CONTENTS
- Rapid Reference 🚀
- Overview
- Pathophysiology
- Diagnosis
- Labs
- Neuroimaging
- Treatment
- Podcast
- Questions & discussion
- Pitfalls
approach to critical illness possibly due to tick borne disease ✅
#1) when to suspect tick borne illness (more)
- (#1) Sepsis without a definite source of infection.
- (#2) Tick exposure (travel or residence in an endemic region, usually spring through autumn).
- (#3) Other clues:
- Reported tick bite in ~50% of patients.
- Unexplained thrombocytopenia (especially with leukopenia).
- Hemolysis (suggests Babesiosis).
- Suggestive rash or conjunctivitis.
#2) start empiric doxycycline
- Don't delay empiric doxycycline 100 mg BID IV/PO.
- Doxycycline covers all tick borne critical illness, except for babesiosis.
#3) order tick labs (more)
- Complete blood count (if not already done).
- Babesiosis labs if this is a concern (based on epidemiology):
- (a) Hemolysis labs (e.g., lactate dehydrogenase, urinalysis showing hemoglobinuria, haptoglobin).
- (b) Thin blood smear (if hemolysis labs concerning).
- Ferritin.
- PCR for relevant pathogens (e.g., anaplasmosis, ehrlichiosis, rocky mountain spotted fever).
#4) adjust antibiotics (more)
- (a) If labs show babesiosis, this requires adding specific therapy (see below).
- (b) If PCR is negative for anaplasmosis/ehrlichiosis/RMSF, then stop the doxycycline.
lab interpretation (more)
rationale for this chapter
- Tick-borne illnesses are spreading into a wider geographic distribution due to global warming.
- These illnesses are difficult to diagnose (often mimicking more common bacterial pathogens).
- Immediate initiation of treatment may be critical for a good outcome.
focus of this chapter:
- When to suspect possible tick-borne illness.
- Investigation of the patient with possible tick-borne illness.
- Use of empiric therapy while awaiting advanced testing.
- Four diseases are included as these will constitute the vast majority of tick-borne illness encountered in ICU: anaplasmosis, ehrlichiosis, babesiosis, and Rocky Mountain Spotted Fever (RMSF).
- (Although Lyme disease is more common, it is not often seen in the ICU.)
Tickborne illnesses are somewhat unique in that they cause intracellular infection.
babesiosis
- Causes infection & hemolysis of erythrocytes by a protozoan organism (similar to malaria).
- Among tick-borne illnesses, babesiosis is unique in its ability to cause hemolysis.
anaplasmosis & ehrlichiosis
- Obligate intracellular bacteria which infect leukocytes.
- Anaplasmosis: predominantly infects neutrophils.
- Ehrlichiosis chaffeensis (the most likely strain to be encountered in ICU) infects mostly monocytes and macrophages.
- Bacteria don't damage host tissues directly, but instead most organ dysfunction results from an exuberant inflammatory response.
- In severe cases, this overzealous inflammatory response may lead to full-blown HLH (hemophagocytic lymphohistiocytosis).
- In anaplasmosis, infection of neutrophils may lead to secondary opportunistic infections.
rocky mountain spotted fever (RMSF)
- Obligate intracellular bacteria which infect endothelial cells, leading to inflammation of the blood vessels. This may have the following consequences:
- Systemic capillary leak
- Occlusive thrombosis
- Disseminated intravascular coagulation with consumption of platelets and fibrinogen
general epidemiology of tick-borne illnesses
- Tend to peak between April and October. However, transmission can occur year-round in the southern United States.
- The vast majority of patients won't require ICU admission. Risk factors for severe illness are listed below.
key points in exposure history
- (1) History of tick bite is reported in roughly half of patients. Therefore, this cannot be relied upon as a diagnostic clue.
- (2) Exposure to environments with ticks.
- Rural exposure may be highest risk (e.g. hiking). However, tick exposure can occur in suburban locations and even urban parks.
- (3) Clusters of illness may occur among family members, coworkers, or dogs (may resemble influenza, but during the summer).
- (4) Travel history (incubation may be weeks for some pathogens, so recent travel is relevant).
co-infection
- Ticks may harbor multiple pathogens, leading to several simultaneous infections.
- Anaplasmosis, Babesiosis, Lyme, and Powassan virus may occur together (because they may be harbored by the Ixodes scapularis tick).
- Among patients with anaplasmosis, ~10% have co-infection with Lyme disease or babesiosis.(28457353)
babesiosis
- Incubation is ~1-6 weeks.
- Especially endemic within islands off the coast of New England (including Nantucket, Martha's Vineyard, Block Island, Long Island). Babesiosis is increasingly common in the northeastern United States, due to milder winters and an increasing deer population.
- Most infections occur between late spring and early fall (with a peak between June-August).
- Risk factors for severe illness:
- Age.
- Splenectomy or hyposplenism.
- Malignancy.
- Heart failure.
- HIV or immunosuppressive therapy (e.g., TNF-inhibitors or rituximab).
- May also be acquired via blood transfusion, usually with a 1-9 week incubation period (but extending out to several months).(33252652)
anaplasmosis
- Incubation is 5-14 days.
- Most cases occur June-November, but cases can rarely occur during the winter.
- Risk factors for severe illness:
- Age (critical illness can occur in otherwise healthy, older patients).
- Immunosuppressive therapy.
- Chronic inflammatory illness.
- Underlying malignancy.
- Distributed worldwide, including Europe (especially in Slovenia, Sweden, and Norway) and Asia (including China, Korea, and Japan).
- Rates of anaplasmosis are increasing in the northeast United States currently, including several states which previously didn't see many cases (e.g., Vermont and Pennsylvania).
ehrlichiosis
- Incubation 5-14 days.
- Risk factors for severe illness:
- Age (however, fatal disease can occur in previously healthy young adults)
- Immunosuppression, HIV, organ transplantation
- Splenectomy
- Beyond the United States, ehrlichia infections are reported in South America, Africa, and eastern Asia.
rocky mountain spotted fever
- Incubation is 3-12 days.
- Reported in all 48 contiguous states of the United States (including a city park in the Bronx).(3130574)
- Transmission usually peaks in in the late spring and summer, but may occur all year in warmer regions.
- Risk factors for severe illness: older age, alcoholism, glucose-6-phosphate dehydrogenase deficiency, immunocompromise.
- Beyond the United States, RMSF may be seen in Central and South America (including Argentina, Brazil, Columbia, Panama, Costa Rica, and Mexico).
initial flu-like syndrome:
- 🔑 All of these infections will generally begin with a a nonspecific “flu-like” illness including fever, myalgia, headache, malaise, and gastrointestinal symptoms (nausea, vomiting, diarrhea).
- The symptoms below focus on more unique features, which may assist with diagnosis. However, don't rely on seeing these unique features!
babesiosis
- Initial symptoms nonspecific (e.g., fatigue, weakness, fever, headache, myalgia, anorexia, nausea, dry cough, arthralgia).
- Intravascular hemolysis (and occasionally also warm autoimmune hemolytic anemia):
- Hemoglobinuria (pink/dark urine).
- Jaundice.
- Conjunctivitis, petechiae, or ecchymosis may be seen.(28696196)
- Multi-organ failure can occur:
- Confusion, coma.
- ARDS.
- Shock, heart failure.
- Splenic rupture.
- Renal failure.
- Disseminated intravascular coagulation.
anaplasmosis
- Erythema migrans rash seen in ~2-10% (this may reflect co-infection with Lyme disease).
- Confusion (20%), neck stiffness (45%).
- May cause severe organ dysfunction:
- ARDS.
- Rhabdomyolysis.
- Renal failure.
- Carditis.
- Pancreatitis.
- DIC with hemorrhagic manifestations.
- Hemophagocytic lymphohistiocytosis (HLH).
- Invasive opportunistic infections with viral and fungal pathogens may occur, following anaplasmosis.
ehrlichiosis
- Commonly manifests with nonspecific findings: fever (>90%), headache, malaise, myalgia.
- Gastrointestinal symptoms may be prominent (nausea, vomiting, diarrhea).
- Rash seen in ~20% of patients; may be petechial, maculopapular, or diffuse erythroderma.(28457353)
- Major end-organs which can be affected are brain and lungs:
- (1) Meningitis or meningoencephalitis occur in ~20% of patients, may progress to seizure and coma.
- (2) Cough or respiratory symptoms occur in about a third of patients, occasionally progressing to ARDS.
- Can evolve into multi-organ failure, including hepatic and renal failure.
- May trigger hemophagocytic lymphohistiocytosis (HLH), resembling bacterial septic shock.
rocky mountain spotted fever (RMSF)
early (1-4 days)
- Fever (>90%), headache, malaise, myalgia.
- Early rash (~2-5 days)
- Starts at wrists and ankles, later spreads to trunk (sometimes on palms and soles).
- Begins as blanching pink macules, which later become maculopapular and then petechial.
- Absent in 10% of patients (“spotless” fever is seen more often in the elderly and in patients with dark skin). Furthermore, in fulminant RMSF, the rash may appear only shortly prior to death.
- Nondependent edema around eyes and on backs of hands (endothelial dysfunction).
- Gastrointestinal symptoms (nausea, vomiting, anorexia, abdominal pain).
- Photophobia, meningismus, and conjunctival suffusion may occur.
late (day 5+)
- Neurologic
- Altered mental status, meningoencephalitis (may include coma, tremor, rigidity, deafness, or seizures).(Louis 2021)
- Late rash
- Petechial rash appears ~ day 6.
- Coalescence of rash may lead to areas of ulceration or gangrene (potentially requiring amputation).
- Multiorgan failure including renal failure and ARDS.
To synthesize the above sections on epidemiology and presentation, there are six key clues to consider the presence of tick-borne illness.
reported tick bite
- Present in perhaps half of patients.
- Obvious red-flag to tick-borne illness. However, lack of a tick-bite history cannot exclude tick-borne illness.
travel or residence in an endemic region
- Tick-borne illnesses are widespread, but there are some regions which are notoriously endemic (e.g. babesiosis in Nantucket and Block Island).
- Among areas with low a low burden of tick-borne illnesses, recent travel to an endemic region may be a red flag.
- Note that incubation periods may last for weeks, so travel may have occurred a while previously.
rash or conjunctivitis
- Most commonly seen in Rocky Mountain Spotted Fever (although it may be entirely absent in 10% of such patients).
- Rash may also be seen in ehrlichiosis (various forms) or anaplasmosis (usually Erythema Migrans rash).
- Conjunctivitis may also be a useful clue, as this is typically not seen with bacterial sepsis.
immunocompromise
- Whenever you are thinking about overwhelming post-splenectomy sepsis (OPSS), also consider babesiosis or ehrlichiosis.
thrombocytopenia
- Mild thrombocytopenia is often seen in septic shock, but unusually severe thrombocytopenia may suggest a tick-borne illness.
- The combination of thrombocytopenia plus leukopenia may be even more suggestive.
hemolysis
- Hemolysis is a hallmark of babesiosis.
- This manifests with clinically with anemia, hemoglobinuria, and elevated indirect bilirubin.
Tick-borne illnesses tend to cause relatively nonspecific abnormalities within commonly obtained labs (table below). Perhaps the most notable finding is thrombocytopenia (combined with leukopenia in anaplasmosis or ehrlichiosis).
babesiosis
- Hemolytic anemia is a key diagnostic feature:
- Lactate dehydrogenase (LDH) should be markedly elevated (absence of hemolysis excludes babesiosis).
- Urinalysis may suggest the presence of cell-free hemoglobin (heme-positive dipstick, but no erythrocytes seen on microscopy).
- Thin blood smears may identify parasites.
- Will generally be positive in severe cases, but multiple smears may be needed.
- Level of parasitemia varies from 1-80%; usually low early in the disease course. Parasitemia >10% may be an indication for exchange transfusion.
- Thick blood smears not recommended (organism is small and may be missed).(27115378)
- PCR is more sensitive than blood smears for mild disease, but turn-around time is longer.
- Serologic testing is not recommended.(33252652) Serology may remain positive following resolution of infection, so this doesn't prove an acute infection.
- Ferritin levels may be quite elevated. It's unclear whether this is a reflection of systemic inflammation or merely the presence of hemolysis.(25472945)
anaplasmosis
- Blood smear may reveal bacterial inclusion bodies (morulae) inside neutrophils. However, detection of intracellular morulae will vary depending on expertise of the laboratory.
- Blood count:
- Thrombocytopenia is often a useful clue suggestive of anaplasmosis, especially if accompanied by leukopenia.
- Alternatively, platelets >300 K/uL strongly argues against anaplasmosis, in the context of critically ill patients (figure below).
- Inflammatory markers may be quite elevated.
- One study of 11 patients found CRP 121 mg/L (range 15-314 mg/L) and procalcitonin 2.5 ug/L (range 0.3 – 7.2 ug/L).(16481557)
- 💡 Procalcitonin may be quite elevated. This shouldn't lead to the conclusion that the patient is infected with a typical bacterial pathogen.
- Ferritin elevation correlates with disease severity.(29468169) Severely elevated ferritin may suggest that anaplasmosis is triggering hemophagocytic lymphohistiocytosis (more on this below).
- PCR is the definitive test of choice.
ehrlichiosis
- PCR is the test of choice.
rocky mountain spotted fever (RMSF)
- Laboratory abnormalities are nonspecific (see table above).
- PCR or serology may be used. However, either test may be negative early in the course of infection.
- CSF analysis:(Louis 2021)
- Pleocytosis (typically <100 cells/uL) is usually lymphocytic, but neutrophilic predominance occurs in up to a third of patients.
- Protein concentration is often moderately elevated (100-200 mg/dL), with normal glucose levels.
anaplasmosis & ehrlichiosis
- MRI with gadolinium contrast may show leptomeningeal enhancement in patients with meningoencephalitis.(Louis 2021)
rocky mountain spotted fever (RMSF)
- The classic finding is a “starry sky” pattern with innumerable foci of subcortical and periventricular infarcts. As would be expected for infarction, these lesions are bright on T2/FLARE and DWI, while being dark on ADC.
- Other findings may be less dramatic:
- Meningeal enhancement.
- Nonspecific punctate abnormalities in the subcortical white and deep gray structures (e.g., the thalamus).(Louis 2021)
doxycycline hits everything other than babesiosis
- Doxycycline is treatment of choice for anaplasmosis, ehrlichiosis, and RMSF.
- Empiric doxycycline should be initiated if there is suspicion for any of these diseases (don't delay treatment while awaiting confirmatory testing).
- The usual dosing is 100 mg doxycycline PO/IV q12hr.
- Clinical response should be brisk (e.g., defervescence within 24-48 hours). Persistent fever or clinical deterioration suggests an alternative diagnosis or superimposed hemophagocytic lymphohistiocytosis (more on this below).
- Doxycycline allergy or contraindication:
- Rifampin 300 mg BID may be used as a 2nd line agent, but only for anaplasmosis or ehrlichiosis. (Louis 2012)
- Chloramphenicol may be used as a second-line agent for RMSF.(28696196)
- Depending on the allergy history, doxycycline may be considered using either a graded challenge or supervised desensitization protocol.
babesiosis
- Unlike other tick-borne illnesses:
- (1) Babesiosis isn't covered by doxycycline.
- (2) Treatment should be initiated only following confirmation of the diagnosis. Fortunately, diagnosis is usually rapid, based on blood smear.
- Antibiotic regimens for babesiosis:(33252652)
- Preferred: Atovaquone 750 mg PO q12hr plus azithromycin 500 mg IV q24 until symptoms improve, then convert to entirely oral therapy.
- Alternative: Clindamycin 600 mg IV q6hr plus quinine sulfate 650 mg PO q8hr until symptoms improve, then convert to entirely oral therapy.
- Treatment duration is usually 7-10 days, but may need to be extended among immunocompromised patients.
- Exchange transfusion can achieve 90% reduction in parasitemia. Potential indications for exchange transfusion are listed below. Risks of exchange transfusion include transfusion reactions, exacerbation of thrombocytopenia, and complications associated with venous access devices. (28696196, 33252652)
- High-grade parasitemia (>10%) is a generally accepted indication, although some patients will do well with this (so exchange transfusion isn't necessarily required).
- Severe pulmonary, renal, or hepatic compromise.
- Severe hemolysis (e.g., hemoglobin <10 mg/dL).
- The level of parasitemia should be monitored daily until it falls below 5%.(28696196)
treat other organ-system complications
- Anaplasmosis may cause rhabdomyolysis: check creatine kinase and treat as described in the chapter on rhabdomyolysis.
- Support other organ failures as necessary (e.g., renal failure, ARDS).
ehrlichiosis & anaplasmosis: treatment for intercurrent hemophagocytic lymphohistiocytosis (HLH)
- Ehrlichiosis and anaplasmosis are established infectious triggers of hemophagocytic lymphohistiocytosis (HLH), a cytokine storm state resembling septic shock.
- The front-line therapy here is doxycycline. By treating the cause of HLH, doxycycline alone is often sufficient to cause clinical improvement. (28584460)
- Additional treatments directed towards HLH may be considered as well. The literature contains reports of therapies ranging from corticosteroid alone to the entire HLH-2004 regimen (a chemotherapeutic protocol that includes etoposide, cyclosporine, and dexamethasone).(26227842, 30524954)
- A reasonable approach to severe disease with HLH might be to initiate dual therapy with doxycycline and corticosteroid, with further escalation if needed (e.g., addition of anakinra).(32723647) Emerging data might eventually suggest that ruxolitinib could be a safer option here.(29417621)
- More on the treatment of HLH here.
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- Don't forget that the incubation of these diseases may be weeks, so patients may be at risk long after they went to a trip to an endemic area.
- For a critically ill patient, don't withhold therapy while awaiting a definitive diagnosis (instead, consider initiation of empiric doxycycline).
- Patients may be co-infected with numerous tick-borne illnesses. Therefore, diagnosing one tick-borne illness should prompt consideration and testing for others (e.g. Lyme disease).
- Absence of a known tick bite doesn't exclude these diseases. Only about half of patients are aware of a tick bite.
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References
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- 16481557 Lotric-Furlan S, Rojko T, Strle F. Concentration of procalcitonin and C-reactive protein in patients with human granulocytic anaplasmosis and the initial phase of tick-borne encephalitis. Ann N Y Acad Sci. 2005 Dec;1063:439-41. doi: 10.1196/annals.1355.081 [PubMed]
- 25472945 Cunha BA, Raza M, Schmidt A. Highly elevated serum ferritin levels are a diagnostic marker in babesiosis. Clin Infect Dis. 2015 Mar 1;60(5):827-9. doi: 10.1093/cid/ciu960 [PubMed]
- 26227842 Otrock ZK, Gonzalez MD, Eby CS. Ehrlichia-Induced Hemophagocytic Lymphohistiocytosis: A Case Series and Review of Literature. Blood Cells Mol Dis. 2015 Oct;55(3):191-3. doi: 10.1016/j.bcmd.2015.06.009 [PubMed]
- 27115378 Sanchez E, Vannier E, Wormser GP, Hu LT. Diagnosis, Treatment, and Prevention of Lyme Disease, Human Granulocytic Anaplasmosis, and Babesiosis: A Review. JAMA. 2016 Apr 26;315(16):1767-77. doi: 10.1001/jama.2016.2884 [PubMed]
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- 29417621 Zandvakili I, Conboy CB, Ayed AO, Cathcart-Rake EJ, Tefferi A. Ruxolitinib as first-line treatment in secondary hemophagocytic lymphohistiocytosis: A second experience. Am J Hematol. 2018 May;93(5):E123-E125. doi: 10.1002/ajh.25063 [PubMed]
- 29468169 Camacci ML, Panganiban RP, Pattison Z, Haghayeghi K, Daly A, Ojevwe C, Munyon RJ. Severe Human Granulocytic Anaplasmosis With Significantly Elevated Ferritin Levels in an Immunocompetent Host in Pennsylvania: A Case Report. J Investig Med High Impact Case Rep. 2018 Feb 13;6:2324709618758350. doi: 10.1177/2324709618758350 [PubMed]
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