ICMR guidelines on Management of Acute Fever

Fever is a common physiologic response that has been the source of great concern to the patients as well as caregivers. Fever has been respected by many physicians, including Thomas Sydenham, who wrote in the 1600s, "Fever is a mighty engine which Nature brings into the world for the conquest of her enemies."In recent times, fever has become a product of disease that is feared by parents and clinicians alike. Management of fever is not only restricted to bringing it down but also finding its cause and treating it simultaneously. Indian Council of Medical Research has released its guidelines on Management of Acute Fever.

Management of community-onset acute undifferentiated fever in adults

The purpose of the guidelines is to ensure appropriate antimicrobial treatment while at the same time limiting the inappropriate use of antibiotics in the management of infections by addressing issues like antibiotic selection, dosing, route, duration, adverse drug events, and cost and prevention of unintended collateral damage.

2. Some general principles

• Antibiotic use will need to be classified with respect to type (high- and low-risk) and the patient's place in the treatment pathway (untreated, treated, and posttreatment).


• The choice of medication may vary depending on differences in the case-mix of patients, various drugs (of a same or different class) listed in the formulary or clinical practice guidelines already in place at different institutions in similar patient care locations.


• Timely use of diagnostic tests or documentation of symptoms supporting the presence of infection would be best. Cultures (two sets of blood cultures and other appropriate samples as clinically indicated e.g. normally sterile body fluids, deep pus etc.) should be taken before starting empiric antibiotic treatment.


• Empiric antibiotic treatment for common infections should be limited to conditions where early initiation of antibiotics has been shown to be beneficial, e.g. severe sepsis and septic shock, acute bacterial meningitis, community-acquired pneumonia, necrotizing fasciitis, etc.


• Re-assessment of the situation within 48 hours based on the test results and examination of the patient is required. If needed, the drug's dosage and duration can be adjusted or the antibiotic regimen should be de-escalated (to the narrowest spectrum, least toxic and least expensive antibiotic) based upon patient response and culture and susceptibility reports.

3. Case Definition

• Previously healthy (non-immunosuppressed) community (urban or rural) dwelling adult (ages 19-64 yrs.) reporting no previous medical illness or recent hospitalization (in the preceding 30 days) presenting with acute onset of fever > 38.3° C (101.0° F) for >2 days and lasting up to 14 days and having received no
  specific treatment for this current illness with antimalarials or antibiotics.


• Seen in ambulatory care settings at the primary level (PHC), doctor's office/clinic, an emergency room in a Community Hospital, including referrals from primary health care or community physicians.


• With a history of no localizing symptoms (except accompaniments of fever such as – chills, headaches, retro-orbital pain, myalgia, malaise, nausea or vomiting). On examination found to have normal vital signs (excepting fever) and lacking organ or system-specific physical signs*.

* A complete and thorough physical examination is mandatory. Record of vital signs is essential. A search is required for hidden foci such as throat examination, sinus tenderness, renal or hepatic tenderness, heart murmurs, chest examination, lymph nodes and splenomegaly. Fundus examination (if headache or bleeding tendency) and examination of the skin for eschar and petechiae or purpura must be made.

4. Common pathogens causing "tropical fevers", "seasonal fevers" "endemic /epidemic /outbreak fever", "monsoon fever":

• Suspect malaria in all cases of acute undifferentiated fever (there are no key differentiating features between this and other causes (see below). Despite historical claims, fever patterns are not especially helpful in establishing a specific diagnosis.
  Malaria is especially to be suspected after a visit to a high malaria endemic zone.


• Viruses cause febrile illness or specific viral "influenza-like- illness" (with mild sore throat and cough).


• If rash or exanthem is present without drug exposure (rule out drug allergy), consider mononucleosis syndrome (EBV, CMV, HIV) or an exanthematous viral
  illness (measles, rubella, etc).


• Primary or secondary dengue may be accompanied by maculopapular rash or polyarthralgia. Tourniquet test may be inappropriate as a general discriminating test without hemorrhagic manifestations or the shock syndrome. Consider hemorrhagic fever with two or more hemorrhagic symptoms - hemorrhagic or purpuric rash, epistaxis, conjunctival hemorrhage, bleeding gums, bleeding at puncture sites, hematuria, hematemesis, hemoptysis, blood in the stool.


• Scrub typhus or murine typhus may present with skin eschar, regional lymphadenopathy, and maculopapular rash.


• Leptospirosis can present with conjunctival suffusion, muscle tenderness and jaundice (ask for flood water or sewage exposure).


• Typhoid should be suspected in the presence of continuous fever, gastrointestinal symptoms, and splenomegaly.


• Community-acquired secondary bacteremia: Primary source may be occult. In most instances, it is either from underlying pneumonia, intra-abdominal infection or urosepsis. Symptoms related to these systems may not be manifest, especially in the elderly.


• Hepatitis A or E can cause fever that usually subsides with the onset of jaundice.


• Chikungunya presents with fever and polyarthralgia /polyarthritis.


• Consider rheumatic fever caused by Group A beta-hemolytic streptococci if there is migratory arthritis with preceding significant sore throat.


• Tuberculosis should be considered in any patient with prolonged undifferentiated fever, especially if there is weight loss.

5. Diagnostic Investigations (where facilities are available)

• One blood smear and/or RDT at least is required for malarial parasite detection (repeat blood smear once more if the initial smear is negative in an endemic
  region).


• Complete blood count: Anemia, leucopenia /leukocytosis, elevated hematocrit or thrombocytopenia are all helpful in diagnosis.


• Diagnostic blood cultures (at least two sets) are to be drawn prior to the start of empiric antibiotics.


• Liver enzymes and bilirubin


• Urinalysis – white blood cells, proteinuria and hematuria.


• Chest roentgenogram (if chest findings are present, to rule out early pneumonia or TB)


• Ultrasonography of abdomen if fever persists to rule out hepatic, renal or intra abdominal sources of infection.


• Within 96 hours of the onset of fever, antigen-based serological tests are likely to be positive whereas antibody tests are generally positive after at least 5-7 days of
  illness.
  
  
  
  • Dengue rapid NS1 antigen
  
  
  • IgM ELISA for Dengue, Scrub typhus and Leptospira
  
  
  
  

6. Prevalent AMR status in common pathogens

Malaria: P. vivax is susceptible to chloroquine which remains the drug of choice. P. falciparum resistance to chloroquine is seen in at least 25% of cases nationwide, and therefore artemisinin-based combination therapies (ACT) should be the first-line treatment for P. falciparum malaria and where species is unclear. Artemisinin (especially oral) monotherapy should be strongly discouraged as it leads to resistance to this class.

Typhoid fever: Quinolone resistance is increasing and is as high as 69% for Salmonella Typhi and 23% for Salmonella Paratyphi A. Resistance rates are low for co-trimoxazole, chloramphenicol and third-generation cephalosporins. Though sensitivity testing is not validated for azithromycin, the response is good in most clinical studies. However, defervescence times are significantly longer with third-generation cephalosporins compared with other classes and bone marrow depression is a concern with chloramphenicol.

Gram negative organisms: There is increasing resistance among Enterobacteriaceae (E. coli and Klebsiella) to both quinolones (up to 80%) and third-generation cephalosporins (up to 75% on account of ESBL production). Initial empiric therapy for infections caused by these organisms {pyelonephritis, severe intraabdominal infections (IAI), etc} should be with an agent active against ESBL producers e.g.a carbapenem or with a beta-lactam/beta-lactamase inhibitor for less severely ill patients.

Gram-positive organisms: Community-acquired organisms such as S. aureus are usually susceptible to methicillin i.e. standard anti staphylococcal drugs such as cloxacillin and first cephalosporins may be used. Penicillin still remains the drug of choice for pneumococcal infection.

7. Principles of empiric therapy

1. Supportive: Acetaminophen 650 mg every 6 hours round the clock is advisable, accompanied by tepid sponging for fever >1030 F. Replace fluid and electrolytes as required.


2. No antibiotics are required for the majority of patients with acute febrile illness without an obvious clinical diagnosis.


3. Start antibiotics for a presumed bacterial infection promptly, but adjust the drug's dosage and duration, switch to a new drug, or end antibiotic therapy when results do not support or justify the need to continue.


4. Re assess the situation within 48 hours based on test results and patient status.


5. Corticosteroids are not recommended in the treatment of acute undifferentiated fever.


6. In patients with fever and thrombocytopenia, platelet transfusions are not recommended in general.


7. Consider platelet transfusion when platelet counts are <10,000 cu mm or in the presence of clinical bleeding in cases of dengue hemorrhagic fever.


8. Empirical treatment with doxycycline for patients with undifferentiated fever and negative rapid diagnostic tests for malaria and dengue is an option for the clinician.

A. Day 1 or 2: Defer investigation and anti-microbials
B. Day 3 or 4: Total leukocyte count with differential, Malaria parasite slide and
rapid diagnostic kits, may test for Dengue if suspicion high.
C. > 5 days: As per (B) plus paired blood cultures. May test for Dengue,
Chikungunya, Scrub typhus, Leptospirosis if suspicion high.
D. > 7 days: As per (C) plus X-ray chest and USG abdomen

Table 2.1: Antimicrobial choice for disease conditions

* All these regimens need to be tailored according to susceptibility patterns at individual centres.

Table 2.2: Standard doses of antimicrobials