Therapeutic Parasite Reduction or Removal of Harmful Materials Yanyun Wu, MD, PhD Chief Medical Officer
None Conflict of Interest
Puget Sound Blood Center is now Bloodworks Northwest After 70 years Puget Sound Blood Center is changing our name! November 20, 2015, ASFA regional Meeting
Cases Case 1 A 53-year-old male resident of Connecticut was admitted to ER in July. He recently had a week-long camping trip. He presented with high fevers (40 C), shaking chill, weakness, and fatigue. He had severe hemolytic anemia (Hct of 21%)/pancytopenia (platelet count of 33K), with signs of disseminated intravascular coagulation, acute renal failure, and respiratory failure. He was intubated and transferred to ICU overnight. There was no history of splenectomy or immunodeficiency.
Cases Case 2 60 year old woman with a prolonged hospital stay (7 months) due to multiple medical and surgical issues. For the last week, patient has been spiking temp of 39 to 40 C. Significant DAT negative hemolytic anemia (Hct of 27%) She received transfusion of 4 units RBC 4 weeks ago. And she has a history of splenectomy
Kyle Noskoviak, M.D., and Elizabeth Broome, M.D. N Engl J Med 2008; 358:e19April 24, 2008DOI: 10.1056/NEJMicm070903
N Engl J Med 2012;366:2397-407.
Human babesiosis summary Causative pathogen: protozoal parasite in phylum Apicomplexa Target tissue: red blood cells Transmission: Ixodid ticks (Ixodes scapularis) Blood transfusion Perinatal/transplacental Diagnosis: epidemiology, symptoms, microscopy, PCR, antibody Treatment: atovaquone/azithromycin or clindamycin/quinine, exchange transfusion Courtesy of Dr. Peter Krause, Yale
Babesia species causing human infection Vannier and Krause, N. Engl. J. Med., 2012 US B. microti B. duncani B. divergens-like Europe B. divergens B. venatorum B. microti Asia B. microti-like K01 Courtesy of Dr. Peter Krause, Yale
Number cases Babesiosis in the US 1986-2011 1100 1000 900 800 700 600 500 400 300 200 100 0 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 10 11 One of the most common infections of free-living animals worldwide and an emerging infection in humans Year Courtesy of Dr. Peter Krause, Yale
Human babesiosis Require both a competent vertebrate and nonvertebrate host to maintain transmission cycles Transmitted by ixodid ticks to their vertebrate hosts Replicate in the vertebrate hosts red blood cells
Transmission of Babesia microti by the Ixodes scapularis Tick Courtesy of Dr. Peter Krause, Yale Vannier E and Krause PJ. New Engl J Med, 2012
Life cycle of Babesia microti Sporoblasts/Sporozoites in salivary glands Trophozoite Zygote enters gut epithelium Gametes fuse in the gut Pre-gametocyte Merozoite Courtesy of Dr. Peter Krause, Yale
Life cycle of Babesia microti
Babesiosis
Babesiosis clinical manifestations 1. Asymptomatic infection 2. Viral-like illness Fever, chills, sweats, headache, fatigue 3. Severe illness and death (5-21%) >50, asplenic, HIV, malignancy, blood transfusion recipients Persistent, relapsing illness HIV/AIDS, malignancy, asplenic, immunosuppressive drugs The incubation period is usually 1 3 weeks Courtesy of Dr. Peter Krause, Yale
Babesiosis: persistent parasitemia (DNA) Courtesy of Dr. Peter Krause, Yale Krause, Spielman, Telford, et al., New Engl J Med, 1998
Transfusion transmitted babesiosis Symptoms delayed as long as 1 week to 6 months after transfusion Symptoms similar to those of tick-transmitted disease but often more severe because blood recipients are often immunocompromised Mortality rate ranges from about 10% to 21% Courtesy of Dr. Peter Krause, Yale
Babesiosis in highly immunocompromised patients Clinical characteristic Median number of antibiotic courses (range) Median number hospital admissions (range) Cases (n=14) Median weeks of therapy (range) 13 (4-102) Controls (n=46) P value 4 (2-10) 1 <0.001 1.5 (0-4) 1 (0-1) <0.001 1 (0.5-1.5) <0.001 Number with complications (percent) 8 (57) 2 (4) <0.001 Number with fatal infection (percent) 3 (21) 0 <0.02 Krause, Gewurz, Hill, et al. Clin Inf Dis, 2008 Courtesy of Dr. Peter Krause, Yale
Babesiosis in highly immunocompromised patients People suffering from broad-based immunosuppression are at risk of persistent relapsing Babesia microti infection Adaptive immunity (B and T cell) are important for resolution of infection These patients generally require anti-babesial therapy for at least 6 weeks, including 2 weeks after babesia are no longer detected on blood smear Courtesy of Dr. Peter Krause, Yale
General approach to diagnosis Epidemiology Medical history Physical examination Laboratory testing Courtesy of Dr. Peter Krause, Yale
Specific laboratory diagnosis Microbial detection Blood smear Polymerase chain reaction Small rodent inoculation Antibody detection IFA Immunoblot ELISA Courtesy of Dr. Peter Krause, Yale
Diagnostic algorithm for babesiosis Cunha et al, Clinical Infectious Diseases 2015;60(5):827 9
Diagnosis Cunha et al, Clinical Infectious Diseases 2015;60(5):827 9
Treatment of babesiosis caused by Babesia microti Mild illness Atovaquone (PO) + azithromycin (PO) Administration for 7-10 days Severe illness Clindamycin (IV or PO) + quinine (PO) Administration for 7-10 days Persistent or relapsing illness Atovaquone (PO) + azithromycin (PO) OR Clindamycin (IV or PO) + quinine (PO) Administration for at least 6 wks, including 2 wks after parasites are no longer detected on blood smear Courtesy of Dr. Peter Krause, Yale
Babesiosis
Babesiosis What are we removing? What are we adding back? Have we changed patient outcome? Give me the proof! Show me the data!
Babesiosis Readings: 1. Dorman et al, TRANSFUSION Volume 40, March 2000 2. Spaete et al, Journal of Clinical Apheresis 24:97 105 (2009)
Babesiosis Dorman et al, TRANSFUSION Volume 40, March 2000
Dorman et al, TRANSFUSION Volume 40, March 2000
Dorman et al, TRANSFUSION Volume 40, March 2000
Dorman et al, TRANSFUSION Volume 40, March 2000
Dorman et al, TRANSFUSION Volume 40, March 2000
15 males (63%) Summary The mean age: 56 years (SD 16; range, 25 77) The mean pretransfusion hemoglobin: 8.1 g/dl (SD 2.5; range, 4.7 13.7). The mean prerce or prewbe level of parasitemia was 18% (SD 14; range, 1.6 60) The mean postexchange level of parasitemia was 3.6% (SD 3.8; range, 0.1 13.8) with a median of 2% Fifteen (63%) of the 24 patients were asplenic Two of four who died were asplenic, and a third was reported to have necrotic splenic lesions on postmortem exam
Spaete J et al, J Clin Apher. 2009;24(3):97-105. Babesiosis
Babesiosis
Babesiosis Harmful Materials: Parasite: from RBC only? Cytokine? Free Heme Others?
ASFA guideline: Rationale for therapeutic apheresis 1. First, it helps to lower the level of parasitemia by physically removing the infected RBCs from the blood stream and replacing them with noninfected RBCs. Because babesia organisms do not have an exo-erthrocytic phase, removal of RBC-associated parasites might be very effective. 2. Second, by removal of rigid infected cells, RBC exchange could decrease obstruction in the microcirculation and tissue hypoxia caused by adherence of RBCs to vascular endothelium. 3. Finally, the hemolytic process produces vasoactive compounds, including a variety of cytokines (including INF-g, TNF-a, IL-1, IL-6), nitric oxide and thromboplastin substances, which can promote renal failure and DIC. RBC exchange may help to remove the proinflammatory cytokines.
Babesiosis Shaio MF et al. Am J Trop Med Hyg. (1998)
Babesiosis Shaio MF et al. Am J Trop Med Hyg. (1998)
Courtesy of Dr. Peter Krause, Yale Krause PJ, et al. Trends in Parasitology, 2007;23:605-610.
Pathogenesis Excessive erythrocyte cytoadherence: Additionally, erythrocytes infected with some babesia species undergo membrane changes that cause these erythrocytes to adhere to the vascular endothelium Excessive pro-inflammatory cytokine production During a babesia infection, inflammatory cytokines including tumor necrosis factor a (TNF-a) and interleukin 6, and adhesion molecules such as Eselectin, intracellular adhesion molecule 1 and vascular-cell adhesion molecule 1 are upregulated While moderate synthesis of these factors may be protective, excessive upregulation may result in severe babesiosis Krause PJ, Daily J, Telford SR, et al. Trends Parasitol, 2007 Sloan et al, Journal of Clinical Apheresis 00:00 00 (2014)
Erythrocyte cytoadherence Cytoadherence most thoroughly studied in B. bovis infection Cattle infected by B. bovis die from encephalopathy as erythrocytes obstruct brain blood vessels. B. bovis encephalopathy similar to human P. falciparum cerebral malaria Cytoadherence is beneficial for the parasite as it delays or prevents filtering/removal of infected RBCs by the spleen. Courtesy of Dr. Peter Krause, Yale
Pro-inflammatory cytokines Severe disease occurs without erythrocyte cytoadherence for B. microti, suggesting other pathogenic mechanisms. Pro-inflammatory cytokines such as TNF-α and IFN-γ protect the host against B. microti infection but if produced in excess may cause severe symptoms and complications. Courtesy of Dr. Peter Krause, Yale
Babesiosis When do you start or stop? How to exchange? Patient consent? Others?
Babesiosis Ziggy Vote 1. Agree with ASFA Category? 2. More Study? a. RCT? b. CT? c. Registry? 3. What kind of exchange? a. RBC b. RBC+ Plasma? c. Whole Blood?