ß-globin gene, This point mutation results in replacement oft e

normalglutamic acid residue by a valine and alters the solubil-

ityor stability of the hemoglobin.

Hematology

Most common and the hallmark of sickle cell

• Clinicallypresents with acute, severe pain in the
affected region. It commonly involves bones, lungs.
liverand spleen.
Bone: Sudden attacks of bone pain are due to
ischemia and infarction.Avascularnecrosisof the
head offemuris also Common.
• Lung:involvementpresents withfever,cough,chest
painand pulmonaryinfarctsand knownas acute
chestSyndrome(dangerous).These are sometimes
failure
initiatedbya simple lunginfection.
Acute chest
Spleen:Acute abdominal pain caused by infarcts Of
spleenand leads to autosplenectomy.
Other sites of infarction:Mesenteric infarction re- Renal infarcts
and papillary
sultsin acute abdominalpain, cerebralinfarctions
resultin hemiplegia. infarctionof renal papillae re- Autosplenectorny Pigment
sultsin hematuria.And retinalmicroinfarctsresult Susæptibdity
in lossof vision. infections

. Aplastic crisis: Temporary suppression of bone

marrowerythropoiesis maydevelopdue to an acute
infectionof erythroidprogenitorcells by parvovirus Aseptic bone
B19.
Hemolyticcrisis is characterizedby episodesof in- OstwnyeMis
creasedsequestrationand destructionof red cells.
It presentswith marked increasein hemolysiswith a "OS trait
ulcers
suddenloweringof hemoglobin,rapid enlargement of
liverand spleen and reticulocytosis.
Sequestrationcrisis (describedabove).
Othercrisisencounteredrarelyis hypoplasticcrisisand
crisis (due to inadequate folate). Fig. 8.20: Various effects of vascular occlusion and hemolysis
megaloblastic
in sickle cell anemia.
Writeshort essay/noteon long-term complications of
sickle cell anemia.
Describedin Ihble 8.14.
Investigations
• Evidencesof hemolysis (refer page 572)
• Bloodcount: Hb is in the range 6-8 g/dL with a high reticulocyte count
(10-20%).
• Peripheralsmear: Thecharacteristicred cell whichappearsin smear
is thesicklecell (Fig.8.21).Theseappearas long,curvedcellswith
pointedends. Features of hyposplenism include: Howell-Jollybodies
(smallnuclear remnants), target cells (due to red cell dehydration)
and ovalocytes.
02
Sicklingtest is induced by adding a reducing (oxygen-consuming)
agent like 2% sodium metabisulfite or sodium dithionite to blood
sample.
Sicklesolubility test: A mixture of HbS in a reducing solution (e.g.
sodiumdithionite) gives a turbid appearance because of precipitation Fig. 8.21: Peripheral blood smear with sickle
OfHbS,whereas normal Hb gives a clear solution. cells (arrows).
Hemoglobin electrophoresis: There is no Hb-A, 80-95%Hb-SS and 2-20% HbE HbS is slow moving hemoglobin com-
pared to HbAand HbF. In sickle cell trait (heterozygous state) Hb-S is 20-40%and the rest is Hb-A.
Tests for iron overload: Serum ferritin levels, transferrin saturation, liver iron concentration using liver biopsy specimen,
measurement of liver iron using MRI.
Prenatal diagnosis can be done by analysis offetal DNAobtained by amniocentesis or chorionic villous biopsy.
 Exam Preparatory Manual for Undergraduates—Medicine

Table 8.14: Long-term complications of sickle cell anemia.

Impaired growth and development with IOWweight and delayed sexual maturation
• Chronic infarcts of bones nephritis)
tubulointerstitiat
Infections of bones (Salmonella osteomyelitis), lungs. kidneys (pyelonephritis, chronic
Leg ulcers
cardiomyopathy
Cardiac: Cardiomegaly. arrhythmias. myocardial infarctions and iron overload
hemorrhage and coma
Neurological: Transient ischemic attacks, seizures, cerebral infarction. cerebral
Cholelithiasis
Liver: Chronic hepatomegaly,liver dysfunction.

Iron overload due to repeatedtransfusions

and retinal detachments
Eye: Background retinopathy. proliferative retinopathy, vitreous hemorrhages and fetal death
Pregnancy: Spontaneous abortion, intrauterine growth retardation, preeclampsia

Management
General Measures
Sickle cell disease is a chronic disorder which requires following general measures:
patients with hemolysis.
Good nutrition and folic acid supplementation (5 mg daily) to be given to all
meningitidls, Haemophilus influenzae type B. and
Timely immunizations against Streptococcuspneumoniae. seasonal influenza, Neisseria
hepatitis B virus.
Antibiotic prophylaxis with phenoxymethyl penicillin 500 mg daily starting at the age of 2 months. Older children do not
need continued antibiotic prophylaxis.
Precipitating factors should be avoided or treated quickly. These include avoidance of cold, dehydration and hypoxia.
Prevention. prompt identification and treatment of infections with antibiotics.

Transfusionsshould only be given for clear indications. Transfusion should not be given to patient with chronic stable anemia, those
having minor surgery or having painful episodes without complications.
Indicationsfor blood transfusion:Transfusionis requiredto increasethe oxygen carrying capacity. replace the rigid, sickle-shaped
RBCswith normalcells and to restoreblood flow. Acute transfusionswith packed RBCs can be life-saving and chronic transfusims
reduce the incidence and severityof most complications.
— Heart failure,TIAs,strokes.acute chest syndrome and severe anemia due to aplastic crises and acute splenic sequestration.
Repeated transfusions may be used to reduce the proportion Ofcirculating HbS to less than 20% to prevent sickling. before elective
operations and during pregnancy. Chronic RBC transfusion reduces the chance of recurrent ischemic stroke.
Exchange transfusions may be necessary in patients with severe or recurrent crises or before emergency surgery.
Whethe
exchange transfusionis preferable to simple transfusion in the acute chest syndrome, stroke or Other
acute complications has
been established by clinical trials.
— Infarctioncrises are managed with hydration, oxygen. ana:gesict, nad transfusion
with RBC concentrate in selected cases.
• Iron overload: With repeatedtransfusion,iron overload inevitabiy
develops and can result in heart and liver failure and other
complications. Iron overload is treated by using iron chelatocs
tde/ejcxamine or deferasirox).
Hydroxycarbamide(hydroxyurea):May be used as therapy
for patients with severe symptoms. Hydroxyurea (10-30 mg/kg per day)
increasesfetal hemoglobin and suppress the neutrophil and reticulocyte counts (which
cell crisis).Hydroxycarbamidereduces the may play a major role in the pathogenesis ofsickk
episodes of pain, the acute chest syndrome, and
Senicapoc. a the need for blood transfusions.
Gardos channel inhibitor, prevented erythrocyte
antiplasmodium activity. dehydration in clinical trials of patients with sickle
cell disease. This drug has
Acute Painful Crisis
Require supportive therapy With
intravenous fluids. oxygen,
narcotic.analgesia(morphine) antimicrobial agents and adequate analgesia. Acute
severe pain is treated with
and milderpaincan be relieved
function, reduces vascular by codeine, paracetamol and NSAlDs.
adhesion of red cells and is also Inhaled nitric oxide inhibitsplatelet
requirementsin acutepainful a vasodilator. It can provide short-term
episodes.But, should be restricted to pain relief and shown to reduce opiate
should be employed as experts to avoid hypoxia and respiratory depression. Nasaloxygen
appropriate to protect
Acute chest syndrome arterial saturation.
is treated With antibiotics,
maintenance of arterial oxygenation,
pain relief, bronchodilators. and if required
Chronic leg ulcers: Elevation
of limb. daily dressings with zinc sulfate
and exchange transfusion in
extreme cases.
• Bonemarrow/stem
cell transplantation:
(strokes, recurrent in children and
chest syndrome, or adolescents younger than 16 years
refractory pain) can provide definitive cure. of age who have severe complicati0ß
 Hematology 577

HEREDITARYSPHEROCYTOSIS
WriteShort note on hereditary spherocytosis (HS).
Mostcommoninheritedhemolyticanemia in adults.
. Autosomal dominant inheritance in more than 75%cases.
. DefectintheRBCmembraneisdue tocytoskeletonprotein(e.g ankyrimband3,spectrinorbandprotein 4.2) deficiency.
. Thisresultsin red cells losingpart of the cell membrane they pass throughthe spleen and assume spheroidal shape
as
(spherocytes)that are less deformable (rigid)and more susceptibleto osmotic lysis.
Redcells have decreased life span of as low as Oto 20 days.

ClinicalFeatures
. Diseasemaypresent duringanytime fromthe neonatalperiodto adulthood.
Familyhistory: Most(75%)HSare inheritedas autosomaldominant trait and there is strong familyhistory of anemia,
jaundice,splenomegaly and cholelithiasis.
• Anemiais usuallymild to moderate
Jaundice:Intermittent attacks ofjaundice
splenomegaly:Moderatesplenic enlargementis characteristicand Box 8.4: Complicatbns Of hereditary spherocytosis.
constantfeature. • Cholelithiasis(pigment gallstones)
• Children:Growthretardationdue to hemolysisand bone changes due • Chronic leg ulcers parvovirus B 19
crises due to
Aplastic
to marrow hyperplasia. • Hernolytic crises (rare)
• Adults:Anemia.intermittentjaundiceand moderatesplenomegaly.
• Complicationsof hereditary spherocytosis are listed in Box8.4.
Investigations
Box 8.5: Specific diagnostic tests for hereditary
• Anemia:Usuallymild, but occasionallycan be severe. spherocytosis.
• Peripheralblood filmshowsspherocytes(Fig. 8.22)and reticulocytes.
MCHCis increased. Osmotic fragility testing
Ektacytometry
• Demonstrationof a hemolyticstate: Raisedserum bilirubinand • Acidified glycerol lysis test
urinary urobilinogen. Cryohemo/ysis test
• Specificdiagnostictests are listedin Box8.5.Increasedosmoticfragility • Eosins-maleimide binding test
maybe absentin mild casesand maybe positivein autoimmune
hemolyticanemia.
• NegativeCoombstest.
• Strongfamilyhistory will be present.

Splenectomy is the treatment of choice and sheul± not be done before the
age of 6 years. Splenectomy corrects the anemia and its complications, but
increases the risk of infections. Hence. it should be preceded by pneumococcal
and Haemophi'us influenzae immunization, and followed by lifelong penicillin
prophylaxis).
• Folicacid supplementation in patients without splenectomy.
• Regular blood transfusions are required in few patients with severe disease.
indicatedonly for symptomaticgallstones.
• Cholecystectomyis Fig. 8.22: Peripheral blood smear with numerous
spherocytes (arrow) in hereditary spherocytosis.
THALASSEMIASYNDROME
Writeshort essay/noteon definition, common forms and genetics of thalassemias.
Thalassemiasyndrome is a heterogeneous group of inherited disorders which result fromreduced or absence Ofsynthesis of
Oneofthe globinchains (either a or globin chain).
Classification
syndromes are mainlyclassifiedinto twomain types depending on the defective globinchain a or thalassemia
Thalassemic
8•6).Mode of inheritance is autosomal recessive.Rarely,HBBgene mutation is inherited as autosomal dominant.
(BOX
 Exam PreparatoryManualfor Undergraduates—Medicine

3enetics Box 8.6: Classification of thalassemic syndrort*s.

I-thalassemia syndromes are classifiedinto 3 types depending on the a-thalassemia (synthesis of a chains is affected)
;enetic defect (ß• or ß0): • Silent carrier state
l. ß-lhalassemia major also called Cooley'sanemia, Mediterranean • a-Thalassemia trait
• Hemoglobin H disease
anemia, transfusion-dependentthalassemia is the homozygous Hydrops fetalis (Hb Barts)
disorder and is the most severe form of ß-lhalassemia. Ihere is either ß-thalassemia (synthesis of Chainsis affected)
no productionof ß-chains(ß0)or ß-chainproductionis markedly • ß.thalassemia minor (heterozygous state)
reduced • ß-thalassemia intermedia
The anemia is of severe degree and is transfusion • "-thalassemia major anemia homozygous
dependent. There is high level of HbF in the blood. state)
ß-Thalassemiaintermedia is the double heterozygousstate and
anemia is moderately severe and not transfusion dependent.
ß-lhalassernia minor or P-thalassemia trait is the heterozygousstate and is asymptomatic with mild anemia.
-ThalassemiaSyndromes
ch cell has fourgenes coding fora-globin, twoon each chromosome. Each of the four a-globin genes normally contributes
of the total a-globin chains. Severityof a-thalassemia depends on the number of a-globin genes deleted or affected.
leted genes may vary from 1 to 4.
• Silentcarrier statedevelopswith deletionof one a-chain gene
• a-thalassemia trait: Due to deletion of two a-genes
• HbH disease: Withdeletion ofthree a-genes
• Hb Barts(hydropsfetalis):Developsif all four genes are absent. It is incompatible with life and the infants are either
stillbornor die shortlyafterbirth. Theyare pale,edematous, and have large liver and spleen.
Classicalthalassemiasyndromes(genotypesand laboratoryfindings)are presented in Table8.15.

Table 8.15: Classicalthalassemiasyndromes (genotypes and laboratory findings).

Syndrome Typical findings on CBC Hemoglobinanalysis(HPLCor
electrophoresis)
Alpha thalassemias (reduction in alpha globin chains)
Hydrops fetalis with (—€—€/—€—€) Severe microcytic anemia with hydrops Hb Barts (y globin tetramers); Hb Portland
Hb Barts fetalis;usually fatal in utero (embryonic hemoglobin); no HbF, HbA or
HbA2
HbH disease Moderate microcytic anemia HbH (up to 30%); HbA2 (up to
or

Minor
Mild microcyt:c anemia
or Hb Barts (3 to 8%)

Silent carrier
Normal hemoglobin, normal MCV
Beta thalassemias (reduction Normal
in beta globin chains)
Major (transfusion- ß0/ß0
dependent) Severe microcytic anemia with target
or cells (typical Hb 3 to 4 g,'dL) HbA2 (5% or more); HbF (up to 95%); no
ß0/ß•
Intermedia
(non-transfusion- Moderate microcytic anemia
HbAa (4% or more); HbF (up to
dependent)
Minor (also called
trait or carrier)
ß/ß0 Mild microcytic anemia
or
HbA2 (4% or more); HbF (up to 5%)

MAJOR
Discussthe clinical features,
salient investigations,diagnosis
and management
ß-thalassemiamajor (Mediterranean of ß-thalassemia major (cooleys
or Cooley'sanemia)
is the homozygous
form of ß-thalassemia characterized
 common among
India. it is
. is most common in Mediterranean countries. parts of Africaand Southeast Asia.In South India.
communities(e.g. Sindhi. Punjabi,Gujarati,Parsee) in NorthIndia and less common in extravascularhemolysi$
. Anemia is produced due to diminished symthesisof HbA.ineffectiveerythropoiesisand
leading
production by kidney
Markederythroidhyperplasia:Severehemolyticanemia stimulateserythropoietin (EPO)
to marrowerythroid hyperplasia.
Changes in the bone: Thalassemicfaciesand hair on end appearance of skullX-ray.
Extramedullaryhematopoiesis.
ClinicalFeatures 6 to 9 months
. severe anemia: Infants with thalassemia major are well at birth but develop moderate to severe anemia
retardation) and die
Retardationof growth and development: Untreated/untransfusedchildrenfail to thrive (growth infections.
earlywithin4-5 years of age from the effectsof anemia. Theyare susceptible to recurrent bacterial
. changesinbone:Thosewhosurvivelonger, causeexpansionandwideningofrnarrowandgiVe
bonemarrowhyperplasia
the classical X-ray changes. (frontal bossing
Thalassemic (Chipmunk) facies (Fig.8.23):Due to enlargement and distortion of craniofacial bones tends to
of the skull,prominent malar eminence, depression ofbridge of nose. and hypertrophy of the maxillae, which
exposethe upper teeth).
_ llairon end ('crew-cut') appearance (Fig.8.24):In the skullX-raydue to new bone formation.
. splenomegaly may be massive and enlarges up to 1,500g due to hyperplasia and extramedullary hematopoiesis.
. (hepatornegaly) and lymph nodes also may show extramedullaryhematopoiesis.
• Hemosiderosis:Althoughblood transfusionsimprovethe anemia but iron overloadwill
leadto hemosiderosisand secondaryhemochromatosis.Thismay be due to increased
gastrointestinalabsorption of iron. It damages organs like heart, liver and pancreas.
Cardiachemosiderosisresults in arrhythmias,heart blocksand congestiveheart
failure.
Hepatichemosiderosis results in cirrhosis
. Pancreatichemosiderosisresultsin diabetes.
- Pituitary:Leadsto hypogonadotropic hypogonadism.
• Treatedpatients can survivebeyond 40 years of age.

Investigations
• Peripheralsmear (Fig.8.25):Markedmicrocytichypochromicanemia withmoderate
Manytarget cells (hemoglobincollectsin the
tomarkedanisocytosisand poikilocytosis.
center of RBCs)and nucleated red cells.
• HbFlevel is increased (30-92%)on hemoglobin electrophoresis.
• Markedlyreduced or absent hemoglobin A (HbA). Fig. 8.23: Chipmunk facies in
• Osmoticfragilitytest shows increased resistanceto hemolysis. thalassemia.
• Skullradiographshows a 'hair on end'/crew cut appearance.
• Evidence ofthalassemiaminorin both parents.
• Redcell distribution width (RDW)within normal limits (in contrast to iron deficiencyanemia).
Management
• Aims of treatment: To suppress ineffective erythropoiesis, prevent deformities of bone and allow normal activity and development.
Blood transfusions may be required every weeks. Hyper transfusion to maintain Hb level between 10—12g/dL is probably adequate.
It decreases the effect of chronic anemia and prevents abnormal growth and development. Super-transfusion wherein Hb level is
maintainedat 12 g'dL is designed to completely suppress hematopoiesis.
• Maintenanceof Hb level: Long-term folic acid supplement and regularblood transfusionsto keep the Hb g/dL
• Treatment of iron overload: The iron-chelating agent, desferrioxamine (administered parenterally) is indicated if serum ferritin
pg/L Ascorbicacid 200 mg daily along with desferrioxamineincreases the urinary excretion of iron in response to desferrioxamine.
Deferiprone and deferasirox are oral iron chelators.
• Splenectomy is indicated in children with massive symptomatic splenomegaly and those with progressively increasing requirement
of blood transfusion or hypersplenism.
• Bonemarrowtransplantation in young patients.
• Management of associated complications: For example, congestive heart failure and endocrinopathies.
 Exam Preparatory Manual for
Undergraduates—Medicine

ß-Thalassemia Minor (Trait)

Write short essay/note on thalassemia minor (trait) and thalassemia
interrnedia.
ß•thalassemiaminor is more common than ß-thalassemiamajor.
It isa common carrier(heterozygous) state and isusuallyasymptomatic.
Anemia is mild or absent.
Peripheral blood smear shows severemicrocyticand hypochromic
red cells with target cells. It may be confused with iron deficiency.
Serum ferritin and the iron stores are normal.
• 11belectrophoresis usuallyshows a raised HbA2(3.5-7.5%)and often
a raised HbF.
• Iron should not be given to these patients unless there is associated
irondeficiency.
Genetic counseling to prevent transmission of carrier state from both
parents. Fig. 8.24: Skull X-ray showing crew-cut
appearance due to new bone formation.
Prenatal diagnosisbychorionicVillibiopsyat I weeks.
It may be associatedwith other hemoglobin abnormalities. Examples,
HbS/ß-thalassemia, HbC/ß-thalassernia, HbE/ß-thalassemia. c
ß-Thalassemia Intermedia
• Clinicalentityin whichpatientshavea clinicalspectrum intermediate
between thalassemiatrait and thalassemia major. 00
• Patientsare anemic and generally have mild to moderate anemia (Hb
7-9 g/dL).
o
• Nottransfusiondependent.
• Mildsplenomegaly,bonedeformities,gallstonesand chronic leg ulcers OO
may be seen.
• Folicacid supplementation should be given. o
GLUCOSE-6-PHOSPHATEDEHYDROGENASE (G6PD) Fig. 8.25: Peripheral blood smear in
DEFICIENCY ß-thalassemia showing target cell (arrows).
Discuss the etiology, precipitating causes, and management of glucose-6-phosphate
dehydrogenase(G6PD) deficiency.
Glucose-6-phosphatedehydrogenase (GGPD)is the initial and rate-limiting
step in the hexose monophosphate (HMP)
shunt of the Embden-MeyerhOfpathway.
• G6PDis the onlysource of NADPHand NADPH
is required for the generation of glutathione (GSH), which protectred
cellsfromoxidativeStress(Fig.8.26).
• G6PD-deficient patientsmaydevelopacute hemolytic anemia after
• G6PDdeficiencyis an X-Iinked exposure to any oxidative stress.
disorder and is the most
common enzyme deficiency. Glucose-6-phosphate
• RBCsdeficientin G6PI)are
in reducedstate.These unable to keep glutathione
RBCSare susceptibleto injury
oxidantsof both exogenousand by
• Morethan fourhundred endogenous origin.
G6PDgenetic variants are
but most are harmless.The known, NADP
three common variants
G6PDA: The minus are:
sign indicates absence of
activity.Hemolysisdevelops enzyme Glutathione
drugs (primaquine) or when exposed to oxidant
infections.The hemolysis reductase
to moderate and is limited is mild
to the older RBC-s.
G6PD or G6PD GSH
prevalent in the MiddleMediterranean/Wi1d type: It
East and is the severe is
deficiency.This is the form of Glutathione
India. Other variants inmost common variant
seen in
Kalyan,and G6PDOdisha.India include G6PD Kerala- Ont%lnts
G6PDCanton seen in druqa
Chinese.
Fig. 8.26: Role of G6PD
against injury
 Hematology

Clinical Features
. Mostpatients with G6PDdeficiencyremain
clinicallyasymptomatic;however,all of them have an increased risk Of
developingclinicallysignificantsyndromes:( 1)
acute hemolyticanemia (AHA).(2) neonatal jaundice (NNJ).and rarely,
(3)Chronic non-spherocytic hemolyticanemia
(CNSHA).
. Acute hemolytic anemia: Due
to intravascularhemolysisis the most dramaticclinicalpresentationof G6PDdeficiency.
It developsafter exposure to an oxidative
stressand the triggersinclude:
Drugs: Antimalarials(primaquine,quinine, chloroquine).sulfonamides(sulfamethoxazole). antibacterial/antibi-
otics (cotrimoxazole,nitrofurantoins).antipyretics/analgesics(acetanilidephenazopyridine)dapsone, quinidine,
methyleneblue,nitrofurantoins,etc.
2. Favabeans.
3. Infections:Viraland bacterial.
The exposureto triggeringagents produceshemolytic
attackwith rapid developmentof anemia and hemoglobinuria
(colacoloredurine). Rarelyacute renal failuremay develop.
Ihe onset can be extremelyabrupt, especiallyfollowingingestion
ofthebroadbeans (favisrn) in children.
. Neonataljaundice is a feature of Mediterraneantype. Hemolyticanemia is very rarelysevere. Jaundice may be due to
decreasedhepatic elimination of bilirubin.Severe neonatal jaundice if not adequatelytreated with phototherapy may
resultin kernicterus or even death.
• Chronic verysmallminorityofpatients,Suchpatient isalways
a male and usuallyhas a historyof severe neonatal jaundice, chronic anemia. The degree of chronic anemia is variable
and some patients have may require intermittent transfusions.Ibey have reticulocytosis,gallstones and splenomegaly.
Hemolysisis mainlyextravascular.
G6PDdeficiency(Africanvariety) has a protectiveeffectagainst Plasmodiumfalciparum.
LaboratoryFindings (Investigations)
• Evidenceofintravascular Raisedunconjugated
bilirubin,hemoglobinemia, highLDH,and
hemoglobinuria,
lowor absent plasmahaptoglobin.
• Anemia: Usuallyrange from moderate to extremelysevere. It is due to both intravascularand extravascularhemolysis.
• Peripheralbloodfilm:
Normocyticand normochromicwith anisocytosis,polychromasia(reticulocytosis), poikilocytesand spherocytes.
Bite(blister) cells are red cells in which parts cf them appear bitten away.
Heinzbodiesconsistof membrane-bound
precipitatesof denaturedhemoglobin(methemoglobin)and represents
oxidativedamage. They are seen as dark inclusions within red cells and can be demonstrated by supravital staining
withmethylviolet.
• Confirmationof diagnosis: By estimatingG6PDactivityof the red cell.'Ibis should be estimated severaldays after the
acutehemolyticepisode.Thisis becauseif done during or immediateiyafter acute hemolysismay give a falselynormal
valueas the young red cells and reticulocytes have near normal G6PD levels.

Treatment(management) of G6PD deficiency

• Removal of the triggering agent and avoiding its further exposure to triggering factors in previously screened patients. Once cause is
recognized, in most cases no specific treatment is required. Management of neonatal jaundice is similar to any other cause of neonatal
hyperbilirubinemia.
• Supportive therapy for anemia:
Blood transfusion
— Regular folic acid supplements in CNSHA
• Treatmentof infection and genetic counseling.

MISCELLANEOUS ANEMIAS
Writeshort essay/note on the causes and management of normocytic anemia.

NormocyticNormochromic Anemia
Ormocytic,normochromic anemia is characterized by normal size of the RBCsand normal MCV(Ikible 8.16).
 anemia.
ble 8.16: Various causes of normocyttc. normochrorntc
redcenproduction loss
Acute blood
Anernia of chronic disease
Chronic renal fajure Hematological disorders cell disease)
Chronic liver disease Hemoglobinopathies (sickle
Endocrine disorders Hereditary spherocytosis
dehydrogenase(G6PO)
— Hypopituitarism Glucose-ephosphate
(disserninated intravascular
Hypothyroidism Microangiopathic anemias
thrombotic thrombocytopenic purpura,
Hypoadrenalism coagulation (DIC).
syndromes)
Hematological disorders hemolytic uremic
anemia
Marrow hypoplasia or aplasia Autoimmune hemolytic
hemoglobinuria
Myeloproliferativeneoplasms Paroxysmal nocturnal

— Sideroblastic anemia
of plasma volume: Pregnancy

disease.
Treatment of the underlying
8.17)
Hypochromic Microcytic Anemias (Table
ifferential Diagnosis of anemia. How will you
differentiate various causes of hypoch-
microcytic hypochromic
write short note on causes of
romic microcytic anemias?

Anemiaofchronic Sideroblasticanemia
Iron deficiency Thalassemiatrait
disease
Low normal or normal Low in inheritedtype
Reduced Very low for degree of often raised in acquired type
anemia
Reduced (<50 ugldL) Raised
Reduced (<30 pg/dL) Normal to high
Serum iron (normal 170 pg/dL) Normal
Normal Reduced(<300 pg/dL)
Serum TIBC (total iron binding
Raised (>350 pg/dL)
capacity) (normal 300-350 pg/dL)
Normal (50-30 Normal or raised (30—200 Raised
m ferritin (normal 15-300 Reduced (<15 gg/dL)
gg/dt) pg/L)
Normal Normal or raised
Increased Normat or raised
erum soluble transferrin receptors
Present Present
Absent Present
in marrow
Present Absent or reduced Ring forms
in erythroblasts Absent
Increased Normal Reduced
lobin Aa (normal <3%) Reduced
Normal Normat High
led cell distribution width (ROW) High

Ideroblastic Anemias
Writeshortessay/noteon sideroblastic anemias.
efinition
deroblasticanemiasare rare inherited or acquired disorders of refractory anemia, characterized by:
Adimorphic peripheral blood picture. Microcytic hypochromic red cells in hereditary form and macrocytic in the acq
forms of the disease mixed with normochromic cells.
' Presenceof ring sideroblasts, excessstorage iron in the bone marrow and increased serum iron concentration•
diagnosticfeatureis the presenceof ring sideroblasts in d
the bone marrow. The iron-laden mitochondria surround
nucleusof erythroblastsand appear as the pathognomonic
'rings' of iron granules with Prussian blue staining(Per
reaction).
Tinyiron-containinginclusionscalledas Pappenheimer
bodies in the red blood cells (stain positively by Prussian
staining).
Ineffective erythroid hyperplasia due to non-viable
sideroblasts.
 Hematology 583

cwsification of Sideroblastic Anemia (Box

8.7) Box 8.7: Classificationof sideroblastk anemia.

%thdrawal of causativeagent: Sorne patients Inherited sideroblastk anemia

respond when the drugs, • X.linked disease—transmittedby females
toxins or alcohol are withdrawn. Acquired sideroblastic anemia
• cases may responds to pyridoxine • Primary: Myelodysplasia
Supcx»rtivetreatrnent with transfusions folic acid. • Secondary
Drugs. e.g. isoniazid. cycloserine. chloramphenicol,
busulfan. D-penicillarnine
Microcytosisis often seen in hereditary forms, but Alcohol abuse
or even macrocytic RBCsmay be seen, normochromic, Lead toxicity
especiallyin Myeloproliferative neoplasms
the settingof myelodysplasiaor in a rare X-Iinkedhereditary Myeloid leukemia
as Pearson's syndrome. form
known Primary pyridoxine deficiency
— Others (e.g. rheurnatoid arthritis. carcinoma)
HereditarySideroblastic Anemias
Hereditarysideroblasticanemias comprise a clinically,
disorders.It may be inherited as X-Iinked or an geneticallyand hematologicallyheterogeneousgroup of rare
autosomal (dominant or recessive)disorder."Ihese patients generally have
Jowlevelsofö-aminolevulinicacid synthase (ALAS)
enzyme in the normoblastsleadingto defectivesynthesis ofhemoglobin.
paroxysmalNocturnal Hemoglobinuria
Writeshort essay/note on paroxysmal nocturnal hemoglobinuria (PNH).
paroxysmal nocturnal hemoglobinuria(PNH)is a rare acquired non-malignant, genetic defect due to mutation in the
hematopoieticstem cell. These clone of red cells are particularly sensitive to destruction by activated complement.
plateletsand granulocytes are also affectedand there may be thrombocytopeniaand neutropenia.
Etiologyand Pathogenesis
Thestemcellsand their progenyhave deficient synthesisof glycosylphosphatidylinositol(GPI) linked proteins namely
(l) decay-accelerating factor or CD55, (2) membrane inhibitor of reactive lysisor CD59.This is most important and a potent
inhibitorofCn3and prevents activationof the alternative complement pathwayon their membrane. In PNH,the red cells are
abnormallysensitive to complement-mediated intravascularhemolysis.Severityofhemolysis is proportional to the number
oftheseabnormal red cells. The molecular basis of PNHis the mutationsin the pig-A(phosphatidylinositolglycan protein A)
responsiblefor synthesis of the GPIanchor.
Clinical
Features
• Mainlyseen in adults, usually in middle age.
• Bothsexes equally affected.
• Intravascular
hemolysis:Characteristically,
onlythe urinevoidedat night(nocturnal)and in the morningon waking
isdarkin color.The hemolysis is due to reduced pH of blood during sleepwhich enhances the activityof complement.
Hemoglobinin acidic urine is converted into acid hematin which colorsthe urine dark brown. Urinary iron loss may be
to cause irondeficiency.Otherfeaturesinclude:abdominalpain/dysphagia,erectiledysfunction,pulmonary
sufficient
hypertension
and renalinsufficiency.
• Mildjaundiceand mild hepatosplenomegaly
oftenpresent.
• Thrombosis:Verycommon involving the hepatic (Budd-Chiari syndrome), portal or cerebral veins is often the leading
cause of death.
• Maybegin or progress to aplastic anemia.
Diagnosis
• Peripheral smear: Anemia, reticulocytosis, varying degrees of thrombocytopenia and leukopenia (pancytopenia).
• Featuresof intravascular hemolysis like raised bilirubin, hemoglobinemia, hemoglobinuria and hemosiderinuria are
present.
• Bonemarrow is sometimes hypoplastic (or even aplastic) despite hemolysis.
tests cannot reliablydetect small populations ofaffected
• Diagnosisis confirmed by Ham's test and sucrose lysis test, These
redcells.
become more fragilewhen they are placed in mild acid.
Ham's acidified serum test: Checkswhether red blood cells
anemia.
Ham test can also be positive in congenital dyserythropoietic
Sucrose hemolysis test: PNH patient's red cell undergoes lysis when incubated low-tonic-strength solution Ofsugar
sucrose. It can be positive in megaloblastic anemia and autoimmune hemolytic anemia.
 584 Exam Preparatory Manual for Undergraduates—Medicine

a rapid and sensitive

• Flowcytometry: Detectsred cells that are deficientin GPI-linked proteins (CD55and CD59).It is
test for diagnosis.
• NAPscore: (norma140to100),becauseNAPisaGPI linked

infections.
Supportive measures: Blocxi transfusions (for patients with severe anemia) and control of
• Iron therapy Often necessary due to loss in urine.
the cleavage ofC5
• Anti-complementtherapy:Eculizumab isa humanized monoclonal antibodythat prevents transfusion.
and the need for
Of the membrane attack complex) and reduces intravascular hemolysis. hemoglobinuria
Long-term anticoagulants may be necessary for patients with recurrent thrombotic episodes.
• Steroids may be useful in some cases.
• Bone marrow (stem cell) transplantation is Curative.
acute myelogenous leukemiaor a
Progress: PNHpatientsare also at increasedrisk for developingaplasticanemia or
myelodysplastic
syndrome.
Methemoglobinemia
Writeshort essay/noteon methemoglobinemia.
• Normaloxygentransportdependson the maintenance of iron in hemoglobin in ferrous (reduced) form
• Methemoglobin(Ili) is a hemoglobinin whichthe iron is in oxidizedferricformand unable to combinewithoxygen.
Normal RBCscontain less than 1% methemoglobin.Increasedamount of methemoglobin in the RBCs is called
methemoglobinernia.
• Clinically,when methemoglobinlevelis more than 1.5g/dL, the patient developscyanosis.At higher levels,it produces
headache, weaknessand breathlessness.At higher methemoglobin levels,respiratory depression, altered sensoriurn.
coma, shock, seizures,and death may occur.
Causes of Methemoglobinemia
• Hereditary.Deficiencyofmethemoglobinreductase,cytochromeB5reductasedeficiency.
Acquired:Exposureto certaindrugs and toxins (e.g. nitrites and nitrates, nitofurantoin, chloroquine, napthalene, local
aneshthetics (procaine, lidocaine), primaquine, dapsone, Box 8.8:
Classificationof autoimmunehemolyticanemia
sulfa drugs phenacetin, phenazopyridine, metoclopramide, according to type of antibody.
nitroglycerine),copper sulfate.
Basedon antibody type
Warm antibody type (lgG antibodies active at 37 •C)
• Methemoglobin reductase deficiency: Ora! methylene blue or Primary (Idiopathic)
ascorbic acid. Secondary
• Severe methemoglobinemia: Intravenous methylen•.• • Autoimmune disorders (systemic lupuserythernatoms
Ensure Others)
adequate tissue oxygenation.
• Drugs (e.g. methyldopa. penicillins, quinidine)
• Lymphomas, HodgkinS lymphoma, Chronic
Autoimmune Hemolytic Anemia (AIHA) lymphatic leukemia
Autoimmune hemolytic anemias are a group of acquired • Cold agglutinin type (lgM antibodies active at 4—18•C)
disorders resulting from increased red cell destruction due to Acute
red • Mycoplasmal infection
cell autoantibodies. • Infectious mononucleosis
Chronic
Writeshort essay/note on autoimmune hemolytic
anemias. Idiopathic
Classificationof Autoimmune Hemolytic Anemia • Lymphomas
• Cold hemolysin type (Donath-Landsteiner antibodies)
It may be classifiedbased on: Rare; seen mainly in children; usually postviral
I. IYpeofantibody: Interaction of the
autoantibody with the red
cell antigen is dependent on the temperature, Box 8.9: Classification of autoimmune
i.e. warm or cold hemolytic anemia basd
type (Box 8.8). on etiology.
2. Etiology(Box8.9).
• Idiopathic acquired hemolytic
anemia (50%)
WarmAntibody Immunohemolytic Anemia • Secondary acquired hemolytic anemia
(50%)
— Drugs: For example, methyldopa,
• Warm antibody type is the most penicillins,
common type (50-70%). Mycoplasmal infection
• The antibodies are mainly ofIgG type. — Infectious mononucleosis
The antibodies combine
with red cell antigen at 370C and hence known Autoimmune disorders(systemiclupus erythenutNß
antibody. as warm others)
— Lymphomas
 585
Hematology

features
Theymayoccurat all ages and in both sexes.although most frequent in middle-agedfemales•
Theymaypresent withanemia. jaundice. hepatosplenomegalyand manifestationsand underlying disease.
Excludeunderlyingsystemic lupus erythematosus,lymphoma and leukemia.

of hemolyticanemia
Evidence
spherocytosis(due to red cell damage) and macrocytes in peripheral blood.
Directantiglobulin(Coombs)test is positive.
. Autoantibodiesmay have specificityfor the Rhbloodgroup system (e.g. for the e antigen).
Insomecases,autoimmune thrombocytopenia and/or neutropenia mayalso be present (Evans' syndrome).
(Coombs)test (Fig.8.27)
Antig/obu/in
Writeshort essay/note on significance of Coombs test.
Thereare twotypes namely direct and indirect.
Writeshortnote on Coombs test.
Direct(Coombs)antiglobulin test (DAT)detects the immunoglobulin(IgG)antibody and/or C3 complement
on patient'sRBCs.Patient's red cells are washedand suspendedin saline.Antiglobulinserum is
(usuallyCn3d)
added.Agglutinationof red cells indicates the presenceof antibodyon the surface of RBCsand interpreted as
positive DAT.
2. Indirect(Coombs)antiglobulin test (IAT) detects the immunoglobulin (lgG) antibody or C3 complement (usually
C3d)in thepatient'sserum.ORh +venormal red cells and antiglobulinserum is added to the patient's serum.
ofRBCsindicatesthe presenceofantibodiesin the patient's serum and test is reported as positive for
indirect antiglobulin test.

• (e.g. prednisolone in doses Of rng/kg daily) are effective in about 8096 Of patients. Initially for first 2—4weeks.
prednisolone60 mg daily, followed by gradual tapering of the dose. When a dose of 20 to 30 mg daily achieves a persistent remission
(indicatedby the stable Hb level and decreasing reticulocyte count), it is recommended to give prednisone on alternate day. Patients
withrapid hemolysis may require intravenous methylprednisolone at a dose of 250—1000mg/day for 1 to 3 days.
• AWE blood transfusion as far as possible, because autoantibodies may cause difficulty in cross-matching the blood.
• Danazo/can be used in along with prednisone as first line therapy allowing for a shorter duration of prednisone therapy.
Splenectomy may be necessary.
- Ifthereisno response to corticosteroids
- Ifthe remission is not maintained when the dose of pred't;soJone reduced
Requirethe equivalent of more than 10-15 mg prednisone per day to maintain an acceptable hemoglobin level.
• Intravenousimmunoglobulin may also be used as a temporary measure before performing splenectomy for patients refractory to
conventionaltherapy with corticosteroids.
• Rituximab isa monoclonal antibody directed against the CD20 antigen expressed on B lymphocytes.
Use: Useful in refractory cases and also in secondary type of warm AIHA.
Adverse effects: Hypotension, fever, chills, rigors, hypertension. bronchospasm, pulmonary infiltrates, acute respiratory distress
syndrome,myocardial infarction, cardiogenic shock.
- Contraindication: Untreated hepatitis B infection.
• Otherimmunosuppressive drugs (e.g azathioprine, cyclophosphamide and cyclosporine) may be effective when there is no response
to Steroids, rituximab and splenectomy.

ColdAgglutinin Autoimmune Hemolytic Anemia

Discusscold hemagglutinin disease (CHAD) in brief.
• Itisless common than the warm antibody type is caused by so-called cold agglutinins.
• Theseantibodiesbind to red cell antigens at low temperatures (4-18 oc), i.e.avidityof red cell to antibody
increases as the
temperaturefalls.
• Theantibodiesare oflgM type.
• Clinically,it presentsacrocyanosis(i.e. blue color ofthe fingertips, toes, nose and ear lobes) afterexposure to
areadvisedto avoid cold. Patients
exposure to cold.
ions
Redcellsagglutinate in the cold or at room temperature.
 Exam PreparatoryManualfor Undergraduates—Medicine

Patienrs RBCs coated

with antibodies

(Coomt:sJ test-IAI
Coombs serum

Patient's serum
with free antibodies

000
•O •ve red cells
00 coated with antibodies
Patmrs serum
with free antibodies rod cells
Fig. 8.27: Method of direct and indirect methods of antiglobulin test (Coombs test).
• Direct antiglobulin test is positive with complement alone.
• MonoclonalIgMantibodies.
Treatment: Rituximab (anti-CD20) is successful in some cases. It does not respond to steroids alkylating agents and splenectomy.

Paroxysmal ColdHemoglobinuria
Writeshort essay/note on paroxysmal cold I?C.F).
• Paroxysmal cold hemoglobinuria (PCI/) isa rare condition often followscommon childhood viral infections (e.g.
mumps and chickenpox).
• TheautoantibodiesareIgGtypeandbindtored cellsat lowtemperaturcsandfixthecomplement.lheseareautoantibodie
directedagainst the P antigen system on red cells.
• Since complement cascade functions more efficiently at 370C, upon warming, complement gets activated resultingin
intravascularhemolysisand hemoglobinuria.
• Donath-Landsteinertest: Hemolysisis demonstrated in vitro by incubating the patient's red cells and serumat
then warming it to 37'C.
• Hemolysisis usuallytransient and found mostly in children. Supportive transfusions of warmed blood may be
• DATis usually negative.

Anemias Due to Blood Loss

Write short essay/note on anemias due to blood loss.
Anemias due to bloodlosscan be acute or chronic.Bloodloss causes anemia by two main mechanisms:
I. By the direct loss of RBCs.
2. Continuousbloodlossgraduallydepletes the iron stores resulting in iron deficiency.
Anemias Due to AcuteBloodLoss
A healthy adult can lose about 500 mL of whole blood without any untoward effect (e.g. blood donation). Acuteblood
(hemorrhage) causes loss of intravascularvolume over a short period and if
massive can lead to hypovolemicshod and
death.Theclinicalfeaturesof acutebloodloss anemiadepend on:
• Rateofhemorrhage
• Nature of the bleeding (externalor internal).
 Hematology

CÆnkal features
Afterthe sudden loss of a large volumeofblood be identified.
. Stage I: The dominant feature is hypovolemia overshort period—threeclinical/pathophysiologicstages canThe pulse rate
and sweating.
is raised and blood pressure is maintained. during which the patient appears pale, coldare postural hypotension and
Earliestsigns especiallywith internal bleeding affected.
tachycardia.Anordinarybloodcount willnot show
anemia becausethe hemoglobinconcentrationis not
. Stage2: During this stage,the bodywillshift
fluid from the extravascular to the compartment, producing
intravascular
hemodilution.Thus, the hypovolemiagradually
converts to anemia. Anemia appears in 24-36hours.
• Stage 3:
_ If bleeding stops, anemia gets
corrected in a fewweeks,providedbody iron supplyis normal.
If bleedingcontinues,compensatorymechanisms
failand hypovolemicshockdevelopsand resultsin death.
Investigations
Hemoglobinand hematocrit:
- Normalin earlystages(beforehemodilution)
Reduced in 24—36hours due to hemodilution
. peripheralsmear shows normocyticnormochromic tran-
anemia and polychromasia(due to increasedreticulocytes).A
sient leukoerythroblastic blood picture may be seen in very early stages.
Treatment: Replacement of blood loss by transfusion of whole blood or packed red cells.

Anemiaof ChronicBlood Loss

In chronicblood loss,compensatorymechanisms replenishthe plasmavolumeand red cell loss.It produces anemia when
the rateof blood loss exceedsthe regenerativecapacityof the bone marrowor when iron reservesare depleted and results
inirondeficiencyanemia.
Anemia of Chronic Disease
Writeshort essay/note on anemia of chronic disease.
Oneofthemostcommontypesofanemiain developingcountries,occurringin patientswithchronicinfections(alsoknown
asanemiaofinflammation).
Causes
It occursin a wide variety of chronic diseases.
• Chronicinfections: Infectiveendocarditis,tuberculosis,osteomyelitis
• Chronicimmune disorders: Crohn'sdisease,rheumatoidarthritis,systemiclupuserythematosus(SLE)
• Associatedwith malignant tumors (e.g.carcinomaoflungand breast).
li•rmanemiaof chronicdiseaseis not usuallyappliedto anemiasassociatedwithrenal,hepaticor endocrinedisorders.
Pathogenesis
• Impairediron utilization: Chronicinflammatorydiseasesactivmemacrophagesto secrete cytokineslike interleukin-6
(IL-6)and tumor necrosisfactor(TNF).'lherr is decreasedtransferof iron from the storage pool to bone erythroid
precursors.
• Decreasederythropoietin (EPO) production and response: Resultingin inadequate proliferation of progenitors.
• DecreasedRBCsurvival is due to extracorpuscular defect.
Investigations
• Peripheralsmear mainly shows normocytic normochromic red cells.
• Increasedstorage iron in the marrowand revealedbyPrussianbluestaining.
• Raisedserum ferritin becauseof the inflammatoryprocess.
• Reduced total iron-binding capacity (TIBC).
• Reduced serum iron.
• Reduced transferrin levels.
• Normalserumsolubletransferrinreceptorlevel.

• Treatthe underlying disorder.

• Recombinanterythropoietin therapy may be tried ifthe anemia is not corrected after treatment ofthe underlying disorder.
 Exam Preparatory Manual for Undergraduates—Medicine

Aplastic Anemia
management of aplastic
Define aplastic anemia. Discuss the etiology/causes, clinical features. investigations and

Definition
Aplastic anemia is characterizedbypancytopenia (anemia, neutropenia and thrombocytopenia) with hypocellular (aplasia)
bone marrow(Jessthan 30%cellularity),and there are no leukemic or other abnormal cells in the peripheral blood or bone

Causes (Table 8.18)

ClinicalFeatures
Insidiousin onset and initialpresenting feature depends on which cell line is predominantly affected.
• Anemia:Causesprogressiveweakness,lassitude,fatigability,pallor and dyspnea.
• Neutropenia:Presentsasfrequent infections(mucocutaneous bacterial) or fatal infections. Ihese include sore throat,oral
and pharyngeal ulcers,feverwithchillsand sweating, chronic skin infections, recurrent respiratory infections, pneumonia
and septicemia.
• Thrombocytopenia:Resultsin bleedingmanifestationsin the form of petechiae,bruises and ecchymoses.Theseinclude:
bleeding into skin (ecchymoses,petechiae), epistaxis, menorrhagia, bleeding from gums and Gl tract, retinal hemorrhage
and cerebralhemorrhage.Bleedingis often the predominant initial presentation with bruising, with minimal traumaor
blood blisters in the mouth.
Physicalfindings:Includeecchymoses,bleedinggums and epistaxis.Mouth infectionsare common. Lymphadenopathy
and hepatosplenomegalyare rare. In the presenceof splenomegaly,the diagnosis of aplastic anemia should not be made.
• Aplasticanemia may coexistor progressto clonal disorders,
such as paroxysmalnocturnal hemoglobinuria (PNH), myelo- Table 8.18: Common causes of aplastic anemia.
dysplastic syndrome (MDS)or acute myeloid leukemia.
Fanconi'sAnemia Fanconi anemia
Diamond-Blackfananemia
• Fanconi'sanemia is inherited as an autosomal recessive Telomerase defects
disorder
• It is associated with skeletal (short stature), renal (ectopic Acquired
kidney,horse-shoekidney)and centralnervoussystem(hy- Idiopathic of aplastic
• Acquired defects in stem cell anemia
drocephalus)abnormalities.It usuallypresents between5
to • Immune mediated • Idiopathic
10years of age. Progressivepancytopenia. Predisposition
to he- Secondary Ingestion of drugs
matologicmalignancies (MDS< acute myeloid leukemia) and chemicals
solidtumors(squamouscell carcinomasof head and • Chemicalagents
Idiosyncratic
and neck and Dose related • Irradiation
anogenitalregion).
• Cytotoxicdrugs (alkylating Infections
Investigations agents, antimetabolites) • Inherited
Diagnosisis made with: (I) pancytopenia, • Benzene
(2)
cytesand (3)hypocellularor aplasticbone absence of reticulo- Inorganic arsenicals
fatspaces.
marrowwith increased • Chloramphenicol
• Hemoglobinis decreased. Idiosyncratic
• PCVdecreased. Chloramphenicol
• Reticulocytopenia(variesfrom Phenyl butazone
0.5 to 1%)is a characteristic Penicillamine
feature.
• Peripheral blood shows Carbamazepine
pancytopenia Gold salts
• Bone marrow study: Marked
of more than 70%of the hypocellularity with replacement — Organic arsenicals
marrowcells by fat. Methylphenylethylhydantoin
Paucityof all erythroid,myeloid Hematopoiesis:
and megakaryocyticprecur- Physical agents: Whole-body
sors. Initial stages may show focal
areas of hematopoiesis. irradiation
Lymphocytesand plasma cells are
iron stores prominent. Bone marrow • Viralinfections
are usually increased.
Hepatitis (unknown type)
Serumiron and transferrin
saturation:
Ferrokineticstudies:DelayedclearanceIncreased
Epstein-Barr virus infections
of radioactiveiron from Cytomegalovirusinfections
the blood and increased uptake
by the liver. Herpes zoster (Varicella
zoster)
HIV
 Hematology

Severeaplasticanemia
presenceof two of the followingfour features is needed to diagnose severe aplasia (i) neutrophil count of COSx 109/L
(Z)platelet count Of< 20 x 109/L, (3) reticulocyte Count of < 40 x IO'/L, 4) marrow cellularity
Treatment/Management
Removal of the causative factor/agent wherever possible (refer causes of aplastic anemia in Table 8.18).
providing supportive care While awaiting bone marrow recovery:
• Preventionand treatment of infections
• TreatmentOf hemorrhage
• Treatment Of anemia by red cell transfusion
Growth factors: Granulocyte colony-stimulating factor (G-CSF), Thrombopoietin (TPO) receptor agonists
Severeaplastic anemia
. Bone marrow (stem cell) transplantation is the treatment Of choice for patients under 40 years of age who have an HCA-identical
sibling donor. Patients over the age of 40 have high risk Of graft-versus-host disease.
. Immunosuppressive therapy is used for patients without HLA•matchedsiblings and those above40 yearsofage.
Eltrombopag. horse ATG. cylcosporine. and prednisone in combination produces hematological response rate of 60—80%. These
agents destroy activated suppressor cells.
. Androgens (e.g. oxymetholone) aresometimes useful in patients not responding toimmunosuppression andthosewith moderately
severe aplastic anemia.
. Steroids havelittle role in severeaplasticanemia butareusefulforserumsicknessinducedbyALG.However, steroidsusedinchildren
with congenital pure red cell aplasia (Diamond-Blackfan syndrome) and in some adults with pure red cell aplasia associated with a

. Anti-IL-2 receptor antibody (daclizumab)and arsenic trioxide have been tried.

AcquiredPRCAmay develop for unknown reasons, but more commonly it develops in association with specific types of
malignancy,infectionor drugs. Mostcommonly,acquiredPRCAdevelopsas a complicationof a neoplasticprocesssuch
as a thymoma B- or T-cell chronic lymphocytic leukemia, non-Hodgkin'slymphoma or an autoimmune disorder such as
rheumatoidarthritis or SLE.
Investigationof a case of anemia is presented in Flowchart 8.1.
pancytopenia
Write short essay/note on the causes of pancytopenia.
Definition:Combination of anemia. leukopenia and thrombocytopenia.
Causesof Pancytopenia (Table 8.19).
Table 8.19: Causes of pancytooelli.*
• Decreasedbone marrow function Tv: nors (Carcinoma)
- Aplastic anemia Granulomatous diseases (e.g. disseminated tuberculosis, Sarcoidosis)
• Idiopathic tqutritional deficiencies:
• Secondary e Megaloblastic anemia (vitamin BIZ and folic acid deficiency)
• Inherited Paroxysmal nocturnal hemoglobinuria
Myelodysplastic syndromes (MDS) Myetofibrosis(rare)
Bone marrow infiltration with: Others: Hemophagocytic syndrome, overwhelming sepsis, systemic
• Leukemia (e.g. Hairy cell leukemia) lupus erythematosus
• Lymphoma Drugs
• Myeloma
• Increasedperipheral destruction
Hypersplenism

DISORDERS OF WHITE BLOOD CELL

NON-NEOPLASTIC DISORDERS OF WBC
Leukocytosis
Writeshort note on leukocytosis.
9
Anincreasein the total number Ofleukocytes in the blood more than 11,000/cumm (11 x 10 /14).Usuallydue to increase
in the neutrophils,but may also be due to increased lymphocytes (or rarely monocytes and eosinophils).
Causes:Commoncauses of leukocytosisare shown in Box8.10.

300 of 632
 Infectious Diseases 173

Nocardiosis
Nocnrdiosisis a gram-positivebacterial infectioncaused by aerobic actinomycetesof the genus Nocardiafound in the

Modeof infection: It is an uncommon infectionwhich occursmost frequentlyby direct traumatic inoculation or

occasionallyvia inhalation or ingestion.
Clinicalfeatures
localizgd cutaneous infection: It causes localizedcutaneous ulcers or nodules, most frequentlyin the lowerlimbs. In
tropicalcountries,chronic destructive infectioncan produce actinomycetoma(refer above on page 172),involvingsoft
tissuesand bone.
systemicNocardia infection: Occursmostlyin immunocomprornisedindividualsand resultsin suppurativedisease
withlungand brain abscesses.
Microscopicappearance: Nocardia spp. appears as long, filamentous, branching gram-positive rods. They are weaklyacid-
fast.Theycan be cultured but need prolonged incubation.

It deperxis on the result of culture and sensitivity.

Systemic infection: Needs combinations of ceftriaxone. meropenem, amikacin and co-trimoxazole. They are to be given for 6—12
months or longer. Abscesses are drained surgically wherever possible.
• Localized cutaneous infection: Usually treated with a single drug for 1-3 months.
Treatmentof actinomycetorna(referabove on page 172)

israelii
Actinomyces
• Actinomyces israeliican produce deep infection in the head and neck, and suppurating disease in the pelvis associated
withintrauterinecontraceptive devices (IUCDs).
• Treatment: penicillinor doxycycline.

ca PROTOZOALINFECTIONS
grains Malaria
Drawa neat labeled diagram of lite •: 4. • malarial parasite. Discuss the etiology, epidemiology, clinical features,
foot) complications, investigations anci of malaria.
(both uncomplicated and complicated
Discussthe clinical features, diagnosis and management of P. falciparum malaria
P. falciform malaria).
caused by one of four species of the
• Malariais a protozoan disease caused by Plasmodium. Human malaria is usually
and (4) P. malariae. Occasionallya species of
genusPlasmodiumnamely ( l) P. falciparum, (2) P. vivax, (3) P. ovate man.
malariausuallyfound in primates namely P. knowlesi (simian parasite) can affect
Plasmodium species. P.vivaxisthe most common
• P.falciparum causes the most severe form of malaria than the other
causeofmalaria in India.
also be transmitted through contaminated
ModeOftransmission: Bythe bite offemale anopheline mosquitoes. Malariacan
bloodtransfusions.
Plasmodium is presented in Table4.40.
Acomparisonof the developmental characteristics ofvarious species of
Plasmodium.
Table 4.40: Developmental characteristics of various species of
P.vivax P.ovale P.malariae
P.fakiparum
48 hours 72 hours
Durationof erythrocytic cycle 48 hours 48 hours
Reticulocytes Mature erythrocytes
Of red cells parasitized All Reticulocytes
NO

No NO
thO resistance

LifeCycle of the Malarial Parasite (Fig. 4.20) and pathogenesis

Writeshort essay on life cycle of malarial parasite.
and mosquitoes.However,the development
Thelifecycleof Plasmodiumspecies is simple because it involvesonlyhumansdistinct forms.Malarialparasites pass its life
morphologically
OftheParasiteis complex, because it passes through several and (2) female anopheles mosquito(definitivehost).
Cyclein twodifferenthosts namely. ( l) human (intermediate host)

92 of 632
Infectious Diseases 175
 undergraduates—MediCine of humans
for
Exam preparatory Manual

Exo-erythr«.ytic
Mosquitot*es
sporozottes) schizont

• Humanbloodstages
PPIC"
Imma ture

(nng stage) gythrof

a blood game
10
cyck
ErythrocytÉ mos'
Mosqui!,

gynete P. fabparurn Aferna)'

Ruptured
parasitt
• Schizont

Gametocytes
• Ihe',

(D• mfedivostage Stages in erythrocytes

(D•Daposbcstage ofhumans
(refer text for description). • Duri
Fig. 4.20: Life cycle of malarial parasites

anopheb Protec
sporozoiteby the bite of infected female
Humancycle(infection)startswith the introductionof infectious During mosquito bite. the mosquito takes a blod
is foundin the salivaryglands of mosquitoes.
mosquito.lhe sporozoite
mealandsporozoitesare releasedintothe human'sblood.The differentstages of human cycle are: • Atta l
Pre-erythrocytic(Primary exoerythrocytic)Stage is re
inside livercells
Sporozitescannot directlyenter erythrocyteto start its erythrocyte stage, but undergoes development (exoerythrocytic)
infectionof the liverand dewelopmentof sporozitesinto merozoites is referred to as the pre-erythrocytic
by the immune response) Clinicc
stage.Withinminutes ofentry ofsporozitesinto the human blood, (those which are not destroyed these
they arecarriedviathe bloodstreamand are rapidly(within 30 minute) taken up by the liver.They enter liver cellsand
malariaparasitesmultiplybyasexualreproduction(intrahepaticschizogony),releasing about 30,000merozoites(asexud ' P. Viva)
haploidforms)wheneachinfectedlivercellsruptures.Ihis stage is asymptomatic and during this phase, the parasi teSare
notfoundin the peripheralblood.lhe infectedhepatocytesrupture and release merozoitesinto the bloodstream•
• Inqandd
• DuringP.falciparuminfection,ruptureof swollenlivercellsusuallyoccurswithin 8 to 12 weeks.P falcipartltn
P.malariaehaveno persistentexoerythrocytic phase but a new outbreakof fever may result from multiplicatiOn
parasitesin red cellswhichhave not been eliminated by treatment and immune processes.
• In contrast.P.vivaxand P.ovalereleasesmerozoitesinto the bloodstream weeks to months after initial infection• pana
Hypnozoite(latent)stage
Ihe pre-erythrocytic phasedisappearscompletelyin P.falciparum,whereas a few parasitespersist in the livercells
dormant formsin P.viva-x and P.ovale.Therestingphase Ofparasite (latent phase) is called as
hypnozoite. These
are capableofdevelopinginto merozoitesmonths or years later,causing relapsing malarial
infection. 'Ihus, the firstatt
clinicalmalariamay developlong after the individualhas left the endemic area.
Erythrocytic
stage
Once merozoitesare releasedfromthe liverinto the bloodstream, they rapidly
membrane.Withinthe red cells(erythrocyticstage) asexual divisionoccurs. invade erythrocyte by penetratiOIi
 InfectiousDiseases 175

Asexualforms: In the red cells parasite developthrough the Stagesofasexual formschanging frommerozoiteto trophozoite,
toschizontand finallyappearing as 8-24 new merozoitesThese asexual formsof parasite can be demonstrated in the thick
blood smears.
Ringform: It is the first stage of the parasite in the red cell and is characterized by the presence of a single chromatin
mass (ring form).
Trophozoite: Duringthis, the parasiteassumesan irregularor ameboidshape.
Schizont:It is the next Stage the parasite has consumed two-thirds of the RBC'shemoglobin and has grown to occupy
mostof the cell. It shows multiple chromatin masses, each of which develops into a merozoite. Ruptureof the schizont
releasesmerozoitesinto the blood.•Ihiscausesfeverand the periodicityof feverdepends on the speciesof parasite.
_ Merozoites;Rupture of the red cell containingmerozoitesreleasesthe merozoitesinto the bloodstream.These
merozoitesare capable of invadingadditionalnew erythrocyteand repeatingthe cycle.'Ihe characteristicclinical
featuresof malaria such as paroxysmalfever,chills,and rigorsdevelopduring the releaseof these merozoitesinto the
blood.
cycleof the above process is called erythrocyticschizogony.The periodicityof such cycletakes about 48 h in
pfalciparum, P. viva.rand P. ovale and about 72 h in P malariae. P. vivaxand P. ovale mainly attack reticulocytes and young
erythrocytes,whereas P. malariae tends to attack old erythrocytes; P.falciparum will parasitize any stage of erythrocyte.
. Sexualforms: Most malaria parasiteswithin the red cellsdevelop into daughter merozoites.A few merozoiteswithin
developnot into trophozoitesbut undergoa differentpathwayof developmentinto sexualformscalled
erythrocytes
gametocytes(male and female gametocytes).These gametocytes are not released from the red cells until taken up by a
feedingmosquito to complete the life cycle. 'Ihese gametocytes are ingested by the mosquito during a blood meal when
mosquitobites the infected human.
Mosquitocycle
Afemaleanophelesmosquitoduringits bloodmeal froman infectedpatient ingestsboth sexualand asexual formsof
parasite,but it is only the mature sexual forms (gametocytes) capable of development.
• lhe maleand femalegametocytesof malarialparasitefuseinsidethe mid-gut (stomach)ofthe mosquito to form azygote.
• •Ihezygotematures to form an ookinete, which penetrates the gut wall and form an oocyst.
• oocystmatures and forms numerous sporozoites. •jhesesporozoiteshave specialpredilectiontowards the salivary
glands and reach maximum in salivary ducts of mosquito. The mosquito at this stage is capable of
transmittingmalarial infection.
• Duringthe bloodmeal these sporozoilesare inoculated into the new human host, thus completingthe life cycleof
Plasmodium.
ProtectionAgainst Malaria
with hemoglobin S
• Redblood cells containing hemoglobin F, C or S impair growth of P.falciparum parasite. Patients
especiallyheterozygotes (AS) are protected against the lethal complications of malaria.
receptor. In P. vivax,this receptor
• Attachmentofmerozoites to red blood cells is mediated via a specificerythrocyte surface
(as of the West
is related to the Duffyblood group antigen (Fyo or Fyi'). Thus, an individual who is Duffy-negative most
Africanpopulation) willbe resistant to infection by P. viva-r.
Clinical
Features
Malariais a very common cause offever in tropical countries. The first symptoms of malaria are nonspecific.
P.vivaxand P.ovale malaria
• Incubation period for P. vivaxis 12-17days, and for P. ovate is 15-18days. with
• Prodromal symptoms include headache, fatigue,abdominal discomfort,and muscleaches.Theseare more severe
P.malariae infections.
Fever starts with a rigor.Ihe febrile
• Fever: most common symptom of these 'benign' malarias is paroxysms of fever.
paroxysm synchronizeswith erythrocyticstage Ofthe parasite.
third day (tertian) interval (with 48hours
- Tertianfever:In P. vivaxand P ovale malaria infections, the fever recurs every
cyclebetween spikes).
• P•vivax:PatientssufferingfromP.vivaxmalariamaydevelopanemia, thrombocytopenia and mild jaundicewith tender
malariapresentlydevelopscomplications
hePatosplenomegaly. Splenic rupture is more common. Occasionally,P.vivax
similarto those of P.falciparum malaria.
viva-rinfection,but anemia is less severe and the
• Ihe acute symptoms of P.ovale maybe as severe as those OfP.
riskof splenic rupture is less common.
• Vivaxand P. ovale.•lhey have a persistent hepatic cycle and a few parasites persist in the liver cells as dormant forms.
Thismaygive rise to relapses.
 Exam Preparatory Manual for Undergraduates—Medicine

P.malariaemalaria
and muscleachesandrnaybemoresevere
fatigue,abdominaldiscomfort.
• Prodromalsymptomsincludeheadache, <cereor.l
P.rivax.
erythrocytic stage ofthe parasite.
• Fever: Thefebrile paroxysm»•nchronizeswith everyfourth day (quartan) interval
(72 hours interval
recurs
Quartanfever:In P.malariaeinfections,the fever
but
splenomegaly, splenic rupture is less common and anemia is less severe.
• It is associated
withgross
nephrotic syndrome. P.malariae does not
relapse,but a
P malariaeinfectionscauseglomeruJonephritisand common
and the riskof splenic rupture less
is
undetectableparasitemiamayproducerepeatedexacerbations
P.fakiparum malaria (malignant tertian or subtertian malaria)
Write short essay on falciparum malaria.
• It is the most dangerous type of malarias and patients may be Box 4.14: Jaundice in malaria.
either'killedor cured'. Causes: Jaundice may be due to severe hemolysis and
• Incubation period: 7-14days (mean 12days). involvement (malarial hepatopathy) by malaria.
• Prodromal symptoms:Onset is often insidious, with malaise, Hemolysis: The malarial parasite. especially P. falcipu•.
headache, myalgia, anorexia and vomiting. infects a large number of RBCs. These are destr%ed
• Fever: Patientsdevelopmild feverhaving no particular pattern the spleen and result in hemolytic anemia. It produce
and may last for severaldays before the onset Ofthe Classical elevation of serum bilirubin (dominant
•malarial paroxysms.' fraction) level without any significant elevation of
A high irregularlyspiking unremittingfever or daily enzymes.
(quotidian) paroxysmis more commonly seen in falciparum • Malarial hepatitis (malarial hepatopathy): This term - 9.

malaria but usuallydue to mixed infection (falciparum plus used to describe dysfunction of liver cells in severeard
his
vivax). complicated malaria. However, inflammation of the liver
parenchyma is never observed
• Physicalfindings:Patientis oftenanemic and jaundiced with
moderatetenderhepatosplenomegaly.
• Neurological
complicationscan manifestas acute headache. irritability,agitation,
11.

seizures, psychosis and impaird

12.
Box4.14lists the jaundice in malaria.
13.
Severemanifestationsand complicationsof
falciparum malaria 14.
Write short essay on:
• Complications of malaria -15. Jau
• Complications offalciparum
malaria.
•
forms of P.falcirarum in the peripheral
smear. Acute renal failure, acute respiratory alongwithpresenceofasen* 17.
distress syndrome and jaundice are
• Athighestriskof complications
frommalariaare nonimmune
people, and children and pregnant females
livein
Cerebral
malaria
write essay on clinical features
and treatment of
write long essay on cerebral cerebral malaria.
Definition:cerebral malaria clinical features and
is definedas diffuse management.
encephalopathyin a patient Motor
Features:Cerebralmalaria WithfalCiparummalaria which is • fixed
manifestsas diffuse • Neu
synmetric encephalopathy.
• convulsions:
generalizedand often
repeated.
in both children
(50%)and adults (10%)butaremo«
• Mildneckstiffnessmay
be seen. however,neck rigidity
and photophobiaand
Signsof raised intracranial tensionare

. ,sior
 Infectious Diseases 177

4.41: Criter.a for seære and complicated malana_

Organization criteria from 1990

1. Cerüalrnalaria Unarousable coma not attributable to any other cause,with a Glasgow Coma Scale score
$9; Gyna should persist for at least 30 min after a generalized

2. *vere atwnia < 15% s5 g/dL the presence Ofparasitecount >

3. Rend failure Urine output <400 mL/24 hours in adults (<12 rnLA9/24 hours in children) and a serum
Creatinine >265 urnol/l_ mg/cn-)despite adequate volume repletion

4. Metabolic(lactic)acidosis Metabolicacidosis is defined an arterial blood pH of <7.35 with a plasma bicarbcmate

5. pulrruury edema or acute respiratory distress
syndromeCARDS)
concentration of <22 mrnoVL: hyßErlactatemia is defined as a plasma lactate
concentration of 2-5 rnmol/L and lactic acidosis is characterized by a pH <7.25 and a
plasma lactate mrnoVL.
lung
Breathlessness. bilateral crackles, and other features of pulmonary edema. The acute
and
injury score is calculatedon the basis of radiographic densities,severity of hypoxemia,
positive end-expiratory pressure

6.
7, Hmtension and shock (algid malaria)
bleeding and/or disseminated
ntravascular coagulation
Whole blood glucose concentration of less than 2.2 mmoVL (less than 40 mg/dL)
Systolic blood pressure mm Hg in children years or mm Hg in patients
25 years; cold and clammy skin or a core-skin temperature difference > 10 •C
Spontaneous bleeding from the gums, nose. gastrointestinal tract. retinal hernorrhages
and/or laboratory evidence of disseminated intravascular coagulation

9. Repeatedgeneralized convulsions 23 generalized seizures within 24 hours

Macroscopic black. brown or red urine; not associated with effects Of oxidant drugs or
10. Herroglobinuria
enzyme defects (like G6PD deficiency)

AddedWorldHealthOrganizationcriteria from2000
the
irnpaired consciousness Various levels of impairment may indicate severe infection although not falling into
definition of cerebral malaria. These patients are generally amusable.

12. Prostration weakness, needs support

p3uaG:ized erythrocytes or parasites/gL (in nonimmune individuals)
13. Hyperparasitemia
14. Hyperpyrexia Core Oody temperature above 40 •C

15. Jaundice (Hyperbilirubinemia) Plasma or serum bilirubin mcrnola (3 mg/dL)

Other(Not included in WHO)

16. Severethrtyntxxytopenia Platelet counts less than 10.000/cumm

17. Fluid and electrolyte disturbances Dehydration. postural hypotension, clinical evidence of hypovolemia
therapy.
18, Vornitingoforal drugs Patients with persistent vomiting may have to be admitted for parenteral

19. Ct%npbcatingor associated infections Aspiration bronchopneumonia, septicemia, urinary tract infection, etc.
20. Malarialretinopathy In children dying with cerebral malaria, malarial retinopathy was found to be a better
reported
indicator of malarial coma. Similar retinopathy in an adult has also been

• Motorabnormalitieslike decerebrate rigidity,decorticaterigidityand opisthotonusoccur.

• Fixedjawclosureand toothgrinding (bruxism)are common.
and multiplecranial nerve involvementare
• Neuropsychiatric manifestations,cerebellar signs,extrapyramidalsyndromes
commonin Indian patients.
• Residualneurologicalsequelae:Theydevelopin about5%of adultsand ofchildren.Ihese includehemiplegia,
cerebralpalsy. corticalblindness, deafness aphasia and ataxia. They are more frequent in patients with prolongeddeep
coma,repeatedconvulsions,those with hypoglycemiaand severe anemia.
Ophthalmological
• Eyes maybe divergentand a pout reflexmay be elicitedby strokingthe sidesof the mouth. 'Ihe corneal reflexesare
maybe found.
Preserved(exceptin deep coma).Transient abnormalitiesofeye movement(especiallydysconjugategaze)
Ophthalmoscopy:Retinalhemorrhages may occur and indicate a poor prognosis.Papilledema is rare.
 Manual for
Exarn Preparatory

respiratoryfailure. fever
severe malaria or due to develop:
Åther due to

• Ibe CSFpressure and mostofteninthe

than 10 CSFlac%ity
cells/pL. of around (€3%). • hypoxemia
unusualin adults in childrgy_
Orebral malariaSl deficitsare manifestationsin malaria tion. particularty
in children•
causesofneuroloøcal god
Box4.15 the hyperparasitemia.
other than
malaria
sh
oliguria .
• Acutekidney in It causesprogressive
progress noninfected red cells
(black water feet) øwnte
and accompanied by reversible
anuria. It is usually • ;yserythropoiesis
eventually resulting in andurea It is
increase • splenornegatycausinq
sequestration
necrosis Erythrrxyte
resultantacutetubularintravas-
• and Hem«iilution instaine
effusion,sequestration
obstructionand due to
massive
;epletion of folate
stores
to thrombocytopenia.ttX
dueto microvascular Hemorrhage secondary
bone
rehydration.
with adequate
but this is reversible vascular
of
Hypoglycem•a is an importantand commoncomplication
problematic occurs of glucose by host
moru
It is particularly • Increased consumption
severefalciparummalaria. stainslik
patients: these Ougs
in three groups of quinine or quinklir*. Both
disease • Treatment with This
l. Childrenwithseverequinineor quinidine strongb•%timulatepancreas to secrete insulüv. detece
2. Patientstreatedwith orange)
mgnantwomen(eitheronadmissionorfollowingquinine
3. coatsme
mechanisms (BOX4.17 ).
develops due to various
Mechanism: In malaria. hypoglycemia

pressure,postural hypotension. oliguria and high urine speci&

• Hypovolemia: by lowjugularvenous
Characterized
hypoglycemia.hyperparasitemiaandrenalfailure Tue "2 se-
• both in blood and CSF.
associatedwithraised lactic acid levels RRtesting
• Lacticacidosis:Itisacommoncomplicationand
RNAor r"
• Itisaseriouscompljcationofseverefalciparummalariainadults.
isusual.
in otherwise uncomplicated vivaxmalaria. where recovery
• It maydevelopseveraldaysafterantimalarial therapyand ata time when the patient's general condition is improving•
and
• Noncardiogenic pulmonaryedema is associatedwith hyperparasitemia, renal failure. pregnancy, hypoglycemia
lacticacidosis.It isagravated by vigorousadministrationof IVfluid.
CirculatorycollapseCAIqidmalaria')
it may
Algidmalariaorhypotensiondue to peripheralcirculatoryfailuremaydevelop suddenly in severe malaria or
the presentingfeaturein some casesofmalaria,with a systolicblood pressure less than 80 mm Hg in the supine
[lessthan50mm Hgin children).a cold,clammy,cyanoticskin.constrictedperipheral veins and rapid feeble pulse
• Thisclinicalpictureis oftenassociatedwitha complicatinggram-negativesepticemia and possible sites Of
infection should be sought in such patients, e.g. lung urinary tract (especially if there is an indwelling catheter),
(meningitis),intravenousinjectionsites.intravenouslines,etc.
• Circulatorycollapseis alsoobservedin patientswith pulmonaryedema. metabolic acidosis, massive
hemorrhage, dehydration and hypovolemia.
• Bloodand urinecultureshouldbe done. Soonafter collectionof the specimen for culture, broad-spectrum an
shouldbe started.

95 of 632
 Infectious Diseases
179

(Blackwater fever)
Wlarialherno»inuria complications ofrnalaria.
Malaria hemoglobinuria is uncommon, and is usually Box4.18:Chrcnic
associatedwithhyperparasitemiaand/or severedisease.It may • Tropical splenornegaty syndrome
or may not be
accompaniedby renal failure. • Quatran malarial nephropathy
patients with glucose-6•phosphate dehydrogenase (G6PD) • lymphoma
deficiencyand other erythrocyte enzyme deficiencies may primaquine.
developvascularhemolysisand hemoglobinuria when treated with oxidantdrugs such as
Blackwater fever typicallyoccurs in nonimmune patientswith chronic falciparum malaria,taking antimalarials
deficiency.
(especiallyquinine and primaquine) irregularly.It occursmore commonly in patients with C,6PD
hemolysiscan occur so rapidlythat the hemoglobinmay drop significantlywithina few hours and it may recur
at intervalsof hoursor days. Patientpresentswithhead ache, nausea, vomiting and severepain in the loins
periodically 4.18lists the Chronic
andprostration.Feverup to 39.4•Cwitha rigoris alsoseen. Urineis dark red to almostblack. Box
complications Of malaria.

Investigationsand Diagnosis
Writeshort essay on låboratory tests in the diagnosis of malaria.
shouldbe consideredin the differentialdiagnosisOffebrileillness.
Malaria
demonstrationofparasite
Microscopic formsof the parasite
peripheralsmear examination:Thediagnosisofmalariadepends on the demonstrationof asexualmalaria is suspected.
instainedperipheral-bloodsmears. Boththin and thick smears shouldbe examinedwhenever
or Giemsa).
Smearsarestained by one of the Romanowskystains (e.g. Wright's.Field's.Iæishman's
even in patient withsevere
• Bonemarrowaspirate: Sometimesparasitescannot be detectedin peripheralbloodsmears,Ofparasitizedcells in deep
malarialinfections.•Ibis may be due to partial antimalarialstreatment or by sequestration parasitesor malaria
vascularbeds.In these circumstancesexaminationof smearsof bone marrowaspiratereveals
pigment.
dark-fieldmicroscopy,and
• Alternativemicroscopicmethods have been tried. includingfastermethods Ofpreparation,
stainslikebenzothiocnrboxypurine,acridineorange and Rhodarnine-123.
• Quantitativeburrycoat analysis (QBC):It is an alternativeand probablymore sensitive test than the peripheral smear
centrifugedbuffycoat is stained with a flurochrome(e.g. acridine
fordetectingthe malarialparasite. In this test, the parasites.'Ihe buffy
orange)that 'lightsup' (microtubeconcentrationmethods with acridine orange staining) malarial
smear is viewed under fluorescence microscopy.
Immunodiagnosis
'Ihe
Serologicaltechniques:Ihey can detect malarialantibodies,but these testsare not specificand are not done routinely.
testsincludeimmunofluorescent assay (IFA)and enzyme- linked immunosorbent a'•esay (ELISA).
Table 4.42showscomparison of rapid diagnostic tests for malaria antigens.
PCR
testing
diagnosisby polymeraseChainreaction(PC.R)amplificationOfparasite nucleicacid (for parasite messenger
• Molecular
or DNA)is moresensitivethan microscopyor rapid diagnostictests.
RNA

Table4.42: Compartsonof rapid diagnostic tests for malaria antigens.

PfHRP2tests PfHRP2and PMAtest test
•ntigen Histidine rich protein 2 of Pan-specific Plasmodium aldolase, Parasite lactate dehydrogenase.
parasite qlycotytic enzyme produced
P.fakiparum. water soluble protein parasiteglycotytic enzyme produced
by all species and PfHRP2 by all species
expressed on RBC membrane
Can detect all 4 species Can &tect all 4 species
Detects P.fakiparum only
Emit parasites/pL HigherforP.vivaxand other 100-2(1) parasitesipl for
non falciparum species P. and P.vivax; may
higher for P. malariae and P.ovale

with Resnrted. high (up to 83% with Not known Reportedlow (33%with rheumatoid
factor)
rheurnatoid factor)
Of Of No Positivetest indicatespresenceof
viable parasitemia
180 Exam PreparatoryManualfor Undergraduates—Medicine

Other laboratory findings

• Blood:
ia.
Normochromicnormocytic anemia. thrombocytopen may be observed in severe
infections.
but neutrophil leukocytosis
Total leukocyte count is low to normal. rate), plasma viscosity. and levels orc-reactive
protein are
(erythrocyte sedimentation
• Acute-phase protein: FSR partial thromboplastin time may be prolonged and
prothrombin time and
• Coagulation study: In severe infections,
antithrombin Ill levelsare decreased.
malaria there may be metabolic acidosis and:
• Other findings in sever malaria: In complicated albumin.
sodium, bicarbonate, calcium, magnesium and
Lowplasma concentrations ofglucose, globulin.
liver enzymes, bilirubin, and gamma
Elevatedlevelsof lactate. BtJN creatinine, muscle and infarcts and hyperintenseareasin Whitematter.
• Neuroirnagingincerebralmalaria mayshowbrainswelling. cortical
Write short essay on:
• Treatment of uncomplicated falciparum malaria malaria.
resistant malaria. Drugs for resistant falciparum
• Drugs used in resistant malaria/drug
• Radical treatment of malaria
• Name antimalarialdrugs

Aims of treatment are presented in Table 4.43.

monotherapies. and to improve treatment outcome. combinations of antimalari*
TOcounter the threat of resistance of P. fakiparum to
are now recommended by WHO for the treatment of falciparum malaria. Two or more blood schizontocidal drugs with independe.t
Combination Theram
modes of actionand thus unrelatedbiochemical targets in the parasite are used and at present Artemisinin-based
(ACT) is the recomrnended treatments for uncomplicated falciparum malaria.
• Artemisinin-based Combination Therapy (ACT)
• Artemisininand its derivatives (artesunate, artemether, arternotil. and dihydroartemisinin) produce rapid clearance of
and rapid resolutionof symptoms.They reduce parasite numbers by a factor of approximately 10.000 in each asexual cycle, which6_
rnore than other current antimalarials (which reduce parasite numbers IOO- to 1000-fold per cycle). Artemisinin and its derivatives are
eliminated rapidly.
• Whengiven in combinationwith rapidly eliminated compounds (tetracyclines,clindamycin), a 7-day course of treatment with
artemisinincorncx»und
is required:but when given in combination Kith eliminated antirna'arials.shorter courses of •4
(3 days) are effective.
Non-artemisininbasedcombinations (non-AGs) include su!faduxine Box 4.19: Chen.oprophy!axis of malaria.
-pyrimethaminewith chloroquine (SP+CQ) or amodiaquine (SP4AQ).
However, the prevailing high levels of resistance have compromised the • shoct-:errn chemoprophylaxis (less than 6 weeks).
efficacy Of these combinations. There is no convincing evidence that a doseof 100 mg daily. It should
SP+CQ provides any additional benefit over SP. so this combination is days before travel and continued for 4 weeks after tie I
recommended. malarious •rea
• The ACT used in the national program in India is • For long-term chemoprophylaxis (rnore than 6 weeks).
artesunate + mefloquine in a dose Of5 mg/kg (up to 250 rng) weekly.It •
Sulfadoxine + pyrimethamine. It is given as:
should be administered 2 weeks before. during and 4 weeks
• 200 mg artesunatealong with sulfadoxine1500 mg and after leaving the area.
pyrirr*thamine 75 mg on day 1.
200 mg artesunate on days 2 and 3.
• Anotheroptionistousequinine600mgsaltthreetimesdailyfor5daysorally.
followedbya singledoseofsulfadoxine
• ACTscanbegiveninsecondandthird
trimesterofpregnancy. Recommended treatment
in first trimester of pregnancy isquini'*•
Chemoprophylaxis of malaria is presented in Box 4.19.

Table 4.43: Aims of treatment

To alleviate symptoms
To prevent relapses
To prevent spread
Symptoms are caused by bkx)d
forms of the pa rasite
Relapses are due to hypnozoites Of P.
Spread is through the
garnetocytes
Blood schizonticidal drugs
Chloroquine. quinine. artemisirüt
combinations
Tissue schizonticidal drugs
Prim aquine
Gametocytocidal drugs
Primaquine for P. falciparum.
Chloroquine for all other
 Infectious Diseases 181

for treating Chjoroquine resistant P falciparumare

as ACT) and haJ0fantnne. Recently. dihydroartemisinin menoquine (15 mgAg followed by 10 mg/kg after 8 hours; generally
(4 rng/kg/day) + Piperaquine (18 mg."kg/day)combination for three days
has been available.
treatment malaria is presented in Table 4.44.
pdiøJ cure of malaria due to P. vivax and P. ovaJe.
pnmaquine is given at a dose of 15 rng daily for 14 days. It destroys the
hypnozoite phase in the liver.
445 outlines the treatment of severe malaria,
Of severe manifestations and complications of falciparum
malaria is presented in Table 4.46.
for treatment Of uncomplicated P. falciparum malaria
in pregnancy is mentioned in Table 4.47.

4.44: Summary of treatment of malaria.

F d"fectioø Suppressivetreatment Radicaltreatment
P ova& Chloroquine 25 mg of salt/kg over 36-48 hours Primaquine0.25 mg/kg for 14 days
Chloroquine 25 rng of salt/kg over 36-48 hours None
Treatment depends On severity and sensitivity Primaquine 0.75 mg/kg in single dose as
Artesunate pyrimethamine•sulphadoxineor gametocytocidal
Other ACTS, OR quinine plus tetracycline
Wxed(P.vSox P. faki;xrum) ACT as for P. falciparum Primaquine as for P. vivax

Table4.45: Treatment of severe malaria

fist Follow-ontreatment (Funcourseofany ACT)
Anesunate24 body weight (bw) IV or 'M on admissiorv then • Artesunate plus sulfadoxine-pyrimethamine
12h and 24 h. then Once a day for at least 24 hours, followed by full • Artesunate plus amodiaquine
• Artesunate plus clindamycin Or doxycycline
k'tefr*ther32 rngAg bw 1Mgiven On admission rhen .6 mg/kg bw • Artemether plus lumefantrine
day at least 24 hours. followed by fuli cou;se ot T • Dihydroartemisinin+Piperaquine
Q.ÅnÉ*.20 mg saltAg on admission (iv infusion do. ided 'M Doxycycline 100 mg BID (2.2 mg/kg BID for <45 kg) for 7 days
then 'Orng/kgbwevery8h; infusion rate should notexceed OR clindamycin 20mg base/kg/daydivided in three dosesfor7daysin
5mg saltA9 bw per hour, course for 3 days pregnancy

Table4.46: Managementof severe manifestauonsand complicattonsof falc.parummalarra.

"andestation/complication
Immediatemanagement (inadditionto antimalarialtreatment)
Cana malaria) Maintain airway. place patient on his or her side. exclude other treatable causes of corna (e.g. hypoglycemia.
bacterial meningitis): avoid harmful ancillary treatment such as corticosteroids, heparin and adrenaline; intubate
if necessary
Administer tepid sponging, fanning, cooling blanket and antipyretic drugs
Maintain airways; treat promptly with intravenous or rectal diazepam or intramuscular paraldehyde
Check blood glucose. correct hypoglycemia and maintain with glucose<ontaining infusion
Transfuse with screened fresh whole blood
pulmonary edema Over-enthusiastic rehydration should be avoided so as to prevent pulmonary edema. Prop patient up at an
angle of 45% give oxygen, give a diuretic. stop intravenous fluids. intubate and add positive end-expiratory
pressure,'continuous positive airway pressure in life-threatening hypoxemia
renal fanure
Exclude prerenal causes. check fluid balance and urinary sodium; if in established renal failure add
hemofiltration Or hemodialysis, or if unavailable. peritoneal dialysis. The benefits Of diuretics/dopamine in acute
renal failure are not proven
and Transfuse with screened fresh whole blood (cryoprecipitate, fresh frozen plasma and platelets if available); give
vitamin K injection
severe add hemofiltration or hemodialysis
Exclude or treat hypoglycemia. hypovolemia and septicemia. If
correct hemodynamic disturbances
Suspect septicemia. take blood for cultures; give parenteral antimicrobials.
Treat with artemisinins. intravenously or orally

96 of 632
 Undergraduates—Medicine
Exam PreparatoryManual for

available
effective treatment
be used if it the only
ACT should for 7 days or quinine
Quinine clindamycin for 7 ciindamycin to be given
First trimester country/region or artesunate
be effective in the
Second and ütird ACT known to for 7 days
clindarnycin to be given
ofchloroquine.
in which Box 410: Uses
ofchloroquine (conditions suppressive .
Write short note onuses for clinical cure and
• Drug Of choice by resistant p.
chloroquine is used). malaria. except that ca used
of all types of
in Box4.20.
Uses of chloroquine are listed falciparum
Amebiasis
(TSS) • Extraintestinal
Tropical Splenomegaly Syndrome arthritis. SLE. chikungunya
• Rheumatoid
tropical splenomegaly syndrome
erythematosus
Write short essay/note on • Discoid lupus
• Lepra reactions
(TSS).
or big spleen disease, also • photogenic
reactions
splenomegaly syndrome (symptomaticrelief)
mononucleosis
Tropical splenomegaly is massive • Infectious
known as hyper-reactivemalarial from abnormal immune
enlargementof the spleen resulting residents
malaria. It is seen among
responseto repeated attacks of p."
of endemic areasof malaria.
malaria.
It is one of the chronic complications of
Lei:
anemia; and
malarialinfections produce hypergammaglobulinemia; normocytic normochromic
• Chronic or repeated
massive splenomegaly.
lgM antibodies to C,D8+T lymphocytes, antibodies to CD5+ area,
• TSSsyndromeis characterizedby the production of cytotoxic continuous IgM production byB
T lymphocytes, and an increasein the ratio of CD'I+to CD8+T cells.These result in
complexes). This stimulates reticuloendothelid Clif
cell and the formationof cryoglobulins(IgM aggregates and immune
hyperplasiaand leads to splenomegaly.
Clinicalfeatures
• Anemiaand some degree ofpancytopenia are usuallyfound. Visc
• Thereis increasedvulnerabilityto respiratoryand skin infections and many may die due to overwhelming sepsis. (COI

• Physicalexaminationshowsmassive splenomegaly, hepatomegaly and occasionally low-grade fever.

The disease generallyruns a benign course. Portal hypertension does not develop and the condition is reversible will
antimalarialtreatment.Some may evolveinto malignant lymphoproli[erative disorder (e.g. CLL).
Diagnosis of TSS
• Antimalarialantibodies: High levelsof antimalarial antibodies are found in blood. lgM levels
are markedly elevatd
(up to 20times).
• 'Ihere is increasein the serum levelsofpolyclonal IgMwith cryoglobulinemia,
reduced (13and the rheumatoid factormaY
be positive.
lifel
• Liverbiopsy.
Lei
Lightmicroscopyof livershows sinusoidal lymphocytosis and
Kupffercell hyperplasia.
Immunofluorescence microscopy shows IgM
aggregates phagocytosed by RE cells.
• Peripheral blood:The peripheralsmear shows
Leukopeniaand thrombocytopenia may also be
normocytic normochromic anemia
with increased reticulocytecount
seen due to hypersplenism.
Malarial parasites are not found in

Treatment of tropical splenomegaly

syndrorne
• Chloroquineweeklyorproguanil
daily have been found to be
useful. These drugs may have to be
• Severe anemia may require
continued for long periods
blood transfusion.
•
• Splenicirradiationorantimnotictherapy in onlypatientswith
are not beneficial and splenic lymphoma.
maybeeven dangerous.
 Infectious Diseases 183

Md.ri• v•ccines
Writeshort note on malarial vaccines.
types
malaria vaccines target the different phases of
the parasite's life cycle
The pre-erythrocytic vaccines target sporozoites Or
schizont infected liver cells and is aimed at preventing infection by stopping the
progression of hepatic stage. Even a single sporozoite
escaping vaccine-induced immunity may cause a fully pathogenic blood stage
infection, as was found during the clinical trials of the latest
antisporozoite RTS. S vaccine.
. The erythrocyticstage vaccines are aimed at reducing
parasite multiplication and growth in order to protect against clinical disease,
particularly Severe disease. These vaccines are designed to
induce antibody responses against the targets on the asexual blood Stage
Of the parasite Such as rnerozoite surface proteins (Such as
MSP• 1) or those contained in specialized organelles associated with invasion
(such as AMA-I). But. the very short duration during which merozoites stay outside the
polymorphic variability, and the use of alternative invasion red cells (about 2 minutes), the high degree of
pathways by P. fakiparum.
. Transmission-blocking vaccines are aimed at reducing malaria
by inducing antibodies
transmission by interrupting the parasite life-cycle in the mosquito
that prevent either
fertilization of the gametes in the mosquito gut or the further development of the zygote
into sporozoites.These vaccines do not protect the immunized individual
by preventing the parasite
but rather provide herd benefit. Antidisease vaccination,
surface protein parasite-derived Plasmodium falciparum erythrocyte
interacting with various vascular endothelial cell-surface receptors, may membrane protein 1 (PfEMP1) from
block the sequestration of parasite-infected erythrocytes and
prevent the serious complications such as cerebral malaria or placental malaria.
All these vaccines are in clinical trial stages. RTS. S is the most recently
developed recombinant vaccine. It consists of the
p.fakjparum circumsporozoite protein from the pre-erythrocytic stage has been approved
to vaccinate children aged 6 weeks to 17 months
outsidethe European Union.

Leishmaniasis
Writeshort note on Leishmaniasis.
Leishmaniasisis a group of diseases caused by unicellular,flagellate,intracellular protozoa of the genus Leishmania, which
are transmitted by the bite of the female phlebotomine sandfly.
ClinicalSyndromes
VisceralLeishmaniasis (Kala-azar)
Writeshort note on kala-azaror
Visceralleishmaniasis (kala-azar) is a generalized viscerai infection caused by the protozoon Leishmania donovani complex
(comprisingL donovani. L. infantum and l..chagasi).
Epidemiology
Modeof transmission: Sandfly of the Genera Phlebotomus.
• Endemic:
- Kala-azaris endemic in several countries. More than 90%of visceralleishmaniasisare found in India, Bangladesh,
SouthernSudan. Nepal and Brazil.
- In India. it is endemic in the states of Bihar,West Bengal, Eastern parts of Uttar Pradesh and partsofOdisha.
• Sporadic cases have been reported from several other parts of India.
Lifecycleof leishmania (Fig.4.21)
Iwishmaniaoccurin two forms:(l) extracellular,flagellatepromastigoteformin the sandflyvectorand (2) intracellular,
nonflagellate
amastigoteform in humans.
Incubationperiod: Usually I -6 months, but may be several years.
Clinical
featuresofkala-azar
• Agegroup: In India, adults and children are equally affected whereas elsewhere it is mainly seen small children and
infants(except in adults with HIV coinfection).
• Organsinvolved:It primarilyaffectsthe host's reticuloendothelialsystem.In visceralleishmaniasis,monocytesand
macrophagesof the spleen, liver, bone marrow and lymph nodes are primarily affected.
• Onset: Great majority ofindividuals infected remain asymptomatic and onset in others may be abrupt.
• Fever: It is the first sign of infection. Fewpatients present with a low-grade fever,whereas others present with a high.
grade.usuallyaccompanied by rigor and chills. The fever is intermittent showing a double rise of temperature in 24 hours
('camelhump fever'). The intensity of fever decreases over time, and patients may be afebrile for intervening periods
rangingfromweeks to months. This is followedby a relapse of fever which is often less intense.
Exam Preparatory Manual for Undergraduates—MediCine

Pru•nastOotes "Wate and

Earru.Aate *larynx
deposited in
punctur
Man acquires
by bite of fernale sandfly

Binary fissdl Life cycle of Leishmania donovani

whkh
by binary

(definitive host)

macrophages

the
infect new
macrophages

AmastOotesingested ArnasW)tes released

by sandfiy into the blood

Fig. 4.21 : Life cycle of leishmaniasis.

Physicalfindings
• Massivesplenomegalyand hepatomegaly: Splenomegalydevelopsin the first fewweeks and becomes
diseaseprogresses.Moderatehepatomegaly developslater.
• Lymphadenopathy:ItiscommoninpatientsinAfrica, the MediterraneanandSouth America.In India itismoreomn—
in patients fromWestBengal.
• Blackishdiscolorationof the skin: Diseasederivedits name; kala-azaris derived fromthe Hindi word for'blackfo€
Generalizedblackishpigmentationwith roughskin is prominentoverface is an observed in advanced stage Ofdiø
and now it is rare.
• Anemia: Moderate to severe anemia develops rapidly, and can produce congestive cardiac failure and associated dirø
features.
Bleeding manifestations: Thrombocytopenia. often associated with hepatic dysfunction, may cause bleeding from
retina,gastrointestinaltract and nose.
Causeof death: Death usuallyoccurs within a year and is either due to bacterial infection or uncontrolled bleeding
Complications
Hypoalbuminemia:Maydevelopin advancedstage and may manifestas pedal edema, ascites and anasarca
generalizededemaand swelling).
• Immunosuppression: As the disease advances, severe immunosuppression may lead to secondary infections
include tuberculosis,pneumonia. malaria, severe amebic or bacillary dysentery, gastroenteritis, herpes zoster
chickenpox.Skininfections(e.g.boils,cellulitis,scabiesand cancrumoris)are common.
Investigations
Directevidences
• Demonstrationofamastigotes (Leishman-Donovanbodies): It can be demonstrated in stained smears Of
bone marrow (50-70%cases),spleen (70-90%cases),liver,lymph nodes or buffycoat of peripheral blood. Dem
of LDbodies in splenicsmears is the most usefulfor the diagnosis(98%sensitivity);however,there is a riskOf
hemorrhage in inexperienced hands. It is the gold standard for the diagnosis of visceral leishmaniasiS (VL).
• Culture:Theaspiratedmaterialcanbe culturedin the Novy-MacNeal-Nicolle
(NNN)mediumforthe organsm•

98 of 632
 InfectiousDiseases 185

jrdject evidences
Blood:Pancytopenia is a common feature (i.e. anemia, granulocytopenia and thrombocytopenia).
Biochemicalfindings:
serum albumin (hypoalbuminernia) and polyclonal hypergammaglobulinemia (high serum globulin), chiefly
lgGfollowedby IgM in advanced cases.
and alkalinephosphatasemay be seen.
liver functiontest: Mildlyelevatedbilirubin,AST/ALT
immunodiagnostictests:
Serological/
lhese are less invasive and are useful in community surveillance studies.
1Æishmanin(Montenegro) skin test: Intradermal injectionOfkilledculture of promastigotesproduces a delayed-type
and is positiveonlyin patientswithcuredkala-azar.
hypersensitivity
Napier'saldehyde (formalgel) test and Chopra'santimonytest: Theseare nonspecifictest and shouldnot be
employedfor the diagnosis of VL.They are used for demonstration of increased immunoglobulins.
DetectionOfspecificantibody:
Varioustest such as complement fixationtest, indirect hemagglutinationtest, indirect fluorescentantibody test and
countercurrentimmunoglobulinshave poor sensitivityand specificity.
test.
. Antigendetection by reverse western blotting. dot-enzyme immunoassay (EIA)and latex agglutination
• PCR:Todetect DNAand identifyspecies.
post-Kala-azarDermal Leishmaniasis (PKDL)
skin lesions due to local
Timeofoccurrence: In India, Sudan and other East African countries, 2-50%of patients develop
parasitic infectionconcurrent with or after apparent recoveryor cure of visceral
leishmaniasis.

Clinicalfeatures
nodulesand can occur in varying
Skinlesions may be of three types namely:hypopigmentedmacules,papules or
combinations:
Hypopigmentedmacules:Earliestlesionsand usuallyfound on the trunk and extremities.
Erythematouspatches: Ibese have butteifly distribution on the face.
on mucus membrane oftongue and eye.
• Yellowishpink nodules: They are generally found on the skin and rarely
dermal tissue.
Diagnosis:Demonstration of parasite in the slit smear or by culture of the

Drugs used to treat kala-azar

intercurrent bacterial infections with antibiotics.
General considerations: Blood transfusions to correct severe anemia and treatment of
antimonialcompounds
Pentavalent
meglumine antimoniate) were the first drugs to be used for the treatment
• Pentavalentantimonial compounds (sodium stibogluconate. for 40 days.
The dose are 20 mg/kg either intravenously or intramuscularly
Ofleishmaniasis and still remain the mainstay of treatment.
However. many patients may fail to respond due to parasitic resistance.
raised liver enzymes, pancreatitis (in immunosuppressed patients), ECG
• Side effects: Include arthralgias, myalgias, abdominal pain,
cardiotoxicity.
changes (T wave inversion and reduced amplitude) and rarely death due to
• For PKDL treatment for 3—4months is necessary.
Amphotericin B
Writeshort note on amphotericin B and its side effects.
Bihar, India. In other parts ofthe world. it is used as a second
Amphotericin B deoxycholate is currently used as a primary drug of choice in
linedrug when patient is unresponsive to initial antimonial treatment.
100%.
• DOSe:O.75-1.OOmg/kggivenoncedailyoronaltematedaysforatotalof15-20infusion.lthasacurerateofalmost
diarrhea and vomiting arecommon.Other
thrombophlebitis,
• Sideeffects:lnfusion-related sideeffects include high fever with chills,
Sideeffects include hypokalemia and renal or hepatic toxicity and thrombocytopenia.
B deoxycholate can be reduced by using lipid-
• Lipid formulations of amphotericin B: Some of above side effects of amphotericin amphotericin B is administered at a total dose
dispersion. In India, liposomal
Preparations B lipid complex and amphotericin B colloidal
over several days. It may be combined with 7—14days of oral
Of 10 or 15 mg/kg, administered in a single dose or as multiple doses
miltefosine.

results. It is the first highly effective. oral drug for treating

• Miltefosine is an alkyl phospholipid administered orally has shown excellent
visceral leishmaniasis.
• kg. and 50 mg twice adayifweightis>25
hepatotoxicity and nephrotoxicity.
• Side effects include vomiting and diarrhea, and occasionally. reversible
 Undergraduates—Medicine
186 Exam Preparatory Manual for

as a second-line drug
days for 5-25 weeks was recommended
of 3-4 mg/kg on alternate and serious side effects@hypogly—
Pentamidineisethionatewas used.Dose abandoned because of its reduced effectiveness
it is
treat antimony resistant case„ However,
mellitus).
hypotension and induction of diabetes It is given

• daily for 21 days;

at dose of 11 mg of baseAg
itraconazole
• Azoles:ketoconazolefluconazole,variable efficacy in leishmaniasis treatment.
agents have
— These oral antifungal

Toxoplasmosis of toxoplasmosis.
manifestations,diagnosis and management
Discuss the etiology, clinical gondii.
Toxoplasma
is causedby the intracellularprotozoanparasite
Toxoplasmosis
Life Cycle of Toxoplasma gondii
is the definitive host.
Man is the intermediate host and cat
Mode of Transmission
ingestionof:
• Humansinfectionoccursvia infected reservoir animal (cat), contaminated salads, vegetables
and water.
Oocystdischarged in the feces of rabbits are the most common mea
meats containing tissue cysts (bradyzoites). Sheep, pigs and
Rawor undercooked
sources.
to fetus may also occur.
• Transplacentalinfectionfrom mother
ClinicalManifestations
toxoplasmosis.
Write short note on clinical features of
Infection in immunocompetent host
unnoticed.
Asymptomatic: Mostacute toxoplasmosisis subclinical and goes feature.It may local
In symptomaticpatients,it is the most common presenting
• Painlesslymphadenopathy:
generalized and cervical lymphadenopathy is most common.
• Other features:
malaise, fatigue, myalgias,sore
- Systemic symptoms are not observed in most patients. If present, these include fever,
throat and headache.
Uncommon features are skin rash and confusion.
- Rarely:Myocarditis,encephalitis, pneumonia, hepatitis, and polymyositis.
• Completelyresolutionoccurs within a few weeks to months.
• Ocularinfection:
—Mostoftenocularinvolvement
(chorioretinitis)
observedin congenitalinfection
Examinationshowsgray white foci of retinal necrosiswith adjacent choroiditis, vasculitis,hemorrhageand Vitreitis
Anterioruveitismayalso be seen.
Infectioninimmunocompromised host
• In immunocompromised patients,toxoplasmosis
is usuallydue to reactivationoflatent infection.
• Central nervous system:
- It is the most common system affected.
- Manifestationsincludeencephalopathy,meningoencephalitis, seizures,headache and focal neurological deficits
• Pneumoniaand ocularinvolvement
mayalsooccur.
Congenitaltoxoplasmosis
Write short note on congenital toxoplasmosis.
Transmission
Acute toxoplasmosisis mostlysubclinical and develops in 0.3-1%of pregnant women.
 Infectious Diseases 187

manifestations
Cbnical
congenitaltoxoplasmosismay be asymptomatic,but can produceseriousdisease.
CNS:Manifestationsinclude hydrocephalus,microcephaly,encephalitis,convulsions,tremors,paralysisand mental
retardation.Cerebrospinalfluidmaybe xanthochromicwithraised proteinand mononuclearcells.Skullradiographmay
showpatchesofcalcificationin the brain.
ophthalmic manifestations: Microphthalmus,nystagmus,chorioretinitis(common)and blindness.
Otherfeatures:Hepatomegaly.jaundice, thrombocytopeniaand purpura may be seen.
Investigations
Blood:Mildlymphocytosis,raised ESRand mild increase in liverenzymes.
serodiagnosis:Presence of significantlevelsof ToxoplasmaspecificIgMantibodyindicates acute infectionand absence
of lgMantibodiesvirtuallyrules out acute infection.However,in immunocompromisedpatients most of the time
toxoplasmosis
is due to reactivationand there is no rise in IgMantibody. Hence, IgGantibodies are used forpresumptive
diagnosis.
Sabin-Feldman methylene blue dye test: A dye test positivewith a titer of I :128is diagnostic of active toxoplasmosis.
Indirectfluorescentantibodytest
Muorescentstain for toxoplasma (Goldman's test): It is usefulfor detectionof parasitesin smears and biopsy
specimens.
ELISAtest.
• PC,Rfor toxoplasma DNAin ocular secretions and amniotic fluid.
• Microscopicexamination of smear or biopsymaterial (froma lymph node or muscle)showsthe parasite.
• Inoculationof suspected material into laboratory-bred mice, guinea pigs may show characteristichistologicalchanges.
'lheseincludeany of the three infectiousstages:tachyzoitesin groups,bradyzoites(tissuecysts)or sporozoiteswithin
oocyst.
• Investigations
in toxoplasmaencephalitis:
CSFmaybe normal or show mild increase in cells and protein
Serum: lgGantibodies to toxoplasma
Radiological:(Il' scan ofhead mayshow mukip:e contrast-enhancinglesions.However,MRIis more sensitivethan
scanin identifyingthe lesions.Single-photonemissioncomputedtomography(SPECT)helps in differentiatingCNS
lymphomafromtoxoplasrnicencephalitis.
Management
• Acquireduncomplicated toxoplasmosis in an immunocompetent individual is self-limiting and does not require treatment
• Treatment for severe (especially eye involvement) or disease and for infection in immunocompromised patients:
- Combinationof sulfadiazine 2—4g daily (1 g 6 hourly) and pyrimethamine in a single loading dose 25 mg daily both for 4—6
weeks, along with folinic acid/leucovorin. Steroids are added to the above regime for ocular toxoplasmosis.
• Ifthe patient is sensitive to sulfonamides, clindamycin or azithromycin can be used.
• Toxoplasmosisin pregnant Women:
- If a seronegative women acquires toxoplasmosis during pregnancy (especially during first trimester), or seroconverts during
pregnancy, there is a greater risk of transmitting the infection to fetus giving rise to an infant with congenital toxoplasmosis. Such
pregnancies should be terminated.
The aim of management of pregnant women with toxoplasmosis is to reduce the risk of fetal complications.
The recommended treatment for a pregnant woman with an established recent infection is spiramycin (3 g daily in divided doses)
until term. However, whether it has any significant effect on the frequency or severity of fetal damage is not well established. Infected
infants should be treated from birth.

INFECTIONS CAUSED BY HELMINTHS

CESTODES(TAPEWORMS)
des (tapeworms)are ribbon-shaped worms which vary from a few millimetersto several meters in length.
Cæsto
Lifecycle (Fig. 4.22)
Thetapeworm
passes its lifecycle in two hosts:
Definitivehost: Human is the definitive host and harbors the adult worm.
• Intermediate host: It may be pig or cattle depending on type of tapeworm and they harbor larval forms.