Disease and Agent
Under—
lying Host Condition(s)
Reservoir(s) or Route(s) of Entry
Common Clinical Manifestations
Diagnostic Laboratory
Test(s) Treatment Phaeohyphomycosis (continued)
Curvularia species
Immunosup- pression;
altered skin integrity;
asthma or nasal polyps; chronic sinusitis
Environment Allergic fungal sinusitis; invasive dermatitis; dis- seminated infection
Culture and histopathologic examination of tissue
Allergic fungal sinusitis: sur- gery and corti- costeroids Invasive disease:
voriconazole, itraconazole,b or L-AMBa Exophiala spe-
cies, Exserohi- lum species
None or trauma or immunosup- pression
Environment Sinusitis; cutane- ous lesions;
disseminated infection; meningi- tis associated with contaminated steroid for epidural use
Culture and histopathologic examination of tissue
Voriconazole,c itraconazole,b L-AMB, or surgi- cal excision
Pseudallesche- ria boydii ( Scedosporium apiospermum) Scedosporium species
None or trauma or immunosup- pression
Environment Pneumonia; dis- seminated infec- tion; osteomyelitis or septic arthritis;
endocarditis
Culture and histopathologic examination of tissue
Voriconazoled or itraconazole
Trichosporonosis Trichosporon species
Immunosup- pression; cen- tral venous catheter
Normal flora of gastrointesti- nal tract
Bloodstream infec- tion; endocarditis;
pneumonitis;
disseminated infection
Blood culture;
histopathologic examination of tissue; urine culture
Voriconazole
Mucormycosis (Formerly Zygomycosis) Rhizopus;
Mucor; Lich- theimia (for- merlyAbsidia) species; Rhizo- mucor species
Immunosup- pression;
hematologic malignant neo- plasm; renal failure; diabetes mellitus; iron overload syndromes
Respiratory tract; skin
Rhinocerebral infection; pulmo- nary infection;
disseminated infection; skin and gastrointestinal tract less commonly
Histopathologic examination of tissue and culture
High dose of L-AMB for initial therapy; surgical excision as fea- sible; posacon- azolee for maintenance therapy (Vori- conazole has no activity.) Abbreviation: L-AMB, liposomal amphotericin B (if the patient is a neonate or young infant, or if L-AMP is not available, amphotericin B, D AMP, can be substituted).
a Consider use of a lipid-based formulation of amphotericin B.
b Itraconazole has been shown to be effective for cutaneous disease in adults, but safety and efficacy have not been established in children younger than 12 years.
c Voriconazole demonstrates activity in vitro, but limited clinical data are available for children.
d Itraconazole may be the treatment of choice, but data on safety and effectiveness in children are limited.
e Posaconazole demonstrates activity in vitro, but few clinical data are available for children.
FuNGAL DiSEASES 181
Image 48.1
Cerebral mucormycosis in a patient with acute lymphoblastic leukemia. Occlusion of the basilar artery and infarct of the pons. The patient had
jaundice. Courtesy of Dimitris P. Agamanolis, mD. Image 48.2Extensive cerebral necrosis in a patient with mucormycosis. Courtesy of Dimitris P.
Agamanolis, mD.
Image 48.3
This slide describes the histopathologic changes seen in zygomycosis due to Rhizopus arrhizus using fluorescent antibody stain technique. R arrhizus, the most common Rhizopus species, is known to be the cause of zygomycosis, an angiotropic disease, which means it tends to invade the blood vessels, thereby facilitating its systemic dissemination. Courtesy of Centers for Disease Control and Prevention/Dr William Kaplan.
Image 48.4
This micrograph reveals a conidia-laden conidiophore of the fungus Bipolaris hawaiiensis.
Bipolaris species are known to be one of the causative agents of the fungal illness
phaeohyphomycosis, which can be superficially confined to the skin or systemically disseminated and involve the brain, lungs, and bones. Courtesy of Centers for Disease Control and Prevention.
Image 48.5
Scanning electron micrograph of Curvularia geniculata. Courtesy of Centers for Disease Control and Prevention/robert Simmons/Janice Haney Carr.
182 FuNGAL DiSEASES
Image 48.6
Note the fine branching tubes of the fungus Exserohilum rostratum, which is the cause of phaeohy pho- mycosis. Phaeohyphomycosis is a fungal infection characterized by superficial and deep tissue involve- ment caused by dematia ceous, dark-walled fungi that form pigmented hyphae, or fine branching tubes, and yeastlike cells in the infected tissues. Courtesy of Centers for Disease Control and Prevention/
Libero Ajello, mD.
Image 48.7
This micrograph depicts multiple conidia-laden conidiophores and phialides of a Penicillium marneffei fungal organism. Penicillium species are known to cause penicilliosis, which usually affects immuno- compromised individuals, such as those with AiDS or undergoing chemotherapy. P marneffei is normally acquired though inhalation of airborne spores. Courtesy of Centers for Disease Control and Prevention/
Libero Ajello, mD.
Image 48.8
This photomicrograph reveals the conidiophores with conidia of the fungus Pseudallescheria boydii from a slide culture. P boydii is pathogenic in humans, especially those who are immunocompromised, causing infections in almost all body regions, and which are classified under the broad heading of pseudallescheriasis. Courtesy of Centers for Disease Control and Prevention/Libero Ajello, mD.
FUSOBACTERIUM iNFECTiONS 183
49
Fusobacterium Infections
(Including Lemierre Disease) Clinical Manifestations
Fusobacterium necrophorum and Fusobacte
rium nucleatum can be isolated from oropha- ryngeal specimens in healthy people, are frequent components of human dental plaque, and may lead to periodontal disease. Invasive disease attributable to Fusobacterium species has been associated with otitis media, tonsil- litis, gingivitis, and oropharyngeal trauma, including dental surgery. Ten percent of cases of invasive Fusobacterium infections are associated with concomitant Epstein-Barr virus infection. Risk can be increased after macrolide use.
Invasive infection with Fusobacterium species can lead to life-threatening disease. Otogenic infection is the most frequent primary source in children and can be complicated by menin- gitis and thrombosis of dural venous sinuses.
Invasive infection following tonsillitis was described early in the 20th century and was referred to as postanginal sepsis or Lemierre disease. Lemierre disease most often occurs in adolescents and young adults and is charac- terized by internal jugular vein septic throm- bophlebitis or thrombosis (JVT), evidence of septic embolic lesions in lungs or other sterile sites, and isolation of Fusobacterium species from blood or other normally sterile sites. Lemierre-like syndromes have also been reported following infection with Arcanobac
terium haemolyticum, Bacteroides species, anaerobic Streptococcus species, other anaero- bic bacteria, and methicillin-susceptible and -resistant strains of Staphylococcus aureus.
Fever and sore throat are followed by severe neck pain (anginal pain) that can be accompa- nied by unilateral neck swelling, trismus, and dysphagia. Patients with classic Lemierre dis- ease have a sepsis syndrome with multiple organ dysfunction. Metastatic complications from septic embolic phenomena associated with suppurative JVT are common and may manifest as disseminated intravascular coagu- lation, pleural empyema, pyogenic arthritis, or osteomyelitis. Persistent headache or other
neurologic signs may indicate the presence of cerebral venous sinus thrombosis (eg, cav- ernous sinus thrombosis), meningitis, or brain abscess.
Jugular vein septic thrombophlebitis or throm- bosis can be completely vasoocclusive. Surgical debridement of necrotic tissue may be neces- sary for patients who do not respond to anti- microbial therapy. Some children with JVT associated with Lemierre disease have evidence of thrombophilia at diagnosis. These findings often resolve over several months and can indi- cate response to the inflammatory, prothrom- botic process associated with infection rather than an underlying hypercoagulable state.
Etiology
Fusobacterium species are anaerobic, nonspore- forming, gram-negative bacilli. Human infec- tion usually results from F necrophorum subsp funduliforme, but infections with other species, including F nucleatum, Fusobacterium gonidi
aformans, Fusobacterium naviforme, Fusobac
terium mortiferum, and Fusobacterium varium, have been reported. Infection with Fusobacte
rium species, alone or in combination with other oral anaerobic bacteria, may result in Lemierre disease.
Epidemiology
Fusobacterium species are commonly found in soil and the respiratory tracts of animals, including cattle, dogs, fowl, goats, sheep, and horses, and can be isolated from the orophar- ynx of healthy people. Fusobacterium infec- tions are most common in adolescents and young adults, but infections, including fatal cases of Lemierre disease, have been reported in infants and young children. Those with sickle cell disease or diabetes mellitus may be at greater risk of infection.
Diagnostic Tests
Fusobacterium species can be isolated using conventional liquid anaerobic blood culture media. However, the organism grows best on semisolid media for fastidious anaerobic organisms or blood agar supplemented with vitamin K, hemin, menadione, and a reducing agent. Many strains fluoresce chartreuse green under ultraviolet light. Most Fusobacterium
184 FUSOBACTERIUM iNFECTiONS
organisms are indole positive. The accurate identification of anaerobes to the species level has become important with the increasing inci- dence of microorganisms that are resistant to multiple drugs. Sequencing of the 16S rRNA gene and phylogenetic analysis can identify anaerobic bacteria to the genus or taxonomic group level and, frequently, to the species level.
The diagnosis of Lemierre disease should be considered in ill-appearing febrile children and adolescents with sore throat and exquisite neck pain over the angle of the jaw. Anaerobic blood culture in addition to aerobic blood cul- ture should be performed to detect invasive Fusobacterium species infection. Computed tomography and magnetic resonance imaging are more sensitive than ultrasonography to document JVT early in the course of illness and to better identify thrombus extension.
Treatment
Fusobacterium species may be susceptible to metronidazole, clindamycin, chloramphenicol, carbapenems (meropenem or imipenem), cefoxitin, and ceftriaxone. Resistance to anti- microbial agents has increased in anaerobic bacteria during the last decade, and suscepti- bility is no longer predictable. Susceptibility testing is indicated for all clinically significant anaerobic isolates. Metronidazole is the treat- ment preferred by many experts but lacks
activity against microaerophilic streptococci that can coinfect some patients. Clindamycin is generally an effective agent. Fusobacterium species are intrinsically resistant to gentamicin, fluoroquinolone agents, and, typically, macro- lides. Tetracyclines have limited activity. Up to 50% of F nucleatum and 20% of F necrophorum isolates produce β-lactamases, rendering them resistant to penicillin, ampicillin, and some cephalosporins.
Because Fusobacterium infections are often polymicrobial, broad-spectrum therapy fre- quently is necessary. Therapy has been advo- cated with a penicillin-β-lactamase inhibitor combination (ampicillin-sulbactam or piperacillin-tazobactam) or a carbapenem (meropenem, imipenem, or ertapenem) or combination therapy with metronidazole or clindamycin in addition to other agents active against aerobic oral and respiratory tract patho gens (cefotaxime, ceftriaxone, or cefuro- xime). Duration of antimicrobial therapy depends on the anatomic location and severity of infection but is usually several weeks. Surgical intervention involving debridement or incision and drainage of abscesses may be necessary.
Antico agulation therapy has been used in adults and children with JVT and cavernous sinus thrombosis. In cases with extensive thrombo- sis, anticoagulation therapy may decrease the risk of clot extension and shorten recovery time.
Image 49.1
vincent stomatitis has been confused with diphtheria, although this infection is usually a mixed infection, including fusiform and spirochetal anaerobic bacteria including Fusobacterium, and is associated with severe pain and halitosis.
Note ulceration of the soft palate with surround- ing erythema. Courtesy of Edgar O. Ledbetter, mD, FAAP.
Image 49.2
This photomicrograph shows Fusobacterium nucleatum after being cultured in a thioglycollate medium for 48 hours. Courtesy of Centers for Disease Control and Prevention.
FUSOBACTERIUM iNFECTiONS 185
Image 49.3
This is a photomicrograph of Fusobacterium russii cultured in a thioglycollate medium for 48 hours. Like the genus Bacteroides, Fusobac
terium species are anaerobic, gram-negative bacteria that are normal inhabiters of the oral cavity, intestine, and female genital tract.
Fusobacterium species are most commonly associated with head and neck, pulmonary, and wound infections. Courtesy of Centers for Disease Control and Prevention/v. r. Dowell Jr, mD.
Image 49.4
This photograph demonstrates the morphology of 4 colonies of Fusobacterium fusiforme bacteria that were grown on blood agar medium for 48 hours. Fusobacterium fusiforme is a spindle- shaped gram-negative bacteria that colonizes the gingival sulcus of the human oral cavity and has also been isolated from infections of the upper respiratory tract. Courtesy of Centers for Disease Control and Prevention/v. r. Dowell Jr, mD.
Image 49.5
An abdominal computed tomography scan of a 15-year-old football linebacker who presented with high fever, abdominal pain, and emesis for 5 days showing abscess collections in the liver.
Aspiration of 3 discrete abscess areas grew only Fusobacterium nucleatum. Courtesy of Carol J.
Baker, mD, FAAP.
Image 49.6
80 mL of purulent material was aspirated from the liver abscess of the patient in image 49.5.
Courtesy of Carol J. Baker, mD, FAAP.
186 GIARDIA INTESTINALIS ( FOrmErLy GIARDIA LAMBLIA AND GIARDIA DUODENALIS) iNFECTiONS
50
Giardia intestinalis
( formerly Giardia lamblia and Giardia duodenalis) Infections
(Giardiasis)
Clinical Manifestations
Symptomatic infection with Giardia intestina
lis causes a broad spectrum of clinical mani- festations. Children can have occasional days of acute watery diarrhea with abdominal pain, or they may experience a protracted, intermit- tent, often debilitating disease characterized by passage of foul-smelling stools associated with anorexia, flatulence, and abdominal dis- tention. Anorexia, combined with malabsorp- tion, can lead to significant weight loss, failure to thrive, and anemia. Humoral immunodefi- ciencies predispose to chronic symptomatic G intestinalis infections. Asymptomatic infec- tion is common; approximately 50% to 75% of people who acquired infection in outbreaks occurring in child care settings and in the community were asymptomatic.
Etiology
G intestinalis is a flagellate protozoan that exists in trophozoite and cyst forms; the infective form is the cyst. Infection is limited to the small intestine and biliary tract.
Epidemiology
Giardiasis is the most common intestinal parasitic infection of humans identified in the United States and globally with a worldwide distribution. Approximately 20,000 cases are reported in the United States each year, with highest incidence reported among children 1 to 9 years of age, adults 35 to 44 years of age, and residents of northern states. Peak onset of ill- ness occurs annually during early summer through early fall. Humans are the principal reservoir of infection, but Giardia organisms can infect dogs, cats, beavers, rodents, sheep, cattle, nonhuman primates, and other animals.
G intestinalis assemblages are quite species- specific, such that the organisms that affect nonhumans are usually not infectious to humans. People become infected directly from
an infected person or through ingestion of fecally contaminated water or food. Most community-wide epidemics have resulted from a contaminated drinking water supply;
outbreaks associated with recreational water have also been reported. Outbreaks resulting from person-to-person transmission occur in child care centers or institutional care settings, where staff and family members in contact with infected children or adults become infected themselves. Although less common, outbreaks associated with food or food han- dlers have also been reported. Surveys con- ducted in the United States have identified overall prevalence rates of Giardia organisms in stool specimens that range from 5% to 7%, with variations depending on age, geographic location, and seasonality. Duration of cyst excretion is variable but can range from weeks to months. Giardiasis is communicable for as long as the infected person excretes cysts.
Incubation Period 1 to 3 weeks.
Diagnostic Tests
Commercially available, sensitive, and specific enzyme immunoassay and direct fluorescence antibody assays are the standard tests used for diagnosis of giardiasis in the United States.
Enzyme immunoassay has a sensitivity of up to 95% and a specificity of 98% to 100% when compared with microscopy. Direct fluores- cence antibody assay has the advantage that organisms are visualized. Diagnosis has traditionally been based on the microscopic identification of trophozoites or cysts in stool specimens; this requires an experienced microscopist, and sensitivity can be subopti- mal. Stool needs to be examined as soon as possible or placed immediately in a preserva- tive, such as neutral-buffered 10% formalin or polyvinyl alcohol. A single direct smear examination of stool has a sensitivity of 75%
to 95%. Sensitivity is higher for diarrheal stool specimens because they contain higher concen- trations of organisms. Sensitivity of micros- copy is increased by examining 3 or more specimens collected every other day. Commer- cially available stool collection kits in child- proof containers are convenient for preserving stool specimens collected at home. When
GIARDIA INTESTINALIS ( FOrmErLy GIARDIA LAMBLIA AND GIARDIA DUODENALIS) iNFECTiONS 187
giardiasis is suspected clinically but the organ- ism is not found on repeated stool examina- tion, inspection of duodenal contents obtained by direct aspiration or by using a commercially available string test (eg, Entero-Test) may be diagnostic. Rarely, duodenal biopsy is required for diagnosis.
Treatment
Some infections are self-limited, and treatment is not required. Dehydration and electrolyte abnormalities can occur and should be cor- rected. Metronidazole, nitazoxanide, and tinid azole are the drugs of choice. Metronida- zole (if used for a 5-day course) is the least expensive of these therapies. A 5- to 10-day course of metronidazole has an efficacy of 80%
to 100% in pediatric patients, but poor palat- ability has been noted for metronidazole sus- pension. A 1-time dose of tinidazole, for children 3 years and older, has a similar efficacy in pediatric patients and has fewer adverse effects than does metronidazole. A 3-day course of nitazoxanide oral suspension also has similar efficacy to metronidazole and has the advantage(s) of treating other intestinal parasites and is approved for use in children 1 year and older.
Symptom recurrence after completing anti- microbial treatment can be attributable to reinfection, post-Giardia lactose intolerance
(occurs in 20%–40% of patients), immune suppression, insufficient treatment, or drug resistance. If reinfection is suspected, a second course of the same drug should be effective.
Treatment with a different class of drug is recommended for resistant giardiasis. Other treatment options include combination of a nitroimidazole plus quinacrine for at least 2 weeks or high-dose courses of the origi- nal agent.
Patients who are immunocompromised because of hypogammaglobulinemia or lymphoproliferative disease are at higher risk of giardiasis, and it is more difficult to treat in these patients. Among HIV-infected children without AIDS, effective combination and anti- parasitic therapy are the major initial treat- ments for these infections. Especially in HIV-infected children without AIDS, combi- nation antiretroviral therapy should be part of the primary initial treatment for giardiasis.
Patients with AIDS often respond to standard therapy; however, in some cases, additional treatment is required. If giardiasis is refractory to standard treatment among patients with AIDS, high doses, longer treatment duration, or combination therapy may be appropriate.
Image 50.1
Three trophozoites of Giardia intestinalis (A, trichrome stain; B and C, iron hematoxylin stain). Each cell has 2 nuclei with a large, central karyosome. Cell length is 9 to 21 µm. Trophozoites are usually seen in fresh diarrheal stool or in duodenal mucus. Courtesy of Centers for Disease Control and Prevention.
188 GIARDIA INTESTINALIS ( FOrmErLy GIARDIA LAMBLIA AND GIARDIA DUODENALIS) iNFECTiONS
Image 50.2
Photomicrograph of a Giardia intestinalis cyst seen using a trichrome stain. G intestinalis is the protozoan organism that causes the disease giardiasis, a diarrheal disorder directly affecting the small intestine. Courtesy of Centers for Disease Control and Prevention.
Image 50.3
Giardia intestinalis cysts (trichrome stain). Person- to-person transmission is the most common mode of transmission of giardiasis.
Image 50.4
Giardiasis. incidence—united States and uS territories, 2012. Courtesy of Morbidity and Mortality Weekly Report.
GIARDIA INTESTINALIS ( FOrmErLy GIARDIA LAMBLIA AND GIARDIA DUODENALIS) iNFECTiONS 189
Image 50.5
Cysts are resistant forms and responsible for transmission of giardiasis. Cysts and trophozoites can be found in the feces (diagnostic stages) (1). The cysts are hardy and can survive several months in cold water. infection occurs by the ingestion of cysts in contaminated water or food or by the fecal- oral route (hands or fomites) (2). in the small intestine, excystation releases trophozoites (each cyst produces 2 trophozoites) (3). Trophozoites multiply by longitudinal binary fission, remaining in the lumen of the proximal small bowel, where they can be free or attached to the mucosa by a ventral sucking disk (4). Encystation occurs as the parasites transit toward the colon. The cyst is the stage found most commonly in nondiarrheal feces (5). Because the cysts are infectious when passed in the stool or shortly afterward, person-to-person transmission is possible. While animals are infected with Giardia, their importance as a reservoir is unclear. Courtesy of Centers for Disease Control and Prevention/Alexander J. da Silva, PhD/melanie moser.