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Cotton Fever: Does the Patient Know Best?


Fever and leukocytosis have many possible etiologies in injection drug users. We present a case of a 22-year-old woman with fever and leukocytosis that were presumed secondary to cotton fever, a rarely recognized complication of injection drug use, after an extensive workup. Cotton fever is a benign, self-limited febrile syndrome characterized by fevers, leukocytosis, myalgias, nausea and vomiting, occurring in injection drug users who filter their drug suspensions through cotton balls. While this syndrome is commonly recognized amongst the injection drug user population, there is a paucity of data in the medical literature. We review the case presentation and available literature related to cotton fever.

Injection drug use is associated with many infectious and non-infectious complications. The most common associated complications faced by managing physicians are soft-tissue infections, overdose, intoxication, and withdrawal.1 A frequent and challenging triage dilemma in this population is that of fever with active injection drug use. Despite numerous unsuccessful attempts to develop discriminating decision rules to guide ambulatory triage in these cases, clinicians are still unable to reliably exclude occult infections such as endocarditis and osteomyelitis.2,3 This often results in short-term hospitalization of these patients, with accrual of health care expenditures.4 An infrequently recognized cause of fever in injection drug users is cotton fever, a poorly characterized systemic febrile inflammatory syndrome seen in this population. Ironically, while there is a paucity of literature and awareness in the medical community, cotton fever is a well-recognized syndrome amongst injection drug users. Originally coined in 1975, cotton fever was described as a benign self-limited febrile syndrome occurring in injection drug users who filtered their drug suspensions through cotton balls.5 We present a case of presumed cotton fever in an active injection heroin user, in whom the diagnosis was only considered upon hearing the patient reference the syndrome after substantial workup had been completed. Additionally, a review of the medical literature and a discussion of the current theories about the pathophysiology of cotton fever are presented.


A 22-year-old woman presented to an outside hospital 4 hours after developing acute onset of fevers, headache, abdominal pain and radiating back pain, which began 20 minutes after injecting heroin. She did not endorse any visual symptoms, chest pain, dyspnea, or rashes. Initial vital signs were notable for a temperature of 39°C and heart rate of 102 beats per minute. At the time, the remainder of her exam was reported as normal except for diffuse abdominal tenderness. In the setting of acute back pain, a lumbar spine MRI was obtained and interpreted as consistent with an L3-S2 epidural abscess. Blood cultures were drawn, and the patient was started on vancomycin and ceftriaxone. Twelve hours after initiation of symptoms, the patient was transferred to our institution for consideration of neurosurgical intervention for presumed epidural abscess. By the time of arrival, the patient’s fever had resolved and her abdominal pain had improved. On examination, her heart rate was 101 beats per minute, blood pressure was 106/64 mmHg, and temperature was 37.6 °C. Her cardiac exam revealed a II/VI systolic crescendo-decrescendo murmur best heard at the left lower sternal border. Her abdomen was diffusely tender without peritoneal signs, and she exhibited lower back allodynia. She had numerous new and old injection tracks on her arms, but no other rashes or stigmata of endocarditis. Her fundus exam revealed a clear vitreous without hemorrhages or Roth spots. Her neck was supple and her pulmonary and neurologic examinations were unremarkable.

On transfer, the patient had a white blood cell count of 22.6 × 109/L without a left shift; the remainder of her laboratory values; including chemistries, urinalysis and cerebrospinal fluid, were all normal. Blood cultures were redrawn and she was continued on broad-spectrum antibiotics. A transthoracic echocardiogram showed no evidence of vegetations and only trace tricuspid insufficiency. Her original MRI was reviewed by our neuroradiologists, who did not identify findings consistent with epidural abscess or osteomyelitis and felt that the original enhancement was likely a normal variant.

Twenty-four hours following transfer, her leukocytosis and abdominal pain resolved. Within two days, her back pain briskly improved and she was able to ambulate fluidly. As her blood cultures at both hospitals remained negative and she remained afebrile, antibiotic treatment was discontinued. With no clear diagnosis but with ongoing clinical improvement, plans were made for discharge. On the day of discharge, she was overheard mentioning aloud to her friend; “I think I had a bad case of cotton fever.” Following a subsequent literature review of cotton fever and with the exclusion of other infectious etiologies for the patient’s fever and leukocytosis, a presumed diagnosis of cotton fever was made.


While our patient’s symptoms, signs, and clinical course were initially worrisome for infection, she rapidly improved and infectious causes were ruled out. Thus, her clinical picture was thought to be consistent with a diagnosis of cotton fever. Cotton fever is a diagnosis of exclusion and is characterized by acute onset of fever and leukocytosis immediately following intravenous drug injection when filtering through cotton. Symptoms begin 15–30 minutes following injection, and are often accompanied by shortness of breath, chills, headache, myalgia, abdominal pain, nausea, vomiting and tachycardia. Although cotton fever is self-limited and normally lasts 6 to 12 hours, it can continue for up to 24 to 48 hours.

While most often associated with injection of heroin,6,7 cotton fever has also been described when injecting hydromophone8 or a combination of pentazocine and methylphenidate.9 The pathophysiology is poorly understood, but three pathogenic theories have been proposed.9 The pharmacologic theory hypothesizes that the extracts of cotton contain water-soluble, steam-labile substances with pyrogenic activity. The immunologic theory proposes that people may have antibodies to cotton itself. However, no evidence has been found to support the immunologic or pharmacologic theory. Finally, the endotoxin theory suggests that cotton fever may result from the release of endotoxins from Gram negative bacilli such as Enterobacter agglomerans, which has been shown to regularly colonize cotton.10 Further supporting this endotoxin theory, a case of cotton fever was described in conjunction with E. agglomerans bacteremia.6

This current case represents a humbling reminder of the significant disparities in medical knowledge and cultural awareness between providers and their patients. Following an extensive inpatient evaluation for an occult infection in a febrile injection drug user, only the serendipitous insight from the patient ultimately led to the diagnosis of cotton fever. There are few publications addressing cotton fever69,11; thus there is no epidemiological data on the incidence of cotton fever, highlighting the general lack of awareness of this clinical entity in current medical practice. However, there are multiple sources of information for injection drug users on “drugs forum”, “opiophile” and “Heroin Helper”, leading to greater awareness of cotton fever amongst the injection drug user population compared to the medical community. One emergency medicine physician estimates that he sees approximately one such patient each month.7 However, injection drug users estimate the incidence of cotton fever to about 5 % per year of use.12 As this is a poorly characterized disease and a diagnosis of exclusion, the true incidence is likely much more common than recognized by the medical community.

The evaluation of a febrile injection drug user continues to present diagnostic challenges for providers. While the majority of injection drug users will have a readily identifiable source of fever such as pneumonia or cellulitis, there is a subset of patients in which the cause of their fever is not readily identifiable, and about 8–11 % are found to have serious infections such as endocarditis.3,13,14 As the presentation of cotton fever and endocarditis are similar, it is important to consider endocarditis prior to making the diagnosis of cotton fever. The incidence of endocarditis in injection drug users is estimated to be 1.5–3.3 cases per 1000 injection drug users per year.15 17 This risk is further increased in the presence of concurrent HIV, which is annually estimated to be present in 6.6 per 1000 injection drug users; this number reflects a dramatic reduction since the advent of highly active anti-retroviral therapies.18 Another rare complication of injection drug use is osteomyelitis, which should be considered in the appropriate clinical context.3

Despite the known burden of disease, the evaluation of a febrile injection drug user can be costly and difficult. Attempts at developing triage and diagnosis algorithms for febrile injection drug users have been unsuccessful in accurately predicting who will and who will not have endocarditis.2,3 Therefore, we still recommend observing febrile injection drug users, who often are unable or unwilling to follow up, until blood cultures are negative.13

In our patient, who ultimately had a self-limited illness, the initially concerning interpretation of the lumbar MRI in the setting of fever, leukocytosis and recent injection drug use, prompted an extensive yet appropriate diagnostic evaluation. Although cotton fever is a diagnosis of exclusion, an increased awareness of this condition would likely improve providers’ ability to provide supportive care while ruling out diseases with increased morbidity such as endocarditis and osteomyelitis.


The importance of recognizing cotton fever is paramount, as early suspicion may reduce expensive secondary evaluations and the length of hospitalization.4 However, given the challenges and limitations in the initial triage and management of febrile syndromes in injection drug users, admission for observation is still warranted and recommended, as cotton fever remains a diagnosis of exclusion.2 Quick resolution of fevers and pain symptoms within 24-48 hours in the setting of negative initial blood cultures is suggestive of cotton fever, an under-recognized but possibly common cause of fever in the injection drug users. Further awareness and study are needed to better characterize the epidemiologic and pathogenesis of this syndrome, as there is currently a paucity of information. This case should again remind us to never underestimate the potential diagnostic and therapeutic insights that are housed in our patients’ awareness—if we only think to ask.


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Conflict of Interest

The authors declare that they do not have a conflict of interest.

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Corresponding author

Correspondence to Bailey A. Pope MD.

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Key Points

• Cotton fever is a benign febrile illness characterized by acute onset fever and leukocytosis, occurring immediately following intravenous drug injection.

• In addition to fever and leukocytosis, patients with cotton fever can exhibit shortness of breath, chills, headache, myalgia, abdominal pain, nausea, vomiting and tachycardia.

• Cotton fever is a diagnosis of exclusion, and likely has a higher prevalence than previously thought.

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Xie, Y., Pope, B.A. & Hunter, A.J. Cotton Fever: Does the Patient Know Best?. J GEN INTERN MED 31, 442–444 (2016).

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  • cotton fever
  • drug abuse
  • case report
  • intravenous drug abuse