Rifampin-induced flu-like syndrome with shock in a patient with tuberculosis infection - CMAJ | Canada News Media
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Rifampin-induced flu-like syndrome with shock in a patient with tuberculosis infection – CMAJ

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Key points

  • 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.16 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.

The section Cases presents brief case reports that convey clear, practical lessons. Preference is given to common presentations of important rare conditions, and important unusual presentations of common problems. Articles start with a case presentation (500 words maximum), and a discussion of the underlying condition follows (1000 words maximum). Visual elements (e.g., tables of the differential diagnosis, clinical features or diagnostic approach) are encouraged. Consent from patients for publication of their story is a necessity. See information for authors at www.cmaj.ca.

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.

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY-NC-ND 4.0) licence, which permits use, distribution and reproduction in any medium, provided that the original publication is properly cited, the use is noncommercial (i.e., research or educational use), and no modifications or adaptations are made. See: https://creativecommons.org/licenses/by-nc-nd/4.0/

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Health Canada approves updated Moderna COVID-19 vaccine

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TORONTO – Health Canada has authorized Moderna’s updated COVID-19 vaccine that protects against currently circulating variants of the virus.

The mRNA vaccine, called Spikevax, has been reformulated to target the KP.2 subvariant of Omicron.

It will replace the previous version of the vaccine that was released a year ago, which targeted the XBB.1.5 subvariant of Omicron.

Health Canada recently asked provinces and territories to get rid of their older COVID-19 vaccines to ensure the most current vaccine will be used during this fall’s respiratory virus season.

Health Canada is also reviewing two other updated COVID-19 vaccines but has not yet authorized them.

They are Pfizer’s Comirnaty, which is also an mRNA vaccine, as well as Novavax’s protein-based vaccine.

This report by The Canadian Press was first published Sept. 17, 2024.

Canadian Press health coverage receives support through a partnership with the Canadian Medical Association. CP is solely responsible for this content.

The Canadian Press. All rights reserved.

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These people say they got listeria after drinking recalled plant-based milks

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TORONTO – Sanniah Jabeen holds a sonogram of the unborn baby she lost after contracting listeria last December. Beneath, it says “love at first sight.”

Jabeen says she believes she and her baby were poisoned by a listeria outbreak linked to some plant-based milks and wants answers. An investigation continues into the recall declared July 8 of several Silk and Great Value plant-based beverages.

“I don’t even have the words. I’m still processing that,” Jabeen says of her loss. She was 18 weeks pregnant when she went into preterm labour.

The first infection linked to the recall was traced back to August 2023. One year later on Aug. 12, 2024, the Public Health Agency of Canada said three people had died and 20 were infected.

The number of cases is likely much higher, says Lawrence Goodridge, Canada Research Chair in foodborne pathogen dynamics at the University of Guelph: “For every person known, generally speaking, there’s typically 20 to 25 or maybe 30 people that are unknown.”

The case count has remained unchanged over the last month, but the Public Health Agency of Canada says it won’t declare the outbreak over until early October because of listeria’s 70-day incubation period and the reporting delays that accompany it.

Danone Canada’s head of communications said in an email Wednesday that the company is still investigating the “root cause” of the outbreak, which has been linked to a production line at a Pickering, Ont., packaging facility.

Pregnant people, adults over 60, and those with weakened immune systems are most at risk of becoming sick with severe listeriosis. If the infection spreads to an unborn baby, Health Canada says it can cause miscarriage, stillbirth, premature birth or life-threatening illness in a newborn.

The Canadian Press spoke to 10 people, from the parents of a toddler to an 89-year-old senior, who say they became sick with listeria after drinking from cartons of plant-based milk stamped with the recalled product code. Here’s a look at some of their experiences.

Sanniah Jabeen, 32, Toronto

Jabeen says she regularly drank Silk oat and almond milk in smoothies while pregnant, and began vomiting seven times a day and shivering at night in December 2023. She had “the worst headache of (her) life” when she went to the emergency room on Dec. 15.

“I just wasn’t functioning like a normal human being,” Jabeen says.

Told she was dehydrated, Jabeen was given fluids and a blood test and sent home. Four days later, she returned to hospital.

“They told me that since you’re 18 weeks, there’s nothing you can do to save your baby,” says Jabeen, who moved to Toronto from Pakistan five years ago.

Jabeen later learned she had listeriosis and an autopsy revealed her baby was infected, too.

“It broke my heart to read that report because I was just imagining my baby drinking poisoned amniotic fluid inside of me. The womb is a place where your baby is supposed to be the safest,” Jabeen said.

Jabeen’s case is likely not included in PHAC’s count. Jabeen says she was called by Health Canada and asked what dairy and fresh produce she ate – foods more commonly associated with listeria – but not asked about plant-based beverages.

She’s pregnant again, and is due in several months. At first, she was scared to eat, not knowing what caused the infection during her last pregnancy.

“Ever since I learned about the almond, oat milk situation, I’ve been feeling a bit better knowing that it wasn’t something that I did. It was something else that caused it. It wasn’t my fault,” Jabeen said.

She’s since joined a proposed class action lawsuit launched by LPC Avocates against the manufacturers and sellers of Silk and Great Value plant-based beverages. The lawsuit has not yet been certified by a judge.

Natalie Grant and her seven year-old daughter, Bowmanville, Ont.

Natalie Grant says she was in a hospital waiting room when she saw a television news report about the recall. She wondered if the dark chocolate almond milk her daughter drank daily was contaminated.

She had brought the girl to hospital because she was vomiting every half hour, constantly on the toilet with diarrhea, and had severe pain in her abdomen.

“I’m definitely thinking that this is a pretty solid chance that she’s got listeria at this point because I knew she had all the symptoms,” Grant says of seeing the news report.

Once her daughter could hold fluids, they went home and Grant cross-checked the recalled product code – 7825 – with the one on her carton. They matched.

“I called the emerg and I said I’m pretty confident she’s been exposed,” Grant said. She was told to return to the hospital if her daughter’s symptoms worsened. An hour and a half later, her fever spiked, the vomiting returned, her face flushed and her energy plummeted.

Grant says they were sent to a hospital in Ajax, Ont. and stayed two weeks while her daughter received antibiotics four times a day until she was discharged July 23.

“Knowing that my little one was just so affected and how it affected us as a family alone, there’s a bitterness left behind,” Grant said. She’s also joined the proposed class action.

Thelma Feldman, 89, Toronto

Thelma Feldman says she regularly taught yoga to friends in her condo building before getting sickened by listeria on July 2. Now, she has a walker and her body aches. She has headaches and digestive problems.

“I’m kind of depressed,” she says.

“It’s caused me a lot of physical and emotional pain.”

Much of the early days of her illness are a blur. She knows she boarded an ambulance with profuse diarrhea on July 2 and spent five days at North York General Hospital. Afterwards, she remembers Health Canada officials entering her apartment and removing Silk almond milk from her fridge, and volunteers from a community organization giving her sponge baths.

“At my age, 89, I’m not a kid anymore and healing takes longer,” Feldman says.

“I don’t even feel like being with people. I just sit at home.”

Jasmine Jiles and three-year-old Max, Kahnawake Mohawk Territory, Que.

Jasmine Jiles says her three-year-old son Max came down with flu-like symptoms and cradled his ears in what she interpreted as a sign of pain, like the one pounding in her own head, around early July.

When Jiles heard about the recall soon after, she called Danone Canada, the plant-based milk manufacturer, to find out if their Silk coconut milk was in the contaminated batch. It was, she says.

“My son is very small, he’s very young, so I asked what we do in terms of overall monitoring and she said someone from the company would get in touch within 24 to 48 hours,” Jiles says from a First Nations reserve near Montreal.

“I never got a call back. I never got an email”

At home, her son’s fever broke after three days, but gas pains stuck with him, she says. It took a couple weeks for him to get back to normal.

“In hindsight, I should have taken him (to the hospital) but we just tried to see if we could nurse him at home because wait times are pretty extreme,” Jiles says, “and I don’t have child care at the moment.”

Joseph Desmond, 50, Sydney, N.S.

Joseph Desmond says he suffered a seizure and fell off his sofa on July 9. He went to the emergency room, where they ran an electroencephalogram (EEG) test, and then returned home. Within hours, he had a second seizure and went back to hospital.

His third seizure happened the next morning while walking to the nurse’s station.

In severe cases of listeriosis, bacteria can spread to the central nervous system and cause seizures, according to Health Canada.

“The last two months have really been a nightmare,” says Desmond, who has joined the proposed lawsuit.

When he returned home from the hospital, his daughter took a carton of Silk dark chocolate almond milk out of the fridge and asked if he had heard about the recall. By that point, Desmond says he was on his second two-litre carton after finishing the first in June.

“It was pretty scary. Terrifying. I honestly thought I was going to die.”

Cheryl McCombe, 63, Haliburton, Ont.

The morning after suffering a second episode of vomiting, feverish sweats and diarrhea in the middle of the night in early July, Cheryl McCombe scrolled through the news on her phone and came across the recall.

A few years earlier, McCombe says she started drinking plant-based milks because it seemed like a healthier choice to splash in her morning coffee. On June 30, she bought two cartons of Silk cashew almond milk.

“It was on the (recall) list. I thought, ‘Oh my God, I got listeria,’” McCombe says. She called her doctor’s office and visited an urgent care clinic hoping to get tested and confirm her suspicion, but she says, “I was basically shut down at the door.”

Public Health Ontario does not recommend listeria testing for infected individuals with mild symptoms unless they are at risk of developing severe illness, such as people who are immunocompromised, elderly, pregnant or newborn.

“No wonder they couldn’t connect the dots,” she adds, referencing that it took close to a year for public health officials to find the source of the outbreak.

“I am a woman in my 60s and sometimes these signs are of, you know, when you’re vomiting and things like that, it can be a sign in women of a bigger issue,” McCombe says. She was seeking confirmation that wasn’t the case.

Disappointed, with her stomach still feeling off, she says she decided to boost her gut health with probiotics. After a couple weeks she started to feel like herself.

But since then, McCombe says, “I’m back on Kawartha Dairy cream in my coffee.”

This report by The Canadian Press was first published Sept. 16, 2024.

Canadian Press health coverage receives support through a partnership with the Canadian Medical Association. CP is solely responsible for this content.

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B.C. mayors seek ‘immediate action’ from federal government on mental health crisis

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VANCOUVER – Mayors and other leaders from several British Columbia communities say the provincial and federal governments need to take “immediate action” to tackle mental health and public safety issues that have reached crisis levels.

Vancouver Mayor Ken Sim says it’s become “abundantly clear” that mental health and addiction issues and public safety have caused crises that are “gripping” Vancouver, and he and other politicians, First Nations leaders and law enforcement officials are pleading for federal and provincial help.

In a letter to Prime Minister Justin Trudeau and Premier David Eby, mayors say there are “three critical fronts” that require action including “mandatory care” for people with severe mental health and addiction issues.

The letter says senior governments also need to bring in “meaningful bail reform” for repeat offenders, and the federal government must improve policing at Metro Vancouver ports to stop illicit drugs from coming in and stolen vehicles from being exported.

Sim says the “current system” has failed British Columbians, and the number of people dealing with severe mental health and addiction issues due to lack of proper care has “reached a critical point.”

Vancouver Police Chief Adam Palmer says repeat violent offenders are too often released on bail due to a “revolving door of justice,” and a new approach is needed to deal with mentally ill people who “pose a serious and immediate danger to themselves and others.”

This report by The Canadian Press was first published Sept. 16, 2024

The Canadian Press. All rights reserved.

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