MALARIA

DR EDESIRI
 Outline
• INTRODUCTION
• EPIDEMIOLOGY
• LIFECYCLE
• PATHOGENESIS
• CLINICAL FEATURES
• DIAGNOSIS
• DIFFERENTIALS
• TREATMENT
• PREVENTION
• CONCLUSION
• REFERENCES
 Introduction
• Malaria is a disease caused by four species of protozoan
parasites of the genus Plasmodium – P. falciparum, P.
vivax, P. ovale and P. Malariae
• It is endemic in the tropics and transmitted by the bite of
infected Anopheles mosquito
• Manifestations of malaria variable
• Differences in clinical manifestation multi-factorial –
mosquito biting and breeding habits, infecting species,
genetic and acquired host resistance.
Historical perspective
Known cause of fevers since ancient times in China,
India, Mesopotamia
• Associated with marshy areas.
• Association with atmospheric poisons – mal ` aria
[bad air]
• Discovery of Parasite – Late 18th Century
- Laveran (first to notice malaria parasites in blood
of a patient in 1880), Mason, McCallum, Ross
Historical perspective
• There have been 4 Nobel prizes for malaria related
research so far:
1. Ronald Ross, 1902
2. Alphonse Laveran, 1907
3. Julius Wagner- Jauregg, 1927
4.Paul Hermann Muller, 1948
EPIDEMIOLOGY
• VECTOR: Malaria is mainly transmitted via the bite of a
hematogenous female adult of the mosquito genus
Anopheles
• MODE OF TRAMISSION: Other comparatively rare
mechanisms for transmission include congenitally
acquired disease, blood transfusion, sharing of
contaminated needles & organ transplantation
Transmission of malaria

•Mosquito bite

•Blood transfusion

•Congenital

•Organ transplant
ANOPHELES SPP
• An. gambiae complex- An. gambiae , An. arabiensis, An.
melas. An. merus

• A. funestus
• A. moucheti
• A. nili
• A. stephensi
EPIDEMIOLOGY
• Malaria occurs throughout most of the tropical regions of the
world
• P. falciparum predominates in Africa, New Guinea, and
Hispaniola
• P. vivax is more common in Central and South America,
Middle East and Asia.
• P. malariae is found in most endemic areas especially
throughout sub-Saharan Africa , though less common
• P. ovale is relatively unusual outside of Africa
• P. knowlesi is mainly on the island of Borneo where the
main hosts, long tailed and pig tailed macaques are found
• In Nigeria, malaria mostly caused by P. falciparum(80%) P.
malariae (15%) and P. ovale (<5%)
EPIDEMIOLOGY
• Globally 3.3 billion people are at risk of malaria
• 0.25 billion affected, 900 000 deaths annually (WHO,
2009)
• 80-90% of the deaths occur in Africa (WHO, 2012)
High Risk Groups
• Children under 5 years
• Pregnant women (Maternal anaemia, still birth, premature
birth, LBW)
• HIV/AIDs
• Non-immune travellers
EPIDEMIOLOGY
• Some 3000 African children die from malaria – equivalent
to one every 30 seconds (WORLD MALARIA DAY –
APRIL 25TH)

• In endemic areas transmission may be measured in terms

of parasitemia or palpable spleen rates in children 2-9
years of age

• The principal determinants of the epidemiology of malaria

are the density, the human-biting habits, and the longevity
of the anopheline mosquito vectors
• Holoendemic: transmission occurs all year long. Spleen
rate >75%; Parasitaemia > 60-70% (eg rural areas of
Nigeria)
• Hyperendemic: intense, but with periods of no
transmission during dry season. Spleen rate >50 <70;
Parasitaemia >50 <70. cerebral malaria more common in
older children eg Gambia
• Mesoendemic: regular seasonal transmission. Spleen rate
>20 <50; < 5 years old Parasitaemia < 20. eg urban areas
of Nigeria
• Hypoendemic: very intermittent transmission. Spleen rate
0 -<10%; Parasitaemia 0 -<10%
Stable Malaria•
• High prevalence, frequently asymptomatic cases
• Infrequent occurrence of fever
• Anemia high in younger ages (particularly under 2 years
of age)
• Greatest mortality under 2years
Unstable Malaria
• Immunity based on personal exposure to Plasmodium
antigens
• Broad range of disease situations from high cerebral
malaria in children 4-6 years old
• Much adult malaria
• Highly symptomatic,
EPIDEMIOLOGY
• Falciparum malaria remains best example of a selective
agent that results in genetic polymorphisms in the host
that might provide partial protection against severe
disease

• Genetic variants of RBC (sickle cell trait, G6PD def,

thalassemia trait and ovalocytosis) may partially protect
against severe disease
Life cycle
Pathogenesis : erythrocyte changes in malaria
• In P. falciparum infections, membrane protuberances
appear on the erythrocyte’s surface 12-15 hours after the
cell’s invasion
• These extrude erythrocyte membrane adhesive protein
(PfEMP1) that mediates attachment to receptors on
venular & capillary endothelium – CYTOADHERENCE
• At the same stage, these P. falciparum – infected RBCs
may also adhere to uninfected RBCs ( ROSETTE
FORMATION) and to other parasitized erythrocytes
(AGGLUTINATION)
Pathogenesis
• These result in the SEQUESTRATION of RBCs
containing mature forms of the parasite in vital organs
where they interfere with microcirculatory flow and
metabolism
• Sequestered parasites continue to develop out of reach of
principal host defense mechanism
• As a consequence, only the younger ring forms of the
asexual parasites are seen circulating in the peripheral
blood in falciparum malaria
Pathogenesis
• In the other 3 human malarias, sequestration does not
occur , and all stages of the parasite development are
evident in peripheral blood smears
Pathogenesis: host response
• The host response to plasmodial infection by activating
non-specific defense mechanism

• Splenic immunologic & infiltrative clearance functions are

augmented

• Parasitized cells escaping splenic removal are destroyed

following rupture by schizonts, thereby inducing the
activation of macrophages & the release of pro-
inflammatory mononuclear cell-derived cytokines
Pathogenesis
• Eventually, exposure to sufficient strains confers
protection from high- level parasitemia & disease but not
from infection (premunition).
Clinical features
• P.falciparum infection generally follows a
relatively mild or uncomplicated course
• In some patients especially children and
non-immune adults falciparum malaria may
become a severe life-threatening disease
Clinical features
• Fever : benign tertain and quartian, malignant tertian
• Alternating profuse sweating
• Malaise
• Headache
• Myalgia
• Anorexia
• Vomiting
• Bitter taste in the mouth
Other symptoms: vague abdominal pain, epigastric pain,
pruritus, dry cough, lethargy
Clinical features
• P.ovale, P.malariae and P.vivax rarely result
in severe disease or death
• Chronic infection or infection in pregnant
women of these ‘benign’ species may lead
to marked morbidity
Clinical features – Pregnant women
• Malaria in pregnancy ↑ risk miscarriage, stillbirth,
prematurity, low birth weight & neonatal death; also
maternal morbidity and mortality

• High fever thought to contribute to foetal distress

• Risk greatest in primigravidae in areas unstable malaria

• Cerebral malaria more common

• Parasitaemia higher, anaemia more profound,

hypoglycaemia & pulmonary oedema more common
Severe malaria
• The result of extensive multi-system
involvement in falciparum malaria
• Onset is rapid with death (especially in
children) occurring within hours
• In travellers to endemic regions most
frequently observed when diagnosis made
late
Severe malaria
• Demonstration of P. falciparum asexual
parasitaemia in a patient +
• no other obvious cause of symptoms +
• the presence of one or more of the
following clinical or laboratory features:
Clinical Features of Severe Malaria
• impaired consciousness or unrousable coma
• prostration, i.e. generalized weakness so that the patient
is unable walk or sit up without assistance
• failure to feed
• multiple convulsions – more than two episodes in 24 h
• deep breathing, respiratory distress (acidotic breathing)
• circulatory collapse or shock, systolic blood pressure < 70
mm Hg in adults and < 50 mm Hg in children
• clinical jaundice plus evidence of other vital organ
dysfunction
• Haemoglobinuria, abnormal spontaneous bleeding
• pulmonary oedema (radiological)
Laboratory Parameters for Severe Malaria
• Hypoglycaemia (blood glucose < 2.2 mmol/l or < 40
mg/dl)
• Metabolic acidosis (plasma bicarbonate < 15 mmol/l)
• Severe normocytic anaemia (Hb < 5 g/dl, packed cell
volume < 15%)
• Haemoglobinuria
• Hyperparasitaemia
(> 2%/100 000/μl in low intensity transmission areas or
> 5% or 250 000/μl in areas of high stable malaria)
• Hyperlactataemia (lactate > 5 mmol/l)
• Renal impairment (serum creatinine > 265 μmol/l)
Cerebral malaria
• Most important complication of falciparum malaria
• Mortality 20%
• Mostly non-immune adults and children
• ‘Unrousable coma in the presence of
parasitaemia where other causes encephalopathy
excluded’
• Take any alteration in conscious level seriously
• Usually no neck rigidity or photophobia, Kernig’s
negative
Cerebral malaria - presentation
• Diffuse cerebral dysfunction with coma
• Convulsions (50% generalised)
• Focal neurological signs
• Retinal haemorrhages in ~15%
Severe Normocytic Anaemia
• All patients with malaria have ↓ in
haemoglobin- normocytic
• Severe anaemia – pallor, SOB, gallop
rhythm, pulmonary oedema, neurological
signs
• Anaemia exacerbated by 2° bacterial
infection, haemorrhage & pregnancy
• Hyperparasitaemia +/- G6PD deficiency
can → massive intravascular haemolysis
Renal Failure
Pre-renal or renal, usually in adults
• ↑Cr & Ur with oliguria/anuria due to ATN
• Renal impairment may occur at time max
parasitaemia or when parasites cleared
• Poor prognosis – 45% die
Hyperparasitaemia
• In endemic areas is parasite density >106
parasites/ml (about 20% cells infected)
• In highly endemic areas patients may
tolerate greater densities without
accompanying clinical features
Hypoglycaemia
• Whole blood glucose <2.2mmol/l
• Due to impaired liver function or quinine / quinidine -
induced hyper-insulinaemia (pregnant ♀ especially)
• Anxiety, sweating, SOB, dilated pupils, hypothermia,
tachycardia, light-headedness
• →↓conciousness, convulsions & coma
• In fasting adult hepatic glycogen stores last 48hrs.
• Indicates poor prognosis
• Risk factor for neurological sequelae
Circulatory Collapse/Algid malaria

• Cold, clammy, cyanotic skin

• Weak rapid pulse, supine systolic
<70mmHg
• Commonly 2° to bacterial infection,
metabolic acidosis, pulmonary oedema,
dehydration or gastrointestinal bleed
Spontaneous Bleeding/DIC
• Due to pathological activation of coagulation
cascade → consumption of clotting factors &
platelets → microthrombi
• Bleeding gums, epistaxis, petechiae,
haematemesis, melaena
• Occurs in <10% pts, more common in non-
immune people (especially travellers)
Repeated Generalised Convulsions

• Malarial convulsions can occur at any temp

• Post - ictal coma may last a few hours
• In deep coma abnormalities of posture and
muscle tone often seen
Lactic acidosis
• pH<7.3 or raised plasma and CSF lactate
levels and low plasma HCO3 = poor
prognosis
• Lactate levels >5mmol/l frequently exceed
the body’s buffering capacity → metabolic
acidosis
Malarial haemoglobinuria/ Blackwater fever

• Massive haemoglobinuria – cause

incompletely characterised
• In some cases follows treatment or
prophylaxis with an oxidant drug e.g.
primaquine
• More common in patients with G6PD def or
other red cell enzyme deficiencies e.g.
Pyruvate kinase deficiency
Malaria diagnosis
Clinical:
“least expensive”
imprecise but the basis of treatment
when laboratory support is out of reach
Parasite-based diagnostic methods
Microscopy of Giemsa stained blood smears
Alternatives: detection of malaria antibodies by –
indirect immunofluorescence assay (IFA);
enzyme-linked immunosorbent assays (ELISA)
Detection of malaria antigens
Immunochromatographic assay: basis of rapid diagnostic
tests (RDTs) – Parasight-F test, OptiMAL IT
Fluorescent stain – Quantitative Buffy Coat (QBC)
Molecular methods: DNA probes and polymerase chain
reaction
 DIAGNOSIS
Peripheral Blood Smear
(The Gold Standard)
DIAGNOSIS
• Giemsa -stained smears of peripheral blood.

• Both thick & thin smears should be examined.

• Thick film: Identifies degree of parasitisation.

• Thin film: Identify the Plasmodium species.

• P. falciparum smears best obtained after a febrile paroxysm.

• A single negative blood smear does not exclude malaria but
makes the diagnosis unlikely especially severe disease.
• Repeat smears may be required every 6-12hrs for 48hrs if
malaria is suspected.
Quantification of parasites (‘plus system’)
• Thick film: number of asexual forms/ul of blood
• Thin film: number of parasites per ul of blood
• Semi quantitative
• 1+ 1-10 asexual forms per 100 thick films
• 2+ 11-100 asexual forms per 100 thick films
• 3+ 1-10 asexual forms per single thick film
• 4+ 11-100 asexual forms per single thick film
Characteristics of P. falciparum
• Red cells not enlarged
• Rings are fine and may be >1 per cell
• Some rings may have 2 chromatin dots
• Presence of marginal form
• Crescent shaped gametocytes
• Maurer’s dot may be present
P. falciparum
P. malariae
• Ring form may have squarish appearance
• Characteristic band forms
• Mature schizont has daisy head
appearance
• Chromatin dot may be on the inner surface
of the ring
• Red cell not enlarged
P. Malariae schizont
• Antibody detection
• Enzymatic immunoassay
• Immunoflourescence
• May be used in surveys
• Not useful in acute malaria (antibodies develop
days or weeks after onset)
• Antigen detection
• Parasight F
• OptiMAL
Malarial antigens

•pLDH
•HRP-2
Quantitative Buffy Coat
• Uses specialized capillary tube pre-coated
with acridine orange (AO)
• The parasite DNA is stained by AO
• Parasitized RBC occupies the top of the
tube and are pressed against the wall by a
float
• These cells are viewed by UV microscope
pLDH detection
• LDH is produced by the parasite
• Thus the enzyme is released by the
parasitized cells
• Isoforms of the enzymes are species
specific
• Monoclonal antibodies detect the enzymes
in blood of infected patients
Detection of HRP-2 (histidine rich protein )
• Another form of antigen detection test
• Monoclonal immunoglobulin raised against
falciparum specific histidine rich antigen-2
• The immunoglobulin is immobilized on the
nitrocellulose strip
• Positive sample: control dashed line and
solid pink line are visible
ANCILLARY INVESTIGATIONS
• FBC
• RVS
• HBsAg, ANTI-HCV
• Liver function test
• SEUC
• Serum proteins
• Lumbar puncture
DIFFERENTIAL DIAGNOSIS
• Viral infections – encephalitis,
gastroenteritis
• Pneumonia
• Typhoid fever
• Connective tissue diseases
• Acquired immunosuppression (HIV)
Indicators of a poor prognosis 1
• Hyperlactataemia (>6mmol/l or arterial pH<7.3)
• Hyperventilation
• Bleeding
• Convulsions
• Hyperparasitaemia (>106 ring stage forms/ml)
• ≥5% of polymorphs contain malarial pigment (haemozoin)
• Decerebrate posturing
• Hypothermia (<35°C)
• Sustained hyperthermia (>41°C)
• Severe anaemia (PCV<15% or Hb<5g/dl)
• Deep coma (3-5 on GCS)
• Jaundice
• Uraemia (>21.4mmol/l)
• Shock
• Hypoglycaemia (plasma glucose<2.2mmol/l)
• Peripheral leucocytosis (>12 000/ml)
• ALT & AST ↑ 3x above normal
ANTIMALARIALS: based on Activity
• Tissue schizonticide (casual ptophylaxis):
pyrimethamine, primaquine
• Blood schizonticide (suppresive
prophylaxis) : chloroquine, quinine,
mefloquine, halofantrine,
pyrimethamine, sulfadoxine, sulfones,
tetracyclines
• Gametocides: primaquine, artemisin, CQ,
quinine, proguanil, pyrimethamine
• Sporontocides: primaquine, chloroguanide
Antimalarial :based on structure
• Aryl amino alcohols: Quinine, quinidine (cinchona
alkaloids), mefloquine, halofantrine.
• 4-aminoquinolines: Chloroquine, amodiaquine.
• Folate synthesis inhibitors: Type 1 – competitive inhibitors
of dihydropteroate synthase – sulphones, sulphonamides;
Type 2 – inhibit dihydrofolate reductase – biguanides like
proguanil and chloroproguanil; diaminopyrimidine like
pyrimethamine
• 8-aminoquinolines: Primaquine
• Antimicrobials: Tetracycline, doxycycline, clindamycin,
azithromycin, fluoroquinolones
• Peroxides: Artemisinin (Qinghaosu) derivatives and
analogues – artemether, arteether, artesunate, artelinic acid
• Naphthoquinones: Atovaquone
ACT
• Artemisinin or Qinghaosu (“ching-how-soo”) is the active
principal of the Chinese medicinal herb Artemisia annua.
• The active antimalarial constituent of this plant was isolated in
1971 and it was named artemisinin.
• A water soluble ester called artesunate and two oil soluble
preparations called artemether and arteether have now been
developed.
TREATMENT-COMBINATION THERAPY

• WHO policy recommendations on treatment of

drug-resistant P. falciparum malaria
• Malaria endemic countries which are
experiencing resistance to currently used
antimalarial chemotherapy (chloroquine,
amodiaquine or S-P) to change treatment
policies to combination therapies, preferably
the highly effective artemisinin-based
combination therapy.
DEFINITION OF ANTIMALARIAL
COMBINATION THERAPY BY WHO
• Is simultaneous use of two or more blood
schizontocidal drugs with independent
modes of action and different biochemical
targets in the parasites (fixed-dose
formulations or co-administered therapy)
• Artemisinin based combination therapy (ACTs):
first-line treatment for P. falciparum malaria.
• P. vivax malaria : chloroquine where it is effective,
or an appropriate ACT in areas where P. vivax is
resistant to chloroquine.
• Treatment of P. vivax should be combined with a
14-day course of primaquine to prevent relapse.
Why?
2006 Recommendations for uncomplicated P.
falciparum malaria.
Artemisinin-based combination therapies (ACTs)
Examples are:
• artemether plus lumefantrine,
• artesunate plus amodiaquine,
• artesunate plus mefloquine, and
• artesunate plus sulfadoxine-pyrimethamine.
Addition WHO 2010 guideline
• Dihydroartemisinin plus piperaquine (DHA+PPQ)
Second-line antimalarial treatment
• alternative ACT known to be effective in the region;
• artesunate plus tetracycline or doxycycline or
clindamycin; any of these combinations to be given
for 7 days;
• quinine plus tetracycline or doxycycline or
clindamycin; any of these combinations should be
given for 7 days
Special conditions: Pregnancy
First trimester: Quinine is safe in 1st trimester
• quinine plus clindamycin to be given for 7 days ((and
quinine monotherapy if clindamycin is not available).

• An ACT is indicated only if this is the only treatment

immediately available, or if treatment with 7-day quinine
plus clindamycin fails or uncertainty of compliance with a
7-day treatment.

• Artesunate plus clindamycin for seven (7) days is

indicated if this treatment fails
Pregnancy - Second and third trimesters:

• ACTs known to be effective in the

country/region or artesunate plus
clindamycin to be given for 7 days, OR
quinine plus clindamycin to be given
for 7 days.
Caution in Pregnancy!
• Quinine is associated with an increased risk of
hypoglycaemia in late pregnancy, and it should be used
only if effective alternatives are not available.
• Primaquine and tetracyclines should not be used in
pregnancy
Lactating women & children
Lactating women:
• Standard antimalarial treatment (including ACTs) except
for dapsone, primaquine and tetracyclines.
Infants and young children:
• ACTs for first-line treatment with attention to accurate
dosing and ensuring the administered dose is retained.
Caution in lactation and children!!
• Tetracycline is contraindicated in breastfeeding mothers
because of its potential effect on the infant’s bones and
teeth.
• Primaquine should not be used in nursing women, unless
the breastfed infant is not G6PD-deficient
Non-immune individuals
Travellers returning to non-endemic countries:
• atovaquone-proguanil;
• artemether-lumefantrine;
• quinine plus doxycycline or clindamycin.
Prevention of malaria in non-immune
• Atovaquone/proguanil (Malarone) 250/100mg daily
• Chloroquine (if parasite sensitive) 300mg base weekly
• Doxycycline 100mg daily
• Hydroxychloroquine 310mg base weekly
• Mefloquine 228mg base weekly
• Primaquine 30mg daily
Severe Malaria – treatment options
• The Cinchona Alkaloids (Quinine and Quinidine)
• AND
• The Artemisinin derivatives (Artesunate, Artemether
and Artemotil or beta arteether)
• EMAL?
Severe Malaria
For adults, artesunate IV or IM:
• quinine is an acceptable alternative if parenteral
artesunate is not available.
For children :
• artesunate IV or IM;
• quinine (IV infusion or divided IM injection);
• artemether IM (should only be used if none of the
alternatives are available as its absorption may be
erratic).
Quinine
• loading dose of quinine (i.e. 20 mg salt/kg body weight –
twice the maintenance dose) reduces the time needed to
reach therapeutic plasma concentrations.
• The maintenance dose of quinine (10 mg salt/kg body
weight) is administered at 8-h intervals, starting 8 h after
the first dose
• administered as a slow, rate-controlled infusion (usually
diluted in 5% dextrose and infused over 4 h
Quinidine
• Is more toxic than quinine, it causes hypotension and QT
prolongation
• Only to be used if no other effective parenteral drugs are
available.
• Its use requires electrocardiographic monitoring and
frequent assessment of vital signs
• Give parenteral antimalarials in the
treatment of severe malaria for a minimum
of 24 h, once started (irrespective of the
patient’s ability to tolerate oral medication
earlier) and, thereafter, complete treatment
by giving a complete course of ACTs
Severe malaria – after parenteral drug(s)
complete treatment by giving:
• artemether plus lumefantrine,
• artesunate plus amodiaquine,
• dihydroartemisinin plus piperaquine,
• artesunate plus sulfadoxine-pyrimethamine,
• artesunate plus clindamycin or doxycycline,
• quinine plus clindamycin or doxycycline.
Drug resistance in malaria
• Defined as the ability of parasite strain to multiply or to
survive in the presence of concentrations of a drug
that normally destroy parasites of the same species or
prevent their multiplication.
• Partial when it yields to increased doses of the drug
tolerated by the host
• Complete when the parasite is able to withstand the
maximum tolerated dose of the drug by the host
• Early treatment failure is defined as persistence or

deterioration of symptoms and presence of parasitaemia

during the first 3 days of follow up
• Late treatment failure is defined as reappearance of

symptoms in the presence of parasitaemia during days 4-

14 of follow up
• Adequate Clinical Response (ACR) is defined as the
either the absence of parasitaemia on day 14 or the
absence of symptoms on day 14 (irrespective of
parasitaemia) in patients who did not meet criteria for ETF
or LTF.
CONTROL

1. Vector control remains the most effective.

Remove all stagnant water
2. Avoid mosquito bites
- do not live near breeding grounds
- ITN, insecticides
- repellants
. Chemicals to kill larvae
: Malaria vaccine
ROLL BACK MALARIA
• RBM is a global movement with a diverse partnership
• RBM Goal is to reduce the burden and mortality of malaria by
50% by the year 2010
• RBM---ELEMENTS OF ACTION
• Early detection, surveillance and building community awareness
• Rapid diagnosis and prompt treatment
• Multi-preventive strategy ie adoption of multiple preventive
methods
• Focused research to develop new medicines, vaccines and
insecticides
• Coordinated efforts to strengthen existing health services, policy
and provide technical support
• Harmonized action to build a dynamic global movement
Conclusion
• Malaria is complex but it is a curable and
preventable disease.
• Lives can be saved if the disease is
detected early and adequately treated.
• Not every Fever is MALARIA.
• TEST, THEN TREAT
Acknowledgment
• Dr Onukak, Infectious Diseases, Departmrnt of Internal
Medicine, UUTH
References
• TheGuardian 09 july 2017, ‘North, resevoir of malaria
parasites in Nigeria’, Prof Wellington Oyibo
• Epidemiology of Malaria in Endemic Areas. Beatrice
Autino et al
• Nmadu P. M. et al, The Prevalence Of Malaria In Childre
Between Ages 2-15 Visiting Gwarinpa General Hospital
Life-camp, Abuja, Nigeria, Journal Of Health Sciences, Vol
5 No. 3, 2015, pp.47-51
• Tropical Medicine by Geoff Gill(5th edition)
• Harrison’s Textbook of Internal Medicine( 18th edition)
• WHO publications
• Kumar and Clark Textbook of Clinical Medicine (8th
edition)
• Internal MedicineUpdate Course (2011,2012,2013)
AT LAST! THANKS FOR
YOUR PATIENCE