White Manual, Green Manual: Evolution of The COVID-19 Diagnostic Criteria

2020-02-20

白皮手册与绿皮手册:新冠肺炎诊断标准之变

Author: YANG Hai, Editor: ZHANG Guo (Ice Point Weekly)

Translator: GAO Yan (COVID-19 Readings)


pedestrian enjoying sunlight
February 16, Wuhan, Hubei, a pedestrian enjoying the sunlight with open arms after snow

On the last day of 2019, several medical specialists were sent to Wuhan by the National Health Commission of China (NHC). Nearly all of them had experienced the 2003 SARS epidemic and some of them had left Chinese people a deep impression in that event.

What was waiting for them was a new infectious disease. After the noon of that day, Wuhan Municipal Health Commission issued their first report about the novel coronavirus pneumonia epidemic: local hospitals diagnosed 27 patients with viral pneumonia, and all of the patients had connections with Huanan Seafood Wholesale Market.

This infectious disease was initially called “Pneumonia of Unknown Cause”. Only until 8th January, its causal agent was identified as a novel coronavirus. Compared to the complete ignorance in beginning, people started to gain gradually deeper understanding of the virus.

On January 16, NHC issued the first version of the “National” Diagnosis and Treatment Plan, which articulated a clear diagnosis standard. Before that, Wuhan, as the origin region of the epidemic, had diagnosed and treated patients relying on the standards explored in the earlier stage.

White Manual and Green Manual

Liu Yue (pseudonym at the request of the interviewee), a director of the emergency department of a Class III Wuhan hospital, told the reporter that after the New Year’s holiday, the hospital held a meeting that all directors of departments were asked to attend. The hospital leader orally conveyed to them a “reporting standard” of the “Pneumonia of Unknown Cause”.

He remembered clearly what the leader had held in hand was a “manual with white cover”.

Liu’s colleague Jing Kun (pseudonym), the director of the ICU, also indicated that he had learned of the so-called “reporting standard” in the same setting.

Li Xia (pseudonym), director of the emergency department of another Class III hospital, also confirmed that a similar meeting was held on January 3 in their hospital.

“The hospital leader required us to convey this reporting standard only face-to-face, by telephone, or WeChat Voice”, Li Xia said.

The “reporting standard” these doctors had referred to was the “Pneumonia of Unknown Cause Eligibility Criteria” released by Wuhan Municipal Health Commission. Cases that did not meet these “Eligibility Criteria” need not be reported.

A source provided the reporter with this “Eligibility Criteria”. It stipulated that patients could only be included if they “have an epidemiological history and clinical manifestations.”

Among them, the “epidemiological history” included four criteria, and patients who meet one of them could be included:

  1. Since December 1, 2019, merchants, employers and staff who have been engaged in trading activities in Huanan Seafood Wholesale Market for a long time.

  2. Since December 1, 2019, people who have worked in Huanan Seafood Wholesale Market on (food) processing, vending, killing, and moving etc. for more than three hours within the previous two weeks before showing symptoms.

  3. Since December 1, 2019, people who have had a clear history of contact with poultry or wild animals in Huanan Seafood Wholesale Market (touching or watching at a close distance within 1 meter, etc.) within the previous two weeks before showing symptoms.

  4. People who lived, studied, accompanied, shared a room with confirmed cases or medical staff who did not take effective protective measures while treating the confirmed cases.

As for “clinical manifestations”, there are also four criteria:

  1. Fever ≥ 38 ° C.

  2. With the imaging features of pneumonia.

  3. The total number of white blood cells in the early stage of the disease is normal or decreased, or the number of lymphocytes is decreased.

  4. After a 3-day standard antibacterial treatment, the condition has shown no obvious improvement or undergoes progressive worsening.

According to the “Eligibility Criteria”, viral pneumonia patients, who cannot be diagnosed with a certain disease, need to meet all four “clinical manifestations” criteria and then one of four “epidemiological history” criteria before being included. After being included, patients need to be tested for other viral types of pneumonia such as influenza virus, adenovirus, mycoplasma, chlamydia pneumonia, and bacterial pneumonia, “cases with a clear diagnosis of other diseases” can then afterwards be excluded.

eligibility criteria
Pneumonia of Unknown Cause Eligibility Criteria

On January 3, the second report from Wuhan Municipal Health Commission announced, “After the epidemic outbreak, the State and Provincial Health Commission attached great importance to sending working groups and expert teams to Wuhan to guide the local epidemic response and decision making. “

However, experts sent by NHC stated that they did not formulate such “Eligibility Criteria”, according to reporters from China Youth Daily and China Youth Network.

“I have never participated in the formulation of the ‘Eligibility Criteria’. Also, NHC did not know the existence of this standard at the beginning.” An expert claimed: “this standard was added by Wuhan”.

This expert said that he later saw the white manual, and the “Eligibility Criteria” was part of it.

A member of the second expert group provided reporters with a manual with a green cover, “Manual of Medical Treatment of Viral Pneumonia of Unknown Cause”, printed by “Wuhan Municipal Health Commission.” The manual contains “Viral Pneumonia of Unknown Cause Diagnosis and Treatment Plan (Trial)”, “Requirements for Centralized Treatment of Viral Pneumonia of Unknown Cause”, and nine documents related to the collection of pathogen diagnostic specimens, patient transfer, and autopsy.

The expert said that white and green manuals had different diagnostic standards.

The aforementioned expert of the first group told reporters that the “Viral Pneumonia of Unknown Cause Diagnosis and Treatment Program (Trial)” in the Green Manual was jointly developed by NHC and provincial local experts, “It was formulated around January 3.”

According to the diagnosis and treatment plan in the Green Manual, the “case definition” entry explained which patients can be identified as “Cases of Viral Pneumonia of Unknown Cause”.

The “definition” included four criteria:fever; imaging features of pneumonia; normal or reduced white blood cell or reduced lymphocyte in the early stage of disease; no significant improvement or progressive worsening of the condition after a 3-day standard antibacterial treatment.

Pneumonia patients who met the above four criteria and couldn not be diagnosed as having other diseases could be identified as “Pneumonia of Unknown Cause (cases)”.

The standard of the Green Manual also mentioned “being exposed to Wuhan Huanan Seafood Wholesale Market or suspected patients”. However, this criterion was not included as a necessary condition, but as a floating condition. If a case had met this criterion, then once it met three of the four previous criteria, it could be confirmed as “Pneumonia of Unknown Cause (case)”.

green manual
Green Manual

Wuhan doctors Liu Yue, Jing Kun, and Li Xia all told the reporter that they had never seen the Green Manual. What they all believe was that the “Eligibility Criteria” of the White Manual was too “stringent” and not conducive to early detection and diagnosis.

The reporter noticed that the only difference between the White Manual and the Green Manual was the addition of “Eligibility Criteria”. Regarding the version issue, the reporter inquired with the Wuhan Municipal Health Commission, but did not receive a response.

green manual white manual
Left: Green Manual index page, Right: White Manual index page

“According to These Criteria, We Couldn’t Report Anybody”

After the hospital meeting on January 3, Jing Kun’s ICU department immediately opened more than 10 isolation beds for patients with pneumonia of unknown cause. As he recalled, the beds were fully occupied in less than 3 days since the first patient moved in.

The hospital where Jing Kun worked has formulated an “Intra-Hospital Report, Diagnosis and Treatment Process for Suspected Cases with Pneumonia of Unknown Cause”. This report didn’t include having contact with Huanan Seafood Market as a necessary criterion for reporting within the hospital.

“Their clinical manifestations were too unique. There was no doubt that they contracted the disease”, Jing Kun insisted. He did not refer to the “Eligibility Criteria”, rather he reported all these suspected cases to the medical affairs office and the hospital infectious disease office.

However, none of the dozen or so patients was included as “case of pneumonia of unknown cause”. None of them fully matched the “Eligibility Criteria”.

“Many patients didn’t have an exposure history to Huanan Seafood Market. There were also patients with a fever below 38°C, and patients who didn’t receive standardized antibacterial treatment.” Jing Kun said.

A screen hung on the doctor’s lounge’s wall in his department showed the surveillance video of these patients.

Usually, doctors used numbers to distinguish them, because their symptoms were too similar. Most people were in a coma with trachea around their necks. Some others lie motionlessly in bed even with ECMO (extracorporeal membrane oxygenation).

Their similarities were also reflected in the lung CT images, “white, completely white”.

“Even such patients did not meet the eligibility criteria”. Jing Kun raised his volume and then remained silent for a few seconds.

Many hospitals in Wuhan have implemented the standard. According to reports, infection among medical staff and hospitalized patients were found in the Youfu Hospital near Huanan Seafood Market in early January, but the hospital didn’t report that because the patients had no exposure history to Huanan Seafood Market and they did not meet eligibility criteria.

Most of the patients with viral pneumonia in Jing Kun’s department were transferred from other hospitals, and some of them “have been wandering outside for more than a week” after showing symptoms.

He quickly received a response for dismissing the standard, which was “severe criticism” from a hospital leader, “complaining that we reported too many”.

Later, after the hospital could use the nucleic acid test, more than 60% of the patients he treated tested positive, confirming that they had contracted COVID-19. He told the reporter that many of the remaining negative patients were close to recovery. In the meantime, false-negative cases had to be considered. Wang Chen, the dean of the Chinese Academy of Medical Sciences, also pointed out that the quality of nucleic acid testing reagents was unstable, causing many false negatives cases.

“According to these criteria, we couldn’t report anybody.” said Jing Kun.

Li Xia was also similarly confused. Two outpatient fever clinics were opened on January 1 in her hospital. Later statistics showed that January 4 was the turning point in the total number of patients. There were 102 fever patients on that day, “quite a few times as many as usual.”

“Our fever clinic was too small and overcrowded, so we could only send these fever patients to the emergency department”, Li Xia said.

On January 15, 261 fever patients flooded into the hospital’s emergency department. There were so many fever patients, there was no place for people to sit, yet they could hardly be reported to the CDC in Wuhan.

“It’s extremely strict. None of them meets the Eligible Criteria”, Li Xia told the reporter. The doctor also had questioned hospital leaders about the “Eligibility Criteria”, especially “why patients must again have a contact history of Huanan Seafood Market”, but without getting any feedback.

“All our preparations were inadequate.” Li Xia sighed. “The infectious disease ward requires three areas and two passages, and the wardrooms must be separated by a certain distance. We couldn’t do that.”

According to the Wuhan Municipal Health Commission, there were no new cases between 11th January and 15th January.

baibuting
Wuhan Baibuting Residential Area

The Analysis of the Epidemiological Characteristics of The Novel Coronavirus Pneumonia (COVID-2019) completed by NHC in February traced back all cases reported in Mainland China by February 11. Based on the onset date, 104 people were infected and 15 had died before December 31, 2019.

Some sooner some later, doctors in different hospitals in Wuhan have all discovered that the number of fever patients suddenly increased. Lü Xiaohong, a doctor from the Fifth Hospital of Wuhan, told the reporter that she had suggested her hospital to set up a fever clinic, because since January 6, the hospital had received many suspected cases.

The well-known local Wuhan Union Medical College Hospital had to transform the entire floor of the Infectious Diseases Section into a quarantine area for respiratory infectious diseases.

On January 23, Wuhan identified the first batch of designated hospitals for the novel coronavirus pneumonia. Before this, many patients who could not be identified as having “pneumonia of unknown cause” or “novel coronavirus pneumonia” had been to hospitals on their own for treatment, without proper isolation.

Wang Guangfa, a member of the second expert group sent by NHC and director of the Department of Respiratory Medicine of the First Hospital of Peking University, arrived in Wuhan on January 8. He was later informed that the incidence of pneumonia in a local hospital in December 2019 increased by 17 % compared with the same period in previous years. While he worked in Wuhan, he contracted COVID-19.

Before the emergency ward managed by Liu Yue was requisitioned as a pneumonia patient isolation ward, medical staffs did not receive any risk warning. “At that time, we wore ordinary surgical masks as routine respiratory protection”.

“I knew about the pneumonia at that time, but there were no confirmed COVID-19 cases in my hospital. Accoding to the official data, the number of patients had not increased. Also, the authority said that there was no obvious person-to-person transmission, so I didn’t take it seriously.” Liu Yue told reporters. “Considering that my emergency department was like this, not to mention how careless other departments were for they were even farther away from infectious diseases”.

On January 20, a high-level expert group of NHC led by Zhong Nanshan held their first press conference after inspecting Wuhan. They confirmed that human-to-human transmission and infection among medical staff had occurred in Wuhan. One of the neurosurgery patients infected 14 medical staff.

In this outbreak, Liu Yue was also one of the infected doctors. He recalled that the only possibility of his infection was that he accepeted and treated a pneumonia patient in his ward on January 6th. He was not informed of any danger at that time. Later, 16 beds he managed were at one time occupied by 4 families, and that’s when he clearly realized that “this disease was transmitted from person to person”.

The Wuhan Municipal Health Commision mentioned in their January 11th report that “early detection, early diagnosis, early isolation and early treatment should be achieved. All medical experts and resources should be unified and utilized to treat patients”.

It was slightly different from the NHC’s “four early” principles which had been mentioned for several times. Here, the CDC in Wuhan replaced “early reporting” in the NHC version with “early diagnosis”.

Multiple Updates on National Standards in Response to The Epidemic Progress

Unlike the 2003 SARS epidemic, this time, China quickly isolated the virus strain, completed genetic sequencing, and shared the sequence with the WHO for global joint research. This action was appreciated by the WHO. On January 8, the pathogen was tentatively identified as a novel coronavirus.

On the same day, the second expert group arrived in Wuhan. One of their tasks was to revise the “Diagnosis and Treatment Plan for Pneumonia of Unknown Cause (Trial)”. Two days later, the Chinese Center for Disease Control and Prevention developed a diagnostic test kit. The novel coronavirus can be detected by the kit and RT-PCR technology.

“What I saw was a green manual. At that time, nucleic acid tests had been developed, so we added a ‘confirmed case’ criterion, and the rest of the sections remained unchanged.” An expert told the reporter.

According to the expert, several days later, a Wuhan doctor called him. The doctor admitted that he had not told the expert group the truth that he had been infected with the novel coronavirus.

The aforementioned three Wuhan doctors told the reporter that the “confirmed cases” criterion was indeed added, but it was based on the White Manual, not the Green Manual.

The reporter found the following expression in a section of the “Diagnosis and Treatment Plan for Pneumonia of Unknown Cause (Trial)”, namely “Case Features”, “Most of the treated cases had a history of exposure to Wuhan Huanan Seafood Market. Some cases demonstrated family clustering and most of these clustered cases had a history of exposure to this market.”

“We knew there was a small scale of clustered cases among the existing cases, but these people were all related to Huanan Seafood Market.” An aforementioned expert said that the expert group drew the conclusion of “limited person-to-person transmission” from what they learned in Wuhan.

On January 16, NHC issued their first edition of “Diagnosis and Treatment Plan for Pneumonia of Novel Coronavirus (Trial)”. At this point, the implementation of Wuhan trial scheme was discontinued.

On this day, the Wuhan Municipal Health Commission reported four new confirmed cases, after several days of “no added cases” in their report.

In the first edition of NHC’s plan, the definition of “observed cases” (later changed to “suspected cases”), “epidemiological history” referred to “Wuhan”, not Huanan Seafood Market. And “Clinical manifestations” prescribed “fever” without a specific temperature standard.

Since then, national standards have been revised several times as the epidemic progressed. Zhang Xiaochun, deputy director of the Department of Medical Imaging at Zhongnan Hospital of Wuhan University, proposed that false negatives could not be ruled out from nucleic acid testing, so he recommended CT imaging as a diagnostic method. Such opinions were adopted in subsequent standards.

Since February 12, the standards in Hubei were further expanded. For the first time, “clinically diagnosed cases” were included in confirmed cases. A total of 14,840 new cases was added in a day, with 13,332 clinically diagnosed cases. Zeng Yixin, deputy director of the NHC, said that the goal of adding clinically diagnosed cases was to help patients be confirmed and isolated earlier, giving them standard treatment and improving the curative ratio. He said, “Because of this project, the confirmed cases indeed increased, which truly reflected the situation in Wuhan.”

On February 19, the NHC issued the sixth edition of the diagnosis and treatment plan. In this latest version, the distinction between Hubei Province and other provinces has been eliminated. All patients are now differentiated into “suspected cases” and “confirmed cases”.

According to the report of the NHC on the morning of February 20, Wuhan added 615 new confirmed cases throughout the day on February 19, and four other cities in Hubei added 13 new cases. But because nucleic acid tests were performed on “clinically diagnosed cases” from 10 cities and counties, cases with negative nucleic acid test results were removed from the original confirmed cases, with a total of 279 cases being confirmed removed. Therefore, Hubei province announced 349 new confirmed cases. This was the first time in many days that new cases in Hubei had dropped to three digits. With deeper understanding of the situation and the revisions of national standards, the goal of “receiving all that should be received, treating all that should be treated” became gradually within reach.

(Reporter WANG Jiaxing contributed to this article.)

(The article was produced by China Youth Daily, first published in China Youth Daily official channels and included in the Woods Plan.)

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