acute febrile illnesses

This is brief overview of commonly encountered acute febrile illnesses

1. Acute Febrile Illness Melaku Yitbarek(M.D.) Internal Medicine Unit Feb 23,2018

2. Outline Introduction Definition Pathogenesis Causes with clinical features & Management

3. Introduction Body temperature is controlled by the hypothalamus In a neutral temperature environment , the human metabolic rate produces more heat than is necessary to maintain the core body temperature in the range of 36.5–37.5°C A normal body temperature is ordinarily maintained despite environmental variations Because the Hypothalamic thermoregulatory center balances the excess heat production derived from metabolic activity in muscle and the liver with heat dissipation from the skin And lungs

4. Definition According to studies of healthy individuals 18–40 years of age, the mean oral temperature is 36.8° ± 0.4°C (98.2° ± 0.7°F), with low levels at 6 a.m. and higher levels at 4–6 p.m. The maximal normal oral temperature is 37.2°C (98.9°F) at 6 a.m . and 37.7°C (99.9°F) at 4 p.m .; these values define the 99th percentile for healthy individuals. In light of these studies, an a.m. temperature of >37.2°C (>98.9°F) or a p.m. temperature of > 37.7°C (>99.9°F) would define a fever. The normal daily temperature variation is typically 0.5°C (0.9°F). Rectal temperatures are generally 0.4°C (0.7°F) higher than oral readings

5. Fever versus Hyperthermia Fever is an elevation of body temperature that exceeds the normal daily variation and occurs in conjunction with an increase in the hypothalamic set point A fever of >41.5°C (>106.7°F) is called hyperpyrexia ,This extraordinarily high fever can develop in patients with severe infections Although most patients with elevated body temperature have fever, there are circumstances in which elevated temperature represents not fever but hyperthermia (heat stroke)

6. Fever versus Hyperthermia Hyperthermia is characterized by an uncontrolled increase in body temperature that exceeds the body’s ability to lose heat. The setting of the hypothalamic thermoregulatory center is unchanged. In contrast to fever in infections, hyperthermia does not involve pyrogenic molecules.

7. Pathogenesis of Fever

8. Acute Febrile Infections Fever is their prominent symptom which is usually high grade and sudden onset. Associated symptoms like chills,rigors,arthalgia,headache,malaise and rash are usually present No Prominent organ specific symptoms and signs E.g cough, coryza, dysuria,chest pain ,frequency,vomiting,diarrhea,abdominal pain, local tenderness…

9. AFI… Common Differentials in our setting: Malaria Typhoid fever Ricketssial diseases(Typhus) Relapsing Fever CNS infections(meningitis)

10. Malaria Introduction : Malaria is a protozoan disease transmitted by the bite of infected Anopheles mosquitoes The most important of the parasitic disease of humans-107 countries, 3 billion people, 1-3 million deaths/ yrly Eliminated from few countries but resurged in many parts of the tropics Four species of the genus plasmodium cause nearly all malarial infections in humans. Almost all deaths are by P.falciparum . The pathogenesis in human is as a result of direct effects of RBC destruction.

11. Major Malaria Parasites P. falciparum (  60%) P. vivax (  40%) P. malariae (rare ) Major Malaria Vectors An. arabiensis (family of An. gambiae comlex )= primary vector An. funestus An. phareonsis An. nili

12. Life cycle Of malaria

13. MALARIA IN ETHIOPIA Malaria is one of the leading public health problems in Ethiopia 75% of the country is malarious (<2000m), with about 68% of the population (  50 million ) at risk Major impediment to socio-economic development, coincides with major planting and harvesting season

14. Malaria Epidemiology Bimodal type of transmission: Major: Sep - Dec , following the main rainy season from Jun to Aug Minor: Apr–May , following a short rainy season from Feb to Mar Major epidemics occur every 5-8 years, focal outbreaks are common Distribution varies from place to place depending on climate and altitude

15. Geographic Distribution of Malaria in Ethiopia

16. Malaria in Ethiopia is Unstable Unstable malaria Seasonal Lack of immunity Epidemic common All age groups affected Malaria in Ethiopia Stable malaria Intense, perennial High immunity Epidemic uncommon Children & pregnant women more affected Many SSA

17. Trend of an epidemic malaria in Adami Tulu District. Microscopically confirmed malaria cases at Zeway MCL, 1999-2004. Malaria in Ethiopia is Seasonal

18. Technical Strategic Approaches for Malaria Prevention and Control Early diagnosis and effective treatment 2. Vector control 3. Epidemic prevention and control

19. Clinical features Uncomplicated Malaria: Fever, Chills, Rigors, Sweating, Severe Headache, Generalized body and joint pain Nausea and or vomiting, Loss of appetite, Abdominal pain (especially in children) Irritability and refusal to feed (in infants), flu-like symptoms, fever above 38°C Splenomegaly, Pallor

20. Clinical features Uncomplicated malaria: Investigations Microscopy-thick and thin blood films for malaria parasites, CBC Rapid diagnostic tests (RDT)-if microscopy is unavailable

21. Clinical … Uncomplicated malaria.. Treatment: Non pharmacologic ; Apply tepid sponging or fanning to reduce body temperature Admit severe complicated cases Pharmacologic: Treatment of uncomplicated P. Falciparum malaria First line: Artemether + Lumefantrine, 20mg + 120mg in a fixed dose combination Alternative: Quinine dihydrochloride, 10mg quinine sulphate salt/kg TID for 7 days.

22. Clinical… Uncomplicated Malaria: Treatment; First line Chloroquine phosphate, 1 g, then 500mg in 6 hours followed by 500mg P.O., QD for 2 days, or 1g at 0 and 24 hrs followed by 0.5g at 48 hrs P.O., Followed by Primaquine, 15mg base P.O., QD for 14 days.

23. Clinical … Complicated P.falciparum malaria: delay in diagnosis or inappropriate treatment of uncomplicated malaria can lead to the rapid development of severe or “complicated malaria”. It mostly occurs in children under 5 years of age, pregnant women and non-immune individuals. Severe malaria may lead to death unless it is diagnosed early and appropriately managed.

24. Clinical… Complicated Malaria: clinical features Inability to take in fluids (or breast milk in children) Repeated profuse vomiting Dark or cola colored urine Passing of very little urine Difficulty in breathing Generalised weakness, inability to walk or sit without assistance Sleepiness, change of behaviour Repeated generalized convulsions Altered consciousness, confusion, delirium, convulsions, coma Tachypnoea, respiratory distress and/or cyanosis

25. Clinical… Complicated Malaria: clinical features… Oliguria, renal failure repeated vomiting hypoglycaemia severe anaemia (Hb < 6 g/ dL ) Hyperpyrexia(axillaries temperature >38.5°C) Extreme pallor (severe anaemia) Circulatory collapse or shock (cold limbs, weak rapid pulse) Crepitations on chest examination Haemoglobinuria (dark or 'cola- coloured ' urine) Spontaneous unexplained heavy bleeding (disseminated intravascular coagulation)

26. Complications of P. falciparum malaria Cerebral malaria ( coma ) Severe anemia Metabolic (Lactic) Acidosis renal failure Pulmonary odema & ARDS hypoglycemia Hypotention & shock Bleeding & clotting disorder(DIC) Algid Malaria(CR-Collapse) Convulsions haemoglobinuria hyperparasitemia Hyperpyrexia Jaundice Prostration

27. Clinical… Complicated Malaria: Investigations Microscopy-thick and thin blood films for malaria parasites Rapid diagnostic test (RDT)-if microscopy is unavailable CBC RBS Blood grouping and cross-matching BUN and creatinine Lumbar puncture to exclude meningitis or cover with appropriate antibiotic.

28. Clinical… Complicated Malaria; Treatment: Non pharmacologic: Clear and maintain the airway. Position semi-prone or on side. Weigh the patient and calculate dosage. Make rapid clinical assessment. Exclude or treat hypoglycemia (more so in pregnant women). Assess state of hydration. Measure and monitor urine output. If necessary insert urethral catheter. Measure urine specific gravity.

29. Clinical… Complicated Malaria: Non pharmacologic TX; Open IV line for 8 hours of intravenous fluids including diluents for antimalarial medicine,glucose therapy and blood transfusion. If rectal temperature exceeds 39°C, remove patient's clothes, use tepid sponge, Consider other infections. Consider need for anti- convulsant treatment

30. Clinical… Complicated Malaria: Pharmacologic Tx: First line Artesunate, 2.4mg/Kg IV or IM given on admission (time = 0), then repeat at 12 hours, and 24 hours, then once a day for up to 5 days. Alternatives Artemether, IM 3.2mg/kg loading dose on the first day followed by 1.6mg/kg daily for five days Quinine dihydrochloride: Loading dose : 20mg/kg in 500ml of isotonic saline or 5% dextrose over 4 hours (4ml/minute) followed by Maintenance dose : should be given 8 hours after the loading dose at a dose of 10mg /kg and it should be given 8 hourly diluted in 500 ml of isotonic saline or 5% dextrose over 4 hours.

31. Clinical… Cerebral Malaria : In falciparum malaria, 10% of all admissions and 80% of deaths are due to the C.N.S. involvement Manifestations of cerebral dysfunction include any degree of impaired consciousness, delirium, abnormal neurological signs, and focal and generalized convulsions For a diagnosis of cerebral malaria, the following criteria should be met: ( i .) Deep, unarousable coma: Motor response to noxious stimuli is non- localising or absent. (ii.) Exclusion of other encephalopathies . (iii.) Confirmation of P. falciparum infection all patients with P. falciparum malaria with neurological manifestations of any degree should be treated as cases of cerebral malaria

32. Typhoid Fever Enteric (typhoid) fever is a systemic disease characterized by fever and abdominal pain and caused by dissemination of S. typhi or S. paratyphi The etiologic agents of enteric fever—S. typhi and S. paratyphi serotypes A, B, and C—have no known hosts other than humans Most commonly, food-borne or waterborne transmission results from fecal contamination by ill or asymptomatic chronic carriers. Sexual transmission between male partners has been described. Health care workers occasionally acquire enteric fever after exposure to infected patients or during processing of clinical specimens and cultures.

33. Typhoid… Risk factors: include contaminated water or , flooding, food and drinks purchased from street vendors, raw fruits and vegetables grown in Fields fertilized with sewage, ill household contacts, lack of hand washing and toilet access, And evidence of prior Helicobacter pylori infection (an association probably related to chronically reduced Gastric acidity).

34. Clinical Course Enteric fever is a misnomer, in that the hallmark features of this disease—fever and abdominal pain—are variable. While fever is documented at presentation in>75% of cases,abdominal pain is reported in only30–40% Thus, a high index of suspicion for this potentially fatal systemic illness is necessary when a person presents with fever

35. Clinical… The incubation period for S. typhi averages 10–14 days but ranges from 5 to 21 days, depending on the inoculum size and the host’s health and immune status The most prominent symptom is prolonged fever(38.8°–40.5°C; 101.8°–104.9 ° F), which can continue for up to 4 weeks if untreated.

36. Clinical… Symptoms: headache (80%), chills (35–45%), cough (30%), sweating (20–25%), myalgias (20%), malaise (10%), a and arthralgia (2–4%). Gastrointestinal manifestations included anorexia (55%), abdominal pain (30–40%), nausea (18–24%), vomiting (18%), and diarrhea (22–28%) more commonly than constipation (13–16%) Signs: coated tongue (51–56%), splenomegaly (5–6%), and abdominal tenderness (4–5%) . Early physical findings of enteric fever include rash (“rose spots”30%), hepatosplenomegaly (3–6%), epistaxis, and relative bradycardiaat the peak of high fever (<50%)

37. Clinical… Complications: Gastrointestinal bleeding (10–20%) and intestinal perforation (1–3%) most commonly occur in the third and fourth weeks of illness and result from hyperplasia, ulceration, and necrosis of the ileocecal Peyer’s patches at the initial site of Salmonella infiltration Neurologic manifestations occur in 2–40% of patients and include meningitis, Guillain-Barré syndrome, neuritis, and neuropsychiatric symptoms Rare complications whose incidences are reduced by prompt antibiotic treatment include disseminated intravascular coagulation,pancreatitis, hepatic and splenic abscesses and granulomas,endocarditis, pericarditis, myocarditis, orchitis, hepatitis,glomerulonephritis,pyelonephritis and hemolytic-uremic syndrome,severe pneumonia, arthritis, osteomyelitis, endophthalmitis, and parotitis

38. Diagnosis Because the clinical presentation of enteric fever is relatively non specific,the diagnosis needs to be considered in any febrile patient. Other than a positive culture, no specific laboratory test is diagnostic for enteric fever In 15–25% of cases, leukopenia and neutropenia are detectable Bone marrow culture is 55–90% sensitive, blood, bone marrow, and intestinal secretions are all cultured, the yield is >90% Serology: Widal Test

39. Treatment Prompt administration of appropriate antibiotic therapy prevents severe complications of enteric fever and results in a case-fatality rate of <1% The initial choice of antibiotics depends on the susceptibility of the S. typhi and S. paratyphi strains in the area of residence or travel ). For treatment of drug-susceptible typhoid fever, fluoroquinolones are the most effective class of agents, with cure rates of ~98%

40. Prevention and Control Personal and environmental hygiene Vaccine Whole cell killed vaccine, Ty21a attuenated, Vicps polysaccharide Indication: Contacts with chronic carriers Lab workers Travellers Monitoring of food handlers

41. Epidemic(Louse born) Typhus The human body louse ( Pediculus humanus corporis) lives in clothing under poor hygienic conditions and usually in impoverished cold areas. Lice acquire R.prowazekii when they ingest blood from a rickettsemic patient. The rickettsiae multiply in the louse’s midgut epithelial cells and are shed in its feces. The infected louse leaves a febrile person and deposits infected feces on its subsequent host during its blood meal; the patient autoinoculate s the organisms by scratching.

42. Epidemic… Brill-Zinsser disease is a recrudescent illness occurring years after acute epidemic typhus, probably as a result of waning immunity. R. prowazekii remains latent for years; its reactivation results in sporadic cases of disease in louse-free populations or in epidemics in louse infested populations.

43. Epidemic … Clinical Manifestions: After an incubation period of ~1–2 weeks, the onset of illness is abrupt, with prostration, severe headache, and fever rising rapidly to 38.8°–40.0°C Cough is prominent, developing in 70% of patients Myalgias are usually severe. A rash begins on the upper trunk, usually on the fifth day, and then becomes generalized, involving the entire body except the face, palms, and soles. Photophobia, with considerable conjunctival injection and eye pain, is Common the tongue may be dry, brown, and furred. Confusion an coma are common. Skin necrosis and gangrene of the digits as well as interstitial pneumonia may occur in severe cases.

44. Epidemic… Diagnosis and Treatment: The Weil Felix serology test with demonstration of a rising/high titer. Doxycycline (200 mg/d, given in two divided doses) is administered orally or—if the patient is comatose or vomiting—intravenously. Although under epidemic conditions a single 200-mg oral dose is effective, treatment is generally continued until 2–3 days after defervescence Prevention :Prevention of epidemic typhus involves control of body lice,Clothes should be changed regularly, and insecticides should be used every 6 weeks to control the louse population

45. Relapsing Fever Recurrent acute episodes of spirochetemia and fever alternate with spontaneous spirochetal clearance and apyrexiya. Two forms: TBRF-a zoonosis transmited from rodents to humans by tick bite LBRF-disease of humans transmited by body louse

46. 46 Relapsing… Etiology: Borrelia spp B. dutoni agent of TBRF B. recurrentis-LBRF B. burgdorferi-Lyme disease Vector: Body louse- transmission is by crashing of pruritic louse bites

47. Relapsing… Risk factors: Overcrowding, impoverishment, unhygienic condition Prisoners, war, famine Cool, rainy season Close contacts Accidental needle prick

48. Relapsing… Pathogenesis: Multiplication in blood- (febrile period) Sequestration at liver, spleen, BM & CNS- (remission) Activation of mediators of inflammation Cytokines: IL-6, IL-8, CRP, TNF-responsible for JH

49. Relapsing… Edema and swelling of organs Histocytic inflammation of myocardium Petechial haemorrhage Haemorrhagic infarction of the spleen, heart, liver and brain

50. Relapsing… Clinical Presentation: Incubation Period: 7 days Sudden high grade fever(>40 ) Chills, rigor, sweats, myalgia, arthralgia Dellirium, prostration, photophobia,cough Tachycardia, tachypnea Meningismus Icterus, petechia in 1/3 of patients Tender Hepatosplenomegaly Symptoms subside after 5 days with spontaneous crisis

51. Relapsing.. Complications: Haemorrhage: GI, CNS Coagulopathy Neurologic: Optic neuritis, lymphocytic meningitis, CN palsy and coma. Pneumonitis Myocarditis Splenic rapture

52. Relapsing Fever Complications: Jarisch-Herxheimer Reaction (JHR) Is a condition of worsening of the patients condition soon after the intiation of antibiotic treatment, caused by mediatiors like TNF Two phases Chill phase: Toxic T>41, rigors, hyper metabolism Increase PVR & decrease in Pul. arterial pressure Lasts 10-30 min Flush phase: Decrease in PVR & increase in Pul. Arterial pressure Decrease in T, diaphoresis, decreased effective circulatory volume Lasts<8 hrs Sleep, exhaustion, recovery with disappearance of spirochetes Mortality reaches 20% in malnourished & stressed population.

53. Relapsing… Diagnosis: Demonstration of spirochetes in blood also in BM & CSF CBC: low platelete Coagulation profile: PT, PTT, BT-prolonged

54. Relapsing… Treatment: Delousing: permethrine dust or liquid Suportive: Rehydration, transfusion Antibiotic: Procaine penicilline TTC Monitor for JHR in 1-4 hrs of therapy

55. Meningitis Acute bacterial Meningitis Acute Viral Meningitis

56. Acute Bacterial Meningitis Definition: Bacterial meningitis is an acute purulent infection within the subarachnoid space It is associated with a CNS inflammatory reaction that may result in decreased consciousness, seizures, raised intracranial pressure (ICP), and stroke

57. Acute Bacterial Meningitis Etiology: S.pneumonia – 50% N.meningitidis – 25% Group B.Strept – 15% L.monocytogenes – 10% H.influenzae - <10%

58. Acute Bacterial Meningitis Predisposing Factors: S. pneumoniae Pneumococcal Pneumonia Otitis media and Sinusitis Alcoholism Diabetes, Splencetomy Hypogammaglobulinemia Head trauma

59. Acute Bacterial Meningitis Predisposing… N. meningitides Colonization of nasopharyngeal Bacterial virulence Host immune defense-complement deficiency Dry season, overcrowding, smoking, recent viral URTI

60. Pathogenesis Bacteria colonizes the nasopharynx A defect in the barrier by URTI or dryness Transmigration to blood and reaches the Pia and Arachnoids matters Inflammatory response Increased permeability of BBB

61. Clinical Presentation The classic clinical triad of meningitis is fever, headache, and nuchal rigidity, but the classic triad may not be present A decreased level of consciousness occurs in >75% of patients and can vary from lethargy to coma Fever and either headache, stiff neck, or an altered level of consciousness will be present in nearly every patient with bacterial meningitis Nausea, vomiting, and photophobia are also common complaints. Seizures occur as part of the initial presentation of bacterial meningitis or during the course of the illness in 20–40% of patients

62. Clinical Presentation Meningeal signs: Nuchal rigidity (“stiff neck”) is the pathognomonic sign of meningeal irritation and is present when the neck resists passive flexion Kernig’s sign is elicited with the patient in the supine position,The thigh is flexed on the abdomen, with the knee flexed;attempts to passively extend the knee elicit pain when meningeal irritation is present. Brudzinski’s sign is elicited with the patient in the supine position and is positive when passive flexion of the neck results in spontaneous flexion of the hips and knees

63. Clinical … Raised ICP is an expected complication of bacterial meningitis and the major cause of obtundation and coma in this disease More than 90% of patients will have a CSF opening pressure >180 mm water, and 20% have opening pressures >400 mm water Signs of increased ICP include a deteriorating or reduced level of consciousness, papilledema,dilated poorly reactive pupils, sixth nerve palsies, decerebrate posturing,and the Cushing reflex (bradycardia,hypertension,andIrregular respirations)

64. Diagnosis When bacterial meningitis is suspected, blood cultures should be immediately obtained and empirical antimicrobial and adjunctive dexamethasone therapy initiated without delay Lumbar puncture(LP) The classic CSF abnormalities in bacterial meningitis are (1) polymorphonuclear (PMN) leukocytosis (>100 cells/µL in 90%), (2) decreased glucose concentration (<2.2 mmol/L [<40 mg/ dL ] and/or CSF/serum glucose ratio of <0.4 in ~60%), (3) increased protein concentration (>0.45 g/L [>45 mg/ dL ] in 90%), and (4) increased opening pressure (>180 mmHO in 90%). CSF bacterial cultures are positive in >80% of patients, and CSF Gram’s stain demonstrates organisms in >60%. Neuro imaging(MRI, CT)

65. Acute bacterial Meningitis Treatment: Bacterial meningitis is a medical emergency. The goal is to begin antibiotic therapy within 60 min of a patient’s arrival in the emergency room. Empirical antimicrobial therapy is initiated in patients with suspected bacterial meningitis before the results of CSF Gram’s stain and culture are known. And adjunct dexamethasone therapy 20 min before antibiotic therapy.

66. Acute viral Meningitis Etiology: The most important agents are enteroviruses (including echoviruses and coxsackie viruses in addition to numbered enteroviruses), varicella-zoster virus (VZV), HSV (HSV-2 > HSV-1), HIV CSF cultures are positive in 30–70% of patients, with the frequency of isolation depending on the specific viral agent. Approximately two-thirds of culture-negative cases of “aseptic” meningitis have a specific viral etiology identified by CSF PCR testing

67. Acute Viral Meningitis Clinical Manifestation : Immunocompetent adult patients with viral meningitis usually present with headache,fever,and signs of meningeal irritation couple with an inflammatory CSF profile Headache is almost invariably present and often characterized as frontal or retroorbital and frequently associated with photophobia and pain on moving the eyes Nuchal rigidity is present in most cases but may be mild and present only near the limit of neck anteflexion Constitutional signs can include malaise, myalgia, anorexia, nausea and vomiting, abdominal pain, and/or diarrhea

68. Acute Viral Meningitis Diagnosis : CSF: Lymphocytic pleocytosis (25-500/ ul ) Protein and glucose slightly increased Normal opening pressure CSF PCR

69. Acute Viral Meningitis Treatment: Supportive: Fluid and electrolyte Analgesics Antiviral: Acyclovir Prognosis is excellent

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