Clarisse M. Machado, M.D. Institute of Tropical Medicine University of So Paulo, So Paulo, Brazil None People in 97 countries are at risk of malaria infection, mostly in Africa, Asia and in Central and South America Awareness of Plasmodium species endemicity is important to early introduction of appropriate treatment (WHO 2014, World malaria report) P.falciparumP.vivax P.malariae e P.ovale Mortality rates vary from 10% to 40%. More harmful in nave recipients from non-endemic areas The prognosis of post transplant malaria depends on: The delay in diagnosis and initiation of treatment The species of Plasmodium involved Type of organ transplanted Type of immunosuppressive therapy The majority of deaths are associated with P. falciparum (Inoue et al., Rev Inst Med Trop 2010) Areas at risk of malaria transmission (Reesink et al., 2010; Machado & Levi, 2012) Blood products Rare (0.2%)*. Symptoms develop earlier (1-3 days) Donor- transmitted 30% of Tx cases. Symptoms develop later (> 1 w) Natural route - Parasite persistence - Exposure to infected mosquitoes in endemic regions * Few cases reported in the last 10 yr Recipient traveled or lived in malaria areas Blood transfusion in endemic regions Donor traveled or lived in malaria areas Pre-transplant screening: Organ wash and cold preservation not enough to prevent transmission Serology not recommended. Performed in some endemic regions Donor travel to malaria areas: defer from donation for 12 months Donor lived in malaria areas: defer from donation for 3 years If not possible, donor should receive empirical treatment before donation (Tomblyn et al., 2009) 1 yr for P.falciparum 3-5 yr for P.vivax e P.ovale As long as 40 yr for P.malariae Without reinfection the persistence of parasite is estimated to be: (Reesink et al., 2010; Machado & Levi, 2012)Microscopy Immuno chromatography PCR High index of suspicious as fever paroxysms generally not present Identification of the species is necessary! Local epidemiology, past travel destination P. falciparum Artemisinin-based combined therapy (artemether 20mg) Lumefantrine (120mg), piperaquine (160mg) or mefloquine* (1250 mg). P.vivax, P.ovale Chloroquine (25mg/kg for 3 days) still used in some countries in the Region of the Americas Primaquine (0.5mg/kg/day for 7 days) is currently the only drug available to treat the liver stage (hypnozoite) of P. vivax infection. (World malaria report 2013;Adults take four tablets twice a day for 3 days (* in regions of susceptible P.falciparum) Blood/graft-transmitted malaria: Primaquine is not necessary, as hepatic hypnozoites are not established in these cases Drug interactions Mefloquine, doxycycline, chloroquine, and primaquine may increase calcineurin inhibitor levels (tacrolimus and cyclosporine A) Test for G6PD activity before primaquine. (World malaria report 2013) Currently there are five drugs recommended for chemoprophylaxis : 250 mg once weekly Start 23 weeks before departure Mefloquine Daily prophylaxis Start 1-2 days before departure Doxycycline Daily prophylaxis Start 1-2 days before departure Atovaquone - proguanil 310 mg (two tablets) weekly Start 1 week before departure Chloroquine Used for the duration of the stay in the malaria risk area, and continued for 4 weeks after the last possible exposure to infection (World malaria report 2013; Dengue is the most rapidly spreading mosquito-borne viral disease in the world and occurs both as an endemic or epidemic disease. Dengue virus - single-stranded RNA virus; 4 distinct serotypes (DEN1, DEN2, DEN3, DEN4). Genus Flavivirus, family Flaviviridae; transmitted by mosquitoes, genus Aedes (aegytpi, albopictus) Incidence increased 30-fold the last 50 years - geographic expansion to new countries and, more recently, from urban to rural areas. An estimated 50 million dengue infections occur annually and approximately 2.5 billion people live in areas where dengue viruses can be transmitted. In tropical and subtropical areas, dengue is endemic in 112 countries In the region of the Americas, 871,150 cases of dengue/severe dengue and 272 deaths were reported up to epidemiological week 16, 2015, with a case fatality rate of More than 85% of those cases occurred in Brazil (WHO 2009; Wilder-Smith & Schwartz. N Engl J Med 2005; PAHO-WHO EW16, 2015 ) Asymptomatic cases: at least triple of dengue fever (DF) cases. Symptomatic cases: Undifferentiated fever Dengue fever (DF) Dengue hemorrhagic fever (DHF). Secondary infection increases the risk of more serious disease (DHF/DSS) Patients with severe dengue have elevated circulating levels of T-cell activation markers, such as IL-8, IL-10, TGF- and interferon- Dengue shock syndrome (DSS) is the most severe forms of DHF (severity grades III and IV) The real incidence, morbidity and mortality of dengue fever and its complications are unknown No prospective study in transplant recipients from endemic areas. Cases of dengue probably underestimated in HSCT and SOT recipients. Disease probably underdiagnosed in endemic areas Most cases are mild and presenting as a flu-like syndrome The actual number may be 5 to 10 times greater than the number reported. The lack of reports of DHF or DSS may reflect the T-cell immunosuppression and the consequent low inflammatory response. (Pandey et al., Arch Virol 2015) Vectorial (mosquito bite): more than 95% of the cases Recipients were living in or have travelled to endemic areas Graft: Few cases described 2 HSCT; 1 liver Tx; 1 Renal Tx (not well documented) Blood transmission: undiagnosed and unreported? Blood-transmitted dengue documented in a SAA patient after platelet transfusion from a regular platelet donor. The other recipient of the same platelet donation did not develop dengue. Donor was asymptomatic at the time of donation, but seroconverted (both IgG/IgM) in the following month (Rigau-Prez et al. 2001; Tan et al., 2005; Saigal et al., 2007; Michael Punzel et al., 2014; Levi et al., 2015) Case 1: Fatal dengue during the epidemics in Puerto Rico DEN4 was detected in blood, ascitic fluid and tissue samples at autopsy. The donor developed fever 2 days after marrow harvesting and dengue was diagnosed by the presence of specific IgM antibodies; DEN4 was confirmed in donor samples Case 2: Donor returning from Sri Lanka 8 days before SC harvesting D-1 donor presented high fever; recipient signed informed consent D+3 dengue was confirmed in donor. Recipient started fever and developed hepatic veno- oclusive disease + Acinetobacter baumanni BSI and died on d+9. NS1 antigen positive in the recipient on d+3. (Rigau-Prez et al. 2001; Michael-Punzel) Among 9 publications of dengue cases, 6 report DHF or DSS Author (year) Transplant Age, gender Time after Tx Clinical manifestation TransmissionDeath Rigau-Perez (2001)HSCT6, ?4 daysDSSGraftYes Chacko (2004)Renal13, female18 moDSSVectorialYes Tan (2005)Renal23, female5 daysDHF, prolonged courseGraft (?)No Garcia (2006)Liver66, male3 weeksDSSVectorialYes Park (2008)Renal29, female13 yrAcute colitisVectorialNo Saigal (2007)Liver38, male6 daysGraft disfunctionGraft (LD)No Michael Punzel (2014)HSCT51, male3 days Hepatic VOD + Acinetobacter BSI GraftYes* (Machado CM. In: Transplant Infections 4 th ed, 2015, in press) 42.8% (*) Death more likely due to BSI Death probably due to DSS in 1/27 pts (3.7%) from the Brazilian renal Tx series Author (year) Transplant No. of cases Median age Median time after Tx Clinical manifestation Mortality Renaud (2007)Renal657 yr 63 mo (3 93) Mild, neutropenia, hepatitis, CMV (4) 0 Azevedo (2007)Renal2737 yr 63 mo (6 -287) Mild, fever, headache, myalgia; 1 case of DHF 1 (3.7%) Machado (2009)HSCT327 yr 15 mo (5.5 19) Mild, fever, myalgia, headache. All with chronic GVHD 0 Nasim (2013)Renal10228 yr Dengue fever 88% DSS or DHF 11% 7 (6.9%)* Costa (2015)Renal1038 yr5d 166 moDHF - 40%0 No prospective study (*) none died by dengue alone (Nasim et al., 2013) Primary / secondary infection: 44 pts (43%) / 58 pts (56.8%) Clinical presentation DF - 88% DHF/DSS % (6.8% in primary infection and 15.5% in secondary infection, p=0.22) IS may affect the course of dengue Less fever in patients on high-dose (>7.5 mg) steroids In secondary infection, patients on CSA based regimen had less severe disease, with DHF/DSS in 22% as opposed to DF in 59% (P < 0.04) In 85.7% of pts with graft dysfunction, creatinine returned to baseline in ~ 12 days 7 patients died (6.9%), 6 of whom had bacteremia with sepsis and 1 had respiratory failure. None died due to dengue infection alone (Nasim et al., 2013) Vector control and community-based programs to keep the environment free of potential breeding sources: discarded tires, uncovered water storage barrels, flower vases, etc. The mosquitoes breed in limpid water. In endemic regions, transplant patients should receive information about dengue transmission and Aedes habits to avoid exposure. Pre-transplant screening for dengue is currently not recommended, but seropositive patients have a theoretical risk of developing severe dengue in case of reinfection during outbreaks. High index of suspicious in endemic areas or during outbreaks. Clinical signs: Thrombocytopenia (>90%) and fever (>80%) are frequent, but IS drugs may alter disease morbidity Fever less frequent if steroid >7.5mg; less severe disease in CSA regimens Prolonged thrombocytopenia is expected (more than 10 days) Diagnosis: first 5 days of illness - NS1 antigen, virus isolation or PCR. After this period, serology is the method of choice (IgM, IgG) No specific antiviral drug. Hydration is the mainstay of dengue treatment. Stepwise approach: overall (history, symptoms, physical examination, mental assessment, and laboratory tests); diagnosis and assessment of dengue severity. The hydration and hemodynamic status of the patient, presence of warning signs, need of hospitalization. No evidence to recommend decreasing immunosuppression! Warning signs Abdominal pain or tenderness Persistent vomiting Clinical fluid accumulation Mucosal bleeding Lethargy Liver enlargement > 2cm Increase in HTC concurrent with rapid decrease in platelet count Alphavirus of the Togaviridae family, historically found only in the Old World, and transmitted to humans primarily by Aedes aegypti; currently also by A. albopictus CHIKV was first isolated in Tanzania in 1953 Outbreak of human febrile illness accompanied by severe arthralgia and rash Kimakonde language (Tanzania and Mozambique) The word chikungunya means that which contorts or bends up and translates in Swahili to the illness of the bended walker (Thiboutot et al., Plos One 2010) Given the wide distribution of the vector, CHIKV is now regarded as the arbovirus most likely to spread globally, including in European countries and the US The incubation time for CHIKV is short, only 26 d Acute stage of CHIKV fever: Fever, arthralgia, maculopapular rash (some cases) Intense joint and muscular pain The chronic stage of CHIKF: Polyarthralgia that can last from weeks to years Risk groups for severe CHIKV Elderly, underlying medical conditions, and children Complications Respiratory failure Cardiovascular decompensation Meningoencephalitis Severe acute hepatitis Severe cutaneous effects Other CNS problems Kidney failure During a CHIKV outbreak in La Reunion (2005) Serum specimen from a corneal donor tested positive for both anti-CHIKV IgM and PCR Corneoscleral rim from the donor CHIKV positive by PCR 69 corneal donors Serology: 58 IgG/IgM negative (84%); 11 IgG and/or IgM positive (16%) qRT-PCR: 3 tested positive (4.3%) Eye tissue (N=12) 4 tested positive by PCR (33.3%) All positive were infective in animal model (Courdec et al., 2012) Potential risk = blood transmission during outbreaks High attack rate, high viremic levels, and great no. of asymptomatic infections CHIKV genome was identified in 1 of 250 donated platelet units screened by PCR during the 2006 epidemic in Reunion Island. Probabilistic model for transfusion risk: Among 26,722 donations, 11 (95% CI, 4-17) to 15 (95% CI, 7-22) donations were predicted to associate with transfusion risk Recommendation: test eye tissue obtained for grafting. In the absence of systematic screening of donors for CHIKV, cornea donation should be banned in areas where CHIKV circulates (Appassakij et al., 2014; Courdec et al., 2012)