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Malaria or typhoid fever: A diagnostic dilemma?

      To the Editor:
      I read with interest the report by Baken et al.
      • Baken J.
      • Nilsson K.R.
      • Mani S.
      Diagnostic dilemma A 57-year-old man with a 6-day headache and fatigue.
      The case presents many malarial teaching points. Malaria has characteristic features that are the basis of syndromic diagnosis. The patient presented recently returned from Nigeria with fever and headache, suggesting typhoid fever or malaria.
      • Harinasuta T.
      • Bunnag T.
      The clinical features of malaria.
      • Rubin R.H.
      • Weinstein L.
      Salmonellosis.
      He had cough and diarrhea, unhelpful in patients returning from tropical areas. Malaria should always be a consideration in patients returning from malarious areas, and his prophylaxis was inadequate for Plasmodium falciparum. Malarial paroxysms may not be present early, but malaria was suggested by thrombocytopenia and anemia.
      • Harinasuta T.
      • Bunnag T.
      The clinical features of malaria.
      • Rubin R.H.
      • Weinstein L.
      Salmonellosis.
      Tender hepatosplenomegaly with malaria is common. The absence of atypical lymphocytes was noteworthy. Automated counts are insensitive to atypical lymphocytes, but manual counts invariably reveal one or more. Malaria, regardless of species or degree of parasitemia, always has ≥1 atypical lymphocytes.
      • Cunha B.A.
      • Bonoan J.T.
      • Schlossberg D.
      Atypical lymphocytes in acute malaria.
      The other test suggesting malaria was an LDH of 1382 IU/L. Although some findings were consistent with typhoid fever, his fever and chills, thrombocytopenia, and increased LDH were characteristic of malaria
      • Harinasuta T.
      • Bunnag T.
      The clinical features of malaria.
      • Cunha B.A.
      Diagnosis of imported malaria in returning travelers.
      (Table).
      TableDifferential diagnosis of typhoid fever vs malaria in returning travelers
      Typhoid feverAcute malaria
      Symptoms
       Apathetic affect+-
       Headache++
       Delirium+-
      Only with P. falciparum.
       Dry cough+-
       Nausea/vomiting+-
       Diarrhea±-
       Malaise/fatigue++
       Malarial paroxysm
      Not described in case/not present.
      -+
      May be absent early.
       (Chills → fever → sweats)
      Signs
       Retinal hemorrhages
      Not described in case/not present.
      -+
      Only with P. falciparum.
       Herpes labialis (fever blisters)
      Not described in case/not present.
      -+
       Single initial chill+-
       Multiple chills (before fever)-+
       Hectic (intermittent) fever
      Not described in case/not present.
      -+
       Continuous (plateau) fever+-
       Relative bradycardia (late)+-
       Abdominal distension/pain+-
       Tender hepatosplenomegaly++
      May be absent early.
       Rose spots+-
      Only with P. falciparum.
      Laboratory tests
       Normal WBC count/mild leukopenia++
       Atypical lymphocytes
      Not described in case/not present.
      -+
      Always ≥1 on manual differential WBC counts.
       Thrombocytopenia-+
       Mild ↑ SGOT/SGPT
      Not described in case/not present.
      ++
       ↑ LDH-+
       ↑ Creatinine-+
       Polyclonal gammopathy on SPEP
      Not described in case/not present.
      ++
      May be absent early.
       Hypoglycemia-+
      Only with P. falciparum.
       ARDS on CXR-+
      Only with P. falciparum.
       Pulmonary edema on CXR-+
      Only with P. falciparum.
       Cerebral edema (head CT/MRI scan)-+
      Only with P. falciparum.
       CSF (cerebral malaria)
        ↑ WBCs (≤ 15/mm3)-+
      Only with P. falciparum.
        ↑ Protein-+
      Only with P. falciparum.
        ↑ Lactic acid-+
      Only with P. falciparum.
      The characteristic findings in malaria are in bold/italics.
      SPEP = serum protein electrophoresis; ARDS = acute respiratory distress syndrome; CXR = chest x-ray; MRI = magnetic resonance imaging; CSF = cerebrospinal fluid.
      low asterisk May be absent early.
      low asterisklow asterisk Only with P. falciparum.
      low asterisklow asterisklow asterisk Always ≥1 on manual differential WBC counts.
      Not described in case/not present.
      Inconsistent with malaria were the burr cells, which probably occurred as a result of smear preparation because there was nothing to suggest other causes of burr cells, ie, gastric carcinoma, bleeding ulcers, or uremia.
      • Kjeldsberg C.R.
      Practical Diagnosis of Hematologic Disorders.
      His focal central nervous system hemorrhage seems to be related to his head blow and not cerebral malaria. Cerebral malaria is characterized by cerebral edema malaria with altered mental status and seizures. Papilledema is rare in cerebral malaria, and 15% have retinal hemorrhages. Computed tomography (CT) and magnetic resonance imaging head scans in cerebral malaria are usually unremarkable but terminally may show evidence of cerebral edema or herniation.
      • Harinasuta T.
      • Bunnag T.
      The clinical features of malaria.
      Jaundice often accompanies cerebral malaria in adults.
      • Harinasuta T.
      • Bunnag T.
      The clinical features of malaria.
      The patient’s dark urine was probably indicative of dehydration, not “blackwater fever.” With P. falciparum, “blackwater fever” presents with abdominal or back pain, vomiting, followed by oliguria or anuria. Urinalysis was not given, and proteinuria, RBCs, hemoglobinuria, or RBC casts are common.
      • Harinasuta T.
      • Bunnag T.
      The clinical features of malaria.
      The patient was treated with quinine plus doxycycline for P. falciparum. He was discharged on primaquine for possible co-infection with other Plasmodia, but there was no mention of co-infection or artifacts mimicking P. ovale or P. malariae. Co-infection was unlikely because P. vivax suppresses P. falciparum, which was not evident.
      • Cunha B.A.
      Essentials of Antimicrobial Therapy.
      • Schoch P.E.
      • Iancu D.
      • Lobato M.
      • Cunha B.A.
      Mixed malarial infectionsP. falciparum and P. vivax.
      • White N.J.
      Malaria.
      The diagnostic lessons from this case are many. First, most cases of imported malaria result from inadequate prophylaxis. Second, malaria is a commonly overlooked diagnosis in returning US travelers. Fever, headache, and leukopenia in a traveler returning from Nigeria suggested typhoid fever or malaria.
      • Harinasuta T.
      • Bunnag T.
      The clinical features of malaria.
      • Rubin R.H.
      • Weinstein L.
      Salmonellosis.
      Third, clues characteristic of malaria were thrombocytopenia with an elevated LDH, which eliminated typhoid fever.
      • Rubin R.H.
      • Weinstein L.
      Salmonellosis.
      • Cunha B.A.
      Diagnosis of imported malaria in returning travelers.

      Cunha BA. The importance of non-specific laboratory tests in suspecting malaria in returning US travelers. Ann Intern Med. 14:e141/7/547 (27 October, 2004).

      Last, the importance of atypical lymphocytes in malaria should not be overlooked. If no atypical lymphocytes are present on a manual WBC count, the diagnosis of malaria should be questioned.
      • Cunha B.A.
      • Bonoan J.T.
      • Schlossberg D.
      Atypical lymphocytes in acute malaria.
      The “red herrings” in this case were artifactual burr cells and focal hemorrhage on head CT scan, which are not features of malaria. The diagnostic dilemmas in this case were apparently unrelated to malaria.

      References

        • Baken J.
        • Nilsson K.R.
        • Mani S.
        Diagnostic dilemma.
        Am J Med. 2005; 118: 222-224
        • Harinasuta T.
        • Bunnag T.
        The clinical features of malaria.
        in: Wernsdorfer W.H. McGregor S.I. Malaria Principles and Practice of Malariology. Churchill Livingstone, Edinburgh, Scotland1988: 709-734
        • Rubin R.H.
        • Weinstein L.
        Salmonellosis.
        in: Stratton Intercontinental Medical Book Corporation, New York, New York1977: 46-58
        • Cunha B.A.
        • Bonoan J.T.
        • Schlossberg D.
        Atypical lymphocytes in acute malaria.
        Arch Intern Med. 1997; 157: 1140-1141
        • Cunha B.A.
        Diagnosis of imported malaria in returning travelers.
        Arch Intern Med. 2001; 161: 1926-1928
        • Kjeldsberg C.R.
        Practical Diagnosis of Hematologic Disorders.
        in: 3rd edn. ASCP Press, Chicago, Illinois2000: 6-7
        • Cunha B.A.
        Essentials of Antimicrobial Therapy.
        in: Physicians Press, Birmingham, Michigan2005: 191-192 (,285)
        • Schoch P.E.
        • Iancu D.
        • Lobato M.
        • Cunha B.A.
        Mixed malarial infections.
        Infect Dis Pract. 1998; 22: 61-63
        • White N.J.
        Malaria.
        in: Cook G.C. Zumla S. Manson’s Tropical Diseases. 21st edn. Elsevier, New York, New York2003: 1211-1240
      1. Cunha BA. The importance of non-specific laboratory tests in suspecting malaria in returning US travelers. Ann Intern Med. 14:e141/7/547 (27 October, 2004).