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Severe plasmodium vivax malaria in Pakistan.

Malaria is endemic to Pakistan and 64% and 36% of malaria cases are attributed to Plasmodium vivax and P. falciparum, respectively (1). The purpose of this study was to identify the complications of P. vivax vi·vax
1. The protozoan (Plasmodium vivax) that causes the most common form of malaria.

2. Vivax malaria.
 among hospitalized malaria patients and compare the prevalence of these complications with those of P. falciparum malaria fal·cip·a·rum malaria
Malaria caused by Plasmodium falciparum and characterized by severe malarial paroxysms that recur about every 48 hours and often by acute cerebral, renal, or gastrointestinal manifestations.

The Study

We conducted a retrospective cross-sectional study using convenience sampling at the Aga Khan University Hospital Aga Khan University Hospital may refer to:
  • Aga Khan University Hospital, Karachi
  • Aga Khan University Hospital, Nairobi
See also
  • Aga Khan Hospital
  • Aga Khan University
 in Karachi, Pakistan. Participants were all adult patients ([greater than or equal to] 16 years of age) who were hospitalized with malaria during January 2009-December 2011. Reasons for hospitalization included intravenous antimalarial antimalarial /an·ti·ma·lar·i·al/ (-mah-lar´e-al) therapeutically effective against malaria, or an agent with this quality.

Preventing or relieving the symptoms of malaria.
 therapy, management of associated diagnoses, and complications. The following data on patients were retrieved through the hospital's electronic and file records: age, sex, infecting Plasmodium plasmodium, name for a stage in the life cycle of a slime mold. Also, Plasmodium is the name given to the genus of the protozoan parasite that causes malaria.  species, malaria diagnosis methods, co-existing conditions, results of biochemical and microbiological investigations, radiographic radiographic (rā´dēōgraf´ik),
adj relating to the process of radiography, the finished product, or its use.
 findings, complications, hospital course, and outcome.

Records showed that Giemsa-stained peripheral blood smears, the malaria rapid diagnostic test (RDT RDT 1. Renal dialysis treatment 2. Retinal damage threshold ), or both, were used for malaria diagnosis. The RDT used antibodies against P. falciparum histidine-rich protein 2 and P. vivax lactate dehydrogenase. For 45 case-patients for which results from peripheral blood smears and RDTs were discordant or unreliable, surface protein-specific PCR PCR polymerase chain reaction.

polymerase chain reaction

Polymerase chain reaction (PCR) 
 was performed by using stored patient blood samples to identify the Plasmodium species (2,3). Clinical syndromes were classified as severe on the basis of the World Health Organization's 2010 severe falciparum malaria criteria (4).

Statistical analysis was performed by using SPSS A statistical package from SPSS, Inc., Chicago ( that runs on PCs, most mainframes and minis and is used extensively in marketing research. It provides over 50 statistical processes, including regression analysis, correlation and analysis of variance.  version 20 ( spss/). Averages, [chi square] test of independence, odds ratios with 95% CIs, and analysis of variance were computed when applicable.

Case-patients with prior co-morbid conditions were excluded from relevant subanalyses, for example, diabetes mellitus patients were excluded from hypoglycemia hypoglycemia: see diabetes.

Below-normal levels of blood glucose, quickly reversed by administration of oral or intravenous glucose. Even brief episodes can produce severe brain dysfunction.
 analysis. All analysis was also repeated after excluding all case-patients with associated infections and comorbid illnesses. The classification "comorbidity" included all conditions in the Charlson comorbidity index for mortality (5). The study was approved by the Aga Khan University's Ethics Review Committee.

A total of 356 patients with malaria (mean [+ or -] SD age 42 [+ or -] 18 years) were hospitalized in the Aga Khan Hospital during 2009-2011. Among these, 296 (83.1%), 47 (13.2%), and 13 (3.7%) were found to have P. vivax infection, P. falciparum infection, and mixed infections (P. vivax and P. falciparum), respectively. Baseline patient demographics are given in Table 1. The proportion of P. vivax infection among hospitalized malaria patients increased from 75.0% in 2009 to 87.7% in 2011 (p < 0.02) (Figure 1, panel A).

One hundred thirty-nine (39.0%) patients had at least 1 complication by World Health Organization criteria (4), among which 111 (79.9%) patients had P. vivax infection. In 24 (51.0%) cases of P. falciparum infections and in 111 cases (37.5%) of P. vivax infections, respectively, severe malaria developed (p = 0.077). As shown in Figure 2, the proportion of severe malaria among P. vivax patients increased from 24.1% in 2009 to 43.2% in 2010 and 39.5% in 2011 (p = 0.02).

The most common complications in the patients are shown in Table 2. P. vivax and P. falciparum were responsible for comparable rates of pulmonary edema, the need for mechanical ventilation, coagulopathy, hypoglycemia, hemoglobinuria hemoglobinuria /he·mo·glo·bin·uria/ (he?mo-glo?bi-nu´re-ah) free hemoglobin in the urine.hemoglobinu´ric

march hemoglobinuria  that seen after prolonged exercise.
, metabolic acidosis acidosis /ac·i·do·sis/ (as?i-do´sis)
1. the accumulation of acid and hydrogen ions or depletion of the alkaline reserve (bicarbonate content) in the blood and body tissues, decreasing the pH.

, renal impairment, liver dysfunction, bleeding, and multi-organ dysfunction. Altered consciousness, anemia, and jaundice were associated with P. falciparum malaria. The mean platelet count for P. vivax patients was 55, significantly lower than that of P. falciparum patients (67.5; p = 0.001) and those with mixed infections (61; p = 0.024).

The mean hospital stay was 4.1 days for P. falciparum patients, 3.6 days for P. vivax patients, and 2.9 days for patients with mixed infections. Three P. vivax malaria patients experienced fatal acute myocardial myocardial /myo·car·di·al/ (-kahr´de-al) pertaining to the muscular tissue of the heart.


pertaining to the muscular tissue of the heart (the myocardium).
 infarctions. One patient, who had metastatic Metastatic
The term used to describe a secondary cancer, or one that has spread from one area of the body to another.

Mentioned in: Coagulation Disorders


pertaining to or of the nature of a metastasis.
 myeloma myeloma /my·elo·ma/ (mi?e-lo´mah) a tumor composed of cells of the type normally found in the bone marrow.

giant cell myeloma  see under tumor (1).
 and P. falciparum malaria, died. The mortality rate was 2.1% for P. falciparum patients and 1.0% for P. vivax patients (p = 0.50).

Analysis was repeated after all patients with comorbid conditions were excluded (Table 1), which left 229 case-patients who had no illness other than malaria. Among these, 30 (13%) patients had P. falciparum infection, 189 (83%) had P. vivax infection, and 10 (4%) had mixed infection (Figure 1, panel B). In these patients, severe malaria appeared significantly more common in falciparum versus vivax malaria (53% and 33%, respectively, p = 0.029); however, 79.5% of the severe cases were caused by P. vivax. Hemoglobinuria and a higher mean creatinine level were more likely to occur with falciparum malaria than with vivax malaria (p < 0.02). Shock and secondary bacterial infections were no longer associated with P. falciparum infection. All other statistical associations held, although the strength of association varied.



A study of hospitalized malaria patients at the Aga Khan University Hospital during 1997-2001 showed that 51.8% of cases were caused by P. vivax and 46.5% by P. falciparum, with mortality rates of 1.5% and 2.0%, respectively (6). Recent studies from elsewhere in Asia reported that 20%- 40% of patients hospitalized with malaria had P. vivax malaria (7), with mortality rates of 0.8%-1.6% (7). In our study, a much greater proportion of malaria cases were caused by P. vivax (83%), which was not unexpected because of the decreasing number of P. falciparum cases during the study period. Despite this high incidence of P. vivax malaria, the mortality rate found in our study is reassuring and stable at 1.0%.

The higher prevalence of jaundice, anemia, and hemoglobinuria seen with falciparum malaria in our study reflect the greater degree of hemolysis hemolysis (hĭmŏl`ĭsĭs), destruction of red blood cells in the bloodstream. Although new red blood cells, or erythrocytes, are continuously created and old ones destroyed, an excessive rate of destruction sometimes occurs.  caused by P. falciparum. P. vivax has been reported elsewhere to cause a similar degree of anemia as P. falciparum (8). Differences in the level of endemic anemia between these study populations and may explain this discrepancy. Similar to our findings, another study reported the incidence of thrombocytopenia Thrombocytopenia Definition

Thrombocytopenia is an abnormal drop in the number of blood cells involved in forming blood clots. These cells are called platelets.
 in hospitalized patients with vivax malaria as high as 96.3% (9). Pulmonary involvement has often been reported in complicated vivax malaria (7), as we found in our study. Hepatic dysfunction with jaundice has been reported in up to 57% of hospitalized P. vivax patients (10); our findings were similar.


To estimate the true effects of severe disease with vivax malaria, researchers have recommended excluding comorbid conditions (7) and other infections (11). In this study, excluding concurrent illness enabled a stronger association between P. falciparum and severe malaria to emerge. Thus, P. falciparum caused a higher likelihood of specific complications such as central nervous system disturbance and hemolysis than did P. vivax. Yet, [approximately equal to] 80% of severe malaria still occurred in patients with P. vivax malaria.

Limitations of the study include its retrospective design, low power, and lack of PCR diagnostics for all the samples. Furthermore, the study findings reflect the malaria situation at a single urban tertiary care hospital, which cannot be generalized without knowing the denominator of all hospitalized malaria cases in the study area.

P. vivax is a major contributor to the disease effects of malaria, including severe malaria, in a tertiary care setting in Karachi, Pakistan. Furthermore, P. falciparum and P. vivax have similar rates for several complications (pulmonary edema, metabolic acidosis, abnormal bleeding, renal impairment) and death.


We acknowledge collaboration with Raymond A. Smego from the University of the Free State The University of the Free State is situated in Bloemfontein, the capital of the Free State Province, South Africa. Bloemfontein is a modern city offering a full range of recreational, commercial and educational facilities, but which also retains a laid-back atmosphere that , Bloemfontein, South Africa, whose intellectual contribution to this study continued until his untimely death.

PCR studies for this project were funded by an Aga Khan University Research Council grant.

Dr Zubairi is an Associate Professor and Section Head in Pulmonary and Critical Care Medicine in the Department of Medicine, Aga Khan University Hospital, Karachi The Aga Khan University Hospital, Karachi (AKUH) was established in 1985 as the primary teaching site of the Aga Khan University’s (AKU) Faculty of Health Sciences. Founded by His Highness the Aga Khan, the hospital provides a broad range of secondary and tertiary care, . His research interests are asthma, interstitial lung disease Interstitial lung disease
About 180 diseases fall into this category of breathing disorders. Injury or foreign substances in the lungs (such as asbestos fibers) as well as infections, cancers, or inherited disorders may cause the diseases.
, and respiratory tract infections.


(1.) World Health Organization. World malaria report: 2011. Geneva Geneva, canton and city, Switzerland
Geneva (jənē`və), Fr. Genève, canton (1990 pop. 373,019), 109 sq mi (282 sq km), SW Switzerland, surrounding the southwest tip of the Lake of Geneva.
: The Organization; 2011.

(2.) Imwong M, Pukrittayakamee S, Griiner AC, Renia L, Letourneur F, Looareesuwan S, et al. Practical PCR genotyping protocols for Plasmodium vivax using Pvcs and Pvmsp1. Malar malar /ma·lar/ (ma´lar)
1. buccal; pertaining to the cheek.

2. zygomatic.

Of or relating to the cheekbone or the cheek.

The cheekbone.
 J. 2005; 4:20. http://

(3.) Zakeri S, Bereczky S, Naimi P, Pedro Gil J, Djadid ND, Farnert A, et al. Multiple genotypes of the merozoite merozoite /mero·zo·ite/ (mer?o-zo´it) one of the organisms formed by multiple fission (schizogony) of a sporozoite within the body of the host.

 surface proteins 1 and 2 in Plasmodium falciparum infections in a hypoendemic area in Iran. Trop Med Int Health. 2005; 10:1060-4. j.1365-3156.2005.01477.x

(4.) World Health Organization. Guidelines for the treatment of malaria, 2nd ed. Geneva: The Organization; 2010.

(5.) Sundararajan V, Henderson T, Perry C, Muggivan A, Quan H, Ghali WA. New ICD-10 version of the Charlson comorbidity index predicted in-hospital mortality. J Clin Epidemiol. 2004; 57:1288-94.

(6.) Beg MA, Sani N, Mehraj V, Jafri W, Khan MA, Malik A, et al. Comparative features and outcomes of malaria at a tertiary care hospital in Karachi, Pakistan. Int J Infect Dis. 2008; 12:37-42. http://dx.doi. org/10.1016/j.ijid.2007.04.006

(7.) Price RN, Douglas NM, Anstey NM. New developments in Plasmodium vivax malaria: severe disease and the rise of chloroquine chloroquine /chlo·ro·quine/ (klor´o-kwin) an antiamebic and anti-inflammatory used in the treatment of malaria, giardiasis, extraintestinal amebiasis, lupus erythematosus, and rheumatoid arthritis; used also as the hydrochloride and  resistance. Curr Opin Infect Dis. 2009; 22:430-5. http://dx.doi. org/10.1097/QCO.0b013e32832fl4cl

(8.) Douglas NM, Anstey NM, Buffet PA, Poespoprodjo JR, Yeo TW, White NJ, et al. The anaemia anaemia

see anemia.
 of Plasmodium vivax malaria. Malar J. 2012; 11:135.

(9.) Sharma A, Khanduri U. How benign is benign tertian malaria? J Vector Borne Dis. 2009; 46:141-4.

(10.) Kochar DK, Das A, Kochar SK, Saxena V, Sirohi P, Garg S, et al. Severe Plasmodium vivax malaria: a report on serial cases from Bikaner in northwestern India. Am J Trop Med Hyg. 2009; 80:194-8.

(11.) Mueller I, Galinski MR, Baird JK, Carlton JM, Kochar DK, Alonso PL, et al. Key gaps in the knowledge of Plasmodium vivax, a neglected human malaria parasite. Lancet Infect Dis. 2009; 9:555-66. http://dx.doi.Org/10.1016/S 1473-3099(09)70177-X

Author affiliations: Aga Khan University, Karachi, Pakistan (A.B.S. Zubairi, S. Nizami, A. Raza, A.F. Rasheed, N.K. Ghanchi, Z.N. Khaled, M.A. Beg); and Aix Marseille Universite, Marseille, France (V. Mehraj)

DOI: 10.3201/eid1911.130495

Address for correspondence: M. Asim Beg, Department of Pathology and Microbiology, The Aga Khan University, Stadium Rd, PO Box 3500, Karachi 74800, Pakistan; email:
Table 1. Demographic profile of study participants with Plasmodium
vivax and P. falciparum malaria, Karachi, Pakistan, 2009-2011 *

                                        Frequency (%)

Characteristic               P. vivax   P. falciparum    Mixed
  F                          98 (33)       12 (25)      6 (46)
  M                          198 (67)      35 (75)      7 (54)
Previously healthy adults    189 (64)      30 (64)      10 (77)
Concurrent illness
  Diabetes                   49 (17)        4 (9)          0
  Ischemic heart disease     37 (12)        2 (4)       3 (23)
  Chronic kidney disease      10 (3)        3 (6)          0
  Co-existing infection      34 (12)       5 (11)          0
  Others ([double dagger])    10 (3)       5 (11)          0
Total ([section])            107 (36)      17 (36)      3 (23)

* n = 356.

([dagger]) Co-existing infections included dengue fever, urinary
tract infection, enteric fever, and hepatitis C, diagnosed by
appropriate serologic testing/culture.

([double dagger]) Other conditions included chronic obstructive
pulmonary disease, chronic liver disease, malignancy, and other
conditions from the Charlson Comorbidity Index (5).

([section]) Many patients had multiple comorbidities; therefore, the
total does not sum the above.

Table 2. Comparison of complication rates in P. falciparum versus P.
vivax infections, Karachi, Pakistan, 2009-20011 *

                                                          No. (%) P.
Complications                    Case definition         cases, n = 47

WHO criteria ([dagger])

  Altered consciousness    Disorientation or confusion     5 (10.6)

  Metabolic acidosis         Plasma bicarbonate <15        5 (10.6)

  Pulmonary edema           Respiratory distress and       6 (12.8)
                                bilateral diffuse
                              infiltrates on chest

  Abnormal spontaneous            Bleeding from             1 (2.1)
  bleeding                      gastrointestinal,
                                genitourinary or
                               respiratory tracts

  Jaundice                 Serum bilirubin >3.0 mg/dL      12 (25.5)

  Hemoglobinuria               Hemoglobin in urine         15 (31.9)

  Shock                    Systolic blood pressure <80      4 (8.5)
                                      mm Hg

  Hypoglycemia               Blood glucose <40 mg/dL        1 (2.1)
  ([double dagger])

  Renal impairment          Serum creatinine >3 mg/dL       2 (4.3)


  Hyperpyrexia                Core body temperature         4 (8.5)

  Thrombocytopenia             Platelets <150,000/         39 (83.0)

  Profound                     <20,000/[mm.sup.3]          5 (10.6)

  Anemia                       Hemoglobin <7 mg/dL         10 (21.3)

  Multiorgan dysfunction       Biochemical and /or         5 (10.6)
                           radiographic evidence of
                           [greater than or equal to]
                                2 organs involved

  Secondary infection             Radiographic/            9 (19.1)
                           microbiological evidence of

  Coagulopathy                  Deranged PT/APTT           5 (10.6)

  Liver dysfunction             ALT level >normal          16 (44.4)

                            No. (%) P.
                           vivax cases,
Complications                n = 296      Odds ratio (CI)   p value

WHO criteria ([dagger])

  Altered consciousness      6 (2.0)      5.7 (1.7-19.7)     0.002

  Metabolic acidosis         17 (5.7)      1.9 (0.7-5.6)     0.203

  Pulmonary edema            23 (7.8)      1.7 (0.7-4.5)     0.253

  Abnormal spontaneous       16 (5.4)     0.4 (0.049-2.9)    0.336

  Jaundice                   28(89.5       3.3 (1.5-7.0)     0.001

  Hemoglobinuria            62 (20.9)      1.8 (0.9-3.4)     0.094

  Shock                      5 (1.7)      5.4 (1.4-20.9)     0.007

  Hypoglycemia               3 (1.0)      2.1 (0.2-20.9)     0.509
  ([double dagger])

  Renal impairment           10 (3.4)      1.3 (0.3-6.0)     0.761


  Hyperpyrexia              32 (10.8)      0.8 (0.4-1.9)     0.416

  Thrombocytopenia          272 (91.9)     0.4 (0.2-1.0)     0.051

  Profound                  58 (19.6)      0.5 (0.2-1.0)     0.141

  Anemia                     15 (5.1)     5.0 (2.1-12.1)     0.000

  Multiorgan dysfunction     21 (7.1)      1.6 (0.6-4.4)     0.394

  Secondary infection        2 (7.4)       2.9 (1.3-6.9)     0.009

  Coagulopathy               17 (5.7)      2.0 (0.7-5.6)     0.203

  Liver dysfunction         97 (40.9)      1.1 (0.5-1.9)     0.690

* WHO, World Health Organization; PT, prothrombin time; APTT,
activated partial thromboplastin time. ALT, alanine aminotransferase.

([dagger]) Source: (4).

([double dagger]) Patients with preexisting diabetes were excluded
from this count; n = 303.

([section]) Patients with preexisting chronic kidney disease were
excluded from this count; n = 343.
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Title Annotation:DISPATCHES
Author:Zubairi, Ali Bin Sarwar; Nizami, Sobia; Raza, Afsheen; Mehraj, Vikram; Rasheed, Anita Fazal; Ghanchi
Publication:Emerging Infectious Diseases
Article Type:Report
Geographic Code:9PAKI
Date:Nov 1, 2013
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