Plasmodium vivax infection causes acute respiratory distress syndrome : a case report

Plasmodium falciparum (Pf) is associated with numerous complications and high mortality, whereas Plasmodium vivax (Pv) infection is generally considered to be benign. However, severe complications, such as acute respiratory distress syndrome (ARDS) in Pv infection, are emerging. This case report highlights the complication of ARDS during the course of Pv infection in a 60-year-old woman. The diagnosis of the patient was made using microscopy, immunochromatography, and polymerase chain reaction assays for Pf and Pv species. The data indicated the presence of mono-Pv infection in the patient’s blood, and Pf infection was specifically ruled out. The patient was discharged after intensive supportive care and antimalarial treatment. Pv infection is associated with ARDS and other complications such as sepsis and multi-organ dysfunction syndrome; this enhanced severity of Pv infection, if unrecognized, can lead to more deaths in malaria-endemic areas.


Introduction
Malaria is a major infectious disease and remains a significant cause of morbidity and mortality worldwide.According to the World Health Organization (WHO)'s 2013 World Malaria Report, there were 207 million diagnosed cases of malaria in 2012, and the total number of malaria cases reported in India alone was 1.06 million [1].The most common species being reported to cause malaria in humans so frequently are Plasmodium vivax (Pv) and Plasmodium falciparum (Pf).Pv infection accounts for more than 80% cases in India [2].However, the severity of malaria is higher in an infection caused by Pf as compared to one caused by Pv.Complications such as renal failure, severe anemia, acute respiratory distress syndrome (ARDS), shock, hypoglycemia, and central nervous system damage are common with Pf infection.Complications are rare during the course of Pv infection [3][4][5].Usually, the presence of such complications with Pv infection is attributed to mixed infection by both Pf and Pv parasites, with Pf being unrecognized [6].The retrospective data analysis of malaria cases in Udupi and Dakshina Kannada coastal districts of Karnataka was done by many authors, who presented an association of Pv infection with acute respiratory distress syndrome [7][8][9][10][11].These retrospective studies do not include Plasmodium species identification by polymerase chain reaction (PCR) methods.However, studies using sensitive PCR methods have been more reliable in detecting mixed infections [12].We report a severe case of Pv infection in an adult female with ARDS.The increasing drug resistance and lack of drug alternatives to kill dormant Pv hypnozoites in the liver gives us a great opportunity to document such unusual cases, which may be a result of climate conditions in the coastal districts of Karnataka state, which are surrounded by the sea and rivers.

Ethical statement
Written prior informed consent was obtained from the patient.The study was approved by the institutional ethics committee of Manipal University in Manipal, India.

Case Report
A 60-year-old woman with no known medical illnesses presented to the emergency triage with a sudden onset of breathlessness.She gave a history of fever with chills for five days prior to the onset of breathlessness, for which she had taken paracetamol for symptomatic treatment at home.On examination, she had tachypnea (24 breaths per minute) along with sinus tachycardia (110 beats per minute) and blood pressure of 100/70 mmHg.There was no fever at the time of presentation.Respiratory examination revealed bilateral crackles.Oxygen saturation by pulse oxymetry was 86%.Arterial blood gas (ABG) analysis done about 10 minutes after starting 60% oxygen inhalation by Venturi device revealed hypoxia (PO 2 66 mmHg, PCO 2 27.5 mmHg) with a 2 /FiO 2 ratio of 110.Chest X-ray showed bilateral infiltrates (Figure 1).She was diagnosed with moderate ARDS and started on conservative management with mechanical ventilation on standby.Meanwhile, she was reported positive for Pv by a rapid immunochromatography test for malaria.She also had mild anemia, leucopenia, and thrombocytopenia (hemoglobin 9.9 g/dL, total white blood cell [WBC] count 3.2×10 3 /mm 3 , and platelet count 35×10 3 /mm 3 ).Her renal and liver function tests were abnormal (serum creatinine 1.7 mg/dL, total bilirubin 5.5 mg/dL, direct bilirubin 4.4 mg/dL, aspartate aminotransferase [AST] 57 IU/L, alanine amino transferase [ALT] 21 IU/L, alkaline phosphatase 193 U/L).Serum electrolytes and prothrombin time were normal.Serum NT-pro-BNP was slightly elevated (2,808 pg/mL) and troponin-T was normal.A subsequent test for malaria using the quantitative buffy coat (QBC) method was also positive for Pv (reported as 4+, indicating severe parasitemia).A blood sample was also diagnosed by PCR to confirm the presence of Plasmodium species.Two sets of primer pairs were used to detect the malaria parasite, primer pairs for pfcrt (forward 5'-TGTGCTCATGTGTTTAAACTT-3' and reverse 5'-CAAAACTATAGTTACCAATTTTG-3') and pvldh (forward 5'-AAGAACCTGGGGGACGTAGT-3' and reverse 5'-TCTCGGTTCCATTCCTTGTC-3') genes specific for Pf and Pv, respectively [13], which showed a positive result for Pv infection and a negative result for Pf, as shown in Figure 2. In view of complicated Pv malaria, the patient was started on intravenous artesunate and oral doxycycline along with supportive therapy.She responded well to the treatment, and her oxygen requirement reduced gradually.Tachypnea and dyspnea also subsided in about three to four hours after the first dose of IV artesunate.A throat swab for influenza (H1N1, H3N2, and B) was negative.Cultures of blood, respiratory secretion, and urine were subsequently reported as sterile.

Discussion
It is known that Pf infection can lead to organ dysfunction and ultimately to death; however, complications in Pv infection are unusual.It is presumed that a patient with Pv infection with complicated malaria is suffering from a mixed infection of Pf and Pv.It is challenging to absolutely rule out the likelihood of Pf by using orthodox diagnostic tools, which may perhaps explain, in various cases, the use of anti-malarial therapy against both Pf and Pv infection [14][15][16].It has been reported that Pv infection alone is also capable of causing sequestration and non-sequestration related  complications; such complications are commonly seen during the period of Pf infection [2].Hence, it is very important to rule out the possibility of mixed infection by using sensitive and reliable methods such as PCR.
It has been shown that the occurrence of mixed infection in our population is up to 2%, consistent with a malaria survey study in a Thai population [17], which used conventional methods.However, another study on a Thai population put the incidence rate of mixed infection up to 30% by using sensitive PCR methods [12].In the case patient, we have shown the complication of ARDS in mono-Pv infection, and specifically ruled out the presence of Pf by using PCR-based assays [13].The exact mechanism of rarely noted ARDS with Pv is still unknown.However, there are chances it may follow the same pathophysiologic mechanism as ARDS in Pf infection, and this has been reported before as well [18,19].In most mixed infections with Pf being unrecognized, the patient is treated only for Pv.The inadvertently untreated Pf infection then gets worse in the background and is responsible for the complications.These complications of Pf are also often falsely attributed to Pv.The uniqueness of this case was that the patient developed ARDS with high parasitemia even before starting the treatment for uncomplicated Pv, which is quite unusual and has been reported before in a 43-year-old Brazilian woman [4].In addition, our patient had features of sepsis (systemic inflammatory response syndrome with evidence of an infection) and multi-organ dysfunction syndrome (MODS) (pulmonary, hepatic and renal dysfunction), in the absence of any other demonstrable infection.These above-mentioned complications are uncommon complications of malaria caused by either Pf or Pv infection [20].

Conclusions
The presence of ARDS, sepsis, and MODS in Pv infection may lead to a greater number of deaths due to malaria.A high index of suspicion is needed to diagnose these complications, even in malariaendemic regions like ours, as these complications can be life-threatening, and Pv malaria is not commonly recognized as a causative agent responsible for such severe presentations.

Figure 1 .
Figure 1.Figures A and B represent the portable chest X-ray in anteroposterior view of a patient with P. vivax malaria infection before treatment (A) and after treatment (B). Figure A shows bilateral infiltrates in the lung fields, suggestive of ARDS. Figure B shows resolution of lung infiltrates.

Figure 2 .
Figure 2. Figures A and B showing PCR amplification product of 145 bp and 182 bp by using pfcrt (specific for P. falciparum) and pvldh (specific for P. vivax) primers pairs, respectively.Lane 2 in Figures A and B represents 100 bp DNA marker.In Figure A, lane 1, lane 3, and lane 4 are Pfpositive PCR control, negative PCR control, and test sample respectively.In Figure B, lane 1, lane 3, and lane 4 are negative PCR control, test sample, and Pv-positive PCR control, respectively.