Fever is defined as a core temperature of 38.3°C/100.94°F or higher according to American College of Critical Care Medicine, Infectious Diseases Society of America, and International Classification of Diseases. It is often associated with cognitive impairment, discomfort, mortality, febrile seizures, morbidity, and decreased outcome in people with brain injury or stroke. It arises due to unknown or known reasons that can be further classified as acute undifferentiated fever (AUF) and pyrexia of unknown origin (PUO).

The three major types of fever are (a) Continuous or sustained fever, (b) Intermittent fever, and (c) Remittent fever. Continuous fever fluctuates around 1.5°F (1°C) for about 24 hrs. However, it never touches normal. On the other hand, intermittent fever is present only for several hours in a day. Remittent fever is a fever with daily fluctuations of greater than 2°C and does not touch the normal at any time.

In India, AUF or acute febrile illness (AFI) is one of the common causes for seeking medical assistance. This fever is characterized by a lack of localizable or organ-specific clinical features and does not extend beyond a fortnight. The paucity of accurate diagnostic methodology and non-specific signs and symptoms present a challenge to the healthcare workers. Those AUFs exhibiting a duration of illness greater than three weeks are known as PUO. To prevent early mortality, the empirical therapy for AUF should be sufficiently broad.

Management of fever includes antipyretic agents for symptomatic relief and a specific or empiric therapeutic arsenal. Pharmacological ways of antipyresis include administering antipyretics that alleviate fever mainly by suppressing prostaglandin E2 (PGE2) formation in the brain. The physical ways of antipyresis incorporate sponging with alcohol or cold water, applying ice packs and cooling fans in conjunction with sponging. Fever may exert deleterious metabolic effects liked elevated heart rate and respiration. This may pose a challenge, particularly in the elderly. Antipyretic agents can improve the accompanying responses and also minimize discomfort.

Numerous antipyretics such as nimesulide, mefenamic acid, ibuprofen, aspirin, paracetamol etc., are available and have been utilized to manage fever for a long time. Nimesulide only weakly suppresses the synthesis of prostaglandin and has different mechanisms of action. It suppresses platelet-activating factor, the release of oxidants from activated neutrophils, scavenges hypochlorous acid, and minimizes histamine release. Its greater affinity for selective inhibition of cyclooxygenase-2 (COX-2) corresponds to greater antipyretic, anti-inflammatory, and analgesic activity. In India, nimesulide has been utilized to manage fever, acute pain, dysmenorrhea, osteoarthritis, and acute tendinitis for patients >12 years of age.

RATIONALE BEHIND RESEARCH

Most studies offering evidence on the antipyretic effect of nimesulide in the adult population date back to two decades. There is a lack of most recent data demonstrating the role of nimesulide in mitigating acute fever in adults from real-world clinical settings in India. Thus, this study was performed.

OBJECTIVE

This retrospective multicenter study was performed to investigate the efficacy of nimesulide in acute fever management in Indian adults in real-world clinical practice.

Study outcomes

• The major endpoint was a decline in fever from the baseline temperature to temperature as recorded in the follow-up visit within 14 days.
• Tolerability was evaluated from the number of participants reporting side effects after ingestion of nimesulide.

Outcomes

Baseline: There were no vital differences reported at baseline.

Study outcomes

• Provisional diagnosis at the baseline visit found major complaints like body ache, fever, fever with abdominal pain, myalgia, and cough.
• Mean baseline body temperature was 103.2±1.5°F with the mean duration of 4.4±2.8 days. It considerably dropped to 99.7±1.8°F following nimesulide therapy (Figure 2).
• Hepatic and kidney profiles were noted to be normal on records, and adverse effects like dyspepsia and nausea were noted only in 2% of participants.

Due to limited resources, most of the physicians in outpatient departments in India try to diagnose fever on the basis of clinical judgment, which includes signs, symptoms, epidemiology of the disease etc. Intermittent fever is linked with lymphomas, septicemia, malaria, schistosomiasis, pyogenic infections, borrelia, tuberculosis, leptospira, and kala-azar. Remittent fever is usually linked with infectious diseases such as rickettsia infections, infective endocarditis, brucellosis, and the rest. Generally, people in India suffer from AUF between June and September. In the case of self-limiting fever, AUF people can be treated initially with antipyretics.

On the other hand, for other fever types, antibiotics and/or specific medicines in combination with antipyretics is suggested. In the present study, 6% (17) of people were treated only with nimesulide alone, 41% (123) of people were treated in combination with antibiotics, and 57% (175) of people were treated along with other specific medicines. Electronic medical records are valuable clinical tools that yield information relevant to possible medical history, diagnosis, prescribing practice, and laboratory investigation data in real-world settings. The evidence of efficacy from the clinical trials of nimesulide established it as antipyretic, while evidence from the current real-world study on 302 patients will additionally supplement this proof. In a post-marketing surveillance study, nimesulide's efficacy and tolerability were reported (by the study clinicians) to be 91.3% and 94% in 401 patients with fever and painful inflammatory states that received 100 mg nimesulide twice a day for seven days.

Patients reported efficacy and tolerability of 87.5% and 67.8%, respectively. No hepatotoxicity (normal serum glutamic oxaloacetic transaminase [SGOT] and serum glutamic pyruvic transaminase [SGPT] values) was noted following nimesulide therapy. In the current study, 44% demonstrated a drop in temperature (≤98.6℉). As found, middle-aged adults (24.8%) showed better effectiveness of nimesulide therapy compared to old adults (7.9%) and young adults (11.6%). Nimesulide's efficacy, evaluated as a decline in fever ≤98.6℉, was comparable between female (21.5%) and male (22.8%) patients.

In a study performed by Goyal PK et al., nimesulide (two doses per 9.8 hours) remarkably lowered the mean temperature with a fewer number of doses in comparison with paracetamol (two doses per 8.21 hours). In the current study, nimesulide considerably minimized fever with an average temperature difference of 3.5°F from the mean baseline temperature with 100 mg twice daily dose. Additionally, a greater percentage (25%) of efficacy was noted in middle-aged adults in comparison with older and young adults. However, the average temperature difference was reported to be similar among all the age groups.

The higher values of total leukocyte count (>11000) indicated viral or bacterial infection. Additional clinical diagnosis illustrated that continuous fever was characterized as typhoid, and other fever linked with infection was characterized as upper/lower respiratory infections and urinary tract infections. Another type of fever noted was intermittent fever characterizing malaria. In the maximum number of participants, viral fever was diagnosed. In a comparative study (nimesulide vs. paracetamol) carried out by Cunietti et al., nimesulide was reported to be a safe and active antipyretic.

In the current study, the laboratory investigations of SGPT and SGOT were proposed by the investigators to 50 and 67 patients, respectively, of which only 42 and 43 patients went for these tests, respectively. In the patients who had given the tests, the SGOT, SGPT values, and urine analysis resulted within the respective normal ranges. But, due to the lack of electronic medical records details on the timing (pre or post-nimesulide) of the test done, conclusive interpretations could not be made. Similar conclusions can be drawn from a post-marketing study of nimesulide in the Indian population. As found, the values of SGPT, SGOT and serum bilirubin did not alter after nimesulide therapy. The tolerability and safety of nimesulide have been well-established in multicenter, double-blind studies.

In this study, only 1% of participants reported nausea and dyspepsia complaints following nimesulide therapy, and 88% of participants had no noted events. Paracetamol is the most frequently used antipyretic (0.5 grams minimum to 4 grams maximum daily dose) and exhibits renal, hepatic, and gastrointestinal adverse effects. On the contrary, nimesulide has rarely been prescribed for fever, despite well-established proof from numerous studies as one of the preferred NSAIDs with potent antipyretic properties and no profound gastroduodenal adverse reactions.

The onset of pain-relieving and antipyretic action of oral nimesulide is 15 to 60 minutes reaching peak plasma concentration in 1.2 to 2.7 hours, and for paracetamol, it is within 30 to 60 min. In comparison to paracetamol (3–6 h), nimesulide exhibits a longer duration of antipyretic action (10-12 h). Nimesulide's short half-life and preferential activity on COX-2 contributes to a rapid onset of antipyretic action, a potent anti-inflammatory and analgesic effect. It also minimizes the levels of matrix metalloproteases and other biomarkers of joint destruction that lowers the advancement of the disease.

All these factors make nimesulide a good choice to manage patients with AUF. Nimesulide minimized fever with a similar effect across the age groups 18-75 years. Thus, the findings of this study show that nimesulide had good efficacy and acceptable tolerability as antipyretic agents in people having acute fever treated in outpatient department settings. Additional studies in a prospective manner where time-correlated decline of fever with nimesulide and other NSAIDs need to be investigated.