those with allergy to tetracyclines. On the other hand, if patients received azithromycin initially, retreatment with moxi floxacin may be most effective. Before the introduction of azithro mycin, up to 60 of patients with M. genitalium NGU developed recurrent or chronic urethritis despite 1 2 weeks of treatment with doxycycline. Sexual partners should also be treated to avoid recurrent disease in the index case. Nongenital mycoplasmal infections may require surgi cal drainage and prolonged antibiotic therapy. Neonates Treatment of these infections in neonates is challenging, and no optimal treatment has been established. Doxycycline and qui nolones are generally avoided at this age because of their associ ated toxicities. In addition, attributing causality may be difficult. In general, therapy for neonates with genital mycoplasma infections is indicated if infections are associated with pure growth of the organism or if the organism is detected by PCR from a normally sterile site in conjunction with compatible disease manifestations to assure the treatment of an infectious process rather than merely colonization. Treatment is usually based on predictable antimicrobial sensitivities because susceptibility testing is not readily available for individual iso lates (see Table 270.1). The treatment of BPD with azithromycin for the treatment of Ureaplasma spp. remains controversial. For infants with symptomatic central nervous system (CNS) infection, cures have been described with chloramphenicol, doxycycline, and quinolones, as they have better penetration into the CSF than macrolides. The long term consequences of asymptomatic CNS infection associated with genital mycoplasmas, especially in the absence of pleocytosis, are unknown. Because mycoplasmas can spontaneously clear from the CSF, therapy should involve minimal risks. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Chlamydia pneumoniae is a common cause of lower respiratory tract diseases, including pneumonia in children and bronchitis and pneu monia in adults. This organism was briefly known as Chlamydophila pneumoniae, and that name is still used as an alternative designation in some sources. ETIOLOGY Chlamydiae are obligate intracellular pathogens that have established a unique niche in host cells. Chlamydiae cause a variety of diseases in animal species at virtually all phylogenic levels. The most significant human pathogens are C. pneumoniae and C. trachomatis (see |
7,526 | Chapter 272). C. psittaci is the cause of psittacosis, an important zoonosis (see Chapter 273). There are now nine recognized chlamydial species. Chlamydiae have a gram negative envelope without detectable pep tidoglycan, although recent genomic analysis has revealed that both C. pneumoniae and C. trachomatis encode proteins forming a nearly complete pathway for synthesis of peptidoglycan, including penicillin binding proteins. Chlamydiae also share a group specific lipopolysac charide antigen and use host adenosine triphosphate for the synthesis of chlamydial proteins. Although chlamydiae are auxotrophic for three of four nucleoside triphosphates, they encode functional glucose catabolizing enzymes that can be used to generate adenosine triphos phate. As with peptidoglycan synthesis, for some reason, these genes are turned off. All chlamydiae also encode an abundant surface exposed protein called the major outer membrane protein. The major outer membrane protein is the major determinant of the serologic clas sification of C. trachomatis and C. psittaci isolates. EPIDEMIOLOGY C. pneumoniae is primarily a human respiratory pathogen. The organ ism has also been isolated from nonhuman species, including horses, koalas, reptiles, and amphibians, where it also causes respiratory infec tion, although the role that these infections might play in transmission to humans is unknown. C. pneumoniae appears to affect individuals of all ages. The proportion of community acquired pneumonias associ ated with C. pneumoniae infection is 219, varying with geographic location, the age group examined, and the diagnostic methods used. Several studies of the role of C. pneumoniae in lower respiratory tract infection in pediatric populations have found evidence of infection in 018 of patients based on serology or culture for diagnosis. In one study, almost 20 of the children with C. pneumoniae infection were coinfected with Mycoplasma pneumoniae. C. pneumoniae may also be responsible for 1020 of episodes of acute chest syndrome in children with sickle cell disease, up to 10 of asthma exacerbations, 10 of epi sodes of bronchitis, and 510 of episodes of pharyngitis in children. Asymptomatic infection appears to be common based on epidemio logic studies. Transmission probably occurs from person to person through respi ratory droplets. Spread of the infection appears to be enhanced by close proximity, as is evident from localized outbreaks in enclosed popula tions, such as military recruits and in nursing homes. Chapter 271 Chlamydia pneumoniae Stephan A. Kohlhoff and Margaret R. Hammerschlag Section 10 Chlamydial 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. 1894 Part XV u Infectious Diseases PATHOGENESIS Chlamydiae are characterized by a unique developmental cycle (Fig. 271.1) with morphologically distinct infectious and reproductive forms: the elementary body (EB) and reticulate body (RB). After infec tion, the infectious EBs, which are 200 400 m in diameter, attach to the host cell by a process of electrostatic binding and are taken into the cell by endocytosis that does not depend on the microtubule system. Within the host cell, |
7,527 | the EB remains within a membrane lined phago some. The phagosome does not fuse with the host cell lysosome. The inclusion membrane is devoid of host cell markers, but lipid markers traffic to the inclusion, which suggests a functional interaction with the Golgi apparatus. The EBs then differentiate into RBs that undergo binary fission. After approximately 36 hours, the RBs differentiate into EBs. At approximately 48 hours, release can occur by cytolysis or by a process of exocytosis or extrusion of the whole inclusion, leaving the host cell intact. Chlamydiae can also enter a persistent state after treatment with certain cytokines such as interferon , treatment with antibiotics, or restriction of certain nutrients. While chlamydiae are in the persistent state, metabolic activity is reduced. The ability to cause prolonged, often subclinical, infection is one of the major characteris tics of chlamydiae. CLINICAL MANIFESTATIONS Infections caused by C. pneumoniae cannot be readily differentiated from those caused by other respiratory pathogens, especially M. pneu moniae. The pneumonia usually occurs as a classic atypical (or non bacterial) pneumonia characterized by mild to moderate constitutional symptoms, including fever, malaise, headache, cough, and often phar yngitis. Severe pneumonia with pleural effusions and empyema has been described. Milder respiratory infections have been described, manifesting as a pertussis like illness. C. pneumoniae can serve as an infectious trigger for asthma, can cause pulmonary exacerbations in patients with cystic fibrosis, and can produce acute chest syndrome in patients with sickle cell anemia. C. pneumoniae has been isolated from middle ear aspirates of children with acute otitis media, most of the time as co infection with other bacteria. Asymptomatic respiratory infection has been documented in 25 of adults and children and can persist for 1 year or longer. DIAGNOSIS It is not possible to differentiate C. pneumoniae from other causes of atypical pneumonia on the basis of clinical findings. Auscultation reveals the presence of rales and often wheezing. The chest radiograph often appears worse than the patients clinical status would indicate and can show mild, diffuse involvement or lobar infiltrates with small pleu ral effusions. The complete blood count may be elevated with a left shift but is usually unremarkable. Specific diagnosis of C. pneumoniae infection has been based on isolation of the organism in tissue culture. C. pneumoniae grows best in cycloheximide treated HEp 2 and HL cells. The optimum site for culture is the posterior nasopharynx; the specimen is collected with wire shafted swabs in the same manner as that used for C. trachomatis. The organism can be isolated from sputum, throat cultures, bronchoal veolar lavage fluid, and pleural fluid, but few laboratories perform such cultures because of technical difficulties. There are two U.S. Food and Drug Administration (FDA)cleared multiplexed nucleic acid ampli fication testing assays available for detection of respiratory viruses; pneumonia pathogens; and C. pneumoniae, M. pneumoniae, and Bor detella pertussis on upper respiratory samples. These systems combine nucleic acid extraction, amplification, detection, and data analysis. Serologic diagnosis can be accomplished using the microimmuno fluorescence |
7,528 | (MIF) or the complement fixation tests. The complement fixation test is genus specific and is also used for diagnosis of lympho granuloma venereum (see Chapter 272.4) and psittacosis (see Chapter 273). Its sensitivity in hospitalized patients with C. pneumoniae infec tion and children is variable. The Centers for Disease Control and Pre vention (CDC) has proposed modifications in the serologic criteria for diagnosis. Although the MIF test was considered to be the only cur rently acceptable serologic test, the criteria were made significantly more stringent. Acute infection, using the MIF test, was defined by a fourfold increase in immunoglobulin (Ig) G titer or an IgM titer of 16; use of a single elevated IgG titer was discouraged. An IgG titer of 16 was thought to indicate past exposure, but neither elevated IgA titers nor any other serologic marker was thought to be a valid indica tor of persistent or chronic infection. Because diagnosis would require paired sera, this would be a retrospective diagnosis. The CDC did not recommend the use of any enzyme linked immune assay for detection of antibody to C. pneumoniae because of concern about the inconsis tent correlation of these results with culture results. Studies of C. pneu moniae infection in children with pneumonia and asthma show that more than 50 of children with culture documented infection have no detectable serum antiC. pneumoniae antibody. Because of the avail ability of FDA cleared nucleic acid test technology, diagnosis of acute infection should not be made using serology. TREATMENT The optimum dose and duration of antimicrobial therapy for C. pneu moniae infections remain uncertain. Most treatment studies have used only serology for diagnosis, and thus microbiologic efficacy cannot be assessed. Prolonged therapy for 2 weeks or longer is required for some patients, because recrudescent symptoms and persistent positive cul tures have been described after 2 weeks of erythromycin and 30 days of tetracycline or doxycycline. Tetracyclines, macrolides (erythromycin, azithromycin, and clar ithromycin), and quinolones show in vitro activity. Like C. psittaci, C. pneumoniae is resistant to sulfonamides. The results of treatment stud ies have shown that erythromycin (40 mgkgday PO divided twice a day for 10 days), clarithromycin (15 mgkgday PO divided twice a day for 10 days), and azithromycin (10 mgkg PO on day 1 and then 5 mg kgday PO on days 2 5) are effective for eradication of C. pneumoniae from the nasopharynx of children with pneumonia in approximately 80 of cases. Resistance to these commonly used drug classes has not been conclusively demonstrated. Persistent symptoms may, however, reflect persistent infection caused by the latent nature of the organism or another etiology and should prompt a thorough reevaluation. PROGNOSIS Clinical response to antibiotic therapy varies. Coughing often persists for several weeks even after therapy. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Phagosome fusion Reorganization EB to RB Attachment and ingestion Extrusion and release of infectious EB Mature inclusion Condensation RB to EB Multiplication of RB 1824 hr 2448 hr4872 hr 818 hr 8 hr 2 hr |
7,529 | RB N EB N N N N N N Fig. 271.1 Life cycle of chlamydiae in epithelial cells. EB, Elementary body; RB, reticulate body. (From Hammerschlag MR. Infections due to Chlamydia trachomatis and Chlamydia pneumoniae in children and adolescents. Pediatr Rev. 2004;25:4350.) 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 272 u Chlamydia trachomatis 1895 Chlamydia trachomatis is subdivided into two biovars, namely, lym phogranuloma venereum (LGV) and trachoma, which is the agent of human oculogenital diseases other than LGV. Although the strains of both biovars have almost complete DNA homology, they differ in growth characteristics and virulence in tissue culture and animals. In developed countries, C. trachomatis is the most prevalent sexually transmitted disease, causing urethritis in men, cervicitis and salpingitis in women, and conjunctivitis and pneumonia in infants. 272.1 Trachoma Margaret R. Hammerschlag Trachoma is the most important preventable cause of blindness in the world. It is caused primarily by the A, B, Ba, and C serotypes of C. trachomatis. It is endemic in the Middle East and Southeast Asia and among Navajo Indians in the southwestern United States. In areas that are endemic for trachoma, genital chlamydial infection is caused by the serotypes responsible for oculogenital disease: D, E, F, G, H, I, J, and K. The disease is spread from eye to eye. Flies are a common vector. Trachoma begins as a follicular conjunctivitis, usually in early childhood. The follicles heal, leading to conjunctival scarring that can result in an entropion, with the eyelid turning inward so that the lashes abrade the cornea. It is the corneal ulceration secondary to the constant trauma that leads to scarring and blindness. Bacterial superinfection can also contribute to scarring. Blindness occurs years after the active disease. Trachoma can be diagnosed clinically. The World Health Organiza tion suggests that at least two of four criteria must be present for a diag nosis of trachoma: lymphoid follicles on the upper tarsal conjunctivae, typical conjunctival scarring, vascular pannus, and limbal follicles. The diagnosis is confirmed by culture or staining tests for C. trachomatis performed during the active stage of disease. Serologic tests are not helpful clinically because of the long duration of the disease and the high seroprevalence in endemic populations. Poverty and lack of sanitation are important factors in the spread of trachoma. As socioeconomic conditions improve, the incidence of the disease decreases substantially. Endemic trachoma is managed by mass drug administration (MDA) with azithromycin in affected communi ties. Endemic communities should receive MDA until clinical signs of active disease in children 1 9 years of age falls below 5. MDA with a single dose of azithromycin to all the residents of a village dramatically reduces the prevalence and intensity of infection. This effect continues for 2 years after treatment, probably by interrupting the transmission of ocular C. trachomatis infection. Visit Elsevier eBooks at |
7,530 | eBooks.Health.Elsevier.com for Bibliography. 272.2 Genital Tract Infections Margaret R. Hammerschlag EPIDEMIOLOGY There are an estimated 3 million new cases of chlamydial sexually transmitted infections each year in the United States. C. trachomatis is a major cause of epididymitis and is the cause of 2355 of all cases of nongonococcal urethritis. As many as 50 of men with gonorrhea may be coinfected with C. trachomatis. The prevalence of chlamydial cervicitis among sexually active women is 235. Rates of infection among girls 15 19 years of age exceed 20 in many urban populations and can be as high as 15 in suburban populations. Children who have been sexually abused can acquire anogenital C. trachomatis infection, which is usually asymptomatic. However, because perinatally acquired rectal and vaginal C. trachomatis infec tions can persist for 3 years or longer, the detection of C. trachomatis in the vagina or rectum of a young child is not absolute evidence of sexual abuse. CLINICAL MANIFESTATIONS The trachoma biovar of C. trachomatis causes a spectrum of disease in sexually active adolescents and adults. Up to 75 of women with C. trachomatis have no symptoms of infection. C. trachomatis can cause urethritis (acute urethral syndrome), epididymitis, cervicitis, salpingi tis, proctitis, and pelvic inflammatory disease. The symptoms of chla mydial genital tract infections are less acute than those of gonorrhea, consisting of a discharge that is usually mucoid rather than purulent. Asymptomatic urethral infection is common in sexually active men. Autoinoculation from the genital tract to the eyes can lead to concomi tant inclusion conjunctivitis. DIAGNOSIS Diagnosis of genital chlamydial infection is now accomplished by nucleic acid amplification tests (NAATs). These tests have high sensi tivity, detecting 1020 more cases than culture, while retaining high specificity. Six FDA approved NAATs are commercially available for detecting C. trachomatis, including polymerase chain reaction (PCR; Amplicor Chlamydia test, Roche Molecular Diagnostics, Nutley, NJ), strand displacement amplification (ProbeTec, BD Diagnostic Systems, Sparks, MD), transcription mediated amplification (Amp CT, Hologic, San Diego, CA), and GeneXpert CTNG assay (Cepheid, Sunnyvale, CA). PCR and strand displacement amplification are DNA amplifi cation tests that use primers that target gene sequences on the cryp togenic C. trachomatis plasmid that is present at approximately 10 copies in each infected cell. Transcription mediated amplification is a ribosomal RNA amplification assay. GeneXpert is an on demand, qualitative, real time PCR. All these assays are also available as co amplification tests for simultaneously detecting C. trachomatis and Neisseria gonorrhoeae. The available commercial NAATs are FDA approved for cervical and vaginal swabs from adolescent girls and women, urethral swabs from adolescent boys and men, and urine, pharyngeal, and rectal swabs from adolescents and adults. Use of urine avoids the necessity for a clinical pelvic examination and can greatly facilitate screening in certain populations, especially adolescents, although several stud ies have now demonstrated that endocervical specimens and vaginal swabs are superior to urine for NAAT. Self collected vaginal speci mens appear to be as reliable as specimens obtained by a healthcare professional. Data on the |
7,531 | use of NAATs for vaginal specimens or urine from children are very limited and are insufficient to allow making a rec ommendation for their use. NAATs can be used, but confirmatory testing must be done. Because of the low prevalence of infection in this population, the positive predictive values of a positive test can be less than 30. Confirmatory testing should consist of testing the orig inal sample with a second FDA approved NAAT that targets a differ ent gene sequence from the initial test or repeating the testing before treatment. Use of non FDA cleared assays is strongly discouraged. The etiology of most cases of nonchlamydial nongonococcal ure thritis is unknown, although Ureaplasma urealyticum and possibly Mycoplasma genitalium are implicated in up to one third of cases (see Chapter 270). Proctocolitis may develop in individuals who have a rec tal infection with an LGV strain (see Chapter 272.4). Chapter 272 Chlamydia trachomatis Margaret R. Hammerschlag 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. 1896 Part XV u Infectious Diseases TREATMENT The first line treatment regimen now recommended by the CDC for uncomplicated C. trachomatis genital and rectal infection in adult and adolescent men and nonpregnant women is doxycycline (100 mg PO twice a day for 7 days). Recent studies have documented that doxy cycline is significantly more effective than single dose azithromycin. Alternative regimens are azithromycin (1 g orally in a single dose) or levofloxacin (500 mg PO once daily for 7 days). Doxycycline and quinolones are contraindicated in pregnant women, and quinolones are contraindicated in persons younger than 18 years. For pregnant women, the recommended treatment regimen is azithromycin (1 g PO as a single dose) or amoxicillin (500 mg PO 3 times a day for 7 days). Empirical treatment without microbiologic diagnosis is recom mended only for patients at high risk for infection who are unlikely to return for follow up evaluation, including adolescents with multiple sex partners. These patients should be treated empirically for both C. trachomatis and N. gonorrhoeae. Sex partners of patients with nongonococcal urethritis should be treated if they have had sexual contact with the patient during the 60 days preceding the onset of symptoms. The most recent sexual partner should be treated even if the last sexual contact was more than 60 days from onset of symptoms. COMPLICATIONS Complications of genital chlamydial infections in women include perihepatitis (Fitz HughCurtis syndrome) and salpingitis. Of women with untreated chlamydial infection who develop pelvic inflammatory disease, up to 40 will have significant sequelae; approximately 17 will suffer from chronic pelvic pain, approxi mately 17 will become infertile, and approximately 9 will have an ectopic (tubal) pregnancy. Adolescent girls may be at higher risk for developing complications, especially salpingitis, than older women. Salpingitis in adolescent girls is also more likely to lead to tubal scarring, subsequent obstruction with secondary infertility, |
7,532 | and increased risk for ectopic pregnancy. Approximately 50 of neonates born to pregnant women with untreated chlamydial infection will acquire C. trachomatis infection (see Chapter 272.3). Women with C. trachomatis infection have a threefold to fivefold increased risk for acquiring HIV infection. PREVENTION Timely treatment of sex partners is essential for decreasing the risk for reinfection. Sex partners should be evaluated and treated if they had sexual contact during the 60 days preceding onset of symptoms in the patient. The most recent sex partner should be treated even if the last sexual contact was 60 days. Patients and their sex partners should abstain from sexual intercourse until 7 days after a single dose regimen or after completion of a 7 day regimen. Annual routine screening for C. trachomatis is recommended for all sexually active female adolescents, for all women 20 25 years of age, and for older women with risk factors such as new or multiple partners or inconsistent use of barrier contraceptives. Sexual risk assessment might indicate more frequent screening of some women. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 272.3 Conjunctivitis and Pneumonia in Newborns Margaret R. Hammerschlag EPIDEMIOLOGY Chlamydial genital infection is reported in 530 of pregnant women, with a risk for vertical transmission at parturition to new born infants of approximately 50. The infant may become infected at one or more sites, including the conjunctivae, nasopharynx, rec tum, and vagina. Transmission is rare after cesarean section with intact membranes. The introduction of systematic prenatal screen ing for C. trachomatis infection and treatment of pregnant women has resulted in a dramatic decrease in the incidence of neonatal chlamydial infection in the United States. However, in countries where prenatal screening is not done, such as the Netherlands, C. trachomatis remains an important cause of neonatal infection, accounting for 60 of neonatal conjunctivitis. Inclusion Conjunctivitis Approximately 3050 of infants born to mothers with active, untreated chlamydial infection develop clinical conjunctivitis. Symptoms usually develop 5 14 days after delivery, or earlier in infants born after prolonged rupture of membranes. The presen tation is extremely variable and ranges from mild conjunctival injection with scant mucoid discharge to severe conjunctivitis with copious purulent discharge, chemosis, and pseudomembrane for mation. The conjunctiva may be very friable and may bleed when stroked with a swab. Chlamydial conjunctivitis must be differenti ated from gonococcal ophthalmia, which is sight threatening. At least 50 of infants with chlamydial conjunctivitis also have naso pharyngeal infection. Pneumonia Pneumonia caused by C. trachomatis can develop in 1020 of infants born to women with active, untreated chlamydial infec tion. Only approximately 25 of infants with nasopharyngeal chlamydial infection develop pneumonia. C. trachomatis pneu monia of infancy has a characteristic presentation. Onset usually occurs between 1 and 3 months of age and is often insidious, with persistent cough, tachypnea, and absence of fever. Auscultation reveals rales; wheezing is occasionally present but is uncommon. The absence of fever and wheezing generally helps to distinguish C. trachomatis pneumonia from respiratory syncytial virus pneu monia. |
7,533 | A distinctive laboratory finding is the presence of periph eral eosinophilia (400 cellsL). The most consistent finding on chest radiograph is hyperinflation accompanied by minimal inter stitial or alveolar infiltrates. Infections at Other Sites Infants born to mothers with C. trachomatis can develop infection in the rectum or vagina. Although infection in these sites appears to be totally asymptomatic, it can cause confusion if it is identified later. Perinatally acquired rectal, vaginal, and nasopharyngeal infections can persist for 3 years or longer. DIAGNOSIS Definitive diagnosis is achieved by isolation of C. trachomatis in cul tures of specimens obtained from the conjunctiva or nasopharynx. Data on the use of NAATs for diagnosis of C. trachomatis in children are limited but suggest that PCR may be equivalent to culture for detecting C. trachomatis in the conjunctiva of infants with conjunctivi tis. However, NAATs are not currently FDA cleared for use with con junctival or nasopharyngeal specimens from infants. Laboratories can do internal validation delineated in the CDC 2014 C. trachomatis and N. gonorrhoeae laboratory guidelines. TREATMENT The recommended treatment regimens for C. trachomatis conjunctivi tis or pneumonia in infants are erythromycin (base or ethylsuccinate, 50 mgkgday divided 4 times a day PO for 14 days) or azithromycin suspension (20 mgkgday once daily PO for 3 days). The rationale for using oral therapy for conjunctivitis is that 50 or more of these infants have concomitant nasopharyngeal infection or disease at other sites, and studies demonstrate that topical therapy with sulfonamide drops and erythromycin ointment is not effective. The failure rate with oral erythromycin remains 1020, and some infants require a second 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 273 u Psittacosis (Chlamydia psittaci) 1897 course of treatment. Mothers (and their sexual contacts) of infants with C. trachomatis infections should be empirically treated for genital infection. An association between treatment with oral erythromycin or oral azithromycin and infantile hypertrophic pyloric stenosis has been reported in infants younger than 6 weeks of age. PREVENTION Neonatal gonococcal prophylaxis with topical erythromycin ointment does not prevent chlamydial ophthalmia or nasopharyngeal coloniza tion with C. trachomatis or chlamydial pneumonia. The most effective method of controlling perinatal chlamydial infection is screening and treatment of pregnant women. In 2015, the Canadian Pediatric Society recommended that neonatal ocular prophylaxis be discontinued and that prenatal screening for chlamydia be enhanced. The program was implemented in 2016. In the United States, implementation of prenatal screening and treatment of pregnant women has resulted in a dramatic decrease in perinatal chlamydial infections. For treatment of C. tracho matis infection in pregnant women, the CDC currently recommends either azithromycin (1 g PO as a single dose) or amoxicillin (500 mg PO 3 times a day for 7 days) as first line regimens. Erythromycin base (250 mg PO 4 times a day for 14 days) and erythromycin ethylsuccinate (800 |
7,534 | mg 4 times a day for 7 days, or 400 mg PO 4 times a day for 14 days) are listed as alternative regimens. Reasons for failure of maternal treatment to prevent infantile chlamydial infection include poor com pliance and reinfection from an untreated sexual partner. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 272.4 Lymphogranuloma Venereum Margaret R. Hammerschlag LGV is a systemic sexually transmitted disease caused by the L1, L2, and L3 serotypes of the LGV biovar of C. trachomatis. Unlike strains of the trachoma biovar, LGV strains have a predilection for lym phoid tissue. Fewer than 1,000 cases are reported in adults in the United States annually. There has been a resurgence of LGV infec tions among men who have sex with men in Europe and the United States. Many of the men were HIV infected and used illicit drugs, specifically methamphetamines. The only pediatric case that has been reported since the emergence of the new clusters of HIV associated cases in 2003 was a 16 year old boy who presented with LGV proc tocolitis after having receptive unprotected anal intercourse with a 30 year old man he met on the Internet. This history was obtained after the boy was found to be HIV positive. The diagnosis of LGV, particularly when it presents with proctocolitis, relies on a high index of suspicion that would lead to emphasizing certain aspects of the history and ordering the pertinent diagnostic tests. Many pediatri cians and pediatric gastroenterologists might not be familiar with the entity and might not entertain it as a diagnostic consideration in pediatric patients. The diagnosis can be further suggested by C. trachomatis testing: commonly by NAATs or culturing the organism if culture is available. Currently available NAATs will not differentiate LGV from other C. trachomatis serovars. NAATs for C. trachomatis are also not FDA cleared for testing rectal specimens, but laborato ries can do an internal validation as recommended in the CDC 2014 C. trachomatis and N. gonorrhoeae laboratory guidelines. NAATs have been found in several clinical studies to perform well with rec tal specimens. Typing of the C. trachomatis specimen can be done by sequencing from the NAAT specimen by many state laboratories. Trying to ascertain the C. trachomatis serovar for confirmation of LGV has therapeutic implications, as LGV needs to be treated with a 3 week course of doxycycline; a single dose of azithromycin will not eradicate the infection. CLINICAL MANIFESTATIONS The first stage of LGV is characterized by the appearance of the pri mary lesion, a painless, usually transient papule on the genitals. The second stage is characterized by usually unilateral femoral or inguinal lymphadenitis with enlarging, painful buboes. The nodes may break down and drain, especially in men. In women, the vulvar lymph drains to the retroperitoneal nodes. Fever, myalgia, and headache are com mon. The third stage is a genitoanorectal syndrome with rectovaginal fistulas, rectal strictures, and urethral destruction. Among men who have sex with men, rectal infection with LGV can produce a |
7,535 | severe, acute proctocolitis, which can be confused with inflammatory bowel disease or malignancy. DIAGNOSIS LGV can be diagnosed by serologic testing or by culture of C. tracho matis or molecular testing for C. trachomatis from a specimen aspi rated from a bubo. Most patients with LGV have complement fixing antibody titers of 1:16. Chancroid and herpes simplex virus can be distinguished clinically from LGV by the concurrent presence of pain ful genital ulcers. Syphilis can be differentiated by serologic tests. How ever, co infections can occur. TREATMENT Doxycycline (100 mg PO bid for 21 days) is the recommended treat ment. Alternative regimens are azithromycin (1 g PO once weekly for 3 weeks) or erythromycin base (500 mg PO 4 times a day for 21 days). As the azithromycin regimen has not been validated, it is recommended that a test of cure with a C. trachomatis NAAT 4 weeks after completion of therapy be performed. Sex partners of patients with LGV should be treated if they have had sexual contact with the patient during the 30 days preceding the onset of symptoms. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Chlamydia psittaci, the agent of psittacosis (also known as parrot fever and ornithosis), is primarily an animal pathogen and rarely causes human disease. In birds, C. psittaci infection is known as avian chlamydiosis. ETIOLOGY C. psittaci affects both psittacine birds (e.g., parrots, parakeets, macaws) and nonpsittacine birds (ducks, turkeys); the known host range includes 130 avian species. The life cycle of C. psittaci is the same as for C. pneumoniae (see Chapter 271). Strains of C. psittaci have been analyzed by patterns of pathogenicity, inclusion morphology in tissue culture, DNA restriction endonuclease analysis, and mono clonal antibodies, which indicate that there are seven avian serovars. The organism has also been found in nonavian domestic animals, Chapter 273 Psittacosis (Chlamydia psittaci) Stephan A. Kohlhoff and Margaret R. Hammerschlag 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. 1898 Part XV u Infectious Diseases including cattle, sheep, pigs, goats, and cats. Nonavian C. psittaci has rarely caused disease in humans. Two of the avian serovars, psitta cine and turkey, are of major importance in the avian population of the United States. Each is associated with important host preferences and disease characteristics. There are four other Chlamydia species that have birds as their primary hosts: C. avium (pigeons, parrots), C. gallinacea (chickens, turkeys, ducks), C. ibdis (ibis), and C. buteonis (hawks, buzzards). C. gallinacea may have the potential to cause out breaks in poultry plants. EPIDEMIOLOGY On average, 11 cases of psittacosis per year in the United States were reported from 2000 to 2017. However, experts believe the disease is potentially underreported and underdiagnosed. In 2018, a mul tistate psittacosis outbreak among poultry plant workers had 13 laboratory confirmed cases. The majority of cases were associated with exposure to birds, |
7,536 | including 70 after exposure to caged pet birds, which were usually psittacine birds, including cockatiels, par akeets, parrots, and macaws. Chlamydiosis among caged nonpsit tacine birds occurs most often in pigeons, doves, and mynah birds. Persons at highest risk for acquiring psittacosis include workers in poultry plants, bird fanciers, owners of pet birds, and pet shop employees. Reported cases most likely underestimate the number of actual infections owing to a lack of awareness and readily available diagnostic tests. Inhalation of aerosols from feces, fecal dust, and nasal secre tions of animals infected with C. psittaci is the primary route of infection. Source birds are either asymptomatic or have anorexia, ruffled feathers, lethargy, and watery green droppings. Psittacosis is uncommon in children, in part because children may be less likely to have close contact with infected birds. One high risk activity is cleaning the cage. CLINICAL MANIFESTATIONS Infection with C. psittaci in humans ranges from clinically inap parent to severe disease, including pneumonia and multiorgan involvement. The mean incubation period is 15 days after expo sure, with a range of 5 21 days. Onset of disease is usually abrupt, with fever, cough, headache, myalgia, and malaise. The fever is high and is often associated with rigors and sweats. The headache can be so severe that meningitis is considered. The cough is usually non productive. Gastrointestinal symptoms are occasionally reported. Crackles may be heard on auscultation. Chest radiographs are usu ally abnormal and are characterized by the presence of variable infiltrates, sometimes accompanied by pleural effusions. The white blood cell count is usually normal but is sometimes mildly elevated. Elevated levels of aspartate aminotransferase, alkaline phosphatase, and bilirubin are common. Nonpulmonary complications include pericarditis, endocarditis, and myocarditis. Mortality occurs in 5 of cases. DIAGNOSIS Psittacosis can be difficult to diagnose because of the varying clinical presentations. A history of exposure to birds or association with an active case can be important clues, but as many as 20 of patients with psittacosis have no known contact. Person to person spread has been suggested but not proved. Other infections that cause pneumo nia with high fever, unusually severe headache, and myalgia include routine bacterial and viral respiratory infections as well as Coxiella burnetii infection (Q fever), Mycoplasma pneumoniae infection, C. pneumoniae infection, tularemia, tuberculosis, fungal infections, and Legionnaires disease. A patient is considered to have a confirmed case of psittacosis if clinical illness is compatible with psittacosis and the case is laboratory confirmed by identification of C. psittaci by polymerase chain reaction (PCR) from respiratory specimens (e.g., sputum, pleural fluid, or lung tissue), blood, or stool. Serologic methods are most available, but these tests have poor specificity and require testing of paired specimens col lected weeks apart, delaying or preventing confirmation of the clinical diagnosis in a timely fashion. A patient is considered to have a probable case of psittacosis if the clinical illness is compatible with psittacosis and there is an epidemiologic exposure. Lower respiratory tract sam ples are the specimen of choice, |
7,537 | although 5 of 13 (38) of the patients in the 2018 multistate outbreak also had C. psittaci DNA detected in their stool specimens. Although C. psittaci will grow in the same culture systems used for isolation of C. trachomatis and C. pneumoniae, very few laboratories culture for C. psittaci, mainly because of the potential biohazard. Real time PCR assays can distinguish C. psittaci from other chlamydial spe cies and identify different C. psittaci genotypes. Currently real time PCR for C. psittaci is only available at the CDC. TREATMENT Recommended treatment regimens for psittacosis are doxycycline (100 mg PO twice daily) or tetracycline (500 mg PO 4 times a day) for at least 10 14 days after the fever abates. The initial treatment of severely ill patients is doxycycline hyclate (4.4 mgkgday divided every 12 hours IV; maximum: 100 mgdose). Erythromycin (500 mg PO 4 times a day) and azithromycin (10 mgkg PO on day 1, not to exceed 500 mg, followed by 5 mgkg PO on days 2 5, not to exceed 250 mg) are alternative agents if tetracyclines are contraindicated (e.g., children 8 years of age and pregnant women) but may be less effective. Remission is usually evident within 48 72 hours. Reinfec tion and clinical disease can develop within 2 months of treatment, indicating that initial infection does not appear to be followed by long term immunity. PROGNOSIS The mortality rate of psittacosis is 1520 with no treatment but is 1 with appropriate treatment. Severe illness leading to respi ratory failure and fetal death has been reported among pregnant women. PREVENTION Several control measures are recommended to prevent transmission of C. psittaci from birds. Bird fanciers should be cognizant of the potential risk. C. psittaci is susceptible to heat and to most disin fectants and detergents but is resistant to acid and alkali. Accurate records of all bird related transactions aid in identifying sources of infected birds and potentially exposed persons. Newly acquired birds, including birds that have been to shows, exhibitions, fairs, or other events, should be isolated for 30 45 days or tested or treated prophylactically before adding them to a group of birds. Care should be taken to prevent transfer of fecal material, feathers, food, or other materials between birdcages. Birds with signs of avian chlamydiosis (e.g., ocular or nasal discharge, watery green drop pings, or low body weight) should be isolated and should not be sold or purchased. Their handlers should wear protective clothing and a disposable surgical cap and use a respirator with an N95 or higher efficiency rating (not a surgical mask) when handling them or cleaning their cages. Infected birds should be isolated until fully treated, which is generally 45 days. 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. Chapter 274 u Spotted Fever Group Rickettsioses 1899 Rickettsia |
7,538 | species were classically divided into spotted fever and typhus groups based on serologic reactions and the presence or absence of the outer membrane protein A gene (ompA). Sequencing of over 150 complete genomes has refined distinctions. However, there is contro versy regarding phylogeny, and some data suggest that diversity and pathogenicity are the result of gene loss and lateral gene transfer from other prokaryotes or even eukaryotes, which further obscures accurate taxonomic classification. One proposal is to divide existing species into spotted fever and transitional groups based on genetic relatedness; both include pathogenic species and species not now known to cause human disease (Table 274.1). Although increasingly more is understood about the molecular basis by which these bacteria cause human illness, an alternative classification system based on pathogenetic mechanisms has not been defined. The list of pathogens and potential pathogens in the spotted fever group has expanded dramatically in recent years. Unfortunately, the most common diagnostic approach uses a serologic method that can not distinguish among related species; thus the CDC classifies sero logically defined cases as spotted fever rickettsiosis to reflect this uncertainty. Among the etiologic agents of spotted fever rickettsio sis are the tick borne agents Rickettsia rickettsii, the cause of Rocky Mountain or Brazilian spotted fever (RMSF); R. conorii, the cause of Mediterranean spotted fever (MSF) or boutonneuse fever; R. sibirica, the cause of North Asian tick typhus; R. japonica, the cause of Ori ental or Japanese spotted fever; R. honei, the cause of Flinders Island spotted fever or Thai tick typhus; R. africae, the cause of African tick bite fever; R. akari, the cause of mite transmitted rickettsialpox; R. felis, the cause of cat fleatransmitted typhus; and R. australis, the cause of tick transmitted Queensland tick typhus. The recognition that R. parkeri and R. philipii (Rickettsia 364D) both cause mild spotted fever in North America and the association of high serop revalence for spotted fever group Rickettsia infections in humans where Amblyomma ticks frequently contain R. amblyommatis sug gest that the full range of agents that can cause spotted fever is still to be discerned. Infections with other members of the spotted fever and transitional groups are clinically similar to MSF, with fever, maculopapular rash, and eschar at the site of the tick bite. Israeli spotted fever (R. conorii infection) is generally associated with a more severe course in children, including death. African tick bite fever is relatively mild, can include a vesicular rash, and often manifests with multiple eschars. New poten tially pathogenic rickettsial species have been identified, including R. slovaca, the cause of tick borne lymphadenopathy or Dermacentor borne necrosis and lymphadenopathy. R. aeschlimannii, R. heilongjian gensis, R. helvetica, R. massiliae, and R. raoultii are all reported to cause mild to moderate illnesses in humans, although few cases have been described. Fortunately, the vast majority of infections respond well to doxycycline treatment if instituted early in illness; however, this is a significant challenge. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 274.1 Rocky Mountain Spotted |
7,539 | Fever (Rickettsia rickettsii) Megan E. Reller and J. Stephen Dumler RMSF is the most severe rickettsial disease in the United States and Western Hemisphere. Although spotted fever rickettsiosis is the most common vector borne disease in the United States after Lyme dis ease, the proportion of these cases caused by R. rickettsii is not known. Although considered uncommon, RMSF is believed to be greatly underdiagnosed and underreported. RMSF should be considered in the differential diagnosis of fever, headache, and rash in the summer months, especially after tick exposure. Because fulminant disease and death are associated with delays in treatment, patients in whom the ill ness is clinically suspected should be treated promptly. ETIOLOGY RMSF results from systemic infection of endothelial cells by the obli gate intracellular bacterium R. rickettsii. EPIDEMIOLOGY The term Rocky Mountain spotted fever is historical, because the agent was discovered in the Bitterroot Range of the Rocky Mountains of Mon tana. Few cases are reported from this region. Cases have been reported throughout the continental United States (except Vermont and Maine), southwestern Canada, Mexico, Central America, and South America, but not from outside of the Western Hemisphere. In 2010, the CDC reporting criteria for RMSF changed to spotted fever group rickettsio sis, because serology often does not distinguish R. rickettsii from infec tion by other spotted fever group Rickettsia. Additionally, cases detected by enzyme immunoassay were classified as probable. Thus in 2012, 2,802 confirmed and probable cases of spotted fever rickettsiosis were reported in Morbidity and Mortality Weekly Reports Summary of Notifi able Diseases. Unlike in prior years, most cases were reported from the west southcentral states, especially from Arkansas, Oklahoma, and Mis souri; high numbers of cases were also reported from North Carolina, Tennessee, Virginia, New Jersey, Georgia, Alabama, and Arizona (Fig. 274.1). The incidence of RMSF cycles over 25 to 35 year intervals, but spotted fever rickettsioses have steadily increased since 1998 over which time approximately 14 occur in individuals younger than 19 years. Habitats favored by ticks, including wooded areas or coastal grassland and salt marshes, and, in the southwestern United States and Mexico, shaded areas where dogs congregate and acquire infected ticks are those that place children at increased risk for infection. Foci of intense risk for infection are found both in rural and urban areas, most recently in Mexico and South America. Clustering of cases within families likely reflects shared environmental exposures. In the United States, 90 of cases occur between April and September, months in which humans spend the most time outdoors. The highest age specific incidence of RMSF among children is seen in those older than 10 years of age, with males outnumbering females; however, the highest case fatality rate for RMSF is observed in those less than 10 years of age. TRANSMISSION Ticks are the natural hosts, reservoirs, and vectors of R. rickettsii and maintain the infection in nature by transovarial transmission (pas sage of the organism from infected ticks to their progeny). Ticks har boring rickettsiae are substantially |
7,540 | less fecund than uninfected ticks; thus horizontal transmission (acquisition of rickettsiae by taking a blood meal from transiently rickettsemic hosts such as small mam mals or dogs) contributes to maintenance of rickettsial infections in ticks. Uninfected ticks that simultaneously feed (co feed) with infected transmitting ticks easily become infected, even if feeding on an immune host, and are also likely to be major contributors to natural transmission and maintenance. Ticks transmit the infectious agent to mammalian hosts (including humans) via infected saliva during feeding. The pathogen R. rickettsii in ticks becomes virulent after exposure to blood or increased temperature; thus the longer the tick is attached, the greater the risk of transmission. The principal tick Chapter 274 Spotted Fever Group Rickettsioses Megan E. Reller and J. Stephen Dumler Section 11 Rickettsial 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. 1 9 0 0 P art X V u Infectious D iseases Table 274.1 Summary of Rickettsial Diseases of Humans, Including Rickettsia, Orientia, Ehrlichia, Anaplasma, Neorickettsia, and Coxiella GROUP OR DISEASE AGENT ARTHROPOD VECTOR, TRANSMISSION HOSTS GEOGRAPHIC DISTRIBUTION PRESENTING CLINICAL FEATURES COMMON LAB ABNORMALITIES DIAGNOSTIC TESTS TREATMENT SPOTTED FEVER GROUP Rocky Mountain spotted fever Rickettsia rickettsii Tick bite: Dermacentor species (wood tick, dog tick) Rhipicephalus sanguineus (brown dog tick) Dogs Rodents Western hemisphere Fever, headache, rash, emesis, diarrhea, myalgias AST, ALT Na (mild) Platelets Leukopenia Left shift Early: IH, DFA, PCR After first wk: IFA Doxycycline Tetracycline Chloramphenicol Mediterranean spotted fever (boutonneuse fever) Rickettsia conorii Tick bite: R. sanguineus (brown dog tick) Dogs Rodents Africa, Mediterranean, India, Middle East Painless eschar (tache noir) with regional lymphadenopathy, fever, headache, rash, myalgias AST, ALT Na (mild) Platelets Leukopenia Left shift Early: IH, DFA, PCR After first wk: IFA Doxycycline Tetracycline Chloramphenicol Azithromycin Clarithromycin Fluoroquinolones African tick bite fever Rickettsia africae Tick bite Cattle Goats? Sub Saharan Africa, Caribbean Fever, single or multiple eschars, regional lymphadenopathy, rash (can be vesicular) AST, ALT Platelets Early: IH, DFA After 1st wk: IFA Doxycycline Tickborne lymphadenopathy (TIBOLA); Dermacentor borne necrosis and lymphadenopathy (DEBONEL) Rickettsia slovaca, Rickettsia raoultii, Rickettsia sibirica mongolo timonae Tick bite: Dermacentor ? Europe Eschar (scalp), painful lymphadenopathy ? PCR Doxycycline Rickettsia spp., 364D genotype Rickettsia philippii Dermacentor occidentalis (Pacific coast tick) California Eschar, fever, headache, lymphadenopathy, malaise Unremarkable PCR Doxycycline Flea borne spotted fever Rickettsia felis Flea bite Opossums Cats Dogs Western hemisphere, Europe Fever, rash, headache ? Early: PCR After first wk: IFA Doxycycline TRANSITIONAL GROUP Rickettsialpox Rickettsia akari Mite bite Mice North America, Russia, Ukraine, Adriatic, Korea, South Africa Painless eschar, ulcer or papule; tender regional lymphadenopathy, fever, headache, rash (can be vesicular) WBC Early: IH, DFA After first wk: IFA Doxycycline Chloramphenicol Queensland tick typhus Rickettsia australis Ixodes holocyclus, I. tasmani Bandicoots and Rodents Australia, Tasmania Fever, eschar, headache, myalgia, lymphadenopathy WBC, platelets Early: PCR on eschar or eschar swab; After first wk: IFA |
7,541 | Doxycycline TYPHUS GROUP Murine typhus Rickettsia typhi Flea feces Rats Opossums Worldwide Fever, headache, rash, myalgias, emesis, lymphadenopathy, hepatosplenomegaly AST, ALT Na (mild) WBC Platelets Early: DFA, PCR After first wk: IFA Doxycycline Chloramphenicol D ow nloaded for m oham ed ahm ed (dr.m m s2020 gm ail.com ) at U niversity of Southern C alifornia from C linicalK ey.com by Elsevier on A pril 21, 2024. For personal use only. N o other uses w ithout perm ission. C opyright 2024. Elsevier Inc. A ll rights reserved. C hap ter 2 7 4 u Sp o tted Fever G ro up R ickettsio ses 1 9 0 1 GROUP OR DISEASE AGENT ARTHROPOD VECTOR, TRANSMISSION HOSTS GEOGRAPHIC DISTRIBUTION PRESENTING CLINICAL FEATURES COMMON LAB ABNORMALITIES DIAGNOSTIC TESTS TREATMENT Epidemic (louse borne) typhus (recrudescent form: Brill Zinsser disease) Rickettsia prowazekii Louse feces Humans South America, Central America, Mexico, Africa, Asia, Eastern Europe Fever, headache, abdominal pain, rash, CNS involvement AST, ALT Platelets Early: none After first wk: IgG IgM, IFA Doxycycline Tetracycline Chloramphenicol Flying squirrel (sylvatic) typhus Rickettsia prowazekii Louse feces? Flea feces or bite? Flying squirrels Eastern United States Same as above (often milder) AST, ALT Platelets Early: none After first wk: IFA Doxycycline Tetracycline Chloramphenicol SCRUB TYPHUS Scrub typhus Orientia tsutsugamushi, Orientia chuto Orientia chiloensis Chigger bite: Leptotrombidium spp. Rodents? South Asia, Japan, Indonesia, Korea, China, Russia, Australia, Africa, Middle East, Chile Fever, rash, headache, painless eschar, hepatosplenomegaly, gastrointestinal symptoms Platelets AST, ALT Early: none After first wk: IFA Doxycycline Tetracycline Chloramphenicol Rifampicin Azithromycin EHRLICHIOSIS AND ANAPLASMOSIS Human monocytic ehrlichiosis Ehrlichia chaffeensis Tick bite: Amblyomma americanum (lone star tick) Deer Dogs United States, Mexico Fever, headache, malaise, myalgias, rash, hepatosplenomegaly, swollen handsfeet AST, ALT WBC Platelets Na (mild) Early: PCR After first wk: IFA Doxycycline Tetracycline Human granulocytic anaplasmosis Anaplasma phagocyto philum Tick bite: Ixodes species Haemaphysalis longicornis Rodents Deer Ruminants United States, Europe, Asia Fever, headache, malaise, myalgias AST, ALT WBC, ANC Platelets Early: PCR, blood smear After first wk: IFA Doxycycline Tetracycline Rifampin Ewingii ehrlichiosis Ehrlichia ewingii Tick bite: Amblyomma americanum (lone star tick) Dogs Deer United States (south central, southeast) Fever, headache, malaise, myalgias AST, ALT, WBC Platelets Early: PCR serology not available Doxycycline Tetracycline Ehrlichia muris eauclairensis infection Ehrlichia muris ssp. eauclairensis Ixodes scapularis ? Minnesota, Wisconsin Fever, headache, malaise, myalgias AST, ALT WBC, Platelets Early: PCR specific serology not available Doxycycline Neoehrlichiosis Neoehrlichia mikurensis Ixodes ricinus Small mammals? Europe, Asia Fever, headache, myalgias, thrombosis Neutrophilia, anemia, elevated CRP, AST, ALT PCR Doxycycline Sennetsu neorickettsiosis Neorickettsia sennetsu Ingestion of fish helminth?, ingestion of fermented fish Fish, trematodes Japan, Malaysia, Laos Fever, mononucleosis symptoms, postauricular and posterior cervical lymphadenopathy Atypical lymphocytosis Early: none After first wk: IFA Doxycycline Tetracycline Table 274.1 Summary of Rickettsial Diseases of Humans, Including Rickettsia, Orientia, Ehrlichia, Anaplasma, Neorickettsia, and Coxiellacontd Continued D ow nloaded for m oham ed ahm ed (dr.m m s2020 gm ail.com ) at U niversity of Southern C alifornia from C linicalK ey.com by Elsevier on A |
7,542 | pril 21, 2024. For personal use only. N o other uses w ithout perm ission. C opyright 2024. Elsevier Inc. A ll rights reserved. 1 9 0 2 P art X V u Infectious D iseases GROUP OR DISEASE AGENT ARTHROPOD VECTOR, TRANSMISSION HOSTS GEOGRAPHIC DISTRIBUTION PRESENTING CLINICAL FEATURES COMMON LAB ABNORMALITIES DIAGNOSTIC TESTS TREATMENT Q FEVER Q Fever: acute (for chronic, see text) Coxiella burnetii Inhalation of infected aerosols: contact with parturient animals, abattoir, contaminated cheese and milk, ?ticks Cattle Sheep Goats Cats Rabbits Worldwide Fever, headache, arthralgias, myalgias, gastrointestinal symptoms, cough, pneumonia, rash (children) AST, ALT WBC Platelets Interstitial infiltrate Early: PCR After first wk: IFA Doxycycline Tetracycline Fluoroquinolones Trimethoprim sulfamethoxazole Rash is infrequently present at initial presentation but appears during the first wk of illness. Preferred treatment is in bold. Often present in children but not adults. ALT, Alanine aminotransferase; ANC, absolute neutrophil count; AST, aspartate aminotransferase; CNS, central nervous system; DFA, direct fluorescent antibody; IFA, indirect fluorescent antibody; IgG, immunoglobulin G; IgM, immunoglobulin M; IH, immunohistochemistry; PCR, polymerase chain reaction; WBC, white blood cell count. Table 274.1 Summary of Rickettsial Diseases of Humans, Including Rickettsia, Orientia, Ehrlichia, Anaplasma, Neorickettsia, and Coxiellacontd D ow nloaded for m oham ed ahm ed (dr.m m s2020 gm ail.com ) at U niversity of Southern C alifornia from C linicalK ey.com by Elsevier on A pril 21, 2024. For personal use only. N o other uses w ithout perm ission. C opyright 2024. Elsevier Inc. A ll rights reserved. Chapter 274 u Spotted Fever Group Rickettsioses 1903 Fig. 274.3 Immunohistochemical stain demonstrating Rickettsia (red) in infection of blood vessel endothelial cells. (From Biggs HM, Beh ravesh CB, Bradley KK, et al. Diagnosis and management of tickborne rickettsial diseases: Rocky Mountain spotted fever and other spotted fe ver group rickettsioses, ehrlichioses, and anaplasmosisUnited States. MMWR Recomm Rep. 2016;65:144, Fig. 20.) hosts of R. rickettsii are Dermacentor variabilis (the American dog tick) in the eastern United States and Canada, Dermacentor andersoni (the wood tick) in the western United States and Canada, Rhipiceph alus sanguineus (the common brown dog tick) in the southwestern United States and in Mexico, and several Amblyomma spp. in Central and South America (Fig. 274.2). Dogs can serve as reservoir hosts for R. rickettsii, can develop RMSF themselves, and can bring infected ticks into contact with humans. Serologic studies suggest that many patients with RMSF likely acquired the illness from ticks carried by the family dog. Humans can also become infected when trying to remove an attached tick, because R. rickettsiicontaining tick fluids or feces can be rubbed into the open wound at the bite site or into the conjuncti vae by contaminated fingers. Inhalation of aerosolized rickettsiae has caused severe infections and deaths in laboratory workers, highlighting another mechanism of infection. PATHOLOGY AND PATHOGENESIS Systemic infection is most obvious on the skin (rash), but nearly all organs and tissues are affected. After inoculation of tick saliva into the dermis, rickettsial outer surface proteins bind to the vascular endothe |
7,543 | lial cell surface proteins, which signals focal cytoskeletal changes and endocytosis. Thereafter, rickettsia phospholipase mediated dissolution of the endosomal membranes allows escape into the cytosol. Members of the spotted fever group actively nucleate actin polymerization on one pole to achieve directional movement, allowing some to propel into neighboring cells despite minimal initial host cell damage. The rickett siae proliferate and injure host cells by oxidative membrane alterations, protease activation, or continued phospholipase activity. It is likely that some aspects of intracellular infection are mediated by rickettsial pro tein effectors delivered into the host cell by bacterial secretion systems. The histologic correlate of the initial macular or maculopapular rash is perivascular infiltration of lymphoid and histiocytic cells with edema but without significant endothelial damage. Proliferation of rickettsiae within the cytoplasm of infected endothelial cells leads to endothelial injury and lymphohistiocytic or leukocytoclastic vasculitis of small venules and capillaries, which allows extravasation of intravascular erythrocytes into the dermis and manifests as a petechial rash (Fig. 274.3). This process is systemic and ultimately results in widespread microvascular leakage, Fig. 274.1 Reported incidence rate of spotted fever rickettsiosis, by countyUnited States, 20002013. As reported through national surveillance, per 1,000,000 persons per year. Cases are reported by county of resi dence, which is not always where the infection was ac quired. Includes Rocky Mountain spotted fever (RMSF) and other spotted fever group rickettsioses. In 2010, the name of the reporting category changed from RMSF to spotted fever rickettsiosis. (From Biggs HM, Behravesh CB, Bradley KK, et al. Diagnosis and management of tickborne rickettsial diseases: Rocky Mountain spot ted fever and other spotted fever group rickettsioses, ehrlichioses, and anaplasmosisUnited States. MMWR Recomm Rep. 2016;65:144. Fig. 1.) 60 20 to 60 5 to 20 0 to 5 0 a b c d e 1 mm Fig. 274.2 Tick vectors of agents of human rickettsial diseases. An unengaged nymph (a), engorged nymph (b), and adult female (c) of Ixodes scapularis (deer tick), the vector of Anaplasma phagocytophilum and Ehrlichia murislike agent (EMLA), the causes of human granulo cytic anaplasmosis and EMLA ehrlichiosis, respectively. An adult female (d) of Amblyomma americanum (lone star tick), the vector of Ehrlichia chaffeensis and Ehrlichia ewingii, the causes of human monocytic ehr lichiosis and ewingii ehrlichiosis, respectively. An adult female (e) of Dermacentor variabilis (American dog tick), the vector of Rickettsia rick ettsii, the cause of Rocky Mountain spotted fever. 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. 1904 Part XV u Infectious Diseases tissue hypoperfusion, and possibly septic shock or end organ ischemic injury. Infrequently, inflammation leads to nonocclusive thrombi. Very rarely, small and large vessels become completely obliterated by thrombi, leading to tissue infarction or hemorrhagic necrosis. Interstitial pneu monitis and vascular leakage in the lungs can lead to noncardiogenic pulmonary edema, and meningoencephalitis can cause significant cere bral edema and herniation. The presence of |
7,544 | the infectious agent initiates an inflammatory cas cade, including release of cytokines and chemokines such as tumor necrosis factor, interleukin 1, interferon , and regulated upon acti vation, normal T cell expressed and secreted (RANTES). Infection of endothelial cells by R. rickettsii induces surface E selectin expression and procoagulant activity followed by chemokine recruitment of lym phocytes, macrophages, and, occasionally, neutrophils. Local inflam matory and immune responses are suspected to contribute to the vascular injury; however, the benefits of effective innate immunity are greater. Blockade of tumor necrosis factor and interferon in animal models diminishes survival and increases morbidity; reactive oxygen intermediates, nitric oxide expression, and sequestration of trypto phan from rickettsiae are mechanisms by which rickettsiae are killed within cells. Direct contact of infected endothelial cells with perforin producing CD8 T lymphocytes and interferon producing natural killer cells, accompanied by rickettsia antibody, helps control the infec tion. The timing and balance between rickettsia mediated increases in vascular permeability and the benefits of induction of innate and adaptive immunity are likely the major determinants of severity and outcome. CLINICAL MANIFESTATIONS The incubation period of RMSF in children varies from 2 to 14 days (median: 7 days). In 49 of cases, patients or their parents report a history of removing an attached tick, although the site of the tick bite is usually inapparent. Epidemiologic clues include living in or visit ing an endemic area, playing or hiking in the woods, typical season, similar illness in family members, and close contact with a dog. In patients presenting for care, the illness is initially nonspecific, and most patients are not diagnosed during their first visit with a health care practitioner. Manifestations often (50) include fever, rash (frequently involving the palms or soles), nausea and vomiting, and headache and, less often (50), myalgias, abdominal pain, diarrhea, conjunctival injection, altered mental status, lymphadenopathy, and peripheral edema. Pain and tenderness of calf muscles are particularly common in children. The typical clinical triad of fever, headache, and rash is observed in 58 of pediatric patients overall, and rash involving the soles and palms first appearing after day 3 is associated with significantly higher risk of death. Fever and headache persist if the illness is untreated. Fever can exceed 40C (104F) and can remain persistently elevated or can fluctuate dramatically. Headache is severe, unremitting, and unre sponsive to analgesics. Rash usually appears after only 1 2 days of illness, and an estimated 35 of children never develop a rash that is recognized. Initially, dis crete, pale, rose red blanching macules or maculopapules appear; char acteristically, this initial rash is observed on the extremities, including the wrists, ankles, or lower legs (Fig. 274.4). In 65 of patients, the initial rash spreads rapidly to involve the entire body, including the soles and palms. The rash can become petechial or even hemorrhagic, sometimes with palpable purpura. In severe disease, the petechiae can enlarge into ecchymoses, which can become necrotic (Fig. 274.5). Severe vascular obstruction secondary to the rickettsial vasculitis and thrombosis |
7,545 | is uncommon but can result in gangrene of the digits, earlobes, scrotum, nose, or an entire limb. Central nervous system infection usually manifests as changes in mental status (33) or as photophobia (18), seizure (17), or meningismus (16). Patients can also manifest ataxia, coma, or audi tory deficits. Cerebrospinal fluid parameters are usually normal, but one third have pleocytosis (10 300 cellsL), either mononuclear or, less often, neutrophil dominated. Some (20) have elevated protein (200 mgdL) in the cerebrospinal fluid; hypoglycorrhachia is rare. Neuroimaging studies often reveal only subtle abnormalities. However, with advanced disease and neurologic signs, a unique but nonspecific starry sky appearance may be observed on brain MRI that reflects the same systemic vasculitis observed with skin lesions. Other Pulmonary disease occurs more often in adults than in children. How ever, 33 of children examined have a chest radiograph interpreted as an infiltrate or pneumonia. The clinical presentation in these cases can manifest as rales, infiltrates, and noncardiogenic pulmonary edema. Other findings can include conjunctival suffusion, periorbital edema, dorsal hand and foot edema, and hepatosplenomegaly. Severe disease can include myocarditis, acute renal failure, and vascular collapse. Persons with glucose 6 phosphate dehydrogenase deficiency are at increased risk for fulminant RMSF, defined as death from R. rickettsii infection within 5 days. The clinical course of fulminant RMSF is char acterized by profound coagulopathy and extensive thrombosis lead ing to kidney, liver, and respiratory failure. Features associated with increased risk of death include altered mental status, admission to an intensive care unit, need for inotropic support, coma, and need for rap idly administered intravenous fluid. Fig. 274.4 Maculopapular rash with central petechiae associated with Rocky Mountain spotted fever. (From Biggs HM, Behravesh CB, Bradley KK, et al. Diagnosis and management of tickborne rickettsial diseases: Rocky Mountain spotted fever and other spotted fever group rickettsi oses, ehrlichioses, and anaplasmosisUnited States. MMWR Recomm Rep. 2016;65:144, Fig. 21.) Fig. 274.5 Late stage petechial purpuric rash involving the sole of the foot in a patient with Rocky Mountain spotted fever. (From Biggs HM, Behravesh CB, Bradley KK, et al. Diagnosis and management of tickborne rickettsial diseases: Rocky Mountain spotted fever and other spotted fever group rickettsioses, ehrlichioses, and anaplasmosis United States. MMWR Recomm Rep. 2016;65:144, Fig. 22.) 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 274 u Spotted Fever Group Rickettsioses 1905 Occasionally, clinical signs and symptoms suggest a localized pro cess such as appendicitis or cholecystitis. Thorough evaluation usually reveals evidence of a systemic process, and unnecessary surgical inter ventions are avoided. LABORATORY FINDINGS Laboratory abnormalities are common but nonspecific. Thrombocyto penia occurs in 60, and the total white blood cell count is most often normal, with leukocytosis in 24 and leukopenia in 9. Other charac teristic abnormalities include a left shifted leukocyte differential, ane mia (33), hyponatremia (135 mEqmL in 52), and elevated serum aminotransferase |
7,546 | levels (50). DIAGNOSIS Delays in diagnosis and treatment are associated with severe disease and death. Because no reliable diagnostic test is readily available to confirm RMSF during illness, which lasts from 10 days to not more than 3 weeks, the decision to treat must be based on compatible epide miologic, clinical, and laboratory features. RMSF should be considered in patients presenting spring through fall with an acute febrile illness accompanied by headache and myalgia (particularly if they report exposure to ticks or contact with a dog or have been in forested or tick infested rural areas). A history of tick exposure, a rash (especially if on the palms or soles), a normal or low leukocyte count with a marked left shift, a relatively low or decreasing platelet count, and a low serum sodium concentration are all clues that can support a diagnosis of RMSF. In patients without a rash or in dark skinned patients in whom a rash can be difficult to appreciate, the diagnosis can be exceptionally elusive and delayed. One half of pediatric deaths occur within 9 days of onset of symptoms. Thus treatment should not be withheld pend ing definitive laboratory results for a patient with clinically suspected illness. Further, prompt response to early treatment is diagnostically helpful. If a rash is present, a vasculotropic rickettsial infection can be diag nosed as early as day 1 or 2 of illness with biopsy of a petechial lesion and immunohistochemical or immunofluorescent demonstration of a specific rickettsial antigen in the endothelium. Although highly spe cific, the sensitivity of this method is probably 70 at most. Further more, it can be adversely influenced by prior antimicrobial therapy, suboptimal selection of skin lesions for biopsy, and examination of insufficient tissue because of the focal nature of the infection. Tissue or blood can also be evaluated for R. rickettsii nucleic acids by polymerase chain reaction (PCR) at the CDC and selected public health or refer ence laboratories; PCR on blood is less sensitive than PCR on tissue and of similar sensitivity to tissue immunohistochemistry, probably because the level of rickettsemia is generally very low (6 rickettsiae mL). Because eschars are rare with RMSF, scab scrapings or skin swabs are not useful specimens for the detection of rickettsemia by PCR. Definitive diagnosis is most often accomplished by serology, which is retrospective, because a rise in titer is not seen until after the first week of illness. The gold standard for the diagnosis of RMSF is a fourfold increase in immunoglobulin G antibody titer by indi rect fluorescent antibody assay between paired acute and convales cent (at 2 4 weeks) sera, including in the case of seroconversion. A single IgG titer is neither sensitive (patients can die before serocon version) nor specific (an elevated titer can represent prior infection). IgM is nonspecific and does not confirm acute infection. With cur rent serologic methods, RMSF cannot be reliably distinguished from other spotted fever group rickettsiae infections, some of which are not known to be pathogenic. |
7,547 | Therefore confirming acute spotted fever group rickettsia infection requires a compatible clinical illness. Cross reactions of spotted fever group rickettsiae with typhus group rickettsiae also occur, but titers may be lower for the typhus group. Cross reactions are not seen with Ehrlichia or Anaplasma infections. Currently, enzyme linked immunosorbent assay (ELISA) serologic methods can only provide probable rather than confirmed evi dence of infection. Weil Felix antibody testing should not be per formed because it lacks both sensitivity and specificity. RMSF and other spotted fever group rickettsioses are reportable diseases in the United States; however, few reported cases include paired IgG serol ogy, PCR with sequencing, and epidemiologic and clinical metadata. Therefore little is known about the breadth, pathogenicity, and epi demiology of different spotted fever group rickettsiae in the United States or across the globe. Chronic infections by spotted fever group rickettsiae are not documented, such that positive serologic tests after 1 month or more do not reflect ongoing spotted fever group rickettsia infection. DIFFERENTIAL DIAGNOSIS Other rickettsial infections are easily confused with RMSF, especially all forms of human ehrlichiosis and murine typhus and novel spotted fever group rickettsioses that result from R. parkeri or R. philipii str. 364D infections. RMSF can also mimic a variety of other diseases, such as meningococcemia and enterovirus infections. Negative blood cul tures can exclude meningococcemia. PCR can differentiate enterovirus from R. rickettsii in patients with aseptic meningitis and cerebrospi nal fluid pleocytosis. Other diseases in the differential diagnosis are typhoid fever, secondary syphilis, Lyme disease, leptospirosis, rat bite fever, scarlet fever, toxic shock syndrome, rheumatic fever, rubella, parvovirus infection, Kawasaki disease, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, Henoch Schnlein purpura, hemolytic uremic syndrome, aseptic meningitis, acute gastro intestinal illness, acute abdomen, hepatitis, infectious mononucleosis, hemophagocytic and macrophage activation syndromes, dengue fever, and drug reactions. TREATMENT The time proven effective therapies for RMSF are tetracyclines and chloramphenicol. The treatment of choice for suspected RMSF in patients of all ages, including children under 8 years of age, is doxycy cline (4 mgkgday divided every 12 hours PO or IV; maximum: 200 mgday). Tetracycline (25 50 mgkgday divided every 6 hours PO; maximum: 2 gday) is an alternative. Chloramphenicol (50 100 mgkg day divided every 6 hours IV; maximum: 4 gday) should be reserved for patients with doxycycline allergy and for pregnant women because chloramphenicol is an independent risk factor for increased mortal ity vs tetracyclines. If used, chloramphenicol should be monitored to maintain serum concentrations of 10 30 gmL. Chloramphenicol is preferred for pregnant women because of potential adverse effects of doxycycline on fetal teeth and bone and maternal liver function. RMSF is a life threatening illness for which prompt therapy is imperative, and multiple recent studies demonstrate a negligible risk for tooth discol oration in children younger than 8 years of age with the use of doxycy cline. Chloramphenicol is rarely associated with aplastic anemia and is no longer available as an oral preparation in the United States. An addi tional benefit of |
7,548 | doxycycline over chloramphenicol is its effectiveness against potential concomitant Ehrlichia or Anaplasma infection. Sul fonamides should not be used because they are associated with greater morbidity and mortality with all rickettsial infections. Other antibiot ics, including penicillins, cephalosporins, and aminoglycosides, are not effective. The use of alternative antimicrobial agents, such as fluoro quinolones and the macrolides (azithromycin and clarithromycin), has not been evaluated. Therapy should be continued for a minimum of 5 7 days and until the patient has been afebrile for at least 3 days. Treated patients usu ally defervesce within 48 hours, so the duration of therapy is usually 10 days. Spotted fever group rickettsia infection resolves within sev eral weeks if treated appropriately; thus patients with remitting clinical manifestations after 1 month do not benefit from continued or addi tional treatment. SUPPORTIVE CARE Most infections resolve rapidly with appropriate antimicrobial therapy and do not require hospitalization or other supportive care. Among those hospitalized, 36 require intensive care. Particular attention to hemodynamic status is mandatory in severely ill children because iatrogenic pulmonary or cerebral edema could be easily precipitated owing to diffuse microvascular injury of the lungs, meninges, and 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. 1906 Part XV u Infectious Diseases brain. Judicious use of corticosteroids for meningoencephalitis has been advocated by some, but no controlled trials have been conducted. COMPLICATIONS Complications of RMSF include noncardiogenic pulmonary edema from pulmonary microvascular leakage, cerebral edema from meningoencephalitis, and multiorgan damage (hepatitis, pancre atitis, cholecystitis, epidermal necrosis, and gangrene) mediated by rickettsial vasculitis andor the accumulated effects of hypoperfusion and ischemia (acute renal failure). Long term neurologic sequelae can occur in any child with RMSF but are more likely to occur in those hospitalized for 2 weeks. Examples of neurologic sequelae include speech or swallowing disorders; global encephalopathy; cer ebellar, vestibular, and motor dysfunction; hearing loss; and corti cal blindness. Learning disabilities and behavioral problems are the most common neurologic sequelae among children who have sur vived severe disease. PROGNOSIS Delays in diagnosis and therapy are significant factors associated with severe illness or death. Before the advent of effective antimicrobial therapy for RMSF, the case fatality rate was 10 for children and 30 for adults. The overall case fatality rate decreased to a historic low (0.3 0.4) from 2003 to 2012; however, many experts attribute this decrease to detection and reporting of other less virulent emerging forms of spot ted fever group rickettsioses that cannot be readily differentiated from RMSF using current serologic tests. The overall case fatality rate of chil dren 0 9 years of age was 1.4, but rates as high as 8.5 and 11.8 were documented in Texas (19861996) and in Arizona (19992007), respec tively, and rates as high as 3040 are now reported from outbreaks in Mexico, Brazil, and other parts of South America. Diagnosis based on serology |
7,549 | alone underestimates the true mortality of RMSF, because death occurs at a median of 7 days (before developing a serologic response). Deaths occur despite the availability of effective therapeutic agents, indicating the need for clinical vigilance and a low threshold for early empiric therapy. Even with administration of appropriate antimicrobi als, delayed therapy can lead to irreversible vascular or end organ dam age and long term sequelae or death. Early therapy in uncomplicated cases usually leads to rapid defervescence within 1 3 days and recovery within 7 10 days. A slower response may be seen if therapy is delayed. In those who survive despite no treatment, fever subsides in 2 3 weeks. PREVENTION No vaccines are available. Prevention of RMSF is best accom plished by preventing or treating tick infestation in dogs, avoid ing areas where ticks reside, using insect repellents containing N,N diethyl 3 methylbenzamide (DEET) or new alternatives (https:www.epa.govinsect repellentsfind repellent right you), wearing protective clothing, and carefully inspecting children after play in areas where they are potentially exposed to ticks. Recovery from infection yields lifelong immunity. Prompt and complete removal of attached ticks helps reduce the risk for transmission because rickettsiae in the ticks need to be reac tivated to become virulent, and this requires at least several hours to days of exposure to body heat or blood. Contrary to popular belief, the application of petroleum jelly, 70 isopropyl alcohol, fingernail polish, or a hot match are not effective in removing ticks. A tick can be safely removed by grasping the mouth parts with a pair of forceps at the site of attachment to the skin and applying gentle and steady pressure to achieve retraction without twisting, thereby removing the entire tick and its mouth parts. The site of attachment should then be disinfected. Ticks should not be squeezed or crushed, because their fluids may be infectious. The removed tick should be soaked in alcohol or flushed down the toilet, and hands should be washed to avoid accidental inoculation into conjunctivae, mucous membranes, or breaks in skin. Typically, prophylactic antimicrobial therapy is not recommended because tetracyclines and chloramphenicol are only rickettsiastatic; however, the evidence to support this position is meager. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 274.2 Mediterranean Spotted Fever or Boutonneuse Fever (Rickettsia conorii) Megan E. Reller and J. Stephen Dumler MSF, or boutonneuse fever, is caused by R. conorii; it is also called by other names, such as Kenya tick typhus, Indian tick typhus, Israeli spot ted fever, and Astrakhan fever. It is a moderately severe vasculotropic rickettsiosis in adults but comparatively milder in children, with more frequent lymphadenopathy; often, MSF is initially associated with an eschar at the site of the tick bite. Minor differences in clinical presenta tion could be associated with genetic diversity of this species. ETIOLOGY MSF is caused by systemic endothelial cell infection by the obligate intracellular bacterium R. conorii. Similar species are distributed glob ally, such as R. sibirica, R. heilongjiangensis, and R. mongolotimonae in Russia, China, Mongolia, |
7,550 | and Pakistan; R. australis and R. honei in Australia; R. japonica in Japan; R. africae in South Africa; and R. parkeri and R. philippii str. 364D in the Americas (see Table 274.1). Analysis of antigens and related DNA sequences show that all are closely related within a broad genetic clade that includes spotted fever group Rickett sia species such as R. rickettsii, the cause of RMSF. EPIDEMIOLOGY R. conorii is distributed over a large geographic region, including India, Pakistan, Russia, Ukraine, Georgia, Israel, Morocco, southern Europe, Ethiopia, Kenya, and South Africa. Reported cases of MSF in southern Europe have steadily increased since 1980, and the seroprevalence is 1126 in some areas. The peak in reported cases occurs during July and August in the Mediterranean basin; in other regions it occurs dur ing warm months when ticks are active. TRANSMISSION Transmission occurs after the bite of the brown dog tick, R. sanguineus, or for other Rickettsia spp. tick genera such as Dermacentor, Haema physalis, Amblyomma, Hyalomma, and Ixodes. Clustering of human cases of boutonneuse fever, infected ticks, and infected dogs implicates the household dog as a potential vehicle for transmission. PATHOLOGY AND PATHOGENESIS The underlying pathology seen with MSF is nearly identical to that of RMSF, except that eschars are often present at the site of a tick bite where inoculation of rickettsiae occurs. The histopathology of the resultant lesion includes necrosis of dermal and epidermal tissues with a superfi cial crust; a dermis densely infiltrated by lymphocytes, histiocytes, and scattered neutrophils; and damaged capillaries and venules in the der mis. Immunohistochemical stains and nucleic acid amplification tests confirm that the lesions contain rickettsia infected endothelial cells and potentially other cells such as macrophages. The necrosis results from both direct rickettsia mediated vasculitis and resultant extensive local inflammation. Thus rickettsiae have ready access to lymphatics and venous blood and disseminate to cause systemic disease. CLINICAL MANIFESTATIONS AND LABORATORY FINDINGS Typical findings in children include fever (37100), a maculopapu lar rash that appears 3 5 days after onset of fever (94100), hepato splenomegaly (2083), myalgias and arthralgias (1042), headache (863), nausea, vomiting, or diarrhea (528), and lymphadenopa thy (5254). In 6090 of patients, a painless eschar, or tache noire, appears at the site of the tick bite, often on the scalp, with accompanying regional lymphadenopathy (5060) (Fig. 274.6). The infection can be severe, mimicking RMSF, although morbidity and fatalities in children 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 274 u Spotted Fever Group Rickettsioses 1907 Fig. 274.6 Various appearances of eschars associated with Rickettsia parkeri rickettsiosis. (From Biggs HM, Behravesh CB, Bradley KK, et al. Diagnosis and management of tickborne rickettsial diseases: Rocky Mountain spotted fever and other spotted fever group rickettsioses, ehrlichioses, and anaplasmosisUnited States. MMWR Recomm Rep. 2016;65:144, Fig. 24.) are less frequent than in adults. Findings can include seizures, purpu ric |
7,551 | skin lesions, meningitis and neurologic deficits, respiratory and or acute renal failure, and severe thrombocytopenia. Even though the case fatality rate can be as high as 10 in adults and severe infections occur in approximately 9 of children, pediatric deaths are rare. As with RMSF, a particularly severe form occurs in patients with glucose 6 phosphate dehydrogenase deficiency and in patients with underlying conditions such as alcoholic liver disease or diabetes mellitus. DIAGNOSIS Laboratory diagnosis of MSF and related spotted fever group rickett sioses is the same as that for RMSF. Cases can be confirmed by immu nohistologic or immunofluorescent demonstration of or amplification of nucleic acids from rickettsiae in eschar crust or skin biopsies, or demonstration of seroconversion, or accompanied by a fourfold rise in serum antibody titer to spotted fever group rickettsiae between acute and convalescent sera. Antibodies to spotted fever group antigens cross react, so RMSF or other spotted fever group rickettsiosis in the United States or MSF in Europe, Africa, and Asia cannot be distinguished by these methods. When eschars are present, biopsy of the eschar with submission of tissue or a swab of the base for PCR provides consider ably higher sensitivity than PCR on blood and is advocated, if available. In vitro cultivation via centrifugation assisted shell vial tissue culture is rarely used for clinical diagnosis. Treatment should not be withheld while waiting for diagnostic test results. DIFFERENTIAL DIAGNOSIS The differential diagnosis includes conditions also associated with single eschars, such as anthrax, bacterial ecthyma, brown recluse spi der bite, rat bite fever (caused by Spirillum minus), and other rickett sioses (such as rickettsialpox, African tick bite fever, R. parkeri or R. philipii str. 364D rickettsiosis, and scrub typhus). The spotted fever group rickettsia R. africae causes African tick bite fever, a milder illness than MSF that is often associated with multiple eschars and occasion ally a vesicular rash. African tick bite fever can be contracted in North Africa, where MSF also occurs, and is a common infection of travel ers to sub Saharan Africa who encounter bush or high grasslands on safari. R. parkeri and R. philipii str. 364D rickettsiosis are emerging infections in North and South America and in the U.S. western states, respectively. Both often present with an eschar and milder clinical manifestations similar to those observed with African tick bite fever. TREATMENT AND SUPPORTIVE CARE In adults, MSF is effectively treated with tetracycline, doxycycline, chloramphenicol, ciprofloxacin, ofloxacin, levofloxacin, azithromycin, or clarithromycin. For children, the treatment of choice is doxycycline (4 mgkgday divided every 12 hours PO or IV; maximum: 200 mg day). Tetracycline and chloramphenicol are alternatives, as for RMSF. Azithromycin (10 mgkgday once daily PO for 3 days) and clarithro mycin (15 mgkgday divided twice daily PO for 7 days) are also used. Specific fluoroquinolone regimens effective for children have not been established, although recent reports suggest that the use of fluoroqui nolones is associated with increased disease severity as compared with doxycycline. Intensive care may be required. COMPLICATIONS The |
7,552 | complications of MSF are similar to those of RMSF. Overall, the case fatality rate is less than 2, but fatalities are rare in children. Par ticularly severe infections have been noted in patients with underly ing medical conditions, including glucose 6 phosphate dehydrogenase deficiency and diabetes mellitus. PREVENTION MSF is transmitted by tick bites, and prevention is the same as recom mended for RMSF. No vaccine is currently available. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 274.3 Rickettsialpox (Rickettsia akari) and Flea Borne Spotted Fever Megan E. Reller and J. Stephen Dumler Rickettsialpox is caused by R. akari, a transitional group Rickettsia species that is transmitted by the mouse mite, Allodermanyssus san guineus. The mouse host for this mite is widely distributed in cities in the United States, Europe, and Asia. Seroepidemiologic studies sug gest a high prevalence of this infection in urban settings. The disease is uncommon and is usually mild. Unlike the situation with most forms of rickettsiosis, the macrophage is an important target cell for R. akari. Rickettsialpox is best known because of its association with a varicel liform rash. In fact, this rash is a modified form of an antecedent typical macular or maculopapular rash like those seen in other vasculotropic rickettsioses and is occasionally seen with other rickettsioses such as African tick bite fever. Clinical descriptions in children are infrequent. At presentation, most patients have fever, headache, and chills. In up to 90 of cases, there is a painless papular, ulcerative lesion, or eschar at the initial site of inoculation, which can be associated with tender regional lymphadenopathy. In some patients, the maculopapular rash becomes vesicular, involving the trunk, head, and extremities. The infection generally resolves spontaneously and does not require ther apy. However, a short course of doxycycline hastens resolution and is sometimes used in patients older than 8 years of age and in young chil dren with relatively severe illness. Complications and fatalities are rare; however, clear examples of severe disease in children like that observed with RMSF are described. Flea borne spotted fever, caused by Rickettsia felis, is often consid ered within the typhus group because of flea transmission; however, phylogenetic studies place it close to the Rickettsia genus spotted fever or within the transitional group. Similarly, a related cat fleaassoci ated agent, R. asembonensis, was isolated from cat fleas; it and other related rickettsiae in fleas have been identified in environmental sam ples over broad geographic regions but are not known to cause human disease. Since the discovery of R. felis in a febrile patient from Texas by use of molecular amplification methods, and its subsequent isola tion from infected cat fleas, molecular and cross reactive serologic tests have purported to identify human infections globally, some at high rates of prevalence. Clinical isolates have yet to be made from infected humans, and many patients identified by molecular methods lack sero logic responses or even clinical signs. Its identification within mos quitoes and in conjunction with malaria further confound its role as |
7,553 | a human pathogen. Until many of the discrepant findings observed with R. felis are resolved, its role as an important infectious agent in humans remains to be resolved. 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. 1908 Part XV u Infectious Diseases Scrub typhus is an important cause of acute febrile illness in South and East Asia and the Pacific and could be emerging in the Middle East, Africa, and South America. The causative agent is distinct from, but related to, Rickettsia species. The infection is transmitted via chigger (larval mite) bites and involves many antigenically diverse strains of Orientia tsutsugamushi or emerging Orientia spp. such as O. chuto and O. chiloensis, hampering vaccine development. ETIOLOGY The causative agent of scrub typhus, or tsutsugamushi fever, is O. tsutsugamushi, which is distinct from other spotted fever and typhus group rickettsiae (see Table 274.1 in Chapter 274). O. tsutsugamushi lacks both lipopolysaccharide and peptidoglycan in its cell wall. Like other vasculotropic rickettsiae, O. tsutsugamushi infects endothelial cells and causes vasculitis, the predominant clinicopathologic feature of the disease. However, the organism also infects macrophages and cardiac myocytes. A new Candidatus species, Orientia chuto, was isolated from a patient in the Middle East, and definitive evidence of infection based on serology andor PCR amplification of O. tsutsuga mushi genes from acute phase blood suggests a wider range for scrub typhus and related infections. Similarly, a scrub typhuslike illness in southern Chile has been attributed to infection by a new species, Ori entia chiloensis. EPIDEMIOLOGY At least 1 million infections occur each year, and it is estimated that more than 1 billion people are at risk. Scrub typhus is recognized mostly in Asia, including areas delimited by Korea, Pakistan, and northern Australia. Outside these tropical and subtropical regions, the disease occurs in Japan, the Primorsky of far eastern Russia, Tajiki stan, Nepal, and nontropical China, including Tibet. Cases imported to the United States and other parts of the world are reported. Endemic scrub typhus has historically been confined to Asia and Oceania and the tsutsugamushi triangle; however, Orientia may be distributed more broadly, with confirmed cases in South America and possible cases in Africa. Most infections in children are acquired in rural areas. In Thailand and Sri Lanka, scrub typhus is the cause of 18 of acute fevers of unknown origin. Infections are most common during rainy months, usually June through November. Reported cases in boys are higher than in girls. TRANSMISSION O. tsutsugamushi is transmitted via the bite of the larval stage (chigger) of a trombiculid mite (Leptotrombidium in Asia, Herpetacarus in Chile, and Microtrombicula in Africa), which serves as both vector and reser voir. Vertical transovarial transmission (passage of the organism from infected mites to their progeny) is the major mechanism for mainte nance in nature. Because only the larval |
7,554 | stage takes blood meals, a role for horizontal transmission from infected rodent hosts to uninfected mites has not been proved, but transmission among co feeding larval mites is a possibility. Multiple serotypes of O. tsutsugamushi are recog nized, and some share antigenic cross reactivity; however, they do not stimulate protective cross immunity. PATHOLOGY AND PATHOGENESIS The pathogenesis of scrub typhus is uncertain. The process may be stimulated by widespread infection of vascular endothelial cells, which corresponds to the distribution of disseminated vasculitic and perivas cular inflammatory lesions observed in histopathologic examinations. In autopsy series, the major result of the vascular injury appears to be hemorrhage. However, data support the concept that vascular injury initiated by the infection is sustained by immune mediated inflamma tion that together cause significant vascular leakage. The net result is significant vascular compromise and ensuing end organ injury, most often manifested in the brain and lungs, as with other vasculotropic rickettsioses. CLINICAL MANIFESTATIONS AND LABORATORY FINDINGS Scrub typhus can be mild or severe in children and can affect almost every organ system. Most patients present with fever for 9 11 days (range: 1 30 days) before seeking medical care. Regional or general ized lymphadenopathy is reported in 2393, hepatomegaly in about two thirds, and splenomegaly in about one third of children with scrub typhus. Gastrointestinal symptoms, including abdominal pain, vomit ing, and diarrhea, occur in up to 40 of children at presentation. A single painless eschar with an erythematous rim at the site of the chig ger bite is seen in 768 of cases, and a maculopapular rash is present in less than half; both can be absent. Hemophagocytic lymphohistio cytosis has been described. Leukocyte and platelet counts are most commonly within normal ranges, although thrombocytopenia occurs in one quarter to one third of children, and leukocytosis is observed in approximately 40 of children. Clinical manifestations often respond dramatically to appropriate treatment. Adverse outcomes in fetuses and newborn infants of infected mothers have been described, result ing from vertical transmission. DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS Owing to the potential for severe complications, diagnosis and deci sion to initiate treatment should be based on clinical suspicion. The reference diagnostic standard for acute scrub typhus remains demon stration of a fourfold rise in IgG antibody titer by indirect fluorescent antibody testing of acute phase and convalescent phase (obtained at 2 to 4 week follow up) sera. The IgG indirect fluorescent antibody assay is 90 sensitive with 11 days or more of fever but does not distinguish acute from past infection in those residing in endemic regions. A positive acute phase IgM is also not definitive evidence of acute scrub typhus. Although the rickettsiae can be cultivated using tissue culture methods, polymerase chain reaction tests are not highly sensitive, and these diagnostic methods are not widely available. The differential diagnosis includes fever of unknown origin, enteric fever, typhoid fever, dengue hemorrhagic fever, other rickettsioses, tularemia, anthrax, dengue, leptospirosis, malaria, and infectious mononucleosis. TREATMENT AND SUPPORTIVE CARE The recommended treatment regimen |
7,555 | for scrub typhus is doxycycline (4 mgkgday PO or IV divided every 12 hours; maximum: 200 mg day). Alternative regimens include tetracycline (25 50 mgkgday PO divided every 6 hours; maximum: 2 gday) or chloramphenicol (50 100 mgkgday divided every 6 hours IV; maximum: 4 g24 hr). If used, chloramphenicol should be monitored to maintain serum concentra tions of 10 30 gmL. Alternatives now supported by data from ran domized trials include azithromycin (10 mgkg PO on day 1, then 5 mgkg PO; maximum: 500 mgday) or clarithromycin (15 30 mgkg day PO divided every 12 hours; maximum: 1 gday). Therapy should be continued for a minimum of 5 days and until the patient has been afe brile for at least 3 days to avoid relapse. However, a single dose of oral doxycycline was reported effective for all 38 children treated with this regimen in a large series from Thailand. Most children respond rapidly to doxycycline or chloramphenicol within 1 2 days (range: 1 5 days). Strains of O. tsutsugamushi with modestly higher doxycycline minimal inhibitory concentrations are reported in some regions of Thailand. Clinical trials showed that azithromycin could be as effective and that rifampicin is superior to doxycycline in such cases and could have a role as an alternative therapy, especially for pregnant women. The use of ciprofloxacin in pregnant women resulted in an adverse outcome in Chapter 275 Scrub Typhus (Orientia tsutsugamushi) Megan E. Reller and J. Stephen Dumler 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 276 u Typhus Group Rickettsioses 1909 five of five pregnancies among Indian women. Intensive care may be required for hemodynamic management of severely affected patients. COMPLICATIONS Serious complications include pneumonitis in 2035 and menin goencephalitis in approximately 1025 of children. Acute renal failure, myocarditis, and septic shock occur less often. Cerebrospinal fluid examination shows a mild mononuclear pleocytosis with normal glucose levels. Chest radiographs reveal transient perihilar or peri bronchial interstitial infiltrates in most children who are examined. The reported case fatality rate varies widely; among 883 patients 20 years of age in 18 published studies, the case fatality rate was 11; the median for the studies was 1.61.8 and ranged as high as 33. In a contemporary systematic review and meta analysis of Indian children, the case fatality rate was 1.1. PREVENTION Prevention is based on avoidance of the chiggers that transmit O. tsu tsugamushi. Protective clothing is the next most useful mode of preven tion. Infection provides immunity to reinfection by homologous but not heterologous strains; however, because natural strains are highly heterogeneous, infection does not always provide complete protection against reinfection. No vaccines are currently available. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Members of the typhus group of rickettsiae (see Table 274.1 in Chapter 274) include Rickettsia typhi, the cause of murine typhus, and Rickettsia prowazekii, the cause of |
7,556 | louse borne or epidemic typhus. R. typhi is transmitted to humans by fleas, and R. prowazekii is transmitted in the feces of body lice. Louse borne or epidemic typhus is widely consid ered to be the most virulent of the rickettsial diseases, with a high case fatality rate even with treatment. Murine typhus is moderately severe and likely underreported worldwide; global warming and increased precipitation may increase cases and spread. The genomes of both R. typhi and R. prowazekii are similar. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 276.1 Murine (Endemic or Flea Borne) Typhus (Rickettsia typhi) Megan E. Reller and J. Stephen Dumler ETIOLOGY Murine typhus is caused by R. typhi, a rickettsia transmitted from infected fleas to rats, other rodents, or opossums and back to fleas. Transovarial transmission (passage of the organism from infected fleas to their progeny) in fleas is inefficient. Transmission depends on infec tion from the flea to uninfected mammals that then sustain transient rickettsemia and serve as sources of the bacterium for uninfected fleas that bite during the period of rickettsemia. Chapter 276 Typhus Group Rickettsioses Megan E. Reller and J. Stephen Dumler EPIDEMIOLOGY Murine typhus has a worldwide distribution and occurs especially in warm coastal ports, where it is primarily maintained in a cycle involving rat fleas (Xenopsylla cheopis) and rats (Rattus species). Peak incidence occurs when rat populations are highest during spring, summer, and fall. Sentinel surveillance studies suggest that travel acquired murine typhus occurs most often in those visiting Southeast Asia and Africa. In the United States, murine typhus was prevalent before eradication efforts using DDT in the 1940s and is now re emerging. The disease is recognized most often in south Texas and Southern California. However, seroprevalence studies among chil dren indicate that murine typhus is acquired across the southeast and southcentral United States, thus expanding the endemic areas in which pediatricians must be alert for this infection. In the coastal areas of south Texas and in Southern California, the disease is seen in all months, but predominantly from January through July, and is associated with a sylvatic cycle involving opossums and cat fleas (Ctenocephalides felis). The marked increase in reported cases in the past decade likely relates to increased recognition, improved surveil lance, and ecologic factors. TRANSMISSION R. typhi normally cycles between rodents or midsize animals such as opossums and their fleas. Human acquisition of murine typhus occurs when rickettsiae infected flea feces contaminate flea bite wounds. Direct inoculation via flea bite is possible, but inefficient. PATHOLOGY AND PATHOGENESIS R. typhi is a vasculotropic rickettsia that causes disease in a manner similar to Rickettsia rickettsii (see Chapter 274.1). R. typhi organisms in flea feces deposited on the skin as part of the flea feeding reflex are inoculated into the pruritic flea bite wound. After an interval for local proliferation, the rickettsiae spread systemically via lymphatics to the blood, after which they infect the endothelium in many tissues. As with spotted fever group rickettsiae, typhus group rickettsiae infect endothelial cells, |
7,557 | but unlike the spotted fever group rickettsiae, they polymerize intracellular actin poorly, have limited intracellular mobil ity, and probably cause cellular injury by either enzymatic membrane or mechanical lysis after accumulating in large numbers within the endothelial cell cytoplasm. Intracellular infection leads to endothelial cell damage, recruitment of inflammatory cells, and vasculitis. The inflammatory cell infiltrates bring in a number of effector cells, includ ing macrophages that produce proinflammatory cytokines, and CD4, CD8, and natural killer lymphocytes, which can produce immune cytokines such as interferon or participate in cell mediated cyto toxic responses. Intracellular rickettsial proliferation of typhus group rickettsiae is inhibited by cytokine mediated mechanisms and nitric oxidedependent and independent mechanisms. Pathologic findings include systemic vasculitis in response to rick ettsiae within endothelial cells. This vasculitis manifests as interstitial pneumonitis, meningoencephalitis, interstitial nephritis, myocarditis, and mild hepatitis with periportal lymphohistiocytic infiltrates. As vas culitis and inflammatory damage accumulate, multiorgan damage can ensue. CLINICAL MANIFESTATIONS In children, murine typhus is generally a self limited infection, but can be severe, similar to other vasculotropic rickettsioses. The incuba tion period varies from 1 to 2 weeks. The initial presentation is often nonspecific and mimics typhoid fever; fever of undetermined origin is the most common presentation. Pediatric patients with murine typhus exhibit symptoms classically attributed to other vasculotropic rickett sioses, such as rash (4880), myalgias (2957), vomiting (2945), cough (1540), headache (1977), and diarrhea or abdominal pain (1040). A petechial rash is observed in 15 of children, and the usual appearance is that of macules or maculopapules distributed on the trunk and extremities. The rash can involve both the soles and palms. Among common clinical features, only abdominal pain, diarrhea, and sore throat are more common in children than in adults, underscoring 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. 1910 Part XV u Infectious Diseases the mild nature of most cases in children. Murine typhusassociated hemophagocytic lymphohistiocytosis (HLH) is described. Although neurologic involvement is a common finding in adults with murine typhus, photophobia, confusion, stupor, coma, seizures, meningis mus, and ataxia are seen in 20 of hospitalized children and 6 of infected children treated as outpatients. Poor neonatal outcomes are reported with infection during pregnancy; however, frequency and clinical spectrum are not well documented. LABORATORY FINDINGS Although nonspecific, laboratory findings are less severe than in adults. Helpful findings include mild leukopenia (2840) with a moderate left shift, mild to marked thrombocytopenia (3060), hyponatremia (2066), hypoalbuminemia (3087), and elevated aspartate aminotransferase (82) and alanine aminotransferase (38). Elevations in serum urea nitrogen are usually a result of pre renal mechanisms. DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS Delays in diagnosis and therapy are associated with increased morbid ity and mortality; thus diagnosis must be based on clinical suspicion. Occasionally, patients present with findings suggesting pharyngitis, bronchitis, hepatitis, gastroenteritis, or sepsis; thus the differential diagnosis may be extensive. Murine typhus can also |
7,558 | mimic SARS CoV 2associated multisystem inflammatory syndrome in children (MIS C). Confirmation of the diagnosis is usually accomplished by compar ing acute and convalescent phase antibody titers obtained with the indirect fluorescent antibody assay (IFA) to demonstrate a fourfold rise in titer. Current objective studies of the diagnostic yield of R. typhi nucleic acid amplification from acute phase whole blood show disap pointingly low sensitivity, and rickettsial culture is not readily avail able. Thus paired (acute and convalescent) serology to demonstrate a fourfold rise in immunoglobulin (Ig) G antibody titer by IFA remains the standard for confirming acute infection. Use of IgM serologic tests is discouraged for diagnosis of rickettsial infections because of both limited sensitivity and specificity. TREATMENT A meta analysis of murine typhus in children reviewed treatment in 261 children, including 54 who received no antimicrobial therapy. Although 15 had complications, there were no deaths. The standard therapy for murine typhus in children was similar to that for adults and focused on use of tetracyclines or chloramphenicol. Quinolones have been used in children, and limited clinical studies show that ciprofloxa cin is as effective as doxycycline and chloramphenicol to treat murine typhus; however, treatment failures are reported. In vitro experiments suggest that minimal inhibitory concentrations of azithromycin and clarithromycin for R. typhi should be easily achieved. However, in adult patients, a prospective randomized clinical trial showed that either a 3 or 7 day course of doxycycline was superior to 3 days of azithromycin for fever clearance. Therefore the time honored recommended treatment for murine typhus remains doxycycline (4 mgkgday divided every 12 hours PO or IV; maximum: 200 mgday). Alternative regimens include tetracycline (25 50 mgkgday divided every 6 hours PO; maxi mum: 2 gday) or chloramphenicol (50 100 mgkgday divided every 6 hours IV; maximum: 4 gday). Therapy should be for a min imum of 3 days and continued until the patient has been afebrile for at least 3 days. SUPPORTIVE CARE Although disease is usually mild, 15 of children have complications and 27 require intensive care for management of meningoencepha litis, a disseminated intravascular coagulationlike condition, or other conditions. As for other rickettsial infections with significant systemic vascular injury, careful hemodynamic management is mandatory to avoid pulmonary or cerebral edema. COMPLICATIONS Complications of murine typhus in pediatric patients are uncommon; however, relapse, stupor, facial edema, dehydration, splenic rupture, and meningoencephalitis are reported. Predominance of abdominal pain has led to surgical exploration to exclude a perforated viscus. PREVENTION Control of murine typhus was dependent on elimination of the flea res ervoir and control of flea hosts, and this approach remains important. However, with the recognition of cat fleas as potentially significant res ervoirs and vectors, the presence of these flea vectors and their mam malian hosts in suburban areas where close human exposures occur poses increasingly difficult control problems. It is not known with cer tainty if infection confers protective immunity; reinfection appears to be rare. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 276.2 Epidemic (Louse Borne) |
7,559 | Typhus (Rickettsia prowazekii) Megan E. Reller and J. Stephen Dumler ETIOLOGY Humans are considered the principal reservoir of R. prowazekii, the causative agent of epidemic or louse borne typhus and its recrudescent form, Brill Zinsser disease. Another reservoir exists in flying squirrels, their ectoparasites, and potentially ticks in a sylvatic cycle with small rodents. R. prowazekii is the most pathogenic member of the genus Rickettsia and multiplies to very large intracellular quantities before rupture of infected endothelial cells. EPIDEMIOLOGY The infection is characteristically seen in winter or spring and espe cially during times of poor hygienic practices associated with crowd ing, war, famine, extreme poverty, and civil strife. As observed in a recent outbreak among youths at a rehabilitation center in Rwanda, infections in children under these conditions can lead to severe adverse outcomes. R. prowazekii has also been associated with sporadic cases of a mild, typhus like illness in the United States; such cases are associ ated with exposure to flying squirrels harboring infected lice or fleas. R. prowazekii organisms isolated from these squirrels appear to be geneti cally similar to isolates obtained during typical outbreaks. Most cases of louse borne typhus in the developed world are spo radic, but outbreaks have been identified in Africa (Ethiopia, Nigeria, Rwanda, and Burundi), Mexico, Central America, South America, Eastern Europe, Afghanistan, Russia, northern India, and China within the past 25 years. After the Burundi Civil War in 1993, 35,000 100,000 cases of epidemic typhus were diagnosed in displaced refugees, result ing in an estimated 6,000 deaths. TRANSMISSION Human body lice (Pediculus humanus) become infected by feeding on persons who have rickettsiae circulating in their blood owing to endo thelial cell infection. The ingested rickettsiae infect the midgut epithe lial cells of the lice and are passed into the feces, which, in turn, are introduced into a susceptible human host through abrasions or perfo rations in the skin, through the conjunctivae, or rarely, through inhala tion as fomites in clothing, bedding, or furniture. CLINICAL MANIFESTATIONS Louse borne typhus can be mild or severe in children. The incuba tion period is usually 14 days. The typical clinical manifestations include fever, severe headache, abdominal tenderness, and rash in most patients, as well as chills (82), myalgias (70), arthralgias (70), anorexia (48), nonproductive cough (38), dizziness (35), 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 277 u Ehrlichiosis and Anaplasmosis 1911 photophobia (33), nausea (32), abdominal pain (30), tinnitus (23), constipation (23), meningismus (17), visual disturbances (15), vomiting (10), and diarrhea (7). However, investigation of recent African outbreaks has shown a lower incidence of rash (25) and a high incidence of delirium (81) and cough associated with pneumonitis (70). The rash is initially pink or erythematous and blanches. In one third of patients, red, nonblanching macules and pete chiae appear predominantly on the trunk. Infections identified during the |
7,560 | preantibiotic era typically produced a variety of central nervous system findings, including delirium (48), coma (6), and seizures (1). Estimates of case fatality rates range between 3.5 and 20 in outbreaks. Brill Zinsser disease is a form of typhus that becomes recrudes cent months to years after the primary infection, thus rarely affecting children. When bacteremic with rickettsiae, these infected patients can transmit the agent to lice, potentially providing the initial event that triggers an outbreak if hygienic conditions permit. TREATMENT Recommended treatment regimens for louse borne or sylvatic typhus are identical to those used for murine typhus. The treatment of choice is doxycycline (4 mgkgday divided every 12 hours PO or IV; maxi mum: 200 mgday). Alternative treatments include tetracycline (25 50 mgkgday divided every 6 hours PO; maximum: 2 gday) or chloram phenicol (50 100 mgkgday divided every 6 hours IV; maximum: 4 g day). Therapy should be continued for a minimum of 5 days and until the patient is afebrile for at least 3 days. Evidence exists that doxycycline as a single 200 mg oral dose (4.4 mgkg if 45 kg) is also efficacious. PREVENTION Immediate destruction of vectors with an insecticide is important in the control of an epidemic. Lice live in clothing rather than on the skin; thus searches for ectoparasites should include examination of clothing. For epidemic typhus, antibiotic therapy and delousing measures inter rupt transmission, reduce the prevalence of infection in the human reservoir, and diminish the impact of an outbreak. Dust containing excreta from infected lice is stable and capable of transmitting typhus, and care must be taken to prevent its inhalation. Infection confers solid protective immunity. However, recrudescence can occur years later with Brill Zinsser disease, implying that immunity is not complete. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. ETIOLOGY Ehrlichiosis in humans was first described in 1987, when clusters of bacteria confined within cytoplasmic vacuoles of circulating leuko cytes (morulae), particularly mononuclear leukocytes, were detected in the peripheral blood of a patient with suspected Rocky Mountain spotted fever (RMSF). The etiologic agent, Ehrlichia chaffeensis, was cultivated from blood of an infected patient in 1990 and identified as the predominant cause of human ehrlichiosis. Investigations showed that infection by E. chaffeensis is transmitted by Amblyomma ameri canum ticks and occurs more often than RMSF in some geographic areas. By 1994, other cases in which morulae were found only in Chapter 277 Ehrlichiosis and Anaplasmosis Megan E. Reller and J. Stephen Dumler neutrophils and lacked serologic evidence for E. chaffeensis infec tion led to the recognition of the species classified as Anaplasma phagocytophilum, which encompasses several previously described veterinary pathogens on at least two different continents and causes anaplasmosis. Since these discoveries, additional species in the Anaplasmataceae family were identified as human pathogens, including (1) Ehrlichia ewingii in 1996, a veterinary pathogen of canine neutrophils trans mitted by A. americanum ticks; (2) the Ixodes scapularistransmit ted Ehrlichia muris subsp. eauclairensis in 2009, only present so far in patients from Minnesota and Wisconsin |
7,561 | in the United States; (3) infections by Candidatus Neoehrlichia mikurensis, presumably Ixo des spp. or Haemaphysalis concinna tick transmitted, recognized in 2010 as a cause of sepsis like infections of immune compromised patients in Europe, and later as a cause of mild febrile illness in healthy individuals in China; (4) Panola Mountain Ehrlichia, a bac terium rarely associated with infections in humans but present in A. americanum ticks in the United States and with genetic features of the ruminant pathogen Ehrlichia ruminantium; (5) Ehrlichia canis, the established canine pathogen that has infected humans in Ven ezuela and possibly Costa Rica; and (6) Anaplasma capra, the cause of mild fever after Ixodes persulcatus tick bites, so far only identified in China. The latter five have not yet been established as causes of infection in children. Although the infections caused by these various genera have been called ehrlichiosis, further study has identified substantial differences in biology and diagnostic approaches such that the CDC now gener ally separates these into ehrlichiosis, anaplasmosis, or undetermined ehrlichiosisanaplasmosis. Human monocytic ehrlichiosis (HME), or simply ehrlichiosis, describes disease characterized by infection of pre dominantly monocytes and is caused by E. chaffeensis; human granu locytic anaplasmosis (HGA), now anaplasmosis, describes disease related to infection of circulating neutrophils by Anaplasma phagocyto philum; and ewingii ehrlichiosis is caused by infection of granulocytes by E. ewingii (see Table 274.1 in Chapter 274). All of these organisms are tick transmitted and are small, obligate intracellular bacteria with gram negative type cell walls. Neorickett sia sennetsu is another related bacterium that is rarely recognized as a cause of human disease and is not transmitted by ticks. E. chaffeen sis alters host signaling and transcription once inside the cell. It survives in an endosome that enters a receptor recycling pathway to avoid phagosome lysosome fusion and growth into a morula, an intravacuolar aggregate of bacteria. A. phagocytophilum survives in a unique vacuole that becomes decorated by microbial proteins that prevent normal endosomal trafficking and lysosome fusion. Little is known about the vacuoles in which E. ewingii and E. muris subsp. eauclairensis grow. These bacteria are pathogens of phagocytic cells in mammals, and characteristically each species has a specific host cell affinity: E. chaffeensis infects mononuclear phagocytes, and A. phago cytophilum and E. ewingii infect neutrophils. Infection leads to direct modifications in function, in part the result of changes in intracel lular signal transduction or modulation of transcription of the host cell that diminishes host defenses toward the bacterium. Yet host immune and inflammatory reactions are still activated and in part account for many of the clinical manifestations in ehrlichiosis, such as overlaps with macrophage activation syndrome or hemophago cytic lymphohistiocytosis. EPIDEMIOLOGY Infections with E. chaffeensis occur across the southeastern, south central, and Mid Atlantic States of the United States in a distribu tion that parallels that of RMSF; cases have also been reported in northern California. Reported cases of ehrlichiosis have more than doubled since adoption of the current surveillance case definition in 2008. |
7,562 | Suspected cases with appropriate serologic and occasion ally molecular evidence have been reported in Europe, Africa, South America, and the Far East, including China and Korea. Human infec tions with E. ewingii have only been identified in the United States in 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 277 u Ehrlichiosis and Anaplasmosis 1911 photophobia (33), nausea (32), abdominal pain (30), tinnitus (23), constipation (23), meningismus (17), visual disturbances (15), vomiting (10), and diarrhea (7). However, investigation of recent African outbreaks has shown a lower incidence of rash (25) and a high incidence of delirium (81) and cough associated with pneumonitis (70). The rash is initially pink or erythematous and blanches. In one third of patients, red, nonblanching macules and pete chiae appear predominantly on the trunk. Infections identified during the preantibiotic era typically produced a variety of central nervous system findings, including delirium (48), coma (6), and seizures (1). Estimates of case fatality rates range between 3.5 and 20 in outbreaks. Brill Zinsser disease is a form of typhus that becomes recrudes cent months to years after the primary infection, thus rarely affecting children. When bacteremic with rickettsiae, these infected patients can transmit the agent to lice, potentially providing the initial event that triggers an outbreak if hygienic conditions permit. TREATMENT Recommended treatment regimens for louse borne or sylvatic typhus are identical to those used for murine typhus. The treatment of choice is doxycycline (4 mgkgday divided every 12 hours PO or IV; maxi mum: 200 mgday). Alternative treatments include tetracycline (25 50 mgkgday divided every 6 hours PO; maximum: 2 gday) or chloram phenicol (50 100 mgkgday divided every 6 hours IV; maximum: 4 g day). Therapy should be continued for a minimum of 5 days and until the patient is afebrile for at least 3 days. Evidence exists that doxycycline as a single 200 mg oral dose (4.4 mgkg if 45 kg) is also efficacious. PREVENTION Immediate destruction of vectors with an insecticide is important in the control of an epidemic. Lice live in clothing rather than on the skin; thus searches for ectoparasites should include examination of clothing. For epidemic typhus, antibiotic therapy and delousing measures inter rupt transmission, reduce the prevalence of infection in the human reservoir, and diminish the impact of an outbreak. Dust containing excreta from infected lice is stable and capable of transmitting typhus, and care must be taken to prevent its inhalation. Infection confers solid protective immunity. However, recrudescence can occur years later with Brill Zinsser disease, implying that immunity is not complete. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. ETIOLOGY Ehrlichiosis in humans was first described in 1987, when clusters of bacteria confined within cytoplasmic vacuoles of circulating leuko cytes (morulae), particularly mononuclear leukocytes, were detected in the peripheral blood of a patient with suspected Rocky Mountain spotted fever (RMSF). The etiologic |
7,563 | agent, Ehrlichia chaffeensis, was cultivated from blood of an infected patient in 1990 and identified as the predominant cause of human ehrlichiosis. Investigations showed that infection by E. chaffeensis is transmitted by Amblyomma ameri canum ticks and occurs more often than RMSF in some geographic areas. By 1994, other cases in which morulae were found only in Chapter 277 Ehrlichiosis and Anaplasmosis Megan E. Reller and J. Stephen Dumler neutrophils and lacked serologic evidence for E. chaffeensis infec tion led to the recognition of the species classified as Anaplasma phagocytophilum, which encompasses several previously described veterinary pathogens on at least two different continents and causes anaplasmosis. Since these discoveries, additional species in the Anaplasmataceae family were identified as human pathogens, including (1) Ehrlichia ewingii in 1996, a veterinary pathogen of canine neutrophils trans mitted by A. americanum ticks; (2) the Ixodes scapularistransmit ted Ehrlichia muris subsp. eauclairensis in 2009, only present so far in patients from Minnesota and Wisconsin in the United States; (3) infections by Candidatus Neoehrlichia mikurensis, presumably Ixo des spp. or Haemaphysalis concinna tick transmitted, recognized in 2010 as a cause of sepsis like infections of immune compromised patients in Europe, and later as a cause of mild febrile illness in healthy individuals in China; (4) Panola Mountain Ehrlichia, a bac terium rarely associated with infections in humans but present in A. americanum ticks in the United States and with genetic features of the ruminant pathogen Ehrlichia ruminantium; (5) Ehrlichia canis, the established canine pathogen that has infected humans in Ven ezuela and possibly Costa Rica; and (6) Anaplasma capra, the cause of mild fever after Ixodes persulcatus tick bites, so far only identified in China. The latter five have not yet been established as causes of infection in children. Although the infections caused by these various genera have been called ehrlichiosis, further study has identified substantial differences in biology and diagnostic approaches such that the CDC now gener ally separates these into ehrlichiosis, anaplasmosis, or undetermined ehrlichiosisanaplasmosis. Human monocytic ehrlichiosis (HME), or simply ehrlichiosis, describes disease characterized by infection of pre dominantly monocytes and is caused by E. chaffeensis; human granu locytic anaplasmosis (HGA), now anaplasmosis, describes disease related to infection of circulating neutrophils by Anaplasma phagocyto philum; and ewingii ehrlichiosis is caused by infection of granulocytes by E. ewingii (see Table 274.1 in Chapter 274). All of these organisms are tick transmitted and are small, obligate intracellular bacteria with gram negative type cell walls. Neorickett sia sennetsu is another related bacterium that is rarely recognized as a cause of human disease and is not transmitted by ticks. E. chaffeen sis alters host signaling and transcription once inside the cell. It survives in an endosome that enters a receptor recycling pathway to avoid phagosome lysosome fusion and growth into a morula, an intravacuolar aggregate of bacteria. A. phagocytophilum survives in a unique vacuole that becomes decorated by microbial proteins that prevent normal endosomal trafficking and lysosome fusion. Little is known about the vacuoles in which E. |
7,564 | ewingii and E. muris subsp. eauclairensis grow. These bacteria are pathogens of phagocytic cells in mammals, and characteristically each species has a specific host cell affinity: E. chaffeensis infects mononuclear phagocytes, and A. phago cytophilum and E. ewingii infect neutrophils. Infection leads to direct modifications in function, in part the result of changes in intracel lular signal transduction or modulation of transcription of the host cell that diminishes host defenses toward the bacterium. Yet host immune and inflammatory reactions are still activated and in part account for many of the clinical manifestations in ehrlichiosis, such as overlaps with macrophage activation syndrome or hemophago cytic lymphohistiocytosis. EPIDEMIOLOGY Infections with E. chaffeensis occur across the southeastern, south central, and Mid Atlantic States of the United States in a distribu tion that parallels that of RMSF; cases have also been reported in northern California. Reported cases of ehrlichiosis have more than doubled since adoption of the current surveillance case definition in 2008. Suspected cases with appropriate serologic and occasion ally molecular evidence have been reported in Europe, Africa, South America, and the Far East, including China and Korea. Human infec tions with E. ewingii have only been identified in the United States in 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. 1912 Part XV u Infectious Diseases areas where E. chaffeensis also exists, perhaps owing to the shared tick vector. Canine infections are documented in both sub Saharan Africa and South America. Although the median age of patients with ehrlichiosis and anaplas mosis is generally older (51 years), many infected children have been identified, and for ehrlichiosis, the case fatality rate is 4 in those 5 years of age. Perinatal transmission of ehrlichiosis and anaplasmosis has been documented in case reports. Little is known about the epi demiology of E. ewingii infections; although infections in children occur, they are recognized at a rate 100 fold less than for E. chaffeen sis. All infections are strongly associated with tick exposure and tick bites and are identified predominantly during May through September. Although both nymphal and adult ticks can transmit infection, nymphs are more likely to transmit disease because they are most active during the summer. TRANSMISSION The predominant tick species that harbors E. chaffeensis and E. ewin gii is A. americanum, the lone star tick (see Fig. 274.2d in Chapter 274). The tick vectors of A. phagocytophilum are Ixodes spp., includ ing I. scapularis (black legged or deer tick) in the eastern United States (see Fig. 274.1 in Chapter 274), Ixodes pacificus (western black legged tick) in the western United States, Ixodes ricinus (sheep tick) in Europe, Ixodes persulcatus in Eurasia, and Haemaphysalis spp. in China. The Ixodes spp. ticks also transmit Borrelia burgdorferi, Bor relia miyamotoi, Borrelia mayonii, Babesia microti, and tick borne encephalitis associated flaviviruses in Europe and Powassan viruses and E. muris subsp. eauclairensis in |
7,565 | North America. Co infections with these agents and A. phagocytophilum are documented in chil dren and adults. Ehrlichia and Anaplasma species are maintained in nature predomi nantly by horizontal transmission (tick to mammal to tick) because the organisms are not transmitted to the progeny of infected adult female ticks (transovarial transmission). The major reservoir for E. chaffeensis is the white tailed deer (Odocoileus virginianus), which is found abun dantly in many parts of the United States. A reservoir for A. phagocy tophilum in the eastern United States appears to be the white footed mouse, Peromyscus leucopus. Deer or domestic ruminants can sustain persistent asymptomatic infections, but the genetic variants in these reservoirs might not be infectious for humans. Efficient transmission requires persistent infections of mammals. Although E. chaffeensis and A. phagocytophilum can cause persistent infections in animals, clear evidence of chronic infections in humans is exceedingly rare. Transmission of Ehrlichia can occur within hours of tick attachment, in contrast to the 1 2 days of attachment required for transmission of B. burgdorferi to occur. Transmission of A. phagocytophilum is via the bite of the small nymphal stage of Ixodes spp., including I. scapularis (see Fig. 274.2a in Chapter 274), and is effective only after 36 hours of attachment on laboratory mice. PATHOLOGY AND PATHOGENESIS Although ehrlichiosis and anaplasmosis often clinically mimic RMSF or typhus, vasculitis is rare. Pathologic findings include mild, diffuse perivascular lymphohistiocytic infiltrates; Kupffer cell hyperplasia and mild lobular hepatitis with infrequent apoptotic hepatocytes and, less frequently, centrilobular necrosis, cholestasis, and steatosis; infiltrates of mononuclear phagocytes in the spleen, lymph nodes, and bone mar row with occasional hemophagocytosis; granulomas of the liver and bone marrow in patients with E. chaffeensis infections; and hyperplasia of one or more bone marrow hematopoietic lineages. The exact pathogenetic mechanisms are poorly understood, but his topathologic examinations suggest diffuse macrophage activation and poorly regulated host immune and inflammatory reactions. This acti vation results in moderate to profound leukopenia and thrombocyto penia despite a hypercellular bone marrow, and deaths often are related to hemorrhage or secondary opportunistic infections. Hepatic and other organ specific injury occurs by a mechanism that appears to be triggered by the bacterium but is more closely related to induction of innate and adaptive immune effectors that are dysregulated in severely affected patients. Meningoencephalitis with a mononuclear cell pleo cytosis in the cerebrospinal fluid (CSF) occurs with ehrlichiosis but is rare with anaplasmosis. CLINICAL MANIFESTATIONS The clinical manifestations of ehrlichiosis, anaplasmosis, and ewin gii ehrlichiosis are similar. Many well characterized infections of ehrlichiosis and anaplasmosis of variable severity have been reported in children, including deaths. Whereas anaplasmosis is more com mon in children, ehrlichiosis appears to be more severe. Children with ehrlichiosis are often ill for 4 12 days, shorter than in adults. Abdomi nal pain may occur disproportionately in children vs adults with anaplasmosis. In a series of children with ehrlichiosis, most required hospitalization and many (25) required intensive care; these statistics might represent preferential reporting of severe cases. However, |
7,566 | review of case reports and electronic surveillance of anaplasmosis to the CDC identified that 42 of patients 5 9 years of age required hospitaliza tion, and the case fatality rate is 4 among children 5 years of age. Population based studies document that seroconversion often occurs in children who are well or who have only a mild illness. Many fewer pediatric cases of E. ewingii infection are reported, so the clinical mani festations related to this infection are less well characterized. The incu bation period (time from last tick bite or exposure) appears to range from 2 days to 3 weeks. Nearly 25 of patients do not report a tick bite. Clinically, ehrlichiosis and anaplasmosis are undifferentiated febrile illnesses. In ehrlichiosis, fever (100), headache (77), and myal gia (77) are most common, but many patients also report abdomi nal pain, nausea, and vomiting. Altered mental status accompanied by other signs of central nervous system involvement is present in 36. Rash is a common feature (60) in children. The rash is usu ally macular or maculopapular, but petechial lesions can occur. The triad of fever, headache, and rash is observed in 50. Photophobia, conjunctivitis, pharyngitis, and arthralgias can occur but are less con sistently present. Lymphadenopathy, hepatomegaly, and splenomegaly are detected in nearly 50 of children with ehrlichiosis. Edema of the face, hands, and feet occurs more commonly in children than in adults, but arthritis is uncommon. Similar but less severe manifestations occur with anaplasmosis in children, including fever (93), headache (73), myalgia (73), and rigors (60). Nausea, vomiting, abdominal pain, and anorexia occur in 30 or less of patients. Cough is present in 20. Rash is infrequent in anaplasmosis and most often is erythema migrans that results from concurrent Lyme disease. Meningoencephalitis with a lymphocyte predominant CSF pleocy tosis is an uncommon but potentially severe complication of ehrlichi osis that appears to be rare with anaplasmosis. CSF protein may be elevated, and glucose may be mildly depressed in adults with ehrlichio sis meningoencephalitis, but CSF protein and glucose in affected chil dren are typically normal. In one series, 19 of adult patients with central nervous system symptoms and abnormal CSF died despite nor mal CTs of the brain. Chronic or persistent disease with low or absent fever is very unlikely to be any form of ehrlichiosis. LABORATORY FINDINGS Characteristically, most children with ehrlichiosis and anaplasmosis present with leukopenia (5780) and thrombocytopenia (3893); cytopenias reach a nadir several days into the illness. Lymphopenia is common in both ehrlichiosis and anaplasmosis. Leukocytosis can also occur, but usually after the first week of illness or with effective anti microbial treatment. Adults with pancytopenia often have a cellular or reactive bone marrow examination, and in nearly 75 of bone marrow specimens from adults with ehrlichiosis, granulomas and granuloma tous inflammation are present; this finding is not a feature of adults with anaplasmosis. Mild to markedly elevated serum hepatic transami nase levels are frequent in both ehrlichiosis (8592) and anaplasmo sis (4050). Hyponatremia (135 mEqL) |
7,567 | is present in most cases. A clinical picture similar to disseminated intravascular coagulopathy has also been reported. 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 277 u Ehrlichiosis and Anaplasmosis 1913 A B Fig. 277.1 Morulae in peripheral blood leukocytes in patients with human monocytic ehrlichiosis and human granulocytic anaplasmosis. A, A morula (arrow) containing Ehrlichia chaffeensis in a monocyte. B, A morula (arrowhead) containing Anaplasma phagocytophilum in a neutrophil. Wright stains, original magnifications 1,200. E. chaffeensis and A. phagocytophilum have similar morphologies but are serologically and geneti cally distinct. DIAGNOSIS Any delays in diagnosis or treatment are major contributors to increased morbidity or mortality in adults, where those not started on doxycycline at hospital admission are much more likely to require intensive care and undergo a significantly longer course of illness and hospitalization. Tick bites are not always reported; thus treatment must begin as early as possible based on epidemiologic (geographic) and clinical suspicion. Because both ehrlichiosis and anaplasmosis can be fatal, therapy should not be withheld while waiting for the results of confirmatory testing. In fact, prompt response to therapy supports the diagnosis. Although several reports document pediatric patients with E. chaffeensis infection diagnosed based on typical Ehrlichia morulae in peripheral blood leukocytes (Fig. 277.1A), this finding is too infre quent to be considered a useful diagnostic approach. In contrast, ana plasmosis in adults presents with a small but significant percentage (140) of circulating neutrophils (see Fig. 277.1B) containing typical morulae in 2060 of patients. E. chaffeensis and A. phagocytophilum infections are currently most frequently established by specific polymerase chain reaction assays used during the acute phase of illness when antibodies are often not detected. Both infections can be confirmed by demonstrating a four fold change in immunoglobulin G titer by indirect immunofluo rescence assay between paired sera. Serologic tests during the acute phase of infection are often negative; consequently, confirmation of acute infection requires demonstration of a fourfold rise in IgG titer in paired samples. A single specific titer of 128 is suggestive, but the use of IgM testing is discouraged owing to a lack of specificity. Identi fication of morulae in monocytes or macrophages for E. chaffeensis or in neutrophils or eosinophils for A. phagocytophilum by microscopy is suggestive. Demonstration of specific antigen in a tissue sample by immunohistochemistry and isolation of the organism in cell culture are not timely and are used infrequently. E. ewingii infection can only be confirmed by polymerase chain reaction because it has not been cultured and serologic antigens are not available. E. ewingii antibod ies cross react with E. chaffeensis in routine serologic tests. Up to 15 of patients with anaplasmosis have serologic cross reactions with E. chaffeensis; thus serodiagnosis depends on testing with both E. chaffeensis and A. phagocytophilum antigens and demonstrating a four fold or higher difference between titers. DIFFERENTIAL DIAGNOSIS |
7,568 | Because of the nonspecific presentation, ehrlichiosis mimics other arthropod borne infections such as RMSF, tularemia, babesiosis, Lyme disease, murine typhus, relapsing fever, and Colorado tick fever. Other potential diagnoses often considered include otitis media, streptococcal pharyngitis, infectious mononucleosis, Kawasaki disease, endocarditis, respiratory or gastrointestinal viral syndromes, hepatitis, leptospirosis, Q fever, collagen vascular diseases, hemophagocytic syndromes, and leukemia. If rash and disseminated intravascular coagulopathy pre dominate, meningococcemia, bacterial sepsis, and toxic shock syn drome should also be suspected. Meningoencephalitis might suggest aseptic meningitis caused by enterovirus or herpes simplex virus, bac terial meningitis, or RMSF. Severe respiratory disease may be confused with bacterial, viral, and fungal causes of pneumonia. Mounting evi dence suggests that ehrlichiosis and anaplasmosis may be precipitating factors for hemophagocytic lymphohistiocytosis. TREATMENT Both ehrlichiosis and anaplasmosis are effectively treated with tetra cyclines, especially doxycycline, and the majority of patients improve within 48 hours. In vitro tests document that both E. chaffeensis and A. phagocytophilum have minimal inhibitory concentrations to chlor amphenicol above blood levels that can be safely achieved. Therefore a short course of doxycycline is the recommended regimen. Doxycycline is used safely in children younger than 8 years of age because tooth discoloration is dose dependent and the need for multiple courses is unlikely; experience has demonstrated that adverse consequences of doxycycline use in children 8 years of age are extremely rare, in particular if courses are relatively short. Few data exist to recommend alternative therapies; however, both E. chaffeensis and A. phagocytophi lum are susceptible in vitro to rifampin, which has been used success fully to treat anaplasmosis in pregnant women and children. The recommended regimen for patients of all ages with severe or complicated ehrlichiosis and anaplasmosis is doxycycline (for those who weigh 45 kg, 4 mgkgday PO or IV divided every 12 hours; maximum 200 mgday). An alternative regimen is tetracycline (25 50 mgkgday divided every 6 hours PO; maximum 2 gday). For children who weigh more than 45 kg, the adult dose, 100 mg twice daily by oral or intravenous route, can be used. Therapy should be continued for 5 days and until the patient has been afebrile for 2 4 days. Other broad spectrum antibiotics, including penicillins, cephalo sporins, aminoglycosides, and macrolides, are not effective. In vitro studies suggest that fluoroquinolones are active against A. phagocyto philum, although at least one patient relapsed when levofloxacin was discontinued. E. chaffeensis is naturally resistant to fluoroquinolones owing to a single nucleotide change in gyrA, which suggests that A. phagocytophilum could also become resistant to fluoroquinolones rapidly. COMPLICATIONS AND PROGNOSIS Fatal ehrlichiosis has been reported in occasional pediatric patients, where the findings included pulmonary involvement and respiratory failure in patients with or without immune compromise. The pattern of severe pulmonary involvement culminating in diffuse alveolar dam age and acute respiratory distress syndrome and secondary nosocomial 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 |
7,569 | Inc. All rights reserved. 1914 Part XV u Infectious Diseases or opportunistic infections is now well documented with ehrlichiosis and anaplasmosis in adults. Of greater concern is the frequency with which secondary hemophagocytic lymphohistiocytosis is diagnosed with ehrlichiosis and anaplasmosis in children. Children and adults who are immunocompromised (e.g., HIV infection, high dose cortico steroid therapy, cancer chemotherapy, immunosuppression for organ transplantation) are at high risk for fulminant E. chaffeensis infection, for E. ewingii infection, and for severe anaplasmosis. PREVENTION Ehrlichiosis, anaplasmosis, and ewingii ehrlichiosis are tick borne dis eases, and any activity that increases exposure to ticks increases risk. Avoiding tick infested areas, wearing appropriate light colored cloth ing, spraying tick repellents on clothing, carefully inspecting for ticks after exposure, and promptly removing any attached ticks diminish the risk. The interval between tick attachment and transmission of the agents may be as short as 4 hours; thus attached ticks should be removed promptly. A role of prophylactic therapy for ehrlichiosis and anaplasmosis after tick bites has not been investigated. It is not known if infection confers protective immunity; however, reinfection appears to be rare. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Q fever (for query fever, the name given after an outbreak of febrile ill ness in an abattoir in Queensland, Australia) is rarely reported in chil dren but is probably underdiagnosed. Symptomatic patients can have acute or chronic disease. ETIOLOGY Although previously classified within the order Rickettsiales, Coxiella burnetii (the causative agent of Q fever) is genetically distinct from the genera Rickettsia, Orientia, Ehrlichia, and Anaplasma. Hence, based on small genome analysis, it best aligns with the order Legionellales, family Coxiellaceae. C. burnetii is highly infectious for both humans and animals; even a single organism can cause infection. The agent has been nationally notifiable since 1999 and is listed as a Category B agent of bioterrorism by the Centers for Disease Control and Pre vention (CDC). Unlike Rickettsia, the organism can enter a sporogenic differentiation cycle, which renders it highly resistant to chemical and physical treatments. C. burnetii resides intracellularly within macrophages. In vitro, the organism undergoes a lipopolysaccharide phase variation similar to that described for smooth and rough strains of Enterobacteriaceae. Unlike Ehrlichia, Anaplasma, and Chlamydia, C. burnetii survives and proliferates within acidified phagosomes to form aggregates of 100 bacteria. EPIDEMIOLOGY The disease is reported worldwide, except in New Zealand. Although seroepidemiologic studies suggest that infection occurs just as often in children as in adults, children less often present with clinical disease than adults. During the large outbreak of Q fever in the Netherlands in 20072009, only 3.5 of those diagnosed with Q fever were age 19 years or younger. Infections are recognized more often in men than in Chapter 278 Q Fever (Coxiella burnetii) Megan E. Reller and J. Stephen Dumler women. Historically, reported cases in boys and girls have been equal, although a recent study reported male predominance. Approximately 60 of infections are asymptomatic, and only 5 of symptomatic patients require hospitalization. Seroprevalence surveys show |
7,570 | that 670 of children in endemic European and African communities have evidence of past infection. In France, the overall incidence of Q fever is estimated to be 50 cases per 100,000 persons. A similar esti mate is not available for Africa, where cases are likely misdiagnosed as malaria. The seroprevalence of Q fever in the United States is estimated to be 3.1. Reported cases of Q fever in the United States have been received from every state, but 35 are reported from four states (Cali fornia, Texas, Colorado, and Illinois). In the United States, reported Q fever cases increased by greater than ninefold from 17 cases in 2000 to 167 cases in 2008, reflecting an increase in incidence, increased report ing after September 11, 2001, improved diagnostic tools, or a combina tion of factors. Cases decreased significantly in 20082013 relative to 2007 but returned to previous high levels in 2014 (173 cases, including 147 acute and 39 chronic). Beginning in 2008, reported cases in the United States have been classified as acute or chronic. Between 2002 and 2014, more than 50 of recognized cases in the United States required hospitalization. Reported cases in Asia and Australia have also increased. Most infections in children are identified during the lamb birthing season in Europe (January through June), after farm vis its, or after exposure to placentas of dogs, cats, and rabbits. The largest (4,000 human cases) community outbreak ever described occurred in the Netherlands in 20072012 and was associated with intensive farming of dairy goats and dairy sheep. In 2011, the first multistate outbreak of Q fever in humans was linked to interstate sale of infected goats; an outbreak of unknown source was also reported. From 2000 to 2010, 60 of cases reported to the CDC occurred in individuals with out reported exposure to livestock. More than 20 of cases of clini cally recognized acute or chronic Q fever occur in immunosuppressed hosts or in persons with prosthetic valves or damaged native valves or vessels. These findings highlight the need for considering Q fever in those with clinically compatible illness, especially but not exclusively in those with likely exposures and in vulnerable hosts. Epidemiologic investigations and control efforts require a One Health approach, with consideration of the interactions between humans, animals, environ ment, and public health. TRANSMISSION In contrast to other rickettsial infections, humans usually acquire C. burnetii by inhaling infectious aerosols (e.g., contaminated barnyard dust) or ingesting (and likely aspirating) contaminated foods. Ticks are rarely implicated. Cattle, sheep, and goats are the primary reservoirs, but infection in other livestock and domestic pets is also described. Organisms are excreted in milk, urine, and feces of infected animals, but especially in amniotic fluids and the placenta. An increase in inci dence is associated with the seasonal mistral winds in France that coin cide with lamb birthing season and with consumption of cheese among children in Greece. In Nova Scotia and Maine, exposure to newborn animals, especially kittens, has been associated with small outbreaks |
7,571 | of Q fever in families. Exposure to domestic ruminants is the major risk in Europe and Australia, although many urban dwellers in France also acquire Q fever without such an exposure. Person to person transmis sion is possible but rare. Clinical Q fever during pregnancy can result from primary infection or reactivation of latent infection and is associ ated with miscarriage, intrauterine growth retardation, and premature births. Obstetricians and other related healthcare workers are at risk for acquiring infection because of the quantity of C. burnetii sequestered in the placenta. Sexual transmission and cases attributable to blood trans fusion or bone marrow transplantation are also reported. Transmission after live cell therapy (injected live animal cells) has also been reported. PATHOLOGY AND PATHOGENESIS The pathology of Q fever depends on the mode of transmission, route of dissemination, specific tissues involved, and course of the infection. When acquired via inhalation, a mild interstitial lymphocytic pneumo nitis and macrophage and organism rich intraalveolar exudates are 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 278 u Q Fever (Coxiella burnetii) 1915 often seen. When the liver is involved, a mild to moderate lymphocytic lobular hepatitis can be seen. Inflammatory pseudotumors can develop in the pulmonary parenchyma or other tissues. Classic fibrin ring (doughnut) granulomas, generally associated with acute, self limited infections, are occasionally identified in liver, bone marrow, meninges, and other organs. Typically, infected tissues are also infiltrated by lym phocytes and histiocytes. Recovery from symptomatic or asymptomatic acute infection can result in persistent subclinical infection, possibly maintained by dys regulated cytokine responses. The persistence of C. burnetii in tissue macrophages at sites of preexisting tissue damage elicits low grade chronic inflammation and, depending on the site of involvement, can result in irreversible cardiac valve damage, persistent vascular injury, or osteomyelitis. Endocarditis of native or prosthetic valves is char acterized by infiltrates of macrophages and lymphocytes in necrotic fibrinous valvular vegetations and an absence of granulomas. CLINICAL MANIFESTATIONS AND COMPLICATIONS Children are less likely to develop symptoms compared with adults. Only approximately 4050 of people infected with C. burnetii develop symptoms. Historically, two forms of symptomatic disease have been thought to occur. Acute Q fever, now better characterized as primary Q fever, is more common and usually manifests as self limited undif ferentiated fever or an influenza like illness with interstitial pneumo nitis. Persistent localized infection with C. burnetii can cause what has historically been referred to as chronic Q fever. In adults, persistent localized infection usually involves the cardiovascular systemnative heart valves, especially those with preexisting valvulopathy, prosthetic valves, or other endovascular prostheses. Q fever osteomyelitis is less common but proportionally more common as a manifestation of infec tion in children. Less common persistent localized C. burnetii infec tions include lymphadenitis, genital infection, and pericarditis. Primary (Acute) Q Fever Acute Q fever develops approximately 3 weeks |
7,572 | (range: 14 39 days) after exposure to the causative agent. The severity of illness in children ranges from subclinical infection to a systemic illness of sudden onset characterized by high fever, severe frontal headache, nonproductive cough, chest pain, vomiting, diarrhea, abdominal pain, arthralgias, and myalgias. Approximately 40 of children with acute Q fever pres ent with fever, 25 with pneumonia or an influenza like illness, 10 with meningoencephalitis, and 10 with myocarditis. Other manifes tations include pericarditis, hepatitis, hemophagocytic lymphohistio cytosis, rhabdomyolysis, and a hemolytic uremiclike syndrome. Rash, ranging from maculopapular to purpuric lesions, is an unusual finding in adults with Q fever but is observed in approximately 50 of pediat ric patients. Rigors and night sweats are common in adults with Q fever and occur less often in children. Prominent clinical findings that can create diagnostic confusion include fatigue, vomiting, abdominal pain, and meningismus. Hepatomegaly and splenomegaly may be detected in some patients. Routine laboratory investigations in pediatric acute Q fever are usu ally normal but can reveal mild leukocytosis and thrombocytopenia. Up to 85 of children have modestly elevated serum hepatic transami nase levels that usually normalize within 10 days. Hyperbilirubinemia is uncommon in the absence of complications. C reactive protein may not be elevated in pediatric Q fever. Chest radiographs are abnormal in nearly 30 of all patients; in children, the most common findings include single or multiple bilateral infiltrates with reticular markings in the lower lobes. Primary Q fever in children is usually a self limited illness, with fever persisting for only 7 10 days compared with 2 3 weeks in adults. However, severe manifestations of acute illness, such as myocarditis requiring cardiac transplantation, meningoencephalitis, pericarditis, hemophagocytosis, thrombosis with antiphospholipid antibody syn drome, and a relapsing febrile illness lasting for several months, have been reported. Persistent Localized Q Fever Infection The risk for developing persistent localized Q fever infection, his torically called chronic Q fever, is strongly correlated with advanc ing age and underlying conditions such as cardiac valve damage or immunosuppression; persistent localized Q fever infection is rarely diagnosed in children. A review identified only five cases of Q fever endocarditis and six cases of osteomyelitis among children, none of whom had known predisposing immune deficiencies. Four of the five cases of endocarditis occurred in children with underlying congenital heart abnormalities and involved the aortic, pulmonary, and tricuspid valves. Four of the six children with Q fever osteomy elitis had a prior diagnosis or clinical course consistent with idio pathic chronic recurrent multifocal osteomyelitis. A long interval before diagnosis and lack of high fever are common in pediatric cases of persistent localized Q fever infectionhistorically chronic Q fever. Although Q fever endocarditis often results in death (2365 of cases) in adults, mortality has not been reported for children. Endocar ditis associated with persistent or chronic Q fever can occur months to years after acute infection and can occur in the absence of recognized acute Q fever and in the absence of clinically recognized valvulopathy. Chronic |
7,573 | hepatitis has also been reported. LABORATORY FINDINGS Laboratory features in children with chronic Q fever are poorly documented; adult patients often have an erythrocyte sedimenta tion rate of 20 mmhr (80 of cases), hypergammaglobulinemia (54), and hyperfibrinogenemia (67). In children, the presence of rheumatoid factor in 50 of cases and circulating immune com plexes in nearly 90 suggest an autoimmune process. The presence of antiplatelet antibodies, antismooth muscle antibodies, antimi tochondrial antibodies, circulating anticoagulants, positive direct Coombs tests, and antiphospholipid antibodies also suggest this possibility. DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS Although uncommonly diagnosed, Q fever in children most often mimics other childhood respiratory infections. It should be considered in children who have an influenza like illness, lower or upper respira tory tract infection, fever of unknown origin, myocarditis, meningo encephalitis, culture negative endocarditis, or recurrent osteomyelitis and who live in rural areas or who are in close contact with domestic livestock, cats, or animal products. The diagnosis of primary (acute) Q fever is most easily and commonly confirmed by testing acute and convalescent sera (3 6 weeks apart), which show a fourfold increase in indirect fluorescent immunoglobulin G antibody titers to phase II C. burnetii antigens. The phase II antibody response to C. burnetii appears first and is higher than the phase I antibody response. Phase II immunoglobu lin G antibodies can remain elevated for months to years, regardless of initial symptoms or lack thereof. In contrast, persistent localized (chronic) Q fever is characterized by a phase I immunoglobulin G antibody titer greater than 800 that is sustained for 6 months or more, such as occurs with Q fever endocarditis in patients with val vular heart disease. Cross reactions with antibodies to Legionella and Bartonella can occur. Although culture has been considered the gold standard, sensitivity (compared with a composite standard including serology and poly merase chain reaction PCR) is low. C. burnetii has been cultivated in tissue culture cells, which can become positive within 48 hours, but isolation and antimicrobial susceptibility testing of C. burnetii should be attempted only in specialized biohazard facilities. Testing by PCR can be performed on blood, serum, and tissue samples and is available only in some public health, reference, or research laboratories. PCR has been helpful in patients with equivocal titers, as occurs with early infection. PCR usually remains positive for 7 10 days after acute infec tion. Sensitivity has been improved by real time methods and the use 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. 1916 Part XV u Infectious Diseases of repeated sequences as targets. Immunohistochemical staining has also been used but is not readily available. PCR should be performed either before or shortly after initiation of treatment. PCR can also confirm a serologic diagnosis of endocarditis in untreated patients. Genotyping has aided epidemiologic investigations to confirm the source of infection. The differential diagnosis depends on |
7,574 | the clinical presentation. In patients with respiratory disease, Mycoplasma pneu moniae, Chlamydophila pneumoniae, legionellosis, psittacosis, and Epstein Barr virus infection should be considered. In patients with granulomatous hepatitis, tuberculous and nontuberculous mycobac terial infections, salmonellosis, visceral leishmaniasis, toxoplasmosis, Hodgkin disease, monocytic ehrlichiosis, brucellosis, cat scratch dis ease (Bartonella henselae), or autoimmune disorders such as sarcoid osis should be considered. Culture negative endocarditis suggests infection with Brucella, Bartonella, HACEK organisms (Haemophi lus, Aggregatibacter, Cardiobacterium hominis, Eikenella corrodens, Kingella), partially treated bacterial endocarditis, nonbacterial endo carditis, or potentially noninfectious inflammatory conditions, includ ing chronic recurrent multifocal osteomyelitis and antiphospholipid syndrome. TREATMENT Selection of an appropriate antimicrobial regimen for children is dif ficult owing to the lack of rigorous studies, the limited therapeutic win dow for drugs that are known to be efficacious, and the potential length of therapy required to preclude relapse. Most pediatric patients with Q fever have a self limited illness that is identified only on retrospective serologic evaluation. However, to prevent potential complications, treatment should be considered for patients who present with suspected acute Q fever within 3 days of onset of symptoms, because therapy started more than 3 days after the onset of illness has little effect on the course of acute Q fever. Early treatment is effective in shortening illness duration and severity. Dox ycycline (100 mg orally 2 timesday for children 8 years or older or 4 mgkgday orally divided 2 timesday for children younger than 8 years, maximum: 200 mgday, for 14 days) is the drug of choice. Doxy cycline may cause permanent tooth discoloration for children younger than 8 years if used repeatedly but is generally safe when used for short courses. Children younger than 8 years with mild illness, pregnant adolescents, and patients allergic to doxycycline can be treated with trimethoprim sulfamethoxazole. For persistent focal Q fever, especially endocarditis and mostly in adults, therapy for 18 36 months is mandatory, because treatment is more difficult and relapses can occur despite appropriate therapy. The current recommended regimen for Q fever endocarditis is a combination of doxycycline and hydroxychloroquine for 18 months or longer. For patients with heart failure, valve replacement could be necessary. PREVENTION Recognition of the disease in livestock or other domestic animals should alert communities to the risk for human infection by aerosol exposures within 15 km. Milk from infected herds must be pasteurized at temperatures sufficient to destroy C. burnetii. C. burnetii is resistant to significant environmental conditions but can be inactivated with a solution of 1 Lysol, 1 formaldehyde, or 5 hydrogen peroxide. Special isolation measures are not required because person to person transmission is rare, except when others are exposed to the placenta of an infected patient. A vaccine is available and provides protection against Q fever for at least 5 years in abattoir workers; however, it is not licensed in the United States. Prospective studies of vaccination in children at high risk are needed. Clusters of cases resulting from intense natural exposures, such as in slaughterhouses or on |
7,575 | farms, are well documented. Clusters of cases that occur in the absence of such an exposure should be investigated as potential sentinel events for bioterrorism. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Invasive fungal infections are a major cause of morbidity and mortality in the growing number of immunocompromised children. The anti fungal armamentarium has markedly increased in recent years (Tables 279.1 and 279.2). POLYENES Amphotericin B The prototype of the oldest antifungal class, the polyene macrolides, is amphotericin B deoxycholate. Amphotericin B was once the pre ferred treatment for most invasive fungal infections and the standard of comparison for all newer antifungal agents. Amphotericin B is so named because it is amphoteric, forming soluble salts in both acidic and basic environments. However, because of its insolubility in water, amphotericin B for clinical use is actually amphotericin B mixed with the detergent deoxycholate. Amphotericin B binds to ergosterol, the major sterol found in fungal cytoplasmic membranes, and acts by cre ating transmembrane channels. The fungicidal activity is the result of a damaged barrier and subsequent cell death through leakage of essential nutrients from the fungal cell. Amphotericin B is released from its carrier and distributes efficiently with lipoproteins and is then taken up preferentially by organs of the reticuloendothelial system. After an initial 24 to 48 hour distributional half life, there is very slow release and a subsequent terminal elimina tion half life of up to 15 days. In addition to conventional amphotericin B deoxycholate, two fundamentally different lipid associated formula tions are currently available that offer the advantage of an increased daily dosage of the parent drug, better delivery to the primary reticuloendo thelial organs (lungs, liver, spleen), and reduced toxicity. Amphotericin B lipid complex (ABLC) is a tightly packed ribbon like structure of a bilayered membrane, and liposomal amphotericin B (L amphotericin B) consists of small uniformly sized vesicles of a lipid bilayer of ampho tericin B. Lipid formulations of amphotericin B generally have a slower onset of action, presumably owing to the required disassociation of free amphotericin B from the lipid vehicle. The ability to safely administer higher daily doses of the parent drugs improves their efficacy, compar ing favorably with amphotericin B deoxycholate but with less toxicity. Lipid formulations have the added benefit of increased tissue concen trations compared with conventional amphotericin B, specifically in the liver, lungs, and spleen. Tolerance to amphotericin B deoxycholate is limited by its acute and chronic toxicities. In addition to interact ing with fungal ergosterol, the drug also interacts with cholesterol in human cell membranes, likely accounting for its toxicity. Up to 80 of patients receiving amphotericin B develop either infusion related tox icity or nephrotoxicity, especially with concomitant therapy with neph rotoxic drugs such as aminoglycosides, vancomycin, cyclosporine, or tacrolimus. Renal function usually returns to normal after cessation of amphotericin B, although permanent renal impairment can occur after larger doses. Amphotericin B nephrotoxicity is generally less severe in infants and children than in adults, likely because of the more |
7,576 | rapid clearance of the drug in children. Lipid formulations appear to stabilize Chapter 279 Principles of Antifungal Therapy William J. Steinbach Section 12 Fungal 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 279 u Principles of Antifungal Therapy 1917 Table 279.1 Suggested Dosing of Antifungal Agents in Children and Neonates DRUG FORMULATIONS SUGGESTED PEDIATRIC DOSAGE COMMENTS Amphotericin B deoxycholate IV 1 mgkgday Generally less toxicity in children than adults; do not start with smaller test doses Lipid amphotericin B formulations IV 5 mgkgday Generally, all lipid formulations are dosed the same; there is no clear indication of one formulation over another for clinical efficacy Fluconazole IV, PO 12 mgkgday Loading dose (25 mgkg) is recommended in neonates based on pharmacokinetic simulations and likely suggested in children, but insufficiently studied Itraconazole PO 2.5 mgkgdose bid Divide dosage twice daily in children; follow trough levels Voriconazole IV, PO 8 mgkgdose bid IV maintenance; 9 mgkgdose bid oral maintenance Linear pharmacokinetics in children requires higher dosing than in adults; 9 mgkgdose bid IV loading, followed by maintenance dosing; follow trough levels carefully Posaconazole IV, PO At least 18 mgkgday divided tid for oral suspension; IV and new powder for oral suspension 6 mgkgday once daily (given bid as a loading dose on first day) Dosage unclear in children at present In adults, max dosage for oral suspension is 800 mg day, and optimally divide this into 2 or 3 doses; follow trough levels; adult dosing for IV and extended release tablet is 300 mg twice on first day, then 300 mg once daily Isavuconazole PO, IV 10 mgkg (q8h on days 1 and 2 and then once daily thereafter) Adult dosing for IV and tablet is 200 mg 3 times on first day, then 200 mg once daily Micafungin IV 2 10 mgkgday Highest dosages in neonates (10 mgkgday) and lower dosages in children; 8 yr of age, use adult dosage Anidulafungin IV 1.5 mgkgday Loading dose of 3 mgkgday Caspofungin IV 50 mgm2day; neonates 25 mg m2day Load with 70 mgm2day, then 50mgm2day as maintenance dosage amphotericin B in a self associated state so that it is not available to interact with the cholesterol of human cellular membranes. A clinical trial comparing L amphotericin B at doses of 3 mgkgday versus 10 mgkgday found no efficacy benefit for the higher dose and only greater toxicity. Therefore it is generally not recommended to use any lipid amphotericin B preparations at very high dosages (5 mg kgday), although some experts report using higher dosing in very dif ficult infections where a lipid amphotericin B formulation is the first line therapy (e.g., mucormycosis). PYRIMIDINE ANALOGS 5 Fluorocytosine 5 Fluorocytosine (5 FC) is a fluorinated analog of cytosine and has anti fungal activity resulting from the rapid conversion into 5 fluorouracil (5 FU) within susceptible fungal cells. Clinical |
7,577 | and microbiologic antifungal resistance develops quickly to 5 FC monotherapy, so clini cians have reserved it for combination approaches. Fungistatic 5 FC is thought to enhance the antifungal activity of amphotericin B, espe cially in anatomic sites where amphotericin B penetration is often sub optimal, such as cerebrospinal fluid (CSF). 5 FC penetrates well into most body sites because it is small, highly water soluble, and not bound by serum proteins to any great extent. One explanation for the synergy detected with the combination of amphotericin B plus 5 FC is that the membrane permeabilizing effects of low concentrations of amphoteri cin B facilitate penetration of 5 FC to the cell interior. 5 FC is only available as an oral formulation in the United States, and the dosage is 150 mgkgday in four divided doses. 5 FC can exacerbate myelosuppression in patients with neutropenia, and toxic levels can develop when used in combination with ampho tericin B, owing to nephrotoxicity of the amphotericin B and decreased renal clearance of 5 FC. Routine serum 5 FC level monitoring is war ranted in high risk patients, and levels should be obtained after 3 5 days of therapy, with a goal to achieve a 2 hour postdose peak 100 gmL (and ideally 30 80 gmL). Levels 100 gmL are associated with bone marrow aplasia. Toxicities can include azotemia, renal tubu lar acidosis, leukopenia, thrombocytopenia, and others and appear in approximately 50 of patients in the first 2 weeks of therapy. Nearly all clinical studies involving 5 FC for cryptococcal meningitis are combination antifungal protocols with amphotericin B. The use of 5 FC for Candida meningitis in premature neonates is discouraged. A study evaluating risk factors and mortality rates of neonatal candidiasis among extremely premature infants showed that infants with Candida meningitis who received amphotericin B in combination with 5 FC had a prolonged time to sterilization of the CSF compared with infants receiving amphotericin B monotherapy. AZOLES The azole antifungals inhibit the fungal cytochrome P45014DM (also known as lanosterol 14 demethylase), which catalyzes a late step in fungal cell membrane ergosterol biosynthesis. Of the older first generation, itraconazole has activity against Aspergillus, but fluconazole is ineffective against Aspergillus and other molds. Second generation triazoles (voriconazole, posaconazole, and isavuconazole) have an expanded antifungal spectrum of activity, including activity against molds, and generally greater in vitro antifungal activity. Fluconazole Fluconazole is fungistatic, and this activity is not influenced by concen tration once the maximal fungistatic concentration is surpassed (con centration independent), in contrast to the concentration dependent 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. 1918 Part XV u Infectious Diseases fungicidal activity of amphotericin B. Fluconazole is available as either an oral or intravenous form, and oral administration has a bioavailability of approximately 90 relative to intravenous adminis tration. Fluconazole passes into tissues and fluids quite rapidly, prob |
7,578 | ably because of its relatively low lipophilicity and limited degree of binding to plasma proteins. Concentrations of fluconazole are 10 to 20 fold higher in the urine than in blood, making it an ideal agent for treating fungal urinary tract infections. Concentrations in the CSF and vitreous humor of the eye are approximately 80 of those found simultaneously in blood. Simple conversion of the corresponding adult dosage of fluconazole on a weight basis is inappropriate for pediatric patients. Fluconazole clearance is generally more rapid in children than in adults, with a mean plasma half life of approximately 20 hours in children and approximately 30 hours in adult patients. Therefore to achieve compa rable exposure in pediatric patients, the daily fluconazole dosage needs to be essentially doubled. Correct pediatric fluconazole dosages should be proportionately higher than adult dosages, generally 12 mgkgday. In neonates, the volume of distribution is significantly greater and more variable than in infants and children, and doubling the dosage for neo natal patients is necessary to achieve comparable plasma concentra tions. The increased volume of distribution is thought to be the result of the larger amount of body water found in the total body volume of neonates. A pharmacokinetic study in premature infants suggests that maintenance fluconazole dosages of 12 mgkgday are necessary to achieve exposures similar to those in older children and adults. In addition, a loading dose of 25 mgkg in neonates has achieved steady state concentrations sooner. Although a fluconazole loading dose has been studied in adult and neonatal patients, this approach has never been formally studied in children, yet makes clinical sense. Side effects of fluconazole are uncommon but generally include gastrointestinal upset (vomiting, diarrhea, nausea) and skin rash. Fluconazole plays an important role in the treatment of invasive can didiasis. Consensus guidelines suggest that use of the fungistatic fluco nazole for invasive candidiasis is acceptable as step down therapy after a good clinical response to initial therapy with an echinocandin. Other clinical scenarios for fluconazole include patients who are not criti cally ill and who are considered unlikely to have a fluconazole resistant Candida species. Although most isolates of Candida albicans remain susceptible to fluconazole, for certain Candida species, fluconazole is not an ideal agent: C. krusei is generally resistant, and C. glabrata is often resistant. There is no confirmed role for combination antifun gal therapy with fluconazole and another antifungal against invasive candidiasis. Prophylaxis with fluconazole to prevent neonatal candidiasis remains a controversial topic. In the first prospective, randomized double blind trial of 100 infants with birthweights 1,000 g, infants who received fluconazole for 6 weeks had a decrease in fungal coloni zation and a decrease in the development of invasive fungal infection (0 vs 20) compared with placebo. Other studies have yielded simi larly encouraging results and have demonstrated that use of flucon azole prophylaxis for 4 6 weeks in high risk infants does not increase the incidence of fungal colonization and infections caused by natively fluconazole resistant Candida species. A |
7,579 | more recent large trial studied fluconazole prophylaxis in extremely low birthweight infants in nurs eries with a lower incidence of candidiasis and found that fluconazole Table 279.2 Suggested Antifungals for Specific, More Common Fungal Pathogens FUNGAL SPECIES AMP FLU ITR VOR POS ISA FLUC CMA Aspergillus calidoustus Aspergillus fumigatus Aspergillus terreus Blastomyces dermatitidis Candida albicans Candida glabrata Candida krusei Candida lusitaniae Candida parapsilosis Coccidioides immitis Cryptococcus spp. Fusarium spp. Histoplasma capsulatum Mucor spp. Scedosporium apiospermum Scedosporium prolificans AMP, amphotericin B formulations; FLU, fluconazole; ITR, itraconazole; VOR, voriconazole; POS, posaconazole; ISA, isavuconazole; FLUC, flucytosine; CMA, caspofungin, micafungin, or anidulafungin. , preferred therapy(ies); , usually active; , variably active; , usually not active. 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 279 u Principles of Antifungal Therapy 1919 prophylaxis led to a decreased incidence of candidiasis but had no effect on mortality. The universal implementation of such a strategy across nurseries is discouraged, because the rate of Candida infections varies greatly among centers. Consensus guidelines now recommend fluconazole prophylaxis only in centers with high rates (10) of neo natal candidiasis. Itraconazole Compared to fluconazole, itraconazole has the benefit of antifungal activity against Aspergillus species but comes with several practical constraints, such as erratic oral absorption in high risk patients and significant drug interactions. These pharmacokinetic concerns have been addressed with a better absorbed oral solution to replace the unpredictable capsules used earlier. Itraconazole has a high volume of distribution and accumulates in tissues, and tissue bound levels are probably more clinically relevant to infection treatment than serum levels. Dissolution and absorption of itraconazole are affected by gas tric pH. Patients with achlorhydria or taking H2 receptor antagonists might demonstrate impaired absorption, and co administration of the capsule with acidic beverages such as colas or cranberry juice can enhance absorption. Administration with food significantly increases the absorption of the capsule formulation, but the oral suspension with a cyclodextrin base is better absorbed on an empty stomach. Side effects are relatively few and include nausea and vomiting (10), elevated transaminases (5), and peripheral edema. There have been reports in adults of development of cardiomyopathy. Because of important drug interactions, prior or concurrent use of rifampin, phe nytoin, carbamazepine, and phenobarbital should be avoided. Itraconazole has its largest role in treating less serious infections with endemic mycoses (histoplasmosis, coccidioidomycosis, and blas tomycosis). The plethora of drug interactions make itraconazole a con cern in complex patients receiving other medications. As with most azole antifungals, monitoring itraconazole serum levels is a key prin ciple in management (generally itraconazole trough levels should be 1 2 gmL; trough levels 5 gmL may be associated with increased toxicity). Concentrations should be checked after 5 days of therapy to ensure adequate drug exposure. When measured by high pressure liquid chromatography, both itraconazole and its bioactive hydroxy itraconazole metabolite are reported, the sum of which |
7,580 | should be con sidered in assessing drug levels. Voriconazole Voriconazole is a second generation triazole and a synthetic derivative of fluconazole. Voriconazole generally has the spectrum of activity of itraconazole and the high bioavailability of fluconazole. Importantly, it is fungicidal against Aspergillus and fungistatic against Candida. It is extensively metabolized by the liver and has approximately 90 oral bioavailability in adults but appears to be closer to 5060 bioavailabil ity in children. The cytochrome P450 2C19 (CYP2C19) enzyme appears to play a major role in the metabolism of voriconazole, and polymor phisms in CYP2C19 are associated with slow voriconazole metabolism. As many as 20 of non Indian Asians have low CYP2C19 activity and develop voriconazole levels as much as fourfold higher than those in homozygous subjects, leading to potentially increased toxicity. Voriconazole is available as an oral tablet, an oral suspension, and an intravenous solution. In adults, voriconazole exhibits nonlinear phar macokinetics, has a variable half life of approximately 6 hours with large interpatient variation in blood levels, and achieves good CSF penetra tion. In contrast to the situation in adults, elimination of voriconazole is linear in children. A multicenter safety, population pharmacokinetic study of intravenous voriconazole dosages in immunocompromised pediatric patients showed that body weight was more influential than age in accounting for the observed variability in voriconazole phar macokinetics, and voriconazole needs to be dosed higher in pediat ric patients than in adult patients. Adult patients load with 6 mgkg dose and then transition to a maintenance dosage of 4 mgkgdose, but children should begin and continue with 9 mgkgdose intrave nously (see Table 279.1) and continue maintenance dosing at 8 mgkg dose. This need for an increased dosage in treating children is crucial to understand and is mandated by the fundamentally different phar macokinetics of this drug in pediatric patients. Obtaining voriconazole serum levels (to achieve 2 gmL) is critical for therapeutic success. Oral voriconazole is best absorbed on an empty stomach. Generally a trough level greater than the minimum inhibitory concentration (MIC) of the infecting organism is preferred, and very high voriconazole lev els have been associated with toxicity (generally 6 gmL). However, many studies have shown an inconsistent relationship between dosing and levels, highlighting the need for close monitoring after the initial dosing scheme and then dose adjustment as needed in the individual patient. Trough levels should be monitored approximately 5 days after initiation of therapy and repeated the following week to confirm the patient remains in the therapeutic range or repeated 4 days after change of dose. The main side effects of voriconazole include reversible dosage dependent visual disturbances (increased brightness, blurred vision) in as many as one third of treated patients, elevated hepatic transaminases with increasing dosages, and occasional skin reactions likely caused by photosensitization. In some rare long term (mean of 3 years of therapy) cases, this voriconazole phototoxicity has developed into cutaneous squamous cell carcinoma. Discontinuing voriconazole is recommended in patients experiencing chronic phototoxicity. The largest prospective clinical trial of voriconazole |
7,581 | as primary therapy for invasive aspergillosis compared initial randomized therapy with voriconazole versus amphotericin B and demonstrated improved response and survival with voriconazole over amphotericin B. Vori conazole is guideline recommended as the preferred primary therapy against invasive aspergillosis. Voriconazole also has a role in treating candidiasis, but its fungistatic nature makes it often less than ideal for treating critically ill or neutropenic patients where the fungi cidal echinocandin antifungals are preferred. Posaconazole Posaconazole is a second generation triazole that is a derivative of itraconazole and is currently available as an oral suspension, an intra venous formulation, and a delayed release tablet. The antimicrobial spectrum of posaconazole is similar to that of voriconazole; however, the former is active against mucormycosis, and voriconazole is not active against these particular mold infections. Effective absorption of the less desirable oral suspension strongly requires taking the medication with food, ideally a high fat meal; tak ing posaconazole on an empty stomach will result in approximately one fourth of the absorption as in the fed state, emphasizing the impor tance of diet to increase serum levels of oral suspension posaconazole (the opposite of voriconazole). Posaconazole exposure is maximized with acidic beverages, administration in divided doses, and the absence of proton pump inhibitors. The tablet formulation has much better absorption because of its delayed release in the small intestine, but absorption will still be slightly increased with food. If the patient can take the large sized tablets, the delayed release tablet is the preferred form because of the ability to easily obtain higher and more consistent drug levels. Importantly, the delayed release tablet cannot be broken for use due to its chemical coating. As a result of the low pH (5) of IV posaconazole, a central venous catheter is required for administration. The IV formulation contains only slightly lower amounts of the cyclo dextrin vehicle than voriconazole, so similar theoretical renal accumu lation concerns exist. Posaconazole causes transient hepatic reactions, including mild to moderate elevations in liver transaminases, alkaline phosphatase, and total bilirubin. In adult patients, dosages of the oral suspension at 800 mgday do not result in increased serum levels, and division of daily dosing into three or four dosesday results in greater serum levels than a once or twice daily dosing scheme when using the oral suspension. The pedi atric oral suspension dose recommended by some experts for treating invasive disease is estimated to be at least 18 mgkgday divided 3 times daily, but even that dose did not achieve target levels when studied. A study with a new pediatric formulation for suspension, essentially the tablet form that is able to be suspended, showed a dose of 6 mg 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. 1920 Part XV u Infectious Diseases kg (given twice a day as a loading dose on the first day and then |
7,582 | once daily) achieved target exposures necessary for antifungal prophylaxis, with a safety profile similar to adult patients. A subsequent study sug gested that posaconazole dosing for the delayed release tablets and IV formulation requires greater daily doses for children 13 years old. Pediatric dosing with the current IV or extended release tablet dosing is not yet fully defined, but adolescents can likely follow the adult dos ing schemes. Similar to itraconazole and voriconazole, posaconazole should be monitored with trough levels (to achieve 1 gmL for treat ment and 0.07 gmL for prophylaxis). In an international randomized, single blinded study of posacon azole versus fluconazole or itraconazole in neutropenic patients undergoing chemotherapy for acute myelogenous leukemia or myelo dysplastic syndromes, posaconazole was superior in preventing inva sive fungal infections. Another multisite international randomized, double blinded study in patients with allogeneic hematopoietic stem cell transplantation and graft versus host disease showed that posacon azole was not inferior to fluconazole in the prevention of invasive fungal infections. Posaconazole is approved for prophylaxis against invasive fungal infections but has shown great efficacy in clinical experience with recalcitrant mold infections. In patients with chronic granulomatous disease (CGD) and proven invasive fungal infection refractory to standard therapy, posaconazole was proved to be well tolerated and quite effective and is the preferred agent against invasive aspergillosis in this patient population. Isavuconazole Isavuconazole is a triazole that was FDA approved in 2015 for treatment of invasive aspergillosis and invasive mucormycosis with oral (capsules only) and IV formulations. Isavuconazole has an antifungal spectrum similar to that of voriconazole and some activity against Zygomycetes such as mucormycosis (yet potentially not as potent against Zygomyce tes as posaconazole). A phase 3 clinical trial in adult patients demon strated noninferiority versus voriconazole against invasive aspergillosis and other mold infections, whereas another study showed good clini cal activity against mucormycosis. Isavuconazole is dispensed as the prodrug isavuconazonium sulfate. Dosing in adult patients is loading with isavuconazole 200 mg (equivalent to 372 mg isavuconazonium sulfate) every 8 hours for 2 days (6 doses), followed by 200 mg once daily for maintenance dosing. The half life is long (5 days), there is 98 bioavailability in adults, and there is no reported food effect with oral isavuconazole. Unlike voriconazole, the IV formulation does not contain the vehicle cyclodextrin, possibly making it more attractive in patients with renal failure. Early experience suggests a much lower rate of photosensitivity and skin disorders as well as visual disturbances compared with voriconazole. A recently completed pediatric pharma cokinetic study reported that a dose of 10 mgkg (q8h on days 1 and 2 and once daily thereafter) resulted in similar exposures and safety as seen in adults. ECHINOCANDINS The echinocandins are a class of antifungals that interfere with cell wall biosynthesis by noncompetitive inhibition of 1,3 d glucan synthase, an enzyme present in fungi but absent in mammalian cells. 1,3 glucan is an essential cell wall polysaccharide and provides structural integrity for the fungal cell wall. Echinocandins are generally fungicidal in |
7,583 | vitro against Candida species, although not as rapidly as amphotericin B, and are fungistatic against Aspergillus. As a class, these agents are not metabolized through the CYP enzyme system, lessening some of the drug interactions and side effects seen with the azole class. The echino candins appear to have a prolonged and dosage dependent fungicidal antifungal effect on C. albicans compared with the fungistatic flucon azole. Three compounds in this class (caspofungin, micafungin, and anidulafungin) are FDA approved for use, but there are others (reza fungin) in late stage clinical trials. Owing to the large size of the mol ecules, the current echinocandins are only available in an intravenous formulation. Because 1,3 glucan is a selective target present only in fungal cell walls and not in mammalian cells, drug related toxicity is minimal, with no apparent myelotoxicity or nephrotoxicity with the agents. The echinocandins are the preferred primary therapy for invasive candidiasis. Caspofungin Caspofungin is administered to adults as a 70 mg loading dose fol lowed by a daily maintenance 50 mg dosage. Caspofungin has been evaluated at double the recommended dosage (100 mgday in adults) with no adverse effects, and it is unclear if higher dosage of this rela tively safe agent results in greater clinical efficacy. At present there is no known maximum tolerated dosage and no toxicity determined maxi mum length of therapy for caspofungin. Pharmacokinetics are slightly different in children, with caspofungin levels lower in smaller children and with a reduced half life. A study evaluated the pharmacokinetics of caspofungin in children with neu tropenia and showed that in patients receiving 50 mgm2day (maxi mum, 70 mgday), the levels were similar to those in adults receiving 50 mgday and were consistent across age ranges. In this study, weight based dosing (1 mgkgday) was suboptimal when compared with body surface area regimens, so caspofungin should be appropriately dosed in children as a loading dose of 70 mgm2day, followed by daily maintenance dosing of 50 mgm2day. Echinocandins like caspofungin are guideline recommended ini tial therapy for invasive candidiasis but should be used against inva sive aspergillosis only in the setting of potential combination therapy or for resistant or refractory disease. In a multicenter trial of patients with invasive candidiasis, 73 of patients who received caspofun gin had a favorable response at the end of therapy compared with 62 in the amphotericin B group. Importantly, caspofungin treat ment performed equally well to amphotericin B treatment for all the major Candida species. Earlier studies suggested that some infec tions with C. parapsilosis do not potentially clear as effectively with an echinocandin, but the echinocandins are still preferred empiric therapy against invasive candidiasis. Caspofungin was also evaluated against L amphotericin B in the empirical treatment of patients with persistent fever and neutropenia and was not inferior to liposomal amphotericin B. A study in children with acute myeloid leukemia demonstrated that caspofungin prophylaxis resulted in a significantly lower incidence of invasive fungal disease compared with fluconazole prophylaxis. A study comparing caspofungin with |
7,584 | triazole prophy laxis in pediatric allogeneic hematopoietic stem cell transplant recipi ents found no difference in the agents. Caspofungin in newborns (25 mgm2day) has been used for refrac tory cases of disseminated candidiasis. Neonates with invasive can didiasis are at high risk for central nervous system involvement; it is not known if the dosages of caspofungin studied provide sufficient exposure to penetrate the central nervous system at levels necessary to cure infection. Therefore caspofungin is not recommended as standard monotherapy in neonatal candidiasis. Micafungin The pharmacokinetics of micafungin have been evaluated in children and young infants. An inverse relation between age and clearance was observed, where mean systemic clearance was significantly greater and mean half life was significantly shorter in patients 2 8 years of age compared to patients 9 17 years of age. Therefore dosing of micafungin in children is age related and needs to be higher in children 8 years old. Doses in children are generally 2 mgkgday, with higher doses needed for neonates, infants, and younger patients, and with a dose of 10 mgkgday for preterm neonates. Several pharmacokinetic studies in term and preterm infants have shown that micafungin has a shorter half life and a more rapid rate of clearance in infants compared with published data in older children and adults. Adult micafungin dos ing (100 or 150 mg once daily) is to be used in patients who weigh more than 40 kg. Unlike the other echinocandins, a loading dose is not required for micafungin. Clinical trials, including those of micafungin used for treatment of invasive candidiasis, as well as prophylaxis studies in patients after 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 280 u Candida 1921 stem cell transplantation, have demonstrated fewer adverse events compared with liposomal amphotericin B and fluconazole. The most common adverse events experienced by these patients are related to the gastrointestinal tract (nausea, diarrhea). Hypersensitivity reactions associated with micafungin have been reported, and liver enzymes are elevated in 5 of patients receiving this agent. Hyper bilirubinemia, renal impairment, and hemolytic anemia related to micafungin use have also been identified in postmarketing surveil lance of the drug. Micafungin at dosages of 100 and 150 mg daily was also noninferior to caspofungin in an international, randomized, double blinded study of adults with candidemia or invasive candidiasis and was found to be superior to fluconazole in the prevention of invasive fungal infections in a randomized study of adults undergoing hematopoietic stem cell transplantation. Of the three drugs within the echinocandin class, micafungin has been the one most extensively studied in children. A pediatric sub study as part of a double blind, randomized, multinational trial com paring micafungin (2 mgkgday) with liposomal amphotericin B (3 mgkgday) as first line treatment for invasive candidiasis showed similar success for micafungin and liposomal amphotericin B. In gen eral, micafungin was better |
7,585 | tolerated than liposomal amphotericin B, as evidenced by fewer adverse events leading to discontinuation of therapy. Anidulafungin Anidulafungin has the longest half life of all the echinocandins (approximately 18 hours). In a study of 25 neutropenic children receiv ing anidulafungin as empirical therapy, four patients in the group receiving 0.75 mgkgday experienced adverse events such as facial erythema and rash, elevation in serum blood urea nitrogen, and fever and hypotension. In a pharmacokinetic study in neonates and young infants, anidulafungin exposures comparable to adults were achieved with doses of 1.5 mgkgday (3 mgkg loading dose). One infant in this cohort supported by extracorporeal membrane oxygenation achieved the lowest exposure, which suggests that dose adjustments are required in this population. The adult dose for invasive candidiasis is a loading dose of 200 mg on the first day, followed by 100 mg daily. An open label study of invasive candidiasis in children showed similar efficacy and minimal toxicity, comparable to the other echinocandins. An additional study showed similar and acceptable pharmacokinetics in patients 1 month to 2 years of age. Ibrexafungerp Ibrexafungerp was approved in 2021 for adults with vulvovaginal candidiasis after two phase 3 studies (VANISH203 and VANISH 306). This is the first new class of antifungals (also called fungerps). Simi lar to the echinocandins, ibrexafungerp noncompetitively inhibits 1,3 glucan synthase and is also fungicidal against Candida spp. and Aspergillus spp. The binding site on the glucan synthase enzyme is not the same as the echinocandins. Resistance or reduced susceptibility to the echinocandins is largely through two hot spot pathogenic vari ants in the FKS1 gene, whereas many resistance mutations to ibrexa fungerp are caused by the FKS2 gene, and ibrexafungerp does have activity against some echinocandin resistant isolates. Ibrexafungerp is the first orally available glucan synthase inhibitor and has a long half life, suggesting once daily dosing for clinical use. Similar to the echinocandins, initial studies show limited to no distribution to the central nervous system and variable distribution to the eye. In a phase 2 study, ibrexafungerp as step down therapy after initial echinocan din therapy for invasive candidiasis was well tolerated and achieved a favorable global response similar to the standard of care. There is an ongoing co administration study with voriconazole in pulmonary invasive aspergillosis (SCYNERGIA) and an ongoing recurrent vul vovaginal candidiasis study (CANDLE), yet no completed pediatric studies. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Candidiasis encompasses many clinical syndromes that may be caused by several species of Candida. Invasive candidiasis (Candida infections of the blood and other sterile body fluids) is a leading cause of infection related mortality in hospitalized immunocompromised patients. C. albicans accounts for most human infections, but C. parapsilo sis, C. tropicalis, C. krusei, C. lusitaniae, C. glabrata, and several other species are commonly isolated from hospitalized children. Species identification and susceptibility testing are important owing to increas ing frequency of fluconazole resistance and increasing prevalence of non albicans Candida species. C. auris is an emerging multiresistant invasive pathogen that has |
7,586 | a global presence and affects immunocom promised patients; nosocomial spread has been reported. Treatment of invasive Candida infections is complicated by the emergence of non albicans strains. Amphotericin B deoxycholate is inactive against approximately 20 of strains of C. lusitaniae. Fluco nazole is useful for many Candida infections but is inactive against all strains of C. krusei and 525 of strains of C. glabrata. Most Candida are susceptible to echinocandins, but resistance is occasionally seen, most often among C. krusei and C. glabrata. Susceptibility testing of these clinical isolates is recommended. 280.1 Neonatal Infections Jessica E. Ericson and Daniel K. Benjamin Jr. Candida is a common cause of oral mucous membrane infections (thrush) and perineal skin infections (Candida diaper dermatitis) in young infants. Rare presentations include congenital cutaneous candidiasis, caused by an ascending infection into the uterus during gestation, and invasive fungal dermatitis, a postnatal skin infection resulting in positive blood cultures. Invasive candidiasis is a common infectious complication in the neonatal intensive care unit (NICU) because of improved survival of extremely preterm infants. EPIDEMIOLOGY Candida species are a common cause of bloodstream infection in premature infants. The incidence varies greatly by individual NICU. Among centers in the National Institutes of Healthsponsored Neona tal Research Network, the cumulative incidence of candidiasis among infants 1,000 g birthweight ranges from 2 to 28. Colonization is associated with a significantly increased risk of future invasive Candida infection. Up to 10 of full term infants are colonized as the result of vertical transmission from the mother at birth, with slightly higher rates of colonization in premature infants. Colonization rates increase to 50 among infants admitted to the NICU by 1 month of age. Histamine 2 blockers, corticosteroids, and broad spectrum antibiotics facilitate Candida colonization and overgrowth. Significant risk factors for neonatal invasive candidiasis include prematurity, low birthweight, exposure to broad spectrum antibiotics, abdominal surgery, endotracheal intubation, and presence of a central venous catheter. PATHOGENESIS Immunologic immaturity along with an underdeveloped layer of skin, need for invasive measures (endotracheal tubes, central venous catheters), and exposure to broad spectrum antibiotics places pre term infants at great risk for invasive candidiasis. Premature infants are also at high risk for spontaneous intestinal perforations and Chapter 280 Candida Jessica E. Ericson and Daniel K. Benjamin Jr. 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. 1922 Part XV u Infectious Diseases necrotizing enterocolitis. Both conditions require abdominal sur gery, prolonged exposure to broad spectrum antibiotics, and total parenteral nutrition administration requiring placement of central venous catheters. Each of these factors increases the risk of invasive candidiasis by decreasing the physiologic barriers that protect against invasive infection. CLINICAL MANIFESTATIONS The manifestations of neonatal candidiasis vary in severity from oral thrush and Candida diaper dermatitis (see Chapter 280.2) to invasive candidiasis that can manifest with overwhelming sepsis (see Chap ter 280.3). Signs of invasive candidiasis among |
7,587 | premature infants are often nonspecific and include temperature instability, lethargy, apnea, hypotension, respiratory distress, abdominal distention, and thrombocytopenia. Central nervous system involvement is common and is most accu rately described as meningoencephalitis. Candida infections involv ing the central nervous system often result in abscesses, leading to unremarkable cerebrospinal fluid parameters (white blood cell count, glucose, protein) even though central nervous system infection is present. Endophthalmitis is an uncommon complication affecting 5 of infants with invasive candidiasis, but candidemia is asso ciated with an increased risk of severe retinopathy of prematurity. Renal involvement commonly complicates neonatal invasive candidi asis. Renal involvement may be limited to candiduria or can manifest with diffuse infiltration of Candida throughout the renal parenchyma or the presence of Candida and debris within the collecting system. Because of the poor sensitivity of blood cultures for Candida, can diduria should be considered a surrogate marker of candidemia in premature infants. Other affected organs include the heart, bones, joints, liver, and spleen. DIAGNOSIS Mucocutaneous infections are most often diagnosed by direct clini cal exam. Scrapings of skin lesions may be examined with a micro scope after Gram staining or suspension in KOH. Definitive diagnosis of invasive disease requires histologic demonstration of the fungus in tissue specimens or recovery of the fungus from normally sterile body fluids. Hematologic parameters are sensitive but not specific. Thrombocytopenia occurs in more than 80 of premature infants with invasive candidiasis, but also occurs in 75 of premature infants with gram negative bacterial sepsis and nearly 50 of infants with gram positive bacterial sepsis. Blood cultures have very low sensitivity for invasive candidiasis. In a study of autopsy proven candidiasis in adult patients, the sensitivity of multiple blood cultures for detecting single organ disease was 28. Blood culture volumes in infants are often only 0.5 1 mL, making the sensitivity in this population almost certainly lower. Blood culture volume should be maximized as much as possible to increase sensitivity. Further assessment of infants in the presence of documented can didemia should include ultrasound or computerized tomography of the head to evaluate for abscesses; ultrasound of the liver, kidney, and spleen; cardiac echocardiography; ophthalmologic exam; lumbar puncture; and urine culture. These tests are necessary to determine if more than one body system is infected, which is commonly the case. PROPHYLAXIS NICUs with a high incidence of invasive candidiasis should consider prophylaxis with fluconazole in infants 1,000 g birthweight as a cost effective method of reducing invasive candidiasis. Twice weekly fluco nazole at 3 or 6 mgkgdose decreases rates of both colonization with Candida species and invasive fungal infections. Use of this dosing strat egy has not been shown to increase the frequency of infections caused by fluconazole resistant strains, but use of an alternative antifungal class for cases of breakthrough infection is suggested. TREATMENT In the absence of systemic manifestations, topical antifungal therapy is the treatment of choice for congenital cutaneous candidiasis in full term infants. Congenital cutaneous candidiasis in preterm infants can progress to systemic disease, |
7,588 | and therefore systemic therapy is war ranted in these patients. Every attempt should be made to remove or replace central venous catheters once the diagnosis of candidemia is confirmed. Delayed removal has been consistently associated with increased mortality and morbidity, including poor neurodevelopmental outcomes. Although no well powered randomized controlled trials exist to guide the length and type of therapy, 21 days of systemic antifungal therapy from the last positive Candida culture is recommended in infants. Antifungal therapy should be targeted based on susceptibil ity testing. Amphotericin B deoxycholate has been the mainstay of therapy for systemic candidiasis and is active against both yeast and mycelial forms. Nephrotoxicity, hypokalemia, and hypomagnesemia are common, but amphotericin B deoxycholate is better tolerated in infants than in adult patients. C. lusitaniae, an uncommon pathogen in infants, is often resistant to amphotericin B deoxycholate. Liposomal amphotericin is associated with worse outcomes in infants and should be used only when urinary tract involvement can reliably be excluded. Fluconazole is often used instead of amphotericin B deoxycholate for treatment of invasive neonatal Candida infections because of its effec tiveness and low incidence of side effects. It is particularly useful for urinary tract infections, obtaining high concentrations in the urine. A loading dose should be given to obtain therapeutic serum concen trations in a timely manner. Fluconazole is inactive against all strains of C. krusei and some isolates of C. glabrata. Additionally, in centers where fluconazole prophylaxis is used, another agent, such as ampho tericin B deoxycholate, should be used for treatment. The echinocan dins have excellent activity against most Candida species and have been used successfully in patients with resistant organisms or in whom other therapies have failed. Two trials comparing an echinocandin with amphotericin B deoxycholate were stopped early because of low recruitment but found similar efficacy for the two treatments among the included patients. Several studies have described the pharmacoki netics of antifungals in infants (Table 280.1). PROGNOSIS Mortality after invasive candidiasis in premature infants has been con sistently reported to be around 20 in large studies but can be as high as 50 in infants 1,500 g birthweight. Candidiasis is also associated with poor neurodevelopmental outcomes, chronic lung disease, and severe retinopathy of prematurity. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 280.2 Infections in Immunocompetent Children and Adolescents Jessica E. Ericson and Daniel K. Benjamin Jr. ORAL CANDIDIASIS Oral thrush is a superficial mucous membrane infection that affects approximately 25 of normal neonates. C. albicans is the most com monly isolated species. Oral thrush can develop as early as 7 10 days of age. The use of antibiotics, especially in the first year of life, can lead to recurrent or persistent thrush. It is characterized by pearly white, curdish material visible on the tongue, palate, and buccal mucosa. Oral thrush may be asymptomatic or can cause pain, fussiness, and decreased feeding, leading to inadequate nutritional intake and dehy dration. It is uncommon after 1 year of age but can occur in older children |
7,589 | treated with antibiotics. Persistent or recurrent thrush with no obvious predisposing reason, such as recent antibiotic treatment, warrants investigation of an underlying immunodeficiency, especially vertically transmitted HIV infection or a primary congenital immune defect. Treatment of mild cases might not be necessary. When treatment is warranted, the most commonly prescribed antifungal agent is topical 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 280 u Candida 1923 nystatin. For recalcitrant or recurrent infections, a single dose of flu conazole may be useful. In breastfed infants, simultaneous treatment of infant and mother with topical nystatin or oral fluconazole may be indicated. DIAPER DERMATITIS Diaper dermatitis is the most common infection caused by Candida (see Chapter 707) and is characterized by a confluent erythematous rash with satellite pustules. Candida diaper dermatitis often compli cates other noninfectious diaper dermatitides and often occurs after a course of oral antibiotics. A common practice is to presumptively treat any diaper rash that has been present for longer than 3 days with topical antifun gal therapy such as nystatin, clotrimazole, or miconazole. If sig nificant inflammation is present, the addition of hydrocortisone 1 may be useful for the first 1 2 days, but topical corticosteroids should be used cautiously in infants because the relatively potent topical corticosteroid can lead to adverse effects. Frequent diaper changes and short periods without diapers are important adjunc tive treatments. UNGUAL AND PERIUNGUAL INFECTIONS Paronychia and onychomycosis may be caused by Candida, although Trichophyton and Epidermophyton are more common causes. Can dida onychomycosis differs from tinea infections by its propensity to involve the fingernails and not the toenails and by the associated par onychia. Candida paronychia often responds to treatment consisting of keeping the hands dry and using a topical antifungal agent. Pso riasis and immune dysfunction, including HIV and primary immu nodeficiencies, predispose to Candida ungual infections. Ungual infections often require systemic antifungal therapy. Once weekly fluconazole for 4 12 months is an effective treatment strategy with fairly low toxicity. VULVOVAGINITIS Vulvovaginitis is a common Candida infection of pubertal and post pubertal female patients. Predisposing factors include pregnancy, use of oral contraceptives, and use of oral antibiotics. Prepubertal children with Candida vulvovaginitis usually have a predisposing factor such as diabetes mellitus or prolonged antibiotic treatment. Clinical manifesta tions can include pain or itching, dysuria, vulvar or vaginal erythema, and an opaque white or cheesy exudate. More than 80 of cases are caused by C. albicans. Candida vulvovaginitis can be effectively treated with either vagi nal creams or troches of nystatin, clotrimazole, or miconazole. Oral therapy with a single dose of fluconazole is also effective. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 280.3 Infections in Immunocompromised Children and Adolescents Jessica E. Ericson and Daniel K. Benjamin Jr. ETIOLOGY Candida albicans is the most common cause of invasive candidiasis among immunocompromised pediatric patients and is associated with |
7,590 | higher rates of mortality and end organ involvement than are non albicans species. CLINICAL MANIFESTATIONS HIV Infected Children Oral thrush and diaper dermatitis are the most common Candida infec tions in HIV infected children. Besides oral thrush, three other types of oral Candida infections can occur in HIV infected children: atrophic candidiasis, which manifests as a fiery erythema of the mucosa or loss of papillae of the tongue; chronic hyperplastic candidiasis, which pres ents with oral symmetric white plaques; and angular cheilitis, in which there is erythema and fissuring of the angles of the mouth. Topical anti fungal therapy may be effective, but systemic treatment with flucon azole or itraconazole is usually necessary. Symptoms of dysphagia or poor oral intake can indicate progression to Candida esophagitis, requiring systemic antifungal therapy. In HIV patients, esophagitis can also be caused by cytomegalovirus, herpes simplex virus, reflux, or lymphoma; Candida is the most common cause, and Candida esopha gitis can occur in the absence of thrush. Table 280.1 Dosing of Antifungal Agents Studied in Infants with Reported Pharmacokinetic (PK) Parameters DRUG PK STUDIED IN INFANTS SUGGESTED DOSE Amphotericin B deoxycholate Yes (multiple) 1 mgkgday Amphotericin B lipid complex Yes (single) 5 mgkgday Liposomal amphotericin B Yes (single) 5 mgkgday Amphotericin B colloidal dispersion No 5 mgkgday Fluconazole Yes (best studied with 250 infant contributing PK samples) 12 mgkgday Voriconazole No drug concentrations reported for a single infant with neonatal candidiasis Posaconazole No drug concentrations reported for a single infant with cutaneous rhizopus infection Micafungin Yes (multiple) 10 mgkgday Caspofungin Yes (single) 50 mgm2day Anidulafungin Yes (single) 1.5 mgkgday Voriconazole and posaconazole dosing have not been investigated in the nursery. Doses are those suggested by experts. A loading dose of 25 mgkg of fluconazole is necessary to achieve therapeutic serum and cerebrospinal fluid concentrations in the early days of therapy. Micafungin has been studied in infants 120 days of life at this dosage. Caspofungin and anidulafungin should generally be avoided because dosing sufficient to penetrate brain tissue has not been studied. 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. 1924 Part XV u Infectious Diseases Candida dermatitis and onychomycosis are more common in HIV infected children. These infections are generally more severe than they are in immunocompetent children and can require systemic antifungal therapy. Cancer and Transplant Patients Fungal infections, especially Candida and Aspergillus infections, are a significant problem in oncology patients with chemotherapy associated neutropenia (see Chapter 223). Greater than 5 days of fever during a neutropenic episode is associated with presence of an invasive fungal infection. Accordingly, empirical antifungal therapy should be started if fever and neutropenia persist for 5 or more days. An echinocandin should be used until sensitivity testing results are available. High risk oncology patients warrant prophylaxis against invasive Candida infection. Both fluconazole and echinocandins are used for this indication, typically at lower |
7,591 | doses than those used for treatment. If an echinocandin is used for prophylaxis, liposomal amphotericin B should be used if empirical treatment becomes warranted. Bone marrow transplant recipients have a much higher risk of fungal infections because of the dramatically prolonged duration of neutropenia. Voriconazole prophylaxis decreases the incidence of candidemia in bone marrow transplant recipients with the addi tional benefit over fluconazole of mold prophylaxis. The use of granulocyte colony stimulating factor reduces the duration of neu tropenia after chemotherapy and is associated with decreased risk for candidemia. When Candida infection occurs in this population, the lung, spleen, kidney, and liver are involved in more than 50 of cases. Solid organ transplant recipients are also at increased risk for superficial and invasive Candida infections. Studies in liver trans plant recipients demonstrate the utility of antifungal prophylaxis with amphotericin B deoxycholate, fluconazole, voriconazole, or caspofun gin in high risk patients (those with prolonged surgical time, comor bidities, recent antibiotic exposure, or bile leak). Catheter Associated Infections Central venous catheter infections occur most often in oncology patients but can affect any patient with a central catheter. Neutrope nia, use of broad spectrum antibiotics, and parenteral alimentation are associated with increased risk for Candida central catheter infec tion. Treatment typically requires removing or replacing the catheter followed by a 2 to 3 week course of systemic antifungal therapy. Removal of the central catheter in place at the time of a positive blood culture and use of a peripheral IV or enteral support for at least 48 hours before obtaining central access is advocated. Removal of the original catheter followed by immediate replace ment with a new central catheter in a different anatomic location is acceptable if an interval without central access is not feasible. Delays in catheter removal are associated with increased risks of metastatic complications and death. DIAGNOSIS The diagnosis is often presumptive in neutropenic patients with pro longed fever because positive blood cultures for Candida occur only in a minority of patients who are later found to have disseminated infection. If isolated, Candida grows readily on routine blood cul ture media, with 90 of positive cultures identified within 72 hours. CT scan may demonstrate findings consistent with invasive fungal infection but also is limited by nonspecific findings and false nega tives. The role of screening by CT scan has not been well defined. In high risk patients, serial serum assays for (1,3) d glucan, a poly saccharide component of the fungal cell wall, may contribute to the diagnosis of invasive Candida infection. However, this test is not sensitive or specific enough to be used without a careful assessment of the limitations of the assay. TREATMENT Echinocandins are favored as empirical therapy for moderately or severely ill children and for those with neutropenia; fluconazole is acceptable for those who are infected with a susceptible organism and are less critically ill; amphotericin B products are also acceptable. Definitive antifungal selection should be made based on susceptibil ity testing results. Fluconazole is not |
7,592 | effective against C. krusei and some isolates of C. glabrata. C. parapsilosis has occasional resistance to the echinocandins, but the overall rate is still low. Amphotericin B deoxycholate is inactive against approximately 20 of the strains of C. lusitaniae, and therefore susceptibility testing should be performed for all strains (Table 280.2). C. auris, a species first identified in 2009 that has caused nosocomial infections worldwide, is resistant to most anti fungals. An echinocandin should be used until sensitivity results are available. PRIMARY IMMUNE DEFECTS Chronic mucocutaneous candidiasis involves Candida infections of the oral cavity, esophagus, andor genital mucosa, as well as involve ment of skin and nails, that is recurrent or persistent and difficult to treat. There is a broad spectrum of genetic immune defects associated with chronic mucocutaneous candidiasis mostly related to severe T cell defects or disorders of interleukin 17 production. Genes or disorders associated with chronic mucocutaneous candidiasis include severe combined immunodeficiency syndrome, NEMO or IKBG deficiency, DOCK8 deficiency, STAT3 deficiency (autosomal dominant hyperim munoglobulin E syndrome), autoimmune polyendocrinopathy type 1, CARD9 deficiency, STAT1 gain of function mutations, and IL17RA mutations. Primary immunodeficiencies associated with an increased risk of invasive Candida infections include severe congenital neutropenia, CARD9 deficiency, chronic granulomatous disease, and leukocyte adhesion deficiency type 1. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Table 280.2 Dosing of Antifungal Agents in Children Older Than 1 Year of Age for Treatment of Invasive Disease DRUG SUGGESTED DOSE Amphotericin B deoxycholate 1 mgkgday Amphotericin B lipid complex 5 mgkgday Liposomal amphotericin B 5 mgkgday Amphotericin B colloidal dispersion 5 mgkgday Fluconazole 12 mgkgday Voriconazole, 8 mgkg every 12 hr Micafungin 2 4 mgkgday Caspofungin 50 mgm2day Anidulafungin 1.5 mgkgday Use adult dosages in children older than 12 yr of age for voriconazole and older than 8 yr of age for micafungin. Loading doses should be used for fluconazole (25 mgkg), voriconazole (9 mgkg q 12 24 hr), caspofungin (70 mgm2), and anidulafungin (3 mgkg). Dosing should be adjusted based on the results of therapeutic drug monitoring. 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 281 u Cryptococcus neoformans and Cryptococcus gattii 1925 ETIOLOGY More than 30 cryptococcal species have been described; however, 2 species (Cryptococcus neoformans and Cryptococcus gattii) cause the vast majority of disease in children and adults. Both C. neoformans and C. gattii are encapsulated, facultative intracellular yeasts that are recognized for their tendency to cause central nervous system (CNS) infection, especially in immunocompromised patients. Although there is significant overlap in the disease caused by these pathogens, there are key differences in epidemiology and clinical presentation, which will be reviewed here. Cryptococcal disease may rarely be caused by other species (e.g., C. laurentii and C. albidus), especially in immunocompro mised individuals (including neonates). These latter species will not be covered in this chapter. EPIDEMIOLOGY Cryptococcosis is primarily acquired from exposure |
7,593 | to contaminated environments. C. neoformans is distributed in temperate climates pre dominantly in soil contaminated with droppings from certain avian species, including pigeons, canaries, and cockatoos. It may also be found on rotting wood, fruits, and vegetables and may be carried by cockroaches. Transmission from pet birds to their owners and via solid organ transplantation of infected organs are uncommon, but have also been described. Disease secondary to C. neoformans occurs primarily in immuno compromised individuals and especially in those with defects in cel lular immunity, though apparently normal individuals can also be affected. A large increase in the incidence of cryptococcosis was noted in association with the AIDS epidemic, with disease generally occur ring with severe immunosuppression (CD4 T cells 100L). How ever, since the development of effective antiretroviral therapies (ART), the incidence of AIDS associated cryptococcosis has decreased dra matically, except in resource limited areas of the world such as sub Saharan Africa, where ART is not readily available. Other risk factors for cryptococcal infection include immunosup pression associated with organ transplantation, diabetes mellitus, renal failure, cirrhosis, corticosteroids, rheumatologic conditions, chemotherapeutics, and immune modulating monoclonal antibod ies (e.g., etanercept, infliximab, and alemtuzumab). In patients who have undergone organ transplantation, cryptococcosis is the third most common fungal infection after candidiasis and aspergillosis. Children with certain primary immunodeficiency diseases may also be at increased risk for cryptococcosis, including those with hyper IgM syndrome, severe combined immunodeficiency, idiopathic CD4 lymphopenia, autoantibodies to granulocyte macrophage colony stimulating factor or interferon , CD40 ligand deficiency, and monoMAC syndrome (monocytopenia, B and natural killer cell lymphopenia). C. gattii was initially recognized for its tendency to cause disease in tropical regions, especially among the native peoples of Austral asia, where the organism can be found in association with eucalyptus trees. In these regions, affected individuals are typically immuno competent. C. gattii disease has also been observed outside these tropical regions. An outbreak of C. gattii disease involving British Columbia and extending into the Pacific Northwest region of the United States was first recognized in 1999. Affected individuals were typically adults, with disease occurring in both immunocompetent and immunocompromised individuals. However, comorbid condi tions were often present, including chronic lung and heart disease. A disproportionate fraction of patients (relative to those infected with C. neoformans) presented with pulmonary disease. An incubation period ranging from 2 to 12 months is typical. Thus in the appropri ate clinical context, cryptococcosis should be considered in the dif ferential diagnosis of residents of the Pacific Northwest and returning travelers. Overall, cryptococcosis (both caused by C. neoformans and C. gat tii) is significantly less common in children than in adults. The basis for this discrepancy is poorly understood but could be related to dif ferences in exposure or immune response. Serologic studies suggest that subclinical infection is common among children living in urban areas after age 2 years. Reactivation of latent infection is thought to be an important mechanism of cryptococcal pathogenesis. It is rea sonable to postulate that children do |
7,594 | not have enough exposures to establish latent infection. During the early AIDS epidemic, the inci dence of cryptococcosis in the United States was reported to be on the order of 10 in adults and 1 in children. The largest series of pediatric cryptococcosis comes from South Africa and describes 361 cases, accounting for 2 of the cryptococcosis cases over a 2 year period. PATHOGENESIS Like many fungi, C. neoformans and C. gattii survive as saprophytes in the environment. Their virulence characteristics appear to have evolved as an adaptive response to environmental stressors and predators, such as amoeba. Several key factors have been identified, including the ability to grow at 37C, encapsulation, and melanin pro duction. These same traits allow the organisms to successfully repli cate within the host cell. The polysaccharide capsule, which is readily recognized by India ink staining of cerebrospinal fluid (CSF), is an essential virulence factor. Disease secondary to acapsular strains is exceedingly rare. The capsular material exhibits a variety of biologic activities that are important in the pathogenesis of disease, includ ing interference with opsonization, inhibition of chemotaxis, and enhancement of nonprotective type 2 helper T cells (TH2) inflam mation. Capsular material is shed by the organism into body tissues and fluids during infection and has been implicated in the develop ment of increased intracranial pressure (ICP), a hallmark of cryp tococcal meningoencephalitis. Detection of shed capsular antigen in the serum and CSF is key to the diagnosis of cryptococcal disease. The organism also has the ability to undergo phenotypic variation in response to environmental changes through a variety of mechanisms and can form large giant cells (on the order 20 times its normal size), which are resistant to phagocytosis. Other recognized virulence fac tors include a secreted urease, which may promote intraphagolyso somal survival. In most cases, infection is believed to be acquired by inhalation of desiccated forms of the organism, which upon deposition within the lungs are engulfed by alveolar macrophages. An additional portal of entry is the transplantation of infected organs. Furthermore, direct inoculation can lead to cutaneous or ophthalmic infection. After entry into the respiratory tract, infection can be latent and later progress (i.e., reactivate) in the context of immunodeficiency, in a manner similar to tuberculosis. Alternatively, infection can immediately progress and disseminate to produce symptomatic disease. Cell mediated immu nity that leads to macrophage activation is the most important host defense and is associated with granulomatous inflammation, which effectively contains infection. The precise mechanism of entry of this yeast into the CNS is not known, though several mechanisms have been hypothesized, including transit via infected macrophages (Trojan horse model), direct uptake by endothelial cells, and entry between the tight junctions of endothelial cells. Chapter 281 Cryptococcus neoformans and Cryptococcus gattii David L. Goldman 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. 1926 Part XV u |
7,595 | Infectious Diseases CLINICAL MANIFESTATIONS The manifestations of cryptococcal infection reflect the route of inocu lation, the infecting strain, and the immune status of the host. Sites of infection include the lung, CNS, blood, skin, bone, eyes, and lymph nodes. MeningitisMeningoencephalitis CNS disease is the most commonly recognized manifestation of cryp tococcosis. The disease is characteristically subacute or chronic (evolv ing over weeks to months). Although the term meningitis is commonly used to describe CNS involvement, some degree of encephalitis is also typically present, with occasional patients developing intracere bral masses, known as cryptococcomas. Importantly, meningeal signs and fever (typical of other forms of meningitis) may be lacking. In a review of pediatric cryptococcosis from Colombia, the most common symptoms were headache (78), fever (69), nausea and vomiting (66), confusion (50), and meningismus (38). Other symptoms include decreased level of consciousness, changes in personality, ataxia, hearing deficits, and visual deficits. Increased intracranial pressure is thought to occur as a result of impaired absorption of CSF and has been reported to occur in more than 50 of adults with cryptococcal meningitis. Despite antifungal therapy, the mortality rate for cryptococco sis remains high, ranging from 1540. Most deaths occur within several weeks of diagnosis. Factors associated with a poor progno sis reflect a high fungal burden and poor host response, including altered mentation, high CSF fungal burden, low CSF white blood cell (WBC) number (10 cellsmm3), and failure to rapidly sterilize the CSF. Increased ICP is a key factor in the morbidity and mortality of cryptococcal meningitis and is especially problematic for patients with C. gattii disease. Appropriate management of increased ICP is therefore essential to the appropriate management of cryptococ cal meningitis (see later). Postinfectious sequelae are common and include hydrocephalus, decreased visual acuity, deafness, cranial nerve palsies, seizures, and ataxia. Pneumonia Cryptococcosis is acquired via inhalation, and pneumonia is the most commonly recognized form of disease after meningitis. As with meningitis, pneumonia occurs in both immunocompetent and immunocompromised individuals. Pulmonary disease can present in isolation or in the context of disseminated diseasemeningitis, which is typical among immunocompromised individuals. Among adults with AIDS associated cryptococcal pneumonia, over 90 had concomitant CNS infection. Thus clinicians should have a high suspicion for cryptococcal meningitisdisseminated disease in patients with cryptococcal pneumonia, especially among immuno compromised individuals, and should pursue a workup to exclude dissemination. Cryptococcal pneumonia is often asymptomatic and may be detected because of radiographs performed for other reasons. In this regard, asymptomatic pulmonary nodules secondary to C. neofor mans can be found in children with sarcomas, who are being evalu ated for metastatic disease. Among symptomatic patients, a wide array of symptoms has been reported, including fever, cough, pleu ritic chest pain, and constitutional symptoms like weight loss. Severe disease may result in respiratory failure. Chest radiographic findings are variable and may demonstrate a poorly localized bronchopneu monia, nodules, masses, or lobar consolidations. Pulmonary cavities and pleural effusions are rare. Immunocompromised patients with disseminated disease can have alveolar and interstitial infiltrates that mimic |
7,596 | the pattern of disease seen in some patients with Pneumocystis pneumonia. Cutaneous Infection Cutaneous disease occurs most commonly in the context of dissemi nated cryptococcosis but rarely can result from local inoculation. The appearance of cutaneous cryptococcosis is both nondistinct and vari able and includes papules, ulcers, subcutaneous nodules, and rarely, cellulitis. The lesions are typically subacute, evolving over weeks to months. Early lesions are often erythematous, are variably indurated and tender, and may be single or multiple. Lesions often become ulcerated with central necrosis and raised borders. Cutaneous cryp tococcosis in immunocompromised patients can also resemble mol luscum contagiosum. Given the variable and nondistinct nature of this disease, a high suspicion of disease, especially in the appropriate clinical context (e.g., immunocompromised host), is needed to make the diagnosis. Skeletal Infection Skeletal infection occurs in approximately 5 of patients with dis seminated infection but rarely in HIV infected patients. Interestingly, chronic infection of the tibia was the first recognized manifestation of cryptococcal disease and was described in 1894. Like other forms of cryptococcosis, the onset of symptoms is insidious and chronic. Bone involvement is typified by soft tissue swelling and tenderness, and arthritis is characterized by effusion, erythema, and pain on motion. Skeletal disease is unifocal in approximately 75 of cases. The ver tebrae are the most common site of infection, followed by the tibia, ileum, rib, femur, and humerus. Concomitant bone and joint disease can result from contiguous spread. Sepsis Syndrome Sepsis syndrome is a rare manifestation of cryptococcosis and occurs almost exclusively among HIV infected patients. Fever is followed by respiratory distress and multiorgan system disease that is often fatal. Immune Reconstitution Inflammatory Syndrome Cryptococcal associated immune reconstitution inflammatory syndrome (C IRIS) occurs in the setting of AIDS and in solid organ transplantation. Improvement of immune function resulting from the administration of ART in AIDS patients (or the reduc tion of immunosuppression in transplant recipients) is thought to enhance and dysregulate inflammation, leading to an exacer bation of symptoms. This situation is similar to IRIS seen with other opportunistic pathogens. More commonly, C IRIS presents as a worsening of symptoms in someone with a known diagnosis of cryptococcosis, often within 1 2 months of initiation of ART. Occasionally, C IRIS, which presents as a meningitis or lymphad enitis, occurs in individuals who were never known to have cryp tococcosis (unmasking IRIS). IRIS is particularly problematic in CNS cryptococcosis and may result in worsening of increased ICP. Although cases of C IRIS have been described in children, the incidence is not well defined. DIAGNOSIS The approach to the diagnosis of cryptococcosis depends on the organ system involved. Recovery of the fungus by culture or dem onstration of the fungus in histologic sections of infected tissue or body fluids by India ink staining is definitive. Cryptococci readily grow on standard fungal and bacterial culture media. Colonies can be seen within 48 72 hours when grown aerobically at standard tem peratures. The CSF profile in patients with cryptococcal meningitis typically reveals |
7,597 | a mild lymphocytosis and elevated protein, but find ings can also be normal. Detection of cryptococcal polysaccharide in the CSF, which can be done by several different methods, is key to the diagnosis of CNS infection. One of the earliest detection tests to be developed is the latex agglutination test, which can detect cryptococcal antigen in serum and CSF. Titers of 1:4 in bodily fluid strongly suggest infec tion, and titers of 1:1,024 reflect high burden of yeast, poor host immune response, and greater likelihood of therapeutic failure. Serial monitoring of cryptococcal antigen levels is not useful in guiding 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 281 u Cryptococcus neoformans and Cryptococcus gattii 1927 therapy, as the polysaccharide antigen is actively shed into the tissue and may persist for prolonged periods. Patients with localized pneu monia typically do not have elevated serum antigen levels (though occasionally low levels of antigen, 1:4, may be detected). Higher serum antigen levels in patients with pulmonary disease are indica tive of dissemination outside the lungs. A point of care, lateral flow assay for polysaccharide detection has been developed and has com parable sensitivity to the latex agglutination assay, with the advantage of being less labor intensive. This assay provides a qualitive positive negative result, but can also be performed to provide a semiquantita tive result. False negatives for both latex agglutination and lateral flow assays may occur in the context of antigen excess, so samples are typi cally run both undiluted and diluted. False positive results can occur with other fungal infections, including infection with Trichosporon spp. and, rarely, by disinfectants. A commercially available ELISA also allows for the detection of cryptococcal polysaccharide in body fluids. Several PCR based film arrays have also been developed for the diagnosis of cryptococcosis. These assays allow for the detection of C. neoformans DNA in the CSF as part of a panel of meningitis encephalitis associated pathogens. Nonetheless, both false positives and false negatives (especially in the context of low burden disease) have been well documented. TREATMENT The choice of treatment for cryptococcosis depends on the sites of involvement and the host immune status. These regimens have not been rigorously studied in children and generally represent extrapo lations from studies done in adults. Guidelines for the treatment of pediatric cryptococcosis have been developed by the Infectious Dis eases Society of America (IDSA) and the World Health Organization (WHO). Pulmonary Disease The immunocompetent patient with asymptomatic or mild disease limited to the lungs should be treated with oral fluconazole (pediatric dose 6 12 mgkgday and adult dose 400 mgday) for 6 12 months to prevent dissemination and progression of disease. Alternative treat ments include itraconazole in solution form (pediatric dose 5 10 mg kgday divided every 12 hours and adult dose 400 mgday), voricon azole, and posaconazole. Fluconazole therapy can also |
7,598 | be used for immunocompromised individuals with isolated mild to moderate pulmonary disease in the absence of dissemination or CNS disease. Longer maintenance therapy with fluconazole to prevent recurrence should be considered in this cohort, especially among AIDS patients if the CD4 T cells remain less than 100L. Adjunctive surgical man agement of pulmonary lesions that are not responsive to surgical management should be considered. Patients with diffuse pulmonary disease or those with severe symptoms (e.g., acute respiratory dis tress syndrome) should be treated in the same manner as those with meningitis. Disseminated Disease and Meningitis For more severe forms of disease, including meningitis and any form of disseminated disease, an initial induction regimen to promote rapid decline in fungal burden is indicated. According to Infectious Diseases Society of America (IDSA) guidelines, induction therapy should consist of amphotericin B (1 mgkgday) plus flucytosine (100 150 mgkgday divided every 6 hours, assuming normal kid ney function) for a minimum of 2 weeks, keeping serum flucytosine concentrations between 40 and 60 gmL. Lipid amphotericin B has replaced standard amphotericin B for the treatment of severe cryp tococcosis in adults, primarily based on its lower toxicity profile. Strong consideration should be given to the use of lipid complex amphotericin B (36 mgkgday) in all affected pediatric patients, especially those with underlying kidney disease or at risk for kidney disease. Alternative induction therapies as outlined by the WHO guidelines include (1) 1 week of amphotericin B in combination with flucytosine, followed by 1 week of high dose fluconazole with amphotericin B; and (2) 2 weeks of amphotericin B in combination with high dose fluconazole. Repeat lumbar puncture is generally recommend at the end of induction therapy to document steriliza tion of CSF. Longer periods of induction (4 6 weeks) should be con sidered in the following scenarios: (1) immunocompetent patients with cryptococcal meningitis, (2) meningitis secondary to C. gat tii, (3) failure to sterilize CSF, and (4) neurologic complications (including cryptococcomas). After induction, consolidation ther apy with oral fluconazole (pediatric dose 10 12 mgkgday, adult dose 400 800 mgday) should be given for 8 weeks. In patients with ongoing immunosuppression, maintenance fluconazole should be used to prevent recurrence. In organ transplant recipients, current recommendations are for 6 12 months of maintenance therapy with fluconazole (pediatric dose 6 mgkgday, adult dose 200 400 mg day). In patients with AIDS, prolonged maintenance therapy should be given. Studies in adults suggest that maintenance therapy can be discontinued once the patient has achieved immune reconstitution (as indicated by CD4 T cells 100L and an undetectable or very low HIV RNA level that is sustained for greater than 3 months). A minimum of 12 months of antifungal therapy is indicated. Use of adjuvant interferon gamma for patients with refractory cryptococ cal meningitis has been described in adults, but not in pediatric patients. Increased ICP. Increased ICP contributes greatly to the morbidity and mortality of cryptococcal meningitis, and aggressive manage ment of this phenomenon is indicated. Current guidelines indicate that in |
7,599 | patients with increased ICP (25 cm H2O), CSF should be removed to establish a pressure 20 cm H2O or by 50 if ICP is extremely high. Serial lumbar punctures may be needed to ensure normalization of ICP, and ventriculoperitoneal shunts can be consid ered for patients with persistently elevated increased ICP. Corticoste roids, mannitol, and acetazolamide are generally not indicated in the treatment of increased ICP, though anecdotal reports describe use in association with cryptococcoma (in patients with C. gattii infection) and C IRIS. C IRIS. To prevent the development of C IRIS, most experts recommend delaying the institution of ART for 4 6 weeks after the initiation of antifungal therapy. Recurrence of disease and emergence of antifungal resistance should be excluded in the context of a diagnosis of C IRIS. Treatment strategies have not been well studied but generally consist of antifungal therapy along with antiinflammatory agents (e.g., NSAIDs and corticosteroids). Reduction of increased ICP through therapeutic lumbar puncture may be necessary. PREVENTION Persons at high risk for cryptococcosis should be advised to avoid exposures to bird droppings. Effective ART for persons with HIV infection significantly reduces the risk of cryptococcal disease. For adolescent patients with AIDS, regular cryptococcal antigen test ing with subsequent diagnostic evaluation and therapy should be considered for individuals with CD4 lymphocyte counts 100L. Cryptococcal antigen screening should also be done before the initia tion of antiretroviral therapy in patients newly diagnosed with HIV infection. In the absence of ability to perform regular screening, flu conazole prophylaxis for all patients with CD4 lymphocyte counts 100L can be considered. However, in children for whom the inci dence of cryptococcosis is relatively low, screening and prophylaxis are generally not needed. 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. 1928 Part XV u Infectious Diseases Members of the genus Malassezia are lipophilic yeasts that are a significant component of the skin microbiome. They have a pre dilection for the sebum rich areas of the skin and are considered normal skin flora. Colonization is established just after birth and rises before puberty, with distribution (both in species and num ber) related to numerous factors, including age, body site, and geo graphic location. The history of Malassezia nomenclature is complex and can be confusing. Yeast forms may appear oval or round, resulting in early designations of both Pityrosporum ovale and Pityrosporum orbicu lare. Additionally, newer technologies, such as matrix assisted laser desorptionionization time of flight mass spectrometry (MALDI TOF MS), are allowing for an improved classification system. The genus Malassezia has recently been assigned its own class, Malas seziomycetes, with 18 currently recognized species. Disease is facil itated by transformation of the yeast form to a hyphal form, with clusters of thick walled blastospores with the hyphae producing the characteristic spaghetti and meatballs appearance of Malassezia spp. |
7,600 | under light microscopy. Malassezia can cause a number of dermatologic conditions, more commonly in tropical environments, to include tinea versicolor (also pityriasis versicolor) (Fig. 282.1; see Chapter 707), neonatal acne, seb orrheic dermatitis, dandruff, Malassezia folliculitis, and onychomyco sis and are linked with atopic dermatitis and psoriasis. M. sympodialis, M. globosa, and M. furfur are the major causes of tinea versicolor. Mal assezia spp. may be isolated from sebum rich skin areas of asymptom atic persons, emphasizing that demonstration of the fungus does not equate with infection. Chapter 282 Malassezia Ashley M. Maranich Fig. 282.1 A young adult with tinea versicolor. Notice the character istic hypopigmented scaling macules. (Courtesy Ashley M. Maranich, MD.) Invasive infections, namely catheter associated fungemia, can occur, with premature infants and immunocompromised individuals (especially those with malignancies) the most high risk populations. M. furfur is the species most commonly causing fungemia, with M. pachydermatis implicated in neonatal intensive care unit outbreaks. The use of lipid emulsions containing medium chain triglycerides inhibits the growth of Malassezia spp. and can prevent infection. Symptoms of catheter associated fungemia are indistinguishable from other causes of catheter associated infections but should be suspected in patients, especially neonates, receiving intravenous lipid infusions. Compared with other causes of fungal sepsis, it is unusual for catheter related Malassezia fungemia to be associated with sec ondary focal infection. Malassezia species do not grow readily on standard fungal media, and successful culture requires overlaying the agar with olive oil. Recovery of Malassezia from blood culture is optimized by supple menting the medium with olive oil or palmitic acid and allowing for prolonged incubation for at least 2 weeks. Topical treatment of skin related conditions is considered first line to minimize the risk of side effects. The traditional primary therapy for tinea versicolor is daily use of topical selenium sul fide 2.5 applied to affected areas for 10 minutes for a week. Additional regimens for skin disorders include topical azole creams, ketoconazole 2 shampoo applied daily for 3 days, and terbinafine 1 cream applied 1 2 times daily for 1 2 weeks. Malassezia associated skin diseases limited to the head and neck can be managed with either 1 ciclopirox, ketoconazole, or zinc pyrithione shampoos. Regardless of the agent chosen, recovery time can be prolonged, with repigmentation not occurring for sev eral months. Continued application of topical treatment on a weekly or monthly basis is frequently recommended to prevent relapse. Recurrence is common and usually responds well to the original treatment regimen. Oral therapy for tinea versicolor with fluconazole or itraconazole is easier to administer (especially with large areas of skin involved) but is more expensive, has higher side effect risks, and may be less effective than topical therapy. Various dosing regimens have been used with success, including fluconazole 300 mg weekly for 2 4 weeks, flucon azole as a single 400 mg dose, and itraconazole 200 mg daily for 5 7 days or 100 mg daily for 2 weeks. Recent studies have examined alter native therapies, with |
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