The Naproxen Test as a Diagnostic Tool in the Causative Differentiation of Fever

Emmanuel Edwin R. Dy, M.D.,* Patrick Gerard L. Moral, M.D.** and Sandra Teresa G. Victorio-Navarra, M.D.***
(*Fellow, Section of Infectious and Tropical Medicine, Division of Medicine, **Resident Physician, Division of Medicine and ***Assistant Professor of Medicine, Faculty of Medicine and Surgery, University of Santo Tomas) ABSTRACT The naproxen test was administered to 78 patients who fulfilled the following criteria: (1) fever of at least 38.3C; (2) duration of at least 2 weeks; (3) suspected or diagnosed neoplastic, connective tissue and infectious causes by history, physical examination and laboratory or ancillary procedures; and (4) there should have been no antimicrobial intake for at least 48 hours prior to the performance of the test. The subjects were given naproxen sodium, 500 mg/tablet, one tablet every 12 hours for 2 days. Fever lysis after or within the time frame of drug administration was interpreted as suggestive of either a neoplastic or a connective tissue disease. Non-response to the regimen was interpreted as suggestive of an infectious condition. Fifty-two (67%) of the 78 patients (67%) responded to the naproxen test. Thirty-seven patients were diagnosed to have either a malignant condition (33) or a connective tissue disease (4). Of these, 31 (98%) with malignancy and 4 (100%) with connective tissue diseases responded to the test with fever lysis. Forty-one patients were initially diagnosed to have infectious conditions; 24 of whom did not respond to the test, yielding a sensitivity of 58.5% for infection. All were later proven to have an infectious condition. This study clearly showed that the test is a very useful tool in detecting malignancy and connective tissue disease as the etiology of prolonged fever. (Phil J Microbiol Infect Dis 1999; 28(3):85-90) Key words: Naproxen test, prolonged fever

INTRODUCTION Fever of whatever etiology still remains a perplexing problem to both clinicians and investigators. Increasingly, its role in connective tissue diseases, malignancies and other inflammatory disorders is slowly supplanting the exclusivity of the symptom to just infectious conditions. The identification of the cause of fever is crucially dependent upon meticulous history taking and thorough physical examination coupled with useful ancillary and laboratory procedures. A dilemma arises when the diagnostic aids do not provide the expected results. Subjecting the patient to more laboratory examinations may provide an ordeal rather than a diagnosis. Shotgun antimicrobial therapy may result in a superinfection rather than a cure. The need to categorize prolonged fever in terms of specific etiology is essential in establishing a direction for the clinician's plan of action. Clinical studies have shown that the most common causes of prolonged fever are infections and neoplasms. Based on this premise, the naproxen test may provide a simple and economical tool in the causative differentiation of fever. A seven-year study by Chang confirmed the naproxen test value in differentiating between infections and neoplasms. Lysis of fever upon administration of the drug favors a presumptive diagnosis of neoplastic fever. On the other hand, failure points to an infectious cause. This study aims to: (1) determine the sensitivity of the naproxen test; and (2) identify the most common neoplastic and collagen vascular diseases, which responded unequivocally to the naproxen test.

MATERIALS AND METHODS All patients with prolonged fever were included in this study based on the following criteria: (1) fever of at least 38.3C; (2) duration of at least two weeks; (3) suspected or diagnosed neoplastic, connective tissue and infectious cases through history, physical examination and laboratory or ancillary procedures (complete blood count, urinalysis, chest X-ray, malarial smear, blood culture and biopsy). In addition, there should have been no antimicrobial intake for at least 48 hours prior to the naproxen test. The patients were given naproxen sodium at 500 mg/tablet, one tablet every 12 hours p.c. for a total of 4 doses. Body temperature was taken orally every two hours prior to, during and after the therapeutic trial noting any change in the temperature curve. Naproxen administration was discontinued if any of the following were noted: (1) hypersensitivity reaction, (2) abdominal complaints, or (3) patient refusal to take the drug. Fever lysis after or within the time frame of drug administration was interpreted as suggestive of either a neoplastic condition or a connective tissue disease. This was further verified with the reappearance of fever upon naproxen discontinuation. Non-response of the fever to the drug was taken to suggest an infectious condition. The final diagnosis if not yet established at the time of the test was pursued based on biopsy and/or culture of accessible organs/fluids as well as accompanying diagnostic laboratory examinations and ancillary procedures. Sensitivity of the naproxen test in recognizing malignancy or connective tissue disease was determined. Sensitivity expresses the likelihood of a positive test result in a person with a disease. This is also termed as the true positive rate (TPR). Sensitivity = Number of positive test responders with either malignancy or connective tissue disease/Number diagnosed to have malignancy or connective tissue disease RESULTS Seventy-eight patients were included in the study. There were 46 males (60%) and 32 females (40%), with the mean age of 34.2 years, ranging from 7 to 76. The duration of fever ranged from two weeks to one hundred four weeks with temperature ranging from 38.3C to 42C, with a mean of 39C. Thirty three (43%) of the study group was diagnosed to have a malignancy, 4(5%) with connective tissue disease and 41 (52%) with an infectious disease. No patient experienced any untoward side effects. Table 1 shows the overall response of the patients. Thirty five (45%) of the population consisted of true positive responders, 17 (22%) with false positive response, 24 (30%) with true negative response and only 2 (3%) with a false negative response. The thirty-five patients with a true positive response had a mean age of 38.4 years old with a range of seven to seventy years of age. There were 17 males and 18 females. Mean temperature was 38.8C ranging from 38.3C to 40C. Mean duration of fever was eight weeks with a range of three to twenty eight weeks. The earliest response to naproxen test was noted as two hours and the latest was at six hours. Of the true positive responders, 8 neoplastic cases and 2 cases of connective tissue disease were placed on continuous naproxen therapy. All subjects were noted to have drenching sweats upon lysis of fever. The cases comprising the true positive group are as follows: malignant lymphoma (9), pulmonary carcinoma (4), pancreatic malignancy (3), hepatocellular carcinoma (3), multiple myeloma (2), retroperitoneal sarcoma (2), Still's disease (2), carcinomatosis (1), choriocarcinoma (1), undiagnosed malignancy (1), juvenile rheumatoid arthritis (1), systemic lupus erythematosus (1). Table 2 shows seventeen subjects (22%) with false positive response had a mean age of 32 years with a range of 13 to 69 years. There were more males (11) than females (6). The

average duration of fever was at 4.5 weeks. The earliest onset of response was noted at two hours. No drenching sweats were noted. The cases comprising this group were as follows: enteric fever (8), amoebic liver abscess (2), extrapulmonary tuberculosis (2), recurrent urinary tract infection (1), pulmonary tuberculosis (1), malaria (1), viral hepatitis (1) and pneumonia (1).
Table 1. Diagnostic categories of unequivocal positive responders* to naproxen test Diagnostic Category No. (%) Malignancy 31 (40%) Carcinomatosis 1 Multiple myeloma 2 Malignant lymphoma 9 Pancreatic carcinoma 3 Hepatocellular carcinoma 3 Pulmonary carcinoma 4 Choriocarcinoma 1 Common bile duct carcinoma 1 Leukemia 1 Retroperitoneal sarcoma 2 Malignant astrocytoma 1 Colonic malignancy 1 Ductal carcinoma 1 Undiagnosed malignancy 1 Connective Tissue Disease 4 (5%) Still's disease 2 Juvenile rheumatoid arthritis 1 Systemic lupus erythematosus 1 *Unequivocal positive response refers to fever lysis after naproxen administration verified by recurrence of fever after drug was discontinued.

Table 3 shows 24 subjects (30%) who manifested with a true negative response had a mean age of 41.9 years ranging from 11 to 76 years. There were more males (17) than females (7). Mean temperature was at 39.2C with the lowest temperature at 38.3C and the highest at 40.7C. Mean duration of fever was four weeks. Patients belonging to this group were diagnosed to have enteric fever (12), malaria (9), influenza (2) and extrapulmonary tuberculosis (1).
Table 2. Diagnostic categories of equivocal responses* to naproxen test Diagnostic Category False Positive False Negative Malignancy 2 (3%) Carcinomatosis 1 Retroperitoneal sarcoma 1 Infectious Disease 17 (22%) Recurrent UTI 1 Enteric fever 8 PTB 1 Amoebic liver abscess 2 Extrapulmonary TB 2 Malaria 1 Influenza Viral Hepatitis 1 Pneumonia 1 *Refers to either persistence of fever despite drug administration or coincidental disappearance of fever i.e. fever did not recur after discontinuation of the drug.

Only 2 subjects with malignancies (3%) gave a false negative response to the naproxen test. These patients each had carcinomatosis and retroperitoneal sarcoma. Of the 2, the latter had a

documented urinary tract infection that could account for the absence of response. The diffuse distribution of the former neoplastic condition explained the persistently negative naproxen test.
Table 3. Diagnostic categories of unequivocal negative responders* to naproxen test

Diagnostic Category Infectious Diseases Enteric fever Extrapulmonary tuberculosis Malaria Influenza

No. (%) 24 (30%) 12 1 9 2

*Refers to persistence of fever despite the administration of naproxen

Chest X-ray, lymph node and bone marrow biopsy were most useful in establishing malignancy as the cause of prolonged fever. CT scan, ANA titer and C3 level were equally used in the diagnosis of connective tissue diseases for patients with a true positive naproxen test. The naproxen test was most sensitive in recognizing connective tissue diseases and malignancies at 100% and 93.9%, respectively. DISCUSSION In essence, fever represents a disturbance in normal thermoregulation. In health, core body temperature is maintained within a narrow range that varies with the time of day and among individuals. The anterior hypothalamus has a thermostatic mechanism that receives thermal information from both peripheral and central receptors. In fever, an upward displacement of the set point occurs so that the body actively seeks to raise its own temperature. The presence of microorganisms, toxins, neoplasms and inflammation activates mononuclear phagocytes that produce interleukin-1 (IL-1) which in turn raises the thermoregulatory set point in the hypothalamus via prostaglandin E2 (PGE2)1 synthesis. Resultant increases in heat production and heat conservation produce fever. The neural mediator of the febrile response to IL-1 is believed to be PGE2. IL-1 binds to the surface receptors on target cells in the preoptic region of the anterior hypothalamus, which activates the calcium channels resulting in a net influx of calcium ions into the cell. Increased intracellular calcium initiates the prostaglandin cascade from which the final product is PGE21 (Figure 1).
Figure 1. Prostaglandin synthesis4

Fever has long been associated with infection. The offending organism sensitizes inflammatory cells, which results in endogenous pyrogen production. In gram-negative organisms, lipopolysaccharides and lipid A elicit the febrile response. The muramyl dipeptide component of a gram-positive organism's cell wall causes a maximal pyrogenic response. Neoplastic conditions have also been associated with fever. In a study by Browder et al,2 fever was directly attributed to cancer in at least 5.4% of the patients. The source of endogenous pyrogen in neoplasms is different from infections. Tumor cells have the ability to produce this substance as seen in patients with leukemias, histiocytic lymphomas and Hodgkin's disease. Tumor necrosis factor (TNF alpha type) is another substance identified as a pyrogenic agent. In neoplastic diseases, TNF was synthesized and secreted continuously either by the malignant cells or by immunocompetent cells reacting to the tumor. Beutler4 hypothesized that TNF may be generated by an inflammatory response to some tumors but that the amount produced is not as spectacular as in bacteremia or septicemia. Connective tissue diseases have fever as one of its common features. In a local study of systemic lupus erythematosus3, fever was a presenting manifestation in 49% of cases. Connective tissue diseases, either induced by auto-antigens of external stimuli (e.g. drugs) have been known for their heightened systemic inflammatory reactions brought about by the interaction of autoantigens and the antibodies formed against these with the consumption of complement. Non-steroidal anti-inflammatory drugs (NSAIDs) have been used as a diagnostic test for neoplastic conditions. Lysis of the fever implies a neoplastic etiology while failure points to an infectious condition. In a study by Beutler,4 ibuprofen was administered to experimental animals and humans receiving IFN which was found to attenuate febrile and endocrine responses, probably via the cyclooxygenase pathway. In the study by Dinarello and Wolff,5, indomethacin was used and the mechanism suggested was that it blocked fever due to a centrally administered muramyl peptide. On the other hand, the drug exerted no effect on the ability of the same pyrogen to stimulate leukocyte endogenous pyrogen production. Neoplasms produce less TNF and subsequently less leukocyte endogenous pyrogen than infectious conditions with the latter causing more prolonged pyrexia, which could not be neutralized adequately by NSAID. Chang6 evaluated 70 febrile patients in which naproxen showed no antipyretic effect in 14 patients who ultimately turned out to have infections. Failure of NSAID to lyse the fever favors infectious etiologies. In this study, a case of poorly differentiated retroperitoneal sarcoma had a negative response to the naproxen test. The non-defervescence of the fever does not exclude the neoplasm; rather, it could imply a superimposed infectious process that may have been hidden from the initial examinations. Diffuse involvement in the case of carcinomatosis increases TNF production, which could be responsible for the negative response. In a study on fever in neoplastic diseases, complications such as intraabdominal fistulae and cutaneous infections following invasion by the tumor were found to have complicated the situation.2 A negative test should prod the physician to investigate further for possible coexisting infectious conditions. Enteric fever registered the largest number among false positive responders. Prior antibiotic use, though less than 48 hours in duration, may manifest its therapeutic effect even with a latent period of seven days that may have been falsely attributed to the administration of naproxen. The onset of response to the naproxen test at 2 hours, with the latest at 6 hours was comparable with the study of Chang, wherein the temperature returned to normal within 12 hours. A similar study with the use of indomethacin on visceral cancers resulted in fever lysis within 24 hours.7 The afebrile state was sustained in all of these studies as long as the patients were maintained on the drug. Continuous naproxen therapy was given to ten of the true positive responders. Those who were not placed on continuous therapy were managed either by surgical means, immunomodulators or chemotherapeutic measures.

The naproxen test exhibited no serious side effects especially for short-term use. The test has been applied even to patients with platelet counts above 30,000/uL. Gastrointestinal irritation and anti-platelet effects are associated with long-term use. The naproxen test demonstrated a high sensitivity. In situations of diagnostic uncertainty, it would be better to express this quantitatively and unambiguously by using probability rather than by adjectives such as possibly and probably.8 A clearer direction for the rational use of available ancillary and laboratory procedures is provided by the naproxen test. A negative test in a known neoplastic condition warrants further investigation for a possible infectious source. On the other hand, a positive response points to a neoplastic source of fever, which may remove the need for further work-ups. The naproxen test is a highly sensitive and cost-effective diagnostic aid, which, if interpreted properly, may help to cut down medical expense, alleviate the physician's stress and relieve the patient's discomfort.8 CONCLUSION AND RECOMMENDATIONS The naproxen test was unequivocally positive in malignancies and connective tissue diseases. Malignant lymphoma was the most common malignancy; only retroperitoneal sarcoma and carcinomatosis yielded a false negative response. Connective tissue diseases included Still's disease, juvenile rheumatoid arthritis and systemic lupus erythematosus. Enteric fever and malaria were the most common infectious diseases with a true negative response. However enteric fever also gave the highest false negative response. Amoebic liver abscess, extrapulmonary tuberculosis, viral hepatitis, pneumonia, recurrent urinary tract infection and pulmonary tuberculosis were the infectious diseases, which responded equivocally to the naproxen test. Other infectious etiologies which gave a true negative response to naproxen test were extrapulmonary tuberculosis and influenza. The likelihood of a positive naproxen test in patients with prolonged fever due to a malignant process or connective tissue disease was high. However, the likelihood of a patient with prolonged fever secondary to an infectious process in a negative naproxen test was minimal. The naproxen test can be used in malignancies and connective tissue diseases either as a diagnostic or therapeutic modality. The test is even more useful in patients with fever of unknown origin, malignancies with superimposed infectious and chronic conditions with developing malignancies. Further validation of the test in a prospective design limited to infections and malignancies with fever lasting for one week or more is currently underway.
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