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A young woman with fever and polyserositis caused by familial Mediterranean fever




  • Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disorder; it is characterized by self-limited episodes of fever, polyserositis and elevated inflammatory markers.

  • While symptoms are nonspecific, FMF should be suspected in patients with recurrent febrile episodes accompanied by peritonitis, pleuritis, pericarditis and elevated C-reactive protein, especially among people of Ashkenazi Jewish descent and other at-risk ethnic groups.

  • Treatment with colchicine prevents clinical flares and the amyloidosis and renal failure that can be associated with the disease.

  • Delayed diagnosis can have grave consequences for patients, including unnecessary surgeries and associated complications.

In 2015, a 28-year-old woman of Ashkenazi Jewish descent presented to the medical genetics clinic with concerns about flexible joints, easy bruising, stretchable skin, chronic back pain and mild scoliosis since childhood. Differential diagnoses included connective tissue disorders such as Ehlers–Danlos (EDS), Marfan and Loeys–Dietz syndromes. She had an elevated Beighton score (6/9), reflecting joint hypermobility, and none of the features consistent with Marfan syndrome or Loeys–Dietz syndrome. Her echocardiogram was normal and her family history was unremarkable. A 13-gene panel was negative for EDS, and she was given a clinical diagnosis of hypermobile EDS.

Over the next 5 years, the patient developed recurrent episodes of fever, elevated C-reactive protein (CRP), abdominal pain and other symptoms (Table 1). Although most episodes lasted 1–3 days, the patient often noted recurrence or worsening of symptoms after interventions, such as fever or abdominal pain after various surgeries.

Table 1:


Chronology of events for a 28-year-old woman with familial Mediterranean fever

In 2016, the patient had an ovarian cystectomy for suspected ovarian torsion (no torsion found), an appendectomy for suspected appendicitis (no appendicitis found) and an endoscopic retrograde cholangiopancreatography with stent placement for presumed chronic pancreatitis. In 2017, she received diagnoses of cholecystitis, chronic pancreatitis and malnutrition, which led to a cholecystectomy and central line placement for total parenteral nutrition. She also had chest pain and shortness of breath with pleural effusions; presumed volvulus, which led to emergency laparotomy, with no evidence of volvulus intraoperatively; and thrombophlebitis of the internal jugular vein. Intermittent abdominal pain, distension and nausea were attributed to colonic dysmotility related to hypermobile EDS. She had serious malnutrition, and her body mass index dropped from 20.3 to 15.8, which led to placement of a gastrojejunostomy tube to support enteral feeds and avoid complications associated with prolonged total parenteral nutrition.

The patient’s clinical status deteriorated through 2018, with flares of abdominal pain, constipation and feeding intolerance, which continued to be attributed to colonic dysmotility secondary to hypermobile EDS. Gram-negative enteric bacteria were identified on blood cultures twice, and were attributed to the impact of her EDS on the integrity of the bowel wall leading to bacterial translocation. Total colectomy and ileostomy were performed, followed by prolonged recovery, with recurrent fevers, elevated CRP and abdominal pain. After a period of stability, reversal of her ileostomy with J-pouch formation was complicated by postoperative abdominal pain, fever and elevated CRP. In 2019, she had episodes of left lower quadrant pain and tenesmus, diagnosed as pouchitis and managed with antibiotics. In 2020, the patient had episodes of pelvic pain and fever lasting 2–3 days, elevated inflammatory markers, pericardial effusion, hepatosplenomegaly and blood cultures positive for Escherichia coli. She was given a diagnosis of urosepsis and prescribed antibiotics.

In 2020 the patient sought a genetics reassessment. No clinical diagnosis was made; however, it was thought that her history could not be explained by hypermobile EDS. A geneticist ordered whole exome sequencing, which found compound heterozygous pathogenic DNA variants in the MEFV gene, namely c.2084A>G (p.Lys695Arg) and c.2177T>C (p.Val726Ala), consistent with familial Mediterranean fever (FMF).

The patient was referred to a rheumatologist and started on colchicine 0.6 mg once a day. During the 2 years since she started taking colchicine, she has had 2 mild, self-resolving flares of FMF that did not require hospital admission or intervention. She has returned to her baseline strength and nutritional status, and has stopped all other medications. She has no evidence of renal amyloidosis; her serum creatinine (71 mmol/L) and urea (4.4 mmol/L) are within normal ranges, and she has no protein in her urine.


Familial Mediterranean fever is the most common monogenic autoinflammatory disorder; it is characterized by self-limited episodes of fever, polyserositis and elevated inflammatory markers.14 The condition is associated with gain-of-function sequence variations in the MEFV gene that encodes for the pyrin protein, and results in uncontrolled production of interleukin-1β and an exaggerated inflammatory response.1,2,4 The disease manifests as recurrent bouts of fever, abdominal pain and chest pain that start abruptly and peak soon after onset, last for 1–4 days and then resolve spontaneously. Patients typically have no symptoms between attacks.2 Familial Mediterranean fever should be considered for patients who have undergone laparotomy or laparoscopy with no pathology identified. Stress, cold exposure, fat-rich meals, infections, vigorous exercise, surgery and the menstrual cycle may all provoke an attack. Familial Mediterranean fever may present uncommonly as erysipelas-like erythema, aseptic meningitis, recurrent urticaria or vasculitis.3

Laboratory abnormalities during attacks are nonspecific and include elevated systemic markers of inflammation, leukocytosis with neutrophilia, and elevated erythrocyte sedimentation rate, CRP and fibrinogen. Serum amyloid A protein is also elevated during attacks, but is not routinely measured unless a diagnosis of FMF is suspected.3 One of the long-term complications of untreated disease is amyloidosis of the kidneys, which has been reported to be present in about 12% of patients with FMF; it can have severe complications, including renal failure. 1,2 Amyloidosis may also develop in the spleen, liver, gastrointestinal tract, thyroid and testes. Small bowel obstruction may develop because of recurrent peritonitis and adhesion formation. Before colchicine was used in the treatment of FMF, infertility was common and was thought to be caused by obstruction of fallopian tubes in females and testicular amyloidosis in males.2,3

Familial Mediterranean fever is common in people of Ashkenazi Jewish descent, with a substantial gene carrier rate (about 1:7.8).5 The prevalence is about 1 in 500 to 1 in 1000 among people of other at-risk ethnic descents, including those of Turkish, Armenian, Arabic, non-Ashkenazi Jewish, North African, Italian, Greek, Chinese and Japanese ancestry. Known risk factors include family history of FMF, present in 30%–50% of people with the condition, and belonging to an at-risk ethnic group.6 More than 95% of genetic carriers are asymptomatic; however, some individuals with a single mutation may manifest symptoms and may benefit from treatment with colchicine.1

Our patient’s many episodes of fever and abdominal pain led to different diagnoses, invasive procedures and complications. Intraoperative findings and postoperative pathology reports were often inconsistent with the initial diagnosis of hypermobile EDS, and hospital admissions were prolonged owing to postoperative flares of pain, fever and elevated CRP. Over the course of her illness, treating clinicians appeared not to have considered FMF.

Hypermobile EDS is the mildest subtype of EDS, with no life-threatening complications, although patients with hypermobile EDS can have various types of gastroesophageal dysmotility such as esophageal dysmotility, gastroparesis, small bowel or colon altered transit time or global dysmotility.7 However, unlike the vascular EDS subtype, hypermobile EDS does not cause bowel wall fragility or rupture. Genes for hypermobile EDS have not yet been identified. Vascular EDS and other EDS subtypes were highly unlikely in this patient, given her negative results from genetic testing. Hypermobile EDS would not explain this patient’s symptoms, except perhaps colonic dysmotility.7

After the patient developed new symptoms in 2015, genetics specialists were not consulted again until the patient requested a follow-up in 2020. She qualified for whole genome sequencing based on the Ministry of Health of Ontario’s testing criteria of severe functional impairment, multisystem involvement and progressive clinical course. When FMF or another periodic fever syndrome is suspected, a gene panel for periodic fever syndromes can identify pathogenic DNA variants. When variants of unknown clinical importance or single pathogenic DNA variants are found, a diagnosis can still be made based on clinical findings, with the help of diagnostic criteria such as the Eurofever-PRINTO classification criteria.1,8 Whole genome sequencing can be useful in patients with severe multisystem involvement, even in the absence of a clear diagnosis. A patient may also have more than 1 genetic disorder, as in our patient with FMF and hypermobile EDS.

Most patients with FMF are symptomatic by age 20 years.4 In hindsight, the patient had fevers with severe abdominal pain a few times a year, starting in early childhood. Familial Mediterranean fever should be considered in a differential for recurrent fevers, peritonitis and elevated CRP (Table 2).

Table 2:

Differential diagnosis for patients with periodic fevers and elevated inflammatory markers

Treatment with colchicine is effective, preventing FMF flares in more than 60% of patients and reducing the number of attacks in a further 20%–30% of patients. Colchicine can also prevent deposition of amyloid fibrils and subsequent renal failure.24,7,9 Anti–interleukin-1 biological therapy can be used in patients unresponsive to colchicine.24

The symptoms of FMF can mimic other conditions and, unfortunately, patients with FMF often experience years of misdiagnosis, unnecessary surgeries and prolonged hospital admissions. 4,6,10 Delays in diagnosis likely occur because of the lack of specificity in symptoms, and the relapsing and remitting pattern of disease. Furthermore, clinicians may not consider the disease in at-risk ethnic populations.4

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


  • 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 article. Kayla Richard and Sara Glazer drafted the first version of the manuscript and have contributed equally. All of the authors revised the manuscript 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:



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Anxiety, your brain, and long Covid: What the research says







Having anxiety and depression before a Covid infection increases the risk of developing long Covid

ISLAMABAD, (ONLINE) – Anxiety, depression, and Covid-19 can be a bad combination for your brain — and your long-term health.

Having anxiety and depression before a Covid infection increases the risk of developing long Covid, researchers have found.

Those with long Covid who develop anxiety and depression after an infection may have brain shrinkage in areas that regulate memory, emotion, and other functions as well as disruption of brain connectivity.

While many questions remain about these intertwined relationships, the associations aren’t a complete surprise. Experts already know that depression and anxiety are associated with inflammation and immune dysfunction, perhaps helping to explain the link between these mental health conditions, the risk of long Covid, and the changes in the brain.

Brain changes accompanying a Covid infection have concerned researchers since earlier in the pandemic, when U.K. Biobank researchers found brain atrophy, loss of grey matter, and decline in cognition in those infected with Covid compared with those not infected.

Common conditions

The ramifications of the research linking anxiety, depression and long Covid are far-reaching. According to the CDC, 12.5% of U.S. adults have regular feelings of anxiety (as well as nervousness and worry), and the latest Gallup Poll found that nearly 18% of adults currently have or are being treated for depression.

Managing symptoms of long Covid

WebMD’s Chief Medical Officer, John Whyte, MD, MPH, speaks with Janna Friedly, MD, MPH, a professor of physical medicine and rehabilitation at the University of Washington, about managing the symptoms of long Covid and her personal journey of recovery.

As of May 8, 10% of U.S. infected adults have long Covid, according to the CDC, and among U.S. adults ever infected, 27% have reported long Covid. Long Covid has been defined by the CDC as symptoms such as fatigue, brain fog, and cough that persist longer than 4 weeks and by the World Health Organization as symptoms persisting for 3 months or more.

Here’s a roundup of what the research shows about mental health and long Covid risk — along with other research finding that paying attention to health habits may reduce that risk.

Pre-existing depression, anxiety, and long Covid risk

A history of mental health issues — including depression, anxiety, worry, perceived stress, and loneliness — raises the risk of long Covid if infection occurs, Harvard researchers have found.

The researchers evaluated data from three large, ongoing studies including nearly 55,000 participants to determine the effects of high levels of psychological distress before a Covid infection.

“Our study was purely survey based,” said Siwen Wang, MD, the study’s lead author and a research fellow at Harvard’s T.H. Chan School of Public Health at Harvard University.

At the start of the survey in April 2020, none of the participants reported a current or previous Covid infection. They answered surveys about psychological distress at the start of the study, at 6 monthly time points, then quarterly until November 2021.

Over the follow up, 3,193 people reported a positive Covid test and 43% of those, or 1,403, developed long Covid. That number may seem high, but 38% of the 55,000 were active health care workers. On the final questionnaire, they reported whether their symptoms persisted for 4 weeks or longer and thus had long Covid by the standard CDC definition.

Wang’s team then looked at the infected participants’ psychological status. Anxiety raised the risk of long Covid by 42%, depression by 32%, worry about Covid by 37%, perceived stress, 46%, and loneliness, 32%.

Covid patients with a history of depression or anxiety are also more likely than others to report trouble with cognition in the weeks after a Covid infection and to develop brain fog and long Covid, UCLA researchers found. They evaluated 766 people with a confirmed Covid infection; 36% said their thinking was affected within 4 weeks of the infection. Those with anxiety and depression were more likely to report those difficulties.

Long Covid, then anxiety, depression, brain changes

Even mild cases of Covid infection can lead to long Covid and brain changes in those who suffer anxiety or depression after the infection, according to Clarissa Yasuda, MD, PhD, assistant professor of neurology at the University of Campinas in Sao Paulo, Brazil. She has researched long Covid’s effects on the brain, even as she is coping with being a long Covid patient.

In one of her studies, presented at the 2023 American Academy of Neurology meeting in April, she found brain changes in people with anxiety, depression, and Covid but not in those infected who did not have either mental health issue. She evaluated 254 people, median age 41, after about 82 days from their positive PCR test for Covid. Everyone completed a standard questionnaire for depression (the Beck Depression Inventory) and another for anxiety (the Beck Anxiety Inventory). She further divided them into two groups — the 102 with symptoms and the 152 who had no symptoms of either depression or anxiety.

Brain scans showed those with Covid who also had anxiety and depression had shrinkage in the limbic area of the brain (which helps process emotion and memory), while those infected who didn’t have anxiety or depression did not. The researchers then scanned the brains of 148 healthy people without Covid and found no shrinkage.

The atrophy, Yasuda said, “is not something you can see with your eyes. It was only detected with computer analysis. Visualization on an MRI is normal.”

The number of people in this study with mental health issues was surprisingly high, Yasuda said. “It was intriguing for us that we noticed many individuals have both symptoms, anxiety and depression. We were not expecting it at that proportion.”

The researchers found a pattern of change not only in brain structure but in brain communication. They found those changes by using specialized software to analyze brain networks in some of the participants. Those with anxiety and depression had widespread functional changes in each of 12 networks tested. The participants without mental health symptoms showed changes in just 5 networks. These changes are enough to lead to problems with thinking skills and memory, Yasuda said.

Explaining the links

Several ideas have been proposed to explain the link between psychological distress and long Covid risk, Wang said. “The first and most mainstream mechanism for long Covid is chronic inflammation and immune dysregulation,” she said. “Several mental health conditions, such as anxiety and depression, are associated with inflammation and dysfunction and that might be the link between depression, anxiety, and long Covid.”

Another less mainstream hypothesis, she said, is that “those with long Covid have more autoantibodies and they are more likely to have blood clotting issues. These have also been found in people with anxiety, depression, or other psychological distress.”

Other researchers are looking more broadly at how Covid infections affect the brain. When German researchers evaluated the brain and other body parts of 20 patients who died from non-Covid causes but had documented Covid infections, they found that 12 had accumulations of the SARS-CoV-2 spike protein in the brain tissue as well as the skull and meninges, the membranes that line the skull and spinal cord. Healthy controls did not.

The findings suggest the persistence of the spike protein may contribute to the long-term neurological symptoms of long Covid and may also lead to understanding of the molecular mechanisms as well as therapies for long Covid, the researchers said in their preprint report, which has not yet been peer-reviewed.



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New treatment shows promise for some women with cervical cancer




Toronto, June 4

A simple hysterectomy, a surgical procedure where the uterus and cervix is removed, is a safe treatment option that can improve quality of life for women with early-stage, low-risk cervical cancer, according to results from the phase III clinical trial.

The study states that a simple hysterectomy resulted in similar outcomes in terms of keeping them cancer-free, compared to the standard radical hysterectomy, which removes the uterus, cervix, upper parts of the vagina and other nearby tissues.


Because radical hysterectomy is a more complex surgery, it is associated with more acute and long-term side effects, as well as potential impacts on quality of life and sexual health for patients.

“Sexual health and quality of life are very important considerations for patients undergoing cancer treatment,” said Dr. Lori Brotto, a professor of obstetrics and gynaecology at University of British Columbia.

“The findings from this study indicate that patients can expect fewer negative effects on sexual health and many other facets of quality of life with simple hysterectomy while not compromising effects on recurrence and survival rates,” Brotto added.

The study looked at the three-year pelvic recurrence rate and other health outcomes in 700 patients from 12 countries receiving both simple and radical hysterectomies.

The findings, presented at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting, showed that the extra-pelvic recurrence-free survival, the relapse-free survival, and the overall survival were comparable between the two groups.

There were fewer intraoperative urological surgical complications and fewer immediate and long-term bladder problems in the simple hysterectomy group.

Several quality-of-life aspects, such as body image, pain, and sexual health, were consistently more favourable in them.

“These results are important because it demonstrates, for the first time, that a simple hysterectomy is a safe option for women with carefully selected early-stage low-risk cervical cancer,” said Dr. Marie Plante, the study lead and a gynecologic oncologist at Universite Laval in Quebec.

“This trial will likely be practice-changing, with the new standard-of-care treatment for patients with low-risk disease being a simple hysterectomy instead of radical hysterectomy.” Worldwide, cervical cancer is the fourth most diagnosed cancer and fourth most common cause of cancer death in women.

About 44 per cent of women with cervical cancer are diagnosed with early-stage disease, of which a significant proportion will meet low-risk criteria, according to the team.

When detected at an early stage, the 5-year relative survival rate for invasive cervical cancer is 92 per cent.




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AstraZeneca’s Tagrisso slashes death risk in certain post-surgery lung cancer patients



By Natalie Grover

LONDON (Reuters) – AstraZeneca’s lung cancer therapy, Tagrisso, cut the risk of death by more than half in patients with a certain form of lung cancer who were diagnosed early enough to have their tumour surgically removed, trial data showed.

Tagrisso is already the crown jewel in the Anglo-Swedish drugmaker’s portfolio, raking in $5.4 billion last year.

The drug has regulatory approvals across multiple geographies for certain patients with so-called non small cell lung cancer (NSCLC) who have a mutation of the EGFR gene.


The latest data, presented at the American Society of Clinical Oncology (ASCO) meeting, establishes Tagrisso as the backbone treatment for EGFR-mutated lung cancer, said Susan Galbraith, executive VP of oncology R&D at AstraZeneca in a statement.

In a 682-patient trial called ADAURA, Tagrisso was evaluated against a placebo in earlier-stage EGFR-mutated NSCLC patients who had undergone surgery to remove their primary tumour.

The majority of such patients eventually see their cancer return despite surgery and add-on chemotherapy.

In the trial, Tagrisso or a placebo was given to patients to assess whether the AstraZeneca therapy could keep their cancer at bay.

Data showed Tagrisso slashed the risk of death by 51% compared to placebo.

“This is a pretty dramatic and remarkable improvement,” said Dave Fredrickson, executive vice president of oncology at AstraZeneca in an interview with Reuters.

An estimated 88% of patients treated with Tagrisso were alive at five years compared to 78% on placebo, trial data also showed.

Outside of chemotherapy, there are no drugs apart from Tagrisso that have shown to help patients with EGFR-mutated lung cancer live longer, Fredrickson highlighted, adding that there are probably a third of eligible patients who are not yet being prescribed Tagrisso.

“We would hope that we would be able to use these data to be able to close that gap,” he said.

AstraZeneca is also expecting to provide details on the impact of combining Tagrisso with chemotherapy in patients with advanced EGFR-mutated lung cancer later this year.

(Reporting by Natalie Grover in London; Editing by Angus MacSwan)



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