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Tick-Borne Diseases , Early Localized Disease Early localized disease typically presents within 4 weeks of infection. Most infected persons (70'2,-80%) develop ery thema migrans (EM), a red, annular skin rash that often has central clearing (Figure L2). Systemic symptoms are variably 't. present. The EM rash is usually painless, nonpmritic, and circum- ferentially enlarging. Atypical presentations of EM, with confluent erythroderma, ulceration, or vesiculation, may con- a { ) ,I / L.eond found the diagnosis. Local cutaneous reactions resulting from !eh9dmg- tqb hoaFor Ca- hypersensitivity to tick saliva may resemble EM but tend to occur earlier, are pmritic, and do not enlarge significantly after onset. t I G U R E 1 0. Lyme disease cases reported during 201 B. Each dot represents the A patient with EM and a compatible exposure history county of residence (not necessarily acquisition)for a confirmed case. does not require confirmatory laboratory testing. In fact, anti Reproduced {rom "Reported Cases of Lyme Disease United States 201 8." Centers for Disease Control and Preven body testing in early localized disease is insensitive because tion, National Center for Emerging and Zoonotic lnfectious Diseases (NCEZID), Division of Vector'Borne Diseases (DVBD). Last updated November 22, 201 9. Available at https://www.cdc.gov/lyme/datasurveillance/maps-recent. seroconversion may be delayed for several weeks after appear html. Accessed Aug usl27 ,2020. ance of an EM rash. Doxycycline offers the advantage of treat- ing incubatrng Anaplasma phagocytophilum, which is also The clinical manifestations, diagnostic testing, and treat- spread by blacklegged ticks and can coinfect patients with ment of Lyme disease vary according to the stage of infection Lyme disease. (Table 13). Early Disseminated Disease Without treatment, hematogenous dissemination occurs in up Blrc'kleggctl'ficl ( I xtdcs scapularis ) to 60% of patients. Symptoms of early disseminated disease present weeks to months after infection. The most common

, Early Localized Disease Early localized disease typically presents within 4 weeks of infection. Most infected persons (70'2,-80%) develop ery thema migrans (EM), a red, annular skin rash that often has central clearing (Figure L2). Systemic symptoms are variably 't. present. The EM rash is usually painless, nonpmritic, and circum- ferentially enlarging. Atypical presentations of EM, with confluent erythroderma, ulceration, or vesiculation, may con- a { ) ,I / L.eond found the diagnosis. Local cutaneous reactions resulting from !eh9dmg- tqb hoaFor Ca- hypersensitivity to tick saliva may resemble EM but tend to occur earlier, are pmritic, and do not enlarge significantly after onset. t I G U R E 1 0. Lyme disease cases reported during 201 B. Each dot represents the A patient with EM and a compatible exposure history county of residence (not necessarily acquisition)for a confirmed case. does not require confirmatory laboratory testing. In fact, anti Reproduced {rom "Reported Cases of Lyme Disease United States 201 8." Centers for Disease Control and Preven body testing in early localized disease is insensitive because tion, National Center for Emerging and Zoonotic lnfectious Diseases (NCEZID), Division of Vector'Borne Diseases (DVBD). Last updated November 22, 201 9. Available at https://www.cdc.gov/lyme/datasurveillance/maps-recent. seroconversion may be delayed for several weeks after appear html. Accessed Aug usl27 ,2020. ance of an EM rash. Doxycycline offers the advantage of treat- ing incubatrng Anaplasma phagocytophilum, which is also The clinical manifestations, diagnostic testing, and treat- spread by blacklegged ticks and can coinfect patients with ment of Lyme disease vary according to the stage of infection Lyme disease. (Table 13). Early Disseminated Disease Without treatment, hematogenous dissemination occurs in up Blrc'kleggctl'ficl ( I xtdcs scapularis ) to 60% of patients. Symptoms of early disseminated disease present weeks to months after infection. The most common Xx x manifestation is a flu-like illness characterized by fevers, arthralgia, myalgia, and lymphadenopathy and often associ- ated with multiple concurrent EM eruptions at sites distant from the original tick attachment. rdult eduh Disseminated infection may also involve the heart and lemrlc mrb nymph l:rva the central nervous system. Lyme myocarditis results in lonc Star Trck (Anhlyomma un*ri<:anum) injury to the conduction system and atrioventricular (AV) nodal block. Progression to complete heart block can occur rapidly despite antibiotic treatment, so hospitalization is indicated for close monitoring of symptomatic patients with

Xx x manifestation is a flu-like illness characterized by fevers, arthralgia, myalgia, and lymphadenopathy and often associ- ated with multiple concurrent EM eruptions at sites distant from the original tick attachment. rdult eduh Disseminated infection may also involve the heart and lemrlc mrb nymph l:rva the central nervous system. Lyme myocarditis results in lonc Star Trck (Anhlyomma un*ri<:anum) injury to the conduction system and atrioventricular (AV) nodal block. Progression to complete heart block can occur rapidly despite antibiotic treatment, so hospitalization is indicated for close monitoring of symptomatic patients with M& Dog Ticlr ( Dcrmttentor variabil is) x fr llOtt: fier;ltlvtl slIc$ ct s*vgrat ircx, ill difiereflt tile ttarr! In$rpjrt fir:lt;f irorrp,i ia,liliii{:r?i !:{l C'l:n. r+ \.tr'i F I G U R E 12.Ihe erythema migrans lesion begins as an expanding macule to

Xx x manifestation is a flu-like illness characterized by fevers, arthralgia, myalgia, and lymphadenopathy and often associ- ated with multiple concurrent EM eruptions at sites distant from the original tick attachment. rdult eduh Disseminated infection may also involve the heart and lemrlc mrb nymph l:rva the central nervous system. Lyme myocarditis results in lonc Star Trck (Anhlyomma un*ri<:anum) injury to the conduction system and atrioventricular (AV) nodal block. Progression to complete heart block can occur rapidly despite antibiotic treatment, so hospitalization is indicated for close monitoring of symptomatic patients with M& Dog Ticlr ( Dcrmttentor variabil is) x fr llOtt: fier;ltlvtl slIc$ ct s*vgrat ircx, ill difiereflt tile ttarr! In$rpjrt fir:lt;f irorrp,i ia,liliii{:r?i !:{l C'l:n. r+ \.tr'i F I G U R E 12.Ihe erythema migrans lesion begins as an expanding macule to form a red annular lesion with a partially clearing middle at the site of tick attachment. FIGURE 1 1. The lifestages ofthree hardtickspeciesthatspread disease. The center may become indurated, vesicular, or necrotic. Some patients will develop concentric rings. Reproduced from Centers for Disease Control and Prevention. Ticks that commonly bite humans. Available at https://www.cdc.gov/ticks/tickbornediseases/ticklD.html. Updated January 1 0, 20,1 9. Accessed January 6, 2020 Figure courtesy of Dr. Karen Bloch.

form a red annular lesion with a partially clearing middle at the site of tick attachment. FIGURE 1 1. The lifestages ofthree hardtickspeciesthatspread disease. The center may become indurated, vesicular, or necrotic. Some patients will develop concentric rings. Reproduced from Centers for Disease Control and Prevention. Ticks that commonly bite humans. Available at https://www.cdc.gov/ticks/tickbornediseases/ticklD.html. Updated January 1 0, 20,1 9. Accessed January 6, 2020 Figure courtesy of Dr. Karen Bloch. 22

Tick-Borne Diseases TABLE t 3" elin ical Manifestations, Diagnostle Testing, and Treatment of Lyme Disease by Stage of lnfection Lyme Stage Onset after Clinical Findings Laboratory Treatmenta lnfection Confirmation Early localized J4 wk EM at site of tick attachment, Not needed if EM Doxycycline, 100 mg PO BID x 10 d (first-line variably with fever, present therapy) lymphadenopathy, myalgia or Amoxicillin,500 mg POTID x14d or Cefuroxime axetil, 500 mg PO BID x 14 d Early 2 wk-6 mo Constitutional : Multiple sites Not needed if EM is 1. Cardiac disseminated of EM, flu-like syndrome presenU otherwise, Hospitalized patients (first-degree block two-tier serologic Cardiac: heart block, with PR interval >300 msec, higher degree testing myocarditis heart block, other arrhythmias, CSF evaluation when myoperica rditis): in itia I lV ceftriaxone with Neurologic: cranial CNS involvement is a transition to oralfortotal of 14-21 days neuropathies, meningitis, concern radicu litis, mononeu ritis Outpatients (first-degree AV block with PR multiplex, spinal cord or interval <300 msec): oral treatment same as brain parenchymal for early localized disease x 14-21 d inflammation 2. Meningoencephalitis: lV penicillin G, lV cefotaxime, or lV ceftriaxone or oral doxycycline x 14-21 d (lV antibiotics preferred for spinal or brain parenchymal involvement) 3. Other manifestations (including facial palsy): oral treatment the same as for early localized disease x 14-21 d Late >6 mo Arthritis; neurologic Two-tier serologic lnitial rheumatologic treatment: same as for disseminated symptoms (peripheral testing early localized but x28 d neuropathy, encephalopathy), or dermatologic symptoms Arthritis unresponsive to initial treatment: lV (acrodermatltis ch ronica ceftriaxone 2-4 weeks atrophicans)

TABLE t 3" elin ical Manifestations, Diagnostle Testing, and Treatment of Lyme Disease by Stage of lnfection Lyme Stage Onset after Clinical Findings Laboratory Treatmenta lnfection Confirmation Early localized J4 wk EM at site of tick attachment, Not needed if EM Doxycycline, 100 mg PO BID x 10 d (first-line variably with fever, present therapy) lymphadenopathy, myalgia or Amoxicillin,500 mg POTID x14d or Cefuroxime axetil, 500 mg PO BID x 14 d Early 2 wk-6 mo Constitutional : Multiple sites Not needed if EM is 1. Cardiac disseminated of EM, flu-like syndrome presenU otherwise, Hospitalized patients (first-degree block two-tier serologic Cardiac: heart block, with PR interval >300 msec, higher degree testing myocarditis heart block, other arrhythmias, CSF evaluation when myoperica rditis): in itia I lV ceftriaxone with Neurologic: cranial CNS involvement is a transition to oralfortotal of 14-21 days neuropathies, meningitis, concern radicu litis, mononeu ritis Outpatients (first-degree AV block with PR multiplex, spinal cord or interval <300 msec): oral treatment same as brain parenchymal for early localized disease x 14-21 d inflammation 2. Meningoencephalitis: lV penicillin G, lV cefotaxime, or lV ceftriaxone or oral doxycycline x 14-21 d (lV antibiotics preferred for spinal or brain parenchymal involvement) 3. Other manifestations (including facial palsy): oral treatment the same as for early localized disease x 14-21 d Late >6 mo Arthritis; neurologic Two-tier serologic lnitial rheumatologic treatment: same as for disseminated symptoms (peripheral testing early localized but x28 d neuropathy, encephalopathy), or dermatologic symptoms Arthritis unresponsive to initial treatment: lV (acrodermatltis ch ronica ceftriaxone 2-4 weeks atrophicans) AV=atrioventricular; BID=twicedaily; CSF=cerebrospinal fluid;CNS=central nervoussystem; EM=erythemamigrans;lV=intravenous; PO=bymouth; TID=threetimesdaily. uDoses are for adults with normal kidney function.

TABLE t 3" elin ical Manifestations, Diagnostle Testing, and Treatment of Lyme Disease by Stage of lnfection Lyme Stage Onset after Clinical Findings Laboratory Treatmenta lnfection Confirmation Early localized J4 wk EM at site of tick attachment, Not needed if EM Doxycycline, 100 mg PO BID x 10 d (first-line variably with fever, present therapy) lymphadenopathy, myalgia or Amoxicillin,500 mg POTID x14d or Cefuroxime axetil, 500 mg PO BID x 14 d Early 2 wk-6 mo Constitutional : Multiple sites Not needed if EM is 1. Cardiac disseminated of EM, flu-like syndrome presenU otherwise, Hospitalized patients (first-degree block two-tier serologic Cardiac: heart block, with PR interval >300 msec, higher degree testing myocarditis heart block, other arrhythmias, CSF evaluation when myoperica rditis): in itia I lV ceftriaxone with Neurologic: cranial CNS involvement is a transition to oralfortotal of 14-21 days neuropathies, meningitis, concern radicu litis, mononeu ritis Outpatients (first-degree AV block with PR multiplex, spinal cord or interval <300 msec): oral treatment same as brain parenchymal for early localized disease x 14-21 d inflammation 2. Meningoencephalitis: lV penicillin G, lV cefotaxime, or lV ceftriaxone or oral doxycycline x 14-21 d (lV antibiotics preferred for spinal or brain parenchymal involvement) 3. Other manifestations (including facial palsy): oral treatment the same as for early localized disease x 14-21 d Late >6 mo Arthritis; neurologic Two-tier serologic lnitial rheumatologic treatment: same as for disseminated symptoms (peripheral testing early localized but x28 d neuropathy, encephalopathy), or dermatologic symptoms Arthritis unresponsive to initial treatment: lV (acrodermatltis ch ronica ceftriaxone 2-4 weeks atrophicans) AV=atrioventricular; BID=twicedaily; CSF=cerebrospinal fluid;CNS=central nervoussystem; EM=erythemamigrans;lV=intravenous; PO=bymouth; TID=threetimesdaily. uDoses are for adults with normal kidney function. cardiac involvement or asymptomatic patients with first- second sequential enzyme immunoassay has been approved degree (or higher grade) AV block and a PR interval of 300 for this purpose. milliseconds or greater. Permanent pacemaker placement is IgM antibody is detectable before IgG antibody in early not necessary because the heart block is reversible with infection; therefore, both antibodies should be tested in antibiotic therapy. patients presenting within 30 days of symptom onset. After Neurologic infection occurs in approximately 15% of this time, the recommendation is to test only IgG antibody untreated patients. Aseptic meningitis, facial palsy (unilat- because, after the first month of symptoms, an isolated IgM eral or bilateral), and radiculopathy can present alone or antibody is likely to be a false positive. Antibodies may remain with skin, musculoskeletal, or cardiac findings. Lumbar detectable for years despite treatment; therefore, serial titers puncture is indicated when central nervous system involve- are not useful. ment is suspected; cerebrospinal fluid lymphocytic pleocy- tosis supports the diagnosis (see Central Nervous System Late Disseminated Disease Infection). Approximately 60% of untreated patients with Lyme disease As with early localized disease, when classic EM is pre- develop a monoarticular or oligoarticular inflammatory sent, laboratory confirmation is unnecessary. Without diag- arthritis as a late complication. The knee and other large joints nostic skin findings, serologic testing should be pursued are disproportionally affected. Even without antibiotic treat- through a two-tiered approach (Figure 13); the initial enzyme- ment, inflammation typically resolves over weeks to months linked immunosorbent assay (ELISA) is highly sensitive but but can have a relapsing-remitting pattern. In approximately lacks specificity, and positive or equivocal tests must be con- 1O% of untreated patients, arthritis persists (see MKSAP 19 firmed. Until recently, Western blot was the recommended Rheumatolory). Late neurologic or skin findings (acroderma- confirmatory test; however, an alternative option using a titis chronica atrophicans and borrelial lymphocytoma) are

cardiac involvement or asymptomatic patients with first- second sequential enzyme immunoassay has been approved degree (or higher grade) AV block and a PR interval of 300 for this purpose. milliseconds or greater. Permanent pacemaker placement is IgM antibody is detectable before IgG antibody in early not necessary because the heart block is reversible with infection; therefore, both antibodies should be tested in antibiotic therapy. patients presenting within 30 days of symptom onset. After Neurologic infection occurs in approximately 15% of this time, the recommendation is to test only IgG antibody untreated patients. Aseptic meningitis, facial palsy (unilat- because, after the first month of symptoms, an isolated IgM eral or bilateral), and radiculopathy can present alone or antibody is likely to be a false positive. Antibodies may remain with skin, musculoskeletal, or cardiac findings. Lumbar detectable for years despite treatment; therefore, serial titers puncture is indicated when central nervous system involve- are not useful. ment is suspected; cerebrospinal fluid lymphocytic pleocy- tosis supports the diagnosis (see Central Nervous System Late Disseminated Disease Infection). Approximately 60% of untreated patients with Lyme disease As with early localized disease, when classic EM is pre- develop a monoarticular or oligoarticular inflammatory sent, laboratory confirmation is unnecessary. Without diag- arthritis as a late complication. The knee and other large joints nostic skin findings, serologic testing should be pursued are disproportionally affected. Even without antibiotic treat- through a two-tiered approach (Figure 13); the initial enzyme- ment, inflammation typically resolves over weeks to months linked immunosorbent assay (ELISA) is highly sensitive but but can have a relapsing-remitting pattern. In approximately lacks specificity, and positive or equivocal tests must be con- 1O% of untreated patients, arthritis persists (see MKSAP 19 firmed. Until recently, Western blot was the recommended Rheumatolory). Late neurologic or skin findings (acroderma- confirmatory test; however, an alternative option using a titis chronica atrophicans and borrelial lymphocytoma) are 23

Tick-Borne Diseases Possible Lyme disease History of tick exposure in Consider alternative diagnosis; if an endemic area? evaluation is negative and clinical suspicion No remains, consider two-tiered testing Yes Erythema migrans No EM, high clinicalsuspicion Nonspecific symptoms or low clinical suspicion No further testing Two-tiered serologic testing required, start therapy Tier one test: EIA or IFA Negative Positive or equivocal result (move to tier two test) Consider alternate diagnosis OR if signs/symptoms <30 days, consider testing convalescent serum Symptoms <30 days: Symptoms >30 days: lgM & lgG Western blot lgG Western blot only No OR OR VISE C6 ELISA VISE C6 ELISA

Consider alternate diagnosis OR if signs/symptoms <30 days, consider testing convalescent serum Symptoms <30 days: Symptoms >30 days: lgM & lgG Western blot lgG Western blot only No OR OR VISE C6 ELISA VISE C6 ELISA lgM: >2/3 bands positive lgG: >5/10 bands positive OR OR lgG: >5/10 bands positive Positive VISE C6 ELISA OR Positive VlSE C6 ELISA Yes Yes No Borrelia burgdorteri infection; treat as Consider alternate diagnosis appropriate for clinical stage F I G U R E I 3 . Serologic testing for tyme disease. EIA/ELISA = enzyme-lin ked im m u n ororbent assay; EM = erythema mig rans; IFA = im m u nofluorescent antibody assay. IPMID: 273118321 doi10.3201/eid2207.151694

Borrelia burgdorteri infection; treat as Consider alternate diagnosis appropriate for clinical stage F I G U R E I 3 . Serologic testing for tyme disease. EIA/ELISA = enzyme-lin ked im m u n ororbent assay; EM = erythema mig rans; IFA = im m u nofluorescent antibody assay. IPMID: 273118321 doi10.3201/eid2207.151694 rare in the United States but more frequent in European infec- post-Lyme disease syndrome. Evaluation for coinfection tions. Laboratory confirmation at this stage is necessary for with another tick-borne pathogen or for a noninfectious diagnosis. Treatment requires prolonged oral antibiotics; cause is indicated. parenteral therapy is used when oral therapy is unsuccessful KEY POI]ITS (see Table 13). o The causative spirochete of Lyme disease may be trans- Post-Lyme Disease Syndrome mitted when an infected lxodes scapularis tick attaches for at least 36 hours. Post-Lyme disease syndrome has been reported in approxi- mately 10% of patients after treatment of EM. Although . Early localized Lyme disease usually presents within HVC often erroneously called "chronic Lyme disease," no micro- 4 weeks of infection and is characterized by erythema

rare in the United States but more frequent in European infec- post-Lyme disease syndrome. Evaluation for coinfection tions. Laboratory confirmation at this stage is necessary for with another tick-borne pathogen or for a noninfectious diagnosis. Treatment requires prolonged oral antibiotics; cause is indicated. parenteral therapy is used when oral therapy is unsuccessful KEY POI]ITS (see Table 13). o The causative spirochete of Lyme disease may be trans- Post-Lyme Disease Syndrome mitted when an infected lxodes scapularis tick attaches for at least 36 hours. Post-Lyme disease syndrome has been reported in approxi- mately 10% of patients after treatment of EM. Although . Early localized Lyme disease usually presents within HVC often erroneously called "chronic Lyme disease," no micro- 4 weeks of infection and is characterized by erythema biologic evidence of chronic or latent infection is found migrans (fU) at the site of tick attachment; patients with after appropriate treatment. Symptoms include fatigue, EM and a compatible exposure history do not require arthralgia, myalgia, and impairment of memory or cogni- confirrnatory laboratory testing and should receive oral tion that can last for years despite treatment. Clinical trials doxycycline. (Continued) have shown no benefit to prolonged antibiotic treatment for 24

Tick-Borne Diseases KEY P0t)$S (onttnacd) TAgLE 14. Treatment {or Babesiosis . Early disseminated Lyme disease can affect the cardio- Severity Regimen vascular and neurologic systems; the diagnosis should be Mild to moderate disease Atovaquone plus oral confirmed through an enzyme-linked immunosorbent azithromycin for 7 -10 days assay followed by confirmatory testing, with parenteral Severe disease requiring ICU Atovaquone plus lV antibiotic treatment indicated depending on disease admission azithromycin f or 7 -10 daysu severity. Highly immunocompromised Atovaquone plus high-dose patients azithromycin (500-1 000 mg) HVC o Post-Lyme disease syndrome (fatigue, arthralgia, myal- for at least 6 weeks gia, and impairment of memory or cognition) can last lV = intravenous. for years, even after appropriate treatment; prolonged aCan transition to oral treatment as step-down therapy following improvement. antibiotics are not effective in treating this condition.

KEY P0t)$S (onttnacd) TAgLE 14. Treatment {or Babesiosis . Early disseminated Lyme disease can affect the cardio- Severity Regimen vascular and neurologic systems; the diagnosis should be Mild to moderate disease Atovaquone plus oral confirmed through an enzyme-linked immunosorbent azithromycin for 7 -10 days assay followed by confirmatory testing, with parenteral Severe disease requiring ICU Atovaquone plus lV antibiotic treatment indicated depending on disease admission azithromycin f or 7 -10 daysu severity. Highly immunocompromised Atovaquone plus high-dose patients azithromycin (500-1 000 mg) HVC o Post-Lyme disease syndrome (fatigue, arthralgia, myal- for at least 6 weeks gia, and impairment of memory or cognition) can last lV = intravenous. for years, even after appropriate treatment; prolonged aCan transition to oral treatment as step-down therapy following improvement. antibiotics are not effective in treating this condition. is diagnostic. With low-level parasitemia, the sensitivity of Babesiosis microscopy is poor. Therefore, polymerase chain reaction Babesiosis is caused by the intraerythrocytic protozoan Babesia should be pursued if the clinical suspicion of babesiosis is microti, which is spread by the blacklegged deer tick and, high. Antibody testing does not differentiate acute from pre- therefore, occurs in areas of Lyme endemicity (see Figure 10). vious infection and is not recommended for diagnosis. Transmission through transfusion of infected blood products The first-line treatment for babesiosis is atovaquone may result in infections outside of endemic regions. plus azithromycin (Table 14). In patients intolerant of this Approximately 20% of infections are asymptomatic, regimen, clindamycin plus quinine is an alternative. with the remainder ranging from mild illness to fatal disease Exchange transfusion may be indicated in patients with (10%). Risk factors for severe disease include age older than severe infection and high-grade (>10%) parasitemia. 50 years, immunocompromise, or asplenia. Symptoms Immunocompromised patients require a longer treatment typically begin within 1 month after tick bite and within duration, typically 2 weeks after documented clearance of 2 months after transfusion of infected blood products. parasites on blood smear. Symptoms are nonspecific and include fever (89%), fatigue (82"/,,), chills (01"t), headache (ql%), myalgia (+a%), and t(EY p0rt{Ts cough (ZSl"1. Physical examination may reveal jaundice, . Babesiosis, an infection caused by an intraerythrocytic hepatomegaly, and splenomegaly, which rarely progresses to protozoan parasite, presents with clinical findings rang- splenic rupture. The hallmark of babesiosis is hemolysis, ing from a mild febrile illness to fatal infection; symp- with anemia almost invariably present. Severe disease may toms are usually nonspecific, but hemolytic anemia is a include thrombocytopenia, elevated serum aminotransferase hallmark of disease. levels, and acute kidney injury. o Babesiosis is diagnosed by direct visualization of the Visualization of B. microti, manifesting as intraerythro- organism on blood smear or polymerase chain reaction. cytic ring forms similar to those seen in malaria or as tetrads . The first-line treatment for babesiosis is atovaquone resembling a Maltese cross (Figure 14), on thin blood smears plus azithromycin, with extended treatment duration recommended for severely immunocompromised patients.

is diagnostic. With low-level parasitemia, the sensitivity of Babesiosis microscopy is poor. Therefore, polymerase chain reaction Babesiosis is caused by the intraerythrocytic protozoan Babesia should be pursued if the clinical suspicion of babesiosis is microti, which is spread by the blacklegged deer tick and, high. Antibody testing does not differentiate acute from pre- therefore, occurs in areas of Lyme endemicity (see Figure 10). vious infection and is not recommended for diagnosis. Transmission through transfusion of infected blood products The first-line treatment for babesiosis is atovaquone may result in infections outside of endemic regions. plus azithromycin (Table 14). In patients intolerant of this Approximately 20% of infections are asymptomatic, regimen, clindamycin plus quinine is an alternative. with the remainder ranging from mild illness to fatal disease Exchange transfusion may be indicated in patients with (10%). Risk factors for severe disease include age older than severe infection and high-grade (>10%) parasitemia. 50 years, immunocompromise, or asplenia. Symptoms Immunocompromised patients require a longer treatment typically begin within 1 month after tick bite and within duration, typically 2 weeks after documented clearance of 2 months after transfusion of infected blood products. parasites on blood smear. Symptoms are nonspecific and include fever (89%), fatigue (82"/,,), chills (01"t), headache (ql%), myalgia (+a%), and t(EY p0rt{Ts cough (ZSl"1. Physical examination may reveal jaundice, . Babesiosis, an infection caused by an intraerythrocytic hepatomegaly, and splenomegaly, which rarely progresses to protozoan parasite, presents with clinical findings rang- splenic rupture. The hallmark of babesiosis is hemolysis, ing from a mild febrile illness to fatal infection; symp- with anemia almost invariably present. Severe disease may toms are usually nonspecific, but hemolytic anemia is a include thrombocytopenia, elevated serum aminotransferase hallmark of disease. levels, and acute kidney injury. o Babesiosis is diagnosed by direct visualization of the Visualization of B. microti, manifesting as intraerythro- organism on blood smear or polymerase chain reaction. cytic ring forms similar to those seen in malaria or as tetrads . The first-line treatment for babesiosis is atovaquone resembling a Maltese cross (Figure 14), on thin blood smears plus azithromycin, with extended treatment duration recommended for severely immunocompromised patients. Southe rn Tick-Associated Rash lllness Southern tick-associated rash illness (STARI) presents with EM identical to that seen in Lyme disease but without clinical progression or complications. STARI is associated with Amblyomma americenl)m, also known as the Lone Star tick, which is endemic to the southeastern, south-central, and east- ern United States (see Figure 11). No infectious cause has been confirmed. Therefore, diagnosis is based on clinical and * geographic features. Because skin findings for STARI and FIGURE 1 4. Peripheral blood smear showing babesiosis. The diagnosis of early-stage Lyme disease are indistinguishable, treatment with babesiosis is typically established by evaluation of a peripheral blood smear showing intraerythrocytic parasites.Occasionally, merozoites are arranged in tetrads, doxycycline is often offered; however, it is uncertain if treat- resembling a Maltese cross, as seen in the center of this image. ment for STARI is necessary or beneficial.

Southe rn Tick-Associated Rash lllness Southern tick-associated rash illness (STARI) presents with EM identical to that seen in Lyme disease but without clinical progression or complications. STARI is associated with Amblyomma americenl)m, also known as the Lone Star tick, which is endemic to the southeastern, south-central, and east- ern United States (see Figure 11). No infectious cause has been confirmed. Therefore, diagnosis is based on clinical and * geographic features. Because skin findings for STARI and FIGURE 1 4. Peripheral blood smear showing babesiosis. The diagnosis of early-stage Lyme disease are indistinguishable, treatment with babesiosis is typically established by evaluation of a peripheral blood smear showing intraerythrocytic parasites.Occasionally, merozoites are arranged in tetrads, doxycycline is often offered; however, it is uncertain if treat- resembling a Maltese cross, as seen in the center of this image. ment for STARI is necessary or beneficial. 25

Tick-Borne Diseases rEY POI IIT o Southern tick-associated rash illness may be clinically indistinguishable from early-stage Lyme disease, so treatment with doxycycline is often offered. Ehrlichiosis and Anaplasmosis Ehrlichiosis and anaplasmosis are clinically similar illnesses spread by different tick vectors and caused by distinct bacterial pathogens. Ehrlichiosis is usually caused by Ehrlichia chaffeen- sis, which is transmitted by the Lone Star tick. Anaplasmosis is caused by Anaplasma phagocytophilum, which is transmit- ted by lxodes ticks, and occurs in areas of Lyme endemicity (see Figure 10). These syndromes typically begin with a nonspecific f'ebrile illness lto 2 weeks after a tick bite (Table 15). Rash is uncommon in adults. Leukopenia, thrombocytopenia, and F tG U R E I 5. Morulae (arrow) appearing as basophilic inclusion bodies in leukocytes of a patient with ehrlichiosis. increased serum aminotransferase levels are often present. Basophilic inclusion bodies called morulae visualized in the cytoplasm of leukocytes (Figure 15) suggest the diagnosis confirmatory. Polymerase chain reaction of whole blood at the but are present in few cases. Antibody tests are often negative time of acute illness is highly sensitive, particularly if in acute illness; a convalescent specimen 2 to 4 weeks after performed before therapy. Doxycycline is the recommended onset of symptoms showing a four fold rise in titer is treatment for ehrlichiosis and anaplasmosis. Because delay in

Ehrlichiosis and Anaplasmosis Ehrlichiosis and anaplasmosis are clinically similar illnesses spread by different tick vectors and caused by distinct bacterial pathogens. Ehrlichiosis is usually caused by Ehrlichia chaffeen- sis, which is transmitted by the Lone Star tick. Anaplasmosis is caused by Anaplasma phagocytophilum, which is transmit- ted by lxodes ticks, and occurs in areas of Lyme endemicity (see Figure 10). These syndromes typically begin with a nonspecific f'ebrile illness lto 2 weeks after a tick bite (Table 15). Rash is uncommon in adults. Leukopenia, thrombocytopenia, and F tG U R E I 5. Morulae (arrow) appearing as basophilic inclusion bodies in leukocytes of a patient with ehrlichiosis. increased serum aminotransferase levels are often present. Basophilic inclusion bodies called morulae visualized in the cytoplasm of leukocytes (Figure 15) suggest the diagnosis confirmatory. Polymerase chain reaction of whole blood at the but are present in few cases. Antibody tests are often negative time of acute illness is highly sensitive, particularly if in acute illness; a convalescent specimen 2 to 4 weeks after performed before therapy. Doxycycline is the recommended onset of symptoms showing a four fold rise in titer is treatment for ehrlichiosis and anaplasmosis. Because delay in TABLE 1 5. Comparison of Epidemiologic and Clinical Features of Ehrlichiosis, Anaplasmosis, and Spotted Fever Rickettsioses Feature Ehrlichiosis Anaplasmosis Spofted Fever Rickettsioses Vector Lone Star tick Blacklegged deer tick American dog tick, brown dog tick, Rocky Mountain wood tick, and others Geography Southeastern, mid-Atlantic, and Northeastern and upper Midwest Throughout the United Statesu south-central United States United States Coinfection Not reported; potential for Lyme d isease, babesiosis; potential Not reported coinfection with STARI, Heartland for coinfection with Powassan virus, virus, or Bourbon virus because of Bo rre ia m iya m otoi, or Eh rl ichi a I

TABLE 1 5. Comparison of Epidemiologic and Clinical Features of Ehrlichiosis, Anaplasmosis, and Spotted Fever Rickettsioses Feature Ehrlichiosis Anaplasmosis Spofted Fever Rickettsioses Vector Lone Star tick Blacklegged deer tick American dog tick, brown dog tick, Rocky Mountain wood tick, and others Geography Southeastern, mid-Atlantic, and Northeastern and upper Midwest Throughout the United Statesu south-central United States United States Coinfection Not reported; potential for Lyme d isease, babesiosis; potential Not reported coinfection with STARI, Heartland for coinfection with Powassan virus, virus, or Bourbon virus because of Bo rre ia m iya m otoi, or Eh rl ichi a I common vector muris eauclairensis because of common vector lncubation period 5-1 4 days 5-1 4 days 3-1 2 days

common vector muris eauclairensis because of common vector lncubation period 5-1 4 days 5-1 4 days 3-1 2 days Presenting signs and Fever, headache, myalgias Fevel headache, myalgias, chills Fever, headache, chills, myalgias, symptoms abdominal pain, meningismus Cutaneous signs Nonspecific rash in <30% of adults, Rash rare (<10%) Maculopapular eruption in >90% with median onset 5 days after of patients, progressing to fever petechia with involvement of palms and soles; onset, median of 3 days after fever Laboratory study Leu kopenia, th rombocytopenia, Leu kopen ia, throm bocytopenia, Th rombocytopenia, increased abnormalities increased seru m a minotransferase increased serum am inotra nsferase serum am i notransferase levels, levels levels hyponatremia Diagnosis Morulae in monocytes (<30%), Morulae in neutrophils (-50%), Acute and convalescent acute and convalescent acute and convalescent serologies, biopsy of skin with serologies, whole-blood PCR serologies, whole-blood PCR immunohistochemical analysis or skin PCR Treatment Doxycycline Doxycycline Doxycycline i Fatal ity 3o/" <1o/o 5"/"-107"

Presenting signs and Fever, headache, myalgias Fevel headache, myalgias, chills Fever, headache, chills, myalgias, symptoms abdominal pain, meningismus Cutaneous signs Nonspecific rash in <30% of adults, Rash rare (<10%) Maculopapular eruption in >90% with median onset 5 days after of patients, progressing to fever petechia with involvement of palms and soles; onset, median of 3 days after fever Laboratory study Leu kopenia, th rombocytopenia, Leu kopen ia, throm bocytopenia, Th rombocytopenia, increased abnormalities increased seru m a minotransferase increased serum am inotra nsferase serum am i notransferase levels, levels levels hyponatremia Diagnosis Morulae in monocytes (<30%), Morulae in neutrophils (-50%), Acute and convalescent acute and convalescent acute and convalescent serologies, biopsy of skin with serologies, whole-blood PCR serologies, whole-blood PCR immunohistochemical analysis or skin PCR Treatment Doxycycline Doxycycline Doxycycline i Fatal ity 3o/" <1o/o 5"/"-107" PCR = polymerase chain reaction; STARI = Southern tick-associated rash illness. oTwo thirds of all spotted fever rickettsial infections occur in Arkansas, Missouri, North Carolina, Oklahoma, and Tennessee

Presenting signs and Fever, headache, myalgias Fevel headache, myalgias, chills Fever, headache, chills, myalgias, symptoms abdominal pain, meningismus Cutaneous signs Nonspecific rash in <30% of adults, Rash rare (<10%) Maculopapular eruption in >90% with median onset 5 days after of patients, progressing to fever petechia with involvement of palms and soles; onset, median of 3 days after fever Laboratory study Leu kopenia, th rombocytopenia, Leu kopen ia, throm bocytopenia, Th rombocytopenia, increased abnormalities increased seru m a minotransferase increased serum am inotra nsferase serum am i notransferase levels, levels levels hyponatremia Diagnosis Morulae in monocytes (<30%), Morulae in neutrophils (-50%), Acute and convalescent acute and convalescent acute and convalescent serologies, biopsy of skin with serologies, whole-blood PCR serologies, whole-blood PCR immunohistochemical analysis or skin PCR Treatment Doxycycline Doxycycline Doxycycline i Fatal ity 3o/" <1o/o 5"/"-107" PCR = polymerase chain reaction; STARI = Southern tick-associated rash illness. oTwo thirds of all spotted fever rickettsial infections occur in Arkansas, Missouri, North Carolina, Oklahoma, and Tennessee 26

Urinary Tract lnfections treatment is associated with increased mortality, empiric ther_ apy should be started even in the absence of confirmatorv testing. r([Y POtl{TS . Ehrlichiosis and anaplasmosis cause a nonspecific febrile illness beginning I to 2 weeks after a tick bite. o Antibody levels are often negative at the time of presen- tation in ehrlichiosis and anaplasmosis but usually become positive within 4 weeks of illness; polymerase chain reaction of whole blood at the time of acute ill- ness may be diagnostic. . Doxycycline is recommended for ehrlichiosis and ana- plasmosis; empiric therapy should be started without FIGURE 16. Petechialand purpuricskin eruption in a patientwith late stage awaiting results of confirmatory testing. Rocky Mountain spotted fever.The rash typically begins on the ankles and wrists and spreads toward the trunk. Spotted Fever Rickettsioses Reprinted with permission Irom Biggs HM, Behravesh CB, Bradley KK, Dahlgren FS, Drexler NA, Dumler JS, et al. Diagnosis and management of tickborne rickettsial diseases: Rocky Mountain spotted fever and other spotted (including Rocky Mountain fever g roup rickeftsioses, eh rlich ioses, a nd a na plasmosis-U lPl\4lD: 271 721 131 doi:1 0.1 5585/mmwr.116502a1 n ited States. M MWR Recom m Rep. 201 6;65:1 -44.

(including Rocky Mountain fever g roup rickeftsioses, eh rlich ioses, a nd a na plasmosis-U lPl\4lD: 271 721 131 doi:1 0.1 5585/mmwr.116502a1 n ited States. M MWR Recom m Rep. 201 6;65:1 -44. Spotted Fever) Spotted fever group rickettsioses (SFR) are a group of closely related tick-borne infections that are serologically indistin- Powassan Virus guishable. The most common and most serious of the SFR in Powassan virus is an emerging tick-borne infection (Table 16) the United States is Rocky Mountain spotted fever (RMSF), spread by lxodes ticks. Most reported infections have pre- caused by Rickettsio rickettsii and transmitted by the dog tick sented with meningoencephalitis, with a high mortality rate. and other vectors (see Figure 11). RMSF has been reported Diagnostic testing is not commercially available but can be throughout the continental United States but occurs most performed through coordination with state health depart- frequently in a linear distribution extending from North ments. No antiviral therapy is available, and treatment is Carolina to Oklahoma. supportive. Clinically, RMSF presents with nonspecific symptoms sim ilar to those of ehrlichiosis and anaplasmosis (see Table 15). The hallmark feature is a rash; however, skin findings are typically delayed by several days after fever onset and may not be appar- Urinary Tract I nfections ent at the initial clinical presentation. The rash evolves from a Epidemiology and Microbiology macular eruption localized to the ankles or wrists, with central Community-acquired urinary tract infections (UTIs) account spread and progression to petechiae or purpura (Figure 16). for approximately 9 million ambulatory visits and 2 million Lesions are found on the palms and soles in as many as 50'X, of hospitalizations annually in the United States, making them patients; the face is generally spared. Purpura fulminans may one of the most common infections for which an antibiotic is occur and result in loss of digits or limbs. Up to 30'/, of patients prescribed. Another 1 million nosocomial UTls are diagnosed present with meningoencephalitis. annually, primarily urinary catheter associated, accounting for Immunohistochemical analysis of skin biopsy samples approximately 4O'/" of health care-associated infections (see may be diagnostic. Serologr is insensitive during acute illness, Health Care-Associated Infections). Approximately half of all and testing convalescent serum is often needed to confirm the women experience a UTI by age 30 years; sexual activity is a diagnosis. Doxycycline should be given empirically when SFR major risk factor. Other risk factors include structural and is suspected because treatment delay is associated with more functional abnormalities, use of spermicidal agents and severe disease and increased mortality. diaphragms, pregnancy, diabetes mellitus, obesity, urethral KEY POIl{IS catheterization (or other urinary tract instrumentation), . Spotted fever rickettsiosis, including Rocky Mountain incontinence, immunosuppression, and genetic factors (female relative with history of UTIs). spotted fever, presents with nonspecific signs and symp- toms such as fever, headache, malaise, myalgia, arthral- UTIs are classified based on anatomic location as lower gia, with a rash developing 3 to 5 days after presentation. (cystitis), upper (pyelonephritis, perinephric abscess), or pros-

Spotted Fever) Spotted fever group rickettsioses (SFR) are a group of closely related tick-borne infections that are serologically indistin- Powassan Virus guishable. The most common and most serious of the SFR in Powassan virus is an emerging tick-borne infection (Table 16) the United States is Rocky Mountain spotted fever (RMSF), spread by lxodes ticks. Most reported infections have pre- caused by Rickettsio rickettsii and transmitted by the dog tick sented with meningoencephalitis, with a high mortality rate. and other vectors (see Figure 11). RMSF has been reported Diagnostic testing is not commercially available but can be throughout the continental United States but occurs most performed through coordination with state health depart- frequently in a linear distribution extending from North ments. No antiviral therapy is available, and treatment is Carolina to Oklahoma. supportive. Clinically, RMSF presents with nonspecific symptoms sim ilar to those of ehrlichiosis and anaplasmosis (see Table 15). The hallmark feature is a rash; however, skin findings are typically delayed by several days after fever onset and may not be appar- Urinary Tract I nfections ent at the initial clinical presentation. The rash evolves from a Epidemiology and Microbiology macular eruption localized to the ankles or wrists, with central Community-acquired urinary tract infections (UTIs) account spread and progression to petechiae or purpura (Figure 16). for approximately 9 million ambulatory visits and 2 million Lesions are found on the palms and soles in as many as 50'X, of hospitalizations annually in the United States, making them patients; the face is generally spared. Purpura fulminans may one of the most common infections for which an antibiotic is occur and result in loss of digits or limbs. Up to 30'/, of patients prescribed. Another 1 million nosocomial UTls are diagnosed present with meningoencephalitis. annually, primarily urinary catheter associated, accounting for Immunohistochemical analysis of skin biopsy samples approximately 4O'/" of health care-associated infections (see may be diagnostic. Serologr is insensitive during acute illness, Health Care-Associated Infections). Approximately half of all and testing convalescent serum is often needed to confirm the women experience a UTI by age 30 years; sexual activity is a diagnosis. Doxycycline should be given empirically when SFR major risk factor. Other risk factors include structural and is suspected because treatment delay is associated with more functional abnormalities, use of spermicidal agents and severe disease and increased mortality. diaphragms, pregnancy, diabetes mellitus, obesity, urethral KEY POIl{IS catheterization (or other urinary tract instrumentation), . Spotted fever rickettsiosis, including Rocky Mountain incontinence, immunosuppression, and genetic factors (female relative with history of UTIs). spotted fever, presents with nonspecific signs and symp- toms such as fever, headache, malaise, myalgia, arthral- UTIs are classified based on anatomic location as lower gia, with a rash developing 3 to 5 days after presentation. (cystitis), upper (pyelonephritis, perinephric abscess), or pros- . Doxycycline should be given empirically when spotted tatitis. The term uncomplicated UTI refers to infections in nonpregnant women without structural or neurologic abnor- fever rickettsiosis is clinically suspected. malities or comorbidities. UTIs in men, pregnant women,

. Doxycycline should be given empirically when spotted tatitis. The term uncomplicated UTI refers to infections in nonpregnant women without structural or neurologic abnor- fever rickettsiosis is clinically suspected. malities or comorbidities. UTIs in men, pregnant women, 27