Intra-erythrocytic, Ring Formed Parasites: A Diagnosis of Malaria or Babesiosis?

CASE

A 19 year-old female with no significant past medical history presented with subjective fevers, generalized upper abdominal discomfort, and headache for the past month.  She described her subjective fevers as intermittent, but had never taken her temperature with a thermometer.  The patient also noted that she recently moved to the area from Guinea Bissau.   

On exam, the patient was afebrile with normal vital signs.  The neurological exam was unremarkable and there was no meningismus.   On abdominal exam, there was no tenderness to palpation with a negative Murphy’s sign.  Laboratory workup was performed, revealing intra-erythrocytic, small ring-shaped bodies.  

DIAGNOSIS 

Plasmodium falciparum infection

DISCUSSION

Background

The case of a patient in Rhode Island who recently traveled from Guinea Bissau with non-specific infectious symptoms and ring formed parasites noted on blood smear presents a diagnostic dilemma, as both malaria and babesiosis share these features.  Here we’ll review these two diseases, comparing and contrasting their clinical presentation, diagnosis, and treatment.

Malaria, a disease caused by infection with Plasmodium spp. and spread by the bite of an infected Anopheles mosquito, is found in 95 countries and affecting over 3 billion people annually (Fig 1A).  There are four species of Plasmodium predominantly responsible for human infection, P. falciparum, P. malariae, P. vivax, and P. ovale. Unique to P. vivax, and P. ovale is a dormant phase where relapsing illness can occur months later by activation of residual hypnozoites in the liver.  Typically, the incubation period of P. falciparum is 12 to 14 days (range 7 to 30 days).[1]  Febrile paroxysms occurring at regular intervals (fevers occurring every other day for P. vivax, P. ovale, and P. falciparum, and every third day for P. malariae) is the hallmark symptom of malaria, but is often not present early in disease.  Other symptoms include arthralgias, myalgias, headache, cough, anorexia, nausea, vomiting, abdominal pain, and diarrhea.  Severe disease can result in altered consciousness with or without seizures, acute respiratory distress syndrome (ARDS), shock, metabolic acidosis, renal failure, hepatic failure, coagulopathy with or without disseminated intravascular coagulation (DIC), severe anemia or massive intravascular hemolysis, and hypoglycemia.

Babesiosis is caused by infection with Babesia spp., most commonly Babesia microti in the United States and Babesia divergens in Europe, and is transmitted primarily by tick vectors (Fig 1B).  Over 94% of cases in the US occur in seven states in the Northeast and upper Midwest: Connecticut, Massachusetts, New Jersey, New York, Rhode Island, Minnesota, and Wisconsin (Fig 2).[2]  More rare forms of transmission include blood transfusion, organ transplantation, and congenital infection.  In Rhode Island between 1999 and 2007, the risk for transfusion-transmitted babesiosis was approximately 1 case per 15,000 RBC units transfused.[3]  Subsequently, in 2019, the Food and Drug Administration (FDA) mandated screening of blood donors nationally, and testing of all blood donations in 15 identified high-risk states.[4]  The incubation period of B. microti infection is typically is 1 to 4 weeks.[5]  Symptoms of babesiosis include gradual onset of fatigue and malaise accompanied by fever, but can also include myalgia, anorexia, headache, nausea, and dry cough.  Severe infection, most frequently occurring in elderly, immunocompromised, or asplenic patients, is predicted by nausea or vomiting and diarrhea.  Other complications of babesiosis include most commonly ARDS, as well as severe anemia, congestive heart failure, renal failure, DIC, shock, and coma.

Figure 1. Maps of (A) areas where malaria transmission occurs globally,[6] and (B) areas where babesiosis (dark color) and its tick vectors (light colors) are endemic, with circles depicting locally-acquired isolated cases.[5]

Figure 2. Map of cases of babesiosis reported in the United States in 2018.[7]

Diagnostic Criteria

Both malaria and babesiosis can be diagnosed by examination of a thin blood smear under microscopy, revealing intra-erythrocytic ring formed parasites (Fig 3A and 3B).  Often, a thorough history including travel, tick exposure, or blood transfusion can differentiate between a diagnosis of babesiosis and malaria. However, if a patient has risk factors for both babesiosis and malaria, some features, if present on thin blood smear, can help differentiate between B. microti and Plasmodium spp. infection.  Babesiosis may be distinguished from malaria by the presence of merozoites arranged in tetrads known as a "Maltese Cross,” an uncommon but pathognomonic finding (Fig 3C), absence of hemozoin deposit (which appear as brownish pigmentation) in ring forms, and absence of gametocytes.  When examining a blood smear, the percent parasitemia (expressed as percentage of erythrocytes that are parasitized) can be determined, with severe infection typically associated with parasitemia ≥4% for B. microti and ≥5% for Plasmodium spp..  

Figure 3. Thin blood smear showing the intra-erythrocytic ring formed parasites in (A) Plasmodium falciparum infection (malaria) and (B) Babesia microti infection (babesiosis), as well (C) B. microti in the rare but pathognomonic tetrad configuration known as a "Maltese Cross.”[8-10]

Definitive diagnosis of both babesiosis and malaria can be accomplished by polymerase chain reaction (PCR) amplification of parasite DNA.   Serology is another diagnostic tool that can be used to differentiate between babesiosis and malaria, though limitations of this method include symptoms proceeding the rise in antibody titer, yielding a negative result early in infection, and antibodies which persist beyond resolution of infection, making it difficult to distinguish current from past infection.  Malaria can also be confirmed by rapid diagnostic tests, which detect malaria parasite antigens and are an important diagnostic tool in resource-limited endemic settings due to their accuracy and ease of use, as they require no electricity or laboratory infrastructure and yield results within 15 minutes.  Of note, these tests provide a qualitative result but cannot provide quantitative information such as parasite density.

Treatment

Treatment for babesiosis is typically oral azithromycin and atovaquone.  In severe disease intravenous azithromycin is substituted.  Alternatively, the Infectious Diseases Society of America guidelines favor intravenous clindamycin plus oral quinine.

Chloroquine can be used to treat patients with chloroquine-sensitive P. falciparum (typically infections in Central America west of Panama Canal, Haiti, the Dominican Republic, and most of the Middle East).  For treatment of uncomplicated P. falciparum malaria in areas with chloroquine resistance, artemisinin combination therapy (ACT, in which artesunate is combined with a second antimalarial agent such as lumefantrine, amodiaquine, or mefloquine) is widely used, or atovaquone-proguanil if not cost-prohibitive.  For severe malaria, intravenous artesunate or intravenous quinine is administered for at least 24 hours and until parasitemia ≤1 percent, at which point the patient is transitioned to oral therapy.

CASE RESOLUTION

As the patient had only recently moved to Rhode Island one week prior and her symptoms had been ongoing for one month, the patient was presumed to have malaria and was treated with atovaquone/proguanil 1000/400 mg once daily for 3 days, with improvement in her symptoms.  Later, PCR speciation revealed infection with Plasmodium falciparum.

TAKE-AWAYS

• Both malaria, an infection with Plasmodium spp widely endemic to tropical and subtropical countries, and babesiosis, an infection with B. microti found predominantly in the Northeast and upper Midwest USA, result in non-specific infectious symptoms and appear as intracellular ring forms on thin blood smear.

• Often the presence of ring formed parasites on thin blood smear, in conjunction with a thorough history (including travel, tick exposure, and blood transfusions) can yield the correct diagnosis.  In cases of diagnostic uncertainty, PCR assays detecting parasite DNA can definitively differentiate between malaria and babesiosis.

• Treatment of malaria and babesiosis differs, emphasizing the importance of arriving at the correct diagnosis.  Treatment of babesiosis typically consists of azithromycin and atovaquone, whereas treatment of malaria is with chloroquine if no suspicion of chloroquine-resistance, otherwise artemisinin combination therapy is widely used or atovaquone-proguanil if not cost-prohibitive. 

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Author: Meagan Barry, MD, PhD is a fourth-year Emergency Medicine resident at Brown University.

Faculty Reviewer: Alison Hayward, MD, MPH is an assistant professor of Emergency Medicine at Brown University. Email: Alison.hayward@brownphysicians.org

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REFERENCES

1. World Health Organization [Internet]. International travel and health: Malaria. [accessed 2020 Aug 10]. Available from: http://www.who.int/ith/diseases/malaria/en/

2. Centers for Disease Control and Prevention (CDC). Babesiosis surveillance - 18 States, 2011. MMWR Morb Mortal Wkly Rep. 2012;61(27):505-509.

3. Asad S, Sweeney J, Mermel LA. Transfusion-transmitted babesiosis in Rhode Island. Transfusion. 2009;49(12):2564-2573.

4. U.S. Department of Health and Human Services Food and Drug Administration [Internet]. Recommendations for reducing the risk of transfusion-transmitted babesiosis: Guidance for industry. [accessed 2020 Aug 10]. Available from: https://www.fda.gov/media/114847/download

5. Vannier E, Krause PJ. Human babesiosis. N Engl J Med. 2012; 366: 2397-2407.

6. Centers for Disease Control and Prevention (CDC) [Internet]. Where Malaria Occurs. [accessed 2020 Aug 15]. Available from: https://www.cdc.gov/malaria/about/distribution.html

7. Centers for Disease Control and Prevention (CDC) [Internet]. Atlanta, Georgia: U.S. Department of Health and Human Services. Surveillance for babesiosis — United States, 2018 Annual Summary. 2020 [accessed 2020 Aug 15]. Available from: https://www.cdc.gov/parasites/babesiosis/resources/babesiosis_surveillance_summary_2018.pdf

8. Centers for Disease Control and Prevention (CDC) [Internet]. Dr. Mae Melvin. Public Health Image Library (PHIL): 22811. 1971 [accessed 2020 Aug 15]. Available from: https://phil.cdc.gov/Details.aspx?pid=22811

9. Centers for Disease Control and Prevention (CDC) [Internet]. Dr. George Healy. Public Health Image Library (PHIL): 18983. 1970 [accessed 2020 Aug 15]. Available from: https://phil.cdc.gov/Details.aspx?pid=18983

10. Centers for Disease Control and Prevention (CDC) [Internet]. Steven Glenn, Laboratory & Consultation Division. Public Health Image Library (PHIL): 5944. 1979 [accessed 2020 Aug 15]. Available from: https://phil.cdc.gov/Details.aspx?pid=5944