enigma
The death of his father has always been a mystery.
In 1993, Lin Teng was 10 years old. Looking back now, many of the scenes in his memory had faded, but he remembered it very clearly that day.
In the village in the north of his hometown of Anhui, it was cold in the waxing moon, and his father went out to guard the orchard for others, and when he went out, he was no different from usual, and he was sent home at night, but he lost his breath.
Lin Teng heard Uncle Da say that his father was "choked to death."
"His throat was swollen so badly that he went to a nearby clinic, and the doctor thought it was an inflammation of the tonsils, prescribed some anti-inflammatory drugs, and told him to go back." After taking the medicine, the person was still uncomfortable, and ran to the clinic to shoot the door to call people, and when the doctor came out, the person could not be saved. In just a few words, he finished talking about his father's last encounter.
Uncle Da remembers that his father fell ill suddenly like this, once when he was not married, "a large blister appeared in his throat, and his face turned purple." Only that time there was no danger, and the "blister" slowly disappeared.
Families have become accustomed to avoiding the topic of their father's death. "When people ask about their father's death, we can't answer it, we can only say strange diseases, and people suddenly disappear."
What the "strange disease" is, no one can tell clearly, Lin Teng can only try his best to recall his father's daily life, remember his habits and experiences, try to piece together the reason at a certain moment, know how his life was taken.
In Lin Teng's memory, his father's stomach ached frequently, and it was common for him to vomit. This disease does not look strange, including the mother, everyone thinks that he is suffering from a "stomach disease", and he has been given many Chinese medicines. Curiously, he also often had swollen hands and feet, "swollen to the point of light transmission, and the epidermis was stretched open, very large and bright, like a bun." ”
At the age of 25, Lin Teng found that he also had swelling in the body, just like his father had done.
At that time, he had left his hometown to make a living in Zhejiang and became a seaman. He found that whenever he used a wrench, screwdriver and other tools to pull or twist hard, the palm of his hand was oppressive, and his hand would swell up at night or the next day, and after a day or two, the swelling would subside. This happens three or four times in a year.
Lin Teng went to the hospital in Hangzhou for allergen screening, and the test results were negative. The doctor prescribed ketotifen fumarate tablets (Note: over-the-counter medicine for allergic rhinitis, allergic bronchial asthma) and instructed him to take it when swelling occurred, he used it several times, but felt that there was no effect.
In the next five or six years, when he encountered swelling of his hands and feet, Lin Tengdu could only wait for the swelling to subside on its own. It wasn't until 2013, once again, that "his hands were swollen like a toad," that his wife took him to a dermatologist he knew and asked what other directions were being taken.
After hearing the symptoms, the doctor took out a thick book, lin Teng saw, he looked through the chapter is "hereditary angioedema", which has a sentence that reads: "May cause fatal laryngeal edema." ”
(Lin Teng's swollen hands.) Patient courtesy of)
Lin Teng immediately thought of his father, and he suspected that his father had this disease, and he was the same. But the first time the doctor came into contact with such a case, he did not know how to diagnose and treat it, and after getting the "clue", Lin Teng could only check the Internet for information about "hereditary angioedema".
He found a QQ group with the same name, there were only more than ten people in the group, the group leader was from Yanbian, Jilin Province, he claimed to be a patient diagnosed with hereditary angioedema, and told Lin Teng: "You must go to Peking Union Medical College Hospital to find Professor Zhang Hongyu, only he can be diagnosed in the country." ”
Lin Teng was half-convinced of his firm advice, and he was a little worried that he was a "medical trust" and had not acted. Until the end of the year, the palm of his hand was swollen again, his fingers were as thick as carrots, and he couldn't even grasp and hold the action, "The mood suddenly fell, and I wanted to know what was wrong with it." He made up his mind that no matter what the result was, he would go to Zhang Hongyu to have a look.
(Lin Teng's swollen hands.) Patient courtesy of)
He still remembers the day he was diagnosed. "Dr. Zhang opened the door and looked out and asked if the person with hereditary angioedema had come." There were many people lining up outside the clinic, but Lin Teng was directly called in, "He knows that we are special patients." ”
It has been 20 years since my father's death, and that is the moment when the mystery is solved, and it is like the moment when fate is pronounced. Lin Teng specially turned on the mobile phone recording, not wanting to miss any word from the doctor.
Zhang Hongyu looked at the blood test list and told Lin Teng that he was suffering from "HAE", that is, hereditary angioedema.
He prescribed him the drug "danazole", this weak androgen has a preventive effect on HAE, Lin Teng groped for the right dosage for himself, currently taking two pills a week, basically no longer sick.
Good luck and regret
If HAE only "slightly punched and kicked" on Lin Teng, then when it pounced on Chen Lichong, it almost devoured him like a beast.
Chen Lichong, who was born in 1978, had swollen skin as early as the age of 8. "At that time, in the rural hometown of Hebei, the first swelling was the genital area, and the doctors in the village could not see what was wrong, nor did it hurt, generally the swelling returned to normal in two days, and the family did not care."
By the age of seventeen or eighteen, Chen Lichong's swelling became more frequent, swelling six or seven times a year, and the location of the swelling was not certain, sometimes swollen hands, feet, and sometimes gastrointestinal edema, onset, vomiting and diarrhea, unable to eat.
"In those years, I was already disheartened with this disease. In my hometown of Baoding, I have visited almost every hospital, but I can't find the cause. Chen Lichong said that swelling often occurs in only one part at a time, such as swelling one arm or one leg, and at the age of 25, there was a severe swelling, and both legs bulged up, like a balloon blowing up. He was afraid in his heart, so he went to Peking Union Medical College Hospital to register his number.
Two swollen legs, after two days, the swelling automatically subsided. Chen Lichong did not wait for the test results to come out and returned to his hometown to ask his friends to help get the test report. The doctor read the report and instructed his friend: "This disease, swollen everywhere is fine, that is, the neck can not be swollen, if the neck is swollen, you must go to the hospital." ”
(Swollen feet.) Patient courtesy of)
In the next five years, Chen Lichong experienced repeated swelling. The gastrointestinal edema was unbearable, so he went to the hospital to beat the hanging bottle, and his feet were so swollen that he could not wear shoes, so he applied anti-swelling and dredging medicine and lay down at home to rest. He no longer expects to treat or relieve the pain of the swelling, and only tries to "make peace" with it, "as long as it does not delay my life, I will leave it alone." ”
In 2008, when he encountered a toothache, Chen Lichong took a pill according to the soil method of his hometown (Note: he later learned that the contraceptive pill was a banned drug for HAE patients).
"At first, it was just swollen gums, but then the whole face and the whole head swollen up, and when I slept at night, I felt panicked and unevenly breathed." He remembered that the doctor had instructed that once the head was swollen, it was likely to swell to the neck, and he should rush to the hospital emergency room early and be prepared to cut the trachea when he was not breathing well. At two o'clock in the morning, his wife drove him to the hospital.
When he went through the hospitalization procedures, Chen Lichong's head had already doubled in size, "I'm afraid this pass will not pass." He began to explain the aftermath to his friends around him, and without saying a few words, he could not hold his breath, his eyes were black, he fainted in the hospital room, and when he woke up, he saw that his clothes had been cut open and a tube had been inserted around his neck.
After walking through the ghost gate, Chen Lichong, on the one hand, felt that he was lucky, and on the other hand, he felt that "his heart has become 'small'." In the past, he always treated "swelling" as improper, but now he was desperate to find out what kind of disease he had.
Listening to the doctors in Baoding, he said that to see this disease, he also got the registration of the Department of Immunology or Allergy department of Peking Union Medical College Hospital. Just happened to encounter a swollen hand, he found Dr. Zhi Yuxiang of Peking Union Medical College Hospital, Zhi Yuxiang is a student of Zhang Hongyu, she has seen the blood test report, and it was confirmed that Chen Lichong's disease is HAE, which has passed 22 years since his first onset.
Unlike the ease with which most patients seek medical treatment for many years and are diagnosed, Yu Lin feels more regret. Her mother died four years ago, also because of HAE.
"My mother often had stomach pains, which the doctor explained were neurotic, and we could only understand it that way." Yu Lin said: "That time she had a more serious swelling, swollen to the face, went to the hospital to get hormones and came home, and then had a seizure in the early morning, swollen to the throat, causing suffocation." ”
Yu Lin has always believed that the death of her mother was related to her low mood and decreased immunity at that time. What she did not expect was that her mother's frequent stomach pain and the choking throat that took her life were caused by the same cause. She also did not know that the swelling of her hands and feet, stomachache and mother's symptoms that she had been experiencing since middle school also stemmed from the same disease.
Until May this year, her sister accidentally pushed An article published on the WeChat public account "Run Shaw Hospital" for Yu Lin, "What disease is so bizarre?" For 30 years, no doctor can diagnose it clearly", the text describes: "When Aunt Zhang's pain attacked, the colic around the navel was like a towel, and nothing could be eaten, and when it was eaten, it would vomit, and the water in the stomach would run out, and after a few days the abdominal pain improved, the ascites in the stomach would also disappear...
Another strange phenomenon is that Aunt Zhang often has edema in the limbs, eyes, mouth and other places. After Yu Lin saw it, she felt that the symptoms were very similar to her own symptoms when she was ill, so she went to Hangzhou Run Hospital for examination and was finally diagnosed with HAE.
At this time, it had been more than 30 years since Yu Lin's first swelling. She realized that her mother, like herself, was a HAE patient.
"My mother has also had a swollen face before, and usually the swelling will slowly subside. That time, no, without understanding the severity of the disease, we took our mother home from the hospital, which led to the worst outcome, which I always felt was the biggest regret. ”
hide
HAE patients are an "absolute minority", there are only about 500 patients in the country's clear diagnosis and treatment, and according to foreign literature, the incidence of HAE is about 1.5/100,000 [1], which also means that nearly 200,000 people with HAE may not know the danger of the disease, which may lead to tragedy.
In 1888, Dr. William Osler, the father of modern medicine, first described HAE, saying that "the disease has a very strong genetic predisposition, edema can occur in any part, with limitations, accompanied by gastrointestinal symptoms", arguing that the cause of the disease is unclear. With the understanding of C1-inhibitor (C1-INH)[3], the medical community has gradually gained an in-depth understanding of the pathogenesis of HAE.
In the article "Expert Consensus on the Diagnosis and Treatment of Hereditary Angioedema" published in the Chinese Journal of Clinical Immunology and Allergy in 2019, hae is due to mutations in C1-INH, FXII, ANGPTI, and PLG genes, resulting in corresponding protein levels and/or functional abnormalities, which in turn causes elevated levels such as bradykinin, telangiectasia, and ultimately leads to the occurrence of edema.
According to the different pathogenic mechanisms, HAE is currently divided into C1-INH deficiency type (HAE-C1-INH) and non-C1-INH deficiency type (HAE-nC1-INH) internationally. The pathogenesis of HAE-C1-INH type is due to the lack of C1-INH protein concentration or functional defects caused by mutations in the C1-INH gene, and is clinically divided into types 1 and 2.
The concentration and function of C1-INH decreased in patients with HAE1 type, accounting for about 85%, and the concentration of C1-INH in PATIENTS with HAE2 type was normal or increased, but the function was reduced, accounting for about 15%.
Because it is an autosomal dominant disorder, the probability of their children suffering from HAE is 50%. Studies have found that 75% of HAE cases occur genetically, and 25% of development is due to genetic mutations[2].
Patients with HAE usually develop the disease before the age of 30 years, worsen during puberty, and are characterized by recurrent, unpredictable submucosal edema, which often presents with acute onset and usually resolves naturally within 3 to 5 days.
Its onset is associated with minor trauma, mood swings, infections, sudden changes in temperature, and menstruation, estrogen-based contraceptives, etc. Edema can occur anywhere in the body and is common in the extremities, face, genitals, respiratory tract, and gastrointestinal mucosa.
The most dangerous episode is respiratory edema, that is, laryngeal edema, if rescue is not timely, can lead to suffocation death, the average time from edema to asphyxia is 4.6 hours, about 58.9% of HAE patients in mainland China have experienced laryngeal edema, and the fatality rate can reach up to 40%.
This is also the reason why the doctor repeatedly told the confirmed patients that "the swelling is fine, that is, the neck cannot be swollen". Zhang Hongyu, a professor at Peking Union Medical College Hospital, diagnosed the first case of hereditary angioedema in China in the 1980s, and since then he has been paying attention to the HAE patient population. In 2015, Zhang Hongyu died, and his student Zhi Yuxiang took over the burden of running for HAE.
Because HAE is relatively rare, the public and doctors have low awareness of it, patients are often misdiagnosed, mistreated, especially when edema occurs in the gastrointestinal tract, there will be similar manifestations of acute abdomen, often misdiagnosed as appendicitis, etc., resulting in unnecessary abdominal surgery in the emergency department. Studies by Peking Union Medical College Hospital show that it takes 12.64 years for HAE patients to go from onset to definitive diagnosis.
Before being diagnosed, Yu Lin had been diagnosed with pelvic inflammatory disease by gynecology and injected anti-inflammatory drugs to "combat" the pain of gastrointestinal edema. In fact, she has long found that the drug does not work for her illness, "in the end, she can only hide at home, vomit all day, and then fall asleep, do not eat or drink, and slowly survive until it is not painful." ”
Another confirmed patient, Qin Lu, was diagnosed with pancreatitis by the Department of Internal Medicine, "The doctor saw that I had a 'effusion' in my stomach, arranged for me to be hospitalized, prepared for surgery, and as a result, when the effusion was withdrawn the next day, it was found that it could not be drawn, and at that time the gastrointestinal edema had subsided." Qin Lu was "lucky" to escape the caesarean probe.
Wang Huiying, deputy director of the Department of Allergy at the Second Affiliated Hospital of Zhejiang University School of Medicine, had seen HAE cases of caesarean section seven times when she was reading the literature, but still had not found out what kind of disease she was suffering from. She was worried about the experiences of these patients, but for a long time she could not find a way to help them.
Ten years ago, Wang Huiying was first exposed to HAE cases, and a female patient claimed to be a patient with hereditary angioedema and wanted to ask Wang Huiying to prescribe weak androgens for prevention.
That was the first time Wang Huiying heard about HAE, she felt strange, consulted a lot of literature, since then met patients with suspected symptoms, she suggested that they go to Peking Union Medical College Hospital for diagnosis, Peking Union Medical College Hospital Allergy Department was once the only department in China that can diagnose HAE.
However, after the patient was diagnosed, the situation that there was no cure at that time made Wang Huiying feel helpless. Treatment of HAE is divided into acute exacerbation treatment and preventive treatment. In the absence of drugs for the treatment of acute onset of HAE in the country, the edema can only be resolved by the import of lyophilized new plasma.
Because HAE is a rare disease and is also plagued by a shortage of blood in the hospital, Wang Huiying's team's attempt to apply plasma for patients has never been successful. Preventive treatment drugs weak androgens have side effects that lead to female masculinization, menstrual disorders, osteoporosis, emotional instability, obesity, etc., so many female HAE patients resist taking it.
After diagnosis, many HAE patients, even if they can learn to accept frequent swelling and reach a reconciliation with the body, they inevitably find themselves different from ordinary people at some moments and fall into depressed emotions again.
For Chen Lichong, this moment occurred in his hometown village, and when people asked about his condition, "I can only take one sentence and reply that I have been optimistic about xiehe hospital." "If the people in the village hear that this is a hereditary disease, they will naturally have prejudices and be bad for (my) children." ”
For Yu Lin, this moment occurred when she was cared for by relatives and friends. "When my mother was alive, we often told her not to be too tired, to be careful when eating, and always thought that she was sick because she did not take good care of herself, and it was inevitable that she would preach to her.
Now I realize that this kind of preaching out of concern actually creates a kind of mental stress in the patient. Yu Lin said: "This makes me always remember that I am a patient, and I am always worried that the next time I go out, edema will occur again." ”
For Lin Teng, this moment occurred when he was discussing with his wife whether to have a second child. His wife decisively rejected his proposal to "have a second child" because of the "fear that the child inherited HAE".
Because of these moments, they prefer to hide themselves and selectively forget that they are a "HAE patient" when they are not sick.
see
Qin Lu does not like to "wait", and he wants to take the initiative to win the attention of the outside world for HAE patients. "This group is actually very large, but the outside world can't find us." "I want more people to know where we are," he said. ”
The appearance of the swelling attack is a "scar" that many HAE patients do not want to mention, but Qin Lu is willing to describe to people what he looked like when he was onset, which he felt would help potential patients recognize the symptoms that occurred to them.
(When Qinlu swelling occurs.) Patient courtesy of)
"Liang Chaowei's appearance in "East Becomes West", sausage mouth, big ears, that can only be regarded as the early stage of my edema." Among all kinds of swelling, the most difficult for Qin Lu to accept is "facial swelling", "if the whole face is swollen, it is much more serious than the HAE patients shown in the pictures of medical textbooks." ”
In March this year, Yao, an allergist at the Second Affiliated Hospital of Zhejiang University School of Medicine, was so frightened that I saw Qin Lu at the time of the swelling attack, and I was so frightened that I even trembled when I spoke. It was also the first time she had seen a seizure in a HAE patient.
"Actually, we've met before, but that time, I didn't recognize him at all." Yao I remember that at that time, she was talking to him calmly, while preparing in her heart, afraid that after a while he would be swollen to the respiratory tract and need to cut the trachea.
Qin Lu couldn't remember under what circumstances the seizure occurred. Some time before that, he recorded the details of each swelling, wrote down what he ate before the swelling attack, what time he slept, etc., and the notebook was full of half a book, but he still did not find the law of the onset.
(When Qinlu swelling occurs.) Patient courtesy of)
This time the swelling started from the forehead, down to the eyelids, the eyelids swollen to "transparent", and then swollen to the cheeks and nose, the nose was upturned, the nostrils were propped up, followed by the upper lip, when the lips began to swell, Qin Lu's wife couldn't help but smile, "Just like the Eight Precepts of the Pig." She teased him. She knew by then that he had begun to tense up, swelled up again, and soon reached the respiratory tract.
The lower lip was swollen in half, and the left and right sides of the lips had swollen "high", leaving a small piece in the middle. Qin Lu began to feel the swelling of his forehead from the early morning of this day, until now, the swelling had been "raging" on the face for 16 hours, at 6 o'clock in the afternoon, he reached out and touched his face, and the swelling finally stopped.
"Swelling" has accompanied Qin Lu for 10 years, and he no longer cares about the eyes of outsiders. "Everyone has physical defects, which are innate and I don't feel ashamed." He said that although he had left the impression of "frailty and illness" on his classmates and friends, "in fact, from the perspective of the case book, in addition to the HAE attack, I am also a person who is physically strong and rarely enters the hospital." ”
(Qin Lu was relieved to be diagnosed at Peking Union Medical College Hospital, and that medical treatment became his "pleasant trip.") Patient courtesy of)
What he cares about is that many patients like him are labeled as "strange diseases", and he is more worried that some patients will experience laryngeal edema and be killed by the disease without knowing it.
"A patient who was still in graduate school, when he had laryngeal edema, the doctor said that after the tracheostomy surgery would leave scars, the family hesitated for a few minutes, and the person could not do it." Qin Lu said, "Originally it was all a tragedy that could be avoided, but we lost the opportunity to save my life in vain, and we have heard too many such stories." ”
Fortunately, in recent years, with the attention of the public and the government to the problems faced by rare diseases and rare disease groups, HAE has more opportunities to be seen.
In May 2018, hae was included in the First Catalogue of Rare Diseases formulated by the National Health Commission and other departments[4]. Finally waiting for the red-headed file, Qin Lu still remembered that on the day the directory was released, the patient group was very lively. "At least it's easier for everyone to communicate with the doctor when they take preventive drugs later, or when they go to the emergency room for an acute attack."
(Qin Lu is now using a preventive drug.) Patient courtesy of)
At present, in addition to Peking Union Medical College Hospital, several large tertiary hospitals such as the Second Affiliated Hospital of Zhejiang University School of Medicine, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Jiangsu Provincial People's Hospital, the Second Affiliated Hospital of Guangzhou Medical University, the Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology, and the West China Hospital of Sichuan University can also diagnose HAE.
Wang Huiying, who serves as the chairman of the Allergy Branch of the Zhejiang Medical Association and the leader of the HAE Working Group of the Zhejiang Rare Disease Working Group, introduced that the Second Affiliated Hospital of Zhejiang University School of Medicine currently has 2,000 HAE free testing places.
"Our hereditary angioedema working group has also begun training work this year, bringing together emergency departments, dermatology, and otorhinolaryngologists in various cities and counties for training." Wang Huiying said: "To let HAE be seen by more people, first of all, let doctors understand how to deal with patients with such rare diseases, and if they can't deal with it, where they should be referred." ”
In December 2020, the world's first monoclonal antibody drug for long-term preventive treatment of HAE, Ranaliyultab Injection, was also approved to enter China for the prevention of HAE attacks in patients aged 12 years and older. "But the price of drugs is high, costing 1.5 million a year." Qin Lu said, "Very few patients can bear this financial pressure. ”
In April 2021, etibant acetate injection for the treatment of acute episodes of HAE in adults, adolescents and children over 2 years of age was also listed in China, and patients can self-administer after receiving subcutaneous injection technology training from medical and health professionals, and the injection price is 9960 yuan / bottle.
There are patients with confirmed HAE paying close attention to this drug, foreign control study data show that etepant acetate injection treatment of acute HAE attacks, almost 100% of patients are relieved, the median HAE symptoms began to remission time of 2.0 to 2.5 hours. For patients who may have laryngeal edema, this is a "life-saving drug".
More people just wait and see, HAE patients can not predict the time of their onset, in addition to the expensive price of nearly 10,000 yuan, they also have to bear the risk of drug expiration.
Qin Lu had been praying, hoping that there would be better news. The adjustment of the 2021 national medical insurance drug list touched his heart, and in the early morning of December 4, he sent a message, "HAE emergency drugs have entered the national medical insurance this time, No. 25." Of the 74 new drugs added to the list, No. 25 negotiated new drugs read "Etibant acetate injection.".
Medicare reimbursement rates were also announced in January 2022. Qin Lu could not suppress his joy, "This time into the medical insurance of rare disease drugs, we are among them, and now it has dropped by half, 4330 yuan, but also can enter the medical insurance, which means that patients not only have drugs available, but also within reach, within the range of affordability." ”
This time, hae patients were not only seen, but also, indeed, spring was ushered in.
(Except for Wang Huiying and Yao I, the characters in the text are pseudonyms.) ）
bibliography
Zhi Yuxiang, Am Lixin, Lai He, et al. Expert consensus on diagnosis and treatment of hereditary angioedema[J]. Chinese Journal of Clinical Immunology and Allergy, 2019.
[2]. National Health Commission, Office of the Expert Committee on Diagnosis, Treatment and Protection of Rare Diseases (Peking Union Medical College Hospital). Guidelines for the Diagnosis and Treatment of Rare Diseases (2019 Edition). 2019; 38–189.
Zhi Yuxiang. Clinical and C1 inhibitor gene mutations of hereditary angioedema[D]. Peking Union Medical College, China, 2003.
[4]. National Health Commission, Ministry of Science and Technology, Ministry of Industry and Information Technology, State Drug Administration, State Administration of Traditional Chinese Medicine. The first batch of rare diseases directory, National Health Medical Development (2018) No. 10.
Author: Shin Yi
Editors: Wu Jiaxiang, Zhang Jie, Ye Zhengxing
Typesetting: Han Ningning | Proofreader: Wu Yihe
Operations: Li Yongmin | Coordinator: Ye Zhengxing