1. By: Dr.Geethika REDDY.P Moderator:Dr.B.S.K.Prusty
Tropical Fevers in ICU
By:
Dr.Geethika REDDY.P
Moderator:Dr.B.S.K.Prusty

2. Introduction:
Every year different parts of India are hit by seasonal fevers in the post monsoon period.
A large number of these patients require (ICU) care like MV, RRT, vasopressor support, blood and blood component therapy due to single or MOF. some fevers leading to very high morbidity and mortality.
The clinical picture of these diseases is so overlapping that it is almost impossible to achieve D/Dof these diseases in emergency and ICU settings when the time available for intervention is limited.

3. Tropical fevers:
Tropical diseases were defined as diseases that are prevalent in, or unique to tropical and subtropical regions.
The diseases are less prevalent in temperate climates, due in part to the occurrence of a cold season, which controls the insect population by forcing hibernation.
Most often disease is transmitted by an Vector insect “bite”.
The Indian subcontinent by its very location represents one of the largest tropical and subtropical regions with many of these infections being prevalent.
Some of these occur throughout the year and some are greatly influenced by the seasons (especially rainy season) and geography

4. Few tropical infections :
Malaria
Typhoid
Dengue fever
Leptospirosis
Chikungunya
Viral hepatitis A and E
Typhus
Tuberculosis
Brucellosis
Hepatic amebiasis
Visceral leishmaniasis P
arasitic hyperinfection ( Strongyloides )
Relapsing fever
Viral hemorrhagic fever
Yersiniosis
Plague
Tularemia
Trypanosomiasis

5. Syndromic approach
For ease of diagnosis these infections were divided into five major syndromes:
1.Undifferentiated fever,
2.Fever with rash/thrombocytopenia,
3.Fever with acute respiratory distress syndrome (ARDS),
4.Fever with encephalopathy and
5.Fever with multi organ dysfunction syndrome.

6. Syndromic approach
Undifferentiated fever:patients with acute onset fever without any localizing signs oral temp>101f
1.Malaria (P. falciparum)
2.scrub typhus
3. leptospirosis,
4. typhoid,
5.dengue and other common viral illness.
Fever with rash/thrombocytopenia:Acute onset fever with a transient skin rash or exanthema, with or without thrombocytopenia (platelet count < 100,000)
1.Dengue,
2. rickettsial infections,
3.meningococcal infection,
4.malaria (usually falciparum),
5. leptospirosis,
6. measles,
7.rubella

7. Fever with ARDS:Acute onset fever with respiratory distress in the form of SpO2 <90% at room air or frank ARDS with PaO2/FiO2 ratio <200.
1.Scrub typhus,
2.Falciparum malaria,
3.Influenza ,
4. Leptospirosis,
5.Hantavirus infection,
6.Severe community acquired pneumonias and
7.Diffuse alveolar hemorrhage due to collagen vascular diseases.

8. Febrile encephalopathy :
1.Encephalitis (Herpes simplex virus encephalitis, Japanese B and other viral encephalitis),
2.meningitis ,
3. scrub typhus,
4.cerebral malaria and
5.typhoid encephalopathy.
Fever with multiorgan dysfunction :
1.Bacterial sepsis,
2. falciparum malaria,
3.leptospirosis,
4.scrub typhus,
5. dengue,
6. hepatitis A or E with fulminant hepatic failure and
7.hepato-renal syndrome

9. Back drop :
Evident that many infections can have an overlapping presentation, a clinician should be aware of the common etiological agents and their epidemiology in the defined geographic region to be able to make a diagnosis and initiate treatment.
This would go along way in managing acutely ill patients empirically.

10. Algorthmic approach for diagnosis & management

15. Z

19. To Focus on most common FEVER’s:
Dengue
Leptospirosis
Scrub typhus
Thyphoid
Japanees enchepahalitis
Malaria(usually due to Plasmodium falciparum)
Influenza (H1N1)

20. Specific infections in detail:
Causative organism: Dengue virus (Flavivirus) serotypes 1-4.
Vector: Aedes mosquitoes
Dengue is endemic throughout India
The virus initially replicates in the skin and lymph nodes before dissemination in the blood stream.

21. Following a mosquito bite, viraemia begins and usually lasts up to 7 days.
Infection with one of the four serotypes (primary infection) provides life-long immunity against that serotype, but not against the other serotypes (secondary infection).
studies suggest that the risk of severe disease (DHF/DSS) is significantly higher in secondary infection than in primary infection

23. Risk factors for DHF/DSS
Virus strain
Pre exsisting anti dengue antibody
Host genetics /age
Higher risk in secondary infections

24. Pathogenesis:
Cross-reactive (but non-neutralizing) anti-dengue antibodies from previous infection enhance newly infecting strain with viral uptake of monocytes and macrophages
Amplified cascade of cytokines and complement activation Endothelial dysfunction, platelet destruction and consumption of coagulation factors, Plasma leakage and hemorrhagic manifestations.

26. The clinical presentation varies from mild febrile illness to severe haemorrhagic fever. Most infections are asymptomatic.
WHO classifies dengue infection as
1. Undifferentiated fever,
2.Dengue fever (DF),
3.Dengue haemorrhagic fever (DHF)/Dengue shock syndrome (DSS)
DF incubation period of 3–14 days and is characterised by the sudden onset of fever, severe headache, retro-orbital pain on moving the eyes, and fatigue.
It is often associated with severe myalgia and arthralgia (breakbone fever). Maculopapular rash, flushed facies and injected conjunctiva are common

27. DHF
Haemorrhagic manifestations can occur in DF and should not be confused with DHF.
It is important to watch for the onset of DHF, which typically occurs 4–7 days after the onset of the disease. Decrease in platelet count and rise in haematocrit are useful clue.

28. DHF The following must all be present:
1. Fever, or history of fever, lasting for 2-7 days, occasionally biphasic
2. Hemorrhagic tendencies evidenced by at least one of the following:
a. (+) tourniquet test
b. Petechiae, ecchymosis, purpura
c. Bleeding from the mucosa, GIT, injection sites or other locations
d. Hematemesis or melena
3. Thrombocytopenia ( 100,000 cells/mm3 or less
4. Evidence of plasma leakage due to increased vascular permeability, manifested by at least one of the following
a. A rise in the hematocrit equal to or greater than 20%
b. A drop in the hematocrit following volume replacement treatment equal to or greater than 20% of baseline
c. Signs of plasma leakage such as pleural effusion, ascites and hypoproteinemia

29. DSS:
Dengue shock syndrome is characterised by profound hypotension and shock.
All of the 4 criteria for DHF must be present , plus evidence of circulatory failure manifested by: 1.Rapid and weak pulse,
2. Narrow pulse pressure < 20mmHg OR manifested by:
3.Hypotension for age, AND Cold clammy skin and restlessness
Expanded dengue syndrome:Encephalitis, myocarditis, hepatitis, renal failure, ARDS, hemophagocytosis.

30. Diagnosis
1.The gold standard is the detection of antibodies by hemagglutination inhibition assay showing at least 4 fold rise in titre of neutralizing antibody in paired samples. 2. ELISA test for IgM antibodies which appear around the 6th day of illness and last from 1-3 months. IgG antibodies appear after 7-10 days and last for months to years, they too can be detected by ELISA. In secondary dengue IgG antibodies are present in high titre early in illness 3. Virus isolation techniques, which are not easily available. 4. RT- PCR :Detection of the virus within 1-2 days of manifestations with test being negative later in the illness

31. Treatment
Supportive therapy for shock, especially appropriate and prompt fluid replacement can reduce mortality. Fluid management is complex
Isotonic fluid infusion just sufficient to maintain effective circulation during the period of plasma leakage; guided by serial hematocrit determinations. (Level IA) .
Blood transfusion is done only with overt bleeding/ rapid fall in hematocrit.

39. Leptospirosis
Causative organism: Leptospira interrogans Source of infection: Direct contact of skin or mucosa with water contaminated with urine or body fluid of an infected animal.
Peak incidence during the rainy season. Rampant in southern, western and eastern India. Increasing incidence in “non-endemic” northern India

40. pathophysiology
Leptospires present in water bodies enter through breaks in the skin and mucus membranes multiply in the small blood vessel endothelium, resulting infever, establish organ invovlment in kidney and liver,produces hemorrhage and necrosis in the tissues causing organ dysfunction

41. Clinical presentation
It has two phases: septicaemic phase and immune phase.
Clinical features include conjunctival suffusion or haemorrhages (useful diagnostic clue), uveitis, severe muscle tenderness, non-oliguric renal failure, hypokalaemia, hepatic dysfunction, pulmonary haemorrhage, ARDS, myocarditis, rhabdomyolysis, thrombocytopenia, DIC, haemorrhage into the skin and internal organs, and digital gangrene.
Severe leptospirosis:Weil’s syndrome is characterised by hepatorenal dysfunction, bleeding diathesis and pulmonary involvement

43. Labs:
Laboratory findings : The white cell count is often <10,000 ranging from
CUE:shows proteinuria, pyuria, granular casts and hematuria.
The CPK is often elevated along with AST ALT and LDH
CSF may show an aseptic meningitis like picture
chest x-ray often shows dense confluent shadows suggestive of pulmonary hemorrhage can also include diffuse pneumonitis, nonsegmental or basal linear opacities and pleural effusions
Arrhythmias due to significant cardiac irritability have been documented.
The arrhythmias observed were AF, atrial flutter, atrial tachycardia and VPC.
Echocardiograms may reveal pericarditis and small pericardial effusion, in few cases.

44. Laboratory criteria Presumptive diagnosis:
A positive result of a rapid screening test such as IgM ELISAand SAT Sensitivity 52-89%, specifi city > 94%) early diagnosis upto 2days.
latex agglutination test (Sensitivity 30-63%, specifi city > 97%) dipstick etc.
Confirmatory diagnosis:Isolation from blood(before 10th day) /urine(10th day onwards)/CSF.culture of pathogenic leptospires.
Diagnosis is made with serology with the microscopic agglutination test (MAT) as the gold standard with either a four fold rise in titres or a single titre of >1:800 being diagnostic obtained at least 2 weeks apart.
PCR (presently investigational) appear to be sensitive, specific, positive early in disease, and able to detect leptospiral DNA in blood, urine, cerebrospinal fluid (CSF) and aqueous humor. Currently major disadvantage with these tests is that these are genus specific, not serovar specific
Clutures will take upto 6weeks to be positive.

45. WHO GUIDELINES: Faine’s Criteria For Diagnosis Of Leptospirosis

46. A presumptive diagnosis of leptospirosis may be made
if: (i) Parts A and B score = 26 or more (Part C laboratory report is usually not available before fifth day of illness; thus it is mainly a clinical and epidemiologic diagnosis during early part of disease) (ii) Part A+B+C = 25 or more A score between 20 and 25 : Suggests a possible but unconfirmed diagnosis of leptospirosis.

47. Treatment
Since the antibodies may not be demonstrable in serum during the first week of illness, initial treatment is often empirical
Treatment : crystalline penicillin at a dose of 6 million units daily (DOC) for days.
ceftriaxone 1 gram every 12 hourly.
Besides penicillin, doxycycline in a dosage of 100 mg twice daily for 7 days is effective in treatment of mild and moderate leptospirosis.
Effective prophylaxis consists of doxycycline, 200 mg orally once weekly, during the risk of exposure
Other therapy involves supportive measures like dialysis, ventilation and the use of blood products

48. Prognosis:
The prognosis of leptospirosis depends on the severity of the disease and the associated complications.
Anicteric leptospirosis usually has a good prognosis. Without jaundice the disease is almost never fatal;
however, fatal pulmonary hemorrhage and myocarditis have been reported occasionally in anicteric cases.
The case fatality rate for Weil’s disease is 15-40%, and is higher for patients over 60 years of age.

49. Scrub thypus Causative organism: Orientia tsutsugamushi
Vector: chiggers (larva of Trombiculid mite).
The organism is a Gram-negative coccobacillus that infects vascular endothelium with subsequent vascular injury in organs like the skin, liver, kidneys, meninges and brain.
The vascular injury causes a DIC with platelet consumption, vascular leak, pulmonary edema, shock, hepatic and renal failure
The organism is inoculated into skin by the bite of larval forms of tromiculid mites, these larvae are called as chiggers.
The disease occurs 7-10 days after the bite and patients present with fever, relative bradycardia,severe myalgias, a nonpruritic maculopapular rash sometimes with an accompanying eschar at bite site(Diagnostic) and lymphadenopathy.
The disease lasts for 2-3 weeks if untreated and complications due to vasculitis in different organs occur usually in the 2nd week of illness

50. Diagnosis
The diagnosis is made by history of exposure, appropriate physical findings, thrombocytopenia, deranged LFTs, elevated creatinine
Serology: Weil-Felix: poor sensitivity and specifi city
Indirect fluorescent antibody: “Gold standard” (Level IIA)
Enzyme-linked immunosorbent assay (ELISA) for immunoglobulin G (IgG) and IgM antibodies: sensitivity and specifi city > 90%.
Hemagglutination test is gold standard for scrub thypus

51. Treatment:First line: Doxycycline 100 mg BD for 7 days (Level IA)
Azithromycin or Rifampicin or chloramphenicol as alternatives in children and pregnant women. (Level IIB).

52. Typhoid fever
Causative organism: Salmonella typhi, serovar paratyphi A, B or C
Transmission: focally contaminated food and water
Most prevalent in urban areas, with high incidence in children 15 years of age and younger
Acute generalized infection of the reticuloendothelial system, intestinal lymphoid tissue,and the gallbladder

55. The incubation period is 5–21 days.
Typhoid presents non-specifically with fever, chills, abdominal pain and constitutional symptoms.
Constipation may be more frequent than diarrhoea.
Hepatosplenomegaly, erythematous macular rash (30%) and relative bradycardia may be present. Relative bradycardia is not specific for enteric fever, but is a useful clue

56. Presentation:
Time frame „Occurs gradually over a few weeks after exposure to the bacteria.The condition may last for weeks or even a month or longer without treatment.
First-Stage Typhoid Fever The beginning stage is characterized by high fever,fatigue, weakness, headache, sore throat, diarrhea, constipation, stomach pain and a skin rash on the chest and abdominal area.

57. Second-stage typhoid fever is characterized by weight loss, high fever, severe diarrhea and severe constipation. Also, the abdominal region may appear severely distended.
Typhoid State When typhoid fever continues untreated for more than two or three weeks, the effected individual may be delirious or develop cns manifestations. At this point fatal complications may emerge

58. Clinical manifestations:
Manifestations: 1st week - fever, headache, relative bradycardia
2nd week - Abdominal pain, diarrhea, constipation, hepatoslenomegaly, encephalopathy
3rd week - Intestinal bleeding, perforation, MODS.

59. Diagnosis:
Typhidot (RDT) – Sensitivity 95-97%, Specifi city > 89%, (Level III).
Widal test-non-specific.
Blood culture – Gold standard, positive in 40-80% of patients.
Bone marrow cultures – sensitivity 80-95%; may remain positive even after 5 days of pre-treatment.

60. Treatment
Supportive measures : such as oral or IV hydration, the use of antipyretics, and appropriate nutrition and blood transfusions if indicated.
First line: Ceftriaxone i.v mg/kg/day for days (Level IA) to cover MDR S. typhi. Azithromycin and Ciprofl oxacin are alternatives Consider dexamethasone 3 mg/kg followed by 1 mg/kg 6 hourly for 48 h in selected cases with encephalopathy, hypotension or DIC

61. Dexamethasone reduces mortality in severe typhoid feverwithout increasing incidence of complications, carrier states, or relapse among survivors. delirium, obtundation, stupor, coma or shock.
Ileal perforation, which may occur late, classically in the third week of febrile illness, requires prompt surgical intervention, and segmental resection has been recommended as the procedure of choice

63. Carrier eradication:
In order to eradicate S. typhi carriage, amoxicillin or ampicillin (100 mg per kg per day) + probenecid (1g orally or 23 mg per kg for children)or TMP-SMZ (160 to 800 mg twice daily) is administered for six weeks;
About 60% of persons treated with either regimen can be expected to have negative cultures on follow-up.
Clearance of up to 80% of chronic carriers can be achieved with the administration of 750 mg of ciprofloxacin twice daily for 28 days or 400 mg of norfloxacin.
Other quinolone drugs may yield similar results

64. Japneese enchephalitis
Causative organism: Japanese encephalitis virus
Vector: Culex tritaeniorhynchus
The WHO recommended case definition for suspect Japanese Encephalitis as:
A case of acute encephalitis syndrome is defined as a person of any age, at any time of year with the acute onset of fever and a change in mental status (including symptoms such as confusion, disorientation, coma, or inability to talk) AND/OR new onset of seizures (excluding simple febrile seizures*).
Other early clinical findings may include an increase in irritability, somnolence or abnormal behaviour greater than that seen with usual febrile illness.

66. PATHOGENESIS:
Birds and pigs are natural hosts of virus and humans are dead end hosts.
The incubation period lasts from 5-14 days.
After inoculation into the skin the virus replicates in the subcutaneous tissues, the lymphnodes and blood stream before entering the brain.
Virus reaches CNS through leukocytes and affects various parts of the brain to cause vascular congestion, microglial proliferation, formation of gliomesenchymal nodules, focal or confluent areas of cystic necrosis and cerebral edema.

68. Previous infection due to other flaviviruses like dengue may protect against severe disease due to the presence of protective crossreacting antibodies.
Factors which govern severe illness include:
a. Failure to produce neutralizing antibodies
b. Genetic susceptibility to infection by flaviviruses
c. Advanced age-possibly due to a breakdown in the blood-brain barrier due to cerebrovascular disease
d. Neurocysticercosis : due to a breakdown in the blood-brain barrier due to inflammation
e. Virulent genotypes of the virus

69. CLINICAL PRESENTATIONS
Most infections are Asymptomatic
The virus can infect brain parenchyma (especially the thalamus and basal ganglia) of the cerebral hemispheres, the brainstem and the anterior horn cells of the spinal cord.
The spectrum of disease can present as a mild flu like illness, aseptic meningitis or severe encephalomyelitis
60-75% of symptomatic patients present with encephalitis and 5- 10% present with meningitis.

70. Clinical manifestations :
Patients with encephalitis present with altered sensorium, seizures and abnormal posturing.
Severe brainstem injury can cause a ‘lockedin’ state. Involvement of the basal ganglia can present with a parkinsonian syndrome, opisthotonus, myoclonic jerks.
Flaccid weakness with absent reflexes may occur in 20-60% of patients with encephalitis.
This may involve the respiratory and bulbar musculature and occurs due to direct invasion of the anterior horn cells, acute painful retention of urine may be present.

71. Diagnosis :
Presence of JE virus-specific IgM antibody in a single sample of cerebrospinal fluid (CSF) Sensitivity 65-80%, Specificity % or
serum as detected by an IgM-capture ELISA specifically for JE viru sensitivity %, Specificity 96-98%.
Initial leucocytosis may be followed by leukopenia.
CSF may show a pleocytosis. MRI is more sensitive than CT for showing characteristic lesions involving the thalamus and basal ganglia.EEG may show a generalized slowing.
Nerve conduction studies show reduced or absent action potentials with preserved sensory action potentials and normal conduction velocities.

72. Treatment There is no specific treatment available
Supportive-Airway management, seizure control and management of raised intracr anial pressure

73. Prevention and control:
Mainly by mosquito control and immunization.
Classical methods like insectiside and bed nets are been widely used.
Thermal fogging with ultra low volume insectisides like pyrethrum or malathion has been recommended
Vaccine provides active immunisation against JEV.

74. Malaria
Causative organism: Plasmodium protozoa (P. falciparum, Plasmodium vivax,,Plasmodium malariae [Odisha]),plasmodium ovale,plasmodium knowlesi .
Vector: Anopheles mosquito
The incubation period is 7 days (usual range 9–14 days), but this may be prolonged
Plasmodium species are unevenly distributed across India. Orissa, Chhattisgarh, West Bengal, Jharkhand and Karnataka contribute the most to the endemicit.

75. After development in the liver, there is invasion of red cells by parasites, which is followed by their multiplication, and rupture of the red cells. The cycle is then repeated in red cells.
Mechanical microcirculatory obstruction caused by cytoadherence to the vascular endothelium of parasitized RBC and sequestration Intra-vascular hemolysis.

76. P. falciparum infects RBCs of all ages
P. falciparum infects RBCs of all ages. The parasite avoids splenic sequestration and destruction of infected RBC’s.
This occurs by the formation of knobs on the RBC membrane.These knobs appear about 16 hours into the asexual cycle and attach to specific receptors on the endothelium of capillaries in the brain and other organs.
The infected RBCs also attach to uninfected RBCs by a process called as rosetting.
The attachment to the endothelium of the capillaries and the rosetting causes the blockage of capillaries and venules and leads to end-organ dysfunction.

77. The infected cells eventually rupture and the contents cause macrophages to release cytokines like TNF-alpha, which cause a febrile response.
T Helper cells appear to play an important role in the immune response.
Temperatures >40 C damage parasites and cause synchronization of the parasitic cycle leading to a tertian fever pattern

79. Uncomplicated P. falciparum Malaria
Presentation highly variable mimics other diseases. fever is common, often intermittent and may be absent in some cases.
The fever is typically irregular initially and associated with chills. True rigors are unusual in acute falciparum malaria.
The patient complains of fever, headache, aches and pains elsewhere in the body and occasionally abdominal pain and diarrhoea.
On physical examination, fever may be the only sign.
In some patients, the liver and spleen are palpable.
This clinical presentation is usually indistinguishable from those of influenza and a variety of other common causes of fever.

80. SEVERE FALCIPARuM MALARIA
Risk factors for severe malaria
Children under 5 years in endemic regions
Adults and children in areas of low endemicity
Non-immune travellers to endemic areas.
Clinical features of severe malaria
Impaired consciousness (including unrousable coma);
Prostration, i.e. generalized weakness so that the patient is unable to sit, stand or walk without assistance;
Multiple convulsions: more than two episodes within 24h;
Deep breathing and respiratory distress (acidotic breathing);
Acute pulmonary oedema and acute respiratory distress syndrome;
Circulatory collapse or shock, systolic blood pressure < 80mm Hg in adults and < 50mm Hg in children;
Acute kidney injury;
Cinical jaundice plus evidence of other vital organ dysfunction;
Abnormal bleeding.

81. Laboratory findings include:
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%/ /µL in low intensity transmission areas or >5% or /µL in areas of high stable malaria transmission intensity)
Hyperlactataemia (lactate >5 mmol/L)
Renal impairment (serum creatinine >3mg/dl).

82. Cerebral malaria
The term is restricted to the syndrome in which altered consciousness due to malaria could not be attributed to convulsions, sedatives, hypoglycaemia or to a non-malarial cause.
Usually manifests as a diffuse symmetric encephalopathy without focal signs. Patients often have extensor posturing and upgoing plantars.
Seizures may occur especially in children and cerebral venous thrombosis or cerebral infarcts may be found.

83. Clinical, histopathological and laboratory studies have suggested two potential mechanisms:
Mechanical Hypothesis: cytoadherence of parasitised erythrocytes
Cytotoxic Hypothesis: neuronal injury by malarial toxin and excessive cytokine production.
Clinical findings include:
1. coma 2.convulsions 3.raised ICP4.hypoglycaemia 5. acidosis 6.abnormalities of tone and posture (the commonest being symmetrical pyramidal signs)
7. retinopathy – retinal haemorrhages, cotton wool spots, papilloedema, retinal whitening and retinal vessel abnormalities – all of which are more common in children.

84. aCute kidney injury
Clinical features : raised se creatinine and urea Although oliguria is usual, normal urine output. Renal impairment may be part of multi-organ dysfunction in fulminant infections, is caused by acute tubular necrosis and is always reversible in survivors. poor prognosis
Management :Exclude dehydration (hypovolaemia) by clinical examination,If dehydrated, isotonic saline to correct hypovolaemia,
If the patient remains oliguric after adequate rehydration urea and creatinine continue to rise, then RRT especially for acute fulminant disease
Massive intravascular hemolysis can cause hemoglobinuria which also damages the tubules.
These patients often require hemodialysis or CRRT to deal with the metabolic derangements of a hypercatabolic state.

85. Acute respiratory failure :
A non-cardiogenic pulmonary edema often develops about 4 days after therapy has been started.
The pathogenesis involves release of cytokines that increase capillary permeability.
In this setting fluid administration should be guided by CVP prevent worsening of the oxygenation status.
Pulmonary oedema in malaria has the features of acute respiratory distress syndrome, implying increased pulmonary capillary permeability

86. Hepatic dysfunction :
Jaundice results from a combination of hemolysis, cholestasis and hepatocyte dysfunction. Rarely hepatocyte dysfunction may be severe enough to cause hypoglycemia, coagulopathy, encephalopathy and lactic acidosis.
Clinical features Bleeding gums, epistaxis, petechiae and subconjunctival haemorrhages may occur occasionally. DIC, complicated by clinically significant bleeding, occurs in < 5% of patients
Management :transfuse fresh blood, clotting factors or platelets as required.
vitamin K, 10mg, by slow intravenous injection.
gastric protection with a parenteral H2-receptor blocker or a PPI
Thrombocytopenia is almost invariably present in falciparum malaria (black water fever), usually with no other coagulation abnormalities.

87. Hypoglycemia : This occurs due to reduced gluconeogenesis (and in the case of the liver reduced glycogenolysis), increased utilization of glucose by both the host and the parasite and the use of insulin secretagogues like quinine.
Acidosis : Lactic acidosis is secondary to increased anerobic glycolyis in tissues with sequestered parasites, increased lactate production by parasites, decreased lactate clearance by the liver and kidneys and hypotension.

88. Hematologic derangements : Severe parasitemia can lead to a rapid fall in the hematocrit which if severe enough can give the urine a cola colour due to the presence of free hemoglobin. Besides anemia, severe thrombocytopenia with platelet counts <20,000/mm3 may contribute to bleeding from the GI and GU tracts. DIC is common in severe malaria.
Poor prognostic indicators : Deep coma, convulsions, shock, anuria, hypoglycemia<45-50 mg/dl, Lactate>5 mmol/L, creatinine >3.0 mg/dl, platelets<50,000/mm3, PCV<15% bilirubin>3.0 mg/dl, AST and ALT>3X normal, parasitemia>100000/microlitre in non-immune individuals

89. Diagnosis
Microscopy of thick and thin films remains the gold standard diagnosis, and to follow the efficacy of treatment.
Rapid diagnostic tests (RDT) that detect specific antigens (proteins) produced by malaria parasites are useful in diagnosis.
Current tests are based on the detection of histidine-rich protein 2 (HRP2) (which is specific for P. falciparum), pan-specific or speciesspecific parasite lactate dehydrogenase (pLDH) or other pan-specific antigens such as aldolase.
Many commercial assays are available. Some tests detect only one species (P. falciparum), whereas others detect one or more of the other three species. RDTs do not give information about the parasite load and their sensitivity and specificity decrease at low parasitaemia.
Hence, it is important to seek microbiological advice regarding the RDT tests used locally.

90. PCR tests based on detecting malarial DNA are more sensitive than microscopy but are expensive and do not give estimates of parasite load.
In areas where two or more species of malaria parasites are common, only microscopy will permit a species diagnosis. Where mono-infection with
P. vivax is common and microscopy is not available, it is recommended that a combination RDT, which contains a pan-malarial antigen, is used. Where
P. vivax, P. malariae or P. ovale occur, almost always as a co-infection with P. falciparum.
RDT detecting P. falciparum alone may be sufficient; the treatment for non-falciparum malaria is given only to cases with a negative test result and where no other obvious cause of illness is present.
Treatment solely on the basis of clinical suspicion should only Be considered when a parasitological diagnosis is not accessible.

91. Basic supportive care
The intravascular volume should be maintained at the lowest level sufficient for adequate systemic perfusion. In hypotension early use of inotropic support is indicated rather than overhydration.
Negative fluid balance is critical to avoid exacerbating acute lung injury, but is balanced against the risk for precipitating acute renal failure
The patient may need to be intubated because of impaired consciousness or because of acute lung injury. Mechanical ventilation with lower tidal volume improves the clinical outcome
A higher positive end-expiratory pressure may be needed to maintain optimal arterial oxygenation. In respiratory acidosis, the plateau pressure should be in excess of 25cm H2O and the ventilator rate should be increased.
Surfactant therapy, inhaled nitric oxide, and corticosteroids have no effect on survival or duration of ventilation in patients with ARDS

92. Comatose patients should be placed in a semirecumbent position to reduce the risk for aspiration.
Serum sodium, arterial carbon dioxide tension, se. glucose, and arterial should be monitored frequently.
Seizures with anticonvulsants, but The efficacy of hypertonic mannitol in treatment of cerebral edema is not proven.
Early institution of renal replacement therapy may avoid the development of ARDS.
Patients with hypotension tolerate CRRT better than conventionaL/ intermittent hemodialysis. In addition, a continuous regulation of body fluid avoids periods of volume overload and depletion

93. Acidosis is usually multifactorial in origin, with causes including tissue hypoxia, liver dysfunction, and impaired renal handling of bicarbonate . Blood transfusion should be considered if the hematocrit falls below 20%, but volume overload should be avoided.

94. Anti malarial therapy:

95. Influenza-H1N1
It is an enveloped RNA virus and belongs to the family orthomyxoviridae.
The size of the virus is nm / micron in diameter.
Three levels of nomenclature
1. Type—influenza "A, B, or C”
2. Subtype—specific HA, NA: influenza A
3. Strain—specific site and year of isolation
Pandemic 2009 H1N1 virus derives 6 genes from triple-reassortant North American swine virus and2 genes (encoding neuraminidase and matrix proteins) from Eurasian swine virus lineages.
Although the 2009 H1N1 virus is antigenically distinct from other human and swine influenza A (H1N1) viruses,4 strains of this virus have been antigenically homogeneous, and the A/California/7/2009 strain that was selected for pandemic influenza

96. A Confirmed case of Pandemic Influenza A (H1N1) virus infection is defined as an individual with laboratory confirmed new influenza A (H1N1) virus infection by one or more of the following:
real-time RT-PCR,
viral culture
four-fold rise in new influenza A(H1N1) virusspecific neutralizing antibodies

97. Clinical presentation:
The incubation period appears to be approximately 1.5 to 3 days may extend to 7 days.
Infection with the 2009 H1N1 virus causes a broad spectrum of clinical syndromes, ranging from afebrile upper respiratory illness to fulminant viral pneumonia.
High Risk Groups- These risk groups include:
Children younger than 5 years old; •
Adults 65 years of age and older; •
Chronic pulmonary condition , renal, hepatic, hematological, neurologic, neuromuscular,
Immunosuppression, including that caused by medications or by HIV; • Pregnant women; •
Residents of nursing homes and other chronic-care facilities; •
Obesity

98. Mild illness without fever and cough, symptoms that are sometimes accompanied by sore throat and rhinorrhea
Gastrointestinal symptoms (including nausea, vomiting, and diarrhea) occur more commonly than in seasonal influenza, especially in adults
Dyspnea, tachypnea in children, chest pain, hemoptysis or purulent sputum, prolonged or recurrent fever, altered mental status, manifestations of dehydration, and reappearance of lower respiratory tract symptoms after improvement are signs of progression to more severe disease or complications

99. The principal clinical syndrome leading to hospitalization and intensive care is diffuse viral pneumonitis associated with severe hypoxemia, ARDS, and sometimes shock and renal failure.
This syndrome has accounted for approximately 49 to 72% of ICU admissions. Rapid progression is common, typically starting on day 4 to 5 after the onset of illness, and intubation is often necessary within 24 hours after admission
Radiographic findings commonly include diffuse mixed interstitial and alveolar infiltrates, although lobar and multilobar distributions occur, particularly in patients with bacterial co infection

100. Chest CT has shown multiple areas of ground-glass opacities, air bronchograms, and alveolar consolidation, particularly in the lower lobes.Small pleural effusions occur, but an increased volume suggests volume overload or possibly empyema.
Sporadic cases of neurologic manifestations (confusion, seizures, unconsciousness, acute or postinfectious encephalopathy, quadriparesis, and encephalitis) and myocarditis have been reported, including some fulminant cases
Laboratory findings in patients with severe disease include normal or low-normal leukocyte counts with lymphocytopenia and elevations in levels of serum aminotransferases, LDH, creatine kinase, and creatinine
Myositis and rhabdomyolysis have occurred in severe cases.
A poor prognosis is associated with increased levels of creatine kinase, creatinine, and perhaps lactate dehydrogenase, as well as with the presence of thrombocytopenia and metabolic acidosis

101. DIAGNOSIS:
Viral RNA detection by conventional or real-time reverse- transcriptase–polymerase-chain-reaction (RT-PCR) assay remains the best method for the initial diagnosis of H1N1 virus infection.
Nasopharyngeal aspirates or swabs taken early after the onset of symptoms are suitable samples, but endotracheal or bronchoscopic aspirates have higher yields in patients with lower respiratory tract illness

102. At first, all individuals seeking consultations for flu like symptoms should be screened at designated healthcare facilities or examined by a doctor and these will be categorized as under:
Category- A:
Patients with mild fever plus cough / sore throat with or without body ache, headache, diarrhoea and vomiting will be categorized as Category-A. They do not require Oseltamivir and should be treated for the symptoms mentioned above. The patients should be monitored for their progress and reassessed at 24 to 48 hours by the doctor.
No testing of the patient for H1N1 is required.
Patients should confine themselves at home and avoid mixing up with public and high risk members in the family.

103. Category-B
In addition to all the signs and symptoms mentioned under Category-A, if the patient has high grade fever and severe sore throat, he/she may require home isolation and Oseltamivir;
In addition to all the signs and symptoms mentioned under Category-A, individuals having one or more of the following high risk conditions shall be treated with Oseltamivir
Children less than 5 years old; Pregnant women; Persons aged 65 years or older;
Patients with lung diseases, heart disease, liver disease, kidney disease, blood disorders, diabetes, neurological disorders, cancer and HIV/ AIDS;
Patients on long term cortisone therapy. 
No tests for H1N1 are required for Category-B (i) and (ii)
All patients of Category-B (i) and (ii) should confine themselves at home and avoid mixing with public and high risk members in the family. 

104. Category-C:
In addition to the above signs and symptoms of Category-A and B, if the patient has one or more of the following:
Breathlessness, chest pain, drowsiness, fall in blood pressure, sputum mixed with blood, bluish discoloration of nails;
Irritability among small children, refusal to accept feed;
Worsening of underlying chronic conditions.
All these patients mentioned above in Category-C require testing, immediate hospitalization and treatment including Oseltamivir

105. Early therapy with oseltamivir may reduce the duration of hospitalization and the risk of progression to severe disease requiring ICU admission or resulting in death
In severely ill patients, viral RNA may be detectable in endotracheal aspirates for several weeks after the initiation of oseltamivir therapy.
An increased dose of the drug (e.g., 150 mg twice daily in adults) and particularly an increased duration of therapy (e.g., a total of 10 days) with avoidance of treatment interruptions are reasonable in patients with pneumonia or evidence of clinical progression

106. INFLUENZA A H1N1 VACCINE
There are two types of Flu vaccines, trivalent and Quadrivalent.
Trivalent vaccine is being used for prophylaxis Trivalent vaccine protects against 3 strains of the flu, A/H3N2, A/H1N1 and Influenza B.
The Quadrivalent vaccine protects against four stains of the flu, A/H3N2, A/H1N1 and two strains of Influenza B. This vaccines is available as :
Traditional flu shots, approved for any one 6 months and older
Nasal spray approved for healthy people from 2 years to 49 years, except pregnant women.
Currently only trivalent vaccine is available In India.