The heterogeneous syndrome of non-infectious causes of persistent fever in neutropenic patients with hematologic malignancy: another opportunity for stewardship?

Although occult fungal, viral and multidrug-resistant bacterial infections can cause persistent fever in neutropenic patients with hematologic cancer, a variety of non-infectious entities should be considered in case-by-case basis in the context of negative diagnostic workup for infection.

Fever and reversible laboratory abnormalities associated with prolonged use of piperacillin/tazobactam: A case report.

Piperacillin/tazobactam is a widely used anti-infective agent. However, prolonged use can lead to adverse drug reactions, primarily presenting as fever and various abnormal laboratory test results. Certain abnormal test outcomes may mislead clinical assessments. We present a case of a 50-year-old Chinese woman who developed a fever and abnormal blood tests after receiving piperacillin/tazobactam for more than 2 weeks. These tests showed elevated levels of C-reactive protein, procalcitonin, transaminases, myocardial enzymes, and a significant increase in D-dimer. After stopping piperacillin/tazobactam, all relevant test results returned to normal within 10 days. It is imperative for clinicians to be vigilant of this adverse effect in patients undergoing extended piperacillin/tazobactam treatment, as early recognition can prevent unnecessary diagnostic tests and therapeutic interventions.

Morphine-induced fever: a case report and review of the literature.

BACKGROUND: Morphine is widely used to treat moderate-to-severe cancer pain. However, it causes various adverse effects, with morphine-induced fever being an extremely rare and poorly understood symptom. CASE PRESENTATION: We report the case of a 58-year-old Chinese woman with advanced lung cancer. Due to the ineffectiveness of tramadol for pain relief, her treatment regimen was switched to morphine. Following the change, she developed nausea, vomiting, dizziness, and elevated body temperature. A similar episode occurred subsequently. After a drug review, the pharmacist speculated that morphine was the most likely causative agent. Upon discontinuation of morphine, her body temperature returned to baseline levels. CONCLUSIONS: This case highlights the need for healthcare providers to consider morphine as a potential cause of unexplained fever in patients. The fever may be caused by a hypersensitive response, as there was a significant increase in eosinophils during the fever episodes.

A case of drug fever in the treatment of Brucella arthritis in a child: a case report.

Brucellosis, a zoonotic ailment induced by the Brucella and some patients may present with joint involvement. This report describes a pediatric patient diagnosed with Brucella arthritis, presenting with swelling and pain in the right knee. The patient had a reoccurrence of fever due to sulfamethoxazole-trimethoprim allergy during treatment. Symptoms improved after adjusting the antimicrobial regimen to ceftriaxone and rifampicin. This case emphasizes the importance of the need for brucellosis as a differential diagnosis for arthralgia and fever in brucellosis- endemic areas. Furthermore, it emphasizes the importance of timely recognition that recurrent fever after effective anti-infective therapy must be considered as a possibility of drug fever.

Risedronate-Induced Chronic Drug Fever in a Case of Parkinson's Disease.

We present an atypical case of risedronate-induced chronic fever in an 85-year-old woman with Parkinson's disease, with a dosage regimen of 17.5 mg/week. Our patient had been administered an analgesic/antipyretic drug, acetaminophen, at a rate of 600 mg/day for treatment of a vertebral fracture that occurred relatively frequently, which might have masked the fever caused by risedronate. We noted two clinically significant indications. Firstly, blood test results do not necessarily show the cause of risedronate-induced fever, as white blood cell counts and C-reactive protein levels vary. A simple way to diagnose risedronate-induced fever is to suspend risedronate for a certain period and observe if the patient's fever lowers. Secondly, in general, cases receiving polypharmacy tend to include an analgesic antipyretic agent, which may mask the drug-induced fever. Even in patients with Parkinson's disease whose body temperature is generally unstable due to autonomic nerve system disorder, if they are administered risedronate and experience chronic fever of unknown cause, the possibility of drug fever may be considered. This study concludes that risedronate-induced chronic fever, as observed in our case, represents a rare phenomenon, and it may be necessary to reconsider treatment methods for osteoporosis.

Prevalence of Drug Fever among Cases of Nosocomial Fever: A Systematic Review and Meta-analysis.

Objective Drug fever is defined as a fever that temporally coincides with the start of a culprit drug and disappears after discontinuation of the drug. It is a common cause of nosocomial fever, which refers to a fever that develops beyond the first 48 h after hospital admission. However, the exact prevalence of drug fever among cases of nosocomial fever is unclear, as is the variation in prevalence depending on the clinical setting and most common causative drugs. Methods PubMed MEDLINE, Dialog EMBASE, Cochrane Central Register of Controlled Trials, World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov were systematically searched. Studies that reported the prevalence of drug fever in patients with nosocomial fever were included. Two of the four reviewers conducted independent assessments of the inclusion, data extraction, and quality. Pooled adjusted odds ratios were generated using a random-effects model and presented with 95% confidence intervals (CIs). Results Fifteen meta-analysis from 15 studies were included. Ten studies did not report the definition of drug fever or excluded febrile patients who were admitted to the hospital within 24-48 h. The pooled prevalence of drug fever among cases of nosocomial fever was 3.0% (95% CI, 0.6-6.8%), which was largely consistent across the settings, except for at oriental medicine hospital. Only four studies reported the causative agents, and antibiotics were the most frequently reported. Conclusions The prevalence of drug fever is low in patients with nosocomial fever. Clinicians should recognize that drug fever is a diagnosis of exclusion, even in cases of nosocomial fever.

Drug fever: a narrative review.

Drug fever is an adverse drug reaction accompanied by a febrile response and is a common problem among clinicians, hence an updated knowledge of drug fever is important. A consensus regarding the definition of drug fever is lacking. Thus, descriptions of drug fever in previous literature are often inconsistent. In this narrative review, we summarized various features of drug fever, including its definition, epidemiology, risk factors, clinical presentation, diagnosis, treatment and prognosis, based on the earliest literature. Recent advances in information technology have encouraged researchers to use pharmacovigilance databases for clinical and pharmacological research. We outlined how a pharmacovigilance database, along with recently developed research methods, could be used to research drug fever.

Heparin-induced persistent hyperthermia with recurrent hyponatremia in hip fracture: Case report and review of literature.

WHAT IS KNOWN AND OBJECTIVE: Heparin is a commonly used anticoagulant in clinic. Persistent hyperthermia with recurrent hyponatremia caused by heparin is an extremely rare drug fever, which is difficult to judge in the early stage and is often misdiagnosed. CASE SUMMARY: A 74-year-old elderly woman was admitted to our hospital due to left hip pain with limited mobility for 9 h. She was diagnosed with a femoral neck fracture, and continuous heparin anticoagulation was initiated. On the night of surgery, the patient developed high fever with a drop in the serum sodium concentration. Based on the patient's symptoms, signs, and results of the laboratory tests, postoperative absorptive heat and infectious fever were ruled out. After heparin discontinuation, her temperature and serum sodium concentration returned to the baseline levels. WHAT IS NEW AND CONCLUSION: Heparin can cause persistent or recurrent hyponatremia and should be considered in the identification of the aetiology this condition.

Vancomycin-Induced Fever and Neutropenia in an Immunocompetent Patient With Complicated Community-Acquired Pneumonia.

Drug-induced fever can be caused by many medications through several mechanisms. One of the most common mechanisms is an immunologic reaction mediated by drug-induced antibodies. Herein, we report the case of a rare adverse reaction with vancomycin. A six-year-old girl being treated for necrotizing pneumonia with vancomycin developed mild neutropenia, skin rash, and fever two weeks into her therapy. These resolved after stopping vancomycin, with noted reversal of neutropenia and leukopenia. Upon rechallenging the patient with vancomycin, she developed a fever in less than 24 h from the administration. Vancomycin-induced fever was made as a diagnosis of exclusion after all other possible causes were ruled out.

Dexmedetomidine-Induced Fever in a 66-Year-Old Male With Pneumonia and Pleural Effusion.

Drug-induced fever is a significant adverse effect as many commonly used medications can cause this. The incidence of drug fever is even higher in critical care settings because multiple medications are being administered simultaneously. This poses a serious problem in critical care settings as any new fever in these settings also implies any new infection or worsening of preexisting conditions. This may lead to a detailed investigation for the cause of fever, which can be time-consuming, invasive, costly, and may also increase the duration of stay along with an associated increase in morbidity and mortality. We want to highlight an adverse drug event through a documented case of Dexmedetomidine-induced fever in a critical care patient with multiple pathologies.

Differentiating probable nitrofurantoin-induced drug fever from antipsychotic-induced hyperthermia in a patient receiving clozapine.

Nitrofurantoin (NIT) is a commonly utilized antibiotic for the treatment of UTIs. Although well tolerated, NIT is not without potential adverse reactions. This case report details the observation of probable NIT-induced drug fever in a patient receiving clozapine. A 61-year-old female with treatment-refractory schizoaffective disorder was admitted to a psychiatric unit with paranoia and auditory hallucinations, prompting clozapine initiation during day 1 of hospitalization. Due to worsening hallucinations and anxiety, antibiotic therapy with NIT for a presumed UTI was initiated 8 days after admission. Febrile episodes were observed beginning on hospital day (HD) 9, leading to concern for possible neuroleptic malignant syndrome (NMS), which led to clozapine discontinuation. The patient received a total of 3 doses of NIT with continued fever until discontinuation on HD 10. No further complications were encountered, and clozapine was safely resumed on HD 13. Although sparsely described in the medical literature, occurrences of drug fever attributable to NIT are previously reported. A review of the medical literature identified only 5 previously published articles specific to NIT-induced drug fever, none of which specified interruptions of psychotropic therapy for a patient with acute psychiatric decompensation. This case highlights the differential diagnosis of fever related to NIT in a patient receiving clozapine when NMS was initially suspected.

Rifampicin-induced fever during treatment against staphylococcal biofilm in a patient with periprosthetic joint infection.

Periprosthetic joint infection (PJI) after total knee arthroplasty remains a challenging complication. The treatment options for PJI include different procedures; however, regardless of the strategy, antibiotics are required. The combination of different antibiotics increased the rates of PJI eradication. For almost 3 decades, rifampicin has been used as part of antibiotic therapy for PJI. Drug fever, a febrile response that coincides with the onset of drug administration and disappears after drug discontinuation in the absence of other underlying conditions that could cause fever, is frequently misdiagnosed. We present the case of a 72-year-old man with PJI 6 months after total knee arthroplasty. Two-stage revision surgery was followed by culture-directed antibiotic treatment (ciprofloxacin and rifampicin) against Staphylococcus aureus isolated from the periprosthetic tissue. On the fifth day of antibiotic treatment, the patient became febrile and, in the next 5 days, he had an intermittent fever of up to 40°C, although he showed clinical improvement. The patient was normotensive without a maculopapular rash, urticaria or clotting abnormalities. A drug fever was suspected, and rifampicin was discontinued. A re-challenge test was performed, and the fever recurred. Antibiotic treatment with ciprofloxacin was continued and, after 12 months of follow-up, the patient was doing well. Clinicians should be aware that fever could be a clinical presentation of drug fever. If it occurs during an infection, drug fever could necessitate additional diagnostic procedures for further evaluation, inadequate antibiotic therapy and prolonged hospitalisation.

Drug fever induced by antibiotics of ß-lactams in a patient after posterior cervical spine surgery-A case report and literature review.

Drug fever is a febrile reaction that emerges temporarily with the administration of a drug or a variety of drugs and disappears after cessation of the targeting agent. There are a few previous reports about drug fever, but they pertain mainly to patients accompanied by no surgical intervention. Based on the literature reviewed, drug fever in patients after posterior cervical spine surgery has never been mentioned before; therefore, we present a 56-year-old man diagnosed with drug fever after posterior cervical spine surgery for traumatic cervical myelopathy. Fortunately, his body temperature rapidly came down in 2 days after discontinuing the antibiotics. He was discharged after two more days of observation, and the patient recovered well without any further complaints. Early diagnosis of drug fever may greatly reduce inappropriate and potentially detrimental diagnostic and therapeutic interventions. For patients with persistent fever, if it happened days after surgery, particularly when it is without any infectious evidence, then it is necessarily important to consider a possible reason of drug-induced fever.

Celecoxib-induced drug fever: A rare case report and literature review.

WHAT IS KNOWN AND OBJECTIVE: Drug fever is frequently misdiagnosed, especially during concurrent infection. Celecoxib causes various adverse effects; however, celecoxib-induced drug fever is rarely reported. CASE SUMMARY: A 32-year-old man presented with pyrexia after 17 days of celecoxib therapy, which was reintroduced following 3-day total drug cessation. His fever recurred after this unsuspected rechallenge, which aided in the ultimate identification of the offending drug. A Naranjo Score of 8 led us to infer that drug fever was "probably" caused by celecoxib. WHAT IS NEW AND CONCLUSION: This is the first report of celecoxib-induced drug fever, aimed at assisting its diagnosis, particularly with rarely suspected causative drugs.

Drug fever induced by carboplatin-based regimens: Higher incidence in a women's hospital.

OBJECTIVE: Previous studies have reported low incidence of carboplatin-related drug fever in early cancer treatment cycles. This study describes and analyzes relatively higher incidence rate of carboplatin-related drug fever associated with gynecologic cancer chemotherapy in order to allay anxiety in patients and avoid unnecessary interventions. MATERIALS AND METHODS: All gynecologic cancer cases treated with carboplatin in a women's hospital in 2017 and 2018 were retrospectively reviewed and analyzed. Data for patients who experienced carboplatin-induced drug fever and those who received the same treatment but did not experience drug fever were compared for statistical significance. Risk factors for drug fever were identified by logistic regression analysis. RESULTS: In total, 318 females with a mean age of 52 years were included in the analysis. Drug fever was observed in 25 patients (7.86%) in 45 cycles of total 1605 carboplatin-containing infusions. Fever occurred at a median of the third (range: 1-7) cycle, starting at 10.62 h (range: 1.18-50.35 h) after carboplatin infusion, and was generally controlled within 3 days. After chemotherapy rechallenge, the mean frequency of drug fever was 2 times per patient (range: 1-4 times). There were 35/45 drug fever incidents (77.78%) that were classified as grade II; in 15/45 cases (33.33%), antibiotic treatment was immediately initiated to prevent infection. Younger age was found to be a risk factor for drug fever following carboplatin treatment (odds ratio = 0.126, 95% confidence interval: 0.025-0.628; p < 0.05). CONCLUSIONS: The retrospective analysis demonstrated that carboplatin-induced drug fever, which occurred on post treatment 3 days, was a type of delayed hypersensitivity reaction with an incidence rate of 7.86% in gynecologic cancer. Younger age was identified as a risk factor. Drug fever is generally tolerated by patients, who insist on chemotherapy. Knowledge of carboplatin-induced drug fever may help physicians reach timely recognition for appropriate interventions.

Pantoprazole: An Unusual Suspect in a Patient with Fever.

Drugs can cause fever of unknown origin. Drug fever is a diagnosis of exclusion and can lead to unnecessary investigations and prolonged hospitalization. Any drug can be responsible. Here, we describe the case of a woman admitted because of acute hepatitis. Pantoprazole was started for stress ulcer prophylaxis when she was admitted to the ICU. Fever developed a few days later and an extensive diagnostic work-up was negative. Fever remitted after pantoprazole discontinuation and the diagnosis of drug fever was established. LEARNING POINTS: Despite extensive diagnostic work-up, the aetiology of acute liver failure remains unclear in a large proportion of cases.Drug fever is a diagnosis of exclusion and must be considered in every patient with unexplained fever; any drug should be seen as a possible offending agent.Pantoprazole, a commonly prescribed drug, can be a rare cause of fever.

A case of COVID-19 diagnosed with favipiravir-induced drug fever based on a positive drug-induced lymphocyte stimulation test.

As of October 2020, there is still no specific drug to treat COVID-19 as it rages worldwide. Favipiravir, indicated for the treatment of new and re-emerging influenza infections, has been suggested to be effective against SARS-CoV-2, although this is not yet fully validated. We administered favipiravir to a 64-year-old female patient with COVID-19. Her symptoms resolved quickly after the start of treatment, with reduction of SARS-CoV-2 viral load, but she developed a fever again on day 12. Since the fever was relieved by discontinuation of favipiravir, and based on positive results with a drug-induced lymphocyte stimulation test, we diagnosed her with favipiravir-induced drug fever. A decrease in the serum concentration of favipiravir was observed along with resolution of the fever. The present case suggests that drug fever should be considered in the differential diagnosis of relapsing fever episodes in COVID-19 patients receiving favipiravir.

Drug Fever Due to Favipiravir Administration for the Treatment of a COVID-19 Patient.

A 55-year-old Japanese man was hospitalized with the novel coronavirus disease 2019 (COVID-19). On the 14th day after the start of favipiravir administration, the patient developed a fever with a temperature of 38.1°C. His pulse rate also became elevated to 128 bpm, so relative bradycardia was not suspected. Since he was in good overall health and no concomitant symptoms and signs were apparent, we considered it to be drug fever due to favipiravir. After the completion of favipiravir treatment, the patient's temperature normalized within 24 hours. We herein report this case of drug fever caused by favipiravir.

Intermittent Asymptomatic Fever in a Psoriasis Patient.

Acitretin, an active metabolite of etretinate, is the most widely used systemic retinoid in the treatment of psoriasis. Several side effects of acitretin have been reported such as teratogenicity, cheilitis, xerosis, dyslipidemia, and photosensitivity. Here, we reported a case of acitretin-induced intermittent asymptomatic fever in a 79-year-old male psoriasis patient. To the best of our knowledge, only one such case has been reported in the literature so far. We report our case to draw clinical attention that acitretin may cause drug fever, which might not be a rare phenomenon.

A Favipiravir-induced Fever in a Patient with COVID-19.

We herein report the first case of a fever induced by favipiravir, a potential coronavirus disease 2019 therapeutic drug. An 82-year-old man diagnosed with bilateral pneumonia was transferred to our hospital following a positive severe acute respiratory syndrome coronavirus 2 polymerase chain reaction test. He was treated with compassionate use of favipiravir. Both his oxygen demand and fever gradually improved after admission; however, his fever relapsed, and the C-reactive protein (CRP) levels increased on day 7. We diagnosed his fever as being favipiravir-induced. The fever resolved a few days after favipiravir discontinuation, demonstrating the accuracy of the diagnosis. This case revealed that favipiravir can induce a fever.