Gut · Tao | Cao Qing: What secret weapon is there in the face of refractory infections in children?

2019-09-17 | Mr. Zeal |

"Gut · Tao" is a TED-like speech program recorded by the Enthusiastic Gut Institute. This article is the content of the third speaker of the fifth session, Cao Qing, please watch the video: talks / s / 0cdbcfd11a904053bcd49889c8b0a4b8

Introduction: How do infectious diseases continue to threaten humans? Vaccination rates have fallen, terrible child infections or comebacks? What new technologies can detect unknown pathogens? What are the secret weapons in the face of refractory infections in children?

Introduction of Speaker

Director, Department of Infectious Diseases, Shanghai Children's Medical Center; Deputy Leader of Infection Youth Group, Pediatrics Branch, Chinese Medical Association; Enthusiastic intestinal think tank expert

Doctor of Medicine, Chief Physician, Master's Supervisor, Director of Infectious Diseases, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Deputy Director of Institute of Pediatric Infection and Translational Medicine, and Adjunct Assistant Professor at Ottawa Medical School, Canada, Shanghai Jiaotong University.


Hello everyone! This is Cao Qing from Shanghai Children's Medical Center. I am very happy to have the opportunity to talk to you about the "break" and "establishment" of refractory infections in children.

As an infectious physician working in the clinical frontline, in fact, I have many cases of refractory children and stories of pathogenic microorganisms that I have to tell.

For centuries, widespread infectious diseases have left a deadly mark on human history. Plague, cholera, and smallpox, just talking about these names, still makes people shudder.

Even now, deadly bacteria and viruses are still resisting medical advances, with more than 14 million deaths associated with infectious diseases each year. New pathogens are also emerging, with population explosion and globalAnd the threat has expanded globally.

We will find that for nearly a century, many infectious diseases have occurred on average periodically every 5 years. What will happen next? Who will be affected? Are we able to defend against these infectious diseases? In fact, humans resistFighting of all infectious diseases has begun.

In the past two years, the major media may have the most attention in the winter and spring seasons. Influenza may have spread. Every flu outbreak spreads quickly to the north and south. In fact, the flu is an ancient disease. As early as 2400 years ago, HippoA general description of Cradice.

For modern society, the most affected and earliest disease was the 1918 influenza pandemic, which happened to be 100 years ago. In the history of 100 years of influenza, humans have experienced 5 influenza pandemics. During this period, hundreds of millions of people have accumulated.Infections and tens of millions of deaths have dealt a heavy blow to human health and socioeconomics.

Last year, a "Beijing Middle Age Under the Flu" gave everyone a deep understanding of the threat of severe flu.

As a doctor of infectious diseases, I faced the flu for the first time in 2009. At that time, we were fighting side by side with many children with severe infections. At that time, we felt that we could not make accurate diagnosis quickly.

But now in 2019, we will find that for many influenza pathogens, we can quickly diagnose. New technology allows our clinicians to know what it is in a short time, a day or even an hourSuch pathogens are affecting human health.

Technology is advancing, times are advancing, and more problems are also facing our clinicians.

In 2017, we performed a rapid molecular diagnosis and clinical analysis of 775 patients with lower respiratory tract infection in our hospital. In this study, we unexpectedly found that 6.3% of children were infected with Pertussis.

Since the implementation of the expanded immunization program in China in 1978, the incidence of pertussis has dropped from 200 / 100,000 in the 1960s and 1970s to 1 / 100,000 in the late 1990s.

But in recent years, the incidence of whooping cough has increased significantly worldwide.

In addition to being closely related to the immune drift of the vaccine, we also found that some severe pertussis cases have been encountered clinically, and the mortality rate of these cases is also relatively high. In the United States, the death cases of severe pertussis announced by the CDC in 2017 reached20 cases.

These vaccines can prevent severe cases in the clinic and sound the alarm in our hearts.

Also last year, an article titled "The King of Vaccines" quickly exploded in the WeChat circle of friends, with a click rate of over one million, which pushed the safety issue of vaccines to the forefront and caused panic among countless parents.

In fact, vaccines are still the most cost-effective way to defend against infectious diseases. The defense force of vaccines needs to be adequately vaccinated by the population, and the decline in the vaccination rate will not only prevent unvaccinated children from losing their protection, but also the surrounding population will also be in danger.Among them.

For infectious diseases, the most difficult problem for clinicians is that the pathogen is unknown. Even now, there are still 20% -25% of severe pneumonia, 40% -50% of sepsis, 50% -60% ofThe cause of encephalitis and meningitis is unknown.

For infectious physicians, the diagnosis of pathogens is urgently needed and very urgent. In the face of thousands of known and unknown pathogens, how do we make a rapid diagnosis? In the past, traditional tests may have many tests.Negative, doctors need more empirical judgment.

With the development of modern technology, molecular diagnosis with its unique advantages and fast and sensitive characteristics, makes up for the lack of traditional pathogenic diagnosis, especially the diagnosis of NGS, which has led to a rapid improvement in clinical diagnosis.

NGS is also called next-generation sequencing, which can perform rapid detection of more than 2,700 pathogens at the same time. Both DNA and RNA pathogens can be detected at the same time.

The first report of NGS for the diagnosis of infectious disease pathogens was in 2014.

This is a 14-year-old boy with combined immunodeficiency. He traveled abroad with his family in 2013 and developed fever after returning home. He was diagnosed with meningitis at that time and quickly developed into hydrocephalus and epilepsy after admission.

He performed 38 items of pathogenic tests during the 6 weeks of hospitalization, and used 5 types of anti-infective treatments, but the cause was not found, and the child was in a coma for a time.

His doctor in charge used metagenomic sequencing. After 48 hours, he unexpectedly found 475 Leptospira sequences in his cerebrospinal fluid. After switching to penicillin, the child was discharged quickly within 32 days.

NGS diagnosis of infectious diseases has improved rapidly in the past two years, and we have personal experience.

We have encountered such a girl in the clinic, because of repeated breathing difficulties, chest pain for more than three months, and moved to many hospitals, multiple pathogen tests have no clear results.

However, in the course of the disease, in fact, the serum antibody of the child detected the infection of Schizophrenia mansoni, but the antibody to the serum Schizophrenia is not the gold standard for diagnosis. Its sensitivity only reaches 85%. There are many reasons for this.Its cross false positive.

And the child still has recurrent fever and chest pain after taking praziquantel during the treatment.

We found in the child's physical examination that there was a mass at the root of her right thigh, and we performed a pathological biopsy of the mass seeing the worm body in the pathological biopsy is a gold standard for the diagnosis of Manchurian splithead.

But for this child, we only found tunnel-like necrosis and an increase in eosinophils during the test. So, is this child infected with Schizophrenia mansoni? At this time, the next-generation sequencing solved usConfusion.

We performed second-generation sequencing of her pathological tissue, and as a result, a high-band count 4,750 of Taenia mansoni was found, which further confirmed that this child was infected with Schizophrenia mansoni.

So we are clinically confident and given a sufficient dose of praziquantel for treatment, and after eight months of follow-up, the child did not experience any recurrence.

This is the first time that the next-generation sequencing is used for the diagnosis of a rare disease of Manchurian head sclerosis. It also shows that NGS has a prominent and significant effect in the diagnosis of difficult infection cases.

We will also encounter some patients with difficult infections clinically: the pathogens of children are clearly diagnosed, and our treatment is accurate, but the clinical effect is not good. What is the reason for this? The next oneThe case may give us some inspiration.

We encountered such a 10-year-old boy who repeatedly increased eosinophils for more than a year. His eosinophils accounted for 40% -50% in peripheral blood.

He has been diagnosed with allergic diseases and idiopathic eosinophilia in foreign hospitals, and has repeatedly applied anti-allergic and hormonal treatments, but eosinophils have not decreased significantly.

When he came to our infectious disease department for treatment, we first had to consider whether it was a parasite infection. When we ruled out the parasite infection, we found in his physical examination that thrush can be seen in his oral mucosa.

At the same time, his head MRI and CT of the chest and abdomen can see multiple infections. We found Candida albicans infection in the cerebrospinal fluid of this child, and this strain of Candida albicans was resistant to allFungal drugs are all sensitive.

We have used a combination of antifungal drugs, but the clinical effect is not good. Is there any reason to cover up the truth of the disease?

Many years of clinical experience tells me that this child may have an immunodeficiency, but for this child, our routine cellular and humoral immune tests are normal, what is the reason for this?

There are 1.5 million deaths each year in patients with recurrent and invasive fungal infections. There are two reasons for this: the first is because the late diagnosis of Candida albicans has caused severe cases;Two are ineffective antifungal treatments.

So, what causes the antifungal treatment to be ineffective? We performed high-throughput sequencing on this child and found that the child turned out to be a homozygous defect in CARD9.

CARD9 is closely related to our body's innate immunity. Its defects have led to a decrease in the cytokine interleukin-17, which is a major cytokine that regulates neutrophil function.

This also explains why our conventional antifungal treatments are ineffective in the clinic.

So, what kind of treatment plan should we use for such children?

We consulted the literature, there was only one report of children with invasive fungal infection and CARD9 immunodeficiency in the world, which were treated with G-CSF granulocyte colony-stimulating factor.

So, we used G-CSF combined with oral antifungal therapy for this child. Stop all antifungal intravenous therapy and switch to oral therapy.

One month later, the child's imaging has improved significantly, eosinophils in peripheral blood have also decreased significantly, and the cerebrospinal fluid has returned to normal. At the two-month follow-up, all the imaging of the child recovered.Normal, the number of cells in the cerebrospinal fluid is zero, and at the same time, the cytokines completely return to normal.

These patients give us some hints: for some clinically refractory infections, when the cure is not good, we must consider the patient's immune problems. Maybe these immune problems can not use the previous conventional cellular immunity and humoral immunityTo explain, but suitable for immunogenetics.

Some genes related to high-risk populations, we also call microdeletions of immunity, these susceptible genes cause the human body to be particularly susceptible to certain pathogens.

So I often tell our infectious disease doctors that when we diagnose infectious diseases, it is like Holmes is solving the case and cannot be covered up by the appearance of the disease. We often look for the real cause of the disease through the appearance.

This also helps us to judge the healing of the disease, especially the individualized fine treatment.

We will encounter many cases of super bacteria, multidrug resistance, immunodeficiency, and clinical anti-infective treatments are ineffective. When anti-infective treatments are ineffective, how should we cope?

In the past we might say that we have done our best, we are really powerless, but in the past two years we may say that we can try a faecal transplant.

We have encountered a parent of such a two-year-old child. When she took the child to see the doctor, the child was already life-threatening due to severe diarrhea, high fever, hypertoxemia, and severe malnutrition.

In addition to the refractory diarrhea associated with refractory infection, the child's diarrhea is also caused by an immune deficiency caused by FOXP3 deficiency.

When conventional drug treatment is ineffective, hematopoietic stem cell transplantation is the only way to cure him. However, due to severe diarrhea, the child's physical condition and nutritional status are extremely poor, and hematopoietic stem cell transplantation cannot be tolerated at all.

Therefore, we have used the method of faecal transplantation to cleverly cure the child with immunodeficiency suffering from diarrhea. After two faecal transplants, the child's diarrhea was improved and his weight increased.Treatment has gained a first-line vitality.

At present, the child has successfully undergone hematopoietic stem cell transplantation, and the implantation was successful. This is the first case at home and abroad to successfully perform a hematopoietic stem cell transplantation after a fecal bacteria transplant for an immunodeficiency child.

So, the times are advancing, and many new technologies are urgently needed for clinical use. This is also a problem that our clinicians need to think about and practice.

Of course, the application of fecal bacteria transplantation in children is still in its infancy, especially for some children with refractory immune deficiency, and they lack clinical experience.

At present, many basic studies of intestinal flora have found that the patterns of intestinal flora of patients with various diseases are different.

We analyzed the intestinal flora of children with different status of sepsis, and surprisingly found that their intestinal flora was significantly different from healthy children, and the levels of intestinal flora such as phylum, class, order, family, etc. could be significant.Differentiate the severity of sepsis in children, and it is closely related to the recovery of children with sepsis.

This suggests that fecal bacteria transplantation may be a feasible solution for accurate treatment of sepsis in children in the future.

In the past, when we were doing fecal bacteria transplantation, we generally used the method of placing the tube in the stomach and jejunum, which was very difficult for many parents and children in clinical practice.

Recently we have developed a faecal capsule by ourselves, which can be used for oral faecal transplantation. Such faecal transplantation may bring more to some older children, especially some mildly infected children.benefit.

So we think that fecal bacteria transplantation may bring new hope to more children with refractory infections in the future.

Next, I would like to give some warm tips for your healthy childcare as an infectious physician.

One of the most questions that parents ask me is, should we use antibiotics for infectious diseases?

This is a difficult question to answer. Everyone knows that in infectious diseases, there may be tens of millions of pathogens, and it is determined that the pathogens that are infected are actually the first. Therefore, we have always respected and accurately resistedInfection treatment is the best.

For children under 5 years of age, many infections are actually viral infections. These viral infections do not require oral antibiotics. The use of antibiotics may cause intestinal flora disorders in early children.

More and more studies show that disorders of the intestinal flora in early childhood are closely related to later obesity and allergies. Therefore, from the perspective of health and longevity, the reasonable use of early antibiotics may be important for us in the future.The health of your intestinal flora is important.

At the same time, vaccines are still the most effective method for the prevention of all infectious diseases.

As a National Children's Medical Center, our Department of Infectious Diseases mainly treats all patients with fever and refractory infections.

We have good molecular detection methods that can help more difficult cases to determine whether it is an infection. We also have a good faecal transplantation platform to help more patients with difficult diarrhea get a good relief.

Finally, I want to thank my entire research team and all the medical staff, especially Dr. Moxie of our infection team. She is a PI researcher from the United States. She gave up the opportunity of high salary and joined our pediatricianWorking for children's health.

Thank you all!

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Mr. Zeal
Founder of Enthusiastic Bowel Research Institute, Tsinghua Life Science and Medical Alumni Association, Secretary-General of Health blogger, headline article author

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