Objective: To study the presentations of afebrile malaria with respect to febrile malaria.
Study Design: Cross sectional descriptive.
Place and Duration of Study: Combined Military Hospital (CMH) Mangla Cantt, from Jan 2015 to Jan 2017. Material and Methods: A retrospective cross sectional descriptive study was conducted on patients received at CMH Mangla during the study period. Permission from the ethical committee of hospital was obtained for the study. Malaria was diagnosed by exam of peripheral blood film slide on Leishman,s stain. Typing of the parasite was done using ICT immunochromatographic strip test. All consecutively advised malarial parasite (MP) tests on febrile and afebrile patients were included in the study. All repeated MP test on the same patients were excluded from the study. No co-incidental/asymptomatic case was diagnosed or included in the study.
Results: A total of 5372 MP tests of patients were advised out of which total 1120 cases were reported positive for malaria infection during above study period. A total of 205 cases of suspected afebrile malarial patients were advised MP test. Out of which 116 cases of afebrile malaria were confirmed at Lab. The percentage ratio of total positive MP test was 21%. The ratio of positive febrile to afebrile total MP positive cases was 10:1. Among 116 afebrile patients the presentations were refractory anemia in 42 cases, elevated ALT in 35 cases, thrombocytopenia in 3 cases, and jaundice in 8 cases. All presentations of afebrile malarial patients were normalized after antimalarial treatment. Data were analyzed in excel. Descriptive statistics was applied on qualitative variables. Frequency and percentage documented.
Conclusion: Malaria without fever is a statistically significant cause of morbidity among patients. Although simple to diagnose and easy to treat, omission of lab diagnosis leads to accumulation of untreated cases of afebrile malaria who are advised expensive and time wasting investigations burdening the Medicare system.
Keywords: Afebrile, Alanine aminotransferase, Malaria, Refractory anemia, Thrombocytopenia.
Malaria without fever is symptomatic disease caused by plasmodium infection in which fever is absent. Today malaria is the 4th leading cause of disease burden in developing countries1,2.
Although malaria is recognized as major cause of fever among patients received at military hospitals, yet malaria without fever is a big miss among afebrile chronically ill patients3. Among American troops returning from Afghanistan in 2002, the median time to diagnose malaria was nearly 8 months after their home return. Afebrile malaria was observed commonly in pregnancy, plasmodium falciparum malaria, patients at extremes of age, troops on chemoprophylaxis for malaria, recurrent infections of malaria, immune-compromised patients and patients with end stage organ failure1,5,6.
Malarial plasmodium is parasites of five different species1,6,7,9.
Plasmodium falciparum malaria can occur without mosquito bite by recrudescence. Plasmo-dium ovale, malariae and vivax malaria can occur without mosquitoe bite by recurrence. Incubation period of malaria is upto three years. These stated facts undermine the seasonal and expected incubational pattern of disease10-12.
Afebrile malaria is (premunition), a delayed clinical presentation of acute infection due to partial humoral immunity by IgM, IgG, and IgA antibodies against plasmodium toxins, or incomplete treatment which results in subcritical parasitemia10-12.
For P. falciparum, the Erythrocyte-binding antigen 175 (EBA-175) is required for erythrocyte adhesion and invasion. For P. vivax, this receptor is related to the Duffy blood-group antigen Fya or Fyb.
The disease in human beings is caused by, the direct effects of the asexual parasite, RBC invasion, RBC destruction and by the hosts immune reaction2,13,14.
During intrahepatic or pre-erythrocytic merogony, the swollen infected liver cells eventually burst, discharging motile merozoites into the bloodstream. In P. vivax and P. ovale infections, a proportion of the intrahepatic forms do not divide immediately but remain inert for a period ranging from 3 weeks to [greater than or equal to]1 year before reproduction begins1,15,16. These dormant forms, or hypnozoites, are the cause of the relapses that characterize infection with these two species. In P. Falciparum sequestration of infected RBCs in brain and kidney is cause of later recrudescence1,17.
In P. falciparum infections, membrane protuberances appear on the erythrocyte's surface after the red cell's invasion. These "knobs" present erythrocyte membrane adhesive protein (PfEMP1) that mediates cytoadherence to receptors on venular and capillary endo-thelium,17,18. The processes of RBC cytoad-herence, RBC resetting, and RBC agglutination are central to the pathogenesis of falciparum malaria. They result in the sequestration of RBCs containing mature forms of the parasite in vital organs (particularly the brain), where they interfere with microcirculatory flow and metabolism. Sequestered parasites continue to develop out of reach of the principal host defense mechanism, the splenic processing and filtration. In the other human malarias, sequestration does not occur. Parasites may persist in the blood for months or years (or, in the case of P. malariae, for decades) if effective treatment is not given18-20.
This study was conducted to specifically target segment of afebrile symptomatic malaria patients who had measureable secondary feature which were reversed to normal after effective eradication of plasmodium parasite. Aim is to enlighten the clinicians to advise laboratory diagnostic tests for malaria even in the absence of fever if any of the measureable secondary features is observed in their patients.
MATERIAL AND METHODS
A descriptive cross sectional study was conducted on all cases of laboratory diagnosed malaria at CMH Mangla between Jan 2015 to Jan 2017. Total sample of 1120 cases of malaria were included in the study by non-probability consecutive sampling technique. This sample study included total of 205 suspected cases of afebrile malaria comprising patients with refractory anemia, thrombocytopenia, leukocy-tosis and elevated alanine transaminase (ALT) or bilirubin with negative viral screen in the study. All these cases were advised MP test. Only thin blood film was examined. A total of 116 cases of afebrile malaria and 1004 cases of febrile malaria were reported positive by laboratory. Repeat MP exam of the same patient were not added to the total count. Coincidental laboratory finding of plasmodium or asymptomatic carrier and patients with intermittent fever were not included in afebrile category. Demographic and clinical data was collected in a predesigned performa.
This study was irrespective of sex, race, ethnicity and geographical distribution. Peripheral smear stained by Leishman,s stain were examined under microscope for diagnosis of malaria. All slide negative cases were checked negative on ICT. If positive on smear visual reconfirmation of all cases was done by the author, typing by using ICT ([alpha] easy check 4758 Beechnut Street, Houston TX USA 77096) was done for confirmation. ICT is immunochromato-graphic capture assays with monoclonal anti-bodies to species-specific antigens (histidine-rich protein2 [PfHRP2]), aldolase of plasmodium falciparum and conserved plasmodium antigens (lactate dehydrogenase). For recording secondary measurable feature following cut off levels were laid. Anemia (Hb<9 gm/dl), Thrombocytopenia platelet count (18 micro m/l and raised ALT >55 IU/L, Leukocytosis (>11,000/uL).
Haematology counter Sysmex XP-100 and automated chemistry analyzer Selectra Pro-M were used for measurements. Data was analyzed using percentage of ratios.
Table-I: Febrile malaria total positive cases 1004/5372.
Secondary analytical features###Number###Percentage Ratio
Table-II: Afebrile malaria total positive cases 116/205.
Secondary analytical features###Numbers###Percentage ratio
In this study total number of patients was 5372. Comprising a total of 5167 cases of suspected febrile malaria and 205 cases of suspected afebrile malaria. Among febrile patients 51% were falciparum, 24% were mixed and 25% vivax infection (table-I). Among the afebrile malaria patients 44% were falciparum and 12% mixed and 54% were vivax infections (table-II).
Common clinical presentations in afebrile malaria were weakness, headache, body ache, back ache, joint pains, jaundice, dizziness, vertigo, altered behavior, acute psychosis. The probable cause of afebrile malaria in this study was pregnancy, drug resistance or malaria chemoprophylaxis during UN Missions in Africa.
Anemia (Hb <9 gm/dl) pregnancy, 34 out of a total of 42, were the largest segment of refractory anemia patients21,22 who responded to antimalaria therapy with rapid improvement in Hb and generalized well-being.
Hb<9 gm/dl was taken as positive finding; it results from accelerated RBC removal by the spleen, obligatory RBC destruction at parasite schizogony, and ineffective erythropoiesis. Splenic immunologic and filtrative clearance functions are augmented in malaria, and the removal of both parasitized and uninfected erythrocytes is accelerated. The spleen is able to remove damaged ring-form parasites and return the once infected erythrocytes to the circulation, where their survival period is shortened. The parasitized cells escaping splenic removal are destroyed when the schizont ruptures.
Chronic fatigue was the most common complaint made by patients who were later diagnosed with afebrile malaria with or without anemia.
Thrombocytopenia, decreased platelet count (12,000/uL) increase in absolute neutrophil count occurs in acute response to foreign antigen of plasmodium and bacterial superadded infection. Occurrence rate was 2.4% in febrile and 20.7% in afebrile patients.
Mild jaundice and raised ALT. Jaundice with serum bilirubin >18 um/l was observed in 6.8% of afebrile patients19,20. Hepatocytic injury and cholestatic components of jaundice results when infected hepatocytes are destroyed by hepatic merogony and CD4 + and CD8 + T cells which kill intrahepatic parasites. Hemolytic component of jaundice occur due to shizogony of infected RBCs and by cell-mediated and antibody-dependent cytotoxicity to kill intra-erythocytic parasites.
In this study, four soldiers returning from operational area in Waziristan presented after 3 months with non-viral jaundice which normalized after effective antimalarial treatment. ALT was raised in upto 30.2% of afebrile malaria patients,with and without jaundice. Observed elevation was between 56-200 IU/l. All cases reverted back to < 55 IU/l after anti malarial treatment. ALT elevation was observed most frequently in combination with thrombo-cytopenia and anemia.
Afebrile malaria is prevalent among patients presenting with chronic fatigue and laboratory derangements. More resources should be invested in acquiring better stains and allied facilities for diagnosing plasmodium infection in hospital laboratories.
CONFLICT OF INTEREST
This study has no conflict of interest to declare by any author.
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|Publication:||Pakistan Armed Forces Medical Journal|
|Date:||Apr 30, 2018|
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