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8,001 | USEFUL ANCILLARY TESTS DURATION OF ILLNESS sCJD Dementia, myoclonus, ataxia Unknown Worldwide; 1 21 million yr; 8595 of all CJD cases in the United States EEG PSWCs; CSF 14 3 3; RT QuIC, MRI DWI 1 24 mo (mean: 4 6 mo) fCJD Dementia, myoclonus, ataxia Genetic association (PRNP pathogenic variants) Worldwide; geographic clusters; 100 known families; 515 of CJD cases Gene testing; EEG PSWC; CSF 14 3 3, RT QuIC, MRIDWI Mean 15 mo iCJD Incoordination, dementia (late) Cadaveric dural grafts, human pituitary hormones, corneal transplantation, neurosurgical instruments, EEG depth electrodes 1 of CJD cases in toto (cadaveric dural grafts); human pituitary hormones, 100 cases; corneal transplantation, three cases; neurosurgical instruments, six cases, including two from cortical depth electrodes; RBC transfusions, four cases of vCJD infection, three clinical, one preclinical (United Kingdom); human plasmaderived factor VIII, one preclinical case of vCJD (United Kingdom) EEG PSCW, CSF 14 3 3, RT QuIC, MRI DWI 18 mo 30 yr vCJD Mood and behavioral abnormalities, paresthesias, dementia Linked to BSE in cattle, transfusion plasma products 230 clinical cases (see iatrogenic vCJD): none living, May 2017 Tonsil biopsy may show PrPTSE MRI FLAIR 8 36 mo (mean 14 mo) Kuru Incoordination, ataxia, tremors, dementia (late) Linked to cannibalism Fore tribe of Papua New Guinea (2,600 known cases) EEG no PSWCs; CSF 14 3 3 often negative; MRI (?) 3 24 mo GSS Incoordination, chronic progressive ataxia, corticospinal tract signs, dementia (late), myoclonus (rare) 90 genetic (PRNP pathogenic variants) Worldwide; 50 families; 1 10100 millionyr PRNP gene sequencing 2 12 yr (mean 57 mo) FFI Disrupted sleep, intractable insomnia; autonomic hyperactivation; myoclonus, ataxia; corticospinal tract signs; dementia PRNP gene pathogenic variant (D 178L); very rare sporadic cases 27 families in Europe, United Kingdom, United States, Finland, Australia, China, Japan PRNP testing; EEG PSWCs only rarely positive; MRI no DWI abnormalities; CSF 14 3 3 positive in 50 8 mo to 6 yr (mean: PRNP 129 MM 12 4 mo 129 MV 21 15 mo) BSE, Bovine spongiform encephalopathy; CSF, cerebrospinal fluid; CJD, Creutzfeldt Jakob disease; DWI, diffusion weighted image; fCJD, familial Creutzfeldt Jakob disease; FFI, fatal familial insomnia; FLAIR, fluid attenuation inversion recovery MRI; GSS, Gerstmann Strussler Scheinker syndrome; iCJD, iatrogenic Creutzfeldt Jakob disease; PRNP, prion proteinencoding gene; PrPTSE, abnormal prion protein; PSWCs, periodic sharp wave complexes; RBC, red blood cell; RT QuIC, real time quaking induced conversion; sCJD, sporadic Creutzfeldt Jakob disease; vCJD, variant Creutzfeldt Jakob disease. NOTE: PRNP 129 MM, homozygous, encoding the amino acid methionine at both codons 129 of the prion proteinencoding (PRNP) gene on chromosome 20; 129 MV, heterozygous at PRNP codon 129, encoding methionine on one chromosome 20 and valine on the other. Modified from Mandell GL, Bennett JE, Dolin R, eds. Principles and Practice of Infectious Diseases. 6th ed. Philadelphia: Elsevier; 2005: p. 2222; Love S, Louis DN, Ellison DW, eds. Greenfields Neuropathology. 8th ed. London: Hodder Arnold; 2008: p. 1239. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April |
8,002 | 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. 2120 Part XV u Infectious Diseases of abnormal PrP have been proposed as providing a plausible molecu lar basis for the coding. It fails to explain why pure PrP uncontami nated with nucleic acid from an infected host has not consistently transmitted a typical spongiform encephalopathy associated with a serially self propagating agent. Also troubling is the fact that abnormal PrP and infectivity were not consistently associated in several experi mental models and human illnesses. Particularly problematic is the finding that some illnesses associated with pathogenic variants in the PRNP gene and accompanied by abnormal PrP failed to transmit infec tion to animals. If the TSE agents ultimately prove to consist of protein and only protein, with no obligatory nucleic acid component, then proponents of the prion hypothesis will have been prescient. If the agents are ultimately found to contain small nucleic acid genomes, then they might better be considered atypical viruses, for which the term virino was once suggested. Until the actual molecular struc ture of the infectious TSE pathogens and the presence or absence of a nucleic acid genome are rigorously established, it seems accept able to continue calling them TSE agents (a term that remains popular among some European authorities). Most U.S. authorities now prefer the term prion (sometimes referring to the infectious agents of TSEs and sometimes to abnormal PrP, even when not transmissible). The earliest evidence that abnormal proteins are associated with the TSE was morphologic: scrapie associated fibrils (SAFs) were found by negative stain electron microscopy in detergent treated extracts of brain tissues from patients and animals with TSEs but not in brain tissues of unaffected persons. SAFs resemble but are distin guishable from the amyloid fibrils that accumulate in the brains of patients with Alzheimer disease. Antigenically related protease resistant PrPs (PrP res) proved to be components of SAFs and to be present in the amyloid plaques found in the brains of patients and animals with TSEs. The abnormal forms of PrP have been vari ously designated PrPSc (scrapie type PrP), PrP res, PrPTSE (TSE associated PrP), or PrPD (also PrPDis, for disease associated PrP) by different authorities. It remains unclear whether abnormal PrP constitutes the complete infectious particle of spongiform encephalopathies, is a component of those particles, or is a pathologic host protein not usually separated from the actual infectious entity by current techniques. The demon stration that PrP is encoded by a normal host gene seemed to favor the last possibility. (A possible model for mammalian prions was provided by several studies. The model suggested that agent specific pathogenic information can be transmitted and replicated by different conforma tions of fungal proteins having the same primary amino acid sequence without participation of any agent specific nucleic acids, although those transmissions required microinjections and misfolded proteins were apparently not naturally transmitted to recipient fungi as infec tious elements.) Whatever its relationship to the actual |
8,003 | infectious TSE particles, PrP clearly plays a central role in susceptibility to infection, because the normal PrP must be expressed in mice and cattle to infect them. Furthermore, inherited normal variations (genetic polymorphisms) in PrP genotype are associated with increased susceptibility to vCJD and, to a lesser extent, to sCJD and with occurrence of two familial TSEs (fCJD and GSS). PrPs are glycoproteins that have the physi cal properties of amyloid proteins when misfolded and aggregated into protease resistant PrPTSE. The PrPs of different species of ani mals are very similar in their amino acid sequences and antigenic ity but are not identical in structure. The primary structure of PrP is encoded by the host and is not altered by the source of the infectious agent provoking its formation. The function of the normal ubiquitous protease sensitive PrP precursor (designated either PrPC or PrP sen, for protease sensitive PrP, by different authorities) in normal cells is unknown; it binds copper and may play some role in normal synaptic transmission but is not required to sustain life or for relatively normal cerebral function in mice and cattle. As noted, animals must express PrP to develop overt TSE as well as to support replication of the TSE agents. The degree of homology between amino acid sequences of PrPs in different animal species may correlate with a species barrier that affects susceptibility of animals of one species to infection with a TSE agent adapted to grow in another species, although the degree of sequence homology does not always predict susceptibility to the same TSE agent. Attempts to find particles resembling those of known viruses or virus like agents in brain tissues of humans or animals with spongi form encephalopathies have been unsuccessful. Peculiar tubulovesicu lar structures reminiscent of some viruses have been seen repeatedly in thin sections of TSE infected brain tissues and cultured cells but not in normal brain cells; it has never been established that those structures are associated with infectivity. EPIDEMIOLOGY Kuru once affected many children of both sexes 4 years of age, adoles cents, and young adults (mainly women) living only in a limited area of Papua New Guinea. The complete disappearance of kuru among people born after 1957 suggests that the practice of ritual cannibalism (thought to have ended that year) was probably the only mechanism by which the infection spread in Papua New Guinea. The probable incu bation periods of some cases of kuru have exceeded 50 years. Kuru has not been diagnosed since 2005. sCJD is the most common human spongiform encephalopathy. Most countries with surveillance for CJD have identified between one and two cases of sCJD per million total population per year (0.25 2 cases per million population, not age adjusted). That figure is some what misleading in that the Centers for Disease Control and Preven tion (CDC) has estimated the lifetime risk of sCJD in the United States to be as many as 1 in 6,000 persons, taking into account the number of recognized |
8,004 | iCJD cases attributed to use of cadaveric pituitary hor mones, typical advanced age of CJD cases at onset, and probable incu bation periods of decades. sCJD was formerly thought to occur only in older adults; however, sCJD and sporadic fatal insomnia have also affected a few young people (to date, seven cases reported in adoles cents, one in a 14 year old girl). vCJD, however, has a peculiar pre dilection for younger people. Of 174 cases of vCJD reported through 2010 in the United Kingdom, all except 23 were in people younger than 40 years of age and 22 were younger than 20 years of age; the youngest age at onset was 12 years. Proponents of the prion hypothesis are convinced that PrP can spontaneously misfold, becoming self replicating and causing sCJD; skeptics favor the hypothesis of infection with some ubiquitous TSE agent that, fortunately, has a very low attack rate except in persons with certain pathogenic variants in the PRNP gene or possibly non PRNP genetic risk factors. Neither possible etiology has been proven. fCJD, the second most common human TSE, accounts for only 10 or 15 of total cases of CJD. fCJD occurs in a foci of considerably higher inci dence in Israel (among Libyan Jews), in isolated villages of Slovakia, and in other limited areas. sCJD has not been convincingly linked to any prior exposure to other cases and the source of infection remains unknown. Person to person spread has been confirmed only for iatrogenic cases. Spouses and household contacts of patients are not at increased risk of acquiring CJD, although two instances of conjugal CJD have been reported. However, medical personnel exposed to brains of patients with CJD may be at some increased risk; at least 20 healthcare workers have been recognized with the disease. In 2019 a young laboratory worker in France died after a 2 year illness confirmed at autopsy to be vCJD; her infection was plausibly attributed to an accidental penetrating wound 7.5 years before onset by a for ceps contaminated with brain tissue from a mouse experimentally infected with BSE agent. The striking resemblance of CJD to scrapie prompted a concern that infected sheep tissues might be a source of spongiform encepha lopathy in humans. No reliable epidemiologic evidence suggests that exposure to potentially scrapie contaminated animals, meat, meat 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 324 u Transmissible Spongiform Encephalopathies 2121 products, or experimental preparations of the scrapie agent have transmitted a TSE to humans. The potential of the CWD agent to infect human beings has also not been demonstrated but remains under investigation by the CDC and Canadian authorities. Con sumption of contaminated venison from animals infected with the CWD agent has not been implicated as a risk factor for human TSE by epidemiologic studies. However, a Canadian study reported that CWD |
8,005 | had been experimentally transmitted to monkeys fed venison from overtly healthy infected deer, prompting a health advisory from Canadian authorities (https:www.thetyee.caDocuments2017062 4Risk Advisory Opinion CWD 2017.pdf). The same thing is not true for vCJD, which is clearly a zoonosis acquired by humans after dietary exposure to the BSE agent. The out break of BSE among cattle (possibly infected by eating scrapie agent contaminated meat and bone meal and later bovine contaminated meal added to feed) was first recognized in the United Kingdom in 1986 and later reported in cattle of 27 other countries, including Can ada and the United States. More than 190,000 cases of BSE have been reported to the World Organization for Animal Health (OIE), almost 97 of those from the United Kingdom. Cases of BSE progressively declined in the United Kingdom after 1992 and somewhat later in other countries; in 2016 only two cases worldwide were reported to the OIE (from France and Spain) and none from the United King dom. A single case of BSE was recognized in the United States in 2018. Rare sporadic cases of BSE in old cows, associated with an atypical PrPTSE having somewhat different electrophoretic proper ties from those of the PrPTSE in younger cattle with classic cases of BSE during the epidemic, stimulated the hypothesis that atypical BSE was caused by spontaneous generation of a PrPTSE rather than by a feed borne infection; that hypothesis, however intriguing and appealing to some agricultural authorities, remains unconfirmed though little investigated. The finding of a new TSE in ungulate and feline animals in British zoos and later in domestic cats first raised a fear that the BSE agent might have acquired a range of susceptible hosts broader than that of scrapie, posing a potential danger for humans. A broadening of the host range of BSE agent remains the most plausible explanation for the later appearance of human vCJD, first described in adolescents in Britain in 1996 and, as of August 2021, eventually affecting at least 178 people potentially exposed to a BSE agent in the United Kingdom (not counting a disturbing number of people with evidence of pos sible asymptomatic or preclinical vCJD infection) and more than 50 in 11 other countries (total 231 cases worldwide): 28 in France, 5 in Spain, 4 in Ireland, 3 in the Netherlands, 3 in Italy, 2 in Portugal, and single cases in Japan and Saudi Arabia. vCJD has also occurred in former residents in the United Kingdom (for more than 6 months) later living in Ireland (two cases), France (one case), Canada (one case), Taiwan (one case), and the United States (two cases). Two cases of vCJD, one in the United States and one in Canada, have been reported in former long time residents of the Kingdom of Saudi Ara bia, a country that has not recognized BSE but might have imported infected cattle or contaminated halal beef products from Britain. A third case of vCJD was previously confirmed in a Saudi citizen resid ing in |
8,006 | the Kingdom of Saudi Arabia. The most recent case of vCJD diagnosed in the United States occurred in an immigrant deemed by the CDC to have been infected during years spent in Kuwait or, less likely, Russia. No case of vCJD has been confirmed in anyone born in the United Kingdom after 1989. However, examination by immunohistochem istry of resected appendices in the United Kingdom for evidence of subclinical vCJD infection suggested that about 1 in 2,000 tissues tested had detectable accumulations of PrPTSE in lymphoid follicles. It remains controversial whether those accumulations result from sub clinical vCJD or other TSE (https:app.box.comshhhhg857fjpu2bnx hv6e12936396377917961565061); none of the PrPTSE positive sub jects to date has been reported with overt TSE. Iatrogenic transmissions of CJD (iCJD) have been recognized for more than 30 years (Table 324.2). Such accidental medical transmis sions of CJD have been attributed to use of contaminated neurosurgical instruments (no case reported since 1980), cortical electrodes contami nated during epilepsy surgery, injections of human cadaveric pituitary growth hormone and gonadotropin (neither currently marketed in the United States), transplantation of human dura mater allografts for merly used as a surgical patching material (especially in Japan), and, rarely, contaminated corneal transplants. Pharmaceuticals and tissue grafts derived from or contaminated with human neural tissues, par ticularly if obtained from unselected donors and large pools of donors, pose special risks. Studies of animals experimentally infected with TSE agents first suggested that blood and blood components from humans with pre clinical CJD infections might pose a risk of transmitting disease to recipients. Since the 1980s such blood components have been with drawn as a precaution in the United States when a donor was later found to have CJD and blood products were still in date. A surveil lance program in the United Kingdom reported vCJD in three recipi ents of nonleukoreduced red blood cells from donors later diagnosed with vCJD; there was autopsy evidence of a preclinical vCJD infec tion in a fourth red cell recipient who died of another disease. (vCJD has not occurred in anyone exclusively transfused with leukoreduced red blood cells from a donor who later developed vCJD.) A study initiated more than 20 years ago by the American Red Cross and CDC found no recipient of blood components obtained from donors later diagnosed with sCJD (and from one donor with fCJD) had ever developed a TSE. Evidence of a preclinical vCJD infection was found at autopsy in a British patient with hemophilia A treated with a human plasma derived coagulation factor VIII to which at least one vCJD infected donor contributed; the coagulation factor involved was never licensed or marketed in the United States. Authorities in the United Kingdom described two recipients of plasma derived coagulation factors (both having history of transfusion with blood components as well) who later developed sCJD, concluding that the finding, while of concern, might be coincidental. PATHOGENESIS AND PATHOLOGY The probable portal of entry for the TSE agent in kuru is thought to have been either |
8,007 | through the gastrointestinal tract or lesions in the mouth or integument incidentally exposed to the agent during can nibalism. Patients with vCJD (and animals with BSE and BSE related TSEs) are thought to have been similarly infected with the BSE agent by consuming contaminated beef products. Except after direct intro duction into the nervous system, the first site of replication of TSE agents appears to be in tissues of the reticuloendothelial system. TSE agents have been detected in low titers in blood of experimentally infected animals (mice, hamsters, cervids, sheep, and monkeys) and in the blood of persons with vCJD; infectivity was mainly associated with nucleated cells, although plasma contained a substantial portion of total infectivity in blood. Mice must have circulating lymphoid cells to be infected by peripheral routes. Limited evidence suggests that TSE agents can also spread to the central nervous system (CNS) by ascend ing peripheral nerves. In kuru, it seems probable that the only portal of exit of the agent from the body, at least in quantities sufficient to infect others, was through infected tissues exposed during cannibalism. In iatrogeni cally transmitted CJD, the brains and eyes of patients with sCJD have been the probable sources of contamination. Experimental transmission of the agent to animals from kidney, liver, lung, lymph node, and spleen sampled at autopsies of patients with sCJD showed that those tissues as well as cerebrospinal fluid (CSF) sometimes contained the CJD agent; none of those sources has been implicated in accidental transmissions of CJD to humans. At no time during the course of any TSE have antibodies or cell mediated immunity 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. 2122 Part XV u Infectious Diseases to the infectious agents been convincingly demonstrated in either patients or animals. However, mice must be immunologically com petent to be infected with the scrapie agent by peripheral routes of inoculation. Typical changes in TSE include vacuolation and loss of neurons with hypertrophy and proliferation of glial cells, most pronounced in the cerebral cortex in patients with CJD and in the cerebellum in those with kuru. The lesions are usually most severe in or even confined to gray matter, at least early in the disease. Loss of myelin appears to be secondary to degeneration of neurons. There generally is no inflam mation, but a marked increase in the number and size of astrocytes is usual. Spongiform changes are not a striking autopsy finding in patients with FFI, and neuronal degeneration and gliosis are largely restricted to thalamic nuclei. Amyloid plaques are found in the brains of all patients with GSS and in at least 70 of those with kuru. These plaques are less common in patients with CJD. Amyloid plaques are most com mon in the cerebellum but occur elsewhere in the brain as well. In brains of patients with vCJD, plaques |
8,008 | surrounded by halos of vacuoles (described as flower like or florid plaques) have been a consistent finding. TSE amyloid plaques react with antiserum prepared against PrP. Even in the absence of plaques, extracellular PrPTSE can be detected in the brain parenchyma by immunostain ing, Western blotting, and enzyme linked immunosorbent assay (ELISA). CLINICAL MANIFESTATIONS Kuru was a progressive degenerative disease of the cerebellum and brainstem with less obvious involvement of the cerebral cortex. The first sign of kuru was usually cerebellar ataxia followed by progressive incoordination. Coarse, shivering tremors were characteristic. Vari able abnormalities in cranial nerve function appeared, frequently with impairment in conjugate gaze and swallowing. Patients died of inani tion and pneumonia or of burns from cooking fires, usually within 1 year after onset. Although changes in mentation were common, there was no frank dementia or progression to coma, as seen in CJD. There were also no signs of acute encephalitis such as fever, headaches, and convulsions. Patients with sCJD initially have either sensory disturbances (most often visual) or confusion and inappropriate behavior, progressing over weeks or months to frank dementia, akinetic mutism, and ultimately coma. Some patients have cerebellar ataxia early in disease, and most patients experience myoclonic jerking movements. Mean survival of patients with sCJD has been 4 6 months from the earliest signs of ill ness, although approximately 10 live for 2 years. vCJD (Table 324.3) differs from the more common sCJD: patients with vCJD are much younger at onset (as young as 12 years) and more often present with complaints of dysesthesia and subtle behavioral changes, often mis taken for psychiatric illness. Severe mental deterioration occurs later in the course of vCJD. Patients with vCJD have survived substantially longer than those with sCJD. (Attempts have been made to subclas sify cases of CJD based on electrophoretic differences in PrPTSE and variation in its sensitivity to digestion with the proteolytic enzyme pro teinase PK; the different variants are said to have somewhat different clinical features, including duration of illness, though all are ultimately fatal.) GSS is a familial disease somewhat resembling CJD but with more prominent cerebellar ataxia or parkinsonian syndrome and amyloid plaques. Dementia may appear only late in the course of GSS, and the average duration of illness is longer than that of typical sCJD (5 years). Progressively severe insomnia and dys autonomia as well as ataxia, myoclonus, and other signs resem bling those of CJD and GSS characterize FFI and sporadic fatal insomnia. GSS has not been diagnosed in children or adolescents. A case of sporadic fatal insomnia has been described in a young adolescent. DIAGNOSIS Diagnosis of spongiform encephalopathies is most often determined on clinical grounds after excluding other diseases. The presence of the 14 3 3 protein (see the section Laboratory Findings) in CSF may aid in distinguishing between CJD and Alzheimer disease, which is not a consideration in children. Elevations of 14 3 3 protein levels in CSF are not specific to TSEs and are common in viral encephalitis |
8,009 | and other conditions causing rapid necrosis of brain tissue. A research use PrP peptide amplification test (real time quaking induced conversion RT QuIC) appears to be sensitive and specific for antemortem diagnosis of sCJD when applied to CSF or nasal brushings but may be less sensi tive in younger patients compared with older individuals with TSEs. Brain MRI has proven clinically useful (see later). Brain biopsy may be diagnostic for all forms of CJD but can be recommended only if a potentially treatable disease remains to be excluded or some other reason compels an antemortem diagnosis and may result in a false negative result depending on tissue quality, type, and TSE. Defini tive diagnosis usually requires microscopic examination of brain tis sue obtained at autopsy. The demonstration of PrPTSE in brain extracts augments histopathologic diagnosis. Accumulation of the abnormal PrP in lymphoid tissues, even before the onset of neurologic signs, is typical of vCJD. Tonsil biopsy may avoid the need for brain biopsy when antemortem histologic diagnosis of vCJD is indicated. To date no blood based test has been validated for antemortem testing of either humans or animals, though one cumbersome PrPTSE research use test (protein misfolding cyclic amplification PMCA) shows promise. Transmission of disease to susceptible animals by inoculation of brain suspension, while sensitive, specific, and reliable, must be reserved for cases of special research interest. Diagnosis usually rests on recogniz ing the typical constellation of clinical findings, course of illness, and Table 324.2 Iatrogenic Transmission of Creutzfeldt Jakob Disease by Products of Human Origin PRODUCT PATIENTS (NO.) INCUBATION TIME MEAN RANGE Cornea 3 17 mo 16 18 mo Dura mater allograft 100 7.4 yr 1.3 16 yr Pituitary extracts Growth hormone 100 12 yr 5 38.5 yr Gonadotropin 4 13 yr 12 16 yr Red blood cells 4 ? 6 yr 6.3 8.5 yr Plasma derived coagulation factor VIII 1 ? 11 yr There have been 28 cases reported among approximately 8,000 recipients of human cadaveric growth hormone in the United States; the remaining cases have been reported in other countries. The second transfusion transmitted case of vCJD (Peden AH, Head MW, Ritchie DL, et al. Preclinical vCJD after blood transfusion in a PRNP codon 129 heterozygous patient. Lancet. 2004;364:527529) died of unrelated causes about 5 years after transfusion but was found to have accumulations of abnormal PrP in spleen and cervical lymph node, a finding unique to vCJD and interpreted as probable preclinical infection. The diagnosis of vCJD infection attributed to treatment with human plasma derived coagulation factor VIII (UK Health Protection Agency vCJD abnormal prion protein found in a patient with haemophilia at post mortem. Press release 17 February 2009. http:webarchive.nationalarchives.gov.uk20140714 084352http:www.hpa.org.ukwebwHPAwebHPAwebStandardHPAwebC 1234859690542?p1231252394302) was also supported by immunohistochemical testing for abnormal PrP in the spleen of a person who died of other causes. Both patients with preclinical infections are thought to have died during the asymptomatic incubation period of vCJD. Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April |
8,010 | 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 324 u Transmissible Spongiform Encephalopathies 2123 testing (CSF examination, MRI, EEG), confirmed by histopathology and detection of PrPTSE in brain tissues at autopsy (or, less often, by tonsil or brain biopsy). LABORATORY FINDINGS Virtually all patients with typical sporadic, iatrogenic, and familial forms of CJD have abnormal EEGs as the disease progresses; the background becomes slow and irregular with diminished ampli tude. A variety of paroxysmal discharges such as slow waves, sharp waves, and spike and wave complexes may also appear, and these may be unilateral or focal or bilaterally synchronous. Paroxysmal discharges may be precipitated by loud noise. Many patients have typical periodic suppression burst complexes of high voltage slow activity on EEG at some time during the illness. Patients with vCJD have only generalized slowing, without periodic bursts of high voltage discharges on EEG. CT or MRI may show cortical atro phy and large ventricles late in the course of CJD. Most cases of sCJD and many cases of familial TSE demonstrate hyperintensity in cortex or basal ganglia diffusion by weighted imaging (DWI). Many patients with vCJD have an increase in density of the pulvi nar on fluid attenuated inversion recovery (FLAIR) MRI sequences. Reliable interpretation of the images is best left to experienced radiologists. There may be modest elevation of CSF protein content in patients with TSE. Unusual protein spots were observed in CSF specimens from sCJD patients separated by two dimensional gel electropho resis and silver staining; the spots were later identified as 14 3 3 proteins, normal proteins not related to PrP that are abundant in neurons but not ordinarily detected in CSF. However, 14 3 3 pro tein, as noted previously, has also been detected in CSF specimens from some patients with acute viral encephalitides and recent cere bral infarctions, and is not specific to CJD. Finding the 14 3 3 pro tein in CSF is neither sensitive nor specific but can help confirm the diagnosis of sCJD, especially when accompanied by increases in other cellular proteins. Tests for 14 3 3 in CSF are often negative in patients with vCJD. TREATMENT No treatment has proven effective for any TSE, and it seems unlikely that treatment can reverse the severe brain damage found in late dis ease. Studies of cell cultures and rodents experimentally infected with TSE agents suggested that treatments with chlorpromazine, quinacrine, and tetracyclines might be of benefit, especially during the incubation period; however, results of clinical trials based on those studies have been discouraging. Infusions with pentosan polysulfate directly into the cerebral ventricles may have delayed the progression of vCJD in at least one patient but did not reverse earlier brain damage. On the basis of experimental studies in animals, several prophylactic postexposure treatment regimens have been suggested, but none has been validated or widely accepted. Results of some preliminary studies suggested that treatments with antisense oligonucleotides or other molecular genetic therapies |
8,011 | might impair translation of the prion protein gene, poten tially ameliorating the degenerative process of TSE if initiated before CNS damage has appeared; such early treatment would have to be directed to otherwise healthy persons bearing a pathogenic variant known to occur in familial TSE, because those destined to develop the more common sCJD cannot be identified before brain damage appears. Appropriate compassionate supportive care should be provided to all CJD patients as for those with other progressive fatal neurologic diseases. GENETIC COUNSELING TSEs occur in some families in a pattern consistent with an autoso mal dominant mode of inheritance. In patients with a family history of CJD, the clinical and histopathologic findings are similar to those seen in sporadic cases. In the United States, only approximately 10 of cases of CJD are familial. GSS and FFI are always familial. In some affected families, approximately 50 of siblings and children of a patient with a familial TSE eventually acquire the disease; in other families, the pen etrance of illness is lower. The gene encoding PrP is closely linked if not identical to that con trolling the incubation periods of scrapie in sheep and both scrapie and CJD in mice. The same gene in humans is designated the PRNP Table 324.3 Clinical and Histopathologic Features of Patients with Variant and Typical Sporadic Creutzfeldt Jakob Disease FEATURE VARIANT CJD (FIRST 10 PATIENTS) SPORADIC CJD (185 PATIENTS) Years of age at death (range) 29 (19 74) 65 Duration of illness, mo (range) 12 (8 23) 4 6 Presenting signs Abnormal behavior, dysesthesia Dementia, ataxia Later signs Dementia, ataxia, myoclonus Ataxia, myoclonus Periodic complexes on EEG Rare Most PRNP 129 MetMet All tested (except one transfusion transmitted case, one plasma derivative transmitted case; one possible clinical case in United Kingdom where no tissue was available to confirm) 83 Histopathologic changes Vacuolation, neuronal loss, astrocytosis, plaques (100) Vacuolation, neuronal loss, astrocytosis, plaques (15) Florid PrP plaques 100 0 PrPTSE glycosylation pattern BSE like Not BSE like Median age and duration for variant CJD; averages for typical sporadic CJD. Dense plaques with a pale periphery of surrounding vacuolated cells. Characterized by an excess of high molecular mass band (diglycosylated) and 19 kDa nonglycosylated band glycoform of PrP res (Collinge J, Sidle KC, Meads J, et al. Molecular analysis of prion strain variation and the aetiology of new variant CJD. Nature. 1996;383:685690). BSE, Bovine spongiform encephalopathy; CJD, Creutzfeldt Jakob disease; Met, codon 129 of one PRNP gene encoding for methionine; PRNP, prion proteinencoding gene; PrP, prion protein. Modified from Will RG, Ironside JW, Zeidler M, et al. A new variant of Creutzfeldt Jakob disease in the UK. Lancet. 1996;347:921925. 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. 2124 Part XV u Infectious Diseases gene, located on the short arm of chromosome 20. It has an open reading frame of about 759 |
8,012 | nucleotides (253 codons), in which more than 20 different point pathogenic variants and a variety of inserted sequences encoding extra tandem repeated octapeptides have been linked to the occurrence of spongiform encephalopathy in families, a disease expressed in a pattern consistent with autosomal dominance of variable penetrance. The E200K point pathogenic variant has been the most common worldwide. The same nucleotide substitution at codon 178 of the PRNP gene (D178N) associated with CJD in some families has also been found in all patients with FFI but associated with linkage to a different polymor phic amino acid at codon 129 of the PRNP gene on the same chromo some (fCJD with 129V and FFI with 129M). Homozygosity for valine (V) and especially for methionine (M) at codon 129 seems to increase susceptibility to both iCJD and sCJD. All but three patients with vCJD to be genotyped have been homozygous for methionine at codon 129 of the PRNP gene. A few probable preclinical vCJD infections and two clinically typical cases of vCJD (one confirmed and another not com pletely evaluated) occurred in persons with the 129 MV heterozygous genotype. It is of interest that when the PRNP genes from appendices containing accumulations of what appears to be PrPTSE in the United Kingdom were sequenced, a surprising number were homozygous for 129Vthe genotype of only approximately 10 of British subjectsand never found in a case of overt vCJD. The significance of this finding is not clear. Authorities in the United Kingdom adopted the precautionary assumption that some persons with PrPTSE in lymphoid tissues may have latent infections; as time goes by without detecting any overt cases of vCJD in those persons, that assumption becomes less likely. Whether the blood or tissues of such persons are infectious remains unknown. Although the interpretation of these findings in regard to the prion hypothesis remains controversial, persons from families with CJD or GSS who have the associated pathogenic variants in the PRNP gene clearly have a high probability of eventually developing TSE. Bearers of TSE associated pathogenic variants have successfully employed preimplanta tion genetic diagnosis and in vitro selection of embryos to avoid passing the mutant gene to offspring. The significance of pathogenic variants in the PRNP genes of individuals from families with no history of spon giform encephalopathy is not known. It seems wise to avoid alarming those from unaffected families who have miscellaneous pathogenic vari ants in the PRNP gene, because the implications are not yet clear. In the United States, persons are currently deferred from donating blood if a blood relative has been diagnosed with a familial TSE unless the donor (the relative or implicated parent) has no TSE related mutation. PROGNOSIS The prognosis of all spongiform encephalopathies is uniformly poor. Approximately 10 of patients may survive for longer than 2 years but the quality of life is poor. FAMILY SUPPORT The CJD Foundation (http:www.cjdfoundation.org), orga nized and maintained by family members and friends of patients with CJD and related disorders, working closely with |
8,013 | the CDC (www.cdc.govprionsindex.html) and with the National Prion Dis ease Pathology Surveillance Center, Case Western Reserve University, Cleveland, Ohio (http:www.cjdsurveillance.com), is a support and educational group and a useful source of information regarding avail able resources for those dealing with the diseases. PREVENTION Exposure to the BSE agent in meat products clearly poses a special dan ger, which is now greatly reduced. Authorities in Canada, the United States, and other countries responded by implementing progressively more stringent agricultural and public health measures during the past 25 years, with prohibition of most bovine derived materials from feeds for ruminants probably the most effective measure. Three cases of BSE in native cattle were recognized in the United States from 2004 through 2012; a case was also found in a Canadian cow imported into the United States in 2003. Canada found 20 native cattle with BSE between 2003 and 2015 (and imported a case from the United Kingdom in 1993). In spite of encouraging epidemiologic studies that failed to implicate exposure to scrapie or CWD agents in human TSEs, it seems prudent to avoid exposing children to meat and other products likely to be con taminated with any TSE agent. The safety of human blood, blood components, and plasma deriv atives in the United States and Canada is protected by deferring, as a precaution, some donors with histories suggesting an increased risk of exposure to TSE agents: persons treated with human cadav eric pituitary hormones or dura mater allografts (neither currently marketed in the United States) and donors who voluntarily disclose history of familial TSE (fCJD, GSS, FFI) unless sequencing shows that the TSEaffected relative or the donor has no TSErelated muta tion in either PRNP gene (https:www.fda.govvaccinesblood biologicsguidancecomplianceregulatoryinformationbiologics biologicsguidances). In principle, it would be better to identify the very few blood and tissue donors actually infected with a TSE rather than deferring all those at increased risk of exposure, because most of them are unlikely to have been infected. Antemortem screening tests that might eventu ally identify donors with preclinical TSE infections are currently under development though not clinically validated. It seems unlikely that any test would be adopted to screen blood donors without simultaneously implementing a highly specific validated confirmatory test to avoid the serious adverse implications resulting from the inevitable false positive screening results. In any case, the current risk of transfusion transmitted TSE in the United States appears to be extremely low. Postmortem testing of brain tissue from cadaveric tissue donors would be feasible and more justifiable in view of the surprisingly high lifetime risk of sCJD; tissue transplantationassociated TSE has not been rec ognized since donors with history of dementia and other neurologic disease have been excluded. Standard universal precautions should be used to handle all human tissues, blood, and body fluids. Materials and surfaces contaminated with tissues and CSF from patients suspected of having CJD must be treated with great care, paying special attention to preventing injuries with needles and other sharp instruments. Whenever possible, discard contaminated |
8,014 | instruments as medical pathological waste by care ful packaging and incineration. Contaminated tissues and biologic products probably cannot be completely freed of infectivity without destroying their structural integrity and biologic activity; therefore the medical and family histories of individual tissue donors should be carefully reviewed to exclude a diagnosis of TSE or other neurologic disease. Histopathologic examination of brain tissues of cadaveric donors and rapid testing for abnormal PrP might eventually be per formed where feasible (no rapid diagnostic test is currently marketed for use with human tissues, though commercial animal TSE tests detect PrPTSE in human CJD brains) to provide some additional assurance of safety. Although no method of sterilization can be relied on to remove all infectivity from contaminated surfaces, exposures to moist heat, sodium hydroxide, chlorine bleach, concentrated formic acid, acidified detergent, and guanidine salts markedly reduced infectivity in experi mental studies. 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 325 u Principles of Antiparasitic Therapy 2125 Parasites are divided into three main groups taxonomically: protozo ans, which are unicellular, and helminths and ectoparasites, which are multicellular. Chemotherapeutic agents appropriate for one group may not be appropriate for the others, and not all drugs are readily available (Table 325.1). Some drugs are not available in the United States, and some are available only from the manufacturer, specialized compounding pharmacies, or the Centers for Disease Control and Prevention (CDC). Information on the availability of drugs and expert guidance in manage ment can be obtained by contacting the CDC Parasitic Diseases Branch (1 404 718 4745; e mail parasitescdc.gov (M F, 8 am 4 pm, Eastern time). For assistance in the management of malaria, healthcare providers should call the CDC Malaria Hotline: 1 770 488 7788 or 1 855 856 4713 toll free, e mail malariacdc.gov (M F, 9 am 5 pm, Eastern time). For all emergency consultations after hours, clinicians can contact the CDC Emer gency Operations Center at 1 770 488 7100 and request to speak with a CDC Malaria Branch clinician or on call parasitic diseases physician. Some antiparasitic drugs are not licensed for use in the United States but can be obtained as investigational new drugs (INDs) from the CDC; pro viders should call the CDC Drug Service, Division of Scientific Resources and Division of Global Migration and Quarantine, at 1 404 639 3670. SELECTED ANTIPARASITIC DRUGS FOR PROTOZOANS Nitazoxanide (Alinia) Nitazoxanide is a nitrothiazole benzamide, initially developed as a veterinary anthelmintic. Nitazoxanide inhibits pyruvate: ferredoxin oxidoreductase, which is an enzyme necessary for anaerobic energy metabolism. In humans, nitazoxanide is effective against many proto zoans and helminths. Nitazoxanide is approved for the treatment of diarrhea caused by Cryptosporidium parvum and Giardia intestinalis in patients 1 year of age. Nitazoxanide is available as a tablet (500 mg) and an oral suspen sion |
8,015 | (100 mg5 mL), which has a pink color and strawberry flavor. The bioavailability of the suspension is 70 compared with the tablet. The drug is well absorbed from the gastrointestinal tract but should be taken with food due to approximately twofold higher absorption. One third is excreted in urine, and two thirds is excreted in feces as the active metabolite, tizoxanide. Although in vitro metabolism studies have not demonstrated cytochrome P450 enzyme effects, no pharma cokinetic studies have been performed in patients with compromised renal or hepatic function. In addition, limited studies have been per formed in pregnant or lactating women; nevertheless, CDC Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV recommend nitazoxanide for the treat ment of severe cryptosporidiosis after the first trimester. Tizoxanide is known to be excreted in breast milk, but decisions to breastfeed dur ing therapy can be individualized. Common adverse effects include abdominal pain, diarrhea, nausea, and urine discoloration. Rare side effects include anorexia, flatulence, increased appetite, fever, pruritus, and dizziness. Intriguingly, nitazoxanide has in vitro activity against multiple other pathogens, including influenza virus, rotavirus, hepa titis C virus, and SARS CoV 2, although the clinical use of the agent against these viruses remains investigational. Tinidazole (Tindamax) Tinidazole is a synthetic nitroimidazole with a chemical structure simi lar to metronidazole. It is approved by the Food and Drug Administra tion (FDA) for patients 3 years of age and older and for treatment of trichomoniasis, giardiasis, and amebiasis. In the treatment of giardia sis, it has the advantages of very few side effects and only requiring a single dose. It is available as a tablet, which can be crushed and admin istered with food. Its mechanism of action against Trichomonas may be secondary to the generation of free nitro radicals by the protozoan. The mechanism of action against Giardia lamblia and Entamoeba his tolytica is unknown. Like metronidazole, it can cause a disulfiram like reaction if combined with alcohol. After oral administration, tinidazole is rapidly and completely absorbed and is distributed into almost all tis sues and body fluids; it can cross the blood brain barrier and placental barrier. It is excreted via urine and feces. Hemodialysis increases clear ance of the drug. No studies have been performed for patients under going peritoneal dialysis or for patients with compromised hepatic function. Tinidazole is known to cross the placenta and enter fetal circulation; the safety in pregnancy has not been well evaluated, and alternative agents are preferred. It can also be detected in breast milk, and breastfeeding should be interrupted during treatment and for 3 days after treatment. AtovaquoneProguanil (Malarone) Atovaquone is a hydroxynaphthoquinone and has been used in the past predominantly against Pneumocystis pneumonia in AIDS patients. Its mechanism of action is via disruption of the mitochondria membrane potential through interaction with cytochrome b. How ever, atovaquone can also effectively inhibit liver stages of all Plasmo dium species, and in 2000 the FDA approved atovaquoneproguanil for the prevention and |
8,016 | treatment of acute, uncomplicated Plasmodium falciparum malaria in adults and children 11 kg. Atovaquone alone and in combination with proguanil is the only drug to completely inhibit the liver stage, providing the advantage of only needing to use the drug for 7 days after departing a malaria endemic area (compared with several weeks). Proguanil inhibits the parasite dihydrofolate reductase enzyme by the active form, cycloguanil. When used alone, it has poor efficacy for prophylaxis, but when administered with atovaquone, it acts in synergy on the cytochrome b enzyme in Plasmodia mitochondria, though the exact mechanism of synergy is unknown. Two double blind, randomized clinical trials assessing malaria pro phylaxis demonstrated that atovaquoneproguanil was at least compa rable to (and perhaps better than) chloroquine plus proguanil, and that atovaquoneproguanil was comparable to mefloquine. Atovaquone proguanil was better tolerated than chloroquine plus proguanil and mefloquine. Atovaquoneproguanil treatment of acute uncomplicated P. falciparum infection has demonstrated higher or comparable cure rates when compared with other P. falciparum treatment drugs. Com pared with other antimalarial therapies, atovaquoneproguanil has the highest cost. There are limited data on use during pregnancy, and phar macokinetics may be altered during pregnancy so alternative regimens are preferred for malaria in pregnancy if available. ARTEMISININ DERIVATIVES (ARTEMETHER, ARTESUNATE) AND COMBINATION THERAPIES (ARTEMETHERLUMEFANTRINE OR COARTEM) Artemisinin is a sesquiterpene lactone isolated from the weed Artemisia annua. It was developed in China, where it is known as qinghaosu. Artemisinin and its derivatives act very rapidly against Plasmodium vivax as well as chloroquine sensitive and chloroquine resistant P. falciparum. Artemisinins are also rapidly eliminated. Resistance to artemisinins has been documented in Cambodia, Laos, Myanmar, Thailand, and Vietnam. Coartem is the first artemisinin containing Chapter 325 Principles of Antiparasitic Therapy Beth K. Thielen Section 14 Antiparasitic Therapy 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. 2126 Part XV u Infectious Diseases Table 325.1 Drugs for Parasitic Infections Parasitic infections are found throughout the world. With increasing travel, immigration, use of immunosuppressive drugs, and the spread of HIV, physicians anywhere may see infections caused by previously unfamiliar parasites. This table lists first choice and alternative drugs for most parasitic infections. INFECTION DRUG ADULT DOSAGE PEDIATRIC DOSAGE ACANTHAMOEBA KERATITIS Drug of choice: See footnote1 AMEBIASIS (ENTAMOEBA HISTOLYTICA) Asymptomatic Drug of choice: Iodoquinol (Yodoxin)2 650 mg PO tid 20 days 30 40 mgkgday (max 1950 mg) in 3 doses PO 20 days or Paromomycin 25 35 mgkgday PO in 3 doses 5 10 days 25 35 mgkgday PO in 3 doses 5 10 days Alternative: Diloxanide furoate3 500 mg tid PO 10 days 20 mgkgday PO in 3 doses 10 days Mild to moderate intestinal disease Drug of choice: Metronidazole 500 750 mg tid PO 7 10 days 35 50 mgkgday PO in 3 doses 7 10 days or Tinidazole4 2 g PO once daily 3 days 50 mgkgday PO (max |
8,017 | 2 g) in 1 dose 3 days Either followed by: Iodoquinol2 650 mg PO tid 20 days 30 40 mgkgday PO in 3 doses 20 days (max 2 g) or Paromomycin 25 35 mgkgday PO in 3 doses 7 days 25 35 mgkgday PO in 3 doses 5 10 days Alternative: Nitazoxanide5 500 mg bid 3 days 1 3 yr: 100 mg bid 3 days 4 11 yr: 200 mg bid 3 days 12 yr: use adult dosing Severe intestinal and extraintestinal disease Drug of choice: Metronidazole 750 mg PO tid 7 10 days 35 50 mgkgday PO in 3 doses 7 10 days or Tinidazole4 2 g PO once daily 5 days 50 mgkgday PO (max 2 g) 5 days Either followed by: Iodoquinol2 650 mg PO tid 20 days 30 40 mgkgday PO in 3 doses 20 days (max 2 g) or Paromomycin 25 35 mgkgday PO in 3 doses 510 days 25 35 mgkgday PO in 3 doses 7 days Amebic meningoencephalitis, primary and granulomatous NAEGLERIA FOWLERI Drug of choice: Amphotericin B deoxycholate6,7 1.5 mgkgday IV in 2 divided doses 3 days, then 1 mgkg daily IV 11 days 1.5 mgkgday IV in 2 divided doses 3 days, then 1 mgkg daily IV 11 days plus Amphotericin B deoxycholate6,7 1.5 mgkg intrathecally daily 2 days, then 1 mgkg intrathecally every other day 8 days 1.5 mgkg intrathecally daily 2 days, then 1 mg kg intrathecally every other day 8 days plus Rifampin7 10 mgkg (max 600 mg) IV or PO daily 28 days 10 mgkg (max 600 mg) IV or PO daily 28 days plus Fluconazole7 10 mgkg (max 600 mg) IV or PO daily 28 days 10 mgkg (max 600 mg) IV or PO daily 28 days plus Azithromycin7 500 mg IV or PO daily 28 days 10 mgkg (max 500 mg) IV or PO daily 28 days 1For treatment of keratitis caused by Acanthamoeba, 0.02 topical polyhexamethylene biguanide (PHMB) and 0.02 chlorhexidine have been successfully used individually and in combination in a large number of patients (Tabin G, et al. Cornea. 2001;20:757; Wysenbeek YS, et al. Cornea. 2000;19:464). The expected treatment course is 6 12 mo. PHMB is no longer available from Leiters Park Avenue Pharmacy but is available from the OBrien Pharmacy (1 800 627 4360; distributes in many states) and the Greenpark Pharmacy (1 713 432 9855; Texas only). Combinations with either 0.1 propamidine isethionate (Brolene) or hexamidine (Desomedine) have been used (Seal DV. Eye. 2003;17:893) successfully, but these are not available in the United States. Neomycin is not recommended due to high levels of resistance (Acanthamoeba keratitis: Treatment guidelines from The Medical Letter, 143, 812013). In addition, the combination of chlorhexidine, natamycin (pimaricin), and debridement also has been successful (Kitagawa K, et al. Jpn J Ophthalmol. 2003;47:616). 2The drug is not available commercially but can be compounded by Expert Compounding Pharmacy, 6744 Balboa Blvd, Lake Balboa, CA 91406 (1 800 247 9767 or 1 818 988 7979 or infoexpertpharmacy.org). 3This drug is |
8,018 | not available commercially in the United States. 4A nitroimidazole similar to metronidazole, tinidazole was approved by the FDA in 2004 and appears to be as effective and better tolerated than metronidazole. It should be taken with food to minimize GI adverse effects. For children and patients unable to take tablets, a pharmacist may crush the tablets and mix them with cherry syrup (HUMCO, and others). The syrup suspension is good for 7 days at room temperature and must be shaken before use. Ornidazole, a similar drug, is also used outside the United States. 5Nitazoxanide is FDA approved as a pediatric oral suspension for treatment of Cryptosporidium in immunocompetent children 1 yr of age. It has also been used in some small studies for Balantidium coli infection. It may also be effective for mild to moderate amebiasis (Diaz E, et al. Am J Trop Med Hyg. 2003;68:384; Rossignol JF, et al. Trans R Soc Trop Med Hyg. 2007;101:1025) and as an alternative therapy for microsporidiosis (published dosing for microsporidiosis: Bicart See A, et al. Antimicrob Agents Chemother. 2000;44:167), 2020 CDC Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents with HIV). Nitazoxanide is available in 500 mg tablets and an oral suspension; it should be taken with food. 6Naegleria infection has been treated successfully with IV and intrathecal use of both amphotericin B and miconazole plus rifampin and with amphotericin B, rifampin, and ornidazole (Seidel J, et al. N Engl J Med. 1982;306:346; Jain R, et al. Neurol India. 2002;50:470). Other reports of successful therapy are less well documented. 7An approved drug, but usage is considered off label for this condition by the FDA. 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 325 u Principles of Antiparasitic Therapy 2127 Table 325.1 Drugs for Parasitic Infectionscontd INFECTION DRUG ADULT DOSAGE PEDIATRIC DOSAGE plus Miltefosine68 50 mg PO tid 28 days 45 kg: 50 mg bid (max 2.5 mgkg) 28 days 45 kg: use adult dosing plus dexamethasone 0.6 mgkgday IV in 4 divided doses 4 days 0.6 mgkgday IV in 4 divided doses 4 days ACANTHAMOEBA Drug of choice: See footnote7,8 BALAMUTHIA MANDRILLARIS Drug of choice: See footnote7,9,10 SAPPINIA DIPLOIDEA Drug of choice: See footnote11 ANCYLOSTOMA CANINUM (EOSINOPHILIC ENTEROCOLITIS) Drug of choice: Albendazole7 400 mg PO once 10 kg2 yr12 2 yr: see adult dosing or Mebendazole 100 mg PO bid 3 days 100 mg PO bid 3 days13 or Pyrantel pamoate (OTC)7 11 mgkg PO (max 1 g) 3 days 11 mgkg PO (max 1 g) 3 days or Endoscopic removal ANCYLOSTOMA DUODENALE, (see Hookworm infection) ANGIOSTRONGYLIASIS (ANGIOSTRONGYLUS CANTONENSIS, ANGIOSTRONGYLUS COSTARICENSIS) Drug of choice: See footnote14 ANISAKIASIS (ANISAKIS SPP.) Treatment of choice: Surgical or endoscopic removal Alternative: Albendazole7,15 400 mg PO bid 6 21 days 10 kg2 yr12 2 yr: see adult dosing ASCARIASIS (ASCARIS LUMBRICOIDES, ROUNDWORM) Drug of choice: |
8,019 | Albendazole7 400 mg PO once 10 kg2 yr: see adult dosing12 2 yr: see adult dosing or Mebendazole 100 mg PO bid 3 days or 500 mg PO once 100 mg PO bid 3 days or 500 mg PO once13 or Ivermectin7 150 200 gkg PO once 15 kg: not indicated 15 kg: see adult dosing 8If you have a patient with suspected free living amoeba infection, please contact the CDC Emergency Operations Center at 1 800 CDC INFO to consult with a CDC expert regarding the use of this drug. Miltefosine has been reported to successfully treat primary amebic meningoencephalitis due to Naegleria fowleri, although controlled trials have not been conducted (Linam WM, et al. Pediatrics. 2015;135:e744). 9Strains of Acanthamoeba isolated from fatal granulomatous amebic encephalitis are usually susceptible in vitro to pentamidine, ketoconazole, flucytosine, and (less so) amphotericin B. Chronic Acanthamoeba meningitis has been successfully treated in two children with a combination of oral trimethoprim sulfamethoxazole, rifampin, and ketoconazole (Singhal T, et al. Pediatr Infect Dis. 2001;J 20:623), and in an AIDS patient with fluconazole, sulfadiazine, and pyrimethamine combined with surgical resection of the CNS lesion (Seijo Martinez M, et al. J Clin Microbiol. 2000;38:3892). Disseminated cutaneous infection in an immunocompromised patient has been treated successfully with IV pentamidine isethionate, topical chlorhexidine, and 2 ketoconazole cream, followed by oral itraconazole (Slater CA, et al. N Engl J Med. 1994;331:85). 10A free living leptomyxid ameba that causes subacute to fatal granulomatous CNS disease. Several cases of Balamuthia encephalitis have been successfully treated with flucytosine, pentamidine, fluconazole, and sulfadiazine plus either azithromycin or clarithromycin (phenothiazines were also used) combined with surgical resection of the CNS lesion (Deetz TR, et al. Clin Infect Dis. 2003;37:1304; Jung S, et al. Arch Pathol Lab Med. 2004;128:466). Case reports and in vitro data suggest miltefosine may have some antiamebic activity (Aichelburg AC, et al. Emerg Infect Dis. 2008;14:1743; Martnez DY, et al. Clin Infect Dis. 2010;51:e7; Schuster FL, et al. J Eukaryot Microbiol. 2006;53:121). Miltefosine (Impavido) is now commercially available. Contact the Centers for Disease ControlAgency for Toxic Substances Disease Registry at 1 770 488 7100 or 1 800 232 4636 (main number) for guidance on treatment. 11A free living ameba not previously known to be pathogenic to humans. It has been successfully treated with azithromycin, IV pentamidine, itraconazole, and flucytosine combined with surgical resection of the CNS lesion (Gelman BB, et al. J Neuropathol Exp Neurol. 2003;62:990). 12Limited data in children 2 yr but has been used successfully for treatment of cutaneous larva migrans in children as young as 8 mo at a dose of 200 mg daily 3 days (Black MD, et al. Australas J Dermatol. 2010;51:281). The WHO also recommends albendazole in children 2 yr for treatment of taeniasis, strongyloidiasis, filariasis, hookworms, roundworms, pinworms, and threadworms. 13Limited safety data in children 2 yr of age. 14Most patients have a self limited course and recover completely. Analgesics, corticosteroids, and careful removal of CSF at frequent intervals can relieve symptoms from increased intracranial |
8,020 | pressure (Lo Re V III, Gluckman SJ. Am J Med. 2003;114:217). No anthelmintic drug is proven to be effective, and some patients have worsened with therapy (Slom TJ, et al. N Engl J Med. 2002;346:668). Mebendazole or albendazole and a corticosteroid appeared to shorten the course of infection (Sawanyawisuth K, et al. Trans R Soc Trop Med Hyg. 2008;102:990; Chotmongkol V, et al. Am J Trop Med Hyg. 2009;81:443). 15(Repiso Ortega A, et al. Gastroenterol Hepatol. 2003;26:341.) Successful treatment of a patient with anisakiasis with albendazole has been reported (Moore DA, et al. Lancet. 2002;360:54). Continued 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. 2128 Part XV u Infectious Diseases Table 325.1 Drugs for Parasitic Infectionscontd INFECTION DRUG ADULT DOSAGE PEDIATRIC DOSAGE BABESIOSIS (BABESIA MICROTI) Drugs of choice:16 Atovaquone7 750 mg PO bid 7 10 days 20 mgkg (max 750 mg) PO bid 7 10 days plus azithromycin7 500 1,000 mg once, then 250 mg daily 7 10 days. Higher doses (600 1,000 mg) andor prolonged therapy (6 wk or longer) may be required for immunocompromised patients 10 mgkg PO on day 1 (max 500 mgdose), then 5 mgkgday (max 250 mgdose) PO days 2 10 or Clindamycin7 300 600 mg IV qid or 600 mg tid PO 7 10 days 20 40 mgkgday IV or PO in 3 or 4 doses 7 10 days (max 600 mgdose) plus quinine7 542 mg base (650 mg salt) tid PO 7 10 days 6 mg basekg (8 mg saltkg) (max 542 mg base or 650 mg salt dose), PO tid 7 10 days Balamuthia mandrillaris, see Amebic meningoencephalitis, primary BALANTIDIASIS (BALANTIDIUM COLI) Drug of choice: Tetracycline7,17 500 mg PO qid 10 days 8 yr: not indicated 8 yr: 10 mgkg (max 500 mg) PO qid 10 days Alternatives: Metronidazole7 750 mg PO tid 5 days 35 50 mgkgday PO in 3 divided doses 5 days or Iodoquinol2,7 650 mg PO tid 20 days 30 40 mgkgday (max 2 g) PO in 3 divided doses 20 days or Nitazoxanide5,7 500 mg PO bid 3 days 1 3 yr: 100 mg PO bid 3 days 4 11 yr: 200 mg PO bid 3 days 12 yr: see adult dosing BAYLISASCARIASIS (BAYLISASCARIS PROCYONIS) Drug of choice: Albendazole7,18 400 mg PO bid 10 20 days 10 kg2 yr: 25 50 mgkgday PO in 1 2 divided doses 10 20 days12 2 yr: 25 50 mgkgday PO in 1 2 divided doses 10 20 days BLASTOCYSTIS HOMINIS INFECTION Drug of choice: See footnote19 CAPILLARIASIS (CAPILLARIA PHILIPPINENSIS) Drug of choice: Mebendazole7 200 mg PO bid 20 days 200 mg PO bid 20 days13 Alternative: Albendazole7 400 mg PO daily 10 days 10 kg2 yr 12 15 kg2 yr: see adult dosing CHAGAS DISEASE, SEE TRYPANOSOMIASIS CLONORCHIS SINENSIS, SEE FLUKE INFECTION CRYPTOSPORIDIOSIS (CRYPTOSPORIDIUM PARVUM) Immunocompetent Drug of choice: Nitazoxanide5 500 mg PO bid |
8,021 | 3 days 1 3 yr: 100 mg PO bid 3 days 4 11 yr: 200 mg PO bid 3 days 12 yr: see adult dosing 16Exchange transfusion has been used in severely ill patients and those with high (10) parasitemia (Hatcher JC, et al. Clin Infect Dis. 2001;32:1117). Clindamycin and quinine is the preferred therapy for severely ill patients. In patients who were not severely ill, combination therapy with atovaquone and azithromycin was as effective as clindamycin and quinine and may have been better tolerated (Krause PJ, et al. N Engl J Med. 2000;343:1454). Highly immunosuppressed patients should be treated for a minimum of 6 wk and at least 2 wk past the last positive smear (Krause PJ, et al. Clin Infect Dis. 2008;46:370). High doses of azithromycin (600 1,000 mg) have been used in combination with atovaquone for the treatment of immunocompromised patients (Weiss LM, et al. N Engl J Med. 2001;344:773). Resistance to atovaquone plus azithromycin has been reported in immunocompromised patients treated with a single subcurative course of this regimen (Wormser GP, et al. Clin Infect Dis. 2010;50:381). Most asymptomatic patients do not require treatment unless parasitemia persists 3 mo (Wormser GP, et al. Clin Infect Dis. 2006;43:1089). 17Use of tetracyclines has historically been contraindicated in pregnancy and in children younger than 8 yr. The American Academy of Pediatrics now recommends that doxycycline can be administered for short durations (i.e., 21 days or less) without regard to the patients age (Kimberlin DW, et al. Red Book: 2021 2024 Report of the Committee on Infectious Diseases. 32nd ed. Elk Grove Village, IL: American Academy of Pediatrics; 2021. p 866). 18No drugs have been consistently demonstrated to be effective. The combination of albendazole 37 mgkgday PO and high dose steroids has been used successfully (Peters JM, et al. Pediatrics. 2012;129:e806; Haider S. Emerg Infect Dis. 2012;18:347). Albendazole 25 mgkgday PO 20 days started as soon as possible (up to 3 days after possible infection) might prevent clinical disease and is recommended for children with known exposure, as in the setting of ingestion of raccoon stool or contaminated soil (Murray WJ, et al. Clin Infect Dis. 2004;39:1484). Mebendazole, levamisole, or ivermectin could be tried if albendazole is not available. Ocular baylisascariasis has been treated successfully using laser photocoagulation therapy to destroy the intraretinal larvae. 19Clinical significance of these organisms is controversial; metronidazole 750 mg tid 10 days, iodoquinol 650 mg tid 20 days, or trimethoprim sulfamethoxazole 1 DS tablet bid 7 days has been reported to be effective (Stenzel DJ, et al. Clin Microbiol Rev. 1996;9:563; Ok UZ, et al. Am J Gastroenterol. 1999;94:3245). Metronidazole resistance may be common (Haresh K, et al. Trop Med Int Health. 1999;4:274). Nitazoxanide has been effective in children (Diaz E, et al. Am J Trop Med Hyg. 2003;68:384). 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 325 |
8,022 | u Principles of Antiparasitic Therapy 2129 Table 325.1 Drugs for Parasitic Infectionscontd INFECTION DRUG ADULT DOSAGE PEDIATRIC DOSAGE HIV infected Drug of choice: See footnote20 CUTANEOUS LARVA MIGRANS (ANCYLOSTOMA BRAZILIENSE, ANCYLOSTOMA CANINUM, DOG AND CAT HOOKWORM, CREEPING ERUPTION) Drug of choice: Albendazole7,21 400 mg PO daily 3 7 days 10 kg2 yr: 200 mg PO daily 3 days12 2 yr: see adult dosing or Ivermectin7 200 gkg PO daily 1 2 days 15 kg: not indicated 15 kg: see adult dosing Alternative: Thiabendazole Apply topically tid 7 days Apply topically tid 7 days CYCLOSPORIASIS (CYCLOSPORA CAYETANENSIS) Drug of choice: Trimethoprim sulfamethoxazole (TMP SMX)7,22 TMP 160 mgSMX 800 mg (1 DS tab) PO bid 7 10 days 4 5 mgkg TMP component (max 160 mg) PO bid 7 10 days CYSTICERCOSIS, SEE TAPEWORM INFECTION CYSTOISOSPORIASIS (CYSTOISOSPORA BELLI, FORMERLY KNOWN AS ISOSPORA BELLI) Drug of choice: TMP SMX7 TMP 160 mgSMX 800 mg (1 DS tab) PO bid 10 days 4 5 mgkg TMP component (max 160 mg) PO bid 10 days Alternative: Pyrimethamine 50 75 mg PO divided bid x 10 days plus leucovorin 10 25 mg PO daily 10 days or Ciprofloxacin7 500 mg PO bid 7 10 days Dientamoeba fragilis infection23 Paromomycin7 25 35 mgkgday PO in 3 doses 7 days 25 35 mgkgday PO in 3 divided doses 7 days or Iodoquinol2 650 mg PO tid 20 days 30 40 mgkgday PO (max 2 g) in 3 divided doses 20 days or Metronidazole7 500 750 mg tid 10 days 35 50 mgkgday in 3 divided doses 10 days DIPHYLLOBOTHRIUM LATUM, SEE TAPEWORM INFECTION DRACUNCULUS MEDINENSIS (GUINEA WORM) INFECTION Treatment of choice: Slow mechanical extraction of worm24 ECHINOCOCCUS, SEE TAPEWORM INFECTION ENTAMOEBA HISTOLYTICA, SEE AMEBIASIS ENTEROBIUS VERMICULARIS (PINWORM) INFECTION25 Drug of choice: Albendazole7 400 mg PO once; repeat in 2 wk 10 kg2 yr: 200 mg PO once; repeat in 2 wk12 2 yr: see adult dosing or Mebendazole 100 mg PO once; repeat in 3 wk 100 mg PO once; repeat in 3 wk13 or Pyrantel pamoate (OTC) 11 mgkg base PO once (max 1 g); repeat in 2 wk 11 mgkg base PO once (max 1 g); repeat in 2 wk 20Nitazoxanide has not consistently been shown to be superior to placebo in HIV infected patients (Amadi B, et al. Lancet. 2002;360;1375). For HIV infected patients, potent antiretroviral therapy (ART) is the mainstay of treatment. Nitazoxanide 500 1,000 mg for 14 days, paromomycin 500 mg 4 times daily 14 21 days, or a combination of paromomycin and azithromycin may be tried to decrease diarrhea and recalcitrant malabsorption of antimicrobial drugs, which can occur with chronic cryptosporidiosis (Pantenburg B, et al. Expert Rev Anti Infect Ther. 2009;7:385). 21Albanese G, et al. Int J Dermatol. 2001;40:67. 22HIV infected patients may need a higher dosage and long term maintenance (Kansouzidou A, et al. J Trav Med. 2004;11:61). 23Norberg A, et al. Clin Microbiol Infect. 2003;9:65. 24Treatment of choice is slow extraction of worm combined with wound care (MMWR Morbid Mortal |
8,023 | Wkly Rep. 2011;60:1450). Instructions for this can be found at https:www.cdc.g ovparasitesguineawormtreatment.html. Ten days of treatment with metronidazole 250 mg tid in adults and 25 mgkgday in 3 doses in children is not curative, but it decreases inflammation and facilitates removal of the worm. Mebendazole 400 800 mgday 6 days has been reported to kill the worm directly. 25Because all family members are usually infected, treatment of the entire household is recommended. Continued 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. 2130 Part XV u Infectious Diseases Table 325.1 Drugs for Parasitic Infectionscontd INFECTION DRUG ADULT DOSAGE PEDIATRIC DOSAGE FASCIOLA HEPATICA, SEE FLUKE INFECTION FILARIASIS26 Lymphatic filariasis (Wuchereria bancrofti, Brugia malayi, Brugia timori) Drug of choice:27 Diethylcarbamazine28,29 6 mgkg once or 6 mgkg PO in 3 divided doses 12 days30 18 mo: no indication 18 mo: see adult dosing LOA LOA 8,000 microfilariamL29 Drug of choice: Diethylcarbamazine28,29 9 mgkg PO in 3 doses 14 days30 18 mo: no indication 18 mo: see adult dosing Alternatives: Albendazole28 200 mg PO bid 21 days 10 kg2 yr12 2 yr: see adult dosing 8,000 microfilariamL29,31 Treatment of choice: Apheresis or Albendazole28 200 mg PO bid 21 days 10 kg2 yr12 2 yr: see adult dosing Either followed by: Diethylcarbamazine28,29 8 10 mgkg PO in 3 doses 21 days30 18 mo: no indication 18 mo: see adult dosing MANSONELLA OZZARDI Drug of choice: See footnote32 MANSONELLA PERSTANS Drug of choice: Doxycycline7,17,33 100 mg bid PO 6 wk 4 mgkgday in 2 doses PO 6 wk MANSONELLA STREPTOCERCA34 Drug of choice: Diethylcarbamazine28 6 mgkgday PO 14 days 6 mgkgday PO 14 days or Ivermectin7 150 gkg PO once 15 kg: not indicated 15 kg: see adult dosing TROPICAL PULMONARY EOSINOPHILIA (TPE)35 Drug of choice: Diethylcarbamazine28 6 mgkg once or 6 mgkg PO in 3 divided doses 14 21 days27 18 mo: no indication 18 mo: see adult dosing 26Antihistamines or corticosteroids may be required to decrease allergic reactions due to disintegration of microfilariae from treatment of filarial infections, especially those caused by Loa loa. Endosymbiotic Wolbachia bacteria may have a role in filarial development and host response and may represent a new target for therapy. Treatment with doxycycline 100 or 200 mgday 4 6 wk in lymphatic filariasis and onchocerciasis has resulted in substantial loss of Wolbachia with subsequent blocking of microfilariae production and absence of microfilaria when followed for 24 mo after treatment (Hoerauf A, et al. Med Microbiol Immunol. 2003;192:211; Hoerauf A, et al. BMJ. 2003;326:207). 27Most symptoms caused by adult worm. Single dose combination of albendazole (400 mg) with either ivermectin (200 gkg) or diethylcarbamazine (6 mgkg) is effective for reduction or suppression of Wuchereria bancrofti microfilaria but does not kill the adult forms (Addiss D, et al. Cochrane Database Syst Rev. 2004;(1):CD003753). 28This drug is not FDA approved and not commercially available but is available |
8,024 | under IND application through the CDC Drug Service (CDC Drug Service, Division of Scientific Resources, telephone at 1 404 639 3670). 29Diethylcarbamazine is contraindicated in patients co infected with Onchocerca volvulus due to risk of a life threatening Mazzotti reaction and in patients with Loa loa infection and microfilaria levels 8,000 mm3 due to risk of encephalopathy and renal failure. Some experts use a cutoff of 2,500 mm3. 30For patients with microfilaria in the blood, Medical Letter consultants would start with a lower dosage and scale up: day 1, 50 mg; day 2, 50 mg tid; day 3, 100 mg tid; day 4 14, 6 mgkg in 3 doses (for Loa loa, day 4 14, 9 mgkg in 3 doses). Multidose regimens have been shown to provide more rapid reduction in microfilaria than single dose diethylcarbamazine, but microfilaria levels are similar 6 12 mo after treatment (Andrade LD, et al. Trans R Soc Trop Med Hyg. 1995;89:319; Simonsen PE, et al. Am J Trop Med Hyg. 1995;53:267). A single dose of 6 mgkg is used in endemic areas for mass treatment (Figueredo Silva J, et al. Trans R Soc Trop Med Hyg. 1996;90:192; Noroes J, et al. Trans R Soc Trop Med Hyg. 1997;91:78). 31In heavy infections with Loa loa, rapid killing of microfilariae can provoke encephalopathy. Apheresis has been reported to be effective in lowering microfilarial counts in patients heavily infected with Loa loa (Ottesen EA. Infect Dis Clin North Am. 1993;7:619). Albendazole or ivermectin has also been used to reduce microfilaremia; albendazole is preferred because of its slower onset of action and lower risk for encephalopathy (Klion AD, et al. J Infect Dis. 1993;168:202; Kombila M, et al. Am J Trop Med Hyg. 1998;58:458). Albendazole may be useful for treatment of loiasis when diethylcarbamazine is ineffective or cannot be used, but repeated courses may be necessary (Klion AD, et al. Clin Infect Dis. 1999;29:680). Diethylcarbamazine, 300 mg once a week, has been recommended for prevention of loiasis (Nutman TB, et al. N Engl J Med. 1988;319:752). 32Diethylcarbamazine has no effect. Ivermectin 200 gkg once has been effective. 33Doxycycline is preferred for strains that carry Wolbachia bacteria. Combination therapy with diethylcarbamazine and mebendazole and monotherapy with mebendazole have been used successfully in strains that do not carry Wolbachia. Evidence is limited, and optimal therapy is uncertain. Ivermectin and albendazole appear to be ineffective. 34Diethylcarbamazine is potentially curative because of activity against both adult worms and microfilariae. Ivermectin is only active against microfilariae. (The Medical Letter: Drugs for parasitic infections, vol 11, 2013.) 35Relapse occurs and can be treated with diethylcarbamazine. 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 325 u Principles of Antiparasitic Therapy 2131 Table 325.1 Drugs for Parasitic Infectionscontd INFECTION DRUG ADULT DOSAGE PEDIATRIC DOSAGE ONCHOCERCA VOLVULUS (RIVER BLINDNESS) Drug of choice: Ivermectin36 150 gkg PO once, repeated every 6 |
8,025 | 12 mo until asymptomatic 15 kg: not indicated 15 kg: see adult dosing FLUKE, HERMAPHRODITIC, INFECTION Clonorchis sinensis (Chinese liver fluke) Drug of choice: Praziquantel 25 mgkg PO tid 2 day 25 mgkg PO tid 2 day37 or Albendazole7 10 mgkg PO 7 days 10 kg2 yr12 2 yr: see adult dosing Fasciola hepatica (sheep liver fluke) Drug of choice: Triclabendazole7,38,39 10 mgkg PO once or twice 10 mgkg PO once or twice Alternative: Nitazoxanide7 500 mg PO bid 7 days 1 3 yr: 100 mg PO bid 4 11 yr: 200 mg PO bid 2 yr: see adult dosing or Bithionol3,7 30 50 mgkg PO on alternate days 10 15 doses 30 50 mgkg PO on alternate days 10 15 doses Fasciolopsis buski, Heterophyes heterophyes, Metagonimus yokogawai (intestinal flukes) Drug of choice: Praziquantel7 25 mgkg PO tid 1 day 25 mgkg PO tid 1 day37 Metorchis conjunctus (North American liver fluke)40 Drug of choice: Praziquantel7 25 mgkg PO tid 1 day 25 mgkg PO tid 1 day37 Nanophyetus salmincola Drug of choice: Praziquantel7 20 mgkg PO tid 1 day 20 mgkg PO tid 1 day37 Opisthorchis viverrini (Southeast Asian liver fluke), Opisthorchis felineus (cat liver fluke) Drug of choice: Praziquantel 25 mgkg PO tid 2 days 25 mgkg PO tid 2 days37 or Albendazole7 10 mgkg PO 7 days 10 kg2 yr12 2 yr: see adult dosing Paragonimus westermani (lung fluke) Drug of choice: Praziquantel7 25 mgkg PO tid 2 days 25 mgkg PO tid 2 days37 or Triclabendazole7,41 10 mgkg PO bid 1 day or 5 mgkg daily 3 days 10 mgkg PO bid 1 day or 5 mgkg daily 3 days or Bithionol3,7 30 50 mgkg PO on alternate days 10 15 doses 30 50 mgkg PO on alternate days 10 15 doses GIARDIASIS (GIARDIA INTESTINALIS, ALSO KNOWN AS GIARDIA DUODENALIS OR GIARDIA LAMBLIA) Drugs of choice: Metronidazole7 250 mg PO tid 5 days 5 mgkg (max 250 mg) PO tid 5 days or Nitazoxanide5 500 mg PO bid 3 days 1 3 yr: 100 mg PO every 12 hr 3 days 4 11 yr: 200 mg PO every 12 hr 3 days 12 yr: see adult dosing 36Annual treatment with ivermectin, 150 gkg, can prevent blindness from ocular onchocerciasis (Mabey D, et al. Ophthalmology. 1996;103:1001). Ivermectin kills only the microfilaria but not the adult worms; emerging evidence suggests doxycycline is effective in killing adult worms and sterilizing females. The recommended regimen from the CDC is doxycycline 100 200 mg PO daily for 6 wk begun 1 wk after a dose of ivermectin is given to reduce the microfilaria burden. Diethylcarbamazine and suramin were formerly used for treatment of this disease but should no longer be used because of the availability of less toxic therapies. 37Limited safety data in children 4 yr of age but has been used in mass prevention campaigns with no reported adverse effects. 38Unlike infections with other flukes, Fasciola hepatica infections do not respond to praziquantel. Triclabendazole may be safe and effective, but |
8,026 | data are limited (Graham CS, et al. Clin Infect Dis. 2001;33:1). In the United States, the drug is not approved by the FDA and is not yet commercially available. However, it is available to physicians licensed in the United States through the CDC Drug Service, under a special protocol, which requires that both the CDC and FDA agree that the drug is indicated for treatment of a particular patient. Providers should contact the CDC Drug Service, Division of Scientific Resources, at 1 404 639 3670. It is available from Victoria Pharmacy, Zurich, Switzerland (www.pharmaworld.com). The drug should be given with food for better absorption. A single study has found that nitazoxanide has limited efficacy for treating fascioliasis in adults and children (Favennec L, et al. Aliment Pharmacol Ther. 2003;17:265). 39Richter J, et al. Curr Treat Options Infect Dis. 2002;4:313. 40MacLean JD, et al. Lancet. 1996;347:154. 41Triclabendazole may be effective in a dosage of 5 mgkg once a day 3 days or 10 mgkg bid 1 day (Calvopia M, et al. Trans R Soc Trop Med Hyg. 1998;92:566). In the United States, it is not approved by the FDA and is not yet commercially available. However, it is available to physicians licensed in the United States through the CDC Drug Service, under a special protocol, which requires both the CDC and FDA to agree that the drug is indicated for treatment of a particular patient. Providers should contact the CDC Drug Service, Division of Scientific Resources, at 1 404 639 3670. The drug is available from Victoria Pharmacy, Zurich, Switzerland; Phone, 41 43 344 60 60; FAX, 41 43 344 60 69; http:www.pharmaworld.com; e mail, infopharmaworld.com. Continued 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. 2132 Part XV u Infectious Diseases Table 325.1 Drugs for Parasitic Infectionscontd INFECTION DRUG ADULT DOSAGE PEDIATRIC DOSAGE GIARDIASIS (GIARDIA INTESTINALIS, ALSO KNOWN AS GIARDIA DUODENALIS OR GIARDIA LAMBLIA) Drugs of choice: Metronidazole7 250 mg PO tid 5 days 5 mgkg (max 250 mg) PO tid 5 days or Tinidazole4 2 g PO once 50 mgkg PO once (max 2 g) Alternatives42 Paromomycin7,43 25 35 mgkgday PO in 3 doses 7 days 25 35 mgkgday PO in 3 doses 7 days or Furazolidone3 100 mg PO qid 7 10 days 6 mgkgday PO in 4 doses 7 10 days or Quinacrine2 100 mg PO tid 5 days 2 mgkg tid PO 5 days (max 300 mgday) GNATHOSTOMIASIS (GNATHOSTOMA SPINIGERUM) Treatment of choice:44 Albendazole7 400 mg PO bid 21 days 10 kg2 yr12 2 yr: see adult dosing or Ivermectin7 200 gkgday PO 2 days 15 kg: not indicated 15 kg: see adult dosing Surgical removal GONGYLONEMIASIS (GONGYLONEMA SP. )45 Treatment of choice: Surgical removal or Albendazole7 400 mg PO daily 3 days 10 mgkgday PO 3 days HOOKWORM INFECTION (ANCYLOSTOMA DUODENALE, NECATOR AMERICANUS) Drug of choice: Albendazole7 400 mg PO |
8,027 | once 10 kg2 yr12 2 yr: see adult dosing or Mebendazole 100 mg PO bid 3 days or 500 mg once 100 mg PO bid 3 days or 500 mg once13 or Pyrantel pamoate (OTC)7 11 mgkg (max 1 g) PO 3 days 11 mgkg (max 1 g) PO 3 days HYDATID CYST, SEE TAPEWORM INFECTION HYMENOLEPIS NANA, SEE TAPEWORM INFECTION LEISHMANIA INFECTION46 Visceral47 Drugs of choice: Liposomal amphotericin B (AmBisome)48,49 3 mgkgday IV on days 1 5, 14, and 21 (total dose 21 mgkg) 3 mgkgday IV on days 1 5, 14, and 21 (total dose 21 mgkg) or Miltefosine50 30 44 kg: 50 mg PO bid 28 days 12 yr: 2.5mgkg daily 28 days7 45 kg: 50 mg PO tid 28 days 12 yr: see adult dosing or Sodium stibogluconate (Pentostam)28,51 20 mg Sbkgday IV or IM 28 days 20 mg Sbkgday IV or IM 28 days or Amphotericin B deoxycholate7 1 mgkg IV daily or every 2 days for 15 20 doses 1 mgkg IV daily or every 2 days for 15 20 doses 42Albendazole 400 mg daily 5 days alone or in combination with metronidazole may also be effective (Hall A, et al. Trans R Soc Trop Med Hyg. 1993;87:84; Dutta AK, et al. Indian J Pediatr. 1994;61:689; Cacopardo B, et al. Clin Ter. 1995;146:761). Combination treatment with standard doses of metronidazole and quinacrine given for 3 wk has been effective for a small number of refractory infections (Nash TE, et al. Clin Infect Dis. 2001;33:22). In one study, nitazoxanide was used successfully in high doses to treat a case of Giardia infection resistant to metronidazole and albendazole (Abboud P, et al. Clin Infect Dis. 2001;32:1792). 43Not absorbed; may be useful for treatment of giardiasis in pregnancy. 44de Gorgolas M, et al. J Travel Med. 2003;10:358. All patients should be treated with a medication regardless of whether surgery is attempted. 45Eberhard ML, et al. Am J Trop Med Hyg. 1999;61:51; Wilson ME, et al. Clin Infect Dis. 2001;32:1378. 46Consultation with physicians experienced in management of this disease is recommended. To maximize effectiveness and minimize toxicity, the choice of drug, dosage, and duration of therapy should be individualized based on the region of disease acquisition, likely infecting species, number, significance and location of lesions, and host factors such as immune status (Murray HW. Lancet. 2005;366:1561; Aronson N, et al. Clin Infect Dis. 2016;63:e202). Some of the listed drugs and regimens are effective only against certain Leishmania speciesstrains and only in certain areas of the world (Sundar S, et al. Expert Opin Pharmacother. 2013;14:53). 47Visceral infection is most commonly caused by the Old World species Leishmania donovani (kala azar) and Leishmania infantum and the New World species Leishmania chagasi. Treatment duration may vary based on symptoms, host immune status, species, and area of the world in which the infection was acquired. Liposomal amphotericin B is the treatment of choice in the IDSA leishmaniasis guidelines (Aronson N, et al. Clin Infect Dis. 2016;63:e202). 48Three lipid formulations of amphotericin B |
8,028 | have been used for treatment of visceral leishmaniasis. Largely based on clinical trials in patients infected with Leishmania infantum, the FDA approved liposomal amphotericin B (AmBisome) for treatment of visceral leishmaniasis (Meyerhoff A. Clin Infect Dis. 1999;28:42). Amphotericin B lipid complex (Abelcet) and amphotericin B cholesteryl sulfate (Amphotec) have also been used with good results but are considered investigational for this condition by the FDA. 49The FDA approved dosage regimen for immunocompromised patients (e.g., HIV infected) is 4 mgkgday on days 1 5 and 4 mgkgday on days 10, 17, 24, 31, and 38. The relapse rate is high; maintenance therapy may be indicated, but there is no consensus as to dosage or duration. (Russo R, et al. J Infect. 1996;32:133). 50For treatment of kala azar in adults in India, oral miltefosine 100 mgday (205 mgkgday) for 3 4 wk was 97 effective after 6 mo (Jha TK, et al. N Engl J Med. 1999;341:1795; Sangraula H, et al. J Assoc Physicians India. 2003;51:686). GI adverse effects are common, and the drug is contraindicated in pregnancy. The dose of miltefosine in an open label trial in children in India was 2.5 mgkgday 28 days (Bhattacharya SK, et al. Clin Infect Dis. 2004;38:217). Miltefosine (Impavido) has been approved by the FDA for treatment of leishmaniasis due to Leishmania donovani; cutaneous leishmaniasis due to L. braziliensis, Leishmania guyanensis, and Leishmania panamensis, and mucosal leishmaniasis due to L. braziliensis since 2014 and is now commercially available. 51May be repeated or continued; a longer duration may be needed for some patients (Herwaldt BL. Lancet. 1999;354:1191). 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 325 u Principles of Antiparasitic Therapy 2133 Table 325.1 Drugs for Parasitic Infectionscontd INFECTION DRUG ADULT DOSAGE PEDIATRIC DOSAGE Alternative: Meglumine antimonate3,51 20 mg pentavalent antimonykgday IV or IM 28 days 20 mg pentavalent antimonykgday IV or IM 28 days or Pentamidine7 4 mgkg IV or IM daily or every 2 days for 15 30 doses 4 mgkg IV or IM daily or every 2 days for 15 30 doses Cutaneous52,53 Drugs of choice: Sodium stibogluconate28,51 20 mg Sbkgday IV or IM 20 days 20 mg Sbkgday IV or IM 20 days or Liposomal amphotericin B (AmBisome)7 3 mgkgday IV on days 1 5 and 10 or 1 7 (total dose 18 21 mgkg) 3 mgkgday IV on days 1 5 and 10 or 1 7 (total dose 18 21 mgkg) or Amphotericin B deoxycholate7 0.5 1 mgkg IV daily or every 2 days (total dose 15 30 mgkg) 0.5 1 mgkg IV daily or every 2 days (total dose 15 30 mgkg) or Miltefosine50 30 44 kg: 50 mg PO bid 28 days 12 yr: 2.5mgkg daily 28 days7 45 kg: 50 mg PO tid x 28 days 12 yr: see adult dosing Alternatives: Meglumine antimonate3,51 20 mg pentavalent antimonykgday IV or IM |
8,029 | 20 days 20 mg pentavalent antimonykgday IV or IM 20 days or Pentamidine7,54 3 4 mgkg IV or IM every 2 days 3 4 doses 2 3 mgkg IV or IM daily or every 2 days 4 7 doses or Paromomycin7,55 Topically 2day 10 20 days Topically 2day 10 20 days or Ketoconazole7 600 mg daily 28 days or Fluconazole7 200 mg daily 6 wk or Local therapy including cryotherapy, thermotherapy, intralesional SbV, topical paromomycin, photodynamic or laser therapy Mucosal56 Drugs of choice: Sodium stibogluconate28,51 20 mg Sbkgday IV or IM 28 days 20 mg Sbkgday IV or IM 28 days or Liposomal amphotericin B (AmBisome)7 3 mgkgday IV 10 days or 4 mgkg days 1 5, 10, 17, 24, 31, and 38 (total dose 20 60 mgkg) 2 4 mgkgday IV 10 days or 4 mgkg days 1 5, 10, 17, 24, 31, and 38 (total dose 20 60 mgkg) or Amphotericin B deoxycholate7 0.5 1 mgkg IV daily or every 2 days (total dose 20 45 mgkg) 0.5 1 mgkg IV daily or every 2 days (total dose 20 45 mgkg) or Miltefosine50 30 44 kg: 50 mg PO bid 28 days 12 yr: 2.5 mgkg daily 28 days7 45 kg: 50 mg PO tid 28 days 12 yr: see adult dosing Alternative: Meglumine antimonate3,51 20 mg pentavalent antimonykgday IV or IM 28 days 20 mg pentavalent antimonykgday IV or IM 28 days LICE (HEAD AND BODY) INFESTATION (PEDICULUS HUMANUS CAPITIS, PEDICULUS HUMANUS HUMANUS) Drugs of choice: 0.5 Malathion (Ovide)57 Topically 2, 1 wk apart Topically 2, 1 wk apart, approved for 6 yr or 1 Permethrin (Nix) (OTC)57 Topically 2, 1 wk apart Topically 2, 1 wk apart, approved for 2 mo or Pyrethrins with piperonyl butoxide (A 200, Proto, RC, Rid, Triple X) (OTC)58 Topically 2, 1 wk apart Topically 2, 1 wk, approved for 2 yr 52Cutaneous infection is most commonly caused by the Old World species Leishmania major and Leishmania tropica and the New World species Leishmania mexicana, Leishmania (Viannia) braziliensis, and others. Treatment duration may vary based on symptoms, host immune status, species, and area of the world where infection was acquired. 53In a placebo controlled trial in patients 12 yr old and older, oral miltefosine was effective for the treatment of cutaneous leishmaniasis caused by Leishmania (Viannia) panamensis in Colombia but not Leishmania (Viannia) braziliensis in Guatemala at a dosage of about 2.5 mgkgday for 28 days. Motion sickness, nausea, headache, and increased creatinine were the most frequent adverse effects (Soto J, et al. Clin Infect Dis. 2004;38:1266). For treatment of Leishmania major cutaneous lesions, a study in Saudi Arabia found that oral fluconazole, 200 mg onceday 6 wk, appeared to speed healing (Alrajhi AA, et al. N Engl J Med. 2002;346:891). 54At this dosage, pentamidine has been effective against leishmaniasis in Colombia, where the likely organism was Leishmania (Viannia) panamensis (Soto Mancipe J, et al. Clin Infect Dis. 1993;16:417; Soto J, et al. Am J Trop Med Hyg. 1994;50:107); its effect |
8,030 | against other species is not well established. Updated based on Leishmania practice guidelines (Aronson N, et al. Clin Infect Dis. 2016;63:e202). 55Topical paromomycin should be used only in geographic regions where cutaneous leishmaniasis species have low potential for mucosal spread. A formulation of 15 paromomycin12 methylbenzethonium chloride (Leshcutan) in soft white paraffin for topical use has been reported to be partially effective in some patients against cutaneous leishmaniasis due to Leishmania major in Israel and against Leishmania mexicana and Leishmania (Viannia) braziliensis in Guatemala, where mucosal spread is very rare (Arana BA, et al. Am J Trop Med Hyg. 2001;65:466). Methylbenzethonium is irritating to the skin; lesions may worsen before they improve. 56Mucosal infection is most commonly due to the New World species Leishmania (Viannia) braziliensis, Leishmania (Viannia) panamensis, or Leishmania (Viannia) guyanensis. Treatment duration may vary based on symptoms, host immune status, species, and area of the world where infection was acquired. 57Yoon KS, et al. Arch Dermatol. 2003;139:994. Continued 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. 2134 Part XV u Infectious Diseases Table 325.1 Drugs for Parasitic Infectionscontd INFECTION DRUG ADULT DOSAGE PEDIATRIC DOSAGE or 0.5 Ivermectin lotion (Sklice) Topically, once Topically once, approved for 6 mo or 0.9 Spinosad suspension (Natroba) Topically once, second dose in 1 wk if live adult lice seen Topically once, second dose in 1 wk if live adult lice seen, approved for 6 mo or Ivermectin7,59 200 400 gkg PO 2, 1 wk apart 15 kg: not indicated 15 kg: see adult dosing or 5 Benzyl alcohol lotion (Ulesfia) Topically 2, 1 wk apart Topically 2, 1 wk apart LICE (PUBIC) INFESTATION (PHTHIRUS PUBIS)60 Drugs of choice: 1 Permethrin (Nix) (OTC)57 Topically 2, 1 wk apart Topically 2, 1 wk apart, approved for 2 mo or Pyrethrins with piperonyl butoxide (A 200, Proto, RC, Rid, Triple X) (OTC)53 Topically 2, 1 wk apart Topically 2, 1 wk apart, approved for 2 yr or 0.5 Malathion (Ovide)57 Topically 2, 1 wk apart Topically 2, 1 wk apart, approved for 6 yr or 0.5 Ivermectin lotion (Sklice) Topically, once Topically once, approved for 6 mo or Ivermectin7,59 200 400 gkg PO 2, 1 wk apart 15 kg: not indicated 15 kg: see adult dosing LOA LOA, SEE FILARIASIS MALARIA (PLASMODIUM FALCIPARUM, PLASMODIUM OVALE, PLASMODIUM VIVAX, AND PLASMODIUM MALARIAE) TREATMENT Uncomplicated infection due to P. falciparum or species not identified acquired in areas of chloroquine resistance or unknown resistance61 Drugs of choice:62 Atovaquoneproguanil (Malarone) Adult tabs: 50 mg atovaquone100 mg proguanil Pediatric tabs 62.5 mg atovaquone25 mg proguanil)63 4 adult tabs PO once daily or 2 adult tabs PO bid 3 days64 5 kg: not indicated 5 8 kg: 2 pediatric tabs PO daily 3 days 9 10 kg: 3 pediatric tabs PO daily 3 days 11 20 kg: 1 adult tab PO daily 3 days 21 30 |
8,031 | kg: 2 adult tabs PO daily 3 days 31 40 kg: 3 adult tabs PO daily 3 days 40 kg: 4 adult tabs PO daily 3 days or Coartem (artemether lumefantrine) Fixed dose of 20 mg artemether and 120 mg lumefantrine per tablet 4 tablets per dose. A 3 day treatment schedule with a total of 6 oral doses is recommended for both adult and pediatric patients based on weight. These 6 doses should be administered over 3 days at 0, 8, 24, 36, 48, and 60 hr 5 to 15 kg: 1 tablet PO per dose 15 to 25 kg: 2 tablets PO per dose 25 to 35 kg: 3 tablets per dose 35 kg: 4 tablets PO per dose 58A second application is recommended 1 wk later to kill hatching progeny. Lice are increasingly demonstrating resistance to pyrethrins and permethrin (Meinking TL, et al. Arch Dermatol. 2002;138:220). Ivermectin lotion 0.5 was approved by the FDA in 2012 for treatment of head lice in persons 6 mo of age and older. It is not ovicidal, but it appears to prevent nymphs from surviving. It is effective in most patients when given as a single application on dry hair without nit combing (www.cdc.govparasitesliceheadtreatment.html). 59Ivermectin is effective against adult lice but has no effect on nits (Jones KN, et al. Clin Infect Dis. 2003;36:1355). 60For infestation of eyelashes with Phthirus pubis lice, use petrolatum; Trimethoprim sulfamethoxazole (TMP SMX) has also been used (Meinking TL. Curr Probl Dermatol. 1996;24:157). For pubic lice, treat with 5 permethrin or ivermectin as for scabies. TMP SMX has also been effective, together with permethrin for head lice (Hipolito RB, et al. Pediatrics. 2001;107:E30). 61Chloroquine resistant Plasmodium falciparum occurs in all malarious areas except Central America west of the Panama Canal Zone, Mexico, Haiti, the Dominican Republic, and most of the Middle East (chloroquine resistance has been reported in Yemen, Oman, Saudi Arabia, and Iran). For treatment of multidrug resistant P. falciparum in Southeast Asia, especially Thailand, where resistance to mefloquine is frequent, atovaquoneproguanil, artesunate plus mefloquine, or artemether plus mefloquine may be used (Luxemburger C, et al. Trans R Soc Trop Med Hyg. 1994;88:213; Karbwang J, et al. Trans R Soc Trop Med Hyg. 1995;89:296). 62Uncomplicated or mild malaria may be treated with oral drugs. 63To enhance absorption and reduce nausea and vomiting, it should be taken with food or a milky drink. Safety in pregnancy is unknown, and use is generally not recommended. In a few small studies, outcomes were normal in women treated with the combination in the second and third trimesters (Paternak B, et al. Arch Intern Med. 2011;171:259; Boggild AK, et al. Am J Trop Med Hyg. 2007;76:208). The drug should not be given to patients with severe renal impairment (creatinine clearance 30 mLmin). There have been isolated case reports of resistance in Plasmodium falciparum in Africa, but Medical Letter consultants do not believe there is a high risk for acquisition of Malarone resistant disease (Schwartz E, et al. Clin Infect Dis. |
8,032 | 2003;37:450; Farnert A, et al. BMJ. 2003;326:628; Kuhn S, et al. Am J Trop Med Hyg. 2005;72:407; Happi C, et al. Malar J. 2006;5:82). 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 325 u Principles of Antiparasitic Therapy 2135 Table 325.1 Drugs for Parasitic Infectionscontd INFECTION DRUG ADULT DOSAGE PEDIATRIC DOSAGE or Quinine sulfate 542 mg base (650 mg salt) PO tid 3 7 days64 8.3 mg basekg (10 mg saltkg) PO tid 3 7 days65 plus doxycycline7,17 100 mg PO bid 7 days 4 mgkgday PO in 2 doses 7 days or plus tetracycline7,17 250 mg PO qid 7 days 6.25 mgkg PO qid 7 days or plus clindamycin7,66 20 mgkgday PO in 3 divided doses 7 days67 20 mgkgday PO in 3 doses 7 days Alternative: Mefloquine68,69 750 mg PO followed 12 hr later by 500 mg 15 mgkg PO followed 12 hr later by 10 mgkg Uncomplicated infection due to P. falciparum or species not identified acquired in areas of chloroquine sensitivity or uncomplicated P. malariae or P. knowlesi Drug of choice: Chloroquine phosphate (Aralen) 600 mg base (1,000 mg salt) PO, then 300 mg base (500 mg salt) PO at 6, 24, and 48 hr 10 mg basekg (16.7 mg saltkg) PO, then 5 mg basekg (8.3 mg saltkg) PO at 6, 24, and 48 hr or Hydroxychloroquine (Plaquenil)70 620 mg base (800 mg salt) PO, then 310 mg base (400 mg salt) PO at 6, 24, and 48 hr 10 mg basekg (12.9 mg saltkg) PO, then 5 5 mg basekg (6.5 mg saltkg) PO at 6, 24, and 48 hr or Artemether lumefantrine (Coartem)10 (1 tab: 20 mg artemether 120 mg lumefantrine) Adults: 4 tabs PO per dose Three day course: day 1: initial dose and second dose 8 hr later; days 2 and 3: 1 dose bid 5 to 15 kg: 1 tab PO per dose 15 to 25 kg: 2 tabs PO per dose 25 to 35 kg: 3 tabs PO per dose 35 kg: 4 tabs PO per dose Three day course: day 1: initial dose and second dose 8 hr later; days 2 and 3: 1 dose bid Uncomplicated infection with P. vivax acquired in areas of chloroquine resistance71 Drugs of choice: Atovaquoneproguanil (Malarone) Adult tabs: 50 mg atovaquone100 mg proguanil Pediatric tabs 62.5 mg atovaquone25 mg proguanil)63 4 adult tabs PO once daily 3 days 5 kg: not indicated 5 8 kg: 2 pediatric tabs PO daily 3 days 9 10 kg: 3 pediatric tabs PO daily 3 days 11 20 kg: 1 adult tab PO daily 3 days 21 30 kg: 2 adult tabs PO daily 3 days 31 40 kg: 3 adult tabs PO daily 3 days 40 kg: 4 adult tabs PO daily 3 days plus primaquine72 30 mg base PO daily 14 days 0.5 mgkgday PO 14 days |
8,033 | or Quinine sulfate 542 mg base (650 mg salt) PO tid 3 7 days64 8.3 mg basekg (10 mg saltkg) PO tid 3 7 days58 plus doxycycline7,17 100 mg PO bid 7 days 4 mgkgday PO in 2 doses 7 days or plus tetracycline7,17 250 mg PO qid 7 days 6.25 mgkg PO qid 7 days or plus clindamycin7,66 20 mgkgday PO in 3 divided doses 7 days67 20 mgkgday PO in 3 doses 7 days plus primaquine72 30 mg base PO daily 14 days 0.5 mgkgday PO 14 days 64Although approved for once daily dosing, Medical Letter consultants usually divide the dose into 2 doses to decrease nausea and vomiting. 65In Southeast Asia, relative resistance to quinine has increased and treatment should be continued for 7 days. 66For use in pregnancy. 67Lell B, et al. Antimicrob Agents Chemother. 2002;46:2315. 68At this dosage, adverse effects, including nausea, vomiting, diarrhea, dizziness, a disturbed sense of balance, toxic psychosis, and seizures can occur. Mefloquine should not be used for treatment of malaria in pregnancy unless there is no other treatment option, because of an increased risk for stillbirth (Nosten F, et al. Clin Infect Dis. 1999;28:808). It should be avoided for treatment of malaria in persons with active depression or with a history of psychosis or seizures and should be used with caution in persons with psychiatric illness. Mefloquine can be given to patients taking blockers if they do not have an underlying arrhythmia; it should not be used in patients with conduction abnormalities. Mefloquine should not be given together with quinine, quinidine, or halofantrine, and caution is required in using quinine, quinidine, or halofantrine to treat patients with malaria who have taken mefloquine for prophylaxis. Resistance to mefloquine has been reported in some areas, such as the Thailand Myanmar and Thailand Cambodia borders and in the Amazon basin, where 25 mgkg should be used. In the United States, a 250 mg tablet of mefloquine contains 228 mg mefloquine base. Outside the United States, each 275 mg tablet contains 250 mg base. 69Plasmodium falciparum with resistance to mefloquine is a significant problem in the malarious areas of Thailand and in areas of Myanmar and Cambodia that border on Thailand. It has also been reported on the borders between Myanmar and China, Laos and Myanmar, and in Southern Vietnam. In the United States, a 250 mg tablet of mefloquine contains 228 mg mefloquine base. Outside the United States, each 275 mg tablet contains 250 mg base. 70If chloroquine phosphate is not available, hydroxychloroquine sulfate is as effective; 400 mg of hydroxychloroquine sulfate is equivalent to 500 mg of chloroquine phosphate. 71Plasmodium vivax with decreased susceptibility to chloroquine is a significant problem in Papua New Guinea and Indonesia. There are also a few reports of resistance from Myanmar, India, the Solomon Islands, Vanuatu, Guyana, Brazil, Colombia, and Peru. 72Primaquine phosphate can cause hemolytic anemia, especially in patients whose red cells are deficient in glucose 6 phosphate dehydrogenase (G6PD). This deficiency is most common in |
8,034 | African, Asian, and Mediterranean peoples. Patients should be screened for G6PD deficiency before treatment. Primaquine should not be used during pregnancy. For those with intermediate G6PD deficiency, weekly primaquine may be used (45 mgwk) for 8 wk with close monitoring for hemolysis. Those with G6PD deficiency may be given chloroquine 300 mg (base) PO weekly for 1 yr for acute infection to prevent relapses. Continued 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. 2136 Part XV u Infectious Diseases Table 325.1 Drugs for Parasitic Infectionscontd INFECTION DRUG ADULT DOSAGE PEDIATRIC DOSAGE or Artemether lumefantrine (1 tab: 20 mg artemether120 mg lumefantrine) Weight based treatment schedule for both adult and pediatric patients. Patients take initial dose, followed by a second dose 8 hr later, then 1 dose twice a day for the next 2 days (total of 6 oral doses over 3 days) 5 kg to 15 kg: 1 tablet per dose 15 kg to 25 kg: 2 tablets per dose 25 kg to 35 kg: 3 tablets per dose 35 kg: 4 tablets per dose Not recommended for people taking mefloquine prophylaxis or for children weighing 5 kg, or people breastfeeding infants weighing 5 kg or Mefloquine68 750 mg PO followed 12 hr later by 500 mg PO 15 mgkg PO followed 12 hr later by 10 mgkg PO plus primaquine72 30 mg base PO daily 14 days 0.5 mgkgday PO 14 days Uncomplicated infection with P. ovale and P. vivax acquired in areas without chloroquine resistance71 Drug of choice: Chloroquine phosphate (Aralen) 600 mg base (1,000 mg salt) PO, then 300 mg base (500 mg salt) PO at 6, 24, and 48 hr 10 mg basekg (16.7 mg saltkg) PO, then 5 mg basekg (8.3 mg saltkg) PO at 6, 24, and 48 hr plus primaquine72 30 mg base PO daily 14 days 0.5 mgkgday PO 14 days or Hydroxychloroquine (Plaquenil)70 620 mg base PO, then 310 mg base PO at 6, 24, and 48 hr 10 mgkg base PO, then 5 mgkg base PO at 6, 24, and 48 hr plus primaquine72 30 mg base PO daily 14 days 0.5 mgkgday PO 14 days or Tafenoquine (Krintafel)73 300 mg PO 1 dose 16 yr: see adult dosing Severe malaria due to all Plasmodium spp. Drugs of choice:74 Artesunate28,75 2.4 mgkgdose IV 3 days, at 0, 12, and 24 hr 2.4 mgkgdose IV 3 days, at 0, 12, and 24 hr Followed by: Artemether lumefantrine (preferred), or Atovaquone proguanil, or Quinine plus doxycycline or clindamycin, or Mefloquine (only if no other options available) Dosing as above Dosing as above Alternative: Coartem (Artemether lumefantrine) Fixed dose of 20 mg artemether and 120 mg lumefantrine per tablet (preferred) 4 tablets per dose. A 3 day treatment schedule with a total of 6 oral doses is recommended for both adult and pediatric patients based on weight. |
8,035 | These 6 doses should be administered over 3 days at 0, 8, 24, 36, 48, and 60 hr 5 to 15 kg: 1 tablet PO per dose 15 to 25 kg: 2 tablets PO per dose 25 to 35 kg: 3 tablets per dose 35 kg: 4 tablets PO per dose or Atovaquoneproguanil (Malarone) Adult tabs: 50 mg atovaquone100 mg proguanil Pediatric tabs 62.5 mg atovaquone25 mg proguanil)63 4 adult tabs PO once daily 3 days 5 kg: not indicated 5 8 kg: 2 pediatric tabs PO daily 3 days 9 10 kg: 3 pediatric tabs PO daily 3 days 11 20 kg: 1 adult tab PO daily 3 days 21 30 kg: 2 adult tabs PO daily 3 days 31 40 kg: 3 adult tabs PO daily 3 days 40 kg: 4 adult tabs PO daily 3 days 73Tafenoquine received regulatory approval in the United States in 2018 for prophylaxis of malaria and radical cure of Plasmodium vivax. Tafenoquine is associated with hemolytic anemia in those with glucose 6 phosphate dehydrogenase (G6PD) deficiency. Prior to use, quantitative G6PD testing is needed to confirm normal activity. 74Exchange transfusion has been helpful for some patients with high density (10) parasitemia, altered mental status, pulmonary edema, or renal complications (Miller KD, et al. N Engl J Med. 1989;321:65). 75Artesnuate is considered first line therapy for severe malaria. If not available within 24 hours, contact CDCs Malaria Hotline. To avoid the development of resistance, adults treated with artesunate must also receive oral treatment doses of either atovaquoneproguanil, doxycycline, clindamycin, or mefloquine; children should take either atovaquoneproguanil, clindamycin, or mefloquine (Nosten F, et al. Lancet. 2000;356:297; van Vugt M. Clin Infect Dis. 2002;35:1498; Smithuis F, et al. Trans R Soc Trop Med Hyg. 2004;98:182). If artesunate is given IV, oral medication should be started when the patient is able to tolerate it (SEAQUAMAT group. Lancet. 2005;366:717; Duffy PE, et al. Lancet. 2005;366:1908). If oral therapy is not tolerated, consider administration via nasogastric (NG) tube or after an antiemetic. If parasitemia 1, continue IV artesunate at the same dose daily up to 6 more days until parasite density 1. When parasite density 1, give complete follow up on oral regimen as listed earlier. Reduced susceptibility to artesunate characterized by slow parasitic clearance has been reported in Cambodia (Rogers WO, et al. Malar J. 2009;8:10; Dundorp AM, et al. N Engl J Med. 2009;361:455). 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 325 u Principles of Antiparasitic Therapy 2137 Table 325.1 Drugs for Parasitic Infectionscontd INFECTION DRUG ADULT DOSAGE PEDIATRIC DOSAGE or Quinine sulfate 648 mg salt PO tid 3 7 days64 10 mg saltkg PO tid 3 7 days58 plus doxycycline7,17 100 mg PO bid 7 days 4 mgkgday PO in 2 doses 7 days or plus tetracycline7,17 250 mg PO qid 7 days 6.25 mgkg PO qid |
8,036 | 7 days or plus clindamycin7,66 20 mgkgday PO in 3 divided doses 7 days67 20 mgkgday PO in 3 doses 7 days or Artemetherlumefantrine (1 tab: 20 mg artemether120 mg lumefantrine) Weightbased treatment schedule for both adult and pediatric patients. Patients take initial dose, followed by a second dose 8 hr later, then 1 dose twice a day for the next 2 days (total of 6 oral doses over 3 days) 5 kg to 15 kg: 1 tablet per dose 15 kg to 25 kg: 2 tablets per dose 25 kg to 35 kg: 3 tablets per dose 35 kg: 4 tablets per dose Not recommended for people taking mefloquine prophylaxis or for children weighing 5 kg, or people breastfeeding infants weighing 5 kg or Mefloquine68 750 mg PO followed 12 hr later by 500 mg PO 15 mgkg PO followed 12 hr later by 10 mgkg PO Prevention of relapses: P. vivax and P. ovale only Drug of choice: Primaquine phosphate72 30 mg baseday PO 14 days 0.6 mg basekgday PO 14 days or Tafenoquine (Krintafel)73 300 mg PO 1 dose 16 yr: see adult dosing MALARIA PREVENTION76 Chloroquine sensitive areas61 Drug of choice Chloroquine phosphate7779 500 mg salt (300 mg base), PO oncewk beginning 1 2 wk before travel to malarious area and 4 wk after leaving 5 mgkg base oncewk, up to adult dose of 300 mg base beginning 1 2 wk before travel to malarious area and 4 wk after leaving or Hydroxychloroquine (Plaquenil)70 400 mg (310 mg base) PO oncewk beginning 1 2 wk before travel to malarious area and 4 wk after leaving 5 mgkg base oncewk, up to adult dose of 310 mg base beginning 1 2 wk before travel to malarious area and 4 wk after leaving Chloroquine resistant areas61 Drug of choice: Atovaquone proguanil63,78,80 1 adult tab PO per day beginning 1 2 days before travel to malarious area and 7 days after leaving 11 20 kg: 1 pediatric tab POday 21 30 kg: 2 pediatric tabs POday 31 40 kg: 3 pediatric tabs POday 40 kg: 1 adult tab POday or Mefloquine48,78,79,81 1 adult tab PO per day beginning 1 2 wk before travel to malarious area and 4 wk after leaving 9 kg: 5 mgkg salt oncewk 9 19 kg: 14 tab oncewk 19 30 kg: 12 tab oncewk 31 45 kg: 34 tab oncewk 45 kg: 1 tab oncewk 76No drug regimen guarantees protection against malaria. If fever develops within a year (particularly within the first 2 mo) after travel to malarious areas, travelers should be advised to seek medical attention. Insect repellents, insecticide impregnated bed nets, and proper clothing are important adjuncts for malaria prophylaxis (Med Lett. 2003;45:41). Malaria in pregnancy is particularly serious for both the pregnant individual and the fetus; therefore, prophylaxis is indicated if exposure cannot be avoided. 77In pregnancy, chloroquine prophylaxis has been used extensively and safely. 78For prevention of attack after departure from areas where Plasmodium vivax and Plasmodium ovale are endemic, |
8,037 | which includes almost all areas where malaria is found (except Haiti), some experts prescribe in addition primaquine phosphate 30 mg baseday or, for children, 0.6 mg basekgday during the last 2 wk of prophylaxis. Others prefer to avoid the toxicity of primaquine and rely on surveillance to detect cases when they occur, particularly when exposure was limited or doubtful. See also footnote71. 79Beginning 1 2 wk before travel and continuing weekly for the duration of stay and for 4 wk after leaving malarious zone. Most adverse events occur within three doses. Some Medical Letter consultants favor starting mefloquine 3 wk before travel and monitoring the patient for adverse events; this allows time to change to an alternative regimen if mefloquine is not tolerated. Mefloquine should not be taken on an empty stomach; it should be taken with at least 8 oz of water. For pediatric doses less than tablet, it is advisable to have a pharmacist crush the tablet, estimate doses by weighing, and package them in gelatin capsules. There are no data for use in children weighing 5 kg, but based on dosages in other weight groups, a dose of 5 mgkg can be used. 80Beginning 1 2 days before travel and continuing for the duration of stay and for 1 wk after leaving malarious zone. In one study of malaria prophylaxis, atovaquoneproguanil was better tolerated than mefloquine in nonimmune travelers (Overbosch D, et al. Clin Infect Dis. 2001;33:1015). The protective efficacy of Malarone against Plasmodium vivax is variable, ranging from 84 in Indonesian New Guinea (Ling J, et al. Clin Infect Dis. 2002;35:825) to 100 in Colombia (Soto J, et al. Am J Trop Med Hyg. 2006;75:430). Some Medical Letter consultants prefer alternate drugs if traveling to areas where P. vivax predominates. 81Mefloquine has not been approved for use during pregnancy. However, it has been reported to be safe for prophylactic use during the second or third trimester of pregnancy and possibly during early pregnancy, as well. Mefloquine is not recommended for patients with cardiac conduction abnormalities, and patients with a history of depression, seizures, psychosis, or psychiatric disorders should avoid mefloquine prophylaxis. Resistance to mefloquine has been reported in some areas, such as the Thailand Myanmar and Thailand Cambodia borders; in these areas, atovaquoneproguanil or doxycycline should be used for prophylaxis. Continued 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. 2138 Part XV u Infectious Diseases Table 325.1 Drugs for Parasitic Infectionscontd INFECTION DRUG ADULT DOSAGE PEDIATRIC DOSAGE or Doxycycline7,82 100 mg PO daily 8 yr: 2 mgkgday, up to 100 mgday or Tafenoquine (Arakoda) 200 mg once daily for 3 days before travel to a malarious area, then 200 mg weekly while in the malarious area, then 200 mg as a single dose, 7 days after leaving malarious area No dosing data for children Alternatives for areas with primarily P. |
8,038 | vivax: Primaquine7,83 30 mg base PO daily beginning 1 2 days before travel to malarious area and 7 14 days after leaving 0.5 mgkg base (max 30 mg) daily beginning 1 2 days before travel to malarious area and 7 14 days after leaving MALARIA PRESUMPTIVE SELF TREATMENT84 Drugs of choice: Atovaquoneproguanil (Malarone) Adult tabs: 50 mg atovaquone100 mg proguanil Pediatric tabs 62.5 mg atovaquone25 mg proguanil)63 4 adult tabs PO once daily 3 days 5 kg: not indicated 5 8 kg: 2 pediatric tabs PO daily 3 days 9 10 kg: 3 pediatric tabs PO daily 3 days 11 20 kg: 1 adult tab PO daily 3 days 21 30 kg: 2 adult tabs PO daily 3 days 31 40 kg: 3 adult tabs PO daily 3 days 40 kg: 4 adult tabs PO daily 3 days or Quinine sulfate64 648 mg salt PO tid 3 7 days 10 mg saltkg PO tid 3 7 days plus doxycycline7,17 100 mg PO bid 7 days 4 mgkgday PO in 2 divided doses 7 days or Mefloquine68,69 750 mg PO followed 12 hr later by 500 mg 15 mgkg PO followed 12 hr later by 10 mgkg MICROSPORIDIOSIS Ocular (Encephalitozoon hellem, Encephalitozoon cuniculi, Vittaforma corneae Nosema corneum) Drug of choice: Albendazole7,85 400 mg PO bid 10 kg2 yr: 15 mgkgday in 2 doses12 2 yr: see adult dosing plus fumagillin86 Topical Fumidil B (fumagillin bicyclohexylammonium) in saline (to achieve concentration of 70 mgmL of fumagillin) 2 drops per eye every 2 hr for 4 days, then 2 drops qid Intestinal (Enterocytozoon bieneusi, Encephalitozoon Septata intestinalis) E. bieneusi87 Drug of choice: Fumagillin 60 mgday PO 14 days in 3 divided doses Alternatives: Nitazoxanide5,7 1000 mg PO bid 3 days E. intestinalis Drug of choice Albendazole7,85 400 mg PO bid 21 days 10 kg2 yr 15 mgkgday in 2 doses:12 2 yr: see adult dosing Disseminated (E. hellem, E. cuniculi, E. intestinalis, Pleistophora sp., Trachipleistophora sp., and Brachiola vesicularum) Drug of choice88 Albendazole7,85 400 mg PO bid 10 kg2 yr12 2 yr: see adult dosing 82Beginning 1 2 days before travel and continuing for the duration of stay and for 4 wk after leaving. Use of tetracyclines is contraindicated in pregnancy and in children younger than 8 yr old. Doxycycline can cause GI disturbances, vaginal moniliasis, and photosensitivity reactions. 83Studies have shown that daily primaquine beginning 1 day before departure and continued until 3 7 days after leaving the malarious area provides effective prophylaxis against chloroquine resistant Plasmodium falciparum (Baird JK, et al. Clin Infect Dis. 2003;37:1659). Some studies have shown less efficacy against Plasmodium vivax. Nausea and abdominal pain can be diminished by taking with food. 84A traveler can be given a course of atovaquoneproguanil, mefloquine, or quinine plus doxycycline for presumptive self treatment of febrile illness. The drug given for self treatment should be different from that used for prophylaxis. This approach should be used only in very rare circumstances when a traveler cannot promptly get to medical care. 85For HIV |
8,039 | infected patients, continue until resolution of ocular symptoms and until CD4 count 200 cellsL for 6 mo after initiation of antiretroviral therapy. 86Ocular lesions caused by Encephalitozoon hellem in HIV infected patients have responded to fumagillin eyedrops prepared from Fumidil B (bicyclohexyl ammonium fumagillin) used to control a microsporidial disease of honey bees (Diesenhouse MC. Am J Ophthalmol. 1993;115:293), available from Leiters Park Avenue Pharmacy (San Jose, CA; 1 800 292 6773; www.leiterrx.com). For lesions caused by Vittaforma corneae, topical therapy is generally not effective and keratoplasty may be required (Davis RM, et al. Ophthalmology. 1990;97:953). 87Oral fumagillin (Sanofi Recherche, Gentilly, France) has been effective in treating Enterocytozoon. bieneusi (Molina J M, et al. N Engl J Med. 2002;346:1963), but it has been associated with thrombocytopenia. HAART may lead to microbiologic and clinical response in HIV infected patients with microsporidial diarrhea (Benson CA, et al. MMWR Recomm Rep. 2004;53(RR 15:1). Octreotide (Sandostatin) has provided symptomatic relief in some patients with large volume diarrhea. 88Molina J M, et al. J Infect Dis. 1995;171:245. There is no established treatment for Pleistophora. For disseminated disease caused by Trachipleistophora or Brachiola, itraconazole 400 mg PO onceday plus albendazole may also be tried (Coyle CM, et al. N Engl J Med. 2004;351:42). 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 325 u Principles of Antiparasitic Therapy 2139 Table 325.1 Drugs for Parasitic Infectionscontd INFECTION DRUG ADULT DOSAGE PEDIATRIC DOSAGE MITES, SEE SCABIES MONILIFORMIS MONILIFORMIS INFECTION Drug of choice: Pyrantel pamoate (OTC)7 11 mgkg PO once, repeat twice, 2 wk apart 11 mgkg PO once, repeat twice, 2 wk apart NAEGLERIA SPECIES, SEE AMEBIC MENINGOENCEPHALITIS, PRIMARY NECATOR AMERICANUS, SEE HOOKWORM INFECTION OESOPHAGOSTOMUM BIFURCUM Drug of choice: See footnote89 ONCHOCERCA VOLVULUS, SEE FILARIASIS OPISTHORCHIS VIVERRINI, SEE FLUKE INFECTION PARAGONIMUS WESTERMANI, SEE FLUKE INFECTION PEDICULUS CAPITIS, PEDICULUS HUMANUS, PHTHIRUS PUBIS, SEE LICE PINWORM, SEE ENTEROBIUS PNEUMOCYSTIS JIROVECII (FORMERLY PNEUMOCYSTIS CARINII) PNEUMONIA (PCP)90 Moderate to severe disease Drug of choice: TMP SMX 15 20 mgkgday TMP component IV in 3 4 divided doses 21 days (change to PO after clinical improvement) 15 20 mgkgday TMP component IV in 3 4 divided doses 21 days (change to PO after clinical improvement) Alternatives: Pentamidine 3 4 mg IV daily 21 days 3 4 mg IV daily 21 days or Primaquine 30 mg base PO daily 21 days 0.3 mgkg base PO (max 30 mg) daily 21 days plus clindamycin7 600 900 mg IV tid or qid 21 days, or 300 450 mg PO tid or qid 21 days (change to PO after clinical improvement) 15 25 mgkg IV tid or qid 21 days, or 10 mgkg PO tid or qid (max 300 450 mgdose) 21 days (change to PO after clinical improvement) Mild to moderate disease Drug of choice: TMP SMX 320 mg1600 mg (2 DS tablets) PO tid 21 days TMP 15 20 |
8,040 | mgkgday PO in 3 or 4 doses 21 days Alternative: Dapsone 100 mg PO daily 21 days 2 mgkgday (max 100 mg) PO 21 days plus trimethoprim 15 mgkgday PO in 3 doses 15 mgkgday PO in 3 doses or primaquine 30 mg base PO daily 21 days 0.3 mgkg base PO daily (max 30 mg) 21 days plus clindamycin 300 450 mg PO tid or qid 21 days 10 mgkg PO tid or qid (max 300 450 mgdose) 21 days or atovaquone 750 mg PO bid 21 days 1 3 mo: 30 mgkgday PO in 2 doses 21 days Primary and secondary prophylaxis91 Drug of choice: TMP SMX 1 tab (single strength or greater) PO daily or 1 DS tab PO 3 dayswk TMP 150 mgm2 in 1 2 doses daily or on 3 consecutive dayswk Alternatives:91 Dapsone7 50 mg PO bid, or 100 mg PO daily 2 mgkgday (max 100 mg) PO or 4 mgkg (max 200 mg) PO each wk or Dapsone7 50 mg PO daily or 200 mg PO each wk plus pyrimethamine92 50 mg PO or 75 mg PO each wk or Pentamidine aerosol 300 mg inhaled monthly via Respirgard II nebulizer 5 yr: 300 mg inhaled monthly via Respirgard II nebulizer or Atovaquone7 1,500 mgday PO in 1 or 2 doses 1 3 mo: 30 mgkgday PO 4 24 mo: 45 mgkgday PO in 2 doses 21 days 24 mo: 30 mgkgday PO in 2 doses 21 days 89Albendazole or pyrantel pamoate may be effective (Ziem JB, et al. Ann Trop Med Parasitol. 2004;98:385). 90Pneumocystis has been reclassified as a fungus. In severe disease with room air Po2 70 mm Hg or A a O2 gradient 35 mm Hg, prednisone should also be used (Gagnon S, et al. N Engl J Med. 1990;323:1444; Caumes E, et al. Clin Infect Dis. 1994;18:319). 91Primarysecondary prophylaxis in patients with HIV can be discontinued after the CD4 count increases to 200 106L for longer than 3 mo. 92Plus leucovorin 25 mg with each dose of pyrimethamine. Continued 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. 2140 Part XV u Infectious Diseases Table 325.1 Drugs for Parasitic Infectionscontd INFECTION DRUG ADULT DOSAGE PEDIATRIC DOSAGE ROUNDWORM, SEE ASCARIASIS SAPPINIA DIPLOIDEA, SEE AMEBIC MENINGOENCEPHALITIS, PRIMARY SCABIES (SARCOPTES SCABIEI) Drug of choice: 5 Permethrin93 Topically, 2 at least 1 wk apart Topically 2, 1 wk apart, approved for 2 mo Alternatives:93 Ivermectin7,93,94 200 gkg PO 2 at least 1 wk apart 15 kg: not indicated 15 kg: see adult dosing 10 Crotamiton Topically overnight on days 1, 2, 3, and 8 Topically overnight on days 1, 2, 3, and 8 SCHISTOSOMIASIS (BILHARZIASIS) Schistosoma haematobium or Schistosoma intercalatum Drug of choice: Praziquantel 40 mgkgday PO in 1 or 2 doses 1 day 40 mgkgday PO in 1 or 2 doses 1 day37 Schistosoma japonicum or Schistosoma mekongi |
8,041 | Drug of choice: Praziquantel 60 mgkgday PO in 2 or 3 doses 1 day 60 mgkgday PO in 3 doses 1 day37 Schistosoma mansoni Drug of choice: Praziquantel 40 mgkgday PO in 1 or 2 doses 1 day 40 mgkgday PO in 1 or 2 doses 1 day37 Alternative: Oxamniquine95,96 15 mgkg PO once 20 mgkgday PO in 2 doses 1 day Sleeping sickness, see Trypanosomiasis Strongyloidiasis (Strongyloides stercoralis) Drug of choice:97 Ivermectin 200 gkgday PO 2 days 15 kg: not indicated 15 kg: see adult dosing Alternative: Albendazole7,98 400 mg PO bid 7 days 10 kg2 yr12 2 yr: see adult dosing TAPEWORM INFECTION Adult (intestinal stage) Diphyllobothrium latum (fish), Taenia saginata (beef), Taenia solium (pork), Dipylidium caninum (dog) Drug of choice: Praziquantel7 5 10 mgkg PO once 5 10 mgkg PO once37 Alternative: Niclosamide 2 g PO once 50 mgkg PO once Hymenolepis nana (dwarf tapeworm) Drug of choice: Praziquantel7 25 mgkg PO once 25 mgkg PO once37 Alternative: Niclosamide99 2 g PO daily 7 days 11 34 kg: 1 g PO on day 1 then 500 mgday PO 6 days 34 kg: 1.5 g PO on day 1 then 1 gday PO 6 days Larval (tissue stage) Echinococcus granulosus (hydatid disease cystic echinococcosis) Drug of choice:100 Albendazole7 400 mg PO bid 1 6 mo 10 kg2 yr: 10 15 mgkgday (max 800 mgday) PO, in 2 doses12 2 yr: 15 mgkgday PO (max 400 mg) 1 6 mo 93In some cases, treatment may need to be repeated in 10 14 days (Currie BJ, et al. N Engl J Med. 2010;362:717). A second ivermectin dose taken 2 wk later increased the cure rate to 95, which is equivalent to that of 5 permethrin (Usha V, et al. J Am Acad Dermatol. 2000;42:236). Ivermectin, either alone or in combination with a topical scabicide, is the drug of choice for crusted scabies in immunocompromised patients (del Giudice P. Curr Opin Infect Dis. 2004;15:123). 94Ivermectin, either alone or in combination with a topical scabicide, is the drug of choice for crusted scabies in immunocompromised patients (del Giudice P. Curr Opin Infect Dis. 2004;15:123). The safety of oral ivermectin in pregnancy and young children has not been well studied. Ivermectin is included on the KIDS list (Meyers RS, et al. J Pediatr Pharmacol Ther. 2020;25:175) due to concerns about encephalopathy, but more recent studies suggest that it may be used safely (Levy M, et al. Br J Dermatol. 2020;182:1003). 95Oxamniquine has been effective in some areas in which praziquantel is less effective (Stelma FF, et al. J Infect Dis. 1997;176:304). Oxamniquine is contraindicated in pregnancy. 96In East Africa, the dose should be increased to 30 mgkg, and in Egypt and South Africa to 30 mgkgday 2 days. Some experts recommend 40 60 mgkg over 2 3 days in all of Africa (Shekhar KC. Drugs. 1991;42:379). 97In immunocompromised patients or disseminated disease, it may be necessary to prolong or repeat therapy or to use other agents. Veterinary parenteral and enema formulations of ivermectin |
8,042 | have been used in severely ill patients unable to take oral medications (Chiodini PL, et al. Lancet. 2000;355:43; Orem J, et al. Clin Infect Dis. 2003;37:152; Tarr PE. Am J Trop Med Hyg. 2003;68:453). 98Albendazole must be taken with food; a fatty meal increases oral bioavailability. 99Niclosamide must be thoroughly chewed or crushed and swallowed with a small amount of water. Nitazoxanide may be an alternative (Juan JO, et al. Trans R Soc Trop Med Hyg. 2002;96:193; Chero JC, et al. Trans R Soc Trop Med Hyg. 2007;101:203; Diaz E, et al. Am J Trop Med Hyg. 2003;68:384). 100Optimal treatment depends on multiple factors, including size, location, and number of cysts and presence of complications. In some patients, medical therapy alone is preferred, but some patients may benefit from surgical resection or percutaneous drainage of cysts. Praziquantel is useful preoperatively or in case of spillage of cyst contents during surgery. Puncture aspiration injection reaspiration (PAIR) with ultrasound guidance plus albendazole therapy has been effective for management of hepatic hydatid cyst disease (Smego RA Jr, et al. Clin Infect Dis. 2003;37:1073). 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 325 u Principles of Antiparasitic Therapy 2141 Table 325.1 Drugs for Parasitic Infectionscontd INFECTION DRUG ADULT DOSAGE PEDIATRIC DOSAGE Echinococcus multilocularis (alveolar echinococcosis) Treatment of choice: See footnote101 Neurocysticerosis Taenia solium (pork) 1 2 viable parenchymal cysticerci115 Treatment of choice:102,115 Albendazole 400 mg bid PO 8 30 days; can be repeated as necessary 10 kg2 yr: 15 mgkgday PO in 2 doses (max dose 1200 mgday) for 10 14 days with food 2 yr: 15 mgkgday PO in 2 doses (max 1200 mgday) for 10 14 days with food 2 viable parenchymal cysticerci115 Albendazole plus praziquantel 15 mgkgday for 10 14 days 50 mgkgday for 10 14 days Single enhancing lesions (SELs) from cysticercosis115 Albendazole 15 mgkgday bid with meals for 12 weeks Single enhancing lesions (SELs) from cysticercosis115 Albendazole 15 mgkgday bid with meals for 12 weeks Calcified parenchymal lesions115 Symptomatic therapy alone plus steroids or Surgical removal 101Surgical excision is the only reliable means of cure. Reports have suggested that in nonresectable cases, the use of albendazole or mebendazole can stabilize and sometimes cure infection (Craig P. Curr Opin Infect Dis. 2003;16:437). Medical treatment is prolonged up to 2 yr or more. 102Initial therapy for patients with inflamed parenchymal cysticercosis should focus on symptomatic treatment with antiseizure medication. Treatment of parenchymal cysticerci with albendazole or praziquantel is controversial (Maguire JH. N Engl J Med. 2004;350:215). Patients with live parenchymal cysts who have seizures should be treated with albendazole together with steroids (6 mg dexamethasone or 40 60 mg prednisone daily) and an antiseizure medication (Garcia HH, et al. N Engl J Med. 2004;350:249). Some recent studies have shown improved outcomes with combination albendazole and praziquantel (Garcia HH, et al. Lancet Infect Dis. 2014;14:687). |
8,043 | Patients with subarachnoid cysts or giant cysts in the fissures should be treated for at least 30 days (Proao JV, et al. N Engl J Med. 2001;345:879). Surgical intervention or CSF diversion is indicated for obstructive hydrocephalus; prednisone 40 mgday may be given with surgery. Arachnoiditis, vasculitis, or cerebral edema is treated with prednisone 60 mgday or dexamethasone 4 6 mgday together with albendazole or praziquantel (White AC Jr. Annu Rev Med. 2000;51:187). Any cysticercocidal drug may cause irreparable damage when used to treat ocular or spinal cysts, even when corticosteroids are used. An ophthalmic exam should always precede treatment to rule out intraocular cysts. 115For patients with 1 2 viable parenchymal cysticerci, albendazole monotherapy for 10 14 days compared to either no antiparasitic therapy (strong, high) or combination antiparasitic therapy (weak, moderate). We recommend albendazole (15 mgkgday) combined with praziquantel (50 mgkgday) for 1014 days rather than albendazole monotherapy for patients with 2 viable parenchymal cysticerci (strong, moderate). We suggest retreatment with antiparasitic therapy for parenchymal cystic lesions persisting for 6 months after the end of the initial course of therapy (weak, low). We suggest albendazole therapy rather than no antiparasitic therapy for all patients with SELs (weak, moderate). Remarks: albendazole (15 mgkgday in twice daily doses up for 12 weeks) should be given with meals. We recommend symptomatic therapy alone instead of antiparasitic drugs in patients with calcified parenchymal lesions (strong, moderate). (Infectious Diseases Society of America IDSA and the American Society of Tropical Medicine and Hygiene ASTMH. Diagnosis and treatment of neurocysticercosis: 2017 Clinical Practice Guidelines by the CID. Published 2222018. Clin Infect Dis 2018;66(8):e49e75.) Continued 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. 2142 Part XV u Infectious Diseases Table 325.1 Drugs for Parasitic Infectionscontd INFECTION DRUG ADULT DOSAGE PEDIATRIC DOSAGE TOXOCARIASIS, SEE VISCERAL LARVA MIGRANS TOXOPLASMOSIS (TOXOPLASMA GONDII)103 (ACQUIRED OR OCULAR INFECTION) Drugs of choice:104,105 Pyrimethamine106 Dosage is adjusted for weight, but 50 mg PO bid on days 1 and 2, then 50 mg qd is maximum. Duration depends on clinical response, treating at least 1 2 wk beyond complete resolution and end of any immune compromise or immaturity. Please see Chapter 336 1 mgkg (max 50 mg) bid 2 days, then 1 mgkg qd (max 50 mg). Duration depends on clinical response, treating at least 1 2 wk beyond complete resolution and end of any immune compromise or immaturity. Please see Chapter 336107 Calcium leucovorin is always given with pyrimethamine and in the week after discontinuing Please see formulation and instructions for infants in Chapter 336 In the United States pyrimethamine serum levels can be measured at NMS Laboratories in Philadelphia Pyrimethamine cannot be given in the first trimester of pregnancy plus sulfadiazine 1.5 g PO bid is a standard dose for a 100 lb person, maximum 2 g PO bid. Duration depends on clinical response, treating at |
8,044 | least 1 2 wk beyond complete resolution and end of any immune compromise or immaturity. Please see Chapter 336. 1.5 g PO bid is a standard dose for a 100 lb person, maximum 2 g PO bid. Duration depends on clinical response, treating at least 1 2 wk beyond complete resolution and end of any immune compromise or immaturity. Please see Chapter 336 This is used with pyrimethamine for synergy Alternative for sulfadiazine or for suppression prophylaxis Trimethoprim sulfamethoxazole (TMP SMX) 1 double strength tablet daily. Alternative dosing: one double strength tablet 3 times weekly. Adult alternative regimen: Trimethoprim sulfamethoxazole (TMP SMX) 5 mgkg trimethoprim and 25 mgkg sulfamethoxazole given PO or IV bid Clindamycin (600 mg IV or PO 4 times daily) plus oral pyrimethamine (200 mg loading dose followed by 50 mg daily among patients 60 kg or 75 mg daily among patients 60 kg) plus oral leucovorin (10 to 25 mg daily). TMP SMX 150750 mgm2 body surface area once daily PO TRICHINELLOSIS (TRICHINELLA SPIRALIS) Drugs of choice: Steroids for severe symptoms Prednisone 30 60 mg PO daily 10 15 days plus Albendazole7 400 mg PO bid 8 14 days 10 kg2 yr12 2 yr: see adult dosing Alternative: Mebendazole7 200 400 mg PO tid 3 days, then 400 500 mg PO tid 10 days 200 400 mg PO tid 3 days, then 400 500 mg PO tid 10 days13 TRICHOMONIASIS (TRICHOMONAS VAGINALIS) Drug of choice:108 Metronidazole 2 g PO once or 500 mg PO bid 7 days 15 mgkgday PO in 3 doses 7 days or Tinidazole4 2 g PO once 50 mgkg PO once (max 2 g) TRICHOSTRONGYLUS INFECTION Drug of choice: Pyrantel pamoate7 11 mgkg base PO once (max 1 g) 11 mgkg PO once (max 1 g) Alternative: Mebendazole7 100 mg PO bid 3 days 100 mg PO bid 3 days13 or Albendazole7 400 mg PO once 10 kg2 yr12 2 yr: 15 mgkgday PO (max 800 mg) 1 6 mo 103In ocular toxoplasmosis with macular involvement, corticosteroids are recommended in addition to antiparasitic therapy for an antiinflammatory effect. 104To treat CNS toxoplasmosis in HIV infected patients, some clinicians have used pyrimethamine 50 100 mgday (after a loading dose of 200 mg) with sulfadiazine and, when sulfonamide sensitivity developed, have given clindamycin 1.8 2.4 gday in divided doses instead of the sulfonamide. Atovaquone plus pyrimethamine appears to be an effective alternative in sulfa intolerant patients (Chirgwin K, et al. Clin Infect Dis. 2002;34:1243). Treatment is followed by chronic suppression with lower dosage regimens of the same drugs. For primary prophylaxis in HIV patients with 100 106L CD4 cells, either trimethoprim sulfamethoxazole, pyrimethamine with dapsone, or atovaquone with or without pyrimethamine can be used. Primary or secondary prophylaxis may be discontinued when the CD4 count increases to 200 106L for more than 3 mo (Benson CA, et al. MMWR Recomm Rep. 2004;53(RR 15:1). 105Women who develop toxoplasmosis during the first trimester of pregnancy can be treated with spiramycin (3 4 gday). After the first |
8,045 | trimester, if there is no documented transmission to the fetus, spiramycin can be continued until term. If transmission has occurred in utero, therapy with pyrimethamine and sulfadiazine should be started (Montoya JG, et al. Lancet. 2004;363:1965). Pyrimethamine is a potential teratogen and should be used only after the first trimester. 106Plus leucovorin 10 25 mg with each dose of pyrimethamine. 107Congenitally infected newborns should be treated with pyrimethamine every 2 or 3 days and a sulfonamide daily for about 1 yr (Remington JS, et al., eds. Infectious Disease of the Fetus and Newborn Infant. 5th ed. Philadelphia: WB Saunders; 2001: p. 290). 108Sexual partners should be treated simultaneously. Metronidazole resistant strains have been reported and can be treated with higher doses of metronidazole (2 4 gday 7 14 days) or with tinidazole (Hager WD. Sex Transm Dis. 2004;31:343). 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 325 u Principles of Antiparasitic Therapy 2143 Table 325.1 Drugs for Parasitic Infectionscontd INFECTION DRUG ADULT DOSAGE PEDIATRIC DOSAGE TRICHURIASIS (TRICHURIS TRICHIURA, WHIPWORM) Drug of choice: Mebendazole 100 mg PO bid 3 days 100 mg PO bid 3 days13 Alternative: Albendazole7 400 mg PO 3 days 10 kg2 yr12 2 yr: see adult dosing or Ivermectin7 200 gkg PO daily 3 days 15 kg: not indicated 15 kg: see adult dosing TRYPANOSOMIASIS109 Trypanosoma cruzi (American trypanosomiasis, Chagas disease) Drug of choice: Benznidazole28 5 7 mgkgday PO in 2 divided doses 60 days 12 yr: 5 7.5 mgkgday PO in 2 divided doses 60 days 12 yr: see adult dosing Alternative: Nifurtimox28,110 8 10 mgkgday PO in 3 4 doses 90 days 10 yr: 15 20 mgkgday PO in 3 4 doses 90 days 11 16 yr: 12.5 15 mgkgday in 3 4 doses 90 days 16 yr: see adult dosing Trypanosoma brucei gambiense (West African trypanosomiasis, sleeping sickness) Hemolymphatic stage Drug of choice111 Pentamidine isethionate7 4 mgkgday IM 7 10 days 4 mgkgday IM or IV 7 10 days Alternative: Suramin28 100 mg (test dose) IV, then 1 g IV on days 1, 3, 7, 14, and 21 2 mgkg (test dose) IV, then 20 mgkg IV on days 1, 3, 7, 14, and 21 Late disease with CNS involvement Drug of choice: Eflornithine28,112 100 mgkg IV qid 14 days 100 mgkg IV qid 14 days Alternative: Melarsoprol28,113 2 3.6 mgkg (max 200 mg) daily IV (progressively increased during series) 3 days After 7 days, 3.6 mgkg daily 3 days After 7 days, give a third series of 3.6 mgkg daily 3 days. 2 3.6 mgkg (max 200 mg) daily IV (progressively increased during series) 3 days After 7 days, 3.6 mgkg daily 3 days After 7 days, give a third series of 3.6 mgkg daily 3 days Trypanosoma brucei rhodesiense (East African trypanosomiasis, sleeping sickness) Hemolymphatic stage Drug of choice: Suramin28 100 mg (test dose) IV, |
8,046 | then 1 g IV on days 1, 3, 7, 14, and 21 2 mgkg (test dose), then 20 mgkg IV on days 1, 3, 7, 14, and 21 Late disease with CNS involvement 109Barrett MP, et al. Lancet. 2003;362:1469. 110The addition of interferon to nifurtimox for 20 days in experimental animals and in a limited number of patients appears to shorten the acute phase of Chagas disease (McCabe RE, et al. J Infect Dis. 1991;163:912). 111For treatment of Trypanosoma brucei gambiense, pentamidine and suramin have equal efficacy but pentamidine is better tolerated. 112Eflornithine is highly effective in Trypanosoma brucei gambiense but not against Trypanosoma brucei rhodesiense infections. It is available in limited supply only from the WHO and the CDC. Eflornithine dose may be reduced to 400 mgkg IV in 2 doses for 7 days when used in conjunction with nifurtimox at a dose of 5 mgkg PO tid 10 days (Priotto G, et al. Lancet. 2009;374:56). 113In frail patients, begin with as little as 18 mg and increase the dose progressively. Pretreatment with suramin has been advocated for debilitated patients. Corticosteroids have been used to prevent arsenical encephalopathy (Ppin J, et al. Trans R Soc Trop Med Hyg. 1995;89:92). Up to 20 of patients with Trypanosoma brucei gambiense fail to respond to melarsoprol (Barrett MP. Lancet. 1999;353:1113). Consultation with experts at the CDC is recommended. Continued 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. 2144 Part XV u Infectious Diseases drug approved for use by the FDA for patients 5 kg. It is a fixed dose combination of two novel antimalarials, artemether (20 mg) and lume fantrine (120 mg). It is a highly effective 3 day malaria treatment, with cure rates of 96, even in areas of multidrug resistance. It can be used to treat chloroquine resistant uncomplicated malaria during the sec ond and third trimesters of pregnancy and as an alternative agent in the first trimester. Artesunate was approved by the FDA for intravenous (IV) treatment for severe malaria in 2020. SELECTED ANTIPARASITIC DRUGS FOR HELMINTHS AND ECTOPARASITES Albendazole (Albenza) Albendazole is a benzimidazole carbamate structurally related to mebendazole and has similar anthelmintic activity. Its absorption from the gastrointestinal tract is poor but improved with a concomitant high fat meal. Albendazole sulfoxide, the principal metabolite with anthelmintic activity, has a plasma half life of 8.5 hours. It is widely distributed in the body, including the bile and cerebrospinal fluid. It is eliminated in bile. Albendazole is FDA approved for treatment of two cestode (tapeworm) infections: neurocysticercosis and hydatid diseases (Echinococcus granulosus). It is used off label for numerous other helminth infections, including cutaneous larva migrans (Ancy lostoma caninum and Ancylostoma braziliense), ascariasis (Ascaris lum bricoides), liver flukes (Clonorchis sinensis and Opisthorchis viverrini), pinworm (Enterobius vermicularis), lymphatic filariasis (Wuchereria bancrofti, Brugia malayi, Brugia timori), gnathostomiasis (Gnathos toma spp. ), hookworms (Ancylostoma duodenale and |
8,047 | Necator america nus), microsporidiosis, trichinellosis (Trichinella spiralis), and visceral larva migrans (Toxocara canis and Toxocara cati). Albendazole is gener ally well tolerated. Common adverse effects include headache, nausea, vomiting, and abdominal pain. Serious adverse effects include elevated liver enzymes and leukopenia, which have occurred in a few patients with treatment of hydatid disease. Rare adverse effects include acute renal failure, pancytopenia, granulocytopenia, and thrombocytopenia. Despite the fact that albendazole and other antiparasitic drugs, includ ing mebendazole, praziquantel, and pyrimethamine, have been in use for decades, the number of manufacturers is small and costs have risen in recent years. Data are limited in pregnancy, and treatment during pregnancy generally deferred if possible. Albendazole is excreted in breast milk but is generally considered compatible with breastfeeding by the WHO. Ivermectin (Stromectol, Mectizan) Ivermectin is a semisynthetic derivative of one of the avermectins, which is a group of macrocyclic lactones produced by Streptomyces avermitilis. After oral administration, ivermectin has peak plasma concentrations after approximately 4 hours and a plasma elimination half life of approximately 12 hours. It is excreted as metabolites over a 2 week period via feces. It is FDA approved for treatment of two nematode (roundworm) infections: onchocerciasis (Onchocerca volvu lus) and strongyloidiasis (Strongyloides stercoralis). It may have some effect in treating a broad range of other helminths and ectoparasites, including cutaneous larva migrans (Ancylostoma braziliense), ascaria sis (Ascaris lumbricoides), loiasis, pinworm (Enterobius vermicularis), whipworm (Trichuris trichiura), gnathostomiasis (Gnathostoma spini gerum), Mansonella infections, lice (Pediculus humanus and Phthirus pubis), mites (Demodex spp. ), and scabies (Sarcoptes scabiei). Com bination therapies of ivermectin with albendazole or diethylcarbam azine are being used to treat lymphatic filariasis. Combination therapy with albendazole and the off label use of veterinary injectable formu lations have been used to treat complicated Strongyloides infections, including disseminated disease and hyperinfection syndrome. Though there has been significant public interest in ivermectin as a treatment for SARS CoV 2, clinical studies have not shown efficacy. Common adverse events include dizziness, headache, pruritus, and gastroin testinal effects. Serious adverse events include encephalopathy due to pathogenic variants in the ABCB1 transporter and Mazzotti reac tions in patients with onchocerciasis, including arthralgia, synovitis, enlarged lymph nodes, rash, and fever secondary to microfilaria death. A topical formulation is available for treatment of head lice, which are increasingly becoming very resistant to over the counter medications such as permethrins. Data are limited in pregnancy, and other agents are preferred if available for a given condition. Ivermectin is excreted in breast milk, and decisions to use this medication while breastfeeding should consider the risks and benefits of therapy based on the specific indication. Table 325.1 Drugs for Parasitic Infectionscontd INFECTION DRUG ADULT DOSAGE PEDIATRIC DOSAGE Drug of choice: Melarsoprol28,112 2 3.6 mgkg (max 200 mg) daily IV (progressively increased during series) 3 days After 7 days, 3.6 mgkg daily 3 days After 7 days, give a third series of 3.6 mgkg daily 3 days 2 3.6 mgkg (max 200 mg) daily IV (progressively increased during series) 3 days |
8,048 | After 7 days, 3.6 mgkg daily 3 days After 7 days, give a third series of 3.6 mgkg daily 3 days VISCERAL LARVA MIGRANS (TOXOCARIASIS)114 Drugs of choice: Albendazole7 400 mg PO bid 5 days 10 kg2 yr12 2 yr: see adult dosing or Mebendazole7 100 200 mg PO bid 5 days 100 200 mg PO bid 5 days13 WHIPWORM, SEE TRICHURIASIS WUCHERERIA BANCROFTI, SEE FILARIASIS 114Optimum duration of therapy is not known; some consultants would treat for 20 days. For severe symptoms or eye involvement, corticosteroids can be used in addition. bid, Twice a day; CDC, Centers for Disease Control and Prevention; CNS, central nervous system; CSF, cerebrospinal fluid; DEC, diethylcarbamazine; DS, double strength; FDA, U.S. Food and Drug Administration; GI, gastrointestinal; HAART, highly active antiretroviral therapy; IDSA, Infectious Disease Society of America; IM, intramuscularly; IND, investigational new drugs; IV, intravenously; OTC, over the counter; PO, by mouth; qd, once a day; qid, four times a day; tid, three times a day; WHO, World Health Organization. Adapted from Drugs for parasitic infection. Med Lett. 2013;11(Suppl):e1e23. Available at http:www.medicalletter.org 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 326 u Primary Amebic Meningoencephalitis 2145 Praziquantel (Biltricide) Praziquantel achieves its antiparasitic activity via the pyrazino isoquinoline ring system and was originally synthesized as a potential tranquilizer. After oral administration, praziquantel is rapidly absorbed, with peak levels in 1 2 hours and a plasma half life of about 1 3 hours. Elimination via the urine and feces is 80 complete after 24 hours. Praziquantel is metabolized in the liver by the microsomal cytochrome P450 (especially 2B1 and 3A). Bioavailability of praziquantel is increased with concomitant administration of agents that inhibit cytochrome P450. Praziquan tel is FDA approved for treatment of several species of trematodes (flatworms) including the Chinese liver fluke (Clonorchis sinensis), Southeast Asian liver fluke (Opisthorchis viverrini), and schisto somiasis (Schistosoma spp.). It is used off label for treatment of additional trematode pathogens, including the North American liver fluke (Metorchis conjunctus), Nanophyetus salmincola, intes tinal flukes (Fasciolopsis buski, Heterophyes heterophyes, Meta gonimus yokogawai), and lung flukes (Paragonimus westermani, Paragonimus kellicotti). It is also used off label for multiple cestode (tapeworm) infections. Adverse effects can be seen in 3060 of patients, although most are mild and disappear within 24 hours. Common adverse effects include headache, abdominal pain, dizzi ness, and malaise. Serious but rare adverse effects include arrhyth mias, heart block, and convulsions. Section 15 Protozoan Diseases Chapter 326 Primary Amebic Meningoencephalitis Matthew D. Eberly Naegleria, Acanthamoeba, Balamuthia, and Sappinia are small, free living amebae that cause human amebic meningoencephalitis, which has two distinct clinical presentations. The more common is an acute, fulminant, and usually fatal primary amebic meningoencephalitis caused by Naegleria fowleri that occurs in previously healthy children and young adults. Granulomatous amebic meningoencephalitis, which is caused by Acanthamoeba, Balamuthia, and Sappinia, is a more |
8,049 | indolent infection that typically occurs in immunocompromised hosts and may also present with a disseminated form of the disease. ETIOLOGY Naegleria is an ameboflagellate that can exist as cyst, trophozoite, and transient flagellate forms. Temperature and environmental nutri ent and ion concentrations are the major factors that determine the stage of the ameba. Trophozoites are the only stages that are invasive, although cysts are potentially infective because they can convert to the vegetative form very quickly under the proper environmental stimuli. Although there are over 40 species of Naegleria, only Naegleria fowleri has been shown to be pathogenic for humans. Acanthamoeba exists in cyst and motile trophozoite forms; only the trophozoite form is invasive. Cases of Acanthamoeba keratitis usu ally follow incidents of trivial corneal trauma followed by flushing with contaminated tap water. Infections can also occur among contact lens wearers who come into contact with contaminated water during swimming or use contact lenses cleaned or stored in contaminated tap water. Granulomatous amebic encephalitis from Acanthamoeba occurs worldwide and is associated with an immunocompromising condition such as HIV infection, diabetes mellitus, chronic liver disease, renal failure, immunosuppressive therapy, or radiation therapy. Balamuthia mandrillaris has been implicated as an etiology of granulomatous amebic encephalitis. Although the clinical presenta tion is similar to infection with Acanthamoeba, most patients are not immunocompromised. Other free living amebae can also cause infection, as illustrated by a case report of Sappinia pedata granulomatous encephalitis. EPIDEMIOLOGY The free living amebae have a worldwide distribution. Naegleria spe cies have been isolated from a variety of freshwater sources, includ ing ponds and lakes, domestic water supplies, hot springs and spas, thermal discharge of power plants, groundwater, and, occasionally, from the nasal passages of healthy children. Acanthamoeba species have been isolated from soil, mushrooms, vegetables, brackish water, and seawater, as well as most of the freshwater sources for Naegleria. It can also be found in tap water because chlorination does not kill Acanthamoeba. Balamuthia is present in soil and may be transmitted by inhalation or contamination of preexisting skin lesions. Naegleria meningoencephalitis has been reported from every conti nent except Antarctica. Most of the cases occur during the summer months in previously healthy individuals who have a history of swim ming in or contact with freshwater lakes and rivers before their illness. Between 1962 and 2022, 157 cases of primary amebic meningoenceph alitis (PAM) were reported in the United States. Most of the reports have come from the southern and southwestern states, particularly Florida and Texas, but infections have occurred in Kansas, Indiana, and Minnesota. Of note, cases have been linked to sinus irrigation with neti pots containing contaminated tap water; exposure to a lawn water slide, which derived its tap water from a treated public drinking water system; a chlorinated recreational splash pad; a swimming pool sup plied by an overland water pipe; and rafting on an artificial whitewater river. PATHOGENESIS The free living amebae enter the nasal cavity by inhalation or aspira tion of dust or water contaminated |
8,050 | with trophozoites or cysts. Naegle ria gains access to the central nervous system through the olfactory epithelium and migrates via the olfactory nerve to the olfactory bulbs located in the subarachnoid space and bathed by the cerebrospinal fluid (CSF). This space is richly vascularized and is the route of spread to other areas of the central nervous system. Grossly, there is wide spread cerebral edema and hyperemia of the meninges. The olfactory bulbs are necrotic, hemorrhagic, and surrounded by a purulent exu date. Microscopically, the gray matter is the most severely affected, with severe involvement in all cases. Fibrinopurulent exudate may be found throughout the cerebral hemispheres, brainstem, cerebellum, and upper portions of the spinal cord. Pockets of trophozoites may be seen in necrotic neural tissue, usually in the perivascular spaces of arteries and arterioles. The route of invasion and penetration in cases of granulomatous amebic meningoencephalitis caused by Acanthamoeba and Balamuthia may be by direct spread through olfactory epithelium or hematogenous spread from a primary focus in the skin or lungs. Pathologic exami nation reveals granulomatous encephalitis, with multinucleated giant cells mainly in the posterior fossa structures, basal ganglia, bases of the cerebral hemispheres, and cerebellum. Both trophozoites and cysts may be found in the central nervous system lesions, primarily located in the perivascular spaces and invading blood vessel walls. The olfac tory bulbs and spinal cord are usually spared. The single case of Sap pinia encephalitis followed a sinus infection, and evaluation revealed a solitary 2 cm temporal lobe mass with mild ring enhancement. 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. 2146 Part XV u Infectious Diseases CLINICAL MANIFESTATIONS The incubation period of Naegleria infection may be as short as 2 days or as long as 15 days. Symptoms have an acute onset and progress rap idly. Infection is characterized by a sudden onset of severe headache, fever, pharyngitis, nasal congestion or discharge, and nausea and vom iting, followed by altered mental status, nuchal rigidity, photophobia, confusion, somnolence, seizures, and ultimately coma. Most cases end in death within 3 10 days after onset of symptoms. Granulomatous amebic meningoencephalitis may occur weeks to months after the initial infection. The presenting signs and symp toms are often those of single or multiple central nervous system space occupying lesions and include hemiparesis, ataxia, personal ity changes, seizures, and drowsiness. Altered mental status is often a prominent symptom. Headache and fever occur only sporadically, but stiff neck is seen in a majority of cases. Cranial nerve palsies, especially of cranial nerves III and VI, may be present. There is also one report of acute hydrocephalus and fever with Balamuthia. Granulomatous amebic meningoencephalitis is usually fatal after 4 6 weeks of illness. Results of neuroimaging studies of the brain usually demonstrate mul tiple low density lesions resembling infarcts or enhancing lesions of granulomas (Fig. 326.1). DIAGNOSIS |
8,051 | The CSF in Naegleria infection may mimic that of herpes simplex encephalitis early in the disease and that of acute bacterial meningitis later in the disease, with a neutrophilic pleocytosis, elevated protein level, and hypoglycorrhachia. Motile amebae may be visualized on a wet mount of freshly drawn CSF using Wright or Giemsa stains, but they are often mistaken for lymphocytes or macrophages. Because Naegleria are the only amebae that differentiate into the flagellate state in a hypotonic environment, placing a drop of fresh CSF in 1 mL of distilled water and watching for the development of swimming flagellates after 1 2 hours can confirm the diagnosis of Naegleria. Naegleria can also be grown on a non nutrient agar plate coated with Escherichia coli, on which they feed. Polymerase chain reaction (PCR) and immunofluorescence assays for Naegleria performed on CSF and biopsy material are available through the U.S. Centers for Disease Control and Prevention (CDC). The diagnosis of granulomatous amebic meningoencephalitis relies on the isolation or histologic identification of Acanthamoeba trophozoites or cysts from brain tissue specimens. The CSF find ings of granulomatous meningoencephalitis reveal lymphocytic pleocytosis, moderately elevated protein, and low glucose concen trations. However, motile trophozoites of Acanthamoeba are more difficult to isolate than Naegleria, and the CSF is typically sterile. Acanthamoeba may be cultured from the same agar used for grow ing Naegleria, but Balamuthia must be grown on mammalian cell cultures. Pediatric cases of Balamuthia meningoencephalitis have been diagnosed antemortem by brain biopsy as well as postmortem. PCR and immunofluorescence assays can be used on specimens to identify Acanthamoeba and Balamuthia species, and are also avail able from the CDC. TREATMENT Naegleria infection is nearly always fatal, but early recognition and treatment are crucial to survival. Until 2013, there had been only two known survivors in North America, with treatment regimens of amphotericin B, either alone or in combination with other agents such as rifampin, chloramphenicol, fluconazole, ketoconazole, and dexamethasone. In 2013, however, the CDC made available the anti leishmanial drug miltefosine for the treatment of primary amebic meningoencephalitis. That summer, two children who contracted Naegleria both survived; both patients received oral miltefosine as part of their treatment, and one underwent external ventricular drain placement and therapeutic hypothermia. Miltefosine is now commer cially available in the United States (www.impavido.com). The recom mended drug treatment for primary amebic meningoencephalitis by the CDC includes intravenous and intrathecal amphotericin B, oral miltefosine, along with azithromycin, fluconazole, rifampin, and dexamethasone. Early identification, early initiation of combi nation therapy, and aggressive management of increased intracranial pressure remain key elements for a successful outcome. For suspected cases, clinicians should contact the CDC Emergency Operations Cen ter at (770) 488 7100 for assistance. The optimal therapy for granulomatous amebic meningoencephalitis is uncertain. However, miltefosine has likewise been used to success fully treat patients with Balamuthia and disseminated Acanthamoeba infections. Strains of Acanthamoeba isolated from fatal cases are usu ally susceptible in vitro to pentamidine, ketoconazole, and flucytosine and less so to amphotericin B. One |
8,052 | patient was successfully treated with sulfadiazine and fluconazole, and another was successfully treated with intravenous pentamidine followed by oral itraconazole. Acanthamoeba keratitis responds to long courses of topical propamidinepolymyxin B sulfate or topical polyhexamethylene biguanide or chlorhexidine gluconate, and antifungal azoles plus topical steroids. Limited success has been demonstrated in Balamuthia infection with systemic azole therapy combined with flucytosine. More recently, the combination of flucytosine, pentamidine, fluconazole, sulfadiazine, azithromycin, and phenothiazines resulted in the survival of two patients with Bala muthia meningoencephalitis, although both were left with mild neu romotor and cognitive impairment. Corticosteroids before initiating effective therapy appear to have a detrimental effect, contributing to rapid progression of disease. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. A CB Fig. 326.1 A and B, MRIs of the brain of a patient with Balamuthia mandrillaris granulomatous amebic encephalitis. Multiple enhancing lesions are seen in the right hemisphere, left cerebellum, midbrain, and brainstem. C, Photomicrograph of the brain lesion from the same patient showing perivascular amebic trophozoites. A round amebic cyst with a characteristic double wall is seen in the top center (hematoxylin and eosin, original magnification 100). (From Deol I, Robledo L, Meza A, et al. Encephalitis due to a free living amoeba Balamuthia mandrillaris: case report with literature review. Surg Neurol. 2000;53:611616.) 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 327 u Amebiasis 2147 Entamoeba species infect or colonize up to 10 of the worlds popula tion, with a disproportionate burden of illness in resource limited set tings. In most infected individuals, Entamoeba histolytica or a related species infects the lumen of the gastrointestinal tract and causes few symptoms or sequelae. Although E. histolytica is the only confirmed invasive species, other Entamoeba species have been implicated in human disease. Molecular epidemiology is helping detail the role that these diverse protozoans play in human health. Invasive E. histolytica infection can lead to amebic colitis, amebic liver abscess, and, less commonly, abscesses in other extraintestinal sites. ETIOLOGY Four morphologically identical but genetically distinct species of Ent amoeba are known to infect humans. Entamoeba histolytica, the main pathogenic species, causes a spectrum of disease and can become inva sive in 410 of infected patients. Entamoeba dispar, the most prevalent species, does not cause symptomatic disease. Entamoeba moshkovskii, can cause diarrhea in infants and children, and asymptomatic infec tion with E. moshkovskii may be as common as E. dispar infection in some communities. Patients previously described as asymptomatic carriers of E. histolytica based on microscopy findings were likely har boring E. dispar or E. moshkovskii. A fourth species, E. bangladeshi, was discovered in Bangladesh in 2012 and has recently been found in South Africa. The potential for E. bangladeshi to cause human disease remains unclear. Four other species of nonpathogenic Entamoeba are known to colonize the human gastrointestinal tract: Entamoeba coli, E. hartmanni, E. gingivalis, and E. |
8,053 | polecki. A fifth species, E. nuttalli, typically infects nonhuman primates such as macaques, but a case of asymptomatic infection has been described in a zookeeper. Infection is usually acquired through the ingestion of parasite cysts, which measure 10 18 m in diameter and contain four nuclei. Cysts are resistant to harsh environmental conditions, including chlorine concen trations commonly used in water purification, but can be killed by heating them to 55C (131F). Cysts are resistant to gastric acidity and digestive enzymes and germinate in the small intestine to form trophozoites. These large, actively motile organisms colonize the lumen of the large intestine and may invade the mucosal lining. Some eventually transform to cysts and are passed out in the stool to infect other hosts anew. EPIDEMIOLOGY The prevalence of infection with E. histolytica varies greatly by region and socioeconomic status. Early prevalence studies did not distinguish between E. histolytica and E. dispar, but more recent estimates show that infection with E. histolytica causes 100 million cases of symptom atic disease and 2,000 to 17,000 deaths annually. Molecular studies have put the global prevalence of E. histolytica at 3.55, ranging from 1.72 to 21.58 in different regions of the world. Prospective studies have shown that 410 of individuals infected with E. histolytica develop amebic colitis and that 1 of infected indi viduals develop disseminated disease, including amebic liver abscess. These numbers vary by region; for example, in South Africa and Viet nam, liver abscesses form a disproportionately large number of the cases of invasive disease due to E. histolytica. Amebic liver abscesses occur equally in male and female children but are generally rare in childhood. Peak abscess formation occurs in individuals between 30 60 years old and is 10 12 times more prevalent in adult males than females. Amebiasis causes its largest burden of disease in Africa, Southeast Asia, and the Eastern Mediterranean. In the United States, amebiasis is seen most frequently in travelers to and immigrants from develop ing countries. Residents of mental health institutions and men who have sex with men are at increased risk for invasive amebiasis. Food or drink contaminated with Entamoeba cysts and oral anogenital sex are the most common means of infection. Untreated water and night soil (human feces used as fertilizer) are important sources of infection in resource limited settings. Food handlers shedding amebic cysts play a role in spreading infection. PATHOGENESIS Trophozoites are responsible for tissue invasion and destruction. E. his tolytica secretes many proteases, the best described of which is amebic cysteine protease 5 (EhCP5). EhCP5 cleaves MUC2 mucin, degrading the intestinal mucus layer and exposing colonic epithelial cells. MUC2 is also involved in regulating antimicrobial peptide production by Pan eth cells during E. histolytica infection. Amebae then attach using a galactose and N acetyl d galactosaminespecific lectin. This lectin also provides resistance to complement mediated lysis, and its inter mediate subunit has been found to have hemagglutinating, hemolytic, and cytolytic activity. Once attached to the colonic mucosa, trophozoites penetrate the epithelial |
8,054 | layer, destroying host cells by cytolysis and induction of apoptosis. Cytolysis is mediated by trophozoite release of amebapores (pore forming proteins), phospholipases, and hemolysins. Once host cells are partially digested by amebic proteases, the degraded mate rial is internalized through phagocytosis. Trogocytosis is another mechanism that amebae use to kill host cells. This involves ingesting pieces of living cells, inducing intracellular calcium elevation leading to apoptosis. Early invasive amebiasis produces significant inflammation, owing in part to parasite mediated activation of nuclear factor B. Once E. his tolytica trophozoites invade the intestinal mucosa, the organisms multiply and spread laterally underneath the intestinal epithelium to produce the characteristic flask shaped ulcers. Amebae produce similar lytic lesions if they reach the liver. These lesions are commonly called abscesses, although they contain no granulocytes. Well established ulcers and amebic liver abscesses demonstrate little local inflammatory response. Immunity to infection is associated with a mucosal secretory IgA response against the galactoseN acetyl d galactosamine lectin. Macrophages are among the earliest responders, mediating phago cytosis and secreting cytokines to recruit other inflammatory cells. Eosinophilia is common in parasitic infections and may play a role in IgA regulation. Neutrophils are generally protective and exert amebi cidal activity by phagocytosis, degranulation, and formation of neu trophil extracellular traps (NETs). The disparity between the extent of tissue destruction by amebae and the absence of a local host inflamma tory response in the presence of systemic humoral and cell mediated responses may reflect both parasite mediated apoptosis and the ability of the trophozoite to kill not only epithelial cells but also neutrophils, monocytes, and macrophages. The E. histolytica genome is functionally tetraploid, and there is evi dence of lateral gene transfer from bacteria. The amebapore A (Ap A) gene, along with other important genes, can be epigenetically silenced using plasmids with specifically engineered sequences or short hair pin RNAs. Transcriptional profiling using proteomics and micro arrays has identified multiple virulence factors, including cysteine proteases, which modulate lysosome and phagosome function, as well as excretory secretory proteins. Many calcium binding proteins are encoded and are involved in motility, adhesion, cytolysis, and phago cytosis. Some of these proteins bind directly to actin to modulate pseu dopod formation and phagocytosis. The bacterial microbiome has also been shown to influence E. histolytica pathogenicity by affecting lec tin expression, with increased Prevotella copri populations associated with higher rates of diarrhea in infected children. Enteropathogenic Escherichia coli have been linked to increased E. histolytica virulence through upregulation of amebic proteolytic activity. Enteric bacteria improve survival of these anaerobic amebae during times of oxidative stress. Decreased bacterial diversity has been linked to an increase in symptomatic amebic infections in children. Chapter 327 Amebiasis Edsel Maurice T. Salvana and Robert A. Salata 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. 2148 Part XV u Infectious Diseases CLINICAL MANIFESTATIONS Clinical presentations range from |
8,055 | asymptomatic cyst passage to amebic colitis, amebic dysentery, ameboma, and extraintestinal disease. Up to 10 of infected persons develop invasive disease within a year, and asymptomatic carriers should be treated. Severe disease is more com mon in young children, pregnant women, malnourished individuals, and persons taking corticosteroids. Invasive disease is more common in men. Extraintestinal disease usually involves the liver, but less com mon extraintestinal manifestations include amebic brain abscess, pleu ropulmonary disease, skin ulcers, and genitourinary lesions. Amebic Colitis Amebic colitis may occur within 2 weeks of infection or may be delayed for months. The onset is usually gradual, with colicky abdominal pain and frequent bowel movements (6 8day). Diarrhea is frequently associated with tenesmus. Almost all stool is heme positive, but most patients do not present with grossly bloody stools. Generalized consti tutional symptoms and signs are characteristically absent, with fever documented in only one third of patients. Amebic colitis affects all age groups but is strikingly common in children 1 5 years of age. Severe amebic colitis in infants and young children tends to be rapidly pro gressive, with more frequent extraintestinal involvement and high mortality rates, particularly in tropical countries. Amebic dysentery can result in dehydration and electrolyte disturbances. Amebic Liver Abscess Amebic liver abscess, a serious manifestation of disseminated infec tion, is uncommon in children. Although diffuse liver enlargement has been associated with intestinal amebiasis, liver abscesses occur in 1 of infected individuals and may appear in patients with no clear history of intestinal disease. Amebic liver abscess may occur months to years after exposure, so obtaining a careful travel history is critical. In children, fever is the hallmark of amebic liver abscess and is frequently associated with abdominal pain, abdominal distention, and enlargement and ten derness of the liver. Changes at the base of the right lung may also occur, including elevation of the diaphragm and atelectasis or effusion. LABORATORY FINDINGS Laboratory examination findings are often unremarkable in uncompli cated amebic colitis. Laboratory findings in amebic liver abscess are a slight leukocytosis, moderate anemia, high erythrocyte sedimentation rate, and elevations of hepatic enzyme (particularly alkaline phospha tase) levels. Stool examination for amebae is negative in more than half of patients with documented amebic liver abscess. Ultrasonography, CT, or MRI can localize and delineate the size of the abscess cavity (Fig. 327.1). The most common finding is a single abscess in the right hepatic lobe. DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS A diagnosis of amebic colitis is made in the presence of compatible symptoms with detection of E. histolytica either by stool antigen testing or PCR. This approach has a greater than 95 sensitivity and specificity, and when it is coupled with a positive serology test, it is the most accu rate means of diagnosis in developed countries. Several approved stool antigen kits are commercially available in the United States, but most cannot distinguish between E. histolytica and E. dispar. Microscopic examination of stool samples has a sensitivity of 60. Sensitivity can be increased to 8595 by |
8,056 | examining three stools. Microscopy cannot dif ferentiate between E. histolytica, E. dispar, E. moshkovskii, and E. ban gladeshi unless phagocytosed erythrocytes (specific for E. histolytica) are seen. Endoscopy and biopsies of suspicious areas should be performed when stool sample results are negative and suspicion remains high. Vari ous serum antibody tests are available. Serologic results are positive in 7080 of patients with invasive disease (colitis or liver abscess) at pre sentation and in 90 of patients after 7 days. Indirect hemagglutination is the most sensitive serologic test and yields a positive result even years after invasive infection. Therefore many uninfected adults and children in highly endemic areas demonstrate antibodies to E. histolytica. Conventional and real time multiplex PCR performed on stool is the most sensitive and preferred method for distinguishing E. histolyt ica from nonpathogenic E. dispar, E. moshkovskii, and E. bangladeshi. Different multiplex formats have also been developed, including enteric pathogen panels with varying sensitivities and specificities. Tetraplex assays that can distinguish between all four morphologically identical isolates have also been developed. Isothermal nucleic acid methods using recombinase and loop mediated amplification (LAMP) in point of care diagnostics are promising and will greatly facilitate treatment, especially in developing countries. A small study using quantitative PCR detected E. histolytica DNA in the serum of patients with amebic liver abscess with a sensitivity of 89.5 and a specificity of 100. The differential diagnosis for amebic colitis includes colitis due to bacterial, mycobacterial, and viral pathogens, as well as noninfectious causes such as inflammatory bowel disease. Pyogenic liver abscess due to bacterial infection, hepatoma, and echinococcal cysts are in the dif ferential diagnosis for amebic liver abscess. However, echinococcal cysts are rarely associated with systemic symptoms such as fever, unless there is cyst rupture or leakage. COMPLICATIONS Complications of amebic colitis include acute necrotizing colitis, ame boma, toxic megacolon, extraintestinal extension, and local perfora tion and peritonitis. Less commonly, a chronic form of amebic colitis develops, often recurring over several years. Amebomas are nodular foci of proliferative inflammation that sometimes develop in the wall of the colon. Amebiasis should be excluded before initiating corticoste roid treatment for inflammatory bowel disease because steroid treat ment of E. histolytica is associated with high mortality rates. An amebic liver abscess may rupture into the peritoneum, pleural cavity, skin, and pericardium. Cases of amebic abscesses in extrahe patic sites, including the lung and brain, have been reported. TREATMENT Invasive amebiasis is treated with a nitroimidazole such as metronida zole or tinidazole and then a luminal amebicide (Table 327.1). Tinida zole may have better clinical efficacy than metronidazole, with shorter and simpler dosing, and is better tolerated. Adverse effects include nau sea, abdominal discomfort, and a metallic taste that disappears after completion of therapy. Therapy with a nitroimidazole should be followed by treatment with a luminal agent, such as paromomycin (which is pre ferred) or iodoquinol. Diloxanide furoate can also be used in children 2 years of age but is no longer available in the United States. |
8,057 | Paromomy cin should not be given concurrently with metronidazole or tinidazole because diarrhea is a common side effect of paromomycin and may con fuse the clinical picture. Asymptomatic intestinal infection with E. his tolytica should be treated, preferably with paromomycin or alternatively with either iodoquinol or diloxanide furoate. For fulminant cases of amebic colitis, some experts suggest adding dehydroemetine (1 mgkg Fig. 327.1 Abdominal CT scan of a patient with an amebic liver ab scess. (From Miller Q, Kenney JM, Cotlar AM. Amebic abscess of the liv er presenting as acute cholecystitis. Curr Surg. 2000;57:476479. Fig. 1.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 328 u Giardiasis and Balantidiasis 2149 day subcutaneously or intramuscularly, never intravenously), available only through the Centers for Disease Control and Prevention (CDC). Patients should be hospitalized for monitoring if dehydroemetine is administered. Dehydroemetine should be discontinued if tachycardia, T wave depression, arrhythmia, or proteinuria develops. Nitazoxanide has been shown to be amebicidal in several clinical trials, but more stud ies are needed to define optimal dosing and duration of treatment. Broad spectrum antibiotic therapy may be indicated in fulminant colitis to cover possible spillage of intestinal bacteria into the peritoneum and translocation into the bloodstream. Intestinal perforation and toxic megacolon are indications for surgery. In amebic liver abscess, image guided aspiration of large lesions or left lobe abscesses may be necessary if rupture is imminent or if the patient shows a poor clinical response 4 6 days after administration of amebicidal drugs. A Cochrane meta analysis comparing metronidazole and metronidazole plus aspiration in uncomplicated amebic liver abscess showed that there is insufficient evi dence to make any recommendation for or against this approach. Chlo roquine, which concentrates in the liver, may also be a useful adjunct to nitroimidazoles in the treatment of amebic liver abscess or in cases of treatment failure or intolerance. To confirm cure, stool examination should be repeated every 2 weeks after completion of therapy until clear. PROGNOSIS Most infections evolve to either an asymptomatic carrier state or eradi cation. Extraintestinal infection carries about a 5 mortality rate. PREVENTION Control of amebiasis can be achieved by exercising proper sanitation and hygiene. Regular examination of food handlers and thorough Table 327.1 Drug Treatment for Amebiasis MEDICATION ADULT DOSAGE (ORAL) PEDIATRIC DOSAGE (ORAL) INVASIVE DISEASE Metronidazole Colitis or liver abscess: 500 mg tid for 7 10 days Colitis or liver abscess: 35 50 mgkgday in 3 divided doses for 7 10 days Or Tinidazole Colitis: 2 g once daily for 3 days Colitis: 50 mgkgday once daily for 3 days Liver abscess: 2 g once daily for 3 5 days Liver abscess: 50 mg kgday once daily for 3 5 days Followed by: Paromomycin (preferred) 500 mg tid for 7 days 25 35 mgkgday in 3 divided doses for 7 days Or Diloxanide furoate 500 mg |
8,058 | tid for 10 days 20 mgkgday in 3 divided doses for 7 days Or Iodoquinol 650 mg tid for 20 days 30 40 mgkgday in 3 divided doses for 20 days ASYMPTOMATIC INTESTINAL COLONIZATION Paromomycin (preferred) As for invasive disease As for invasive disease Or Diloxanide furoate Or Iodoquinol All pediatric dosages are up to a maximum of the adult dose. Not available in the United States. investigation of diarrheal episodes may help identify the source of infection. No prophylactic drug or vaccine is available. Immunization with different E. histolytica antigens has shown promis ing protective responses in animal models. Amebic surface protein LecA, galactoseN acetyl d galactosamine lectin, serine rich E. histolytica pro tein (SREHP), heparan sulfate binding proteins, and other antigens have elicited protective immune responses, especially in combination with different adjuvants. Acquired immune response can be protective as evi denced by anti lectin IgA in stool among Bangladeshi children. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Chapter 328 Giardiasis and Balantidiasis 328.1 Giardia duodenalis Chandy C. John Giardia duodenalis is a flagellated protozoan that infects the duodenum and jejunum. Infection results in clinical manifestations that range from asymptomatic colonization to acute or chronic diarrhea and mal absorption. Infection is more prevalent in children than in adults. Giar dia is endemic in areas of the world with poor levels of sanitation. It is also an important cause of morbidity in developed countries, where it is associated with urban childcare centers, residential institutions for the developmentally delayed, and waterborne and foodborne out breaks. Giardia is a particularly significant pathogen in children with malnutrition and certain immunodeficiencies (IgA deficiency, com mon variable immunodeficiency, X linked hypogammaglobulinemia). ETIOLOGY The life cycle of G. duodenalis (also known as Giardia lamblia or Giardia intestinalis) is composed of two stages: trophozoites and cysts. Giardia infects humans after ingestion of as few as 10 100 cysts, which measure 8 10 m in diameter. Each ingested cyst produces two trophozoites in the duodenum. After excystation, trophozoites colonize the lumen of the duodenum and proximal jejunum, where they attach to the brush border of the intestinal epithelial cells and multiply by binary fission. The body of the trophozoite is teardrop shaped, measuring 10 20 m in length and 5 15 m in width. Giardia trophozoites contain two oval nuclei ante riorly, a large ventral disk, a curved median body posteriorly, and four pairs of flagella. As detached trophozoites pass down the intestinal tract, they encyst to form oval cysts that contain four nuclei. Cysts are passed in stools of infected individuals and may remain viable in water for as long as 2 months. Their viability often is not affected by the usual con centrations of chlorine used to purify water for drinking. Giardia strains that infect humans are diverse biologically, as shown by differences in antigens, restriction endonuclease patterns, DNA fin gerprinting, isoenzyme patterns, and pulsed field gel electrophoresis. Studies suggest that different Giardia genotypes may cause unique clinical manifestations, but these findings appear to vary according |
8,059 | to the geographic region tested. EPIDEMIOLOGY Giardia occurs worldwide and is the most common intestinal parasite identified in public health laboratories in the United States, where it is estimated that up to 2 million cases of giardiasis occur annually. Giar dia infection usually occurs sporadically, but Giardia is a frequently identified etiologic agent of outbreaks associated with drinking water. The age specific prevalence of giardiasis is high during childhood and begins to decline after adolescence. The asymptomatic carrier rate of G. 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. 2150 Part XV u Infectious Diseases lamblia in the United States is as high as 2030 in children younger than 36 months of age attending childcare centers. Asymptomatic car riage may persist for several months. Risk of acquiring and transmitting Giardia is increased in chil dren and employees in childcare centers, individuals who drink con taminated water, international travelers, men who have sex with men, immunodeficient individuals, and individuals exposed to farm ani mals. Children visiting friends and relatives are at increased risk for Giardia infections during international travel. The major reservoir and vehicle for spread of Giardia appears to be water contaminated with Giardia cysts, but foodborne transmission also occurs. The seasonal peak in age specific case reports coincides with the summer recre ational water season and may be a result of the extensive use of com munal swimming venues by young children, the low infectious dose, and the extended periods of cyst shedding that can occur. In addition, Giardia cysts are relatively resistant to chlorination and to ultraviolet light irradiation. Boiling is effective for inactivating cysts. Person to person spread also occurs, particularly in areas of low hygiene standards, frequent fecal oral contact, and crowding. Indi vidual susceptibility, lack of toilet training, crowding, and fecal con tamination of the environment all predispose to transmission of enteropathogens, including Giardia, in childcare centers. Childcare centers play an important role in transmission of urban giardiasis, with secondary attack rates in families as high as 1730. Children in child care centers may pass cysts for several months. Campers who drink untreated stream or river water, particularly in the western United States, and residents of institutions for the developmentally delayed are also at increased risk for infection. Humoral immunodeficiencies, including common variable immu nodeficiency and X linked agammaglobulinemia, predispose humans to chronic symptomatic Giardia infection, suggesting the importance of humoral immunity in controlling giardiasis. Selective immunoglob ulin A deficiency is also associated with Giardia infection. Although many individuals with AIDS have relatively mild Giardia infections, Giardia infection refractory to treatment may occur in a subset of indi viduals with AIDS. Human milk contains glycoconjugates and secre tory immunoglobulin A antibodies that may provide protection to nursing infants against Giardia. CLINICAL MANIFESTATIONS The incubation period of Giardia infection usually is 1 2 weeks but may be longer. A broad |
8,060 | spectrum of clinical manifestations occurs, depend ing on the interaction between G. lamblia and the host. Children who are exposed to G. lamblia may experience asymptomatic excretion of the organism, acute infectious diarrhea, or chronic diarrhea with per sistent gastrointestinal tract signs and symptoms, including failure to thrive and abdominal pain or cramping. Giardia was the cause of 15 of nondysenteric diarrheal illnesses in children examined in U.S. out patient clinics in one study. Most infections in children and adults are asymptomatic. There is usually no extraintestinal spread, but occasion ally trophozoites may migrate into bile or pancreatic ducts. Symptomatic infections occur more frequently in children than in adults. Most symptomatic patients usually have a limited period of acute diarrheal disease with or without low grade fever, nausea, and anorexia; in a small proportion of patients, an intermittent or more protracted course characterized by diarrhea, abdominal distention and cramps, bloating, malaise, flatulence, nausea, anorexia, and weight loss develops (Table 328.1). Stools initially may be profuse and watery and later become greasy and foul smelling and may float. Stools do not contain blood, mucus, or fecal leukocytes. Varying degrees of malab sorption may occur. Abnormal stool patterns may alternate with peri ods of constipation and normal bowel movements. Malabsorption of sugars, fats, and fat soluble vitamins is well documented and may be responsible for substantial weight loss. Giardia has been associated with iron deficiency in internationally adopted children. Extraintes tinal manifestations of Giardia appear to be more common in adults than children and include arthritis and, in one report after an outbreak, chronic fatigue syndrome. Giardiasis in children has been associated with growth stunting, and repeated Giardia infections correlate with a decrease in cognitive function in children in endemic areas. DIAGNOSIS Giardiasis should be considered in children who have acute nondysen teric diarrhea, persistent diarrhea, intermittent diarrhea and constipa tion, malabsorption, chronic crampy abdominal pain and bloating, failure to thrive, or weight loss. It should be particularly high in the differential diagnosis of children in childcare centers, children in con tact with an index case, children with a history of recent travel to an endemic area, and children with humoral immunodeficiencies. Testing for giardiasis should be standard for internationally adopted children from Giardia endemic areas, and screening for iron deficiency should be considered in internationally adopted children with giardiasis. Stool enzyme immunoassay (EIA) or direct fluorescent antibody tests for Giardia antigens are the tests of choice for giardiasis. EIA is less reader dependent and more sensitive for detection of Giardia than microscopy. Some studies report that a single stool is sufficiently sensitive for detec tion of Giardia by EIA, whereas others suggest that sensitivity is increased with testing of two samples. A diagnosis of giardiasis was traditionally established by microscopy documentation of trophozoites or cysts in stool specimens, but three stool specimens are required to achieve a sensitivity of 90 using this approach. In patients in whom other parasitic intesti nal infections are in the differential diagnosis, microscopy examination of stool |
8,061 | allows evaluation for these infections in addition to Giardia. Polymerase chain reaction and gene probebased detection systems specific for Giardia have been used in environmental monitoring and clinical testing. Multiplex polymerase chain reaction testing for mul tiple parasitic pathogens is a viable option for testing. In patients with chronic symptoms in whom giardiasis is suspected but in whom testing of stool specimens for Giardia yields a negative result, aspiration or biopsy of the duodenum or upper jejunum should be considered. In a fresh specimen, trophozoites usually can be visualized by direct wet mount. An alternate method of directly obtaining duodenal fluid is the commercially available Entero Test (Hedeco Corp, Mountain View, CA), but this method is less sensitive than aspiration or biopsy. The biopsy can be used to make touch preparations and tissue sections for identification of Giardia and other enteric pathogens and also to visu alize changes in histology. Biopsy of the small intestine should be con sidered in patients with characteristic clinical symptoms, negative stool and duodenal fluid specimen findings, and one or more of the following: abnormal radiographic findings (such as edema and segmentation in the small intestine); an abnormal lactose tolerance test result; an absent secretory immunoglobulin A level; hypogammaglobulinemia; or achlor hydria. Duodenal biopsy may show findings consistent with chronic inflammation, including eosinophilic infiltration of the lamina propria. Radiographic contrast studies of the small intestine may show non specific findings such as irregular thickening of the mucosal folds. Blood cell counts usually are normal. Giardiasis is not tissue invasive and is not associated with peripheral blood eosinophilia. Table 328.1 Clinical Signs and Symptoms of Giardiasis SYMPTOM FREQUENCY () Diarrhea 64100 Malaise, weakness 7297 Abdominal distention 4297 Flatulence 3597 Abdominal cramps 4481 Nausea 1479 Foul smelling, greasy stools 1579 Anorexia 4173 Weight loss 5373 Vomiting 1435 Fever 028 Constipation 027 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 328 u Giardiasis and Balantidiasis 2151 TREATMENT Children with acute diarrhea in whom Giardia organisms are identi fied should receive therapy. In addition, children who manifest failure to thrive or exhibit malabsorption or gastrointestinal tract symptoms such as chronic diarrhea should be treated. Asymptomatic excreters generally are not treated, except in specific instances such as outbreak control, prevention of household transmis sion by toddlers to pregnant women and patients with hypogamma globulinemia or cystic fibrosis, and situations requiring oral antibiotic treatment where Giardia may produce malabsorption of the antibiotic. The FDA has approved tinidazole and nitazoxanide for the treatment of Giardia in the United States. Both medications have been used to treat Giardia in thousands of patients in other countries and have excellent safety and efficacy records against Giardia (Table 328.2). Tinidazole has the advantage of single dose treatment and very high efficacy (90), while nitazoxanide has the advantage of a suspension form, high efficacy (8090), and very few adverse effects. |
8,062 | Metronidazole, although never approved by the FDA for treatment of Giardia, is also highly effective (8090 cure rate), and the generic form is considerably less expensive than tinidazole or nitazoxanide. For children 3 year of age, tinidazole is the preferred treatment, with nitazoxanide as alternative, while for chil dren 1 2 years, nitazoxanide is the preferred treatment, since tinidazole is approved only for children 3 years of age. Metronidazole is the drug of choice for children 12 months and an alternative to tinidazole and nitazoxanide for children 12 months. Recent reports on travelers to South Asia document resistance rates as high as 30 to metronidazole, so nitazoxanide or tinidazole may be preferred for children who have traveled to or are from this area. Frequent adverse effects are seen with metronidazole therapy, and it requires 3 times a day dosing for 5 7 days. Suspension forms of tinidazole and metronidazole must be compounded by a pharmacy; neither drug is sold in suspension form. Second line alternatives for the treatment of patients with giardiasis include albendazole, paromomycin, and quinacrine (see Table 328.2). Albendazole may be of similar efficacy to metronidazole. Albendazole has few adverse effects and is effective against many helminths, making it useful for treatment when multiple intestinal parasites are identified or suspected. Paromomycin is a nonabsorbable aminoglycoside and is less effective than other agents but is recommended for treatment of preg nant women with giardiasis because of the potential teratogenic effects of other agents. Quinacrine is effective and inexpensive but is not available commercially and must be obtained from compounding pharmacies (see Table 328.2). Quinacrine can also rarely have serious side effects, including hallucinations and psychosis. Refractory cases of giardiasis have been successfully treated with a number of regimens, including nitazoxanide, prolonged courses of tinidazole, or combination therapy, most commonly a 3 week course of metronidazole and quinacrine. PROGNOSIS Symptoms recur in some patients in whom reinfection cannot be documented and in whom an immune deficiency such as an immuno globulin abnormality is not present, despite use of appropriate therapy. Several studies have demonstrated that variability in antimicrobial sus ceptibility exists among strains of Giardia, and in some instances resis tant strains have been demonstrated. Combined therapy may be useful for infection that persists after single drug therapy, assuming reinfec tion has not occurred and the medication was taken as prescribed. PREVENTION Infected persons and persons at risk should practice strict handwash ing after any contact with feces. This point is especially important for caregivers of diapered infants in childcare centers, where diarrhea is common and Giardia organism carriage rates are high. Methods to purify public water supplies adequately include chlori nation, sedimentation, and filtration. Inactivation of Giardia cysts by chlorine requires the coordination of multiple variables such as chlorine concentration, water pH, turbidity, temperature, and contact time. These variables cannot be appropriately controlled in all municipalities and are difficult to control in swimming pools. Individuals, especially children in diapers, should avoid swimming if they have diarrhea. Individuals should also |
8,063 | avoid swallowing recreational water and drinking untreated water from shallow wells, lakes, springs, ponds, streams, and rivers. Travelers to endemic areas are advised to avoid uncooked foods that might have been grown, washed, or prepared with water that was potentially contaminated. Purification of drinking water can be achieved by a filter with a pore size of 1 m or that has been rated by the National Sanitation Foundation for cyst removal, or by brisk boil ing of water for at least 1 minute. Treatment of water with chlorine or iodine is less effective but may be used as an alternate method when boiling or filtration is not possible. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. 328.2 Balantidiasis Chandy C. John Balantidium coli is a ciliated protozoan and is the largest protozoan that parasitizes humans. Both trophozoites and cysts may be identified in feces. Disease caused by this organism is uncommon in the United States and generally is reported where there is a close association of humans with pigs, which are the natural hosts of B. coli. Because the organism infects the large intestine, symptoms are consistent with large bowel disease, similar to those associated with amebiasis and trichuriasis, and include nausea, vomiting, lower abdominal pain, tenesmus, and bloody diarrhea. Symptoms associated with chronic infection include abdomi nal cramps, watery diarrhea with mucus, occasionally bloody diarrhea, and colonic ulcers similar to those associated with Entamoeba histolytica. Extraintestinal spread of B. coli is rare and usually occurs only in immu nocompromised patients. Most infections are asymptomatic. Diagnosis using direct saline mounts is established by identification of trophozoites (50 100 m long) or spherical or oval cysts (50 70 m in diameter) in stool specimens. Trophozoites usually are more numer ous than cysts. The recommended treatment regimen is metronidazole (2550 mg kgday divided tid PO; maximum: 750 mgdose) for 5 days, or tetracy cline (40 mgkgday divided qid PO; maximum: 500 mgdose) for 10 days for persons older than 8 years of age. An alternative is iodoquinol (40 mgkgday divided tid PO; maximum: 650 mgdose) for 20 days. Prevention of contamination of the environment by pig feces is the most important means for control. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Table 328.2 Drug Treatment for Giardiasis MEDICATION ADULT DOSAGE (ORAL) PEDIATRIC DOSAGE (ORAL) RECOMMENDED Tinidazole 2 g once 3 yr: 50 mgkg once Nitazoxanide 500 mg bid for 3 days 1 3 yr: 100 mg (5 mL) bid for 3 days 4 11 yr: 200 mg (10 mL) bid for 3 days 12 yr: 500 mg bid for 3 days Metronidazole 250 mg tid for 5 7 days 15 mgkgday in 3 divided doses for 5 7 days ALTERNATIVE Albendazole 400 mg once a day for 5 days 6 yr: 400 mg once a day for 5 days Paromomycin 500 mg tid for 5 10 days Not recommended Quinacrine 100 mg tid for 5 7 days 6 mgkgday in 3 divided doses for 5 days All pediatric dosages are up to a |
8,064 | maximum of the adult dose. Not commercially available. Can be compounded by Medical Center Pharmacy in New Haven, CT (203 688 8970) or Panorama Compounding Pharmacy in Van Nuys, CA (818 988 7979). 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. 2152 Part XV u Infectious Diseases The spore forming intestinal protozoa Cryptosporidium, Cystoisospora (formerly Isospora), and Cyclospora are important intestinal pathogens in both immunocompetent and immunocompromised hosts. Crypto sporidium, Cystoisospora, and Cyclospora are coccidian parasites that predominantly infect the epithelial cells lining the digestive tract, and all are transmitted by the fecal oral route. Microsporidia were formerly considered spore forming protozoa but have been reclassified as fungi. Microsporidia are ubiquitous, obligate intracellular organisms that infect many other organ systems in addition to the gastrointestinal tract and cause a broader spectrum of disease. CRYPTOSPORIDIUM Cryptosporidium is recognized as a leading protozoal cause of diarrhea in children worldwide and is a common cause of outbreaks in child care centers; it is also a significant pathogen in immunocompromised patients. Etiology Cryptosporidium hominis and Cryptosporidium parvum cause most cases of cryptosporidiosis in humans. Disease is initiated by inges tion of infectious oocysts that were excreted in the feces of infected humans and animals. The oocysts are immediately infectious to other hosts or can reinfect the same host. The ingested oocysts release spo rozoites that attach to and invade the intestinal epithelial cells. Epidemiology Cryptosporidiosis is associated with diarrheal illness worldwide and is more prevalent in developing countries and among children younger than 2 years of age. It has been implicated as an etiologic agent of per sistent diarrhea in the developing world and as a cause of significant morbidity and mortality from malnutrition, including permanent effects on growth. Risk factors for infection include animal contact, diarrhea in a household member, open defecationlack of toilet facili ties, and poor drinking water quality. Transmission of Cryptosporidium to humans can occur by close association with infected animals, via person to person transmission, or from environmentally contaminated water and food. Although zoonotic transmission, especially from cows, occurs in persons in close association with animals, person to person transmission is probably responsible for cryptosporidiosis outbreaks within hospitals and childcare centers, where transmission rates as high as 67 have been reported. Recommendations to prevent outbreaks in childcare centers include exclusion of children with diarrhea from attending, strict handwashing, elimination of water play or swimming activi ties, use of protective clothes or diapers capable of retaining liquid diarrhea, and separation of diapering and food handling areas and responsibilities. Outbreaks of cryptosporidial infection are associated with contami nated community water supplies and recreational waters, including lakes and chlorinated swimming pools. Wastewater in the form of raw sewage and runoff from dairies and grazing lands can contaminate both drinking and recreational water sources. It is estimated that Cryp tosporidium oocysts are present in 6597 of the |
8,065 | surface water in the United States. The organisms small size (4 6 m in diameter), resis tance to chlorination, and ability to survive for long periods outside a host create problems in public water supplies. Clinical Manifestations The incubation period is 2 10 days (average, 7 days) after infection. Cryptosporidium infection is associated with profuse, watery, non bloody diarrhea that can be accompanied by diffuse crampy abdomi nal pain, nausea, vomiting, and anorexia. Although less common in adults, vomiting occurs in more than 80 of children with cryptospo ridiosis. Nonspecific symptoms such as myalgia, weakness, and head ache also may occur. Fever occurs in 3050 of cases. Malabsorption, lactose intolerance, dehydration, weight loss, and malnutrition often occur in severe cases. The clinical spectrum and disease severity have been linked with both the infecting species and host human leukocyte antigen class I and class II alleles. In immunocompetent persons, the disease is usually self limiting, typically 5 10 days, although diarrhea may persist for several weeks and oocyst shedding may persist for many weeks after symptoms resolve. Chronic diarrhea is common in young infants and individuals with immunodeficiency, such as congenital hypogammaglobulinemia or HIV infection. Symptoms and oocyst shedding can continue indefi nitely and may lead to severe malnutrition, wasting, anorexia, and even death. Cryptosporidiosis in immunocompromised hosts is often associated with biliary tract disease, characterized by fever, right upper quadrant pain, nausea, vomiting, and diarrhea. It also is associated with pancre atitis. Respiratory tract disease is rare. Diagnosis Infection can be diagnosed by microscopy using modified acid fast stain or polymerase chain reaction (PCR), but immunodetection of antigens on the surface of the organism in stool samples using mono clonal antibodybased assays is the current diagnostic method of choice because of the high sensitivity and specificity. Multiplex molec ular test panels for gastrointestinal pathogens that include Cryptospo ridium are available and are a standard test. In stool, oocysts appear as small, spherical bodies (2 6 m) and stain red with modified acid fast staining. Because Cryptospo ridium does not invade below the epithelial layer of the mucosa, fecal leukocytes are not found in stool specimens. Oocyst shedding in feces can be intermittent, and several fecal specimens (at least three for an immunocompetent host) should be collected for micro scopic examination. Serologic diagnosis is not helpful in acute cryptosporidiosis. In tissue sections, Cryptosporidium organisms can be found along the microvillus region of the epithelia that line the gastrointestinal tract. The highest concentration usually is detected in the jejunum. Histologic section results reveal villus atrophy and blunting, epithelial flattening, and inflammation of the lamina propria. Treatment Often the diarrheal illness attributable to cryptosporidiosis is self limited in immunocompetent patients and requires no specific antimi crobial therapy. Treatment should focus on supportive care, including rehydration orally or, if fluid losses are severe, intravenously. A 3day course of nitazoxanide (100 mg bid PO for 3 days for children 1 3 years of age; 200 mg bid PO for children 4 11 years of age; |
8,066 | 500 mg bid PO for children 12 years of age) is approved for treatment of diarrhea caused by Cryptosporidium. A recent meta analysis revealed a favorable clini cal response to treatment with nitazoxanide compared with placebo, although the parasitologic response was no different than the response to placebo. Clinical studies have not definitively demonstrated that nitazoxanide is superior to placebo in trials of HIV infected (with low CD4 counts) or immunocompromised patients. However, given the severity of the infection in these populations, nitazoxanide treatment Chapter 329 Cryptosporidium, Cystoisospora, Cyclospora, and Microsporidia Sarah M. Heston and Patricia M. Flynn 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 329 u Cryptosporidium, Cystoisospora, Cyclospora, and Microsporidia 2153 is usually initiated. Immune function should be optimized in immu nocompromised patients, with combination antiretroviral therapy in patients living with HIV and decreased immunosuppression in trans plant recipients, if possible. Other agents that have been suggested for treatment in clinical reports or small studies include orally adminis tered human serum immunoglobulin or bovine colostrum, paromo mycin, spiramycin, azithromycin, and roxithromycin or a combination of antibiotics. Clofazimine was recently investigated as a potential therapy among adults living with HIV; however, it failed to show effi cacy based on clinical and parasitologic outcomes. Prevention mea sures include adequate hand hygiene, avoiding untreated ice or water, especially in areas with poor sanitation, and exclusion of children with diarrhea from public pools. CYSTOISOSPORA Like Cryptosporidium, Cystoisospora belli is implicated as a cause of diarrhea in institutional outbreaks and in travelers and has also been linked with contaminated water and food. Cystoisospora appears to be more common in tropical and subtropical climates and in developing areas, including South America, Africa, and Southeast Asia. Cystoisos pora has not been associated with animal contact. It is also an infre quent cause of diarrhea in patients with AIDS in the United States but may infect up to 15 of AIDS patients in Haiti. The life cycle and pathogenesis of infection with Cystoisospora spe cies are similar to those of Cryptosporidium organisms except that oocysts excreted in the stool are not immediately infectious and must undergo further maturation at temperatures below 37C (98.6F). Thus direct person to person transmission is unlikely. The incu bation period averages approximately one week. The most common clinical manifestation is watery, nonbloody diarrhea. Symptoms of infection are indistinguishable from those of cryptosporidiosis, although fever may be a more common finding. Eosinophilia may be present in up to 50 of cases, contrasting with other enteric pro tozoan infections. The diagnosis is established by detecting the oval, 22 to 33 m long by 10 to 19 m wide oocysts by using modified acid fast staining of the stool. Fecal leukocytes are not detected. Oocysts are shed in low numbers, underscoring the need for repeated stool examinations. The presence of oocysts in the gastrointestinal tract is |
8,067 | almost always associated with clinical symptoms. The histo logic appearance of the gastrointestinal epithelium reveals blunting and atrophy of the villi, acute and chronic inflammation, and crypt hyperplasia. Cystoisosporiasis responds promptly to treatment with oral trimethoprim sulfamethoxazole (TMP SMX: 5 mg TMP and 25 mg SMXkgdose maximum: 160 mg TMP and 800 mg SMX dose bid for 10 days). In patients with AIDS, relapses are common and often necessitate higher doses of TMPSMX andor mainte nance therapy. Combination antiretroviral therapy associated with immune recovery may also result in improved symptoms. Cipro floxacin or a regimen of pyrimethamine alone or with folinic acid is effective in patients intolerant of sulfonamide drugs. In endemic areas, Cystoisospora can be avoided by ensuring water used for drinking, food preparation, and washing fresh produce has been filtered or boiled. CYCLOSPORA Cyclospora cayetanensis is a coccidian parasite similar to but larger than Cryptosporidium. The organism infects both immunocompro mised and immunocompetent individuals and is more common in children younger than 18 months of age. The pathogenesis and patho logic findings of cyclosporiasis are similar to those of cystoisosporiasis. Asymptomatic carriage of the organism has been found, but travelers who harbor the organism almost always have diarrhea. Most cases of cyclosporiasis in the United States are domestically acquired. Out breaks of cyclosporiasis are linked with contaminated food and water and occur most frequently during spring and summer months. Impli cated foods include raspberries, lettuce, snow peas, basil, cilantro, and other fresh food items. After fecal excretion, the oocysts must sporulate outside the host to become infectious. This finding explains the lack of person to person transmission. The clinical manifestations of cyclosporiasis are similar to those of cryptosporidiosis and cystoisosporiasis and follow an incuba tion period of approximately 7 days. Moderate Cyclospora ill ness is characterized by a median of 6 stoolsday with a median duration of 10 days (range: 3 25 days). The duration of diarrhea in immunocompetent persons is characteristically longer in cyclospo riasis than in the other intestinal protozoan illnesses. Associated symptoms frequently include anorexia; fatigue; abdominal bloating or gas; abdominal cramps or pain; nausea; muscle, joint, or body aches; low grade fever; chills; headache; and weight loss. Vomiting may occur. Bloody stools are uncommon. Biliary disease has been reported. Intestinal pathology includes inflammation with villus blunting. The diagnosis is established by identification of oocysts in the stool or molecular diagnostic testing. Oocysts are wrinkled spheres, measure 8 10 m in diameter, and resemble large Cryptosporidium organisms. The organisms can be seen by using modified acid fast, auramine phenol, or modified trichrome staining, but stain less consistently than Cryptosporidium. They can also be detected with phenosafranin stain and by autofluorescence using strong green or intense blue under ultraviolet epifluorescence. Multiple stool samples enhance identifica tion of the pathogen. Fecal leukocytes are not present. Commercially available multiplex molecular test panels for gastrointestinal patho gens that include Cyclospora are now available and may become the new standard. The sensitivity of molecular testing and the inclusion of Cyclospora |
8,068 | on multiplex molecular testing may be partly respon sible for the increased number of reported cases in the United States in recent years. The treatment of choice for cyclosporiasis is TMP SMX (5 mg TMP and 25 mg SMXkgdose bid maximum 160 mg TMP and 800 mg SMXdose for 10 days.) Ciprofloxacin or nitazoxanide is effective in patients intolerant of sulfonamide drugs. MICROSPORIDIA Microsporidia are ubiquitous and infect most animal groups, includ ing humans. They are classified as fungi, and multiple species of the phylum Microsporidia have been linked with human disease in both immunocompetent and immunocompromised hosts. The species most commonly associated with gastrointestinal disease are Enterocytozoon bieneusi and Encephalitozoon intestinalis. The global prevalence of microsporidial infections among children is 7.5, although prevalence is likely higher among pediatric patients living with HIV, oncology patients, and transplant recipients. Although still not definitive, the source of human infections is likely zoonotic. Like Cryptosporidium, there is concern for water borne transmission through occupational and recreational contact with contaminated water sources. There is also the potential for food borne outbreaks; the organisms have been identified on vegetables as a consequence of contaminated irrigation water. Vector borne transmission is hypothesized because one species, Brachiola algerae, typically infects mosquitoes. Finally, transplacental transmission has been reported in animals but not in humans. Once infected, intracel lular division produces new spores that can spread to nearby cells, disseminate to other host tissues, or be passed into the environment via feces. Spores also have been detected in urine and respiratory epithelium, suggesting that some body fluids may also be infectious. Once in the environment, microsporidial spores remain infectious for up to 4 months. Initially, microsporidial intestinal infection had been almost exclu sively reported in patients with AIDS, but there are increasing reports of microsporidial infections in transplant recipients, including donor derived infections in solid organ transplant recipients. There is increas ing evidence that immunocompetent individuals are also commonly infected. Microsporidia associated diarrhea is intermittent, watery, copious, and nonbloody. Abdominal cramping and weight loss may be present; fever is unusual. Stromal keratitis and encephalitis may 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. 2154 Part XV u Infectious Diseases also be associated with microsporidia infections. Disseminated disease involving most organs, including liver, heart, kidney, bladder, biliary tract, lung, bone, skeletal muscle, central nervous system, skin, and sinuses, has been reported. Microsporidia stain with modified trichrome, hematoxylin eosin, Giemsa, Gram, periodic acidSchiff, and acid fast stains but are often overlooked because of their small size (1 5 m) and the absence of associated inflammation in surrounding tissues. Electron microscopy remains the reference method of detection. An immunofluorescence assay is available. The Centers for Disease Control and Prevention (CDC) offer a molecular identification of Enterocytozoon bieneusi, Encephalitozoon intestinalis, Encephalitozoon hellem, and Encephalito zoon cuniculi using species specific PCR assays. There is no proven therapy for |
8,069 | microsporidial intestinal infections. Albendazole (adult dose 400 mg bid PO for 3 weeks; for children, 7.5 mgkg body weight maximum 400 mgdose bid PO) is usually effective against E. intestinalis infection but is ineffective against infec tion caused by some microsporidial species. Fumagillin (adult dose 20 mg tid PO for 2 weeks) was effective in a small controlled study of adults with E. bieneusi infection, and topical therapy with this agent was also demonstrated to be effective in HIV infected adults with ker atoconjunctivitis. Fumagillin is not currently available in the United States. Supportive care with hydration, correction of electrolyte imbal ances, and nutrition should be used in gastrointestinal infection when clinically indicated. Improvement in underlying HIV infection with combination antiretroviral therapy also improves microsporidiosis symptoms. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Chapter 330 Trichomoniasis (Trichomonas vaginalis) Edsel Maurice T. Salvana and Robert A. Salata Trichomoniasis is caused by the protozoan Trichomonas vaginalis. It is the second most common sexually transmitted infection world wide. Vulvovaginitis is the symptomatic disease form, but T. vaginalis has been implicated in pelvic inflammatory disease, pregnancy loss, chronic prostatitis, and an increased risk of HIV transmission. EPIDEMIOLOGY Over 156 million new cases of trichomoniasis occur annually around the world. Most men and up to 30 of women are asymptomatic. Although the disease is easily treated, sequelae of untreated infec tion remain a significant cause of morbidity because of high reinfec tion rates from untreated partners, underrecognition of asymptomatic cases, and insensitive diagnostics. Trichomoniasis is the most common parasitic infection in the United States, with a prevalence of 2.6 million cases and 6.9 mil lion incident infections per year. Among the factors associated with a higher prevalence of infection are female sex, belonging to underrepresented minorities, poverty, lower educational attainment, younger age at first sex, multiple sexual partners, and a recent Chla mydia infection. Vaginal trichomoniasis is rare until menarche, and its presence in a younger child should raise the possibility of sexual abuse. Trichomoniasis may be transmitted to neonates during passage through an infected birth canal. Infection in this setting is usually self limited, but rare cases of neonatal vaginitis and respiratory infection have been reported. PATHOGENESIS T. vaginalis is an anaerobic, flagellated protozoan parasite. Infected vaginal secretions contain 101 to 105 or more protozoamL. T. vagina lis is pear shaped and exhibits characteristic twitching motility in wet mount (Fig. 330.1). Reproduction is by binary fission. It exists only as vegetative cells; cyst forms have not been described. T. vaginalis has hydrogenosomes, which are organelles that produce energy in anaero bic environments and have hydrogen as a waste product. Hydrogeno somes are derived from mitochondria, suggesting that T. vaginalis may have had an aerobic ancestor. Many types of adhesion molecules allow attachment of T. vaginalis to host cells. Tv lipoglycan is a surface glycoconjugate that binds human galectin 1 and galectin 3 and plays a major role in adhesion, patho genicity, and immune modulation. In addition, hundreds of putative membrane proteins, BspA proteins, and |
8,070 | tetraspanins are involved in cellular attachment. Adhesion is a prerequisite for cytolysis and, once attached, the parasite secretes hydrolases, proteases, and cytotoxic mol ecules that destroy or impair the integrity of host cells. Trichomonas is highly dependent on iron for its growth and metabo lism. Cysteine proteinase mRNAs have been shown to interact with other parasite proteins for posttranscriptional regulation in the absence of iron regulatory proteins. The T. vaginalis genome is very large at 160 Mbps, with multiple repetitive sequences and transposable elements making up over 60,000 genes and with apparently nonfunctional but transcribed pseudogenes. Macrophage migration and cytokine production have been shown to be downregulated by the parasite in successful infection. Parasite specific antibodies and lymphocyte priming occur in response to infection, but durable protective immunity does not occur, possibly also owing to degradation of antibodies by parasitic cysteine proteases. Trichomonas infection has been linked to dysregulation of the vagina microbiota and is frequently associated with concomitant bacterial vaginosis. Trichomonas can host Mycoplasma genitalium as a symbiont, and the presence of both microorganisms can significantly increase the risk of bacterial vaginosis, pelvic inflammatory disease, and adverse pregnancy outcomes. CLINICAL MANIFESTATIONS The incubation period in females is 5 28 days. Symptoms may begin or worsen with menses. Most infected women eventually develop symptoms, although up to one third remain asymptomatic. Common signs and symptoms include a copious malodorous gray, frothy vaginal discharge, vulvovaginal irritation, dysuria, and dyspareunia. Physical examination may reveal a frothy discharge with vaginal erythema and A B Fig. 330.1 Trichomonas vaginalis trophozoites stained with Giemsa (A) and iron hematoxylin (B). (From the Centers for Disease Control and Prevention: Laboratory identification of parasites of public health con cern. Trichomoniasis website. https:www.cdc.govdpdxtrichomonia sisindex.html) 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 331 u Leishmaniasis (Leishmania) 2155 cervical hemorrhages (strawberry cervix). The discharge usually has a pH of 4.5. Abdominal discomfort is unusual and should prompt evaluation for pelvic inflammatory disease (see Chapter 163). Most infections in males are asymptomatic. Symptomatic males usually have dysuria and scant urethral discharge. Trichomonads occasionally cause epididymitis, prostatic involvement, and superficial penile ulceration. Infection is often self limited, spontaneously resolv ing in about one third of men. Trichomonas has been implicated as a cause of recurrent or relapsing urethritis and can be isolated in 320 of men with nongonococcal urethritis. Treatment failures with stan dard therapy for gonorrhea and Chlamydia are frequently treated with antitrichomonal therapy. DIAGNOSIS Trichomonads may be recognized in vaginal secretions by wet mount microscopy, which has a sensitivity of 5165 in vaginal specimens and a lower sensitivity in specimens from men. Although Trichomonas is sometimes seen on Pap smears and urine microscopy, these methods are not considered reliable tests for disease. Culture of the organism used to be the gold standard for detection, but this is increasingly being replaced by nucleic acid |
8,071 | amplification tests, which are more sensitive. The APTIMA TV (HologicGen Probe, Inc., Marlborough, MA) assay and the BD Probe Tec TV Qx Amplified DNA Assay (Becton Dickin son, Franklin Lakes, NJ) are U.S. Food and Drug Administration (FDA) cleared commercial NAATs for testing of samples from women. Xpert TV (Cepheid Inc., Sunnyvale, CA) is a cartridge based near point of care nucleic acid test that is FDA cleared for men and women, with a sensitivity of 95 for self collected vaginal swabs and up to 100 for symptomatic endocervical swabs. Three point of care kits for rapid testing, Affirm VP III (BD Diagnostic Systems, Sparks, MD), OSOM Trichomonas Rapid Test (Sekisui Diagnostics, Lexington, MA), and Solana Trichomonas Assay (Quidel, San Diego, CA) are FDA cleared for women and can yield results in 45 minutes or less. Patients with T. vaginalis should be screened for other sexually transmitted infections. COMPLICATIONS Untreated trichomoniasis has been associated with pelvic inflamma tory disease, premature delivery, low birthweight, endometritis, salpin gitis, and vaginal cuff cellulitis. The association between trichomoniasis and infertility is relatively weak, but there is some evidence that co infection with other sexually transmitted infections increases the over all risk of pelvic inflammatory disease. T. vaginalis infection increases the risk of acquisition and transmission of HIV. In HIV infected indi viduals, trichomoniasis is associated with higher viral loads in cervical secretions and semen, as well as higher levels of infected lymphocytes in urogenital fluids. TREATMENT In the United States, metronidazole and tinidazole are used; in other countries, secnidazole, azanidazole, and ornidazole are also used. Both metronidazole (single dose regimen of 2 g orally as a single dose for adolescents and adults; alternative regimen, 500 mg orally bid for 7 days) and tinidazole (single 2 g dose orally in adolescents and adults) are used as first line treatments. For children infected before adoles cence, the recommended regimen is metronidazole 15 mgkgday divided in three doses orally for 7 days; tinidazole is not approved for dosing in younger children. For HIV infected patients, the 7 day course of metronidazole is superior to and recommended over the singledose regimen. Sexual partners should be treated simultaneously to prevent reinfection. Recent studies have shown that single dose metronidazole is less effective than a multidose regimen in women. A small num ber of patients with severe nitroimidazole hypersensitivity have been treated with intravaginal suppositories of boric acid, nitazoxanide, and paromomycin with varying degrees of success. Desensitization to metronidazole with a validated protocol under an allergy specialist is recommended if possible. Treatment failures have been reported with metronidazole and tini dazole. Metronidazole resistance in Trichomonas is estimated to be 4.39.6, and tinidazole resistance is about 1. Second line treatment is a 7 day course of metronidazole 500 mg twice daily. If this approach fails, either metronidazole or tinidazole at 2 g daily for 7 days is recom mended. Further treatment failure should be referred to an infectious diseases specialist. Susceptibility testing is available from the Centers for Disease Control and |
8,072 | Prevention (CDC). Higher dose tinidazole (2 3 g for 14 days) in combination with intravaginal tinidazole or paromomycin have been used in nitroimidazole resistant infections. Metronidazole has not been shown to be teratogenic but is currently classified as a category C drug. Treatment of trichomoniasis in preg nancy should always be considered, especially in symptomatic patients, and may decrease the risk of perinatal transmission. PREVENTION Prevention of T. vaginalis infection is best accomplished by treatment of all sexual partners of an infected person, and by programs aimed at prevention of all sexually transmitted infections (see Chapter 163). No vaccine is available, and drug prophylaxis is not recommended. A recent randomized controlled trial showed that T. vaginalis infection with concurrent bacterial vaginosis responded better to metronidazole treatment when intravaginal probiotics were co administered, consis tent with findings that altered vaginal microflora plays a significant role in T. vaginalis pathogenesis. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Chapter 331 Leishmaniasis (Leishmania) Peter C. Melby The leishmaniases are a diverse group of diseases caused by intracellu lar protozoan parasites of the genus Leishmania, which are transmitted by phlebotomine sand flies. Multiple species of Leishmania are known to cause human disease involving the skin and mucosal surfaces and the visceral reticuloendothelial organs (Table 331.1). Cutaneous dis ease is usually localized and mild but may cause cosmetic disfigure ment. Rarely, cutaneous infection can disseminate or involve the skin diffusely. Mucosal and visceral forms of leishmaniasis are associated with significant morbidity and mortality. ETIOLOGY Leishmania organisms are members of the Trypanosomatidae family and include two subgenera, Leishmania (Leishmania) and Leishmania (Viannia). The parasite is dimorphic, existing as a flagellate promasti gote in the insect vector and as an aflagellate amastigote that resides and replicates within mononuclear phagocytes of the vertebrate host. Within the sand fly vector, the promastigote changes from a noninfec tive procyclic form to an infective metacyclic stage (Fig. 331.1). Ampli fication of the number of metacyclic promastigotes in the infected sand fly occurs following a second blood meal. Fundamental to metacyclo genesis are changes that take place in the terminal polysaccharides of the surface lipophosphoglycan, which allow forward migration of the infective parasites to be inoculated in the host skin during a blood meal. Metacyclic lipophosphoglycan also plays an important role in the entry and survival of Leishmania in the vertebrate host cells. Once within the macrophage, the promastigote transforms to an amastigote and resides and replicates within a phagolysosome. The parasite is resistant to the acidic, hostile environment of the macrophage and eventually ruptures the cell and goes on to infect other macrophages. Infected macrophages have a diminished capacity to initiate and respond to an inflammatory response, thus providing a safe haven for the intracellular parasite. 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. 2 1 5 6 P art X V u Infectious D iseases |
8,073 | Table 331.1 Clinical and Epidemiologic Characteristics of Main Leishmania Species SUBGENUS CLINICAL FORM MAIN CLINICAL FEATURES NATURAL PROGRESSION RISK GROUPS MAIN RESERVOIR HIGH BURDEN COUNTRIES OR REGIONS ESTIMATED ANNUAL WORLDWIDE INCIDENCE Leishmania donovani Leishmania VL, PKDL Persistent fever, splenomegaly, weight loss, and anemia in VL; multiple painless macular, papular, or nodular lesions in PKDL VL is fatal within 2 yr; PKDL lesions self heal in up to 85 of cases in Africa but rarely in Asia Predominantly adolescents and young adults for VL; young children in Sudan and no clearly established risk factors for PKDL Humans India, Bangladesh, Ethiopia, Sudan, and South Sudan 50,000 90,000 VL cases; unknown number of PKDL cases Leishmania tropica Leishmania CL, LR, rarely VL Ulcerating dry lesions, painless, and frequently multiple CL lesions often self heal within 1 yr No well defined risk groups Humans, but zoonotic foci exist Eastern Mediterranean, Middle East, northeastern and southern Africa 200,000 400,000 CL Leishmania aethiopica Leishmania CL, DCL, DsCL, oronasal CL Localized cutaneous nodular lesions; occasionally oronasal; rarely ulcerates Self healing, except for DCL, within 2 5 yr Limited evidence; adolescents Hyraxes Ethiopia, Kenya 20,000 40,000 CL Leishmania major Leishmania CL Rapid necrosis, multiple wet sores, severe inflammation Self healing in 50 of cases within 2 8 mo; multiple lesions slow to heal, and severe scarring No well defined risk groups Rodents Iran, Saudi Arabia, North Africa, Middle East, Central Asia, West Africa 230,000 430,000 CL Leishmania infantum Leishmania VL, CL Persistent fever and splenomegaly in VL; typically single nodules and minimal inflammation in CL VL is fatal within 2 yr; CL lesions self heal within 1 yr and confers individual immunity Children 5 yr old and immunocompromised adults for VL; older children and young adults for CL Dogs, hares, humans China, Southern Europe, Brazil, and South America for VL and CL; Central America for CL 6,200 12,000 cases of Old World VL and 4,500 6,800 cases of New World VL; unknown number of CL cases Leishmania mexicana Leishmania CL, DCL, DsCL Ulcerating lesions, single or multiple Often self healing in 3 4 mo No well defined risk groups Rodents, marsupials South America Limited number of cases, included in the 187, 200 300,000 total cases of New World CL Leishmania amazonensis Leishmania CL, DCL, DsCL Ulcerating lesions, single or multiple Not well described No well defined risk groups Possums, rodents South America Limited number of cases, included in the 187, 200 300,000 total cases of New World CL Leishmania braziliensis Viannia CL, MCL, DCL, LR Ulcerating lesions can progress to mucocutaneous form; local lymph nodes are palpable before and early on in the onset of the lesions Might self heal in 6 mo; 2.5 of cases progress to MCL No well defined risk groups Dogs, humans, rodents, horses South America Majority of the 187, 200 300,000 total cases of New World CL Leishmania guyanensis Viannia CL, DsCL, MCL Ulcerating lesions, single or multiple that can progress to mucocutaneous form; palpable lymph nodes Might self heal within 6 mo |
8,074 | No well defined risk groups Possums, sloths, anteaters South America Limited number of cases, included in the 187, 200 300,000 total cases of New World CL Old World leishmaniasis. New World leishmaniasis. Estimates are of all New World leishmaniases, with Leishmania braziliensis comprising the vast majority of these cases. CL, Cutaneous leishmaniasis; DCL, diffuse cutaneous leishmaniasis; DsCL, disseminated cutaneous leishmaniasis; LR, leishmaniasis recidivans; MCL, mucocutaneous leishmaniasis; PKDL, postkala azar dermal leishmaniasis; VL, visceral leishmaniasis. Adapted from Burza S, Croft SL, Boelaert ML. Leishmaniasis. Lancet. 2018;392:951966. Table 1. 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 331 u Leishmaniasis (Leishmania) 2157 EPIDEMIOLOGY The leishmaniases are estimated to affect 10 20 million people in endemic tropical and subtropical regions on all continents except Aus tralia and Antarctica (Fig. 331.2). The different forms of the disease are distinct in their causes, epidemiologic characteristics, transmission, and geographic distribution. The leishmaniases may occur sporadically throughout an endemic region or may occur in epidemic waves. With only rare exceptions, the Leishmania organisms that primarily cause cutaneous disease do not cause visceral disease. Localized cutaneous leishmaniasis (LCL) in the Old World is caused by L. (Leishmania) major and L. (L.) tropica in North Africa, the Middle East, Central Asia, and the Indian subcontinent. L. (L.) aethi opica is a cause of LCL and diffuse cutaneous leishmaniasis (DCL) in Kenya and Ethiopia. In the New World, L. (L.) mexicana causes LCL in a region stretching from Texas through Central America. L. (L.) amazonensis, L. (L.) pifanoi, L. (L.) garnhami, and L. (L.) venezuelen sis cause LCL in South America, the Amazon basin, and northward. These parasites can also cause DCL. Members of the Viannia subgenus (L. Viannia braziliensis, L. V. panamensis, L. V. guyanensis, and L. V. peruviana) cause LCL and mucosal leishmaniasis (ML) from the northern highlands of Argentina northward to Central America. Some species, particularly L. (V.) braziliensis, rarely cause disseminated leishmaniasis (DL). Visceral leishmaniasis (VL) in the Old World is caused by L. (L.) donovani in Kenya, Sudan, India, Pakistan, and China and by L. (L.) infantum in the Mediterranean basin, Middle East, and central Asia. L. tropica also has been recognized as an uncommon cause of visceral disease in the Middle East and India. VL in the New World is caused by L. (L.) infantum (formerly also called L. chagasi), which is distributed from Mexico (rare) through Central and South America. L. infantum can also cause LCL in the absence of visceral disease in this same geographic distribution. The maintenance of Leishmania in most endemic areas is through a zoonotic transmission cycle. In general, the dermotropic strains in both the Old and the New World are maintained in rodent reservoirs, and the domestic dog is the usual |
8,075 | reservoir for L. infantum. The trans mission between reservoir and sand fly is highly adapted to the spe cific ecologic characteristics of the endemic region. Human infections occur when activities bring them in contact with the zoonotic cycle. Anthroponotic transmission, in which humans are the presumed res ervoir for vector borne transmission, occurs with L. tropica in some urban areas of the Middle East and Central Asia, and with L. donovani in India and Sudan. Congenital transmission of L. donovani or L. infan tum has been reported. There is a resurgence of leishmaniasis in long standing endemic areas as well as in new foci. Tens of thousands of cases of LCL occurred in outbreaks in Syria and Kabul, Afghanistan; severe epidemics with 100,000 deaths from VL have occurred in India and Sudan. VL is most prevalent among the poorest of the poor, with substandard hous ing contributing to the vector borne transmission and undernutrition leading to increased host susceptibility. The emergence of the leish maniases in new areas is the result of (1) movement of a susceptible population into existing endemic areas, usually because of agricultural or industrial development or timber harvesting; (2) increase in vec tor andor reservoir populations as a result of agriculture development projects andor climate change; (3) increase in anthroponotic trans mission resulting from rapid urbanization in some focuses; and (4) increase in sand fly density resulting from a reduction in vector control programs. PATHOLOGY Histopathologic analysis of the skin lesions of LCL and DL show intense chronic granulomatous inflammation involving the epidermis and der mis with relatively few amastigotes. Occasionally, neutrophils and even microabscesses can be seen. The lesions of DCL are characterized by dense infiltration with vacuolated macrophages containing abundant amastigotes. ML is characterized by an intense granulomatous reaction with prominent tissue necrosis, which may include adjacent cartilage or bone. In VL there is prominent reticuloendothelial cell hyperpla sia in the liver, spleen, bone marrow, and lymph nodes. Amastigotes are abundant in the histiocytes and Kupffer cells. Late in the course of disease, splenic infarcts are common, centrilobular necrosis and fatty infiltration of the liver occur, the normal marrow elements are replaced by parasitized histiocytes, and erythrophagocytosis is present. PATHOGENESIS Cellular immune mechanisms determine resistance or susceptibility to infection with Leishmania. Resistance is mediated by interleukin (IL) 12driven generation of a T helper 1 (Th1) cell response, with interferon (IFN) inducing classic macrophage (M1) activation and parasite killing. Susceptibility is associated with expansion of IL 4 producing Th2 cells andor the production of IL 10 and transforming growth factor (TGF) , which are inhibitors of macrophage mediated parasite killing, and the generation of regulatory T cells and arginase producing (M2) macrophages. An exuberant innate inflammatory response involving inflammasome activation and IL 1 production in lesions is associated with greater local pathology and delayed healing. Patients with ML exhibit a hyperresponsive cellular immune reaction that contributes to the prominent tissue destruction seen in this form of the disease. Patients with DCL or active VL demonstrate |
8,076 | reduced or altered Leishmania specific cellular immune responses, with promi nent generation of IL 10, but these responses recover after successful therapy. Fig. 331.1 Leishmania life cycle. (From Reithinger R, Dujardin JC, Louzir H, et al. Cutaneous leishmaniasis. Lancet Infect Dis. 2007;7:581596. Fig. 5.) Sandfly takes a blood meal and regurgitates promastigotes into skin 1 Promastigotes are phagocytosed by macrophages 2 Promastigotes transform into amastigotes inside macrophages 3 Amastigotes multiply in cells, including macrophages, of various tissues 4 Amastigotes transform into promastigote stage in gut 7 Divide in gut and migrate to proboscis 8 Sandfly takes a blood meal5 Ingestion of parasitized cell6 Sandfly stages Human stages 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. 2158 Part XV u Infectious Diseases Within endemic areas, people who have had a subclinical infec tion can be identified by a positive delayed type hypersensitivity skin response to leishmanial antigens (Montenegro skin test) or by antigen induced production of IFN in a whole blood assay. Sub clinical infection occurs considerably more frequently than does active cutaneous or visceral disease. Host factors (genetic back ground, concomitant disease, nutritional status), parasite factors (virulence, size of the inoculum), and possibly vector specific fac tors (vector genotype, immunomodulatory salivary constituents) influence the expression as either subclinical infection or active disease. Within endemic areas, the prevalence of skin test positivity increases with age, and the incidence of clinical disease decreases with age, indicating that immunity is acquired in the population over time. Individuals with prior active disease or subclinical infec tion are usually immune to a subsequent clinical infection; how ever, latent infection can lead to active disease if the patient is immunosuppressed. CLINICAL MANIFESTATIONS The different forms of the disease are distinct in their causes, epidemio logic features, transmission, and geographic distribution. Localized Cutaneous Leishmaniasis LCL (Oriental sore) can affect individuals of any age, but children are the primary victims in many endemic regions. It may present as one or a few papular, nodular, plaque like, or ulcerative lesions that are usually located on exposed skin, such as the face and extremities (Fig. 331.3). Rarely, 100 lesions have been recorded. The lesions typically begin as a small papule at the site of the sand fly bite, which enlarges to 1 3 cm in diameter and may ulcerate over the course of several weeks to months. The shallow ulcer is usually nontender and surrounded by a sharp, indurated, erythematous margin. There is no drainage unless a bacterial superinfection develops. Lesions caused by L. major and L. mexicana usually heal spontaneously after 3 6 months, leaving a depressed scar. Lesions on the ear pinna caused by L. mexicana, called chiclero ulcer because they were common in chicle harvesters in Mex ico and Central America, often follow a chronic, destructive course. In general, lesions caused by L. (Viannia) species tend to be larger and more |
8,077 | chronic. Regional lymphadenopathy and palpable subcutaneous nodules or lymphatic cords, the so called sporotrichoid appearance, are also more common when the patient is infected with organisms of the Viannia subgenus. If lesions do not become secondarily infected, there are usually no complications aside from the residual cutaneous scar. Diffuse Cutaneous Leishmaniasis DCL is a rare form of leishmaniasis caused by organisms of the L. mexi cana complex in the New World and L. aethiopica in the Old World. DCL manifests as large, non ulcerating macules, papules, nodules, or plaques that often involve large areas of skin and may resemble lepro matous leprosy. The face and extremities are most often involved. Dis semination from the initial lesion usually takes place over several years. These patients are anergic to the Montenegro skin test, and it is thought that an immunologic defect underlies this severe form of cutaneous leishmaniasis. Disseminated Leishmaniasis In rare cases, parasites can spread (likely by the hematogenous route) in an immunocompetent host from a primary lesion to cause DL. This is defined as 10 lesions (usually in the hundreds) involving at least two noncontiguous areas of the skin. DL has been most often attributed to L. (V.) braziliensis. The lesions are typically inflam matory papules or ulcers, in contrast to the nodular and plaque like lesions of DCL, and about one third of patients have mucosal involvement. Mucosal Leishmaniasis ML (espundia) is an uncommon but serious manifestation of leish manial infection resulting from hematogenous spread of parasites to the nasal or oropharyngeal mucosa from a cutaneous infection. It is usually caused by parasites in the L. (Viannia) complex. Approxi mately half of the patients with mucosal lesions have had active cuta neous lesions within the preceding 2 years, but ML may not develop until many years after resolution of the primary lesion. ML occurs in 5 of individuals who have, or have had, LCL caused by L. (V.) bra ziliensis. Patients with ML typically have nasal mucosal involvement and present with nasal congestion, discharge, and recurrent epistaxis. Oropharyngeal and laryngeal involvement is less common but associ ated with severe morbidity. Marked soft tissue, cartilage, and even bone destruction occurs late in the course of disease and may lead to visible 1000 500999 100499 100 0 No autochthonous cases reported No data Not applicable Number of new cases of visceral leishmaniasis reported Fig. 331.2 Status of endemicity of visceral leishmaniasis worldwide in 2016. (From World Health Organization. Recognizing Neglected Tropical Diseases Through Changes on the Skin: A Training Guide for Front Line Health Workers. Geneva: WHO; 2018.) Downloaded for mohamed ahmed (dr.mms2020gmail.com) at University of Southern California from ClinicalKey.com by Elsevier on April 21, 2024. For personal use only. No other uses without permission. Copyright 2024. Elsevier Inc. All rights reserved. Chapter 331 u Leishmaniasis (Leishmania) 2159 deformity of the nose or mouth, nasal septal perforation, and tracheal narrowing with airway obstruction. Visceral Leishmaniasis VL (kala azar) typically affects children 5 years old in the New World and Mediterranean region |
8,078 | (L. infantum) and older children and young adults in Africa and Asia (L. donovani). After inoculation of the organism into the skin by the sand fly, the child may have a com pletely asymptomatic infection or an oligosymptomatic illness that either resolves spontaneously or evolves into active kala azar. Children with asymptomatic infection are transiently seropositive but show no clinical evidence of disease. Children who are oligosymptomatic have mild constitutional symptoms (malaise, intermittent diarrhea, poor activity tolerance) and intermittent fever; most will have a mildly enlarged liver. In most of these children the illness will resolve with out therapy, but in approximately 25 it will evolve to active kala azar within 2 8 months. Extreme incubation periods of several years have rarely been described. During the first few weeks to months of dis ease evolution, the fever is intermittent, there is weakness and loss of energy, and the spleen begins to enlarge. The classic clinical features of high fever, marked splenomegaly, hepatomegaly, and severe cachexia typically develop 3 6 months after the onset of the illness, but a rapid clinical course over 1 month has been noted in up to 20 of patients in some series (Fig. 331.4). At the terminal stages of kala azar, the hepa tosplenomegaly is massive, there is gross wasting, the pancytopenia is profound, and jaundice, edema, and ascites may be present. Ane mia may be severe enough to precipitate heart failure. Bleeding epi sodes, especially epistaxis, are frequent. The late stage of the illness is often complicated by secondary bacterial infections, which frequently are a cause of death. A younger age at the time of infection, HIV co infection, and underlying malnutrition are risk factors for the develop ment, rapid evolution, and severe disease of active VL. Death occurs in 90 of patients without specific antileishmanial treatment and in 410 of treated patients. VL is a known cause of hemophagocytic lymphohistiocytosis in endemic areas. VL is an opportunistic infection associated with HIV infection. Most cases have occurred in southern Europe and Brazil, often as a result of needle sharing associated with illicit drug use, with the potential for many more cases as the endemic regions for HIV and VL converge. Leishmaniasis may also result from reactivation of a long standing subclinical infection. Frequently there is an atypical clini cal presentation of VL in HIV infected individuals with prominent involvement of the gastrointestinal tract and absence of the typical hepatosplenomegaly. A small percentage of patients previously treated for VL develop dif fuse skin lesions, a condition known as postkala azar dermal leish maniasis. These lesions may appear during or shortly after therapy (Africa) or up to several years later (India). The lesions of postkala azar dermal leishmaniasis are hypopigmented, erythematous, or nodu lar and usually involve the face and torso. They may persist for several months or for many years. LABORATORY FINDINGS Patients with cutaneous leishmaniasis or ML generally do not have abnormal laboratory results unless the lesions are secondarily infected with bacteria. Laboratory findings associated |
8,079 | with classic kala azar include anemia (hemoglobin, 5 8 mgdL), thrombocy topenia, leukopenia (2,000 3,000 cellsL), elevated hepatic trans aminase levels, and hyperglobulinemia (5 gdL) that is mostly immunoglobulin G. DIFFERENTIAL DIAGNOSIS Diseases that should be considered in the differential diagnosis of LCL include sporotrichosis, blastomycosis, chromomycosis, lobo mycosis, cutaneous tuberculosis, atypical mycobacterial infection, leprosy, ecthyma, syphilis, yaws, and neoplasms. Infections such as syphilis, tertiary yaws, histoplasmosis, and paracoccidioidomycosis, as well as sarcoidosis, granulomatosis with polyangiitis, midline gran uloma, and carcinoma, may have clinical features similar to those of ML. VL should be strongly suspected in the patient with prolonged fever, weakness, cachexia, marked splenomegaly, hepatomegaly, cyto penias, and hypergammaglobulinemia who has had potential expo sure in an endemic area. The clinical picture may also be consistent with that of malaria, typhoid fever, miliary tuberculosis, schistoso miasis, brucellosis, amebic liver abscess, infectious mononucleosis, lymphoma, and leukemia. DIAGNOSIS The development of one or several slowly progressive, nontender, nod ular, or ulcerative lesions in a patient who had potential exposure in an endemic area should raise suspicion of LCL. Serologic tests for diagnosis of cutaneous or mucosal disease gener ally have low sensitivity and specificity and offer little for diagnosis. Serologic testing by enzyme immunoassay, indirect fluorescence assay, or direct agglutination is very useful in VL because of the very high level of antileishmanial antibodies. An immunochromatographic strip test using a recombinant antigen (K39) has a diagnostic sensitivity and specificity for VL of 8090 and 95, respectively. Serodiagnostic tests have positive findings in only about half the patients co infected with HIV. A CB Fig. 331.3 Cutaneous disease. A, Old World infection (Leishmania major) acquired in Iraq; note five papular and nodular lesions on neck. B, New World infection (Leishmania panamensis) in Colombia; purely ulcerative lesion is characteristic of New World disease. C, Healed in fection in patient shown in B 70 days after 20 days of meglumine anti monate treatment; note paper thin scar tissue over flat reepithelialized skin. (A, Courtesy P. Weina; B, Courtesy J. Soto. A C, Modified from Murray HW, Berman JD, Davies CR, et al. Advances in leishmaniasis. Lancet. 2005;366:15611577.) A B Fig. 331.4 Visceral leishmaniasis (Leishmania donovani) in Bihar State, India. A, Hepatosplenomegaly and wasting in a young man. B, Children with burn marks over enlarged spleen or liver evidence of a local shamans unsuccessful remedy. (A, Courtesy D. Sacks; B, Courtesy R. Kenney; A and B, Adapted from Murray HW, Berman JD, Davies CR, et al. Advances in leishmaniasis. Lancet. 2005;366:15611577.) 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. 2160 Part XV u Infectious Diseases Definitive diagnosis of leishmaniasis is established by the demon stration of amastigotes in tissue specimens or isolation of the organism by culture. Amastigotes can be identified in Giemsa stained tissue sec tions, aspirates, or impression smears in about half the cases of LCL but |
8,080 | only rarely in the lesions of ML. Culture of a tissue biopsy or aspirate, best performed by using Novy MacNeal Nicolle biphasic blood agar medium, yields a positive finding in only approximately 65 of cases of cutaneous leishmaniasis. Identification of parasites in impression smears, histopathologic sections, or culture medium is more readily accomplished in DCL than in LCL. In patients with VL, smears or cul tures of material from splenic, bone marrow, or lymph node aspirations are usually diagnostic. In experienced hands, splenic aspiration has a higher diagnostic sensitivity, but it is rarely performed in the United States because of the risk for bleeding complications. A positive culture result allows speciation of the parasite, usually by isoenzyme analysis by a reference laboratory, which may have therapeutic and prognostic significance. TREATMENT Specific antileishmanial therapy should be individualized for each patient. It is not routinely indicated for immunocompetent persons having uncomplicated simple LCL (single or few lesions, lesion diam eter 1 cm, no mucosal involvement) caused by strains that have a high rate of spontaneous resolution and self healing (L. major, L. mexicana). Lesions that are extensive, severely inflamed, or located where a scar would result in disability (near a joint) or cosmetic disfigurement (face or ear), that involve the lymphatics, or that do not begin healing within 3 4 months should be treated. Cutaneous lesions suspected or known to be caused by members of the Viannia subgenus (New World) should be treated because of the low rate of spontaneous healing and the potential risk for development of mucosal or disseminated disease. Similarly, patients with lesions caused by L. tropica (Old World), which are typically chronic and nonhealing, should be treated. All patients with VL or ML should receive therapy. The pentavalent antimony compounds (sodium stibogluconate Pentostam, GlaxoSmithKline, Uxbridge, UK and meglumine anti moniate Glucantime, Aventis, Strasbourg, France) have been the mainstay of antileishmanial chemotherapy for 40 years. These drugs have similar efficacies, toxicities, and treatment regimens. Currently, for sodium stibogluconate (available in the United States from the Centers for Disease Control and Prevention, Atlanta, GA), the recom mended regimen is 20 mgkgday intravenously (IV) or intramuscu larly (IM) for 20 days (for LCL and DCL) or 28 days (for ML and VL). Repeated courses of therapy may be necessary in patients with severe cutaneous lesions, ML, DCL, DL, or VL. An initial clinical response to therapy usually occurs in the first week of therapy, but complete clinical healing (reepithelialization and scarring for LCL and ML, and regres sion of splenomegaly and normalization of cytopenias for VL) is usu ally not evident for weeks to a few months after completion of therapy. Cure rates with this regimen of 90100 for LCL, 5070 for ML, and 80100 for VL were common in the 1990s, but treatment failures, especially in children, have become common in parts of India, East Africa, and Latin America. Relapses are common in patients who do not have an effec tive antileishmanial cellular immune response (DCL or HIV co infection). |
8,081 | Adverse effects of antimony therapy are dose and duration dependent and include fatigue, arthralgias, and myalgias (50), abdominal discomfort (30), elevated hepatic transaminase level (3080), elevated amylase and lipase levels (almost 100), mild hematologic changes (slightly decreased leukocyte count, hemoglobin level, and platelet count) (1030), and nonspecific T wave changes on electrocardiography (30). Sudden death from cardiac toxicity has rarely been reported with use of very high doses of pentavalent antimony. Amphotericin B desoxycholate and liposomal amphotericin B are very useful in the treatment of VL, ML, or DL, and in some regions have replaced antimony as first line therapy, especially in HIV infected patients. However, the prohibitively high cost of these drugs precludes their use in many resource poor regions of the world. Amphotericin B desoxycholate at doses of 0.5 1.0 mgkg every day or every other day for 14 20 doses achieved a cure rate for VL of close to 100, but renal toxicity associated with amphotericin B was common. Lipo somal amphotericin B (AmBisome, Gilead Sciences, Foster City, CA) is especially attractive for treatment of leishmaniasis because the drug is concentrated in the reticuloendothelial system and is less nephrotoxic. It is approved by the U.S. Food and Drug Administra tion (FDA) for treatment of VL at a recommended dose for immuno competent patients of 3 mgkg on days 1 5, 14, and 21 (total dose 21 mgkg) and should be considered for first line therapy in the United States. It is highly effective, with a 90100 cure rate for VL in immu nocompetent children, including those who were refractory to anti mony therapy. Therapy for immunocompromised patients should be prolonged (recommended total dose 40 mgkg). A single high dose of liposomal amphotericin B (10 mgkg) was found to be effective in India (approximately 95 efficacy) but was less effective in East Africa (58 efficacy). Parenteral treatment of VL with the aminoglycoside paromo mycin (aminosidine) has efficacy (95) similar to that of ampho tericin B in India. A dose sparing regimen of the combination of sodium stibogluconate and paromomycin is effective and used in East Africa. Miltefosine, a membrane activating alkyl phospho lipid, has been approved as the first oral treatment for VL and has a cure rate of 8090 in Indian patients with VL when administered orally at 50 100 mgday (or 2.5 mgkg for children 12 years old) for 28 days. Miltefosine is indicated for cutaneous infection caused by L. braziliensis, L. guyanensis, and L. panamensis; ML caused by L. braziliensis; and VL caused by L. donovani. Gastrointestinal adverse effects were frequent but did not require discontinuation of the drug. An increased rate of relapse (up to 20) has been seen in children treated with miltefosine. Dose sparing combination regi mens are being actively investigated for treatment of VL. Treatment of LCL with oral drugs has had only modest success. Ketoconazole has been effective in treating adults with LCL caused by L. major, L. mexicana, and L. panamensis, but not L. tropica or L. braziliensis. Fluconazole |
8,082 | in high doses (up to 8 mgkgday) for 4 8 weeks was demonstrated to be effective in treating LCL in studies in both the Old and New World; however, the experience in young children is limited. Miltefosine, 2.5 mgkgday orally for 20 28 days, was effec tive in 7090 of patients with LCL in the Americas. Local therapy, including heat, cryotherapy, and topical 15 paromomycin oint ment has been effective treatment for LCL in selected areas in both the Old and the New World. Enhanced drug development efforts and clinical trials of new drugs are clearly needed, especially in children. PREVENTION Personal protective measures should include avoidance of exposure to the nocturnal sand flies and, when necessary, the use of insect repel lent and permethrin impregnated mosquito netting. Where peridomi ciliary transmission is present, community based residual insecticide spraying has had some success in reducing the prevalence of leish maniasis, but long term effects are difficult to maintain. Control or elimination of infected reservoir hosts (e.g., seropositive domestic dogs) has had limited success. Where anthroponotic transmission is thought to occur, as in south Asia, early recognition, diagnosis, and treatment of cases and vector control measures are essential for prog ress toward elimination. Several vaccines have been demonstrated to have efficacy in experimental models, and vaccination of humans or domestic dogs may have a role in the control of the leishmaniases in the future. 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 332 u African Trypanosomiasis (Sleeping Sickness; Trypanosoma brucei Complex) 2161 Sixty five million people in 36 countries are at risk for infection with Trypanosoma brucei complex, the causative agent of sleeping sickness. Also known as human African trypanosomiasis (HAT), this disease is restricted to sub Saharan Africa, the range of the tsetse fly vector. It is a disease of extreme poverty, with the highest disease burden observed in remote rural areas. HAT comes in two geographically and clinically distinct forms. Trypanosoma brucei gambiense causes a chronic infec tion and affects people who live in western and central Africa (West African sleeping sickness, Gambian trypanosomiasis). Trypanosoma brucei rhodesiense is a zoonosis that presents as an acute illness lasting several weeks and usually occurs in residents or travelers from east ern and southern Africa (East African sleeping sickness, Rhodesian trypanosomiasis). ETIOLOGY HAT is a vector borne disease caused by parasitic, extracellular, flagel lated kinetoplastid protozoans of two subspecies of T. brucei. It is trans mitted to humans through the bite of Glossina, commonly known as the tsetse fly. Humans usually contract East African HAT when they venture from towns to rural areas to visit woodlands or livestock, highlight ing the importance of zoonotic reservoirs in this disease. West Afri can HAT is contracted closer to settlements and only requires a small vector population, making it difficult to |
8,083 | eradicate. Animal reservoirs occur, but the main source of infection remains chronically infected human hosts. LIFE CYCLE T. brucei undergoes several stages of development in the insect and mammalian host. On ingestion with a blood meal, nonproliferative short stumpy (SS) forms of the parasite transform into procyclic forms in the insects midgut. These procyclic forms proliferate and undergo further development into epimastigotes, which then become infective metacyclic forms that migrate to the insects salivary glands. The life cycle within the tsetse fly takes 15 35 days. On inoculation into the mammalian host, the metacyclic stage transforms into pro liferative long slender (LS) forms in the bloodstream and the lym phatics, eventually penetrating the central nervous system (CNS). LS forms appear in waves in the peripheral blood, with each wave followed by a febrile crisis and heralding the formation of a new antigenic variant. Once a critical density of LS forms is reached, a quorum sensing mechanism causes most of these to transform into nonproliferative SS forms that are ingested by Glossina and start the cycle anew. Quorum sensing controls peak parasitemia to ensure that the host survives infection long enough for the parasite to complete its life cycle. Direct transmission to humans has been reported, either vertically to infants or mechanically through contact with tsetse flies with via ble LS forms on their mouthparts from a recent blood meal from an infected host. EPIDEMIOLOGY HAT occurs mainly in sub Saharan Africa between latitudes 14 degrees north and 29 degrees south, where the annual rainfall cre ates optimal climatic conditions for Glossina. In 2009, new HAT cases annually fell below 10,000 as a result of intensive control efforts. In 2018, new cases fell to 977, the lowest level in 80 years since the start of systematic data collection. In the last 10 years, 70 of cases were reported from the Democratic Republic of Congo. Gambian trypano somiasis is targeted for sustainable elimination as a public health problem by 2030. T. brucei rhodesiense infection is restricted to the eastern third of the endemic area in tropical Africa, stretching from Ethiopia to the north ern boundaries of South Africa. T. brucei gambiense, which accounts for 95 of HAT cases, occurs mainly in the western half of the conti nents endemic region. Rhodesian HAT, which has an acute and often fatal course, greatly reduces chances of transmission to tsetse flies. The ability of T. brucei rhodesiense to multiply rapidly in the bloodstream and infect other species of mammals helps maintain its life cycle. HAT is infrequently reported in non endemic countries, usually in return ing travelers or migrants. PATHOGENESIS At the site of the Glossina bite, tsetse fly salivary antigens, peptides, and proteins promote an immune tolerant microenvironment that facilitates parasite invasion. Injected metacyclic parasites transform into LS forms, which rapidly divide by binary fission. The parasites, along with the attendant inflammation, cellular debris, and metabolic products, may give rise to a hard, painful, red nodule known as a trypanosomal chancre within 5 15 |
8,084 | days postinoculation. Parasites directionally migrate from the skin to the lymphatics via an unknown mechanism and pass into the draining lymph node and onward into the main lymphatic ducts. Dissemination into the blood and lym phatic systems follows, with subsequent localization to the CNS. Histopathologic findings in the brain are consistent with meningoen cephalitis. The appearance of morula cells of Mott (large, strawberry like cells, supposedly derived from plasma cells) is a characteristic finding in chronic disease. Mechanisms underlying virulence in HAT are still incompletely understood but seem to be mediated by a complex interplay of try panosomal, human, and Glossina factors. T. brucei gambiense uti lizes at least three mechanisms to evade lysis by human sera. These include reduced binding to trypanolytic factor 1 (TLF1) via reduced expression and mutation of a haptoglobin hemoglobin receptor; expression of a specific glycoprotein TgsGP, which reduces try panosomal membrane fluidity; and a cysteine protease mediated reduction of sensitivity to apolipoprotein L 1 (APOL1). T. brucei rhodesiense, on the other hand, expresses a protein known as serum resistanceassociated protein (SRA), which counteracts trypano lytic APOL1 in human serum. APOL1 and the hemoglobin binding protein haptoglobin related protein (HPR) are major components of two high density lipoprotein complexes called TLF1 and TLF2, which protect humans against non human trypanosomes. Trypano somes also secrete a host of biologically active molecules that can dampen immune responses. Antigenic variation of variant surface glycoprotein (VSG) on the trypanosome surface has long been recognized as a major factor in evading acquired immunity during infection. This antigenic diversity is generated by a tightly controlled system of DNA double stranded breaks with associated homologous recombination. VSG also inhibits complement activation and antibody mediated aggregation, facilitat ing establishment and maintenance of infection. Soluble VSG is hyper secreted, especially at the peak of parasitemia, and may serve as a decoy for antibodies and complement factor, diverting immune responses away from trypanosomes. CLINICAL MANIFESTATIONS Clinical presentations vary not only because of the two subspecies of organisms but also because of differences in host response in the Chapter 332 African Trypanosomiasis (Sleeping Sickness; Trypanosoma brucei Complex) Edsel Maurice T. Salvana and Robert A. Salata 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. 2162 Part XV u Infectious Diseases indigenous population of endemic areas and in newcomers or visitors. Visitors usually suffer more from the acute symptoms, but if untreated, death usually follows for natives and visitors alike. Symptoms usually occur within 2 3 weeks of infection. The clinical syndromes of HAT are trypanosomal chancre, hemolymphatic stage, and meningoencepha litic stage. Trypanosomal Chancre The site of the tsetse fly bite may be the first presenting feature. A nod ule or chancre (3 4 cm) develops in 2 3 days and becomes a painful, hard, red nodule surrounded by an area of erythema and swelling within 1 week. Nodules are typically |
8,085 | seen on the lower limbs and some times also on the head. They subside spontaneously in about 2 weeks, leaving no permanent scar. Hemolymphatic Stage (Stage 1) The most common presenting features of acute HAT occur at the time of invasion of the bloodstream by the parasites, 2 3 weeks after infection. Patients usually present with irregular episodes of fever, each lasting up to 7 days, accompanied by headache, sweating, and generalized lymphadenopathy. Attacks may be separated by symptom free intervals of days or even weeks. Painless, nonmatted lymphadenopathy, most often of the posterior cervical and supra clavicular nodes, is one of the most constant signs, particularly in the Gambian form. A common feature of trypanosomiasis is the presence of blotchy, irregular, nonpruritic, erythematous macules, which may appear any time after the first febrile episode, usually within 6 8 weeks. The majority of macules have a normal central area, giving the rash a circinate outline. This rash is seen mainly on the trunk and is evanescent, fading in one place only to appear at another site. Examination of the blood during this stage may show anemia, leukopenia with relative monocytosis, and elevated levels of immunoglobulin M (IgM). Cardiac manifestations of HAT have also been reported but are generally limited to nonspecific ST T wave electrocardiographic abnormalities. Histopathologic charac terization shows a lymphomonohistiocytic infiltrate in the intersti tium, with no penetration of the myocardial cells, unlike that for American trypanosomiasis (see Chapter 333). The perimyocarditis is usually self limited and does not typically progress to congestive heart failure. Meningoencephalitic Stage (Stage 2) Neurologic symptoms and signs are nonspecific, including irritabil ity, insomnia, and irrational and inexplicable anxieties with frequent changes in mood and personality. Neurologic symptoms may precede invasion of the CNS by the organisms. In untreated T. brucei rhode siense infections, CNS invasion occurs within 3 6 weeks and is associ ated with recurrent bouts of headache, fever, weakness, and signs of acute toxemia. Death occurs in 6 9 months as a result of secondary infection or cardiac failure. In Gambian HAT, cerebral symptoms appear within 2 years after the acute symptoms. An increase in drowsiness during the day and insom nia at night reflect the continuous progression of infection and may be accompanied by anemia, leukopenia, and muscle wasting. The chronic, diffuse meningoencephalitis without localizing symptoms is the form referred to as sleeping sickness. Drowsiness and an uncontrollable urge to sleep are the major features of this stage and become almost continuous in the terminal stages. Tremor or rigidity with stiff and ataxic gait suggest involvement of the basal ganglia. Psychotic changes occur in one third of untreated patients. Although most untreated dis ease is fatal, in rare cases, individuals remain asymptomatic, clear para sitemia, and become seronegative. DIAGNOSIS Definitive diagnosis can be established during the early stages by exam ination of a fresh, thick blood smear, which permits visualization of the motile active forms (Fig. 332.1). HAT can also be detected from blood using a variety of sensitive |
8,086 | techniques, such as quantitative buffy coat smears and mini anion exchange resins. Dried, Giemsa stained smears should be examined for the detailed morphologic features of the organ isms. If a thick blood or buffy coat smear is negative, concentration techniques may help. Aspiration of an enlarged lymph node can also be used to obtain material for parasitologic examination. If positive, cerebrospinal fluid (CSF) should also be examined for the organisms. The presence of trypanosomes, or 5 white blood cells (WBCs)L, or both, is indicative of stage 2 disease. If trypanosomes are absent in the CSF, some authorities use a count of 10 20 WBCsL as a cutoff for diagnosing late stage disease. The card agglutination trypanosomiasis test (CATT) is of value for epidemiologic purposes and for screening for T. brucei gambiense. Lat eral flow formats of CATT have enabled point of care testing. Because CATT detects antibodies against particular VSG molecules, it cannot distinguish present from past infection. Polymerase chain reactionbased tests have been shown to be highly sensitive and specific, but these tests require laboratory facilities. Field based loop mediated isothermal amplification tests have been devel oped and validated. Other areas of active research for diagnostics include new biomarkers, cytokine profiles, proteomics, and polysom nography, which are being used not only to identify disease but to dif ferentiate disease stages. TREATMENT The choice of chemotherapeutic agents for treatment depends on the stage of the infection and the causative organisms. Stage 1 Treatment Hematogenous forms of both Rhodesian and Gambian HAT have been traditionally treated with either suramin or pentamidine. Sura min is a polysulfonated symmetric naphthalene derivative given as a 10 solution for intravenous (IV) administration. A test dose (10 mg for children; 100 200 mg for adults) is initially administered to detect rare idiosyncratic reactions of shock and collapse. The dose for subse quent IV injections is 20 mgkg (maximum 1 g) administered on days 1, 3, 7, 14, and 21. Suramin is nephrotoxic; thus a urinalysis should be performed before each dose. Marked proteinuria, blood, or casts is a contraindication to continuation of suramin. Resistance is rare but has been reported. Pentamidine isethionate (4 mgkgday intramuscularly IM daily or on alternate days for 7 10 days) concentrates to high levels in trypanosomes and is highly trypanocidal. It is better tolerated than suramin but carries significant risk of hypoglycemia, nephrotoxicity, hypotension, leukopenia, and liver enzyme elevation. Because of its A B Fig. 332.1 Trypanosoma brucei sp. trypomastigotes in thick blood smear stained with Giemsa (A) and thin blood smear stained with Wright Giemsa (B). (From Centers for Disease Control and Prevention: Laboratory identification of parasites of public health concern. Trypano somiasis, African website, 2018. https:www.cdc.govdpdxtrypanoso miasisafricanindex.html) 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 333 u American Trypanosomiasis (Chagas Disease; Trypanosoma cruzi) 2163 potency, long half life, and toxicity, short course |
8,087 | treatment is desirable and is being investigated. Fexinidazole has recently been approved for oral treatment of stage 1 and 2 Gambian HAT in 6 years of age and older and weigh ing at least 20 kg. Dosing is weight based over 10 days. For 35 kg and above, a loading dose of 1,800 mg for 4 days followed by a mainte nance dose of 1,200 mg over 6 days is recommended. For 20 kg to 35 kg, the loading dose is 1,200 mg over 4 days and 600 mg main tenance over 6 days. Common side effects include gastrointestinal upset, asthenia, headache, tremors, and dizziness. Some patients may develop neutropenia. Stage 2 Treatment Combination eflornithine and nifurtimox (NECT) is the current treatment of choice for T. brucei gambiense CNS infection. Eflornithine is given at 400 mgkgday IV divided every 12 hours for 7 days, along with nifurtimox, 15 mgkgday orally divided every 8 hour for 10 days. If nifurtimox is unavailable, eflornithine monotherapy can be given at 400 mgkgday IV divided every 6 hours for 14 days. Adverse reac tions to these regimens include fever, hypertension, and seizures, with NECT having less frequent events. Fexinidazole is a safe and effective, all oral alternative to NECT for stage 2 Gambian HAT. However, it is associated with lower efficacy in severe disease (86.9 with fexinidazole vs 98.7 for NECT). Dosing and duration are the same as for stage 1 disease. Melarsoprol is an arsenical compound and is the only effective treatment for late T. brucei rhodesiense disease. Treatment of children is initiated at 0.36 mgkg IV once daily, with gradually escalating doses every 1 5 days to 3.6 mgkg once daily; treatment is usually 10 doses (18 25 mgkg total dose). Treatment of adults is with melar soprol 2 3.6 mgkg IV once daily for 3 days; and after 1 week, 3.6 mgkg once daily for 3 days, which is repeated after 10 21 days. An alternative regimen is 2.2 mgkg once daily for 10 days. Guidelines recommend 18 25 mgkg total over 1 month. Reactions such as fever, abdominal pain, and chest pain are rare but may occur during or shortly after administration. Serious toxic effects include encepha lopathy and exfoliative dermatitis. Following on the success of fexinidazole, other candidate oral drugs for HAT are being studied. This includes acoziborole, which is currently in clinical trials as a single dose oral treatment for stage 2 HAT. PREVENTION A vaccine or consistently effective prophylactic therapy is not avail able and is particularly challenging because of the antigenic variation caused by VSGs. Virus like particles are being explored as an adjuvant to hurdle the complexities of the immunologic response. A single injec tion of pentamidine (3 4 mgkg IM) provides protection against Gam bian trypanosomiasis for at least 6 months, but the effectiveness against the Rhodesian form is uncertain. Vector control programs against Glossina have been essential in controlling disease, coupled with the use of screens, traps, insecti cides, and sanitary measures. Neutral |
8,088 | colored clothing may reduce tsetse fly bites. Control of infection in animal reservoirs with mass administration of trypanocidal drugs in cattle has met with some success. The full genome of T. brucei with about 9,000 genes has been sequenced. Approximately 10 of these genes encode VSGs. CRISPR Cas9 based gene editing has helped identify genes relevant to the disease and its possible prevention, as well as the design of new anti trypanosomal drugs, including those that target specific metabolic pathways. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Chapter 333 American Trypanosomiasis (Chagas Disease; Trypanosoma cruzi) Edsel Maurice T. Salvana and Robert A. Salata American trypanosomiasis or Chagas disease is caused by the proto zoan Trypanosoma cruzi. Its natural vectors are the reduviid insects, specifically triatomines, variably known as wild bedbugs, assassin bugs, or kissing bugs. It can also be transmitted orally from contami nated food, vertically from mother to child, and through blood trans fusion or organ transplantation. Signs and symptoms of acute Chagas disease are usually nonspecific, whereas chronic disease may mani fest as cardiomyopathy or severe gastrointestinal (GI) dilation and dysfunction. ETIOLOGY American trypanosomiasis is caused by T. cruzi, a parasitic, flagellated kinetoplastid protozoan. The main vectors for T. cruzi are insects of the family Reduviidae, subfamily Triatominae, which includes Triatoma infestans, Rhodnius prolixus, and Panstrongylus megistus. LIFE CYCLE T. cruzi has three recognizable morphogenetic phases: amastigotes, trypomastigotes, and epimastigotes (Figs. 333.1 and 333.2). Amas tigotes are intracellular forms found in mammalian tissues that are spherical and have a short flagellum but form clusters of oval shapes (pseudocysts) within infected tissues. Trypomastigotes are spindle shaped, extracellular, nondividing forms that are found in blood and are responsible for both transmission of infection to the insect vec tor and cell to cell spread of infection. Epimastigotes are found in the midgut of the vector insect and multiply in the midgut and rectum of arthropods, differentiating into metacyclic forms. Metacyclic trypo mastigotes are the infectious form for humans and are released onto the skin of a human when the insect defecates close to the site of a bite, entering through the damaged skin or mucous membranes. Once in the host, these multiply intracellularly as amastigotes, which then dif ferentiate into bloodstream trypomastigotes and are released into the circulation when the host cell ruptures. Blood borne trypomastigotes circulate until they enter another host cell or are taken up by the bite of another insect, completing the life cycle. There is some variability in these stages. Reverse transitions can occur; epimastigote like forms have been found in the mammalian hosts, and trypomastigotes have been observed to replicate. Amastigotes can also quickly transform into quiescent forms upon drug exposure and can maintain persistent infection despite treatment. EPIDEMIOLOGY Natural transmission of Chagas disease occurs in North and South America, most frequently in continental Latin America. The disease may arise elsewhere because of migration and transmission through contaminated blood. World Health Organization (WHO) and Pan American Health Organizationled efforts in large scale vector control, blood donor |
8,089 | screening to prevent transmission through transfusion and case finding, and treatment of chronically infected 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. 2164 Part XV u Infectious Diseases Fig. 333.1 Stages of Trypanosoma cruzi. A, Amastigote. B, Trypomastig ote. C, Epimastigotes. (From Centers for Disease Control and Prevention. Laboratory identification of parasites of public health concern. Trypanoso miasis, American website, 2018. https :www.cdc.govdpdxtrypanosomiasis americanindex.html) B CA Trypomastigotes transform into epimastigotes, and epimastigotes replicate by binary fission (midgut) Epimastigotes migrate to the hindgut and rectum, and differentiate into metacyclic trypomastigotes that are released by defecation Infective metacyclic trypomastigotes released onto skin of a mammalian host in feces Metacyclic trypomastigotes enter the host through rubbing or scratching of the bite wound, or through permissive mucosal or conjunctival surfaces Triatoma infestans Rhodnius prolixus Triatoma dimidiata Skin or mucosa Foregut Bloodmeal Trypomastigote in blood smear Trypomastigotes in bloodstream Infection of new cells Cell lysis Romaa sign Chagoma Myocardial cell full of amastigotes After decades Megaesophagus Megacolon Cardiomyopathy Recruitment and fusion of lysosomes from the host cell are needed for trypomastigotes to penetrate local cells Trypomastigote in lysosomederived membranebound vacuole Escape from vacuole Spread of infection Replication of amastigotes by binary fission Transformation of amastigotes into trypomastigotes Differentiation into amastigotes Signs of portal of entry Acute phase of Chagas diseaseChronic phase of Chagas disease Triatomine insect Mammalian host Fig. 333.2 Vector borne transmission and life cycle of Trypanosoma cruzi. (From Rassi A Jr, Rassi A, Marin Neto JA. Chagas disease. Lancet. 2010;375:13881400. Fig. 1.) mothers and newborn infants have effectively halted transmission in a number of areas of South America. The number of cases has dropped from a peak of 24 million in 1984 to a current estimate of 6 7 million. Incident cases are estimated at 30,000 infections per year, including 8,000 newborns from vertical transmission. Chagas disease causes 10,000 12,000 deaths annually. This is likely an underestimate as long term complications of Chagas disease as a cause of death may not be properly attributed to undiagnosed, chronically infected persons. Infection is divided into two main phases: acute and chronic (Table 333.1). Acute infection can manifest as fever, lymphadenopathy, organomegaly, myocarditis, and meningoencephalitis but is otherwise asymptomatic in up to 95 of infected individuals. Chronic infec tion in 6070 of patients is indeterminate, meaning the patient is asymptomatic but has a positive antibody titer. Approximately 30 of infected persons proceed to chronic determinate or symptomatic T. cruzi infection. The T. cruzi genome has been fully sequenced and contains 12,000 genes, the most widely expanded among trypanosomatids, and may reflect its ability to invade virtually any nucleated cell type within reach. Significant variability is present, along with extensive epigen etic modification of surface proteins, which may contribute to immune evasion. Seven genetic lineages, known as discrete typing units (DTUs) are recognized. These are referred to as TcI through TcVI, |
8,090 | and Tcbat for 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 333 u American Trypanosomiasis (Chagas Disease; Trypanosoma cruzi) 2165 Table 333.1 Clinical Features and Diagnosis of Chagas Disease GEOGRAPHIC DISTRIBUTION CLINICAL SIGNSSYMPTOMS DIAGNOSIS ACUTE FORMS Vectorial Endemic countries Incubation period: 1 2 wk Signs of portal of entry: indurated cutaneous lesion (chagoma) or palpebral edema (Romaa sign) Most cases are mild disease (9599) and unrecognized Persistent fever, fatigue, lymphadenopathy, hepatomegaly, splenomegaly, morbilliform rash, edema In rare cases, myocarditis or meningoencephalitis Anemia, lymphocytosis, elevated ASTALT concentrations Risk of mortality: 0.20.5 Direct parasitologic methods: patent parasitemia up to 90 days Microscopic examination of fresh blood, Giemsa stained thin and thick blood films, or buffy coat Concentration methods: microhematocrit and Strout method PCR techniques Serology is not useful Congenital Endemic and nonendemic countries Incubation period: birth to several weeks Most are asymptomatic or have mild disease Prematurity, low birthweight, abortion, neonatal death Fever, jaundice, edema, hepatomegaly, splenomegaly, respiratory distress syndrome, myocarditis, meningoencephalitis Anemia and thrombocytopenia Risk of mortality: 2 Direct parasitologic methods Concentration methods: microhematocrit, Strout method Direct microscopy also useful PCR: most sensitive technique Serology: after 9 mo or later Oral Restricted areas of endemic countries (Amazon basin) and local outbreaks Incubation period: 3 22 days Fever, vomiting, periocular edema, dyspnea, fever, myalgia, prostration, cough, splenomegaly, hepatomegaly, chest pain, abdominal pain, digestive hemorrhage Risk of mortality: 135 Same as for vectorial Transfusion and transplant Endemic and nonendemic countries Incubation period: 8 160 days; persistent fever Clinical characteristics similar to those of vectorial cases (excluding portal of entry signs) Risk of mortality is variable and depends on the severity of baseline disease Same as for vectorial PCR techniques usually yield positive results days to weeks before trypomastigotes are detectable in blood Tissue samples are needed in some circumstances Reactivation in HIV infected patients Endemic and nonendemic countries Behaves as other opportunistic infections Reactivation with 200 CD4 cellsL (mostly with 100) Affects CNS (7590) as single or multiple space occupying lesions or as severe necrohemorrhagic meningoencephalitis Cardiac involvement (1055): myocarditis, pericardial effusion or worsening of previous cardiomyopathy Risk of mortality: 20 Direct parasitologic methods, as in vectorial cases Parasite can be found in CSF, other body fluids, and tissue samples PCR: not useful for diagnosis of reactivation Serology: indicative of chronic infection and helpful in cases of suspected disease Reactivation in other immunosuppressed patients Endemic and nonendemic countries Reactivation after transplantation or in patients with hematologic malignancies Clinical characteristics similar to those of patients who undergo transfusion and those with panniculitis and other skin disorders Risk of mortality is variable and depends on severity of baseline disease and prompt diagnosis Direct parasitologic methods, as in vectorial cases Parasite can be found in tissue samples PCR: increasing parasite load detected with real time PCR in serial specimens could be indicative of a high risk of reactivation CHRONIC |
8,091 | FORMS Indeterminate Endemic and nonendemic countries Asymptomatic Normal chest radiograph and 12 lead ECG Serology: detection of IgG PCR: low sensitivity 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. 2166 Part XV u Infectious Diseases Table 333.1 Clinical Features and Diagnosis of Chagas Diseasecontd GEOGRAPHIC DISTRIBUTION CLINICAL SIGNSSYMPTOMS DIAGNOSIS Cardiac and gastrointestinal Endemic and nonendemic countries Cardiac manifestations: fatigue, syncope, palpitations, dizziness, stroke; late manifestations: chest pain (atypical), dyspnea, edema, left ventricular dysfunction, congestive heart failure; alterations in 12 lead ECG, echocardiography, or other heart function tests Gastrointestinal: dysphagia, regurgitation, severe constipation (dilated esophagus or colon); alterations in esophageal manometry, barium swallow, or barium enema Serology: detection of IgG PCR: low sensitivity Including reactivation in immunosuppressed patients. ALT, Alanine transaminase; AST, aspartate transaminase; CNS, central nervous system; CSF, cerebrospinal fluid; PCR, polymerase chain reaction. From Prez Molina J, Molina I. Chagas disease. Lancet. 2018;391:8292. Table 2. the seventh DTU. DTUs may differ in geographic distribution and pre dominant vector and hosts and may also vary in disease manifestations and response to treatment. A recent meta analysis showed that TcI, the most widespread DTU, may be less susceptible to benznidazole. T. cruzi infection is primarily a zoonosis, and humans are incidental hosts. T. cruzi has a large sylvan reservoir and has been isolated from numerous animal species. The presence of reservoirs and vectors of T. cruzi and the socioeconomic and educational levels of the population are the most important risk factors for vector borne transmission to humans. Insect vectors are found in rural, wooded areas and acquire infection through ingestion of blood from humans or animals with cir culating trypomastigotes. Housing conditions are very important in the transmission chain. Incidence and prevalence of infection depend on the adaptation of the triatomines to human dwellings, as well as the vector capacity of the species. Animal reservoirs of reduviid bugs include dogs, cats, rats, opossum, guinea pigs, monkeys, bats, and raccoons. Humans often become infected when land in enzootic areas is developed for agricultural or commercial purposes. An estimated 240,000 to 350,000 immigrants from endemic countries living in the United States are likely infected with T. cruzi. Seventy six cases of autoch thonous transmission in the United States have also been reported from 2000 to 2018; more than half of the cases were described in Texas. The risk of congenital Chagas disease transmission is 15. Heavy parasite loads are associated with higher risk of vertical transmission. Transplacental infection is associated with premature birth, fetal wast age, hepatomegaly, and anemia. Infected infants are mostly asymptom atic at birth, although 1040 may have signs suggestive of congenital infection. Untreated infected infants are at risk for developing Chagas cardiomyopathy later in life. Disease transmission can occur through blood transfusions in endemic areas from asymptomatic blood donors. The risk for trans mission through a single blood transfusion from a chagasic donor |
8,092 | is 1323. Blood screening for Chagas disease in the United States has detected 2,462 confirmed cases between 2007 and 2019 (www.aabb.org). Percutaneous injection from laboratory accidents is a documented mode of transmission. Oral transmission through contaminated food can occur. Although transmission from breastfeeding is uncommon, women with acute infections should not nurse until they have been treated. PATHOGENESIS Acute Disease At the site of entry or puncture site, neutrophils, lymphocytes, macro phages, and monocytes infiltrate. T. cruzi organisms are engulfed by macrophages and are sequestered in membrane bound vacuoles. Try panosomes lyse the phagosomal membrane, escape into the cytoplasm, and replicate. A local tissue reaction, the chagoma, develops and the process extends to a local lymph node (see Fig. 333.2). Blood forms appear, and the process disseminates. A multitude of innate response mechanisms are deployed at the beginning of infection but are largely ineffective for controlling invasion. However, this initial response is essential for setting up the more potent subsequent adaptive response. Peak parasite numbers are seen after 2 3 weeks and drop quickly when the adaptive immune response comes into play. This response, while efficient at clearing up to 95 of the parasites, is not sterilizing and parasites can persist in more susceptible tissues such as muscle and ganglion cells. Chronic Disease The pathophysiology of chronic Chagas disease involves several mech anisms and most significantly affects two main target organs: the heart and the GI tract. Development of pathology in these organs is linked to parasite tropism and persistence in susceptible tissue types against the background of an otherwise effective T. cruzispecific systemic immune response. In the case of cardiac pathology, parasite dependent myocardial damage plays some role because of invasion of myocardial cells. The extent of injury seems to be less severe compared to acute disease, and its actual proportional contribution to overall tissue destruction is unclear. Additional damage comes from chronic immune mediated myocardial injury as a result of delayed type IV hypersensitivity to par asite persistence in myocardial cells. This causes mononuclear myo carditis and myocytolysis, leading to fibrosis and contributing to the development of cardiomyopathy. Dysautonomia due to direct damage to ganglion cells and antineuronal autoimmune reactions leads to the development of cardiomyopathy as an effect of excess catecholamine stimulation. This phenomenon in turn increases myocardial irritability resulting in a higher risk of malignant arrhythmias and sudden car diac death. Microvascular disturbances also further exacerbate cardiac damage from intimal proliferation and fibrosis due to parasite induced perivascular inflammation and cell necrosis. In patients with GI tract involvement, myenteric plexus destruc tion leads to pathologic organ dilation. There is a diminution in the Auerbach and the Meissner plexus, as well as preganglionic lesions and a reduction in the number of dorsal motor nuclear cells of the vagus nerve. Loss of ganglia in the esophagus results in abnormal dilation. Antibodies involved in resistance to T. cruzi invasion are related to the phase of infection. IgG antibodies to several major surface antigens mediate immunophagocytosis of T. cruzi by |
8,093 | macrophages. Activation 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 333 u American Trypanosomiasis (Chagas Disease; Trypanosoma cruzi) 2167 of autoreactive T and B cell clones (with B cell clones resulting in the production of autoantibodies) is a well described phenomenon during T. cruzi infection. However, the contribution of this activa tion to pathology seems to be dependent on persistence of infec tion. Conditions that depress cell mediated immunity increase the severity of T. cruzi infection. There is evidence that host genetic factors play a significant role in progression and severity of chronic disease. CLINICAL MANIFESTATIONS Acute Chagas disease in children is usually asymptomatic or is asso ciated with mild febrile illness characterized by malaise, facial edema, and lymphadenopathy (see Table 333.1). Infants often demonstrate local signs of inflammation at the site of parasite entry, which is then referred to as a chagoma. Approximately 50 of children come to medical attention with the Romaa sign (unilateral, painless eye swelling), conjunctivitis, and preauricular lymphadenitis. Patients complain of fatigue and headache. Fever can persist for 4 5 weeks. More severe systemic presentations can occur in children 2 years old and may include lymphadenopathy, hepatosplenomegaly, and menin goencephalitis. A cutaneous morbilliform eruption can accompany the acute syndrome. Anemia, lymphocytosis, hepatitis, and throm bocytopenia have also been described. The heart, central nervous system (CNS), peripheral nerve ganglia, and reticuloendothelial system are often heavily parasitized. The heart is the primary target organ. The intense parasitism can result in acute inflammation and in four chamber cardiac dilation. Intrauterine infection in pregnant women can cause spontane ous abortion or premature birth. In children with congenital infec tion, severe anemia, hepatosplenomegaly, jaundice, and seizures can mimic congenital cytomegalovirus infection, toxoplasmosis, and erythroblastosis fetalis. T. cruzi can be visualized in the cerebrospi nal fluid in cases of meningoencephalitis. Children usually undergo spontaneous remission in 8 12 weeks and enter the indeterminate chronic phase with lifelong low grade parasitemia and development of antibodies to many T. cruzi cell surface antigens. In acute dis ease, mortality is 510, with deaths caused by acute myocarditis, with resultant heart failure, or meningoencephalitis. Acute Cha gas disease should be differentiated from malaria, schistosomiasis, visceral leishmaniasis, brucellosis, typhoid fever, and infectious mononucleosis. Autonomic dysfunction and peripheral neuropathy can occur. CNS involvement in Chagas disease is uncommon. If granulomatous encephalitis occurs during acute infection, it is usually fatal. Chronic Chagas disease may be asymptomatic or symptomatic. The most common presentation of chronic T. cruzi infection is car diomyopathy, manifested by congestive heart failure, arrhythmia, and thromboembolic events. ECG abnormalities include partial or complete atrioventricular block and right bundle branch block. Left bundle branch block is unusual. Myocardial infarction has been reported and may be secondary to left apical aneurysm emboliza tion or necrotizing arteriolitis of the microvasculature. Left ven tricular apical aneurysms are pathognomonic of chronic chagasic cardiomyopathy. GI |
8,094 | manifestations of chronic Chagas disease occur in 810 of patients. Characteristically, this involvement presents clinically as megaesophagus and megacolon. Sigmoid dilation, volvulus, and fecalomas are often found in megacolon. Megaesophagus pres ents as dysphagia, odynophagia, and cough. The esophagus can reach up to 26 times its normal weight and hold up to 2 L of excess fluid. Esophageal body abnormalities occur independently of lower esophageal dysfunction. Megaesophagus can lead to esophagitis and cancer of the esophagus. Aspiration pneumonia and pulmonary tuberculosis are also more common in patients with megaesophagus. Immunocompromised Persons T. cruzi infections in immunocompromised persons may be caused by transmission from an asymptomatic donor of blood products or reactivation of prior infection. Organ donation to allograft recipients can result in a devastating form of the illness. Cardiac transplantation for Chagas cardiomyopathy has resulted in reactivation, despite pro phylaxis and postoperative treatment with benznidazole. HIV infec tion also leads to reactivation in about 20 of cases; cerebral lesions are more common in these patients and can mimic Toxoplasma encephali tis. Myocarditis is also frequently observed, and secondary prophylaxis may be of benefit in some HIVco infected patients. In immunocom promised patients at risk for reactivation, serologic testing and close monitoring are necessary. DIAGNOSIS A careful history with attention to geographic origin and travel is important. A peripheral blood smear or a Giemsa stained smear during the acute phase of illness may show motile trypanosomes, which is diagnostic for Chagas disease (see Fig. 333.1). These are only seen in the first 6 12 weeks of illness. Buffy coat smears may improve yield. Most persons seek medical attention during the chronic phase of the disease, when parasites are not found in the bloodstream and clinical symptoms are not diagnostic. Serologic testing is used for diagnosis, most commonly enzyme linked immunosorbent assay (ELISA), indirect hemagglutination, and indirect fluorescent anti body testing. No single serology test is sufficiently reliable to make the diagnosis, so repeat or parallel testing using a different method or antigen is required to confirm the result of an initial positive serologic test, and in the case of discordant results, a third test may be employed. Two tests, the Ortho T. cruzi ELISA Test System and the Abbott Prism Chagas Assay, are approved by the U.S. Food and Drug Administration (FDA) for screening of blood donors but not for clinical samples. For clinical samples in suspected Chagas cases in the United States, contact the Centers for Disease Control and Prevention (CDC) for further guidance. Confirmatory tests include the radiologic immunoprecipitation assay (Chagas RIPA, currently for research or limited clinical testing only) and Western blot assays based on trypomastigote excreted secreted antigens (TESA WB). The Abbott Enzyme Strip Assay Chagas (ESA Chagas) using recom binant T. cruzi antigens is the only FDA approved confirmatory test in the United States. Nonimmunologic methods of diagnosis are available. Mouse inoculation and xenodiagnosis (allowing uninfected reduviid bugs to feed on a patients blood and examining the intestinal contents of those bugs 30 days after the |
8,095 | meal) are cumbersome and not rou tinely performed. Parasites can be cultured in Novy MacNeal Nicolle (NNN) media. Polymerase chain reaction (PCR) tests of nuclear and kinetoplast DNA sequences have been developed and can be highly sensitive in acute disease but are less reliable in chronic disease. PCR has been used as an early indicator of treatment failure in therapeu tic clinical trials, and to detect reactivation in chronically infected patients at risk because of immunosuppression. PCR is not suffi ciently sensitive for blood screening. Moreover, there is significant variability among methods and parasite strains. Diagnosis of congen ital transmission in newborns cannot be made at birth with serology because of the presence of maternal antibodies in the first 6 months of life. Microscopic examination, parasite culture, or PCR can be used. However, a serologic test at 6 12 months is recommended to exclude infection definitively. TREATMENT Biochemical differences between the metabolism of American trypano somes and that of mammalian hosts have been exploited for chemo therapy. Trypanosomes are very sensitive to oxidative radicals and do not possess catalase or glutathione reductaseglutathione peroxidase, which are key enzymes in scavenging free radicals. All trypanosomes also have an unusual, reduced nicotinamide adenine dinucleotide phosphate (NADPH)dependent disulfide reductase. Drugs that stim ulate hydrogen peroxide (H2O2) generation or prevent its utilization are potential trypanosomicidal agents. Other biochemical pathways 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. 2168 Part XV u Infectious Diseases that have been targeted include ergosterol synthesis using azole com pounds and the hypoxanthine guanine phosphoribosyltransferase pathway using allopurinol. Drug treatment for T. cruzi infection is currently limited to nifur timox and benznidazole. Both are effective against trypomastigotes and amastigotes and have been used to eradicate parasites in the acute stages of infection. Treatment responses vary according to the phase of Chagas disease, duration of treatment, dose, age of the patient, and geographic origin of the patient. For acute disease, the average cure rate is about 6080. Cure of chronic disease is difficult to assess due to the different definitions of cure, whether with a negative serology or quantitative PCR. Other drugs that have been tried include posacon azole, ravuconazole, and fexinidazole but have not been as successful as traditional treatment. Benznidazole, a nitroimidazole derivative, is the most effective treatment for Chagas disease. Benznidazoles primary mechanism of action involves covalent binding with trypanosomal protein thiols and low molecular weight thiols, resulting in depletion of these molecules and disruption of the parasite metabolism. The recommended treat ment regimen for children 2 12 years old is 5 8 mgkgday orally (PO), which can be divided twice daily (bid) for 60 days. For those 12 years old, 5 7 mgkgday for 60 days is recommended. The tablets can be administered as a slurry for children who have difficulty swallowing. A recent meta analysis suggests a 30 day regimen may |
8,096 | be noninferior to a 60 day regimen. Cure rates for chronic disease as assessed by PCR is 6691 at the end of treatment, but this drops to 82 at 1 year, 55 at 2 years, and 47 at 5 years. This drug is associated with significant toxicity, including rash, photosensitivity, peripheral neuritis, granulo cytopenia, and thrombocytopenia. Nifurtimox generates highly toxic oxygen metabolites through the action of nitroreductases, which produce unstable nitroanion radicals, which in turn react with oxygen to produce peroxide and superoxide free radicals. The FDA recently approved nifurtimox for the treatment of Chagas disease in pediatric patients from birth to 18 years of age and weighing at least 2.5 kg. The recommended total daily dose in pediatric patients is 10 20 mgkgday orally divided into three doses for 60 days for children 40 kg, and 8 10 mgkgday orally divided into three doses for children 40 kg. Nifurtimox has been associated with weakness, anorexia, GI disturbances, toxic hepatitis, tremors, seizures, and hemolysis in patients with glucose 6 phosphate dehydrogenase deficiency. With the adoption by WHO of control and elimination strategies for Chagas disease, both acute and chronic disease should be treated. Serologic conversion is seen as an appropriate treatment response for chronic disease, although some patients who achieve this still even tually develop symptoms. One study reported cure rates as high as 97 for chronic disease in patients 16 years old and supports early and aggressive case findings and treatment. Infants suspected of con genitally acquired Chagas disease should be properly evaluated and treated immediately upon confirmation of the diagnosis. Women who give birth to infants with congenital Chagas disease should be offered treatment to prevent congenital transmission in subsequent pregnan cies. Continuing efforts for elimination will necessitate development of more accurate diagnostics and more effective drugs, particularly for chronic disease. Treatment of congestive heart failure is generally in line with rec ommendations for management of dilated cardiomyopathy from other causes. Adrenergic blockers have been validated in the management of these patients. Digitalis toxicity occurs frequently in patients with Chagas cardiomyopathy. Pacemakers may be nec essary in cases of severe heart block. Although cardiac transplanta tion has been used successfully in chagasic patients, it is reserved for those with the most severe disease manifestations. Plasmapheresis to remove antibodies with adrenergic activity has been proposed for refractory patients; this approach has worked in patients with dilated cardiomyopathy from other causes, but its application to Chagas dis ease is unproved. A light, balanced diet is recommended for megaesophagus. Surgery or dilation of the lower esophageal sphincter treats megaesophagus; pneumatic dilation is the superior mode of therapy. Nitrates and nife dipine have been used to reduce lower esophageal sphincter pressure in patients with megaesophagus. Treatment of megacolon is surgical and symptomatic. In accidental infection when parasitic penetration is certain, treat ment should be immediately initiated and continued for 10 15 days. Blood is usually collected and serologic samples tested for seroconver sion at 15, 30, and 60 days. PREVENTION Massive coordinated |
8,097 | vector control programs under the auspices of WHO and the Pan American Health Organization and the institu tion of widespread blood donor screening and targeted surveillance of chronically infected mothers and infants at risk have effectively elimi nated or at least drastically reduced transmission in most endemic countries. Chagas disease remains linked to poverty; thus improve ment of living conditions is likewise essential to successful control and eradication. Education of residents in endemic areas, use of bed nets, use of insecticides, and destruction of adobe houses that harbor reduviid bugs are effective methods to control the bug population. Syn thetic pyrethroid insecticides help keep houses free of vectors for up to 2 years and have low toxicity for humans. Paints incorporating insecti cides have also been used. Because immigrants can carry this disease to nonendemic areas, serologic testing should be performed in blood and organ donors from endemic areas. Potential seropositive donors can be identified by determining whether they have been or have spent extensive time in an endemic area. Questionnaire based screening of potentially infected blood and organ donors from areas endemic for infection can reduce the risk for transmission. Seropositivity should be considered a con traindication to organ donation, particularly for heart transplantation. Prophylactic and therapeutic vaccine development is being pursued but is hampered by the ability of the parasite to evade immune mecha nisms and persist in different body compartments. Nucleic acidbased techniques and viral vectors are being explored, along with novel adju vants and strategies for addressing significant genetic variability among the DTUs. Visit Elsevier eBooks at eBooks.Health.Elsevier.com for Bibliography. Chapter 334 Malaria (Plasmodium) Chandy C. John and Robert O. Opoka Malaria is a vector borne disease caused by intraerythrocytic proto zoa of the genus Plasmodium and transmitted by an infective female Anopheles mosquito. Malaria is an acute illness characterized by parox ysms of fever, chills, sweats, fatigue, anemia, and splenomegaly. It has played a major role in human history, causing harm to more people than perhaps any other infectious disease. Although substantial prog ress has been made in combating malaria in endemic areas, with a 22 reduction in malaria incidence since 2010, malaria remains one of the leading causes of morbidity and mortality worldwide, with an esti mated 229 million cases and 409,000 deaths in 2019. Malarial deaths in areas of high malaria transmission occur primarily in children 5 years of age, but in areas of low transmission, a large percentage 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 334 u Malaria (Plasmodium) 2169 Fig. 334.1 Spatial distribution of malaria in the Eastern and Western hemispheres. In this map, countries with areas endemic for malaria are shaded completely even if transmission occurs only in a small part of the country. For more specific within country malaria transmission information, see the Yellow Fever Malaria Informa tion, by Country |
8,098 | section in in the Centers for Disease Control and Prevention (CDC) link in this caption. (From Tan RK, Arguin PM. Malaria. In Centers for Disease Con trol and Prevention. CDC Yellow Book 2020: Health Information for International Travel. New York: Oxford University Press; 2017. Maps 4.8 and 9 https:wwwnc.c dc.govtravelyellowbook2020travel related infectious diseasesmalaria5217) Endemic country Nonendemic country deaths may occur in older children and adults. Although malaria is not endemic in the United States, 1,500 2,000 imported cases are seen in the United States each year. Physicians practicing in non endemic areas should consider the diagnosis of malaria in any febrile child who has returned from a malaria endemic area within the previous year, because delay in diagnosis and treatment can result in severe illness or death. ETIOLOGY Malaria is caused by intracellular Plasmodium protozoa transmitted to humans by female Anopheles mosquitoes. Before 2004, only four species of Plasmodium were known to cause malaria in humans: P. falciparum, P. malariae, P. ovale, and P. vivax. In 2004, P. knowlesi (a primate malaria species) was also shown to cause human malaria, and cases of P. knowlesi infection have been documented in Malay sia, Indonesia, Singapore, and the Philippines. Malaria also can be transmitted through blood transfusion and use of contami nated needles and transplacentally from a pregnant woman to her fetus. The risk for blood transmission is low in the United States, but may occur through transfusion of whole blood, packed red blood cells (RBCs), platelets, and leukocytes and through organ transplantation. EPIDEMIOLOGY Malaria is a major worldwide problem, occurring in 87 countries that comprise approximately half the worlds population (Fig. 334.1). World wide malaria cases decreased from an estimated 238 million cases in 2010 to 229 million cases of in 2019. The principal areas of transmis sion are Africa, Asia, and South America. P. falciparum and P. malariae are found in most malarious areas. P. falciparum is the predominant species in Africa, Haiti, and New Guinea. P. vivax predominates in Bangladesh, Central America, India, Pakistan, and Sri Lanka. P. vivax and P. falciparum predominate in Southeast Asia, South America, and Oceania. P. ovale is the least common species and is transmitted pri marily in Africa. Transmission of malaria has been eliminated in most of North America (including the United States), Europe, and most of the Caribbean, as well as Australia, Chile, Israel, Japan, Lebanon, and Taiwan. In 2021, the World Health Organization (WHO) certified that China had eliminated malaria, a landmark achievement for this area of 1 billion people. P. falciparum is the parasite most commonly associated with severe illness and death, typically among young children. P. falciparum is the predominant species in Africa, Haiti, and New Guinea. Over 99 of cases in Africa are caused by P. falciparum, and 94 of all malaria deaths occur in Africa. Previously malarial deaths were predominantly in children under 5 years of age but over the years more older children are being affected, with the percentage of total malaria deaths among children age |
8,099 | under 5 years dropping from 84 in 2000 to 67 in 2019. P. vivax, contributes to about 3.3 of global malaria. P. vivax is respon sible for 75 of malaria cases in central America and 50 of cases in Southeast Asia (World Malaria Report 2019). Most cases of malaria in the United States occur among previously infected visitors to the United States from endemic areas and among U.S. citizens who travel to endemic areas without appropriate che moprophylaxis. Due to the increase in global travel, the number of imported malaria cases has been increasing over the last 40 years, with 2,161 cases reported in 2017. Most cases were acquired in Africa (87), with Asia (8), South America (1.9), and Cen tral America (1.5) contributing most remaining cases. Among all cases, P. falciparum accounted for the majority of infections (1,523; 70.5), followed by P. vivax (216; 10.0), P. ovale (119; 5.5), and P. malariae (55; 2.6). Among all reported cases of malaria in 2017, a total of 312 (14.4) were classified as severe malaria, and 6 of these 312 persons (1.9) died. Cases peak during the summer travel months. Children comprised 18 of all malaria cases in the United States in 2017, and 39 of pediatric cases occurred in U.S. resident children, 70 of whom were visiting friends or relatives. Severe malaria was more slightly common in children (18.4) than adults (13.6). Local transmission of malaria can rarely occur in the United States, as demonstrated in 2003, when eight cases were diagnosed among non travelers in Palm Beach, Florida, and as demonstrated again in 2023 in Florida, Texas, and Maryland. These cases may result from transmission from untreated and often asymptomatic infected indi viduals from malaria endemic countries who travel to the United States and infect local mosquitoes or from infected mosquitoes from malaria endemic areas that are transported to the United States on airplanes. Transfusion transmitted malaria can also occur in the United States. PATHOGENESIS Plasmodium species exist in a variety of forms and have a complex life cycle that enables them to survive in different cellular environments in the human host (asexual phase) and the mosquito (sexual phase) (Fig. 334.2). A marked amplification of Plasmodium, from approxi mately 102 to as many as 1014 organisms, occurs during a two step pro cess in humans, with the first phase in hepatic cells (pre erythrocytic phase) and the second phase in the RBCs (erythrocytic phase). The pre erythrocytic phase begins with inoculation of sporozoites into the bloodstream by a female Anopheles mosquito. Within minutes the 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. 2170 Part XV u Infectious Diseases sporozoites enter the hepatocytes of the liver, where they develop and multiply asexually as a schizont. After 1 2 weeks, the hepatocytes rupture and release thousands of merozoites into the circulation. The tissue schizonts of P. |
8,100 | falciparum, P. malariae, and apparently P. knowlesi rupture once and do not persist in the liver. There are two types of tissue schizonts for P. ovale and P. vivax. The primary type ruptures in 6 9 days, and the secondary type remains dormant in the liver cell for weeks, months, or as long as 5 years before releasing merozoites and causing relapse of infection. The erythrocytic phase of Plasmodium asexual development begins when the merozoites from the liver penetrate erythrocytes. Once inside the erythrocyte, the parasite transforms into the ring form, which then enlarges to become a trophozoite. These latter two forms can be identified with Giemsa stain on blood smear, the primary means of confirming the diagnosis of malaria (Fig. 334.3). The trophozoite multiplies asexu ally to produce a number of small erythrocytic merozoites that are released into the bloodstream when the erythrocyte membrane rup tures, which is associated with fever. Over time, some of the mero zoites develop into male and female gametocytes that complete the Plasmodium life cycle when they are ingested during a blood meal by the female anopheline mosquito. The male and female gametocytes fuse to form a zygote in the stomach cavity of the mosquito. After a series of further transformations, sporozoites enter the salivary gland of the mosquito and are inoculated into a new host with the next blood meal. Pathophysiology and pathogenesis in malaria differ according to species. Infection with all species leads to fever, caused by the host immune response when erythrocytes rupture and release merozo ites into the circulation, and anemia, caused by hemolysis and bone marrow suppression. Severe malaria is more common in P. falci parum because of several processes, including higher density para sitemia, which may lead to excessive production of proinflammatory cytokines; cytoadherence of P. falciparum infected erythrocytes to the vascular endothelium; and polyclonal activation, resulting in both hypergammaglobulinemia and the formation of immune com plexes. Cytoadherence of infected erythrocytes to vascular endothe lium can lead to obstruction of blood flow and capillary damage, with resultant vascular leakage of blood, protein, and fluid and tissue anoxia. Parasite anaerobic metabolism may also lead to hypoglyce mia and metabolic acidosis. The cumulative effects of these patho logic processes may lead to cerebral, cardiac, pulmonary, renal, and hepatic failure. Immunity after Plasmodium sp. infection is incomplete, prevent ing severe disease but still allowing future infection. In some cases, parasites circulate in small numbers for a long time but are prevented from rapidly multiplying and causing severe illness. Repeated episodes P. vivax P. falciparum P. ovale P. malariae Liver cell Human Liver Stages Mosquito Stages Human Blood Stages Infected liver cell Schizont Schizont Gametocytes Gametocytes Immature trophozoite (ring stage) Mature trophozoite Ruptured schizont Ruptured schizont Mosquito takes a blood meal (ingests gametocytes) Mosquito takes a blood meal (injects sporozoites) Exflagellated microgametocyte Microgamete entering macrogamete Macrogametocyte Ookinete Sporogonic Cycle Oocyst Ruptured oocyst Infective Stagei i i d 12 11 10 9 8 4 2 3 5 6 7 7 C B A |
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