Chinese Medical Journal 2004;117(1):14-18
Comparison of clinical course of patients with severe acute respiratory syndrome among the multiple generations of nosocomial transmission

WU Wei 伍 卫,  WANG Jing-feng 王景峰,  LIU Pin-ming 刘品明,  JIANG Shan-ping 江山平,  CHEN Qing-yu 陈庆瑜,  CHEN Wei-xian 陈为宪,  YIN Song-mei 尹松梅,  YAN Li 严 励,  ZHAN Jun 詹 俊,  CHEN Xi-long 陈锡龙,  LI Jian-guo 李建国

WU Wei 伍 卫 (The SARS Working Group, Second Affiliated Hospital, Sun Yat-sen University, Guangzhou 510120, China)

WANG Jing-feng 王景峰 (The SARS Working Group, Second Affiliated Hospital, Sun Yat-sen University, Guangzhou 510120, China)

LIU Pin-ming 刘品明 (The SARS Working Group, Second Affiliated Hospital, Sun Yat-sen University, Guangzhou 510120, China)

JIANG Shan-ping 江山平 (The SARS Working Group, Second Affiliated Hospital, Sun Yat-sen University, Guangzhou 510120, China)

CHEN Qing-yu 陈庆瑜 (The SARS Working Group, Second Affiliated Hospital, Sun Yat-sen University, Guangzhou 510120, China)

CHEN Wei-xian 陈为宪 (The SARS Working Group, Second Affiliated Hospital, Sun Yat-sen University, Guangzhou 510120, China)

YIN Song-mei 尹松梅 (The SARS Working Group, Second Affiliated Hospital, Sun Yat-sen University, Guangzhou 510120, China)

YAN Li 严 励 (The SARS Working Group, Second Affiliated Hospital, Sun Yat-sen University, Guangzhou 510120, China)

ZHAN Jun 詹 俊 (The SARS Working Group, Second Affiliated Hospital, Sun Yat-sen University, Guangzhou 510120, China)

CHEN Xi-long 陈锡龙 (The SARS Working Group, Second Affiliated Hospital, Sun Yat-sen University, Guangzhou 510120, China)

LI Jian-guo 李建国 (The SARS Working Group, Second Affiliated Hospital, Sun Yat-sen University, Guangzhou 510120, China)

Correspondence to:Wu Wei.Liu Pin-ming,Department of Medicine, Second Affiliated Hospital of Sun Yat-sen University, Guangzhou 510120, China (Tel: 86-20-81332507. Fax:86-20-81332853. E-mail:liupinming@hotmail.com)
Keywords
severe acute respiratory syndrome;nosocomial infection;chain of transmission;clinical course
Abstract
Background Severe acute respiratory syndrome (SARS) is characterized by both an atypical pneumonia and efficient nosocomial transmissin. However, it remains unknown whether the infectivity and the virulence of the pathogen will change throughout the successive transmission. This study was conducted to compare the clinical features and management regimens of patients with SARS among the multiple generations from nosocomial transmission initiated by a super-spreader.
Methods The clinical data of 84 epidemiologically-linked SARS patients from a hospital outbreak were retrospectively studied. All patients, in whom a clear-cut transmission generation could be noted, had a direct or indirect exposure to the index patient and the epidemic successively propagated through the multiple generations of cases within a short period of time.
Results There were 66 women and 18 men with mean age of (29.2 ± 10.3) years in this cluster; and 96.4% of whom were health care workers. Detailed contact tracing identified 35 (41.7%) first-generation cases, 34 (40.5%) second-generation cases, and 15 (17.8%) third-generation cases. No statistical differences among the multiple generations of transmission were found in terms of age, gender, incubation period and length of hospital stay. With the advanced transmission generations, the initial temperature lowered, the number of cases with dry cough decreased. There were no statistical differences in the peak temperature and duration of fever, other accompanying symptoms, leucopenia; however, the time from initial pulmonary infiltrates to radiographic recovery shortened (P<0.05). No differences were found in maximum number of lung fields involved, duration from the onset of fever to the occurrence of pulmonary infiltrates and time from the initial pulmonary infiltrate to its peak among the multiple transmission generations (P>0.05). No statistical differences were found in modes of oxygen therapy and sorts of antibiotics prescribed among the various transmission generations (P>0.05); however, as with the advanced transmission generations, the number of cases prescribed with methylprednisolone, human γ-globulin, interferon-α, antiviral drugs (oral ribavirin or oseltamivir) increased (P<0.05) and time from admission to starting these medication shortened (P<0.05).
Conclusions There is no evidence that SARS infection will evolve or transmit within a fashion that permits it to become less powerful throughout the successive transmission within a short time.</FONT
Severe acute respiratory syndrome (SARS) is a newly recognized infectious disease that first manifested in humans in the Guangdong province of China in November 2002 and has subsequently spread worldwide.[1] It is characterized by both an atypical pneumonia and efficient nosocomial transmission. On April 16, 2003 the World Health Organization (WHO) officially declared that the new disease was caused by a novel coronavirus-SARS-associated coronavirus. However, it remains largely unknown whether the infectivity and the virulence of this etiological agent will change throughout the successive transmission among the population. On January 30, 2003, a patient who has been later categorized as a super-spreader of SARS was hospitalized in this hospital, followed by the successive transmission and an outbreak of SARS among health care workers.[2] These patients were characterized by clear-cut chains of the successive transmission, being infected from the same source within a short period of time, which gave us the opportunity to study the clinical course of SARS with regard to the multiple transmission generations. We compared the main clinical features, management regimens, and severity and frequency of complications of SARS patients in this homogeneous cohort in order to explore whether the clinical course would differ among the multiple generations of nosocomial successive transmission.

METHODS

Patient population
As we described in recent publications,[1,2] the super-spreader triggering this hospital outbreak of SARS was a 44-year old man. He had developed a fever and a nonproductive cough for 5 days and his chest X-ray showed a patchy infiltrate in the right upper lung. Therefore, lobar pneumonia was considered and he was admitted to the Service of Respiratory Diseases on the afternoon of January 30, 2003. The patient became seriously ill two days later characterized by respiratory distress and worsening hypoxemia and then SARS was suspected. He was transferred to the SARS designated hospital on the morning of February 1, 2003. Since February 3, health care workers had contracted the disease, manifested as successive transmission and a hospital outbreak of the new infectious disease; all the patients traced to the index patient.

The cases in the cluster met the following conditions: (1) confirmed SARS cases who had direct or indirect links to the index patient; (2) health care workers and/or their family members; (3) admission to the isolation wards between February 5 to March 10, 2003; (4) a clearly identifiable generation among the chains of successive transmission; (5) on the basis of the case definitions for SARS recommended by Guangdong Bureau of Health in February 2003. Patients were excluded if a clear-cut transmission generation could not be identified. The information retrieved included the following: demographic characteristics, symptoms and physical findings on admission, chest radiographs, laboratory tests, and management regimens.Chains of transmission
Transmission process was evaluated through detailed contact tracing. The patients who became infected through contact or exposure to the super-spreader were defined as the first-generation or primary cases. The patients, infected by exposure to the primary cases, were defined as the second-generation or secondary cases. Similarly, the patients who were infected by exposure to the secondary cases were defined as third-generation or tertiary cases.

Statistical analysis
Data were expressed as mean±standard deviation. One-factor analysis of variance (ANOVA) and chi-square test were employed. A P value <0.05 was considered statistically significant.

RESULTS

Patient characteristics
This series comprised 66 female and 18 male patients, with mean age of (29.2±10.3) (16-62) years, including 81 (96.4%) health care workers and 3 (3.6%) family members. Of the health care workers with SARS, 40 were nurses; 21 physicians; and 20 persons with other occupations (interns, attendants, cleaning supervisors, a porter and a driver). The peak admission period was between February 5 and 25, 2003 (81/84, 96.4%). Apart from 3 (3.6%) patients with coexisting arterial hypertension, the remaining 81 (96.4%) cases had been previously healthy.

There were 35 (41.7%) first-generation cases, 34 (40.5%) second-generation cases and 15 (17.8%) third-generation cases in this cohort. As shown in Table 1 , there were no differences among the multiple transmission generations as for age, gender, incubation period and hospitalization duration. Of these patients, 83 (98.8%) had a clinical recovery, and 1 (1.2%) patient, who was among the first-generation cases, died of progressive acute respiratory distress syndrome.

Clinical manifestations
As shown in Table 2 , the initial temperature of SARS patients had a trend to decline along with the advanced transmission generations; however, there was no difference among the multiple transmission generations in terms of the maximum temperature. As with the advancement of transmission generations, the fever duration of the SARS patient had a tendency to shorten, but no statistical significance was recorded (P>0.05).

As with the advancement of transmission generations, fewer cases with dry cough were observed (P<0.05). There were no differences among the multiple transmission generations in terms of other symptoms, and the occurrence of leukopenia. The incidence of hypoxemia had a trend to decrease, but there was no statistical significance.

Chest X-ray
Chest radiographs showed variable focal or patchy, or even diffuse opacities. These involved unilateral or bilateral lung fields which became larger patchy exudates within 1 week and in the late stage there could be evidence of consolidation. Some cases were characterized by shifting radiological infiltrate. As with the advancement of transmission generations, the interval between initial radiographic infiltrates and a complete or basic radiographic recovery shortened (P<0.05). There were no differences among the three successive transmission generations with regard to the maximum number of lung fields involved, the interval from the onset of fever to the initial occurrence of abnormal chest X-ray, and the interval from the initial pulmonary changes to the peak pulmonary involvement ( Table 3 ).

Treatment
Treatment regimens to SARS were shown in Table 4 . There were no differences among the three successive transmission generations as for the modes of oxygen therapy and sorts of antibiotics administered. However, with the advancement of transmission generations, the number of cases who received methylprednisolone, human γ-globulin, interferon-α, and antiviral agents (ribavirin or oseltamivir) increased (P<0.05). In addition, the intervals between hospital admission and starting use of these drugs shortened. As with the advanced transmission generations, the maximum dose of methylprednisolone was reduced (P<0.01), while the duration of administration increased; the maximum dose of human γ-globulin also increased (P<0.01).

DISCUSSION

As the results we have published recently,[1,2] SARS began to spread to health care workers in this hospital prior to the recognition of likely route of transmission of the disease. No specific respiratory isolation precautions were implemented at the very beginning. Furthermore, the outbreak of this disease resulted from the emergence of a new virus; during the early stages of the epidemic, the overall population contained no specific immunity to this etiological agent. Under such a circumstance, once a super-spreader exists, the epidemic will take off exponentially and maintenance of transmission will happen eventually. Hospital workers appeared to be at the highest risk, suggesting that close contact with a patient is required for SARS infection, unlike more highly contagious diseases such as influenza. Our current knowledge regarding the transmission of SARS is growing rapidly, but understanding the transmission dynamics of the spread of the disease, which is a challenge that promises to yield valuable information on both planning and implementation of surveillance and control measures in the future, still remains to be deepened.

The unique, and most striking features of this patient group were as follows: (1) younger age, uncompromized with preexisting diseases; (2) relatively homogenous chorot with epidemiological linkage; (3) successive multiple transmission generations initiated by one source patient. These have allowed us to make a comparison of clinical course of patients among the multiple generations in this cohort feasibly and reliably. Our results give insight into the fact that a basically identical and consistent clinical course of the illness has been observed among the multiple transmission generations of SARS patients.

One key link of transmission of an infectious disease is the etiological agent; however, until SARS appeared, human coronaviruses, which belong to single stranded RNA viruses, were known as the cause to which about one-third of colds are ascribed. Most human coronaviruses do not grow in cultured cells, therefore relatively little is known about them. One of the achievements about the response against the SARS outbreak was the discovery of a novel coronavirus as the causative agent,[3,4] which could be readily isolated from patients’ lungs and sputum and cultivated in a monkey kidney cell line. Nevertheless, we do not know whether this new coronavirus will mutate or recombine in a fashion that permits it to become less infectious throughout the process of successive transmission.

It is evident that SARS is fading globally, but it seems unlikely that the SARS infection among humans has been completely extinguished ever since. The identical and consistent clinical course, shifting radiological infiltrates and progression profile may suggest that the wane of the SARS epidemic is not related to the subsidence of the infectivity and virulence of the etiological agent itself, but may be related to reductions in population contact rates and improved hospital infection control,[5,6] and also might be as a result of higher temperature, which makes the virus difficult to survive. Global surveillance, aggressive isolation of suspected cases and quarantine measures proved efficacious to bring the SARS epidemic under control.

However, SARS could come back in some ways, as long as an animal reservoir of SARS coronavirus exists, which is so-called the natural host. Other respiratory diseases, such as influenza, virtually disappear during the summer and bounce back every winter. It is suggested that lower temperature, humidity, and ultraviolet light during the winter may increase viral stability. People huddling indoors may facilitate the spread of the diseases as well. We therefore hypothesize SARS will too prove to be a seasonal disease, and we have to remain on the alert for the possibility that the cold winter months could revive of the virus, much like past influenza epidemics.

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