This week is Morning Report we discussed an approach to a patient who returned from travel to Africa and developed a fever for ~3 days. We reviewed the approach to this presentation and important elements in the history that can inform your differential diagnosis. Next we discussed the diagnosis for our patient which was malaria and reviewed testing for malaria and treatment.

1. Taking the History for a Patient with Fever After Returning From Travel

When taking a history for a patient who has returned with a fever after travel, the history can be divided into three main components

Pre-Travel Assessment	Travel-Related Assessment	Post-Travel Assessment
Past medical history Medications Allergies Social history Pre-travel consultation Travel immunizations (ex. hepatitis A/B, yellow fever) Chemoprophylaxis taken via travel (ex. malaria)	Type of accommodation Purpose of travel Itinerary Precautions taken (ex. insect repellent) Medical Care while Overseas (Transfusions) Exposures (see below)	Timing of fever Pattern of fever Other clinical symptoms

Asking about exposures is important when understanding what was involved in the patient’s trip. These would include:
– Insect bite, tick bites, mosquito bites (mosquito bites –> dengue, malaria)
– Exposure to fresh-water lakes and streams that may increase risk of schistosomes or leptospires
– Eating certain foods (example unpasteurized milk or dairy and Brucellosis)
– Undercooked food (risk of cholera, nontyphoidal salmonellosis, trichinosis, typhoid fever)
– Ask about sexual contact or new partners (HIV, sexually transmitted infections or diseases such as syphilis, gonorrhea, hepatitis B)
– Exposure to sheep or cattle (Q fever), other animals (brucellosis, rabies, tularemia)
– Sick contacts (Meningococcal disease, tuberculosis, viral hemorrhagic fevers)

Time course is important as certain travel-related infections have longer incubation periods, for instance, the incubation period for P. falciparum malaria can be from eight to 40 days. Symptoms of dengue fever and typhus usually begin within 10 days but typhoid fever up to 21 days.

Examples of Salmonella typhi are Typhi, Sendia, Paratyphi A, B, or C and compared to non-typhoidal salmonella, Salmonella typhi infections are more common in developing countries. Pathogens usually spread through the fecal-oral route, and usually present with “enteric fever:”

• Sustained fever 39 to 40 degrees Celsius
• Chills, abdominal pain, hepatosplenomegaly, rash (rose spots), nausea, anorexia, diarrhea or constipation, headache, and a dry cough

2. Differential Diagnosis

This can often be divided into travel-related and non-travel-related.

Travel-Related and Infectious

• Malaria
• Dengue, Zika, Chikungunya
• Typhoid/enteric fever
• COVID-19 (Travel or community-related, depending on clinical context)
• Viral hepatitides
• Tuberculosis
• Others: Rickettsiae, Brucellosis, Leptospirosis
• Schistosomiasis

Travel-Related Non-Infectious

• Venous thromboembolism
• Drug reaction
• Side effects of recreational drug use (intoxication, withdrawal)

Non-Travel-Related

• Urinary tract infection
• Community acquired pneumonia
• Meningitis
• C. difficile
• Mononucleosis

3. Investigations for a Patient with Fever After Returning From Travel

The NEJM article linked below (2017) has an excellent approach on page 550 of the paper (or page 3 of 13) with an approach to assessment. Some investigations you would want to send include:

• CBC + differential
• Malaria smears thick and thin x 3 (over 24 hours)
  • Rapid diagnostic test
• Electrolytes, creatinine, urea, glucose, AST, ALT, ALP, bilirubin, INR/PTT, albumin
• Infectious
  • Blood cultures x 2 peripherally from different sites 30 minutes apart
  • Urinalysis and urine culture
  • If diarrhea, stool C&S, C difficile, O&P
  • COVID-19 swab
  • +/- Hepatitis serology
  • +/- HIV, screening for sexually transmitted infections
  • +/- NP swab for viral infections such as influenza A/B, RSV
  • +/- dengue, chikungunya, zika PCR or serology
• Imaging
  • Chest X-ray

4. Species of Malaria and Severity of Malaria

There are six species of malaria can cause human infection including Plasmodium falciparum, P. ovale, P. vivax, P. malariae, P. knowlesi, P. simiun.

Uncomplicated malaria refers to symptomatic malaria without evidence of severe disease or organ dysfunction. Severe or complicated malaria refers to symptomatic malaria with hyperparasitemia or end organ dysfunction as below:

Clinical Manifestation	Laboratory test
Prostration / impaired consciousness	Severe anemia (hematocrit < 20%, Hb ≤ 70 g/L
Respiratory distress	Hypoglycemia (blood glucose < 2.2 mmol/L)
Multiple convulsions	Acidosis (arterial pH < 7.25 or bicarbonate < 15 mmol/L)
Circulatory collapse	Renal impairment (creatinine > 265 𝜇mol/L)
Pulmonary edema	Hyperlactatemia
Abnormal bleeding	Hyperparasitemia
Jaundice	≥ 2% for children < 5 years
Hemoglobinuria	≥ 5% for non-immune adults and children ≥ 5 years
	≥ 10% for semi-immune adults and children ≥ years

5. Malaria Treatment

See the algorithm from Health Canada below on management of malaria.

The treatments of choice for uncomplicated P. falciparum malaria are below. If a patient is not being admitted, need to monitor patient in the ER to ensure tolerating oral therapy. Drug options include:

• Oral atovaquone-proguanil
• Oral quinine combined with oral doxycycline or clindamycin
• Combination therapy with an artemisinin derivative (not yet available in Canada)

For severe P. falciparum, parenteral aretesunate is recommended as first-line treatment (parenteral quinine as an alternative). Treatment should be completed with one full course of multidrug follow-on therapy.

Exchange transfusion may have benefit in cases of hyperparesitemia of P. falciparum.

To prevent relapse of P. vivax and P. ovale, primaquine phosphate (30 mg base daily for 2 weeks) should be given with or immediately after chloroquine treatment (after G6PD deficiency has been excluded).

References:

1. Lo Re III, Vincent & S. J. Gluckman. (2003). Fever in the Returned Traveler. AAFP. Accessed at: https://www.aafp.org/afp/2003/1001/afp20031001p1343.pdf
2. Thwaites, G. E. & N. P. J. Day. (2017). Approach to Fever in the Returning Traveler. NEJM. 376:548-60. DOI: 10.1056/NEJMra1508435
3. Government of Canada page on Malaria – https://www.canada.ca/en/public-health/services/catmat/canadian-recommendations-prevention-treatment-malaria/chapter-7-treatment.html#a7
4. Gal-Mor O, Boyle EC, Grassl GA. Same species, different diseases: how and why typhoidal and non-typhoidal Salmonella enterica serovars differ. Front Microbiol. 2014;5:391. Published 2014 Aug 4. doi:10.3389/fmicb.2014.00391 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4120697/

If you have any questions or comments, feel free to email at cmr@wchospital.ca