Rifamycin-based regimens are increasingly used for the management of patients with tuberculosis infection because of lower rates of hepatic adverse drug reactions and higher completion rates than other regimens.
Rifampin-induced flu-like syndrome is usually a mild illness associated with intermittent dosing regimens (i.e., weekly) but can also occur with low-dose daily administration.
Mild flu-like symptoms can be managed by short-term, over-the-counter analgesia.
If treatment is temporarily stopped because of flu-like syndrome, patients can uncommonly have a more severe reaction, including shock, after resuming treatment.
Patients should be encouraged to resume treatment in a location where medical care is available in case life-threatening symptoms develop.
A 15-year-old girl, born in a country with a high burden of tuberculosis (TB), was in the care of a tertiary care infectious disease clinic for TB infection (TBI) based on a positive QuantiFERON gold test. She had no evidence of TB disease. She had a history of iron deficiency anemia (hemoglobin 97–104 [normal 112–151] g/L) and moderately active systemic lupus erythematosus (SLE), given her symmetric nonerosive polyarthritis, nonscarring alopecia, photosensitivity and Raynaud phenomenon, as well as positivity for antinuclear, anti-Smith and anti-ribonucleoprotein antibodies. Her medications were naproxen (375 mg, twice daily) and hydroxychloroquine (5.5 mg/kg/d); she had not taken corticosteroids for several years. The patient began treatment with 600 mg rifampin (10 mg/kg/d) and tolerated the medication well for 11 days. For the next 3 days, she had chills and myalgias that began a few hours after rifampin ingestion and resolved a few hours later. She stopped treatment for 3 days without symptom recurrence.
After an in-person assessment, with a normal physical examination aside from arthritis in 2 joints, the patient was advised to resume rifampin. Within 1 hour of taking the medication, she developed sudden onset severe neck pain, myalgias, arthralgias, shortness of breath and chest pain. During ambulance transport to the emergency department, she received a fluid bolus for hypotension (80/40 mm Hg). On physical examination, she was febrile (38.3°C), tachypneic (28 breaths/min, 99% saturation) and tachycardic (123 beats/min) with a low-to-normal blood pressure (91/52 mm Hg). Her weight was 60 kg. She had no angioedema, rash, wheezing or gastrointestinal symptoms. She received intravenous fluids and empiric vancomycin and ceftriaxone. Three hours after symptom onset, she became hypotensive again (89/36 mm Hg) and diaphoretic, requiring fluid resuscitation and norepinephrine and epinephrine infusions. She was admitted to the intensive care unit (ICU).
On physical examination, the patient had no rash or mucous membrane involvement. Blood work showed a decreased leukocyte count at admission (2.84 [normal 4.23–9.99] × 109/L), which increased to 17.34 × 109/L 6 hours later, with low eosinophil counts throughout (0.00 [normal 0.02–0.51] × 109/L). Her hemoglobin level decreased to 74 g/L on the second day of admission after fluid resuscitation. Her bilirubin and haptoglobin levels were normal, a direct antiglobulin test was negative and her blood film did not show schistocytes.
Inflammatory markers were elevated, with a C-reactive protein (CRP) level of 13.6 (normal < 1.7) mg/L at admission, increasing to 101.8 mg/L about 24 hours later. The patient’s aspartate aminotransferase level increased from 71 (normal < 31) U/L to 99 U/L during this time. Her complement C3 level was slightly decreased at 0.76 (normal 0.83–1.52) g/L and her C4 level remained within normal range. Her creatinine kinase level was normal. Given a previous finding of a partially empty sella turcica on magnetic resonance imaging, the patient’s cortisol level was tested and found to be increased at 605 nmol/L (normal range 30–254 nmol/L for evening sampling).
Given the presence of severe neck pain, nuchal rigidity and shock, the critical care team suspected sepsis and performed additional investigations. A computed tomography (CT) scan of the head and an echocardiogram were normal; CT angiography of the neck did not show an infected thrombus or edematous retropharyngeal soft tissue but showed localized myositis. A chest radiograph showed mild pulmonary edema attributed to fluid resuscitation, which responded to diuresis; CT imaging of the lungs showed bilateral increased septal thickening with ground glass opacities. All infectious work-up — including cultures of blood, sputum, throat and cerebrospinal fluid samples, and serology for Epstein–Barr virus, cytomegalovirus and mycoplasma — was negative. The patient was negative for SARS-CoV-2 on polymerase chain reaction.
Because infection was suspected, she received 1 dose of rifampin in the ICU, which led to a decreased blood pressure of 93/39 mm Hg. In response, her vasopressor dose was increased for 6 hours (norepinephrine 0.04–0.06 μg/kg/min). Rifampin was stopped, and the patient was weaned off vasopressors within 30 hours of admission. Our teams became involved after this episode, and we attributed her presentation to a rifampin-induced adverse drug reaction. We started her on isoniazid for TBI and she successfully completed 9 months of therapy. We told her to avoid rifamycin-based medications in the future.
Discussion
Rifampin-induced flu-like syndrome is a type III hypersensitivity reaction that typically develops 1–4 hours after ingestion of a dose, but delayed reactions up to 8–12 hours later have been reported. Symptoms usually last for 8 hours and often include fever, chills, malaise, headache and arthralgias. When treatment is resumed after stopping because of adverse drug reactions, patients may uncommonly develop hypotension and shock, which generally resolve within 24 hours.1–6 The terminology in the literature is inconsistent; we refer to this severe clinical presentation as rifampin-induced flu-like syndrome with shock.
Rifampin-induced flu-like syndrome has been reported for all rifamycin compounds, the drug class to which rifampin belongs.1,2,4 The pathophysiology remains unclear, but the occurrence of this syndrome has been associated with the presence of anti-rifampin antibodies. Because patients may be symptomatic in the absence of anti-rifampin antibodies, and antibodies have been found in patients tolerating rifampin, measurement of antirifampin antibodies is not helpful in the diagnosis or management of this condition.1,3 The diagnosis can be made based on a clinical assessment of presenting symptoms, physical examination and available laboratory investigations, and exclusion of other causes.
Female sex and increasing age have been shown to increase the likelihood of rifampin-induced flu-like syndrome.7 Patients with HIV have been found to have a lower risk;8 however, SLE or other autoimmune diseases have not been reported as risk factors for the development or severity of rifampin-induced flu-like syndrome.9 Treatment-specific risk factors include prolonged treatment duration (i.e., > 3 mo), intermittent dosing (i.e., once weekly) and increased dose (although there is no clear definition for what constitutes an increased dose in this context); however, patients can develop the syndrome without these risk factors.10
Our patient’s presentation was typical for an adverse drug reaction to rifampin, although it was important to consider alternative diagnoses. Infections were excluded, and her clinical presentation was atypical for an SLE flare. She had no signs of pulmonary embolus to explain the hypotension, nor serositis or hemophagocytic syndrome to explain the increased CRP, which is unusual in an SLE flare. Our patient did not have adrenal insufficiency, which can present with hypotension and shock. A Jarisch–Herxheimer reaction that could cause a flu-like syndrome has not been reported in TBI without disease. Although a relatively acute onset of hypotension can suggest anaphylaxis, a pure type I hypersensitivity reaction was unlikely, given the associated symptoms such as fever and raised inflammatory markers. Finally, she had no thrombocytopenia, hemolysis or acute renal failure, which are all uncommon adverse drug reactions to rifamycins.1,2
The Canadian TB Standards strongly endorse 2 rifamycin-based regimens as the preferred treatment of TBI, namely daily rifampin for 4 months or 12 weekly doses of rifapentine (a long-acting rifamycin) and isoniazid.11 These regimens have the advantage of decreasing hepatic adverse drug reactions compared with 9 months of daily isoniazid treatment, and are associated with higher completion rates.12 Among patients receiving the rifapentine regimen for TBI, around 3.5% develop a flu-like reaction;12 a minority (0.2%) develop hypotension requiring intravenous fluid therapy and, occasionally, vasopressors. The rate of flu-like syndrome with the daily rifampin regimen is not reported, but it is thought to be rare.13 Based on the updated treatment recommendations in the Canadian TB Standards, we expect increased usage of rifamycin compounds for TBI in Canada, which will likely result in a higher absolute number of patients with rifamycin-induced adverse drug reactions, particularly rifampin-induced flu-like syndrome. Management guidelines for TBI and TB disease should be updated to provide specific guidance regarding patient counselling and rechallenge with rifamycins.9,13 We suggest that patients should be advised to speak to their prescribing provider if experiencing a possible adverse drug reaction to a rifamycin-based medication to limit unnecessary treatment interruptions. If treatment is stopped because of an adverse drug reaction, patients should discuss when to restart treatment with their provider. Patients who develop a mild flu-like syndrome on weekly rifapentine treatment may tolerate a daily rifampin regimen.1,2,5 Patients on daily rifampin treatment who develop mild flu-like symptoms can be treated with over-the-counter anti-pyrectic and analgesic agents. However, the effectiveness of these treatments is not known. If rifamycin-based therapy is resumed after stopping because of flu-like symptoms, there is a very small risk the patient will develop a more severe reaction.2 Providers should consider the accessibility of appropriate care (e.g., intravenous fluid administration) when planning treatment restart. Intramuscular epinephrine should be considered when intravenous vasopressors are unavailable, although no data regarding its effectiveness are available. For patients who tolerate rifamycin-based treatment upon rechallenge, an observation period of 1 hour appears reasonable based on the available literature. For patients who have had a severe reaction, rifamycin compounds should be avoided. In cases where no alternative treatment is available (e.g., isoniazid drug resistance), rifamycin-based treatment should be resumed under the guidance of a provider experienced in the management of this severe adverse drug reaction. No data are available regarding the success of desensitization for flu-like syndrome.
Given better overall safety and completion rates, rifamycin-based regimens are now the preferred therapy for TBI. It is important that health care providers recognize flu-like symptoms caused by rifamycin compounds, appropriately counsel patients before starting treatment and consider accessibility of appropriate care in case of rechallenge, if the medication has been stopped for this reason.
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Footnotes
Competing interests: None declared.
This article has been peer reviewed.
The authors have obtained patient consent.
Contributors: All of the authors contributed to the conception and design of the work. Gousia Dhhar and Jeanine McColl drafted the manuscript. All of the authors revised it critically for important intellectual content, gave final approval of the version to be published and agreed to be accountable for all aspects of the work.
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The Canadian government says it will donate up to 200,000 vaccine doses to fight the mpox outbreak in Congo and other African countries.
It says the donated doses of Imvamune will come from Canada’s existing supply and will not affect the country’s preparedness for mpox cases in this country.
Minister of Health Mark Holland says the donation “will help to protect those in the most affected regions of Africa and will help prevent further spread of the virus.”
Dr. Madhukar Pai, Canada research chair in epidemiology and global health, says although the donation is welcome, it is a very small portion of the estimated 10 million vaccine doses needed to control the outbreak.
Vaccine donations from wealthier countries have only recently started arriving in Africa, almost a month after the World Health Organization declared the mpox outbreak a public health emergency of international concern.
A few days after the declaration in August, Global Affairs Canada announced a contribution of $1 million for mpox surveillance, diagnostic tools, research and community awareness in Africa.
On Thursday, the Africa Centres for Disease Control and Prevention said mpox is still on the rise and that testing rates are “insufficient” across the continent.
Jason Kindrachuk, Canada research chair in emerging viruses at the University of Manitoba, said donating vaccines, in addition to supporting surveillance and diagnostic tests, is “massively important.”
But Kindrachuk, who has worked on the ground in Congo during the epidemic, also said that the international response to the mpox outbreak is “better late than never (but) better never late.”
“It would have been fantastic for us globally to not be in this position by having provided doses a much, much longer time prior than when we are,” he said, noting that the outbreak of clade I mpox in Congo started in early 2023.
Clade II mpox, endemic in regions of West Africa, came to the world’s attention even earlier — in 2022 — as that strain of virus spread to other countries, including Canada.
Two doses are recommended for mpox vaccination, so the donation may only benefit 100,000 people, Pai said.
Pai questioned whether Canada is contributing enough, as the federal government hasn’t said what percentage of its mpox vaccine stockpile it is donating.
“Small donations are simply not going to help end this crisis. We need to show greater solidarity and support,” he said in an email.
“That is the biggest lesson from the COVID-19 pandemic — our collective safety is tied with that of other nations.”
This report by The Canadian Press was first published Sept. 13, 2024.
Canadian Press health coverage receives support through a partnership with the Canadian Medical Association. CP is solely responsible for this content.
HALIFAX – The Nova Scotia government says it could be months before it reveals how many people are on the wait-list for a family doctor.
The head of the province’s health authority told reporters Wednesday that the government won’t release updated data until the 160,000 people who were on the wait-list in June are contacted to verify whether they still need primary care.
Karen Oldfield said Nova Scotia Health is working on validating the primary care wait-list data before posting new numbers, and that work may take a matter of months. The most recent public wait-list figures are from June 1, when 160,234 people, or about 16 per cent of the population, were on it.
“It’s going to take time to make 160,000 calls,” Oldfield said. “We are not talking weeks, we are talking months.”
The interim CEO and president of Nova Scotia Health said people on the list are being asked where they live, whether they still need a family doctor, and to give an update on their health.
A spokesperson with the province’s Health Department says the government and its health authority are “working hard” to turn the wait-list registry into a useful tool, adding that the data will be shared once it is validated.
Nova Scotia’s NDP are calling on Premier Tim Houston to immediately release statistics on how many people are looking for a family doctor. On Tuesday, the NDP introduced a bill that would require the health minister to make the number public every month.
“It is unacceptable for the list to be more than three months out of date,” NDP Leader Claudia Chender said Tuesday.
Chender said releasing this data regularly is vital so Nova Scotians can track the government’s progress on its main 2021 campaign promise: fixing health care.
The number of people in need of a family doctor has more than doubled between the 2021 summer election campaign and June 2024. Since September 2021 about 300 doctors have been added to the provincial health system, the Health Department said.
“We’ll know if Tim Houston is keeping his 2021 election promise to fix health care when Nova Scotians are attached to primary care,” Chender said.
This report by The Canadian Press was first published Sept. 11, 2024.
ST. JOHN’S, N.L. – Newfoundland and Labrador‘s chief medical officer is monitoring the rise of whooping cough infections across the province as cases of the highly contagious disease continue to grow across Canada.
Dr. Janice Fitzgerald says that so far this year, the province has recorded 230 confirmed cases of the vaccine-preventable respiratory tract infection, also known as pertussis.
Late last month, Quebec reported more than 11,000 cases during the same time period, while Ontario counted 470 cases, well above the five-year average of 98. In Quebec, the majority of patients are between the ages of 10 and 14.
Meanwhile, New Brunswick has declared a whooping cough outbreak across the province. A total of 141 cases were reported by last month, exceeding the five-year average of 34.
The disease can lead to severe complications among vulnerable populations including infants, who are at the highest risk of suffering from complications like pneumonia and seizures. Symptoms may start with a runny nose, mild fever and cough, then progress to severe coughing accompanied by a distinctive “whooping” sound during inhalation.
“The public, especially pregnant people and those in close contact with infants, are encouraged to be aware of symptoms related to pertussis and to ensure vaccinations are up to date,” Newfoundland and Labrador’s Health Department said in a statement.
Whooping cough can be treated with antibiotics, but vaccination is the most effective way to control the spread of the disease. As a result, the province has expanded immunization efforts this school year. While booster doses are already offered in Grade 9, the vaccine is now being offered to Grade 8 students as well.
Public health officials say whooping cough is a cyclical disease that increases every two to five or six years.
Meanwhile, New Brunswick’s acting chief medical officer of health expects the current case count to get worse before tapering off.
A rise in whooping cough cases has also been reported in the United States and elsewhere. The Pan American Health Organization issued an alert in July encouraging countries to ramp up their surveillance and vaccination coverage.
This report by The Canadian Press was first published Sept. 10, 2024.
