laboratory tests

2009-03-09T10:13:00.000-07:00

B - erythrocytic cycle - immature trophozoite ( ring form )

Ring-form trophozoites of P. vivax usually have a thick cytoplasm with a single, large chromatin dot. Rings may be difficult to distinguish from those of P. ovale. The cytoplasm becomes amoeboid and Schüffner's dots may appear as the trophozoites mature. Infected RBCs are often larger than uninfected RBCs. Multiply-infected RBCs are not uncommon.

B - erythrocytic cycle - mature trophozoite ( no ring form anymore but slowly become amaboid form)

2009-03-09T09:22:00.000-07:00

A 40 year old man, resident of the United States, presents to an emergency room with a 5-day history of fever, chills, nausea, vomiting, and myalgias. He returned 2 weeks ago from a 16-day visit to Zambia.

Question 1: What chemoprophylaxis regimen (if any) should be recommended for travel to Zambia? (more than one might apply)
Chloroquine
Chloroquine-proguanil
Sulfadoxine-pyrimethamine
Mefloquine
Doxycycline
Atovaquone-proguanil (Malarone®)

For this travel to Zambia, the patient had been prescribed chloroquine. However, he took only a few doses during his visit. On the return flight home, the patient had fever, nausea, and myalgias. Upon arrival to the United States, the symptoms dissipated and the patient did not seek medical care. Nine days later, he had again fever, chills, nausea, vomiting, and myalgias. He went to an outpatient clinic where he was diagnosed with viral syndrome and sent home.

Question 2: Based on the observed time intervals, could the symptoms experienced by the patient be due to malaria?
Malaria could not have caused the symptoms experienced during the return flight, nor could it have caused the symptoms that started after return to the U.S.
Malaria could have caused the symptoms experienced during the return flight, but not the symptoms that started after return to the U.S.
Malaria could not have caused the symptoms experienced during the return flight, but could have caused the symptoms that started after return to the U.S.
Malaria could have caused both the symptoms experienced during the return flight and the symptoms that started after return to the U.S.

Some days later, the patient was seen at another clinic, where on a routine CBC malaria parasites were seen. He was then referred to a hospital, where he presents to the emergency room, at 4 am, with continuing fever, nausea, vomiting, and myalgias. On physical examination, the patient is febrile (102°F), tachycardic. jaundiced and pale. He is well oriented but slow in answering questions. A thin blood smear obtained while in the emergency room is read as Plasmodium, species not determined. Other laboratory findings include: hematocrit 33% , creatinine 3.6 mg/dL, and total bilirubin 11.0 mg/dL. The urine is dark, with a measured output of 40 mL/6 hours.

Question 3: Which one of the following would be the best next step in the clinical management of this case?
Send the patient home with a prescription for mefloquine
Keep the patient under observation in the emergency room until the Plasmodium species is determined; in the meantime, initiate treatment with chloroquine
Admit the patient and treat with oral quinine and oral doxycycline
Admit the patient and treat with IV quinidine plus doxycycline

The patient is admitted to the medical intensive care unit and treated with oral quinine and doxycycline. Later that day, the blood smear is reviewed by more experienced personnel for speciation.

Question 4: What is the diagnosis?
Plasmodium falciparum
Plasmodium vivax
Plasmodium ovale
Plasmodium malariae
Not malaria

The smears are diagnosed as P. falciparum, and a parasite quantification shows that 17% of the erythrocytes are infected. The patient's mental status deteriorates and his urine output decreases.

Question 5: Which of the following measures would be appropriate?
Continue existing treatment (oral quinine and doxycycline)
Switch treatment to intravenous quinidine and doxycycline
Switch treatment to intravenous clindamycin
Consider exchange transfusion
Administer corticosteroids intravenously

Treatment with oral antimalarials is continued and an exchange transfusion is ordered. While preparing for the exchange transfusion, the patient becomes hypotensive, requiring a dopamine drip. During the exchange transfusion, the patient becomes increasingly tachypneic and develops atrial flutter, which exacerbates the hypotension. DC cardioversion is attempted without success. The patient develops asystole and expires 17 hours after admission to the medical intensive care unit.

An autopsy was performed, but after a delay of 8 days. The gross findings show a slight swelling of the cerebral gyri, with consequent narrowing of the sulci; some blood vessels are engorged, with scattered petechial hemorrhage. The hematoxylin-eosin section of the brain shows autolysis, some pycnotic nuclei, and scattered pigment felt to be malarial in origin. The pigment and pinpoint hemorrhages are felt to be pre-mortem.

Main points:
Visitors to malaria endemic areas should take appropriate prophylaxis.
Malaria should always be suspected in a febrile patient who has recently traveled in a malaria endemic area.

Blood smears for malaria should be examined by experienced staff, without delay.
When there is suspicion of severe malaria, the patient should be hospitalized and parenteral treatment should be initiated urgently.

Exchange transfusion should be considered when parasite density is high (>10%) or when signs of cerebral or renal complications develop (another indication, not present in this case, is non-overload pulmonary edema).

2009-03-09T09:11:00.000-07:00

A company plans to send a large number of employees to work in Afghanistan, for variable periods of time. Their employees’ health service inquires about potential need for malaria prevention.
Question 1: Will there be a malaria risk in Afghanistan? And if yes, where and when?
No risk
Risk in all areas, year-round
Risk in areas below 2,000 m (6,561 ft), year-round
Risk in all areas, between April and December
Risk in areas below 2,000 m (6,561 ft), between April and December

Question 2: For a 34-year-old male employee, with no known medical problems, which of the following drugs would constitute appropriate chemoprophylaxis? (More than one answer might be correct.)
Chloroquine
Amodiaquine
Sulfadoxine-pyrimethamine
Mefloquine
Doxycycline
Atovaquone-proguanil (Malarone®)

Question 3: Which one of these drugs would be appropriate for a 30-year-old woman, at her 20th week of pregnancy, traveling to Afghanistan?
Chloroquine
Amodiaquine
Sulfadoxine-pyrimethamine
Mefloquine
Doxycycline
Atovaquone-proguanil (Malarone®)

Question 4: Which of these drugs would be appropriate for a 64-year-old man traveling to Afghanistan, who has a history of cardiac conduction abnormalities, but no other medical problems? (More than one answer might be correct.)
Chloroquine
Amodiaquine
Sulfadoxine-pyrimethamine
Mefloquine
Doxycycline
Atovaquone-proguanil (Malarone®)

Main points:
Recommendations about chemoprophylaxis should take into account:
transmission patterns (areas of risk, time of year)
Plasmodium species being transmitted
patterns of drug resistance
travelers' personal and medical characteristics
duration and intensity of exposure

Question 1: Correct Answer
Risk in areas below 2,000 m (6,561 ft), between April and December
There is malaria risk in Afghanistan. Recent estimates by the World Health Organization are that 2-3 millions clinical cases occur annually, of which 10-20% are due to Plasmodium falciparum (the balance being due to P. vivax). Chloroquine-resistant P. falciparum has been reported, and transmission does occur in urban areas. Transmission however does not occur during the cooler seasons or at higher altitudes: low temperatures prevent the parasites from completing their extrinsic incubation in the mosquitoes

Question 2: Correct Answer
Mefloquine
Doxycycline
Atovaquone-proguanil (Malarone®)

Question 3: Correct Answer
Mefloquine
Mefloquine would be the only drug recommended for a pregnant woman traveling to Afghanistan. Current information suggests that its use at prophylactic doses during the second and third trimesters of pregnancy is not associated with adverse fetal or pregnancy outcomes. More limited data suggest it is also safe to use during the first trimester.
Doxycycline would be contraindicated because of potential adverse effects on the fetus (discoloration and dysplasia of the teeth and inhibition of bone growth). Because of insufficient information on the use of atovaquone-proguanil, this drug is not currently recommended for prevention of malaria in pregnant women. However, if at all possible, women who are pregnant or likely to become pregnant should be advised to avoid travel in areas with malaria risk, because: a) malaria in pregnant women can be more severe than in non-pregnant women; b) malaria can increase the risk of adverse pregnancy outcomes, including prematurity, abortion and stillbirth; and c) no chemoprophylactic regimen offers complete protection.

Question 4: Correct Answer
Doxycycline
Atovaquone-proguanil (Malarone®)

2009-03-09T08:42:00.000-07:00

A 65 year old Caucasian woman has lived for 30 years in Nigeria. She has taken chemoprophylaxis with primaquine, on a weekly basis. Whenever suspecting a malaria attack, she has treated herself with chloroquine or artesunate.
Question 1: Among the chemoprophylaxis regimens below, which THREE would be most suitable for Nigeria?
Primaquine
Chloroquine
Chloroquine and proguanil
Mefloquine
Doxycycline
Atovaquone-proguanil (Malarone®)

Question 2: If someone develops a suspected malaria attack while in Nigeria, but cannot get laboratory confirmation within the next 24 hours, which ONE of the options below would be the best for presumptive treatment? (Assume that the person was not taking any chemoprophylaxis.)
Artesunate
Quinine plus doxycycline
Halofantrine
Mefloquine
Chloroquine
Atovaquone-proguanil (Malarone®)

This woman has recently arrived in the United States. Six days after her arrival, she falls and fractures her right wrist. The fracture is treated with a splint and analgesics. Four days later she wakes up at 3 am with nausea, retching and vomiting. She is taken by her daughter to a hospital where she is found to be febrile to 103.4°F. This, combined with the history of stay in Nigeria, prompts a blood smear that shows Plasmodium falciparum with an estimated parasitemia of 3%. Admission is advised but declined, and the patient goes home under the care of her daughter (a physician), with prescriptions for oral quinine and doxycycline. She starts taking the drugs but vomits again. The following day her daughter finds her to be lethargic, hardly able to lift a cup or to answer questions. The patient is brought to another hospital. There, she is found to be febrile, obtunded and unresponsive to painful stimuli. Laboratory findings include: leucocytes 6,300/µL, platelets 40,000/µL, Hb 11 g/dL, creatinine 0.5 mg/dL, glucose 116 mg/dL. Seven hours later, she passes dark urine, which is +++ for blood, +++ for protein, with 10-20 RBCs. Other laboratory findings at that time include: hemoglobin 8.6 g/dL; reticulocytes 2.4%; total bilirubin 6.2 mg/dL; LDH 444 U/L; AST 39 U/L; ALT 16 U/L; alkaline phosphatase 61 U/L.
A blood smear shows the following:

Blood smear of patient, Clinical Case No 3
Question 3: What is the most likely diagnosis?
Babesiosis
Plasmodium vivax malaria
Plasmodium ovale malaria
Uncomplicated Plasmodium falciparum malaria
Severe Plasmodium falciparum malaria

Question 4: Which of the following would be suitable for treatment? (more than one might apply) Quinine or quinidine intravenous drip
Quinine orally
Doxycycline
Exchange transfusion
Primaquine
Corticosteroids

An intravenous drip of quinidine is started. During the perfusion a prolongation of the QT interval is noted (QT/QTC 444/534 ms), which resolves upon readjustment of the quinidine drip. Shortly after the start of the IV drip the patient's neurologic status improves. Thus, while preparations had been made for an exchange transfusion, this is not carried out. Two units of whole blood are transfused. The parasitemia decreases to 2% the day after admission. On day 2 post admission, the parasites have cleared. On day 4 post-admission the patient has completely recovered.

Main points:
Malaria should be considered in any patient who develops fever following travel to a malaria-endemic area.

Plasmodium falciparum malaria especially in older patients is a potentially serious disease and should be treated as a medical emergency.

When complications develop (such as cerebral malaria and hemolysis) an aggressive treatment with intravenous quinine/quinidine and doxycycline can be life saving. If doxycycline cannot be used, clindamycin could be an alternative.

Question 2: Correct Answer
Atovaquone-proguanil (Malarone®)
Atovaquone-proguanil would be the drug of choice because of its demonstrated efficacy, low frequency of side effects, and relative ease of administration (single daily dose for 3 days). Mefloquine would also be effective but has a greater risk of side effects at therapeutic doses. Quinine plus doxycycline would also be effective, but requires a more complex regimen of administration over seven days, and quinine can produce side effects (tinnitus). Artesunate would be effective, but requires a complex regimen of administration over 5 - 7 days, and is not yet approved by the US Food and Drug Administration. Halofantrine is not recommended because of its association with cardiotoxicity.
(If the person has been taking prophylaxis when the suspected malaria attack occurs, the drug used for presumptive treatment should not be the same as the drug used for prophylaxis!)

Question 3: Correct Answer
Severe Plasmodium falciparum malaria
There are many ring stage parasites. The estimated parasitemia is 3%. Typical characteristics of Plasmodium falciparum are seen on the smear: there is a multiply infected red cell, and several parasites are pressed against the red cell wall (appliqué forms). Because this patient has developed neurologic symptoms and hemoglobinuria, her malaria would be classified as severe.

Correct Answer ( more than one answer )
Quinine or quinidine intravenous drip

Quinine orally

Doxycycline

Exchange transfusion

case study 2

2009-03-09T08:28:00.000-07:00

(contributed by Prof. Jacques Le Bras, Hôpital Bichat - Claude Bernard, Paris, France)

A 30 year-old woman, HIV-positive, delivers by planned cesarean section an apparently normal female baby, weight 3.2 kg (7 lbs). At delivery AZT is administered IV for 7 hours. The mother is a native of the Democratic Republic of Congo (DRC) who came to France 2 years ago and has not traveled outside France since then. The only abnormality found in the baby at delivery is an anemia (12.3 g/dL hemoglobin) attributed to antiretroviral drugs toxicity (ARV given to mother?)

At 6 weeks post-delivery, the infant is brought in for a fever of one-day duration. She is found to have a temperature of 38.5°C and both hepatomegaly (3 cm) and splenomegaly (3 cm). Serologic tests for HBs and HCV are negative, and PCR, DNA and RNA for HIV are negative. More routine laboratory exams show: hemoglobin 6.4 g/dL, platelets 122,000/µL, LDH 1080 IU/mL, and blood smears showing the following:

Question 1. What is your diagnosis?
No malaria
Plasmodium falciparum
Plasmodium vivax
Plasmodium ovale
Plasmodium malariae
Mixed infection (several Plasmodium species)

A transfusion of 125 mLs of blood (serologically negative for CMV) is given to the child.
Question 2. What antimalarial drug would you administer to the infant?
Chloroquine
Quinine-Doxycycline
Mefloquine
Halofantrine
Primaquine

Following treatment with the orally administered antimalarial drug, parasitemia drops to 1% by day 3. At day 7, some parasite remnants are found and the child is afebrile. Drug testing in vitro of the parasite shows it to be sensitive to chloroquine.
Question 3. What test(s) would you perform to confirm current infection of the mother?
Thin blood smear
Thick blood smear
PCR for malaria
Serology

A thick blood smear of the mother, taken 5 days after that of the infant, is indeed positive, while on the thin smear no parasites can be detected.

Main Points
Congenital malaria should be considered in febrile newborns and infants from women who could have been parasitemic during their pregnancy.

Malaria parasitemia during pregnancy can result because the mother became infected during her pregnancy, but it can also result from an infection acquired months or years before.
The woman in this case probably was infected in DR Congo more than 2 years before delivery. Untreated Plasmodium malariae infection can persist >40 years and remain relatively asymptomatic.

Plasmodium vivax and P. ovale can similarly cause malaria several months or years after the original infection, by reactivation of dormant liver stage parasites.

Diagnostic procedures for detecting active malaria infection are, in order of increasing sensitivity: thin blood smear, thick blood smear, and PCR. Serology does not detect active infection, but measures past (and current) experience with malaria.

Question 1: Correct Answer
Plasmodium malariae : The most likely diagnosis, based on microscopy and clinical history. Note the typical microscopic characteristics: all stages of parasites present; band - form trophozoite (image 1); round, rosette-shaped schizont (image 2); and round gametocyte (image 3, at right). The microscopic diagnosis of P. malariae was confirmed by PCR. The parasitemia is 1.8%, which is high for P. malariae (note that in image 3, four parasites are crowded in a relatively small field). The mild or absent symptoms of malaria in the mother is compatible with P. malariae, a parasite that can persist for years, even a lifetime, with minimal symptoms . Plasmodium malariae is known to occur in DR Congo, where it is second in prevalence (by far) to P. falciparum .

Question 2: Correct Answer
Chloroquine: This is the drug of choice for the treatment of Plasmodium malariae. P. malariae is chloroquine-sensitive, and additionally chloroquine is one of the safest antimalarial drugs available.
Doxycycline is contraindicated in young children, and halofantrine can have cardiotoxic effects.
Primaquine is not necessary because there are no dormant liver stages in this parasite species. At the usual doses, primaquine would have no effect on the blood stage parasites (it targets mainly the liver stage parasites, and the gametocytes).
Even in congenital malaria caused by P. vivax and P. ovale (which have liver stage parasites) primaquine treatment of the infant is not necessary because no liver stages are transmitted from the mother to the child.

case study

2009-03-09T08:05:00.000-07:00

A 44-year-old male is seen at a physician's office in the United States, during a week-end, for suspected malaria.

The patient was born in Pakistan but has lived in the US for the past 12 years. He travels frequently back to Pakistan to visit friends and relatives. His last visit there was for two months, returning 11 months before the current episode. He did not take malaria prophylaxis then.

Five weeks ago, he was diagnosed with malaria and treated at a local hospital. The blood smear at that time was reported by the hospital as positive for Plasmodium malariae (schizonts, trophozoites). He was then treated with 2 days of IV fluids (nature unknown) and tablets (nature unknown), and recovered.

The patient now presents with a history of low grade fever for the past few days, with no other symptoms . A blood smear is taken and examined at a hospital laboratory by the technician (no pathologist is available on this week-end). Through a telephone discussion, the technician states that she sees 4 parasites per 1000 red blood cells, with rings, "other forms with up to four nuclei", and that some of the infected red blood cells are enlarged and deformed.

Question 1. What is your most probable diagnosis?
Not malaria
Plasmodium falciparum
Plasmodium vivax
Plasmodium ovale
Plasmodium malariae
Babesia

Question 2. What treatment approach would you recommend, based on this clinical history and on the fact that the microscopy findings will not be confirmed by a pathologist for at least 24 hours?
Do not start treatment until a formal microscopic diagnosis is made (in 12-24 hours)
Treat as if chloroquine-sensitive Plasmodium falciparum malaria
Treat as if chloroquine-resistant Plasmoidum falciparum malaria
Treat as if Plasmodium vivax malaria

Question 3. To prevent further relapses from dormant liver stages, what would you recommend?
No further measures needed
A lab test to determine if the patient has dormant liver stages
Treatment directly with a drug that kills dormant liver stages
A lab test, followed by treatment

Question 4. Should this patient have taken preventive measures against malaria for his visit to Pakistan, considering that he was born there, and probably would have visited only cities?
No
Yes

Main Points
Travelers to Pakistan (including those visiting friends and relatives) need to take prophylaxis (atovaquone-proguanil (Malarone®), doxycycline or mefloquine).
Clinical history and travel history, and careful microscopic examination, probably would have directed the diagnosis toward P. vivax during the earlier episode.
P. vivax malaria should be treated with chloroquine, except when acquired in Papua New Guinea and Indonesia, areas with high prevalence of chloroquine-resistant P. vivax. After a normal G6PD test, patients should get a radical cure with primaquine (30 mg per day for 14 days).

Question 1 : Correct Answer - P.vivax

This is the most probable diagnosis. The reported microscopic findings are compatible with P. vivax: some infected red cells are enlarged and deformed, and the "other forms with four nuclei" are compatible with the presence of schizonts. Plasmodium vivax does occur in Pakistan, where it is found in slightly more than 50% of malaria cases.
The history suggests a relapse of P. vivax malaria, following an earlier episode five weeks ago. The earlier treatment apparently did not include primaquine, thus allowing the persistence of hypnozoites which caused this relapse.
An alternate explanation would be that the earlier infection was caused by chloroquine-resistant P. vivax (which has been reported in Pakistan), with recrudescence of blood-stage parasites occurring after an unsuccessful earlier treatment (if indeed the earlier treatment included chloroquine). However, recrudescences usually occur within 28 days of the intial episode, rather than at five weeks as described here.
The other species are less likely:
While P. falciparum does occur in Pakistan (slightly less than 50% of malaria cases), this patient reportedly did not develop symptoms until 10 months after departure from the exposure area: most cases of P. falciparum would have become symptomatic earlier
P. ovale occurs mainly in Africa and has been found only occasionally in Asia (in the western Pacific)
P. malariae occurs worldwide, but its distribution is spotty, and its frequency in Pakistan is low to negligible. The diagnosis of P. malariae made during the earlier episode is not consistent with the current microscopic findings: red cells infected with P. malariae would not be enlarged and deformed, as described here.
Babesia would not fit with the microscopic description; in addition, babesiosis has not been reported in Pakistan, although admittedly the disease might have escaped detection

Question 2a: Correct Answer - Treat as if chloroquine-resistant P. falciparum malaria
A reasonable option, signifying that in the absence of definitive microscopic diagnosis, you prefer to play it safe and treat the patient for the most dangerous and rapidly progressing infection possible.
The safest course of action is to initially admit all cases of proven or suspected P. falciparum to the hospital until one can begin treatment and ensure that they are improving clinically and parasitologically.
However in this case, if the patient is only minimally symptomatic, one might elect against hospitalization and instead treat as an outpatient provided that close follow-up can be arranged. Once the definitive microscopic diagnosis is made the following day, you can always switch treatment.

Question 2b: Correct Answer
Treat as if P. vivax malaria
A reasonable option, signifying that you have enough confidence in the clinical history and the provisional microscopic diagnosis to decide that P. vivax is a high probability. However, while awaiting for the definitive microscopic confirmation the following day, you might consider taking additional precautionary measures, such as keeping the patient under observation in the hospital, in case the infection is actually due to P. falciparum

Question 3: Correct Answer
A lab test, followed by treatment
Correct answer. You should exclude G6PD deficiency first, then give the patient primaquine, 30 mg per day for 14 days; note that this dosage is higher than that previously recommended.
In case of partial G6PD deficiency, an alternative regimen of primaquine 45 mg weekly for 8 weeks can sometime be used. If this is considered, consultation with an expert in infectious diseases or tropical medicine is advised. Ttreatment with primaquine is justified because this patient probably has already had a relapse, and is at risk for further relapses. No test exists to detect the presence of liver stage parasites

Question 4: Correct Answer
Yes
Correct answer. Even to visit friends and relatives, preventive measures must be taken. Malaria risk is present also in cities in Pakistan. Chloroquine-resistant Plasmodium falciparum occurs in Pakistan, and thus the drugs recommended would be atovaquone-proguanil (Malarone®), doxycycline or mefloquine; "terminal prophylaxis" with primaquine is not necessary unless the traveler has heavy, prolonged exposure to P. vivax. Other preventive measures against mosquito bites also apply. Even though the patient was born in Pakistan, whatever acquired immunity he has developed would most likely have waned; negligence of preventive measures often occurs in individuals visiting friends and relatives, a situation that needs to be remedied.

The microscopic diagnosis of P. vivax is based on the following: a) the infected red cells are enlarged and deformed; b) the schizont shown contains 20 merozoites (schizonts of P. malariae and P. ovale have fewer merozoites; and in P. falciparum schizonts are not usually seen in the peripheral blood); c) the round gametocyte shown, contained in an enlarged red cell. (In this case, the typical Schüffner's dots were not visible, probably due to staining problems