Malaria Update 2015

Mark Polhemus Director, Center for Global Health and

Translational Science

97 countries with ongoing transmission 3.2 billion people at risk 584,000 deaths in 2013

• 77 studies with 46,000 cases of severe vivax malaria • Mostly SW Asia • 353 Deaths • Only 17/77 studies from before 2000

Fever in Returning Traveler

• 30-year-old Canadian citizen who emigrated from India in 2007 returned from a five-week trip to New Delhi and Mumbai

• He did not take antimalarial chemoprophylaxis • Twelve days after returning to Canada, he presented to his

general practitioner with fever and chills • prescribed clarithromycin 500 mg orally twice daily for five days

• Presented to the emergency department with complaints of ongoing fever, increasing weakness, dizziness, nausea and diarrhea

• DDx?

Jan 2015

Fever in Returning Traveler

• BP 77/46 mm Hg, HR 140 beats/min, and RR 40 breaths/min • platelets 15,000/μL, creatinine 3.6 mg/dL), bilirubin 5.3

mg/dL, and lactate 50 mg/dL • Despite 2 liters of saline and 2 units of platelets he remained

hypotensive and norepinephrine was initiated • The patient was prescribed ceftriaxone as empiric coverage of

enteric fever (e.g. Salmonella typhi) • P. falciparum?

Jan 2015

Fever in Returning Traveler

• Thick and thin blood films showed malaria parasites

• Parasitemia was quantified at 1.3%

• Rapid diagnostic P. falciparum assay was negative, but positive for non-P. falciparum malaria

• Artesunate and Malarone were prescribed • Severe Malaria with P. vivax at <2% parasitemia?

Jan 2015

Fever in Returning Traveler

• The following day, molecular testing confirmed Plasmodium vivax and atovaquone/proguanil was changed to chloroquine

• Severe Malaria with P. vivax at <2% parasitemia!

Jan 2015

Fever in Returning Traveler

• 39-year-old Spanish man presented to a hospital in Madrid with 15 day history of daily and evening fever spikes, temperatures to 40° C, arthralgia, myalgia, low back pain, chills and malaise.

• Recently returned from a six-month holiday in Southeast Asia • Stayed in rural areas and had “contact with simians” but

denies mosquito bites • Friends had dengue and malaria so started prophylaxis on trip • Reported taking 80% of his Malarone prophylaxis • Enlarged liver and spleen on exam • DDX?

Malaria Journal 2010

Fever in Returning Traveler

• Hemoglobin 12.7 g/dl • Moderate leukopenia (3.82 × 103 /mm3) • Significant thrombocytopenia (86 × 103 /mm3) • Elevated ALT and AST (twice normal) • Serology and PCR for dengue, Q fever, rickettsiosis negative • Smear negative • Nested PCR (from reference lab) for four plasmodium species

negative • DDx?

Fever in Returning Traveler

• Real time PCR from authors lab found P. knowlesi • Re-look with Binax Now Malaria Test (Binax, Inc., USA),

negative for both P. falciparum HRP-2 and for pan-malarial aldolase antigen, suggesting NOT malaria

• Retrospective examination of Giemsa-stained thin blood films showed infected erythrocytes with an inconclusive morphologic appearance.

• 250 parasites/μl blood (about 0.003% parasitemia)

Malaria Journal 2010

20 parasites/μl (.0004%) required for positive thick film 100,000 parasites/μl= 2% parasitemia

CID 2011:52

Comparison of Severity and Duration

P. vivax P. ovale P. malariae P. falciparum P. knowlesi

Initial Paroxysm Severity

Moderate to Severe Mild Mild to

Moderate Severe Moderate to Severe

Avg Parasitemia/ul 20,000 9,000 6,000 50,000-

500,000 100- 100,000

Maximum Parasitemia/ul 50,000 30,000 20,000 2,500,000 750,000

Symptom Duration (untreated)

3-8+ weeks 2-3 weeks 3-24 weeks 2-3 weeks ???

Maximum Infection Duration (untreated)

5-8 years 12-20 months 20-50+ years 6-17 months <1 year

Complications Mod Anemia Renal Profound anemia, cerebral

Profound platelet decrease

P. knowlesi

• First isolated in 1931 from a long-tailed macaque (Macaca fascicularis)

• Early experiments were by Knowles and Das Gupta • They demonstrated P. knowlesi was infectious to humans by

blood passage and that it has a short erythrocytic cycle leading to fever spikes every 24 hours

• Short erythrocytic cycle prompted the use of P. knowlesi as a pyretic agent for the treatment of patients with neurosyphillis until the mid 1950s

Med J Malaysia 2010

P. knowlesi

• First study to recognize P. knowlesi as a causative organism of human malaria in Sarawak, Malaysia

• Cases that were identified by microscopy as P. malariae had negative PCR results

• When new primers were applied, 58% of the cases originally PCR negative for P. malariae were positive for P. knowlesi

• Look back of archived smears in Sarawak showed P. knowlesi in humans back to 1994

• Subsequently, human knowlesi malaria cases have been reported in other parts of East and West Malaysia, Thailand, Myanmar, Singapore, the Philippines, Vietnam and Indonesia

Med J Malaysia 2010

Singh B, Kim Sung L, Matusop A, et al. A large focus of naturally acquired Plasmodium knowlesi infections in human beings. Lancet 2004;363:1017-24

Plasmodium knowlesi infections reported in humans and macaques and limits of natural distribution of mosquito vectors and of macaques.

Balbir Singh, and Cyrus Daneshvar Clin. Microbiol. Rev. 2013;26:165-184

Complications and outcomes (A) and the number of complications and outcomes (B) for 86 cases of severe knowlesi malaria.

Balbir Singh, and Cyrus Daneshvar Clin. Microbiol. Rev. 2013;26:165-184

P. knowlesi Presentation

• Thrombocytopenia very common and can be <50,000/ul • No cerebral malaria (in this series) • No severe anemia (yet) • ARDS, hypotension, acute renal failure, hepatic dysfunction,

hypoglycemia and metabolic acidosis all occur • Parasitemia is a strong predictor of complications • Application of the WHO criteria for severe falciparum malaria

seems to work for knowlesi

Med J Malaysia 2010

Severe Malaria

Severe malaria occurs when infections are complicated by serious organ failures or abnormalities in the patient's blood or metabolism. The manifestations of severe malaria include: • Cerebral malaria, with abnormal

behavior, impairment of consciousness, seizures, coma, or other neurologic abnormalities

• Severe anemia due to hemolysis • Hemoglobinuria due to hemolysis • Abnormalities in blood coagulation

• ARDS, which may occur even after the parasite counts have decreased in response to treatment

• Low blood pressure caused by cardiovascular collapse

• Acute kidney failure • Hyperparasitemia, more than 5%

of RBCs are infected • Metabolic acidosis, often in

association with hypoglycemia • Hypoglycemia - may also occur in

pregnant women with uncomplicated malaria, or after treatment with quinine

CDC 2014

Askling et al. Malaria Journal 2012

Lactic Acidosis and Disease Severity

WHO 2014: Acidosis was the major independent risk factor for death and was also strongly associated with hypoglycaemia

Three negative tests required to rule out malaria

Malaria RDTs

Binax NOW is the only brand of malaria RDT approved for use in the United States.

Malaria RDTs • The use of the RDT does not eliminate the need for malaria

microscopy. The RDT may not be able to detect some infections with lower numbers of malaria parasites circulating in the patient’s bloodstream. Also, there is insufficient data available to determine the ability of this test to detect the 2 less common species of malaria, P. ovale and P. malariae. Therefore all negative RDTs must be followed by microscopy to confirm the result.

• In addition, all positive RDTs also should be followed by microscopy. The currently approved RDT detects 2 different malaria antigens; one is specific for P. falciparum and the other is found in all 4 human species of malaria. Thus, microscopy is needed to determine the species of malaria that was detected by the RDT. In addition, microscopy is needed to quantify the proportion of red blood cells that are infected, which is an important prognostic indicator.

CDC

P. knowlesi Diagnosis

• Blood smear is difficult for P. knowlesi • Early trophozoite stages of are morphologically identical to

those of P. falciparum • Later blood stages are similar to those of P. malariae • Be suspicious if:

• P. malariae diagnosis by microscopy • recent travel to SE Asia with any falciparum on microscopy

Med J Malaysia 2010

Upstate

• Skilled microbiologists

• Malaria smear begins an interaction with lab

• Initial malaria smear results within 90 min

• Definitive speciation and parasitemia during daylight hours

• BinaxNow is not available

Treat early and expect the worst

Treatment

Treatment

Treatment

CDC Guidelines P. knowlesi

• There has been no widespread evidence of chloroquine resistance in P. knowlesi species; therefore, chloroquine (or hydroxychloroquine) may still be used.

• In addition, any of the regimens listed for the treatment of chloroquine-resistant malaria may be used for the treatment of P. knowlesi infections • Malarone • Coartem • Quinine sulfate plus doxy • Quinidine • Artesunate

Upstate Treatment Options

• Coartem, malarone and doxycycline available

• Quinidine available

• Artesunate through CDC

Artesunate

• High quality-intravenous artesunate is available only to malaria patients hospitalized in the United States who need intravenous treatment because of: • severe malaria disease • high levels of malaria parasites in the blood • inability to take oral medications • lack of timely access to intravenous quinidine • quinidine intolerance or contraindications • quinidine failure

• The drug will be provided to the hospitals, upon request and on an emergency basis, by the CDC Drug Service or by one of the CDC Quarantine Stations located around the country.

• To enroll a patient with severe malaria in this treatment protocol, contact the CDC Malaria Hotline: 770-488-7788 (M-F, 8am-4:30pm, eastern time) or after hours, call 770-488-7100 and request to speak with a CDC Malaria Branch clinician.

CDC Guidelines

The Herald of Randolph

• Chambers v. Dartmouth-Hitchcock Alliance, the family of Roxanne Munger are seeking damages from the Alliance, Gifford Medical Center, and Susan S. Wiedenkeller, physician's assistant at the Gifford emergency room, in connection with Munger's death Nov. 11, 2000 of malaria, which she had contracted while studying in Ghana. She died in a dorm room at Goddard College in Plainfield.

• The lawsuit claims that Munger was examined by PA in the emergency room Nov. 7, 2000 and was treated for a urinary tract infection. Plaintiffs say that because Munger had recently returned from Ghana, malaria should have been suspected.

• The defendants responded that such a possibility was discussed but the patient thought it unlikely, and that she disregarded instructions to call in if she did not show quick improvement.

Chicago Tribune

Malaria amputee sues Northwestern February 04, 2010|By John Keilman • Dawn Dubsky, the Chicago woman whose battle against malaria

was the subject of a Tribune series last year, is suing the hospital where she first received treatment, contending that medical malpractice allowed her condition to deteriorate so thoroughly that her arms and legs had to be amputated.

• Dubsky, 34, traveled to Ghana in February 2008. Upon her return to Chicago, increasingly severe headaches and fatigue prompted her to visit the emergency room at Northwestern Memorial Hospital.

• "They treated her as if she had simple, non-complicated malaria, and the evidence was to the contrary," said attorney Jeanine Stevens.

• Six days after arriving at Northwestern Memorial, she was transferred to the University of Chicago Medical Center, where a surgeon amputated her arms and legs.

Fever in a Traveler

• 34-year-old Nigerian woman who was on vacation in the United States. No significant past medical history.

• Two days after she arrived in the United States, she presented to an emergency department with complaints of a sore throat, dry cough, severe headache, generalized weakness, and fever.

• The fever was without chills, continuous, fluctuated from 37.7°C to 38°C (100°F to 100.5°F), and responded to Tylenol.

• Her rapid influenza antigen test was negative and she was treated symptomatically for a presumptive influenza-like illness.

• The patient felt better over the next 4 h and was therefore discharged from the ED with advice to follow-up with a physician. She continued with her travel.

Fever in a Traveler

• The following day (after 24 h in the US), she presented to our ED with 4 h of worsening headache, photophobia, and severe letharg, dry cough associated with right-sided pleuritic CP and severe generalized myalgia.

• Temp was 38.3°C (101°F), pulse101 beats/min, BP 130/80 mm Hg, and she was tachypenic at 22 breaths/min, with an oxygen sat of 99% on room air.

• Patient preferred the room in darkness. Neurological exam revealed minimal neck stiffness with negative Kernig and Brudzinski. Abdominal examination was benign with no organomegaly. Chest exam was normal.

• Routine labs revealed WBC count of 6.8 × 109/L with 79% neutrophils, hemoglobin of 13.1 g/dL, platelets of 87 × 109/L, and aminotransferase level of 87 U/L. The remaining laboratory parameters were normal.

• CT of the head and CXR were normal. CSF analysis was normal. Legionella (urine) antigen, rapid HIV, and influenza antigen test were all negative.

• In the ED, the patient was treated empirically for atypical pneumonia with ceftriaxone and azithromycin .

• In view of the severe headache, photophobia, and recent travel, a stat peripheral blood smear was also ordered.

Fever in a Traveler

• Patient was admitted • Within 4 h, the lab reported that ring forms of P. falciparum

were noted on the blood smear. Parasitemia was 1%. • As the patient came from a chloroquine-resistant endemic

area, she was treated with quinine and doxycycline. • The patient was afebrile within 24 h and the headache,

photophobia, and lethargy resolved within 48 h. The parasitemia cleared on the third day.

Journal of Emergency Medicine 2011

Letter to the Editor …the best way to avoid misdiagnoses or delayed diagnoses is to consider every returning traveler with fever (especially those who visited sub-Saharan Africa) as infected by malaria unless proven otherwise. In fact, no symptoms or signs can accurately predict malaria. In other words, the clinical suspicion should be raised not by presenting symptoms but, rather, based on the underlying epidemiology. Every patient presenting with fever to the Emergency Department (ED) should be asked: “Unde venis?” (e.g., “Where do you come from?”).

Summary

• Malaria is changing • Think malaria in traveler/returning traveler

• Regardless of symptoms • Sick/not sick is all that matters

• Regardless of parasitemia • Parasitemia >2% in returning traveler = sick

• Even if not sick • Acidosis is a major independent risk factor for death • Diagnosis is microscopy

• Let the lab help • Three negative smears required to rule out malaria • Treatment options are simple via CDC

• But based on sick/not sick • You can never go wrong by being overcautious with malaria